JP2002220336A - Preventive and therapeutic agents for diabetes containing condensed heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound in which solubility is improved and good oral absorbability is exhibited. SOLUTION: The preventive and therapeutic agents for diabetes contain a hydrochloride of a compound represented by the structural formula (I). [5- 4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine- 2,4- dione].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to hyperglycemia, impaired glucose tolerance (IGT), diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), and hyperlipidemia. Disease and gestational diabetes (Gestational)
The present invention relates to the use of a hydrochloride of a fused heterocyclic compound having excellent oral absorbability by improving diseases caused by insulin resistance such as Diabetes Mellitus (GDM), polycystic ovary syndrome and the like.

Further, the present invention relates to diabetes, hyperglycemia, impaired glucose tolerance, diabetic complications (for example, retinopathy, nephropathy, neuropathy, etc.) containing a hydrochloride of a condensed heterocyclic compound as an active ingredient.
Cataract, coronary artery disease), hyperlipidemia, obesity, hypertension,
Caused by fatty liver, arteriosclerosis, diseases caused by insulin resistance, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease), atherosclerosis or ischemic heart disease. Cell damage (eg, brain injury caused by stroke), gout, inflammatory disease (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic disease, asthma GI ulcer, cachexia, autoimmune disease, pancreatitis),
The present invention relates to a prophylactic and therapeutic agent for cancer, osteoporosis, cataract and the like.

Further, the present invention provides an excellent insulin resistance improving effect, a blood glucose lowering effect, an anti-inflammatory effect, an immunomodulating effect,
Aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonism, adipocyte promotion, cancer cell growth inhibitory action, condensation having calcium antagonism The present invention relates to the use of a hydrochloride of a heterocyclic compound.

[0004]

2. Description of the Related Art Conventionally, as an agent for treating diabetes and hyperglycemia,
Insulin and sulfonylurea compounds such as tributamide and glipizide are used. Recently, thiazolidinedione derivatives such as troglitazone, pioglitazone, and rosiglitazone are known as therapeutic agents for insulin-independent diabetes.

In particular, 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)
Benzyl] thiazolidine-2,4-dione is disclosed in
295970, EP 0745600, and US Pat. No. 5,886,014. However, the hydrochloride salt of the compound of the present invention does not describe biological test data in the above-mentioned document, nor does it specifically describe physical properties.

[0006]

SUMMARY OF THE INVENTION The present inventors have found that hyperglycemia, impaired glucose tolerance, diabetic complications, hyperlipidemia, and insulin resistance such as gestational diabetes mellitus, polycystic ovary syndrome, etc. As a result of intensive studies on the synthesis of compounds that improve the disease and the like and their pharmacological activities, it was found that excellent pharmacological activities can be exhibited by using known condensed heterocyclic compounds as hydrochlorides.

That is, the above-mentioned 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione which is a known condensed heterocyclic compound is converted to a hydrochloride. Thus, the hydrochloride of the novel condensed heterocyclic compound obtained by the above method has significantly improved solubility compared to its free form (compound that does not form a salt), and exhibits excellent oral absorbability. Due to this excellent oral absorption, a sufficient blood concentration can be ensured even with a smaller amount, and excellent pharmacological activity can be obtained.

[0008]

SUMMARY OF THE INVENTION The present invention provides a 5- [4-
(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,
This is an application of 4-dione hydrochloride (hereinafter, referred to as “compound A”).

[0009] Specifically, the present invention relates to a method for treating diabetes, hyperglycemia, impaired glucose tolerance, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract,
Coronary artery disease), hyperlipidemia, obesity, hypertension, fatty liver,
Atherosclerosis, a disease caused by insulin resistance, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease), cell damage caused by atherosclerosis or ischemic heart disease ( For example, brain damage caused by stroke), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, G
I ulcer, cachexia, autoimmune disease, pancreatitis), cancer, osteoporosis, cataract and the like.

More specifically, the present invention relates to an insulin sensitizer, a hypoglycemic agent, an anti-inflammatory agent, an immunomodulator, an aldose reductase inhibitor, a 5-lipoxygenase inhibitor, comprising Compound A as an active ingredient. A lipid peroxide production inhibitor, a PPAR activator, an anti-osteoporosis agent, a leukotriene antagonist, an adipogenesis promoter, a cancer cell growth inhibitor, and a calcium antagonist.

5- is a free form of the compound A of the present invention.
[4- (6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (hereinafter referred to as “compound B”) has the following structural formula (I)

[0012]

Embedded image

[0013]

The compound A has various isomers. For example, there are optical isomers derived from the asymmetry of the 5-position carbon of the thiazolidine ring. In the structural formula (I), stereoisomers based on these asymmetric carbon atoms and equivalent and unequal mixtures of these isomers are all represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, the compound A may become a solvate by absorbing moisture or a recrystallization solvent when left in the air or recrystallized, and such a solvate is also used. Included in the present invention.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The compound A of the present invention is prepared by first synthesizing a compound B according to Example 1 (1) described later and according to a known method, as in Example 1 (2). It can be produced by converting into a hydrochloride.

The compound A of the present invention is useful for treating diabetes, hyperglycemia,
Insufficient glucose tolerance, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease), hyperlipidemia, obesity, hypertension, fatty liver, arteriosclerosis, diseases caused by insulin resistance Gestational diabetes, polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease), cell damage caused by atherosclerosis or ischemic heart disease (eg, brain damage caused by stroke), Gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis) ,
It is useful as an agent for preventing and treating cancer, osteoporosis, cataract and the like.

Examples of the dosage form of the compound A of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections, suppositories or eye drops. it can. These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents and the like.

Here, as the excipient, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-
Starch derivatives such as starch, dextrin, carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; Organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; And inorganic excipients such as sulfates.

Examples of the lubricant include metal stearates such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay wax; boric acid: adipic acid; Sodium sulfate, DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; And the above-mentioned starch derivatives.

Examples of the binder include polyvinylpyrrolidone, macrogol and the same compounds as the above-mentioned excipients.

Examples of the disintegrant include compounds similar to the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.

As the stabilizer, for example, methyl paraben,
Paraoxybenzoic acid esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. be able to.

Examples of the flavoring agent include, for example, commonly used sweeteners, sour agents, flavors and the like.

The amount of the hydrochloride of the compound having the compound A of the present invention varies depending on symptoms, age, administration method and the like.
For example, in the case of oral administration, for adults,
It is desirable to administer 0.01 mg (preferably 0.1 mg) as the lower limit and 2000 mg (preferably 500 mg, more preferably 100 mg) as the upper limit once or several times depending on the symptoms. In the case of intravenous administration, the lower limit is 0.001 m / day for adults.
g (preferably 0.01 mg), with an upper limit of 500 m
It is desirable to administer g (preferably 50 mg) once or several times depending on the symptoms.

[0026]

【Example】

[0027]

Example 1 5- [4- (6-methoxy-1-methyl-
1H-benzimidazol-2-ylmethoxy) benzyl
H ] thiazolidine-2,4-dione hydrochloride (1) 5- [4- (6-methoxy-1-methyl-1H-
Benzimidazol-2-ylmethoxy) benzyl] thio
Azolidine-2,4-dione (compound B) 5-methoxy-N-methyl-1,2-phenylenediamine (see Reference Example 9 of JP-A-9-295970) 2
1.8 g, 5- (4-methoxycarbonylmethoxybenzyl) thiazolidine-2,4-dione (JP-A-9-29)
No. 5970, Reference Example 21) 63.4 g, 1,4-
A mixture of 250 ml of dioxane and 750 ml of concentrated hydrochloric acid was heated under reflux for 60 hours. After the reaction mixture was ice-cooled, the precipitate was collected by filtration. 800 ml of a 5% aqueous sodium hydrogen carbonate solution was added to the precipitate, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was collected by filtration, dissolved in a mixed solution of N, N-dimethylformamide (1000 ml) and methanol (200 ml), and activated carbon was added to remove the color. After filtering off the activated carbon, the solvent was concentrated to about 50 ml. To this was added 750 ml of diethyl ether, and the mixture was allowed to stand at room temperature for 2 days. The precipitate was collected by filtration.
f-value = 0.68 (silica gel thin layer chromatography;
20.1 g of the target compound having (5% ethanol-methylene chloride solution) was obtained. (2) 5- [4- (6-methoxy-1-methyl-1H-
Benzimidazol-2-ylmethoxy) benzyl] thio
Azolidine-2,4-dione hydrochloride (Compound A) 5- [4- (6-Methoxy-1-methyl-) obtained in (1)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (compound B) 1
0.6 g and 4N hydrochloric acid-1,4-dioxane 100
The ml mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, ethyl acetate was added, and the precipitated product was collected by filtration and washed with ethyl acetate to obtain 11.0 g of the desired compound having a melting point of 275-277 ° C.

¹ H-nuclear magnetic resonance spectrum: δ (pp
m): in deuterated dimethyl sulfoxide, TMS as internal standard
¹ H-nuclear magnetic resonance spectrum (400 MHz) measured using (tetramethylsilane): δ (ppm) is as follows.

3.11 (1H, dd, J = 14 Hz and 9 Hz), 3.34 (1
H, dd, J = 14Hz and 4Hz), 3.89 (3H, s), 3.98 (3H, s),
4.91 (1H, dd, J = 9Hz and 4Hz), 5.64 (2H, s), 7.14
(2H, d, J = 9Hz), 7.15 (1H, d, J = 9Hz) 7.25 (2H, d, J
= 9Hz), 7.50 (1H, s), 7.70 (1H, d, 9Hz), 12.04 (1
H, s, disappeared by addition of D ₂ O).

[0030]

[Test example]

[0031]

Test Example 1 Biological Test Example Male spontaneously diabetic rats (ZDF / Gmi-fa / fa) aged 8 to 10 weeks were used.

The test compound was suspended in a 0.5% CMC solution and orally administered by gavage at a dose of 0.33 mg / ml / kg for 2 weeks.

[0033] The blood sugar level was measured according to a conventional method. That is, the tail (about 1 mm) of the tail of a rat was cut, and blood collected in a hematocrit tube anticoagulated with heparin was centrifuged.
(A & T) was measured.

The results of the test for the hypoglycemic effect of the compound of the present invention, Compound A, the non-administered group and Compound B are as shown in Table 1.

The values in Table 1 are the average values of the test results using six spontaneously diabetic rats (ZDF / Gmi-fa / fa).

[0036]

[Table 1]

From the results shown in Table 1, Compound A, which is the compound of the present invention, showed a better blood glucose lowering effect than Compound B, which is its free form.

In the non-administration group, the blood glucose level increased with time.

[0039]

[Test Example 2] Solubility test example JP 1st solution (7.0 g of hydrochloric acid in 2.0 g of sodium chloride)
And water to make 1000 mL) 200
Add 40 mg of Compound A or Compound B to the mL, and add 300 mg
The mixture was stirred with a stirrer at 37 ° C in a mL conical beaker. One hour later, 10 mL was sampled, and filtered using Acrodisc LC13 (PVDF, manufactured by Germaniscience). Discard the initial 3mL, then 7mL
Was placed in a test tube. Of this, 5 mL was accurately taken with a whole pipette, transferred to a test tube accurately containing 2 mL of methanol in advance, and mixed.

For quantification, the solubility was determined by HPLC using a calibration curve prepared as follows.

The calibration curve shows that the standard solution of Compound A in methanol was used at 400 μg / mL, 100 μg / mL, and 20 μg / mL.
2 mL of each standard solution.
Made by adding mL, mixing and quantifying using HPLC. HPLC conditions ・ Analysis column: L-column ODS (4.6 mmID × 15 cm, (goods))
・ Mobile phase: 0.01 mol / L acetate buffer (pH 5.0) / acetonitrile mixture (13: 7) ・ Flow rate: about 1.0 mL / min ・ Column temperature: 40 ℃ ・ Detector: UV absorption Photometer (measuring wavelength: 290 nm) The results are shown in Table 2.

[0042]

[Table 2]

From the results shown in Table 2, it was found that the solubility of Compound B, in which Compound B was converted to the hydrochloride, was remarkably improved as compared with Compound B.

[0044]

[Preparation Example] A preparation containing the compound A of the present invention as an active ingredient can be produced, for example, by the following method.

[0045]

Formulation Example 1 Powder 4 g of compound A, which is a compound of the present invention, 10 g of polyvinylpyrrolidone, and hydroxypropylmethylcellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.)
When 0.5 g is mixed and pulverized for 30 minutes using a vibration mill,
A powder is obtained.

[0046]

Formulation Example 2 Capsules 20 g of compound A and 20 g of polyvinylpyrrolidone are dissolved in a mixed solvent of 100 g of acetone and 100 g of ethanol, and the mixed solution is sprayed on 200 g of croscarmellose sodium using a fluidized bed granulator to obtain granules. . Hydroxypropyl methylcellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.) is added to 10 g of the granules.
Mix 0.1 g of lactose and 1.9 g of lactose. A gelatin capsule is then filled with 0.24 g of this mixture to give a capsule. The capsule contains 0.1 g of compound A per capsule.

[0047]

Formulation Example 3 Tablets 1 g of Compound A and 1 g of polyvinylpyrrolidone are dissolved in a mixed solvent of 5 g of acetone and 5 g of ethanol, and the organic solvent is distilled off under reduced pressure using a rotary evaporator. When the solid thus obtained is pulverized, fine particles are obtained. 1 g of the fine granules are added to crystalline cellulose.
25 g, low-substituted hydroxypropylcellulose
25 g, hydroxypropyl methylcellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.) 0.05
g, lactose 0.18 g and magnesium stearate
After mixing 0.2 g, the mixture is compressed using a tablet machine to give tablets.

[0048]

The compound of the present invention, 5- [4- (6-
Methoxy-1-methyl-1H-benzimidazole-2
-Ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride has excellent insulin resistance improving action, hypoglycemic action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, peroxidation It exhibits lipogenesis-suppressing action, PPAR-activating action, anti-osteoporosis action, leukotriene antagonism, adipocyte-promoting action, cancer cell growth inhibitory action, and calcium antagonism.

Accordingly, the compounds of the present invention are useful for treating diabetes, hyperglycemia, impaired glucose tolerance, diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, coronary artery disease), hyperlipidemia, obesity, Hypertension, fatty liver, arteriosclerosis, diseases caused by insulin resistance, gestational diabetes mellitus, polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease), atherosclerosis or ischemic heart disease Cell damage caused (eg, brain damage caused by stroke), gout, inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic Disease, asthma, GI ulcer, cachexia, autoimmune disease,
Pancreatitis), cancer, osteoporosis, cataract and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 5/50 A61P 5/50 9/08 9/08 9/10 9/10 101 101 9/12 9 / 12 15/00 15/00 19/06 19/06 19/10 19/10 27/02 27/02 29/00 29/00 35/00 35/00 // C07D 417/12 C07D 417/12 (72) Inventor Takashi Izumi 1-58, Hiromachi, Shinagawa-ku, Tokyo F-term within Sankyo Co., Ltd. 4C063 AA01 BB08 CC62 DD26 EE01 4C086 AA01 AA02 BC82 GA07 GA10 MA01 MA04 NA14 ZA33 ZA39 ZA40 ZA42 ZA45 ZA59 ZA68 ZA70 ZA70 ZA81 ZA89 ZA96 ZA97 ZB07 ZB11 ZB13 ZB15 ZB26 ZC03 ZC33 ZC35 ZC41

Claims (9)

[Claims] (1) 5- [4- (6-methoxy-1-methyl-)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient. (2) 5- [4- (6-methoxy-1-methyl-)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient, a prophylactic or therapeutic drug for hyperglycemia. (3) 5- [4- (6-methoxy-1-methyl-)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient, a prophylactic or therapeutic drug for impaired glucose tolerance. (4) 5- [4- (6-methoxy-1-methyl-)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient, a prophylactic or therapeutic drug for diabetic complications. (5) 5- [4- (6-methoxy-1-methyl-)
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient, a prophylactic or therapeutic agent for a disease caused by insulin resistance. 6. A method for preparing 5- [4- (6-methoxy-1-methyl-).
1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride as an active ingredient. 7. A method for producing a pharmaceutical composition for improving insulin resistance, which comprises preparing 5- [4- (6-methoxy-1).
-Methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride. 8. A method for preventing or treating hyperglycemia, comprising the steps of:
Use of the hydrochloride salt of [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione. 9. A drug for preventing or treating diabetes complications,
Use of the hydrochloride salt of 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.