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WO2009109999A1 - Novel protein tyrosine phosphatase - ib inhibitors - Google Patents

Novel protein tyrosine phosphatase - ib inhibitors Download PDF

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Publication number
WO2009109999A1
WO2009109999A1 PCT/IN2009/000136 IN2009000136W WO2009109999A1 WO 2009109999 A1 WO2009109999 A1 WO 2009109999A1 IN 2009000136 W IN2009000136 W IN 2009000136W WO 2009109999 A1 WO2009109999 A1 WO 2009109999A1
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Prior art keywords
compound
benzylidene
thiazol
oxo
dihydro
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PCT/IN2009/000136
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French (fr)
Inventor
Sudershan Kumar Arora
Rakesh Banerjee
Rajender K . Kamboj
Rajesh Loriya
Sindhu Mathai
Manjusha Joshi
Bharat Suthar
Raju Cheerlavancha
Ganesh Gote
Rahul Bagul
Rajesh Wetal
Sapana Patel
Ruchi Dixit
Amol Waghchoure
Rajan Goel
K . H . Sreedhara Swamy
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Lupin Ltd
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Lupin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is related to novel compounds of the general formula and their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods of making the above compounds, and their use as Protein tyrosine phosphatase IB (PTP-IB) inhibitors, which are useful in the treatment or prevention of diseases in which PTP-IB enzyme is known to be involved in the pathogenesis.
  • PTP-IB Protein tyrosine phosphatase IB
  • the PTPlB inhibitors would also find use in the treatment of diseases such as cancer, inflammatory disorders, autoimmune diseases and osteoporosis
  • Type 2 diabetes mellitus (hereafter referred as type 2 diabetes, also known as non-insulin-dependent diabetes mellitus, NIDDM) is a heterogeneous disorder, with both genetic and environmental factors contributing to its development.
  • the pathogenesis of type 2 diabetes involves multiple mechanisms leading to hyperglycemia, most notably increased hepatic glucose production, impaired insulin secretion by pancreatic ⁇ cells and reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin resistance).
  • Type 2 diabetic patients are at substantially increased risks of macro vascular disease including coronary heart disease and stroke and microvascular disease including retinopathy, nephropathy and neuropathy.
  • Type 2 diabetes is a therapeutic area with huge market potential.
  • the number of diabetic patients is projected to increase from 170-175 million in 2000 to over 350 million by 2030 (Wild, S., et al. Diab.Care 27, 1047-1053, 2004; Yach, D., et al. Nat. Med. 12, 62-66, 2006).
  • the major part of this numerical increase is expected to occur in developing countries and India will have the distinction of having the largest number of diabetic patients in the world by 2030.
  • the treatment approaches for type 2 diabetes include diet, exercise, and a variety of pharmacological agents.
  • Clinically established therapies for type 2 diabetes include insulin and its analogs and various oral hypoglycemic agents: sulfonylureas, metformin, ⁇ - glucosidase inhibitors (acarbose, miglitol), non- sulfonylurea insulin secretagogues (repaglinide, nateglinide) and thiazolidinedione (TZD) derivatives (rosiglitazone, pioglitazone) acting via PPAR ⁇ agonism (Matthaei, S., et al. Endocrine Rev. 21, 585-618, 2000; Skyler, J.S.
  • J.MedChem. 47, 4113-4117, 2004 act by different mechanisms to normalize blood glucose levels, but are limited in their abilities, either alone or in combination, to prevent the onset of diabetic complications. Further, each of the above oral agents suffers either from generally inadequate efficacy or number of adverse effects. For example, sulfonylureas, which have been the mainstay of oral treatment for over 5 decades, are known to be associated with a high rate of secondary failure and hypoglycemia.
  • the TZD class of antidiabetic agents improves glucose utilization without stimulating insulin release, but their use is associated with undesirable effects (e.g. risk of myocardial infarction, cardiac hypertrophy, liver toxicity, weight gain).
  • PTPs Protein tyrosine phosphatases
  • Alonso A, et al., Cell; 117. 699-711, 2004 play essential roles in intracellular signal transduction by regulating the cellular level of tyrosine phosphorylation to control cell growth and differentiation, metabolism, cell migration, gene transcription, ion-channel activity, immune response, cell apoptosis, and bone development (Hunter T., Cell 100, 1 13-127, 2000).
  • Unregulated operation of PTPs is responsible to many human diseases including cancer (BIume- Jensen P., Nature 41 1. 355-365. 2001), diabetes (Montalibet J., Drug Discov Today: Therap. Strateg. 2, 129-135, 2005), obesity (Cook W.S., Developmental Cell 2, 385-387, 2002), and osteoporosis (Schiller K.R., J. Cell Biochem. 96, 262-277, 2005).
  • PTPlB protein tyrosine phosphatase IB activates c-Src inhuman breast cancer (Bjorge J.D., J Biol Chem 275, 41439-41446, 2000), and also influences the down regulation of insulin signaling by dephosphorylating the insulin receptor including insulin receptor substrate- 1 (TRS-I) and insulin receptor substrate-2 (IRS-2) (WalchJi S.. J Biol Chem 275, 9792-9796. 2000). Therefore, PTPl B can be a useful target for diabetes and cancer, and inhibitors of PTPl B may be promising drugs to treat these diseases.
  • TRS-I insulin receptor substrate- 1
  • IRS-2 insulin receptor substrate-2
  • PTPlB knockout mice are resistant to obesity
  • PTPlB plays critical role in development of obesity (Klaman L.D., MoI Cell Biol 20, 5479-5489, 2000).
  • PTPlB inhibitor against diabetes, obesity, and cancer
  • T-cell PTP (TCPTP) has an 80% homology to PTPlB in the catalytic domains, non-selective inhibition gives rise to severe side effects (Tiganis T., J Biol Chem 274, 27768-27775, 1999; You-Ten K.E., J Exp Med 186, 683-693, 1997) and although, recently, there are different opinions that PTPlB and TCPTP coordinately regulate an insulin signaling process (Galic S., MoI Cell Biol 25, 819-829, 2005).
  • PTP especially PTPlB
  • Thiazolidine moiety had been screened by various inventors for diversified biological activities (WO2004047760, WO2005082901, WO2006002829.. WO2006040050, WO2006040052, WO2006047269). Some thiazolidine derivatives were described in WO2007032028 as PTPlB inhibitors.
  • the main objective of the present invention is therefore to provide novel compounds of the general formula I, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, process and intermediates for the preparation of the compounds given in Formula I which have inhibitory activity against PTP IB.
  • Another objective of the present invention to develop novel compounds which are effective and useful to lower increased levels of glucose, lipids, to improve insulin resistance, to decrease body weight, for the treatment and/ or prophylaxis of metabolic disorders such as type II diabetis, obesity, hyperlipidemia, with better efficacy and lower toxicity.
  • the present invention provides a process for the preparation of novel organic compounds of the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them.
  • a further aspect of the present invention is to provide novel intermediates, a process for their preparation and their use in methods of making compounds of the general formula (I).
  • novel organic compounds of present invention represented by the general formula (I) is useful for reducing blood glucose, lowering lipid levels, cholestrol and reducing body weight and also have some excellent effects in the treatment and/or prophylaxis of diseases caused by insulin resistance such as type II diabetes, hyperlipidemia, obesity, impaired glucose tolerance, diabetic complications with better efficacy, potency, without or reduced toxicity.
  • the present invention is related to the compounds of the general formula T
  • G2 is selected from hydrogen, fluoro and methoxy; and G3 is selected from a group of formulae:
  • G 4 is selected from O or N-CH 3 ;
  • G 5 is selected from
  • n is 0 or 1
  • m is 0, 1 or 2.
  • h and 1 are independently selected from 0 or 1.
  • the condensation of aromatic aldehyde of formula (i) with Rhodanine (ii) is carried out using standard Knoevenagel condensation condition such as in refluxing acetic acid in the presence of sodium acetate or in presence of ammonium acetate in toluene.
  • the resulting compound of formula (iii) is treated with methyl iodide at room temperature in ethanol in the presence of diisopropylethylamine to methylate the thio group to produce the compound of formula (iv).
  • the compound of formula (iv) is treated with suitable amine to produce the compound of formula I. This reaction is carried out in ethyl alcohol at reflux temperature in the presence of a base such as diisopropylethylamine.
  • Amine is selected from: Alternatively rhodanine (ii) was treated with appropriate amine as shown in scheme II in the presence of mercuric chloride and diisopropylethylamine to afford intermediate V.
  • the Knoevenagel condensation of compound of formula V with aldehyde of formula T catalysed by ammonium acetate, sodium acetate or the like in a suitable solvent produces compound of formula I.
  • Amine is selected from the group as provided under scheme I.
  • the intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent in vaccum and re crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloro
  • Salts are obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which contains the desired acid or base or two which the desired acid or base is then added as described in, Berge S. M. et al.
  • a chlorinated hydrocarbon such as methyl chloride or chloroform
  • a low molecular weight aliphatic alcohol for example, ethanol or isopropanol
  • the present invention also provides pharmaceutical compositions containing compounds of general formula I as defined above and their pharmaceutically acceptable salts in combination with the ' usual pharmaceutically employed carrier, diluents and the like.
  • Step-1 Preparation of 4-cyclohehyl benzoic acid ethyl ester
  • Step-2 Preparation of (4-Cyclohexyl-phenyl)-methanol
  • lithium aluminium hydride 980 mg, 25.86 mmol
  • dry tetrahydrofuran 25 ml
  • 4-cyclohehyl benzoic acid ethyl ester (2 g, 8.62 mmol) in tetrahydrofuran (10 ml) via addition funnel.
  • the reaction was continued for another 2 h.
  • the reaction mixture was quenched at 0 0 C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl (30 ml). It was extracted in ethyl acetate (3x25 ml).
  • the combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford color less oil (1.6Og , 98 %).
  • Step-4 Preparation of 4-(4-Cyclohexyl-benzyloxy) ⁇ benzaldehyde
  • 4-hydroxybenzaldehyde 970 mg, 7.95 mmol
  • N 5 N- dimethylformamide 20 ml
  • potassium carbonate 2.20 g , 15.90 mmol
  • l-Chloromethyl-4-cyclohexyl-benzene 1.65 g, 7.93 mmol
  • Step-1 Preparation of 4-(l-Ethyl-propoxy)-benzaldehyde:
  • Step-2 4-(l-Ethyl-propoxy)-phenyl] -methanol:
  • Step-3 l-Chloromethyl-4-(l-ethyl-propoxy)-benzene : To a stirred solution of 4-(l-Ethyl-propoxy)-phenyl]-methanol (1.35 g, 6.95 mmol) in dichloromethane (30 ml) at 0 0 C was added thionyl chloride (0.670 ml, 9.40 mmol). The reaction was continued for 30 min. The reaction mixture was neutralized with saturated sodium bicarbonate solution (20 ml). The organic layer was separated, washed with water (30 ml) and brine (20 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford product as colorless oil (1.45 g, 98 %).
  • Step-4 Preparation of 4- [4-( 1 -Ethyl-propoxy)-benzyloxy] -benzaldehyde :
  • Step-1 Preparation of p-aminobenzoic acid ethylester :
  • Step-2 Preparation of 4-Pyrrol- 1 -yl-benzoic acid ethyl ester: To a stirred solution of p-aminobenzoic acid ethyl ester (4 g , 24.24 mraol) in acetic acid (15 ml) was added 2,5-dimethoxytetrahydrofuran (3.5 ml, 26.66 mmol) and heated under reflux for 1 h. The reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and poured in cold water (50 ml).
  • Step-3 Preparation of (4-Pyrrol-l-yl-phenyl)-methanol: To a stirred suspension of lithium aluminium hydride (0.530 mg, 13.94 mmol) in dry tetrahydrofuran (20 ml) at 0 0 C was added 4-Pyrrol-l -yl-benzoic acid ethyl ester (1 gm, 4.65 mmol) in tetrahydrofuran (10 ml) via addition funnel. The reaction was continued for another 2 h. It was monitored by thin layer chromatography. The reaction mixture was quenched at 0 0 C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl (20 ml). It was extracted in ethyl acetate (3x20 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford brown solid (800 mg, 99 %).
  • Step-4 Preparation of l-(4-Chloromethyl-phenyl)-lH-pyrrole :
  • the reaction was monitored by thin layer chromatography.
  • the reaction mixture was cooled to room temperature and then poured in to cold water (30 ml).
  • the solid precipitate was filtered and washed with water (15 ml).
  • the crude product was further purified by silica gel column using ethyl acetate-hexane (12:88) as the eluent to furnish the product as a white solid (350 mg, 35 %).
  • the product was further purified by silica gel column chromatography using 10 % solution of ethyl acetate in hexane as the eluent to afford the product as a yellow oil. ((0.18 g, 69 %).
  • Step 2 l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-one: To a stirred solution of 2-Methyl-l-p-tolyl-propan-l-one (Ig , 6.17 mmol) in dry carbon tetrachloride (15 ml) was added n-bromo succinimide (1.09 g , 6.17 mmol) and benzoyl peroxide (0.074 g , 0.31 mmol) and heated under reflux for 1.5 h. Reaction mixture was cooled to room temperature and solid was removed by filtration.The solution was then concentrated under reduced pressure to obtain the product as a colorless oil (0.98 g , 66%).
  • Step 3 l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-ol:
  • Step 4 4-[4-(l -Hydroxy-2-methyl-propyl)-benzyloxy]-benzaldehyde
  • l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-ol 1.3g , 5.3 mmol
  • p- hydroxy benzaldehyde 653 mg , 5.3 mmol
  • the mixture was then heated to 80 C. After stirring fpr 5 h
  • reaction mixture was cooled to room temperature and diluted with water (30 ml) and the product was extracted using ethyl acetate (3x25 ml). The combined organic extracts was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was further purified by silica gel column using 15 % solution of ethyl actete in hexane as the eluent to furnish the product as a colorless oil.
  • Step 1 4-(4-Fluoro-benzyloxymethyl) benzoic acid ethyl ester :
  • Reaction mixture was extracted with ethyl acetate (60 ml.) and washed with brine (10 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was further purified by silica gel column using 5 % solution of ethyl acetate in hexane as the eluent to furnish the product as a colorless oil. (0.468g , 40 %). .
  • Step 3 4(4-fluoro-benzyloxy methyl) benzaldehyde: To a solution of [4(4-Fluoro-benzyloxy methyl)-phenyl] methanol (0.56 g, 2.2 mmol) in anhydrous dichloromethane (15 ml) was added PCC (0.98 g, 4.55 mmol) and stirred at room temp for 1 h. The inorganic substances were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column using 10% ethyl acetate-hexane as the eluent to afford the product as colorless oil ((0.48 g, 89%).
  • Step-2 Preparation of 4-Bromomethyl-benzoic acid ethyl ester : To a stirred solution of 4-Methyl-benzoic acid ethyl ester (5 g, 30.49 mmol)) in carbon tetrachloride (35 ml) was added N-bromosuccinimide (5.90 g, 33.53 mmol) and benzoyl peroxide (720 mg, 1.52 mmol). The feaction mixture was heated under reflux for 4 h. It was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and then filtered. The filtrate was evaporated under vacuo to afford color less oil (7.25 g, 98 %).
  • Step-4 Preparation of (4-[(4-methylphenoxy)methyl]phenyl) methanol : To a stirred suspension of lithium aluminum hydride (750 mg, 19.77 mmol) in dry tetrahydrofuran (20 ml) at 0 0 C was added p-Tolyloxymethyl-benzoic acid ethyl ester (1.78 g, 6.59 mmol) in tetrahydrofuran (10 ml) via addition funnel. The reaction was continued for another 2 h. The reaction mixture was quenched at 0 0 C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl to pH 2. It was extracted in dichloromethane (3x20 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford colorless oil (1.2 g, 86 %).
  • Step-1 Preparation of 4-methylbenzyl alcohol
  • p-tolualdehyde 3 g, 25 mmol
  • EtOH 50 ml
  • sodium borohydride 1 g, 35 mmol
  • the reaction was continued for 30 min.
  • the reaction mixture was concentrated, acidified by careful addition of 2N HCl to pH 2. It was extracted with dichloromethane (2x 20 ml). The combined organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (3 g, 98 %).
  • Step-2 Preparation of 4-methylbenzyl chloride:
  • Step-3 Preparation of methyl-(4 ⁇ methyl ⁇ benzyl)-amine : To a stirred solution of 4-methylbenzyl chloride (2.5 g, 17.85 mmol) in EtOH (15 ml) was added 40 % methylamine solution (5 ml) and stilted for 4 h. It was monitored by thin layer chromatography. The reaction mixture was evaporated, quenched with water (30 ml) and extracted in dichloromethane (2x 25 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuo to afford yellow oil (2.1 g, 87%).
  • Step 1 4-(p-Tolylamino-methyl) benzoic acid ethyl ester : .
  • p-toluidine 2 g, 18.66mmol
  • dry DMF 75 ml
  • potassium carbonate 10 g, 74.6 mmol
  • 4-bromomethyl benzoic acid ethyl ester 4.98 g, 20.52 mmol
  • the reaction mixture was heated to 70-75 0 C and stirring was continued for 4 h. After cooling to room temperature, it was diluted with water (30 ml) and the product was extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography using 20 % solution of ethyl acetate in hexane as the eluent to obtain the pure product as brown oil (2.86 g, 53 %).
  • Step 2 4-[(Methyl-p " tolyl-amino)-methyl]-benzoic acid ethyl ester
  • 4-(p-Tolylamino-methyl) benzoic acid ethyl ester Ig , 3.7 mmol
  • DMF dimethyl sulfoxide
  • methyl iodide (1.06 g, 7.4mmol) was added via syringe and stirring continued for 3.5 h.
  • the reaction was quenched by slow addition of cold water (20 ml) and the product was extracted with ethyl acetate (3x20 ml).
  • the combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as brown oil (0.8 g,76 %), which was directly used for the next reaction without further purification.
  • Step 3 ⁇ 4-[(Methyl-p-Tolylamino)-methyl] -phenyl ⁇ methanol : To a suspension of LAH (0.12g , 3.41 mmol) in dry THF (20 ml) was added 4-(p- Tolylamino-methyl) benzoic acid ethyl ester (0.8 g , 2.84 mmol), dissolved in dry THF (5 ml) O 0 C under nitrogen atmosphere . After stirring for 4.5 h, the reaction was quenched by adding ethyl acetate (15 ml). To the reaction mixture cold water (20 ml) was added and solid precipitated was removed by filteration.
  • reaction mixture was allowed to come to room temperature and poured in to water (25 ml). Organic layer was separated , dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was achieved by silica gel column chromatography using 10% solution of ethyl acetate in hexane as the eluent to furnish the product as pale yellow oil (0.18 g, 60. %).
  • Step 1 Preparation of 4-(2,3-Dihydro-indol-l-ylmethyl)-benzoic acid ethyl ester
  • indoline 1.5g , 12.58 mmol
  • dry DMF 50 ml
  • potassium carbonate 3.47g , 25.17 mmol
  • 4-bromomethyl ethyl benzoate 3.05 g , 13.84 mmol
  • reaction mixture was heated at 60 0 C for 8 h.
  • the reaction mixture was cooled to room temperature and then water (40 ml) was added and extracted with ethyl acetate (3x25 ml).
  • the combined extracts was dried over anhydrous sodium sulfate and concentrated in vacuo.
  • Product was purified by silica gel column using 2% ethyl acetate in hexane as a eluent to afford brown liquid (1.52 g, 43.18 %)
  • Triethyl amine(1.13 g, 11.2 mmol) was added to the above reaction mixture and slowly warmed to room temperature. The reaction mixture was then poured into water (25 ml) and diluted with DCM (20 ml). The organic layer was separated, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography using 10 % solution of ethyl acetate in hexane as the eluent to afford the product as colorless oil (0.47 g, 71 %).
  • MS m/z 269 (M+l) 4-(4-Propyl-phenoxymethyl)-benzaldehyde.
  • MS m/z 255 (M+ 1) 4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzaldehyde.
  • MS m/z 238 (M+l) 4-[(4-Isopropyl-benzyl)-methyl-amino]-benzaldehyde.
  • MS m/z 268 (M+l) 4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzaldehyde.
  • MS m/z 308 (M+l) 4- ⁇ [(4-Fluoro-phenyl)-methyl-amino]-methyl ⁇ -benzaldehyde.
  • MS m/z 244 (M+l) 4- ⁇ [(4-Isobutyl-phenyl)-methyl-amino]-methyl ⁇ -benzaldehyde.
  • MS m/z 282 (M+l) 4- ⁇ [Methyl-(4-propyl-phenyl)-amino]-methyl ⁇ -benzaldehyde.
  • MS m/z 268 (M+l) 4- ⁇ [(4-Isopropyl-phenyl)-methyl-amino]-methyl ⁇ -benzaldehyde.
  • MS m/z 268 (M+l)
  • Step-1 C,C,C-Trifluoro-N-(4-nitro-phenyl)-methanesulfonamide
  • Step-2 N-(4-Amino-phenyl)-C,C,C-trifluoro-methanesulfonamide
  • Step-1 Reduction of 5-Nitro N-Acetyl indoline.
  • Step-2 N-(l-Acetyl-2,3-dihydro-lH-indol-5-yl)-C,C 5 C-trifluoro-methanesulfonamide
  • Step-3 N-(2,3-Dihydro-lH-indol-5-yl)-C,C,C-trifluoro-methanesulfonamide
  • ION HCl (2 ml) was added at 5 0 C.
  • the reaction mixture was heated under reflux for 2 h.
  • Step 2 (4-Nitrophenyl)-N-Sulfamido-glycine methyl ester
  • t- Butanol (1.66 ml, 17 mmol) was added dropwise at 0° C under nitrogen atmosphere and stirred for 30 min. This solution was added dropwise maintaining 0° C to a solution of (4- nitrophenyl) acetic acid methyl ester (2.0 g, 14 mmol) and diisopropylethylamine (4.03 ml, 28 mmol) in DCM (50 ml ).
  • reaction mixture was stirred at rt for 3 h. and quenched by addition of 0.1N HCl (50 ml).
  • Reaction mixture was extracted with DCM (50 ml). The combined DCM layer was washed with water (40 ml), dried over Sodium sulphate.
  • Trifluoro actic acid 35 ml was added to the extract containing Boc-Procteted sulfamide at 0 0 C. and the solution was stirred for 3 h.
  • the solution was washed with saturated sodium bicarbonate solution ( 50 ml ) and water( 2x50 ml) . Solution was evaporated to dryness and to the residue hexane ( 20 ml ) was added to afford yellow color solid product (2.1 g., 77.7 % ).
  • Step 3 l,l-dioxo-5-(4-nitrophenyl)-[l,2,5]thiadiazolidin-3-one.
  • a solution of 2M NaOH 0.331 g., 8.28 mmol was added to a suspension of (4- Nitrophenyl)-N-Sulfamido-glycine methyl ester (2.0 g., 6.9 mmol) in ethanol (50 ml) at 0 0 C and stirred until a thick precipitate formed.
  • the mixture was acidified to pH 5.0 by adding 6 M HCl.
  • the solid precipitate was collected by filtration and washed with diethyl ether (50 ml) and dried under reduced pressure to give yellow color solid (1.5 g., 84.7 %).
  • MS m/z 256 [M-I].
  • Step 4 5-(4-Aminophenyl)-l,l-dioxo-[l,2,5]-thiadiazolidin-3-one.
  • Step 1 Nitration of N-acetyl indoline.
  • N-acetyl indoline 5 g , 31mmol
  • acetic acid 50 ml
  • cone nitric acid (2.6 ml ) was added drop wise at 0 0 C .
  • the reaction mixture was stirred at room temperature for Ih. Reaction mixture was carefully added in to cold water ( 80 ml ) and precipitate was filtered and dried to afford yellow solid ( 5.2 g , 81.31% ).
  • MS m/z 206
  • Step 2 Deacetylation of 5-Nitro N-acetyl Indoline.
  • Step 1 N-[(5-nitro indoline)sulfamoyl]acetamide .
  • Step 2 N-[(5-aminoindoline)sulfamoyl]acetamide.
  • Step-1 C,C,C-Trifluoro-N-[4-(4-oxo-4,5-dihydro-thiazol-2-ylamino)-phenyl]- methanesulfonamide .
  • Step 2 C,C,C-Trifluoro-N-(4- ⁇ 5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino ⁇ -phenyl)-methanesulfonamide.
  • a 4-(4-Methyl-benzyloxy)-benzaldehyde 200 mg.,0.88 mmol
  • thiaone 284 mg, 0.840 mmol
  • ammonium acetate 203.2 mg, 2.64 mmol
  • the phosphatase activity of human recombinant PTPlB was determined by following a previously described procedure (Methods 35, 2-8, 2005), but with certain modifications.
  • the principle of the assay is based on the hydrolysis of 6,8-difluoiO-4-methylumbelliferyl phosphate (DiFMUP) and the fluorometric quantitation of the liberated difiuoromethylumbelliferone (DiFMU) .
  • Assays were routinely carried out in 96-well flat-bottom black microwell plates.
  • the reaction mixture (100 ⁇ l) contained 15 ng/well of human recombinant PTPlB enzyme (produced in- house or procured from R&D Systems, USA) in the assay buffer (50 mM Hepes, pH 7.2, 50 mM NaCl, 1 mM EDTA, 1 mM DDT and 0.01 % Triton X-100) and 25 ⁇ M DiFMUP.
  • test compounds The inhibition of PTPlB activity by test compounds was routinely assessed by preincubating the enzyme with test compound (0.1 and 1 ⁇ M for primary screening and 7 concentrations from 0.01 to 10 ⁇ M for the dose-response study) or vehicle (1 % DMSO) for 10 min at 30 0 C, in a total volume of 90 ⁇ l.
  • Test compounds were dissolved in DMSO at a concentration of 10 mM and suitably diluted further in assay buffer.
  • the enzyme reaction was initiated by the addition of DiFMUP, followed by incubation of assay plates for 5 min at 30 0 C and the liberated product was measured as described above.
  • a known inhibitor of PTPlB positive control was always included in the assay. Test compounds at various concentrations were always evaluated in duplicate, along with substrate blanks, vehicle controls and positive controls.
  • PTPlB inhibitors with desired potencies were evaluated for their selectivity against the closely related, T-cell protein tyrosine phosphatase (TCPTP), employing assay conditions similar to that used for PTPlB (see above).
  • the reaction mixture (100 ⁇ l in 96-well flat- bottom black-well plates) contained assay buffer (50 mM Hepes, pH 7.2, 50 mM NaCl, 1 mM EDTA, 1 mM DDT and 0.01 % Triton X-100), 25 ⁇ M substrate (DiFMUP) and 125 mU/well of human recombinant enzyme (procured from New England Biolabs, UK), with or without test compound.
  • assay buffer 50 mM Hepes, pH 7.2, 50 mM NaCl, 1 mM EDTA, 1 mM DDT and 0.01 % Triton X-100
  • 25 ⁇ M substrate DiFMUP
  • 125 mU/well human recombinant
  • TCPTP was preincubated with test compound (ranging from 0.01 ⁇ M to 10 ⁇ M) or vehicle (1 % DMSO) for 10 min at 30 0 C, in a total volume of 90 ⁇ l.
  • test compound ranging from 0.01 ⁇ M to 10 ⁇ M
  • vehicle (1 % DMSO vehicle
  • the reaction was started by the addition of 10 ⁇ l substrate (250 ⁇ M running stock in assay buffer) and further incubated for 5 min at 30 0 C.
  • the liberated DIFMU was monitored in a fluorescence microplate reader (SpectraMax M5, Molecular Devices, USA), with excitation and emission wavelengths set at 358 nm and 450 nm, respectively.
  • IC 50 was computed using GraphPad Prism software, version 5.0.
  • the specificity of inhibition of selected PTPlB inhibitors against TCPTP is shown in Table 2.
  • Test compounds were evaluated in genetically obese and insulin resistant male ob/ob and db/db mice (8-10 weeks of age) at the dose of 10 or 30 mg/kg. Test compounds were administered once daily by oral route for desired duration of treatment. Non-fasted animals were bled under light anesthesia two days before OGTT. OGTT was performed in overnight fasted animals using a glucose load of 1 g/kg/po. Effect of test compounds on body weight gain was also evaluated relative to the vehicle treated animals. Table 4 : Effect of compounds 8 and 18 in ob/ob mice

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Abstract

The present invention relates to the novel compounds of the general formula (I), wherein the symbols are same as described in specification, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, to process and intermediates for the preparation of the above said compounds, having the utility of these compounds in medicine and to methods for their therapeutic use, and their use in the treatment of metabolic disorders.

Description

NOVEL PROTEIN TYROSINE PHOSPHATASE - IB INHIBITORS
Field of the Invention
The present invention is related to novel compounds of the general formula and their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods of making the above compounds, and their use as Protein tyrosine phosphatase IB (PTP-IB) inhibitors, which are useful in the treatment or prevention of diseases in which PTP-IB enzyme is known to be involved in the pathogenesis. In addition to its therapeutic benefits against type 2 diabetes and obesity, the PTPlB inhibitors would also find use in the treatment of diseases such as cancer, inflammatory disorders, autoimmune diseases and osteoporosis
Figure imgf000003_0001
Background of the invention
Diabetes mellitus is a major, growing health problem worldwide (Yach, D., et al. Nat. Med. 12, 62-66, 2006). Type 2 diabetes mellitus (hereafter referred as type 2 diabetes, also known as non-insulin-dependent diabetes mellitus, NIDDM) is a heterogeneous disorder, with both genetic and environmental factors contributing to its development. The pathogenesis of type 2 diabetes involves multiple mechanisms leading to hyperglycemia, most notably increased hepatic glucose production, impaired insulin secretion by pancreatic β cells and reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin resistance). Type 2 diabetic patients are at substantially increased risks of macro vascular disease including coronary heart disease and stroke and microvascular disease including retinopathy, nephropathy and neuropathy. Type 2 diabetes is a therapeutic area with huge market potential. The number of diabetic patients is projected to increase from 170-175 million in 2000 to over 350 million by 2030 (Wild, S., et al. Diab.Care 27, 1047-1053, 2004; Yach, D., et al. Nat. Med. 12, 62-66, 2006). The major part of this numerical increase is expected to occur in developing countries and India will have the distinction of having the largest number of diabetic patients in the world by 2030.
The treatment approaches for type 2 diabetes include diet, exercise, and a variety of pharmacological agents. Clinically established therapies for type 2 diabetes include insulin and its analogs and various oral hypoglycemic agents: sulfonylureas, metformin, α- glucosidase inhibitors (acarbose, miglitol), non- sulfonylurea insulin secretagogues (repaglinide, nateglinide) and thiazolidinedione (TZD) derivatives (rosiglitazone, pioglitazone) acting via PPARγ agonism (Matthaei, S., et al. Endocrine Rev. 21, 585-618, 2000; Skyler, J.S. J.MedChem. 47, 4113-4117, 2004). These agents act by different mechanisms to normalize blood glucose levels, but are limited in their abilities, either alone or in combination, to prevent the onset of diabetic complications. Further, each of the above oral agents suffers either from generally inadequate efficacy or number of adverse effects. For example, sulfonylureas, which have been the mainstay of oral treatment for over 5 decades, are known to be associated with a high rate of secondary failure and hypoglycemia. The TZD class of antidiabetic agents (glitazones) improves glucose utilization without stimulating insulin release, but their use is associated with undesirable effects (e.g. risk of myocardial infarction, cardiac hypertrophy, liver toxicity, weight gain).
Considering together the facts that about 90% of all diabetic cases account for NIDDM and the inadequacy of the currently available treatment, the clinical need and market potential for new oral antidiabetic drugs, which maintain tight glycemic control and prevent diabetic complications are very high. Protein tyrosine phosphatases (PTPs), a large family of signaling enzymes (Alonso A, et al., Cell; 117. 699-711, 2004), play essential roles in intracellular signal transduction by regulating the cellular level of tyrosine phosphorylation to control cell growth and differentiation, metabolism, cell migration, gene transcription, ion-channel activity, immune response, cell apoptosis, and bone development (Hunter T., Cell 100, 1 13-127, 2000). Unregulated operation of PTPs is responsible to many human diseases including cancer (BIume- Jensen P., Nature 41 1. 355-365. 2001), diabetes (Montalibet J., Drug Discov Today: Therap. Strateg. 2, 129-135, 2005), obesity (Cook W.S., Developmental Cell 2, 385-387, 2002), and osteoporosis (Schiller K.R., J. Cell Biochem. 96, 262-277, 2005).
Among the various PTP family, protein tyrosine phosphatase IB (PTPlB) activates c-Src inhuman breast cancer (Bjorge J.D., J Biol Chem 275, 41439-41446, 2000), and also influences the down regulation of insulin signaling by dephosphorylating the insulin receptor including insulin receptor substrate- 1 (TRS-I) and insulin receptor substrate-2 (IRS-2) (WalchJi S.. J Biol Chem 275, 9792-9796. 2000). Therefore, PTPl B can be a useful target for diabetes and cancer, and inhibitors of PTPl B may be promising drugs to treat these diseases. In addition, considering that PTPlB knockout mice are resistant to obesity, PTPlB plays critical role in development of obesity (Klaman L.D., MoI Cell Biol 20, 5479-5489, 2000). In spite of the therapeutic potential of PTPlB inhibitor against diabetes, obesity, and cancer, it is difficult to develop selective PTPlB inhibitor over other PTPs including SHP, VHR, LAR, CD45, and cdc25C, because of structural homologies in PTPs (Cheng A., Eur J Biochem 269, 1050-1059, 2002; Penninger J.M., J Nat Immunol 2, 389-396, 2001 ; Qu C.K., Biochim Biophys Acta 1592, 297-301 , 2002; Hoffman B.T., Curr Pharm Des 10, 1161- 1 181 , 2004). In particular, because T-cell PTP (TCPTP) has an 80% homology to PTPlB in the catalytic domains, non-selective inhibition gives rise to severe side effects (Tiganis T., J Biol Chem 274, 27768-27775, 1999; You-Ten K.E., J Exp Med 186, 683-693, 1997) and although, recently, there are different opinions that PTPlB and TCPTP coordinately regulate an insulin signaling process (Galic S., MoI Cell Biol 25, 819-829, 2005). The therapeutic potentials of PTP (especially PTPlB) inhibitors in treating human diseases have been extensively reviewed (Lee K.. Ciirr Top Med Chem 3, 797-807, 2003; Zhang Z.Y., Ace Chem Res 36, 385-392. 2003; Hooft van Huijsduijnen R.H., J Med Chem 47, 4142-4146, 2004; Dewang P.M., Curr Med Chem 12, 1-22, 2005; Bialy L., Artgew Chem Im Ed 44, 3814-3839, 2005; Zhang Z.Y., Curr Opin Chem Biol 5, 416^23, 2001; Burke T.R., Biopolymers (Peptide Science) 47. 225-241 , 1998). Especially, structural biology, mechanism, and inhibitors of PTPl B were reviewed by Taylor in Curr Top Med Chem 3, 759-782, 2003 and the small molecule approach to study the function of PTPl B was reviewed by Zhang in Methods 35, 9-21, 2005 which introduced the initial strategies for finding potent and specific PTPlB inhibitors, the synthesis of cell permeable analogs for cellular studies, and the application of those inhibitors to dissect the role of PTPlB in the insulin signaling pathway. Structural and biological features of small molecular PTP IB- specific inhibitors were discussed in depth by Seokjoon Lee and Qian Wang in Medicinal Research Reviews 27, 553-573, 2007, with an emphasis on specificity of small molecular inhibitors against PTPlB over other PTPs. Various classes of Investigational small molecules active against PTPl B enzyme as discussed by Seokjoon Lee et al. are listed below:
1. Substituted acelophenone, cinnamic acid and analogs.
2. N-oxalylarylaminobenzoic acid derivatives.
3. Isoxazolecarboxylic acid analogs. 4. peptidomimetics.
5. Tetrasubstituted methine derivatives.
6. 3-formylchromone.
7. Pyridazine Derivatives.
8. Abietane-Type Diterpene Pigments. 9. 1 ,2-Naphthoquinone.
Thiazolidine moiety had been screened by various inventors for diversified biological activities (WO2004047760, WO2005082901, WO2006002829.. WO2006040050, WO2006040052, WO2006047269). Some thiazolidine derivatives were described in WO2007032028 as PTPlB inhibitors.
Although various kinds of researches about PTP inhibitors including inhibition mechanistic study of inhibitors against PTP, structure-activity relationship study, and synthetic and pharmacological study, have been performed in many research groups recently, it is still very challenging to discover specific inhibitors of PTPl B and utilize them in clinical trials. The structural homogeneity of active and secondary-binding sites in PTPs family highlights the importance in developing drugs specifically antagonizing PTPlB.
Objective of the Invention
The main objective of the present invention is therefore to provide novel compounds of the general formula I, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, process and intermediates for the preparation of the compounds given in Formula I which have inhibitory activity against PTP IB.
Another objective of the present invention to develop novel compounds which are effective and useful to lower increased levels of glucose, lipids, to improve insulin resistance, to decrease body weight, for the treatment and/ or prophylaxis of metabolic disorders such as type II diabetis, obesity, hyperlipidemia, with better efficacy and lower toxicity.
Summary of the Invention
Acccording to one aspect of the present invention there is provided novel organic compounds represented by the general formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or mixture thereof.
In yet another aspect, the present invention provides a process for the preparation of novel organic compounds of the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them. A further aspect of the present invention is to provide novel intermediates, a process for their preparation and their use in methods of making compounds of the general formula (I).
Detailed Description of the Invention
The novel organic compounds of present invention represented by the general formula (I) is useful for reducing blood glucose, lowering lipid levels, cholestrol and reducing body weight and also have some excellent effects in the treatment and/or prophylaxis of diseases caused by insulin resistance such as type II diabetes, hyperlipidemia, obesity, impaired glucose tolerance, diabetic complications with better efficacy, potency, without or reduced toxicity. The present invention is related to the compounds of the general formula T
Figure imgf000008_0001
(D wherein, Gl = (a)
Figure imgf000008_0002
(b)
Figure imgf000008_0003
Figure imgf000009_0001
(A)
Figure imgf000009_0002
G2 is selected from hydrogen, fluoro and methoxy; and G3 is selected from a group of formulae:
Figure imgf000009_0003
G4 is selected from O or N-CH3 ; G5 is selected from
(a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, Ci-6 acyl, straight chain or branched Ci-6 alkyloxy, unsubstituted straight chain or branched Ci-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Ci-4 alkoxy; (b) the group of formulae:
Figure imgf000010_0001
n is 0 or 1, and m is 0, 1 or 2.; h and 1 are independently selected from 0 or 1.
A compound and its pharmaceutically acceptable salts as described herein above wherein the compound of the general formula (I) is selected from:
C,C,C-Trifluoro-N-{4-[4-oxo-5-(4-phenethyloxy-benzylidene)}-4,5-dihydro-thiazol-2- ylamino] -phenyl }-methanesulfonamide (Compound 1)
C,C,C-Trifluoro-N-(4-{5-[4-(4-fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-methanesulfonamide (Compound 2)
C,C,C-Trifluoro-N-{4-[4-oxo-5-(4-phenoxymethyl-benzylidene)-4,5-dihydro-thiazol-2- ylamino]-phenyl}-methanesulfonamide. (Compound 3)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-phenyl)-methanesulfonamide (Compound 4)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino } -phenyl)-methanesulfonamide. (Compound 5)
C,C,C-TrifluoiO-N-(4-{5-[4-(4-fluoro-benzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5- dihydro-thiazol-2-ylamino } -phenyl)-methanesulfonamide. (Compound 6) N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino) - phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 7)
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino} - phenyl)-C,C,O-trifluoro-methanesulfonamide sodium salt. (Compound 8)
N-(4-{5-[4-(4-Cyano-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 9).
5-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-2,3- dihydro-indole-1 -sulfonic acid benzoylamide. (Compound 10).
C,C3C-Trifluoro-N-(4-{5-[4-(4-isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 11)
C,C,C-Trifiuoro-N-{l-[4-oxo-5-(4-phenethyloxy-benzylidene)-4,5-dihydro-thiazol-2-yl]-2,3- dihydro-lH-indol-5-yl}-methanesulfonamide. (Compound 12)
N-(l-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,3- dihydiO-lH-indol-S-y^-CjCjC-trifluoiO-methanesulfonamide. (Compound 13)
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -pheny^-CjQC-trifluoro-methanesulfonamide. (Compound 14)
C,C,C-Trifluoro-N-(l-{5-[4-(4-fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- yl}-2,3-dihydro-lH-indol-5-yl)-methanesulfonamide. (Compound 15)
C,C,C-Trifluoro-N-{4-[5-(4-{[(4-fluoro-phenyl)-methyl-amino]-methyl}-benzylidene)-4- oxo-4,5-dihydro-thiazol-2-ylamino]-phenyl) -methanesulfonamide. (Compound 16) C,C,C-Trifluoro-N-(4-{5-[4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 17)
5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 18)
C,C,C-Trifluoro-N-[4-(5-{4-[2-(4-fluoiO-phenyl)-ethoxy]-benzylidene}-4-oxo-4,5-dihydro- thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 19)
5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 20)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-tliiazol- 2-ylamino } -phenyl)-methanesulfonamide. (Compound 21)
N-(4-{5-[4-(4-sec-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- plienyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 22)
N-[4-(5-{4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 23)
N- [4-(5- {4- [4-( 1 -Ethoxy-propyl)-benzyloxy] -benzylidene} -4-oxo-4,5 -dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 24)
N-[4-(5-{4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzylidene}-4-oxo-4,5-di hydro- thiazol-2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 25) 5-(4-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 26)
N-(4-{5-[4-(4-Chloro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 27)
5-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 28)
5-(4-{5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6- [ 1 ,2,5]thiadiazolidin-3 -one. (Compound 29)
C,C,C-Trifluoro-N-[4-(5-{4-[(4-isopropyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5- dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 30)
5-(4-{5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino)- phenyl)-l,l-dioxo-lλ6- [1,2,5] thiadiazolidin-3-one. (Compound 31)
N-[4-(5-{4-[4-(l -Ethyl-propyl)-benzyloxy] -benzylidene } -4-oxo-4,5 -dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 32)
N-(4-{5-[4-(4-Cyclopentyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino} - phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 33)
N-(4-{5-[4-(4-Cyclopentyloxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 34)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 35) 5-(4-{5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3 -one. (Compound 36)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutyryl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 37)
C,C,C-Trifluoro-N-(4-{5-[4-(2-fluoro-4-nitro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 38)
5-(4-{5-[4-(3-Fluoro-4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 39)
5-(4-{5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -benzyl)- 1,1 -dioxo- lλ6- 1,2,5] thiadiazolidin-3-one. (Compound 40)
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 41 )
5-(4-{5-[4-(4-Ethyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 42)
N-(4- { 5 - [4-(4-tert-Butyl-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 43)
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλό-l,2,5] thiadiazolidin-3-one. (Compound 44) 5-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- pheny I)- l,l-dioxo-lλ6-[ 1,2,5] thiadiazolidin-3-one. (Compound 45)
C,C3C-Trifluoro-N-(4-{4-oxo-5-[4-(4-pyrrol-l-yl-benzyloxy)-benzylidene]-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 46)
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 47)
C,C,C-Trifluoro-N-(4-{5-[4-(2-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- tbJazol-2-ylamino } -pheny l)-methanesulfonamide. (Compound 48)
5 -(4- { 5 - [4-(Indan-5-ylmethoxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 49)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-trifluoromethyl-benzyloxy)-benzylidene]-4,5-dihydro- thiazol-2-ylamino}-benzyl)-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 50)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 51)
5-(4-{5-[4-(4-Ethyl-benzyloxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 52)
5-(4-{5-[4-(3-Methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l , 1 -dioxo- 1 λ6-[l ,2,5]thiadiazolidin-3-one. (Compound 53)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4, 5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[ 1,2,5] thiadiazolidin-3-one. (Compound 54) 5-[4-(5-{4-[4-(l-Ethyl-ρropyl)~benzyloxy]-benzylidene}-4-oxo-4, 5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 55)
5-(4-{5-[4-(4-Isopropyl~phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 56)
5 -(4- { 5 - [4-(4-Isobutqxy-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - benzyl)- 1,1-dioxo-lλ6- 1,2,5] thiadiazolidin-3-one. (Compound 57)
5-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 58)
5-(4-{5-[4-(2,3-Dihydro-indol-l-ylmethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-ρhenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 59)
5-(4-{5-[4-(4-Fluoro-benzyloxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 60)
5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 61)
5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenjd)~l,l-dioxo-lλδ-[l,2,5] thiadiazolidin-3-one. (Compound 62)
5-(4-{5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino} -phenyl)- l,l-dioxo-lλό-[ 1,2,5] thiadiazolidin-3-one. (Compound 63) C,C,C-Trifluoro-N-(4-{5-[4-(indan-5-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-methanesulfonamide. (Compound 64)
N-({l-[(5Z)-5-({4-[(4-fluorophenyl) methoxy]phenyl}methylidene)-4-oxo-4,5-dihydro-l,3- thiazol-2-yl]-2,3-dihydro-lH-indol-5-yl}sulfamoyl)acetamide. (Compound 65)
C,C,C-Trifluoro-N-[4-(5-{4-[4-(l-hydroxy-2-methyl-propyl)-benzyloxy]-benzylidene}-4- oxo-4,5-dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 66)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-enzyloxy)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-phenyl)-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 67)
5-[4-(5-{4-[(Methyl-p-tolyl-amino)-methyl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλό-l,2,5] thiadiazolidin-3-one. (Compound 68)
N-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 69)
N-(4-{5-[4-(5-tert-Butyl-oxazol-2-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 70)
N-(4-{5-[4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -pheny^-QQC-trifluora-methanesulfonamide. (Compound 71)
N-(4-{5-[4-(l-Cyclohexylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzylidene]-4-oxo-4,5- dihydro-thiazol-2-ylamino} -phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 72)
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydiO-thiazol-2- ylamino)-phenyl]-C,C,C-tπfluoro-methanesulfonamide. (Compound 73) N-[4-(5-{4-[3-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 74)
5-(4-{5-[4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5] thiadiazolidin-3 -one. (Compound 75)
5-(4-{5-[4-(4-Methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 76)
5-(4-{5-[4-(4-Chloro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 77)
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1,1 -dioxo- lλ6-[ 1,2,5] thiadiazolidin-3 -one. (Compound 78)
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λδ-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 79)
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3 -one. (Compound 80)
5-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3 -one. (Compound 81)
5-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3 -one. (Compound 82) 5-[4-(5-{4-[(4-Isopropyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλδ-[l,2,5] thiadiazolidin-3-one. (Compound 83)
4-(4-{4-Oxo-2-[4-(l,l,4-trioxo-lλ6-[l,2,5]thiadiazolidin-2-ylmethyl)-phenylamino]-4H- thiazol-5-ylidenemethyl}-phenoxymethyl)-benzonitrile. (Compound 84)
4-(4-{4-Oxo-2-[4-(l,l,4-trioxo-lλ6-[l,2,5]thiadiazolidin-2-yl)-phenylamino]-4H-thiazol-5- ylidenemethyl}-phenoxymethyl)-benzonitrile. (Compound 85)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino} -phenyl)- 1 λδ-[ 1 ,2,5]thiadiazolidin-3 -one. (Compound 86)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino } -benzyl)- lλδ-[ 1,2, 5] thiadiazolidin-3-one. (Compound 87)
l,l-Dioxo-5-{4-[4-oxo-5-(4-p-tolyloxymethyl-benzylidene)-4,5-dihydro-thiazol-2-ylamino]- benzyl}-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 88)
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino] benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]- 1 , 1 -dioxo- 1 λό-[ 1 ,2,5] thiadiazolidin-3-one. (Compound 89)
N-(4-{5-[4-(4-Amino-2-fluoro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 90)
5-(4-{5-[l-[4-(4-Fluoro-benzyloxy)-phenyl]-meth-(Z)-ylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -benzyl)- 1 , 1 -dioxo- 1 λδ-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 91 ) The compounds of the invention were prepared as outlined below according to the methods described herein. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the literature.
The condensation of aromatic aldehyde of formula (i) with Rhodanine (ii) is carried out using standard Knoevenagel condensation condition such as in refluxing acetic acid in the presence of sodium acetate or in presence of ammonium acetate in toluene. In the next step, the resulting compound of formula (iii) is treated with methyl iodide at room temperature in ethanol in the presence of diisopropylethylamine to methylate the thio group to produce the compound of formula (iv). The compound of formula (iv) is treated with suitable amine to produce the compound of formula I. This reaction is carried out in ethyl alcohol at reflux temperature in the presence of a base such as diisopropylethylamine. (Scheme I)
Figure imgf000021_0001
Amine is selected from:
Figure imgf000021_0002
Figure imgf000021_0003
Alternatively rhodanine (ii) was treated with appropriate amine as shown in scheme II in the presence of mercuric chloride and diisopropylethylamine to afford intermediate V. The Knoevenagel condensation of compound of formula V with aldehyde of formula T catalysed by ammonium acetate, sodium acetate or the like in a suitable solvent produces compound of formula I.
Scheme II
HgCLDIEA, MeCN, R
Amine
Figure imgf000022_0002
ammonium toluene
Figure imgf000022_0001
Figure imgf000022_0003
(Compound I)
Amine is selected from the group as provided under scheme I.
The intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent in vaccum and re crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations.
Salts are obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which contains the desired acid or base or two which the desired acid or base is then added as described in, Berge S. M. et al.
"Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1-19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland Camille G.wermuth , wiley- VCH (2002).
The present invention also provides pharmaceutical compositions containing compounds of general formula I as defined above and their pharmaceutically acceptable salts in combination with the' usual pharmaceutically employed carrier, diluents and the like.
The following examples are provided to further illustrate the present invention and therefore should not be construed to limit the scope of the invention. Proton NMR spectra were obtained at 200 and 400 MHz Bruker instruments, with CDC13/DMSO as solvent. Chemical shifts (S) are given in ppm relative to tetramethylsilane [(S) 0 ppm] or to residual protons in the solvent as internal standard. Melting points correspond to capillary melting points at a heating rate of l°C/min. Molecular ion peaks of all the compounds were determined on Applied Biosystems API-3000 mass spectrometer.
Example 1 Preparation of C,C,C-Trifluoro-N-(4-{5-[4-(4-fluoro-benzyloxy)-benzylidene]-4-oxo-4,5- dihydro-thiazol-2-ylamino}-phenyl)-methanesulfonamide (Compound 2)
Figure imgf000024_0001
A suspension of 5-[4-(4-Fluoro-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one
(300 mg, 0.917 mmol), N-(4-Amino-phenyl)-C,C,C-trifluoro-methanesulfonamide (220 mg,
0.917 mmol) and diisopropyl ethyl amine (591 mg, 4.585 mmol) in absolute ethanol (40 ml) was heated under reflux for 8 h. The reaction mixture was allowed to cool to room temperature and solvent was evaporated under reduced pressure. Residue was suspended in methanol (15 ml) and treated with 2 N HCl (15 ml), solid was filtered and washed with water(10 ml) to afford crude product. The crude product was further purified by silica gel column using ethyl acetate-hexane (50:50) as the eluent to furnish yellow solid product (310 mg., 61.3 %).
1H NMR (DMSO^6) δ: 5.12-5.17 (2H, d) 7.11-7.79(13H m), 11.64(lH,bs) MS: m/z 550 (M-I), melting point: 262-2640C
Example 2 Preparation of compound of formula I
Analogously, by practicing the chemistry as described in example 1 with appropriate change in the reactants and reaction conditions, following compounds were prepared.
C,C,C-Trifluoro-N-{4-[4-oxo-5-(4-phenethyloxy-benzylidene)}-4,5-dihydro-thiazol-2- ylamino]-phenyl}-methanesulfonamide (Compound 1) MS: m/z 546 (M-I) Melting point: 160-1620C 1H NMR (DMSO-de) δ: 3.03-3.04(2H, t), 4.22-4.27(2H,t) 7.05-7.09(3H, m), 7.22-7.31 (6H,m) 7.44-7.46(lH,d), 7.55-7.60(2H,m), 11.6 (IH, s)12.3(lH, bs).
C,C,C-Trifluoro-N-{4-[4-oxo-5-(4-phenoxymethyl-benzylidene)-4,5-dihydro-thiazol-2- ylamino]-phenyl}-methanesulfonamide. (Compound 3) Melting point: 259-2610C MS: m/z 532(M-I) 1H NMR (DMSO-d6) δ: 5.12-5.17(2H,d), 7.0-7.17(4H5ra),7.21-7.28(4H,m),7.54-7.71(7H,m)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-
2-ylamino}-phenyl)-methanesulfonamide (Compound 4)
MS: m/z 546 (M-I)
Melting point: 270-2710C
1H NMR (DMSO-d6) δ: 2.29(3H,s), 5.09-5.12 (2H, d), 7.20-7.60 (13H, m)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 5)
MS: m/z 562 (M-I)
Melting point: 190-1920C 1H NMR (DMSOd6) δ: 3.74 (3H, s), 5.05-5.08 (2H, d), 6.97-7.60(13H, m).
C,C,C-Trifluoro-N-(4-{5-[4-(4-fluoro-benzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5- dihydro-thiazol-2-ylamino } -phenyl)-methanesulfonamide. (Compound 6) Melting point: 172-1740C 1H NMR (DMSOd6) δ: 3.74-3.84 (3H, d), 5.05-5.10 (2H, d), 7.02-7.82(13H, m), 1 1.64- 11.65(lH,m) MS: m/z 580 (M-I) N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 7) Melting point: 304-306°C MS: m/z 614 (M-I) 1H NMR (DMSOd6) δ:1.05-1.12(m, 5H), 1.32-1.37(m, 5H), 2.81-2.93(m,lH), 5.08-5.13(d, 2H), 7.00-7.17 (ra, 7H), 7.21-7.24 (m, 2H), 7.45-7.67 (m, 4H), 11.52 (bs, IH), 12.24 (s, IH).
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide sodium salt. (Compound 8) Melting point: 340-3420C
MS: rø/z 614 (M-23)
1H NMR (DMSOd6) δ:1.30-1.38 (m, 5H), 1.67-1.78 (m, 5H), 2.87-2.91(m, IH), 5.08-5.13(d,
2H), 6.89(s, IH), 6.97-6.99(d, 2H), 7.12-7.18(dd, 2H), 7.21-7.27(t, 2H), 7.33-7.38(t, 2H),
7.46-7.49(m, 2H), 7.55-7.56(m, 2H), 11.33(bs, IH).
N-(4-{5-[4-(4-Cyano-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 9).
Melting point: 273 -275 °C
MS: m/z 557(M-I) 1H NMR (DMSOd6) δ: 5.26-5.31(2H, d), 7.0-7.8 (13H, m)
5-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-2,3- diliydro-indole-1 -sulfonic acid benzoylamide. (Compound 10). Melting point: 209-210°C 1H NMR (DMSOd6) δ: 3.09-.21(2H,m),4.29-4.38(2H,t),5.13-5.17(2H,d),6.95-
6.97(lH,m),7.07-7.31(4H,m), 7.44-7.73(7H,m), 7.82-7.86(lH,d), 11.55 (IRs), 12.45(lH,s) MS: m/z 627 (M-I) C,C,C-Trifluoro-N-(4-{5-[4-(4-isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 11) Melting point: 257-258°C MS: m/z 574(M-I) 1HNMR (DMSOd6) δ: 1.13-1.16(6H,d),2.70-2.81(lH,m)5.09-5.13(2H,d), 6.91-7.05(2H,m), 7.10-7.73(12H,m), 11.69(lH,s), 12.42(lH,bs)
C,C,C-Trifluoro-N-{ l-[4-oxo-5-(4-phenethyloxy-benzylidene)-4,5-dihydro-thiazol-2-yl]-2,3- dihydro-lH-indol-5-yl}-methanesulfonamide. (Compound 12) Melting point: 287-2890C MS: m/z 572(M-I)
1H NMR (DMSOd6) δ: 2.91-3.13(2H,m), 3.21-3.43 (2H,m), 4.28-4.35(4H,d), 6.80- 7.1 l(2H,d),7.09-7.48(7H,m), 7.61-7.78(3H,m)8.23-8.38(lH,d)
N-(I -{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,3- dihydiO-lH-indol-S-y^-CjCjC-trifluoro-methanesulfonamide. (Compound 13)
Melting point: 289-2910C
MS: m/z 640 (M-I).
1H NMR (DMSO-d6) δ: 1.32-1.37 (m, 5H), 1.75-1.79 (m, 5H), 2.88-2.92 (m, IH), 3.39-3.41 (t, 2H), 4.31-4.39 (t, 2H), 5.13 (s, 2H), 7.15-7.34 (m, 8H), 7.61-7.73 (m, 3H), 8.30-8.34 (d,
IH), 12.32 (s, IH).
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -plieny^-CjQC-trifluoro-methanesulfbnamide. (Compound 14) Melting point: 283-285 0C MS: m/z 644 (M-I)
1H NMR (DMSOd6). δ: 1.27-1.38 (m, 5H), 1.68-1.79 (m, 5H), 2.86-2.91 (m, IH), 3.65 (s, 3H), 5.06-5.1 1 (d, 2H), 6.88-6.90 (m, 2HO, 7.21-7.23 (m, 5H), 7.32-7.37(m, 2H), 7.54-7.59 (d,lH), 7.68-7.73 (m, IH), 8.29 (s, IH), 11.52 (bs, IH), 12.33 (s, IH). C,C,C-Trifluoro-N-(l-{5-[4-(4-fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- yl}-2,3-dihydro-lH-indol-5-yl)-methanesulfonamide. (Compound 15) MS: m/z 576(M-I) Melting point: 287-289°C
1H NMR (DMSO-d6) δ: 3.18-3.36(2H,m), 4.29-4.45(2H,m), 5.18(2H,s), 7.12-7.32(6H,m), 7.53-7.74(6H,m),8.26-8.39(lH,d)
C,C,C-Trifluoro-N-{4-[5-(4-{[(4-fluoro-phenyl)-methyl-amino]-methyl}-benzylidene)-4- oxo-4,5-dihydro-thiazol-2-ylamino]-phenyl}-methanesulfonamide. (Compound 16)
Melting point: 171 -1730C
MS: m/z 563 (M-I)
1H NMR (DMSO-d6) δ: 2.49 (3H,s) 3.02-3.06(2H,d), 4.59-4.64(2H,d), 6.96-7.2(4H,m),
7.27-7.29(3H,m),7.32-7.81(6H,m).
C,C,C-Trifluoro-N-(4-{5-[4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 17)
Melting point: 262-264°C
MS: m/z 573 (M-I) 1H NMR (DMSOd6) δ: 1.15-1.1.23(6H,d) 2.87-2.89(lH,m), 5.09-5.14(2H,d), 7.08-
7.13(3H,t), 7.17-7.46(6H,m), 7.48-7.82(4H,m), 11.71(lH,s), 12.80(lH,bs)
5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 18) melting point: 305-3070C MS: m/z 601 (M-I).
1H NMR (DMSOd6) 8:1.22-1.37 (m, 5H), 1.71-1.76 (m, 5H), 2.72-2.88 (m, IH), 4.06(s, 2H), 5.06-5.13 (d, 2H), 7.03-7.05 (d, IH), 7.11-7.13 (m, 3H), 7.17-7.25 (m, 3H), 7.33-7.38 (m, 2H), 7.46-7.48 (d, IH), 7.56-7.57 (d, 2H), 7.65-7.69 (m, IH), 11.45 (s, IH), 12.55 (s, IH).
C,C,C-Trifluoro-N-[4-(5-{4-[2-(4-fluoro-phenyl)-ethoxy]-benzylidene}-4-oxo-4,5-dihydro- thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 19)
Melting point: 205-207°C
MS: m/z 564 (M-I)
1H NMR (DMSO-(I6)" δ: 2.95-3.12(2H,t), 4.10-4.24(2H,t)7.04-7.08(5H,m), 7.29-7.54(5H,m),
7.63-7.75(3H,m).
5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 20) melting point: 253-2550C
MS: m/z 615 (M-I), 1H NMR (DMSO^6) δ: 1.22-1.37 (m, 5H), 1.67-1.76 (m, 5HO, 2.72-2.88 (m, IH), 4.06 (s,
2H), 5.08-5.23 (d, 2H), 7.03-7.05 (d, IH), 7.11-7.13 (m, 3HO, 7.17-7.25 (m, 3HO, 7.33-7.38
(m, 2H), 7.46-7.48 (d, IH), 7.56-7.57 (d, 2H), 7.65-7.69 (m, IH), 11.45 (bs, IH), 12.55 (s,
IH).
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-diliydro-thiazol-
2-ylamino}-phenyl)-methanesulfonamide. (Compound 21)
Melting point: 282-284°C.
MS: m/z 588 (M-I)
1H NMR (DMSO^6) δ: 0.84-0.85(6H,d), 1.80-1.83(lH,m), 2.43-2.45(2H,d), 5.09- 5.14(2H,d), 7.08-7.17(5H,m), 7.26-7.38(4H,m), 7.46-7.48(lH,m), 7.57-7.61(lH,m),
7.70(lH,s), 7.80-7.82(lH,d).
N-(4-{5-[4-(4-sec-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 22) Melting point: 321-322°C MS: 7^ 588 (M-I)
1H NMR (DMSC-Cl6) δ: 0.74-0.78(4H,m),1.12-1.15(4H,m), 1.50-1.52(2H,m), 5.05- 5.12(2H,d), 7.12-7.30(12H,m), 7.58-7.68(lH,m), 7.76-7.801H,m)
N-[4-(5-{4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzylidene) -4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 23) Melting point: 281-283°C MS: m/z 628 (M-I) 1H NMR (DMSOd6) δ: 1.21-1.35(6H,m),1.52-1.53(3H,d), 1.66-1.74(5H,m),2.31-
2.49(lH,m), ,5.51-5.59(lH,m),7.00-7.08(3H,m), 7.16-7.20(2H, t), 7.26-7.33(4H,m),7.37-7.39 (lH,d), 7.48-7.63(2H,m),7.79-7.89(lH,d),11.63(lH,s).
N-[4-(5-{4-[4-(l-Ethoxy-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methaήesulfonamide. (Compound 24)
Melting point: 255-2560C
MS: m/z 618 (M-I)
1H NMR (DMSOd6) δ: 0.75-0.77(3H,d), 0.98-1. l(3H,m), 1.25-1.27(lH,m)1.51-
1.53(lH,m),1.65-1.67(lH.m),3.20-3.21(2H,m),4.07-4.08(lH,m), 5.10-5.15(2H,d), 6.94- 7.00(2H,m), 7.11-7.18(3 H,m), 7.27-7.34(4H,m)7.54-7.813H,m), 1.78(lH,s),12.49(lH,bs).
N-[4-(5-{4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzylidene) -4-oxo-455-di hydro- thiazol-2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 25) Melting point: 233-2350C MS: m/z 644 (M-I)
1H NMR (DMSOd6) δ: 1.21-1.35(6H,m), 1.66-1.74(5H,m),2.31-2.49(lH,m), (4H,m),5.51- 5.59(lH,m),7.00-7.08(3H5m), 7.16-7.20(2H, t), 7.26-7.33(4H,m),7.37-7.39 (lH,d), 7.48- 7.63(2H,m),7.79-7.89(lH,d),11.63(lH,s) 5-(4-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 26) melting point: 278-280°C MS: m/z 537 (M-I) 1H NMR (DMSO^6) δ: 4.34 (s, 2H), 5.11-5.17 (d, 2H), 7.07-7.09 (d, IH), 7.12-7.14 (d, 2H), 7.17-7.26 (m, 4H), 7.47-7.52 (m, 3H), 7.57-7.59 (m, 2H), 7.67-7.74 (m, IH), 11.47 (bs, IH), 12.53 (s, IH).
N-(4-{5-[4-(4-Chloro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 27)
Melting point: 271-2730C
MS: m/z 566 (M-I)
'H NMR (DMSO-de) δ: 5.1(2H,d),7.1 1-7.30(5H,m) 7.46(5H,s),7.46- -
7.61(2H,m),7.70(lH,d),11.62(lH,s), 12.4(lH,s)
5-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 28) melting point: 258-26O0C
1H NMR (DMSO^6) δ: 1.2(9H, s), 3.83-3.87(2H,d), 4.23(2H,s)5.09-5.14(2H,d),7.05- 7.19(3H,m),7.36-7.45 (6H,m), 7.47-7.59(2H,m), 7.69-7.75(lH,m), 11.57(lH,s)
MS: m/z 589 (M-I)
5-(4-{5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6- [1 ,2,5]thiadiazolidin-3-one. (Compound 29) melting point: 275-2760C
'H NMR (DMSO-d6) δ: 0.78-0.82(6H, d), 1.79-1.83(lH,m)s 2.36-2.40(2H,d),3.79-3.83(2H,d),4.18-4.21 (2H,d),5.10-5.15(2H,d),7.18-7.77 (12H,m),11.56(lH,s) MS: m/z 575 (M-I) C,C,C-Trifluoro-N-[4-(5-{4-[(4-isopiOpyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5- dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 30) Melting point: 264-265°C MS: m/z 587 (M-I)
1H NMR (DMSO-d6) δ: 1.15-1.16(6H,d), 2.83(lH,s), 3.07-3.10(3H,m),4.60- 4.64(2H,d),6.81-6.85(2H,m), 7.09-7.81(10H,m), 11.60(lH,bs).
5-(4-{5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 31)
M.P.-254-255°C
MS: ;7?/z 561 (M-I)
1H NMR (DMSO-d6) δ: 1.17-1.20 (d, 6H), 2.87 (m, IH), 4.40 (s, 2H), 5.08-5.14 (d, 2H),
7.10-7.26 (m, 7H), 7.33-7.36 (d, 2H), 7.45-7.49 (d, IH), 7.58-7.67 (m, 2H), 7.72-7.76 (m, IH), 11.53 (bs, IH), 12.53 (s, IH).
N-[4-(5-{4-[4-(l -Ethyl -propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 32) Melting point: 260-2610C MS: m/z 602 (M-I)
1H NMR (DMSO-d6) δ: 0.67-0.86(6H,t), 1.52-1.6 l(4H,m), 2.25-2.42(lH,m), 5.08-5.10 (2H,d), 7.16-7.78(13H,m),11.65(lH,bs), 12.36(lH,s)
N-(4-{5-[4-(4-Cyclopentyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 33) Melting point: 283-284°C. MS: m/z 600 (M-I)
1H NMR (DMSOd6) δ: 1.50-1.75(6H,m), 1.97-1.99 (2H,m), 2.94-2.96 (lH,m), 3.35(lH,s), 5.09-5.14(2H,d), 7.1-7.3(12H,m). N-(4-{5-[4-(4-Cyclopentyloxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyi)-C,C,C-trifluoro-methanesulfonamide. (Compound 34) Melting point: 252-255°C MS: m/z 616 (M-I)
1H NMR (DMSOd6) δ: 1.50-1.90(8H,m), 4.80-4.91(lH,m), 5.03-5.08(2H,d), 6.9-7.79(14H,m), 11.6(lH,bs).
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 35)
Melting point: 152-153°C
MS: m/z 604 (M-I).
1H NMR (DMSOd6) δ: 0.92-0.94(6H,d)1.96(lH,bs), 3.68-3.72(2H,d),5.04-5.09(2H,d),
6.91-6.95(2H,m),7.08-7.18(3H,m), 7.27-7.38(4H,m), 7.40-7.79(4H,m), 11.76 (lH,m).
5-(4-{5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 36)
Melting point: 268-27O0C.
1H NMR (DMSO-d6) δ: 1.19-1.20(6H,d),2.88 (2H, s), 3.92-3.96(1H, m), 4.24(2H,s), 5.16- 5.22 (2H, s), 7.08-7.72(1 IH ,m)
MS: m/z 579 (M-I).
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutyryl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 37) Melting point: 246-248°C MS: m/z 602 (M-I).
1H NMR (DMSOd6) δ: 1.09(6H,d J=6.4Hz), 3.61-3.67(lH,m), 5.25(lH,s), 5.30(lH,s),7.09- 7.05(2H,m),7.21(lH,d, J=8Hz),7.27-7.34(2H,m) ,7.48(lH,d, J=8.4Hz) 7.56-7.61 (3H,m), 7.70(lH,s), 7.81(lH,d)7.97-8.01(2H,m)> 11.6(lH,bs), 11.9(lH,bs)
C,C,C-Trifluoro-N-(4-{5-[4-(2-fluoro-4-nitro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 38) Melting point: 259-2600C MS: m/z 5Sl (M-I)
1H NMR (DMSO-d6) δ: 7.07-7.12(lH,d),7.21-7.34(5H,t),7.60-7.77(4H,m), " 8.00-8.23(lH,d),8.30-8.50(lH,d),11.74 (lH,s).
5-(4-{5-[4-(3-Fluoro-4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 39)
Melting point: 278-279°C
1H NMR (DMSOd6) δ: 1.10-1.30(3H,t), 5.0-5.01 (2H,d), 4.21-4.31 (2H,s), 7.05-
7.27(1 lH,m) MS: m/∑ 551 (M-I)
5-(4- { 5 - [3 -Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 40) Melting point: 292-294°C. 1H NMR (DMSO^6) δ: 1.09-1.121 (6H,d),2.8(2H, s), 4.1(2H,s), 4.2(2H,s), 5.10-5.15(2H, d), 7.03-7.72(12H ,m), 11.6(lH,s),12.37(lH,s) MS: m/∑ 593 (M-I)
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 41) Melting point: 178-179°C MS: m/z 618 (M-I)
1H NMR (DMSOd6) δ: 0.84-0.92(6H, t), 1.56-1.63 (4H3 m), 1.23-1.28 (IH, m), 4.18 -4.21 (IH, m), 5.01-5.04(2H,d) 6.8-6.9 (2H,d), 7.05-7.09(3H, m), 7.2-7.6(5H,m), 7.7-7.9 (2H,m). 5-(4-{5-[4-(4-Ethyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 42) Melting point: 257-259°C 1H NMR (DMSO-d6) δ: 1.16-1.25 (3H,t),2.51-2.57(2H, d), 4.26-4.41 (2H,s), 5.08- 5.14(2H,d), 7-10-.7.72(13H ,m) MS: m/z 547 (M-I)
N-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 43)
Melting point: 291 -293 °C
MS: m/z 588 (M-I)
1H NMR (DMSO-d6) δ: 1.29 (9H,s), , 5.10-5.15(2H,d), 7.08-7.26(3H,m), 7.28-7.82(10H,m),
11.66(lH,s),12.33(lH,bs)
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6- 1,2,5] thiadiazolidin-3-one. (Compound 44) melting point: 248-249°C
]H NMR (DMSO-d6) δ: 0.5-.0.8((6H,d)1.50-1.63(4H,d), 2.32-2.49(lH,m), 4.94-5.13(2H,d), 7.0-7.7(12H,m), 11.31(lH,s).
MS: m/z 589 (M-I)
5-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[ 1,2,5] thiadiazolidin-3-one. (Compound 45) melting point: 260-262°C
'H NMR (DMSO-d6) δ: 1.25(9H,s), 4.16-4.17(2H,d), 5.09-5.15 (2H,d), 7.05-7.19(5H,m),
7.34-7.48(5H,m), 7.56-7.71(3H,m).
MS: m/z 575 (M-I) C,C,C-Trifluoro-N-(4- {4-0X0-5- [4-(4-pyrrol-l-yl-benzyloxy)-benzylidene] -4,5 -dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 46) Melting point: 235-237°C MS: m/z 597 (M-I) " 1H NMR (DMSOd6) δ: 5.10-5.30 (2H,d), 6.25(2H,s, 7.10-7.76(14H,m)
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 47) Melting Point: 210-2110C 1H NMR (DMSO-d6) δ: 0.6-0.8(6H, t), 1.6-1.8(4H,m), 1.9(lH,m), 2.2-2.4(2H,m), 4.04(lH,s), 5.04-5.2(2H,d), 7.1-7.7(12H,m) MS: m/z 603 (M-I)
C,C,C-Trifluoro-N-(4-{5-[4-(2-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 48)
Melting Point: 202-2040C
MS: m/z 604 (M-I).
1H NMR (DMSOd6) δ: 0.92-0.96 (6H,m), 1.98-2.01(lH,m),3.77-3.79 (2H,d), 5.09-
5.15(2H,d),6.91-6.95 (lH,q), 7.00-7.03(lH,t), 7.10-7.193(3H,m), 7.27-7.39(4H,m), 7.47-7.49(lH,d),7.52-7.60(lH,m),7.67-7.79 (IH, m) 7.75-7.81(lH,d),l 1.71(lH,s).
5-(4- { 5 -[4-(Indan-5 -ylmethoxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - benzyl)-l,l-dioxo-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 49) Melting Point: 232-235°C MS: m/z 573 (M-I) ,
1H NMR (DMSOd6) δ: 1.99-2.02 (2H,m),2.80-2.91(4H, m), 3.81-3.85(2H, d), 4.21- 4.22(2H,d), 5.08-5.13 (2H,d), 7.0-7.2 l(5H,m) 7.29(lH,d), 7.39-7.45(3H,m), 7.54-7.66(2H,m) 7.54-7.74 (lH,d) 1 1.57(lH,s) l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-trifluoromethyl-benzyloxy)-benzylidene]-4,5-dihydro- thiazol-2-ylamino}-benzyl)-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 50) 1HNMR (DMSO-d6) δ: 3.81-3.85(2H,d),4.22-4.25(2H,d),5.09-5.121(2H,d),7.10- 7.78(12H,m), 11.56(lH,s) MS: m/z 547 (M-I)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λ6-[l ,2,5]thiadiazolidin-3-one. (Compound 51) Melting point: 268-27O0C MS: m/z 575 (M-I) 1H NMR (DMSOd6) δ: 0.83-0.86 (d, 6H), 1.81 (m, IH), 2.49-2.50 (d, 2H), 4.26 (s, 2H), 5.08-5.14 (d, 2H), 6.97-7.35 (m, 7H), 7.45-7.66 (m, 6H), 11.56 (bs, IH), 12.56 (s, IH).
5-(4-{5-[4-(4-Ethyl-benzyloxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino} -benzyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 52) Melting Point: 267-269°C
1H NMR (DMSOd6) δ: 1.14-1.25(3H, m), 2.58-2.62 (2H,q),3.94-3.98(2H,d),4.26-4.28
(2H,d),5.16-5.22 (2H,d),7.05-7.07 (lH,d) , 7.20-7.29 (3H,m), 7.34-7.49(6H,m), 7.58(lH,s),
7.75-7.78(lH,d).
MS: m/z 579 (M-I)
5-(4-{5-[4-(3-Methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλό-[l,2,5]thiadiazolidin-3-one. (Compound 53)
Melting point: 266-268°C
1H NMR (DMSOd6) δ: 2.2(3 H,s),3.9-4.17 (2H, d), 4.25(2H, s), 5.07-5.11 (2H, d), 7.06- 7.72(13H, m)
MS: m/z 547 (M-I)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4, 5-dihydro-thiazol-2-ylamino}- benzyl)- 1,1 -dioxo- lλ6-[ 1,2,5] thiadiazolidin-3-one. (Compound 54) Melting Point: 319-320°C
1H NMR (DMSOd6) δ: 0.84-0.85 (6H,d), 1.79-1.82(lH,m), 2.44-2.56(2H,d), 3.91-3.95 (2H,d), 4.25-4.26 (2H, d), 5.09-5.14(2H,d), 7.0-7.7 (12H, m), 11.56 (lH,s), MS: m/z 589 (M-I).
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4, 5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6- 1,2,5] thiadiazolidin-3-one. (Compound 55) Melting Point: 265-267°C MS: m/z 603 (M-I) 1H NMR (DMSOd6) δ: 0.71 -0.74(3 H,t), 1.12-1.15 (3H,m), 1.46-1.49 (2H, m), 5.08-
5.2(2H,d), 4.26-4.28(2H, d), 3.95-3.99 (2H,d), 6.88-6.94 (2H,m) 7.05-7.10(3H,m), 7.39-7.74 (7H5 m), 11.68-11.80 (lH,m).
5-(4-{5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 56)
Melting Point: 270-271°C
1HNMR (DMSOd6) δ: 1.13-1.16(6H,d), 2.76-2.91 (lH,m)4.14(2H,m), 5.08-5.13(2H,d),
6.87-6.97 (2H,m), 7.06-7.2(5H,q), 7.53-7.75(6H,m)
MS: m/z 575 (M-I)
5-(4-{5-[4-(4-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 57) Melting Point: 238-239°C 1H NMR (DMSO-d6) δ: 0.94-0.93 (6H, d), 1.96-2.02 (IH , m), 3.58-3.71 (4H,m), 4.21(2H,s), 5.04-5.08(2H,d),6.91-7.13(5H,m), 7.58-7.67(2H,m),7.79-7.96(lH,d). MS: m/z 605 (M-I) 5-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 58) Melting Point: 212-215°C
1H NMR (DMSO-de) δ: 0.83-0.86 (6H, t), 1.54-1.56 (4H , m), 3.78-3.86 (2H,m), 4.1- 4.2(4H,d), 4.9-5.03 (2H,d), 6.8-7.7 (12H, m) (M-I) 619
5-(4-{5-[4-(2,3-Dihydro-indol-l-ylmethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 59) Melting Point: 320-322°C. 1H NMR (DMSO^6) δ: 2.86-2.93(2H,m),3.23-3.32(2H,m),4.29-4.38(4H,m),6.56-
6.63(2H,m),6.95-7.10(4H,m),7.17-7.22(2H,m),7.44-7.53(3H,m),7.60-7.62(lH,m),7.70-
7.75(lH,m)
MS: m/z 544 (M-I)
5-(4-{5-[4-(4-Fluoro-benzyloxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 60)
Melting Point: 308-3100C
'H NMR (DMSO-d6) 4.13(2H,s)4.50-4.59(4H,m),7.04-7.17(5H,m),7.36-7.70(8H,m)
MS: m/z 551 (M-I)
5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 61)
Melting Point: 286-288°C
1H NMR (DMSCKI6) δ: 0.71-0.74(3H,t)?1.12-1.15(3H,m),1.46-1.49(2H,m), 1.46- 1.49(2H,m), 5.08-5.20(2H,d), 4.26-4.28(2H,d), 3.95-3.99(2H,d),6.88-6.94(2H,m), 7.05-
7.10(3H,m) 7.39-7.74(7H,m), 11.68-11.80(lH,m)
MS: m/z 589 (M-I) 5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 62) Melting Point: 298-299°C.
1H NMR (DMSO-(I6) δ: 0.66-0.7 l(3H,t),l.07- l.l l(3H,m),l.43- 1.46(2H,m), 4.1 (2H,s) 5.08- 5.09(2H,d), 6.85-6.90(2H,m), 7.04-7.10 (5H,m)7.40-7.60(5H,m), MS: m/z 575 (M-I)
5-(4-{5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 63) Melting Point: 309-3110C.
1H NMR (DMSOd6) δ: 1.13-1.16(6H,d),2.76-2.91(lH, m), 4.14(2H,s)5.08-5.13(2H,d),
6.87-6.97(2H,m),7.06-7.2(5H,q),7.53-7.75(6H,m)
MS: m/z 561(M-I)
C,C,C-Trifluoro-N-(4-{5-[4-(indan-5-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-methanesulfonamide. (Compound 64)
Melting Point: 261-265°C.
1H NMR (DMSOd6) δ: 1.90-2.10(2H, m), 2.75-2.95(4H, m), 5.07-5.13 (2H, d) 7.10-
7.80(14H, m), 11.64((lH,s), 12.36 (IH, s) MS: m/z 571 (M-I).
N-({l-[(5Z)-5-({4-[(4-fluorophenyl) methoxy]phenyl}methylidene)-4-oxo-4,5-diliydro-l,3- thiazol-2-yl]-2,3-dihydro-lH-indol-5-yl}sulfamoyl)acetamide. (Compound 65) 1H NMR (DMSOd6) δ: 1.89-1.92(3H,d), 3.09-3.17(2H, m), 4.18-4.23(2H,t), 5.13- 5.18(2H,d),6.90-6.95(lH,d),7.11-7.13(lH,d), 7.16-7.26(4H,m), 7.47-7.54(3H,m),7.57- 7.64(lH,d), 7.66-7.73(lH,d). MS: m/z 565 (M-I). Melting Point: 241-243 C,C,C-Trifluoro-N-[4-(5-{4-[4-(l-hydroxy-2-methyl-propyl)-benzyloxy]-benzylidene}-4- oxo-4,5-dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 66) MS: m/z 604 (M-I)
1H NMR (DMSOd6) δ: 0.68-0.71(3H,d), 0.80-0.83(3H,d), 1.77-1.80 (lH,m), 4.25-4.27 (IH5 d), 5.12-5.13(2H,d), 7.07-7.6 (13H, m)
1 , 1 -Dioxo-5-(4- {4-oxo-5-[4-(4-propyl-enzyloxy)-benzylidene]-4!,5-dihydro-thiazol-2- ylamino}-phenyl)-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 67) 1H NMR (DMSOd6) δ: 0.81-0.86(3H, t), 1.19-1.23 (2H, m), 1.50-1.57 (2H,m), 5.05-5.10 (2H, d) 4.3(2H,s)7.05-7.70(12H, m) MS: m/z 561 (M-I) Melting Point: 244-245 0C
5-[4-(5-{4-[(Methyl-p-tolyl-amino)-methyl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]- 1 , 1 -dioxo- 1 λ6- 1 ,2,5] thiadiazolidin-3-one. (Compound 68) 1H NMR (DMSOd6) δ: 2.18(3H,s), 3.02(3H,s), 4.23(2H,s), 4.59 (2H,s), 6.80(2H,m),7.00-7.32(5H,m),7.38-7.73(6H,m). MS: m/z 546 (M-I)
N-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-
2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 69)
MS: m/z 627 (M-I)
1H NMR (DMSO-d6) δ: 1.23-1.28(5H,m),
1.66-1.68(5H,m),2.50-2.51(lH,m), 3.07(3H,s),4.5 (2H,s), 6.8-7.8(13H,m), 11.4(lH,s), 11.9(1H5S).
Melting Point: 292-295 0C
N-(4-{5-[4-(5-tert-Butyl-oxazol-2-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -phenyO-CjCjC-trifluoro-methanesulfonamide. (Compound 70) MS: m/z 579 (M-I)
1H NMR (DMSO-Cl6) δ: 1.24(9H,s), 5.20-5.25(2H, d),6.87(lH,s),7.11-7.30(5H,m),7.48- 7.79(4H,m),11.65(lH,bs). Melting Point: 304-306
N-(4-{5-[4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino} -phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 71) MS: m/z 557 (M-I).
1H NMR (DMSOd6) δ: 2.91-3.10(3H,m), 3.1-3.6(4H,m),4.50-4.54(2H,m),5.7(lH,m), 7.06- 7.66(12H,m), 11.4(lH,m), 12.09(1 H,m) Melting Point: 26O0C.
N-(4-{5-[4-(l-Cyclohexylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzylidene]-4-oxo-4,5- dihydro-thiazol-2-ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 72) MS: m/z 619 (M-I)
1H NMR (DMSO-d6) δ:0.90-1.14(5H,m)1.45-1.62(6H,m),4.21(2H,d, J=6.7Hz), 5.18-5.23 (2H,m) 7.08-7.30(5H,m),7.46-7.79(4H,m) 8.21(lH,s), 11.65(lH,bs) Melting Point: 265-267
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 73) MS: m/z 618 (M-I).
1H NMR (DMSOd6) δ: 0.84-0.92(6H,t),1.23-1.28(lH,m),1.56-1.63(4H,m),4.18- 4.21(lH,m), 5.01-5.04(2H,d),6.80-6.91(2H,m),7.05-7.09 (3H,m), 7.21-7.60(5H,m), 7.73- 7.91(4H,m)
Melting Point: 258-260 0C
N-[4-(5-{4-[3-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 74) MS: m/z 618 (M-I)
1H NMR (DMSO-(I6) δ: 0.81-0.83(6H,t),1.21-1.23(2H,d),1.52-1.54(4H,m),4.13-4.15(lH,m), 5.06-5.08(2H,d), 6.80-7.40 (9H,m), 7.50-7.70 (4H,m). Melting Point; 208-2100C.
5-(4-{5-[4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[l ,2,5]thiadiazolidin-3-one. (Compound 75) MS: m/z 563 (M-I)
1H NMR (DMSOd6) δ:, 3.96-4.00(2H,d),4.10(3H,s), 4.27-4.29(2H,d),5.10-5.15(2H,d), 6.86-6.92(2H,m)s7.06-7.1(3H,m)J7.40-7.46(2H,m), 7.52(2H,s)7.58-7.79(4H,m) Melting Point:" 231 -233°C.
5-(4-{5-[4-(4-Methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 76) MS: m/z 547 (M-I)
1H NMR (DMSOd6) δ: 2.21(3H,s), 3.96-4.00(2H,d), 4.27-4.29(2H,d),5.10-5.15(2H,d), 6.86-6.92(2H,m)/7.06-7.1(3H,m),7.40-7.46(2H,m), 7.52(2H,s)7.58-7.79(4H,m) Melting Point: 247-2490C.
5-(4-{5-[4-(4-Chloro:benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[l ,2,5]thiadiazolidin-3-one. (Compound 77)
MS: m/z 567 (M-I)
1H NMR (DMSOd6) δ: 3.93-3.96(2H,d),4.20(2H,s),5.14-5.20(2H,d),7.06-7.20 (4H,m),7.46-
7.76(9H,m), 11.58(1 H,s) Melting Point: 267-269°C.
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 78) MS: m/z 605 (M-I) 1H NMR (DMSO-Cl6) δ: 0.91-0.94(6H,d),1.91-2.12(2H,m), 3.79-3.88(2H,d),3.99- 4.03(2H,d), 4.17(2H,s), 5.09-5.14(2H,d), 6.09-7.75(13H,m) Melting Point: 227-230°C.
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-.ylamino}- phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3 -one. (Compound 79) 1H NMR (DMSOd6) δ: 0.83-0.94(6H,d),1.98-1.99(lH,m),3.77-3.79(2H,d), 4.39(2H,s), 5.09-5.14(2H,d), 6.93-7.75(13H,m) MS: m/z 591 (M-I) Melting Point: 258-2600C
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 80) 1H NMR (DMSO-d6) δ: 2.49(3H,s),3.03-3.13(3H,d)4.20(2H,s),4.54-4.60(2H,d),6.78- 8.95(13H,m).
MS: m/z 546 (M-I) Melting Point: 237-2390C.
5-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 81)
1H NMR (DMSOd6) S: 1.27-1.31(6H,m),1.68-1.7(5H,m),3.0(3H,s),3.57(2H,s),
4.10(2H,s),4.5- 4.6(2H,m), 6.7-7.6(13H,m).
MS: m/z 628 (M-I)
Melting Point: 263~265°C.
5-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-
2-ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 82)
1H NMR (DMSOd6) δ: 1.24-1.28(6H,m), 1.66- 1.68(5H,m), 3.04(3 H,s),4.10(2H,s), 4.40-
4.60(2H,d), 6.7-7.6(12H,m). MS: m/z 614 (M-I) Melting Point: 281-282 °C
5-[4-(5-{4-[(4-Isopropyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 83)
1H NMR (DMSOd6) δ: l.l l-1.14(6H,d), 3.05-3.08(3H,d), 4.04(2H,s), 4.50-
4.61(2H,d),6.80-7.72(12H,m).
MS: m/z 51 A (M-I)
Melting Point: 259-260 0C
4-(4-{4-Oxo-2-[4-(l,l,4-trioxo-lλδ-[l,2,5]thiadiazolidin-2-ylraethyl)-phenylamino]-4H- thiazol-5-ylidenemethyl}-phenoxymethyl)-benzonitrile. (Compound 84)
MS: m/z 558 (M-I)
1H NMR (DMSOd6) δ: 3.40-3.44 (2H,d) 4.04-4.06(2H,d),5.21-5.25(2H,d),7.05- 7.80(12H,m)
Melting Point: 264-266°C
4-(4-{4-Oxo-2-[4-(l,l,4-trioxo-lλ6-[l,2,5]thiadiazolidin-2-yl)-phenylamino]-4H-thiazol-5- ylidenemethyl}-phenoxymethyl)-benzonitrile. (Compound 85) MS: m/z 545 (M-I)
1H NMR (DMSO-d6) δ: 4.14(2H,s),5.21-5.26(2H,d),7.05-7.17(5H,m),7.42-7.68(6H,m),7.79-
7.81(2H, m),
Melting Point: 282-284°C
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-phenyl)-lλδ-[l,2,5]thiadiazolidin-3-one. (Compound 86) 1H NMR (DMSO^6) δ: 0.82-0.89(3H,t),1.47-1.58(2H,q), 2.31(2H,s), 4.33(2H,s), 4.33(2H,s), 5.08-5.13(2H,d)6.86-6.94(2H,t)7.08-7.20(5H,m), 7.54-7.76(6H,m) MS: m/z 561 (M-I) Melting Point: 306-3100C
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-benzyl)-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 87) MS: m/z 575 (M-I)
1H NMR (DMSO-d6) δ: 0.82-0.89(3H,t),1.51-1.58(2H,q), 3.45-3.61(2H,m), 3.97- 4.00(2H,d),4.28(2H,s)5.08-5.013(2H,d), 6.86-6.90(2H,t)7.00-7.23(3H,d), 7.39-7.80(8H,m) Melting Point: 266-268°C
l,l-Dioxo-5-{4-[4-oxo-5-(4-p-tolyloxymethyl-benzylidene)-4,5-dihydro-thiazol-2-ylamino]- benzyl}-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 88)
MS: m/z 547 (M-I) 1H NMR (DMSO-d6) δ: 2.21(3H,s), 3.96-4.00(2H,d),4.27-4.29(2H,d),5.08-5.13(2H,d), 6.86-
6.92(2H,m)57.06-7.1(3H,m),7.40-7.46(2H,m),7.52(2H,s)7.58-7.79(4H,m) Melting Point: 277-279°C
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino] benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλδ-[ 1,2,5] thiadiazolidin-3-one. (Compound 89) MS: m/z 560 (M-I) 1H NMR (DMSO-d6,) δ: 2.2(3H,s), 3.04-3.08(3H,d),3.84-3.87(2H,d),4.21 (2H,s), 4.55- 4.60(2H,d), 7.40-6.73-7.71(13H,m). Melting Point: 247-249°C.
N-(4-{5-[4-(4-Amino-2-fluoro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 90)
1H NMR (DMSO-d6) δ5.22-5.40(2H,m),6.40-6.49(lH,m),6.77-6.97(7H,m)7.39-7.72(4H5m), MS: m/z 551 (M-I) Melting Point: 248-2510C. 5-(4- { 5 - [ 1 - [4-(4-Fluoro-benzyloxy)-phenyl] -meth-(Z)-ylidene] -4-oxo-4,5 -dihydro-thiazol-2- ylamino} -benzyl)- 1,1-dioxo-lλ -[l,2,5]thiadiazolidin-3-one. (Compound 91)
IH NMR (DMSO-d6): 3.84-3.88 (d, 2H)5 4.22-4.24 (d, 2H), 5.12-5.17 (d,2H),7.04-7.77 (m,
12 H), 11.5 (bs, IH).
MS: m/z 551 (M-I).
Melting Point: 278-2800C.
Example 3:
Preparation of 5-[4-(4-Fluoro-benzyIoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one
Figure imgf000047_0001
To a stirred solution of 5-[4-(4-Fluoro-benzyloxy)-benzylidene]-2-mercapto-thiazol-4-one (300 mg, 0.0.870 mmol) and diisopropylethylamine (224 mg, 1.741 mmol) in absolute ethanol (20 ml) was added methyl iodide (185mg , 1.30 mmol) and stirred aj room temperature for 1 h . Water (10 ml) was added to the reaction mixture and obtained solid was collected by filtration, washed with water (3x5ml) and dried to obtain a yellow solid (286 mg , 92.2% ) .
Example 4: Preparation of compound of formula 'iv'
Analogously, by practicing the chemistry as described in Example 5 with appropriate change in the reactants and reaction conditions, following compounds were prepared.
2-Methylsulfanyl-5-(4-phenethyloxy-benzylidene)-thiazol-4-one. MS = m/z 356 (M+ 1) 5-[4-(4-Fluoro-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 360 (M+l)
2-Methylsulfanyl-5-(4-phenoxymethyl-benzylidene)-thiazol-4-one. MS = m/z 342 (M+l)
5-[4-(4-Methyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 356 (M+l)
5-[4-(4-Methoxy-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 372 (M+l)
5-[4-(4-Fluoro-benzyloxy)-3-methoxy-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 390 (M+l)
5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 424 (M+l)
5-(4-Benzyloxy-benzylidene)-2-methylsulfanyl-thiazol-4-one. MS = m/z 342 (M+l)
4-[4-(2-Methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxymethyl]-benzonitrile. MS = m/z 367 (M+l)
5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-2-methylsulfanyl-tliiazol-4-one. MS = m/z 384 (M+l)
5-[4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 454 (M+l) 5-(4-{[(4-Fluoro-phenyl)-methyl-amino]-methyl}-benzylidene)-2-methylsulfanyl-thiazol-4- one. MS = m/z 373 (M+l)
5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 384 (M+l)
5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 374 (M+l)
5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 398 (M+l)
5-[4-(4-sec-Butyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 398 (M+l)
5-{4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 438 (M+l)
5-{4-[4-(l-Ethoxy-propyl)-benzyloxy]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 428 (M+l)
5-{4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzylidene}-2-methylsulfanyl-thiazol-4- one. MS = m/z 454 (M+l)
5-[4-(4-Chloro-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 376 (M+l)
5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-2-methylsulfaiiyl-thiazol-4-one. MS = m/z 398 (M+l) 5-{4-[(4-Isopropyl-benzyl)-methyl-amino]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 397 (M+l)
5-[4-(4-Cyclopentyl-phenoxymethyl)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 410 (M+l)
5-[4-(4-Cyclopentyloxy-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 426 (M+l)
5-[4-(4-Isobutoxy-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 414 (M+l)
5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 402 (M+l)
5-[4-(4-Isobutyryl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 412 (M+l)
5-[4-(2-Fluoro-4-nitro-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 391 (M+l)
5-[4-(3-Fluoro-4-methyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 374 (M+l)
5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 428 (M+l) 5-[4-(4-Ethyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 370 (M+ 1)
5-{4-[(4-Ethyl-propyl)-benzyloxy]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 412 (M+ 1)
2-Methylsulfanyl-5-[4-(4-pyrrol-l-yl-benzyloxy)-benzylidene]-thiazol-4-one. MS = m/z 408 (M+ 1)
5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 414 (M+ 1)
5-[4-(Indan-5-ylmethoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 382 (M+ 1)
2-Methylsulfanyl-5-[4-(4-trifluoromethyl-benzyloxy)-benzylidene]-thiazol-4-one. MS = m/z 356 (M+ 1)
5-[4-(3-Methyl-benzyloxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 356 (M+l)
5-{4-[4-(l-Ethyl-propyl)-phenoxymethyl]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 412 (M+l)
5-[4-(2,3-Dihydro-indol-l-ylmethyl)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 367 (M+l)
5-[4-(4-FluoiO-benzyloxymethyl)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 374 (M+l) 5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 398 (M+l)
5-{4-[4-(l-Hydroxy-2-methyl-propyl)-benzyloxy]-benzylidene}-2-methylsulfanyl-thiazol-4- one. MS = m/z 414 (M+l)
2-Methylsulfanyl-5-[4-(4-propyl-benzyloxy)-benzylidene]-thiazol-4-one. MS = m/z 384 (M+l)
2-Methylsulfanyl-5-{4-[(methyl-p-tolyl-amino)-methyl]-benzylidene}-thiazol-4-one.'MS = m/z 369 (M+l)
5 - {4- [(4-Cyclohexyl-benzyl)-methyl-amino] -benzylidene } ^-methylsulfanyl-thiazoM-one. MS = m/z 437 (M+l)
5-[4-(5-tert-Butyl-oxazol-2-ylmethoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 389 (M+l)
5-[4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzylidene]-2-methylsulfanyl-thiazol-4-one. MS = m/z 367 (M+l)
5-[4-(l-Cyclohexylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzylidene]-2-methylsulfanyl- thiazol-4-one. MS = m/z 429 (M+l)
5-(4- { [(4-Isobutyl-phenyl)-methyl-amino] -methyl} -benzy lidene)-2-methylsulfanyl-thiazol-4- one. MS = m/z 411 (M+l) 5-(4-{[(4-Butyl-phenyl)-methyl-araino]-methyl) -benzylidene)-2-methylsulfanyl-thiazol-4- one. MS = m/z 411 (M+l)
5-{4-[Methyl-(4-methyl-benzyl)-amino]-benzylidene}-2-methylsulfanyl-thiazol-4-one. MS = m/z 369 (M+l)
5-(4-{[(4-Isopropyl-phenyl)-methyl-amino]-methyl)-benzylidene)-2-methylsulfanyl-thiazol- 4-one. MS = m/z 397' (M+l)
2-Methylsulfanyl-5-(4-p-tolyloxymethyl-benzylidene)-thiazol-4-one. MS = m/z 356 (M+l)
Example 5 Preparation of 5-[4-(4-Fluoro-benzyloxy)-benzylidene]-2-mercapto-thiazol-4-one
Figure imgf000053_0001
To a stirred solution of 4-(4-Fluoro-benzyloxy)-benzaldehyde (250 mg, 1.09 mmol) , rhodanine (145 mg., 1.09 mmol) in acetic acid (10 ml) was added sodium acetate (357 mg, 4.36 mmol) and heated under reflux for 7 h . After cooling to room temperature, water (15ml) was added and solid precipitate was filtered ,washed with water (10ml) and hexane(10 ml) and dried under vacuum to afford a yellow solid product (340 mg , 91.15%). Example 6
Preparation of compound of formula 'iii'
Analogously, by practicing the chemistry as described in Example 3 with appropriate change in the reactants and reaction conditions, following compounds were prepared. 5-(4-Phenethyloxy-benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 340 (M-I)
5-[4-(4-Fluoro-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 344 (M-I)
5-(4-Phenoxymethyl-benzylidene)-2~thioxo-thiazolidin-4-one. MS = m/z326 (M-I)
5-[4-(4-Methyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 340 (M-I)
5-[4-(4-Methoxy-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 356 (M-I)
5-[4-(4-Fluoro-benzyloxy)-3-methoxy-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 374(M-I)
5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 408(M- 1)
5-(4-Benzyloxy-benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 326 (M-I)
4-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxymethyl]-benzonitrile. MS = m/z 351(M-I)
5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 368(M-I)
5-[4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 438 (M-I) 5-(4-{[(4-Fluoro-phenyl)-methyl-amino]-methyl}-benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 357(M-I)
5-[4-(4-Isopropyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 368 (M-I)
5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 358 (M-I)
5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 382(M-I)
5-[4-(4-sec-Butyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 382 (M-I)
5-{4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 422(M-I)
5-{4-[4-(l-Ethoxy-propyl)-benzyloxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 412(M-I)
5-{4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 438(M-I) ■
5-[4-(4-Chloro-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 360 (M-I)
5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 382(M-I)
5-{4-[(4-Isopropyl-benzyl)-methyl-amino]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 381(M-I)
5-[4-(4-Cyclopentyl-phenoxymethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 394 (M-I).
5-[4-(4-cyclopentyloxy-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 410(M-I)
5-[4-(4-Isobutoxy-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 398(M-I)
5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 386 (M-I)
5-[4-(4-Isobutyryl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 396 (M-I)
5-[4-(2-Fluoro-4-nitro-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 375 (M-
1)
5-[4-(3-Fluoro-4-methyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 358 (M-I)
5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 412 (M-I)
5-[4-(4-Ethyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 354 (M-I)
5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 396 (M-I)
5-[4-(4-Pyrrol-l-yl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 391 (M- D 5-[4-(2-Isobutoxy-beήzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 398 (M- I)-
5-[4-(Indan-5-ylmethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 366 (M-I)
2-Thioxo-5-[4-(4-trifluoromethyl-benzyloxy)-benzylidene]-thiazolidin-4-one. MS = m/z 394 (M-I)
5-[4-(3-Methyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 340 (M-I)
5-{4-[4-(l-Ethyl-propyl)-phenoxymethyl]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 396 (M-I)
5-[4-(2,3-Dihydro-indol-l-ylmethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 351 (M-I)
5-[4-(4-Fluoro-benzyloxymethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 358 (M-I)
5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 382 (M-I)
5-{4-[4-(l-HydiOxy-2-methyl-propyl)-benzyloxy]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 398 (M-I)
5-[4-(4-Propyl-benzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 368 (M-I)
5-{4-[(Methyl-p-tolyl-amino)-methyl]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 353 (M-I) 5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 421(M-I)
5-[4-(5-tert-Butyl-oxazol-2-ylmethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 373 (M-I)
5-[4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 351 (M-I)
5-[4-(l-Cyclohehxylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzylidene]-2-thioxo- thiazolidin-4-one. MS = m/z 413 (M-I)
5-(4-{[(4-Isobutyl-phenyl)-methyl-amino]-methyl} -benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 395 (M-I)
5-(4-{[(4-Butyl-phenyl)-methyl-amino]-methyl}-benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 395 (M-I)
5-{4-[Methyl-(4-methyl-benzyl)-amino]-benzylidene}-2-thioxo-thiazolidin-4-one. MS = m/z 353 (M-I)
5-[4-methyl-phenoxymethyl)-benzylidene]-2-thioxo-thiazolidin-4-one. MS = m/z 340 (M-I)
5-(4-{[(4-methyl phenyl)-methyl-amino]-methyl}-benzylidene)-2-thioxo-thiazolidin-4-one. MS = m/z 353 (M-I) Example 7 Preparation of 4-(4-Fluoro~benzyloxy)-benzaldehyde
Figure imgf000059_0001
To a stirred solution of 4-hydroxy benzaldehyde (2g, 16.39 mmol) in N, N- dimethylformamide (60 ml) at room temperature was added potassium carbonate (3.4 g , 24.59 mmol) and p-fluorobenzyl bromide (3.1 g , 16.40 mmol). The reaction mixture was heated at 60 0C for 2 h. The reaction mixture was cooled to room temperature, poured in cold water (50 ml) and precipitated solid was filtered, washed with water (100 ml) and dried under vacuo to afford off white solid (3.70 g , 98 %).
1H NMR: 400 MHz (CDCl3) δ 5.11 (s, 2H), 7.06-7.11 (m, 4H), 7.39-7.43(dd, 2H), 7.83- 7.85(d, 2H), 9.89(s, IH)
Example 8 Preparation of 4-(4-Nitro-benzyloxy)-benzaIdehyde
Figure imgf000059_0002
To a stirred solution of 4-hydroxy benzaldehyde (2g, 16.39 mmol) in N, N- dimethylformamide (20 ml) at room temperature was added potassium carbonate (3.4 g, 24.59 mmol) and p-nitro benzyl bromide (3.5 g , 16.39 mmol). Reaction mixture was heated at 60 0C for 2 h. Reaction mixture was cooled to room temperature and poured in cold water (50 ml). The precipitated solid was filtered, washed with water (30 ml) and dried under vacuo to afford off-white solid (4.10 g , 98 %). 1H NMR: 400 MHz (CDCl3) δ 5.25 (s, 2H), 7.06-7.08(d, 2H), 7.60-7.62(d, 2H), 7.85-7.87(d, 2H), 8.25-8.27(d, 2H), 9.90(s, IH).
Example 9 Preparation of 4-(4-cyclohexyl-benzyloxy)-benzaldehyde
Figure imgf000060_0001
Step-1: Preparation of 4-cyclohehyl benzoic acid ethyl ester
To a stirred solution of 4-cyclohehyl benzoic acid (1O g , 49.00 mmol) in ethanol (100 ml) was added sulfuric acid (2 ml) and heated under reflux temperature for 5 h. The reaction mixture was concentrated under vacuo and quenched with saturated sodium bicarbonate solution (50ml). The precipitated solid was filtered, washed with water (25 ml) and dried under reduced pressure to afford white solid (11. 30 g , 99 %).
Step-2: Preparation of (4-Cyclohexyl-phenyl)-methanol To a stirred suspension of lithium aluminium hydride (980 mg, 25.86 mmol) in dry tetrahydrofuran (25 ml) at 0 0C was added 4-cyclohehyl benzoic acid ethyl ester (2 g, 8.62 mmol) in tetrahydrofuran (10 ml) via addition funnel. The reaction was continued for another 2 h. The reaction mixture was quenched at 0 0C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl (30 ml). It was extracted in ethyl acetate (3x25 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford color less oil (1.6Og , 98 %).
Step-3: Preparation of l-Chloromethyl-4-cyclohexyl-benzene
To a stirred solution of (4-Cyclohexyl-phenyl)-methanol (1.6 g, 8.25 mmol) in dichloromethane (25 ml) at 0 0C was added thionyl chloride (0.800 ml, 10.72 mmol). The reaction was continued for 30 min. The reaction mixture was neutralized with saturated sodium bicarbonate solution (50 ml). The organic layer was separated, washed with water (20 ml) and brine (15 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (1.65 g, 97 %).
Step-4: Preparation of 4-(4-Cyclohexyl-benzyloxy)~benzaldehyde To a stirred solution of 4-hydroxybenzaldehyde (970 mg, 7.95 mmol) in N5N- dimethylformamide (20 ml) at room temperature was added potassium carbonate (2.20 g , 15.90 mmol) and l-Chloromethyl-4-cyclohexyl-benzene(1.65 g, 7.93 mmol). The reaction mixture was heated at 60 0C for 2 h. Reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and then poured in to cold water (40 ml). The precipitated solid was filtered and washed with water (20 ml) to afford off white solid product (2.30 g, 98 %).
1H NMR: 200 MHz (CDCl3) δ 1.36-1.45 (m, 5H), 1.60-1.95(m, 5H), 2.5 l(m, IH), 5.10(s, 2H), 7.06-7.10(d, 2H), 7.22-7.26 (d, 2H), 7.34-7.38 (d, 2H), 7.82-7.86(d, 2H), 9.88(s, IH)
Example 10 Preparation of 4-(Indan-5-ylmethoxy)-benzaldehyde
Figure imgf000061_0001
Step-1: Preparation of Indane-5-yl-carbaldehyde
To a stirred solution of indane (2 g, 16.90 mmol) in trifluoroacetic acid (25 ml) was added hexamethylenetetraamine (2.60 g) and heated to 100 0C for 5 h. The reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate solution. It was extracted in ethyl acetate (2x 25 ml). The combined organic layer was washed with water (25 ml), brine (25 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford brown oil (2.0 g, 84 %) Step-2: Preparation of indan-5-yl-methanol
To a stirred solution of Indan-5-carbaldehyde (2 g, 13.69 mmol) in EtOH (20 ml) at 0 0C was added sodium borohydride (676 mg, 17.80 mmol). The reaction was continued for 30 min. and monitored by thin layer chromatography. The reaction mixture was concentrated, acidified by addition of 2N HCl to pH 2. It was extracted with dichloromethane (2x 25 ml). The combined organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (1.95 g , 96 %).
Step-3: Preparation of 5-chloromethyl-indan
To a stirred solution of Indan-5-yl-methanol (1.90 g, 12.83 mmol) in dichloromethane (30 ml) at 0 0C was added thionyl chloride (1.24 ml, 16.68 mmol). The reaction was continued for 30 min. It was monitored by thin layer chromatography. The reaction mixture was neutralized with saturated sodium bicarbonate solution (60 ml). The organic layer was separated, washed with water (25 ml) and brine (10 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford product as colorless oil (2.10 g, 98 %).
Step-4: Preparation of 4-(indan-5-ylmethoxy)-benzaldehyde
To a stirred solution of 4-hydroxybenzaldehyde (1.47 g, 12.04 mmol) in N, N- dimethylformamide (50 ml) at room temperature was added potassium carbonate (3.32 g,
24.08 mmol) and 5-Chloromethyl-indan (2.0 g , 12.04 mmol) and heated at 60 0C for 3 h.
The reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and then poured in to cold water (25 ml). The precipitated solid was filtered and washed with water (20 ml) to afford off white solid (2.95 g, 98 %). 1H NMR 200 MHz (CDCl3): δ 2.04-2.19 (p, 2H), 2.91-2.98(t, 4H), 5.13(s, 2H), 7.08-7.12(d,
2H), 7.19-7.32 (m, 3H), 7.84-7.88 (d, 2H), 9.90 (s, IH). Example 11 Preparation of 4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzaIdehyde
Figure imgf000063_0001
Step-1: Preparation of 4-(l-Ethyl-propoxy)-benzaldehyde:
To a stirred solution of 4-hydroxybenzaldehyde (1 g, 8.19 mmol) in N, N- dimethylformamide (40 ml) at room temperature was added potassium carbonate (2.26 g, 16.39 mmol) and 3-bromopentane (1.2 gm, 9.00 mmol). The reaction mixture was heated at 60 0C for 8 h. The reaction mixture was cooled to room temperature. The reaction mixture was poured into cold water (40 ml). It was extracted in ethyl acetate (2x 25 ml). The combined organic layer was washed with water (30 ml) and brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (1.5 g , 96 %).
Step-2: 4-(l-Ethyl-propoxy)-phenyl] -methanol:
To a stirred solution of 4-(l-Ethyl-propoxy)-benzaldehyde (1.4 g, 7.29 mmol) in EtOH (25 ml) at 0 0C was added sodium borohydride (360 mg, 9.47 mmol). The reaction was continued for 30 min. and monitored by thin layer chromatography. The reaction mixture was concentrated, acidified by addition of 2N HCl to pH 2. It was extracted with dichloromethane (2x 25 ml). The combined organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (1.4 g, 99 %).
Step-3: l-Chloromethyl-4-(l-ethyl-propoxy)-benzene : To a stirred solution of 4-(l-Ethyl-propoxy)-phenyl]-methanol (1.35 g, 6.95 mmol) in dichloromethane (30 ml) at 0 0C was added thionyl chloride (0.670 ml, 9.40 mmol). The reaction was continued for 30 min. The reaction mixture was neutralized with saturated sodium bicarbonate solution (20 ml). The organic layer was separated, washed with water (30 ml) and brine (20 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford product as colorless oil (1.45 g, 98 %).
Step-4 : Preparation of 4- [4-( 1 -Ethyl-propoxy)-benzyloxy] -benzaldehyde :
To a stirred solution of 4-hydroxybenzaldehyde (805 mg, 6.60 mmol) in N5 N- dimethylformamide (25 ml) at room temperature was added potassium carbonate (1.36 gm, 9.90 mmol) and chloromethyl-4-(l-ethyl-propoxy)-benzene(1.40 g, 6.60 mmol). It was heated at 60 0C for 2 h. The reaction mixture was allowed to come at room temperature and then poured in to ice water (50 ml). It was extracted in ethyl acetate(2x 25 ml). The combined organic layer was washed with water (30 ml) and brine (15 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford pale yellow oil (1.90 g, 97 %). 1H NMR: 200 MHz (CDCl3) δ 0.92-0.99 (t, 6H), 1.62-1.75(p, 4H), 4.07-4.18(p, IH), 5.06(s, 2H), 6.90-6.94(d, 2H), 7.05-7.09(d, 2H), 7.31-7.35 (d, 2H), 7.82-7.86 (d, 2H), 9.88 (s, IH).
Example 12 Perparation of 4-(4-Pyrrol-l-yl-benzyIoxy)-benzaldehyde
Figure imgf000064_0001
Step-1 : Preparation of p-aminobenzoic acid ethylester :
To a stirred solution of p-aminobenzoic acid (10 g, 72.99 mmol) in ethanol (100 ml) was added sulfuric acid (5 ml) and heated under reflux temperature for 5 h. The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated under vacuo, neutralized with saturated sodium bicarbonate solution (100 ml). The precipitated solid was filtered, washed with water (50 ml) and dried under reduced pressure to afford white solid (11. 5O g, 96 %).
Step-2 Preparation of 4-Pyrrol- 1 -yl-benzoic acid ethyl ester: To a stirred solution of p-aminobenzoic acid ethyl ester (4 g , 24.24 mraol) in acetic acid (15 ml) was added 2,5-dimethoxytetrahydrofuran (3.5 ml, 26.66 mmol) and heated under reflux for 1 h. The reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and poured in cold water (50 ml). It was extracted in ethyl acetate (2x50 ml), washed with water (2x20 ml), dried over anhydrous sodium sulfate and evaporated under vacuo. The crude product was further purified by silica gel column using ethyl acetate-hexane (15:85) as the eluent to furnish the product as pale yellow oil (1 g, 19 %).
Step-3 Preparation of (4-Pyrrol-l-yl-phenyl)-methanol: To a stirred suspension of lithium aluminium hydride (0.530 mg, 13.94 mmol) in dry tetrahydrofuran (20 ml) at 0 0C was added 4-Pyrrol-l -yl-benzoic acid ethyl ester (1 gm, 4.65 mmol) in tetrahydrofuran (10 ml) via addition funnel. The reaction was continued for another 2 h. It was monitored by thin layer chromatography. The reaction mixture was quenched at 0 0C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl (20 ml). It was extracted in ethyl acetate (3x20 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford brown solid (800 mg, 99 %).
Step-4: Preparation of l-(4-Chloromethyl-phenyl)-lH-pyrrole :
To a stirred solution of 4-Pyrrol-l-yl-phenyl)-methanol (800 mg, 4.52 mmol) in dichloromethane (20 ml) at 0 0C was added thionyl chloride (0.440 ml, 6.00 mmol). The reaction was continued for 30 min. It was monitored by thin layer chromatography. The reaction mixture was quenched with saturated sodium bicarbonate solution (25 ml). The organic layer was separated, washed with water (20 ml) and brine (20 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford brown oil (800 mg, 92 %). Step-5: Preparation of 4-(4-Pyrrol-l-yl-benzyloxy)-benzaldehyde:
To a stirred solution of 4-hydroxybenzaldehyde (460 mg, 3.77 mmol) in N5N- dimethylformamide (15 ml) at room temperature was added potassium carbonate (1.16 g, 8.40 mmol) and l-(4-Chloromethyl-phenyl)-lH-pyrrole (735 mg, 3.77 mmol) and heated at
60 0C for 3 h. The reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and then poured in to cold water (30 ml). The solid precipitate was filtered and washed with water (15 ml). The crude product was further purified by silica gel column using ethyl acetate-hexane (12:88) as the eluent to furnish the product as a white solid (350 mg, 35 %).
1H NMR: 400 MHz (CDC13) δ 5.16 (s, 2H), 6.36-6.37(t, 2H), 7.08-7.14(m, 4H), 7.40- 7.44(m, 2H), 7.48-7.50(d, 2H), 7.85-7.87 (d, 2H).
Example 13 Preparation of 4-(5-tert-ButyI-oxazol-2-yl-methoxy)-beπzaldehyde
Figure imgf000066_0001
To a stirred solution of 5-tert-butyl-2-chloromethyloxazole [(0.18g, 1.03 mmol), prepared as per the process described in Journal of medicinal chemistry, 2004, 47, 1719-1728] in dry DMF (5 ml) was added potassium carbonate (0.55 g, 4 mmol). Reaction mixture was heated at 65-70 0C and p-hydroxy benzaldehyde ( 0.12 g, 0.98 mmol ) was added to the reaction mixture. After striring for 6 hr, the reaction mixture was cooled to room temperature and diluted with water (25 ml). Product was extracted using dichloromethane (3x 20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was further purified by silica gel column chromatography using 10 % solution of ethyl acetate in hexane as the eluent to afford the product as a yellow oil. ((0.18 g, 69 %).
IH NMR (CDC13) δ : 1.29 (s , 9H), 5.17 (s , 2H), 6.72(s,lH) 7.14 (d , J = 8.8 Hz , 2H), 7.85 (d , J = 8.8 Hz , 2H), 9.90 (s, IH), MS = m/z 260 (M+l)
Example 14 Preparation of 4-[4-(l~Hydroxy-2-methyl-propyl)-benzyloxy]-benzaldehyde
Figure imgf000067_0001
Step 1: 2-Methyl-l-p-tolyl-propan-l-one:
A suspension of aluminum chloride (6.5g, 48.3 mmol) in dry toluene (20 ml) was heated to 500C . After stirring for 15 min, isobutyryl chloride (2.5 g, 23 mmol) was added and reaction continued for 2 h. Reaction mixture was cooled to room temperature and poured in to cold water (30 ml) . Dichloromethane (30 ml) was added to reaction mixture and organic layer was separated , washed with 2N HCl (10 ml). Organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the product as colorless oil (2.75g, 73%).
Step 2: l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-one: To a stirred solution of 2-Methyl-l-p-tolyl-propan-l-one (Ig , 6.17 mmol) in dry carbon tetrachloride (15 ml) was added n-bromo succinimide (1.09 g , 6.17 mmol) and benzoyl peroxide (0.074 g , 0.31 mmol) and heated under reflux for 1.5 h. Reaction mixture was cooled to room temperature and solid was removed by filtration.The solution was then concentrated under reduced pressure to obtain the product as a colorless oil (0.98 g , 66%).
Step 3: l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-ol:
To a stirred solution of l-(4-Bromomethyl-phenyl)-2-methyl-propan~l-one (2.5 g, 10.37 mmol) in methanol (20 ml) at O0C was added sodium borohydride (0.43 g, 11.4 mmol) portionwise and stirred for 30 min and diluted with water (10 ml). Methanol was removed under reduced pressure and product was extracted with dichloromethane (2x25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the product as a colorless oil (2.1 g , 86 %). IH NMR (CDCl3) δ : 0.77-0.84 (m,3H) , 0.97-1.02 (m,3H), 1.86-2.03 (m, IH), 4.41 (d,J = 6.6 Hz, IH), 4.50 (s, 2H), 7.30-7.39 (m, 4 H).
Step 4: 4-[4-(l -Hydroxy-2-methyl-propyl)-benzyloxy]-benzaldehyde To a solution of l-(4-Bromomethyl-phenyl)-2-methyl-propan-l-ol (1.3g , 5.3 mmol) and p- hydroxy benzaldehyde (653 mg , 5.3 mmol) in dry DMF (20 ml) was added potassium carbonate (3.65 g , 26.5 mmol) and the mixture was then heated to 80 C. After stirring fpr 5 h
, the reaction mixture was cooled to room temperature and diluted with water (30 ml) and the product was extracted using ethyl acetate (3x25 ml). The combined organic extracts was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was further purified by silica gel column using 15 % solution of ethyl actete in hexane as the eluent to furnish the product as a colorless oil.
(450 mg, 30 %).
IH NMR (CDCl3 ) δ: 0.82 (d , J=6.8 Hz, 3H), 1.00 (d,J=6.7 Hz, 3H), 1.87 (br s,lH), 1.92- 2.05 (m,lH), 4.40 (d, J=6.4 Hz, IH), 5.14 (s,2H), 7.08 (d, J=8.7 Hz, 2H), 7.33-7.43 (m,4 H),
7.84 (d , J=8.7Hz, 2H), 9.89 (s, IH).
Example 15 Preparation of 4(4-fluoro-benzyloxy methyl) benzaldehyde :
Figure imgf000068_0001
Step 1: 4-(4-Fluoro-benzyloxymethyl) benzoic acid ethyl ester :
To a suspension of sodium hydride (0.147 g , 6.1 mmol) in 15 ml of anhydrous THF at 0 0C was added 4-fluorobenzyl alcohol (0.52 g, 4.1 mmol) via syringe, under nitrogen atmosphere. After stirring for 5 min., 4-bromomethyl-benzoic acid ethyl ester (1 g , 4.1 mmol) dissolved in anhydrous THF (5 ml) was added dropwise. The reaction mixture was stirred for 40 min. and then quenched by slow addition of cold water (15 ml). Reaction mixture was extracted with ethyl acetate (60 ml.) and washed with brine (10 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was further purified by silica gel column using 5 % solution of ethyl acetate in hexane as the eluent to furnish the product as a colorless oil. (0.468g , 40 %). .
Step 2: [4(4-Fluoro-benzyloxy methyl)-phenyl] methanol :
To a suspension of LAH (0.11 g , 2.9 mmol) in 15 ml of anhydrous THF at O0 C was added 4(4-Fluoro-benzyloxy methyl)-benzoic acid ethyl ester (0.7 g , 2.4 mmol)dissolved in THF (10 ml) under nitrogen atmosphere. The reaction was continued for 30 min and then quenched by careful addition of cold water (15 ml). Solid residue was removed by filtration and filtrate was extracted with dichloromethane (3x 20 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to deliver the product as colorless oil (0.59 g, 99 %).
Step 3: 4(4-fluoro-benzyloxy methyl) benzaldehyde: To a solution of [4(4-Fluoro-benzyloxy methyl)-phenyl] methanol (0.56 g, 2.2 mmol) in anhydrous dichloromethane (15 ml) was added PCC (0.98 g, 4.55 mmol) and stirred at room temp for 1 h. The inorganic substances were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column using 10% ethyl acetate-hexane as the eluent to afford the product as colorless oil ((0.48 g, 89%).
IH-NMR (CDCl3)δ: 4.57 (s, 2H), 4.63 (s , 2H) , 7.03-7.01 (m , 2H), 7.32-7.36 (m ,2H)5 7.53 (d, J = 8Hz , 2H), 7.86 (d , J = 8 hz, 2H), 10.01 (s, IH).
Example 16: Preparation of 4-p-Tolyloxymethyl-benzaldehyde
Figure imgf000069_0001
Step-1 Preparation of 4-Methyl-benzoic acid ethyl ester:
To a stirred solution of p-toluic acid (10 g, 73.52 mmol) in EtOH (100 ml) was added concentrated sulfuric acid (2 ml) and heated under reflux for 5 h. The reaction was monitored by thin layer chromatography. The reaction mixture was evaporated under vacuo and neutralized with saturated sodium bicarbonate solution (100 ml). The product was extracted with ethyl acetate (3x 40 ml). The combined extracts was washed with water (100 ml), dried over sodium sulfate and concentrated under vacuo to afford colorless oil (11 g, 91 %).
Step-2 Preparation of 4-Bromomethyl-benzoic acid ethyl ester : To a stirred solution of 4-Methyl-benzoic acid ethyl ester (5 g, 30.49 mmol)) in carbon tetrachloride (35 ml) was added N-bromosuccinimide (5.90 g, 33.53 mmol) and benzoyl peroxide (720 mg, 1.52 mmol). The feaction mixture was heated under reflux for 4 h. It was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and then filtered. The filtrate was evaporated under vacuo to afford color less oil (7.25 g, 98 %).
Step-3 Preparation of 4-p-Tolyloxymethyl-benzoic acid ethyl ester:
To a stirred solution of p-cresol (0.885 g, 8.19 mmol) in N, N-dimethylformamide (30 ml) was added potassium carbonate (1.70 g, 12.31 mmol) and 4-bromomethylbenzoic acid ethyl ester (2 g, 8.19 mmol). Reaction mixture was heated at 60 0C for 5 h. It was monitored by thin layer chromatography. The reaction mixture was allowed to come at room temperature and poured in cold water (50 ml). It was extracted in ethyl acetate (2x20 ml), dried over anhydrous sodium sulfate and evaporated under vacuo. The crude was purified by silica gel column chromatography (EtOAc: Hexane 12:88) to afford title compound as off white solid (1.8 g, 81 %).
Step-4 Preparation of (4-[(4-methylphenoxy)methyl]phenyl) methanol : To a stirred suspension of lithium aluminum hydride (750 mg, 19.77 mmol) in dry tetrahydrofuran (20 ml) at 0 0C was added p-Tolyloxymethyl-benzoic acid ethyl ester (1.78 g, 6.59 mmol) in tetrahydrofuran (10 ml) via addition funnel. The reaction was continued for another 2 h. The reaction mixture was quenched at 0 0C by addition of ethyl acetate (5 ml) and then acidified with 2N HCl to pH 2. It was extracted in dichloromethane (3x20 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml) and evaporated under vacuo to afford colorless oil (1.2 g, 86 %).
Step-5 Preparation of 4-p-Tolyloxymethyl-benzaldehyde :
To a stirred solution of {4-[(4-methylphenoxy)methyl]phenyl}methanol (1.1 g, 4.8 mmol) in dichloromethane (30 ml) at 0 C was added pyridinium chlorochromate (1.1 g, 5.1 mmol) and stirred for 1 h. It was monitored by thin layer chromatography. The reaction mixture was filtered and filtrate was concentrated under vacuo. The crude residue was purified by silica gel column chromatography (EtOAc: Hexane 11 :89) to afford white solid (700mg, 61%). IH NMR (CDCl3) δ: 2.49 (s,3H), 5.04 (s, 2H), 6.85-6.87 (d, 2H), 7.07-7.09 (d,2H), 7.32-7.34 (d, 2H), 7.83-7.85 (d, 2H), 10.02 (s, IH).
Example 17:
Synthesis of 4-[Methyl-(4-methyl-benzyl)-amino]-benzaldehyde
Figure imgf000071_0001
Step-1 Preparation of 4-methylbenzyl alcohol To a stirred solution of p-tolualdehyde (3 g, 25 mmol) in EtOH (50 ml) at 0 0C was added sodium borohydride (1.33 g, 35 mmol). The reaction was continued for 30 min. The reaction mixture was concentrated, acidified by careful addition of 2N HCl to pH 2. It was extracted with dichloromethane (2x 20 ml). The combined organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (3 g, 98 %). Step-2 Preparation of 4-methylbenzyl chloride:
To a stirred solution of 4-methylbenzyl alcohol (3 g, 24.59 mmol) in dichloromethane (30 ml) at 0 0C was added thionyl chloride (2.0 ml, 27.05 mmol). The reaction was continued for 30 min. It was monitored by thin layer chromatography. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 ml). The organic layer was separated, washed with water (20 ml) and brine (20 ml). It was dried over anhydrous sodium sulfate and concentrated under vacuo to afford colorless oil (3.3 g, 97%).
Step-3 Preparation of methyl-(4~methyl~benzyl)-amine : To a stirred solution of 4-methylbenzyl chloride (2.5 g, 17.85 mmol) in EtOH (15 ml) was added 40 % methylamine solution (5 ml) and stilted for 4 h. It was monitored by thin layer chromatography. The reaction mixture was evaporated, quenched with water (30 ml) and extracted in dichloromethane (2x 25 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuo to afford yellow oil (2.1 g, 87%).
Step-4 4-[Methyl-(4-methyl-benzyl)-amino]-benzaldehyde
To a stirred solution of methyl-(4-methyl-benzyl)-amine (2 g, 14.81 mmol) in N5N- dimethylformamide (20 ml) at room temperature was added potassium carbonate (6.7 g, 48.55 mmol) and 4-Fluorobenzaldehyde (1.83 g, 14.81 mmol). The reaction mixture was heated at 70 0C for 1O h. The reaction was monitored by thin layer chromatography. The reaction mixture was poured in to 40 ml cold water and extracted in ethyl acetate (2x 25 ml). The combined organic layer was washed with water (25 ml) and brine (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel column EtOAc: Hexane (5: 95) to afford yellow oil (1.8 gm, 51 %).
1H NMR (CDCl3) δ: 2.33 (s, 3H), 3.12 (s, 3H), 4.62 (s, 2H), 6.75-6.77 (d, 2H) 7.06-7.08 (d, 2H), 7.24-7.26 (d , 2H), 7.71-7.73 (d , 2H), 9.73 (s, IH). Example 18 Preparation of 4 [(Methyl-p-tolylamino) methyl] benzaldehyde:
Figure imgf000073_0001
Step 1: 4-(p-Tolylamino-methyl) benzoic acid ethyl ester : . To a stirred solution of p-toluidine (2 g, 18.66mmol) in dry DMF (75 ml) was added potassium carbonate (10 g, 74.6 mmol) and 4-bromomethyl benzoic acid ethyl ester (4.98 g, 20.52 mmol). The reaction mixture was heated to 70-75 0C and stirring was continued for 4 h. After cooling to room temperature, it was diluted with water (30 ml) and the product was extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20 % solution of ethyl acetate in hexane as the eluent to obtain the pure product as brown oil (2.86 g, 53 %).
Step 2: 4-[(Methyl-p"tolyl-amino)-methyl]-benzoic acid ethyl ester To a solution of 4-(p-Tolylamino-methyl) benzoic acid ethyl ester (Ig , 3.7 mmol) in DMF (20 ml), was carefully added sodium hydride (0.1 g, 4.4 mmol) at 0° C under nitrogen atmosphere. After stirring for 5 min , methyl iodide (1.06 g, 7.4mmol) was added via syringe and stirring continued for 3.5 h. The reaction was quenched by slow addition of cold water (20 ml) and the product was extracted with ethyl acetate (3x20 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as brown oil (0.8 g,76 %), which was directly used for the next reaction without further purification.
Step 3: {4-[(Methyl-p-Tolylamino)-methyl] -phenyl } methanol : To a suspension of LAH (0.12g , 3.41 mmol) in dry THF (20 ml) was added 4-(p- Tolylamino-methyl) benzoic acid ethyl ester (0.8 g , 2.84 mmol), dissolved in dry THF (5 ml) O 0C under nitrogen atmosphere . After stirring for 4.5 h, the reaction was quenched by adding ethyl acetate (15 ml). To the reaction mixture cold water (20 ml) was added and solid precipitated was removed by filteration. Filtrate was extracted with ethyl acetate (2x25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 15% solution of ethyl acetate in hexane as the eluent to afford the product as pale yellow oil (0.32g, 47 %).
• Step 4: 4-[(Methyl-p-Tolylamino)-methyl] benzaldehyde :
To a solution of oxalyl chloride (0.24g , 1.89 mmol) in dry DCM (30 ml) was added dry DMSO (0.29 g, 3.8 mmol) at -78 0C under nitrogen atmosphere . After 30 min. stirring , a solution of {4-[(Methyl-p-Tolylamino)-methyl] -phenyl } methanol (0.3g, 1.26 mmol) in dry DCM (10 ml) was added to the above solution .The reaction was continued for 1.5 hr at - 78 0C and triethyl amine (0.51 g, 5.06 mmol) was added after warming to -60 to -65 0C. The reaction mixture was allowed to come to room temperature and poured in to water (25 ml). Organic layer was separated , dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was achieved by silica gel column chromatography using 10% solution of ethyl acetate in hexane as the eluent to furnish the product as pale yellow oil (0.18 g, 60. %).
1H NMR (CDCl3) δ: 2.25 (s, 3H), 3.02 (s, 3H), 4.56 (s, 2H), 6.68 (d, J = 7.2 Hz ,2H) 7.04 (d, J = 8.4 Hz, 2H), 7.41 (d , J = 8Hz , 2H), 7.82 (d , J =8 Hz, 2H), 9.98 (s, IH).
, Example 19 Preparation of 4-(2,3-Dihydro-indol-l-ylmethyl)-benzaldehyde
Figure imgf000074_0001
Step 1 Preparation of 4-(2,3-Dihydro-indol-l-ylmethyl)-benzoic acid ethyl ester To a stirred solution of indoline (1.5g , 12.58 mmol) in dry DMF (50 ml), potassium carbonate (3.47g , 25.17 mmol) and 4-bromomethyl ethyl benzoate (3.05 g , 13.84 mmol) was added and reaction mixture was heated at 60 0C for 8 h. The reaction mixture was cooled to room temperature and then water (40 ml) was added and extracted with ethyl acetate (3x25 ml). The combined extracts was dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified by silica gel column using 2% ethyl acetate in hexane as a eluent to afford brown liquid (1.52 g, 43.18 %)
Step 2 [4-(2,3-Dihydro-indol- 1 -ylmethyl)-phenyl] -methanol
To a stirred suspension of lithium aluminium hydride (0.202 g, 5.3 mmol) in dry THF (20 ml) was added 4-(2,3-Dihydro-indol-l-ylmethyl)-benzoic acid ethyl ester (Ig, 3.5 mmol) dissolved in THF (10 ml) at O0C under nitrogen atmosphere and stirred for 30 min. The reaction was quenched by slow addition of cold water (15 ml). The solid precipitated was removed by filtration and the product was extracted by ethyl acetate (3x20 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as a pale brown oil (0.7 g, 84 %).
Step 3: 4-(2,3-Dihydro-indol-l-ylmethyl)-benzaldehyde
To a solution of oxalyl chloride (0.53g , 4.2 mmol) in dry DCM (15 ml) at -780C was added slowly dry DMSO (0.66g, 8.4 mmol) dissolved in dry DCM (5 ml) under nitrogen atmosphere. After stirring for 30 min, [4-(2,3-Dihydro-indol-l-ylmethyl)-phenyl]-methanol (0.67 g, 2.8 mmol) was added dissolved in dry DCM (10 ml). The reaction was continued for Ih at -78 0C and then warmed to -60to -650C . Triethyl amine(1.13 g, 11.2 mmol) was added to the above reaction mixture and slowly warmed to room temperature. The reaction mixture was then poured into water (25 ml) and diluted with DCM (20 ml). The organic layer was separated, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography using 10 % solution of ethyl acetate in hexane as the eluent to afford the product as colorless oil (0.47 g, 71 %).
IH NMR (CDCl3) δ: 3.00-3.04 (m, 2H), 3.36 (t , J= 8.4 Hz, 2H), 4.33 (s, 2H), 6.45 (d,J= 8 Hz, IH), 6.69-6.72 (m,lH), 7.04-7.15 (m, 2H), 7.55 (d, J =8.4 Hz, 2 H), 7.86 (d, J=8.4 Hz, 2 H), 10.01 (s,lH).
Example-20: Preparation of 4-(2-Fluoro-4-nitro-phenoxy)-benzaldehyde
Figure imgf000076_0001
To a stirred mixture of 4-hydroxy benzaldehyde (1.12 g, 9.02 mmol) and potassium carbonate ( 2.8 g, 16.4 mmol ) in DMF ( 25 ml ), 3,4-difluoronitro benzene (1.3 g, 8.2 mmol) was added and heated to 60 C for 3 h. The reaction mixture was cooled to room temperature and poured into cold water (25 ml). The solid precipitate was filtered and dried to afford white solid product (1.8 g, 84.5 %).
IH NMR (DMSO-d6) δ: 7.33-7.35 (d, 2H), 7.45-7.49 (t, IH), 7.99-8.01 (d, 2H), 8.15-8.17 (d, IH), 8.40-8.43 (d, IH), 9.90 (s, IH).
Example-21: Preparation of compound of formula 'i'
Analogously, by practicing the chemistry described in Examples 7 to 20 with appropriate change in the reactants and reaction conditions, following aldehyde compounds of formula T were prepared.
4-Phenethyloxy-benzaldehyde, MS = m/z 227 (M+l) 4- [2-(4-Fluoro-phenyl)-ethoxy] -benzaldehyde. MS = m/z 245 (M+l)
4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzaldehyde. MS = m/z 325 (M+l) 4-(4-Methyl-benzyloxy)-benzaldehyde. MS = m/z 227 (M+ 1)
4-(4-Methoxy-benzyloxy)-benzaldehyde. MS = m/z 243 (M+ 1)
4-(4-Fluoro-benzyloxy)-3~methoxy-benzaldehyde MS = m/z 261 (M+ 1)
4-(4-Formyl-phenoxymethyl)-benzonitrile MS = m/z 238 (M+ 1) 4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzaldehyde. MS = m/z 325 (M+ 1)
4-(4-Isopropyl-benzyloxy)-benzaldehyde. MS = m/z 255 (M+ 1)
4-(4-Isobutyl-benzyloxy)-benzaldehyde. MS = m/z 269 (M+ 1)
4-(4-sec-Butyl-benzyloxy)-benzaldehyde. MS = m/z 269 (M+ 1)
4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzaldehyde. MS = m/z 309 (M+ 1) 4-[4-(l-Ethoxy-proρyl)-benzyloxy]-benzaldehyde. MS = m/z 299 (M+ 1)
4-(4-Chloro-benzyloxy)-benzaldehyde. MS = m/z 247 (M+l)
4-(4-Cyclopentyloxy-benzyloxy)-benzaldehyde. MS = m/z 297 (M+l)
4-(4-Isobutoxy-benzyloxy)-benzaldehyde. MS = m/z 285 (M+l)
4-(4-Isobutyryl-benzyloxy)-benzaldehyde. MS = m/z 283 (M+l) 4-[4-(l-Ethyl-propyl)-benzyloxy]-benzaldehyde. MS = m/z 283 (M+l)
4-(4-tert-Butyl-benzyloxy)-benzaldehyde. MS = m/z 269 (M+l)
4-(2-Isobutoxy-benzyloxy)-benzaldehyde. MS = m/z 285 (M+l)
4-(l-Cyclohexylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzaldehyde. MS = m/z 300 (M+l)
4-[3-(l-Ethyl-propoxy)-benzyloxy]-benzaldehyde. MS = m/z 299 (M+l) 3-Fluoro-4-(4-isopropyl-benzyloxy)-benzaldehyde. MS = m/z 273 (M+l)
4-(3-Fluoro-4-methyl-benzyloxy)-benzaldehyde. MS = m/z 245 (M+l)
4-(4-Ethyl-benzyloxy)-benzaldehyde. MS = m/z 241 (M+l)
4-(4-Propyl-benzyloxy)-benzaldehyde. MS = m/z 255 (M+l)
4-Phenoxymethyl-benzaldehyde. MS = m/z 213 (M+l) 4-(4-Isopropyl-phenoxymethyl)-benzaldehyde. MS = m/z 255 (M+l)
4-[4-(l-Ethyl-propyl)-phenoxymethyl]-benzaldehyde. MS - m/z 283 (M+l)
4-(4-Cyclohexyl-phenoxymethyl)-benzaldehyde. MS = m/z 295 (M+l)
4-(4-Cyclopentyl-phenoxymethyl)-benzaldehyde. MS = m/z 281 (M+l)
4-(4-sec-Butyl-phenoxymethyl)-benzaldehyde. MS = m/z 269 (M+l) 4-(4-Propyl-phenoxymethyl)-benzaldehyde. MS = m/z 255 (M+ 1) 4-(3,4-Dihydro-lH-isoquinolin-2-yl)-benzaldehyde. MS = m/z 238 (M+l) 4-[(4-Isopropyl-benzyl)-methyl-amino]-benzaldehyde. MS = m/z 268 (M+l) 4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzaldehyde. MS = m/z 308 (M+l) 4-{[(4-Fluoro-phenyl)-methyl-amino]-methyl}-benzaldehyde. MS = m/z 244 (M+l) 4-{[(4-Isobutyl-phenyl)-methyl-amino]-methyl}-benzaldehyde. MS = m/z 282 (M+l) 4-{[Methyl-(4-propyl-phenyl)-amino]-methyl}-benzaldehyde. MS = m/z 268 (M+l) 4-{[(4-Isopropyl-phenyl)-methyl-amino]-methyl}-benzaldehyde. MS = m/z 268 (M+l)
Example 22:
Preparation of N-(4-Amino-phenyI)-C,C,C-trifluoro-methanesulfonamide
Figure imgf000078_0001
Step-1 : C,C,C-Trifluoro-N-(4-nitro-phenyl)-methanesulfonamide
To a stirred suspension of 4-nitro aniline (2 g, 14.4 mmol) and sodium bicarbonate (2.43 g, 28.9 mmol) in DCM (70 ml), trifluoromethane sulfonic anhydride (2.93 ml, 17.39 mmol) was added at 10° C. and stirred at rt for 5 h. Reaction mixture was filtered and residue was washed with DCM (50 ml), filtrate was washed with water (2x50 ml) and dried over sodium sulfate and evaporated under reduced pressure to get solid residue, which was washed with hexane (30 ml) and dried to give yellow solid product (3.2 g, 82 %). MS = m/z 270 [M-I].
Step-2: N-(4-Amino-phenyl)-C,C,C-trifluoro-methanesulfonamide
A mixture of C,C,C-Trifluoro-N-(4-nitro-phenyl)-methanesulfonamide (3.1 g, 11.4 mmol ), and 10 % Pd/C (600 mg) in methanol: THF ( 50 : 50 ml) was stirred at rt under H2 atmosphere (50 psi) for 3 h. Reaction mixture was filtered through celite and washed with methanol (50 ml). Solvent was evaporated under reduced pressure to give solid residue. Product was washed with ether (20 ml) and dried to afford off white solid (2.5 g, 92.5 %). MS = m/z 240 [M+l]. Example 23:
Preparation of N-(2,3-Dihydro-lH-indol-5-yI)-C,C,C-trifluoro-methanesulfonamide hydrochloride
Figure imgf000079_0001
Step-1: Reduction of 5-Nitro N-Acetyl indoline.
A mixture of 5-Nitro N-acetyl Indoline (2 g, 9.7 mmol), and 10 % Pd/C (400 mg) in methanol (70 ml) was stirred at rt under H2 atmosphere (50 psi) for 3 h. Reaction mixture was filtered through a pad of celite and washed with methanol (50 ml). Solvent was evaporated under reduced pressure to give solid residue, which was washed with ether ( 30 ml ) and dried to afford white solid product (1.6 g, 94 %). MS = m/z 177 [M+l].
Step-2: N-(l-Acetyl-2,3-dihydro-lH-indol-5-yl)-C,C5C-trifluoro-methanesulfonamide
To a stirred Suspension of 5 -Amino N- Acetyl indoline (1.5 g, 8.5 mmol) and Sodium bicarbonate (1.43 g, 17.0 mmol ) in DCM ( 50 ml), Trifluoromethane sulfonic anhydride (1.72 ml, 10.2 mmol) was added at 100C and stirred at rt for 5 h. Reaction mixture was filtered and residue was washed with DCM ( 50 ml), filtrate was washed with water ( 2x50 ml ) and dried on sodium sulfate and evaporated under reduced pressure to get solid residue which was washed with hexane ( 30 ml) and dried to afford yellow solid (2.1 g, 80 %). MS = m/z 307 [M-I].
Step-3: N-(2,3-Dihydro-lH-indol-5-yl)-C,C,C-trifluoro-methanesulfonamide To a stirred . solution of N-(l-Acetyl-2,3-dihydro-lH-indol-5-yl)-C,C,C-trifluoro- methanesulfonamide • (2 g , 6.4 mmol) in ethanol ( 50 ml ), ION HCl (2 ml) was added at 50C. The reaction mixture was heated under reflux for 2 h. Reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure to get solid, which was washed with ether (50 ml) and dried to afford off white solid (1.7 g, 89 %). MS = m/z 266 [M-I].
Example 24: Preparation of 5-(4-Aminophenyl)-l,l-dioxo-[l,2,5]-thiadiazolidin-3-one
Figure imgf000080_0001
Step 1: (4-Nitrophenyl) acetic acid methyl ester
To a stirred suspension of 4-Nitroaniline (1.5 g, 10.8 mmol), Sodium Bicarbonate (2.7 g., 32.6 mmol ) in DMF (30 ml) , Methyl bromoacetate (1.99 g., 13.0 mmol) was added and reaction mixture was stirred at 70-75 ° C for 3 h. Reaction mixture was cooled at rt and water (200 ml) was added, product separated was filtered and washed with water (2x 50ml). The yellow solid product was dried under reduced pressure (2.1 g., 91.1 %). MS = m/z 211 [M+ 1]
Step 2: (4-Nitrophenyl)-N-Sulfamido-glycine methyl ester To a stirred solution of chlorosulfonyl isocyanate (1.51 ml, 17 mmol) in DCM (50 ml ), t- Butanol (1.66 ml, 17 mmol) was added dropwise at 0° C under nitrogen atmosphere and stirred for 30 min. This solution was added dropwise maintaining 0° C to a solution of (4- nitrophenyl) acetic acid methyl ester (2.0 g, 14 mmol) and diisopropylethylamine (4.03 ml, 28 mmol) in DCM (50 ml ). After addition, reaction mixture was stirred at rt for 3 h. and quenched by addition of 0.1N HCl (50 ml). Reaction mixture was extracted with DCM (50 ml). The combined DCM layer was washed with water (40 ml), dried over Sodium sulphate. Trifluoro actic acid (35 ml ) was added to the extract containing Boc-Procteted sulfamide at 0 0 C. and the solution was stirred for 3 h. The solution was washed with saturated sodium bicarbonate solution ( 50 ml ) and water( 2x50 ml) . Solution was evaporated to dryness and to the residue hexane ( 20 ml ) was added to afford yellow color solid product (2.1 g., 77.7 % ).
Step 3: l,l-dioxo-5-(4-nitrophenyl)-[l,2,5]thiadiazolidin-3-one. A solution of 2M NaOH (0.331 g., 8.28 mmol) was added to a suspension of (4- Nitrophenyl)-N-Sulfamido-glycine methyl ester (2.0 g., 6.9 mmol) in ethanol (50 ml) at 0 0C and stirred until a thick precipitate formed. The mixture was acidified to pH 5.0 by adding 6 M HCl. The solid precipitate was collected by filtration and washed with diethyl ether (50 ml) and dried under reduced pressure to give yellow color solid (1.5 g., 84.7 %). MS = m/z 256 [M-I].
Step 4: 5-(4-Aminophenyl)-l,l-dioxo-[l,2,5]-thiadiazolidin-3-one.
A solution of l,l-dioxo-5-(4-nitrophenyl)-[l,2,5]thiadiazolidin-3-one(1.4 g., 5.44 mmol) in methanol (50 ml) was treated with 10% Pd/C (300 mg.) under hydrogen atmosphere for 5 h. The catalyst was removed by filtration. The solution was concentrated under reduced pressure and residue was washed with ether to give off white solid (1.0 g., 83.3 %). MS = m/z 226 [M-I].
Example 25: Preparation of 5-(4-AminobenzyI )-l,l-dioxo-[l,2,5]-thiadiazolidin-3-one
Figure imgf000081_0001
5-(4-Aminobenzyl )-l,l-dioxo-[l,2,5]-thiadiazolidin-3-one was prepared from N-(4- nitrobenzyl)-glycine ethyl ester by following the process described in Example 24. Example 26: Preparation of 7V-[(5-aminoindoline)sulfamoyI]benzamide:
Figure imgf000082_0001
Step 1: Nitration of N-acetyl indoline. To a stirred solution of N-acetyl indoline ( 5 g , 31mmol) in acetic acid ( 50 ml), cone, nitric acid (2.6 ml ) was added drop wise at 0 0C .The reaction mixture was stirred at room temperature for Ih. Reaction mixture was carefully added in to cold water ( 80 ml ) and precipitate was filtered and dried to afford yellow solid ( 5.2 g , 81.31% ). MS = m/z 206
[M+l] .
Step 2: Deacetylation of 5-Nitro N-acetyl Indoline.
To a stirred solution of 5-Nitro N-acetyl Indoline (5 g , 31mmol) in ethanol (50 ml ), 30% aq HCl (10ml ) was added at 50C .The reaction mixture was heated under reflux for 2 h.
Reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. Residue was basifϊed with ammonium hydroxide ( pH 9) solution , filtered and dried to afford the product as a yellow solid (3.8 g , 97.43 %). MS = m/z 164 [M+l].
Step 3: tert-bntyl [(4-nitrophenyl)sulfamoyl] carbamate
To a stirred solution of chlorosulfonyl isocyanate ( 3.67 g , 26 mmol) in DCM ( 5 ml ), t- butanol (2.07g , 28 mmol) was added dropwise at 0° C under nitrogen atmosphere and stirred for 15 min. This mixture was added to a solution of 5-Nitroindoline (3.7 g, 22 mmol) and TEA ( 6.66 g , 66 mmol) in DCM ( 50 ml ) at 0° C under nitrogen atmosphere and stirred at rt for 8 hr . Solvent was evaporated , water (30 ml ) was added to the residue & the yellow solid was filtered and dried (7.53 g , 90.24%). MS - m/z 343 [M-I]. Step 4: iV-(5-nitro Indoline) sulfamoyl amide
To a stirred solution of tert-buty\ [(5 -nitroindoline)sulfamoyl] carbamate (7.5 g, 21mmol) in DCM (50 ml), TFA (9.94 g , 87 mmol ) was added at 10° C. After addition reaction mixture was stirred at rt for 1 h. Solvent was evaporated under reduced pressure and water was added to residue to get solid, which was filtered and washed with water (50 ml) and hexane (20 ml) and dried to afford titled compound as a yellow solid (4.72 g, 89.61%). MS = m/z 243 [M-I].
Step 5: 7V-[(5-nitroindoline)sulfarnoyl]benzamide
To a stirred solution of JV-(5-nitroindoline) sulfamoyl amide (2.35 g, 9.6 mmol) and TEA (1.9 g, 19 mmol ) in DCM ( 50 ml), benzoyl chloride (1.26g, 9.6 mmol ) was added at 10° C and stirred at rt for 4 h. Solvent was evaporated under reduced pressure and to the residue ethyl acetate ( 30 ml ) was added and washed with water (20 ml ). Ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford yellow solid (2.96 g, 88.99 %). MS = m/z 347 [M-I].
Step 6: Λf-[(5-aminoindoline)sulfamoyl]benzamide
A mixture of Λf-[(5-Nitro indoline)sulfamoyl]benzamide (2.9 g, 6.2 mmol ) and 10 % Pd/C (500 mg) in methanol ( 30 ml) and THF ( 20ml ) was stirred at rt under H2 atmosphere (50 psi) for 5 h. Reaction mixture was filtered through celite and residue was washed with methanol (50 ml). Solvent was evaporated under reduced pressure to give solid residue which was washed with ether (25 ml ) and dried to afford off white solid (2.3 g, 94.79 %). MS = m/z 317 [M-I].
Example 27: Preparation of N-[(5-aminoindoline)suIfamoyl]acetamide
Figure imgf000083_0001
Step 1: N-[(5-nitro indoline)sulfamoyl]acetamide .
A solution of iV-(5-nitroindoline) sulfamoyl amide (2.35 g , 9.6 mmol) , DIPEA (2.47g , 19 mmol ), DMAP (0.585g , 4.8mmol) and acetic acid ( 0.549g , 9 mmol) in THF ( 50 ml ) was stirred at room temperature under nitrogen atmosphere. After 15 minutes, EDCI (2.20 g , 1.152 mmol) was added and reaction mixture was stirred for 4h. Solvent was evaporated under reduced pressure, water (50 ml ) was added , neutralized with 2N-HC1 & extracted with ethyl acetate (3x15 ml ). Combined ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to give yellow solid (2.39 g, 87% ). MS = m/z 285 [M-I]
Step 2: N-[(5-aminoindoline)sulfamoyl]acetamide.
A mixture of JV-[(5-Nitro indoline)sulfamoyl]acetamide (2.39 g , 8.32 mmol ), and 10 % Pd/C (500 mg) in methanol ( 30 ml) was stirred at rt under H2 atmosphere (50 psi) for 2 h. Reaction mixture was filtered through celite and residue was washed with methanol (30 ml). Solvent was evaporated under reduced pressure to give solid residue which was washed with ether (20 ml )and dried to afford off white solid ( 2.03 g , 95.5%). MS - m/z 255 [M-I].
Example 28:
Preparation of C,C,C-Trifluoro-N-(4-{5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo- 4,5-dihydro-thiazol-2-ylamino}-phenyl)-methanesulfonamide (compound 4)
Figure imgf000084_0001
Step-1: C,C,C-Trifluoro-N-[4-(4-oxo-4,5-dihydro-thiazol-2-ylamino)-phenyl]- methanesulfonamide .
To a stirred solution of N-(4-Amino-phenyl)-C,C,C-trifluoro-methanesulfonamide (500 mg, 2.06 mmol ) and rhodanine (302 mg, 2.27 mmol ) in acetonitrile (30 ml), DIPEA (129.3 mg,
5.16 mmol) was added . The reaction mixture was allowed to cool and mercuric chloride
(271.5 mg, 2.57 mmol) was added at 0-5 °C. After addition, the suspension was stirred at room temperature for 16 h. Black reaction mixture was filtered and residue was washed with acetonitrile (10 ml). Filtrate was evaporated under reduced pressure and residue was dissolved in DCM (15 ml) and washed with water (5 ml). DCM solution was evaporated under vaccum to afford brown solid (294 mg, 42 %). MS = m/z 338 (M-I).
Step 2: C,C,C-Trifluoro-N-(4- {5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino} -phenyl)-methanesulfonamide. To a stirred mixture of a 4-(4-Methyl-benzyloxy)-benzaldehyde (200 mg.,0.88 mmol ) and thiaone ( 284 mg, 0.840 mmol ) in toluene (25 ml ), ammonium acetate ( 203.2 mg, 2.64 mmol ) was added and heated under reflux for 6 h. Reaction mixture was cooled to room temperature and solvent was evaporated under vaccum. Residue was suspended in methanol (10 ml ) and treated with 2 N HCl (10 ml), solid was filtered and washed with water (10 ml ) to afford crude product. Crude compound was suspended in ethanol (15 ml), stirred at 700C for 30 min. and allowed to cool to room temp. Solid product was filtered and washed with ethanol (5 ml) and diethyl ether (5ml) to afford a yellow solid product (245 mg., 56 %). 1H NMR (DMSO-d6) δ: 2.29(3H,s), 5.09-5.12 (2H, d), 7.20-7.60 (13H, m). Meltig point: 270-271 0C, MS = m/z 546 (M-I). Demonstration of In Vitro Efficacy of Test Compounds
A. Inhibition of human recombinant PTPlB
The phosphatase activity of human recombinant PTPlB was determined by following a previously described procedure (Methods 35, 2-8, 2005), but with certain modifications. The principle of the assay is based on the hydrolysis of 6,8-difluoiO-4-methylumbelliferyl phosphate (DiFMUP) and the fluorometric quantitation of the liberated difiuoromethylumbelliferone (DiFMU) .
Assays were routinely carried out in 96-well flat-bottom black microwell plates. The reaction mixture (100 μl) contained 15 ng/well of human recombinant PTPlB enzyme (produced in- house or procured from R&D Systems, USA) in the assay buffer (50 mM Hepes, pH 7.2, 50 mM NaCl, 1 mM EDTA, 1 mM DDT and 0.01 % Triton X-100) and 25 μM DiFMUP. After incubation of assay plates at 300C for 5 min, the hydrolysis of DiFMUP was monitored in a fluorescence microplate reader (SpectraMax M5 Molecular Devices, USA), with excitation and emission wavelengths set at 358 nm and 450 nm, respectively.
The inhibition of PTPlB activity by test compounds was routinely assessed by preincubating the enzyme with test compound (0.1 and 1 μM for primary screening and 7 concentrations from 0.01 to 10 μM for the dose-response study) or vehicle (1 % DMSO) for 10 min at 300C, in a total volume of 90 μl. Test compounds were dissolved in DMSO at a concentration of 10 mM and suitably diluted further in assay buffer. The enzyme reaction was initiated by the addition of DiFMUP, followed by incubation of assay plates for 5 min at 300C and the liberated product was measured as described above. A known inhibitor of PTPlB (positive control) was always included in the assay. Test compounds at various concentrations were always evaluated in duplicate, along with substrate blanks, vehicle controls and positive controls.
The results are expressed as percent inhibition of the enzyme activity relative to vehicle controls. Dose-response studies were conducted for those compounds exerting > 50% inhibition of activity at 1 μM in primary screening. The inhibition data, expressed as IC50, the inhibitor concentration that caused 50% decrease of the activity under assay conditions. The IC5O was computed using GraphPad Prism software, version 5.0. The PTPlB inhibition data (expressed as IC5o) is presented in Table 1. Table 1 : Compounds exerting inhibition of human recombinant PTPlB (IC=;n,<
IuM)
Compound No • IC50 μM Compound No. IC50 μM
7 0.286 ±0.065 40 0.444 ± 0.097
8 0.515 ±0.056 42 0.317 ±0.055
9 0.535 ±0.04 44 0.990 ±0.167
10 0.564 ±0.10 45 0.356 ±0.013
11 0.527 ±0.023 50 0.399 ±0.071
13 0.352 ±0.096 51 0.361 ±0.013
14 0.251 ±0.029 52 0.272 ± 0.027
15 0.592 ±0.057 53 0.586 ±0.012
18 0.240 ±0.046 55 0.543 ±0.073
20 0.145 ±0.015 56 0.193 ±0.014
23 0.714± 0.176 57 0.360 ±0.053
26 0.235 ±0.035 59 0.805 ±0.161
28 0.360 ±0.026 61 0.273 ± 0.029
29 0.184 ± 0.013 62 0.348 ± 0.074
31 0.282 ±0.089 63 0.223 ± 0.021
35 0.872 ±0.146 67 0.420 ±0.011
36 0.417 ±0.032 87 0.217 ±0.052
B. Determination of Selectivity of PTPlB Inhibitors PTPlB inhibitors with desired potencies were evaluated for their selectivity against the closely related, T-cell protein tyrosine phosphatase (TCPTP), employing assay conditions similar to that used for PTPlB (see above). The reaction mixture (100 μl in 96-well flat- bottom black-well plates) contained assay buffer (50 mM Hepes, pH 7.2, 50 mM NaCl, 1 mM EDTA, 1 mM DDT and 0.01 % Triton X-100), 25 μM substrate (DiFMUP) and 125 mU/well of human recombinant enzyme (procured from New England Biolabs, UK), with or without test compound. Routinely, TCPTP was preincubated with test compound (ranging from 0.01 μM to 10 μM) or vehicle (1 % DMSO) for 10 min at 300C, in a total volume of 90 μl. The reaction was started by the addition of 10 μl substrate (250 μM running stock in assay buffer) and further incubated for 5 min at 300C. The liberated DIFMU was monitored in a fluorescence microplate reader (SpectraMax M5, Molecular Devices, USA), with excitation and emission wavelengths set at 358 nm and 450 nm, respectively. IC50 was computed using GraphPad Prism software, version 5.0. The specificity of inhibition of selected PTPlB inhibitors against TCPTP is shown in Table 2.
Table 2: Selectivity of PTP-IB inhibitors against TCPTP
Figure imgf000088_0001
Demonstration of In Vivo Efficacy of Test Compounds A. Evaluation in Diet-Induced Obese (DIO) Mice Male healthy C57BL/6J mice were randomized into two groups at 4 weeks of age and fed either Lard Control diet (D12450B, 10% kcal from Lard) or High-fat diet (D12451, 45% kcal from Lard) from Research Diets Inc., USA, for 16-26 weeks. Animals were selected on the basis of glucose intolerance to a glucose challenge of 2 g/kg, done at 20-30 weeks of age. Glucose intolerant animals from the high-fat diet group were randomized and grouped on the basis of body weight and plasma triglycerides. Animals were dosed once daily by oral route for 23 days. On day 21st of treatment non-fasted animals were bled from retro-bulbar venous plexus under light anesthesia to evaluate the effect of test compounds on different metabolic parameters in plasma. Oral glucose tolerance test (OGTT) was performed on day 23 in overnight fasted animals using 2 g/kg/po of glucose load. Effect of test compounds on body weight gain was also evaluated against the vehicle treated animals.
Table 3 : Effect of compound 8 in DIO C57BL/6J Mice
Figure imgf000089_0001
B. Evaluation in Genetically Diabetic and Obese mice
Test compounds were evaluated in genetically obese and insulin resistant male ob/ob and db/db mice (8-10 weeks of age) at the dose of 10 or 30 mg/kg. Test compounds were administered once daily by oral route for desired duration of treatment. Non-fasted animals were bled under light anesthesia two days before OGTT. OGTT was performed in overnight fasted animals using a glucose load of 1 g/kg/po. Effect of test compounds on body weight gain was also evaluated relative to the vehicle treated animals. Table 4 : Effect of compounds 8 and 18 in ob/ob mice
Figure imgf000089_0002
Table 5: Effect of compound 53 in db/db mice
Figure imgf000090_0001
ND= NoI determined

Claims

1. A compound of the general formula I
Figure imgf000091_0001
(I) wherein, Gl = (a)
Figure imgf000091_0002
(b)
Figure imgf000091_0003
(Φ
Figure imgf000091_0004
G2 is selected from hydrogen, fluoro and methoxy; and G3 is selected from a group of formulae:
Figure imgf000092_0001
G4 is selected from O or N-CH3; G5 is selected from
(a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, Ci- 6 acyl, straight chain or branched Ci-6 alkyloxy, unsubstituted straight chain or branched Ci-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Cj-4 alkoxy;
(b) the group of formulae:
Figure imgf000092_0002
n is 0 or 1 , and m is O5 1 or 2.; h and 1 are independently selected from 0 or 1.
2. A compound and its pharmaceutically acceptable salts as claimed in claim 1 wherein the compound of the general formula (I) is selected from C,C,C-Trifluoro-N-{4-[4-oxo-5-(4-henethyloxy-benzylidene)}-4,5-dihydro-thiazol-2- ylamino]-phenyl}-methanesulfonamide (Compound 1)
C5C,C-Trifluoro-N-(4-{5-[4-(4-fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-methanesulfonamide (Compound 2)
C,C,C-TrifluoiO-N-{4-[4-oxo-5-(4-phenoxymetliyl-benzylidene)-4,5-dihydro-thiazol-2- ylamino] -phenyl }-methanesulfonamide. (Compound 3)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol- 2-ylamino}-phenyl)-methanesulfonamide (Compound 4)
C,C,C-Trifluoro-N-(4-{5-[4-(4-methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 5)
C,C,C-Trifluoro-N-(4-{5-[4-(4-fluoro-enzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5- dihydro-tmazol-2-ylamino} -phenyl)-methanesulfonamide. (Compound 6)
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 7)
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide sodium salt. (Compound 8)
N-(4-{5-[4-(4-Cyano-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 9). 5-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-2,3- dihydro-indole-1 -sulfonic acid benzoylamide. (Compound 10).
C,C,C-Trifluoro-N-(4-{5-[4-(4-isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 11)
C,C,C-Trifluoro-N-{l-[4-oxo-5-(4-henethyloxy-benzylidene)-4,5-dihydro-thiazol-2-yl]-2,3- dihydro-lH-indol-5-yl} -methanesulfonamide. (Compound 12)
N-( 1 - { 5 - [4-(4-Cyclohexyl-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-yl} -2,3 - dihydro-lH-indol-5-yl)-C,C,C-trifluoro-methanesulfonamide. (Compound 13)
N-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 14)
C,C,C-Trifluoro-N-( 1 - { 5 - [4-(4-fluoro-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2- yl}-2,3-dihydro-lH-indol-5-yl)-methanesulfonamide. (Compound 15)
C,C,C-Trifluoro-N-{4-[5-(4-{[(4-fluoro-phenyl)-methyl-amino]-methyl} -benzylidene)-4- oxo-4,5-dihydro-thiazol-2-ylamino]-phenyl}-methanesulfonamide. (Compound 16)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 17)
5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 18)
C,C,C-Trifluoro-N-[4-(5-{4-[2-(4-fluoro-phenyl)-ethoxy]-benzylidene) -4-oxo-4,5-dihydro- thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 19) 5-(4-{5-[4-(4-Cyclohexyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 20)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol- 2-ylamino}-phenyl)-methanesulfonamide. (Compound 21)
N-(4-{5-[4-(4-sec-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 22)
N-[4-(5-{4-[l-(4-Cyclohexyl-phenyl)-ethoxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 23)
N-[4-(5-{4-[4-(l-Ethoxy-propyl)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 24)
N-[4-(5-{4-[2-(4-Cyclohexyl-phenyl)-2-hydroxy-ethoxy]-benzylidene}-4-oxo-4,5-di hydro- thiazol-2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 25)
5-(4-{5-[4-(4-Fluoro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λ6- [ 1 ,2,5]thiadiazolidin-3-one. (Compound 26)
N-(4- { 5- [4-(4-Chloro-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino }- phenyl)-C,C,C-trifluoiO-methanesulfonamide. (Compound 27)
5-(4-{5-[4-(4-tert-Bvιtyl-benzyloxy)-benzylidene]-4-oxo-4,5-diliydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 28) 5 -(4- { 5 - [4-(4-Isopropyl-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 29)
C,C,C-Trifluoro-N-[4-(5-{4-[(4-isopropyl-benzyl)-methyl-amino]-benzylidene} -4-oxo-4,5- dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 30)
5-(4- { 5- [4-(4-Isopropyl-benzyloxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino }- phenyl)-l,l-dioxo-lλδ-[l,2,5] thiadiazolidin-3-one. (Compound 31)
N- [4-(5 - { 4- [4-( 1 -Ethyl-propyl)-benzyloxy] -benzylidene ) -4-oxo-4,5 -dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 32)
N-(4-{5-[4-(4-Cyclopentyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- pheny^-CjCjC-trifluoro-methanesulfonamide. (Compound 33)
N-(4-{5-[4-(4-Cyclopentyloxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 34)
C,C,C-Trifluoro-N-(4-{5-[4-(4-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino}-phenyl)-methanesulfonamide. (Compound 35)
5-(4-{5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 36)
C,C,C-TrifluoiO-N-(4-{5-[4-(4-isobutyryl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO- thiazol-2-ylamino)-phenyl)-methanesulfonamide. (Compound 37)
C,C,C-Trifluoro-N-(4-{5-[4-(2-fluoro-4-nitro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino] -phenyl)-methanesulfonamide. (Compound 38) 5-(4-{5-[4-(3-Fluoro-4-methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 39)
5-(4-{5-[3-Fluoro-4-(4-isopropyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 40)
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 41)
5-(4-{5-[4-(4-Ethyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λδ-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 42)
N-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 43)
5- [4-(5 - { 4- [4-( 1 -Ethyl-propyl)-benzyloxy] -benzylidene } -4-oxo-4,5 -dihydro-thiazol-2- ylamino)-phenyl]~l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 44)
5-(4-{5-[4-(4-tert-Butyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 45)
C5C,C-Trifluoro-N-(4-{4-oxo-5-[4-(4-pyrrol-l-yl-benzyloxy)-benzylidene]-4,5-dihydro- thiazol-2-ylamino } -phenyl)-methanesulfonamide. (Compound 46)
5 - [4-(5 - {4- [4-( 1 -Ethyl-propyl)-benzyloxy] -benzylidene } -4-oxo-4,5 -dihy dro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 47) C,C,C-TrifluoiO-N-(4-{5-[4-(2-isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro- thiazol-2-ylamino) -phenyl)-methanesulfonamide. (Compound 48)
5-(4-{5-[4-(Indan-5-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 49)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-trifluoromethyl-benzyloxy)-benzylidene]-4,5-dihydro- thiazol-2-ylamiήo} -benzyl)-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 50)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino} - phenyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 51)
5-(4-{5-[4-(4-Ethyl-benzyloxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 52)
5 -(4- { 5 - [4-(3 -Methyl-benzyl oxy)-benzylidene] -4-oxo-4,5 -dihydro-thiazol-2-ylamino } - benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 53)
5-(4-{5-[4-(4-Isobutyl-benzyloxy)-benzylidene]-4-oxo-4, 5-dihydro-thiazol-2-ylamino}- benzyl)- l,l-dioxo-lλδ-[ 1,2,5] thiadiazolidin-3-one. (Compound 54)
5-[4-(5-{4-[4-(l-Ethyl-propyl)-benzyloxy]-benzylidene}-4-oxo-4, 5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 55)
5-(4-{5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 56)
5-(4-{5-[4-(4-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-l,2,5] thiadiazolidin-3-one. (Compound 57) 5-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 58)
5-(4-{5-[4-(2,3-Dihydro-indol-l-ylmethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino } -phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3 -one. (Compound 59)
5-(4-{5-[4-(4-Fluoro-benzyloxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1,1 -dioxo- lλ6-[ 1,2,5] thiadiazolidin-3-one. (Compound 60),
5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino} -benzyl)- 1,1 -dioxo- lλ -[1,2,5] thiadiazolidin-3-one. (Compound 61)
5-(4-{5-[4-(4-sec-Butyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 62)
5-(4-{5-[4-(4-Isopropyl-phenoxymethyl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 63)
C,C,C-Trifluoro-N-(4-{5-[4-(indan-5-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-methanesulfonamide. (Compound 64)
N-({l-[(5Z)-5-({4-[(4-fluorophenyl) methoxy]phenyl}methylidene)-4-oxo-455-dihydro-l,3- thiazol-2-yl]-2,3-dihydro-lH-indol-5-yl}sulfamoyl)acetamide. (Compound 65)
CjCjC-Trifluoro-N- [4-(5 - {4- [4-( 1 -hydroxy-2-methyl-piOpyl)-benzyloxy] -benzylidene } -4- oxo-4,5-dihydro-thiazol-2-ylamino)-phenyl]-methanesulfonamide. (Compound 66) l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-enzyloxy)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-phenyl)-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 67)
5-[4-(5-{4-[(Methyl-p-tolyl-amino)-methyl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6- 1,2,5] thiadiazolidin-3-one. (Compound 68)
N-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 69)
N-(4-{5-[4-(5-tert-Butyl-oxazol-2-ylmethoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 70)
N-(4- { 5-[4-(3 ,4-Dihydro- 1 H-isoqvιinolin-2-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 71)
N-(4-{5-[4-(l-Cyclohexylmethyl-lH-[l,2,3]triazol-4-ylmethoxy)-benzylidene]-4-oxo-4,5- dihydiO-thiazol-2-ylamino}-phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 72)
N-[4-(5-{4-[4-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoro-methanesulfonamide. (Compound 73)
N-[4-(5-{4-[3-(l-Ethyl-propoxy)-benzyloxy]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-C,C,C-trifluoiO-methanesulfonamide. (Compound 74)
5-(4-{5-[4-(4-Methoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 75)
5-(4-{5-[4-(4-Methyl-benzyloxy)-benzylidene]-4-oxo-4,5-dihydiO-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 76) 5-(4-{5-[4-(4-Chloro-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 77)
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- benzyl)-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 78)
5-(4-{5-[4-(2-Isobutoxy-benzyloxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}- phenyl)- 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5]thiadiazolidin-3-one. (Compound 79)
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino]-benzylidene}-4-oxo-4,5-dihydiO-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 80)
5 - [4-(5 - { 4- [(4-Cyclohexyl-benzyl)-methyl-amino] -benzylidene } -4-oxo-4,5 -dihydro-thiazol- 2-ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 81)
5-[4-(5-{4-[(4-Cyclohexyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol- 2-ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 82)
5-[4-(5-{4-[(4-Isopropyl-benzyl)-methyl-amino]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-phenyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 83)
4-(4-{4-Oxo-2-[4-(l,l,4-trioxo-lλ6-[l,2,5]thiadiazolidin-2-ylmethyl)-phenylamino]-4H- thiazol-5-ylidenemethyl} -phenoxymethyl)-benzonitrile. (Compound 84)
4_(4_ {4-Oxo-2- [4-( 1 , 1 ,4-trioxo- 1 λ6- [ 1 ,2,5]thiadiazolidin-2-yl)-phenylamino] -4H-thiazol-5 - ylidenemethyl}-phenoxymethyl)-benzonitrile. (Compound 85) l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-phenyl)-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 86)
l,l-Dioxo-5-(4-{4-oxo-5-[4-(4-propyl-phenoxymethyl)-benzylidene]-4,5-dihydro-thiazol-2- ylamino}-benzyl)-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 87)
l,l-Dioxo-5-{4-[4-oxo-5-(4-p-tolyloxymethyl-benzylidene)-4,5-dihydro-thiazol-2-ylammo]- benzyl}-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 88)
5-[4-(5-{4-[Methyl-(4-methyl-benzyl)-amino] benzylidene}-4-oxo-4,5-dihydro-thiazol-2- ylamino)-benzyl]-l,l-dioxo-lλ6-[l,2,5] thiadiazolidin-3-one. (Compound 89)
N-(4-{5-[4-(4-Amino-2-fluoro-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino} -phenyl)-C,C,C-trifluoro-methanesulfonamide. (Compound 90)
5-(4-{5-[l-[4-(4-FluoiO-benzyloxy)-phenyl]-meth-(Z)-ylidene]-4-oxo-4,5-dihydro-thiazol-2- ylamino}-benzyl)-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-3-one. (Compound 91)
3. A process for preparation of a compound of formula (I),
Figure imgf000102_0001
wherein, Gl = (a)
Figure imgf000103_0001
(b)
Figure imgf000103_0002
(d)
Figure imgf000103_0003
G2 is selected from hydrogen, fluoro and methoxy; and
G3 is selected from a group of formulae:
Figure imgf000103_0004
G4 is selected from O or N-CH3; G5 is selected from
(a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, Ci- 6 acyl, straight chain or branched Ci-6 alkyloxy, unsubstituted straight chain or branched Ci-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Cj-4 alkoxy;
(b) the group of formulae:
Figure imgf000104_0001
n is 0 or 1, and m is 0, 1 or 2.; h and 1 are independently selected from 0 or 1 ;
said process comprises the steps of:
[a] reaction of a compound of formula (i) or salts thereof,
Figure imgf000104_0002
(i) wherein, Gl = (a)
Figure imgf000105_0001
(b)
Figure imgf000105_0002
(C)
Figure imgf000105_0003
(d)
Figure imgf000105_0004
G2 is selected from hydrogen, fluoro and methoxy; and G4 is selected from O or N-CH3; G5 is selected from (a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, Cj- 6 acyl, straight chain or branched C]-6 alkyloxy, unsubstituted straight chain or branched Ci-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Ci-4 alkoxy;
(b) the group of formulae:
Figure imgf000106_0001
n is 0 or 1, and m is O5 1 or 2.; h and 1 are independently selected from 0 or 1 ;
with rhodanine of formula (ii)
Figure imgf000106_0002
(ii) in presence of sodium acetate in acetic acid or ammonium acetate in toluene to obtain compound of formula (iii);
Figure imgf000106_0003
(iii)
[b] reaction of compound of formula (iii) with methyl iodide in presence of a base such as diisopropylethyl amine at an ambient temperature in ethanol to obtain compound of formula (iv);
Figure imgf000107_0001
(iv)
[c] reaction of compound of formula (iv) with suitable amine selected from
Figure imgf000107_0002
Figure imgf000107_0003
in presence of base such as diisopropylethylamine in ethyl alcohol at reflux temperature to obtain compound of formula I; such that, at each step the product is optionally isolated and purified by standard techniques.
4. A process 'for preparation of a compound of formula (I),
Figure imgf000108_0001
(I) wherein, Gl - (a)
Figure imgf000108_0002
(b)
Figure imgf000108_0003
(c)
Figure imgf000108_0004
(d)
Figure imgf000108_0005
G2 is selected from hydrogen, fluoro and methoxy; and G3 is selected from a group of formulae:
Figure imgf000109_0001
G4 is selected from O or N-CH3; G5 is selected from
(a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, Q- 6 acyl, straight chain or branched Cj-6 alkyloxy, unsubstituted straight chain or branched Ci-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Ci-4 alkoxy;
(b) the group of formulae:
Figure imgf000109_0002
n is 0 or 1 , and m is 0, 1 or 2.; h and 1 are independently selected from 0 or 1 ;
which comprises the steps of:
[a] reaction of rhodanine of formula (ii) or salts thereof,
Figure imgf000110_0001
(>') with appropriate amine selected from
Figure imgf000110_0002
Figure imgf000110_0003
in presence of mercuric chloride and a base such as diisopropylamine to obtain compound of formula (v);
Figure imgf000110_0004
(V)
[b] condensation of compound of formula (v) with aldehyde of formula (i);
Figure imgf000110_0005
wherein, Gl = (a)
Figure imgf000111_0001
(b)
Figure imgf000111_0002
(d)
Figure imgf000111_0003
G2 is selected from hydrogen, fluoro and methoxy; and G4 is selected from O or N-CH3; G5 is selected from
(a) unsubstituted phenyl or phenyl substituted with one or two substituents independently selected from group consisting of chloro, fluoro, methyl, methoxy, cyano, nitro, trifluoromethyl, pyrrole, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, C1. 6 acyl, straight chain or branched Ci-6 alkyloxy, unsubstituted straight chain or branched Cj-6 alkyl, straight chain or branched Ci-6 alkyl substituted with one substituent selected from hydroxy or Cj-4 allcoxy; (b) the group of formulae:
Figure imgf000112_0001
n is 0 or 1, and m is 0, 1 or 2.; h and 1 are independently selected from 0 or 1; under Standard Knoevenagel condensation condition such as in presence of ammonium acetate in toluene or sodium acetate in acetic acid to obtain compound of formula I; such that, at each step the product is optionally isolated and purified by standard techniques.
5. A pharmaceutical composition, which comprises a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier, diluent, excipients.
Figure imgf000112_0002
(I)
6. A pharmaceutical composition as claimed in claim 5, in the form of a tablet, capsule, suspension, powder, syrup, and solution.
7. A method of preventing or treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, impaired glucose tolerance, obesity, atherosclerosis, insulin resistance or diseases in which the underlying cause is insulin resistance or related diseases, which comprises administering of compound of formula (I) or a pharmaceutical composition as claimed in claims 5 or 6.
8. A method according to claim 7, wherein the disease is type-2 diabetes and insulin resistance, impaired glucose tolerance, dyslipidemia and disorders related to Syndrome X such as hypertension, obesity, eating disorders, hyperlipidemia, atherosclerosis, coronary artery disease, cardiovascular disorders, diseases related to endothelial dysfunction, nephropathy, neuropathy, retinopathy, osteoporosis, polycystic ovary syndrome, pancreatitis, inflammatory bowel diseases, xanthoma or cancer.
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