CA1277323C - Thiazolidinedione derivatives, their production and use - Google Patents

Thiazolidinedione derivatives, their production and use

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Publication number
CA1277323C
CA1277323C CA000499769A CA499769A CA1277323C CA 1277323 C CA1277323 C CA 1277323C CA 000499769 A CA000499769 A CA 000499769A CA 499769 A CA499769 A CA 499769A CA 1277323 C CA1277323 C CA 1277323C
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Prior art keywords
pharmaceutically acceptable
compound
salt
pyridyl
ethoxy
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French (fr)
Inventor
Kanji Meguro
Takeshi Fujita
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • C07D417/12—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

Abstract

Abstract Thiazolidinedione derivatives of the formula:

Description

lZ~7~73Z3 Thiazolidinedione Derivatives, Their Production and Use This invention relates to novel thiazolidinedione derivatives, a method of preparing them and antidiabetic agents containing same, which is utilized in the field ~` of medicines.
A variety of biguanide and sulfonylurea derivatives have been used clinically as antidiabetic agents.
-~ However, the biguanides are now scarecely used, because they tend to cause lactic acidosis, and use of the sulfonylureas, though they have strong hypoglycemic activities, requires sufficient precaution, because they cause serious hypoglycemia frequently. Therefore, a new type of antidiabetic agent free from these defects has been desired.
On the other hand, in Japanese Unexamined Patent Publication Nos. 22636/1980 and 64586~1980,~Chemical &
Pharmaceutical Bulletin,~30, p. 3563 (1982), ibid, 30, p. 3580 (1982)r and ibid, 32, p. 2~67 (1984), reference is made to a variety of thiazolidlnediones;having blood glucose and lipid lowerin~ actions. Antidiabetic activity o~ clglitazone was also reported in~Diabetest 32, p. 804 ~1983). Those compounds, however, have not yet been put to practical use. As the reasons, 1~ insufficient activities or/and 2) serious toxicities may be mentioned.

~ ,~t7.~3;~ 3 2~2~5-655 The present inventors synthesi~ed various compounds which are not concretely descrlbed in the above-mentioned puhllcations of unexamined patent appllcations and have made skudies on them to find the compounds exhibitin~ potent pharmacological effects with lower toxicity.
The present invention :Ls to provide aompounds ~hich aan be prac~ically used as antidiabetic agents~Vingabroad safety margin between pharmacolo~ical effect and toxiclty or unfavourable side reactions.
10The present invention provides.
1. A compound of the formula:

C2H5 ~ 2 2 ~ ~ 2 ¦ < (I~
b~
O
or a pharmaceutically acceptable salt thereof, 2. A process for preparin~ a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which aomprises ; 20 hydrolyzlng a compol~nd of the formula, C2E15 ~ CH2~H~- 0 r ~ - CE12 ~H (II) S
NH
:
:

,~
3~3 and if reyuired, converting a hydrolysis product into a pharmaceutically acceptable salt thereof, and 3. An antidlabetic agent comprising a pharmaceutically acceptable carrier, excipient or filler and a compound of the formula (I) or a pharmaaeutically aaceptable salt thereof in an amount sufficient to lower blood glucose or blood lipid level.
The compounds representable by the above ~ormula ~I) include, specifically stating, the ~ollowiny ones.

, .

~.2773Z3 5-[4-[2-(3-ethyl~2-pyridyl)ethoxy~benzyl~ 2,4-thiazolidinedione, 5-[4-[2-(4-ethyl-2-pyridyl)ethoxy~benzyl]-2,4-thiazolidisedione, 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy~benzyl]-2,4-thiazolidinedione, 5-[4-[~-(6-ethyl-2-pyridyl)ethoxy~benzyll-2,4-thiazolidinedione.
The compound (I) of this invention contains both basic nitrogen and acid nitrogen in its molecule, and it can be led to a pharmac~utically acceptable salt, when desired, by using a suitable acid or base.
Such acid salts are exemplified by mineral salts (e.g. hydrochloride, hydrobromide, s~lfate, etc.), organic acid salts te.g. succinate, maleate, fumarate, malate, tartrate, etc.) and sulfonates ~e.g. methane-sulfonate, benzenesulfonate, toluenesulfonate, etc.).
Such basic salts are exemplified by alkali metal salts e.g. sodium salt, potassium salt, alkaline earth metal salts,e.g. calcium salt, etc. All of these salts can be prepared by E~ se known means.
The compound (I) of this invention or a pharma-cologically acceptable salt thereoi exhibits blood-glucose and blood-lipid lowering action with lower toxicity, which can be used as it is or in admixture with a ~ se known pharmace~tically acceptable carrier, excipient or filler as an antidiabetic agent for mammals including man.
The antidiabetic agent is usually administered orally as tablets, capsules ~including soft capsules and microcapsules), powders, granules, etc. and depending on cases, parenterally as injections, suppositories, pellets, etc. Oral administration to an adult patient is desirably 0.05-10 mg/kg body weight/day~, and parenterally 0.01-10 mg/kg body weight~day, once daily , ~

~D~1~ ~ J
_ ~ _ or divided into 2-4 times a week.
The compound represented by the above mentioned general formula (I) and pharmaceutically acceptable salts thereof [hereinafter collectively referred to as "Compound (I)"] can be prepared by subjacting a compound represented by the general formula (II) to hydrolysis.
This reaction proceeds advantageously in a proper solvent by employing a minexal acid. The solvent i8 exemplified by alcohols (e.g. methanol, ethanol, propanol, butanol, isobutanol, 2-methoxyethanol, etc.), dimethyl-sulfoxide, sul~olane, dioxane, te~rahydrofuran, dimethoxyethane, etc., and the mineral acid is exemplified by hydrochloric acid, hydrobromic acid, sulfuric acid, etc. The reaction temperature ranges from 20C to 150C. The reaction time i5 0.5 - 20 hours.
The compound (I) or a pharmaceutically acceptable salt thereof produced as mentioned above can be isolated and purified by conventional means such as concentration, extraction, recrystallization, chromatography, etc.
The compound xepre~en~d by the above-mentioned general formula ~II) can be produced by the following reactions:
F~NO2 (If ) C~H~\O >
~y~cH2cH2oH
~m) C2Hs~3~ Hæ/Pd~C
N CH2CH20-~N02 >
(V) C2Hs~ 1) NaNO2/HBr N CH2CH20 ~ NH2 2) CH2 - CHCOOR (~) >
(~) t :~

~ ;2773~23 C 2 Hs ~ ~ thiourea N CH 2 CH 2 O ~CH 2 CHCOOR -- ~ ( 11 ) (Vm ) Br [wherein R stands for hydrogen or lower alkyl].

The lower alkyl group represented by R is exemplified hy ~Cl 4) ones such as methyl, ethyl, propyl, isopropyl and butyl.
The reaction for producing compound (V) from compound (III) and compound (IV) is conducted in the presence of, for example, sodi~m hydride. This reaction can be carried out in a solvent e.g. dimethylformamide and tetrahydro-furan at a temperature ranging from -10C to 30C. The reaction from compound (V) to compound (VI) can easily be conducted by conventional catalytic reduction employing,for example,palladium-carbon as the catalyst. Compound (VI) may be isolated as the pure product or can be subjected to the subsequent reaction step without isolation and purification.
Compound (VIII) can be produced by subjecting compound (VI) to diazotization in the presence of an aqueous solution of hydrobromic acid, then allowing the resultant to react with acrylic acid or its lower alkyl ester (VII) in the presence of a copper catalyst e.g. cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, etc. (Meerwein arylation). Compound (VIII) :' ~ 2~73;~.3 can bepurified by e.g. chromatography, and subjected to the subsequent reaction without isolation or purification.
Compound (VIII) is then allowed to react with thiourea to give compound (II). This reaction is carried out usually in alcohols (e.g. methanol, et:hanol, propanol, butanol, isobutanol, 2-methoxyethanol, etc.), dimethylsulfoxide, sulfolane, etc. The reaction temperature is usually 20 -180C,preferably 60 - 150C. The amount of thiourea to be employed is l- 2 moles relative to one mole of compound (VIII).
In this reaction, as the reaction proceeds, hydrogen brcmide is produced as the by-prodùct, and, for capturin~ this by-product, the reaction may be conducted in the presence of sodium acetate; potassium acetate, etc., in an amount of usually l - 1.5 mole relative to 1 mole of compound ; (VlII)o The resultant compound (II) can be isolated, but may be led to the hydrolysis step directly without isolatlon:

`: ~

:` : :

~ 2~73~3 The compound (I) of the present invention has an excellent blood glucose and lipid lowering activity and is remarkably low in toxicity, which is supported by the following experlmental data, Experimental Examples 1. Blood glucose and lipid lowering activity in mice To male KKAY mice (8-10 weeks old, 5 mice/group), the test compounds (at three dosage levels) were given as a dietary admixture in CE-2 powdered diet (CLEA Japan) with free accessto water for 4 days.
Blood samples were taken from the orbital vein on the 5th day.
Blood glucose and plasma triglyceride (TG) were deter-mined by a glucose oxidase method and by using a commercially available assay kit, Cleantech TG-S (Iatron, Japan~, respectively. Based on dose-response curves for blood glucose and plasma TG lowering activity, effective dose of each test compound in 25% decrease from the control value was calculated as the value of ED25 (mg/kg/day).
The results are shown in Table 1.
2. Lipid lowering activity in rats Male Sprague-Dawley rats (7 weeks old, 5 rats/group) were maintained on the laboratory chow (CE-2, CLEA, Japan) with freeaccess to water. All the test compounds (at three dosage levels) suspended in 5% gum arabic solution were *Trade mark 31 ~t773Z3 force~ly administeredto the animals orally for 4 days. Blood samples were taken from the tail vein ,~on the 5th day. Plasma TG was determined using a commercially available assay kit, Cleantech TG~S (Iatron~. ~ased on dose-response curves for lipidlowering activity, effective dose of each test compound in 25% decrease from the control value was calculated as the value of ED25 (mg/kg/day). The results are shown in Table 1.
3. Two-week toxicity study in rats ~ ale andfemale Sprague-Dawley r~ts (5 weeks old, 5 rats/
group) were maintained on the laboratory chow (CE-2, CLEA
Japan) with free access to water. All the test compounds suspended in 5~ gum arabic solution were forcedly administ-ered orally to the animals for,2 weeks once daily. The dose was 100 mg/kg/day for every test compound. The animals were sacrificed in about 20 hours of fasting after termination of the two-week administration by withdrawing blood samples from the abdominal aorta using heparinized syringes under ether anesthesia. Liver and heart were .
removed and weighed. Hematology analysis was alsocarried out using an automatic cell counter. The data represent ~ % increase or decrease from the control value (non-drug ; ~ treated) as shown in Table 1 *Trade mark :

~ 27732~

o o 3 30 R _ ~ + ~ 20 ~ rC 0~ CD 0 3, o ' YA 3 G ~ ~ o ~ o ~ ~ + + -t + -t +

3 ,C _ lo oo o ~ , ~: 3 _ c~ + + ,- + +
~ ~ ~1 ~ C- ~
_ ~ ~ l _+ + + + , _ , nS c~ _ I 1 1 )= ~V~ 3 c~ q~ ~ o ,J~l ~

'~ : : :S ~ _ o ~
N +,, N C~ J~ C`l O
~ ~ ~ ~ ~ ~ V
¦ ~; N e~ ~ ~Z ~ ~ ~ 35~
~: ~ _~ C~ IJ
~ ~ ~ ~ ^~ a ^~

~ ;~'7~3~3 In Table 1, Compound (I) is a compound under the coverage ofthepresent invention, compounds(a) and (b) are known compounds concretely referred to in the Japanese unexamined Patent Publication No.22636/1980.
While compounds (c), (d) and (e) are not concretely referred to in the above-mentioned patent publication, they are cited for comparison, since they are similar to compound (I) of this invention in their chemical structures. As is apparent from the experimental results given in Table 1, Compound (I) of this invention is superior to the compounds (a), (c), (d) and (e) and comparable to the compound (b) in hypoglycemic and hypolipidemic activities, while showing extremely low toxicity as compared with the compounds (a), (b), (d) and (e). Such an effect as above caused by the introduction of an ethyl group is quite unexpected.
Thus, compound (I) of the present invention exhibit~ excellent hypoglycemic and hypolipidemic acivities, and little toxicity to internal organs and blood even by continuous administration for a long period of time.
herefor, compound (I) is of value as a therapeutic agent for Type II diabetes accompanied by obesity or hyperlipemia in mammals including man.~

:

3~3 Example 1 a) To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0g). The mixture was stirred under ice-cooling for one hour then at room temperature for30 minutes, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4).
The solvent was evaporated off to give 4-[2-t5-ethyl-2 pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%).
~ecrystallization from ether-hexane gave colorless prisms, m.p. 53-54C.
b) A solution of 4-[2-(5-ethyl-2-pyridyl)ethoxy]-nitrobenzene (60.0 g) in methanol (500 ml) was hydrogenated at room temperature under one atmospherlc pressure in the presence of 10% Pd-C (50% wet, 6.0 g). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in acetone (S00 ml)-methanol (200 ml). To the solution was added a 47~ HBr aqueous solution (152 g). The mixture was cooled, to ~hich was added dropwise a solution of Na~O2 (17.3 g) in: water (30 ml) at a ~Y~rature not hi~her than 5C. The whole mi~ture was stirred at 5C for 20 minutes, then methyl acrylate (112 g) was added ~hereto and the b~rature was raised to 38C. C~prous oxide (2.0 g) was added to the mixture in small portions with vigorous stirring. The reaction mixture was stirred until 3.~

nitrogen gas evolution ceased, which was concentrated under reduced pressure. The concentrate was made alkaline with concentrated aqueous ammonia,and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried ~MgSO4). The solvent was evaporated off to leave methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}propionate as a crude oil (74.09 g, 85.7%). IR(neat)cm~l:1735. NMR ~(ppm) in CDC13: 1.21 (3H,t,J=7), 2.60(2H,q,J=7), 3.0 - 3.6(4H,m), 3.66(3H,s), 4.30(2H,t,J=7), 4.3(lH,m),6.7 - 7.5(6H,m), 8.35(1H,d,J=2).
c) A mixture of the crude oil of methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl} propionate (73.0 g) obtained in b) thiourea (14.2 g), sodium acetate (15.3 g) and ethanol (500 ml) was s~irredfor 3 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the concentrate wa~neutralized with a saturated agueous solution of sodium hydrogencarbonate, to whlch were added water (200 ml) and ether (100 mlj.
The whole mixture was stirred for 10 minutes to yield 5-{4-l2~ e=lyl-2-p,rldyl~ethoxy]phenyl}-2 imino-4-: ~ , . ..

27773;~:~

thiazolidinone as crystals (0.3 g, 523.0~). Recrystallization from methanol gave colorless prisms, m~p. 187-188C (decomp.).
Elemental analysis for ClgH21M3O2S

Calcd: C ,6~.20; I-I,5.95; N ,1l.820 Found: C ,6~.20; H ,5.8~1: N ,11. 730 d) A solution of 5-{4-[2--(5-ethyl-2-pyridyl) ~thoxy]benzyl}-2-imino-4-thiazolidlnedinone (23.5 g) in 2N HCl (200 ml) was refluxed for 6 hours. The solvent was evaporated off under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals (23.5 g, 97.5~) which precipitated were collected by filtration and re-crystallized from DMF-H20 to give 5-{4-l2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as colorless needles (20.5 g, 86.9~), m.p. 183-1~4C
Elemental~Analysis for C19H20N2O3S

Calcd:- C ,6~ 02 H, 5 66; N, 7 . 86O
Found: C 63.70; H ,5.88; N 8. Olo ' ' e~ To a suspension of 5-{4-[2-(S-ethyl-2-pyridyl) ethoxy]benzyl}-2,4-thiazolidinedione (356 mg) in methanol (l~ ml) was added 28~ sodium methylate/methanol solution (0.2 g) to make a solution.
This solution was concen-trated and diluted with ethyl ether to yield crystals.

. .

~.27~7~3 mhe crystals were collected by filtration and re-crystallized from methanol-ethanol to give the slium salt of 5-{4 [2-(5-ethyl-2-pyridyl)ethoxy]benxyl}-2,4-thiazolidine-dione as colorless crystals (298 mg, 78.8%), m.p. 26Z-263C (decanp.).
Elemental analysis for CLgHlgN2O3SNa:
Calcd.: C,60.31; H,5.06; N,7.40 Found : C,60.20; H,5.07; N,7.52 Example 2 (1) 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione 100 g (2) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose calcium 44 g (5) Magnesium stearate 1 g 210 g The whole amounts of (1), (2) and (3) and 30 g of (4)were kneaded with water and dried in ~7acuo, followed by granulatlon. With the resultant granules were mixed 14 g of (4) and 1 g of (5) and the whole mixture was tableted with a tableting machine to give 1000 tablets 8 mm in diameter and each ~containing 100 mg of (1) .
Reference Example 1 The compounds listed in Table 2 were prepared in accordance with Example l-a).

~ , .

.2t7~73~3 ~CH2CH20-~N02 __ _ R mP ~ecrystalization solvent yield _ 3 - CH3 1 1 6 - 1 1 7 C ethyl acetate-hexane6 2 . 9 %
_ _ 4 - CH3 7 3 - 7 4 C ethyl acetate-hexane5 7 . 3 %
_ _ 5 - CH3 9 7 - 9 8 C ethyl acetate-hexane7 2 . 3 %

Reference Example 2 In accordance with Example l-b), the following compounds were prepared.
Methyl 2-bromo-3-{4~[2-(3-methyl-2-pyridyl)ethoxy]phenyl}
propionate; IR(Neat)cm~l~ 1735. N~R ~(ppm) in CDC13:
2.34(3H,s), 3.10(1H,dd, J=14 and 7), 3.25(2H,t,J=6), 3.38(lH,dd, J=14 and 7), 3.67(3H,s), 4.29(lH,t,J=7), 4.37(2H,t,J=6), 6.8-7.5(6H,m), 8.35(1H,dd, J=S and 2).

~ 2773Z3 2-Bromo-3-{4-[2-(4-methyl-2-pyridyl]ethoxy]phenyl}

propionic acid methyl ester; IR(Neat)cm~l: 1735.
NMR ~(ppm) in CDC13: 2.30(3H,s), 3.10~(1H, dd, J=14 and 7), 3.26(3H,t,J=7), 3.37(1H,dd, J=14 and 7), 3.67(3H,s), 4.30(31I,t,J=7), 6.7-7.36(6~,m)j 8.37(lH,d,J=6) Reference Example 3 A solution of 4-[2-(5-methyl-2-pyridyl)ethoxy] nitro-henzene (15.0 g) in methanol (150 ml) was subjected to catalytic reduction under 1 atmospheric pressure in the presence of 10% Pd-C (50% wet, 2.0 g). The catalyst was filtered off, and the filtrate was concentrated to give 4-[2-(5-methyl-2-pyridyl)ethoxy]aniline as crystals (12.3 g, 92.5~). Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p. 74-75C~
Elemental analysis for C14H16N2O:

Calcd.: C 773.66; H ,7.06; N ,12.270 Found: C 73.84; H ,?.17~ 2.06O

;

3~

Reference Example 4 To a mixture of 4-[2-(5-methyl-2-pyridyl)ethoxy]aniline (12.0 g), 47% aqueous HBr solution (36.5 g) and methanol (40 ml)-acetone (80 ml) was added dropwise a solution o~

NaNo2 (4.0 g) in water (lO ml) at 5C or below. The whole mixture was stirred at 5C for 20 minutes, then methyl acrylate (27.0 g) was added thereto and the temperature was raised to 38C. Cuprous oxide (1.0 g) was added to the mixture in small portions with vigorous stirring. ~fter nitrogen gas evolution had ceased, the reaction mixture was concentrated under redused pressure. The concentrate was made alkaline with concentrated aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (rlgSO4). The solvent was evaporated off to leave methyl 2-bromo-3-{4-[2-(5-methyl-2-pyridyl)ethoxy~phenyl}-propionate as a crude oil (17.5 g, 87.5%). IR(Neat)cm~l: 1735. NMR ~(ppm) in CDC13: 2.27(3H,s), 3.10(lH,dd,J=14 and 7), 3.22(2H,t, J=6), 3.38(lH,dd,J=14 and 7),3.66(3H,s), 4.29(2H,t, J=6), 4.32(lH,t,J=7), 6.7-7.5(6H,m), 8.34~1H,d,J=2).

773~3 Reference Example 5 The compounds listed in Table 3 were prepared in accordance with Example l-c).

H2CHzO- ~ S NH

NH
_ mp (decomp.) Recrystalization solvent yield 3 -CH3 230-231~C chroroform-methanol 7 5. 5 %

4 - CH 3 190-191C methanol 4 8 . O %

5 -CH3 203-Z04C chroro~orm~methanol 5 8. 2 %

Reference Example 6 The compounds listed ln Table 4 were prepared in accordance with Example l-d).
.
:: 4 :~
~=` ~

R ~ ~ ~ ~ S NH :
o : R mp Recrystalization solvent yield _ : .
3 -CH3 2l0-2L1C DMF-water 6 5. 7 . . _ ._ 4 -CH3 178-179C chroroform-methanol 7 5. 3 %
:: __ .~ .

-,: , ~ Z~773~

Reference Example 7 A mixture of 2-imino-5-{4-[2-(5-methyl-2-pyridyl~
ethoxy]benzyl}-4-thiazolidinone (8.0 g), 2_ HCl (80 ml) and ethanol (80 ml) was refluxed for 16 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarhonate to yield crystals. The crystals were collected by filtration and re-crystallized from ethanol to give 5-{4-E2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as_colorless prisms (7.0 g, 87.5%), m.p. 192-193C.
Elemental Analysis for C18H18N2O3:
Calcd.: C,63.14: H,5.30; N,8.18 Found : C,63.22; H,5.40: N, 8.11 . ~

Claims (20)

1. A compound of the formula:

(I) or a pharmaceutically acceptable salt thereof.
2. A process for preparing a compound of the formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, which process comprises hydrolyzing a compound of the formula:

(II) and if required, converting a hydrolysis product into a pharmaceutically acceptable salt thereof.
3. A process as claimed in claim 2, wherein C2H5 is in the 3-position of the pyxridine ring.
4. A process as claimed in claim 2, wherein C2H5 is in the 4-position of the pyridine ring.
5. A process as claimed in claim 2, wherein C2H5 is in the 5-position of the pyridine ring.
6. A process as claimed in claim 2, wherein C2H5 is in the 6-position of the pyridine ring.
7. A process as claimed in claim 2, 3 or 4, wherein the hydrolysis is carried out using a solvent and a mineral acid.
8. A process as claimed in claim 5 or 6, wherein the hydro-lysis is carried out using a solvent and a mineral acid.
9. A process as claimed in claim 2, 3 or 4, wherein the hydrolysis product is converted to its pharmaceutically acceptable acid addition salt.
10. A process as claimed in claim 5 or 6, wherein the hydro-lysis product is converted to its pharmaceutically acceptable acid addition salt.
11. A process as claimed in claim 2, 3 or 4, wherein the hydrolysis product is converted to its pharmaceutically acceptable base salt.
12. A process as claimed in claim 5 or 6, wherein the hydro-lysis product is converted to its pharmaceutically acceptable base salt.
13. A process for preparing 5-(4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzyl)-2,4-thiazolidinedione or a pharmaceutically accept-able acid addition or base salt thereof, which process comprises:
hydrolyzing 5-(4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl)-2-imino-4-thiazolidinedione, and if required, converting a hydrolysis product into a pharmaceutically acceptable acid addition or base salt thereof.
14. A process as claimed in claim 13, wherein the hydrolysis product is converted to its sodium salt.
15. A process as claimed in claim 13 or 14, wherein the hydrolysis is carried out using hydrochloric acid.
16. A process as claimed in claim 13 or 14, wherein the starting material is prepared by reacting methyl 2-bromo-3-(4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl)propionate with thiourea.
17. A process as claimed in claim 14, wherein the hydrolysis product is treated with sodium methylate to convert the product into its sodium salt.
18. The compound 5-(4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl)-2,4-thiazolidinedione, or a pharmaceutically acceptable acid addition or base salt thereof.
19. The compound sodium salt of 5-(4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzyl)-2,4-thiazolidinedione.
20. An antidiabetic agent which comprises a pharmaceutically acceptable carrier, excipient or filler and the compound or salt according to clam 1, 18 or 19 in an amount sufficient to exhibit blood glucose- or blood lipid-lowering action.
CA000499769A 1985-01-19 1986-01-17 Thiazolidinedione derivatives, their production and use Expired - Lifetime CA1277323C (en)

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Families Citing this family (271)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK305884A (en) * 1983-06-24 1984-12-25 Yamanouchi Pharma Co Ltd PHENOXYDER DERIVATIVE, PROCEDURE FOR PREPARING THEREOF AND PHARMACEUTICAL PREPARATION CONTAINING SUCH DERIVATIVE
CN1003445B (en) * 1984-10-03 1989-03-01 武田药品工业株式会社 The preparation method of thiazolidine diketone derivative
US4812570A (en) * 1986-07-24 1989-03-14 Takeda Chemical Industries, Ltd. Method for producing thiazolidinedione derivatives
FI91869C (en) * 1987-03-18 1994-08-25 Tanabe Seiyaku Co Process for the preparation of benzoxazole derivatives as antidiabetic agents
HU203330B (en) * 1987-06-10 1991-07-29 Pfizer Process for producing oxazolidin-2-one derivatives and hypoglychemic pharmaceutical compositions containing them
GB8713861D0 (en) * 1987-06-13 1987-07-15 Beecham Group Plc Compounds
EP0295828A1 (en) * 1987-06-13 1988-12-21 Beecham Group Plc Novel compounds
US4798835A (en) * 1987-12-02 1989-01-17 Pfizer Inc. dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione as an anti-atherosclerosis agent
US4791125A (en) * 1987-12-02 1988-12-13 Pfizer Inc. Thiazolidinediones as hypoglycemic and anti-atherosclerosis agents
GB8820389D0 (en) * 1988-08-26 1988-09-28 Beecham Group Plc Novel compounds
GB8919417D0 (en) 1989-08-25 1989-10-11 Beecham Group Plc Novel compounds
US4997948A (en) * 1989-10-27 1991-03-05 American Home Products 5-[(1- and 2-naphthalenyl) sulfonyl]-2,4-thiazolidinediones and derivatives thereof
KR0170416B1 (en) * 1990-02-09 1999-02-18 로버트 에이. 아미테이지 Use of insulin sensitizing agents to treat hypertension
US5356913A (en) * 1990-02-09 1994-10-18 The Upjohn Company Use of insulin sensitizing agents to treat hypertension
EP0839812A1 (en) * 1990-04-27 1998-05-06 Sankyo Company Limited Preparation of benzylthiazolidine derivatives
GB9023584D0 (en) * 1990-10-30 1990-12-12 Beecham Group Plc Novel compounds
US5158966A (en) * 1991-02-22 1992-10-27 The University Of Colorado Foundation, Inc. Method of treating type i diabetes
CA2106967C (en) * 1991-04-11 2003-12-09 Takashi Sohda Thiazolidinedione derivatives, production and use thereof
US5441971A (en) * 1991-04-11 1995-08-15 The Upjohn Company Thiazolidinedione derivatives, production and use thereof
US5183823A (en) * 1991-04-11 1993-02-02 Takeda Chemical Industries, Ltd. Pyridine n-oxide compounds which are useful as hypoglycemic and hypolipidemic agents
FR2680512B1 (en) * 1991-08-20 1995-01-20 Adir NOVEL 2,4-THIAZOLIDINEDIONE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
GB9124513D0 (en) * 1991-11-19 1992-01-08 Smithkline Beecham Plc Novel process
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives
GB9218830D0 (en) * 1992-09-05 1992-10-21 Smithkline Beecham Plc Novel compounds
IL106877A (en) * 1992-09-10 1998-03-10 Lilly Co Eli Rhodanine derivatives for use as medicaments for the treatment of alzheimer's disease
JP2845743B2 (en) * 1992-12-28 1999-01-13 三菱化学株式会社 New naphthalene derivatives
US5594016A (en) * 1992-12-28 1997-01-14 Mitsubishi Chemical Corporation Naphthalene derivatives
USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
US6046222A (en) * 1993-09-15 2000-04-04 Warner-Lambert Company 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
US5874454A (en) * 1993-09-15 1999-02-23 Warner-Lambert Company 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
CA2171827C (en) * 1993-09-15 2004-06-29 Jerrold Olefsky Use of thiazolidinediones to prevent or delay onset of niddm
US5478852C1 (en) * 1993-09-15 2001-03-13 Sankyo Co Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus
ES2135711T4 (en) * 1994-03-08 2000-01-01 American Home Prod DERIVATIVES OF TIAZOLIDINDIONA AS ANTI-HYPERGLYCEMIC AGENTS.
US6251928B1 (en) * 1994-03-16 2001-06-26 Eli Lilly And Company Treatment of alzheimer's disease employing inhibitors of cathepsin D
US5693651A (en) * 1994-10-20 1997-12-02 Nippon Chemiphar Co., Ltd. Quinoline derivatives
US5708012A (en) * 1995-04-28 1998-01-13 Sankyo Company, Limited Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of insulin resistant subjects with normal glucose tolerance in order to prevent or delay the onset of noninsulin-dependent mellitus
WO1996035688A1 (en) * 1995-05-08 1996-11-14 Nippon Chemiphar Co., Ltd. 2,4-thiazolidinedione or oxazolidinedione derivatives and hypoglycemic agent
TW438587B (en) 1995-06-20 2001-06-07 Takeda Chemical Industries Ltd A pharmaceutical composition for prophylaxis and treatment of diabetes
NZ286920A (en) * 1995-07-03 1997-06-24 Sankyo Co Use of combination of hmg-coa reductase inhibitors and of insulin sensitizers for the prevention/treatment of arteriosclerosis or xanthoma
EP0783888A1 (en) 1995-12-26 1997-07-16 Sankyo Company Limited Use of troglitazone and related thiazolidinediones in the manufacture of a medicament for the treatment and prophylaxis of osteoporosis
NZ314406A (en) * 1996-03-18 2000-12-22 Sankyo Co Treatment or prophylaxis of pancreatitis with a medicament containing an insulin sensitiser including oxazoles and thiazoles
JP2000511883A (en) * 1996-04-19 2000-09-12 ノボ ノルディスク アクティーゼルスカブ Modulators of molecules with phosphotyrosine recognition units
US5958957A (en) * 1996-04-19 1999-09-28 Novo Nordisk A/S Modulators of molecules with phosphotyrosine recognition units
CA2257284C (en) * 1996-05-31 2005-10-04 Sankyo Company Limited Remedy for autoimmune diseases
US5952509A (en) * 1996-06-27 1999-09-14 Takeda Chemical Industries, Ltd. Production of benzaldehyde compounds
DE69738809D1 (en) * 1996-11-08 2008-08-14 Nippon Chemiphar Co MEANS FOR REDUCING OVEN FATS
DE69838789T2 (en) * 1997-03-12 2008-10-30 Suzanne Cambridge de la Monte METHOD FOR TREATING OR PREVENTING ALZHEIMER'S DISEASE
US5908859A (en) * 1997-08-11 1999-06-01 Eli Lilly And Company Benzothiophenes for inhibiting hyperlipidemia
HUP9902721A2 (en) * 1997-11-25 1999-12-28 The Procter & Gamble Co. Concentrated fabric softening composition and highly unsaturated fabric softener compound therefor
WO1999030739A1 (en) * 1997-12-16 1999-06-24 Sankyo Company, Limited Leukemia remedy
GB9726568D0 (en) * 1997-12-16 1998-02-11 Smithkline Beecham Plc Novel pharmaceutical
US20040058873A1 (en) * 1998-03-12 2004-03-25 Esmond Robert W. Method for treating or preventing Alzheimer's disease
CA2350599A1 (en) * 1998-11-20 2000-06-02 Genentech, Inc. Method of inhibiting angiogenesis
US6191154B1 (en) 1998-11-27 2001-02-20 Case Western Reserve University Compositions and methods for the treatment of Alzheimer's disease, central nervous system injury, and inflammatory diseases
TWI249401B (en) * 1999-04-14 2006-02-21 Takeda Chemical Industries Ltd Agent for improving ketosis
AU4314000A (en) 1999-04-28 2000-11-17 Institute Of Medicinal Molecular Design. Inc. Heterocyclic carboxylic acid derivatives
JP2001072592A (en) 1999-07-01 2001-03-21 Kyowa Hakko Kogyo Co Ltd Telomerase inhibitor
WO2001002377A1 (en) * 1999-07-01 2001-01-11 Geron Corporation Telomerase inhibitors and methods of their use
US7390824B1 (en) * 1999-09-07 2008-06-24 Bristol-Myers Squibb Company Method for treating diabetes employing an aP2 inhibitor and combination
US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
US6878749B2 (en) 1999-09-17 2005-04-12 Novartis Ag Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes
AR028299A1 (en) 1999-09-17 2003-05-07 Novartis Ag A PHARMACEUTICAL COMPOSITION THAT INCLUDES NATEGLINIDA, A PROCESS FOR ITS PREPARATION AND THE USE OF SUCH COMPOSITION FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF METABOLIC DISORDERS, ESPECIALLY DIABETES, OR A DISEASE OR CONDITION ASSOCIATED WITH DIABETY.
ES2156574B1 (en) * 1999-11-18 2002-02-01 Vita Invest Sa NEW DERIVATIVES OF TIAZOLIDINDIONA AS ANTIDIABETIC AGENTS
US6589963B2 (en) 1999-12-03 2003-07-08 Kyoto Pharmaceutical Industries, Ltd. Heterocyclic compounds and salts thereof and medicinal use of the same
PT1741447E (en) 2000-01-21 2013-12-11 Novartis Ag Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents
US6958355B2 (en) * 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6680387B2 (en) * 2000-04-24 2004-01-20 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6784199B2 (en) * 2000-09-21 2004-08-31 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals
IL152224A0 (en) * 2000-04-25 2003-05-29 Kyorin Seiyaku Kk Stable crystals of thiazolidinedione derivative and process for the preparation thereof
US6982251B2 (en) * 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US6452014B1 (en) 2000-12-22 2002-09-17 Geron Corporation Telomerase inhibitors and methods of their use
ATE341343T1 (en) * 2000-12-26 2006-10-15 Sankyo Co MEDICAL COMPOSITIONS CONTAINING DIURETIC AND INSULIN RESISTANCE IMPROVEMENT AGENT
JP2004517916A (en) * 2001-01-26 2004-06-17 シェーリング　コーポレイション Combination of nicotinic acid and its derivatives and sterol absorption inhibitors, and treatment of vascular indications
BR0206644A (en) * 2001-01-26 2004-02-25 Schering Corp Sterol absorption inhibitor (s) combinations with cardiovascular agent (s) for the treatment of vascular conditions
PT1413331E (en) * 2001-01-26 2007-12-18 Schering Corp Combinations of the peroxisome proliferator-activated receptor (ppar) activator fenofibrate with sterol absorption inhibitor ezetimibe for vascular indications
JP2004517920A (en) * 2001-01-26 2004-06-17 シェーリング　コーポレイション Combination of sterol absorption inhibitors and blood conditioning agents to treat vascular conditions
IL156422A0 (en) * 2001-01-26 2004-01-04 Schering Corp The use of substituted azetidinone compounds for the treatment of sitosterolemia
US7071181B2 (en) * 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
AU2002241956A1 (en) * 2001-01-26 2002-08-06 Schering Corporation Combinations of bile acid sequestrant(s) and sterol absorption inhibitor(s) and treatments for vascular indications
KR100883277B1 (en) * 2001-02-24 2009-02-12 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 Pharmaceutical composition comprising xanthine derivative and process for the preparation thereof
KR200249057Y1 (en) * 2001-03-22 2001-10-19 김진환 Sewage backflow integrated into the lid and base. Odor Prevention Device
ATE423559T1 (en) * 2001-04-04 2009-03-15 Ortho Mcneil Janssen Pharm COMBINATION THERAPY USING GLUCOSE ABSORPTION INHIBITORS AND PPAR MODULATORS
US20060047000A1 (en) * 2001-04-24 2006-03-02 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
DE60237594D1 (en) * 2001-04-25 2010-10-21 Takeda Pharmaceutical USE OF THE ABC EXPRESSION PROMOTOR PIOGLITAZONE FOR THE TREATMENT OF ARTERIOSCLEROSIS OBLITERANS
ATE355286T1 (en) * 2001-04-26 2006-03-15 Zentiva As METHOD FOR PRODUCING PIOGLITAZONE AS AN ANTIDIABETIC AGENT
KR20040030647A (en) * 2001-05-29 2004-04-09 교토 야쿠힝 고교 가부시키가이샤 Novel heterocyclic compound and medicinal use thereof
CZ20033415A3 (en) * 2001-05-29 2004-06-16 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic derivatives and medicinal utilization thereof
EP1413315A4 (en) * 2001-08-03 2006-08-16 Takeda Pharmaceutical Sustained-release medicines
WO2003026644A1 (en) * 2001-09-21 2003-04-03 Schering Corporation Methods for treating or preventing vascular inflammation using sterol absorption inhibitor(s)
US7056906B2 (en) * 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US20030119808A1 (en) * 2001-09-21 2003-06-26 Schering Corporation Methods of treating or preventing cardiovascular conditions while preventing or minimizing muscular degeneration side effects
US7053080B2 (en) * 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
ATE345793T1 (en) * 2001-09-21 2006-12-15 Schering Corp TREATMENT OF XANTHOMA USING AZETIDINONE DERIVATIVES AS STEROL ABSORPTION INHIBITORS
WO2003026586A2 (en) * 2001-09-28 2003-04-03 Teva Pharmaceutical Industries Ltd. Pioglitazone hydrochloride
US20050101638A1 (en) * 2002-11-08 2005-05-12 Webb Randy L. Combination of organic compounds
EP1465881A4 (en) * 2001-12-20 2005-04-13 Teva Pharma Hydrogenation of precursors to thiazolidinedione antihyperglycemics
US20050187258A1 (en) * 2001-12-20 2005-08-25 Ben-Zion Dolitzky Hydrogenation of precursors to thiazolidinedione antihyperglycemics
ITRM20020016A1 (en) * 2002-01-15 2003-07-15 Sigma Tau Ind Farmaceuti FENYL ACID DERIVATIVES (ALCHYL) CARBOXYL AND DYNIC PHENYLALKYL THEROCYCLIC DERIVATIVES, THEIR USE AS MEDICATIONS WITH HYPOGLYCEMIC ACTIVITY
WO2003062427A1 (en) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Method of screening drug for improving insulin resistance
US7015345B2 (en) * 2002-02-21 2006-03-21 Asahi Kasei Pharma Corporation Propionic acid derivatives
KR100450700B1 (en) * 2002-03-22 2004-10-01 주식회사종근당 Thiazolidinedione derivatives and pharmaceutical composition comprising the same
US20050119314A1 (en) * 2002-04-05 2005-06-02 Sankyo Company, Limited Pharmaceutical composition comprising an ACAT inhibitor and an insulin resistance reducing agent
US8911781B2 (en) 2002-06-17 2014-12-16 Inventia Healthcare Private Limited Process of manufacture of novel drug delivery system: multilayer tablet composition of thiazolidinedione and biguanides
US8993773B2 (en) 2002-07-16 2015-03-31 Cadila Healthcare Limited Process to prepare pioglitazone via several novel intermediates
DE60316152D1 (en) * 2002-07-16 2007-10-18 Cadila Healthcare Ltd PROCESS FOR THE PRODUCTION OF PIOGLITAZONE VIA DIFFERENT INTERMEDIATE LEVELS
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
WO2004024059A2 (en) * 2002-09-12 2004-03-25 Themis Laboratories Private Limited, Improved process for preparation of thiazolidinedione derivatives
US9060941B2 (en) * 2002-09-20 2015-06-23 Actavis, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7959946B2 (en) 2002-09-20 2011-06-14 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8084058B2 (en) 2002-09-20 2011-12-27 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
ES2529180T3 (en) 2002-09-20 2015-02-17 Andrx Labs Llc Multi-stage formulation containing a biguanide and a thiazolidinedione derivative
US7785627B2 (en) * 2002-09-20 2010-08-31 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
WO2004043456A1 (en) * 2002-11-06 2004-05-27 Schering Corporation Cholesterol absorption inhibitors for the treatment of demyelination
US7208486B2 (en) 2003-03-07 2007-04-24 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7235543B2 (en) * 2003-03-07 2007-06-26 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
EP1606287B1 (en) 2003-03-07 2013-10-02 Merck Sharp & Dohme Corp. Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia
US20040242566A1 (en) 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
WO2004108721A1 (en) * 2003-04-01 2004-12-16 Sun Pharmaceutical Industries Limited Process for the preparation of 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl]-2,4-thiazolidinedione
ES2219180B1 (en) * 2003-05-09 2006-03-01 Medichem, S.A. INTERMEDIATE COMPOUND USEFUL FOR THE PREPARATION OF PIOGLITAZONA.
EP1640374A1 (en) * 2003-05-13 2006-03-29 Synthon B.V. Pioglitazone salts, such as pioglitazone sulfate, and pharmaceutical compositions and processes using the same
US20050059708A1 (en) * 2003-05-13 2005-03-17 Karel Pospisilik Processes for making thiazolidinedione derivatives and compounds thereof
US7230016B2 (en) * 2003-05-13 2007-06-12 Synthon Ip Inc. Pioglitazone salts, such as pioglitazone sulfate, and pharmaceutical compositions and processes using the same
US20050004179A1 (en) * 2003-05-22 2005-01-06 Pedersen Ward A. Methods and materials for treating, detecting, and reducing the risk of developing Alzheimer's Disease
WO2004106542A1 (en) * 2003-05-29 2004-12-09 Sankyo Company, Limited Insulin resistance curative and method of screening the same
CA2753318A1 (en) 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Substituted pyrrole derivatives
US7579357B2 (en) 2003-08-13 2009-08-25 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20070078170A1 (en) * 2003-08-28 2007-04-05 Khanduri Chandra H Process for the preparation of pioglitazone
AU2003269479A1 (en) * 2003-09-03 2005-03-16 Biocon Limited Phosphoric acid salt of 5-((4-(2-(5-ethyl-2-pyridinyl) ethoxy) phenyl) methyl)-2, 4-thiazolidinedione
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
JP5140881B2 (en) * 2003-09-17 2013-02-13 要 川杉 Pharmaceutical composition
JP2007510659A (en) * 2003-11-05 2007-04-26 シェーリング　コーポレイション Combinations of lipid modulators and substituted azetidinones and treatment of vascular conditions
US7501426B2 (en) * 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
WO2005080387A2 (en) * 2004-02-20 2005-09-01 Synthon B.V. Processes for making pioglitazone and compounds of the processes
BRPI0418639B8 (en) 2004-03-15 2021-05-25 Takeda Pharmaceutical dipeptidyl peptidase inhibitor compounds, as well as pharmaceutical composition containing the same
WO2005092382A1 (en) * 2004-03-29 2005-10-06 Sankyo Company, Limited Therapeutic agent for diabetes containing insulin resistance improving agent
US7161756B2 (en) * 2004-05-10 2007-01-09 Tandberg Data Storage Asa Method and system for communication between a tape drive and an external device
US20060025478A1 (en) * 2004-07-27 2006-02-02 Keisuke Inoue Medicine for prevention or treatment of diabetes
TW200608967A (en) * 2004-07-29 2006-03-16 Sankyo Co Pharmaceutical compositions containing with diabetic agent
US20070259927A1 (en) * 2004-08-26 2007-11-08 Takeda Pharmaceutical Company Limited Remedy for Diabetes
WO2006035459A1 (en) * 2004-09-28 2006-04-06 Morepen Laboratories Limited An improved process for the production of derivatives of thiozolidinediones and their precursors
US20060089387A1 (en) * 2004-10-26 2006-04-27 Le Huang Stabilized pharmaceutical composition comprising antidiabetic agent
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
US7833513B2 (en) 2004-12-03 2010-11-16 Rhode Island Hospital Treatment of Alzheimer's Disease
EP1828192B1 (en) 2004-12-21 2014-12-03 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
KR101302838B1 (en) * 2005-03-08 2013-09-03 다케다 게엠베하 Roflumilast for the treatment of diabetes mellitus
US20070269486A1 (en) * 2005-03-14 2007-11-22 Conor Medsystems, Llc. Methods and Devices for Reducing Tissue Damage After Ischemic Injury
EP1858845A2 (en) * 2005-03-18 2007-11-28 Orchid Chemicals and Pharmaceuticals Limited Novel tyrosine derivatives
WO2006117654A1 (en) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Processes for the preparation of pioglitazone or salts thereof
EP1905450A1 (en) * 2005-07-12 2008-04-02 Daiichi Sankyo Company, Limited Pharmaceutical composition containing ppar gamma agonist
WO2007029062A2 (en) * 2005-07-29 2007-03-15 Orchid Research Laboratories Limited Novel pyridine derivatives
DE102005035891A1 (en) * 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
CN101374523B (en) * 2005-09-14 2012-04-11 武田药品工业株式会社 Dipeptidyl peptidase inhibitors for treating diabetes
JP5122462B2 (en) 2005-09-16 2013-01-16 武田薬品工業株式会社 Dipeptidyl peptidase inhibitor
TW200738266A (en) * 2005-09-29 2007-10-16 Sankyo Co Pharmaceutical agent containing insulin resistance improving agent
EP1948599A1 (en) 2005-11-08 2008-07-30 Ranbaxy Laboratories Limited Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
TW200730173A (en) * 2005-12-16 2007-08-16 Sankyo Co Pharmaceutical composition enhancing production of adiponectin
NZ571872A (en) * 2006-03-16 2011-05-27 Metabolic Solutions Dev Co Combination therapies of thiazolidinedione analogues and glucocorticoid agonists
EP2001469B1 (en) * 2006-03-16 2012-05-23 Metabolic Solutions Development Company LLC Thiazolidinedione analogues
PL2902026T3 (en) * 2006-03-16 2018-03-30 Metabolic Solutions Development Company Llc Thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease
PE20110235A1 (en) * 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
CN101437823B (en) 2006-05-04 2014-12-10 勃林格殷格翰国际有限公司 Polymorphs
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
CA2654661C (en) 2006-06-26 2012-10-23 Amgen Inc. Compositions comprising modified lcat and use thereof for treating atherosclerosis
KR100791399B1 (en) 2006-09-06 2008-01-07 동우신테크 주식회사 Process for preparing of pioglitazone hcl
MEP8509A (en) 2006-09-07 2011-12-20 Combination treatment for diabetes mellitus
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US20080182880A1 (en) * 2006-09-28 2008-07-31 Mailatur Sivaraman Mohan Pioglitazone composition
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
CN101657460A (en) * 2006-12-13 2010-02-24 基利得科学公司 The phosplate that is used for the treatment of lung inflammation and bronchoconstriction as the mutual prodrugs of anti-inflammatory signal transduction modulators (AISTM ' S) and beta-2-agonists
WO2008075380A2 (en) * 2006-12-21 2008-06-26 Ind-Swift Laboratories Limited Process for the preparation of thiazolidine derivatives
WO2008091624A2 (en) * 2007-01-22 2008-07-31 Teva Pharmaceutical Industries Ltd. Polymorphic forms of rosiglitazone hydrobromide and processes for preparation thereof
ES2354397T3 (en) * 2007-02-01 2011-03-14 Takeda Pharmaceutical Company Limited SOLID PREPARATION THAT INCLUDES ALOGLIPTINA AND PIOGLITAZONA.
CA2677661A1 (en) 2007-02-07 2008-08-14 Kyowa Hakko Kirin Co., Ltd. Tricyclic compounds
WO2008105326A1 (en) * 2007-02-28 2008-09-04 Ohara Chemical Industries, Ltd. Process for production of 2-imino-4-thiazolidinone derivative and 2,4-thiazolidinedione derivative
WO2008112166A2 (en) 2007-03-09 2008-09-18 Indigene Pharmaceuticals Inc. Combination of metformin r-(+) lipoate and antihyperlipidemic agents for the treatment of diabetic hyperglycemia and diabetic complications
US8093236B2 (en) * 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8012931B2 (en) 2007-03-30 2011-09-06 Ambrx, Inc. Modified FGF-21 polypeptides and their uses
WO2008124122A1 (en) * 2007-04-09 2008-10-16 Scidose, Llc Combinations of statins and anti-obesity agent and glitazones
US20160331729A9 (en) * 2007-04-11 2016-11-17 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
ES2586433T3 (en) 2007-04-11 2016-10-14 Omeros Corporation Compositions and methods for prophylaxis and addiction treatment
EA020466B1 (en) 2007-06-04 2014-11-28 Синерджи Фармасьютикалз Инк. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
CA2963857A1 (en) 2007-06-04 2008-12-11 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
EP2489730B1 (en) 2007-07-26 2015-12-30 Amgen, Inc Modified lecithin-cholesterol acyltransferase enzymes
CN101784278A (en) * 2007-08-17 2010-07-21 贝林格尔.英格海姆国际有限公司 Purin derivatives for use in the treatment of FAB-related diseases
WO2009035997A2 (en) * 2007-09-14 2009-03-19 Cara Therapeutics, Inc. Benzo-fused heterocycles
ES2398313T3 (en) 2007-09-14 2013-03-15 Metabolic Solutions Development Company Llc 5- (4- (2- (3-Methoxyphenyl) -2-oxoethoxy) benzyl) thiazolidin-2,4-dione for use in the treatment of diabetes
US8304441B2 (en) 2007-09-14 2012-11-06 Metabolic Solutions Development Company, Llc Thiazolidinedione analogues for the treatment of metabolic diseases
US8722710B2 (en) * 2007-09-26 2014-05-13 Deuterx, Llc Deuterium-enriched pioglitazone
US20090118514A1 (en) * 2007-11-06 2009-05-07 Raghupathi Reddy Anumula Processes for preparing pioglitazone and its pharmaceutically acceptable salts
JP5334422B2 (en) * 2008-02-13 2013-11-06 株式会社トクヤマ Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2-imino-4-thiazolidinone
JP5197063B2 (en) * 2008-02-21 2013-05-15 株式会社トクヤマ Process for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate
PE20091730A1 (en) 2008-04-03 2009-12-10 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
EP2310367A1 (en) * 2008-04-28 2011-04-20 ERREGIERRE S.p.A. A process for the preparation of 4-ý2-(5-ethyl-2-pyridyl)ethoxy¨nitrobenzene and pioglitazone
PE20100156A1 (en) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int NAFLD TREATMENT
JP2011522828A (en) 2008-06-04 2011-08-04 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer, and other disorders
CA2730603C (en) 2008-07-16 2019-09-24 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2327690A4 (en) 2008-08-06 2012-03-28 Kyowa Hakko Kirin Co Ltd Tricyclic compound
BRPI0916997A2 (en) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh DPP-4 INHIBITOR AND ITS USE
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
US8846315B2 (en) 2008-08-12 2014-09-30 Zinfandel Pharmaceuticals, Inc. Disease risk factors and methods of use
SI2324126T1 (en) 2008-08-12 2014-07-31 Zinfandel Pharmaceuticals, Inc. METHOD OF IDENTIFYING Alzheimer's DISEASE RISK FACTORS
JP5906086B2 (en) * 2008-08-15 2016-04-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Purine derivatives for use in the treatment of FAB-related diseases
JP5553759B2 (en) * 2008-09-02 2014-07-16 株式会社トクヤマ Dehydrobromination inhibitor
KR20110067096A (en) 2008-09-10 2011-06-21 베링거 인겔하임 인터내셔날 게엠베하 Combination therapy for the treatment of diabetes and related conditions
CN102149669A (en) * 2008-10-10 2011-08-10 株式会社德山 Process for producing carbonyloxy compound
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
JP5473303B2 (en) * 2008-12-01 2014-04-16 株式会社トクヤマ Process for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate
US20100144140A1 (en) * 2008-12-10 2010-06-10 Novellus Systems, Inc. Methods for depositing tungsten films having low resistivity for gapfill applications
KR20110103968A (en) 2008-12-23 2011-09-21 베링거 인겔하임 인터내셔날 게엠베하 Salt forms of organic compound
AR074990A1 (en) 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
WO2010084638A1 (en) * 2009-01-20 2010-07-29 株式会社トクヤマ Method for inhibiting dehydrobromination of methyl 2-bromo-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl]propionate
JP2010208957A (en) * 2009-03-06 2010-09-24 Tokuyama Corp 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone having crystal structure and method for producing the same
KR20170093264A (en) 2009-03-11 2017-08-14 오메로스 코포레이션 Compositions and methods for prophylaxis and treatment of addictions
JP5733841B2 (en) 2009-06-25 2015-06-10 アルカーメス ファーマ アイルランド リミテッド Heterocyclic compounds for the treatment of neurological and mental disorders
US8686009B2 (en) * 2009-06-25 2014-04-01 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds
US20110065756A1 (en) * 2009-09-17 2011-03-17 De Taeye Bart M Methods and compositions for treatment of obesity-related diseases
CA2780683A1 (en) 2009-11-13 2011-05-19 Toray Industries, Inc. Therapeutic or prophylactic combination of a prostaglandin i2 and a thiazolidine for diabetes
EA034869B1 (en) 2009-11-27 2020-03-31 Бёрингер Ингельхайм Интернациональ Гмбх Treatment of genotyped diabetic patients with dpp-4 inhibitors such as linagliptin
CA2783468C (en) 2009-12-15 2018-10-09 Metabolic Solutions Development Company, Llc Ppar-sparing thiazolidinedione salts for the treatment of metabolic diseases
US10429384B2 (en) 2010-01-22 2019-10-01 Dana-Farber Cancer Institute, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of metabolic disorders
WO2011120923A1 (en) 2010-03-30 2011-10-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
BR112012028136A2 (en) 2010-05-05 2016-08-09 Boehringer Ingelheim Int combination therapy
KR20130093012A (en) 2010-06-24 2013-08-21 베링거 인겔하임 인터내셔날 게엠베하 Diabetes therapy
WO2012028934A1 (en) 2010-09-01 2012-03-08 Lupin Limited Pharmaceutical composition comprising metformin and pioglitazone
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
KR20180050420A (en) 2011-01-10 2018-05-14 진판델 파마슈티컬스 인코포레이티드 Methods and drug products for treating alzheimer's disease
WO2012153312A1 (en) 2011-05-11 2012-11-15 Ranbaxy Laboratories Limited Process for the purification of pioglitazone
EP2731947B1 (en) 2011-07-15 2019-01-16 Boehringer Ingelheim International GmbH Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes
JP6086865B2 (en) 2011-08-03 2017-03-01 協和発酵キリン株式会社 Dibenzooxepin derivatives
WO2013068486A1 (en) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the diagnosis and treatment of male infertility
JP6635655B2 (en) 2011-12-08 2020-01-29 アムジエン・インコーポレーテツド Human LCAT antigen binding proteins and their use in therapy
JP5952912B2 (en) 2011-12-15 2016-07-13 アルカーメス ファーマ アイルランド リミテッド Prodrugs of secondary amine compounds
US20130158077A1 (en) 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2638898A1 (en) 2012-03-16 2013-09-18 Sanovel Ilac Sanayi ve Ticaret A.S. Metformin and Pioglitazone Formulation with Different Release Profiles
JP6224084B2 (en) 2012-05-14 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Xanthine derivatives as DPP-4 inhibitors for the treatment of glomerular epithelial cell related disorders and / or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
AU2013340478B2 (en) 2012-11-05 2018-08-23 Commissariat A L'energie Atomique Et Aux Energies Alternatives (Cea) Combination of an anti-cancer agent such as a tyrosinekinase inhibitor and a STAT5 antagonist, preferably a thiazolidinedione, for eliminating hematologic cancer stem cells in vivo and for preventing hematologic cancer relapse
CA2941562C (en) 2013-03-14 2021-09-21 Deuterx, Llc Deuterium-enriched 2,4-thiazolidinediones and methods of treatment
JP2016514670A (en) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase receptor agonists in combination with other drugs
AU2014235215A1 (en) 2013-03-15 2015-10-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
US20140275138A1 (en) * 2013-03-15 2014-09-18 Cba Pharma, Inc. Method and products for treating diabetes
KR102272746B1 (en) 2013-06-05 2021-07-08 보슈 헬스 아일랜드 리미티드 Ultra-pure agonists of guanylate cyclase c, method of making and using same
US9815777B2 (en) 2013-09-22 2017-11-14 Jiva Pharma, Inc. Metformin salts to treat Type2 diabetes
EP3065757A4 (en) 2013-10-09 2017-08-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for downregulation of pro-inflammatory cytokines
KR20160094956A (en) 2013-11-05 2016-08-10 벤-구리온 유니버시티 오브 더 네게브 리서치 앤드 디벨럽먼트 어쏘러티 Compounds for the treatment of diabetes and disease complications arising from same
ES2831326T3 (en) 2014-01-15 2021-06-08 Poxel Sa Methods to treat neurological, metabolic, and other disorders using deuterium-enriched enantiopure pioglitazone
ES2950384T3 (en) 2014-02-28 2023-10-09 Boehringer Ingelheim Int Medical use of a DPP-4 inhibitor
KR101606547B1 (en) * 2014-06-02 2016-03-28 김동연 Airport passenger position inquiry system
CN114805532A (en) 2014-10-24 2022-07-29 百时美施贵宝公司 Modified FGF-21 polypeptides and uses thereof
US10034868B2 (en) 2014-11-04 2018-07-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prevention and the treatment of rapidly progressive glomerulonephritis
MA39929A (en) 2014-11-27 2016-06-01 Arven Ilac Sanayi Ve Ticaret As MULTI-LAYER TABLET CONTAINING METFORMIN AND PIOGLITAZONE
MX2018014938A (en) 2016-06-08 2019-05-16 Support Venture Gmbh Pharmaceutical combinations for treating cancer.
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
MX2019001819A (en) 2016-08-17 2019-06-13 Support Venture Gmbh Method of preventing or treating hearing loss.
TR201620309A2 (en) 2016-12-30 2018-07-23 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical compositions of metformin hydrochloride and pioglitazone hydrochloride
NZ757557A (en) 2017-04-04 2022-10-28 Kinarus Ag Methods of preventing or treating ophthalmic diseases
WO2019154895A1 (en) 2018-02-08 2019-08-15 Strekin Ag Gel formulation for preventing or treating hearing loss
WO2019154893A1 (en) 2018-02-08 2019-08-15 Strekin Ag Oral extended release pharmaceutical compositions for preventing or treating hearing loss
CN112423754A (en) 2018-03-05 2021-02-26 奥克梅斯制药爱尔兰有限公司 Aripiprazole administration strategy
US20210267983A1 (en) 2018-07-13 2021-09-02 Kinarus Ag Combinations of ppar agonists and p38 kinase inhibitors for preventing or treating fibrotic diseases
CN111875598B (en) * 2020-05-23 2023-10-10 白银京宇新药业有限公司 Preparation method of pioglitazone
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
US20230263803A1 (en) 2020-08-11 2023-08-24 Kinarus Ag Methods of preventing or treating covid-19 and related viral diseases or disorders
WO2022068878A1 (en) 2020-09-30 2022-04-07 映恩生物制药（苏州）有限公司 Antitumor compound, and preparation method therefor and use thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) * 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative
US4582839A (en) * 1984-03-21 1986-04-15 Takeda Chemical Industries, Ltd. 2,4-thiazolidinediones
CN1003445B (en) * 1984-10-03 1989-03-01 武田药品工业株式会社 The preparation method of thiazolidine diketone derivative

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