Patent Application
20090012069
The present invention relates to novel heterocyclic compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.
The compounds of the general formula (I) 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) 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) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. These compounds of general formula (I) 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 hyperinsulinemia, 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.
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 el. al., Br. Med. J. 282, 1741-1744 (1981); Picardo et al., Arteriosclerosis, 6, 434-441 (1986); Macikinnon et al., 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. It 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 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 Thiazolidinediones like troglitazone, rosiglitazone and pioglitazone are prescribed alone or in combination with other anti-diabetic agents.
These are useful in 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 [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, hyperlipidaemia 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. PPAR∝, PPARγ and PPARδ have been identified as subtypes of PPARs. Extensive reviews regarding PPAR, their role in different diseased conditions are widely published [Endocrine Reviews, 20(5), 649-699 (1999); J. Medicinal Chemistry, 43(4), 58-550 (2000); Cell, 55, 932-943 (1999); Nature, 405, 421-424 (2000); Trends in Pharmacological Sci., 469-473 (2000)]. PPARγ 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, 803-812 (1995); Cell, 99, 239-242 (1999)]. PPARγ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristic of 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 PPARPγ activation leads to expression of CAP gene [Cell Biology, 95, 14751-14756, (1993)], however, the exact link from PPARγ activation to changes in glucose metabolism and decrease in insulin resistance in muscle has not been clear. PPARα is involved in stimulating β-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 PPAR-Y 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 PPARγ is expressed in certain cells consistently, PPARγ 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 α agonists have been found useful in the treatment of obesity (WO 97/36579). Dual PPAR α and γ agonists have been suggested to be useful for Syndrome X (WO 97/25042). PPAR γ agonists and HAG-CoA reductase inhibitors have exhibited synergism and indicated the usefulness of the combination in the treatment of atherosclerosis and xanthoma (EP 0753 298).
Most recently PPAR delta was reported to modulate lipid metabolism in which PPAR delta serves as a widespread regulator of fat burning. In vitro activation of PPAR delta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. It has also been reported that PPAR delta deficient mice challenged with high-fat diet show reduced energy uncoupling and are prone to obesity (Wang Y X et. al., Cell (2003), 113(2), 159-170). The transcriptional repression of atherogenic inflammation by ligand-activated PPAR delta was also reported, which further indicates the importance of PPAR delta in combating cardiovascular diseases (Lee, C H et al., Science 302, 453-457, 2003).
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)].
Several compounds have been reported which are dual agonists of PPAR α and γ like alkoxy phenyl propanoic acid derivatives, aryloxy propanoic acid derivatives, benzyl glycine derivatives etc have been reported and are in various developmental stages.
US 20030166697 (Nippon Shinayaku) discloses compounds of the following general formula:
R1-Het-D-E
wherein
R1 represents (un)substituted aryl, aromatic heterocyclic or cycloalkyl groups; ‘Het’ is an optionally substituted divalent aromatic heterocyclic group; W is —CH— or N; m=1-10; n=0-9; p=0-2; Y=O or S; R3 is H or alkyl; Z=carboxy, alkoxy carbonyl etc.
WO 2000004011 discloses compounds having the following general formula for the treatment of dyslipidemia, atherosclerosis and diabetes;
where X, Y=CH2, O, S, NRa (Ra=H, alkyl aryl, etc.); R=H, alkyl, cycloalkyl, etc.; R1=H, alkyl, hydroxyalkyl, —(CH2)t—COORc where t=0-6 & Rc represents H or alkyl group, etc.; R2 & R3=H, alkyl cycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C7)alkyl, 3-10 membered optionally substituted heterocyclic group etc.; or R2 & R3 optionally form a chain —(CH2)r1 (r=2-5), etc.; R4-R7=H, alkyl, (un)substituted aryl, etc.
However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime
Surprisingly, we have found that the novel compounds of formula (I) are useful 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, and methods for their preparation. Also surprisingly, the compounds of formula (I) have been found to be useful as hypocholesterolemic, hypolipidaemic, hypolipoproteinemic, anti-obesity and antihyperglycemic agents with reduced side effects. Also, the compounds showed preferable affinity towards PPAR subtypes.
In an embodiment of the present invention is provided novel substituted heterocyclic compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
In another embodiment of the present invention is provided a process for the preparation of novel substituted heterocyclic compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts.
In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Accordingly, the present invention provides novel compounds of the general formula (I),
their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, wherein
‘A’ represents an optionally substituted single or fused group selected from aryl, heteroaryl, heterocyclyl groups; or
wherein ‘Ar’, ‘Ar1’ and Ar2′ may be the same or different and independently represents an optionally substituted single or fused aryl, heteroaryl or a heterocyclic group;
‘X’ represents oxygen, sulfur or nitrogen;
‘Y’ represents COOR1, CONR1R2;
Z represents a bond or —CH2—;
‘m’ is an integer from 1-3;
R, R1 & R2 may be same or different and independently represents hydrogen, optionally substituted groups selected from linear or branched alkyl or aryl groups.
When any one of ‘A’, ‘Ar1’ or ‘Ar2’ is substituted, the substituents may be selected from hydroxy, oxo, halo, thio, nitro, amino, cyano, formyl, or optionally substituted groups selected from amidino, hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, 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, hydroxylamino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives; preferably the substituents may be selected from hydroxy, halo, oxo, or optionally substituted groups selected from alkyl, monosubstituted or disubstituted amino, alkoxy, acyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkoxy, heterocyclyloxy, alkylthio, arylthio, alkylsulfonylamino, alkylsulfonyloxy, carboxylic acid and its derivatives such as esters and amides,
The substituents on ‘A’, ‘Ar1’ or ‘Ar2’ may further be optionally substituted by any of the groups as mentioned above;
When the groups representing ‘Ar’ are substituted, the substituents may be selected from halogen, optionally substituted groups selected from linear or branched alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl, arylaminoalkyl, aminoalkyl groups.
In a preferred embodiment the groups, radicals described above may be selected from:
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
Particularly useful compounds may be selected from
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention.
i. reduction of compound of formula (II) wherein all the symbols are as defined earlier to compound of formula (III) wherein all the symbols are as defined earlier.
ii. reacting compound of formula (III) wherein all the symbols are as defined earlier with suitable ketoester of the formula RC(O)Y wherein R is as defined earlier and Y is COOR1 where R1 is alkyl or aryl to yield compound of formula (Ia) wherein Y represents COOR1 where R1 is alkyl or aryl and all other symbols are as defined earlier.
iii. hydrolysis of compound of general formula (Ia) wherein Y is COOR1 where R1 is alkyl or aryl and all other symbols are as defined earlier to yield compound of general formula (I) wherein Y is COOH and all other symbols are as defined earlier.
iv. compound of formula (I) where Y represents COOH or (Ia) where Y represents COOR1 where R1 represents alkyl or aryl and all other symbols are as defined earlier may optionally be converted to further compound of formula (I) where Y represents CONR1R2 where in all the symbols are as defined earlier by reacting with appropriate amine. The reactions can be carried out by suitable modifications of methods & techniques known to those skilled in the art. As an example of general techniques and methods which may be used, the techniques described in “Comprehensive Organic Transformations” R. C. Larock (2nd Ed., 1999) (VCH Publishers Inc.) and “Advanced Organic Chemistry”, J. March (4th Ed.), John Wiley & Sons may be used with appropriate modifications.
Method A: The diester of the formula (II) may be reduced to diol of formula (III). Suitable reducing agents may be hydrides such as LiAlH4, NaBH4, diborane, NaBH4/BF3OEt2, LiBH4, DIBAH, and the like. Reaction may be carried out in suitable solvents appropriate for the reducing agent used e.g. with LiAlH4, NaBH3, diborane, NaBH4/BF3OEt2 aprotic solvents such as THF, ether and the likes or their combinations are preferred. With NaBH4, LiBH4 etc. alcoholic solvents used alone or as mixtures may also be used. The reaction may be carried out at a temperature in the range 0° C. to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 24 hours.
Method D: The diol of formula (I) may be converted to dioxane of formula (Ia) by reacting with appropriate ketoester (RC(O)COOR1) in presence of a Lewis acid e.g. boron trifluoride etherate complex and the like. Reaction may be conducted in an appropriate solvent e.g., polar solvent such as acetonitrile or N,N-dimethyl formamide (DMF), ether solvent such as tetrahydrofuran (THF) or diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as chloroform or dichloromethane, hydrocarbon solvent such as benzene, toluene, hexane, heptane or a mixtures of appropriate solvents selected from those described above. The reaction may be carried out at a temperature in the range −20° C. to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
Method D: The compound of formula (Ia) may be hydrolysed to compound of formula (I) using suitable base e.g., NaOH, LiOH, KOH and the like. Reaction may be conducted in suitable solvents e.g., alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like, THF, water or mixtures thereof. The reaction may be carried out at a temperature in the range 20° C. to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
i. reacting compounds of general formula (IV) where all symbols are as defined earlier and L represents a leaving group such as halogen, mesylate, tosylate, triflate & the like with compounds of general formula (V), where all symbols are as defined earlier and Y represent COOR1 where R1 represents alkyl or aryl to yield compound of general formula (Ia) where all symbols are as defined earlier and Y represent COOR1 where R1 represents alkyl or aryl.
ii. hydrolysis of compound of general formula (Ia) wherein Y is COOR1 where R1 represents alkyl or aryl and all other symbols are as defined earlier to yield compound of general formula (I) where in Y is COOH and all other symbols are as defined earlier.
Method C: The compound of formula (Ia) may be prepared by reacting compound of formula (IV) with compound of formula (V) under suitable conditions. The reaction may be carried out in presence of solvents such as acetone, tetrahydrofuran, dimethyl sulfoxide, dioxane, acetonitrile, dimethyl formamide, benzene, toluene, petroleum ether, heptane, hexane, 2-butanone, xylene, alcohols such as methanol, ethanol, propanol, butanol, iso-butanol tertbutanol, pentanol and the like or mixtures of appropriate solvents selected from those above. Bases such as alkali metal carbonates such as K2CO3, Na2CO3, CsCO3, and the like; or alkali metal hydroxides such as NaOH, KOH and the like, may be used in this reaction. Alkali metal hydrides such as NaH, KH can be used whenever solvent employed is not protic or contain carbonyl group. The reaction may be carried out at a temperature in the range 0° C. to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours. The intermediate of general formula (V) may be prepared by one or more routes or combinations of reactions outlined in scheme III outlined below which comprises:
i. reduction of compound of formula (VI) to compound of formula (VII) wherein all the symbols are as defined earlier and P represents a suitable protecting group for e.g. benzyl, methoxymethyl and the like.
ii. reacting compound of formula (V with suitable ketoester of the formula RC(O)Y wherein R is as defined earlier and Y represents COOR1 where R1 is alkyl or aryl to yield compound of formula (VIII) wherein P represents a suitable protecting group i.e benzyl, methoxymethyl and the like and Y represents COOR1 where R1 is alkyl or aryl and all other symbols are as defined earlier.
iii. reprotection of compound of formula (VIII) to yield compound of formula (V) wherein Y represents COOR1 where R1 represents alkyl or aryl and all other symbols are as defined earlier.
Method A: The compound of formula (VI) may be reduced to compound of formula (VII) by a suitable reducing agent as described in method A earlier.
Method B: The diol of formula (VI) may be converted to a compound of formula (VIII) by a procedure similar to that described in method B earlier.
method E: The compound of formula (VIII) may be deprotected to yield compound of formula (V). Suitable deprotecting methods known in the art for e.g. in T. W. Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, John Wiley L, Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein may be employed depending on the protecting group used.
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
It will be appreciated that one or more of the processes described in the general schemes above may be used to prepare the compounds of the present invention.
1H spectral data given in the tables (vide infra) are recorded using a 300 MHz spectrometer (Bruker A VANCE-300) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCl3 using tetramethyl silane as the internal standard.
To a solution of 2-{4-[2-(5-Methyl-2-p-tolyl-oxazol-4-yl)-ethoxy]-benzyl}-propane-1,3-diol (1 g) in acetonitrile (10 mL) was added methyl pyruvate (0.94 mL) followed by 98% boron trifluoride diethyl ether complex (0.65 mL) and the reaction mixture was stirred at ambient temperature for extended hours (tlc). The reaction mixture was poured in to a solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product was flash chromatographed over silicagel using a mixture of ethyl acetate and petroleum ether as eluent to obtain 910 mg of pure product.
1H NMR: 1.59 (3H, s), 2.26 (2H, s), 2.35 (3H, s), 2.38 (3H, s), 2.91-2.97 (3H, m), 3.45 (2H, t, J=10.9 Hz), 3.7-3.9 (5H, m), 4.2 (2H, t, J=6.7 Hz), 6.82 (2H, t) J=7.2 Hz), 6.97 (1H, d, J=8.46 Hz), 7.09 (1H, t, J=8.48 Hz), 7.23 (2H, d, J=8.07 Hz), 7.85 (2H, d, J=8.07 Hz).
Yield: 74%
2-(4-Benzyloxy-benzyl)-propane-1,3-diol (37 g) was dissolved in 200 mL of acetonitrile, and 50.3 mL of methyl pyruvate was added. To the mixture, 39.2 mL of boron trifluoride diethyl ether complex (98%) was added with stirring at ambient temperature, and stirring was continued for 3-6 hours at ambient temperature. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The crude product was flash chromatographed over silica gel using a mixture of ethyl acetate and petroleum ether as eluent to obtain 18 g of pure product.
To a suspension of 10% palladium on charcoal (3.4 g) in methanol (100 mL) was added Methyl-5-(4-benzyloxy-benzyl)-2-methyl-[1,3]dioxane-2-carboxylate (18 g) prepared in step 1 above followed by ammonium formate (13 g) and the reaction mixture was heated to reflux for 2-5 hours. The reaction mixture was cooled to ambient temperature and the catalyst was filtered off. The filtrate was evaporated, the residue was taken in ethyl acetate and washed with water. The organic extract was dried over sodium sulfate and evaporated under reduced pressure to yield 13 g of product. This was re-crystallised from a mixture of ethyl acetate and petroleum ether to obtain 7 g of the desired product.
A mixture of cis methyl-5-(4-hydroxy-benzyl)-2-methyl-[1,3]dioxane-2-carboxylate (prepared in step 2 above) (750 mg) 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl methane sulfonate (790 mg) and potassium carbonate (780 mg) in anhydrous dimethyl formamide (10 mL) was stirred at 80° C. for extended periods in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product was flash chromatographed over silica gel using a mixture of ethyl acetate and petroleum ether as eluent to obtain 971 mg of pure product.
1H NMR: 1.49 (3H, s), 2.27 (3H, s), 2.32 (3H, s), 2.96 (2H, t, J=6.66 Hz), 3.45 (2H, t, J=10.4 Hz), 3.83-3.9 (5H, m), 4.21 (2H, t, J=6.72 Hz), 6.73-6.75 (3H, dd, J=6.57 & 2.01 Hz), 6.97 (3H, dd, J=3.55 & 6.57 Hz), 7.39-7.44 (2H, m), 7.97 (1H, dd, J=7.92 & 2.46 Hz).
Yield: 76%
The following compounds are prepared by procedure similar to those described in examples 1 or 2 with appropriate variations of reactants, reaction conditions and quantities of reagents.
1H NMR: 1.49 (3H, s), 2.26 (3H, s), 2.37 (3H, s), 2.91-2.99 (3H, q, J=13.74 & 6.69 Hz), 3.45 (2H, t, J=10.44 Hz), 3.73-3.93 (5H, m), 4.21 (2H, t, J=6.72 Hz), 6.82 (3H, t, J=7.23 Hz), 6.98 (1H, d, J=8.55 Hz), 7.10 (1H, d, J=8.43 Hz), 7.42 (3H, d, J=5.76 Hz), 7.98 (2H, t, J=2.37 Hz).
Yield: 21.4%
1H NMR: 1.5 (3H, s), 2.3 (3H, m), 2.4 (3H, s), 3.5 (1H, t, J=11.3 Hz), 3.7 (1H, m), 3.8 (3H, s), 3.9 (2H, m), 4.9 (2H, s), 6.9 (2H, t, J=7.9 Hz), 7.0 (2H, d, J=8.5 Hz), 7.4 (3H, m), 8.0 (2H, m).
Yield: 62.0%
1H NMR: 1.5 (3H, s), 2.1 (2H, m), 2.2 (2H, m), 2.26 (3H, m), 3.3 (2H, m), 3.5 (3H, m), 3.8 (3H, s), 3.9 (2H, m), 4.2 (1H, dd, J=9.1 & 3.1 Hz), 4.5 (1H, m), 6.4 (1H, d, J=8.5 Hz), 6.5 (1H, t, J=5.9 Hz), 6.9 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.4 (1H, m), 8.1 (1H, d, J=4.0 Hz).
Yield: 44%
1H NMR: 1.5 (3H, s), 2.3 (3H, m), 3.1 (3H, s), 3.4 (2H, m), 3.7 (2H, m), 3.9 (3H, s), 3.9 (231, t, J=5.6 Hz), 4.1 (2H, t, J=5.5 Hz), 6.5 (2H, m), 6.8 (2H, d, J=3.4 Hz), 7.0 (2H, d, J=8.4 Hz), 7.4 (1H, m), 8.1 (1H, d, J=4.3 Hz).
Yield: 76%
1H NMR: 1.49 (3H, s), 2.28 (2H, s), 2.94-2.97 (1H, d, J=7.86 Hz), 3.46 (2H, t, J=12.39 Hz), 3.74 (3H, s), 3.82-3.94 (5H, s) 5.15 (2H, d, J=2.16 Hz), 6.95-7.05 (1H, d, J=8.46 Hz), 7.14-7.17 (1H, d, J=8.46 Hz), 7.51 (1H, t, J=6.75 Hz), 7.69-7.79 (2H, m), 8.30 (1H, t, J=7.92 Hz).
Yield: 56.8%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 2.39 (3H, s), 2.41 (3H, s), 3.4 (2H, t, J=10.9 Hz), 3.8 (3H, s), 3.9 (2H, m), 4.9 (2H, s), 6.9 (23 d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, m), 7.9 (2H, d, J=8.1 Hz).
Yield: 97%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 3.4 (2H, t, J=10.2 Hz), 3.8 (3H, s), 3.9 (2H, m), 4.3 (2H, t, J=6.0 Hz), 4.7 (2H, t, J=6.0 Hz), 6.7 (2H, d, J=8.4 Hz), 6.9 (2H, d, J=8.4 Hz), 7.2 (2H, m), 7.5 (4H, m), 8.1 (2H, d, J=7.7 Hz).
Yield: 77%
1H NMR: 1.5 (3H, s), 2.26 (3H, m), 3.4 (2H, m), 3.9 (5H, m), 4.2 (2H, t, J=5.57 Hz), 4.5 (2H, t, J=5.66 Hz), 6.5 (1H, d, J=2.5 Hz), 6.7 (2H, d, J=7.1 Hz), 6.9 (2H, d, J=8.3 Hz), 7.1 (1H, t, J=7.4 Hz), 7.2 (2H, d, J=3.3 Hz), 7.4 (1H, m), 7.6 (1H, d, J=7.8 Hz).
Yield: 55.5%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 2.9 (2H, m), 3.5 (2H, m), 3.7 (2H, t, J=5.7 Hz), 3.77 (2H, m), 3.8 (5H, m), 3.9 (2H, m), 4.1 (2H, m), 4.2 (2H, t, J=4.4 Hz), 6.6 (1H, m), 6.7 (1H, m), 6.7-6.8 (4H, complex), 7.0 (1H, d, J=8.5 Hz), 7.1 (1H, d, J=8.5 Hz).
Yield: 97%
1H NMR: 1.6 (3H, s), 2.2 (3H, m), 2.3 (3H, s), 2.5 (3H, s), 3.5 (2H, t, J=11 Hz), 3.8 (3H, s), 3.9 (2H, dd, J=12 & 3.6 Hz), 4.9 (2H, s), 6.7 (1H, m), 6.9 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.4 (1H, d, J=3.5 Hz).
Yield: 80%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 2.3 (3H, s), 2.5 (3H, s), 2.9 (2H, t, J=6.5 Hz), 3.4 (2H, m), 3.9 (5H, m), 4.2 (2H, t, J=6.6 Hz), 6.7 (1H, m), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.3 (1H, d, J=3.6 Hz).
Yield: 55.5%
1H NMR: 1.49 (3H, s), 2.21-2.35 (5H, m), 3.46 (2H, t, J=10.86 Hz), 3.82-3.91 (5H, m), 4.13 (4H, t, J=6.03 Hz), 6.81-7.06 (1H, m), 7.30 (2H, m)
Yield: 72.7%
1H NMR: 1.49 (3H, s), 2.27 (3H, s), 3.09 (2H, t, J=6.57 Hz), 3.13 (3H, s), 3.45 (2H, t, J=11.73 Hz), 3.82-3.92 (5H, m), 4.13 (2H, t, J=6.15 Hz), 6.79 (2H, d, J=8.46 Hz), 7.00 (2H, d, J=3.46 Hz), 7.23 (2H, d, J=8.55 Hz), 7.33 (2H, d, J=8.43 Hz).
Yield: 100%
1H NMR: 1.37 (9H, s), 1.57 (3H, s), 6.29 (6H, d, J=7.29 Hz), 3.46 (2H, m), 3.84-3.90 (5H, m), 4.85 (2H, s), 6.88 (2H, d, J=8.31 Hz), 7.00 (2H, d, J=8.01 Hz).
Yield: 100%
1H NMR: 1.50 (3H, s), 2.28 (3H, m), 2.50 (3H, s), 3.47 (2H, t, J=5.73 Hz), 3.84 (3H, s), 3.86-3.90 (2H, m), 5.17 (2H, s), 6.72-6.97 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.54 Hz), 7.67 (2H, d, J=8.19 Hz), 8.01 (2H, d, J=8.28 Hz).
Yield: 95.1%
1H NMR: 1.5 (3H, s), 2.3 (3H, m), 3.4-3.5 (2H, t, J=10.45 Hz), 3.8 (3H, s), 3.9 (2H, m), 4.3 (4H, s), 6.8-7.0 (11H, complex), 7.3 (2H, m).
Yield: 66%
1H NMR: 1.5 (3H, s), 2.3 (3H, m), 3.4-3.5 (2H, t, J=10.8 Hz), 3.8 (3H, s), 3.9 (2H, m), 5.1 (2H, s), 6.9 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.1 (2H, m), 7.3 (1H, m), 7.5 (1H, m).
Yield: 79%
1H NMR: 1.5 (3H, s), 2.27 (3H, m), 3.4 (2H, t, J=10.7 Hz), 3.9-4.0 (7H, m), 4.1 (2H, t, J=6.6 Hz), 6.6 (6H, m), 6.7 (4H, m), 7.0 (2H, d, J=8.4 Hz).
Yield: 93%
1H NMR: 1.5 (3H, s), 2.28 (3H, m), 3.4 (2H, s), 3.8 (5H, m), 4.0 (1H, m), 4.2 (31H, m), 4.9 (1H, m), 6.8 (2H, d, J=8.4 Hz), 7.0 (2H, d, J=8.3 Hz), 7.1 (1H, t, J=7.3 Hz), 7.4 (2H, t, J=7.5 Hz), 7.5 (2H, d, J=7.9 Hz).
Yield: 75.0%
1H NMR: 1.49 (3H, s), 2.25 (3H, s), 3.04 (2H, d, J=5.11 & 2.83 Hz), 3.5 (2H, t), 3.70-3.90 (9H, m), 4.14 (2H, t, J=5.85 Hz), 6.62 (1H, t), 6.71 (1H, d, J=7.98 Hz), 6.79 (2H, d, J=8.58 Hz), 6.95-7.10 (4H, m).
Yield: 88.2%
1H NMR: 1.49 (3H, s), 2.26 (3H, s), 3.45 (2H, t, J=10.89 Hz), 3.77-3.94 (5H, m), 4.29 (4H, s), 6.80 (2H, d, J=8.58 Hz), 6.91-6.97 (6H, m), 7.09-7.31 (4H, m).
Yield: 100%
1H NMR: 0.88 (3H, m), 1.33 (6H, m), 1.50 (3H, s), 1.65 (2H, m), 2.19-2.27 (5H, m), 3.48 (2H, m), 3.84-3.93 (7H, m), 4.15-4.20 (2H, m), 4.77 (1H, m), 6.81 (2H, d, J=8.58 Hz), 6.91-7.32 (6H, m).
Yield: 60%
1H NMR: 1.49 (3H, s), 2.24 (3H, s), 2.36 (3H, s), 2.51 (3H, s), 3.44 (2H, t, J=10.8 Hz) 3.83 (3H, s), 3.87-3.93 (4H, m), 4.26 (2H, t, J=6.57 Hz), 5.95 (it d, J=3.12 Hz), 6.03 (1H, d, J=3.36 Hz), 6.58 (2H, d, J=8.49 Hz), 6.93 (2H, d, J=3.43 Hz), 7.26-7.33 (4H, m).
Yield: 47.6%.
1H NMR: 1.33 (9H, s), 1.49 (3H, s), 2.20 (3H, s), 2.23 (3H, s), 2.86 (2H, t, J=6.75 Hz), 3.45 (2H, t, J=10.44 Hz), 3.84-3.90 (5H, m), 4.12 (2H, t, J=6.63 Hz), 6.76 (2H, dd, J=13.71 & 8.55 Hz), 6.94-7.00 (2H, m).
Yield: 100%.
1H NMR: 1.49 (3H, s), 2.04 (3H, s), 3.46 (2H, t, J=10.65 Hz), 3.84 (3H, s), 3.88 (2H, dd, J=11.7 & 3.27 Hz), 4.25 (2H, t, J=5.07 Hz), 4.57 (2H, t, J=4.62 Hz), 6.83 (2H, d, J=8.58 Hz), 6.99 (2H, d, J=8.55 Hz), 7.27-7.29 (1H, m), 7.40 (5H, m), 7.66-7.73 (2H, m), 8.61 (1H, d, J=4.59 Hz).
Yield: 72.5%.
1H NMR: 1.49 (3H, s), 2.04 (3H, s), 3.46 (21, J=10.65 Hz), 3.84 (3H, s), 3.88 (2H, dd, J=11.7 & 3.27 Hz), 4.23 (21, J=5.10 Hz), 4.50 (2H, t, J=4.86 Hz), 6.83 (2H, d, J=8.58 Hz), 6.99 (2H, d, J=8.55), 7.29-7.36 (41H, m), 7.45 (2H, dd, J=7.44 & 1.56 Hz), 7.53 (1H, d, J=7.8 Hz) 7.60 (1H, m), 8.70 (1H, d, J=4.8 Hz).
Yield: 66%.
1H NMR: 1.49 (3H, s), 2.04 (3H, s), 2.35 (3H, s), 2.38 (3H, s), 2.95 (2H, t, J=6.69 Hz) 3.45 (2H, t, J=9.0 Hz), 3.84-3.90 (5H, m), 4.20 (2H, t, J=13.5 Hz), 6.74 (2H, d, J=8.43 Hz), 6.80 (2H, d, J=8.55 Hz), 6.97 (2H, dd, J=8.37 & 6.12 Hz), 7.85 (2H, d, J=8.16 Hz).
Yield: 79%
1H NMR: 1.3 (9H, s), 1.5 (3H, s), 2.3 (3H, m), 2.4 (3H, s), 3.5 (2H, t, J=11 Hz), 3.8 (3H, s), 3.9 (2H, dd, J=12 & 3 Hz), 4.8 (2H, s), 6.4 (1H, s), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.2 Hz), 7.4 (2H, d, J=8.3 Hz).
Yield: 50%.
1H NMR: 1.50 (2H, s), 1.61 (1H, s), 2.44-2.46 (2H, m), 3.14 (1H, d, J=7.95 Hz), 3.53 (1H, t, J=10.92 Hz), 3.80-3.97 (6H, m), 5.24 (2H, s), 7.08-7.34 (6H, m), 7.47 (1H, s), 7.53-7.69 (3H, s).
Yield: 60%.
1H NMR: 1.50 (2H, s), 1.61 (1H, s), 2.48 (2H, m), 3.12 (1H, d, J=7.68 Hz), 3.53 (1H, t, J=10.77 Hz), 3.80-3.97 (6H, m), 5.17 (2H, s), 7.20-7.68 (11H, m).
Yield: 60%.
2-(4-Benzyloxy-phenyl)-propane-1,3-diol (40 g) was dissolved in 200 mL of acetonitrile, and 56.4 mL of methyl pyruvate was added. To the mixture, 39.2 mL of boron trifluoride diethyl ether complete (98%) was added with stirring at ambient temperature, and stirring was continued for 2 hours at ambient temperature. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The crude product was flash chromatographed over silica gel using 7% ethyl acetate in petroleum ether as eluent and the fractions eluted earlier were evaporated to obtain 19.3 g of pure product.
To a suspension of 10% palladium on charcoal (2.0 g) in methanol (100 mL) was added Methyl-5-cis-(4-benzyloxy-phenyl)-2-methyl-[1,3]dioxane-2-carboxylate (19.3 g) prepared in step 1 above followed by ammonium formate (14.2 g) and the reaction mixture was heated to reflux and continued heating. The reaction mixture was cooled to ambient temperature and the catalyst was filtered off. The filtrate was evaporated, the residue was taken in ethyl acetate and washed with water. The organic extract was dried over sodium sulfate and evaporated under reduced pressure to yield 13.7 g of product.
A mixture of Methyl-5-cis-(4-hydroxy-phenyl)-2-methyl-[1,3]dioxane-2-carboxylate (prepared in step 2 above) (600 mg) 4-Chloromethyl-5-methyl-2-phenyl-oxazole (494 mg) and potassium carbonate (657 mg) in anhydrous dimethyl formamide wag stirred at 55° C. for 18 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel using ethyl acetate in petroleum ether as eluent to obtain 850 mg of pure product.
1H NMR: 1.58 (3H, s), 2.42 (3H, s), 3.2 (1H, m), 3.8 (2H, d, J=11.8 Hz), 3.88 (3H, s), 4.05 (2H, dd, J=4.6 & 11.8 Hz), 4.96 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.4 (3H, m), 8.00 (2H, m).
Yield: 34%
The fractions eluted later in step 1 of example 33 were evaporated to obtain 24.0 g of pure product.
To a suspension of 10% palladium on charcoal (2.6 g) in methanol (100 mL) was added Methyl-5-trans-(4-benzyloxy-phenyl)-2-methyl-[1,3]dioxane-2-carboxylate (26 g) prepared in step 1 above followed by ammonium formate (19.16 g) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to ambient temperature and the catalyst was filtered off. The filtrate was evaporated, the residue was taken in ethyl acetate and washed with water. The organic extract was dried over sodium sulfate and evaporated under reduced pressure to yield 17.2 g of product.
A mixture of Methyl-5-trans-(4-hydroxy-phenyl)-2-methyl-[1,3]dioxane-2-carboxylate (prepared in step 2 above) (1.2 g) 4-Chloromethyl-5-methyl-2-phenyl-oxazole (1.0 g) and potassium carbonate (1.3 g) in anhydrous dimethyl formamide (10 mL) was stirred at 55° C. for 18 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product was recrystallised from a mixture of ethyl acetate and petroleum ether to obtain 1.3 g of pure product.
1H NMR: 1.6 (3H, s), 2.43 (3H, s), 2.7 (1H, m), 3.86 (3H, s), 4.1 (2H, dd, J=2.9 & 12.3 Hz), 4.25 (2H, dd, J=3.7 & 12.0 Hz), 4.99 (2H, s), 6.98 (2H, d, J=8.7 Hz), 7.4 (5H, m), 8.0 (2H, m).
Yield: 68.9%.
The following compounds are prepared by procedure similar to that described in example 33 or 34 with appropriate variations of reactants, reaction conditions and quantities of reagents.
1H NMR: 1.57 (3H, s), 2.36 (3H, s), 2.95 (2H, d, J=6.6 Hz), 3.21 (1H, m), 3.8 (2H, d, J=11.8 Hz), 3.87 (3H, s), 4.05 (2H, dd, J=4.7 & 11.8 Hz), 4.2 (2H, t, J=6.6 Hz), 6.8 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.4 (3H, m), 7.98 (2H, m).
Yield: 57.7%.
1H NMR: 1.57 (3H, s), 3.2 (1H, m), 3.8 (2H, d, J=11.76 Hz), 3.88 (3H, s), 3.95 (2H, t, J=6.5 Hz), 4.05 (2H, dd, J=4.6 & 11.8 Hz), 4.15 (2H, t, J=6.5 Hz), 6.6 (6H, m), 6.8 (4H, m), 7.0 (2H, d, J=8.5 Hz).
Yield: 38.3%.
1H NMR: 1.57 (3H, s), 3.2 (1H, m), 3.72 (3H, s), 3.80 (2H, d, J=11.8 Hz), 3.87 (3H, s), 4.05 (2H, dd, J=4.6 & 11.9 Hz), 5.16 (2H, s), 6.99 (2H, d, J=8.7 Hz), 7.08 (2H, d, J=8.7 Hz), 7.5 (1H, m), 7.75 (2H, m), 8.3 (1H, d, J=7.8 Hz).
Yield: 61.4%.
1H NMR: 1.57 (3H, s), 3.15 (1H, m), 3.8 (2H, d, J=11.79 Hz), 3.87 (3H, s), 4.0 (2H, dd, J=4.6 & 11.8 Hz), 4.23 (2H, t, J=6.5 Hz), 4.5 (2H, t, J=5.6 Hz), 6.5 (1H, d, J=3.0 Hz), 6.78 (2H, d, J=9.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.1 (1H, t, J=7.4 Hz), 7.2 (2H, m), 7.39 (1H, d, J=8.19 Hz), 7.6 (1H, d, J=7.8 Hz).
Yield: 53.2%.
1H NMR: 1.23 (3H, t, J=7.6 Hz), 1.57 (3H, s), 2.63 (2H, q, J=7.6 Hz), 3.20 (3H, m), 3.79 (2H, d, 11.78 Hz), 3.87 (3H, s), 4.0 (2H, dd, J=4.6& 11.9 Hz), 4.3 (2H, t, J=6.6 Hz), 6.82 (2H, d, J=8.56 Hz), 7.06 (2H, d, J=8.56 Hz), 7.18 (1H, d, J=8.09 Hz), 7.45 (1H, dd, J=1.85 & 7.83 Hz), 8.38 (1H, s).
Yield: 27.27%
1H NMR: 1.58 (3H, s), 2.40 (3H, s), 2.42 (3H, s), 3.2 (1H, m), 3.8 (2H, d, 11.6 Hz), 3.88 (3H, s), 4.05 (2H, dd, J=4.6 & 11.8 Hz), 5.00 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=7.65 Hz), 7.96 (2H, d, J=8.0 Hz).
Yield: 90%.
1H NMR: 1.58 (3H, s), 2.35 (3H, s), 2.38 (3H, s), 2.95 (2H, t, J=6.6 Hz), 3.2 (1H, m), 3.8 (2H, t, J=11.9 Hz), 3.88 (3H, s), 4.05 (2H, dd, J=4.7 & 12.0 Hz), 4.2 (2H, t, J=6.7 Hz), 6.8 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.0 Hz), 7.86 (2H, d, J=8.16 Hz).
Yield: 42.8%
1H NMR: 1.58 (3H, s), 3.0 (2H, t, J=6.6 Hz), 3.13 (3H, s), 3.2 (1H, m), 3.8 (2H, d, J=11.8 Hz), 3.88 (3H, s), 4.0 (2H, dd, J=4.6 & 11.9 Hz), 4.13 (2H, t, J=6.6 Hz), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=8.5 Hz).
Yield: >99%.
1H NMR: 1.6 (3H, s), 2.39 (3H, s), 2.42 (3H, t, s), 2.7 (1H, m), 3.86 (3H, s), 4.1 (2H, dd, J=2.9 & 12.3 Hz), 4.25 (2H, dd, J=3.7 & 12.0 Hz), 4.97 (2H, s), 7.0 (2H, d, J=3.64 Hz), 7.22 (2H, d, J=−8.1 Hz), 7.4 (2H, d, J=8.61 Hz), 7.9 (2H, d, J=8.64 Hz).
Yield: 98.3%.
1H NMR: 1.59 (3H, s), 2.38 (3H, s), 2.7 (1H, m), 3.0 (2H, t, J=6.6 Hz), 3.86 (3H, s), 4.0 (2H, dd, J=2.8 & 12.1 Hz), 4.2 (4H, m), 6.8 (2H, d, J=8.6 Hz), 7.4 (5H, m), 7.99 (2H, m).
Yield: 80.7%.
1H NMR: 1.6 (3H, s), 2.35 (3H, s), 2.37 (3H, s), 2.7 (1H, m), 2.9 (2H, m), 3.86 (3H, s), 4.04 (2H, dd, J=2.16 & 11.97 Hz), 4.2 (4H, m), 6.8 (2H, d, J=8.6 Hz), 7.2 (2H, d, J=8.0 Hz), 7.3 (2H, d, J=9.1 Hz), 7.87 (2H, d, J=−8.1 Hz).
Yield: 87.4%.
1H NMR: 1.6 (3H, s), 2.52 (3H, s), 2.7 (1H, m), 3.87 (3H, s), 4.1 (2H, dd, J=2.2 & 12.12 Hz), 4.2 (2H, dd, J=3.6 & 11.9 Hz), 5.2 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.5 (2H, d, J=8.6 Hz), 7.6 (2H, d, J=8.2 Hz), 8.0 (2H, d, J=8.1 Hz).
Yield: 61.2%.
1H NMR: 1.53 (3H, s), 2.5 (3H, s), 3.2 (1H, m), 3.8 (5H, m), 4.0 (2H, m), 5.1 (2H, s), 6.9 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.6 (2H, d, J=8.1 Hz), 8.0 (2H, d, J=8.1 Hz).
Yield: 57.5%.
1H NMR: 1.56 (3H, s), 2.35 (3H, s), 2.52 (s, 3H), 3.15 (1H, m), 3.9 (7H, m), 4.0 (2H, dd, J=4.6 & 11.9 Hz), 4.25 (2H, t, J=6.6 Hz), 5.95 (1H, d, J=2.8 Hz), 6.08 (1H, d, J=3.3 Hz), 6.5 (2H, d, J=8.6 Hz), 6.9 (2H, d, J=3.6 Hz), 7.3 (4H, m).
Yield: 74.5%
1H NMR: 1.36 (9H, s), 1.58 (3H, s), 2.30 (s, 3H), 3.2 (1H, m), 3.80 (2H, d, J=11.8 Hz), 3.95 (3H, s), 4.0 (2H, dd, J=4.5 & 11.8 Hz), 5.3 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz).
Yield: 95.3%.
1H NMR: 1.37 (9H, s), 1.6 (3H, s), 2.31 (s, 3H), 2.7 (1H, m), 3.86 (3H, s), 4.0 (2H, dd, J=2.7 & 12.1 Hz), 4.2 (2H, dd, J=3.7 & 12.1 Hz), 4.88 (2H, s), 6.9 (2H, d, J=8.7 Hz), 7.4 (2H, d, J=8.6 Hz).
Yield: 94.5%.
1H NMR: 1.58 (3H, s), 3.2 (1H, m), 3.8 (2H, t, J=11.8 Hz), 3.88 (3H, s), 4.0 (2H, dd, J=4.65 & 11.9 Hz), 4.29 (4H, s), 6.88-6.99 (7H, m), 7.0 (4H, d, J=8.5 Hz), 7.3 (2H, m).
Yield: 86.83%
1H NMR: 1.60 (3H, s), 2.7 (1H, m), 3.87 (3H, s), 4.0 (2H, d, J=12.0 Hz), 4.25 (2H, dd, J=3.5 & 11.98 Hz), 4.31 (3H, s), 6.92-7.07 (9H, m), 7.3 (21H, m), 7.43 (2H, d, J=8.6 Hz).
Yield: 85.33%
1H NMR: 1.58 (3H, s), 3.2 (1H, m), 3.8 (2H, d, J=11.77 Hz), 3.88 (3H, s), 4.08 (2H, dd, J=4.6 & 11.9 Hz), 5.1 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.0 (3H, d, J=8.6 Hz), 7.1 (1H, m), 7.3 (1H, m), 7.45 (1H, t, 7.3 Hz).
Yield: 78.8%.
1H NMR: 1.60 (3H, s), 2.7 (1H, m), 3.86 (3H, s), 4.0 (2H, d, J=12.01 Hz), 4.25 (2H, dd, J=3.57 & 11.97 Hz), 5.1 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.05-7.18 (2H, m), 7.3 (1H, m), 7.4 (2H, d, J=8.6 Hz), 7.5 (1H, t, 7.3 Hz).
Yield: 78.5%.
1H NMR: 1.35 (9H, t, s), 1.58 (3H, s), 2.38 (3H, s), 3.2 (1H, m), 3.85 (2H, d, J=11.64 Hz), 3.88 (3H, s), 4.0 (2H, dd, J=4.56 & 11.61 Hz), 4.8 (2H, s), 6.39 (1H, s), 6.88 (2H, d, J=8.43 Hz), 7.06 (2H, d, J=8.43 Hz), 7.2 (2H, d, J=8.1 Hz), 7.4 (2H, d, J=8.1 Hz).
Yield: 61.3%.
1H NMR: 1.36 (9H, s), 1.60 (3H, s), 2.36 (3H, s), 2.7 (1H, m), 3.87 (3H, s), 4.06 (2H, d, J=11.1 Hz), 4.25 (2H, d, J=9.18 Hz), 4.9 (2H, s), 6.41 (1H, s), 6.90 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=7.86 Hz), 7.4 (4H, t, J=7.4 Hz).
Yield: 59.9%.
1H NMR: 1.59 (3H, s), 2.69 (1H, m), 3.86 (3H, s), 4.0 (3H, m), 4.2 (5H, m), 4.99 (1H, m), 6.9 (2H d, J=8.2 Hz), 7.15 (1H, m), 7.4 (4H, m), 7.59 (2H, d, J=7.78 Hz).
Yield: 66.1%.
1H NMR: 1.58 (3H, s), 3.2 (1H, m), 3.84 (2H, d, J=11.82 Hz), 3.88 (3H, s), 4.0 (3H, m), 4.2 (3H, m), 4.9 (1H, m), 6.8 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.1 (1H, t, J=7.4 Hz), 7.3 (2H, m), 7.5 (2H, d, J=7.98 Hz).
Yield: 73.9%
1H NMR: 1.59 (3H, s), 2.69 (1H, m), 3.1 (5H, m), 3.86 (3H, s), 4.05 (2H, d, J=11.0 Hz), 4.14-4.25 (4H, m), 6.8 (2H, d, J=8.4 Hz), 7.2 (2H, d, J=8.4 Hz), 7.33-7.41 (4H, m).
Yield: 68.9%.
1H NMR: 1.59 (3H, s), 2.7 (1H, m), 3.72 (3H, s), 3.86 (3H, s), 4.0 (2H, dd, J=2.2 & 12.17 Hz), 4.2 (2H, dd, J=3.6 & 12.69 Hz), 5.18 (2H, s), 7.0 (2H, d, J=8.7 Hz), 7.4 (2H, d, J=8.7 Hz), 7.5 (1H, m), 7.7 (2H, m), 8.3 (1H, d, J=7.83 Hz).
Yield: 59.43%
To a solution of Methyl-2-methyl-5-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-[1,3]dioxane-2-carboxylate (263 mg) in methanol was added a solution of sodium hydroxide (46.5 mg) in water and the reaction mixture was stirred at ambient temperature for 15 hours. The solvents were evaporated and the residue was dissolved in water, acidified with 1N HCl and extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was flash chromatographed over silica gel using 2% methanol in chloroform as eluent to obtain 160 mg of pure product.
1H NMR: 1.54 (3H, s), 2.25 (3H, s), 2.38 (3H, s), 2.86 (1H, m), 2.96-3.03 (2H, m), 3.52-3.57 (2H, m), 3.90-3.93 (2H, m), 4.21 (2H, t, J=6.9 Hz), 6.82 (2H, d, J=3.43 Hz), 7.07 (2H, d, J=8.49 Hz), 7.32-7.43 (3H, m), 7.96-7.99 (2H, m).
Yield: 63.0%
The following compounds were prepared by a procedure similar to those described in example 57 with appropriate variations of reactants, reaction conditions and quantities of reagents.
1H NMR: 1.55 (3H, s), 2.24 (2H, s), 2.37 (3H, s), 2.38 (3H, s), 2.86 (1H, d, J=7.77 Hz), 2.96-3.03 (2H, m), 3.49-3.72 (2H, m), 3.87-3.92 (2H, m), 4.20 (2H, t, J=6.72 Hz), 6.78-6.85 (2H, m), 6.93-7.09 (2H, m), 7.22 (2H, m), 7.85-7.87 (2H, m).
Yield: 58.4%
1H NMR: 1.52 (3H, s), 2.29 (3H, m), 2.43 (3H, s), 3.6 (2H, t, J=10.8 Hz), 3.9 (2H, m), 4.96 (2H, s), 6.9 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.4 (3H, m), 8.0 (2H, m).
Yield: 85.0%
1H NMR: 1.5 (3H, s), 2.1 (3H, m), 2.2 (4H, m), 3.6 (4H, m), 3.8 (21H, m), 3.9 (1H, t), 4.1 (1H, m), 4.5 (1H, m), 6.5 (1H, d, J=8.5 Hz), 6.6 (1H, t, J=5.9 Hz), 6.8 (2H, d, J=8.31 Hz), 6.9 (2H, d, J=8.22 Hz), 7.5 (1H, t, J=7.2 Hz), 8.2 (1H, m).
Yield: 65.0%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 3.1 (3H, s), 3.6 (2H, t, J=10.52 Hz), 3.8 (2H, m), 4.0 (2H, t, J=5.0 Hz), 4.2 (2H, m), 6.6 (2H, m), 6.7 (2H, d, J=8.28 Hz), 6.9 (2H, d, J=8.4 Hz), 7.5 (1H, m), 8.2 (1H, m).
Yield: 55.5%
1H NMR: 1.3 (3H, s), 2.1 (1H, m), 2.2 (2H, d, J=6.9 Hz), 3.4 (2H, t, J=1.3 Hz), 3.6 (3H, s), 3.7 (2H, dd, J=11.7 & 4.2 Hz), 5.2 (2H, s), 7.0 (2H, d, J=8.5 Hz), 7.1 (2H, d, J=8.3 Hz), 7.5 (1H, t, J=7.5 Hz), 7.6 (1H, d, J=8.04 Hz), 7.8 (1H, t, J=7.1 Hz), 8.1 (1H, d, J=7.8 Hz).
Yield: 95%
1H NMR: 1.5 (3H, s), 2.26 (3H, m), 3.5 (2H, t, J=10.4 Hz), 3.9-4.0 (41H, m), 4.1 (2H, t, J=6.5 Hz), 6.6 (6H, m), 6.7 (4H, m), 7.0 (2H, d, J=8.5 Hz), 7.1 (2H, d, J=8.5 Hz).
Yield: 57.0%
1H NMR: 1.3 (3H, s), 2.1 (1H, m), 2.2 (2H, d, J=6.9 Hz), 2.3 (3H, s), 2.4 (3H, s), 3.4 (2H, t, J=11.4 Hz), 3.7 (2H, dd, J=11.55 & 4.1 Hz), 4.9 (2H, s), 6.9 (2H, d, J=8.4 Hz), 7.1 (2H, d, J=8.4 Hz), 7.3 (2H, d, J=8.1 Hz), 7.8 (2H, d, J=8.1 Hz).
Yield: 95.0%
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 3.5 (2H, t, J=10.7 Hz), 3.9 (2H, m), 4.3 (2H, t, J=5.9 Hz), 4.7 (2H, t, J=5.9 Hz), 6.7 (2H, d, J=8.5 Hz), 6.9 (2H, d, J=8.5 Hz), 7.2 (2H, m), 7.5 (4H, m), 8.1 (2H, d, J=7.8 Hz).
Yield: 35.0%
1H NMR: 1.5 (3H, s), 2.2 (31H, m), 3.5 (2H, t, J=10.7 Hz), 3.9 (2H, dd, J=17.9 & 4.6 Hz), 4.2 (2H, t, J=−5.6 Hz), 4.5 (2H, t, J=5.6 Hz), 6.5 (1H, d, J=3.3 Hz), 6.7 (2H, d, J=8.6 Hz), 6.9 (2H, d, J=8.5 Hz), 7.1 (1H, m), 7.2 (2H, m), 7.4 (1H, d, J=8.1 Hz), 7.6 (1H, d, J=7.8 Hz).
Yield: 39.0%
1H NMR: 1.2 (3H, s) (trans), 1.5 (3H, s), 2.3 (3H, m), 2.9 (2H, m) (trans), 3.4 (2H, m) (trans), 3.5 (2H, t, J=4.2 Hz), 3.7 (2H, t, J=5.6 Hz), 3.8 (2H, m), 3.9 (2H, m), 4.1 (2H, t, J=5.6 Hz), 4.2 (2H, t, J=4.3 Hz), 6.6 (1H, t, J=7.5 Hz), 6.7 (1H, d, J=7.3 Hz), 6.7-6.8 (4H, complex), 7.1 (1H, d, J=8.4 Hz).
Yield: 66%.
1H NMR: 1.5 (3H, s), 2.2 (3H, m), 2.4 (3H, s), 2.5 (3H, s), 3.5 (2H, t, J=11.1 Hz), 3.9 (2H, m), 4.9 (2H, s), 6.7 (1H, d, J=2.8 Hz), 6.9 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.55 Hz), 7.4 (1H, d, J=3.6 Hz).
Yield: 64.0%
1H NMR: 1.56 (3H, s), 2.26-2.31 (3H, m), 3.02-3.05 (2H, m), 3.54 (2H, t, J=6 Hz), 3.70-3.79 (4H, m), 3.93 (2H, dd, J=13.38 & 4.14), 4.14 (2H, t, J=5.67 Hz), 6.64 (1H, d, J=0.96 Hz), 6.71 (1H, d, J=7.74 Hz), 6.80 (2H, d, J=8.589 Hz), 6.95-7.05 (4H, m).
Yield: 76.0%
1H NMR: 1.55 (3H, s), 2.30 (3H, s), 3.50 (2H, m), 3.91 (2H, dd, J=9.69 & 4.17 Hz), 4.29 (4H, s), 6.81 (2H, d, J=3.58 Hz), 6.91-7.01 (6H, m), 7.13-7.13 (4H, m).
Yield: 64.0%
1H NMR: 0.88 (3H, t, J=6.81 Hz), 1.25-1.37 (6H, m), 1.56 (3H, s), 1.64 (2H, m), 2.20-2.27 (5H, m), 2.32 (1H, m), 3.53 (2H, t, J=10.77 Hz), 3.88-3.95 (4H, m), 4.14-4.19 (2H, m), 4.78 (1H, dd, J=9.24 & 3.99 Hz), 6.81 (2H, d, J=8.58 Hz), 6.95-7.05 (6H, m).
Yield: 60.2%
1H NMR: 1.55 (3H, s), 2.2 (3H, m), 2.3 (3H, s), 2.5 (3H, s), 2.9 (2H, m), 3.5 (2H, m), 3.9 (2H, d, J=9.96 Hz), 4.2 (2H, t, J=6.3 Hz), 6.7 (1H, s), 6.8 (2H, d, J=8.2 Hz), 6.9 (2H, d, J=8.0 Hz), 7.4 (1H, s).
Yield: 46%
1H NMR: 1.54 (3H, s), 2.29 (3H, s), 2.37 (3H, s), 2.97 (2H, t, J=6.69 Hz), 3.51-3.55 (2H, m), 3.91 (2H, dd, J=12.57 & 4.2 Hz), 4.21 (2H, t, J=6.72 Hz), 6.82 (2H, d, J=8.55 Hz), 6.99 (2H, d, J=8.52 Hz), 7.41 (3H, m), 7.95-7.99 (24 dd, J=7.83 & 2.88 Hz).
Yield: 32%
1H NMR: 1.55 (3H, s), 2.25-2.31 (5H, m), 3.52 (2H, t, J=10.29 Hz), 3.91 (2H, d, J=9.57 Hz), 4.14 (4H, t, J=5.71 Hz), 6.82-7.05 (1H, m), 7.28 (2H, s).
Yield: 77%
1H NMR: 1.55 (3H, s), 2.27 (3H, s), 3.07-3.11 (2H, t, J=6.72 Hz), 3.13 (3H, s), 3.44-3.55 (2H, m), 3.90 (2H, dd, J=13.74 & 4.2 Hz), 4.16 (2H, t, J=6.69 Hz), 6.80 (2H, d, J=8.49 Hz), 6.99 (2H, d, J=8.49 Hz), 7.23 (2H, d, J=8.61 Hz), 7.33 (2H, d, J=8.49 Hz).
Yield: 73.1%
1H NMR: 1.38 (9H, s), 1.51 (3H, s), 2.12 (2H, d, J=7.2 Hz), 2.26 (1H, m), 2.33 (3H, s), 3.43 (2H, t, J=11.28 Hz), 3.82 (2H, dd, J=11.82 & 4.11 Hz), 4.90 (2H, s), 6.92 (4H, dd, J=19.11 & 3.67 Hz).
Yield: 49%
1H NMR: 1.55 (3H, s), 2.33 (3H, s), 2.50 (3H, s), 3.53 (2H, d, J=11.01 Hz), 3.93 (2H, dd, J=14.28 & 3.87 Hz), 5.18 (2H, s), 6.90 (2H, d, J=8.55 Hz), 7.01 (2H, d, J=8.55 Hz), 7.68 (2H, d, J=8.18 Hz), 8.01 (2H, d, J=8.07 Hz).
Yield: 52.1%
1H NMR: 1.56 (3H, s), 2.3 (3H, s), 3.54 (2H, t, J=10.59 Hz), 3.93 (2H, d, J=9.33 & 3.54 Hz), 4.00 (4H, s), 6.86-7.07 (1H, m), 7.27-7.32 (2H, m).
Yield: 94%
1H NMR: 1.56 (3H, s), 2.32 (3H, s), 3.54 (2H, t, J=10.5 Hz), 3.91-3.94 (2H, m), 5.11 (2H, s), 6.90 (2H, d, J=8.5 Hz), 7.01-7.18 (4H, m), 7.30-7.32 (1H, m), 7.49 (1H, t, J=6.78 Hz).
Yield: 99%
1H NMR: 1.54 (3H, s), 2.27 (3H, s), 2.36 (3H, s), 2.52 (3H, s), 3.51 (2H, t J=10.62 Hz), 3.91 (4H, t, J=6.48 Hz), 4.26 (2H, t, J=8.82 Hz), 5.96 (1H, d, J=2.55 Hz), 6.09 (1H, d, J=3.3 Hz), 6.60 (2H, d, J=9.0 Hz), 6.92 (2H, d, J=8.43 Hz), 7.21-7.33 (4H, m).
Yield: 79.9%
1H NMR: 1.35 (9H, s), 1.54 (3H, s), 2.24 (3H, s), 2.27 (3H, s), 2.89-2.96 (2H, dd, J=15.03 & 8.13 Hz), 3.50 (2H, t, J=9.48 Hz), 3.84-3.89 (2H, m), 4.12 (2H, t, J=6.66 Hz), 6.78 (2H, d, J=8.34 Hz), 6.92 (2H, d, J=8.1 Hz).
Yield: 20%
1H NMR: 1.50 (3H, s), 2.36 (3H, d, J=6.12 Hz), 3.50 (2H, t, J=11.49 Hz), 3.88 (2H, dd, J=8.79 Hz), 4.29 (2H, t), 4.55 (2H, t), 6.85 (2H, d, J=8.49 Hz), 6.97 (2H, d, J=8.25 Hz), 7.29 (3H, m), 7.39 (3H, m), 7.67-7.74 (2H, m), 8.63 (1H, d, J=4.2 Hz).
Yield: 72.4%
1H NMR: 1.50 (3H, s), 2.38 (3H, s), 3.49 (2H, t, J=7.62 Hz), 3.87 (2H, dd, J=9.06 Hz), 4.24 (2H, t), 4.50 (2H, t), 6.82 (2H, d, J=8.37 Hz), 6.97 (2H, d, J=8.31 Hz), 7.34 (4H, m), 7.43 (2H, d, J=7.56 Hz), 7.53 (1H, d, J=7.74 Hz), 7.80 (1H, t, J=6.54 Hz), 8.74 (1H, d, J=6.54 Hz).
Yield: 56%
1H NMR: 1.61 (3H, s), 2.46 (3H, s), 3.07 (1H, m), 3.64 (2H, t, J=11.5 Hz), 3.75 (2H, dd, J=4.8 & 11.7 Hz), 5.05 (2H, s), 69 (4H, m), 7.47 (31 ml), 3.05 (2H, m).
Yield: 51.72%
1H NMR: 1.63 (3H, s), 2.40 (3H, s), 3.06 (2H, t, J=6.5 Hz), 3.17 (1H, m), 3.89 (2H, t, J=11.5 Hz), 4.01 (2H, dd, J=4.8 & 11.6 Hz), 4.2 (2H, t, J=6.6 Hz), 6.76 (2H, d, J=8.5 Hz), 6.95 (21, J=8.5 Hz), 7.42 (3H, m), 8.00 (2H, m).
Yield: 80.93%
1H NMR: 1.65 (3H, s), 3.22 (1H, m), 3.86-3.97 (4H, m), 4.05-4.17 (4H, m), 6.6 (6H, m), 6.7-6.85 (4H, m), 7.0 (2H, d, J=8.13 Hz).
Yield: 89.2%
1H NMR: 1.41 (3H, s), 3.1 (1H, m), 3.59 (3H, s), 3.75 (2H, t, J=11.5 Hz), 3.9 (2H, dd, J=4.5 & 11.5 Hz), 5.25 (2H, s), 7.05 (2H, d, J=8.6 Hz), 7.1 (2H, d, J=8.6 Hz), 7.56 (1H, t, J=7.4 Hz), 7.65 (1H, d, J=8.0 Hz), 7.83 (1H, t, J=7.0 Hz), 8.16 (1H, d, J=9.0 Hz).
Yield: 70.8%
1H NMR: 1.63 (3H, s), 3.21 (1H, m), 3.87 (2H, t, J=11.6 Hz), 4.0 (2H, dd, J=4.6 & 11.9 Hz), 4.25 (2H, J=5.6 Hz), 4.5 (2H, t, J=5.6 Hz), 6.5 (1H, d, J=7.76 Hz), 6.76 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.1 (1H, t, J=7.2 Hz), 7.2 (2H, m), 7.4 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=7.86 Hz).
Yield: 69.13%
1H NMR: 1.3 (3H, t, J=7.1 Hz), 1.63 (3H, s), 2.7 (2H, m), 3.1 (1H, m), 3.5 (2H, m), 3.96 (4H, m), 4.3 (2H, m), 6.7 (2H, d, J=8.1 Hz), 6.95 (2H, d, J=8.1 Hz), 7.5 (1H, d, J=7.8 Hz), 7.8 (1H, d, J=6.9 Hz), 8.6 (1H, s).
Yield: 68.66%
1H NMR: 1.6 (3H, s), 2.4 (3H, s), 2.45 (3H, s), 3.0 (1H, m), 3.5-3.7 (4H, m), 5.05 (2H, s), 6.86 (2H, d, J=8.6 Hz), 6.96 (2H, d, J=8.6 Hz), 7.29 (2H d, J=8.0 Hz), 7.95 (2H, d, J=8.0 Hz).
Yield: 90.2%
1H NMR: 1.64 (3H, s), 2.38 (3H, s), 2.39 (3H, s), 3.07 (21, J=6.5 Hz), 3.16 (1H, m), 3.88 (2H, t, J=11.5 Hz), 4.00 (2H, dd, J=4.8 & 11.7 Hz), 4.19 (2H, d, J=6.6 Hz), 6.75 (2H, d, J=8.5 Hz), 6.93 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=9.96 Hz), 7.86 (2H, d, J=8.1 Hz).
Yield: 94.23%
1H NMR: 1.65 (3H, s), 3.1 (2H, t, J=6.7 Hz), 3.13 (3H, s), 3.2 (1H, m), 3.9 (2H, t, J=11.7 Hz), 4.0-4.15 (4H, m), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.5 Hz), 7.3 (2H, d, J=8.5 z).
Yield: 82.6%
1H NMR: 1.62 (3H, s), 2.44 (3H, s), 2.67 (1H, m), 4.05 (2H, dd, J=2.5 & 11.67 Hz), 4.2 (2H, dd, J=3.2 & 11.8 Hz), 5.02 (2H, s), 7.01 (2H, d, J=8.5 Hz), 7.5 (2H, d, J=8.5 Hz), 7.45 (3H, m), 8.02 (2H, m).
Yield: 75.85%
1H NMR: 1.63 (3H, s), 2.39 (3H, s), 2.43 (3H, s), 2.68 (1H, m), 4.05 (2H, dd, J=3.3 &, 11.9 Hz), 4.2 (2H, dd, J=3.7 & 11.9 Hz), 5.01 (2H, s), 7.00 (2H, d, J=8.6 Hz), 7.2 (2H, d, J=6.8 Hz), 7.39 (2H, d, J=8.6 Hz), 7.9 (2H, d, J=8.1 Hz).
Yield: 86.8%
1H NMR: 1.65 (3H, s), 2.39 (3H, s), 2.7 (1H, m), 3.0 (2H, t, J=6.6 Hz), 4.0 (2H, dd, J=3.7 & 11.8 Hz), 4.2 (4H, t, J=6.7 Hz), 6.9 (2H, d, J=8.5 Hz), 7.3 (2H, d, J=8.5 Hz), 7.4 (3H, m), 8.0 (2H, m).
Yield: 94.9%
1H NMR (CD3OD): 1.5 (3H, s), 2.35 (3H, s), 2.37 (3H, s), 2.67 (1H, m), 2.9 (2H, t, J=6.5 Hz), 3.9 (2H, d, J=9.9 Hz), 4.2 (4H, m), 6.85 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.1 Hz), 7.4 (2H, d, J=8.5 Hz), 7.8 (2, d, J=8.1 Hz).
Yield: 45.25%
1H NMR: 1.67 (3H, s), 2.52 (3H, s), 2.81 (1H, m), 4.1 (2H, dd, J=3.2 & 11.7 Hz), 4.3 (2H, dd, J=3.5 & 11.9 Hz), 5.2 (2H, s), 6.95 (2H, J=8.5 Hz), 7.4 (2H, d, J=8.5 Hz), 7.66 (2H, d, J=8.1 Hz), 8.01 (2H, d, J=8.1 Hz).
Yield: 44.41%
1H NMR: 1.65 (3H, s), 2.51 (3H, s), 3.2 (1H, m), 3.9 (2H, t, J=11.6 Hz), 4.1 (2H, dd, J=4.5 & 11.8 Hz), 5.17 (2H, s), 6.9 (2H, d, J=8.55 Hz), 7.1 (2H, d, J=8.55 Hz), 7.68 (2H, d, J=8.1 Hz), 8.0 (2H, d, J=8.0 Hz).
Yield: δ 09.93%
1H NMR 1.65 (3H, s), 2.35 (3H, s), 2.51 (s, 3H), 3.2 (1H, m), 3.9 (4H, m), 4.05 (2H, dd, J=4.6 & 11.9 Hz), 4.25 (2H, t, J=6.6 Hz), 5.95 (1H, d, J=3.3 Hz), 6.07 (1H, d, J=3.3 Hz), 6.55 (2H, d, J=8.6 Hz), 6.99 (2H, d, J=8.6 Hz), 7.3 (4H, m).
Yield: 88.7%
1H NMR: 1.41 (9H, s), 1.62 (3H, s), 2.34 (s, 3H), 3.0 (1H, m), 3.5 (2H, t, J=11.5 Hz), 3.66 (2H, dd, J=4.8 & 11.6 Hz), 4.95 (2H, s), 6.8 (2H, d, J=8.6 Hz), 6.9 (2H, d, J=8.6 Hz).
Yield: 85.5%.
1H NMR: 1.38 (9H, s), 1.62 (3H, s), 2.32 (3H, s), 2.71 (1H, m), 4.0 (2H, dd, J=3.8 & 11.8 Hz), 4.2 (2H, dd, J=3.7 & 11.9 Hz), 4.9 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.3 (2H, d, J=8.6 Hz).
Yield: 80.3%
1H NMR: 1.65 (3H, s), 3.22 (1H, m), 3.9 (2H, t, J=11.5 Hz), 4.1 (2H, dd, J=4.3 & 11.6 Hz), 4.29 (4H, s), 6.9 (8H, m), 7.0 (3H, t, J=8.6 Hz), 7.29 (2H, t, J=8.2 Hz).
Yield: 84.4%
1H NMR (DMSO-D6): 1.39 (3H, s), 2.7 (1H, m), 3.9 (2H, d, J=11.4 Hz), 4.1 (2H, d, J=11.7 Hz), 4.28 (4H, s), 6.9-7.12 (9H, m), 7.36 (2H, t, J=8.0 Hz), 7.4 (2H, t, J=8.5 Hz).
Yield: 74.74%
1H NMR: 1.66 (3H, s), 3.2 (1H, m), 3.9 (2H, J=11.7 Hz), 4.1 (2H, dd, J=4.5 & 11.9 Hz), 5.1 (2H, s), 6.9 (2H, d, J=8.6 Hz), 7.05-7.17 (4H, m), 7.3 (1H, m), 7.45 (1H, t, J=7.4 Hz).
Yield: 93.7%
1H NMR: 1.68 (3H, s), 2.8 (1H, m), 4.1 (21 dd, J=3.9 & 11.4 Hz), 4.25 (2H, dd, J=3.7 & 11.9 Hz), 5.1 (2H, s), 6.99 (2H, d, J=8.6 Hz), 7.06-7.19 (2H, m), 7.30 (1H, m), 7.38 (2H, d, J=8.6 Hz), 7.5 (1H, t J=7.3 Hz).
Yield: 69.4%
1H NMR: 1.36 (9H, s), 1.6 (3H, s), 2.3 (3H, s), 3.2 (1H, m), 3.8 (2H, t, J=11.7 Hz), 4.0 (2H, dd, J=4.62 & 11.7 Hz), 4.86 (2H, s), 6.4 (1H, s), 6.88 (2H, d, J=8.6 Hz), 7.0 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.1 Hz), 7.4 (2H, d, J=8.2 Hz).
Yield: 63.24%
1H NMR: 1.37 (9H, s), 1.6 (3H, s), 2.36 (3H, s), 2.8 (1H, m), 4.1 (2H, dd, J=3.8 & 11.9 Hz), 4.2 (2H, dd, J=3.8 & 11.9 Hz), 4.9 (2H, s), 6.4 (1H, s), 6.9 (2H, d, J=8.6 Hz), 7.2 (2H, d, J=8.16 Hz), 7.3 (2H, d, J=8.6 Hz), 7.4 (2H, d, J=8.2 Hz).
Yield: 51.23%
1H NMR (DMSO-d6): 1.39 (3H, s), 2.7 (1H, m), 3.9 (3H, m), 4.1-4.28 (5H, m), 5.0 (1H, m), 6.9 (2H, d, J=8.4 Hz), 7.1 (1H, t, J=7.2 Hz), 7.4 (4H, m), 7.57 (2H, d, J=7.8 Hz).
Yield: 66.8%
1H NMR (DMSO-d6): 1.40 (3H, s), 3.1 (1H, m), 3.7 (2H, t, J=1.6 Hz), 3.9 (3H, m), 4.2 (3H, m), 5.0 (1H, m), 6.9 (2H, d, J=8.5 Hz), 7.1 (3H, m), 7.38 (2H, t, J=8.0 Hz), 7.55 (2H, d, J=8.3 Hz).
Yield: 70.44%.
1H NMR: 1.67 (3H, s), 2.8 (1H, m), 3.08 (2H, d, J=6.7 Hz), 3.13 (3H, s), 4.10 (2H, dd, J=3.8 & 11.9 Hz), 4.14 (2H, t, J=6.7 Hz), 4.27 (2H, dd, J=3.75 & 11.9 Hz), 6.88 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.56 Hz), 7.35 (4H, dd, J=3.4 & 8.66 Hz).
Yield: 86.6%
1H NMR (DMSO-d6): 1.38 (3H, s), 2.7 (1H, m), 3.67 (3H, s), 3.9 (2H, d, J=11.37 Hz), 4.1 (2H, m), 5.25 (2H, s), 7.07 (2H, d, J=8.6 Hz), 7.4 (2H, d, J=8.6 Hz), 7.55 (1H, t, J=7.6 Hz), 7.66 (1H, d, J=8.1 Hz), 7.82 (1H, t, J=7.1 Hz), 8.16 (1H, d, J=7.83 Hz).
Yield: 92.04%
1H NMR: 1.57 (3H, s), 2.40-2.53 (3H, m), 3.60 (2H, t, J=10.95 Hz), 3.96 (2H, dd, J=12.39 & 4.35 Hz), 5.24 (2H, s), 7.11-7.34 (6H, m), 7.48 (1H, s), 7.55-7.56 (1H, m), 7.69 (21H, m).
Yield: 42%
1H NMR: 1.56 (3H, s), 2.41-2.52 (3H, m), 3.60 (2H, t, J=10.95 Hz), 3.96 (2H, dd, J=12.39 &e; 4.35 Hz), 5.17 (2H, s), 7.20-7.24 (3H, m), 7.34-7.43 (3H, m), 7.49 (3H, d, J=7.23 Hz), 7.66 (2H, dd, J=8.67 & 4.17 Hz).
Yield: 47%
1H NMR: 1.54 (3H, s), 2.29 (3H, s), 2.37 (3H, s), 2.97 (2H, t, J=6.69 Hz), 3.51-3.55 (2H, m), 3.91 (2H, dd, J=12.57 & 4.2 Hz), 4.21 (2H, t, J=6.72 Hz), 6.82 (2H, d, J=8.55 Hz), 6.99 (2H, d, J=8.52 Hz), 7.41 (3H, m), 7.95-7.99 (2H, dd, J=7.83 & 2.88 Hz).
Yield: 32%.
1H NMR: 1.3 (9H, s), 1.5 (3H, s), 2.3 (3H, m), 2.35 (3H, s), 3.5 (2H, t, J=10.9 Hz), 3.9 (2H, m), 4.9 (2H, s), 6.4 (1H, s), 6.8 (2H, d, J=8.5 Hz), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.1 Hz), 7.4 (2H, d, J=8.3 Hz).
Yield: 72%.
1H NMR: 1.54 (3H, s), 2.27 (3H, s), 2.36 (3H, s), 2.38 (3H, s), 2.98 (2H, t, J=6.72 Hz), 3.52 (2H, t, J=10.74 Hz), 3.90 (2H, m), 4.20 (2H, t, J=6.66 Hz), 6.81 (2H, d, J=8.46 Hz), 6.95 (2H, d, J=8.46 Hz), 7.23 (2H, d, J=8.34 Hz), 7.85 (2H, d, J=8.13 Hz).
Yield: 32%.
A mixture of Methyl-5-trans-(4-hydroxy-benzyl)-2-methyl-[1,3]dioxane-2-carboxylate (isolated from the mother liquor after the crystallization of cis isomer in step 2 of example 2 above) (750 mg), 12-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl methane sulfonate (790 mg) and potassium carbonate (780 mg) in anhydrous dimethyl formamide (10 mL) was stirred at 80° C. for extended periods in an inert atmosphere. Reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel using a mixture of ethyl acetate and petroleum ether as eluent to obtain 971 mg of pure product.
To a solution of Methyl-2-methyl-5-trans-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-[1,3]dioxane-2-carboxylate (263 mg) in methanol was added another solution of sodium hydroxide (46.5 mg) in water and the reaction mixture was stirred at ambient temperature for 15 hours. Solvents were evaporated and the residue was dissolved in water, acidified with 1N HCl and extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel using 2% methanol in chloroform as eluent to obtain 160 mg of pure product.
1H NMR: 1.61 (3H, s), 2.38 (4H, s), 2.87 (2H, d, J=7.8 Hz), 3.01 (2H, t, J=6.90 Hz), 3.72 (2H, d, J=10.95 Hz), 3.92 (2H, d, J=9.51 Hz), 4.21 (2H, t, J=6.99 Hz), 6.82 (2H, d, J=8.55 Hz), 7.06 (2H, d, J=8.511 Hz), 7.41-7.45 (3H, m), 7.96 (2H, dd, J=4.35 & 7.74 Hz).
Yield: 52%
The following compounds were prepared by procedure similar to those described in example 121 with appropriate variations of reactants, reaction conditions and quantities of reagents.
Sodium and potassium sales of the compounds described above were prepared by following the general procedure described below.
To a solution of carboxylic acid derivatives of the novel compounds (1 mmol) in alcoholic solvent like methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like was added a solution of sodium or potassium alkoxide (0.95 mmol) in alcoholic solvent and the reaction mixture was stirred for 3 hours at 25-30° C. Solvent was evaporated and the residue was triturated with dry diethyl ether or diisopropyl ether to obtain the salt of the corresponding carboxylic acid.
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 vitro as well as in vivo animal experiments.
In vitro hPPAR α & hPPARγ activities were determined as per in-house protocols and the results of representative compounds are provided below as a proof of the efficacies of the novel class of compounds disclosed above.
i) Serum Triglyceride and Total Cholesterol Lowering Activity in Swiss Albino Mice:
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 was used. The protocol approved by Institutional Animal Ethics Committee is being used.
The test compounds were administered orally to Swiss albino mice at 0.001 to 50 mg/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 Carboxymethyl cellulose; 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:
ii) Serum triglyceride and total cholesterol lowering activity in Hamster of Syrian golden stain:
Male and Female Hamster of Syrian golden stain were bred in Zydus animal house. All these animals were maintained under 12-hour light and dark cycle at 22±3 degree C. The protocol approved by Institutional Animal Ethics Committee is being used. Animals of 3-12 weeks age (80-150 gm body weight) were taken for study. Near the end of the acclimatization period, animals judged to be suitable for testing will bee weighed. Six animals will be selected for normal NIN (NIN, Hyderabad, India) diet average bodyweight was not significantly different from the rest of the animals. Other animals were put on HF-HC (High fat and high cholesterol) diet for 14 days. On day 14 all the HF-HC diet fed animals were selected which had gained their body weight significantly more than the normal diet group animals. The selected animals were divided into different groups in such a way that the average bodyweight of the animals in each group was not significantly different from the other groups.
Each animal received a single dose of ZY compounds at 0.001 to 50 mg/kg/ as a carbomethoxy cellulose or polyethylene glycol in the evening administered as an oral gavage daily for 15 days. On day 14, after 1 hr of dose administration, non-fasted blood samples were collected in non heparinized capillary from animals for determination of total cholesterol (TC), triglyceride (TG) (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 (Pointe Scientific.Inc.USA.) And on day 14 night all animals will be kept for fasting for 12-16 hours. On day 15, after 1 hour of dose administration fasted blood samples will be collected from animals for determination of high density lipoprotein (HDL), and low density lipoprotein (LDL) in serum. The animals will then be euthanized by carbon-dioxide asphyxia (and cervical dislocation, if necessary) and heart, kidney and liver will be resected and weighed.
Percentage reduction in triglycerides/total cholesterol were calculated according to the formula:
Percentage reduction(%)=(TT−TC)/TC*100
TC=Test day control group TT=Test day treated group.
The compounds of the present invention improves insulin sensitivity, impaired glucose tolerance and reduced serum glucose levels, TG, FFA and cholesterol in db/db, ob/ob mice and zucker fa/fa rats.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 901/MUM/2004 | Aug 2004 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN05/00215 | 6/24/2005 | WO | 00 | 8/17/2007 |
