97322-87-7

Usage

Uses

Used in Pharmaceutical Industry:
Troglitazone is used as an oral hypoglycemic agent for improving insulin sensitivity and decreasing hepatic glucose production. It is an antidiabetic drug that helps manage type 2 diabetes by increasing insulin sensitivity, upregulating glucose transporter expression, enhancing glucose utilization, and reducing hepatic gluconeogenesis.
Used in Research and Development:
Troglitazone is used as a peroxisome proliferator-activated receptors activator in research and development for studying the role of PPARγ in various biological processes and its potential therapeutic applications.
Used in Type 2 Diabetes Treatment (withdrawn):
Troglitazone was approved for the treatment of insulin resistance and hyperglycemia in Type II diabetes under the trade name Rezulin. However, it was withdrawn from the market due to hepatotoxicity concerns. It was a potent and selective PPARγ agonist, but its use was limited due to safety issues.
Used in Cancer Research:
Troglitazone also has potential applications in cancer research, as it induces cell cycle arrest and apoptosis in several cancer cell lines. Its mechanism of action in this context is still under investigation, but it may provide insights into the development of new cancer therapies targeting PPARγ pathways.

Manufacturing Process

A mixture of 70 g of ethyl-3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2- ylmethoxy)phenyl]-2-chloropropionate, 13.12 g of thiourea and 80.2 ml of sulpholane was reacted for 80 min, under a nitrogen stream at 115°-120°C. Subsequently, a 656.2 ml acetic acid, 218.7 ml conc. hydrochloric acid and 109.4 ml water was added to this and the resulting mixture was further heated for 12 h at 85°-90°C. The reaction mixture was cooled to room temperature and 196.8 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 40 g of the required 5-{4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl)thiazolidine-2,4- dione (Troglitazone) with a HPLC purity of about 67-70%. The elution of column was continued further to yield 5-[4-(6-hydroxy-2,5,7,8- tetramethylchroman-2-yl-methoxy)benzyl]-2-iminothiazolidine-4-one with HPLC purity of about 70%.

Biological Activity

Selective PPAR γ receptor agonist (EC 50 values are 780 and 555 nM at murine and human PPAR γ receptors respectively). Displays no activity at PPAR α or PPAR δ receptors. Antidiabetic agent; exerts potent glucose-lowering effects in insulin-resistant diabetic mice. Displays anti-invasive effect on human breast cancer cells; reduces migration, adhesion and spreading on fibronectin-coated plates. Also inhibits lamellipodia formation and actin polymerization.

Biochem/physiol Actions

Primary TargetPeroxisome proliferator-activated receptors γ (PPARγ)

in vitro

troglitazone pparγ ligands showed potent inhibitory effect on proliferation, and could induce rcc cell apoptosis, suggesting that the pparγ ligands have potential antitumor effects on renal carcinoma cells [1].

in vivo

troglitazone increased ec proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses (400 and 800 mg/kg) after four weeks of treatment [2].

References

γ1) Kodera et al. (2000) Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators; J. Biol. Chem., 275 33201 2) Tchoukalova et al. (2000) Enhancing effect of troglitazone on porcine adipocyte differentiation in primary culture: a comparison with dexamethasone; Obes. Res., 8 664 3) Tsubouchi et al. (2000) Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis; Biochem. Biophys. Res. Commun.270 4) Wyttenbach & Kuentz (2017),?Glass-forming ability of compounds in marketed amorphous drug products; Eur. J. Pharm. and Biopharm.,?112?204 [Focus Citation]

InChI:InChI=1/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)

Synthetic route

5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzylidene]-2,4-thiazolidinedione → Troglitazone (97322-87-7)

Conditions	Yield
With sodium tetrahydroborate; dimethylaminoacetic acid; sodium hydroxide In tetrahydrofuran; water at 20℃;	84%
With hydrogen; acetic acid In water; palladium

5-[4-(6-benzyloxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzyl]-thiazolidine-2,4-dione (199441-78-6) → Troglitazone (97322-87-7)

Conditions	Yield
With hydrogenchloride; acetic acid at 70 - 80℃; debenzylation;	70%

thiourea (17356-08-0) + Ethyl 3-<4-<(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxy>phenyl>-2-chloropropionate (97322-68-4) → Troglitazone (97322-87-7) + 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one (97323-08-5)

Conditions	Yield
With hydrogenchloride; acetic acid 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h; Yield given. Multistep reaction. Yields of byproduct given;

Troglitazone glucuronide (127040-01-1) → Troglitazone (97322-87-7)

Conditions	Yield
enzymatic treatment using glusulase;

4-fluorobenzaldehyde (459-57-4) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium tert-butoxide / dimethylformamide / 8 h / 80 °C 2: AcOH; piperidine / toluene / 4 h / Heating 3: HCl / methanol / 0.25 h 4: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme

trolox (56305-04-5, 53188-07-1) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: imidazole / dimethylformamide 2: LAH / 3 h / 20 °C 3: potassium tert-butoxide / dimethylformamide / 8 h / 80 °C 4: AcOH; piperidine / toluene / 4 h / Heating 5: HCl / methanol / 0.25 h 6: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme
Multi-step reaction with 8 steps 1: toluene-4-sulfonic acid / 12 h / Reflux 2: dmap / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 4: pyridine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 48 h / 2 °C / Inert atmosphere 6: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 7: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 8: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

(6-t-butyldimethylsilyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzo[1,2-b]pyran-2yl)methanol (228114-44-1) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium tert-butoxide / dimethylformamide / 8 h / 80 °C 2: AcOH; piperidine / toluene / 4 h / Heating 3: HCl / methanol / 0.25 h 4: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme

6-tert-butyl(dimethyl)silyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (716320-66-0) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: LAH / 3 h / 20 °C 2: potassium tert-butoxide / dimethylformamide / 8 h / 80 °C 3: AcOH; piperidine / toluene / 4 h / Heating 4: HCl / methanol / 0.25 h 5: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme

4-[6-(tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethyl-chroman-2-ylmethoxy]-benzaldehyde (716320-67-1) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: AcOH; piperidine / toluene / 4 h / Heating 2: HCl / methanol / 0.25 h 3: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme

5-[1-{4-[6-(tert-Butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethyl-chroman-2-ylmethoxy]-phenyl}-meth-(E)-ylidene]-thiazolidine-2,4-dione → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / methanol / 0.25 h 2: 84 percent / CoCl2; DMG; NaBH4 / NaOH / tetrahydrofuran; H2O / 20 °C View Scheme

4-fluorobenzaldehyde (459-57-4) → Troglitazone (97322-87-7) + PhCO-X

Conditions	Yield
Multi-step reaction with 4 steps 1.1: t-BuOK / dimethylformamide / 1 h / 25 °C 1.2: 60 percent / dimethylformamide / 15 h / 25 °C 2.1: benzoic acid; piperidine / toluene / 4 h / 120 °C 3.1: 54 percent / Mg; MeOH / 8 h / 45 °C 4.1: 70 percent / HCl; AcOH / 70 - 80 °C View Scheme

(6-Benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methanol (171270-07-8) → Troglitazone (97322-87-7) + PhCO-X

Conditions	Yield
Multi-step reaction with 4 steps 1.1: t-BuOK / dimethylformamide / 1 h / 25 °C 1.2: 60 percent / dimethylformamide / 15 h / 25 °C 2.1: benzoic acid; piperidine / toluene / 4 h / 120 °C 3.1: 54 percent / Mg; MeOH / 8 h / 45 °C 4.1: 70 percent / HCl; AcOH / 70 - 80 °C View Scheme

4-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzaldehyde (138564-69-9) → Troglitazone (97322-87-7) + PhCO-X

Conditions	Yield
Multi-step reaction with 3 steps 1: benzoic acid; piperidine / toluene / 4 h / 120 °C 2: 54 percent / Mg; MeOH / 8 h / 45 °C 3: 70 percent / HCl; AcOH / 70 - 80 °C View Scheme

TG-12 (906357-28-6) → Troglitazone (97322-87-7) + PhCO-X

Conditions	Yield
Multi-step reaction with 2 steps 1: 54 percent / Mg; MeOH / 8 h / 45 °C 2: 70 percent / HCl; AcOH / 70 - 80 °C View Scheme

2-hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol (79907-49-6) → Troglitazone (97322-87-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: 1.) NaH / 1.) DMF, rt, 1 h, 2.) benzene, rt, 1 h 2: 1.) NaH / 1.) DMSO, benzene, 60 deg C, 20 min, 2.) 60 deg C, 1 h 3: 94 percent / AcOH, 10percent H2SO4 / 0.17 h / 60 °C 4: 94 percent / pyridine / 1.) 10 deg C to rt, 2.) 30 deg C, 1 h 5: 98 percent / H2 / 10percent Pd-C / methanol; benzene / 3 h / 2325.2 - 2850.2 Torr 6: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 7: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

2-hydroxymethyl-6-methoxymethoxy-2,5,7,8-tetramethylchroman (107188-55-6) → Troglitazone (97322-87-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) NaH / 1.) DMSO, benzene, 60 deg C, 20 min, 2.) 60 deg C, 1 h 2: 94 percent / AcOH, 10percent H2SO4 / 0.17 h / 60 °C 3: 94 percent / pyridine / 1.) 10 deg C to rt, 2.) 30 deg C, 1 h 4: 98 percent / H2 / 10percent Pd-C / methanol; benzene / 3 h / 2325.2 - 2850.2 Torr 5: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 6: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

6-Hydroxy-2,5,7,8-tetramethyl-2-<(4-nitrophenoxy)methyl>chroman (107188-58-9) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 94 percent / pyridine / 1.) 10 deg C to rt, 2.) 30 deg C, 1 h 2: 98 percent / H2 / 10percent Pd-C / methanol; benzene / 3 h / 2325.2 - 2850.2 Torr 3: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 4: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

6-acetoxy-2-[(4-aminophenoxy)methyl]-2,5,7,8-tetramethylchromane (107188-37-4) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 2: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

2,5,7,8-tetramethyl-6-acetoxy-2-(4-nitrophenyloxy)methylchroman (118070-83-0) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98 percent / H2 / 10percent Pd-C / methanol; benzene / 3 h / 2325.2 - 2850.2 Torr 2: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 3: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

6-(Methoxymethoxy)-2,5,7,8-tetramethyl-2-<(4-nitrophenoxy)methyl>chroman (118070-84-1) → Troglitazone (97322-87-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: 94 percent / AcOH, 10percent H2SO4 / 0.17 h / 60 °C 2: 94 percent / pyridine / 1.) 10 deg C to rt, 2.) 30 deg C, 1 h 3: 98 percent / H2 / 10percent Pd-C / methanol; benzene / 3 h / 2325.2 - 2850.2 Torr 4: 1.) aq. NaNO2, conc. HCl, 2.) Cu2O / 1.) acetone, 0 deg C, 2.) 40 to 43 deg C, 30 min 5: 2.) AcOH, conc. HCl / 1.) sulfolane, 115 to 120 deg C, 80 min, 2.) H2O, 85 to 90 deg c, 12 h View Scheme

(+/-)-5-<4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl>thiazolidine-2,4-dione (107187-56-4) → Troglitazone (97322-87-7)

Conditions	Yield
In methanol; palladium

2-methoxy-ethanol (109-86-4) + Ethyl 3-<4-<(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxy>phenyl>-2-chloropropionate (97322-68-4) → Troglitazone (97322-87-7)

Conditions	Yield
With hydrogenchloride; thiourea In sulfolane

carbonic acid tert-butyl ester 2-{4-[2,4-dioxo-thiazolidin-(5Z)-ylidenemethyl]phenoxymethyl}-2,5,7,8-tetramethyl-chroman-6-yl ester (1375483-15-0) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 2: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

carbonic acid tert-butyl ester 2-{4-[2,4-dioxothiazolidin-5-ylmethyl]phenoxymethyl}-2,5,7,8-tetramethylchroman-6-yl ester (1375483-24-1) → Troglitazone (97322-87-7)

Conditions	Yield
With hydrogenchloride; water In acetonitrile for 0.75h; Reflux;

C20H27F3O7S → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 48 h / 2 °C / Inert atmosphere 2: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 3: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 4: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

6-tert-butoxycarbonyloxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid ethyl ester (1375483-09-2) → Troglitazone (97322-87-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: pyridine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 2 °C / Inert atmosphere 4: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 5: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 6: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

carbonic acid tert-butyl ester 2-hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-yl ester (1375483-11-6) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 48 h / 2 °C / Inert atmosphere 3: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 4: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 5: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

carbonic acid tert-butyl ester 2-(4-formylphenoxymethyl)-2,5,7,8-tetramethyl-chroman-6-yl ester (1375483-13-8) → Troglitazone (97322-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 3: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

ethyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylate (53174-07-5) → Troglitazone (97322-87-7)

Conditions

Yield

Multi-step reaction with 7 steps 1: dmap / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3: pyridine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 48 h / 2 °C / Inert atmosphere 5: piperidine / ethanol / 12 h / Inert atmosphere; Reflux 6: palladium 10% on activated carbon; hydrogen / 1,4-dioxane / 20 h / 20 °C / 3620.13 Torr 7: hydrogenchloride; water / acetonitrile / 0.75 h / Reflux View Scheme

acetic anhydride (108-24-7) + Troglitazone (97322-87-7) + benzene (71-43-2) → 5-<4-<(6-Acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxy>benzyl>-2,4-thiazolidinedione benzene monoadduct

Conditions	Yield
With pyridine for 48h; Ambient temperature;	80%

Troglitazone (97322-87-7) + 3-PyCO-X → 5-[4-(2,5,7,8-tetramethyl-6-nicotinoyloxychroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (97323-02-9)

Conditions	Yield
	75%

succinic acid anhydride (108-30-5) + Troglitazone (97322-87-7) → succinic acid mono-{2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetramethyl-chroman-6-yl} ester

Conditions	Yield
With dmap In dichloromethane for 48h; Reflux;	63%
With pyridine at 85℃; for 6h;
With pyridine In cyclohexane

Troglitazone (97322-87-7) + PhCO-X → 5-[4-(6-benzoyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (97323-01-8)

Conditions	Yield
	62%

Troglitazone (97322-87-7) + PrCO-X → 5-[4-(6-butyryloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (97323-00-7)

Conditions	Yield
	56%

Troglitazone (97322-87-7) + (2S,3S,4S,5R,6S)-3,4,5,6-Tetraacetoxy-tetrahydro-pyran-2-carboxylic acid methyl ester (7355-18-2) → methyl 2,3,4-tri-O-acetyl-1-O-<2-<4-<2,4-dioxothiazolidin-5-ylmethyl>phenoxymethyl>-2,5,7,8-tetramethylchroman-6-yl>-β-D-glucopyranuronate (127040-00-0)

Conditions	Yield
With toluene-4-sulfonic acid In nitrobenzene at 85℃; under 20 Torr; for 4h;	23%

Troglitazone (97322-87-7) → Troglitazone glucuronide (127040-01-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 23 percent / p-toluenesulfonic acid monohydrate / nitrobenzene / 4 h / 85 °C / 20 Torr 2: 100 percent / 2.4percent aq.NaOH / methanol / 1 h / Ambient temperature View Scheme

bromoacetic acid tert-butyl ester (5292-43-3) + Troglitazone (97322-87-7) → Di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl ]-2,4-dioxothiazolidine-3,5-diyl}diacetate (107187-69-9)

Conditions	Yield
With potassium carbonate In acetone

Upstream product

• 109-86-4 2-methoxy-ethanol 
• 97322-68-4 Ethyl 3-<4-<(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxy>phenyl>-2-chloropropionate 
• 53174-07-5 ethyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylate 
• 1375483-09-2 6-tert-butoxycarbonyloxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid ethyl ester 
• 1375483-15-0 carbonic acid tert-butyl ester 2-{4-[2,4-dioxo-thiazolidin-(5Z)-ylidenemethyl]phenoxymethyl}-2,5,7,8-tetramethyl-chroman-6-yl ester 
• 107187-56-4 (+/-)-5-<4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl>thiazolidine-2,4-dione 
• 118070-84-1 6-(Methoxymethoxy)-2,5,7,8-tetramethyl-2-<(4-nitrophenoxy)methyl>chroman 
• 118070-83-0 2,5,7,8-tetramethyl-6-acetoxy-2-(4-nitrophenyloxy)methylchroman 
• 107188-37-4 6-acetoxy-2-[(4-aminophenoxy)methyl]-2,5,7,8-tetramethylchromane 
• 107188-58-9 6-Hydroxy-2,5,7,8-tetramethyl-2-<(4-nitrophenoxy)methyl>chroman 
• 107188-55-6 2-hydroxymethyl-6-methoxymethoxy-2,5,7,8-tetramethylchroman 
• 79907-49-6 2-hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol 
• 906357-28-6 TG-12 
• 138564-69-9 4-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzaldehyde 

Downstream Products

• 127040-00-0 methyl 2,3,4-tri-O-acetyl-1-O-<2-<4-<2,4-dioxothiazolidin-5-ylmethyl>phenoxymethyl>-2,5,7,8-tetramethylchroman-6-yl>-β-D-glucopyranuronate 
• 107187-69-9 Di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl ]-2,4-dioxothiazolidine-3,5-diyl}diacetate 
• 97323-06-3 Monosodium salt of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 
• 1375483-25-2 5-((3aS,4S,6aR)-2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid 2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetramethyl-chroman-6-yl ester 
• 127040-01-1 Troglitazone glucuronide 
• 97323-02-9 5-[4-(2,5,7,8-tetramethyl-6-nicotinoyloxychroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 
• 97323-01-8 5-[4-(6-benzoyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 
• 97323-00-7 5-[4-(6-butyryloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 

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The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.

USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS

The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula

Agent for improving ketosis

An agent for improving ketosis which comprises an insulin sensitizer, which has an excellent action and low toxicity.

Structure-activity requirements for the antiproliferative effect of troglitazone derivatives mediated by depletion of intracellular calcium

Depletion of calcium from the endoplasmic reticulum has shown to affect protein synthesis and cell proliferation. The anticancer effect of troglitazone was reported to be mediated by depletion of intracellular calcium stores resulting in inhibition of translation initiation. The unsaturated form of troglitazone displays similar anticancer properties in vitro. In this letter, we report our findings on the minimum structural requirements for both compounds to retain their calcium release and antiproliferative activities.

Drug comprising combination

A TNF-α inhibitor comprising an insulin sensitizer in combination with an HMG-CoA reductase inhibitor is useful as an agent for the prophylaxis or treatment of an inflammatory disease and the like.

Neovascularization inhibitors

An angiogenesis inhibitor containing a compound represented by the formula wherein R4 is an optionally substituted hydrocarbon group and the like; Xa is a bond and the like; k is an integer of 1 to 3; Ya is an oxygen atom and the like; ring Ea is a benzene ring optionally having additional substituent(s); p is an integer of 1 to 8; R5 is a hydrogen atom and the like; q is an integer of 0 to 6; r is 0 or 1; R8 is a hydroxy group and the like; and R6 and R7 are hydrogen atoms and the like, or a salt thereof is useful as an agent for the prophylaxis or treatment of tumor and the like.

Combinations comprising dipeptidylpeptidase-iv inhibitor

The invention relates to a combination which comprises a DPP-IV inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.

Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus

Novel methods of using thiazolidinone derivatives and related antihyperglycemic agents to treat populations at risk for developing noninsulin-dependent diabetes mellitus (NIDDM) and complications arising therefrom are disclosed. In one embodiment, the compounds of the invention are used to treat polycystic ovary syndrome in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus. In another embodiment, the compounds of the invention are used to treat gestational diabetes in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus.

Use of thiazolidinedione derivatives in the treatment of insulin resistance

The present invention provides methods of using thiazolidinedione in the treatment of insulin resistance.