Patent Application
20110301200
The present invention relates to novel compounds of general formula (I) which are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta including their tautomeric forms, isomers including their stereo & regioisomers, their pharmaceutically acceptable salts, their polymorphic forms as well as novel intermediates involved in their synthesis. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.
Thyroid hormones (TH) are synthesized in the thyroid in response to thyroid stimulating hormone (TSH), which is secreted by the pituitary gland. Production of T4, and T3, by the thyroid gland is under negative feedback control. TSH, also known as thyrotropin, is responsible for normal thyroid gland function and thyroid hormone secretion. It is synthesized in the anterior pituitary gland, and its secretion is controlled by thyroid releasing hormone (TRH) that is synthesized in the hypothalamus.
The natural thyroid hormones (TH) T3 and T4 is an important endocrine signaling hormone. Thyroid hormones are iodinated tyrosine analogues excreted into the circulation primarily as T4. T4 is converted to T3 rapidly by deiodination in local tissues which is the most potent thyroid hormone. It plays important role in normal development, differentiation and maintenance of metabolic balance, control of cholesterol levels through interaction with thyroid hormone receptors (THR). Natural thyroid hormone, T3 exhibit its physiological effect by acting on a Thyroid Hormone Receptor (THR), which belongs to the nuclear hormone receptor super family. There are two different isoforms of Thyroid Hormone Receptors, THR-α and THR-β. Further, these two isoforms are sub-classified as α1; α2 and β1; β2 subtypes. THRβ1 is prevalent in liver (85%), while THR α1 is mainly present in cardiac tissue (Yen P. M. Physiol. Rev; 2001; 81:1097-1142).
At normal levels, T3 maintains body weight, metabolic rate, body temperature, mood and regulate serum cholesterol. Hypothyroidism is associated with weight gain, high levels of low-density lipoproteins (LDL) cholesterol and depression. Hyperthyroidism leads to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, bone loss and anxiety.
The natural thyroid hormone T3 does not show any selectivity in binding to both of the THR isoforms (THR α1 and THR β1). Thus, administration of T3 lowers plasma cholesterol, low-density lipoprotein (LDL) and triglyceride levels in animal models and humans. However, T3 cannot be used therapeutically to treat hypercholesterolemia and obesity due to its cardiac side effects such as tachycardia and arrhythmia. However, knockout animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the THR α1 isoform. Thus, some effects of T3 may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation (Cheng S. Steroids; 2005; 70: 450-454).
Development of specific and selective thyroid hormone receptor ligands, particularly THR β agonist could lead to specific therapies for disorders such as obesity and hyperlipidemia, while avoiding the cardiovascular and other toxicities of native thyroid hormones. Thus, compounds mimicking only the beneficial effects of the thyroid hormone and lacking their cardiac side effects (tachycardia and arrhythmia) potentially could be used to treat a number of conditions such as obesity and dyslipidemia. In this regard, THR agonists that interact selectively with the β isoform of the THR offer an especially attractive method for avoiding cardiotoxicity (J. D. Baxter. Trends Endocrinol. Metab. 2004;15:154-157). Selective THR β agonist exhibit modest cardiac sparing in rodents and primates and lower lipids but it may induce the THR β mediated suppression of the THA.
Two strategies have been attempted for the development of Thyromimetics.
One is by making isoform selective compounds (Johan Malm, J. Med. Chem. 2003, 46, 1580-1588) and another is by making Liver selective Thyromimetics (Mark D. Erion, PNAS 2007 15490-15495). Liver selective compounds are expected not to suppress the thyroid hormone axis (THA). Thus thyromimetic which has isoform selectivity incorporated with liver selectivity can be expected to be devoid of cardiac toxicity and will not suppress THA.
Various compounds have been disclosed as possible agonists of THR including those which claim to be liver selective. Some of the more relevant ones for the present invention includes WO 0039077, WO 2004067482, U.S. Pat. No. 6,344,481, U.S. Pat. No. 6,787,652, US20070173548, WO2006128058, WO 20080221210 and WO 2009089093 which are incorporated herein as reference.
However, none of these compounds have been commercially developed and looking at the beneficial potential and medical need for such compounds, specifically compounds having better liver selectivity while retaining its therapeutic efficacy, there remains a need for developing further compounds with better therapeutic and/or safety profile. Herein, we disclose novel compounds which shows activity as THR β agonists, some of which also have better liver selectivity.
The present invention describes novel compounds that are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta 1, which are useful for the treatment of a number of conditions such as obesity and dyslipidemia. The novel compounds are defined by the general formula (I) as given below.
The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of selective thyroid hormone receptor gene expression. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of obesity and dyslipidemia.
The main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of obesity and dyslipidemia.
In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, isomers including their stereo & regioisomers, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphic forms and pharmaceutical compositions containing them.
In another embodiment is provided pharmaceutical compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of obesity and dyslipidemia, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
Accordingly, the present invention relates to compounds of the general formula (I),
wherein R═OR1, NHR1
In a still preferred embodiment, the aryl group is selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl groups; the heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl group;
The substituents on alkyl, aryl, aralkyl, aryloxy, aralkoxy, heteroaryl or cycloalkyl groups as defined above may be selected from hydroxyl, halo, cyano, optionally substituted groups selected from (C1-C6)alkyl, haloalkyl; alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups, with the further option that when any of these groups are further substituted, the substituents on these substitutes may be selected from any of the groups described above;
In a still preferred embodiment, the substitutions on R2 when present, is selected from halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy 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.
Preferred compounds according to the present invention include but not limited to:
The compounds of this invention may be prepared using the reactions and techniques described in the following section including the schemes 1-4. 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. It will also be appreciated that some routine alterations/modifications including requirement of one or more additional steps which may be required for obtaining the compounds of the present invention in preferred yields but are considered to be within the scope of a person skilled in the art, are to be considered to be within the scope of the present invention.
Reacting protected phenol of formula 2, wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein), & R2 is as defined earlier, with aldehyde compound of formula 3 wherein R3 and R4 are as defined earlier and ‘Z’ is halogen, to give coupled product 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K2CO3, NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R7 & R8 are as defined earlier) using suitable base such as K2CO3, Cs2CO3, KOH, NaH and the like afforded ester compound of formula 6. Deprotection and hydrolysis of compound 6 using appropriate reagents will lead to compound of formula (I).
Reacting protected phenol of formula 2, wherein ‘PG’ represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, John Wiley &
Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein), & R2 is as defined earlier, with aldehyde compound of formula 3 wherein R3 and R4 are as defined earlier and ‘Z’ is halogen to give coupled product 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K2CO3, NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R7 & R8 are as defined earlier) using suitable base such as K2CO3, Cs2CO3, KOH, NaH afforded ester compound 6. Compound of formula 6 was reacted with suitable aromatic acids or suitable aromatic acid chlorides and appropriate acylating agents to obtain compound of Formula 7. Deprotection and hydrolysis of compound of formula 7, using suitable reagents & techniques as is known in the art, gives compound of formula (I)
Starting from compound of formula 7 (Scheme 2) deprotection and then reduction of carbonyl group using suitable reducing agents like NaBH4, LAH and the like in suitable solvents like THF, Diethyl ether etc. to afford compound of formula 9. Finally hydrolysis of compound of formula 9, using suitable reagents & techniques as is known in the art, gives compound of formula (I)
Reacting protected phenol of formula 2, wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein), with aldehyde compound of formula 3 wherein R3 and R4 are as defined earlier and Z is halogen to give coupled product of formula 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K2CO3, NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R7 & R8 are as defined earlier) using suitable base such as K2CO3, Cs2CO3, KOH, NaH and the like afforded ester compound 6. Compound of formula 6 was reacted with chlorosulfonic acid at suitable temp. to give chlorosulfonated product of formula 7 which was then reacted with suitable aliphatic or aromatic amine R5R6NH, (where R5 & R6 are as defined earlier) to afford compound of formula 8, on deprotection and hydrolysis of compound 8 gives compound of formula (I).
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.
1H NMR spectral data given in the examples (vide infra) are recorded using either a 300 MHz spectrometer (Bruker AVANCE-300) or a 400 MHz spectrometer (Bruker Avance2) 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 3-isopropyl-4-methoxyphenol (0.37 g, 2.22 mmol) in DMF (3.7 mL) was added K2CO3 (0.50 g, 3.64 mmol) and 3,5-dichloro-4-iodobenzaldehyde (0.61 g, 2.02 mmol). The reaction was stirred at 130-135° C. for 5 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethylacetate 90:10) to afford pure 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde. (0.2g, 30% yield)
1H NMR:(CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 3.27-3.30(1H, m), 3.79(3H, s), 6.44-6.47 (1H, dd, J=3.2&9.2 Hz), 6.70(1H, d, J=8.8 Hz), 6.85(1H, d, J=3.2 Hz), 7.91(2H, s).
A mixture of 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde (0.2 g, 0.589 mmol) in EtOH (0.4 mL) and H2O (0.6 mL) and Hydroxyl amine hydrochloride (0.04 g, 0.589 mmol) was heated at 75° C. for 3 hrs. The reaction mixture was poured over ice. The product was taken up in, ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to afford pure 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde oxime (0.19 g, 91%).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=7.2 Hz), 3.24-3.31(1H, m), 3.78(3H, s), 6.44-6.47 (1H, dd, J=2.8&8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.84(1H, d, J=2.8 Hz), 7.61(214, s), 8.05(1H, s).
To a solution of 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde oxime (0.19 g, 0.536 mmol) in DMF (1.5 mL) was added Cs2CO3 (0.26 g, 0.805 mmol). To that added Ethyl bromo acetate (0.1 g, 0.59 mmol) and the reaction mixture was stirred at 20-25° C. for 3 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethylacetate 90:10) to afford pure Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4-methoxy phenoxy)benzylidene)amino)oxy)acetate as an oil (0.19 g, 80%).
1H NMR:(CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 1.27-1.29(3H, m),3.24-3.31(1H, m), 3.78 (3H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.3-6.46(1H, dd, J=3.2&8.8 Hz), 6.70(1H, d, J=9.2 Hz), 6.83 (1H, d, J=3.2 Hz), 7.61(2H, s), 8.12 (1H, s).
To a solution of Ethyl 2-(4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichloro benzylidene aminooxy)acetate (0.19 g, 0.431 mmol) in dichloromethane (1.9 mL) was cooled to −60 to −70° C. under N2 atomsphere. To that 1M BBr3 solution in dichloromethane (1.72 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25° C. over 5 h. then diluted with more CH2Cl2 (25 mL) and quenched with H2O. After stirring at 20-25° C. for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (chloroform:methanol) gradient elution from 95:5 to 90:10 to give pure 2-(((3,5-dichloro-4-(4-hydroxy-3-isopropyl phenoxy)benzylidene)amino)oxy)acetic acid (0.065 g, 38%).
1H NMR:(DMSO-D6, 400 MHz): 1.10(6H, d, J=6.8 Hz), 3.16-3.17(1H, m), 4.65(2H, s), 6.30-6.33(1H, dd, J=3.2&8.8 Hz), 6.64-6.69(2H, m), 7.80(2H, s), 8.34(1H, s).
Using appropriate starting materials and suitable modifications of one or more of the process steps described above, either alone or in suitable combination, including suitable addition and/or deletion of steps as may be necessary, & which are well within the scope of a person skilled in the art, the following compounds were prepared in an analogous manner
1H NMR:(CDCl3, 400 MHz): 0.85(3H, t, J=7.4 Hz), 1.19(3H, d, J=6.8 Hz), 1.51-1.63(2H, m), 2.89-2.95(1H, m), 4.79(2H, s), 6.40-6.43(1H, dd, J=2.8&8.8 Hz), 6.64(1H, d, J=8.8 Hz), 6.72(1H, d, J=2.8 Hz), 7.60(2H, s), 8.11(1H, s). % Yield: 61%
1H NMR:(CDCl3, 400 MHz): 1.22(6H, d, J=6.8 Hz), 3.13-3.20(1H, m), 4.79(2H, s), 6.36-6.39 (1H, dd, J=3.2&8.8 Hz), 6.63(1H, d, J=8.8 Hz), 6.79(1H, d, J=2.8 Hz), 7.82(2H, s), 8.12(1H, s). % Yield: 66%
1H NMR:(CD3OD, 400 MHz): 4.57(2H, s), 6.58-6.61(1H, dd, J=3.2&8.8 Hz), 6.70(1H, d, J=3.2 Hz), 6.81(1H, d, J=8.8 Hz), 7.28(1H, d, J=7.6 Hz), 7.36(2H, t, J=7.6 Hz), 7.49(2H, d, J=7.2 Hz), 7.73(2H, s), 8.16(11-1, s). % Yield: 13%
2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dichlorobenzylidene)amino)oxy)acetic acid
1H NMR:(CD3OD, 400 MHz): 3.87(2H, s), 4.71(2H, s), 6.42-6.43(1H, m), 6.46(1H, d, J=2.8 Hz), 6.69(1H, d, J=8.4 Hz), 7.11-7.16(3H, m), 7.19-7.23(2H, m), 7.68(2H, s), 8.18(1H, s). % Yield: 55%
1H NMR:(CDCl3, 400 MHz): 0.86(3H, t, J=7.2 Hz), 1.17(3H, d, J=6.8 Hz), 1.48-1.62(2H, m), 2. 97-3.02(1H, m), 4.68(2H, s), 6.36-6.39(1H, dd, J=2.4&8.4 Hz), 6.64(1H, d, J=8.4 Hz), 6.68(1H, d, J=2.8 Hz), 7.80(214, s), 8.10(1H, s). % Yield: 29%
1H NMR: (CDCl3, 400 MHz): 4.79(2H, s), 6.69-6.75(2H, m), 6.91(1H, d; J=8.8 Hz), 7.45-7.48 (5H, m), 7.82(2H, s), 8.11(1H, s). % Yield: 23%
1H NMR:(CDCl3, 400 MHz): 1.22(6H, d, J=7.2 Hz), 1.60(3H, d, J=6.8 Hz), 3.15-3.18(114, m), 4.88-4.90(1H, m), 6.37-6.40(1H, dd, J=2.8 &8.8 Hz), 6.62(1H, d, J=8.8 Hz), 6.81(1H, d, J=3.2 Hz), 7.60(2H, s), 8.09(1H, s). % Yield: 59%
1H NMR:(CDCl3, 400 MHz): 3.93(2H, s), 4.77(2H, s), 6.66(1H, d, J=3.2 Hz), 6.69-6.71(2H, m), 7.18-7.30(5H, m), 7.79(2H, s), 8.10 (1H, s). % Yield: 58%
1H NMR:(CDCl3, 400 MHz): 1.22(6H, d, J=7.2 Hz), 1.60(3H, d, J=6.8 Hz), 3.08-3.20(1H, m), 4.86-4.91(1H, q, J=7.2 Hz), 6.34-6.37(1H, dd, J=3.2&8.8 Hz), 6.62(1H, d, J=8.8 Hz), 6.80(1H, d, J=3.2 Hz), 7.80(2H, s), 8.07(111, s). % Yield: 43%
1H NMR:(CDCl3, 400 MHz): 1.59(3H, d, J=7.2 Hz), 4.85-4.91(1H, q, J=6.8&7.2 Hz), 6.69(1H, d, J=2.8 Hz), 6.72-6.75(1H, d, J=3.2&8.8 Hz), 6.91(1H, d, J=8.4 Hz), 7.37-7.52(5H, m), 7.80(2H, s), 8.01(1H, s). % Yield: 90%
1H NMR:(CDCl3, 400 MHz): 1.22(6H, d, J=7.2 Hz), 1.63(6H, s), 3.13-3.20(1H, m), 6.36-6.38 (1H, dd, J=3.2&8.8 Hz), 6.62(1H, d, J=8.4 Hz), 6.80(1H, d, J=3.2 Hz), 7.80(2H, s), 8.05(1H, s). % Yield: 96%
1H NMR:(DMSO-D6, 400 MHz): 0.95(3H, t, J=6.4 Hz), 1.10(6H, d, J=7.2 Hz), 1.77-1.86(2H, m), 3.10-3.17(1H, m), 4.56-4.60(1H, m), 6.26-6.29(1H, dd, J=3.2 &8.8 Hz), 6.64-6.66(2H, m), 7.95 (2H, s), 8.33(1H, s). % Yield: 84%
1H NMR:(CDCl3, 400 MHz): 0.85(3H, t, J=7.2 Hz), 1.26(314, d, J=7.2 Hz), 1.41-1.66(5H, m), 2.88-2.95(1H, m), 4.85-4.91(1H, q, J=7.2 Hz), 6.38-6.41(1H, dd, J=2.8 Hz&8.8 Hz), 6.64(1H, d, J=8.8 Hz), 6.71(1H, d, J=2.8 Hz), 7.80(2H, s), 8.08(1H, s). % Yield: 10%
1H NMR:(DMSO-D6, 400 MHz): 0.76(3H, t, J=7.2 Hz), 1.06(3H, d, J=6.8 Hz), 1.41-1.54(8H, m), 2.90-2.96(1H, m), 6.31-6.33(1H, dd, J=2.8&8.8 Hz), 6.58(1H, d, J=2.4 Hz), 6.66(1H, d, J=8.8 Hz), 7.93(2H, s), 8.25(1H, s). % Yield: 87%
1H NMR:(DMSO-D6, 400 MHz): 1.41(3H, d, J=6.8 Hz), 3.80(2H, s), 4.72(1H, q, J=6.8 Hz), 6.37-6.40(1H, dd, J=2.8&5.6 Hz), 6.57(1H, d, J=3.2 Hz), 6.69(1H, d, J=8.8 Hz), 7.11-7.25(5H, m), 7.93(2H, s), 8.30(1H, s). % Yield: 54%
1H NMR:(CDCl3, 400 MHz): 0.95(3H, m), 1.05-1.20(2H, m), 3.93(2H, s), 4.73(1H, m), 6.49-6.51(1H, m), 6.69(2H, m), 7.14-7.34(5H, m), 7.78(2H, s), 8.10(1H, s) % Yield: 58%
1H NMR:(DMSO-D6, 400 MHz): 0.76(3H, t, J=7.2 Hz), 1.06(3H, d, J=6.8 Hz), 1.41-1.52(2H, m), 2.90-2.96(1H, m), 5.69(1H, s), 6.31-6.34(1H, dd, J=2.8&8.8 Hz), 6.57(1H, d, J=2.8 Hz), 6.66 (1H, d, J=8.8 Hz), 7.40-7.45(3H, m), 7.47-7.5(2H, m), 7.96(2H, s), 8.40(1H, s). % Yield: 53%
1H NMR:(CD3OD, 400 MHz): 0.81(3H, t, J=7.4 Hz), 1.06(3H, t, J=7.6 Hz), 1.12(3H, d, J=7.2 Hz), 1.50-1.56(2H, m), 1.89-1.95(2H, m), 2.99-3.03(1H, m), 4.67(1H, t, J=6.2 Hz), 6.35-6.38(1H, dd, J=2.8&8.4 Hz), 6.56(1H, d, J=2.8 Hz), 6.65(1H, d, J=8.4 Hz), 7.91(2H, s), 8.18(1H, s). % Yield: 69%
1H NMR:(CD3OD, 400 MHz): 1.56(6H, s), 6.57-6.60(1H, dd, J=3.2 &8.8 Hz), 6.67(1H, d, J=3.2 Hz), 6.81(1H, d, J=9.2 Hz), 7.27(1H, t, J=7.2 Hz), 7.36(2H, t, J=7.6 Hz), 7.49(2H, d, J=7.2 Hz), 7.91(2H, s), 8.11(1H, s). % Yield: 49%
1H NMR:(DMSO-D6, 400 MHz): 0.95(3H, t, J=7.6 Hz), 1.77-1.86(2H, m), 4.57(1H, t, J=6 Hz), 6.59-6.62(1H, dd, J=3.2&8.8 Hz), 6.68(1H, d, J=3.2 Hz), 6.87(1H, d, J=8.8 Hz), 7.27(1H, t, J=7.2 Hz), 7.37(2H, t, J=7.2 Hz), 7.47(2H, d, J=7.6 Hz), 7.96(2H, s), 8.33(1H, s). % Yield: 58%
1H NMR:(DMSO-D6, 400 MHz): 1.46(6H, s), 3.80(2H, s), 6.38-6.41(1H, dd, J=3.2&8.8 Hz), 6.56(1H, d, J=3.2 Hz),6.70(1H, d, J=8.8 Hz), 7.11-7.25(5H, m), 7.91(2H, s), 8.23(1H, s). % Yield: 50%
1H NMR:(CDCl3, 400 MHz): 0.85(3H, t, J=7.6 Hz), 1.19(3H, d, J=6.8 Hz), 1.52-1.60(2H, m), 1.64(3H, d, J=7.2 Hz), 2.90-2.97(1H, m), 4.87-4.91(1H, m), 6.42(1H, dd, J=2.8 Hz&8.4 Hz), 6.63 (1 H, d, J=8.4 Hz), 6.74(111, s), 7.59(2H, s), 8.08(1H, s). % Yield: 45%
1H NMR:(CDCl3, 400 MHz): 1.38(9H, s), 1.66(3H, d, J=7.2 Hz), 4.88(1H, q, J=7.2 Hz), 6.32-6.34(1H, dd, J=3.2 Hz & 8.8 Hz), 6.53(1H, d, J=8.8 Hz), 6.92(1H, d, J=3.2 Hz), 7.80(2H, s), 8.08 (1H, s). % Yield: 30%
1H NMR:(CDCl3, 400 MHz): 1.21(3H, t, J=7.2 Hz), 1.60(3H, d, J=6.8 Hz), 2.56-2.62(2H, q, J=7.2&7.6 Hz), 4.86-4.91(1H, q, J=6.8&7.2 Hz), 6.42-6.45(1H, dd, J=2.8&8.8 Hz), 6.65(1H, d, J=8.4 Hz), 6.68(1H, d, J=2.8 Hz), 7.81(2H, s), 8.18(1H, s). % Yield: 50%
To a solution of 4-methoxyphenol (1.6 g, 12.9 mmol) in DMF (16 mL) was added K2CO3 (3.25 g, 25.8 mmol) and 3,5-bromo-4-iodobenzaldehyde (4.6 g, 12.9 mmol). The reaction was stirred at 130-135° C. for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to afford pure 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde (2.0 g, 44% yield)
A mixture of 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde (2.0 g, 5.18 mmol) in EtOH (14 mL) and H2O (14 mL) and hydroxyl amine hydrochloride (1.44 g, 20.74 mmol) was heated at 90° C. for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to afford pure 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde oxime (1.92 g, 96%).
1H NMR:(CDCl3, 400 MHz): 3.77(3H, s), 6.74-6.76 (2H, m), 6.82-6.89 (2H, m), 7.82 (2H, s), 8.03 (1H, s).
To a solution of 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde oxime (0.6 g, 1.496 mmol) in DMF (3.75 mL) was added Cs2CO3 (0.73 g, 2.24 mmol). To that was added Ethyl-2-bromo propanoate (0.29 g, 1.64 mmol) and then reaction mixture was stirred at 20-25° C. for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 95:05) to afford pure ethyl 2-(((3,5-dibromo-4-(4-methoxyphenoxy)benzylidene)amino)oxy)propanoate as an oil (0.68 g, 90%).
1H NMR: (CDCl3, 400 MHz): 1.30-1.35(3H, m), 1.51-1.53(3H, m), 3.77(3H, s), 4.22-4.28(2H, q, J=7.2 Hz), 4.79-4.85(1H, q, J=7.2 Hz), 6.74(2H, d, J=9.2 Hz), 6.82(2H, d, J=9.2 Hz), 7.79(2H, s), 8.07(1H, s).
A mixture of ethyl 2-(((3,5-dibromo-4-(4-methoxyphenoxy)benzylidene)amino)oxy)propanoate (0.5 g, 0.998 mol) and 4-chlorobenzoic acid (0.31 g, 1.99 mmol) in Eaton's reagent (6.33 mL) was heated at 95° C. for 16 h. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 95:05) to afford pure ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-methoxy phenoxy)benzylidene)amino)oxy)propanoate (0.143 g, 28%).
1H NMR: (CDCl3, 400 MHz): 1.22-1.27(3H, m), 1.45-1.58(3H, m), 3.69(3H, s), 4.23-4.28(2H, m), 4.81-4.87(1H, m), 6.82(1H, d, J=2.8 Hz), 6.91-6.98(2H, m), 7.24(1H, m), 7.39-7.42(2H, d, J=8.4 Hz), 7.73-7.77(3H, m), 8.19(1H, s)
A solution of ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy)benzylidene)amino)oxy)propanoate (0.143 g, 0.223 mmol) in dichloromethane (1.4 mL) was cooled to −60 to −70° C. under N2 atomsphere. To that 1M BBr3 solution in dicloromethane (0.89 mL) was added dropwise. The reaction mixture was allowed to warm up to −20° C. over 2 h. Then diluted with more CH2Cl2 (25 mL) and quenched with H2O. After stirring at 20-25° C. for 10 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (hexane:ethylacetate 95:05) to give pure ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy)benzylidene)amino)oxy)propanoate. (0.139 g, 100%).
1H NMR: (CDCl3, 400 MHz): 1.22-1.27 (3H, m), 1.45-1.58(314, m), 4.23-4.28(2H, m), 4.81-4.87 (1H, m), 6.97-7.06(3H, m), 7.44(2H, d, J=8.8 Hz), 7.63(2H, d, J=8.4 Hz), 7.77(2H, s), 8.19(1H, s).
The ester obtained from step 5 above (0.139 g, 0.22 mmol) was dissolved in EtOH (0.84 mL) and to that solution of NaOH (0.011 g, 0.29 mmol) in H2O (0.42 mL) was added and it was stirred at 50° C. for 2 hr. Ethanol was evaporated from the reaction mixture and H2O was added & washed with diethyl ether. The aqueous layer was acidified to pH 4 using 10% HCl solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give pure product 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid (0.04 g, 30%)
1H NMR: (CD3OD, 400 MHz): 1.52 (3H, d, J=6.8 Hz), 4.79-4.81(1H, m), 6.76(1H, d, J=2.8 Hz), 7.02 (1H, d, J=8.8 Hz), 7.12-7.15(1H, dd, J=3.2&9.2 Hz), 7.49(2H, d, J=8.4 Hz), 7.66(2H, d, J=8.8 Hz), 7.92(2H, s), 8.14(1H, s).
To a solution of ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy)benzylidene)amino)oxy)propanoate (0.25 g, 0.39 mmol Example 26, step 5 above) in MeOH (2.5 mL) was added NaBH4 (13mg, 0.35 mmol) at 0-10° C. The reaction was stirred at same temperature for 2-3 hrs. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to afford pure ethyl 2-(((3,5-dibromo-4-(3-((4-chlorophenyl)(hydroxy)methyl)-4-hydroxy phenoxy)benzylidene)amino)oxy)propanoate (0.25 g, 100%) which was hydrolyzed similar to the procedure given in (Example 26, step 6) to afford 2-(((3,5-dibromo-4-(3-((4-chlorophenyl)(hydroxy)methyl)-4-hydroxy phenoxy)benzylidene)amino)oxy)propanoic acid (0.113 g, 62%)
1H NMR: (CD3OD, 400 MHz): 1.50(3H, d, J=7.2 Hz), 4.77-4.79(1H, m), 6.00(1H, s), 6.53-6.56 (1H, dd, J=3.2&8.8 Hz), 6.68(1H, d, J=8.8 Hz), 6.79(1H, d, J=2.8 Hz), 7.25(2H, d, J=8.8 Hz), 7.31 (2H, d, J=8.4 Hz), 7.90(2H, s), 8.15(1H, s).
Using appropriate starting materials and suitable modifications of one or more of the processes described above, either alone or in suitable combination of the steps disclosed therein, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art, the following compounds (Examples 28-35) were prepared in an analogous manner to that of Examples 26 & 27
1H NMR:(DMSO-D6, 400 MHz): 4.63(2H, s), 6.74(1H, m), 6.92(2H, m), 7.57(2H, d, J=8.4 Hz), 7.68(2H, d, J=8.8 Hz), 7.97(2H, s), 8.32(1H, s). % Yield: 9%
1H NMR:(DMSO-D6, 400 MHz): 4.57(2H, s), 5.82-5.85(1H, m), 6.46-6.49(1H, dd, J=3.2&8.8 Hz), 6.67(1H, d, J=8.8 Hz), 6.88(1H, d, J=3.2 Hz), 7.30(4H, m), 7.96(2H, s), 8.31(1H, s). % Yield: 58%
1H NMR: (DMSO-D6, 400 MHz): 1.41(3H, d, J=6.8 Hz), 4.71-4.72(1H, m), 6.74(1H, d, J=3.2 Hz), 6.93-6.99(2H, m), 7.54(1H, d, J=8.0 Hz), 7.61-7.62(2H, m), 7.69(1H, d, J=8.8 Hz), 7.96(2H, s), 8.30(1H, s). % Yield: 24%
1H NMR: (DMSO-D6, 400 MHz): 4.63(2H, s), 6.74(1H, m), 6.92(2H, m), 7.60(2H, d, J=8.8 Hz), 7.72(2H, d, J=8.4 Hz), 7.97(2H, s), 8.32 (1H, s). % Yield: 8%
1H NMR: (DMSO-D6, 400 MHz): 4.61(2H, s), 5.82(1H, s), 6.46-6.49(1H, dd, J=3.2&8.8 Hz), 6.67(1H, d, J=8.8 Hz), 6.88(1H, d, J=3.2 Hz), 7.24(2H,d, J=8.4 Hz), 7.44(2H, d, J=8.4 Hz), 7.97 (2H, s), 8.32(1H, s). % Yield: 60%
1H NMR: (DMSO-D6, 400 MHz): 4.58(2H, s), 6.72(1H, d, J=2.8 Hz), 6.94-6.98(2H, m), 7.53(1H, m), 7.61-7.62(2H, m), 7.69(1H, d, J=8.4 Hz), 7.97(2H, s), 8.34(1H, s). % Yield: 16%
1H NMR:(DMSO-D6, 400 MHz): 1.41(3H, d, J=6.8 Hz), 4.86-4.91(1H, q, J=6.8&7.2 Hz), 5.89 (1H, s), 6.50-6.53(1H, m), 6.68(1H, d, J=8.8 Hz), 6.87(1H, d, J=3.2 Hz), 7.23-7.29(4H, m), 7.96 (2H, s), 8.31(1H, s). % Yield: 20%
1H NMR:(DMSO-D6, 400 MHz): 4.66(2H, s), 5.85(1H, m), 6.50-6.53(1H, dd, J=3.2&8.8 Hz), 6.68(1H, d, J=8.4 Hz), 6.87(1H, d, J=3.2 Hz), 7.21-7.31(4H, m), 7.97(2H, s), 8.32(1H, s). % Yield: 49%
Chlorosulfonic acid (0.99 g) was added to ethyl 2-(((3,5-dibromo-4-(4-methoxy phenoxy)benzylidene)amino)oxy)propanoate (Example 26, step 3) (0.89 g, 1.59 mmol) at 0-10° C. The reaction was stirred at 25° C. for 1 hr. Reaction mixture was poured in to ice-H2O and taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate to afford ethyl 2-(((3,5-dibromo-4-(3-(chlorosulfonyl)-4-methoxy phenoxy)benzylidene)amino)oxy)propanoate (1 g, 100% yield)
To a solution of ethyl 2-(((3,5-dibromo-4-(3-(chlorosulfonyl)-4-methoxy phenoxy)benzylidene)amino)oxy)propanoate (0.41 g, 0.68 mmol) in dichloromethane (4.0 mL) was added piperidine (0.11 g, 1.36 mmol) at 0-10° C. followed by triethyl amine (0.138 g, 1.36 mmol). The reaction mixture was stirred at 20-25° C. for 2 hrs. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane:ethyl acetate 90:10) to afford pure ethyl 24(3,5-dibromo-4-(4-methoxy-3-(piperidin-1-yl sulfonyl)phenoxy)benzylidene)amino)oxy)propanoate (0.2 g, 45% yield)
1H NMR:(CDCl3, 400 MHz): 1.22-1.26(3H, m), 1.33-1.52(9H, m), 3.10-3.13(4H, m), 3.81(3H, s), 4.16-4.21(2H, q, J=6.8 & 7.2 Hz), 4.73-4.78(1H, q, J=6.8 & 7.2 Hz), 6.87(1H, d, 6.90-6.93(1H, dd, J=2.8&8.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.73(2H, s), 8.00 (1H, s)
A solution of ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-1-yl sulfonyl)phenoxy)benzylidene)amino)oxy)propanoate (0.18 g, 0.277 mmol) in dichloromethane (1.8 mL) was cooled to −60 to −70° C. under N2 atomsphere. To that 1M BBr3 solution in dicloromethane (1.18 mL) was added dropwise. The reaction mixture was allowed to warm up to −20° C. over 4 h. then diluted with more CH2Cl2 (25 mL) and quenched with H2O. After stirring at 20-25° C. for 10 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (Chloroform:Methanol 95:05) to give pure 2-(((3,5-dibromo-4-(4-hydroxy-3-(piperidin-1 -ylsulfonyl)phenoxy)benzylidene)amino)oxy)propanoic acid (0.12 g, 68% Yield)
1H NMR:(CD3OD, 400 MHz): 1.49-1.52(6H, m), 1.57(3H, m), 3.10-3.13(4H, m), 4.87(1H, m), 6.94(1H, d, J=2.8 Hz), 6.98(1H, d, J=8.8 Hz), 7.03(1H, d, J=3.2 Hz), 7.96(2H, s), 8.17(1H, s).
Using appropriate starting materials and suitable modifications of one or more of the processes described above (Example 36) either alone or in suitable combination of the steps disclosed therein, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art, the following compounds (Examples 37-42) were prepared in an analogous manner
1H NMR: (CD3OD, 400 MHz): 1.03(6H, d, J=6.8 Hz), 1.51(3H, d, J=7.2 Hz), 3.31-3.34(1H, m), 4.80-4.82(1H, m), 6.95(1H, d, J=8.8 Hz), 7.00-7.03(2H, m), 7.95(2H, s), 8.17(1H, s). % Yield: 50%
1H NMR: (CD3OD, 400 MHz): 1.07(6H, t, J=7.2 Hz), 1.51(3H, d, J=6.8 Hz), 3.28-3.34(4H, m), 4.79-4.82(1H, m), 6.93(1H, d, J=8.8 Hz), 6.99(1H, d, J=3.2 Hz), 7.01-7.03(1H, m), 7.95(2H, s), 8.17(1H, s). % Yield: 54%
1H NMR: (CDCl3, 400 MHz): 1.11-1.22(6H, m), 1.51-1.55(4H, m), 1.61(3H, d, J=7.2 Hz), 3.11-3.14(1H, m), 4.89-4.91(11-1, m), 6.93(1H, d, J=2.8 Hz), 7.00(1H, d, J=8.8 Hz), 7.05-7.08(1H, dd, J=3.2&9.2 Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 57%
1H NMR:(CDCl3, 400 MHz): 1.25-1.27(3H, m), 1.41-1.48(4H,m), 1.60-1.67(4H,m), 2.06(1H, bs), 2.21(1H, bs), 3.12-3.13(1H, m), 4.87-4.92(1H, q, J=7.2 Hz), 6.92 (1H, d, J=2.8 Hz), 7.02 (1H, d, J=8.8 Hz), 7.06-7.09(1H, dd, J=2.8&9.2 Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 12%
1H NMR:(DMSO-D6, 400 MHz): 1.72(4H, t, J=6.8 Hz), 3.22(4H, t, J=6.6 Hz), 4.55(2H, s), 6.94 (1H, d, J=2.0 Hz), 7.00-7.05(2H, m), 7.99(2H, s), 8.31(1H, s). % Yield: 45%
1H NMR:(CDCl3, 400 MHz): 1.61(3H, d, J=7.2 Hz), 1.81(4H, t, J=3.4 Hz), 3.25(4H, t, J=6.8 Hz), 4.89-4.91(1H, q, J=7.2 Hz), 6.91(1H, d, J=3.2 Hz), 7.02(1H, d, J=9.2 Hz), 7.08(1H, dd, J=2.8 & 8.8 Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 52%
For the synthesis of the above mentioned compounds following intermediates were prepared.
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 1.27-1.29(3H, m),3.24-3.31(1H, m), 3.78 (3H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.43-6.46(1H, dd, J=3.2&8.8 Hz), 6.70(1H, d, J=9.2 Hz), 6.83(1H, d, J=3.2 Hz), 7.61(2H, s), 8.12(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.87-0.89(3H, m), 1.15(3H,d, J=7.2 Hz), 1.28-1.33(3H, m), 1.46-1.61(2H, m), 3.03-3.08(1H, m), 3.77(314, s), 4.23-4.29(2H, m), 4.72(2H, s), 6.47-6.50(1H, dd, J=3.2&9.2 Hz), 6.72(1H, d, J=8.8 Hz), 6.75-6.76(1H, m), 7.61(2H, s), 8.12(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 1.31(3H, t, J=7.8 Hz), 3.26-3.29(1H, m), 3.78(3H, s), 4.24-4.30(2H, q, J=7.2 Hz), 4.73(2H, s), 6.41-6.44(1H, dd, J=2.8&8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.82(1H, d, J=3.2 Hz), 7.81(2H, s), 8.11(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.25-1.32(3H, m), 3.76(3H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.75-6.78(1H, dd, J=3.2&9.2 Hz), 6.82(1H, d, J=3.2 Hz), 6.89(1H, d, J=8.8 Hz), 7.31(1H, t, J=7.2 Hz), 7.39(2H, t, 7.49(2H, d, J=7.2 Hz), 7.61(2H, s), 8.11(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.27-1.33(3H, m), 3.7(3H, s), 3.94(2H, s), 4.24-4.29(2H, q, J=6.8 Hz), 4.72(2H, s), 6.52-6.55(1H, dd, J=3.2&8.8 Hz), 6.67(1H, d, J=3.2 Hz), 6.73(1H, d, J=8.8 Hz), 7.17-7.19(3H, m), 7.24-7.27(2H, m), 7.58(2H, s), 8.10(1H, s).
1H NMR:(CDCl3, 400 MHz): 0.83(3H, t, J=7.2 Hz), 1.15(3H, d, J=6.8 Hz), 1.30(3H, t, J=6.8 Hz), 1.31(2H, q, J=7.2 Hz), 3.03-3.09(1H, m), 3.77(3H, s), 4.26(2H, q, J=6. Hz), 4.72(2H, s), 6.47(1H, m), 6.72(2H, d, J=8.8 Hz), 7.81(2H, s), 8.1(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.25-1.32(3H, m), 3.77(3H, s), 4.23-4.29(2H, m), 4.72(2H, s), 6.73-6.76(1H, dd, J=3.2&9.6 Hz), 6.81(1H, d, J=3.21 Hz), 6.90(1H, d, J=9.2 Hz), 7.30-7.31(1H, m), 7.37-7.41(2H, m), 7.50-7.52(2H, m), 7.82(2H, s), 8.11(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=7.2 Hz), 1.29(3H, d, J=7.2 Hz), 1.54(3H, d, J=7.2 Hz), 3.24-3.31(1H, m), 3.78(3H, s), 4.23-4.28(2H, m), 4.79-4.85(1H, q, J=7.2 Hz), 6.43-6.46(1H, dd, J=2.8&8.8 Hz), 6.69(1H, d, J=8.8 Hz), 6.84(1H, d, J=3.2 Hz), 7.59(2H, s), 8.08(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.27-1.33(3H, m), 3.76(3H, s), 3.93(2H, s), 4.24-4.29(2H, q, J=6.8 & 7.2 Hz), 4.73(2H, s) 6.51-6.54(1H, dd, J=3.2&8.8 Hz), 6.65(1H, d, J=3.21 Hz), 6.73(1H, d, J=8.8 Hz), 7.15-7.19(3H, m), 7.24-7.29(2H, m), 7.79(2H, s), 8.10(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 1.29(3H, t, J=7.2 Hz), 1.56(3H, d, J=7.2 Hz), 3.24-3.31(1H, m), 3.78(3H, s), 4.22-4.29(2H, m), 4.80-4.85(1H, q, J=7.2 Hz), 6.41-6.44(1H, dd, J=2.8&8.8 Hz),6.70(1H, d, J=8.8 Hz), 7.82(1H, d, J=2.8 Hz), 7.80(2H, s), 8.07(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.30(3H, t, J=7.0 Hz), 1.54(3H, d, J=6.8 Hz), 3.77(3H, s), 4.23-4.28 (2H, q, J=6.8&7.2 Hz), 4.79-4.84(1H, q, J=6.8&7.2 Hz), 6.73-6.76(1H, dd, J=3.2&9.2 Hz), 6.81(1H, d, J=2.8 Hz), 6.89(1H, d, J=8.8 Hz), 7.29-7.33(1H, m), 7.39(2H, t, J=7.2.0 Hz), 7.51(2H, t, J=7.2 Hz), 7.80(2H, s), 8.06(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.22(6H, d, J=7.2 Hz), 1.31(3H, t, J=7 Hz), 1.56(3H, s), 1.58(3H, s), 3.13-3.20(1H, m), 3.96(3H, s), 4.21-4.27(2H, q, J=7 Hz), 6.41-6.45(1H, dd, J=3.2&8.81 Hz), 6.69(1H, d, J=8.4 Hz), 6.99(1H, d, J=3.2 Hz), 7.77(2H, s), 8.02(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.05(3H, t, J=7.2 Hz), 1.18(6H, d, J=6.8 Hz), 1.30(3H, t, J=7.2 Hz), 1.89-1.97(2H, m), 3.24-3.31(1H, m), 3.78(3H, s), 4.21-4.29(2H, m), 4.66-4.69(1H, q, J=5.6& 7.2 Hz), 6.41-6.44 (1H, dd, J=3.2&8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.82(1H, d, J=2.8 Hz), 7.80(2H, s), 8.09(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.83(3H, t, J=7.2 Hz), 1.15(3H, d, J=6.8 Hz), 1.30(3H, t, J=7.2 Hz), 1.52-1.55(2H, m), 1.57(3H, d, J=7.2 Hz), 3.03-3.09(1H, m), 3.77(3H, s), 4.23-4.28(2H, q, J=7.2 Hz), 4.79-4.85(1H, q, J=7.2 Hz), 6.45-6.48(1H, dd, J=3.2 Hz&8.8 Hz), 6.71(1H, d, J=8.8 Hz), 6.74 (1H, d, J=3.2 Hz), 7.79(2H, s), 8.07(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.83(314, t, J=7.4 Hz), 1.15(3H, d, J=6.8 Hz), 1.26-1.3(3H, m), 1.47-1.56(2H, m), 1.58(6H, s), 3.04-3.09(1H, m), 3.77(3H, s), 4.21-4.26(2H, q, J=6.8 Hz &7.2 Hz), 6.44-6.47(1H, dd, J=3.2&8.8 Hz), 6.71(1H, d, J=8.8 Hz), 6.75(1H, d, J=3.2 Hz), 7.77(2H, s), 8.01 (1H, s).
1H NMR:(CDCl3, 400 MHz): 1.27(314, t, J=7.2 Hz), 1.54(3H, d, J=6.8 Hz), 3.75(3H, s), 3.92(2H, s), 4.22-4.27(2H, q, J=7.2 Hz), 4.79-4.84(1H, q, J=7.2 Hz), 6.51-6.54(1H, dd, J=3.2&8.8 Hz), 6.65(1H, d, J=3.2 Hz), 6.73(1H, d, J=8.8 Hz), 7.12-7.27(5H, m), 7.77(2H, s), 8.08(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.05(3H, t, J=7.2 Hz), 1.30(3H, t, J=7.2 Hz), 1.90-196(2H, m), 3.75(3H, s), 3.92(2H, s), 4.25(2H, q, J=7.2 Hz), 4.67(1H, t, J=5.6 Hz), 6.51-6.54(1H, dd, J=3.2 & 8.8 Hz), 6.65(1H, d, J=3.2 Hz), 6.73(1H, d, J=8.8 Hz), 7.17-7.27(5H, m), 7.77(2H, s), 8.08(1H, s).
1H NMR:(CDCl3, 400 MHz): 0.83(3H, t, J=7.4 Hz), 1.15(3H, d, J=6.8 Hz), 1.26(3H, t, J=7.0 Hz), 1.46-1.60(2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 4.18-4.32(2H, m), 5.70(1H, s), 6.45-6.48 (1H, dd, J=3.2&8.8 Hz), 6.70-6.74(2H, m), 7.39-7.5(3H, m), 7.5-7.53(2H, m), 7.81(2H, s), 8.2(1H, s).
1H NMR:(CDCl3, 400 MHz): 0.85-0.92(3H, m), 1.06(3H, t, J=7.2 Hz), 1.14(3H, d, J=7.2 Hz), 1.30(3H, d, J=6.8 Hz), 1.44-1.61-(2H, m), 1.89-1.99(2H, m), 3.03-3.09(1H, m), 3.77(3H, s), 4.21-4.29(2H, m), 4.66-4.69(1H, m), 6.45-6.48(1H, dd, J=2.8&8.8 Hz), 6.72(1H, d, J=9.2 Hz), 6.74 (1H, d, J=3.2 Hz), 7.79(2H, s), 8.09(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.26(3H, t, J=7.2 Hz), 1.58(6H, s), 3.76(3H, s), 4.20-4.26(2H, q, J=6.8 &7.2 Hz), 6.73-6.76(1H, dd, J=2.8&8.8 Hz), 6.81(1H, d, J=3.2 Hz), 6.89(1H, d, J=8.8 Hz), 7.29-7.33(1H, m), 7.37-7.40(2H, m), 7.48-7.51(2H, m), 7.77(2H, s), 8.00(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.05(3H, t, J=7.2 Hz), 1.30(3H, t, J=7.2 Hz), 1.88-1.95(2H, m), 3.76(3H, s), 4.22-4.28(2H, m), 4.67(1H, t, J=5.6 Hz), 6.74(1H, dd, J=3.2&8.8 Hz), 6.8(1H, d, J=3.2 Hz), 6.89(1H, d, J=9.2 Hz), 7.29-7.33(1H, m), 7.37-7.41(2H, m), 7.49-7.52(2H, m), 7.8(2H, s), 8.08(1H,s).
1H NMR: (CDCl3, 400 MHz): 1.28(3H, t, J=7.2 Hz), 1.55(3H, s), 1.58(3H, s), 3.75(3H, s), 3.92 (2H, s), 4.21-4.26(2H, q, J=7.2 Hz), 6.51-6.54(1H, dd, J=3.2&8.8 Hz), 6.65(1H, d, J=2.8 Hz), 6.73 (1H, d, J=9.2 Hz), 7.12-7.19(3H, m), 7.23-7.27(2H, m), 7.75(2H, s), 8.00(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.83(3H, t, J=7.6 Hz), 1.15(3H, d, J=6.8 Hz), 1.30(3H, t, J=7.2 Hz), 1.55-1.61(5H, m), 3.03-3.08(1H, m), 3.77(3H, s), 4.22-4.28(2H, m), 4.79-4.85(1H, q, J=6.8& 7.2 Hz), 6.46-6.49(1H, dd, J=3.2 Hz&8.8 Hz), 6.72(1H, d, J=8.8 Hz), 6.76(1H, d, J=3.2 Hz), 7.59(2H, s), 8.08(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.28(3H, t, J=7.2 Hz), 1.34(9H, s), 1.58(3H, d, J=6.8 Hz), 3.78(3H, s), 4.22-4.28(2H, q, J=6.8&7.2 Hz), 4.79-4.84(1H, q, J=6.8&7.2 Hz), 6.40-6.43(1H, dd, J=3.2& 8.8 Hz), 6.71(1H, d, J=8.8 Hz), 6.93(1H, d, J=3.2 Hz), 7.79(2H, s), 8.06(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.15-1.18(3H, t, J=7.2 Hz), 1.27-1.29(3H, t, J=7.2 Hz), 1.56(3H, d, J=8.4 Hz), 2.57-2.62(2H, q, J=7.2&7.6 Hz), 3.78(3H, s), 4.23-4.28(2H, q, J=7.2 Hz), 4.8-4.85(1H, q, J=6.8&7.2 Hz), 6.47-6.50(1H, dd, J=3.2&8.8 Hz), 6.69-6.72(2H, m), 7.80(2H, s), 8.07(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.22-1.27 (3H, m), 1.45-1.58(3H, m), 3.69(3H, s), 4.23-4.28(2H, m), 4.81-4.87(1H, m), 6.82(1H, d, J=2.8 Hz), 6.91-6.98(2H, m), 7.24(1H, m), 7.39-7.42(2H, d, J=8.4 Hz), 7.73-7.77(3H, m), 8.19(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.22-1.27(3H, m), 1.45-1.58(3H, m), 4.23-4.28(2H, m), 4.81-4.87 (1H, m), 6.97-7.06(3H, m), 7.44(2H, d, J=8.8 Hz), 7.63(2H, d, J=8.4 Hz), 7.77(2H, s), 8.19 (1H, s).
1H NMR: (CDCl3, 400 MHz): 1.31(3H, t, J=7.2 Hz), 4.24-4.27(2H, q, J=7.2 Hz), 4.72(2H, s), 6.97 (1H, d, J=2.8 Hz), 7.03-7.09(2H, m), 7.45(2H, d, J=8.4 Hz), 7.64(2H, d, J=6.8 Hz), 7.79(2H, s), 8.09(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.22-1.27(3H, m), 1.45-1.58(3H, m), 4.24-4.29(2H, q, J=7.2 Hz), 4.80-4.85 (1H, q, J=6.8 Hz), 6.86(1H, d, J=2.8 Hz), 7.08(1H, d, J=9.2 Hz), 7.17-7.20(1H, dd, J=3.2 &9.2 Hz), 7.40(1H, t, J=8.0 Hz), 7.53-7.63(3H, m), 7.78(2H, s), 8.05(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.31(3H, t, J=7.2 Hz), 4.24-4.27(2H, q, J=7.2 Hz), 4.72(2H, s), 6.97 (1H, d, J=2.8 Hz), 7.04-7.08(2H, m), 7.55(2H, d, J=8.4 Hz), 7.62(2H, d, J=8.4 Hz), 7.79(2H, s), 8.09(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.31(3H, t, J=7.2 Hz), 4.24-4.29(2H, q, J=7.2 Hz), 4.72(2H, s), 6.87 (1H, d, J=3.2 Hz), 7.06(1H, d, J=9.2 Hz), 7.16-7.19(1H, dd, J=2.8&9.2 Hz), 7.39(1H, t, J=7.8 Hz), 7.52-7.61(3H, m), 7.79(2H, s), 8.08(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.22-1.26(3H, m), 1.33-1.52(91-1, m), 3.10-3.13(4H, m), 3.81(3H, s), 4.16-4.21(2H, q, J=6.8&7.2 Hz), 4.73-4.78(1H, q, J=6.8 &7.2 Hz), 6.87(1H, d, J=8.8 Hz), 6.90-6.93(1H, dd, J=2.8&8.8 Hz), 7.26(1H, d, J=2.8 Hz), 7.73 (2H, s), 8.00(1H, s)
1H NMR: (CDCl3, 400 MHz): 1.05(6H, d, J=6.8 Hz), 1.29-1.33(3H, t, J=7.2 Hz), 1.56(3H, d, J=5.6 Hz), 3.40-3.45(1H, m), 3.95(3H, s), 4.23-4.28(2H, q, J=6.8&7.2 Hz), 4.74-4.85(1H, q, J=6.8 &7.2 Hz), 6.95-7.03(2H, m), 7.36(1H, d, J=3.2 Hz), 7.80(2H, s), 8.20(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.09(6H, t, J=7.2 Hz), 1.29-1.32(3H, t, J=7.2 Hz), 1.56-1.51(3H, m), 3.30-3.36(4H, q, J=7.2 Hz), 3.89(3H, s), 4.23-4.28(2H, q, J=7.2 Hz), 4.80-4.85(1H, q, J=6.8&7.2 Hz), 6.90-7.01(2H, m), 7.38(1H, d, J=2.8 Hz), 7.80(2H, s), 8.07(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.09-1.16(6H, m), 1.20-1.25(4H, m), 1.31(3H, t, J=7.0 Hz), 1.55 (3H, d, J=6.8 Hz), 2.04-3.13(1H, m), 3.95(3H, s), 4.23-4.26(2H, q, J=7.2 Hz), 4.81-4.85(1H, m), 6.97(1H, d, J=8.8 Hz), 7.01-7.03(1H, dd, J=3.2&9.3 Hz), 7.33(1H, d, J=2.8 Hz), 7.80(2H, s), 8.07 (1H, s).
1H NMR: (CDCl3, 400 MHz): 0.98-0.99 (3H, m), 1.10-1.18(3H, m), 1.28-1.33(6H, m), 1.37-1.41 (2H, m), 2.02-2.04(2H, m), 3.09-3.13(1H, m), 3.96(3H, s), 4.23-4.28(2H, q, J=7.2 Hz), 4.80-4.86(1H, q, J=6.8 Hz), 6.97(1H, d, J=9.2 Hz), 7.02-7.05(1H, dd, J=3.2&9.2 Hz), 7.34 (1H, d, J=3.2 Hz), 7.80(2H, s), 8.07(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.31(3H, t, J=7.2 Hz), 1.83(4H, t, J=3.6 Hz), 3.37(4H, t, J=7 Hz), 3.90(3H, s), 4.24-4.30(2H, q, J=7.2 Hz), 4.73(2H, s), 6.96-6.97(2H, m), 6.39(1H, d, J=2.8 Hz), 7.82(2H, s), 8.11(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.31(3H, t, J=7.0 Hz), 1.55(3H, d, J=6.8 Hz), 1.82-1.84(4H, m), 3.37(4H, t, J=6.6 Hz), 3.90(3H, s), 4.23-4.28(2H, q, J=7.2 Hz), 4.08-4.85(1H, q, J=7.2 Hz), 6.94(1H, d, J=9.2 Hz), 6.97-7.00(1H, dd, J=2.8&8.8 Hz), 7.38(1H, d, J=2.8 Hz), 7.80(2H, s), 8.06(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=7.2 Hz), 3.24-3.31(1H, m), 3.78(3H, s), 6.44-6.47(1H, dd, J=2.8 & 8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.84(1H, d, J=2.8 Hz), 7.61(2H, s), 8.05(1H,s).
1H NMR: (CDCl3, 400 MHz): 0.83(3H, t, J=7.4 Hz), 1.15(3H, d, J=6.8 Hz),1.46-1.55(2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 6.47-6.50(1H, dd, J=3.2&8.8 Hz), 6.72(1H, d, J=9.2 Hz), 6.77(1H, d, J=3.2 Hz), 7.61(2H, s), 8.04(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 3.26-3.30(1H, m), 3.78(3H, s), 6.42-6.45(1H, dd, J=2.8&8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.83(1H, d, J=3.2 Hz), 7.82(2H, s), 8.04(1H, s)
1H NMR: (CDCl3, 400 MHz): 3.75(3H, s), 3.93(2H, s), 6.54-6.56(1H, dd, J=2.8&8.8 Hz), 6.68(1H, d, J=3.2 Hz), 6.73(1H, d, J=9.2 Hz), 7.15-7.19(3H, m), 7.24-7.27(2H, m), 7.58(2H, s), 8.03(1H, s).
1H NMR:(CDCl3, 400 MHz): 0.83(3H, t, J=7.4 Hz), 1.15(3H, d, J=6.8 Hz), 1.46-1.61(2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 6.45-6.48(1H, dd, J=3.2 Hz&8.8 Hz), 6.72(1H, d, J=8.8 Hz), 6.75(1H, d, J=3.2 Hz), 7.81(2H, s), 8.04(1H, s).
1H NMR: (CDCl3, 400 MHz): 3.75(3H, s), 3.92(2H, s), 6.52-6.55(1H, dd, J=3.2&8.8 Hz), 6.66(1H, d, J=2.8 Hz), 6.73(1H, d, J=8.8 Hz), 7.15-7.19(3H, m), 7.23-7.27(2H, m), 7.79(2H, s), 8.02(1H, s).
1H NMR:(CDCl3 400 MHz): 1.34(9H, s), 3.79(3H, s), 6.41-6.44(1H, dd, J=3.2&8.8 Hz), 6.71(1H, d, J=8.8 Hz), 6.94(1H, d, J=3.2 Hz), 7.81(2H, s), 8.04(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.17(3H, t, J=7.6 Hz), 2.57-2.63(2H, q, J=7.6 Hz) 3.78(3H, s), 6.48-6.50(1H, dd, J=2.8 & 8.8 Hz), 6.71(1H, d, J=9.2 Hz), 6.73(1H, d, J=3.2 Hz), 7.82(2H, s), 8.04(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 3.27-3.30(1H, m), 3.79(3H, s), 6.44-6.47(1H, dd, J=3.2&9.2 Hz), 6.70(1H, d, J=8.8 Hz), 6.85(1H, d, J=3.2 Hz), 7.91(2H, s), 9.93(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.88-0.89(3H, m), 1.15(3H, d, J=6.8 Hz), 1.47-1.61(2H, m), 3.03-3.11(1H, m), 3.78(3H, s), 6.47-6.50(1H, dd, J=3.2&8.8 Hz), 6.72(1H, d, J=8.8 Hz), 6.77(1H, d, J=2.8 Hz), 7.91 (2H, s), 9.93(1H, s).
1H NMR: (CDCl3, 400 MHz): 1.18(6H, d, J=6.8 Hz), 3.20-3.30(1H, m), 3.79(3H, s), 6.43-6.44(1H, dd, J=3.2&8.8 Hz), 6.70(1H, d, J=8.8 Hz), 6.83(1H, d, J=3.2 Hz), 8.10(2H, s), 9.92(1H, s).
1H NMR: (CDCl3, 400 MHz): 3.76(3H, s), 3.92(2H, s), 6.54-6.57(1H, dd, J=3.2&8.8 Hz), 6.66(1H, d, J=3.2 Hz), 6.74(1H, d, J=9.2 Hz), 7.15-7.29(5H, m), 7.88(2H, s), 9.91(1H, s).
1H NMR: (CDCl3, 400 MHz): 0.85(3H, t, J=7.4 Hz), 1.14(3H, d, J=6.8 Hz), 1.47-1.59(2H, m), 3.07-3.09(1H, m), 3.77(3H, s), 6.45-6.48(1H, dd, J=3.2&8.8 Hz), 6.72(1H, d, J=8.8 Hz), 6.75(1H, d, J=3.2 Hz), 8.11(2H, s), 9.90(1H, s).
1H NMR:(CDCl3, 400 MHz): 3.76(3H, s), 3.93(2H, s), 6.52-6.55(1H, dd, J=2.8&8.8 Hz), 6.64(1H, d, J=3.2 Hz), 6.76(1H, d, J=8.8 Hz), 7.17-7.19(5H, m), 8.08(2H, s),9.91(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.34(9H, s), 3.85(3H, s), 6.40-6.43(1H, dd, J=3.2 Hz & 8.8 Hz), 6.72(1H, d, J=8.8 Hz), 6.93(1H, d, J=3.2 Hz), 8.11(2H, s), 9.92(1H, s).
1H NMR:(CDCl3, 400 MHz): 1.17(3H, t, J=7.6 Hz), 2.57-2.63(2H, q, J=7.2&7.6 Hz), 3.79(314, s), 6.48-6.51(1H, dd, J=3.2&8.8 Hz), 6.70-6.74(2H, m), 8.11(2H, s),9.92(1H, s).
In vitro TR-α & TR-β activities were determined as per in-house protocols and the results of representative compounds are provided in tables 1 & 2 below as a proof of the efficacies of the novel class of compounds disclosed above.
The data above clearly indicates that several of the novel compounds of the present invention are selective to TR-beta receptor and therefore have potential therapeutically beneficial properties.
Cholesterol lowering effect of T3 and selected compounds disclosed in the present invention on cholesterol lowering and change in heart rate in cholesterol-fed rats (treated for 7 days) was determined according to the general protocol described in PNAS, vol. 100 (17) 10067-10072 and Endocrinology 145(4):1656-1661 Many of the compounds were found to be reducing cholesterol and having very little effect on the heart rate. Therefore, these compounds have the potential to be further developed as selective TR-beta agonists for the treatment of human & other animals in need of such treatment.
The novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as Thyroid hormone receptor ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2312/MUM/2008 | Oct 2008 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN2009/000598 | 10/22/2009 | WO | 00 | 6/29/2011 |
