WO1985004170A1

WO1985004170A1 - Thiazolidinedione derivatives, process for their preparation, and medicinal composition containing same

Info

Publication number: WO1985004170A1
Application number: PCT/JP1984/000117
Authority: WO
Inventors: Kanji Meguro; Takeshi Fujita
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1984-03-21
Filing date: 1984-03-21
Publication date: 1985-09-26
Also published as: JPS60208980A; WO1985004171A1; JPH0570633B2

Abstract

Thiazolidinedione derivatives represented by general formula (I), wherein R1 and R2 may be the same or different and each represents hydrogen or lower alkyl, R3 represents hydrogen or acyl, and n represents 0 or 1, and their salts are novel compounds showing an effect of lowering blood sugar level and blood lipid level, and are useful as agents for treating diabetes and hyperlipemia.

Description

Harm

Thiazolidinedione tsuba conductor, method for producing the same, and pharmaceutical composition containing the same

Technical field

TECHNICAL FIELD The present invention relates to a novel thiazolidinedione derivative having excellent blood sugar and blood lipid lowering effects, a method for producing the same, and a pharmaceutical composition comprising the same.

Back _ ^ _ ¾ _

Conventionally, various biguanide compounds and salts have been used as therapeutic agents for diabetes.

ΛHoleurea compounds are used. However, biguanide compounds cause lactic acidosis and are therefore rarely used at present, and phororerea compounds have potent hypoglycemic activity, but often cause severe hypoglycemia. , Care must be taken in use. As a result of various studies to find a compound having a blood glucose lowering action without such a defect, the present inventors have found a novel thiazolidinedione derivative having an excellent blood serum and blood lipid lowering action.

The Age of Discovery:

The present invention

L — general formula

[In the formula, H ¹ and !! ² are the same or different and represent hydrogen or a lower alkyl group, R ³ represents hydrogen or an acyl group, and n represents 0 or 1. A thiazolidinedione derivative represented by the formula:

,

OMPI

? o 2. —General formula

(I)

(CH ₂ ) _n X

t

OR ⁴

Wherein R ¹ , !! ² and n have the same meanings as above. R ⁴ is hydrogen or a group, R ⁵ is hydrogen or a lower group, X is a halogen atom, and n is n Indicates 0 or 1, respectively. Is reacted with thiourea to give

[Each symbol in the formula is as defined above. A method for producing a thiazolidinedione derivative represented by the formula (I), which is characterized in that the compound represented by the formula and

a — a pharmaceutical composition comprising a thiazolidine conductor represented by formula (I) or a salt thereof,

It is something to do.

Formula (I), (2) and (Summer) Medium Rl, as the low-Hi key group represented by R ^2, for example methylcarbamoyl, E Ji, Burobi, I, knobs port bi, butyrate etc. carbon atoms 1 Among them, those having 4 to 3 carbon atoms are preferred, and those having 1 to 3 carbon atoms are preferable, and these may be substituted at any position of the pyridine ring. Examples of the acyl group represented by R ³ include, for example,

O PI ― There are 1 to 8 carbon ash groups such as dibutyl, brobion! /, Butyric, isobutyryl, penzoi W, and toy *. Examples of the ash group represented by R ⁴ include the same as the ash group represented by. Examples of the lower aki group represented by R ¹ include the same as the lower aki group represented by R ¹ . Examples of the halogen atom represented by 3C include chlorine, bromine and iodine.

—The four thiazolidinedione compounds represented by the formula (I) are amphoteric compounds having an acidic nitrogen in the thiazolidine ring and a basic nitrogen in the viridine 黢, and have both {salt and base}. The boundary of the thiazolidinedione conductor (I) is as a salt such as hydrochloride, hydrogen bromide completion, sulfuric acid, phosphoric acid, methansulfone, etc. Organic plants such as acid salts, salt, malt salt, maleic acid, fumanore salt, succinic acid, tartaric acid, malic acid, etc. Metal salts such as lithium salt, aluminum-palladium salt, magnesium salt, and casium are listed.

Specific examples of the thiazolidinedione-conductor represented by formula (I) according to the present invention and the thiazolidinedione-conductor include the following compounds.

5-1 {4-1-1 [2-hydroxy 2- (5-methyl-2-bi) ethoxy] benzy} 1-2,4-thiazolidine

5— {4- [2-acetoxy 2- (5-methyl-2-pyridy) ethoxy] penti} -1,4-thiazolidinedione

5— {4- (3-droxy 2- (3-meth-1-2-bilge) 7 * ropoxy) pent}}-1,4-thiazolidin

5— {4- (3-acetoxy 2 -— (3-meth-1-2-bilge)) lip-opening {penzi}} 1,2,4-thiazolidinedione

' 5— {4-I- (3-Pezo-Ioki 2 -— (3-Methyl-I-2-Bidyl) Broboki) Benzi; —2,4-Thiadaridinedione

5— {4- [2- (5-ethyl-1-2-1) 1-2-hydroxy] pent}} 2,4-thiazolidinedione

5— {4—1—2— (5—1—2—bilidine) 1—2—Hydroxy pentoxy u) —2,4—Thiazolyzindione

5— {4- (2-acetoxy 2-(5-eth); —2-bi) ethoxy) benzy;} — 2,4-thiazoli

5- (4- (2- (5-Et-1-2-bi) -1) 2-Brovio-pyroxyethoxy) penti) 1-2,4-Thiazolidinedione

5— {4—1—2— (5—2 × 1) 1—2—Butyloki Shetki) Peng} 1—2,4—Thiazoli

5— {4-1 (2- (5-ethyl-2-bi) -1) -2-isobutyryloxyethoxy] pent Λ} —2,4-thiazolidinedione

5— {4- (2- (5-ethyl-1-2-pyridyl) -1-2-norreloxy shetoxy) pent}-2,4,1-thiazoli

5- {4- [2-benzoxy-1-2- (5-ethyl-1-bibenzyl) ethoxy] penti} -1,2,4-thiazolidinedione

5— {4—1—2— (5—1—2—bilyl) 1—3—Hydroxybloboxy} peng} 1—2,4—Thiazolyzindione

5- {4- [3-acetoxy-2- (5-ethyl-2-viridyl) buoxy] benzyl} -1,2-thiazolidinedione

5-1 {4-1 [2-Hydroxy Pxy 2— (2-Bridge) ethoxy] pent} 1, 2, 4 Thiazolidinedione

5— {4- (2-acetoxy 2 -— (2-pyridy) ethoxy) pen Di / «} — 2,4—thiazoli

5— {4- (2-Brobi-Roxy 2— (2-Bilizy) etoki ^] Benzy} -2 »4-Thiazolidinedione

5- {4- [2-benzoxy-1- (2- (2-bi) oxy) ethoxy] benzene; u} —2,4-thiazolidinedione

5- {4- [3-hydroxy 2- (2-biloxy) oxy] benzene}-2,4-thiazolidinedione

5-1 {4- [3-acetoxy 2- (2-viridyl) oxy] benzyl} 1-2,4-thiazolidindione

5-1 {4-1 (2-Hydroxy-2- (5-methyl-2-viridyl) ethoxy) benzyu} —2,4-thiazolidinedione

5-{4-C 2 -acetoxy 2-(5-methinolate 2-bilge) ethoxy] benzene}-2,4-thiazoli

5— {4- (2- (5-methyl-2-pyridyl) 1-2-blovi-old-year-old ethoxyethoxy) pent}} — 2,4-thiazolidinedione

5— {4- (2-benzoxy) 2 -— (5-methyl-2-pyridyl) ethoxy] benzene /!}-2,4,1-thiazolidine

5- {4- [3-hydroxy-2- (5-methyl-2-viridyl) propoxy] benzy} -1,2,4-thiazoli

5— {4- [2-hydroxy-2- (3-methyl-2-viridyl) ethoxy] penzil} -1,2,4-thiazolidinedione

5— {4- (2-acetoxy-1- (3-methyl-2-bis) ethoxy) penzil} —1,2,4-thiazolidine

5— {4—1—2-Benoxy-1—2- (3-Methyl-2-vizi) ethoxy) benzy} —1,2,4-Thiazoli 5— {4- [2-droxy 2- (4-meth-1-2-viridyl) ethoxy] pent]} 2-4-thiazolidinedione

5— {4- (2-Acetoxy 2 -— (4-Meth-1-2-Byryl> ethoxy) pent)} — 2,4-Triazolidinedione

5— {4- [2-hydroxy-2- (4,6-dimethy1-2-viridyl) ethoxy] Penzi A} —2,4-thiazolidindione

5— {4-2-acetoxy 2 -— (4,6-dimethy1-2-viridyl) ethoxy] penti} —1,2,4-thiazolidinedione

The reaction between the compound represented by the general formula () and thiourea is usually carried out with a class of alcohols (eg, methanoic, ethano, * ropano; W, 2-propanol, butano, isobbutano; u, 2-methyl) It is carried out in any solvent such as toki ^ ethanol, dimethyl sulphoxide and suholane. The degree of reversal is usually 2 to 180, preferably 60 to 150. The amount of thiourea used is 1-2 mol per 1 mol of the compound (S). In this reaction, hydrogen halide is by-produced with the progress of the reaction. To remove this, a dehydrating agent such as sodium phosphate or potassium acetate may be added to carry out the reaction. The acid stabilizer is generally used in an amount of 1 to 1.5 moles per mole of the compound (H). Such anti-FS! The compound (an is produced and, if desired, can be isolated; however, the compound may be directly led to the next hydrolysis step without (().

The hydrolysis of the compound (π) is usually performed in a suitable solvent in the presence of water and a mineral acid. Examples of the solvent include those used for the reaction between the compound (2) and thiourea. Examples of the mineral acid include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The amount of the mineral acid to be used is α1 to 10 mol, preferably <12 to 3 mol per mol of the compound (). The amount of water to be added depends on compound (I) It is usually a large surplus for l. This reaction is usually performed under heating or heating.

The reaction temperature is usually 60 to 150 watts. The heating time is usually several hours to over ten hours.

According to this reaction, a compound in which R ^{s in} D-killing formula (I) is hydrogen [may be referred to as a lower hydroxy compound (Γ)] can be obtained. .

The hydroxy form (]) may be subjected to the following Aich reaction as necessary.

The acylation reaction of the hydroxyl form () is usually carried out by reacting an acylating agent in an appropriate solvent in the presence of a ¾ group. Examples of the solvent include yeast esters, esthetics, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers, such as acetic acid, diisobromo, etc./ether, tetrahydrofuran, and dioxane. For example, ketones such as acetone and methetic ketone-such as dichloromethane, chloromethane, carbon tetrachloride, chlorinated hydrocarbons, and dimethyformamide. Can be Examples of the facilitating agent include gi, g, umami, araliphatic, and aromatic sai anhydrides and halides. The aliphatic power is, for example, vinegar ^, brobion.

■ Carbon, such as ，, ^ acid, iso ^ 醆, completed Yoshikusa, completed Iso Yoshikusa, hexane ^

6, the aromatic aromatic carbons are, for example, charcoal cords 8 to 9 such as Hua-vinegar sai and the ferrocarbons, and the aromatic carbons are, for example, benzoic acid, Paramethyi benzoic acid such as those having 7 to 8 carbon atoms, and further on these aromatic rings, for example, halogens (eg, fluorene, chlorine, bromine, etc.), akoxy (eg, methoxy, ethoxy, etc.) , Trifluoromethyl group and the like may be substituted.

The amount of the acylating agent to be used is usually 1 to 1 mol of the hydroxy form (I '). 10 ¾ Λ Preferably, it is 1-2. Examples of the azo group include viridin and thietamine, such as, for example, sodium carbonate * potassium carbonate * sodium bicarbonate, potassium hydrogen carbonate, carbonic acid, and hydrogen peroxide. The base is usually used in an equimolar amount or in excess of the acylated compound. (4) When pyridine is used as the group, a large excess amount of pyridine is used.] It can also serve as a solvent. This reaction is generally carried out at a temperature of from 20 t to 40, and the reaction time is usually from 10 minutes to 24 hours. According to this anti-IS, a compound in which R ³ is an ash group in the killing formula (I) [may also be referred to as a lower alcohol form (（')] can be obtained.

The thiazolidinedione derivative (I) is necessary]. It can also be reacted with an acid or a sulfonic group according to a conventional method and led to the boundary.

The thiazolidinedione thus obtained and the thiazolidinedione are obtained by known means of separation and purification, for example, by using concentrated pestle, is, solvent extraction, crystallization, recrystallization, dissolution, chromatography and the like. can do.

Compound (I) and its 廑 at the side of this report show excellent blood 锗 and lipid lowering effects on mammals (eg, mice, dogs, cats, cats, horses, humans). The toxicity is low in both acute and subacute toxicities. For example, 5- {4-1- [2-hydroxy-2- (6-methyl-2-pyridyl) ethoxy] benzene1} 12,4-thiazolidinedione, 5 1- {4-1- [3-hydroxy-2- (3-methyl-2-pyridyl) propoxy] benzy;} — 2,4-thiazolidinedione, 5 -— {4-1- [2 -— (5-ethyl-2-) (Viridyl) 1-2-hydroxy) benzene 1-2 · 4- thiazolidinedione, 5- {4- 1 [2- (5-tech 2-bilge) 1-3-doxyboxy oxy] benzene} 1 2 , 4-thiazolidinezine *, 5- {4- [2-acetoxy-12- (6-meth-2-1-)-ethoxy] benzy} -1,2-4-1 Thiazolidinedione, 5- (4- [3-acetoxy-2- (5-ethyl-1-bilidine) broboxy ^] penzi}-2,4,1 Oral administration of thiazolidinedinone in mice The LD 50 at that time was more than 500 Ο ^ / ^. From these points, it is expected that thiazolidinedione hypoconductor (I) and its salt are useful for treating hyperlipidemia and diabetes in humans and their complications. The method of administration is usually orally used, for example, as pills, capsules, powders, granules, etc., but in some cases it can be given non-periodically as injections, suppositories, or pellets. When used as an agent for treating syphilia, α ο 5 J ~ i ^ is usually administered orally (X 0 1 -1 o ^ z ^ ¾ parenterally, or lipolipidemic) per adult per day. When used as an agent for the treatment of infectious diseases, α55 to 10 can be administered orally and αοι ^ to iοο¾? Ζ ^ can be administered non-radially per adult per day. It is desirable to administer this amount once a day or two to four times a week.

The starting compound (π) of the present invention can be produced, for example, by the following method.

I) —Preparation of compound where η in formula (π) is 0

[Wherein R ^1, R ² and X are as defined above der]), R ⁴ 'A ^ groups and Toki significance der represented by R ³ or R ^4] ?, lower represented by R ⁵ I agree with Akiki. ]

The oxidation reaction of compound (W) to compound (V) is achieved by reacting compound (IV) with hydrogen peroxide or an organic peracid! ? Can be easily done. Examples of such organic peracids include, for example, formic acid, peroxide, pertriprostatic, perbenzoic acid, m-chloroperbenzoic acid, and the like. It can be performed according to the method. Compound

The assimilation reaction from (V) to chemical ^ 5 (IT) is achieved by reacting the chemical with ^ J (V)! The reaction is usually performed with anhydrous or halide

80 ~ 150 by ripening! ? Easily done. The hydrolysis reaction from compound (H) to compound (IT) can be performed by a usual method using sodium hydroxide or potassium hydroxide.

8) Production of a compound in which n is 1 in the general formula ()

Η¾ι, _Η - ^{¾ Rl} "C o¾

CB ^ ® C¾0H

(W) (¾)

OH One U—

(Each symbol in the formula is as defined above)

The reaction from compound (w) to compound (W) is achieved by combining compound (g) with compound 01> in the presence of sodium hydride! ) Done. This reaction can be carried out at a temperature of 10 t to 20 watts in a solution of dimethiformamide, titro- drofuran, or the like. The reaction from the compound (¾!) To the compound () is carried out by catalytic reduction of the compound (W) using, for example, palladium carbon as a catalyst in a conventional manner. In the reaction from compound (κ) to compound or), compound () is diazotized in the presence of hydrogen halide. (HX), and acrylic acid or its esthetics (X) is further converted to a copper catalyst (eg, oxidative oxidation). The reaction is carried out under the condition of copper, copper oxide, copper chloride, cupric chloride, ferrous bromide, cupric bromide, etc.). The reaction from the compound ^^ (ΊΤ) to the compound (3T) is performed by converting the compound ¾8 (IT) into a compound. This reaction can be carried out in the same manner as in the method for converting the compound (V) into a compound.

BEST MODE FOR CARRYING OUT THE INVENTION ^

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Examples, but the present invention is not limited thereto.

Example 1

3- {4- (2-acetoxy-2- (6-methyl-2-vinyl) ethoxy) phenyl} 2-grombropion-methyl (2?), Thiourea (55), sodium aya (5 9 9), Ethanor

After heating and arresting the mixture for 4 hours, 6N-hydrochloric acid (30 ») was added, and the mixture was refluxed for 16 hours. Extracted with neutralized after black hole Ho arm with aqueous sodium bicarbonate, the black hole ho beam layer was water ^ post-drying (MgS0 _4). The soot is distilled off, and the residue is subjected to column chromatography using silica gel (100?).

. .. "" ^ f! PO And eluted with benzeneacetone (10: 1,)]? 5-1 {4- [2-hydroxy-2- (6-methyl-2-viridyl) ethoxy] pent}} 2,4 - give the thiazole ¹ Jinjion as crystals. Mass 0L95 9. Recrystallization from xanthyl group [xan] ?? Colorless prism crystals were obtained.

As Elemental analysis _{_{_{_{C 18 H ia N 2 0 4}}}} S

Calculation 值 ··· 32ϊ 5., 5.06; Η, 7. 82

Experimental value: C, 60 · 53 ί 5., 5.24; Ν, 7.75

Example 2

(1) 2-bromo-1--3-4-droxy-2- (3-meth-1-2-viridity) proho. A mixture of methicone (4.7), thiourea (875), ^^ sodium (943 * 1?), And ethanol (50 ml) was heated and circulated for 3 hours. The mixture was diluted with water, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with acid. ^ After washing twill E Ji layers dried (GS0 _4), and by the fact the solvent was distilled off]) 5- {4 one [3-hydroxy-one 2- (3-methylcarbamoyl one 2- Biriji) Buroho.キ ^ ペン Penzi} -1 2-mino 4-thiazolidinone was obtained as crystals. Yield 2 · 5. This was recrystallized from Kouguchi-Methanol) to obtain a colorless bryth crystal <mp 21 3 -2 1 4 t!

Elemental 髖髖 C ₁₉ H ₂₁ N ₃ 0 ₃ S

Calculated: C, 61. "; H, 5.70; 31

Experiment B: C, 61 · 14; H, 5.62; N.10.99

(5-1 {4- [3-hydroxy-2- (3-methyl-1-bipyridine) broboxy] penti) obtained in (1)} 1-imino-4 thiazolidinone (2.3) ¾r2K-1 ¾ 醆 ( 2 and Ethanor (2 compound Dissolved and arrested for 4 hours heating. Extracted with neutralized after black hole Ho arm in TanShun hydrogen sodium solution, click port ho beam layer was washed with water dried practitioners (MgSO _4). The solvent was distilled off to obtain 5- {4- [3-hydroxy-2- (3-methyl-1-biphenyl!) Buoxy] benzyl]} 1,4-thiazolidinedione as crystals. . Yield L?. Recrystallization from ethanol gave colorless bristles.

As elemental analysis ϋ C ₁₉ H _₂ oR ₂ 04S

Calculated values: C, 61 · 27; H, 5.41; M, 7.52

Experimental value ··· C, 61. 57; H, 5.49; N, 7. 74

Example 3

3— {4- [2-Acetoxy 2 -— (5- ヱ 2--1-Bizyme A-ethoxy) fe-}-1-2-Brombu methine (1α0-), thiourea ( 2)), the completed sodium (2.2-) is reacted in ethanol as in Example 1 and then hydrolyzed. (5-Ethyl-2-pyridyl) -2-hydroxyethoxy] benzyl} 1,2,4-thiazolidinedione was obtained as crystals. Yield & 2 9. Recrystallization from peroxidic acid hexane, yellowish bristles,, Ι 29-1 30 Elemental analysis: C ₁₉ fl20 »20 ₄ S

Calculation 攛: C, 61 · 27; H, 5.41 ί 7., 7.52

Experimental value: C, 61.36; H, 5.71 J H, 7.08

Example 4

2-brom-one 3— {4-1 (2- (5-ethyl-2-bi) -1-3—hydroxypoxy-hydroxyl) phenol} bubion meth (12.29), thiourea (2.2 ), Sodium (2.4), and ethanol (100) were heated to reflux for 3 hours, and 3 3-salt ^ (10 was added.

/ OMPI Heated for 12 hours. After expulsion, the mixture was neutralized with an aqueous solution of sodium bicarbonate and extracted with severe acid. Su鲮E Ji layer was evaporated the solvent ¾ washed with water and Inuizo (MgSO _4). The residue was chromatographed using silica gel (200-) and eluted with pentane-acetone (5: 1,). Pyridi) -1-hydroxy ^ propoxy] benzi ^)-2,4-thiazolidinedione was obtained as an oily b yield 4.8 »(42.9%). This was dissolved in methanol (15i) to give sodium dimethyl methylate. (28% Methanol solution, 2.9?) Was added, followed by addition of ethanol (150 «f)] to obtain sodium chem. As crystals. Yield 4.8 (4 α7%). This was recrystallized from ethanol, colorless bristles, point 2 3 7—2 3 8

As elemental析毓C ₂₀ H ₂₁ ½0 ₄ S.Ha

Calculated: 58 · 81; H, 5.18; iT, 6.86

Real winner: 0,59. 06ϊ 4., 4.94; Μ, 6. 97

Jeongjeon 5

5-1 {4-1 (2-Hydroxy-21- (6-methynoleic 2-pyridyl) ethoxy)} benzyl-1,12-, 4-thiazolidinedione (3.50 ^), pyridine (5i) and acetic anhydride (

After standing for 2 days, the mixture was poured into water and extracted with ethyl acetate. Acetic E Ji grinding was distilled off Mizu洙, Inui澡(GS0 ₄₎ and the solvent. The residue was subjected to column chromatography using silica gel (20?) And eluted with benzene-aceton (15: l, V / 7).] 5— {4-1—2— Acetoxy-1- (6-methyl-2-viridyl) ethoxy] penti} -2,1-thiazolidinedione was obtained as an oil. . Yield 360 ^ (89.8%) IR ( Neat): 1740, 1690, 123 ΟΛ- 1 · NMR (CDC1 3) δ: 2.1

OMH

^{Vf? C>} s), 2.51 (3H, s), 3.02 (1H, dd, Jl4 and 9Hz), 3.41 (1 ,, dd, J-14 and 4Hz), 437 (2H, d, J-5Hz), 44 ( 1 H, dd,;. Γ »9 and 4 Hz), 6.13 (lH, t, J-5Hz) .a83 (2 H. d J-9Ha), 7.09 (2H f d, J = -9Hz), 7.0 -7.7 (3fl, m).

5— {4—1—2— (5—2—1—2—1) —3—Hydroxyb loxo) penzil} —2,4,1—thiazolidinedionnatum (

408, kink Gin (1 0, poured into water was stirred for 8 hours a mixture of anhydrous醉鲮(0.1 at room temperature, and extracted with ^ acid Echiru. Gun鲮E Chi layer was washed with water, dried (MgSO ₄₎ the solvent And the residue is removed

Column chromatography using (209). Elution with benzene-aceton (10: 1 V-V), and 5- {4- [3-acetoxy ^-1- (5-ethyl-2-bi) oxy) pentoxide} 41 The thiazolidinediene was obtained as an oil. IR (Neat): 1740, 1690, 12 Z0c * ^ ¹ _o NMR (CDCl ₃ ): 1.24 (3H, t, J-7Hz), 2.00 (3H, s) ), 2.64 (2H, q, J = 7 Hz), 03 (lH, dd, J = l 4i¾>'9 H z), 3.45 (1 H, dd, J = l 4 and 9 Hz), 3.60 (lH, m), 4.3 l (2H _t d _t J-5Hz), 4.47 (1H, dd, J = 9 and 4 Hz), 4.55 (2H, d, J = 5 Hz).

6.80 (2H. D, J = 9Hz), 7.10 (2H, d t J = 9Hz), 7.20 (1 H, d, J-8H2) .7.48 (lH, dd, J = «8 and 2 Hz), & 42 (1H, d, J = 2Hzs) Example 7 Tablet Production Example

(1) 5— {4 1 [2— (5—et 1—2—bilge) ethoxy] pen

OMPI

', VIPO- 1 2, 4-thiazolidine 1 0 0?

(^ Lactose 50

(3) To * mouth 3 ^ starch 1 5 9

(4) Carboxymethyl sigma-squash 449 (5) Stearyl magnetatum 1 9

1100 tablets 2 10? Knead all of the yokan (1), (2) and (3) and 309 (4) with water, dry in vacuum, and granulate. By mixing 14 <θ (4) and 13¾5) into the granules, the mixture is made into a tablet by a tableting machine. D. A tablet with a diameter of 8∞ containing 0 per tablet

100 pieces are manufactured.

Reference example 1

(1) 2-Bromo-3- (4- (2- (6-Meth-2-2-Viridyl A ethoxy))-Five Methyl Bionate (1α0 ^) in methanol solution —Chlorobenzoic acid (content 70%; 7.1 f) was added and the mixture was heated under reflux for 30 minutes, and then an aqueous solution of sodium was added to decompose the agent for i), water was added, and water was added. extracted ₀齚酸E Ji water, potassium 2 Ichimizusan reduction, was distilled off and lavage of water瞩dried (MgSO ₄₎ after溶緙, 2 Bed Lom one 3- {4 - 2- ( 6-Methyl 2-Bridge) Ethoxy] Hue

-} Bubion Methi ir A crude oil of one-year-old oxide was obtained. Yield

10.1 9. IR (Neat): 1740 , 1250 «« one ¹

(2) 2-bromo-1-3- [4- [2- (6-methyl-2-viridyl) ethoxy] phene} obtained in (1) methoxide bromide (1αΐ)

9) The mixture of acetic anhydride (50 W) was concentrated at 110 under reduced pressure for 1 hour, and the residue was subjected to column chromatography using silica gel (2010). Elution with benzene-aceton (50 ·· 1, Υ / Τ) Thus, 3- {4- [2-acetoxy-2- (6-methyl-2-vinylidoxy) ethoxy] phen-II} -1-bromobutionate was obtained as an oil, and the β yield was 3.3? IR (Neat): 174 ¹ (broad) .N UR (CDC1 ₃ ) ^: 2.13 (3H _fs ), 2.53 (3Hs), ai4 (lH, dd, J = l4 and 7 Hz), a40 ( lH, dd, J = -l 4 and 7 Hz), ¾70 (3H, a), 4.2--4.5 (3Η, a), 6.15 (1Η, t, J = 6Η), 6.8-7.6 (7Η) , m)

Reference Example 2

(1) 2- (3-Methyl-2-1-bilidi) -1 · 3-Brobilenglycol / ^ (1QQ9) and dimethylformamide (100) of ρ-boronitropentene (& 45f) »/) 60% oily sodium hydride (2.89) was added little by little to the liquid while stirring under ice cooling. After stirring under water cooling for 1 hour, the reaction solution was poured into ice water and extracted with vinegar. Acetate Echiru prisoner is washed with water, dried was distilled off (MgSO ₄₎ After Ban medium, the residue is. Subjected to Karamukuroma Togurafi one Te use the Li force gain (2 Fei 0-9). It is eluted with a hexahedral hexane (3: 1 »/ Ί)]) 4- [3-hydroxy 2- (3-methyl-2-bilidine) bropho. G)-benzene was obtained as crystals. Yield ¾6 9. 齚ェェ》 ^ ^ ^ Colorless bristles were obtained by recrystallization from xane. Points 1 3 5— 1 3 6

Elemental analysis as Ci ₅ Hi6N204

Total: C, 62 · 49; H, 5.59; N, 9.72

Experiment II: C, 62 · 60; H, 5.69; N, 9.93

(2) Dissolve the 4- [3-hydroxy-2- (3-methyl-2-viridi) broboxy] -trobenzene (ao9) obtained in (1) in methanol (10) and add 10% palladium carbon. The contact reduction was carried out at normal temperature and pressure at room temperature. After removing the medium by filtration, the dissolved at was distilled off. Next, the residue was dissolved in a mixture of methanol (acetone), acetone (20 W) and a 47% aqueous solution of hydrobromic acid (2 L59), and sodium nitrite was added at a temperature of 5 t under ice cooling. Add a solution of (4-) in water (5 »), add 5 more for 30 minutes (M. Stir. Add methacrylate (15.9-) to the mixture, warm to about 40, and stir vigorously. Cuprous oxide (7.0?) Was added in small portions, and the mixture was stirred under a reaction temperature of 45 t for about 3 hours until nitrogen generation ceased. in and extracted with an a force ¹ / resistance 7t after齚酸E Ji. severe Shun E Chi layer was distilled off washed with water and dried (MgSO ₄₎ the solvent, Te use the residue by silica lateral gate (230?) Elution with ethyl acetate-hexane-triethynoleamine (75: 25: 1,7 / T) was performed by elution with 2-bromo-1--3- (4- [3-hydroxy- 2— ( .. 3 Mechi-2-pyridinium) Buroho ³ carboxy] Hue -} Purobion竣give the methylation as an oil 7¾1 Yield 4.8 9. IR (Neat): 3370 , 1735 cm- 1 N il R (CDC1 3) 3 : 235 (3H, s), i9— 34 (2H, a), 3.3-3.7 (1Η, a), 363 (3Η, a), 3> 9 (1 (, broad), 4.07 (2H, d _t J »3Hz) _t 4.1-4-6 (3H .a), 6.76 (2H, d, J '= 9 Hz), 7.04 (2H .d, J = 9Hz) _f 7.3 ~ 7.6 (2H , a), a30 (lH, dd, J «5 and 2Hz)

Reference example 3

(1) 2-Bromo-3- (4- [2- (5-eth-2-1-2-ethoxy) ethoxy] fu-} Brobion-methyl (1 & 5) is the same as Reference Example 1-1 (1) Oxidized with at-chloro perbenzoic acid and oxidized with 2-bromo-1-benzoic acid 2- 2-bromo- (4- (5-ethyl-1-2-bis) ethoxy) fu = = methionic brobionic acid as an oil Obtained. Yield 1a 2. (2) 2-Brom-1 3- (4-1) obtained in (1) [2- (5-Et-1-2-Viridi)

/ «) Ethoxy] Hue-} Brobion

Refer to 9) Reference Example 11 As in (2), react with anhydrous alcohol and purify the product by lizard column chromatography.], 3— {4-1 (2-acetoxy 2-— (5- Methyl 2-biradine) ethoxy] phen-; meth-2-bromobrobionate was obtained as an oil. . Yield 1 0.29 IR (eat):. 1730ο »" 1 MMR (CDC1 3) ^: L23 (. 3H, t J = 7Hz), 2.13 (3H, s), 2.66 (2H, q, J »7Hz), 3.12 (l H, dd, Jl 4¾2> * 7Ηζ), 3.40 (l H, dd, J «l 4 and 7 Hz), 3.70 (3H, s) t .33 (lH. t, J-7Hz) t 40 (2H, d, J- 5Hz) , 6.l 7 (lH, t f J = 5Hz), 6.83 (2H, d, J »9Ha), 7.1 l (2H, d t J = 9Hz), 7.33 (lH , d, J = 8Hz), 7.54 (lH, dd, J-8 and 2Hz), & 43 (1H, d, 3 "= 2Hz)

Litigation example 4

The following compound was obtained in the same manner as in Reference Example 2.

(1) 4- [2- (5-E Ji one 2-pyrid-A - 3- arsenide Dorokishiburo carboxy] - DOO σ benzene oil,; ER (Heat): 3250 , 1330 «" N MR (CDC1 3) _{3: L23 (3H, t f} J = 7Hz), 2.63 (2H, q »J» 7Hz), 3.35 (l H, m), 4.10 (2H, d, J = »4Hz), .50 (3H, m ), 6.93 (2H, d _f

8H¾),

7.51 (1 H .d d. = 82¾ * 2Ηζ), & 13 (2H, d, J »9Hz), & 35 (1H, d.J» 2Hz)

(2) 2-Bromo-3- (4- (2- (5-Et-1-2-Viridi) -13-hydroxyl). G) -Fe-Methyl methacrylate: oil. IR (Neat): 3300, 1730 »" ^1. NR (CDC1 _S ) ^: L23 (3H, t, J-7Hz), 2.62 (2H, q »J-7Hz) _f 3« 0 ~ 5 (3H, m), 3.68 (3H »s), 09 (2H, d _f J = 4Hs) _r 2-6 (3H, m), 6.7-7.6 (6H, a), & 35 (1H d, J-2Hz)

Hypoglycemic and lipid-lowering effects in mice The test compound was mixed with powdered feed (CE-2, CLEA Japan) (005%) and freely mixed with KKA mice (male, 8-: L0 week old, 15 mice). Water was given ad libitum during this period, blood was collected from the bacterium, blood was collected by the glucose assay, and plasma triglyceride levels were determined by the fistula method!) By using Cleantech TG-S kit (Chatron)]. Each value was shown as a reduction rate () with respect to the drug non-administration group. Compound Hypoglycemic action Lipid-lowering action

(Example ) (%)

45 47

2 22

3 32 35

4 45 38

Industrial use

The novel thiazolidinedione derivative (I) according to the present invention has an excellent blood and blood lipid-returning effect, and is useful as a pharmaceutical such as a therapeutic agent for diuresis and a therapeutic agent for hyperlipidemia.

Claims

The scope of the claims

L — general formula

0

[Wherein, R ¹ and R ² are the same or different and each represents hydrogen or a lower alkyl group; R ³ represents hydrogen or an acyl group; and n represents 0 or 1. Thiazolidinedione ϋ conductor or its ¾

[In the formula, R ¹ and R ² are the same or different and each represents hydrogen or a lower alkyl group, R ⁴ represents a hydrogen or an acyl group, R ⁵ represents a hydrogen or a lower alkyl group, X represents a halogen atom, n represents 0 or 1, respectively. Thiourea is reacted with the compound represented by

[Each of the formulas in the formula is as defined above. ], Which is then hydrolyzed and, if necessary, is converted to a further compound.

O PI CH ₂ -CH-1 C = -0

i r

(CH ₂ ) _n S NH

ヽ

OR ³ II

0

[Wherein, R ¹ and _n are as defined above, and I R3 represents hydrogen or an acyl group. Method for producing thiazoline ^^^^^-

[Wherein, R ¹ and R ² are the same or different and each represents hydrogen or a lower alkyl group; R ³ represents hydrogen or an acyl group; and n represents 0 or 1. A composition comprising a thiazolidinedione derivative or a salt thereof represented by the formula: