Title of Invention

NOVEL SUBSTITUTED ARALKYL DERIVATIVES HAVING ANTIDIABETIC HYPOLIPIDEMIC, HYPOCHOLESTEREMIC ACTIVITIES PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE IN MEDICINE

Abstract The present invention relates to novel substituted aralkyl derivatives of the general formula (I) & (Ilia), their derivatives, their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, pharmaceutical compositions containing them, use of these compounds in medicine and the intermediates involved in their preparation.
Full Text FORM 2
The PATENT ACT, 1970
(39 of 1970)
Complete Specification
(See Section 10)


NOVEL SUBSTITUTED ARALKYL DERIVATIVES HAVING ANTIDIABETIC
HYPOLIPIDEMIC, HYPOCHOLESTEREMIC ACTIVITIES, PROCESS FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM AND THEIR USE IN MEDICINE
CADILA HEALTHCARE LTD, Zydus Research Centre Zydus Tower, Satellite Cross Road, Sarkhej-Gandhinagar Highway, Ahmedabad-
380015, Gujarat, India.
The following specification describes the nature of the invention and the manner in which it is performed.


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FIELD OF INVENTION
The present invention relates to novel antidiabetic, hypolipidaemic and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel substituted aralkyl derivatives of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, pharmaceutical compositions containing them, use of these compounds in medicine and the intermediates involved in their preparation.
A-(CH2)n-X-Ar^^G2
G> (I)
The present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them.
The present invention also discloses novel compounds of formula (Ilia) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The compounds of formula (Ilia) are useful as intermediates for the preparation of compounds of formula (I).
-V
0
A-(CH2)n-X-Ar
G, (Ilia)
The compounds of the general formula (I) & (IIIa) lower blood glucose, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density lipoproteins (HDL)
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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, vascular restenosis, diabetes and many other related conditions .
The compounds of general formula (I) & (Ilia) 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 diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.
These compounds of general formula (I) & (Ilia) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulineima, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non-insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or 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 neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.
The compounds of the present invention can be useful as aldose reductase inhibitors; for improving cognitive functions in dementia, and in the treatment and/or prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia.
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The compounds of the present invention are useful in the treatment of the diseases mentioned herein, alone or in combination with one or more hypoglycemic, antihyperglycemic, hypolipidaemic, hypolipoproteinemic agents. antioxidants, antihypertensives, such as HMG CoA reductase inhibitor, fibrate. statins, glitazones, sulfonyl ureas, insulin, a-glycosidase inhibitors, nicotinic acid, cholestyramine, cholestipol or probucol, and the like.
BACKGROUND OF THE INVENTION
Hyperlipidaemia has been recognized as the major risk factor in causing cardiovascular diseases due to atherosclerosis. Atherosclerosis and other such peripheral vascular diseases affect the quality of life of a large population in the world. The therapy aims to lower the elevated plasma LDL cholesterol, low-density lipoprotein and plasma triglycerides in order to prevent or reduce the risk of occurrence of cardiovascular diseases. The detailed etiology of atherosclerosis and coronary artery diseases is discussed by Ross and Glomset [New Engl. J. Med., 295, 369-377 (1976)]. Plasma cholesterol is generally found esterified with various serum lipoproteins and numerous studies have suggested an inverse relationship between serum HDL-cholesterol level and risk for occurrence of cardiovascular disease. Many studies have suggested an increased risk of coronary artery diseases (CAD) due to elevated LDL and VLDL-cholesterol levels [Stampfer et al., N. Engl. J. Med., 325, 373-381(1991)]. The other studies illustrate protective effects of HDL against progression of atherosclerosis. Thus. HDL has become a crucial factor in treating diseases with increased levels of cholesterol [Miller et. al., Br. Med. J. 282, 1741-1744(1981); Picardo et al.. Arteriosclerosis, 6, 434-441 (1986); Macikinnon eta/.. J. Biol. Chem. 261, 2548-2552 (1986)].
Diabetes is associated with a number of complications and also affect a large population. This disease is usually associated with other diseases such as obesity, hyperlipidemia, hypertension and angina, ft is well established that improper treatment can aggravate impaired glucose tolerance and insulin resistance, thereby leading to frank diabetes. Further, patients with insulin resistance and type 2 diabetes often have raised triglycerides and low HDL-cholesterol concentrations and therefore, have greater risk of cardiovascular diseases. The present therapy for these diseases includes sulfonylureas and
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biguanides along with insulin. This type of drug therapy may lead to mild to severe hypoglycemia, which may lead to coma or in some cases may lead to death, as a result of unsatisfactory glycaemic control by these drugs Recent addition of drugs in the treatment of diabetes are the thiazolidinediones, drugs having insulin-sensitizing action. Thiazolidmediones like troglitazone, rosiglitazone and pioglitazone are prescribed alone or in combination with other anti-diabetic agents.
These are useful iii treating diabetes, lipid metabolism but are suspected to have ■tumor-inducing potential and cause hepatic dysfunction, which may lead to liver failure. Further, serious undesirable side-effects have occurred in animal and/or human studies which include cardiac hypertrophy, hema dilution and liver toxicity in a few glitazones progressing to advanced human trials. The drawback is considered to be idiosyncratic. Presently, there is a need for a safe and an effective drug, to treat insulin resistance, diabetes and hyperlipidemia.f Exp. Clin. Endocrinol. Diabetes: 109(4), S548-9 (2001)]
Obesity is another major health problem being associated with increased morbidity and mortality. It is a metabolic disorder, in which excess of fat is accumulated in the body. Although, its etiology is unclear, the general feature includes excess of calorie intake than it is consumed. Various therapies such as dieting, exercise, appetite suppression, inhibition of fat absorption etc. have been used to combat obesity. However, more efficient therapies to treat this abnormality is essential as obesity is closely related to several diseases such as coronary heart disease, stroke, diabetes, gout, osteoarthritis, hyperhpidaemia and reduced fertility. It also leads to social and psychological problems [Nature Reviews: Drug Discovery: 1(4), 276-86 (2002)].
Peroxisome Proliferator Activated Receptor (PPAR) is a member of the steroid/ retinoid/ thyroid hormone receptor family. PPARcc, PPARy and PPAR5 have been identified as subtypes of PPARs. Extensive reviews regarding PPAR, their role in different diseased conditions are widely published [Endocrine Reviews, 20(5), 649-688 (1999); J. Medicinal Chemistry, 43(4), 58-550 (2000); Cell, 55, 932-943 (1999); Nature, 405, 421-424 (2000); Trends in Pharmacological ScL, 469-473 (2000)]. PPARy activation has been found to play a central role in initiating and regulating adipocyte differentiation [Endocrinology 135, 798-800, (1994)] and energy homeostasis, [Cell, 83,
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803-812 (1995); Cell, 99, 239-242 (1999)]. PPARy agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristic o\' a more differentiated, less malignant state. During adipocyte differentiation, several highly specialized proteins are induced, which are being involved in lipid storage and metabolism. It is accepted that PPARy activation leads to expression of CAP gene [Cell Biology, 95, 14751-14756, (1998)], however, the exact link from PPARy activation to changes in glucose metabolism and decrease in insulin resistance in muscle has not been clear. PPARa is involved in stimulating P-oxidation of fatty acids [Trends Endocrine. Metabolism, 4, 291-296 (1993)] resulting in plasma circulating free fatty acid reduction [Current. Biol., 5, 618-621 (1995)]. Recently, role "of PPARy activation in the terminal differentiation of adipocyte precursors has been implicated in the treatment of cancer. [Cell, 79, 1147-1156 (1994); Cell, 377-389 (1996); Molecular Cell, 465-470 (1998); Carcinogenesis, 1949-1953 (1998); Proc. Natl. Acad. Sci., 94, 237-241 (1997); Cancer Research, 58, 3344-3352 (1998)]. Since PPARy is expressed in certain cells consistently, PPARy agonists would lead to nontoxic chemotherapy. There is growing evidence that PPAR agonists may also influence the cardiovascular system through PPAR receptors as well as directly by modulating vessel wall function [Med. Res. Rev.. 20 (5), 350-366 (2000)].
PPAR a agonists have been found useful in the treatment of obesity (WO 97/36579). Dual PPAR a and y agonists have been suggested to be useful for Syndrome X (WO 97 25042). PPAR y agonists and HMG-CoA reductase inhibitors have exhibited synergism and indicated the usefulness of the combination in the treatment of atherosclerosis and xanthoma (EP 0753 298).
Leptin is a protein when bound to leptin receptors is involved in sending satiety signal to the hypothalamus. Leptin resistance would therefore lead to excess food in-take, reduced energy expenditure, obesity, impaired glucose tolerance and diabetes [Science, 269, 543-46(1995)]. It has been reported that insulin sensitizers lower plasma leptin concentration [Proc. Natl. Acad. Sci. 93, 5793-5796 (1996): WO 98/02159)].
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Phenalkyloxy-phenyl derivatives having general formula as given below, useful in the treatment of insulin resistance has been described in WO 01/401.70 (AstraZeneca AB).



%
[CH2]CHvO-
*)
D"

A typical example of these compounds is shown formula (Ha)

OEi
Aryl hydroxy propanol derivatives having the general formula given below



as agents for treatment of disorders associated with insulin resistance have been described in WO 03008362 (Dr. Reddy's Research Foundation)
A number of compounds belonging to the class of oxazole derivatives have been reported to be useful in the treatment of hyperlipidemia, hypercholesterolemia and hyperglycemia which includes
WO 02092084 (Hoffmann La Roche) describes oxazole compounds having the following general formula


.(CH2)nO
J

wherein, R is aryl or heteroaryl; R", R , R and R""" are independently selected from the group consisting of hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl and lower-alkoxy, wherein at least one of R2, R"\ R4 and R6 is not hydrogen, or R"' and R are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are -CH=CH-S-; -S-CH=CH-, -CH=CH-
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0-, -0-CH=CH-, -CH=CH-CH=CH-, -(CH2)3.5-, -0-(CH2)2-3- or -(CH2)2.3O-
R^ is lower-alkoxy, lower-alkenyloxy, or


—N_
or

^8 Rg
H
—N—'

0

-R

10

.10
R', R', R , each represent H or lower-alkyl; R is aryl; n is 1,2 or 3; the bond between Ca & Ci, represent a carbon-carbon single or double bond;
WO 0216331 (Eli Lilly & Co.) discloses oxazolyl-arylpropionic acid derivatives of the following general formula

(CH2)nWY

COOR5
R3 OR4

where R| is substituted or unsubstituted groups selected from aryl. heteroaryl, cycloalkyl. heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, (CH3)3C-: n = 2, 3, 4; W represents CH2, CH(OH), CO, 0; R? represents H, alkyl, haloalkyl. C6H5; Y represents substituted or unsubstituted group consisting of thiophen-2,5-diyl or phenylene; R3 represents alkyl, haloalkyl; R4 represents substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl, pyridyl, benzo[l,3]dioxol-5-yl: R5 represents H, alkyl, aminoalkyl groups.
WO 9807699 (Japan Tobacco, Inc.) describes propionic acid derivative of the 'following
general structure


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wherein R represents
R5

R,/N

.-^

R is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbons, .an optionally substituted heterocyclic group, or an optionally substituted fused heterocyclic group, R3 is lower alkyl; R4 = H or lower alkyl; R6=H or forms together with R\ a double bond; R is a carboxy, an acyl, an optionally substituted alkoxycarbonyl, an optionally substituted lower alkyl. an optionally substituted carbamoyl, an optionally substituted aryloxycarbonyl, an optionally substituted aralkyloxycarbonyl or a group of the formula -Y-R'"1 wherein Y is -N'H- or an oxygen atom and R* is an optionally substituted acyl or an optionally substituted alkoxycarbonyl; R' = H, an optionally substituted loweralkyl or an optionally substituted alkoxycarbonyl; R u is a hydroxy, an optionally substituted amino, an optionally substituted lower alkoxy, an optionally substituted lower alkyl, an optionally substituted aryloxy or an optionally substituted aralkyloxy, provided that when R7 is an alkoxycarbonyl and R9 is a hydrogen atom, R is not a lower alkoxy.
WO 02100403 (Eli Lilly & Co.) discloses compounds of the following general formula suitable for the treatment of Syndrome X


YV,-H>
V n

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Wherein Y represents
Yla f A). j £
Ykl is H, (C0-C3) alkyl-aryl, C(0)-aryl , hetcroaryl, cycloalkyl, heterocycloalkyl. aryloxy, ere:
0 . ■
is aryl or heteroaryl; V is a bond or 0; X is CH2 or 0, R5 is H or CrC6 alkyl; Y" and Y~ are each independently H, C1-C6, alkyl or Ci-Cf, alkoxy; Y is (C1-C3) alkyl-NR5C(0) -(C0-C5) alkyl-Y7, (C1-C3) alkyl-NR5C 0) -(C2-C5) alkenyl-Y7; (C1-C}) alkyl-NR5C(0) -(C2-C5) alkynyl-Y7, CN etc.; Y7 is H, aryl heteroaryl, C,-C,2 alkyl, C,-C6 alkoxy, cycloalkyl, heterocycloalkyl, aryloxy, C(0)-heteroaryl etc.; n' is 2,3,4 or 5;
US 5232945 (Pfizer Inc.), describes compounds of the following general formula

Wherein Z= H, amino, (C|-C7)alkyl, (C3-C'7)cycioalkyl, phenyl or phenyl mono or disubstituted with (C1-C3)alkyl, CF3, (C|-C3)alkoxy, phenyl, phenoxy, benzyl, benzyloxy, fluoro or chloro; Z1 = H or (C|-C3)alkyl; R = (un)substituted alkyl, cycloalkyl, alkenyl, alkynyl, Ph, phenylalkyl, alkanoyl: X - S, 0, NR2, -CH=CH; -CH=N: -N=CH; R2 = H, alkyl, Ph, CH2Ph; Y = CH, N; X1 = 0, S, SO, S02; Y1 = OH, (un)substituted alkoxy, OPh, OCH2Ph, NH2 etc.; W = 0, CO, CH2, CH(OH), -CH=CH; in = 0, 1, 2;
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Several other oxazole derivatives useful in the treatment of diabetes, hyperlipidemia etc. (Syndrome X) have been reported for e.g. WO 03072100, WO 0320269, WO 0216332, WO 0218355, WO 0216331, WO 0216332, WO 0296895, WO 0296895, WO 0296894, WO 0296893, WO 0262774, WO 0250048, WO 0250047, WO 0276957, WO 0251820. WO 0214291, WO 0138325, WO 01 16120. WO 0100403, WO 01 161 1 L WO 0116120. WO 0179202, WO 0179197, WO 0008002. US 20010008898, JP 2002338555. JP 2001261612 which are incorporated -in their entirety as reference.
However, very few of the compounds described above have reached the market and so there therefore remains the need to develop newer medicines which are better and cost effective, are of better or comparable efficacy with the present treatment regimes, has lesser side effects and requires a lower dosage regime
SUMMARY OF INVENTION
The objective of this invention is to develop novel compounds represented by the general formula (I) & (Ilia) used as hypocholesterolemic. hypolipidaemic, hypolipoproteinemic, anti-obesity and antihyperglycemic agents which may have additional body weight lowering effect and beneficial effect in the treatment and/or prophylaxis of diseases caused by hyperlipidaemia. diseases classified under syndrome X and atherosclerosis.
OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide novel substituted aralkyl derivatives represented by the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof.
Another objective of the present invention is to provide novel substituted aralkyl derivatives represented by the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them

ZRC-MC-009
or their mixtures thereof having enhanced activities, without toxic effects or with reduced toxic effect.
Yet another objective of this invention is to provide a process for the preparation of novel substituted aralkyl derivatives represented by the general formula ([), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
A further objective of the present invention is to provide novel substituted propanoic acid derivatives of formula (IIIa), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof, useful as intermediates in the preparation of compounds of general formula (I).
Another objective of the present invention is to provide novel substituted propanoic acid derivatives represented by the general formula (Ilia), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof having enhanced activities, without toxic effects or with reduced toxic effect.
Yet another objective of this invention is to provide a process for the preparation of novel substituted propanoic acid derivatives represented by the general formula (Ilia), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (Ilia), their derivatives, their
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analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with Suitable carriers, solvents, diluents and other media normally employed in preparing such compositions
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general formula (I),
A-(CH,)n-X-Ar^Y^G2
Gi (I)
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein 'A' represents a substituted or unsubstituted, group selected from aryl, heteroaryl, heterocyclyl groups; 'n' is an integer from 1-3. with the proviso that when A is substituted or unsubstituted phenyl group, then 'Ar' does not represent a divalent phenyl group; 'X' represents oxygen or sulfur;
'Ar' represents a substituted or unsubstituted single or fused divalent aromatic, heteroaromatic or a heterocyclic group;
Gi and G2 may be same or different and independently represent NR1R2, OR1, SR1, S(0)R3 S(0)2R3. N3, CN, COOH, tetrazolyl groups; R, & R2 may be same or different and independently represent hydrogen, substituted or unsubstituted groups selected from linear or branched (Ci-Q)alkyl, (C3-C7)cycloalkyl acyl, aryl, heteroaryl, heterocyclyl, aminocarbonyl, aralkyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaraloxycarbonyl. heterocycloxycarbonyl groups or SO2R3 wherein R3 represents substituted or unsubstituted groups selected from alkyl, aryl, polyhaloalkyl, heterocyclyl, heteroaryl groups; G3 represents hydrogen or (C|-Cv;)alkyl or (C3-C7)cycloalkyl groups.
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Suitable substituents on R|, R2 or R3 may be same or different and independently selected
from hydroxyl. oxo. halo, thio, nitro, amino, cyano, formyl, amidino, guamdmo,
hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy.
cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl,
heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, hererocyclylalkoxy,
heterocyclylalkoxyacyl, acyl," acyloxy, acylamino, • monosubstituted or disubstituted
ammo, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and
amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl. aryloxyalkyl.
aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy.
alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino,
aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
When A is substituted, the substituents may be selected from hydroxyl. oxo, halo, thio,
nitro. ammo, cyano, formyl, or substituted or unsubstituted groups selected from amidino.
guamdmo, hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy. perhaloalkoxy,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy,
alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl,
heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy. heterocyclyloxy,
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, arylthio, alkylsulfonylamino,
alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino,
aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino,
alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
When the substituents on 'A' are further substituted, those substituents are selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, guanidino, hydrazino, alkyl haloalkyl, perhaloalkyl,
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alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, heterocyclyloxy, 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,
arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino,
aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino,
alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives The substituents on the group represented by Ar represents substituted or unsubstituted linear or branched alkyl, alkoxy, thioalkyl, halogen, haloalkyl, haloalkoxy, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives, phosphonic acid and their derivatives.
In another embodiment are provided novel substituted propanoic acid derivatives of formula (Ilia), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutical!)' acceptable solvates,
0
wherein 'A' represents 4-oxazolyl group substituted with one or two substituents selected from substituted or unsubstituted linear or branched (C1-C12)alkyl. substituted or unsubstituted single or fused heteroaryl or heterocyclic groups; 'Ar' represents unsubstituted phenyl; G\ represents OR| or SR|, where R| represents hydrogen, perfluoro(C1-C12)alkyl, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, cyclo(C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or acyl groups; R4 represents OH, alkoxy or aryloxy, aralkoxy or NR1R2 groups, wherein R| & R2 may be
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same or different and independently represent hydrogen, substituted or unsubstituted
groups selected from linear or branched (C1-C8)alkyl, (C3-C7)cycloalkyl, acyl, aryl,
heteroaryl, heterocyclyl, aminocarbonyl, aralkyl, alkylaminocarbonyl,
arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl,
heteroaralkylaminocarbonyl. heterocyclylaminocarbonyl, alkoxycarbonyl.
aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaraloxycarbonyl. heterocycloxycarbonyl groups or SO2R3 wherein R3 represents substituted or unsubstituted groups selected from alkyl, aryl, polyhaloalkyl, heterocyclyl, heteroaryl groups; 'n' is an integer from 1-3; X represents 0 or S.
Suitable substitutions on the substituents on 'A' are selected from hydroxy!, oxo, halo,
thio, nitro, amino, cyano, formyl. or substituted or unsubstituted groups selected from
amidino, guanidino, hydrazine alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy,
perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl,
alkoxy, alkenoxy, cycloalkoxy, aryl. aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl,
heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy,
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. arylthio, alkyisulfonylamino.
alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino,
aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino,
alkoxyamino, hydroxy I amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
The compounds of formula (IIIa) are useful as intermediates for the preparation of compound of formula (I). In addition, compound of formula (Ilia) are also useful in preventing or reducing the risk of developing atherosclerosis, which leads to diseases and conditions such as artereosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. Also, the compounds of formula (IIIa) are useful in the treatment or prevention of diseases associated with Syndrome X.
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The present invention also discloses novel processes for the preparation of compounds of
formula (1) & (Ilia).
The various groups, radicals and substituents used anywhere in the specification are
described in the following paragraphs.
The term "alkyl" used herein, either alone or in combination with other radicals, denotes
a linear or branched radical containing one to twelve carbons, such as methyl, ethyl, n-
propyl, /.iso-propyl, /7-butyl, .vet-butyl, /e/7-butyl, amyl, /-amyl, /7-pentyl, /7-hexyl,- iso-
hexyl, heptyl, octyl and the like.
The term "alkenyl" used herein, either alone or in combination with other radicals.
denotes a linear or branched radical containing two to twelve carbons such as-vinyl, allyl,
2-butenyl, 3-butenyl. 2-pentenyl. 3-pentenyl. 4-pentenyl, 2-hexenyl, 3-hexenyl 4-
hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the
like. The term "alkenyl" includes dienes and trienes of straight and branched chains.
The term "alkynyl" used herein, either alone or in combination with other radicals,
denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1-
propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-
pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. The term
"alkynyl" includes di- and tri-ynes.
The term "cycloalkyl" used herein, either alone or in combination with other radicals,
denotes a radical containing three to seven carbons, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term "cycloalkenyl" used herein, either alone or in combination with other radicals,
denotes a radical containing three to seven carbons, such as cyclopropenyl, 1-
cyclobutenyl, 2-cylobutenyl, l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-
cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, cycloheptadienyl,
cycloheptatrienyl, and the like.
The term "alkoxy" used herein, either alone or in combination with other radicals,
denotes an alkyl radical, as defined above, attached directly to an oxygen atom, such as
methoxy, ethoxy, /7-propoxy, iso-propoxy, /7-butoxy, /-butoxy, iso-butoxy, pentyloxy,
hexyloxy, and the like.
17

ZRC-MC-009
The term "alkenoxy" used herein, either alone or in combination with other radicals, denotes an alkenyl radical, as defined above, attached to an oxygen atom, such as vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like.
The term "cycloalkoxy" used herein, either alone or in combination with other radicals, denotes a cycloalkyl radical as defined above, attached directly to an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. eycloheptyloxy and the Like.
The term "halo" or "halogen" used herein, either alone or in combination with other radicals, such as "haloalkyl", "perhaloalkyl" etc refers to a fluoro, chloro, bromo or iodo group. The term "haloalkyl" denotes a alkyl radical, as defined above, substituted with one or more halogens; such as perhaloalkyl, more preferably, perfhuoro(Ci-C6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl. fluoroethyl, difluoroethyl. trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups. The term "haloalkoxy" denotes a haloalkyl. as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like. The term "perhaloalkoxy" denotes a perhaloalkyl radical, as defined above, directly attached to an oxygen atom, trifluoromethoxy, trifluoroethoxy, and the like.
The term "aryl" or "aromatic" used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, such as phenyl. naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like. The term 'aralkyl" denotes an alkyl group, as defined above, attached to an aryl, such as benzyl, phenethyl, naphthylmethyl, and the like. The term "aryloxy" denotes an aryl radical, as defined above, attached to an alkoxy group, such as phenoxy, naphthyloxy and the like, which may be substituted. The term "aralkoxy" denotes an arylalkyl moiety, as defined above, such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted.
The term "heterocyclyl" or "heterocyclic" used herein, either alone or in combination with other radicals, denotes saturated, partially saturated and unsaturated ring-shaped radicals, the heteroatoms selected from nitrogen, sulfur and oxygen. Examples of
18

ZRC-MC-009
saturated heterocyclic radicals include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazmyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapmyl, thiazepmyl, oxazolidinyl, thiazolidinyl, and the like; examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, and the like.
The term "heteroaryl" or 'heteroaromatic" used herein, either alone or in combination with other radicals, denotes unsaturated 5 to 6 membered heterocyclic radicals containing one or more hetero atoms selected from 0, N or S, such as pyridyl. thienyl, furyl, pyrrolyl, oxazolyl. thiazolyl, isothiazolyl, imidazolyl, isoxazolyl. oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidinyl, pyrazolopyrimidonyl. azaquinazolinyl, azaqumazolinoyl, pyridofuranyl, pyridothienyl. thienopyrimidyl, thienopyrimidonyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, quinazolonyl, pyrimidonyl, pyridazinyl, triazinyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and the like. The term "heterocyclylalkyl" used herein, either alone or in combination with other radicals, represents a heterocyclyl group, as defined above, substituted with an alkyl group of one to twelve carbons, such as pyrrolidinealkyl, piperidinealkyl, morphoiinealkyl, thiomorpholinealkyl, oxazolinealkyl, and the like, which may be substituted. The term "heteroaralkyl" used herein, either alone or in combination with other radicals, denotes a heteroaryl group, as defined above, attached to a straight or branched saturated carbon chain containing 1 to 6 carbons, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like. The terms "heteroaryloxy", "heteroaralkoxy", "heterocycloxy", "heterocylylalkoxy" denotes heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom. The term “acyl" used herein, either alone or in combination with other radicals, denotes a radical containing one to eight carbons such as formyl, acetyl, propanoyl, butanoyl, iso-
19

ZRC-MC-009
butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted.
The term "acyloxy" used herein, either alone or in combination with other radicals, denotes a radical acyl, as defined above, directly attached to an oxygen atom, such as acetyloxy. propionyloxy. butanoyloxy, iso butanoyloxy, benzoyloxy and the like. The term "acylamino" used herein, either alone or in combination with other radicals, denotes an acyl group as defined earlier, may be CH3CONH, C2H5CONH, C3M7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted.
The term "mono-substituted amino" used herein, either alone or in combination with other radicals, denotes an amino group, substituted with one group selected from (C|-Cf,)alkyl, substituted alky!, aryl, substituted aryl or arylalkyl groups. Examples of monoalkylamino group include methylamine, ethylamine, ^-propylamine, /7-butylamine, n-pentylamine and the like.
The term 'disubstituted amino" used herein, either alone or in combination with other radicals, denotes an ammo group, substituted with two radicals that may be same or different selected from (C|-C The term "arylamino" used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, such as phenylamino, naphthylamino, N-methyl anilino and the like.
The term "aralkylamino" used herein, either alone or in combination with other radicals, denotes an arylalkyl group as defined above linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phenethylamino, 3-phenylpropylamino, 1-napthylmethylamino, 2-(l-napthyl)ethylamino and the like.
The term "oxo" or "carbonyl" used herein, either alone (-C=0-) or in combination with other radicals, such as "alkylcarbonyl", denotes a carbonyl radical (-C=0-) substituted with an alkyl radical such as acyl or alkanoyl, as described above. The term "carboxylic acid" used herein, alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and
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ZRC-MC-009
amides. The term "ester" used herein, alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, where the ester moieties are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which maybe substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may be substituted: heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein. the heteroaryl group, is as defined above, which may be substituted: heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may be substituted.
The term "amide" used herein, alone or in combination with other radicals, represents an
aminocarbonyl radical (H2N-OO-), wherein the amino group is mono- or di-substituted
or unsubstituted, such as methylamide, dimethylamide, ethylamide, diethylamide, and the
like. The term "aminocarbonyl" used herein, either alone or in combination with other
radicals, with other terms such as 'aminocarbonylalkyl", "n-alkylaminocarbonyl", "N-
arylaminocarbonyl. "N,N-dialkylaminocarbonyl'\ 'N-alkyl-N-arylaminocarbonyl", "N-
alkyl-N-hydroxyaminocarbonyl", and "N-alkyl-N-hydroxyaminocarbonylalkyl",
substituted or unsubstituted. The terms '"N-alkylaminocabonyl" and "N,N-dialkylaminocarbonyl" denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical 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 amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term "aminocarbonylalkyl" includes alkyl radicals substituted with aminocarbonyl radicals.
The term "hydroxyalkyl" used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
The term "aminoalkyl" used herein, alone or in combination with other radicals, denotes an amino' (-NH2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term "alkylamino" used
21

ZRC-MC-009
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-substi tuted alkylamino.
The term "alkoxyalkyl" used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group, such as methoxymethyl, cthoxymethyl, methoxyethyl, ethoxyethyl and the like. The term "aryloxyalkyl used herein, alone or in combination with other radicals, includes phenoxymethyl, napthyloxymethyl, and the like. The term "aralkoxyalkyl" used herein, alone or in combination with other radicals, includes C6H5CH2OCH2, C6H5CH2OCH2CH2, and the like.
The term "alkylthio" used herein, either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group of one to twelve carbon atoms, as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, such as methylthio, ethylthio, propylthio, butylthio, pentylthio and the like. Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio. cyclohexylthio and the like, which may be substituted.
The term "thioalkyl" used herein, 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. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be substituted.
The term "arylthio' used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through a divalent sulfur atom, having a free valence bond from the sulfur atom such as phenylthio, napthylthio and the like. The term "alkoxycarbonylamino" used herein, alone or in combination with other radicals, denotes an alkoxycarbonyl group, as defined above, attached to an amino group, such as methoxycarbonylamino, ethoxycarbonylamino, and the like. The term "aryloxycarbonylamino" used herein, alone or in combination with other radicals, denotes an aryloxycarbonyl group, as defined above, attached to the an amino group, such as C6H5OCONH, C6H5OCONCH3, C6H5OCONC2H5, C6H4(CH30)CONH, C6H4(OCH3)OCONH, and the like. The term "aralkoxycarbonylamino" used herein,
22

ZRC-MC-009
alone or in combination with other radicals, denotes an aralkoxycarbonyl group, as
defined above, attached to an amino group C6H5CH2OCONH,
C6H5CH2CH2CH2OCONH, C6H5CH2OCONHCH3, C6H5CH2OCONC2H5,
C(1H4(CH;,)CH2OCONH, C6H4(OCH3)OCH2OCONH, and the like.
The term "aminocarbonylamino", "alkylaminocarbonyiamino",
"dialkylaininocarbonylammo" used herein, alone or in combination with other radicals,
denotes.a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or
dialkylamino group respectively, where alkyl group is as defined above.
The term "amidino" used herein, either alone or in combination with other radicals,
denotes a -C(=NH)-NH2 radical. The term "alkylamidino" denotes an alkyl- radical, as
discussed above, attached to an amidino group.
The tern "hydrazino" used herein, either alone or in combination with other radicals,
denotes -NHNH-, suitably substituted with other radicals, such as alkyl hydrazino. where
an alkyl group, as defined above is attached to a hydrazine group.
The term "alkoxyamino" used herein, alone or in combination with other radicals.
denotes an alkoxy group, as defined above, attached to an amino group. The term
"hydroxyamino" used herein, alone or in combination with other radicals, denotes -
NHOH moiety, and may be substituted.
The term "sulfenyl" or "sulfenyl and its derivatives" used herein, alone or in combination
with other radicals, denotes a bivalent group, -SO- or RxSO, where Rx is substituted or
unsubstituted alkyl, aryl, heteroaryl, heterocyclyl, and the like.
The term "sulfonyl" or "sulfones and its derivatives' used herein, either alone or in
combination with other radicals, with other terms such as alkylsulfonyl, denotes divalent
radical -SO2-, or RxS02-, where RX is substituted or unsubstituted groups selected from
alkyl, aryl, heteroaryl, heterocyclyl, and the like. "Alkylsulfonyl" denotes alky] radicals,
as defined above, attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl,
propylsulfonyl and the like. The term "arylsulfonyl" used herein, either alone or in
combination with other radicals, denotes aryl radicals, as defined above, attached to a
sulfonyl radical, such as phenylsulfonyl and the like.
The term "substituted" used alone or in combination with other radicals, denotes suitable
substituents on that radical such as substituted alkyl, substituted alkenyl, substituted
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ZRC-MC-009
alkynyl, substituted cycloalkyl, substituted aryl, etc, mentioned anywhere in the
specification. The suitable substituents include, but are not limited to the following
radicals, alone or in combination with other radicals, such as, hydroxyl, oxo, halo, thio,
nitro, ammo, cyano, formyl, amidino, guanidino, hydrazine alky], haloalkyl.
perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl.
cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy.
aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy.
heteroaralkoxy, heterocyclyloxy, 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.
arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino.
aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino,
alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl
derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
Suitable groups and substituents on the groups may be selected from those described
anywhere in the specification.
Particularly useful compounds according to the present invention includes
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyi]-
propanoate;
Ethyl (2S)-ethoxy-3-|4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxyl-phenyl}-
propanoate;
Ethyl (2S)-ethoxy-3- !4-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl|--propanoate;
Ethyl (2S)-ethoxy-3-(4-f2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxyl-
phenyl-propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl}-propanoate;
Ethyl (2S)-ethoxy-3-(4-|2-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-3-yl-oxazol-4-ylmethoxy)-phenyl]-
24

ZRC-MC-009
propanoate;
Ethyl (2S)-ethoxy-3-j4-[2-(5-methyl-2-thiophen-3-yl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate;
Ethyl 3-[4-(2-benzo[b]thiophen-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-(2S)-
ethoxy-propanoate;
Ethyl 3-{4-[2-(2-benzo[b]thiophen-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-(2S)-
ethoxy-propanoate; _
Ethyl (2S)-ethoxy-3-[4-(2-furan-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-propanoate;
Ethyl (2S)-ethoxy-3-{4-[2-(2-furan-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate;
Ethyl {2S)-ethoxy-3-f4-(5-methyl-2-quinolin-2-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate and its pharmaceutically acceptable salts;
Ethyl (2S)-ethoxy-3-J4-|2-(5-methyl-2-quinolin-2->l-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate and its pharmaceutically acceptable salts;
Ethyl (2S)-ethoxy-3-{4-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-propoxy]-phenyl}-
propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl} -propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl}-propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl ^-propanoate;
Ethyl (2S)-ethoxy-3-|4-[5-methyl-2-(5-methyl-furan-2-yl)-oxazol-4-ylmethoxy]-
phenyl} -propanoate;
Ethyl (2S)-ethoxy-3-(4-{2-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-(4-{2-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-(4-{2-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-yl]-ethoxyl-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-pyridin-2-yl-oxazol-4-ylmethoxy)-phenyl]-
25

ZRC-MC-009
propanoate and its pharmaceutically acceptable salts;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-pyridin-4-yl-oxazol-4-ylmethoxy )-phenyl ]-
propanoate and its pharmaceutically acceptable salts:
!:th\ i (2S)-ethoxy -3-|4- (2-(5-methyl-2-pyridin-3-yl-oxazol-4-yl )-ethoxy}-phenyl j-
propanoate and its pharmaceutically acceptable sails:
Ethyl (2S)-ethoxy-3-|4-(5-methyl-2-pyridin-3-yl-oxazol-4-ylmethoxy)-phenyl|-
propanoate and us pharmaceutically acceptable sails:
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propanol
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl [-propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3- {4-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl} -
propanoic acid and its pharmaceutically acceptable salts:
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl; -
propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4--|2-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-3-yl-oxazol-4-ylmethoxy)-phenyl]-propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-14-[2-(5-methyl-2-thiophen-3-yl-oxazol-4-yl)-ethoxy]-phenyl|'-propanoic
acid and its pharmaceutically acceptable salts;
3-[4-(2-Benzo[b]thiophen-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]- (2S)-ethoxy-
propanoic acid and its pharmaceutically acceptable salts;
3-{4-[2-(2-Benzo[b]thiophen-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-
propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(2-furan-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-propanoic acid
and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(2-furan-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-propanoic
acid and its pharmaceutically acceptable salts;
26

ZRC-MC-009
(2S)-Ethoxy-3-[4-(5-methyl-2-quinolin-2-yl-oxazol-4-ylmethoxy)-phenyl]-propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-quinolin-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-|4-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-propoxy]-phenyl | -
propanoic acid and its pharmaceutically acceptable salts:
(2S)-Ethoxy-3-|4-[5-methyl-2-Benzofuran-2-yl)-oxazol-4-ylmethoxy]-phenyl|--
propanoic acid and its pharmaceutically acceptable salts:
(2S)-Ethoxy-3- !4-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenylj--
propanoic acid and its pharmaceutically acceptable salts:
(2S.)-Ethoxy-3-|4-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl}-
propanoic acid and its pharmaceutically acceptable salts:
(2S)-Ethoxy-3-{4-[5-methyl-2-(5-methyl-furan-2-y!)-oxazol-4-ylmethoxy]-phenyl}-
propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-yi]-ethoxy}-
phenyl)- propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-]2-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)- propanoic acid and its pharmaceutically acceptable salts:
(2S)-Ethoxy-3-(4--|2-[5-methyl-2-(5-bromo-thiophen-2-\i)-oxazol-4-y|]-ethoxy}-
phenyl)- propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-methyl-furan-2-yl)-oxazol-4-yi]-ethoxy}-phenyl)-
propanoic acid and its pharmaceutically acceptable salts:
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-2-yl-oxazol-4-ylmethoxy)-phenyl]- propanoic acid
and its pharmaceutically acceptable salts;
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-4-yl-oxazol-4-ylmethoxy)-phenyl]- propanoic acid
and its pharmaceutically acceptable salts;
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-3-yl-oxazol-4-ylmethoxy)-phenyl]- propanoic acid
and its pharmaceutically acceptable salts;
3-(6-Benzyloxy-naphthalen-2-yl)-2-ethoxy-propan-l-ol;
(2S)-Ethoxy-3-j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propan-l-ol;
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ZRC-MC-009
(2S)-Ethoxy-3- !4-(4-hydroxy-3-methyl-3,4-dihydro-quinazolin-2yl-methoxy)-phenyl}-propan-l-ol;
2-Hydroxy-3-[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propan-l-ol; 3- !4-[2-(2,3-Dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl[-(2S)-ethoxy-propan-l-ol; (2S)-Ethoxy-3-[4-(2-(phenoxazin-10-yl)-ethoxy)-phenyl]-propan-l-ol; 3-[4-(2-(Carbazol-9-yl)-ethoxy)-phenyl]-(2S)-ethoxy-propan-)-ol; 3-j4-f2-(3.4-Dihydro-2H-quinolin-l-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propan-l-ol; (2S)-Ethoxy-3-[4-(2-(indol-l-yl)-ethoxy)-phenyl]-propan-l-ol; (2S)-Ethoxy-3-[4-(2-(phenothiazin-10-yl)-ethoxy)-phenyl]-propan-l-ol; 3-{4-[2-(2,3-Dihydro-benzo[l,4]oxazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propan-l-ol; 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenylsulfanyl-propan-l-ol; (2S)-Ethoxy-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propan-l-ol and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yr)-ethoxy]-phenyl}-propan-l-ol and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propan-l-ol; (2S)-Ethoxy-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol;
(2S)-Ethoxy-3-(4-|2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethoxy|-phenyl )-propan-1 -ol;
(3S)-Ethoxy-4-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-butan-l-ol:.. (2S:)-Ethoxy-3-(4-{2-[5-methyl-2-(4-methylsulfanyl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propan-l-ol;
(2S)-Amino-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol and its pharmaceutically acceptable salts;
(2S)-tert-butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)-phenyl]-propan-l-ol;
(2S)-tert-butoxycarbonylamino-3-{4-[2- (5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol;
(2S)-Ethoxy-3-(4-(2-[2-methyl-5-( benzofuran-2-yl)-pyrrol-l-yl]-ethoxy}-phenyl)-propan-1-ol;
28

ZRC-MC-009
(2$ )-Ethoxy-3-(4--|2-[2-methyl-5-(benzo[l,3]dioxol-5-yl)-pyrrol-l-yl]-ethoxyl -phenyl )-
piopan-l-ol;
(2S)-Ethoxy-3-[4-(l-methyl-lH-benzoimidazol-2-yl methoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-[4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3- !4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-phenyl !-propan-!-ol;
(2S)-Ethoxy-3-[4-(2-benzoimidazol-l-yl-ethoxy)-phenyl]- propan-1-ol;
(.2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propan-l-ol:
(2S)-Ethoxy-3-(4-{2-[2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl]-ethoxy|--
phenyl)-propan-l-ol;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propan-L2-diol:
I -Ethoxy-(2S)-ethoxy-3-[4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-erhoxyl-phenyl]-
propane;
2-((2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl|-propoxy)-
ethanol;
2-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[-propoxy)-
benzoic acid and its pharmaceutical^ acceptable salts;
.(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phen\i} -propyl bromo
acetate;
l-Ethoxy-(2S)-ethoxy-3-[4-{2-(-3,4-Dihydro-2H-benzo[l:4]thiazin-lyl) ethoxylphenyl]-
propane;
l-Propoxy-(2S)-ethoxy-3-[4-{2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy}-phenyl]-
propane;
2-((2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propoxy)-benzoic acid and its pharmaceutical^ acceptable salts;
l-Ethoxy-(2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- propane; (2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-1 - phenoxy propane; (2S)-Ethoxy-l-ethyl sulfinyl-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-propane;
(2S)-Ethoxy-l-ethyl sulfanyl-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-propane;
29

ZRC-MC-009
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-l-isopropoxy
propane;
(3S)-Ethoxy-4-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-butyronitrile;
(2S)-Ethoxy-IH-tetrazole-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propane;
2-Ethoxy-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- pentane-3-ol;
2,3-Diethoxy-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-pentane;
2-Ethoxy-l-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-phenyl}- pentane-3-ol;
2,3-Diethoxy-l--|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- pentane;
((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl j--propoxy)-acetic
acid and its pharmaceutically acceptable salts;.
3-(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl-methanesulfonate;
(2S)-ethoxy-3-[4-(5-methy!-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl methane
sulfonate;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl)-ethoxy]-
phenyl [-propyl-methane sulfonate;
(2S)-Ethoxy-3-|4-[2-(5-methy!-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl-methane
sulfonate;
(2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl j!-propyl
methanesuifonate;
(2S)-ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl[- propyl methanesuifonate:
(2S)-Ethoxy-!-methoxy-3-|4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-
phenyl}- propane;
l-Ethoxy-(2S)-ethoxy-3-(4-{2-[5-methyl-2-(4-methylsulfanyl-phenyl)-oxazol-4-yl]-
ethoxy}-phenyl)- propane;
l-Ethoxy-(2S)-ethoxy -3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl[-
propane;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-l-ethoxy
propane;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-]-yl)-ethoxy]-phenyl [-propyl-
methanesuifonate;
30

ZRC-MC-009
(2S)-Ethoxy-3-|4-[2-(2-methyl-5-benzo[l,3]dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl}-
propyl-methanesulfonate;
(2S)-Ethoxy-3-] 4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yl)-ethoxy]-phenyl [-propyl-
(4-methyl phenyl)-sulfonate;
(2S)-Ethoxy-3--j4-[2-(2-methyl-5-benzo[l,3]dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl}-
propyl-(4-methyl phenyl)-sulfonate;
l-Ethoxy-(2S)-ethoxy-3-[4-( I-methyl-lH-benzoimidazol-2-ylmethoxy)-phenyl]-
propane;
(2S)-Ethoxy-3-!4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-l-propoxy propane;
l-Ethoxy-(2S)-ethoxy-3-[4-(5-methyl-3-phenyl-isoxazol-4-yl methoxy)-phenyl]-
propane;
(2S)-tert-Butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propyl methanesulfonate;
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl [-propyl amine and.
its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-|3-methyl-3H-quinazolin-4-on-2yl methoxyjphenyljpropyl amine and
its pharmaceutically acceptable salts:
((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl)-
lsopropyl-amine and its pharmaceutically acceptable salts;
3-|4-[2-(2,3-Dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propyl amine
and its pharmaceutically acceptable salts;
3r(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl amine and its pharmaceutically acceptable
salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propylamine
and its pharmaceutically acceptable salts.
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propylamine and its
pharmaceutically acceptable salts;
N-tert-Butoxycarbonyl-(2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
Phenyl]-propyl amine;
(2S)-Ethoxy-3-|4-[2-(2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl)-ethoxy]-
phenyl[-propylamine and its pharmaceutically acceptable salts;
31

ZR.C-MC-009
N-((2S)-Ethoxy-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}--propyl)-methane
sulfonamide;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propylamine and its
pharmaceutically acceptable salts;
[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-ethyl-amine
and its pharmaceutically acceptable salts;
[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-isopropyl-
amine and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3--{4-[2-(2-methyl-5-benzo[l,3]dioxol-5-y]-pyrrol-l-yl)-ethoxy]-phenyl}-
propylamine and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yl)-ethoxy]-phenyl |-
propylamine and its pharmaceutically acceptable salts;
N-[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-2,2,2-
trifluoro-acetamide;
N-Ethoxycarbonyl-((2S)-ethoxy-3-!4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-
propylamine;
N-Benzyloxycarbonyl-((2S)-ethoxy-3-|4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
phenyl) -propylamine;
N-[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phen\'l]-propyl]-
acetamide;
(2S)-Hydroxy-3--|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[-propyl azide;
3-(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl azide:
(2S)-Ethoxy-3--j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl [-propyl azide;
(2S)-Ethoxy-3- |4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- propyl azide and its
pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- propyl azide;
(2S)-Ethoxy-3-!4-[2-(2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl)-ethoxy]-
phenyl | - propyl azide;
(2S)-Ethoxy-3-i4-[2-(5-ethyl-pyridine-2-yl)-2-(tert-butyldimethyl-silanyloxy)-ethoxy]-
phenyl \- propyl azide and its pharmaceutically acceptable salts;
32

ZRC-MC-009
(2S)-Ethoxy-3-{4-[2-(5-ethyl-pyridine-2-yl)-2-hydroxy-ethoxy]-phenyl}- propyl azide
and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-J4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}- propyl azide and its
pharmaceutically acceptable salts:
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]- propyl azide;
(2S)-Ethoxy-3-!4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propyl
azide:
(2S)-Hydroxy-3-[4-(5-methyl-2-phenyl-oxazol-4-yl)-methoxy)-phenyl]- propyl azide:
(2S)-Amino-3-!4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[- propyl azide and
its pharmaceutically acceptable salts;
(2S)-Amino-3- j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-methoxy]-phenyl [- propyl azide
and its pharmaceutically acceptable salts;
(2S)-tert-butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propyl azide;
(2S)-tert-butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)-phenyl]-
propyl azide:
(2S)-Ethoxy-3-'!4-[2-(2-methyl-5-benzo[l,3]dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl|-
propyl azide;
(2S)-Ethoxy-3-'|4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yl)-ethoxy]-phenyl|'- propyl
azide:
N-Benzyloxycarbonyl-(2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
phenyl |--propyl amine;
N-tert-Butoxycarbonyl-(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
Phenyl}- propyl amine;
N-tert-Butoxycarbonyl-3- ■|4-[2-(2,3-dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl}-
(2S)-ethoxy-propyl amine;
N-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}propyl)-
acetamide;
3-(4-Benzyloxy-phenyl)- N-tert-butoxycarbonyl -(2S)-ethoxy-propyl amine;
N-tert-Butoxycarbonyl -(2S)-ethoxy -3-(4-hydroxy-phenyl)- -propyl amine;
33

ZRC-MC-009
N-tert-Butoxycarbonyl-(2S)-ethoxy-3-|4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl]-
propyl amine;
(2S)-Ethoxy-1-ethylsulfanyl-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl |-
propane;
(2S)-Ethoxy-l-ethylsulfonyl-3-!4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl|-
propane;
The compounds, of the general formula (I), namely (la), (lb), (Ic), (Id) and (le) may be
prepared by one or more methods described in scheme I.
Scheme I:

A-(CH2)„-X-Ar
'^" r R4
(II
0
G,

Method A

A-(CH2)n-X-Ar^Y^0H
da) Gl
Method B



A-(CH2)„-X-Ai Y^SR, -*-
(10 G|

Method C

A-(CH2)n-X-Ar^Y^0R1 (lb) G,

Method D,
Method D

A-(CH2)-X-A,- y ^3 (Id) G,
A-(CH2)n-X-Ar y XN G,
(le) °>
I) The compounds of general formula (la) wherein all the symbols are as defined earlier may be prepared by reduction of compounds of general formula (III) wherein all the symbols are as defined earlier and R4 represents OH, alkoxy, aryloxy or aralkoxy and the like.
ii) The compounds of general formula (la) wherein all the symbols are as defined earlier may be converted to compounds of general formula (lb) wherein all the symbols are as defined earlier by alkylation, acylation or sulfonation.
34

ZRC-MC-009
iii) The compounds of general formula (lb) wherein all the symbols are as defined earlier and OR| represents leaving groups such as mesylate, tosylate and the like are converted to compounds of general formula (Ic), (Id), or (Ie) wherein all the symbols are as defined earlier by reacting with metal salts of alcohols, phenols, thiols, sodium azide or sodium or potassium cyanide respectively.
Method A: The compounds of general formula (III) are reduced to compounds of general formula (la) by using suitable reducing agents such as LiAlH. NaBH4, diborane, NaBH4 /BF3OEt2, LiBH4. DIBAH, and the like. Suitable solvents appropriate for the reducing agent used may be employed for e.g. with LiAlH4. NaBH4-. diborane. NaBH4/BF3OEt2 aprotic solvents such as THF. ether and the likes are preferred. With NaBH.4, L1BH4 etc. alcoholic solvents may also be used. Reaction may be carried out at temperatures ranging from 0 JC to the reflux temperature of the solvent(s) used. Inert atmosphere may be maintained using N?, He, or argon gas. Reaction time may range from 1 to 48 hours.
Method B: The compounds of general formula (la) may be alkylated, acylated or sulfonated to corresponding compounds of general formula (lb). Alkyl halides, mesylates or tosylates and the like may be employed for alkylation. Acyl halides or anhydrides and suitable sulfonyl halides may be used for acylation and sulfonation respectively. Suitable bases like metal hydrides e.g NaH and the like, alkali metal carbonates e.g. potassium carbonate, sodium carbonate and the like, sodium hydroxide, potassium hydroxide, organic bases e.g. trialkyl amines and the like may be used. Reaction may be earned out in suitable solvents like DMF, DMSO, THF, acetone, dichloromethane, toluene and the like or mixtures thereof. Inert atmosphere may be maintained using N:, He. or argon gas. reaction time may range from I to 48 hours.
Method C: The compounds of general formula (lb) where OR| represents leaving groups such as mesyl, tosyl and the like may be converted to compounds of general formula (Ic) by reacting with thiols in the presence of bases like NaH, KH, Na metal, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. Reaction may be carried out in solvents like DMF, DMSO, toluene, acetone, THF and the like or mixtures thereof. Reaction temperatures may range from 0 °C to the reflux temperature of the solvent(s)
35

ZRC-MC-009
used. Inert atmosphere may be maintained using N2, He, or argon gas. reaction time may range from i to 48 hours.
Method D: The compounds of general formula (lb) where OR| represents leaving groups such as mesyl . tosyl and the like may be converted to the compounds of general formula (Id) or (le) by reacting with metal azides e.g. sodium azide or the like or cyanides e.g. sodium cyanide or potassium cyanide and the like respectively. Reaction may be carried out in solvents like DMF, DMSO, Toluene, THF and the like or mixtures thereof. Reaction temperatures may range from 0 C to the reflux temperature of the solvents) used. Inert, atmosphere may be maintained using N2, He, or argon gas. Reaction time may range from 1 to 72 hours.
The compounds of the general formula (If), and (Ig) may be prepared by one or more methods described in scheme II.
Scheme II:

A-(CH2)n-X-Ar
(III)

G,

0

R
Method A

A-(CH2)n-X-Ar^Y^NH2
G,
(If)



Method A or E

Method B



A-(CH2)n-X-A. y^N3
(Id) °!

A-(CH2),-X-Ar^Y^NR,R2
G,
(ig)

1) The compounds of general formula (III) wherein all the symbols are as defined earlier and R.; represents NH2, NR1R2 where R| and R2 are as defined earlier are reduced to compounds of general formula (If) where in all the symbols are as defined earlier, ii) The compounds of general formula (If) wherein all the symbols are as defined earlier are converted to compounds of general formula (Ig), wherein all the symbols are as defined earlier by alkylation or acylation.
36

ZRC-MC-009
iii) The compounds of general formula (Id) wherein all the symbols are as defined earlier are reduced to compounds of general formula (If) wherein all the symbols are as defined earlier.
Method A: The compounds of general formula (111) where R4 represents NH2 or NR1R2 where R| and R2 are as defined earlier may be reduced to compounds of general formula (If) by a procedure similar to that described in method A of scheme I Method B: The compounds of the general formula (If) may be converted to compounds of general formula (Ig). by a procedure similar to that described in method B of scheme I. Method E: The compounds of general formula (Id) may be reduced to compounds of general formula (If), using suitable reducing agents e.g. Pd on charcoal, Raney Ni and the like. Suitable solvents like alcohols, ethyl acetate and the like or the mixtures thereof may be used. Reaction may be carried out under a pressure of hydrogen gas. Reaction temperature may range from 0 C to the reflux temperature of the solvent(s) used. Reaction may also be carriedout using the presence of PPh3 in moist solvents such as moist THF.
The compounds of the general formula (I) may also be prepared by the general method described in scheme 111
Scheme III
A—(CH2)—L + HX-Ary^G2 Method F, (I)
G1
(IV) (V)
Further the compounds of the general formula (If), and (Ig) may be prepared by one or more methods described in scheme III (a)
37

ZRC-MC-009
Scheme III(a):

G,
A-(CH2)-L + HX-A. y^NRlR2
(IV)
(Va)

Method F

-*D-

A~(CH2)n-X-Ar^\^NRiR2 G,
(ig)

Method G

A-(CH2),-X-Ar' (If)

G,

~NH,

i) The compound of the general formula (Ig) wherein all the symbols are as defined
earlier may be prepared by reacting compounds of general formula (IV) with compounds
of general formula (Va), wherein all symbols are as defined earlier and L represents a
leaving group such as halogen, mesylate, tosylate, triflare & the like.
ii) The compound of general formula (Ig), when one of Ri and R? is hydrogen and the
other is acyl e.g. tert butoxy carbonyl or benzyloxy carbonyl and the like may optionally
be converted to the compounds of general formula (If).
Compounds of the general formula (la) and (lb) may be prepared by one or more
methods described in scheme III (b)
Scheme 111(b):

G,
A-(CH,)-L + HX-Ar-^Y^QR,
(IV)
(Vb)

Method F

-»»-

A-(CH2)n-X-Ar (ib) !■

G,

ORi

2thod H

A-(CH,)-X-Ar

"QH

G,
i) The compound of the general formula (lb) wherein all the symbols are as defined earlier may be prepared by reacting compounds of general formula (IV) with compounds of general formula (Vb), wherein all symbols are as defined earlier and L represents a leaving group such as halogen, mesylate, tosylate. triflate & the like.
38

ZRC-MC-009
ii) The compound of general formula (lb), when R] represents acyl, benzyl, alkoxycarbonyl. aralkoxycarbonyl and the like may optionally be converted to the compounds of general formula (la).
Method F: The compound of the general formula (!g) or (lb) may be prepared by reacting compounds of general formula (IV) where L represents a leaving group such as halogen, mesylate, tosylate, triflate & the like, with compounds of general formula (Va) or (Vb) respectively. Suitable bases like metal hydrides e.g NaH and the like, alkali metal carbonates e.g. potasssium carbonate, sodium carbonate and the like, sodium hydroxide, potassium hydroxide, organic bases e.g. tnalkyl amines and the like may be used. Reaction may be carried out in suitable solvents like DiVlF, DIV1SO, TH-F, acetone, dichloromethane, toluene and the like or the mixture thereof. Reaction temperature may range from 0 C to the reflux temperature of the solvent(s) used. Inert atmosphere may be maintained using N2, He, or argon gas. Reaction time may range from 1 to 72 hours. Method G: The compound of general formula (Ig) wherein one of the Ri and R2 is hydrogen and the other is acyl e.g. tert butoxycarbonyl or benzyloxycarbonyl and the like may optionally be converted to the compounds of general formula (If) by using suitable cleacylation methods e.g trifluroacetic acid to deprotect tertbutoxycarbonyl or hydrogenation using Pd/C and the like under hydrogen pressure to deprotect benzyloxy carbonyl groups. Suitable solvents appropriate for the reagent used may be used .e.g chlorinated hydrocarbons like dichloromethane and the like may be used along with trifluuroacetic acid. Alcohols are preferred for hydrogenation. Reaction temperature may range from 0 UC to the reflux temperature of the solvent(s) used. Reaction time may-range from 1 to 72 hours.
Method H: The compound of general formula (lb) wherein R| is acyl, benzyl, alkoxycarbonyl, aralkoxycarbonyl and the like may optionally be converted to the compounds of general formula (la) by using suitable deacylation or debenzylation methods e.g acidic or alkaline hydrolysis to deprotect acyl group or hydrogenation using Pd/C and the like under hydrogen pressure to deprotect benzyl group. Suitable solvents appropriate for the reagent used may be used .e.g aqueous alcohols are used for hydrolysis reactions. Alcohols, ester solvents or dioxane are preferred for hydrogenation.
39

ZRC-MC-009

Reaction temperature may range from 0 C to the reflux temperature of the solvent(s) used. Reaction time may range from I to 72 hours.
The compounds of formula (IIIa) may be prepared according to the following general scheme
Scheme III(c)
0
A' °
A—(CH2)n—L + HX—Ar^^r^ R4 A-(CH2)n X-Ar
Gi
(Ilia)
(IVa) (Vc)
i. reacting a compound of formula (IVa) wherein 'A' represents 4-oxazolyl group substituted with one or two substitutents selected from substituted or unsubstituted linear or branched (C1-C12)alkyl, substituted or unsubstituted single or fused heteroaryl or heterocyclic groups; 'Ar' represents unsubstituted divalent phenyl; G\ represents OR1 or SR1, where R1 represents hydrogen, perfluoro(C1-C12)alkyl, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, cyclo(C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or acyl groups; R4 represents OH, alkoxy or aryloxy, aralkoxy or NR1R2 groups, where Ri & R? are as defined earlier; 'n' is an integer from 1-3; X represents 0 or S, by a process similar to that described in Method F above.
ii. optionally hydrolysing the compound of formula (Ilia) wherein R4 represents alkoxy, aralkoxy, aryloxy or NR1R2 groups, where R| & R? are as defined earlier, to a further compound of formula (Ilia) wherein R4 represents OH.
The compounds (1) & (Ilia) of the present invention may have asymmetric centers and may occur either as racemates or racemic mixtures as well as individual stereoisomers, including optical isomers, being included in the present invention Mixture of stereoisomers may be resolved by conventional methods such as microbial resolution,

R4

40

ZRC-MC-009
resolving the diastereomeric salts formed with chiral acids or chiral bases. Chirai acids may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral bases may be cinchona alkaloids, (+) or (-) brucine, o.-methyl benzylamine, (-f) or (-) phenyl glycinol, ephedrine, amino sugars such as glucosamines or a basic ammo acid such as lysine, arginine and the like.
The compounds (1) & (1.11a) of the present invention may have asymmetric centers and may occur cither as racemates or racemic mixtures as well as individual diastereomers of any of the possible isomers, including optical isomers, being included in the present invention These can be isolated using conventional techniques known to persons skilled in the art (Jaques et al. "Enantiomers, Racemates and Resolution". Wiley Interseience, 1981: R. A. Sheldon, in "Chirotechnology", Marcel Dekker, Inc. NY. Basel. 1993. 173-204 and references therein; A. N. Collins, G. N. Sheldrack and .1 Crosby, in "Chirahty in Industry IF", John Wiley & Sons, Inc, 1997, 81-98 and references therein: £. L. Eliei and S. 1-1. Wilen, in "Stereochemistry of Organic Compound", Jolin Wiley & Sons, Inc., 1999, 297-464 and references therein).
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. The methods of formation and removal in such protecting groups are those conventional methods appropriate to the molecule being protected. T. W Greene and P. G. M. Wuts "Protective groups in Organic Synthesis". John Wiley & Sons, Inc, 1999, 3,d Ed., 201-245 along with references therein.
It will be appreciated that the above-mentioned preparation of the compounds of Formula (I) or (Ilia), or pharmaceutically acceptable salts thereof, and/or pharmaceutical ly acceptable solvate thereof is a stereoselective procedure and that the compounds of formula (I) or (Ilia), is a single stereoisomer. Favorably, a compound of formula (I) or (Ilia), is present in admixture with less than 50% vv/w of its racemic isomer, suitably 80 - 100 % and preferably 90 - 100 % pure, such as 90 - 95 %. most preferably 95 - 100 %, for example 95 %, 96 %. 97 %, 98 %, 99 % and 99.99 % optically pure.
41

ZRC-MC-009
Preferably the compounds of Formula (I) or (Ilia), or a pharmaceutically acceptable salt thereof, and/or pharmaceutically acceptable solvate thereof is in optically pure form.
The absolute stereochemistry of the compounds may be determined using conventional methods, such as X-ray crystallography.
it will be appreciated that when substituents have different sites where they can be attached, such differently attached substituents are also included in the present invention.
"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. The pharmaceutically acceptable base addition salts forming a part of this invention may be prepared by treating suitable compounds of the invention with 1-6 equivalents of a base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride, magnesium acetate, magnesium alkoxide and the like. Solvents such as water, acetone, ether, THF. methanol, ethanol. t-butanol, 2-butanone. dioxane. propanol, butanol, isopropanol, diisopropyl ether, /e/v-butyl ether or mixtures thereof may be used. Organic bases such as lysine, arginme, methyl benzylamine, ethanolamine. diethanolamine, tromethamine, choline, guanidine and their derivatives may be used. Acid addition salts, wherever applicable may be prepared by treatment with acids such as tartaric acid, mandelic acid, fumaric acid, malic acid, lactic acid, maleic acid, salicylic acid, citric acid, ascorbic acid, benzene sulfonic acid, p-toluene sulfonic acid, hydroxynaphthoic acid, methane sulfonic acid, acetic acid, benzoic acid, succinic acid, palmitic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like in solvents such as water, alcohols, ethers, ethyl acetate, dioxane, THF, acetonitrile, DMF or a lower alkyl ketone such as acetone, or mixtures thereof.
Another aspect of the present invention comprises a pharmaceutical composition, containing at least one of the compounds of the general formula (I) or (Ilia), their derivatives, then' analogs, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, then- pharmaceutically acceptable solvates thereof as an active ingredient, together with pharmaceutically employed carriers diluents and the like.
42

ZRC-MC-009
Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: the Science and Practice of Pharmacy, 19" Ed., 1995. The compositions may be in the conventional forms, such as capsules, tablets, powders, solutions, suspensions, syrups, aerosols or topical applications. They may contain suitable solid or liquid carriers or in suitable sterile media to form injectable solutions or suspensions. The compositions may contain 0.5 to 20 %, preferably 0.5 to 10 % by weight of the active compound, the remaining being pharmaceutically acceptable carriers, excipients. diluents, solvents and the like.
Typical compositions containing a compound of formula (I) or (Ilia) or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipients which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a vehicle, excipients or medium for the active compound. The active compound can be absorbed on a granular solid container for example in a sachet. Some of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil. peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium sterate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acids monoglycerides and diglycerides. pentaerythritol fatty acids esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the earner or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The. formulations may also include wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
43

ZRC-MC-009
The route of administration may be any route, which effectively transports the active drug to the appropriate or desired site of action effectively, such as oral, nasal, transdermal, pulmonary or parental e.g. rectal, depot, subcutaneous, intravenous, intraurethral. intramuscular, intranasal, ophthalmic solution or an ointment, preferably through oral route.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed, in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
For nasal administration, the preparation may contain a compound of formula (I) or (Ilia) dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agent, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
For parental application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablet, dragees or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active ingredient (as free compound or salt thereof) 100 g
Wheat starch 45 g
Maize starch 55 g
Macrocrystalline cellulose 12 g
Ethyl cellulose 8 g
Magnesium stearate 5 g
The coating may compose of the following ingredients in varying compositions
44

ZRC-MC-009
Lac
Gelatin Gum arable Sucrose
Titanium dioxide Beeswax Carnauba wax Ethyl vanilin
The compounds of general formula (I) or (Ilia) or the compositions thereof are useful for the treatment and/or prophylaxis of disease caused by metabolic disorders such as hyperlipidemia. insulin resistance, Leptin resistance, hyperglycemia, obesity, or inflammation.
These compounds are useful for the treatment of hypercholesteremia, familial hypercholesteremia, hypertriglyceridemia, type 2 diabetes, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, atherosclerosis, xanthoma, stroke, peripheral vascular diseases and related disorders, diabetic complications, certain renal diseases such as glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, psoriasis, polycystic ovarian syndrome, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, arteriosclerosis, Xanthoma, pancreatitis and for the treatment of cancer.
The compounds of the invention may be administered to a mammal, especially, a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases mentioned above.
The compounds of the present invention are effective over a wide dosage range, however, the exact dosage, mode of administration and form of composition depends upon the subject to be treated and is determined by the physician or veterinarian responsible for treating the subject. Generally, dosages from about 0.025 to about 200 mg preferably from about 0.1 to about 100 mg, per day may be used. Generally, the unit dosage form comprises about 0.01 to 100 mg of the compound of formula (I) or (Ilia), as an active ingredient together with a pharmaceutically acceptable carrier. Usually suitable dosage forms for nasal, oral, transdermal or pulmonary administration comprises from
45

ZRC-MC-009
about 0.001 mg to about 100 mg, preferably from 0.01 mg to about 50 nig of the active ingredient mixed with a pharmaceutical^ acceptable carrier or diluent.
In another aspect of the present invention, method of treatment and/or prevention of the diseases mentioned above are provided.
In a further aspect of the present invention, use of one or more compounds of the general formula (I) or (Ilia) or pharmaceutical!)' acceptable salts, for the preparation of a medicament thereof for the treatment and/or prevention of diseases mentioned in this document is provided.
In still further aspect of the present invention use of the compounds of the present invention alone or in combination with statins, glitazones, biguanides, angiotensin ii inhibitors, aspirin, insulin secretagogue, sitosterol inhibitor, sulfonylureas, insulin, fibnc acid derivatives, nicotinic acid, cholestyramine, cholestipol or probucol, a-glycosidase inhibitors or antioxidants, which may be administered together or within such a period as to act synergistically together.
The invention is explained in 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.
//-/ NMR spectral data given in the tables (vide infra) are recorded using a 300 MHz
spectrometer (Bruker A VANCE-300) and reported in S scale. Until and otherwise
mentioned the solvent used for NMR is CDCl3 using Tetramethyl si lane as the internal
standard.
Preparation 1
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate (compound No. 1)

'CI-I3
46

ZRC-MC-009
A mixture of Ethyl (2S)-ethoxy-3-(4-hydroxyphenyl)-propanoate (4.09 g). and anhydrous potassium carbonate (3.33 g) in DMF (40 mL) was heated at 80 °C for 1hr. The mixture was cooled to 50 °C and 4-chloromethyl-5-methyl-2-thiophen-2yl-oxazole (4.4 g) was added. The reaction mixture was continued heating at 80 °C for 6. hrs. Later it was cooled to 20 T - 25 °C and water (80 mL) was added and the crude product was extracted with ethyl acetate (2 x 40 mL), washed with water (2 x 50 mL), brine (50mL) and was dried over anhydrous sodium "sulfate. The solvent was evaporated under reduced pressure to obtain an oily product. The crude oily product was chromatographed over silica gel using ethyl acetate:petroleum ether (60-80) (1:9) as an eluent to afford the title product as a colourless solid.
Preparation 2
Ethyl (2S)-ethoxy-3-!4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyi;-
propanoate (compound No.2)

A mixture of Ethyl (2S)-ethoxy-3-(4-hydroxyphenyl)-propanoate (1.9 g), and potassium carbonate (1.51 g) in toluene (15 mL) was heated at 80 °C for lhr. The mixture was cooled to 50 °C and Methyl 2-[5-methyl-2-thiophen-2-yl-oxazol-4yl]-ethylsulfonate (2.56 g) was added. The reaction mixture was continued heating at 80 °C for 16 hrs. Later it was cooled to 20 °C - 25 °C, water (20 mL) was added and the crude product was extracted with ethyl acetate (2 x 25 mL). The organic extract was washed with water (2 x 20 mL), brine (25 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain an oily product. The crude oily product was chromatographed over silica gel using ethyl acetate: petroleum ether (60-80) (1:9) as an eluent to afford the title product as a yellow oil.
In like manner the following compounds in the table 1 are prepared following a method similar to that described in preparations l& 2.
47

ZRC-MC-009

Ir.x. No

R1

FU

Mol.Wt

yield



OEt

OEt

415

51

Jl

CH2


s I
'H : 1.16 (3H, t, .1=7.0 Hz), 1.22 (3H, t, J=7.14 Hz), 2.40 (3H, s ),2.95 (2H , d,
J=6.6 Hz), 3.32-3.37 (IH, m ),3.57-3.62 (IH, m ), 3.97 (IH, t, J=6.3 Hz), 4.15
(2H, q, J=7.12 Hz), 4.95 (2H, s), 6.91 (2H, d, J=8.58 Hz), 7.08-7.l'l (IH, m ),
7.15 (2H, d, J=8.52 Hz), 7.40 (IH, dd, J=4.14 Hz & 0.82 Hz). 7.65 (1H: dd,
J=2.82 & 0.75 Hz).
OEt
78
429
CH-,
OEt
o-/
N
-s
'H : 1.15 (3H, t, J=6.93 Hz), 1.2 (3H, t, J=7.14 Hz), 2.34 (3H, s). 2.92-2.96 (4H, m), 3.30-3.61 (2H, m), 3.95 (IH, t, J=6.6 Hz), 4.12-4.21 (4H, m) , 6.81 (2H, d, .1=8.64 Hz), 7.06-7.09 (IH, m), 7.12 (2H, d, J=8.6 Hz), 7.35 (IH, dd, J=I.l 1& 5.05
! Hz), 7.57 (1H, dd, J=l. 14 & 3.69 Hz).
J. : CH-, | H3C OEt OEt 429 82
'H : 1.16 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.14 Hz), 2.38 (3H. s) 2.52 (3H, s), 2.96 (2H, d, .1=6.63 Hz), 3.32-3.37 (IH, m), 3.57-3.62 (IH, m), 3.97 (IH, t. J=6.66 Hz), 4.17 (2H, q, .1=7.11 Hz), 4.92 (2H, s), 6.73-6.76 (IH, m), 6.92 (2H, d. J=8.61 Hz), 7.17 (2H, d, J=8.55 Hz), 7.42 (IH, d, J=3.6 Hz).
OEt
CH3
75
443
■PY
CHo
OEt

H,C
i^r
H : 1.15 (3H, t, .1=6.9 Hz), 1.2 (3H, t, J=7.12 Hz), 2.3 (3H, s), 2.5 (3H, s), 2.90-
2.94 (4H, m), 3.33-3.36 (IH, m), 3.56-3.58 (IH, m), 3.94 (IH, t, .1=6.67 Hz), 4.1-
4.2 (4H, m), 6.71-6.73 (IH, m), 6.79 (2H, d,J=8.4 Hz), 7.14 (2H, d, J=8.61 Hz),
7.36 (IH, d, .1=3.6 Hz).
,CH3
'H : 1.16 (3H, t, .1=7.0 Hz), 1.22 (3H, t, J=7.12 Hz), 2.4 (3H, s), 2.5 (3H, s), 2.96
( (1H, d,J=4.0 Hz).
48

ZRC-MC-009

7. I


OEt
443

OEt

'H : 1.15 (3H, t, .1=7.0 Hz), 1.21 (3H, t. .1=7.10 Hz), 2.34 (3H. s), 2.55 (3H. s). 2.92-2.96 (4H, m), 3.31-3.36 (IH, m), 3.56-3.59 (IH, in), 3.95 (IH, t. .1=6.66 Hz). 4.12:4.18 (2H, m), 4.19-4.22 (2H, m), 6.82 (2H, d, J=8.58 Hz). 6.89 (IH, d, .1=5.01 Hz), 7.14 (2H, d, J=8.58 Hz), 7.23 ( H^d, J=5.01 Hz).
OEt
415
78
'V CH2
OEt

'H : 1.16 (3H, t, .1=7.01 Hz), 1.21 (3H, t, J=7.14 Hz), 2.40 (314, s) 2.97 (2H, d.
J=6.60 Hz), 3.32-3.40 (IH, m). 3.55-3.62 (IH, m), 3.97 (IH. t. J=6.65 Hz), 4.19
(2H, q, J=7.'12 Hz), 4.94 (2H, s), 6.93 (2H. d, J=8.5 Hz), 7.18 (2H, d," J=8.5 Hz),
7.35-7.37 (IH, m), 7.61 (IH, d, J=5.02 Hz), 7.88-7.89 (1 H,m).
.CH-,
OEt
429
63

0

CH,
//
OEt

9.

'H : 1.15 (3H, t, J=7.0 Hz), 1.21 (3H, t, J=7.10 Hz), 2.34 (314, s), 2.92-2.96 (4H,
m), 3.30-3.36 (IH, m), 3.56-3.61 (IH, m), 3.92 (IH, t, J=6.64 Hz) 4.12-4.16 (2H,
m), 4.17-4.22 (2H, m), 6.82 (2H, d, J=8.58 Hz), 7.14 (2H, d, .1=8.55 Hz), 7.33-7.36
(IH, m), 7.55-7.57 (IH, m), 7.83-7.84 (1H, m).
62
OEt
465
OEt


'H : 1.16 (3H, t, J=6.99 Hz). 1.22 (3H, t. .1=7.1.2 Hz). 2.44 (3H. s), 2.96(2H, d,
.1=6.69 Hz), 3.32-3.38(114, m), 3.57-3.63 (IH, m), 3.97(11-1, t. .1=6.63 Hz),'
4.16(214, q, J=7.12 Hz), 4.97 (214, s). 6.93(214, d, J=8.61 Hz). 7.18(214, d, J=8.58
Hz), 7.36-7.5l(2H,m), 7.79-7.87(314, m).
21
479
OEt
OEt


49

ZRC-MC-009

12. o-xx OEt ! OEt 413 66
'H : 1.15 (3H, t, J=6.93 Hz), 1.2 (3H, t, .1=7.14 Hz), 2.34 (3H, s), 2.92-2.96 (4H. m), 3.3-3.4 (IH, m), 3.5-3.62 (IH, m), 3.95 (IH, t, J=7.l Hz), 4.14 (2H, t, J=7.'12 Hz), 4.22 (2H, t, J=6.65 Hz), 6.49-6.51 (IH, m), 6.81 (2H, d, J=8.6 Hz), 6.9 (IH. d, .1=3.2 Hz), 7.14 (2H, d, J=8.6 Hz), 7.5 (IH, m).
13. OEt OEt 460 51
14- ! ^ 0^/CH3 OEt OEt 474 32j i
15. O /CH3O^XCH2 OEt OEt!i 1 443 34
1H : 1.16 (3H, t, J=6.93 Hz), 1.22 (3H, t, J=7.14 Hz), 2.02-2.1 (2H, qui), 2.24 (3H, s), 2.67 (2H, t, J=7.18 Hz), 2.95 (2H, d, J=7.02 Hz), 3.35-3.37 (IH, m), 3.57-3.59 (IH, m), 3.91-3.98 (3H, m), 4.17 (2H, q, J=7.1 Hz), 6.81 (2H, d, J=8.5 Hz), 7.06-7.08 (IH, m), 7.12 (2H, d, J=8.5 Hz). 7.3 (IH, d, .1=5.0 Hz), 7.59 (IH, d, J=3.48 Hz).
16. (f J CH2 OEt OEt 491 34
'H: 1.16 (3H, t, J=6.99 Hz), 1.22 (3H, ;. J=6.98 Hz), 2.41 (3H, s), 2.96 (2H, d, J=6.66 Hz), 3.32-3.63 (2H, m). 3.97 (IH, t. J=6.66 Hz), 4.16 (2H, q, J=7.05& 7.14 Hz), 4.95 (2H, s), 6.92 (2H, d, .1=8.64 Hz). 7.17 (2H, d, J=8.58 Hz), 7.26-7.43 (4H. m), 7.58 (IH, d, .1=3.87 Hz), 7.63 (2H, d, 7.!4 Hz).
17. Cl S N"\H2 OEt OEt 449.5 55
'H: 1.16 (3H, t, J-7.00 Hz), 1.22 (3H, t, J=7.15 Hz), 2.39 (3H, s), 2.95 (2H, d, .1=6.6 Hz), 3.32-3.62 (2H, m), 3.94 (IH, t, .1=6.63 Hz), 4.12-4.19 (2H, q, .1=7.11& 7.1 1 Hz), 4.92 (2H, s), 6.89-6.92 (3H, m), 7.17 (2H, d, J=8.58 Hz), 7.37 (IH, d. J=3.96 Hz).
18. Br S N"\H2 OEt OEt 494 40
'H: 1.16 (3H, t, J=7.0 Hz), 1.22 (3H, t, J=7.14 H J=6.57 Hz), 3.32-3.63 (2H, m), 3.97 (IH, t, J= J=7.11&7.14 Hz), 4.92 (2H, s), 6.91 (2H, d, J=8.58 7.17 (2H, d, J=8.54 Hz), 7.35 (IH, d, J=3.93 Hz). z), 2.39 (3H,. s), 2.95 (2H, d, 6.64 Hz), 4.12-4.19 (2H, q, Hz), 7.04 (IH, d, J=3.93 Hz),
50

ZRC-MC-009

H,C'^0

PyCHj
CH,

OEt

OEt

413

'H: 1.16 (3H, t, J=6.99 Hz), 1.21 (3H, t, J=6.26 Hz), 2.4! (6H, s), 2.95 (2H, d,
J=6.48 Hz), 3.35-3.37 (2H, m),3.59 (IH. t, J=4.55 Hz), 4.1 1-4.19 (2H. m), 4.98
(2H, s), 6.13 (IH, d, .1=2.68 Hz), 6.75 (2H. d, J=8.46 Hz), 6.96 (IH. d, .1=3.91 Hz).
7.10 (2H,d, J=8.46Hz).

48

20.
'H: 1.15 (3H, t, .1=6.99 Hz), 1.21 (3H, t. i=6.94 Hz), 2.35 (3H. s); 2.92-2.97 (4H, m), 3.31-3.61 (2H, m), 3.95 (IH, t, J=6.6I Hz), 4.08-4.23 (4H, m), 6.81 (214, d. .1=8.61 Hz), 7.13 (2H, d, J=8.57 Hz), 7.26-7.64 (7H, m).

: 2 !.i i C|X-S N'AV/CH2 OEt OEt 463.5 39
'H: 1.14 (3H, t, J=6.96 Hz), 1.21 (3H, t. J=5.6 Hz), 2.33 (3H. s), 2.89-2.94 (4H, m), 3.28-3.63 (2H, m), 3.93 (IH, t, J=6.62 Hz), 4.08-4.20 (4H, m), 6.80 (2H, d, J=7.39 Hz), 6.89 (IH, d, J=3.96 Hz), 7.13 (2H, d, J=8.58 HzJ, 7.33 (IH, d, J=3.96 Hz).
22. XVXf"3Br^S N-^CH2 OEt OEt 507 26
'H: 1.18 (3H, t, J=6.15 Hz), 1.22 (3H, t, J=7.06 Hz), 2.33 (3H, s), 2.90-2.94 (4H, m), 3.28-3.63 (2H, m), 3.95 (IH, t, J=6.63 Hz), 4.12-4.20 (4H, m), 6.80 (2H, d, J=8.60 Hz), 7.03 (IH, d, J=3.92 Hz), 7.13 (2H, d, j=8.53 Hz). 7.30 (IH, d, .1=3.93 | Hz). i
23. /T~\ 0^/CH3 1 OEt "H: 1.16 (3H, t, J=6.9 Hz), 1.24 (3H, t, J=7.1 Hz), 2.55 (3H, s). 2.95-2.98 (2H, m), 3.3-3.6 (2H, m), 3.96-4.0 (IH, m), 4.14-4.21 (2H, q, J=7.14&~.!2 Hz), 5.03 (2H, s), 6.90 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 8.4 (2H, m). 8.8 (2H, m).
^N N^CH2
OEt
24.
35
410
OEt

25.

'H: 1.16 (3H, t, J=6.99), 1.23 (3H, t, J=7.1 Hz), 2.10 (3H, s). 2.48 (2H, m), 3.35
(IH, m), 3.6 (IH, m), 3.97 (IH, m),4.1-4.2 (2H, q, J=7.1 Hz). 5.05 (2H, s), 6.92
(2H, d, J=8.6 Hz) , 7.18 (2H, d, J=8.5 Hz), 7.8 (IH, m), 7.8 (IH, t, J=7.8 Hz), 8.1
(1H, d, J=7.9 Hz) 8.7 (IH, d, J=4.4 Hz).
OEt
OEt
410
68
a
N
0-/CH3
CH2

'H: 1 =8.5 Hz), 7.47 (IH, dd, J=5.0&7.8 Hz), 8.39 (IH, d, J=8.0 Hz), 8.68 (IH, d, J=4.3 Hz), 9.25 (IH, s).

ZRC-MC-009

! i'H: 1.15 (3H, t, J=7.0 Hz), 1.22 (3H, t, J=7.1Hz). 2.4 (3H, s), 2.95 (4H, m), 3.5
! i (2H. m), 3.95 (1H, t, J=6.61 Hz), 4.17 (2H, q, J=14.4 & 7.18 Hz), 4.23 (2H,t, J=6.6
| ! Hz), 6.82 (2H, d, .1=8.58 Hz), 7.13 (2H, d, J=8.52 Hz), 7.36 (1H. dd, .1=7.8 & 4.8
! , Hz), 8.23 (1H, d, J=7.98 Hz), 8.63 (1H, d, J=3.21 Hz) 9.2 (1H, s).
Preparation 3

(2S.)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl
acid (compound No. 27)
0


propanoic

A mixture of Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenylj-propionate (0.5 g), sodium hydroxide (0.062g in 5 mL water) in methanol (10 mL) was stirred at 20 °C to 25 °C for 16 h. Solvents were evaporated under reduced pressure. The residue was diluted with water (10 mL) and was acidified with dilute hydrochloric acid. The product was extracted with ethyl acetate (2 x 25 mL), washed with water (2 x 25 mL), brine (30 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain 0.4 g of title compound. In like manner following compounds in table 2 were prepared following a procedure similar to that described in preparation 3.
52

ZRC-MC-009
Table 2:


| Ex.j No R1 G, R4 Mol.Wt % yield
i 27j ^ JL/°X/CH3s \\ //N—\~CH2 OEt OH 387 95
'H: 1.16 (3H, t, J=7.0 Hz), 2.40 (3H, s), 2.91-2.98 (2H, m): 3.35-3.49 (IH, m), 3.54-3.64 (IH, m), 4.03 (IH, m), 4.95 (2H, s), 6.93 (2H, d, J=8.47 Hz)', 7.01- (IH, t, J=3.69 Hz), 7.15 (2H, d, J=8.47 Hz), 7.40 (IH, d, J=4.89 Hz), 7.65 (IH, d, J=3.45 Hz).
28. oVCH3(V^N>^CH2 OEt OH 401 85
'H: 1.17 (3H, t, J=6.99 Hz), 2.35 (3H, s), 2.92-2.97 (IH, m), 2.95 (2H, t, J- 6.6 Hz), 3.04-3.09 (IH, m), 3.41-3.47 (IH, m), 3.55-3.60 (IH, m), 4.01-4.05 (IH, m), 4.18 (2H, t, J=6.6 Hz), 6.81 (2H, d, J=8.6 Hz), 7.06-7.09 (IH, m), 7.13 (2H, d, J=8.55 Hz), 7.37 (IH, dd, J-1.0 Hz & 4.22 Hz), 7.48 (IH, dd, J=1.0 Hz&2.64 Hz).
29.i CH3 H3C OEt OH 401 73
'H : 1.16 (3H, t, J=6.96 Hz), 2.38 (3H, s), 2.51 (3H, s), 2.90-2.97 (IH, m), 3.03-3.09 (IH, m), 3.38-3.43 (IH, m), 3.57-3.62 (IH, m), 4.00-4.04 (IH, m), 4.92 (2H, s), 6.73-6.75 (IH, m), 6.92 (2H, d, J-8.58 Hz), 7.18 (2H, d, J=8.58 Hz), 7.44 (IH, d, J=3.6Hz).
30. ,CH3 H3C OEt OH 415 76
'H : 1.15 (3H, t, J=6.96 Hz), 2.32(3H, s), 2.50(3H, s), 2.89-2.96(4H. m). 3.40-3.43 (IH, m), 3.56-3.59 (IH, m), 3.99-4.03 (IH, m), 4.16 (2H, t, J=6.58 Hz), 6.72 (IH, d, J-3.54 Hz), 6.81 (2H, d, .1=8.5 Hz),7.15 (2H, d, J=8.5 Hz), 7.39 (IH, d, J=3.6 Hz).
31.1 CH3 f 3 0-/ OEt OH 401 97
'H : 1.16 (3H, t, J=7.0 Hz), 2.4 (3H, s), 2.57 (3H, s), 2.90-2.98 (IH, m), 3.05-3.10 (IH, m), 3.41-3.46 (IH, m), 3.58-3.61 (IH, m), 4.02-4.13 (IH, m), 4.95 (2H, s), 6.9 (IH, d, J=5.0 Hz), 6.94 (2H, d, J=8.6 Hz), 7.18 (2H, d, J=8.55 Hz), 7.27 (IH, d, .1=4.9 Hz).
53

ZRC-MC-009

32. CH3 i ni-t! i J 0—\ OH 415 90
'H : 1.15 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.55 (3H, s), 2.89-3.08 (4H, m), 3.40-3.45 (IH, m), 3.55-3.60 (IH, m), 4.00-4.04 (IH, m), 4.19 (2H, t, J=6.66 Hz), 6.83 (2H, d, j=8.55 Hz), 6.88 (IH. d, J=5.01 Hz), 7.14 (2H, d, J=8.58 Hz),7.23 (IH, d, .1=5.01 Hz).
33. CH3 1 OEt OH 387 73
'H : 1.16 (3H, t, J=6.96 Hz), 2.4 (3H, s). 2.90-2.97 (IH, dd, J=7.62& 7.65 Hz), 3.03-3.09 (IH, dd, J=4.68&4.35 Hz), 3.39-3.44 (IH, m), 3.57-3.62 (IH, m), 4.01-4.05 (IH, m), 4.94 (2H, s), 6.93 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 7.35-7.38 (IH, m), 7.59-7.61 (IH, m), 7.91-7.92 (IH, m).
34. Q /H3 OEt OH 401 73
'H : 1.15 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.89-3.08 (4H, m), 3.40-3.45 (IH, m), 3.55-3.60 (IH, m), 4.00-4.04 (IH, m), 4.19 (2H, t, J=6.66 Hz), 6.83 (2H, d, J=8.55 Hz), 6.88 (IH, d, J=5.01 Hz). 7.14 (2H, d. J=8.5S Hz), 7.23 (IH, d, J=5.01 Hz), 7.86 (IH, d,J=2.58Hz). |
35. /CH3rrv 'H : 1.18 (3H, t, 1=6.99 Hz), 2.45 3.44-3.50 (IH, m), 3.56-3.61 (IH, i d, J=8.55 Hz), 7.18 (2H,d, .1=8.52 (3H, s), 2.92-2. TI), 4.04-4.08 (1 Hz), 7.37-7.4 (2 99 (IH, m), 3.08-3.14(1H, m), H, m), 4.98 (2H, s), 6.94(2H, H, m), 7.79-7.86(3H, m).
36. OEt OH 451 65
'H : 1.16 (3H, t, J=7.0 Hz), 2.38 (3H, s), 2.89-3.06 (4H, m), 3.42-3.57 (2H, m), 4,04-4.06 (IH, m), 4.22 (2H, t. J=6.55 Hz). 6.82 (2H, d, J=8.58 Hz), 7.13 (2H, d, J=8.58 Hz), 7.34-7.4 (2H, m). 7.78-7.86 (3H, m).
37. ever i oa0 N^CH2 | OH 371:i 76
'H : 1.16 (3H, t, J=6.99 Hz). 2.41 (3H, s), 2.9-2.98 (IH, m), 3.04-3.10 (IH, m), 3.40-3.45 (IH, m), 3.57-3.62 (IH, m), 4.04-4.06 (IH, m), 4.96 (2H, s), 6.52 (IH, dd, J=1.68 & 3.42 Hz), 6.92 (2H, d, J=8.58 Hz), 6.98 (IH, d, J=3.39 Hz), 7.17 (2H, d, J=8.55 Hz), 7.54 (IH, d, J=1.17 Hz).
38. o^°xCH3 OEt OH 385 68
'H : 1.16 (3H, t, J=6.96 Hz), 2.35 (3H, s), 2.92-2.97 (3H, m), 3.02-3.12( 3.41-3.44 (IH, m), 3.56-3.59 (IH, m), 4.0-4.04 (IH, m), 4.19(2H, t, 1=6. 6.50 (IH, dd, 1=1.64 & 3.36 Hz), 6.8 (2H, d, J=8.52 Hz), 6.94 (IH, d, J=3.. 7.13 (2H, d, J=8.55 Hz), 7.51(1H, d, J=l.l Hz). H, m), 64 Hz) 39 Hz),
54

ZRC-MC-009

39.

o

CH-,

OEt

OH

432

67


CH?
0=N N' on2

40.

'H N'A\^-CH2


CH3
1 'H : 1.
OEt
IL
CH2
'H (DMSO-D6) : 0.94 (3H, t, J-6.75 Hz), 1.93-1.97 (2H, m) , 2.2 (3H, s), 2.49-2,91 (4H, m), 3.13 (IH, t, .1=7.7 Hz), 3.53-3.7 (2H, m), 3.87 (2H, t, J=5.5 Hz), 6.7 (2H, d, J=8.76 Hz), 7.1-7.15 (3H, m), 7.55 (IH, d, J=2.89 Hz), 7.68 (IH, d, J=4.6 Hz).

42.



OEt

OH

421

59



43.

'H: 1.03 (3H, t, J=6.94 Hz), 2.46 (3H, s), 2.47-2.81 (2H, m), 3.44-3.53 (2H, m), 3.93-3.94 (IH, m), 4.98 (2H, s), 6.94 (2H, d, J=8.55 Hz), 7.15 (2H, d, J=8.52 Hz), 7.33-7.76 (5H,m), 12.59 (IH, s).
82
OEt
OH
421.5




44.
! 45.

'H: 1.18 (3H, t, J=7.00 Hz), 2.39 (3H, s), 2.91-3.13 (2H, m). 3.44-3.61 (2H, m),
4.05 (IH, t, J=5.82 Hz), 4.92 (2H, s), 6.90-6.93 (3H, m), 7.16 (2H, d, J=8.58 Hz),
7.38 (IH, d, J=3.96Hz).
OEt
OH
466
66
n
-s'
)-YCH3
Br'
N
'^CH2
'H: 1.18 (3H, t, J=7.00 Hz), 2.35 (3H, s), 2.91-3.13 (2H, m), 3.14-3.44 (2H, m),
4.06 (IH, t, J=5.8 Hz), 4.92 (2H, s), 6.92 (2H, d, .1=8.55 Hz), 7.05 (IH, d, J=3.93
Hz),_7.J_6 (2H, d, J=8.58 Hz), 7.36 ( H, d, J=3.93 Hz).
64
OH
385
OEt
0^/CH3



CH2
H3C

O

N^\,



nHr 4.04 7.16

1.16 (3H, t, J=6.99 Hz), 2.41 (6H, s), 2.97-3.11 (2H, m), 3.41-3.46 (2H, m),
(IH, t, J=5.94 Hz), 4.96 (2H, s), 6.13 (IH, d, J=2.68 Hz), 6.90-6.93 (3H, m),
(2H, d, J=8.50 Hz).

55

ZRC-MC-009

46.

OEt

OH

477

88




^N.

S N-^V-CH2



47.
48.
49.
50.
51.

CH2


56

ZRC-MC-009
Preparation 4
(2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol
(compound No 64).



OH
0-

.CH-,

0'

OEt

Lithium aluminium hydride (465 mg) was added to an ice cold solution of Ethyl(2S)-ethoxy-3- |4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propanoate (2.7 g) in tetrahydrofuran (30 mL) in portions over a period of 15 minutes and the reaction mixture was stirred for further 15 minutes at the same temperature. The reaction was quenched by carefully adding saturated solution of sodium sulfate in water dropwise. Solids were filtered off and washed with hot ethyl acetate. Combined filtrate was dried over sodium sulfate and evaporated. Crude product was chromatographed over silicagel using 5 to 25 % ethyl acetate in petroleum ether to yield 2.6 g of title compound. In like manner following compounds in the table 3&4 were prepared following the procedure described in preparation 4.
fable 3:


Ex. No

R'

Ar

Mol. Wt

%

yield




53.

CH

OEt

336

40

'H: l.O (3H, t, J=6.9 Hz), 2.0 (lH, t, .1=5.5 Hz), 2.9 (1H, m), 3.0 (1H, m), 3.5 (2H, m), 3.6 (2H, in), 5.1 (2H, s), 7.2 - 7.5 (9H, complex), 7.7 (2H, t, J=9.4 Hz).


54.

OH
I
j-CH,
N CH,

OEt

370

56

'H: 1.2 (3H, t, J=7.11 Hz), 2.7 (1H, dd, J=13.8 & 6.8 Hz), 2.8 (1H. dd, J=13.8 & 5.92 Hz), 3.2 (3H, s), 3.4 - 3.6 (5H, m), 4.0 (IH, dd, J=9.16 & 3.64 Hz), 4.1 (1H, t, J-8.95 Hz), 4.9 (1H, m), 6.66 (IH, d, J=7.98 Hz), 6.7 (2H, dd, J=6.7 & 1.96 Hz), 6.8 (I H. t, .1=7.09 Hz), 7.1 1 (214, d, J=8.58 Hz), 7.2 (1H, m). 7.9 (1H, dd, .1=7.8 & 1.3 Hz).
57

ZRC-MC-009

56.

H: I.I (3H, t, J=6.9 Hz), 2.7 (IH, dd, J=14.0 & 6.9 Hz), 2.8 (IH, dd, J=14.0 &
6.9 Hz), 3.0 (2H, m), 3.4- 3.6 (5H, m), 3.7 (2H, t, J =5.8 Hz), 3.8 (2H, m), 4.1
(2H, t, J=5.9 Hz), 6.6 (IH, m), 6.7 (IH, d, J=8.2 Hz), 6.8 (2H, dd, J=8.6 & 1.95
Hz), 7.0 (2H, m), 7.1 (2H, dd, J=8.6& 1.95 Hz).
62
405
OEt

v^

CH2

57.

'H: 1.1 (3H, t, J=7.0 Hz), 2.7 (IH, dd, J=14.0 & 7.0 Hz), 2.78 (IH, dd, J=I4.7 &
5.9 Hz), 3.4- 3.6 (5H, complex), 3.9 (2H, t, J=6.6 Hz), 4.1 (2H, t, J=6.6 Hz), 6.6
(6H, complex), 6.8 (4H, complex), 7. (2H,d, .1=8.6 Hz). -
389
72

OEt




58.

'H: 1.1 (3H, t, J=7.0 Hz), 1.9 (IH, dd, J=5.3 &1.8 Hz, OH), 2.6 (1H, dd, J= i3.5 &
6.8 Hz), 2.7 (IH, dd, J=14.0 & 6.0 Hz), 3.4 - 3.6 (5H, complex), 4.3 (2H, t, J=6.0
Hz), 4.7 (2H, t, J=6.0 Hz), 6.7 (2H, d, J =8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.2 (2H,
m), 7.5 (4H, m), 8.1 (2H, d, J=7.7 Hz).
98
355
OEt





%CH

59.

'H: 1.17 (3H, t, J=6.99 Hz), 1.97 (3H, m), 2.77 (4H, m), 3.4- 3.6 (7H, complex),
3.7 (2H, t, J=6.15 Hz), 4.12 (2H, t, J=6.1 Hz), 6.6 (2H, dd, J=12.13 & 4.66 Hz),
6.7 (2H, d, J=2.79 Hz), 6.95 (IH, d, J=7.14 Hz), 7.05 (IH, d, J=1.44 Hz), 7.0 - 7.2
(2H, m).
95
339
^
N
OEt


-CH2

60.


s„
'H: 1.1 (3H, t, J=7.0 Hz), 2.6 (lH,dd, J=14.7 & 6.8 Hz), 2.7 (IH, dd, J=14.8 &
6.0 Hz), 3.4 -3.6 (5H, complex), 4.2 (2H, t, J=5.6 Hz), 4.5 (2H, t, J=5.6 Hz), 6.5
(IH, d, J=3.0 Hz), 6.7 (2H, dd, J=8.6 & 1.9 Hz), 7.1 (3H, m), 7.2 (2H,m), 7.4
(1H, d, J=8.2 Hz), 7.6 (IH, d, J=7.8 Hz).
76
421
OEt

58

ZRC-MC-009

61.i a)CH2 XX OEt 357 56
'H: 1.2 (3H, t, J-6.99 Hz), 2.7 (IH, dd. J=13.8 & 6.69 Hz), 2.8 (IH, dd, .1=13.8 & 5.9 Hz) 3.6 (7H, m), 3.7 (2H. t, J=5.64Hz). 4.16 (2H, t, .1=5.7Hz), 4.2 (2H. t. .1= 4.4Hz), 6.7 (2H, m), 6.8 (4H, m), 7.2 (2H. d, J=8.58 Hz).
| 62.i \\ /HI ixn 0H 1 ir^ 20
'H: 2.37 (3H, s), 2.7 (2H, m), 2.99 (1H: t: J=6.69), 3.54 (IH. m), 3.4-3.7 (2H, m), 3.9 (1H, m), 4.2(2H, t, J=6.69), 6.8 (2H, dd. J=1.95 & 6.63). 7.1 (2H, d, J=8.55), 7.4 (3H, m), 7.98 (2H, m).
63. xx: snii 445 20
'H: 2.44 (3H, s), 2.8 (2H, dd, J=7.35 & 2.46 Hz), 3.13 (2H. t, .1=5.89 Hz), 3.37 (IH, m), 3.57 (2H, m), 4.31 (2H, t, J=6.1 Hz), 6.82 (2H, d, J=8.6 Hz), 7.1 (2H, d, J=8.55 Hz), 7.28 (2H, m), 7.39 (2H, m), 7.52 (4H, m), 8.19 (2H, m).
64. 0-iXlcH2 0 OEt 381 84i
'H: 1.1 (3H, t, J=6.9H J=12.9&6.9Hz), 2.9 J=8.55Hz), 7.1 (2H,d z), 2.3 (3H, s), 2.5 (IH, dd, J=13.5 & 6.7 Hz), 2.7 (IH, dd, (2H, t. .1=6.69), 3.5 (5H, m), 4.2 (2H, f. .1=6.69), 6.8 (2H, d, , J=8.5 Hz), 7.2 - 7.4 (3H, m), 7.9 (2H: m).
65. CH3 ^X^ ' OEti 330 96
1H : 1.17 (3H, t, J=6.9 Hz). 1.58 (IH, broad-s), 2.68-2.7 (IH, m), 2.7-2.85 (IH, m), 3.13 (3H, s), 3.48-3.58 (5H. m), 3.97 (2H, t, .1= 5.85 Hz), 4.15 (2H,U=5.64Hz), 6.50-6.56 (2H,m). 6.86 (2H, d, .1=8.64 Hz), 7.07 (2H, d, .1=8.64 Hz); 7.44-7.45 (IH, m). 8.13-8.16 (IH. m).
66. N^CH2)2 XX OEt 329 82
'H: 1.17 (3H,t, J=7.0Hz), 1.24 (3H, t. J=7.6 Hz), 2.59-2.69 (3H, m ), 2.77-2.85 (IH, m), 3.22 (2H, t, J= 6.7 Hz). 3.49-3.58 (5H, m), 4.31 (2H,t, J=6.57 Hz), 6.83 (2H,d, J=8.55 Hz ), 7.1 (2H, d. J=8.58 Hz), 7.17 (IH, d, J=7.92 Hz); 7.45 (IH, m), 8.4 (IH, d, J=1.98Hz).
59

ZRC-MC-009

i 67.iiiii CH3 0 OEr 373 90
'H: 1.17 (3H,t, J=6.9 Hz), 2.4 (3H, s), 2.69-2.81 (2H, m), 3.45-3.62 (5H, m) 4.96 (2H,s), 6.9 (2H, d, J=8.47 Hz), 7.08-7.09 (IH, m), 7.14 (2H,d, J-8.47 Hz), 7.38-7.40 (IH, m), 7.62-7.64 (IH, mi
i 68.i CH3 . XJ OEt 387 97
i ! 'H: 1.17 (3H, t, .1=7.02 Hz), 2.35 (3H, s), 2.67-2.79 (2H, m), 2.94 (2H, t, J=6.63 Hz), 3.42-3.57 (5H, m), 4.2 (2H, t, J=6.63 Hz), 6.82 (2H, d, J=8.58 Hz), 7.06-7.10 (3H, m), 7.35-7.37 (IH, dd, J=1.17 & 5.04 Hz), 7.57- 7.58 (IH, dd, J=l.l 1 & 3.66 Hz).
69. CH3 VN-(CH2)2SCH3 XX OEr 425 95
'H: 1.17 (3H, t, .1=6.9 Hz), 2.36 (314, s), 2.51 (3H, s), 2.6-2.8 (2H, m), 3.4-3.6 (5H, m) 3.92 (2H, t, J=6.47 Hz), 4.29 (2H, t, .1=6.6 Hz), 5.96-5.98 (IH, m), 6.0 (IH, d, J=3.4 Hz), 6.62 (2H, d, J=8.5 Hz), 7.05 (2H, d, J=8.5 Hz), 7.25-7.34 (4H, m).
70. H3cs-f y-( IW °^CH3 XX OEt 427 92
'H: 1.17 (3H, t, J=6.99 Hz), 2.36 (3H, s). 2.52 (3H, s), 2.67-2.69 (IH, m), 2.77-2.79 (IH, m), 2.96 (2H, t, J=6.6 Hz), 3.43-4.13 (5H, m), 4.21 (2H, t, J=6.6 Hz), 6.82 (2H, d, .1=8.5 Hz), 7.08 (2H, d, .1=8.5 Hz), 7.28 (2H, d, J=8.4 Hz), 7.88 (2H, d, J=8.4Hz).
71. V>AJUH2 XX NH2 352 70
'H: 2.37 (3H, s), 2.83 (2H, s), 2.96 (2H, r. .1=6.21 Hz), 3.36-3.65 (3H, m), 4.22 (2H, t, J=6.35 Hz), 6.89-6.91 (2H, in), 7.13-7.19 (2H, m), 7.45-7.48 (3H; m), 7.93-7.96 (2H, m).
72. OCC XX NHBoc 438 100
'H: 1.41 (9H, s), 2.26 (IH, broad-s), 2.43 (3H, s), 2.78 (2H, d, J=7.11 Hz), 3.52-3.58 (IH, m), 3.63-3.7 (IH, m), 3.82 (IH, broad-s), 4.97 (2H, s), 6.96 (2H, d, .1=8.58 Hz), 7.13 (2H, d, J=8.58 Hz), 7.41-7.46 (3H, m), 7.98-8.03 (2H, m).
60

ZRC-MC-009

74.


/
DMSO-d6, 'H: 1.28 (9H, s), 2.34 (3H, s), 2.68-2.72 (IH, m); 2.91 (2H, t, .1=6.52
Hz), 3.02-3.47 (4H, m), 4.15 (2H, t, J=6.58 Hz.), 6.8 (IH. d. .1=8.55 Hz), 7.07
(2H, d, J=8.55 Hz), 7.45-7.52 (3H, m), 7.88-7.91 (2H; m).
OEt
345
77

Ti
-N T OH
XH,



75.

'H: 1.17 (3H, t, J=6.9 Hz), 1.24-1.32 (3H, m), 2.66-2.71 (4H. m). 3.49-3.57 (5H, m), 4.15 (2H, d , J=6.18 Hz), 5.06-5.10 (IH, t, J=5.7 Hz), 6.84 (2H, d, J=8.64 Hz), 7.09 (2H, d, J=8.61 Hz), 7.39 (IH, d, J=8.04 Hz ), 7.54-7.57 (IH, m), 8.42 (lH,s)
99
340

OEt

N

CH,
'H: 1.15 (3H, t, J=6.99 Hz), 2.68 (IH, d, J=6.78 Hz), 2.76 (IH, d, J=6.03 Hz), 3.39-3.57 (5H, m), 4.39 (2H, t, J=5.1 Hz), 4.57 (2H, t, J=5.1 Hz), 6.75 (2H, d, J=8.61 Hz), 7.0 (2H, d, J=8.58 Hz), 7,28-7.33 (2H, m), 7.47 (1H. d, J=6.96 Hz), 7.82 (IH, d, J=6.93 Hz), 8.04 (IH, s)



^
76.

OEt

367

9:


H: 1.17 (3H, t, J=6.99 Hz), 2.4 (3H, s), 2.6-2.8 (2H, m), 3.4 - 3.6 (5H, m), 4.9 j (2H, s), 6.94 (2H, d, J= 8.64 Hz), 7.12 (2H, d, J=8.58 Hz), 7.42 -7.46 ( 3H, m), ' 8.0 - 8.03 (2H, m)
H: 1.07 (3H, t, J=6.9 Hz), 2.26 (3H, s), 2.48 (3H, s), 2.62-2.77 (2H, m), 3.41-3.49 (5H, m), 4.05 (2H, t, J=5.7 Hz), 4.29 (2H, t, J=5.6 Hz), 5.81 (IH, d, J=2.9 Hz), 6.02 (IH, d, J=3.4 Hz), 6.75-6.78 (3H, m), 6.89 (IH, d. .1=3.4 Hz), 7.1 (2H, d, J=8.5 Hz)
61

ZRC-MC-009

79. CH3VX) XJ OEt 419 86i
'l-l : 1.16 (3H, t, .1=6.99 Hz), 2.39 (3H, s), 2.64-2.77 (2H, m), 3.47-3.53 (5H, m). 4.23 (2H, t, .1=6.07 Hz), 4.54 (2H, t, J=6.06 Hz), 5.99 (Hi, d, J-3.57 Hz), 6.56 ! (1H, d, J=3.6 Hz), 6.69 (1H, s), 6.73 (2H, d, J=8.61 Hz), 7.05 (2H, d, J=8.55 Hz), j 7.2-7.5 (4H, m) |
80. CH3 XJ OEt 423 93 j
1H.: 1.17 (3H, r, J=7.0 Hz), 2.35 (3H, s), 2.66-2.77 (2H, m), 3.45-3.57 (4H, m), 3.58-3.74 (1H, m), 3.92 (2H, t, J=6.54 Hz), 4.25 (2H, t, J=6.52 Hz), 5.93 (1H, d, j J=3.12 Hz), 5.99 (2H, s), 6.04 (1H, d, J=3.39 Hz), 6.64 (2H, d. J=8.58 Hz), 6.84- | 6.88 (3H, m), 7.04 (2H, d, J=8.55 Hz)
81.I 0 \y-CH2N'ICH3 XX OEt 340 40
1 i ! 'H : 1.17 (3H, t, J=6.78 Hz), 2.68-2.77 (2H, m), 3.44-3.61 (5H, m), 3.89 (3H, s), 5.36 (2H, s), 6.99 (2H, d, J=8.64 Hz), 7.12 (2H, d, J=8.61 Hz), 7.26-7.79 (4H, m)
J 82.i /N5:r/C6H5VVMe XX OEt 367 | 1001
1 i 'H : 1.19 (3H, t, J=6.97 Hz), 2.49 (3H, s), 2.67-2.83 (2H, m), 3.44-3.62 (5H, m). 4.83 (2H, s), 6.88 (2H, d, J=8.55 Hz), 7.15 (2H, d, J=8.49 Hz), 7.26-7.74 (5H, m)
Table 4:
R10-Ar 1 G2
Gi
62

ZRC-MC-009

lix.No r " " R1" " ■""" Ar G, G2 Mol. Wt 0//uyield
83. CHrc,rCH3 jy OEt CH2OH 394 87
'H: 1.17 (3H, t, J=7.00 Hz), 1.66-1.69 (2H, m), 2.37 (3H, s), 2.59-2.66 (2H, m), 2.97 (2H, t., J=.6.75 Hz), 3.43-3.48 (1H, m), 3.57-3.62 (1H, m), 3.72-3.74 (3H, m), 4.21 (2H, t, .1= 6.7 Hz), 6.83 (2H, d , J=8.6 Hz), 7.06 (2H. d , J=8.6 Hz), 7.39-7.45 (3H, m), 7.95-7.99 (2H, m).
Preparation 5
l-Ethoxy-(2S)-ethoxy-3-[4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy}-phenyl]-propane (compound No 84).

To a stirred suspension of powdered sodium hydroxide (250 mg) in dimethylsulfoxide (10 mL), (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol (compound No 64) (1.15 g) was added and stirred at ambient temperature for 20 minutes. Reaction mixture was cooled in an ice bath and ethyl iodide (0.5 g) was added and stirred for further 30 minutes at the same temperature followed by 17 hours at ambient temperature in nitrogen atmosphere. Reaction mixture was poured in ice cold water and extracted with diethyl ether (3X50mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silicagel using 5% ethyl acetate in petroleum ether to yield 0.6 g of title compound.
Preparation 6
2-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-
benzoic acid (compound No 89).
63

ZRC-MC-009

Step i: Preparation of Methyl-2-((2S)-ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl)--propoxy)-benzoate.
To a solution-of (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl methane sulfonate (compound No 91) (0.9 g) in toluene (10 mL) potassium carbonate (0.5 g) was added followed by methyl salicylate (0.25 mL) and the reaction mixture was refluxed for 3 hours. Reaction mixture was cooled to ambient temperature and poured in ice cold water. It was extracted with ethyl acetate (3X50 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure to yield 818 mg of product.
Step 2: 2-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-benzoic acid.
To a solution of Methyl-2-((2S)-ethoxy-3--|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-
ethoxy]-phenyl|--propoxy)-benzoate. (518 mg) in methanol (10 mL) was added another
solution of sodium hydroxide (241 mg) in water (5 mL) and the reaction mixture was
stirred at ambient temperature for 72 hours. Solvents were evaporated under reduced
pressure. Residue was dissolved in water (50 mL), acidified with IN HC1 and extracted
with diethyl ether (3X50 mL). The combined organic extract was washed with water (50
ml), brine (50 mL), dried over sodium sulfate and evaporated under reduced pressure.
Crude product was recrystalized from a mixture of diisopropyl ether and petroleum ether
to yield 345 mg of product.
Preparation 7
((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yI)-ethoxy]-phenyl}-propoxy)-acetic
acid (compound No 87)
64

ZRC-MC-009
. ,CH3
Step I: Preparation of Ethyl- ((2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-
Ethoxy]-phenyl \ -propoxy)-acetate.
To a stirred suspension of 50% sodium hydride (189 mg) in tetrahydro furan (10 mL) was
added a solution of (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-propan-l-ol (1.0 g) in 5 mL tetrahydrofuran at a temperature below 10 °C and stirred at ambient temperature for 2 hours. Reaction mixture was again cooled below 10 'C and to it was added ethyl bromoacetate (1.75 mL) and stirred at ambient temperature for 15 hours. Reaction mixture was poured into ice cold water (50 mL) and extracted with diethyl ether (3X50 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silicagel using 7% ethyl acetate in petroleum ether to yield 350 mg of title compound and 300 mg of (2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl bromo-acetate (compound no. 90)
o
^ oVCH3 AAA^8*
Step 2: Preparation of ((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-acetic acid.
Title compound was prepared from Ethyl- ((2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl^-propoxy)-acetate following procedure similar to that described in preparation 6, step 2.
Preparation 8
(2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl-methanesulfonate. (compound No 91)
65

ZRC-MC-009

oso2CH3
CK^

To a solution of (2S)-Ethoxy-3- [4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl j -propan-l-ol. (compound 64) (5.4 g) in dichloromethane (80 mL) was added triethyl amine (3.0 nL) and cooled to 10° C. To this was added methanesulfonyl chloride (l.1 mL) dropwise and the reaction mixture was stirred at ambient temperature for 3 hours. Reaction mixture was diluted with dichloromethane (l00mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to yield 6.0 g of title compound.
In like manner following compounds in table 5 were prepared following the procedure described in preparation 5-8 by using appropriate reagents and reaction conditions.
Table 5:


R10-Ar


l-:x No

R'

Ar

G,

G;

Mol.Wt

% Yield




r^
w MA

,-CH2

OEt

OEr

409

:>7



85.

nH: l.l (3H, t, J=6.99 Hz), 1.2 (3H. t. J=6~99 Hz), 2.4 (3H, s). 2.7 (2H, t, .1=6.6 Hz), 3.0 (2H, t, J=6.69 Hz) 3.5 (7H, complex), 4.2 (2H, t, .1=6.69 Hz), 6.8 (2H, dd, J=1.87 & 6.65 Hz), 7.1 (2H, d, J=8.55 Hz) 7.4 (3H, m) 7.9 (2H, m).
,OH
OEt
29
425
O
U-VL
/=\ 0^/CH3

CH2

66

ZRC-MC-009


! 86 n ,CH31 y-X\• -' N" \^CH2 XX OEt 0 ^ 3 423 67 1ji i
'H: 0.9 (3H, t, J=7.4I Hz), 1.1 (3H, t, J=7.0 Hz), 1.59 (2H, m). 2.3 (3H. s). 2.6- ! 2.8 (2H, m), 2.98 (2H, t, J=6.7 Hz), 3.3 (5H, m), 3.5 (2H, m). 4.2 (2H. t, J=6.7 j Hz), 6.8 (2H, dd, J=6.6 & 2.0 Hz), 7.1 (2H, d, J=8.6 Hz), 7.4 (3H. m), 7.9 (211,m). i
87. { HI ex^y^x OEt /\ .OH0 439 80 |i i|i 1
'H: 1.2 (3H, t, 5=1.0 Hz), 2.4 (3H, s). 2.7 (1H, dd, J = 13.S & 7.2 H; dd, .1=13.8 & 5.7 Hz), 3.0 (2H, t, J=6.6 Hz), 3.4 (1H, m), 3.5 - 3.7 ( (2H, s), 4.2 (2H, t, .1=6.6 Hz), 6.8 (2H, d. J=8.5 Hz), 7.0 (2H. d, .1=8 (3H, m), 7.9 (2H, m). -.). 2.8 (IH. 4H.m), 4.0 .5 Hz), 7.4
88. VCH2 XX OEt OEt 401 88
'H: 1.12 (3H, t, 3.38 (2H, dd, 5=4 4.1 (2H,t, .1=5.8 1=7.0 Hz), 1 .5 & 1.17 H -\z), 6.6 (1H .19 (3H, t, J=7.C z), 3.4 (5H, m), 3 ,m),6.7(lH,d, Hz), 2.75 (2H. m). 3 .7 (2H, t, J=5.8 Hz), 3 J=8.2 Hz), 6.8 (2H, d, 0 (2H, m), .8 (2H, m), J=8.6 Hz).
COOH
7.0 (2H, m), 7.1 (2H, d, .1=8.6 Hz).
,CH3
501
89.

j
OEt
N'
,CH2

90.


o
502
OEt
.U1
"^
i 'H: 1.22 (3H, t, J=6.99 Hz), 2.37 (3H, s), 2.79 (IH, dd, J=13.9 & 7.8 Hz). 2.97 ' (3H, m), 3.61 (2H, m), 3.87 (IH, m), 4.0 (IH, dd, J=10.66 & 7.36 Hz), 4.17 (IH, dd, J=9.61 & 3.21 Hz), 4.2 (2H, t, J=6.7 Hz), 6.88 (3H, m), 7.09 (3H, m), 7.41 (4H, m), 7.96 (2H, dd, J=7.53 & 2.19 Hz), 8.16 (IH, d, J=6.03 & 3.0 Hz).


'H: 1.1 (3H, t, J=6.99 Hz), 2.3 (3H, s), 2.7 (2H, m), 2.9 (2H, t. 5=6.1 Hz), 3.4
3.7 (3H, complex), 3.8 (2H, s), 4.0 (IH, m), 4.2 (3H, m), 6.8 (2H, d, .1=8.6 Hz)
7.1 (2H, d, .1=8.6 Hz), 7.4 (3H, m), 7.9 (2H, m).
84
CH-,
OEt
459
Q-y
N '"\.-CH2
^
-OS02CH3

67

ZRC-MC-009


92.

CH-

OEt

—OS02CH3

364

100




93.

ACHih

CH3

OEt

OCH3

401

87

'H: 1.13 (3H, t. .1=6.99 Hz), 2.35 (3H. s), 2.74 (2H, d, .1=6.42 Hz), 2.94 (2H, t, .1=6.57 Hz), 3.33 (3H, s), 3.42-3.58 (5H, m), 4.20 (2H. r. .1=6.61 Hz). 6.8 (2H. d, J=8.32 Hz), 7.06-7.13 (3H, m), 7.35-7.36 (1 H, m), 7.57-7.58 (I H, m).


CH
94.




OEt

OEt

455

88



95.

'H: 1.11 (3H, t, J=6.99 Hz), 1.17 (3H, t, J=7.0 Hz), 2.39 (3H, s); 2.51 (3H, s),
2.70-2.75 (2H, m), 3.04 (2H, t, J=6 Hz), 3.33-3.55 (7H, m), 4.25 (2H, r, J=6.0
Hz), 6.79 (2H, d, J=8.55 Hz), 7.10 (2H, d, J=8.52 Hz), 7.28 (2H, d, J=8.46 Hz),
8.0 (2H, d, J=8.18 Hz).
OEt
OEt
415
50

0 x
.(CHzfe

CH3



97.

'H: 1.12 (3H, t, J=7.0 Hz), 1.25 (3H, t, J=7.0 Hz), 2.35 (3H, s), 2.72-2.8 (2H, m), 2.95 (2H, t, J=6.6 Hz), 3.35-3.38 (2H, m), 3.44-3.56 (5H, m), 4.20 (2H, t, J=6.6 Hz), 6.8 (2H, d, J=8.6 Hz), 7.07-7.10 (IH, m), 7.1 (2H, d, J=8.6 Hz), 7.36-7.38 (IH, m), 7.59-7.60 (IH, in)
'H: 1.11 (3H, t, J=7.0 Hz), 1.17-1.22 (3H, t, J=7.0 Hz), 2.41 (3H, s), 2.74-2.77 (2H, m), 3.36-3.59 (7H, m), 4.95 (2H. s), 6.93 (2H, d, J=8.6 Hz), 7.08-7.11 (IH. m), 7.16 (2H, d, J=8.64 Hz), 7.39-7.41 (IH, m), 7.64-7.66 (IH, m).
OEt
451
78
CH2
Nx
CH3
—OS02CH3




98.

'H: 1.15 (3H, t, J=6.99 Hz), 2.4 (3H, s), 2.77-2.82 (2H, m), 3.03 (314, s), 3.46-3.61 (3H, m), 4.05-4.26 (2H, m), 4.94 (2H, s), 6.94 (2H, d , J=8.6 Hz), 7.08-7.1 1 (IH, m), 7.15 (2H, d , J=8.6 Hz), 7.39-7.40 (IH, m), 7.62-7.64 (IH, m).
OEt
407
[00
-OS02CH3


'H: 1.15 (3H, t , J=6.9 Hz), 1.24 (3H, t, J=7.57 Hz), 2.66-2.80 (4H, m), 3.05
(3H, s ), 3.32 (2H, t , .1=6.4 Hz), 3.49-3.57 (4H, m), 4.02-4.1 (IH, m), 4.34
(2H, t, .1=6.4 Hz ), 6.84 (2H, d , J=8.53 Hz), 7.1 (2H, d . J=8.5 Hz), 7.25 (IH,
d,J=7.97Hz), 7.65 (IH, in), 8.44 (IH, d , J=1.95 Hz).
68

ZRC-MC-009


99.

\J-

CH-,
CH2

NHBoc

—OS02CH3

516

85



(3H, s), 4.05-4.13 (2H, :8.58 Hz), 7.14 (2H, d.
74
100.

'H: 1.42 (9H, s), 2.43 (3H, s), 2.75-2.86 (2H, m), 3.01 m), 4.22-4.25 (IH, m), 4.97 (2H; s), 6.98 (2H, d, J= .1=8.58 Hz), 7.41-7.46 (3H, m), 8.0-8.03 (2H, m).
CH,
OEt
-OS02CH3 I 497
I! I
CH,

r

'H : 1.14 (3H, t, J=6.99 Hz), 2.4 (3H, s), 2.75 (2H, t, J=6.93 Hz), 3.02 (3H. s), 3.45-3.58 (2H, m), 3.56-3.67 (2H. m), 4.0-4.1 (IH, m), 4.24 (2H, t, J=5.91 Hz). 4.54 (2H, t, J=6.0 Hz), 5.99 (I H, d. J=3.6 Hz), 6.56 (1H, d. .1=3.6 Hz), 6.69 (IH, s), 6.74 (2H, d, J=8.49 Hz), 7.06 (2H, d, J=8.49_Hz), 720-7^1 (4H, m)
62
OEt

\^o
-OSO2CH31 501
'H : 1.14 (3H, t, J=6.97 Hz), 2.35 (3H, s), 2.76 (2H, t, .1=6.48 Hz), 3.03 (3H, s),
3.48-3.56 (4H, m), 3.92 (2H, t, J=6.48 Hz), 4.20 (IH, t, .1=5.46 Hz), 4.25 (2H, t,
J=6.31 Hz), 5.92 (IH, d, .1=3.3 Hz), 5.99 (2H, s), 6.03 (IH, d, .1=3.39 Hz), 6.64
(2H, d, J=8.58 Hz), 6.81-6.84 (3H; m), 7.05 (2H, d, J=8.55 Hz)


102.

OEt

i ex iY

Mg

573

77



103.


577

OEt
'H : 1.03 (3H, t, J=6.97 Hz), 2.39 (3H. s), 2.42 (3H, s), 2.65 (2H, d, J-6.39 Hz),
3.33-3.44 (4H, m), 3.92 (2H, t, J=5.28 Hz), 4.19-4.21 (IH, m), 4.54 (2H, t,
.1=6.01 Hz), 5.98 (IH, d, .1=3.6 Hz), 6.56 (IH, d, J=3.6 Hz), 6.67-6.70 (3H. m),
6.97 (2H, d, J=8.46 Hz), 7.21 -7.54 (6H, m), 7.75 (2H, d, J=8.22 Hz)
CL _//
^ Me

'H : 1.03 (3H, t, J=6.99 Hz), 2.35 (3H, s), 2.43 (3H, s), 2.65 (2H, d, .1=6.39 Hz),
3.33-3.56 (3H, m), 3.89-3.94 (4H, m), 4.25 (2H, t, .1=6.48 Hz), 5.92 (IH, d,
.1=3.33 Hz), 5.99 (2H, s). 6.03 (IH. d, j=3.36 Hz) , 6.59 (2H, d, J=8.55 Hz),
6.84-6.90 (3H, m), 6.97 (2H, d, J=8.52 Hz), 7.31 (2H, d, .1=8.4 Hz), 7.76 (2H, d,
J=8.28 Hz)
69

ZRC-MC-009



104.

\y-CH2
N CH3

OEt

OEt

368

92



105.

Tl : 1.13 (3H, t, J=7.0 Hz), 1.27 (3H, t, J=7.06 Hz), 1.53-1.65 (2H. m), 2.43 (3H, s), 2.69-2.84 (2H, m), 3.35-3.45 (5H, m). 3.55-3.61 (2H. m), 4.98 (2H, s),
1 6.93 (2H, d, J= (2H, m) 8.67 Hz), 7.15 (2H, d, .1=8.64 Hz). 7.14-7.46 (3H, m). 8.0-8.04
1 106.j i!i ;wc6H5/ CH2 H3C jy OEt OEt 3951 98
ij 'H : 1.15 (3H, t, J=6.97 Hz), 1.18 (3H, t, J=7.0 Hz), 2.48 (3H, s), 2.78 (2H, d, .1=6.8 Hz), 3.39-3.59 (7H, m), 4.83 (2H, s), 6.87 (2H, d. .1=8.49 Hz), 7.17 (2H, d, .1=8.49 Hz), 7.42-7.74 (5H, m),
107. /=\ /°/H XX1 ... 1 OEt 0i^COOHu 487 85
i 'H : 1.23 (3H, t, J=7.0 Hz), 2.4 (3H, s), 2.8-3.0 (2H, m), 3.5-3.6 (2H, m), 3.6-3.7 (1 H, m), 3.9 (IH, m), 4.0-4.1 (IH. in), 4.9 (2H, s), 6.85 (IH, d, .1=8.31 Hz), 6.97 (2H, d, J=8.52 Hz), 7.10-7.15 (3.H, m), 7.42-7.49 (4H. m ), 8.0-8.15 (2H, m), 8.17(11-1, d, J =6.15 Hz)
108. -- N XCH2 fY 0Et ! -°S°2CH3i ii ii i 446 98
'H : 1.15 (3H, t, .1=6.99 Hz), 2.4 (3H, s), 2.7 - 2.8 (2H, m), 3.0 (3H, s), 3.4 -3.6 (2H, m), 3.6 - 3.7 (IH, m), 4.0 - 4.2 (2H ; m), 4.9 (2H, s ), 6.95 (2H, d, J=8.61), 7.14 (2H, d, J=8.61 Hz), 7.41 - 7.46 (3H, m), 8.0 -8.03 (2H, m)
109. „/CH31CH3 £f OEt —OS02CH3 477 1 90
'H : 1.14 (3H, s), 2.48 (3H, s), 2.74 (3H, s), 2.79 (2H, m),3.03 (3H, s), 3.43-3.57 (3H, m), 4.05 (3H, t, J=6.4 Hz), 4.33 (IH, m), 4.5 (2H, m), 5.9 (IH, d, .1=2.8 Hz), 6.1 (IH, d, .1=3.2 Hz), 6.7 (2H, m), 6.8 (IH, d, J=3.1 Hz), 7.09 (2H, d, .1=8.2 Hz), 7.25 (IH, s)
70

ZRC-MC-009

! 110.1 /=N O^XCH3 XX OEt OEt 395 I 76ii
i 'H : 1.13 (3H, t, J=6.9 Hz), 1.19 (3H, t, 1=6.9 Hz), 2.43 (3H, s), 2.77 (2H, m), 3.37-3.63 (7H, m), 4.97 (2H, s), 6.9 (2H,.d, J=8.6 Hz), 7.17 (2H, d, .1=8.6 Hz). 7.42-7.47 (3H, m), 8.0-8.03 (2H, m)
111. -=\ 0-_/CH3 ^ N XCH2 XX OEt 0 : 443 ' 51X. XOOH 'u
'H : 1.15 (3H, t, J=7.0 Hz), 2.47 (3H, s), 2.89-2.92 (2H, m). 3.5 (IH. m), 3.65 (1H, m), 3.8 (IH, m), 3.9 (2H, in), 5.0 (2H, s), 6.87-6.96 (5H. m), 7.15 (2H. m). 7.25 (2H, m), 7.5 (3H, m), 8.05 (2H, m)
Preparation 9
2-Ethoxy-l--|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxypentane. (Compound. No. 114)

K2CO3 (0.645 g) was added to a solution of 4-(pentane 2-Ethoxy-3-hydroxy (-phenol (700 mg) in toluene (5 mL) at 20-30 °C. The reaction was stirred at reflux temp, for 1 hour. To the reaction mixture was added 2-(2-phenyl-5-methyl-oxazole-4-yl)ethyl methane sulfonate (878 mg).Reaction mixture was stirred for 36 hour at reflux temperature. Reaction mixture was poured in to water (25 mL) and extracted with ethyl acetate (2 x 25 mL). Combined organic layer was washed with water (2 x 50 mL) & brine (50 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silicagel using pet.ether:ethyl acetate (9:1) as an eluent to afford pure 157 mg product.
Preparation 10
2-Ethoxy-l-J4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-ethoxy pentane
(Compound. No. 115)
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K2C03 (0.368 g) was added to a solution of 4-(pentane 2,3-diethoxy)-phenol (403 mg) in toluene (5 mL) at 20-30 °C. The reaction mixture was stirred at reflux temperature for 1 hour. To the reaction mixture was added 2-(2-phenyl-5-methyl-oxazole-4-yl)ethyl methane sulfonate (500 mg). Reaction mixture was stirred for 36 hours at reflux temperature. Reaction mixture was poured in to water (25 mL) and extracted with ethyl acetate (2 x 25 mL). Combined organic layer was washed with water (2 x 50 mL). brine (50 mL) dried over sodium sulfate and evaporated under reduced pressure to yield the crude title compound (206 mg). Crude product was chromatographed over silicagel using pet.ether.ethyl acetate (9:1) as an eluent to afford pure 90 mg product. In like manner following compounds in table 6 were prepared by a method similar to that described in preparation 9-10.
Table 6:
G3 R10-Ar "X °2

Ex. No R1 j Ar G, G2 G;, Mol. Wt % yield
Il2. /=\ , 'H: 0.94 (3H, t, J=7.39 Hz), 1 1.53 (2H, m), 2.43 (3H, s), 2. (2H, d,J=8.5Hz), 7.15(2H, d .02 (3H, t,J 72-2.75 (2H , J=8.43 Hz =7.29 Hz), 1.11 (3H, t, J=6.99 Hz), 1.51-, m), 3.28-3.47 (4H, m), 4.97 (2H, s), 6.94 , 7.42-7.46 (3H, m), 7.99-8.03 (2H, m)
113. /-\_/°YCH3 IX OEt OEt Et 423 26
'H-0.96(3H,t,J=3.6Hz), 1.05 (3H, t, J=3.4 Hz), 1.21 (3H, t, J=7.14 Hz), 1.5 (2H, m), 2.4 (3H, s), 2.68 (2H, m), 3.39-3.47 (2H, m), 3.56-3.59 (4H,m), 4.9 (2H, s), 6.93 (2H, d, J=8.54 Hz), 7.16 (2H, d, J=6.8 Hz), 7.42-7.46 (3H. m), 8.00-8.03 (2H, m)
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114. J\—CH2 XX OEt OH Et 409 21.59
'H : 0.93 (3H, t, .1=7.41 Hz), 1.10 (3H. t, J=6.99 Hz), 1.47-1.52 (2H, m), 2.37 (3H, s), 2.73-2.79 (2H, m ), 2.97 (2H, t, J=6.69 Hz), 3.26-3.47 (4H, m), 4.22 (2H, t, J=6.70 Hz), 6.8 (2H, d, J=8.55 Hz ). 7.1 1 (2H. d, J=8.55 Hz), 7.39-7.45 (3H, m), 7.95-7.99 (2H, m)
115. PhV0VCH3V // N-\\— CH2 xx OEt OEt Et 437 | 26.51 1J
'H : 0.91-0.96 (3H,m), 1.01-1.06 (3H. m), 1.18-1.61 (3H. m), 1.55-1.61 (2H. m), 2.37 (3H, s), 2.61-2.81 (2H, m), 2.97 (2H, 1,1=6.1 Hz), 3.1-3.2 (1H, m), 3.2-3.3 (1H, m), 3.35-3.45 (2H, m), 3.5-3.6 (2H, m), 4.22 (2H, t, J=6.70 Hz ), 6.82 (2H, d. J=8.55 Hz), 7.12 (2H, d, J=8.52 Hz), 7.39-7.45 (3H, m), 7.96-7.99 (2H, m)'
Preparation 11
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl [-propyl azide.
(compound No 116)
To a solution of (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl-methanesulfonate. (compound 91) (6.5 g) in dimethylformamide (30 mL), sodium azide (5.3 g) was added and the reaction mixture was heated at 90 °C for four hours. Reaction mixture was cooled to 25 °C and poured into water and extracted with ethyl acetate (3X100 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was triturated with methanol (30 mL) to yield 4.5 g of title compound. In like manner following compounds in table 7 were prepared by a procedure similar to that described for preparation 11.
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Table 7:

R10~Ar'

1
Gi


| Ex. ! No R Ar ! G|i i iVlol. Wt % yield
j II6. ■O^NX-CH, XX OEr 406 71
I 'H: 1.2 (3H, t, J=7.0 Hz), 2.3 (3H. s), 2.7 (1 H, del. .1=13.5 & 6.6 Hz), 2.8 (1 H, dd. .1=13.5 & 6.2 Hz), 2.9 (2H, t, J=6.7 Hz), 3.1 (2H, m), 3.5 (3H, m), 4.2 (2H, r, J=6.7 Hz), 6.8 (2H, d, J=9.5 Hz), 7.1 (2H, d. J=8.5 Hz), 7.4 (3H, m), 7.9 (2H, m).
117. OCC* XX OH 378 ' 49
'H: 2.38 (3H, s), 2.73 (2H, dd, J=6.8 & 2.6 Hz), 2.97 (2H, r. J=6.8 Hz), 3.2 (IH. dd, J=I2.4 & 6.8 Hz), 3.3 (IH, dd, J=12.4& 3.6 Hz), 3.9 (IH, m), 4.22 (2H, t. J=6.57Hz), 6.83 (2H, d, J=8.64 Hz), 7.15 (2H, d, .1=11.5 Hz). 7.41 (3H, m), 7.97 (2H, dd, .1=7.59 & 2.25 Hz).
118. CXCH2 XX OEt 311 93
'H: 1.1 (3H, t, J=6.9 6.1 Hz), 3.1 (2H, m), J=8.5 Hz), 7.3-7.4(5 Hz), 2.7 (IH, dd, J=13.8 & 6.8 Hz), 2.8 (IH, dd, .1-14.0 & 3.5 (3H, m), 5.0 (2H, s), 6.9 (2H, d, J=8.5 Hz), 7.1 (2H, d. H, m).
119. N ^(CH2)2 XX ] 96
'H: 1.17 (3H, t, J=6.9Hz), 1.24 (3H, r. J=7.6 Hz), 2.61-2.72 (3H, m), 2.78-2.80 (IH, m), 3.13-3.24 (4H, m), 3.50-3.58 (3H, m), 4.31 (2H, r , .1= 6.7 Hz), 6.85 (2H, d , .1=8.5 Hz), 7.1 (2H,d, .1=8.5 Hz). 7.17 (IH, d, J=".S7 Hz), 7.45 (IK m), 8.38 (IH, d,J=2.09Hz).
120. N N CH2 1 CH3 XX OEt 355 82
'H: 1.18 (3H, t, J=6.99 Hz), 2.69-2.8 (2H. m), 3.14 (3H, s). 3.14-3.19 (2H, m), 3.52-3.57 (3H, m), 3.97 (2H, t, J=5.65 Hz), 4.16 (2H, t, J=5.65 Hz), 6.50-6.56 (2H, m), 6.83 (2H, d, J=8.64 Hz), 7.08 (2H, d, J=8.64 Hz). 7.44-7.46 (IH, m), 8.14-8.16 (IH, m).
121. Q~iX°ACH3 XX OEt 398 95
'H: 1.18 (3H, t , J=6.99 Hz), 2.4 (3H, s), 2.72-2.88 (2H, m). 3.17-3.2 (2H, m), 3.48-3.6 (3H, m), 4.94 (2H, s), 6.9 (2H. d, J=8.6 Hz), 7.053-7.151 (3H, m), 7.38-7.40 (lH,m), 7.62-7.64 (lH,m)
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122. E>/jfCH2 XX OEt 412 83
'H: 1.18 (3H, t, J=7.00 Hz), 2.35 (3H, s), 2.69-2.80 (2H Hz), 3.16-3.18 (2H, m), 3.52-3.58 (3H, m),.4.2 (2H, t, J J=8.6Hz), 7.06-7.09(31-1, m), 7.353-7.373 (IH, dd. J= m), 2.94 (2H, t, J=6.66 =6.64 Hz), 6.81 (2H. d, 1.14 & 5.07 Hz), 7.57-
7.58(1H, m).
123.i i fVfNrCH2V==/ . °ACH3 XX OH 363 53
'H: 1.96 (1H, d, J=4.17 Hz), 2.44 (3H, s), 2.7-2.8 (2H, m). 3.25-3.41 (3H, m), 4.98 (2H, s), 6.97 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.76 Hz), 7.4-7.45 (3H, m), 8.0-8.03 (2H, m).
124. CH"C XX NH2 j> / / 20
'H: 2.38 (3H, s), 2.86 (2H, d, J=5.64 Hz), 2.96 (2H, t, j=6.44 Hz), 3.48-3.53 (2H, m). 3.63-3.67 (1H, m), 4.23 (2H, t, J=6.48 Hz), 6.93 (2H, d, J=8.31 Hz), 7.15 (2H, d, .1=8.35 Hz), 7.45-7.48 (3H, m), 7.93-7.96 (2H, m).
125. / \ / ifN"^CH2 XX NH2 1 A"1 40
DMSO-d6, 'H: 2.43 (3H, s), 2.69 (2H, d, J=6.21 Hz), 3.25-3.30 (2H, m), 3.43-3.49 (1H, m), 4.96 (2H, s), 6.98 (2H, d, J=8.58 Hz), 7.15 (2H, d, J=8.58 Hz), 7.51-7.53 (3H, m), 7.91-7.94 (2H, m).
126. «xc XX NHBoc 463 93
'H: 1.42 (9H, s), 2.43 (3H, s), 2.69-2.80 (2H, m), 3.27-3.44 (2H, m), 3.92 (1H, broad s), 4.97 (2H, s), 6.97 (2H, d, .1=8.64 Hz), 7.12 (2H, d, .1=8.52 Hz), 7.42-7.46 (3H, m), 8.0-8.03 (2H, m).
127. 0- 'H: 1.41 (9H, s), 2.37 (3H, s), 2.66-2.78 (2H, m), 2.97 (2H, t, J=6.66 H 3.41 (2H, m), 3.89 (1H, broad s), 4.24 (2H, t, J=6.68 Hz), 6.84 (2H, d , Hz), 7.07 (2H, d , J=8.57 Hz), 7.40-7.446 (3H, m), 7.95-7.99 (2H, m) z), 3.24-J=8.61
128. ^NJyCH2OTBDMS XX OEt 484 65
'H: 0.05 (3H,s), 0.10 (3H,s), 0.91 (9H, s), 1.17 (3H, t, J=6.9 Hz), 1.26 (3H,t, J=7.6 Hz), 2.6-2.7 (4H, m), 3.17 (2H, m), 3.4-3.9 (3H,m), 3.95-3.98 (1H, m), 4.25-4.28 (1H, m), 5.15-5.18 (1H, m), 6.82 (2H, d, J=8.64 Hz), 7.06 (2H, d, .1=8.61 Hz), 7.50 -7.54 (2H, m), 8.3 (1H, s)
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570
90
OEt
CH2
JL
Y
OH
CH3
OEt
592
97
'H: 1.17 (3H, t, J=6.9Hz), 1.26 (3H, t, J=7.6 Hz), 2.66- 2.72 (4H, m), 3.17 (2H, m), 3.49-3.57 (3H, m), 4.15 (2H, d, J=5.82 Hz), 5.08 (IH, t, .1=5.79 Hz), 6.84 (2H, d, .1=8.5 Hz), 7.08 (2H, d, J=8.52 Hz), 7.38 (IH, d; .1=7.95 Hz). 7.54-7.57 (IH, m), 8.41 (IH, s)
=\ o
CH2
W //

'H: 1.18 (3H, t, J=6.99 Hz), 2.4 (3H, s), 2.7 - 2.85 (2H, m), 3.2 (2H, m), 3.45 -3.65 (3H, m), 4.9 (2H, s), 6.95 ( 2H, d, J=8.6), 7.14 (2H, d, J=8.61 Hz), 7.41 -7.46 (3H, m), 8.0 -8.03 (2H, m)

96
424
OEt
^3 | | | |
d.
'H: 1.18 (3H, t, J=6.9 Hz), 2.3 (3H, s), 2.48 (3H, s), 2.65-2.69 (2H. m), 3.16 (2H
m), 3.47-3.57 (3H, m), 4.05 (2H, t, J=6.2 Hz), 4.3 (2H, t, J=6.3 Hz), 5.9 (IH,
.1=3.1 Hz), 6.1(1H, d, J=3.2), 6.7 (3H ,m), 6.8 (IH, d, J=3.3 Hz), 7.04 (2H, d,
.1=8.4 Hz)
448
88
J^o
OEt
'H: 1.17 (3H,t, J=6.96 Hz), 2.3 (3H,s), 2.68-2.78 (2H,dd. J=6.12&6.45 Hz), 3.12- 3.16 (2H, m), 3.49-3.56 (3H, m), 3.92 (2H, t, J=6.39 Hz). 4.25 (2H, r: J=6.3 Hz), 5.92 (IH, d , J=2.79 Hz), 6.0 (IH, d, J=3.27 Hz), 5.98 (2H, s); 6.63 (2H, d, .1=8.46 Hzj, 6.85 (3H, m), 7.03 (2H, d, J=8.4 Hz).


OEt

444

92


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Preparation 12
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl) -propylamine
(compound No 134)
,CH3 0-/
To a slurry of 10 % palladium on charcoal (450 mg) in ethyl acetate, a solution of (2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propylazide (compound 116) (4.5 g) in ethyl acetate (15 mL) was added and the mixture was stirred in hydrogen atmosphere for 17 hours. Catalyst was filtered and the filtrate was evaporated under reduced pressure to yield 3.2 g of title compound.
Preparation 13
(2S)-Ethoxy-3-{4-[2-(5-methyI-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl }- propyl amine
(compound No 134).

To a solution of N-tert-Butoxycarbonyl-(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- propyl amine (compound 152) (500 mg) in dichloro methane (10 mL) was added trifluoroacetic acid (0.3 mL) and the reaction mixture was stirred at ambient temperature for 16 hours. Reaction mixture was diluted with dichloromethane (25 mL) and washed with aqueous solution of sodium bicarbonate (50 mL). The organic extract was dried over calcium carbonate and evaporated under reduced pressure to yield 300 mg of title compound.
Preparation 14
(2S)-Ethoxy-3-(4-{2-[2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl]-ethoxy}-phenyl)-propylamine. (compound.No. 146).
77

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/CH3

VN.

Ov/

ss
CH3
Lithium aluminium hydride (236 mg) was added to an ice cold solution of (2S)-Ethoxy-3- !4-[2-(2-methyl-5-(5-methyl-thiophene-2-yl)-pyrrol-1 -yl)-ethoxy]-phenyl | -1 -azidopropane
(2.4 g) in tetrahydrofuran (25 mL) in portions over a period of 15 minutes and the reaction mixture was stirred for further 3 hours at the same temperature. A saturated solution of sodium sulfate in water was added dropwise with care until crystalline white solid separated. Solids were filtered off and washed with hot ethyl acetate. Combined filtrate was dried over sodium sulfate and evaporated. Crude product was chromatographed over silicagel using 5 to 25 % ethyl acetate in petroleum ether to yield 1.9 g of title compound
Preparation 15
N- {(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl |-methanesulfonamide.(Compound. No. 140)
"NHSO2CH3

W N /\ /\-^ OCH2CH3
s V_// > 0
°^CH3
To a solution of (2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propylamine (200 mg ) in dichloromethane (5 mL) was added triethyl amine (55 mg ) and coo led to 10 °C. To this was added methanesulfonyl chloride (0.042 mL) dropwise and the reaction mixture was stirred at ambient temperature for 3 hours. Reaction mixture was diluted. with dichloromethane (10 mL) and washed with water (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to yield crude 227 mg of product. Crude product was chromatographed over silicagel using 5 to 25 % ethyl acetate in petroleum ether to yield 141 mg of title compound
In like manner compounds in the table 8 were prepared following the procedure described in preparations 12-15
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Table 8:
R10-Ar'

: Ex.. ; No 1 R' Ar | Gi ' G2I i Mol. Wt % Yield
i 134, /=\ ' °YCH3VMJLCH2 XX OEr ; NH,1i 380 76
i 'H: 1.1(3H, t, J=6.91 Hz), 2.3 (3H, s), 2.6-2.8 (4H, m), 2.9 (2H, t, J=6.69 Hz), 3.4-3.5 (3H, m), 4.2 (2H, t, J=6.69 Hz), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.4 Hz), 7.4 (3H, m), 7.9 (2H, m).
135. ^-^CH2 XX OEt 1 NH2 285 68
I 'H: 1.2 (3H, t, J=13.7 Hz), 2.7 (1H, dd, J=13.7 & 6.9 Hz), 2.S (1H, dd, J=14.2 & 5.8 Hz), 3.4 - 3.6 (5H, m), 5.0 (2H, s), 6.8 (2H, d, J=8.6 Hz), 7.1 (2H, d, J=8.6 Hz), 7.3- 7.4 (5H, m).
' 136.i i 0 ^ N CH2 XX OEt ! NH2I i i 367 75
i 'H: 1.1 (3H, t, J=7.0 Hz), 2.7 (3H, m), 3.4 - 3.5 (4H, m). 3.7 (3H, s), 5.1 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.1 (2H. d, J=8.6 Hz). 7.5 (1 H. m). 7.7 (2H, m), 8.3 (1H, dd. J=8.0 & 0.8 Hz).
137. COCH2 XX OEt ! \H2i 372 80
DMSO-d6 'H: 1.0 (3H, t, J=6.9 Hz), 2.6 - 2.8 (4H, complex), 3.0 (2H, m), 3.4-3.8 (7H, m), 4.1 (2H, t, J=5.5 Hz), 6.5 (1H, t, J=7.3 Hz), 6.7 (1H, d, J=8.2 Hz), 6.8 -7.0 (4H, m), 7.1 (2H, d, J=8.4 Hz).
138. o^xCH! XJ OEt H2QV—NH H3C 422 82
DMSO-dA 'H: 1.0 - 1.1 (9H, m), .2.3 (3H. s), 2.7 (3H, m), 2.9 (3H, m), 3.23 (1H, m), 3.4-3.6 (3H, complex), 4.1 (2H, t, J=6.0 Hz), 6.8 (2H, d, J=8.1 Hz), 7.1 (2H, d, J=8.1 Hz), 7.5 (3H, m), 7.8 (2H, m).
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I 139.i XJ OEt NH2 462 50
'H: 1.06 (3H, t, J= 7.0 Hz), 2.4 (3H, s), 2.5-2.85 (4H, m), 3.35-3.51 (2H, m), 3.51-3.6(1 H, m), 4.94 (2H, s), 6.97 (2H, d, J= 8.28 Hz), 7.14-7.2 (3H, m), 7.64(1 H, d, .1=2.7 Hz), 7.7(11-1, d, .1=4.9 Hz).
| 140.ii rwYCH3 XX OEt NHS02iVle 444i i 58
1 'H :.1.18 (3H, t, J=6.99 Hz), 2.13 (3H-, s), 2.6-2.8 (2H, m), 2.93 (3H, s), 2.9-3.1 (2H, m), 3.2-3.4 (IH, m), 3.4-3.6 (2H, m), 4.97 (2H, s), 6.95 (2H, d, J=8.64 Hz), 7.11 (2H, d, .1=8.61 Hz), 7.41-7.46 (3H, m), 8.0-8.3 (2H, m)
141. \> /fX X OEt NH2 366 49
'H : 1.2 (3H, t, J=6.9 Hz), 2.45 (3H, s), 2.68 (2H. d, .1=5.3 Hz), 2.70-2.84 (2H, ra), 3.53-3.62 (2H, m), 3.74-4.05 (IH, m), 5.0 (2H, s), 6.9 (2H, d. J=8.0 Hz), 7.1 (2H, d, J=8.58 Hz), 7.42-7.45 (3H, m), 7.99-8.03 (2H, m)
142. XT OEt NHEt 394 100
'H : 0.85 (3H, t, j=7.29 Hz), 1.12 (3H, t, J=7.21 Hz), 2.43 (3H, s), 2.59-2.83 (6H, m), 3.47-3.65 (3H, m), 4.97 (2H, s), 6.93 (2H, d, J=8.61 Hz), 7.11 (2H, d, J=8.61 Hz). 7.42-8.03 (5H, m)
143. CKC JX OEt HN ( 408 85
'H : 1.09 (3H, t, J=6.8 Hz), 1.17 (6H, d, J=5.52 Hz), 2.77-2.92 (4H, m), 2.43 (3H, s), 3.25 (IH, t, J=6.16 Hz), 3.43-3.92 (2H, m), 4.96 (2H, s). 6.97 (2H, d, J=8.25 Hz), 7.17 (2.H, d. J=8.19 Hz), 7.50-7.92 (5H, m)
-f CH30Co XX OEt NH2j 422 78
'H : 1.07 (3H, t, J=6.6 Hz), 2.27 (3H, s), 2.6-2.7 (4H, m), 3.44 (2H, q, J=7.4 &7.I3 Hz ), 3.45-3.49 (IH, m), 4.19-4.22 (4H, m), 5.80 (IH. d, J=3.08 Hz), 5.89 (IH, d, J=3.34 Hz), 6.03 (2H, s), 6.69 (2H, d, .1=8.1 Hz), 6.8-6.9 (3H, m), 7.06 (2H, d,J=8.12Hz)
145. CH3 L.N^CH26 XX OEt NH2 418 97
'H : 1.03 (3H, t, J=6.0 Hz), 2.34 (3H, s), 2.5-2.7 (4H, m), 3.39-3.57 (3H, m), 4.21 (2H, t, J=4.7 Hz ), 4.50 (2H, t, .1=4.7 Hz), 5.94 (IH, d, J=3.42 Hz), 6.52 (IH, d, J=3.5 Hz ), 6.76 (2H, d, J=8.4 Hz), 6.9 (IH, s), 7.0 (2H, d, J=8.3 Hz), 7.21-7.23 (2H, m), 7.50-7.59 (2H, m)
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146. CH3\sCH3 £f OEt NH2 ! 398i 100
DMSO-d6 'H: 1.07 (3H, t, J=6.9 Hz), 2.26 (3H, s), 2.48 (3H, s), 2.62-2.77 (4H, m), 3.41-3.49 (3H, m), 4.05 (2H, t, j=5.6 Hz), 4.29 (2H, t, J=5.6 Hz), 5.81 (1H, d, J=2.9 Hz), 6.02 (1H, d, J=3.4 Hz), 6.75-6.78 (3H, m), 6.89 (1 H, d. J=3.4 Hz), 7.1 (2H,d, J=8.5Hz)
147. /=\ 0-^-CH3 (^%^'-J N -CH2 ! OEt N(CH3): 394 | 20i
'H : 1.10-1.15 (3H, m), 2.23 (6H, s), 2.28-2.35 (2H, m), 2.43 (3H. s), 2.70-2.77 (2H, m), 3.40-3.55 (3H, m), 4.97 (2H, s), 6.93 (2H, d, J=8.28 Hz). 7.16 (2H, m), 7.42-7.44 (3H, m), 8.0-8.03 (3H, m)
148. i>iXN N^CH2 £f OEt NEtBoc j 494 64
'H : 0.8-1.2 (15H, m), 2.43 (3H, s), 2.65 (2H, m), 3.0 (1H, m), 3.28-3.37 (4H, m), 3.59 (2H, m), 4.97 (2H, s), 6.93 (2H, d, J=8.28 Hz), 7.16 (2H. m). 7.42-7.46 (3H, m), 8.0-8.03 (2H, m)
Preparation 16
N-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl [-propyl )-
acetamide(compound No 151)

To a solution of (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl)--propylamine (compound No. 134) ( 100 mg)
in dichloromethane (5 mL), triethylamine (53 mg) was added followed by acetic anhydride (40 mg) at 10 °C and stirred at the same temperature for 2 hours. The reaction mixture was poured in ice cold water and extracted with diethyl ether (3X50 mL). The combined organic extract was washed with water (50 mL), brine (50mL), dried over sodium sulfate and evaporated under reduced pressure to yield 70 mg of title compound.
81

ZRC-MC-009
Preparation 17
N-tertButoxy carbonyl-(2S)-ethoxy 3-(4-hydroxy-phenyl) -propylamine.(compound No
150).
0
J To a solution of 3-(4-Benzyloxy-phenyl)-N-tert butoxycarbonyl-(2S)-ethoxy-
propylamine.(compound 149) (10.7 g) in methanol (100 mL) were added a slurry of 10 %
palladium on charcoal (1.0 g) in methanol and ammonium formate (7.0 g) and the
mixture was refluxed in nitrogen atmosphere for 2 hours. Catalyst was filtered and the
filtrate was concentrated in vacuum. Water was added to the residue and extracted with
ethyl acetate (3 X 100 mL). The combined extract was washed with water (100 mL),
brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure to yield
8.0 g of title compound.
Preparation 18
N-tert-Butoxycarbonyl-(2S)-Ethoxy-3-[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]~
phenyl}- propyl amine (compound 152)

A mixture of 2-(5- methyl-2-phenyl-oxazol-4-yl)-ethyl methane sulfonate (1.0 g), N-tertbutoxy carbonyl-(2S)-ethoxy-3-(4-hydroxy-phenyl)-propylamine.(compound No 150) (1.0 g) and potassium carbonate (1.0 g) in dimethyl formamide (15 mL) was stirred at 75 °C for 16 hours. Reaction mixture was cooled to 25 °C, poured in to ice cold water and extracted with ethyl acetate (3 X 50 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silicagel using 7 % ethyl acetate in petroleum ether to yield 1.3 g of the title compound.
82

ZRC-MC-009
In like manner compounds in the table 9 were prepared following the procedure described in preparations 16-18 using suitable acylating agents.
Table 9:
FTO-Ar'
Gi

i Ex.
i No

R'

Ar

G,

G,

lol. Wt

% Yield




149.

CH-

OEt

NHBoc

385

61



150.

'H: 1.1 (3H,t, J=6.9Hz), 1.4 (9H, s), 2.6 (IH, dd, J=14.0 & 6.3 Hz), 2.7 (IH, dd.
J=I4.0 & 6.1 Hz), 3.0 (IH, m), 3.3 (IH, m), 3.4 - 3.5 (3H, m), 5.0 (211 s), 6.8
(2H, d, .1=8.6 Hz), 7.1 (2H, d, J=8.6 Hz), 7.3 - 7.4 (5H, m).
96
OEt
295
H
NHBoc

I
'H: 1.1 (3H, t, J=6.4 Hz), 1.4 (9H, s), 2.6 (IH, dd, J=13.8 & 6.8 Hz), 2.7 (IH, dd. J=I3.8 & 6.7 Hz), 3.0 (IH, m), 3.3 (IH, m), 3.4 - 3.5 (3H, m), 6.7 (2H, d, J=8.3 Hz), 7.0 (2H, d, J=8.3 Hz).


CH2
151.

,0^/CH3
K

OEt

NHCOCH

3

422

64

'H: 1.1 (3H, t, J=7.0 Hz), 1.9 (3H, s), 2.3 (3H, s), 2.6 (2H, m), 2.9 (2H, t, J=6.7 Hz), 3.1 (IH, m), 3.5 (4H, m), 4.2 (2H. t. .1=6.7 Hz), 6.8 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.5 Hz), 7.4 (3H, m), 8.0 (2H, dd, J=7.9 & 2.3 Hz).


...CH,
52.

OEt

NHBoc

480 j 83



153.

'H: 1.1 (3H, t, J=7.0 Hz), 1.4 (9H, s), 2.37 (3H, s), 2.6 - 2.8 (2H, m), 2.95 (2H, t. .1=6.7 Hz), 3.0 (Hi, m), 3.3 (IH, m), 3.4-3.6 (3H, complex), 4.2 (2H, t, J=6.7 Hz), 6.8 (2H, d, J=8.6 Hz), 7.1 (2H, d, J=8.6 Hz), 7.4 (3H, m), 7.9 (2H, m).
64
514
OEt
NHCbz


k

OEt

NHBoc

472

73

2H, d, J=8.5 Hz).
83

ZRC-MC-009

155. XX OEt 1 NHBoc j 428|1 1 76
i i 'H: 1.13 (3H, t, J=6.99 Hz), 1.24 (3H, t, J=7.62 Hz), 1.43 (9H, s), 2.64 (2H, q , J=7.62 Hz), 2.72-3.3 (2H, m), 3.21 (2H, t , J=6.69 Hz), 3.44-3.50 (3H, m), 4.31 (2H, t , J=6.68 Hz), 4.81 (IH, broad-s), 6.82 (2H, d . .1=8.61 Hz), 7.06 (2H, d , J=8.61 Hz), 7.18 (IH, d , .1=7.89 Hz), 7.43-7.46 (IH, m), S.38 (IH, d , .1=2.01 Hz).
| 156.j cKH: XXX OEt NHBoc 466 55
'H- 1.13 (3H, t, J=6.9 Hz), 1.4 ( (IH, m), 3.2-3.5 (4H, m), 4.9 (21 Hz), 7.42-7.47 (3H, m), 8.0-8.03 9H, s), 2.43 (3H, s), 2.6-2.S (2H, m), 3.02-3.04 4, s), 6.93 (2H, d, .1=8.6 Hz). 7.12 (2H, d, J=8.6 (2H, m).
157. r=\ /°YCH3 XX OEt NHCOCF3 ! 4621 83
'H : 1.18 (3H, t, J=6.99 Hz), 2.43 (3H, s), 2.6-2.9 (2H, m), 3.15 (IH, m), 3.4-3.6 (4H, m), 4.97 (2H , s), 6.95 (2H, d, .1=8.64 Hz), 7.10 (2H, d. J=8.61 Hz), 7.41-7.46 (3H, m), 8.0-8.3 (2H, m)
158. €KI:I XT OEt NHCOOEt 438 55
'H: 1.14 (3H, t, J=6.99Hz), 1.23 dd, J=6.39&6.15 Hz), 3.42-3.45 4.97 (2H,s), 6.94 (2H,d,J=8.63 (3H, t, J=6.63 Hz), 2.43 (3H, s), 2.68-2 (IH, m), 3.46-3.52 (4H, m). 4.07-4.15 ■iz), 7.12 (2H, d, J=8.58 Hz). 7.42-8.03 ( .77 (2H, ;2H, m), 5H, m)
159. rwYCH3 Xf OEt NHCbz 500 42
'H : 1.12 (3H, t, 2.8-3.3 (IH , m) J=8.46Hz), 7.12 J=6.99 Hz), 2.43 (3H, s), 2.67-2.77 (2H, dd. J=6.39&6.06 Hz), , 3.40-3.53 (4H, m), 4.96 (2H, s). 5.10 (2H, s), 6.93 (2R d, (2H, d, J=8.4 Hz), 7.26-8.03 (10H, m).
160. CKX;I Xf OEt NHCOCH3 408 37
'H : 1.2 (3H, t, J=6.9Hz), 2.1 (31 (IH, m), 3.45-3.53 (4H, m), 4.97 7.12(2H,d,J=8.58 Hz), 7.42-7.4 H, s), 2.43 (3H, s), 2.69-2.77 (2H, m), 2.78-3.44 (2H, s), 5.73 (IH, s), 6.93 (2H, d, J=8.61 Hz), 5 (3H, in), 8.00-8.03 (2H, m)
Preparation 19
(2S)-Ethoxy-l-ethylsulfanyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propane.(compound No 161)
84

ZRC-MC-009
To a stirred mixture of sodium metal (150 mg) and ethanethiol (0.49 mL) in tetrahydro furan (10 mL) was added a solution of (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[-propyl- methanesulfonate (compound No 91) (0.6 g), in 5 mL of tetrahydrofuran dropwise over a period of 10 minutes and the reaction mixture was stirred at ambient temperature for 15 hours. Reaction mixture was poured in to ice cold water and extracted with ethyl acetate (3 X 50 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silica gel using 10-15 % ethyl acetate in petroleum ether as eluent to yield 420 mg of the title compound.
Preparation 20
(2S)-Ethoxy-l-ethyl sulfonyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propane. (compound No 162)
0-/CH3 (^y~Y~°^
O^K/-.0Aj OE, 6
To an ice cold solution of (2S)-Ethoxy-l-ethyl sulfanyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propane.(compound No 161) (250 mg) in acetone (10 mL), oxone (900 mg) was added and the reaction mixture was stirred at the same temperature for 2 hours. Solvent was evaporated under reduced pressure, residue was added to water and extracted with ethyl acetate (3 X 50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and evaporated under reduced pressure. Crude product was chromatographed over silicagel using 15 % ethyl acetate in petroleum ether as eluent to yield 85 mg of title compound.
Preparation 21
(3S)-Ethoxy-4-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-butyronitrile.(Compound. No. 165)
85

ZRC-MC-009



NaCN (0.247 g) was added to a solution of (2S)-Ethoxy-3-,4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy]-phenyl}-propyl-methane sulfonate (1.5 g) in DMF(7.5 mL) at 20-
30 C. The reaction mixture was stirred at 85-90 C for 18 hours. Reaction mixture was poured in to water (20 mL) and product was extracted with ethyl acetate (2 x 20 mL). Combined extract was washed with water (2 x 40 mL), brine (40 mL) dried over sodium sulfate and evaporated under reduced pressure to yield 1.2 g of title compound.
Preparation 22
(2S)-Ethoxy-lH-tetrazole-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propane. (Compound. No. 166)

-N Ph (Bu)3SnN3 (L27 g) was added to (3S)-Ethoxy-4-[4-(5-methyl-2-phenyl-oxazol-4-
ylmethoxy)-phenyl]-butyronitrile (Compound. No. 165) (1.2 g) in xylene (15 mL) at 20-30
UC. The reaction was stirred at reflux temp, for 18 h. The reaction was cooled to 20-30
°C. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 10 % HCI
(20 mL), water (3 x 25 mL), brine (25 mL), organic layer was dried over sodium sulfate
and evaporated under reduced pressure to yield the crude title compound (1.1 g). Crude
product was chromatographed over silicagel using pet.ether:ethyl acetate (9:1) as an
eluent to afford pure product 700 mg in 52 % yield.
In like manner compounds in the table 10 were prepared following the procedure
described in preparations 19-22 using suitable acylating agents.
86

ZRC-MC-009
Table 10:
R10-Ar
G,


Ex. No

R'
•°~V
A

CH3
-CH,

Ar

OEt

SEt

Mol.Wt
425

% Yield
76



162.

'H: 1.13 (3H, t, J=6.9 Hz), 1.2 (3H, t, J=7.45 Hz), 2.37 (3H, s), 2.58 (4H, m), 2.8 (2H, t, J=7.12 Hz), 2.97 (2H, t, J=6.69 Hz), 3.41 (IH, m), 3.53 (2H, dd, J=6.6 & 2.72 Hz), 4.22 (2H, t, J=6.57 Hz), 6.81 (2H, d, J=8.28 Hz), 7.11 (2H, d, J=8.46 Hz), 7.43 (3H, m), 7.97 (2H, dd, J=6.67 & 2.28 Hz).
457
32
OEt
S(0)2Er
r^
orCH3
'\^,CH2

'H: 1.21 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.47 Hz), 2.39 (3H, s), 2.7 (IH, dd, J=13.9 & 7.15 Hz), 2.88 (7H,complex), 3.6 (2H, m), 4.0 (IH, m), 4.23 (2H, t, .1=6.48 Hz), 6.83 (2H, d, J=8.58 Hz), 7.0 (2H, d, J=8.5 Hz), 7.44 (3H, m), 8.0 (2H.

87

ZRC-MC-009

166. ^ /=\ /°YCH3 XX OEt HN N 419 97
'H: 1.22-1.56 (3H, m), 2.45 (3H, s), 3.02-3.04 (3H, m), 3.17 (1H, d 3.50 (1 H, d, .1=6.99 Hz), 3.71 (2H, m), 4.98 (2H, s), 6.96 (2H. d. J= (2H, d, J=8.64 Hz), 7.42 -7.45 (3H, m), 8.0-8.03 (2H, m) , J=3.75 Hz), 8.67 Hz), 7.07
Preparation 23
Bisulphate salt of 2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyi-oxazol-4-yl)-ethoxy]-phenyl
propyl amine (compound.No.167)


NH2 .H0SO4

To (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl [-propyl amine. (compound.No.134) (300 mg), a chilled solution of acetone (3 mL) containing sulfuric acid (77 mg) was added and stirred at 0 °C for 30 minutes. Solvent was evaporated under a flow of nitrogen and the residue was stirred with diisopropyl ether to afford product (138 mg).
Preparation 24
Oxalic acid salt of (2S)-Ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl methoxyl-phenyl}-
propylamine (compound. No. 173)


COOH COOH

To a solution of (2S)-Ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl methoxy]-phenyl}-propylamine (compound No 141) (200 mg), in isopropyl alcohol (5 mL), oxalic acid dihydrate (64 mg) was added and stirred at 28 °C for 30 minutes. Solid separated was filtered and dried to afford the title compound (140 mg).

ZRC-MC-009
In like manner compounds in the table 11 were prepared following the procedure described for the preparation of 23-24.
Table II:

Compound No. Free-base No. Salt prepared Melting Point (°C)*
167. 134 H2S04 175
168. 137 Oxalic acid 115
169. 138 Oxalic acid •122
170. 136 Oxalic acid 193
171. 124 Oxalic acid 150-160
172. 71 Oxalic acid 190
173. 141 Oxalic acid 135
174. 141 H2S04 90
175. 146 Oxalic acid 117
176. 143 Oxalic acid 134
177. 144 Oxalic acid 111i
178. 145 Oxalic acid 126
15 The melting points were uncorrected and may vary in the range of ±_4 C.
The compounds of the present invention lowered triglyceride, total cholesterol, LDL. VLDL and increased HDL and lowered serum glucose levels. This was demonstrated by in vivo animal experiments.
A) Demonstration of in vivo efficacy of compounds:
i) Serum triglyceride and total cholesterol lowering activity in Swiss albino
mice:
89

ZRC-MC-009
Male Swiss albino mice (SAM) were bred in Zydus animal house. All these animals were maintained under 12 hour light and dark cycle at 25±1 °C. Animals were given standard laboratory chow (NIN, Hyderabad, India) and water ad libitum. SAM of 20-30 g body weight range were used.
The test compounds were administered orally to Swiss albino mice at 0.001 to 50 nig / kg/ day dose for 6 days. The compound was administered after suspending it in 0.25 % CMC or dissolving it in water, when compound is water-soluble. Control mice were treated with vehicle (0.25% of Carboxymethylcellulose; dose 10 ml/kg).
The blood samples were collected on 0th day and in fed state 1 hour after drug administration on 6th day of the treatment. The blood was collected in non "heparinised capillary and the serum was analyzed for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H., O., Ed., 1963. 211-214; Trinder, P. Ann. Clin. Biochem. 1969. 6: 24-27). Measurement of serum triglyceride and total cholesterol was done using commercial kits (Zydus-Cadila, Pathline, Ahmedabad, India). Formula for calculation :
Percentage reduction in triglycerides/total cholesterol were calculated according to the formula :
Percentage reduction (%) =


OC = Zero day control group value OT = Zero day treated group value TC = Test day control group TT = Test day treated group
Table
Triglyceride lowering activity in Swiss albino mice:

Example No. Dose(mg/kg/day) % Triglyceride lowering
110 3 78
134 3 54
90

ZRC-MC-009

130 3 51
80 3 50
28 3 78
ii) Cholesterol, lowering activity in hypercholesterolemic rat models
Male Sprague Dawley rats stock bred in Zydus animal house were maintained under 12 hour light and dark cycle at 25±1 °C. Rats of 100-150 g body weight range were used for the experiment. Animals were made hypercholesterolemic by feeding 1 % cholesterol and 0.5 % sodium cholate mixed with standard laboratory chow (NIN, Hyderabad, India) and water ad libitum for 5 days. The animals were maintained on the same diet throughout the experiment [Petit D.. Bonnefis M. T., Rey C and Infante R., Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normal and hyperlipidemic rats, Atherosclerosis, 74, 215-225(1988)].
The test compounds were administered orally at a dose 0.03 to 50 mg/ kg/ day for 4 days, after suspending it in 0.25 % CMC or dissolving it in water when compound is water-soluble. Control group was treated with vehicle alone (0.25% of Carboxymethylcellulose; dose 10 ml/kg).
The blood samples were collected in fed state on 0th and I hour after drug administration on 6th day of the treatment. The blood was collected from the retro-orbital sinus through non-heparinised capillary and the serum samples were analyzed for triglyceride and total cholesterol using commercial kits (Zydus-Cadila, Pathline, Ahmedabad, India). LDL and HDL by commercial kits (Point Scientific, USA). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride.
The reduction in VLDL cholesterol is calculated according to the formula. VLDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - LDL cholesterol
91

ZRC-MC-009
Table 2:

Example No. Dose (mg/kg/day) Total cholesterol reduction (%)
141 3 61
90 3 56
27 3 44
iii) Serum glucose lowering activity in db/db mice models
Homozygous animal CsyBL/KsJ-db/db mice are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., 85, 962-967, 1990), whereas heterozygous are lean and normoglycemic. The homozygous animals very closely mimic the human type II diabetes when blood sugar levels are not sufficiently controlled. Since this type of model resembles human type II diabetes mellitus, the compounds of the invention were tested for their antidiabetic activity in this model.
The compounds of the present invention showed serum glucose and triglycerides lowering activities.
Male Cs? BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 40 to 60 grams, procured from the Jackson Laboratory, USA, were used in the experiment.
Test compounds were suspended on 0.25% carboxymethyl cellulose or dissolved in water when the compound is water soluble and administered to test group containing 6 animals at a dose of 0.001 mg to 50 mg/kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml/kg). On the 6th day, one hour after the drug dosing, blood was collected from retro-orbital sinus and the serum was analyzed for glucose and triglycerides were measured using commercial kits (Zydus-Cadila, Pathline, Ahmedabad, India). The serum glucose and triglyceride lowering activities of the test compound was calculated according of the formula: Serum glucose lowering activity (%) =



92

ZRC-MC-009
OC = Zero day control group value OT = Zero day treated group value
TC = Test day control group TT = Test day treated group

Example No. Dose (mg/kg/day) Serum Glucose reduction (%) Plasma TG reduction (%)
84 3 47. 47 -
64 3 56 74
44 3 61 44
No adverse effects were observed for any of the mentioned compounds of invention. The compounds of the present invention showed good serum glucose, lipid and cholesterol lowering activity in the experimental animals used. These compounds are useful for the testing / prophylaxis of diseases caused by hyperlipidemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia such as NIDDM, cardiovascular diseases, stroke, hypertension, obesity since such diseases are interlinked to each other.
93

ZRC-MC-009
We claim:
1. A compound of the general formula (I),
A-(CH2)n-X-Ar^Y^G2
G, (I)
.their, derivatives, their analogs, their tautomeric forms, their stereoisomers, their
pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein
A represents a substituted or unsubstituted, group selected from aryl, heteroaryl,
heterocyclyl groups; 'n' is an integer from 1-3, with the proviso that .when A is
substituted or unsubstituted phenyl group, then Ar does not represent a divalent phenyl
group; 'X' represents oxygen or sulfur;
'Ar' represents a substituted or unsubstituted single or fused divalent aromatic,
heteroaromatic or a heterocyclic group;
d and G2 may be same or different and independently represent NR1R2, OR|, SR|,
S(0)R3. S(0)2R3. N3, CN, COOH, tetrazolyl groups; R, & R2 may be same or different and
independently represent hydrogen, substituted or unsubstituted groups selected from
linear or branched (Ci-Cx)alkyl, (C3-C7)cycloalkyl, acyl, aryl, heteroaryl, heterocyclyl,
aminocarbonyl, aralkyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,
heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, heterocyclylaminocarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,
heteroaraloxycarbonyl, heterocycloxycarbonyl groups or SO2R3 wherein R3 represents
substituted or unsubstituted groups selected from alkyl, aryl, polyhaloalkyl, heterocyclyl,
heteroaryl groups; G3 represents hydrogen or (Ci-Cs)alkyl or (C3-Cv)cycloalkyl groups.
2. A compound as claimed in claim 1 wherein the substitutents on 'A', R\, R2 & R3
may be same or different and are independently selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, guanidino, hydrazine alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl,
94

ZRC-MC-009
heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy,
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, arylthio, alkylsulfonylamino,
alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino,
aralkyloxycarbonylamino aminocarbohylamino, alkylaminocarbonylamino,
alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid 'and its 0derivatives, phosphonic acid and its derivatives.
3. A compound as claimed in claim 1 wherein, suitable substituents on any
substituent of 'A' may be same or different and are independently selected from
hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted
groups selected from amidino, guanidino, hydrazino, alkyl, haloalkyl, perhaloalkyl,
alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, heterocyclyloxy, 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,
arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino,
aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino,
alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl
derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
4. A compound as claimed in claim 1 wherein 'Ar' represents a substituted or
unsubstituted single or fused aromatic or heteroaromatic or heterocyclic group.
5. A compound according to claim 1, wherein the substituents on the group represented by 'Ar' represents substituted or unsubstituted linear or branched alkyl, alkoxy, thioalkyl, halogen, haloalkyl, haloalkoxy, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives, phosphonic acid and their derivatives.
6. The compounds as claimed in claim 1, selected from
95

ZRC-M.C-009
3-(6-Benzyloxy-naphthalen-2-yl)-2-ethoxy-propan-l-o];
(2S)-Ethoxy-3- {4-[2-(5-methyl-.2-phenyl-oxazol-4-yl)-ethoxy]-phenyl ^-propan-1 -ol;
(2S)-Ethoxy-3-{4-(4-hydroxy-3-methyl-3,4-dihydro-quinazolin-2yl-methoxy)-phenyl|'-
propan-l-ol;
2-Hydroxy-3- |4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl)-propan-l-ol;
3-!4-[2-(2,3-Dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propan-l-o];
(2S)-Ethoxy-3-[4-(2--(phenoxazin-10-yl)-ethoxy)-phenyl]-propan-l-ol;
3-[4-(2-(Carbazol-9-yl)-ethoxy)-phenyl]-(2S)-ethoxy-propan-l-ol;
3-{4-[2-(3,4-Dihydro-21-l-quinolin-l-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propan-l-ol;
(2S)-Ethoxy-3-[4-(2-(indol-l-yl)-ethoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-[4-(2-(phenothiazin-10-yl)-ethoxy)-phenyl]-propan-l-ol;
3-|4-[2-(2,3-Dihydro-benzo[ 1,4]oxazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propan-1-ol;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenylsulfanyl-propan-l-ol;
(2S)-Ethoxy-3-!4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propan-l-ol and its
pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propan-l-ol and its
pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-[4-r2-(5-methy!-2-thiophen-2-yl-oxazol-4-yl')-ethoxy]-phenyl [-propan-1 -
ol;
(2S)-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethoxy]-
phenyl)-propan-l-ol;
(3S)-Ethoxy-4-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-butan-l-ol;
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(4-methylsulfanyl-phenyl)-oxazol-4-yl]-ethoxy}-
phenyl)-propan-l-ol;
(2S)-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propan-l-ol and
its pharmaceutically acceptable salts;
(2S)-tert-butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)-phenyl]-
propan-1-ol;
(2S)-tert-butoxycarbonylamino-3-{4-[2- (5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
phenyl}-propan-l-ol;
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ZRC-MC-009
(2S)-Ethoxy-3-(4-(2-[2-methyl-5-( benzofuran-2-yl)-pyrrol-l-yl]-ethoxy}-phenyl)-
propan-1-ol;
(2S)-Ethoxy-3-(4-{2-[2-methyl-5-(benzo[I,3]dioxol-5-yl)-pyrrol-l-yl]-ethoxy}-phenyl)-
propan-1-ol;
(2S)-Ethoxy-3-[4-(l-methyl-1 H-benzoimidazol-2-yl methoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-[4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-|4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-phenyl}-propan-l-ol:
(2S)-Ethoxy-3-[4-(2-benzoimidazol-l-yl-ethoxy)-phenyl]- propan-1-ol;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propan-l-ol;
(2S)-Ethoxy-3-(4-{2-[2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl]-ethoxy}-
phenyl)-propan-l-ol;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propan-l,2-diol;
l-Ethoxy-(2S)-ethoxy-3-[4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy}-phenyl]-
propane;
2-((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-
ethanol;
2-((2S)-Ethoxy-3--j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-
benzoic acid and its pharmaceutical!)' acceptable salts;
(2S)-Ethoxy-3-j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl J-propyl bromo
acetate;
l-Ethoxy-(2S)-ethoxy-3-[4-{2-(-3,4-Dihydro-2H-benzo[l,4]thiazin-lyl) ethoxy}phenyl]-
propane;
l-Propoxy-(2S)-ethoxy-3-[4-{2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy}-phenyl]-
propane;
2-((2S)-Ethoxy-3-[4-(5-methyl-2-phenyi-oxazol-4-ylmethoxy)-phenyl]-propoxy)-benzoic acid and its pharmaceutically acceptable salts;
l-Ethoxy-(2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- propane; (2S)-Ethoxy-3-[4-(5-rnethyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-1 - phenoxy propane; (2S)-Ethoxy-l-ethyl sulfinyl-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-propane;
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ZRC-MC-009
(2S)-Ethoxy-1 -ethyl sulfanyl--3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl[-
propane;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-l-isopropoxy
propane;
(3S)-Ethoxy-4-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-butyronitrile;
(2S)-Ethoxy-lH-tetrazole-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propane;-
2-Ethoxy-!-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- pentane-3-ol;
2,3-Diethoxy-1 -[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- pentane;
2-Ethoxy-l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- pentane-3-ol;
2,3-Diethoxy-1-|4-[2-(5-methy!-2-phenyi-oxazol-4-yl)-ethoxy]-phenyl}- pentane;
((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propoxy)-acetic
acid and its pharmaceutically acceptable salts;.
3-(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl-methanesulfonate;
(2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl methane
sulfonate;
(2S)-Ethoxy-3-|4-[2-(2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl)-ethoxy]-
phenyl J -propyl-methane sulfonate;
(2S)-Ethoxy-3-j4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl!-propyl-methane
sulfonate;
(2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]}-propyl
methanesulfonate;
(2S)-ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- propyl methanesulfonate;
(2S)-Ethoxy-1-methoxy-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-
phenyl J-- propane;
l-Ethoxy-(2S)-ethoxy-3-(4-{2-[5-methyl-2-(4-methylsulfanyl-phenyl)-oxazol-4-yl]-
ethoxy}-phenyl)- propane;
i-Ethoxy-(2S)-ethoxy -3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-
propane;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-l-ethoxy
propane;
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ZRC-MC-009
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzofuran-2-y!-pyrrol-1 "yl)-ethoxy]-phenyl [-propyl-
methanesulfonate;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzo[!,3]dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl]-
propyl-methanesulfonate;
(2S)-Ethoxy-3--|4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yi)-ethoxy]-phenyl]-propyl-
(4-methyl phenyl)-sulfonate;
(2S)-Ethoxy-3-|4-[2-(2-methyl-5-benzo[ 1.3 "j dioxol - 5 -y j -pyrro 1 -1 -yl)-ethoxy]-phenyl | -
propyl-(4-methyl phenyl)-sulfonate;
l-Ethoxy-(2S)-ethoxy-3-[4-(i-methyl-lH-benzoimidazol-2-ylmethoxy)-phenyl]-
propane;
(2S)-Ethoxy-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-l-propoxy propane;
l-Ethoxy-(2S)-ethoxy-3-[4-(5-methyl-3-phenyl-isoxazol-4-yl methoxy)-phenyl]-
propane;
(2S)-tert-Butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propyl methanesulfonate;
(2S)-Ethoxy-3-{4-[2-(5-methy]-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl|-propyl amine and
its pharmaceutical^ acceptable salts;
(2S)-Ethoxy-3-[4-{3-methyl-3H-quinazolin-4-on-2yl methoxy}phenyl]propyl amine and
its pharmaceutically acceptable salts;
((2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[-propyl)-
isopropyl-amine and its pharmaceutical ly acceptable salts;
3-{4-[2-(2,3-Dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propyl amine
and its pharmaceutically acceptable salts;
3-(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl amine and its phannaceutically acceptable
salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propylamine
and its pharmaceutically acceptable salts.
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propylamine and its
pharmaceutically acceptable salts;
N-tert-Butoxycarbonyl-(2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
phenyl]-propyl amine;
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ZRC-MC-009
(2S)-Ethoxy-3--!4-[2-(2-methyl-5-(5-methyl-thiophen-2-yi)-pyrrol-l-yl)-ethoxy]-
phenyl}-propylamine and its pharmaceutically acceptable salts;
N-((2S)-Ethoxy-3-|4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl}-propyl)-methane
sulfonamide;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propylamine and its
pharmaceutically acceptable salts;
[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-ethyl -amine
and its pharmaceutically acceptable salts;
[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-isopropyl-
amine and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzo[l,3] dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl]--
propylamine and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yl)-ethoxyl-phenyl}-
propylamine and its pharmaceutically acceptable salts;
N-[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-2,2,2-
trifluoro-acetamide;
N-Ethoxycarbonyl-((2S)-ethoxy-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl|-
propyl)amine;
N-Benzyloxycarbonyl-((2S)-ethoxy-3-{4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
Phenyl]--propylamine;
N-[(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl]-
acetamide;
(2S)-Hydroxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl azide;
3-(4-Benzyloxy-phenyl)-(2S)-ethoxy-propyl azide;
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl azide;
(2S)-Ethoxy-3-|4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- propyl azide and its
pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]- propyl azide;
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-(5-methyl-thiophen-2-yl)-pyrrol-l-yl)-ethoxy]-
phenyl}- propyl azide;
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ZRC-MC-009
(2S)-Ethoxy-3-|4-f2-(5-ethyl-pyridine-2-yl)-2-(tert-butyldimethyl-silanyloxy)-ethoxy]-phenyl}-- propyl azide and its pharmaceutically acceptable salts; (2S)-Ethoxy-3-{4-[2-(5-ethyl-pyridine-2-yl)-2-hydroxy-ethoxy]-phenyl]- propyl azide and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-;4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl)- propyl azide and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]- propyl azide: (2S)-Ethoxy-3--|4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-propyl azide:
(2S)-Hydroxy-3-[4-(5-methyl-2-phenyl-oxazol-4-yl)-methoxy)-phenyl]- propyl azide; (2S)-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]- propyl azide and its pharmaceutically acceptable salts;
(2S)-Amino-3--|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-methoxy]-phenyl}- propyl azide and its pharmaceutically acceptable salts;
(2S)-tert-butoxycarbonylamino-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propyl azide:
(2S)-tert- butoxycarbonylamino -3-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)-phenyl]-propyl azide:
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzo[1.3]dioxol-5-yl-pyrrol-l-yl)-ethoxy]-phenyl}-propyl azide:
(2S)-Ethoxy-3-{4-[2-(2-methyl-5-benzofuran-2-yl-pyrrol-l-yl)-ethoxy]-phenyl}- propyl azide;
N-Benzyloxycarbonyl-(2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl[-propyl amine;
N-ten-Butoxycarbonyl-(2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-- propyl amine;
N-ten-Butoxycarbonyl-3-{4-[2-(2,3-dihydro-benzo[l,4]thiazin-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propyl amine;
N-((2S)-Ethoxy-3-|4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propyl)-acetamide; 3-(4-Benzyloxy-phenyl)- N-tert-butoxycarbonyl -(2S)-ethoxy-propyl amine;
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ZRC-MC-009
N-tert-Butoxycarbonyl -(2S)-ethoxy -3-(4-hydroxy-phenyl)- -propyl amine;
N-tert-Butoxycarbonyl-(2S)-ethoxy-3- !4-[2-(5-ethyl-pyridin-2-yi)-ethoxy]-phenyl[-
propyl amine;
(2S)-Ethoxy-1 -ethylsulfanyl-3- !4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propane;
(2S)-Ethoxy-l-ethylsulfonyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propane;
7. A process for the preparation of compounds of formula (I) as claimed in claim 1.
comprising any of the steps below alone or in combination:
a)

(la)
i. converting a compound of formula (III) to a compound of formula (la)
^ A-(CH2)n-X-Ar
A-(CH2)n-X-A.-^v^R4
(IM) G,

G,

OH

ii. converting the compound of formula (la) obtained above to compounds of formula (lb), if desired

A-(CH2)„-X-Ar
da) G|

^OH

A- (C H 2)n-X-A r^^Y^OR, (lb) G,

iii. converting the compound of formula (lb) obtained above to compounds of formula (lc), if desired

A-(CH2)n-X-A. y^OR,
(lb) G,

_^ A-(CH2),-X-Ar^^SRi
.. . G,

iv. converting the compound of formula (lb) obtained above to compounds of formula (Id), if desired

A-(CH2),-X-A.-^Y^OR1 (lb) G,

-*- A-(CH2),-X-Ar-^Y^N3
(Id) G,

102

ZRC-MC-009
v. converting the compound of formula (lb) obtained above to compounds of formula (le), if desired
A-(CH2)n-X-Ar'-N/^OR1 ^ A-fCH^-X-Ar^y^cM
(lb) G, (|e) G,

b)
i. converting the compound of formula (III) to compounds of formula (If)
0
A-(CH2)-X-Ar-^Y^R4 *- A-(CH2)n-X-Ar^Y^NH2
(III) G, (If) - G|
ii. converting compound of formula (If) obtained above to compound of formula (lg), if desired
A-(CH2)n-X-Ar^/^NH2 ► A-(CH2)n-X-Ar^Y^NRlR
(If) G| Gl
tir) (ig)
in. alternatively, converting compound of formula (Id) obtained above, to compound of formula (If), if desired

2

A-(CH2)n-X-Ar^V^N, — -► A-(CH2)„-X-Ar^N^s*NH
~i
(If)
G, „« Gi
(Id)

wherein compounds of formula (lb), (lc), (Id), (le), (If) & (lg) all represent compounds of formula (I) where A, X, Ar, Gi, R|, R2 are as defined in claim 1 and G2 represents OH, OR1, SR1, N3, CN, NH2, NR1R2 respectively.
8. A process for the preparation of compound of formula (I), as claimed in claim 1,
comprising any of the steps below alone or in combination:
i. reacting a compound of formula (IV), with compounds of formula (V)
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ZRC-MC-009
A-(CH2)n— L + HX-Ar-' y G2 ^
Gi
(IV) (V)
ii. reacting a compound of formula (IV) with compound of formula (Va) to obtain compound of formula (Ig)
A-(CH2)-L + HX-Ai^~Y^NRiR2 _ ^ A-(C'H:),--X-AI"^Y^NR.R2
(IV) (Va) Gl (Ig) G|

iii. reacting a compound of formula (IV) with compound of formula (Vb) to obtain compound of formula (lb)
A-(CH2)-L + HX-Ar-y/^QR! ► A-(CH2)|-X-Ar-'\^oR1
(IV) (Vb) Gi (lb) G'
iv. converting the compound of formula (lb) to compound of formula (la)
A-(CH2)n-X-Ar^s^0Ri ^ A-(CH,),-X-Ar
(lb)
G,

wherein compounds of formula (lb), (la), (It) all represent compounds of formula (I) where A, X, Ar, d, R|, R2 are as defined in claim 1. ;L"' represents a leaving group selected from halogen, mesylate, tosylate & triflate and Gi represents OH, OR1, NR1R2, .
9. Novel compounds of formula (Ilia), their derivatives, their analogs, their
tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein 'A' represents 4-oxazolyl group substituted with one or two substitutents selected from substituted or unsubstituted linear or branched (C1-C12)alkyl, substituted or unsubstituted single or fused heteroaryl or heterocyclic groups; 'Ar' represents unsubstituted phenyl; Gi represents OR| or SR| where R| represents hydrogen, perfluoro(C1-C12)alkyl, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, cyclo(C|-Ci?)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, -heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl,
104

ZRC-MC-009

arylaminocarbonyl or acyl groups; R4 represents OH, alkoxy or aryloxy, aralkoxy or
NR1R2 groups, where R| & R7 may be same or different and independently represent
hydrogen, substituted or unsubstituted groups selected from linear or branched (C1-
C8)alkyl, (C3-C7)cycloalkyl, acyl, aryl, heteroaryl, heterocyclyl, aminocarbonyl, aralkyl,
alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,
heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonyl, . aryloxycarbonyl, aralkyloxycarbonyl, . heteroaryloxycarbonyl, heteroaraloxycarbonyl, heterocycloxycarbonyl groups or SO2R3 wherein R3 represents substituted or unsubstituted groups selected from alkyl, aryl, polyhaloalkyl, heterocyclyl, heteroaryl groups; 'n' is an integer from 1-3; X represents 0 or S,
0
A-(CH2),-X-Ar
G, (Ilia)
10. The compounds as claimed in claim 9, wherein the substitutions on the substituents on 'A' are selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, guanidino, hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, 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. arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
11. The compounds of claim 9 selected from
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-
105

ZRC-MC-009
propanoate;
Ethyl (2S)-ethoxy-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate;
Ethyl (2S)-ethoxy-3-(4-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl} -propanoate;
Ethyl (2S)-ethoxy-3-(4- {2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate; - ' .
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl }-propanoate;
Ethyl (2S)-ethoxy-3-(4-{2-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-thiophen-3-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate;
Ethyl (2S)-ethoxy-3-|4-[2-(5-methyl-2-thiophen-3-yl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate;
Ethyl 3-[4-(2-benzo[b]thiophen-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-(2S)-
ethoxy-propanoate;
Ethyl 3-{4-[2-(2-benzo[b]thiophen-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-(2S)-
ethoxy- propanoate;
Ethyl (2S)-ethoxy-3-[4-(2-furan-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-propanoate;
Ethyl (2S)-ethoxy-3-{4-[2-(2-furan-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-quinolin-2-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate and its pharmaceutically acceptable salts;
Ethyl (2S)-ethoxy-3-|4-[2-(5-methyl-2-quinolin-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoate and its pharmaceutical ly acceptable salts;
Ethyl (2S)-ethoxy-3-{4-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-propoxy]-phenyl}-
propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-
phenyl} -propanoate;
Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-ylmethoxy]-
106

ZRC-MC-009
phenyl }-propanoate;
Ethyl (2S)-ethoxy-3-!4-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-ylmethoxy-
Phenyl)-propanoate;
Ethyl (2S)-ethoxy-3- |4-[5-methyl-2-(5-methyl-furan-2-yl)-oxazol-4-ylmethoxy]-
phenyl j-propanoate;
Ethyl (2S)-ethoxy-3-(4- |2-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-(4- j2-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxa/.ol-4-yr]-ethoxy;^-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-(4-{2-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoate;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-pyridin-2-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate and its pharmaceutical^ acceptable salts;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-pyridin-4-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate and its pharmaceutical^ acceptable salts;
Ethyl (2S)-ethoxy-3-[4-{2-(5-methyl-2-pyridin-3-yl-oxazol-4-yl)-ethoxy|--phenyl]-
propanoate and its pharmaceutically acceptable salts;
Ethyl (2S)-ethoxy-3-[4-(5-methyl-2-pyridin-3-yl-oxazol-4-ylmethoxy)-phenyl]-
propanoate and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methy!-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3--|4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl|' -propanoic
acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl}-
propanoic acid and us pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-|2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy[-
phenyl)-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl}-
propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(3-methyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-
phenyl)-propanoic acid and its pharmaceutically acceptable salts;
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(2S)-Ethoxy-3-[4-(5-methyl-2-thiophen-3-yl-oxazol-4-ylmethoxy)-phenyl]-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-[2-(5-methyl-2-thiophen-3-yl-oxazol-4-yl)-ethoxy]-phenyl}-propanoic acid and its pharmaceutically acceptable salts;
3-[4-(2-Benzo[b]thiophen-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]- (2S)-ethoxy-propanoic acid and its pharmaceutically acceptable salts;
3-{4-[2-(2-Benzo[b].thiophen-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-(2S)-ethoxy-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(2-furan-2-yl-5-methyl-oxazol-4-ylmethoxy)-phenyl]-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3--|4-[2-(2-furan-2-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-[4-(5-methyl-2-quinolin-2-yl-oxazol-4-ylmethoxy)-phenyl]-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[2-(5-methyl-2-quinolin-2-yl-oxazol-4-yl)-ethoxy]-phenyl| -propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-propoxy]-phenyl}-propanoic acid and its pharmaceutically acceptable salts; (2S)-Ethoxy-3-{4-[5-methyl-2-Benzofuran-2-yl)-oxazol-4-ylmethoxy]-phenyl propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl|-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-{4-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-ylmethoxy]-phenyl}-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-|4-[5-methyl-2-(5-methyl-furan-2-yl)-oxazol-4-ylmethoxy]-phenyl;-propanoic acid and its pharmaceutically acceptable salts;
(2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-phenyl-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-phenyl)- propanoic acid and its pharmaceutically acceptable salts; (2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-chloro-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-phenyl)- propanoic acid and its pharmaceutically acceptable salts;
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(2S)-Ethoxy-3-(4--!2-[5-methyl-2-(5-bromo-thiophen-2-yl)-oxazol-4-yl]-ethoxy}-phenyl)- propanoic acid and its pharmaceutically acceptable salts; (2S)-Ethoxy-3-(4-{2-[5-methyl-2-(5-methyl-furan-2-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propanoic acid and its pharmaceutically acceptable salts;
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-2-yl-oxazol-4-ylmethoxy)-phenyl]- propanoic acid and its pharmaceutically acceptable salts;
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-;4-yr-oxazol-4-ylmethoxy)-phenyl]- propanoic acid and its pharmaceutically acceptable salts;
2(S)-Ethoxy-3-[4-(5-methyl-2-pyridin-3-yl-oxazol-4-ylmethoxy)-phenyl]- propanoic acid and its pharmaceutically acceptable salts;
12. The compounds as claimed in claims 9-11, suitable as intermediates for the preparation of compounds of formula (I).
13. A process for the preparation of compound of formula (Ilia) as claimed in claims 9-11 comprising
i. reacting a compound of formula (IVa) wherein 'A' represents 4-oxazolyl group
substituted with one or two substitutents selected from substituted or unsubstituted linear
or branched (C1-C12)alkyl, substituted or unsubstituted single or fused heteroaryl or
heterocyclic groups; 'n' is an integer from 1-3; & 'L' represents a leaving group selected
from halogen, mesylate, tosylate & triflate, with a compound of formula (Vc) wherein X
represents oxygen or sulfur; 'Ar' represents unsubstituted phenyl; d represents OR1 or
SR1. where R| represents hydrogen, perfluoro(C1-C12)alkyl. substituted or unsubstituted
groups selected from linear or branched (C1-C12)alkyl, cyclo(C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl,
alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl,
arylaminocarbonyl or acyl groups; R4 represents OH, alkoxy or aryloxy, aralkoxy or
NR1R; groups, where R| & R2 may be same or different and independently represent
hydrogen, substituted or unsubstituted groups selected from linear or branched (C|-
C«)alkyl, (C:,-C7)cycloalkyl, acyl, aryl, heteroaryl, heterocyclyl, aminocarbonyl, aralkyl,
alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,
heteroarylaminocarbonyl, heteroaralkylaminbcarbonyl, heterocyclylaminocarbonyl,
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ZRC-MC-009

alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaraloxycarbonyl, heterocycloxycarbonyl groups or SO2R3 wherein R3 represents substituted or unsubstituted groups selected from alkyl, aryl, polyhaloalkyl, heterocyclyl, heteroaryl groups.
0
0 0
^X
A—(CH2)n—L +■ HX-Ar/^y^R4 . A_(CH2)n_X-Ar
-:' ■ • "&,-•' .-;■-■■-'■-
(Ilia)
(IVa) (Vc)
ii. optionally hydrolysing the compound of formula (Ilia) wherein R4 represents alkoxy, aryloxy, aralkoxy or NR1R2 groups, where R| & R2 are as defined earlier, to a further compound of formula (Ilia) wherein R4 represents OH.
14. A pharmaceutical composition which comprises compounds of formula (I) or (Ilia), as claimed in any preceding claims and a pharmaceutically acceptable carrier, diluent, excipients or solvate.
15. A pharmaceutical composition according to claim 14, in the form of a tablet, capsule, powder, granule, syrup, solution or suspension.
16. A pharmaceutical composition according to claim 14 or 15, in combination with sulfonyl urea, biguanide, angiotensin II inhibitor, aspirin, a-glycosidase inhibitor, insulin secretagogue, insulin, P-sitosterol inhibitor, HMG CoA reductase inhibitor, fibrate, nicotinic acid, cholestyramine, cholestipol or probucol, which may be administered together or within such a period as to act synergistically together to a patient in need thereof.
17. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma, while optionally elevating HDL cholesterol levels comprises administering a compound of formula (I) or (Ilia), as defined in any preceding claims from 1-14, and a pharmaceutically acceptable carrier, diluent, excipients or solvate to a patient in need thereof.
18. A method according to claim 17, wherein the compounds of formula (I) or (Ilia) is given in combination with HMG CoA reductase inhibitor, fibrate, nicotinic acid,
110

ZRC-M.C-009
cholestyramine, cholestipol or probucol, which may be administered together or within such a period as to act synergistically together to a patient in need thereof.
19. A method of reducing blood glucose, triglycerides, cholesterol, or free fatty acids in the plasma, comprising administering a compound as defined in any preceding claims and a pharmaceutically acceptable carrier, diluent or excipients or solvate to a patient in need thereof.
20. A method of preventing or treating diseases caused by hyperlipidaemia. hypercholesteremia, hyperglycemia, obesity, impaired glucose tolerance, leptin resistance, insulin resistance, diabetic complications, comprising administering an effective, non-toxic amount of compound of formula (I) or (Ilia) as defined in any preceding claims to a patient in need thereof.
21. A method of treating diseases wherein insulin resistance is the underlying pathophysiological mechanism, which includes type 2 diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, obesity, atherosclerosis, hyperlipidaemia, coronary artery disease, cardiovascular disorders, renal diseases, microalbuminuria, glomerulonephritis, glomerulosclerosis., nephrotic syndrome, hypertensive nephrosclerosis, diabetic retinopathy, diabetic nephropathy, endothelial cell dysfunction, psoriasis, polycystic ovarian syndrome (PCOS). dementia, end-stage renal disease, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer, comprising administering an effective, non-toxic amount of compound of formula (1) or (Ilia) as defined in any preceding claims to a patient in need thereof.
22. Use of compounds of formula (I) or (Ilia) as defined in any previous claims for the preparation of medicine suitable for the treatment of diseases mentioned in any of the aforesaid claims.
Dated this day of 2003

(President, Zydus Research Centre)1'
For Cadila Healthcare Limited

ZRC-MC-009
Abstract
Title: Novel Substituted Aralkyl Derivatives Having Hypolipidemic, Hypocholesteremic Activities, Process For Their Preparation And Pharmaceutical Compositions Containing Them And Their Use In Medicine
Abstract: The present invention relates to novel substituted aralkyl derivatives of the general formula (I) & (Ilia), their derivatives, their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, pharmaceutical compositions containing them, use of these compounds in medicine and the intermediates involved in their preparation.
A-(CH2)n-X-Ar--YX32
G 0
A-(CH2)-X-Ar^Y^R4 (Ilia)
112

Documents:

992-mum-2002-(diagram)-1.doc

992-mum-2002-(diagram).doc

992-mum-2002-abstract (complete).doc

992-mum-2002-abstract(13-11-2003).doc

992-mum-2002-abstract(13-11-2003).pdf

992-mum-2002-abstract(5-7-2007).pdf

992-mum-2002-abstract(complete)-(13-11-2003).pdf

992-mum-2002-abstract(granted)-(4-2-2008).pdf

992-mum-2002-abstract-complete.pdf

992-mum-2002-cancelled pages(13-11-2003).pdf

992-mum-2002-claims (complete).doc

992-mum-2002-claims(amanded)-(5-7-2007).pdf

992-mum-2002-claims(complete)-(13-11-2003).pdf

992-mum-2002-claims(granted)-(13-11-2003).doc

992-mum-2002-claims(granted)-(13-11-2003).pdf

992-mum-2002-claims(granted)-(4-2-2008).pdf

992-mum-2002-claims-complete.pdf

992-mum-2002-correspondence(18-12-2007).pdf

992-mum-2002-correspondence(6-12-2007).pdf

992-mum-2002-correspondence(ipo)-(31-3-2008).pdf

992-mum-2002-correspondence(ipo)-(4-1-2008).pdf

992-mum-2002-correspondence-received-ver-081203.pdf

992-mum-2002-correspondence-received-ver-131103.pdf

992-mum-2002-correspondence-received-ver-141103.pdf

992-mum-2002-correspondence-received-ver-151102.pdf

992-mum-2002-correspondence-received-ver-170204.pdf

992-mum-2002-correspondence-received-ver-261205.pdf

992-mum-2002-descripiton (complete).pdf

992-mum-2002-descripiton (provisional).pdf

992-mum-2002-description(complete)-(13-11-2003).pdf

992-mum-2002-description(granted)-(4-2-2008).pdf

992-mum-2002-form 1(15-11-2002).pdf

992-mum-2002-form 18(29-12-2005).pdf

992-mum-2002-form 2(complete)-(13-11-2003).pdf

992-mum-2002-form 2(granted)-(13-11-2003).doc

992-mum-2002-form 2(granted)-(13-11-2003).pdf

992-mum-2002-form 2(granted)-(4-2-2008).pdf

992-mum-2002-form 2(title page)-(complete)-(13-11-2003).pdf

992-mum-2002-form 2(title page)-(granted)-(4-2-2008).pdf

992-mum-2002-form 3(18-12-2007).pdf

992-mum-2002-form 3(29-7-2005).pdf

992-mum-2002-form 3(6-12-2007).pdf

992-mum-2002-form 4(11-12-2003).pdf

992-mum-2002-form 5(11-12-2003).pdf

992-mum-2002-form 5(13-11-2003).pdf

992-mum-2002-form 5(13-12-2003).pdf

992-mum-2002-form 5(18-12-2007).pdf

992-mum-2002-form-1.pdf

992-mum-2002-form-18.pdf

992-mum-2002-form-2-complete.pdf

992-mum-2002-form-2-provisional.pdf

992-mum-2002-form-26.pdf

992-mum-2002-form-3-ver-111203.pdf

992-mum-2002-form-3-ver-151102.pdf

992-mum-2002-form-4.pdf

992-mum-2002-form-5-ver-121103.pdf

992-mum-2002-form-5-ver-131103.pdf

992-mum-2002-form-pct-ipea-409(15-11-2002).pdf

992-mum-2002-form-pct-isa-210(15-11-2002).pdf

992-mum-2002-petition under rule 137(6-12-2007).pdf

992-mum-2002-power of authority(15-1-2003).pdf


Patent Number 214134
Indian Patent Application Number 992/MUM/2002
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 04-Feb-2008
Date of Filing 15-Nov-2002
Name of Patentee CADILA HEALTHCARE LIMITED
Applicant Address ZYDUS TOWER SATELLITE CROSS ROADS AHMEDABAD
Inventors:
# Inventor's Name Inventor's Address
1 VIDYA BHUSHAN LOHRAY CADILA HEALTHCARE LIMITED ZYDUS TOWER SATELLITE CROSS ROADS AHMEDABAD 380 015
2 BRAJ NHUSHAN LOHRAY CADILA HEALTHCARE LIMITED ZYDUS TOWER SATELLITE CROSS ROADS AHMEDABAD 380 015
PCT International Classification Number A61K31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA