NZ629360B2 - Novel compounds for the treatment of dyslipidemia and related diseases - Google Patents
Novel compounds for the treatment of dyslipidemia and related diseases Download PDFInfo
- Publication number
- NZ629360B2 NZ629360B2 NZ629360A NZ62936012A NZ629360B2 NZ 629360 B2 NZ629360 B2 NZ 629360B2 NZ 629360 A NZ629360 A NZ 629360A NZ 62936012 A NZ62936012 A NZ 62936012A NZ 629360 B2 NZ629360 B2 NZ 629360B2
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- NZ
- New Zealand
- Prior art keywords
- methyl
- tetrahydro
- acetamide
- phenoxy
- pyran
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- 206010058108 Dyslipidaemia Diseases 0.000 title claims abstract description 7
- 206010061227 Lipid metabolism disease Diseases 0.000 title claims abstract description 7
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 206010062060 Hyperlipidaemia Diseases 0.000 claims abstract description 6
- -1 (C 1-C6) alkenoxy Chemical group 0.000 claims description 242
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 73
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 67
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 46
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- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 200000000019 wound Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Disclosed herein are compounds of formula (I) where the substituents are as defined herein. Also disclosed are pharmaceutical compositions containing them, methods for their preparation, the use of these compounds in medicine and the intermediates involved in their preparation. The compounds are suitable for the treatment of diseases and conditions such as hyperlipidemia and dyslipidemia. Particular examples of the compounds of formula I include 2-(4-(4-methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and 2-(4-(2-(4-chlorophenyl)-4-methylthiazol-5-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide. table for the treatment of diseases and conditions such as hyperlipidemia and dyslipidemia. Particular examples of the compounds of formula I include 2-(4-(4-methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and 2-(4-(2-(4-chlorophenyl)-4-methylthiazol-5-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide.
Description
NOVEL COMPOUNDS FOR THE TREATMENT-OF DYSLIPIDEMIA AND
RELATED ES
FIELD OF INVENTION
The present invention relates to compounds of the general formula (1), their
meric forms, their stereoisomers, their pharmaceutically acceptable salts,
pharmaceutical compositions containing them, methods for their preparation, use of
these compounds in medicine and the intermediates involved in their preparation
The present invention is directed to compounds suitable for the treatment of Disease
conditions such as hyperlipidemia. The compounds of the present invention also lower
LDL-c.
(R2)n
(Rom e 9
e w“H o
(R3)o
The compounds of the general a (I) lower or modulate cholesterol levels
and/or low-density lipoproteins (LDL) and/or triglyceride levels and raises the high-
density lipoproteins (HDL) plasma levels and hence are useful in combating different
medical conditions, where such lowering (and raising) is beneficial. Thus, it could be
used in the treatment and/or prophylaxis of obesity, hyperlipidaemia,
hypercholesteremia, hypertension, atherosclerotic disease events, ar restenosis,
diabetes and many other related conditions.
The compounds of general formula (I) are useful to prevent or reduce the risk of
developing atherosclerosis, which leads to diseases and conditions such as
artereosclerotic cardiovascular diseases, stroke, coronary heart es,
cerebrovascular diseases, peripheral vessel diseases and related disorders.
These compounds of general formula (I) are useful for the treatment and/or
prophylaxis of metabolic ers loosely defined as Syndrome X. The characteristic
features of Syndrome X include initial insulin resistance followed by hyperinsulinemia,
dyslipidemia and ed glucose tolerance. The e intolerance can lead to non-
insulin ent diabetes mellitus (NlDDM, Type 2 diabetes), which is terized
by hyperglycemia, which if not controlled may lead to diabetic complications or
W0 2013/132509
metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be
associated only with glucose metabolism, but it affects anatomical and physiological
parameters, the intensity of which vary depending upon stages/duration and severity of
the diabetic state. The compounds of this invention are also useful in prevention,
halting or slowing progression or reducing the risk of the above mentioned disorders
along with the resulting secondary diseases such as cardiovascular diseases, like
arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic athy and renal
disease including diabetic nephropathy, glomerulonephritis, glomerular sis,
nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like
lbuminuria and albuminuria, which may be result of hyperglycemia or -
hyperinsulinemia.
The compounds of the present ion can be useful as aldose reductase
inhibitors; for improving cognitive functions in dementia, and in the ent and/or
prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS),
cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases,
wound g, ma, pancreatitis, ic dystrophy, endothelial cell
dysfunction and ipidemia.
BACKGROUND OF THE INVENTION
Higher LDL cholesterol levels in the plasma increase cardiovascular risk and
reduction in the levels of LDL would decrease CVD‘ risk by a comparable tage
(PNAS, 2009, 106, 9546-9547). Clearance of LDL cholesterol from plasma is through
the action of LDL receptors in the liver and LDL receptors are cell e
glycoproteins that bind to apoliporpotein BlOO (apoBlOO) on LDL particles with high
affinity and mediate their endocytic uptake (Journal of Biological Chemistry, 2009,
284, 10561-10570). Defect in hepatic cholesterol clearance and elevated levels of
plasma LDL cholesterol that result from the mutations cause familial
hypercholesterolemia. Such mutations are identified in the human LDL receptor and
later in apolipoprotein-B (Nature ural and Molecular Biology, 2007, 14, 413-
419). Recently, mutations within the pro-protein convertase subtilisin/kexin of the
subtype 9 (PCSK 9) gene were found to represent a third class of mutations ated
with autosomal dominant hypercholesterolemia (ADH). Abifadel et al in 2003
discovered pro-protein convertase isin/kexin of the subtype 9 as the third gene
involved in autosomal dominant hypercholesterolaemia (ADH) (Nature Genetics, 2003,
W0 32509 PCT/lN2012/000452
34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434). Several mis sense
mutations , D129G, F216L, D374H, D374Y) are associated with
hypercholesterolemia and premature sclerosis (J Lipid Res. 2008, 49, 1333-
1343). Loss-of-function mutations (R46L, L253F, A433T) lead to ed receptor
abundance, enhancing clearance of LDL cholesterol from the circulation and reducing
cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14, 413-419).
Pro-protein convertase subtilisin/kexin of the subtype 9 belongs to the subtilisin
family of serine proteases and its protein structure consists of a pro-domain, catalytic
, and cysteine/histidine rich C-terminal domain (Structure, 2007, 15, 545-552).
Unlike other pro-protein convertases, wherein the pro-domain is further proteolytically
sed to activate the serine protease, the pro-domain of secreted subtype remains
intact and tightly bound. Within endoplasmic reticulum this enzyme undergoes
autocatalytic process which results in release of ~14 kDa prodomain that remains
associated with the tic/C-terminal domains, wherein the pro-domain serves as
both a folding chaperon and as an inhibitor of enzymatic activity (Journal of Biological
Chemistry, 2009, 284, 10561-10570).
It is well documented that mal growth factor-like repeat A (EGF-A) of
LDLR interacts with this pro-protein subtype mainly with residues 1. This EGF-
A interaction site is located >20 A from the catalytic site of this pro-protein subtype.
Once EGF-A and this otein subtype interacts they form a x with the
LDLR that enters endosomal pathway and hence LDLR recycling is prevented leading
to LDLR degradation. Detailed molecular mechanisms explaining the association of
LDLR and this pro-protein subtype and LDLR degradation is not very clear (Drug
News Perspectives, 2008, 21, 323-330). Because of inhibition of LDLR recycling,
number of LDL receptors on the cell e are decreased and this increases plasma
LDL levels (PNAS, 2009, 106, 9546-9547).
Various approaches for inhibiting this pro-protein subtype are reported,
including gene silencing by siRNA or antisense oligonucleotides, mAb disrupting
n—protein interactions or by peptides; all the above-mentioned strategies have
shown lowering of LDL cholesterol which may be ive therapy for treating
holesterolemia (Biochemical Journal, 2009, 419, 577-584; PNAS, 2008, 105,
11915-11920; Journal of Lipid Research, 2007, 48, 763-767; PNAS, 2009, 106, 9820-
9825). However, very little success has been reported in trying to inhibit this pro-
VIA510685NZPR
303916262
It is a further or alternative object of the present invention to provide a compound of
formula (I), a use of a compound of formula (I) and/or a pharmaceutical ition which
meets the above identified need.
The above objects are to be read disjunctively and with the alternative object of to at
least provide the public with a useful choice.
VIA510685NZPR
303916262
The above and other embodiments are described hereinafter.
In a first aspect, the present ion provides a compound of a (I), its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, and pharmaceutical
compositions containing said compound, wherein
(R2)n
Z X V
(R1)m
W N
ZA H
(R3)o
‘ZA’ represents an optionally substituted single or fused group selected from aryl,
heterocyclyl or cycloalkyl groups; Each of ‘X’ and ‘Z’ independently represents an
optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl
; Alternatively, Z-X- ZA may together form tricyclic 8-15 membered fused ring
system containing 1-4 hetero atoms selected from N, O or S;
R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or branched alkyl,
(C1-C6) linear or branched alkenyl, (C1-C6)linear or branched alkynyl, hydroxy, (C1-C6) alkoxy,
(C1-C6) alkenoxy, hydroxy(C 1-C6)alkyl, alkoxyalkyl, haloalkyl, (C1-C6)cycloalkyl, thio(C1-
C6)alkyl, (C1-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted
amino, amino(C1-C6)alkyl, alkylamino, cyano, formyl, koxy, aryl, aryloxy, aralkyl,
xy, heterocylyl, heterocyclylalkyl, heterocycloxy, cyclylalkoxy groups or the groups
selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl,
alkylsulfonylamino, ulfonyloxy, each of which may be optionally substituted; ‘m’ ‘n’ and
‘o’ independently represents integers from 0 to 5; ‘Y’ represents either a bond, or O, S(O)p or
NR4 wherein R4 represents H, (C1-C6)linear or branched alkyl, (C1-C6)cycloalkyl, aryl,
heterocyclyl, heterocyclylalkyl, cycloalkylalkyl and ‘p’ represents integers from 0 to 2; ‘W’
represents (C1-C6)linear or branched alkyl or (C1-C6)linear or branched cycloalkyl; ‘V’
represents O or S.
In a second aspect, the present invention provides a compound of formula (I) as d
in the first aspect, suitably formulated into a suitable pharmaceutical ition.
In a third aspect, the t invention provides use of a nd of formula (I) as
d in the first aspect, for the cture of a medicament for the treatment of
hyperlipidemia, dyslipidemia, obesity, hypercholesteremia, hypertension, atherosclerosis,
vascular osis and diabetes.
In a fourth aspect, the present invention provides a pharmaceutical composition
comprising a compound of formula (I) as defined in the first aspect in combination with one or
more pharmaceutically active agents selected from group comprising insulin, insulin derivatives
and mimetics, n secretagogues, insulin izers, biguanide , alpha-glucosidase
inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like
peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 activators,
sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone
type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin
tors, anti-thrombotic and anti-platelet agents and besity agents or pharmaceutically
acceptable salts thereof.
DETAILED DESCRIPTON OF THE INVENTION
Accordingly, the present invention relates to nds of the genreal formual (I),
W0 2013/132509
(R2)n
(R1)m e a
a Y\WJ\fi/\OO
(R3)c
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and
pharmaceutical compositions containing them wherein
‘ZA’ represents an optionally substituted single or fused group selected fiom aryl,
heterocyclyl or cycloalkyl groups;
Each of ‘X’ and ‘2’ independently represents an Optionally tuted single or
fused group selected from aryl, heterocyclyl or cycloalkyl groups;
In a preferred embodiment, ‘X’ is selected from optionally substituted aryl or
heterocyclyl groups;
In a further preferred embodiment, the aryl group may be selected from substituted or
unsubstituted monocyclic' or bicyclic aromatic groups;
In a still further preferred embodiment, the aryl group is an optionally substituted
phenyl group.
In an embodiment, when ‘X’ represents a heterocyclyl group, the heterocyclyl group
may be selected from single or fused mono, bi or tricyclic ic or non-aromatic groups
containing one or more hetero atoms ed fi'om O, N or S;
[n a preferred embodiment, the heterocyclyl group may be selected from pyridyl,
thienyl, furyl, yl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl,
lthiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl,
azaindolinyl, lopyrimidinyl, azaquinazolinyl, furanyl, pyridothienyl,
pyrimidyl, quinolinyl, dinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl,
benzimidazolyl, benzotriazolyl, phthalazynil, ylidinyl, purinyl, carbazolyl,
phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl,
lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl,,
benzopyranonyl, benzodihydrofuranyl, ihydrothienyl, pyrazolopyrimidonyl,
azaquinazolinoyl, pyrimidonyl, quinazolonyl, donyl, benzoxazinyl,
benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl and the like; .
In a preferred embodiment, either or both of ‘Z’ and"ZA’ is independently selected
from optionally substituted aryl or heterocyclyl groups;
W0 2013/132509
In a r preferred embodiment, when either of ‘Z’ and ‘ZA’ independently
represents an aryl group, the aryl group may be selected from substituted or unsubstituted
monocyclic or bicyclic aromatic groups;
In a still further preferred embodiment, such aryl group is an optionally substituted
phenyl group.
In another embodiment, when either of ‘Z’ and ‘ZA’ independently represents a
cyclyl group, the heterocyclyl group may be selected from single or fiised mono or bi
cyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from 0,
N or S;
In a still preferred embodiment, when either of ‘Z’ and ‘ZA’ independently represents
heteroaromatic group, the heteroaromatic group may be selected from l, thienyl, furyl,
pyrrolyl, yl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl,
lopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl,
quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl,
benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl,
benzoxazolyl, benzothiazolyl groups. '
Alternatively Z-X- 2,, may together form tricyclic 8-15 ed fused ring system
containing l-4 hetero atoms selected from N, O or S.
R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or
branched alkyl, (Cl-C6) linear or ed alkenyl, (Cl-C6) linear or branched alkynyl,
hydroxy, (Cl-C6) alkoxy, (C1-C6) alkenoxy, hydroxy(C.-C5)alkyl, alkoxyalkyl,
haloalkyl, (C3-C6) lkyl, thio(Cl-C6)alkyl, )alkylthio, halo, oxo, imino,
nitro, aryl, heterocyclyl, optionally tuted amino, amino(Cl-C5)alkyl, alkylamino,
cyano, , haloalkoxy, raryl, aryloxy, aralkyl, aralkoxy, heterocylyl,
heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected
from carboxylic acid and its derivatives such as esters and , alkylsulfonyl,
alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted;
‘m’ ‘n’ and ‘0’ independently represents integers from 0 to 5;
‘Y’ represents either a bond, or O, S(O)p or ~NR4 wherein R4 represents H, (C1-
C6) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, cyclyl, heterocyclylalkyl,
lkylalgl and ‘p’ represents integers from 0 to 2;
‘W’ represents (Cl-C6) linear or branched alkyl or (C3-C6) linear or branched
cycloalkyl;
‘V’ represents 0 or S;
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When any of R., R2 or R3 are substituted, such substituents may be selected
from hydrogen, hydroxyl, oxo, halo, thiol, nitro, amino, cyano, fomtyl, or substituted or
unsubstituted groups selected from amidino, alkyl, kyl, perhaloalkyl, alkoxy,
haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl,
bicycloalkenyl, , xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy,
heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy,
heterocyclylalkoxyacyl, acyl, acyloxy, ac'ylamino, bstituted or disubstituted
amino, arylamino, lamino, carboxylic acid and its derivatives such as esters and
amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, yalkyl,
aralkoxyalkyl, alkylthio, thioalkyl, lkylthio, arylthio, heterocyclylthio,
alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl,
cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino,
cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino,
alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy,
alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino,
aminocarbonylamino, alkylaminocarbonylamino, amino, hydroxyl amino,
sulfonic acid and its derivatives;
When the aryl group at any occurrence is further substituted, the substituents are
selected from halo, thiol, nitro, amino, cyano, fonnyl, or substituted or unsubstituted
groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy,
oalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl,
alkoxy, alkenoxy, lkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl,
heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl,
acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino,
carboxylic acid and its derivatives such as esters and amides, carbonylamino,
hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,
thioalkyl, cycloalkylthio, io, heterocyclylthio groups;
When the heteroaryl group at any ence is further substituted, the
substituents are selected from halo, thiol, nitro, amino, cyano, formyl, or tuted or
unsubstituted groups selected front alkyl, kyl, alkoxy, haloalkoxy, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, acyl,
W0 2013/132509 ll452
acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino,
carboxylic acid and its derivatives such as esters and amides;
When” the heterocyclyl group at any occurrence is further substituted, the
substituents are selected from halo, amino, cyano, fonnyl, or substituted or
unsubstituted groups selected from o, alkyl, haloalkyl, perhaloalkyl, alkoxy,
koxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy,
alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl,
acyl, acyloxy, acylamino, monosubstituted or tituted amino, arylamino,
aralkylamino, carboxylic acid and its derivatives such as esters and ,
carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl,
alkylthio, thioalkyl, cycloalkylthio, arylthio, cyclylthio groups.
The various groups, radicals and substituents used anywhere in ecification
are described in the following paragraphs.
In a further preferred embodiment the groups, radicals bed above may be
selected from:
- the “alkyl” group used either alone or in combination with other radicals, denotes a
linear or branched radical containing one to six carbons, selected from methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, utyl, amyl, t-amyl, n-pentyl, n-
hexyl, and the like;
- the “alkenyl” group used either alone or in ation with other radicals, is
selected from a radical containing from two to six carbons, referably groups
selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the “alkenyl” group includes dienes
and trienes of straight and branched chains;
- the “alkynyl” group used either alone or in combination with other radicals, is
selected from a linear or branched radical containing two to six carbon atoms, more
preferably thynyl, l-propynyl, ynyl, nyl, 2-butynyl, 3-butynyl, 1-
pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, nyl, and the like. The term
“alkynyl” es di- and tri-ynes wherever applicable;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other
radicals, is selected from a cyclic radical containing three to six carbons, more
preferably cyclopropyl, cyclobutyl, entyl, cyclohexyl and the like; The terms
“bicycloalkyl” means more than one cycloalkyl groups fused together;
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- the “cycloalkenyl” group used either alone or in combination with other'radicals,
are ably selected from ropenyl, l-cyclobutenyl, 2-cylobutenyl, 1-
cyclopentenyl, opentenyl, 3-cyclopentenyl, l-c'yclohexenyl, 2-cyclohexenyl,
3-cyclohexenyl and the like; The terms “bicycloalkenyl” means more than one
cycloalkenyl groups fused together;
- the “alkoxy” group used either alone or in combination with other ls, is
selected from groups containing an alkyl radical, as defined above, attached directly
to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-
propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the
like;
- the “cycloalkoxy” group used either alone orin combination with other radicals, is
selected from a cyclic radical containing three to seven carbons, more ably
cyclopropyloxy, cyclobutylxoy, cyclopentyloxy, cyclohexyloxy and the like; The
terms “bicycloalkyloxy” means more than one cycloalkyl groups fused together;
- the oxy” group used either alone or in combination with other radicals, is
selected from groups containing an alkenyl radical, as defined above, attached to an
oxygen atom, more preferably selected from vinyloxy, allyloxy, xy,
pentenoxy, hexenoxy, and the like;
- the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably
substituted with one or more halogens; such as perhaloalkyl, more preferably,
perfluoro(C|-C6)alkyl such as fluoromethyl, omethyl, trifluoromethyl,
fluoroethyl, roethyl, trifluoroethyl, mono or polyhalo substituted methyl,
ethyl, propyl, butyl, pentyl or hexyl groups;
4 the “haloalkoxy” group is selected from suitable haloalkyl, as defined above,
directly attached to an oxygen atom, more preferably groups selected from
fluoromethoxy, chloromethoxy, fiuoroethoxy, chloroethoxy and the like;
- the “perhaloalkoxy” group is ed from a le perhaloalkyl radical, as
defined above, directly attached to an oxygen atom, more preferably groups
selected from trifluoromethoxy, trifluoroethoxy, and the like;
- the “aryl” or “aromatic” group used either alone or in combination with other
radicals, is selected from a le aromatic system containing one, two or three
rings wherein such rings may be attached together in a pendant manner or may be
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fused, more preferably the groups are selected from phenyl, naphthyl,
tetrahydronaphthyl, indane, biphenyl, and the like;
- the “aryloxy” group used either alone or in combination with other radicals, is
selected from groups containing an aryl l, as defined above, attached directly
to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy,
tetrahydronaphthyloxy, biphenyloxy, and the like;
- the ‘aralkyl” group is selected from suitable aryl group as defined above attached to
an alkyl group as defined above, more preferably selected from benzyl, phenethyl,
ylmethyl, and the like;
— the “aralkoxy” group is selected from a suitable arylalkyl group, as defined above,
attached to an oxygen atom, more ably the groups are selected from
oxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like,
which may be substituted;
- the “heterocyclyl” or “heterocyclic” group used either alone or in combination with
other radicals, is ed from suitable aromatic or non-aromatic radicals
containing one or more hetero atoms selected from O, N or S. The non-aromatic
ls may be saturated, partially saturated or unsaturated mono, bi or tricyclic
radicals, containing one or more heteroatoms selected from nitrogen, sulfur and
oxygen, more ably selected from aziridinyl, azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, iperidinyl, 4-oxopiperidinyl, 24
oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-
oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl,
lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole,
benzopyranyl, benzopyranonyl, ihydrofuranyl, benzodihydrothienyl,
pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl,
pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl,
thieno piperidinyl, and the like; the aromatic ls, may be selected from suitable
single or fused mono, bi or lic aromatic heterocyclic radicals containing one
or more hetero atoms selected from O, N or S, more preferably the groups are
ed from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl,
imidazolyl, olyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl,
benzothienyl, indolinyl, indolyl, azaindolyl, aiaindolinyl, pyrazolopyrimidinyl,
azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl,
W0 2013/132509
pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidaz‘olyl,
benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl,
phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
- the groups “heterocycloxy”, “heterocylylalkoxy” are selected from suitable
cyclyl, heterocylylalkyl groups respectively, as defined above, attached to an
oxygen atom;
- the “acyl” group used either alone or in combination with other radicals, is selected
from a radical containing one to eight carbons, more preferably selected from
forrnyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl,
benzoyl and the like, which may be substituted;
- the “acyloxy” group used either alone or in combination with other radicals, is
ed from a suitable acyl group, as defined above, ly attached to an
oxygen atom, more preferably such groups are selected from acetyloxy,
propionyloxy, butanoyloxy, tanoyloxy, benzoyloxy and the like;
- the “acylamino” group used either alone or in combination with other radicals, is
ed from a suitable acyl group as defined earlier, attached to an amino radical,
more preferably such groups are selected from CH3CONH, C2H5CONH,
C3H7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted;
- the substituted amino” group used either alone or in combination with other
radicals, represents an amino group substituted with one group selected from (C.-
C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined
earlier, more preferably such groups are selected from amine, ethylamine, n-
propylamine, n-butylamine, ylamine and the-like;
- the ‘disubstituted amino” group used either alone or in combination with other
radicals, represents an amino group, substituted with two radicals that may be same
or ent selected from (Cl-C6)alkyl, tuted alkyl, aryl, substituted aryl, or
arylalkyl groups, as defined above, more ably the groups are selected from
dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like;
- the “arylamino” used either alone or in combination with other radicals, represents
an aryl group, as defined above, linked through amino having a free valence bond
from the nitrogen atom, more preferably the groups are selected from phenylamino,
naphthylamino, N-methyl anilino and the like;
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- the “0x0” or “carbonyl” group used either alone ) or in combination with
other radicals such as alkyl described above, for e.g. “alkylcarbonyl”, denotes a
carbonyl radical (—C=O-) substituted with an alkyl radical bed above such as
acyl or yl;
- the “carboxylic acid” group, used alone or in combination with other radicals,
denotes a -COOH group, and es derivatives of ylic acid such as esters
and amides;
- the “ester” group used alone or in combination with other radicals, denotes -COO-
group, and includes carboxylic acid derivatives, more preferably the ester moieties
are selected from alkoxycarbonyl, such as ycarbonyl, ethoxycarbonyl, and
the like, which may optionally be substituted; arylbxycarbonyl group such as
ycarbonyl, napthyloxycarbonyl, and the like, which may optionally be
substituted; aralkoxycarbonyl group such as benzyloxycarbonyl,
phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may
optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein
the heteroaryl group, is as defined above, which may optionally be substituted;
heterocyclyloxycarbonyl, where the heterocyclic group, as definedearlier, which
may optionally be substituted;
- the “amide” group used alone or in combination with other radicals, ents an
aminocarbonyl radical (HzN-C=O), wherein the amino group is mono- or di-
substituted or unsubstituted, more preferably the groups are selected from methyl
amide, dimethyl amide, ethyl amide, diethyl amide, and the like;
- the “aminocarbonyl” group used either alone or in combination with other radicals,
may be selected from ‘aminocarbonyl’, ‘aminocarbonylalkyl”, “
alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”, “N-
alkyl-N-arylaminocarbonyl”, “N;alkyl-N—hydroxyaminocarbonyl”, and “N-alkyl-
N-hydroxyaminocarbonylalkyl”, each of them being ally substituted. The
terms “N-alkylaminocabonyl” and “N,N-dialky|aminocarbonyl” denotes
aminocarbonyl radicals, as defined above, which have been substituted with one
alkyl l and with two alkyl radicals, respectively. Preferred are “lower
alkylaminocarbonyl” having lower alkyl radicals as described above attached to
aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N-
arylaminocarbonyl” denote aminocarbonyl radicals substituted, respectively, with
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one aryl radical, or one alkyl and one aryl radical. The term “aminocarbonylalkyl”
includes alkyl radicals substituted with aminocarbonyl radicals;
- the “hydroxyalkyl” group used either alone or in combination with other radicals, is
selected from an alkyl group, as defined above, substituted with one or more
hydroxy radicals, more preferably the groups are ed from hydroxymethyl,
hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the
like;
- the alkyl” group used alone or in combination with other radicals, denotes
an amino (-Nl-Iz) moiety attached to an alkyl radical, as defined above, which may
be substituted, such as mono- and di-substituted lkyl. The term “alkylamino”
used herein, alone or in combination with other radicals, denotes an alkyl radical, as
defined above, attached to an amino group, which may be substituted, such as
mono- and di-substituted alkylamino;
- the “alkoxyalkyl” group used alone or in combination with other radicals, denotes
an alkoxy group, as defined above, attached to an alkyl group as 'defined above,
more preferably the groups may be selected from methoxymethyl, ethoxymethyl,
methoxyethyl, ethoxyethyl and the like;
- the “alkylthio” group used either alone or in combination with other radicals,
denotes a straight or branched or cyclic monovalent substituent comprising an alkyl
group as defined above, linked through a divalent sulfur atom having a free valence
bond from the sulfur atom, more preferably the groups may be selected from
methylthio, hio, propylthio,
- the “thioalkyl” group used either alone or in combination with other radicals,
denotes an alkyl group, as defined above, attached to. a group of formula —SR’,
where R’ represents hydrogen, alkyl or aryl group, e.g. thyl,
methylthiomethyl, phenylthiomethyl and the like, which may be optionally
tuted.
- the “alkoxycarbonylamino” group used alone or in combination with other ls,
is ed from a suitable alkoxycarbonyl group, as defined above, attached to an
amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and
the like;
- the “arylthio” group used either alone or in combination with other radicals, s
a comprising an aryl group as defined above, linked through a divalent sulfur atom
W0 2013/132509
having a free valence bond from the sulfur atom, more preferably the groups may
be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio,
biphenylthio, and the like;
- the “heterocyclylthio” group used either alone or in combination with other
radicals, s a sing an cyclyl group .as defined above, linked
through a divalent sulfur atom having a free e bond from the sulfur atom;
- the “alkoxycarbonylamino” group used alone or in combination with other radicals,
is selected from a suitable alkoxycarbonyl group, as defined above, ed to an
amino group, more preferably methoxycarbonylamino, ethoxycarbon'ylamino, and
the like;
- the “aminocarbonylamino”, “alkylaminocarbonylamino”,
“dialkylaminocarbonylamino” groups used alone or in combination with other
radicals, is a carbonylamino (—CONHz) group, attached to NH2), alkylamino
group or lamino group respectively, where alkyl group is as defined above;
- the “amidino” group used either alone or in combination with other radicals,
represents a —C(=NH)-NH2 radical; the “alkylamidino” group represents an alkyl
radical, as described above, attached to an amidino group;
- the “alkoxyamino” group used either alone or in combination with other radicals,
represents a suitable alkoxy group as defined above, attached to an amino group;
- the “hydroxyamino” group used either alone or in combination with other radicals,
represents a —NHOH moiety, and may be ally substituted with le
groups selected from those described above;
- the “sulfenyl” group or “sulfenyl derivatives” used alone or in combination with
other ls, represents a bivalent group, —SO- or RXSO, where Rx is an optionally
substituted alkyl, aryl', heteroaryl, heterocyclyl, group selected from those described
above;
- the “sulfonyl” group or “sulfones derivatives” used either alone or in combination
with other radicals, with other terms such as alkylsulfonyl, represents a divalent
radical ~SOz-, or RxSOz-, where Rx is as defined above. More preferably, the
groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals,
selected from those defined above, is attached to a sulfonyl radical, such as
methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, “arylsulfonyl” wherein
W0 2013/132509
an aryl radical, as defined above, is attached to a sulfonyl radical, such as
phenylsulfonyl and the like.
Suitable groups and substituents on the groups may be selected from those
described anywhere in the cation.
The term "Substituted," as used herein, means that any one or more hydrogens on
the designated atom is replaced with a ion from the indicated group, ed that
the designated atom's normal valency is not exceeded, and that the substitution results
in a stable compound. The term "substituted," as used herein, means that any one or
more hydrogens on the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency is not exceeded, and that the
substitution results in a stable compound.
“Phannaceutically acceptable salts” refer to derivatives of the disclosed compounds
wherein the parent nd is modified by making acid or base salts thereof.
Examples of phannaceutically acceptable salts include, but are not limited to, mineral
-or organic acid salts of the basic residues. The phannaceutically acceptable salts
include the conventional quaternary ammonium salts of the parent nd formed,
for example, from non-toxic inorganic or organic acids. '
The term "combination therapy" means the administration of two or more
therapeutic agents to treat a eutic condition or disorder described in the present
disclosure. Such administration encompasses co-administration of these therapeutic
agents in a substantially simultaneous manner, such as in a single capsule having a
fixed ratio of active ingredients or in le, te capsules for each active
ingredient. In addition, such administration also encompasses use of each type of
therapeutic agent in a sequential manner. In either case, the treatment regimen will
e beneficial effects of the drug combination in treating the conditions or
disorders described .
- The phrase "therapeutically effective" is intended to qualify the amount of
active ingredients used in the treatment of a disease or disorder. This amount will
achieve the goal of ng or eliminating the said disease or disorder.
- The term "therapeutically acceptable" refers to those compounds (or salts,
prodrugs, tautomers, rionic forms, etc.) which are suitable for use in contact with
the tissues of patients without undue toxicity, irritation, and allergic response, are
W0 2013/132509
commensurate with a reasonable benefit/risk ratio, and are effective for their ed
use.
- As used , reference to "treatment" of a patient is intended to include
prophylaxis. The term "patient" means all mammals ing humans. Examples of
patients e humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably,
the patient is a human. -
The term ‘optional’ or ‘optionally’ means that the subsequent described event or
circumstance may or may not occur, and the description includes instances where the
event or circumstance occur and instances in which it does not. For example,
‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an
optionally substituted group includes the unsubstituted group also.
Unless otherwise stated in the specification, ures depicted herein are also
meant to include compounds which differ only in the ce of one or more
isotopically enriched atoms. For example, compounds having the present structures
wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is
replaced by 130 or 14C- enriched , are within the scope of this invention.
Particularly useful compounds may be selected from ’
2-(4-(4-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-(4-fluorophenyl)-4~methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide;
2—(4-(5-(4-chlorophenyl)-4~methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(4-methyl-S-(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro—
2H-pyranyl)methyl)acetamide;
2-(4-(4-methyl(p-tolyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(4-methyl~5-phenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-methoxy-l-(4—(trifluoromethyl)phenyl)-1H-pyrazolyl)phenoxy)-N-
((tetrahydro~2H-pyranyl)methyl)acetamide;
W0 2013/132509
2-(4-(1-(4-fluorophenyl)-5~methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro—2H-
pyranyl)methyl)acetamide;
2-(4-(5-methoxyphenyl- l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran—4-
yl)methyl)acetamide;
2-(4-(4-methylphenylthiazol-5 -yl)phenoxy)-N-((tetrahydro-ZH-pyran
yl)methyl)acetamide;
2-(4-(4-methyl(4-(trifluoromethyl)phenyl)thiazoly1)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide;
2-(4-(2-(4-fl uorophenyl)—4-methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4i(2-(4-bromophenyl)—4-methylthiazol-S-yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)mlethyl)acetamide; '
2-(4-(2-(4-chlorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide;
2-(4-(4-methyl—2-(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-methylphenyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide;
2-(4-(5-methyl(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide;
2-(4-fluorophenyI)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran~4-
yl)methyl)acetamide;
2-(4-(2-(4-bromophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-.pyran
yl)methyl)acetamide;
2-(4-(2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-methyl(p-tolyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide; .
2-(4—(2-(4-methoxyphenyl)-5—methyloxazoIyl)phenoxy)-N-((tetrahydro-2H—pyran
yl)methyl)acetamide;
2-(4-(5-methyl(pyridinyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
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N-((tetrahydro-2H-pyranyl)methyl);2-(4-(5-(4-(trifluoromethyl)phenyl)-l,2,4—
oxadiazolyl)phenoxY)acetamide;
-(4—fluorophenyl)—l,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-(4-bromophenyl)- l-,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro—2H-pyran
yl)methyl)acetamide; ‘
2-(4-(5-(4-chlorophenyl)— l ,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
N-((tetrahydro-2H-pyranyl)methyl)(4-(5 4(p-tolyl)-l ,2,4-oxadiazol
yl)phenoxy)acetamide;
2—(4-(5-(4-fluorophenyl)- ] xadiazol-2—yl)phenoxy)-N—((tetrahydro-2H-pyran-4—
hyl)acetamide;
N-((tetrahydro-2H—pyran-4—yl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,3,4-
oxadiazo|yl)phenoxy)acetamide;
2-(4-(5-(4-methoxyphenyl)-l,3,4-oxadiazol$Il)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-Z-yl)phenoxy)-N-((tetrahydro-ZH-pyran
yl)methyl)acetamide;
2-(4-(5-phenyl-1,3 ,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide; '
2-(4-(3-(4-fluorophenyl)oxooxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(3-(4-methoxyphenyl)oxooxazoIidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran-
4-yl)methy|)acetamide;
2-(4—(4-phenyl-1 H- l ,2,3-triazol—l -y|)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamidc;
2-(4-(5—methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazoIyl)phenbxy)—N-
((tetrahydro-ZH-pyranyl)methyl)acetamide;
2-(4-(4,S-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5~(4-bromophenyl)methylisoxazolyl)phenoxy)—N-((tetrahydro-2H-pyran-4—
yl)methyl)acetamide;
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2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyrans
4-yl)methyl)acetamide;
2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isoxazo|yl)phenoxy)-N-((tetrahydro-
2H-pyranyl)methyl)acetamide; ’
2-(4-(5-(4-fluorophenyl)methylisothiazoIyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran-
4-y1)methyl)acetamide;
2-(4-(5-(4-bromophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran-
4-yl)methyl)acetamide;
2-(4-(4-methyl(p-tolyl)isothiaZQlyl)bhenoxy)—N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(4-mefhyl(4-(trifluoromethyI)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro-
2H-pyran-4I-yl)mcthyl)acetamide;
2-(4-(5-(4-methoxyphenyl)methylisothiazol-3 -yl)phenoxy)—N-((tetrahydro-2H-
4-yl)methyl)acetamide;
2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)-N-
ahydro-ZH-pyranyl)methyl)acetamide;
2-(4-(1-(4-chlorophenyl)—5-methoxy-1H-pyrazol-3~yl)phenoxy)—N-((tetrahydro-2H-
pyran—4-yl)methyl)acetamide;
2-(4-(5-methoxy- l -(4—methoxyphenyl)-l H-pyrazolyl)phenoxy)—N-((tetrahydro-2H-
pyfanyl)methyl)acetamide;
2-(4-(5-methoxy- I trifluoromethoxy)phenyl)-1 H-pyrazolyl)phenoxy)-N-
((tetrahydro-ZH-pyranyl)methyl)acetamide;
2-(4-(1-(4-bromophenyl)methoxy-lH-pyrazolyl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide;
2-(4-(5~methoxy— l -(p-tolyl)-l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2-(4-(3 lorophenyl)—2-oxooxazoIidinyI)phenoxy)-N-((tetrahydro-2H-pyran—4—
yl)methyl)acetamide;
2-(4-(2-oxo(4-(trifluoromethyl)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide;
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2-(4-(2-oxo(4¥(trifluoromethoxy)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro-
2H-pyranyl)methyl)acetamide;
2-(4-(3-(4-bromophenyl)—2-oxooxazolidin-S-yl)phenoxy~)—N-((tetrahydro-2H-pyran—4-
hyl)acetamide;
2-(4-(2-oxo(p-tolyl)oxazolidin-S-.yl)phenoxy)—N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
4-(4-chlorophenyl)-l H-l ,2,3-triazolyl)phenoxy)—N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)-1H~1,2,3-
triazol-l ~yl)phenoxy)acetam ide;
N—((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethoxy)phenyl)-l H- l ,2,3-
triazol-l enoxy)acetam ide;
2-(4-(4-(4-bromophenyl)-l H-l ,2,3-triazol-l '-yl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide;
N-((tetrahydro-2H-pyranyl)Vmethyl)(4-(4-(p-tolyl)-1 H-1,2,3 -triazol- l -
yl)phenoxy)acetamide;
2-(4-(4-(4-fluorophenyl)~l H- l ,2,3-triazol- l -yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
4-(4-methoxyphenyl)-l H-l,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran-4—
yl)methyl)acetamide. {does it include the list of compounds at the end (with no data?)}
2-(4-(3-(4-chlorophenyl)-24minooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide;
2—(4-(6-(4-chlorophenyl)pyridinyl)phenoxy)-N-((tetrahydro~2H-pyran
yl)methyl)acetamide
2-(4-(4-(4-chlorophenyl)pyrimidinyl)phenoxy)-N-((tetrahydro-ZH-pyran
yl)methyl)acetamide;
2-((8-(4-chloropheny|)dibenzo[b,d]thiophenyl)oxy)—N-((tetrahydro-2H-pyran-4—
yl)methyl)acetamidel;
2-(4-(7vchlorodibenzo[b,dlthiophen-Z-yl)phenoxy)—N-((tetrahydro-2H-pyran~4-
yl)methy|)acetamide.
The novel compounds of this invention may be prepared using the reactions and
techniques as shown in scheme below and described in this section or elsewhere in the
W0 2013/132509
cation. The reactions are performed in ts appropriate to the reagents and
materials employed and are suitable for the transformations being affected. It is
understood by those skilled in the art that the nature and order of the synthetic steps
presented may be varied for the purpose of optimizing the formation of the compounds
of the present invention. It will also be well appreciated that one or more .of the
reactants may be protected and deprotected for facile synthesis by ques known to
persons skilled in the art. [twill also be appreciated that one or more of the compounds
of the t invention may exist in stereoisomeric and/or diastereomeric forms. Such
stereoisomers and/or diastereoisomers as well as their optical antipodes are to be
construed to be within the scope of the present invention. It will also be well
appreciated that one or more of these compounds may be converted to their salts and
other derivatives based on the specific groups present on the compounds, which can be
well comprehended by persons skilled in the art. Such salts and/or other derivatives, as
the case may be should also be construed to be, within the scope of the present
ion.
Schemezl The compounds of general formula (I) wherein all the s are as
d earlier, may be prepared by reactions outlined in Scheme 1 below which
comprises:
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(R2)n (R2)n
(R1) e a W (mm a a
m 0R5 .w 0R5
Y” + L/ \n/
g MethodA \n’
V a Y —-—>
(Ralo (R3)o
u IV
(R2)n
(Wm % Q ,w OH “New“c
Method B , a o
—-> v ‘
H2N ‘
(R3)o
(R2)n
V ‘
(Ron. 6 a
e “W“H o
(Rah
Method A: The compounds of formula IV wherein R5 ents C1-C6 linear
or branched alkyl or aralkyl groups and all other symbols are as defined earlier may be
prepared by the philic substitution reaction of compound of general formula II
and compounds of general formula [11 wherein ‘L’
represents suitable leaving group ,
and all other symbols are as defined earlier using suitable inorganic base(s) such as
NaOl-l, KOH, K2C03, C52C03 and the like or organic base(s) such as pyridine, triethyl
amine, diisopropyl ethylamine and the like. The reaction may be carried out neat or in
presence of le protic solvent(s) such as methanol, ethanol, butanol and the like or
suitable aprotic t(s) such as yl formamide, tetrahydrofuran,
dichloromethane and the like or suitable mixtures thereof. The reaction may be carried
out at a ature in the range 0 °C to reflux temperature of the solvent(s) used and
the reaction time may range from 1 to 48 hours.
Method B: The compounds of formula IV wherein all the symbols are as
defined r may be hydrolyzed to compound of formula V wherein 'all the symbols
are as defined earlier using suitable base(s) e.g., NaOH, LiOH, KOH and the like.
Reaction may be ted in suitable solvents e.g., alcohols like methanol, ethanol
‘ 22
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and the like, THF, water or the mixtures thereof. The reaction may be carried out at a
temperature in the range 20 °C to reflux temperature of the solvent(s) used and the
reaction time may range from 1 to 24 hours.
Method C: The compounds of formula (I) wherein all the symbols are as
defined earlier may be prepared by coupling reaction of corresponding acids of general
formula V wherein all the symbols are as defined earlier and (tetrahydro-ZH-pyran
yl)methanam~ine as described in scheme 1 under suitable conditions such as those
described in edron, 2005, 61 (46), 10827-10852 with suitable modifications and
alterations as are well known to a skilled person. The reaction may be carried out in
presence of reagents(s) such as N-(3-dimethylaminopropyl)-N’-ethylcarbodimide
hydrochloride (EDCl) & l-Hydroxybenzotriazole (HOBT), and the like. The reaction
may be carried in suitable solvent(s) such as dimethyl fomiamide, tetrahydrofuran,
dichloromethane and the like or mixtures thereof. The reaction may be carried out at a
temperature in the range 0 °C to reflux temperature of the solvent(s) used and the
reaction time may range from 1 to 48 hours.
The pharmaceutical composition is ed by employing tional
techniques. Preferably the composition is in unit dosage form containing an effective
amount of the active component, that is, the compounds of formula (1) according to this
ion.
The quantity of active component, that is, the compounds of formula (1)
ing to this invention, in the pharmaceutical composition and unit dosage form
thereof may be varied or adjusted widely depending upon the particular application
method, the potency of the particular compound and the desired concentration.
Generally, the quantity of active ent will range between 0.5% to 90% by weight
of the ition.
The compounds of the present ion can be used either alone or in
combination with one or more therapeutic agents ed from n, insulin
derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents,
alpha-glucosidase tors, insulinotropic sulfonylurea or ligands, meglitinides,
GLP-l (glucagon like peptide-1), GLP-l analogs, DPPIV (dipeptidyl peptidase IV)
inhibitors, GPR-ll9 activators, sodium-dependent glucose coctransporter )
inhibitors, PPAR modulators, non-glitazone type PPAR.delta agonist, HMG-CoA
W0 2013/132509
reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and
anti-platelet agents and. anti-obesity agents or phannaceutically acceptable salts thereof.
The invention is ned in greater detail by the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.
1H NMR spectral data given in the examples (vide infia) are recorded using a
400 MHz spectrometer (Bruker AVANCE—400) and reported in 6 scale. Until and
ise ned the solvent usedfor NMR is CDC!3 using tetramethyl silane as the
internal standard.
Example 1 .
2-(4-(4-Methy1phenylisoxazolyl)phenoxy)-N-((tetrahydro-ZH—pyran
y1)methyl)acetamide
Step 1: ethyl 2-(4methylphenylisoxazolyl)phenoxy)acetate
To a solution of 4-(4-methylphenylisoxazoly1)phenol ( 1.1 gm, 4.38
mmoles) in DMF (10 ml), K2C03 (1.2 gm, 5.26 ) was added followed by the
addition‘of ethyl chloro acetate (0.64 gm, 5.26 mmoles) at room temperature and the
on mixture was stirred at room temperaturefor 18 hours. The reaction mixture was
poured into ice cold water, solid ted was filtered, washed with water and dried
over P205 under vacuum to yield 1.4 gm of title product as off white solid.
lH NMR: 1.31 (t, J= 5.6 Hz, 3H), 2.31 (s, 3H), 4.27 (q, J= 7.1 Hz, 2H), 4.68 (s, 2H),
7.01-7.05 (m, 2H), 7.42-7.53 (m, 3H), 7.61-7.65 (m, 2H), 7.73-7.76 (m, 2H).
Ste 2: 2- 4- 4-meth 1 hen lisoxazol l henox acetic acid
To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of
methanol (10 ml), THF (30 ml) and H20 (10 ml), lithium hydroxide (0.35 gm, 8.30
mmoles) was added and the reaction mixture was stirred at ambient temperature for 4
hours. The solvents were evaporated under reduced pressure. The residue was dissolved
in water and acidified with 1N HCl. The solid seperated which was filtered, washed
with water & dried over P205 under vacuum to give 1.25 g of title prodUCt as pale
brown solid.
lH NMR: 2.31 (s, 3H), 4.75 (s, 2H), 7.05-7.07 (m, 2H), 7.45-7.53 (m, 3H), 7.65 (dd, J
= 7.0 & 2.2 Hz, 2H), 7.74-7.76 (m, 2H).
Ste 322- 4- 4-meth 1 hen zol‘l
. yl)methyl)acetamide
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To a solution of product of step 2 (309 mg, 1.00 mmoles) in DMF (3 mL),
(tetrahydro-2H-pyranyl)methanamine (126 mg, 1.10 mmoles), HOBT (202 mg, 1.50
mmoles), EDC.HC1 (230 mg, 1.20 mmoles) and N-ethyl morpholine (345 mg, 3.00
mmoles) were added and reaction mixture was d at room temperature for 20 hours
under en atmosphere. The reaction mixture was poured into ice cold water, solid
seperated was filtered, washed with water and dried over P205 under vacuum to yield
260 mg of title product as pale yellow solid.
lH NMR: 1.28-1.39 (m, 2H), 1.61-1.62 (m, 2H), 1.76-1.85 (m, 1H), 2.31 (s, 3H), 3.26
(t, J= 6.6 Hz, 2H), 3.33 (t, J= 11.8 Hz, 2H), 3.95 (dd, J= 11.0 & 3.4 Hz, 2H), 4.57 (s,
2H), 6.65 (bs, NH), 7.03-7.07 (m, 2H), .53 (m, 3H), 7.65-7.68 (m, 2H), 7.73-7.76
(m, 2H).
The following examples were prepared following the l ures given in the
Example 1 with suitable modifications, alterations and other process variations which
are within the scope of a person skilled in the art.
Example 2
2-(4-(5-methy1phenylisoxazolyl)phenoxy)-N-((tetrahydro-ZH-pyran
yl)methy1)acetamide '
lHNMR (DMSO'dé): 1.30-1.36 (m, 2H), 1.55-1.59 (m, 2H), 1.73-1.81 (m, 1H), 2.43 (s,
3H), 3.24 (t, J = 6.6 Hz, 21-1), 3.32 (t, J = 11.8, 2H), 3.94 (dd, J = 11.0 & 3.0 Hz, 2H),
4.48 (s, 2H), 6.83-6.87 (m, 2H), 7.15-7.18 (m, 2H), 7.33-7.42 (m, 5H).
Example 3
2-(4-(5-(4-fluorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran-4—
yl)methy1)acetamide
lH NMR: 1.28-1.39 (m, 2H), 1.61-1.62 (m, 2H), 1.76-1.85 (m, 1H), 2.29 (s, 3H), 3.26
(t, J = 6.6 Hz, 2H), 3.33 (t, J = 11.0 Hz, 2H), 3.95 (dd, J = 11.2 & 3.6 Hz, 2H), 4.57 (s,
2H), 6.65 (bs, NH), 7.03-7.07 (m, 2H), 7.18-7.24 (m, 2H), 7.63-7.67 (m, 2H), 7.72-7.76
(m, 2H).
Example 4
2-(4-(5-(4-chlorophenyl)methylisoxazol-3—y1)phenoxy)-N-((tetrahydro-2H-pyran
hy1)acetamide _
1H NMR (DMSO-dé): 1.07-1.18 (m, 2H), 1.48-1.51 (dd, J = 1.6 & 12.8 Hz, 2H), 1.64-
1.71 (m, 1H), 2.26 (s, 3H), 3.03 (t, J = 6.4 Hz, 2H), 3.17-3.27 (m, 2H), 3.79-3.82 (dd, J
= 2.4 & 11.2 Hz, 2H), 4.58 (s, 2H), 7.12 (d, J = 6.8 Hz, 2H), 7.62-7.68 (m, 4H), 7.80 (d,
J = 6.4 Hz, 2H), 8.17 (t, J = 6.0 Hz, 1H).
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Example 5
2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro-
2H-pyranyl)methyl)acetamide
'H NMR: 1.29-1.59 (m, 2H), 1.61-1.63 (m, 2H), .86 (m, 1H), 2.34 (s, 3H), 3.26
(t, J = 6.6 Hz, 2H), 3.34 (t, J = 11.8 Hz, 2H), 3.95 (dd, J = 1 1.2 & 3.6 Hz, 2H), 4.57 (s,
2H), 6.65 (bs, NH), 7.05-7.08 (m, 2H), 7.64-7.68 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H),
7.87 (d, J = 8.4 Hz, 2H). -
Example 6
2-(4-(4-methyl(p-tolyl)isoxazo|—3-yl)phenoxy)-N-((tetrahydro-2H-pyran
‘y1)methyl)acetamide
lHNMR: 1.25-1.38 (m, 2H), 1.-581.62 (m, 2H), 1761.85 (m, 1H), 2.29 (s, 3H), 2.43
(s, 3H), 3.3(t.l= 6.6Hz, 2H), 3.3.,39(m 2H),3.-953.,99(m 2H), 4.S7(s, 2H),6.66
(bs, NH), 7.03-.,706(m 2H), 7.31 (d J 8.0Hz, 2H), 7.63--7..68(m,4l-l)
Example 7
4-methylphenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide '
1H NMR (DMSO-ds): 1.07-1.18 (m, 2H), 1.48-1.52'(m, 2H), 1.65-1.71 (m, 1H), 2.32
(s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.18-3.25 (m, 2H), 3.79-3.82 (m, 2H), 4.57 (s, 2H),
7.07-7.10 (m, 2H), 7.49-7.59 (m, 5H), 7.64-7.67 (m, 2H), 8.14 (t, J = 6.0 Hz, NH).
Example 8
2-(4-(5-methoxy- l -(4-(trifluOromethyl)phenyl)-1 zolyl)phenoxy)-N-
((tetrahydro-ZH-pyranyl)methyl)acetamide
'H NMR (DMSO-d6)21.08-1.18 (m, 2H),1.49 (dd, J= 12.8 & 1.6 Hz, 2H ), .73
(m,1H), 3.04 (t, J = 6.4 Hz, 2H), 3.19-3.25 (m, 2H), .87 (m, 2H), 4.05 (s, 3H),
4.54 (s, 2H), 6.46 (s, 1H), 7.02-7.06 (m, 2H), 7.80-7.86 (m, 4H), 8.01 (d, J = 8.4 Hz,
2H), 8.13 (t, J= 5.8 Hz, 1H). ‘
2-(4-( l -(4-fluorophenyl)methoxy-1 H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide
'H NMR (DMSO'dfi): 1.10-1.18 (m, 2H),1.49 (dd, J= 12.8 & 1.2 Hz, 2H ), 1.65-1.71
(m,1H), 3.03 (t, J=. 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79 (dd, J=l 1.2 & 2.0 Hz ,2H),
4.00 (s, 3H), 4.52 (s, 2H), 6.38 (s, 1H), 7.00-7.03 (m, 2H), 7.31—7.35 (m, 2H), 7.72-7.76
(m, 2H), 7.77-7.79 (m, 2H), 8.13 (t, J = 6.0 Hz, 1H). ‘
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Example 10
-methoxyphenyl-1 zolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
lH NMR (DMSO'dfi): 1.10-1.15 (m, 2H),1.49-1.52 (m, 2H ), 1.65-1.71 (m, 1H), 3.03 (t,
J= 6.6 Hz, 2H), 3.19-3.25 (m, 2H), 3.83 (dd, J=11.2 & 2.4 Hz ,2H), 4.00 (s, 3H), 4.52
(s, 2H), 6.38 (s, 1H), 7.03 (d, J = 9.2Hz, 2H), 7.33 (d, J = 8.0Hz,1H), 7.49 (t, J =
7.8Hz, 2H),7.74 (dd J= 8.4 & 1.2Hz, 2H) J= 6.8 &1.6 Hz, 2H), 8.13
, 7.80 (d,d , (t,
1H).
Example 11
2-(4-(4-methylphenylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
hyl)acetamide
lH NMR: 1.07-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.66-1.70 (m, 1H), 2.58 (s, 3H),
3.04 (t, J= 6.6 Hz," 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (dd, J= 2.4 & 11.6 Hz, 2H), 4.55
(s, 2H), 7.07 (d, J= 6.8 2, 2H), 7.46-7.52 (m, 3H), 7.68 (d, J= 6.8 Hz, 2H), 7.91 (d, J=
7.6 Hz, 2H), 8.15 (t. J= 6.0 Hz, 1H).
Example 12
2-(4-(4-methyl(4-(trifluoromethyl)pheny1)thiazol-S-yl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide
1H NMR: 1.28-1.39 (m, 2H), 1.59-1.62 (m, 2H), .83 (m, 1H), 2.62 (s, 3H), 3.28
(t, J = 6.4 Hz, 2H), 3.34-3.40 (m, 2H), 3.96 (dd, J = 11.2 & 3.2 Hz, 2H), 4.56 (s, 2H),
6.67 (5, NH), 7.01-7.04 (m, 2H), 7.67-7.72 (m, 4H), 8.04 (d, J = 8.0 Hz, 2H).
Example 13
2-(4-(2-(4-fluorophenyl)methylthiazol-S-y1)phenoxy)-N-((tetrahydro~2H-pyran
yl)methyl)acetamide
1H NMR: 1.25-1.39 (m, 2H), 1.58-1.62 (m, 2H), 1.78-1.84 (m, 1H), 2.58 (s, 3H), 3.27
(t, J= 6.6 Hz, 2H), 3.33-3.40 (m, 2H), 3.95 (dd, J= 10.4 & 4.0 Hz, 2H), 4.56 (s, 2H),
6.67 (bs, NH), 7.01 (d, J= 6.8 2, 2H), 7.08-7.14 (m, 2H), 7.68 (d, J= 6.8 Hz, 2H),
7.90—7.95 (m, 2H). '
Example 14
2-(4-(2-(4-bromopheny1)methylthiazoly1)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO-ds): 1.10-1.15 (m, 2H), 1.50 (d, J= 13.2'Hz, 2H), 1.65-1.70 (m, 1H),
2.58 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 11.2 & 3.6
W0 2013/132509
Hz, 2H), 4.55 (s, 211), 7.06 (d, J= 6.8 Hz, 2H), 7.67-7.71 (m, 4H), 7.86 (d, J= 6.8 Hz,
2H), 8.15 (s, 1H).
Example 15
2-(4-(2-(4-chlorophenyl)methy1thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (d, J = 9.8 Hz, 2H), 1.65-1.70 (m, 1H),
2.58 (s, 3H), 3.03 (t, J.= 6.4 Hz, 2H), 3.22 (t, J= 10.0 Hz, 2H), 3.80 (dd, J= 11.2 & 2.8
Hz, 2H), 4.55 (s, 2H), 7.07 (d, J= 8.8 Hz, 2H), 7.57 (d, J= 8.8 Hz, 2H), 7.68 (d, J= 8.8
Hz, 2H), 7.94 (d, J= 8.4 Hz, 2H), 8.17 (t, J= 5.8 Hz, 1H).
Example 16
2-(4-(4-methyl(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
y1)methyl)acetamide
1H NMR (DMSO'dé): 1.1 1-1.15 (m, 2H), 1.50 (d, J= 11.2 Hz, 2H), 1.65-1.71 (m, 1H),
2.35 (s, 3H), 2.56 (s, 3H), 3.04 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.4 Hz, 2H), 3.80 (dd, J
= 11.6 & 3.2 Hz, 2H), 4.55 (s, 2H), 7.06 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.4 Hz, 2H),
7.67 (d, J= 8.8 Hz, 2H), 7.80 (d, J= 8.0 Hz, 2H), 8.15 (t, J= 5.4 Hz, 1H).
Example 17
2-(4-(5-methylphenyloxazolyl)phenoxy)—N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR ds): 1.10-1.18 (m, 2H), 1.48-1.52 (dd, J = 1.6 & 12.8 Hz, 2H), 1.65-
1.71 (m, 1H), 2.59 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), .25 (m, 2H), 3.79-3.83 (dd, J
= 2.4 & 11.6 Hz, 2H), 4.53 (s, 2H), 7.05-7.08 (m, 2H), 7.49-7.56 (m, 3H), 7.65-7.69
(m, 2H), 7.97-8.00 (m, 2H), 8.14 (t, J= 6.0 Hz, 1H).
e 18
2-(4-(5-methyl—2-(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H—
pyranyl)methyl)acetamide
1H NMR (DMSO'dfi): 1.11-1.18 (m, 2H), 1.52 (d, J= 13.2 Hz,2H), 1.65-1.71 (m, 1H),
2.62 (s, 3H), 3.04 (t, J= 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (dd, J= 2.4 & 11.2
‘Hz, 2H), 4.54 (s, 2H), 7.07 (d, J = 8.8 2, 2H), 7.69 (d, J = 9.2 Hz, 2H), 7.91 (d, J = 8.4
Hz, 2H), 8.13-8.20 (m, 2H). ‘
Example 19
2-(4-(2-(4-fluorophenyl)-5—methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran~4-
yl)methyl)acetamide
W0 32509
1H NMR (DMSQ-dé): 1.08-1.18 (m, 2H), 1.48-1.52 (m, 2H), 1.66-1.70 (m, 1H), 2.58
(s, 3H), 3.02 (t, J= 6.6 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (in, 2H), 4.53 (s, 2H),
7.04-7.08 (m, 2H), 7.35-7.40 (m, 2H), 7.65-7.68 (m, 2H), 8.01 -8.05 (m, 2H), 8.12 (t, J
= 6.0 Hz, NH).
Example 20
2-(4-(2-(4-bromophenyl)methyloxazolyI)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO-ds): 1.07-1.17 (m, 2H), 1.50 (d, J‘—f 12.4 Hz, 2H), 1.65-1.71 (m, 1H),
2.59 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 10.8 Hz, 2H), 3.81 (d, J= 8.4Hz, 2H),
4.53 (s, 2H), 7.06 (d, J= 8.8 Hz, 2H), 7.67 (d, J= 8.8 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H),
7.92 (d, J= 8.4 Hz, 2H), 8.15 (t, J= 5.4 Hz, 1H).
Example 21
2-(4-(2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
y1)methy1)acetamide
1H NMR (DMSO'dé): 1.1 [-1.14 (m, 2H), 1.50 (d, J= 12.8 Hz, 2H), 1.70 (m, 1H), 2.59
(s, 3H), 3.03 (t, J'= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 10.8 & 2.4 Hz,
2H), 4.53 (s, 2H), 7.06 (d, J = 6.8 Hz, 2H), 7.60 (d, J =68 Hz, 2H), 7.66 (d, J = 6.8 Hz,
2H), 7.98 (d, J = 6.8 Hz, 2H), 8.14 (s, 1H).
Example 22
-methyl(p-tolyl)oxazoly1)phenoxy)-N-((tetrahydro-2H-pyran
hy1)acetamide ,
1H NMR (DMSO-ds): 1.09-1.18 (m, 2H), 1.48—1.52 (m, 2H), 1.67-1.68 (m, 1H), 2.37
(s, 3H), 2.58 (s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (m, 2H),
4.53 (s, 2H), 7.04-7.08 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.64-7.68 (m, 2H), 7.87 (d, J
= 8.0 Hz, 2H), 8.11 (t, J= 6.0 Hz, NH).
Example 23
2-(4-(2-(4-methoxyphenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)mcthyl)acetamide
1H NMR (DMSO-ds): 1.10-1.15 (m, 2H), 1.49-1.52 (m, 2H), 1.65-1.71 (m, 1H), 2.57
(s, 3H), 3.03 (t, J = 6.6 Hz, 2H), .25 (m, 2H), 3.79-3.83 (m, 5H), 4.53 (s, 2H),
7.04 - 7.07 (m, 4H), 7.65 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 8.13 (s, NH).
Example 24
2-(4-(5-methyl-2—(pyridinyl)oxazo1yl)phenoxy)-N~((tetrahydro-2H-pyran
y1)methy1)acetamide
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1H NMR: 1.11-1.15 (m, 2H), .52 (m, 2H), 1.67-1.68 (m, 1H), 2.61 (s, 3H), 3.02
(t, J= 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (m, 2H), 4.54 (s, 2H), 7.06 (dd, J= 6.8
& 2.0 Hz, 2H), 7.56-7.59 (m, 1H), 7.67 (dd, J= 7.2 & 2.0 Hz, 2H), 8.13-8.14 (m, 1H),
8.31-8.34 (m, 1H), 8.69-8.70 (m, 1H), 9.16 (d, J= 1.6 Hz, 1H).
Example 25
N-((tetrahydro-2H-pyrany1)methy1)(4-(5-(4-(trifluoromethy1)pheny1)-1,2,4-
oxadiazo1y1)phenoxy)acetam ide
1H NMR (DMSO-ds): 1.12-1.15 (m, 2H), 1.50-1.53 (m, 2H), 1.64-1.68 (m, 1H), 3.02
(t, J= 6.4 Hz, 2H), 3.19-3 .22 (m, 2H), 3.79-3.83 (m, 2H), 4.61 (s, 2H), 7.16 (d, J= 8.0
Hz, 2H), 8.03-8.07 (m, 4H), 8.19 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 8.0 Hz, 2H).
Example 26
2-(4-(5-(4-fluoropheny1)-1 ,2,4—oxadiazo1y1)phenoxy)-N-((tetrahydro-2H-pyran—4-
y1)methyl)acetamide
1H NMR (DMSO-de): .15 (m, 2H), 1.49-1.52 (m, 2H), 1.68-1.69 (m, 1H), 3.02
(t, J= 6.4 Hz, 2H), 3.19-3.22 (m, 2H), .83 (m, 2H), 4.60 (s, 2H), 7.15 (dd, J= 6.8
& 2.0 Hz, 2H), 7.49-7.54 (m, 2H), 8.02 (dd, J= 7.2 & 2.0 Hz, 2H), 8.19 (t, J= 6.0 Hz,
1H), 8.23-8.27 (m, 2H).
Example 27
2-(4-(5-(4-bromopheny1)-1 ,2,4-oxadiazoly1)phenoxy)-N-((tetrahydro-2H-pyran
yl)methy1)acetamide
1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.65-1.71 (m, 1H),
3.03 (1, J = 6.4 Hz, 2H), 3.22 (t, J = 10.8 Hz, 2H), 3.80 (dd, J = 11.2 & 2.4 Hz, 2H),
4.60 (s, 2H), 7.16 (d, J= 8.8 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H),
8.11 (d, J= 8.4 Hz, 2H), 8.19 (1, J= 6.0 Hz, 1H).
Example 28
2-(4—(5 -(4-chloropheny1)- I ,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2 H-pyran
y1)methy1)acetamide
1H NMR (DMSO-ds): 1.08-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.65-1.70 (m, 1H),
3.04 (t, J= 6.4 Hz, 2H), 3.22 (t, J = 10.8 Hz, 2H), 3.80 (dd, J = 1 1.2 & 2.8 Hz, 2H),
4.60 (s, 2H), 7.16 (d, J= 8.8 Hz, 2H), 7.74 (d, J='8.8 Hz, 2H), 8.04 (d, J= 8.8 Hz, 2H),
8.19 (d, J= 8.4 Hz, 3H).
Example 29
N-((tetrahydro-2H-pyrany1)methy1)(4-(5-(p-toly1)-1,2,4-oxadiazol
y1)phenoxy)acetamide
W0 2013/132509
1H NMR (DMSO-ds): 1.11-1.l7(m, 2H), 1.51 (d, J= 13.2 Hz, 2H), 1.65-1.70 (m, 1H),
2.43 (5, 31-1), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 11.6 & 2.8
Hz, 2H), 4.60 (s, 2H), 7.15 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 8.03 (d, J= 8.8
Hz, 2H), 8.07 (d, J= 8.0 Hz, 2H), 8.18 (t, J=‘5.8 Hz, 1H).
Example 30
2-(4-(5-(4-fluoropheny1)—1,3,4-oxadiazoly1)phenoxy)-N-((tetrahydro-2H-pyran
yl)methy1)acetamide
1H NMR(DMSO-d6):1.11-1.18(m,2H), 1.51 (d, J= 12.8 Hz, 2H), 1.67-1.69 (m, 1H),
3.04 (t, J= 6.4 112,211), 3.22 (t, J= 11.6 Hz, 21-1), 3.80 (dd, J= 11.6 & 2.8 Hz, 2H),
4.62 (s, 2H), 7.18 (d, J= 7.2 Hz, 2H), 7.48 (t, J= 8.8 Hz, 2H), 8.08 (d, J= 6.8 Hz, 2H),
8.17-8.21 (m, 3H).
e 31
N-((tetrahydro-2H-pyranyl)methyl)(4-(5~(4-(trifluoromethy1)phenyl)-1,3,4-
oxadiazolyl)phenoxy)acetamide
1H NMR (DMSO-ds): .18 (m, 2H), 1.51 (d, J= 13.2 Hz, 2H), 1.66-1.71 (m, 1H),
3.04 (t, J= 6.4 Hz, 2H), 3.23 (t, J= 11.2 Hz, 2H), 3.81 (d, J= 8.4 Hz, 2H), 4.63 (s,
2H), 7.20 (d, J= 8.8 Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H), 8.11 (d, J= 8.4 Hz, 2H), 8.20
(d, J= 5.2 Hz, 1H), 8.34 (d, J= 8.0 Hz, 2H).
Example 32
2-(4-(5-(4;methoxyphenyl)-1,3,4-oxadiazo|y1)phenoxy)—N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (d, J= 13.2 Hz, 2H), 1.65-1.71 (m, 1H),
3.04 (t, J= 6.4 Hz, 2H), 3.20-3.26 (m, 2H), 3.80 (dd, J= 11.6 & 2.8 Hz, 2H), 3.86 (s,
3H), 4.62 (s, 2H), 7.16-7.19 (m, 4H), 8.04 (dd, J= 8.8 & 2 Hz, 4H), 8.19 (t, J= 5.6 Hz,
1H),
Example 33
2-(4-(5-(4-chlorophenyl)-1 ,3,4-oxadia201y1)phenoxy)-N-((tetrahydro-2H-pyran
hy1)acetamide
1H NMR (DMSO-d6): 1.11-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.67-1.69 (m, 1H),
3.04 (t, J= 6.2 Hz, 2H), 3.23 (t, J= 11.2 Hz, 2H), 3.81 (d, J= 8.8 Hz, 2H), 4.62 (s,
2H), 7.19 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz, 2H), 8.09 (d, J= 8.8 Hz, 2H), 8.14
(d, J= 8.4 Hz, 2H), 8.18 (d, J= 5.2 Hz, 1H).
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Example 34
2-(4-(5-phenyl-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (t, 2 Hz, 2H), 1.66-1.71 (m, 1H),
3.04 (t, J = 6.4 Hz, 2H), 3.19-3.26 (m, 2H), 3.80 (dd, J = 11.2 & 2.4 Hz, 2H), 4.63 (s,
2H), 7.17-7.20 (m, 2H), 7.60-7.66 (m, 3H),8.07-8.08(m, 2H), 8.09-8.14 (m, 2H), 8.20
(t, J= 5.6 Hz, 1H).
Example 35 .
2-(4-(3-(4-fluorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamidc
1H NMR: 1.08-1.16 (m, 2H), 1.46-1.49 (m, 2H), 1.65-1.66 (m, 1H), 2.99 (t, J= 6.4 Hz,
2H), 3.18-3.21 (m, 2H), 3.78-3.82 (m, 2H), 3.98 (t, J= 8.4 Hz, 1H), 4.38 (t, J'= 8.8 Hz,
1H), 4.51 (s, 2H), 5.66 (t, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.22-7.27 (m, 2H),
7.45 (d, J = 8.0 Hz, 2H), 7.60-7.63 (m, 2H), 8.01 (t, J = 6 Hz, 1H).
Example 36 .
2-(4-(3-(4-methoxyphenyl)oxooxazolidinyl)phenoxy)—N-((tetrahydro-2H-pyran-
4-yl)methyl)acetamide
1H NMR d6): 1.05-1.62 (m, 2H), 1.46 (d, J = 12.4 Hz, 2H), 1.63-1.68 (m, 1H),
3.01 (t, J= 6.4 Hz, 2H), 3.18-3.24 (m, 2H), 3.74 (5, 31-1), 3.78 (dd, J= 11.2 & 2.4 Hz,
2H), 3.93-3.97 (m, 1H), 4.36 (t, J= 9.0 Hz, 1H), 4.51 (s, 2H), 5.66 (t, J= 8.4 Hz, 1H),
6.94-6.98 (m, 2H), 7.00-7.03 (m, 2H), 7.43 (dd, J = 9.6 & 2.8 Hz, 2H), 7.47-7.51 (m,
2H), 8.11 (t, J= 5.08 Hz, 1H).
e 37
2-(4-(4-phenyl-1H-l,2,3-triazoly1)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO‘dé): 1.14-1.18 (m, 2H), 1.48-1.52 (m, 2H), .70 (m, 1H), 3.02
(t, J = 6.6 Hz, 2H), 3.19-3.24 (m, 2H), 3.79-3.82 (m, 2H), 4.59 (s, 2H), 7.16-7.20 (m,
2H), 7.35-7.39 (m, 1H), 7.47-7.50 (m, 2H), 7.84-7.88 (m, 2H), 7.91-7.94 (m, 2H), 8.16
(t, J= 6.0 Hz, NH), 9.18 (s, 1H).
Example 38
2-(4-(5-methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazolyl)phenoxy)-N-
((tetrahydro-2H-pyranyl)methyl)acetamide
1H NMR (DMSO'dfi): 1.05-1.12 (m, 2H),l.49 (d, J= 12.8 Hz, 2H ), 1.64-1.67 (m,1H),
3.00 (t, J= 6.4 Hz, 2H), 3.19 (t, J=10.4 Hz, 2H), 3.78 (s, 5H), 4.51 (s, 2H), 5.27 (s,
W0 2013/132509 2012/000452
2H), 5.90 (s, 1H), 7.02 ( d, J=8.8 Hz, 2H ), 7.20 ( d, J=8.0 Hz, 2H ), 7.34 ( d, J=8.8
Hz, 2H ), 7.68 ( d, J=8.0 Hz, 2H ), 8.10 (t, J= 5.8 Hz, 1H).
Example 39
2-(4-(4,5-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
1H NMR (DMSO‘dé): 1.10-1.17 (m, 2H), 1.47-1.51 (m, 2H), 1.64-1.70 (m, 1H), 2.06‘
(s, 3H), 2.29 (s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 11.8 Hz, 2H), .82 (dd, J
= 11.2 & 2.4 Hz, 2H), 4.55 (s, 2H), 7.05 (d, J= 6.8 Hz, 2H), 7.82 (d, J= 6.8 Hz, 2H).
The following compounds can be prepared by procedure similar to those described
above with'appropriate variations of reactions, reaction ions and quantities of
reagents.
Example 40
2-(4-(5-(4-bromophenyl)methylisoxazolyI)phenoxy)-N-((tetrahydro-2H-pyran-44
yl)methyl)acetamide
Example 41
2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)—N-((tetrahydro-2H-pyran-
4-yl)methyl)acetamide
Example 42
2—(4-(4-methy1(4-(trifluoromethoxy)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro-
2H-pyranyl)methyl)acetamide
Example 43
2-(4-(5-(4-fluorophenyl_)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H—pyran~4-
hyl)acetamide
Example 44
2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran-
4-y1)methyl)acetamide
Example 45
2-(4-(5-(4—bromophenyl)—4-methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran-
4-yl)methyl)acetamide
Example 46
2-(4-(4-methyl(p-tolyl)isothiazolyl)phenoxy)-N-((tetrahydro—ZH-pyran
yl)methyl)acetamide
Example 47
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2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro-
2H-pyranyl)methyl)acetamide
Example 48
-(4-methoxyphenyl)methy_lisothiazolyl)phenoxy)-N-((tetrahydrd-2H-
pyranyl)methyl)acetamide ' '
Example 49
4-methyl-S—(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)—N-
((tetrahydro-ZH—pyranyl)methyl)acetamide
Example 50
2-(4—(1-(4-chlorophenyl)methoxy- l H—pyrazolyl)phenoxy)-N—((tetrahydro-2H-
pyranyl)methyl)acetamide
Example 51
2-(4-(5-methoxy(4-methoxyphenyl)-l zolyl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide
Example 52
2-(4-(5-methoxy- l -(4-(trifluoromethoxy)phenyl)-1 H-pyrazolyl)phenoxy)-N-
((tetrahydro-ZH-pyran—4-yl)methyl)acetamide
Example 53 .
2-(4-(1 -(4-bromophenyl)methoxy- l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide
Example 54
2-(4~(5~methoxy- l -(p—tolyl)-l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Example 55
2-(4-(3-(4-chlorophenyl)-2—oxooxazolidin-S-yl)phenoxy)—N-((tetrahydro-2H-pyran—4-
yl)methyl)acetamide '
Example 56
2-(4-(2-ox0(4-(trifluoromethyl)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-
pyranyl)methyl)acetamide
Example 57
2-oxo(4-(trifluoromethoxy)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro-
ZH-pyrany|)methyl)acetamide
Example 58
2-(4-(3-(4-bromophenyl)~2-oxooxazolidin-S-yl)phenoxy)-N-((tetrahydro-ZH-pyran
yl)methyl)acetamide
Example 59
2-(4-(2-oxo(p-tolyl)oxazolidin-S—yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide ’
Example 60
2-(4-(4-(4-chlorophenyl)-1H-l,2_,3-triazol- l-yl)phenoxy)—N-((tetrahydro-2H-pyran—4-
yl)methyl)acetamide
Example 61
N-((tetrahydro-2l-l-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)- l H- l ,2,3-
triazolyl)phenoxy)acetamide
'Example 62
N-((tetrahydro-2H-pyranyl)methyl)—2-(4-(4-(4-(trifluoromethoxy)phenyl)-1 H-1,2,3-
triazol-I enoxy)acetam ide
e 63
2-(4-(4-(4-bromophenyl)- 1 11 ,2,3-triazol- l -yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Example 64
N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(p-tolyl)-1 H-1,2,3-triazol
yl)phenoxy)acetamide
Example 65
2-(4-(4-(4-fluorophenyl)—l 3-triazol-l -yl)phenoxy)-N-((tetrahydro-2H—pyran
yl)methyl)acetamide
e 66
2-(4-(4-(4-methoxyphenyl)- 1 PH ,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran
' yl)methyl)acetamide
Example 67
2—(4-(3,-(4-chlorophenyl)iminooxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide '
Example 68 .
2-(4-(6-(4-chlorophenyl)pyridin-2~yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Example 69
2-(4-(4-(4-chloropheny1)pyrimidinyl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Example 70
2-((8-(4-chlorophenyl)dibenzo[b,d]thiophenyl)oxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Example 71
2-(4-(7-chlorodibenzo[b,d]thiophen-Z-yl)phenoxy)-N-((tetrahydro-2H-pyran
yl)methyl)acetamide
Demonstration of in vitro potency ofcompounds
The PCSK9-LDLR in vitro binding Assay is a quantitative solid phase binding
assay between PCSK9 and recombinant LDLR. _Plates were pre-coated with a
recombinant LDLR-AB domain, which binds PCSK9. Test nd at different
concentration was added to the PCSK9 and added to LDLR lized on the wells.
The amount of bound PCSK9 is measured by binding it with biotinylated anti-His-tag
monoclonal antibody, followed by g with horseradish peroxidase conjugated
streptavidin substrate. The color was quantified by ELISA reader at 450 nM which
reflects the ve amount of PCSK9 that binds to LDLR in presence and absence of
the inhibitor. EC50 values were calculated by nonlinear regression analysis using graph
pad prism software. Each concentration point ents values in duplicates.
Concentration % Inhibition
Example No. '
(pM) PCSK9
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VIA510685NZPR
303916262
Unless the context clearly requires otherwise, throughout the description and the
, the words “comprise”, “comprising”, and the like, are to be construed in an
inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense
of “including, but not limited to”.
VIA510685NZPR
303916262
The reference to any prior art in the specification is not, and should not be taken
as, an ledgement or any form of suggestion that the prior art forms part of the
common general knowledge in New Zealand.
585NZPR
303915590
Claims (22)
1. A compound of formula (I), its tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, and pharmaceutical compositions containing said compound, wherein (R2)n (R1)m Z X W N ZA H (R3)o ‘ZA’ represents an optionally tuted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Each of ‘X’ and ‘Z’ ndently represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Alternatively, Z-X- ZA may er form tricyclic 8-15 membered fused ring system containing 1-4 hetero atoms selected from N, O or S; R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or branched alkyl, (C1-C6) linear or ed alkenyl, (C1-C6)linear or branched l, hydroxy, (C1-C6) alkoxy, (C 1-C6) alkenoxy, hydroxy(C 1-C6)alkyl, alkoxyalkyl, haloalkyl, (C1-C6)cycloalkyl, thio(C1-C6)alkyl, (C1-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, ally substituted amino, amino(C1-C6)alkyl, alkylamino, cyano, formyl, koxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted; ‘m’ ‘n’ and ‘o’ independently represents integers from 0 to 5; ‘Y’ represents either a bond, or O, S(O)p or NR4 wherein R4 represents H, (C1-C6)linear or branched alkyl, (C1-C6)cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl and ‘p’ represents rs from 0 to 2; ‘W’ represents (C1-C6)linear or ed alkyl or (C1- C6)linear or branched cycloalkyl; ‘V’ represents O or S;
2. The compound as claimed in claim 1 n ‘X’ is selected from optionally substituted aryl or heterocyclyl groups.
3. The compound as claimed in claim 2 wherein, the aryl group is selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups. VIA510585NZPR 303915590
4. The compound as claimed in claim 3 wherein the aryl group is an optionally substituted phenyl group.
5. The nd as claimed in claim 1 wherein when ‘X’ represents a cyclyl group, the heterocyclyl group is selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S.
6. The compound as claimed in claim 5 wherein the heterocyclyl group is ed from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, olinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, nyl, benzimidazolyl, benzotriazolyl, azynil, naphthylidinyl, purinyl, carbazolyl, hiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, yranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, olonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl groups.
7. The compound as claimed in claim 1 wherein either of ‘Z’ and ‘ZA’ is independently selected from optionally substituted aryl or heterocyclyl groups.
8. The compound as claimed in claim 7 wherein when either of ‘Z’ and ‘ZA’ independently represents an aryl group, the aryl group is ed from substituted or unsubstituted monocyclic or bicyclic aromatic groups.
9. The compound as claimed in claim 8 wherein the aryl group is an optionally substituted phenyl group.
10. The compound as claimed in claim 7 wherein when either of ‘Z’ and ‘ZA’ independently represents a heterocyclyl group, the heterocyclyl group is selected from single or fused mono or bi cyclic aromatic or omatic groups containing one or more hetero atoms selected from O, N or S.
11. The compound as claimed in claim 10 wherein, when either of ‘Z’ and ‘ZA’ independently represents heteroaromatic group, the heteroaromatic group are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, lyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, nyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, VIA510585NZPR 303915590 pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, azinyl, benzoxazolyl, benzothiazolyl .
12. The compound as claimed in claim 1 n when any of R1, R2 or R3 are substituted, such substituents are selected from hydrogen, yl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, cyclylalkoxyacyl, acyl, acyloxy, ino, monosubstituted or disubstituted amino, arylamino, aralkylamino, ylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfonic acid and its derivatives.
13. The compound as claimed in claim 1 wherein when the aryl group at any occurrence is further substituted, the substituents are selected from halo, thiol, nitro, amino, cyano, , or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, oalkyl, alkoxy, koxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, cyclylalkoxyacyl, acyl, acyloxy, acylamino, bstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio groups.
14. The compound as claimed in claim 1 wherein when the heteroaryl group at any ence is further substituted, the substituents are selected from halo, thiol, nitro, VIA510585NZPR 303915590 amino, cyano, formyl, or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, cyclylalkoxy, acyl, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides.
15. The compound as claimed in claim 1 wherein when the heterocyclyl group at any occurrence is further tuted, the substituents are selected from halo, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, lkyl, cycloalkenyl, alkoxy, xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio .
16. The compound as claimed in claim 1 ed from 2-(4-(4-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 5-(4-fluorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H- 4-yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methylphenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-(5-methoxy(4-(trifluoromethyl)phenyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 2-(4-(1-(4-fluorophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide; 2-(4-(5-methoxyphenyl-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methylphenylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)thiazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-(4-fluorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-bromophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(2-(4-chlorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-(4-fluorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-bromophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(p-tolyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-methoxyphenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(pyridinyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4- oxadiazolyl)phenoxy)acetamide; 2-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(p-tolyl)-1,2,4-oxadiazol yl)phenoxy)acetamide; 2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,3,4- oxadiazolyl)phenoxy)acetamide; 2-(4-(5-(4-methoxyphenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(5-(4-chlorophenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-(5-phenyl-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-fluorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-methoxyphenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-phenyl-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 4,5-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; 2-(4-(5-(4-fluorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-(4-methoxyphenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; 1-(4-chlorophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(4-methoxyphenyl)-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(4-(trifluoromethoxy)phenyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 2-(4-(1-(4-bromophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(p-tolyl)-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-chlorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-oxo(4-(trifluoromethyl)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-oxo(4-(trifluoromethoxy)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(3-(4-bromophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-oxo(p-tolyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 585NZPR 2-(4-(4-(4-chlorophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3- triazolyl)phenoxy)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3- triazolyl)phenoxy)acetamide; 2-(4-(4-(4-bromophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(p-tolyl)-1H-1,2,3-triazol yl)phenoxy)acetamide; 2-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-(4-methoxyphenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-chlorophenyl)iminooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(6-(4-chlorophenyl)pyridinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 4-(4-chlorophenyl)pyrimidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-((8-(4-chlorophenyl)dibenzo[b,d]thiophenyl)oxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(7-chlorodibenzo[b,d]thiophenyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide.
17. The compound as claimed in any one of claims 1 to 16 suitably formulated into a suitable pharmaceutical composition.
18. Use of a compound of formula (I) as claimed in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of hyperlipidemia, dyslipidemia, obesity, hypercholesteremia, hypertension, atherosclerosis, vascular restenosis and diabetes. VIA510585NZPR 303915590
19. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 16 in combination with one or more pharmaceutically active agents selected from group comprising insulin, insulin derivatives and mimetics, insulin agogues, insulin izers, biguanide agents, glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 activators, -dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, itazone type PPAR delta agonist, A reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and besity agents or pharmaceutically acceptable salts thereof.
20. A compound as claimed in claim 1, substantially as hereinbefore bed with particular reference to any one or more of the Examples.
21. Use of a compound of formula (I) as claimed in claim 18, substantially as hereinbefore described with particular reference to any one or more of the Examples.
22. A pharmaceutical composition as claimed in claim 19, substantially as hereinbefore described with particular reference to any one or more of the Examples.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN612MU2012 | 2012-03-07 | ||
IN612/MUM/2012 | 2012-03-07 | ||
PCT/IN2012/000452 WO2013132509A1 (en) | 2012-03-07 | 2012-06-26 | Novel compounds for the treatment of dyslipidemia and related diseases |
Publications (2)
Publication Number | Publication Date |
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NZ629360A NZ629360A (en) | 2016-04-29 |
NZ629360B2 true NZ629360B2 (en) | 2016-08-02 |
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