JP2001131158A - Tetrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new tetrazole derivative having activating action for peroxisome proliferator activation receptor response element(PPRE) and decreasing action for blood sugar and blood lipid and to obtain an antidiabetic drug including the derivative. SOLUTION: This tetrazole derivative is represented by the general formula (I) (wherein R1 is a straight chain, branched chain or cyclic alkyl group; Y is a carbonyl group or a sulfonyl group; and n is 3-7) and includes its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a peroxisomal pyrroliferator-activated receptor response element (PPR).
E) A novel tetrazole derivative having an activating action and a blood sugar and blood lipid lowering action, and a therapeutic agent for diabetes containing the same.

[0002]

2. Description of the Related Art Peroxisomal pyrroliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily.
Is considered a member. As with other nuclear receptors, a response element (PPRE: peroxisome proliferator response e
lement) and activates transcription of the target gene. PPR
The test cells containing E and the test substance coexist
In a method of detecting and measuring the expression of a reporter gene, the activation of PPARγ is said to be an in vivo ligand of PPARγ.
-Deoxy-Delta 12, 14-Prostaglandin J
₂ (15-deoxy- △ ^{12, 14} -prostaglandin J ₂ ) is known to have strong PPRE activating ability. Arachidonic acid,
It has also been found that prostaglandin D ₂ and other prostaglandin J ₂ derivatives have PPRE activating ability.
(Cell, vol. 83, 803-812 (1995)) These results show that this assay system can be used to search for a ligand for PPARγ. The relationship between PPARγ and the onset of insulin resistance is considered to be as follows. It has been known that adipocytes produce and secrete proteins such as leptin (ob gene product), TNFα, and FFA (free fatty acids). In NIDDM (non-insulin-dependent diabetes mellitus), there is some abnormality in the prostaglandin J ₂ metabolic pathway, and 15-deoxy-Δ ^12,14 -prostaglandin J ₂ is not produced. This increases the production of TNFα from adipocytes, which acts as a mediator on skeletal muscle cells and inhibits the action of insulin. Thiazolidine derivative, 15-deo
xy-△ ^{12, 14} serve as -prostaglandin J ₂ structure converter,
Binds to receptors and suppresses TNFα production from adipocytes,
It is said to improve insulin resistance and lower blood sugar.

[0003] Conventionally, sulfonylurea drugs and biguanide drugs have been used as drugs for treating diabetes. However, sulfonylureas can cause severe hypoglycemia, and biguanides can cause severe lactic acidosis. Therefore, the use of these drugs requires great care, and the biguanides are rarely used. Therefore, development of a new drug for treating diabetes that does not have these disadvantages is desired. Recently, drugs that improve hyperglycemia by reducing insulin resistance in peripheral tissues have attracted attention. Representative of such drugs is troglitazone (Sankyo, JP-A-3-
251530), pioglitazone (Takeda Pharmaceutical, Che
m.Pharm.Bull., 39 , 1440 (1991)), Englitazone (Pfizer Pharmaceutical, Chem. Pharm, Bull., 34 , 319 (199)
1)), BRL-49653 (Smith Klein Bee Cham J. Med.C)
hem., 37 , 3977 (1994)). In addition, JP-A-3-90071, JP-A-2-167225,
-92972, JP-A-5-239041, JP-A-6-5
00538 and JP-A-6-503353. However, conventional insulin sensitizers are not yet in a satisfactory state, for example, have weak effects or have side effects, and there is a demand for the development of a drug that is stronger and has fewer side effects.

[0004]

SUMMARY OF THE INVENTION The present inventors have synthesized various compounds and proceeded with screening. As a result, the tetrazole derivative was found to have a strong peroxisomal pyrroliferator-activated receptor response element (PPRE) activation effect and reduced blood glucose. The present invention has been found to have an action and a blood lipid lowering action and has completed the present invention.

[0005]

The present invention provides a compound represented by the general formula (I):

[0006]

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(Wherein R ₁ represents a linear, branched or cyclic alkyl group, Y represents a carbonyl group or a sulfonyl group, and n represents 3 to 7) and a tetrazole derivative represented by the formula: Salt. The present invention is also an activator of peroxisome pyrroliferator-activated receptor response element (PPRE) containing the compound as an active ingredient. Further, the present invention is a drug for treating diabetes containing the above compound as an active ingredient.

Examples of the linear or branched alkyl group represented by R ₁ include a methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl, nonanyl group and the like. Examples of the cyclic alkyl group represented by R ₁ include a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl group and the like. Preferred R ₁ is hexyl,
Heptyl and octyl groups. Preferred Y is a carbonyl group. Desirable n is 5.

[0009]

According to the present invention, a tetrazole derivative represented by the general formula (I) can be synthesized as follows. That is, it is obtained by reacting the compound represented by the general formula (VI) with sodium azide. General formula (VI)
Can be obtained by reacting a compound represented by the general formula (IV) with a halide represented by the general formula (V) in the presence of a base. The compound represented by the general formula (IV) can be obtained by reacting a bromine compound represented by the general formula (II) with the bromine compound represented by the general formula (III) in the presence of a base. All of the compounds are purified by ordinary purification means, for example, recrystallization, thin-layer chromatography such as silica gel, column chromatography, high-performance liquid chromatography and the like.

[0010]

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(Wherein Y, R ₁ and n are as defined above) The compound represented by the general formula (II) is known. Compound (IV) is obtained by reacting compound (II) with compound (III) in the presence of a suitable base. This reaction is carried out in a solvent such as acetone, dioxane, tetrahydrofuran, dimethylformamide using potassium carbonate, triethylamine, pyridine, sodium hydride or the like as a base at a reaction temperature of 0 to 100 ° C.
This is usually performed at room temperature. The reaction time is between 0.5 and 24 hours.

Compound (VI) is obtained by reacting compound (IV) with compound (V) in the presence of a suitable base. This reaction is carried out in a solvent such as acetone, dioxane, tetrahydrofuran, or dimethylformamide using potassium carbonate, triethylamine, pyridine or the like as a base at a reaction temperature of 0 to 100 ° C., but is usually carried out at room temperature. . The reaction time is between 0.5 and 24 hours. Compound (I) is obtained by reacting compound (VI) with sodium azide in a solvent such as dimethylformamide in the presence of ammonium chloride. Reaction temperature is from room temperature to 200
C., but usually at 180.degree. Compound
The purification of (I) is carried out by usual purification means, for example, recrystallization, thin-layer chromatography such as silica gel, column chromatography, high-performance liquid chromatography and the like.

The compound represented by the general formula (I) forms a salt because it has an acidic nitrogen on the tetrazole ring.
The salt is converted into a salt by a known method, for example, neutralization, an ion exchange resin method and the like. Salts include alkali metal salts such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and pharmaceutically acceptable (ie, non-toxic salts) amines. Examples of such amines include organic bases such as methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, isopropylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, and arginine.

When the compound of the present invention is used as a diabetic, it can be administered in an appropriate form such as a tablet, capsule, soft capsule, powder, injection, patch or the like. Excipients, solubilizers, binders, stabilizers, flavoring agents, and the like can be used in various formulations using these dosage forms.

Specific examples of adjuvants which can be mixed with tablets, capsules and the like are as follows. Binders such as tragacanth gum, gum arabic, corn starch or gelatin, excipients such as microcrystalline cellulose, disintegrants such as constarch, fully gelled starch, alginic acid, lubricants such as magnesium stearate, sucrose A sweetener such as lactose or saccharin, a flavoring agent such as peppermint, reddish oil or cherry, and, when the unit use form is a capsule, containing a liquid carrier such as a fatty oil in addition to the above type of material. Can be. Various other materials may be present as coatings or to otherwise alter the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

The sterile composition for injection is water for injection, sesame oil,
By dissolving or suspending the active substance in excipients, such as naturally occurring vegetable oils, such as coconut oil, peanut oil, cottonseed oil, and the like, can be formulated according to conventional pharmaceutical practice. Buffers, preservatives, antioxidants and the like can be mixed as necessary.

The drug of the present invention can be used for intravenous injection, subcutaneous injection,
It can be performed by various injections such as intramuscular injection or various methods such as oral administration and transdermal administration, but it is desirable to administer it as a liquid injection and an infusion. A particularly preferred mode of administration is oral administration, and the dose is generally preferably 1 to 1000 mg / kg per day, and may be administered several times a day. In general, the dose varies depending on the symptoms of diabetes or the method of administration, and the dose can be administered outside the above range.

[0018]

The production examples of the compounds of the present invention are shown below by way of examples, but the present invention is not limited by these examples. Example 1 Synthesis of 6- (2-aminophenoxy) hexanenitrile (Compound 1) 7.0 g of 2-aminophenol was dissolved in 60 ml of anhydrous dimethylformamide, and then 3.0 ml of sodium hydride was added.
Add 8 g and stir at room temperature for 30 minutes. After the end of hydrogen gas generation, 11.31 g of 6-bromohexanitrile is added. After stirring at room temperature for 2 hours, the reaction solution is opened on ice and extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, silica gel column chromatography (hexane:
Purification with ethyl acetate = 2: 1) gave 10.25 of 6- (2-aminophenoxy) hexanenitrile as a red oil.
g (yield 78%).

Example 2 Synthesis of 7- (2-aminophenoxy) heptanenitrile (Compound 2) 5.3 g of 2-aminophenol was dissolved in 60 ml of anhydrous dimethylformamide, and then sodium hydride 2.0 ml.
g and stirred at room temperature for 30 minutes. After the generation of hydrogen gas is completed, 9.3 g of 7-bromoheptanenitrile is added. After stirring at room temperature for 2 hours, the reaction solution was opened on ice,
Extract twice with ethyl acetate. After evaporating the extract under reduced pressure,
Purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1) gave 8.53 g of 7- (2-aminophenoxy) heptanenitrile as a red oil.
(80% yield).

Example 3 Synthesis of 5- (2-aminophenoxy) pentanenitrile (Compound 3) 5.0 g of 2-aminophenol was dissolved in 60 ml of anhydrous dimethylformamide and then dissolved in sodium hydride 2.0 ml.
g and stirred at room temperature for 30 minutes. After the generation of hydrogen gas is completed, 9.3 g of 5-bromopentanenitrile is added. After stirring at room temperature for 2 hours, the reaction solution was opened on ice,
Extract twice with ethyl acetate. After evaporating the extract under reduced pressure,
Purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1) yielded 8.4 g of 5- (2-aminophenoxy) pentanenitrile as a red oil (yield 79%).

Example 4 N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] heptanamide (compound 4) 1.0 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 15 ml of tetrahydrofuran, 1.4 ml of triethylamine and 830 μl of heptanoyl chloride were added, and the mixture was stirred at room temperature for 3 hours. I do. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain N- [2- (5-
1.47 g (yield 95%) of cyanopentyloxy) phenyl] heptanamide was obtained as an oil.

Example 5 : N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] octaneamide (compound 5) 2.0 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 20 ml of tetrahydrofuran, and 1.5 ml of triethylamine and 1.6 ml of octanoyl chloride were added. Stir for hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain N- [2- (5-
2.24 g (yield 70%) of cyanopentyloxy) phenyl] octanamide was obtained as an oil.

Example 6 : N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] nonanamide (compound 6) 1.47 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 15 ml of pyridine, and nonanoyl chloride was dissolved.
Add 1.43 ml and stir at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N- [2- (5-cyanopentyloxy) phenyl] nonanamide as an oily substance. .45 g (99% yield) were obtained.

Example 7 : N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] ethanesulfonamide (compound 7) 2.0 g of 6- (2-aminophenoxy) hexanenitrile is dissolved in 20 ml of pyridine, 1.6 ml of ethanesulfonyl chloride is added, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N- [2- (5-cyanopentyloxy) phenyl] ethanesulfonamide as an oil. 1.6 g (yield 43%) was obtained.

Example 8 : N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] propanesulfonamide (compound 8) 2.0 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 20 ml of tetrahydrofuran, 2.7 ml of triethylamine and 1.1 m of propanesulfonyl chloride.
and stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-
2.5 g (83% yield) of [2- (5-cyanopentyloxy) phenyl] propanesulfonamide was obtained as an oil.

Example 9 : N- [2- (5-cyanopentyloxy)
Synthesis of phenyl] butanesulfonamide (compound 9) 1.0 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 10 ml of tetrahydrofuran, and 1.5 ml of triethylamine and 0.7 ml of butanesulfonyl chloride were dissolved.
And stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-
560 mg (35% yield) of [2- (5-cyanopentyloxy) phenyl] butanesulfonamide was obtained as an oil.

Example 10 : Synthesis of N- [2- (5-cyanopentyloxy) phenyl] octanesulfonamide (compound 10) 3.0 g of 6- (2-aminophenoxy) hexanenitrile was dissolved in 30 ml of tetrahydrofuran. And triethylamine 4.3 ml, octanesulfonyl chloride 2.9 m
and stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-
3.6 g (65% yield) of [2- (5-cyanopentyloxy) phenyl] octanesulfonamide was obtained as an oil.

Example 11 Synthesis of N- [2- (6-cyanohexyloxy) phenyl] ethanesulfonamide (Compound 11) 3.63 g of 7- (2-aminophenoxy) heptanenitrile
Is dissolved in 20 ml of pyridine, 1.6 ml of ethanesulfonyl chloride is added, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N- [2- (6-cyanohexyloxy) phenyl] ethanesulfonamide as an oil. 3.5 g (yield 70
%)Obtained.

Example 12 : Synthesis of N- [2- (6-cyanohexyloxy) phenyl] octanesulfonamide (Compound 12) 2.0 g of 7- (2-aminophenoxy) heptanenitrile was dissolved in 20 ml of tetrahydrofuran. Then, 4.1 ml of triethylamine and 2.1 ml of octanoyl chloride are added, and the mixture is stirred at room temperature for 3 hours. After the reaction is completed, water is added.
Extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain N- [2- (6-
2.68 g (74% yield) of cyanohexyloxy) phenyl] octanesulfonamide was obtained as an oil.

Example 13 Synthesis of N- [2- (4-cyanobutyroxy) phenyl] ethanesulfonamide (Compound 13) 2.58 g of 5- (2-aminophenoxy) pentanenitrile was dissolved in 20 ml of pyridine, and ethanesulfonyl was dissolved. 1.38 ml of chloride is added, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N- [2- (4-cyanobutyroxy) phenyl] ethanesulfonamide as an oil. 0.8 g (73% yield)
Obtained.

Example 14 Synthesis of N- [2- (4-cyanobutyroxy) phenyl] octanesulfonamide (Compound 14) 4.3 g of 5- (2-aminophenoxy) pentanenitrile was dissolved in 20 ml of pyridine, and octanesulfonyl was dissolved. 4.4 ml of chloride are added, and the mixture is stirred at room temperature for 24 hours. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. After evaporating the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give N- [2- (4-cyanobutyroxy) phenyl] ethanesulfonamide as an oil. 9.9 g (yield 70%) was obtained.

Example 15 : Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] heptanamide (compound 15) 970 mg of (5-cyanopentyloxy) phenyl] heptanamide, 760 mg of ammonium chloride and 900 mg of sodium azide were suspended in 20 ml of dimethylformamide and stirred at 180 ° C. for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl]. 690 mg (yield 63%) of heptanamide was obtained as a white powder.

Example 16 : Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] octanamide (Compound 16) 1.5 g of (5-cyanopentyloxy) phenyl] octanamide, 1.24 g of ammonium chloride and 1.46 g of sodium azide were suspended in 20 ml of dimethylformamide and stirred at 180 ° C. for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration.
The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N-
[2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] octanamide as a white powder in an amount of 1.04
g (yield 61%).

Example 17 : Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] nonanamide (Compound 17) 5-cyanopentyloxy) phenyl] nonanamide 9
70 mg, 760 mg of ammonium chloride and 900 mg of sodium azide were suspended in 20 ml of dimethylformamide and stirred at 180 ° C. for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration.
The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N-
690 mg of [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] nonanamide as a white powder
(63% yield).

Example 18 : Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] ethanesulfonamide (compound 18) 1.8 g of-(5-cyanopentyloxy) phenyl] ethanesulfonamide, 1.65 g of ammonium chloride, and 1.95 g of sodium azide were suspended in 20 ml of dimethylformamide, and stirred at 180 ° C for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl]. 1.66 g (yield 77%) of ethanesulfonamide was obtained as a white powder.

Example 19 : Synthesis of N- [2 (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] propanesulfonamide (Compound 19) 2.7 g of (5-cyanopentyloxy) phenyl] propanesulfonamide, 1.93 g of ammonium chloride and 2.33 g of sodium azide were added to 20 ml of dimethylformamide.
And stirred at 180 ° C. overnight. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2 (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] propane. 1.94 g (yield 62%) of sulfoamide was obtained as a white powder.

Example 20 : Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] butanesulfonamide (Compound 20) 2.2 g of-(5-cyanopentyloxy) phenyl] butanesulfonamide, 1.92 g of ammonium chloride and 2.31 g of sodium azide were suspended in 20 ml of dimethylformamide, and the mixture was stirred at 180 ° C for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl]. 960 mg (38% yield) of butanesulfonamide was obtained as a white powder.

Example 21 Synthesis of N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] octanesulfonamide (Compound 21) 970 mg of-(5-cyanopentyloxy) phenyl] octanesulfamide, 760 mg of ammonium chloride and 900 mg of sodium azide were added to 20 m of dimethylformamide.
and stirred at 180 ° C. overnight. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2- (5- (2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl]. Octanesulfoamide was obtained as a white powder (690 mg, yield 63%).

Example 22 Synthesis of N- [2- (6- (2H-1,2,3,4-tetraazol-5-yl) hexyloxy) phenyl] ethanesulfonamide (Compound 22) 1.7 g of [-(6-cyanohexyloxy) phenyl] ethanesulfonamide, 1.5 g of ammonium chloride and 1.8 g of sodium azide were suspended in 20 ml of dimethylformamide, and the mixture was stirred at 180 ° C. for 24 hours. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration.
The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N-
1.19 g (yield 61%) of [2- (6- (2H-1,2,3,4-tetraazol-5-yl) hexyloxy) phenyl] ethanesulfonamide was obtained as a white powder.

Example 23 : Synthesis of N- [6- (2H-1,2,3,4-tetraazol-5-yl) hexyloxy) phenyl] octanesulfonamide (Compound 23) 2.0 g of [-cyanohexyloxy) phenyl] octanesulfonamide, 1.34 g of ammonium chloride and 1.65 g of sodium azide in 20 ml of dimethylformamide
And stirred at 180 ° C. overnight. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [6- (2H-1,2,3,4-tetraazol-5-yl) hexyloxy) phenyl] octanesulfonamide Was obtained as a white powder (yield 50%).

Example 24 : Synthesis of N- [2- (4- (2H-1,2,3,4-tetraazol-5-yl) butyroxy) phenyl] ethanesulfonamide (Compound 24) 1.4 g of [-(4-cyanobutyroxy) phenyl] ethanesulfonamide, 1.3 g of ammonium chloride and 2.31 g of sodium azide were suspended in 20 ml of dimethylformamide, and stirred at 180 ° C. overnight. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration.
The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N-
[2- (4- (2H-1,2,3,4-tetraazol-5-yl) butyroxy) phenyl] ethanesulfonamide as a white powder.
2 g (74% yield) was obtained.

Example 25 : Synthesis of N- [2- (4- (2H-1,2,3,4-tetraazol-5-yl) butyroxy) phenyl] octanesulfonamide (Compound 25) 4.2 g of-(4-cyanobutyroxy) phenyl] octanamide, 3.0 g of ammonium chloride and 3.7 g of sodium azide were suspended in 20 ml of dimethylformamide.
The mixture was stirred at 180 ° C. overnight. The reaction solution was added dropwise to a dilute aqueous hydrochloric acid solution with stirring, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give N- [2- (4
-(2H-1,2,3,4-tetraazol-5-yl) pentyloxy) phenyl] octanesulfonamide as a white powder, 2.8.
g (yield 60%).

¹ H of the compound obtained in Examples 15 to 25
Table 1 shows the measurement results of -NMR (solvent: d6-DMSO).

[0044]

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Table 1 Compounds R ₁ n Y ¹ H-NMR (ppm) 15 CH ₃ (CH ₂ ) ₅ -5 CO 0.85 (3H, t), 1.10-1.81 (14H, m), 2.50 (2H, t) , 2.90 (2H, t), 4.00 (2H, t), 6.86-7.06 (4H, m), 7.84 (1H, dd), 8.73 (1H, t) 16 CH 3 (CH 2) 6 - 5 CO 0.84 ( 3H, t), 1.25-.79 (16H, m), 2.34 (2H, t), 2.90 (2H, t), 4.00 (2H, t), 6.87 (1H, t), 7.00-7.10 (2H, m ), 7.83 (1H, d) , 8.27 (1H, t) 17 CH 3 (CH 2) 7 - 5 CO 0.84 (3H, t), 1.24-1.78 (18H, m), 2.53 (4H, t), 4.18 (2H, t), 6.97 ( 1H, d), 7.06-7.18 (2H, m), 8.49 (1H, d), 9.01 (1H, s) 18 CH 3 CH 2 - 5 SO 2 1.22 (3H, t) , 1.49 (2H, m), 1.75-1.80 (4H, m), 2.91 (2H, t), 2.99 (2H, t), 3.99 (2H, t), 6.99 (1H, d), 7.03 (1H, dd ), 7.15 (1H, d) , 7.27 (1H, dd), 8.78 (1H, s) 19 CH 3 (CH 2) 2 - 5 SO 2 0.93 (3H, t), 1.50 (2H, m), 1.72- 1.79 (6H, m), 2.90 (2H, t), 2.97 (2H, t), 3.99 (2H, t), 6.89 (1H, d), 7.03 (1H, dd), 7.15 (1H, d), 7.27 (1H, dd), 8.77 ( 1H, s) 20 CH 3 (CH 2) 3- 5 SO 2 0.84 (3H, t), 1.17-1.80 (10H, m), 2.89 (2H, t), 2.99 (2H , t), 3.99 (2H, t), 6.89 (1H, d), 7.03 (1H, dd), 7.27 (1H, dd), 8.78 (1H, bs) 21 CH 3 (CH 2) 7 - 5 SO 2 0.82 (3H, t), 1.15-1.48 (10H, m), 1.50-1.60 (2H, m), 1.65-1.85 (6H, m), 2.91 (2H, m t), 2.99 (2H, t), 3.99 (2H, t), 6.89 (1H, d), 7.03 (1H, dd), 7.15 (1H, m), 7.27 (1H, dd), 8.77 (1H, s _{) 22 CH 3 CH 2 - 6} SO 2 1.23 (3H, t), 1.36 (2H, q), 1.48 (2H, h), 1.70-1.77 (4H, m), 2.89 (2H, s), 3.01 (2H , t), 3.89 (2H, t), 6.89 (1H, d), 7.02 (1H, d), 7.15 (1H, t), 7.27 (1H, dd), 8.77 (1H, s) 23 CH ₃ (CH _{2) 7 - 6 SO 2 0.83} (3H, t), 1.15-1.80 (14H, m), 2.88 (2H, t), 2.99 (2H, t), 3.98 (2H, t), 6.89 (1H, t) , 7.02 (1H, d), 7.15 (1H, t), 7.26 (1H, d), 8.77 (1H, s) 24 CH 3 CH 24 SO 2 1.21 (2H, t), 1.81 (2H, q) , 1.91 (2H, q), 2.90-3.10 (4H, m), 4.03 (2H, t), 6.91 (1H, q), 7.05 (1H, q), 7.16 (1H, q), 7.29 (1H, q ), 8.82 (1H, s) 25 CH 3 (CH 2) 7 - 4 SO 2 0.84 (3H, t), 1.18-1.30 (10H, m), 1.66 (2H, m), 1.82 (2H, m), 1.92 (12H, m), 2.29-3.00 (4H, m), 4.03 (2H, t), 6.90 (1H, hp), 7.04 (1H, q), 7.15 (1H, t), 7.28 (1H, q) , 8.81 (1H, s)

The pharmacological efficacy of the compound of the present invention is described below. To confirm the efficacy of the compound of the present invention, PPAR
The gamma response element (PPRE) activation ability and hypoglycemic effect in diabetic rats were examined. PPARγ response element (PPRE) activation ability (in vitro
(Experimental method) The experiment was performed according to the method described in Cell. 83.803-812. (1995). FIG. 1 shows the results of one part of the tetrazole derivative represented by the general formula (I) as the fluorescence intensity (count: CPS) of the PPRE activating ability at 1 × 10 ⁻⁴ M.
The numbers on the horizontal axis correspond to the compound numbers in Table 1. The numbers on the vertical axis indicate count numbers. Figure 1 shows that the compound of the present invention is excellent in PPRE
It has been revealed that it has activating ability.

Hypoglycemic Activity (Materials and Methods) Five KK-Ay mice, each of which was confirmed to be positive for urinary glucose by uristics (Bayer Sankyo), were used. The test drug was orally administered to the mice for 4 days, and blood was collected from the tail vein immediately before the administration and 24 hours after the administration on the 4th day. The blood was centrifuged (3000 rpm, 10 min) to obtain serum, and the amount of glucose was measured with Glucose B Test Wako (Wako Pure Chemical). Table 3 shows one part of the result as a blood glucose lowering rate. The example numbers correspond to the compound numbers in Table 1, respectively.

Table 2 Example No. Dose (mg / kg / day) Hypoglycemic rate (%) 15 30 40.2 16 30 10.0 17 30 26.3 Troglitazone 300 13.0 From Table 2, it can be seen that the compound of the present invention exhibits an excellent hypoglycemic effect. it is obvious.

[Brief description of the drawings]

FIG. 1. P at 1 × 10 ⁻⁴ M of a tetrazole derivative
4 is a graph showing the fluorescence intensity (count: CPS) as the PRE activation ability.

Claims (4)

[Claims] 1. The following general formula: (Wherein R ₁ represents a linear, branched or cyclic alkyl group, Y represents a carbonyl group or a sulfonyl group, and n represents 3 to 7) and salts thereof. 2. A compound represented by the general formula (IV) obtained by reacting a compound represented by the following general formula (II) or a salt thereof with a compound represented by the general formula (III): The method for producing a tetrazole derivative (I) or a salt thereof according to claim 1, which is obtained by reacting a compound represented by the general formula (VI) obtained by reacting a compound represented by the following formula with an azide compound. (Wherein Y, R ₁ and n are as described in claim 1) 3. The tetrazole derivative according to claim 1,
Or a peroxisomal pyrroliferator-activated receptor response element (P
PRE) activator. 4. The tetrazole derivative according to claim 1,
Or a therapeutic agent for diabetes comprising a non-toxic salt thereof as an active ingredient.