AGENT FOR REDUCING VISCERAL FAT WEIGHT

Abstract

An FGF21 production promoting agent containing, as an active ingredient, a compound represented by the following formula (1):

##STR00001##

wherein each of R.sup.1 and R.sup.2, which may be identical to or different from each other, represents, for example, a hydrogen atom; each of R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b, which may be identical to or different from one another, represents, for example, a hydrogen atom or a halogen atom, or R.sup.3a and R.sup.3b or R.sup.4a and R.sup.4b may bond together to form an alkylenedioxy group; X represents an oxygen atom, a sulfur atom, or N—R.sup.5 (R.sup.5 represents, for example, a hydrogen atom or a C.sub.1-4 alkyl group); Y represents, for example, an oxygen atom, an S(O).sub.l group (l is a number of from 0 to 2), or a carbonyl group; Z represents CH or N; n is a number of from 1 to 6; and m is a number from 2 to 6, a salt of the compound, or a solvate of the compound or the salt.

Claims

1. A method for reducing visceral fat weight comprising administering, to a subject in need thereof, a compound represented by the following formula (1): ##STR00003## wherein each of R.sup.1 and R.sup.2, which may be identical to or different from each other, represents a hydrogen atom, a methyl group, or an ethyl group; each of R.sup.3a, R.sup.3b, R.sup.4a and R.sup.4b, which may be identical to or different from one another, represents a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a C.sub.1-4 alkyl group, a trifluoromethyl group, a alkoxy group, a C.sub.1-4 alkylcarbonyloxy group, a di-C.sub.1-4 alkylamino group, a C.sub.1-4 alkylsulfonyloxy group, a C.sub.1-4 alkylsulfonyl group, a C.sub.1-4 alkylsulfinyl group, or a C.sub.1-4 alkylthio group, or R.sup.3a and R.sup.3b or R.sup.4a and R.sup.4b may bond together to form an alkylenedioxy group; X represents an oxygen atom, a sulfur atom, or N—R.sup.5 (R.sup.5 represents a hydrogen atom, a C.sub.1-4 alkyl group, a C.sub.1-4 alkylsulfonyl group, or a C.sub.1-4 alkyloxycarbonyl group); Y represents an oxygen atom, an S(O).sub.l group (l is a number of from 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group; Z represents CH or N; n is a number of from 1 to 6; and m is a number of from 2 to 6, a salt of the compound, or a solvate of the compound or the salt.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows the effect of compound A or fenofibrate on plasma triglyceride (TG) level.

[0056] FIG. 2 shows the effect of compound A or fenofibrate on plasma FGF21 level.

[0057] FIG. 3 shows the correlation between plasma FGF21 level and plasma triglyceride (TG) level in the case of administration of compound A or fenofibrate.

[0058] FIG. 4 shows the effect of compound A or fenofibrate on epididymal fat weight.

MODES FOR CARRYING OUT THE INVENTION

[0059] Examples of the halogen atom represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b in formula (1) include a fluorine atom, a chlorine atom, and a bromine atom. Of these, a fluorine atom and a chlorine atom are particularly preferred.

[0060] Examples of the C.sub.1-4 alkyl group represented by R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, or R.sup.5 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a butyl group. Of these, a methyl group is particularly preferred.

[0061] Examples of the C.sub.1-4 alkoxy group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and a butoxy group. Of these, a methoxy group is particularly preferred.

[0062] Examples of the C.sub.1-4 alkylcarbonyloxy group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a methylcarbonyloxy group, an ethylcarbonyloxy group, an n-propylcarbonyloxy group, an isopropylcarbonyloxy group, and a butylcarbonyloxy group. Of these, a methylcarbonyloxy group is particularly preferred.

[0063] Examples of the di-C.sub.1-4 alkylamino group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a dimethylamino group, a diethylamino group, and a diisopropylamino group. Of these, a dimethylamino group is particularly preferred.

[0064] Examples of the C.sub.1-4 alkylsulfonyloxy group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a methylsulfonyloxy group and an ethylsulfonyloxy group. Of these, a methylsulfonyloxy group is particularly preferred.

[0065] Examples of the C.sub.1-4 alkylsulfonyl group represented by R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, or R.sup.5 include a methylsulfonyl group and an ethylsulfonyl group. Of these, a methylsulfonyl group is particularly preferred.

[0066] Examples of the C.sub.1-4 alkylsulfinyl group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a methylsulfinyl group and an ethylsulfinyl group. Of these, a methylsulfinyl group is particularly preferred.

[0067] Examples of the C.sub.1-4 alkylthio group represented by R.sup.3a, R.sup.3b, R.sup.4a, or R.sup.4b include a methylthio group and an ethylthio group. Of these, a methylthio group is particularly preferred.

[0068] Examples of the alkylenedioxy group formed through bonding of R.sup.3a and R.sup.3b or bonding of R.sup.4a and R.sup.4b include a methylenedioxy group and an ethylenedioxy group. Of these, a methylenedioxy group is particularly preferred.

[0069] Examples of the C.sub.1-4 alkyloxycarbonyl group represented by R.sup.5 include a methyloxycarbonyl group and an ethyloxycarbonyl group. Of these, a methyloxycarbonyl group is particularly preferred.

[0070] It is particularly preferred when both R.sup.1 and R.sup.2 are hydrogen atoms or methyl groups, or when R.sup.1 and R.sup.2 are a methyl group and a hydrogen atom, respectively, or are an ethyl group and a hydrogen atom, respectively.

[0071] X represents an oxygen atom, a sulfur atom, or N—R.sup.5, and is preferably an oxygen atom. Y represents an oxygen atom, S(O).sub.l, a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group, and is preferably an oxygen atom. Z represents CH or N, and is preferably CH. In formula (1), l is a number of from 0 to 2 (preferably 2); n is a number of from 1 to 6 (preferably a number of from 1 to 3); and m is a number of from 2 to 6 (preferably 2 to 4, particularly preferably 2 or 3).

[0072] Among compounds of the present invention, a more preferred compound is (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid or (R)-2-[3-[[N-(5-fluorobenzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]butyric acid.

[0073] The compound of the present invention represented by formula (1) may be produced through, for example, the method described in WO 2005/023777.

[0074] The present invention may employ a salt or solvate of the compound represented by formula (1). The salt or the solvate may be produced through a customary method.

[0075] No particular limitation is imposed on the salt of the compound of the present invention represented by formula (1), so long as it is a pharmaceutically acceptable one. Examples of the salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate.

[0076] Examples of the solvate of the compound of the present invention represented by formula (1) or the salt of the compound include a hydrate and an alcohol solvate (e.g., ethanol solvate).

[0077] The compound of the present invention represented by formula (1) has an asymmetric carbon atom, and thus has optical isomers (R-isomer and S-isomer). The present invention encompasses all the optical isomers.

[0078] As described in the Examples hereinbelow, the compound represented by formula (1) exhibited the effect of markedly reducing plasma triglyceride level and the effect of significantly increasing plasma FGF21 level in an evaluation system employing KK-Ay mice or hyperlipidemic Zucker fatty rats with obesity due to overeating. In addition, the compound significantly reduced visceral fat weight. Therefore, the drug of the present invention is useful for prevention and/or treatment of obesity (in particular, visceral fat obesity) or metabolic syndrome associated with visceral fat obesity.

[0079] The compound of the present invention represented by formula (1), a salt of the compound, or a solvate of the compound or the salt may be prepared, by itself or in combination with a pharmaceutically acceptable carrier, into a variety of dosage forms, including tablet, capsule, granule, powder, lotion, ointment, injection, and suppository. Such a drug product may be produced through any known method. For example, when the compound is provided in the form of a peroral product, the product may be produced by appropriately formulating the compound in combination with, for example, a solubilizer (e.g., tragacanth gum, gum arabic, sucrose fatty acid ester, lecithin, olive oil, soybean oil, or PEG 400), an excipient (e.g., starch, mannitol, or lactose), a binder (e.g., carboxymethylcellulose sodium or hydroxypropylcellulose), a disintegrant (e.g., crystalline cellulose or carboxymethylcellulose calcium), a lubricant (e.g., talc or magnesium stearate), or a fluidity-improving agent (e.g., light silicic anhydride).

[0080] The compound of the present invention represented by formula (1), a salt of the compound, or a solvate of the compound or the salt is orally or parenterally administered. The dose of the drug of the present invention may vary with the body weight, age, sex, symptom, etc. of a patient in need thereof. Generally, the daily dose of compound (1) for an adult is 0.01 to 1,000 mg, preferably 0.1 to 100 mg. Preferably, the daily dose is administered in a divided manner (once to thrice a day).

EXAMPLES

[0081] The present invention will next be described in more detail by way of examples, which should not be construed as limiting the invention thereto.

Example 1 Effects on Zucker Fatty Rat

[0082] This test employed (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (hereinafter will be referred to as “compound A”), which is an optically active substance of the compound disclosed in Example 14 in Patent Document 2. Compound A or fenofibrate was administered to Zucker fatty rats, and the effects of the compound on plasma triglyceride (TG) level, plasma FGF21 level, and epididymal fat weight were determined through the below-described methods.

1. Test Animal and Rearing Environment

[0083] Hyperlipidemic Zucker fatty rats with obesity due to overeating (Crlj: ZUC-Lepr<fa> Genotype: fa/fa) and Zucker lean rats without obesity (Crlj: ZUC-Lepr<fa> Genotype: fa/+ or +/+) were purchased from Charles River Laboratories Japan Inc. (eight weeks old upon test).

[0084] Throughout the test period, the rats were reared in a rearing cage (light-dark cycle (light period by interior lighting: 7:00 a.m. to 7:00 p.m.), temperature: 23±3° C., humidity: 55±15%) under conditions where solid feed (CE-2, product of Oriental Yeast Co., Ltd.) and tap water were fed ad libitum.

2. Drug Preparation

[0085] Each of compound A and fenofibrate was suspended in a 0.5 mass % aqueous solution of methylcellulose (Metolose (registered trademark), SM-400, product of Shin-Etsu Chemical Co., Ltd.) so that the dose of the aqueous solution was adjusted to 2 mL/kg. The resultant suspension was refrigerated in a light-shielding bottle at 4° C., and drug preparation was carried out every seven days.

3. Test Method

[0086] Rats were divided into the following four groups (six rats per group) so that body weights, plasma total cholesterol levels, and plasma triglyceride levels were averaged in the groups: a first group (control), a second group (administration of compound A (1 mg/kg)), a third group (administration of compound A (3 mg/kg)), and a fourth group (administration of fenofibrate (300 mg/kg)). A group of five Zucker lean rats was employed as a negative control group.

[0087] Each drug was orally administered once a day (in the morning) for continuous 14 days. A 0.5 mass % aqueous methylcellulose solution (2 mL/kg) was orally administered to the rats of the first group (control).

[0088] On day 14 after initiation of administration, blood was collected after four-hour fasting following administration, and plasma triglyceride level and plasma FGF21 level were measured through an enzymatic method and ELISA (Human FGF-21 ELISA Kit, product of Biovender), respectively. On the day following blood collection, laparotomy was performed under anesthesia, and then epididymal fat was removed and weighed. Epididymal fat weight is highly correlated with total visceral fat weight, and thus is employed as an indicator for evaluating the effect of a drug on visceral fat weight (FASEB J. 20, 1203-1205 (2006)).

4. Statistical Analysis and Data Processing Method

[0089] The results were represented as mean values ±standard deviation. Comparison between the control group and the Zucker lean rat group was carried out by means of unpaired Student's t-test, and comparison between the control group and each drug administration group was carried out by means of Dunnett's multiple comparison test or Tukey's multiple comparison test (significant difference was considered for p<0.05).

5. Test Results

[0090] FIG. 1 shows data of plasma triglyceride level. Data on the horizontal axis correspond, from left to right, to the first group (control), the second group (administration of compound A (1 mg/kg)), the third group (administration of compound A (3 mg/kg)), the fourth group (administration of fenofibrate (300 mg/kg)), and the negative control group (Zucker lean rat). In FIG. 1, the symbol “*” represents a significant difference (p<0.05), and the symbol “#” represents a significant difference (p<0.001).

[0091] As shown in FIG. 1, the plasma triglyceride level in the third group was significantly (p<0.05) lower than that in the control group; i.e., compound A clearly exhibited the effect of reducing plasma triglyceride level. In contrast, the plasma triglyceride level in the fourth group was only slightly lower than that in the control group.

[0092] FIG. 2 shows data of plasma FGF21 level. Data on the horizontal axis correspond, from left to right, to the first group (control), the second group (administration of compound A (1 mg/kg)), the third group (administration of compound A (3 mg/kg)), the fourth group (administration of fenofibrate (300 mg/kg)), and the negative control group (Zucker lean rat). In FIG. 2, the symbol “***” represents a significant difference (p<0.001).

[0093] As shown in FIG. 2, the plasma FGF21 level in the third group was significantly (p<0.001) higher than that in the control group; i.e., compound A clearly exhibited the effect of promoting production of plasma FGF21. In contrast, the plasma FGF21 level in the fourth group was only slightly higher than that in the control group (P=0.2).

[0094] FIG. 3 shows the correlation between plasma triglyceride level and plasma FGF21 level. As shown in FIG. 3, a significant negative correlation is observed between them.

[0095] The aforementioned data indicate that, in the present animal model, compound A exhibits the effect of reducing plasma TG level and the effect of markedly enhancing expression of FGF21 (i.e., a new glucose/lipid metabolism-improving factor), and suggest that compound A can ameliorate lipid metabolism even in a pathological condition with highly abnormal lipid metabolism, by increasing plasma FGF21 level therein.

[0096] FIG. 4 shows the results of measurement of epididymal fat weight, which is an indicator of visceral fat weight. As shown in FIG. 4, the epididymal fat weight in the group of compound A administration (3 mg/kg) was considerably and statistically significantly lower than that in the control group (*: p<0.05). During the period of compound A administration, adverse events were not particularly observed. In contrast, fenofibrate exhibited only a slight effect on epididymal fat weight, and a statistically significant difference was not observed between the epididymal fat weight in the group of fenofibrate administration and that in the control group. As has been reported, when fenofibrate is administered to rats at a dose of 30 mg/kg or more, various adverse events occur in the rats (Non-Patent Document 9). In the rats of the group of fenofibrate administration (300 mg/kg), feed intake was maintained equal to that in the rats of the control group for 10 days after administration. However, from 11 days to 14 days after administration, feed intake was reduced by 14% in the rats of the group of fenofibrate administration, which raised a concern about the toxicity of fenofibrate. Even under such a situation, fat weight tended to decrease only slightly.

[0097] The aforementioned data indicate that compound A markedly enhances production of FGF21 and thus potently reduces visceral fat weight. Also, the data indicate that these effects of compound A were clearly higher than those of fenofibrate (i.e., an existing fibrate and the most excellent PPARα agonist), and that compound A exhibits high safety.

Example 2 Visceral Fat Weight Reducing Effect on KK-Ay Mice

[0098] This test employed compound A, as well as (R)-2-[3-[[N-(5-fluorobenzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]butyric acid (hereinafter will be referred to as “compound B”), which is an optically active substance of the compound disclosed in Example 229 in Patent Document 2. Compound A, compound B, or fenofibrate was administered to KK-Ay mice, and the effects of the compound on epididymal fat weight and mesenteric fat weight were determined through the below-described methods.

1. Test Animal and Rearing Environment

[0099] Method: Male KK-Ay mice (KK-Ay/TaJcl) were purchased from Clea Japan, Inc. (10 weeks old upon test). Each compound was orally administered to mice once a day for four weeks. Throughout the test period, the mice were reared in a rearing cage (light-dark cycle (light period by interior lighting: 7:00 a.m. to 7:00 p.m.), temperature: 23±3° C., humidity: 55±15%) under conditions where solid feed (CE-2, product of Oriental Yeast Co., Ltd.) and tap water were fed ad libitum.

2. Drug Preparation

[0100] Each of compound A, compound B, and fenofibrate was suspended in a 0.5 mass % aqueous solution of methylcellulose (Metolose (registered trademark), SM-400, product of Shin-Etsu Chemical Co., Ltd.) so that the dose of the aqueous solution was adjusted to 5 mL/kg. The resultant suspension was refrigerated in a light-shielding bottle at 4° C., and drug preparation was carried out every seven days.

3. Test Method

[0101] Animals were divided into the following four groups (six animals per group): a first group (control), a second group (administration of compound A (1 mg/kg)), a third group (administration of compound B (3 mg/kg)), and a fourth group (administration of fenofibrate (300 mg/kg)).

[0102] Each drug was orally administered once a day (in the morning) for 35 days. A 0.5 mass % aqueous methylcellulose solution was orally administered (5 mL/kg) to the animals of the first group (control).

[0103] After completion of administration, epididymal fat and mesenteric fat were removed and weighed.

4. Statistical Analysis and Data Processing Method

[0104] The results were represented as percent reduction (mean value) in fat weight in each compound administration group with respect to the control group.

5. Test Results

[0105] Table 1 shows the results. In the group of compound A administration (1 mg/kg) or the group of compound B administration (3 mg/kg), a more potent fat weight reducing effect was observed, as compared with the group of fenofibrate administration (300 mg/kg). During the period of compound A or compound B administration, adverse events were not particularly observed.

TABLE-US-00001 TABLE 1 Fat weight reducing effect on obesity model mice (KK-Ay mice) Compound A Compound B Fenofibrate Compound (dose) (1 mg/kg) (3 mg/kg) (300 mg/kg) Epididymal fat weight 27% — 15% Mesenteric fat weight 20% 17% 13% —: Not measured