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WO2009109999A1 - Nouveaux inhibiteurs de protéine tyrosine phosphatase - ib - Google Patents

Nouveaux inhibiteurs de protéine tyrosine phosphatase - ib 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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English (en)
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 Limited
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Publication of WO2009109999A1 publication Critical patent/WO2009109999A1/fr

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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

La présente invention concerne les nouveaux composés de formule générale (I), dans laquelle les symboles sont les mêmes que ceux décrits dans la description, leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques les contenant, un procédé et des intermédiaires pour la préparation des composés susmentionnés, l’utilité de ces composés en médecine et des procédés pour leur utilisation thérapeutique, et leur utilisation pour le traitement de troubles métaboliques.
PCT/IN2009/000136 2008-03-03 2009-03-02 Nouveaux inhibiteurs de protéine tyrosine phosphatase - ib WO2009109999A1 (fr)

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Cited By (15)

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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN103304473A (zh) * 2012-03-07 2013-09-18 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
WO2014123203A1 (fr) * 2013-02-06 2014-08-14 京都薬品工業株式会社 Agent thérapeutique destiné à traiter le diabète
US9957213B2 (en) 2013-07-30 2018-05-01 Semiconductor Energy Laboratory Co. Organic compound, liquid crystal composition, liquid crystal element, and liquid crystal display device
WO2018202487A1 (fr) 2017-05-04 2018-11-08 Basf Se 5-(haloalkyl)-5-hydroxy-isoxazoles substitués pour lutter contre des champignons phytopathogènes
WO2021117014A3 (fr) * 2019-12-12 2021-07-22 University Of Sharjah Inhibiteurs à petites molécules de la formation d'hyphes fongiques et de biofilms
WO2023220572A1 (fr) * 2022-05-13 2023-11-16 Ness Therapeutics, Inc. Inhibiteurs de ptpn2

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WO2007032028A1 (fr) * 2005-09-16 2007-03-22 Torrent Pharmaceuticals Ltd. Thiazolinones et oxazolinones et leur utilisation en tant qu'inhibiteurs de ptp1b

Patent Citations (1)

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WO2007032028A1 (fr) * 2005-09-16 2007-03-22 Torrent Pharmaceuticals Ltd. Thiazolinones et oxazolinones et leur utilisation en tant qu'inhibiteurs de ptp1b

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US9040525B2 (en) 2010-10-08 2015-05-26 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
US9072758B2 (en) 2011-04-28 2015-07-07 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN103304473A (zh) * 2012-03-07 2013-09-18 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
CN103304473B (zh) * 2012-03-07 2016-07-06 浙江九洲药业股份有限公司 亚氨基吡格列酮的制备方法及相关中间体
WO2014123203A1 (fr) * 2013-02-06 2014-08-14 京都薬品工業株式会社 Agent thérapeutique destiné à traiter le diabète
US9957213B2 (en) 2013-07-30 2018-05-01 Semiconductor Energy Laboratory Co. Organic compound, liquid crystal composition, liquid crystal element, and liquid crystal display device
WO2018202487A1 (fr) 2017-05-04 2018-11-08 Basf Se 5-(haloalkyl)-5-hydroxy-isoxazoles substitués pour lutter contre des champignons phytopathogènes
WO2021117014A3 (fr) * 2019-12-12 2021-07-22 University Of Sharjah Inhibiteurs à petites molécules de la formation d'hyphes fongiques et de biofilms
WO2023220572A1 (fr) * 2022-05-13 2023-11-16 Ness Therapeutics, Inc. Inhibiteurs de ptpn2

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