JPH10273441A - Body heat production promotive agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject promotive agent which has promotive effective for producing body heat and is useful for prevention or treatment for obesity or diabetic saccharide by formulating a compound which processes a specific partial structure and shows vitamin B1 effect. SOLUTION: The objective promotive agent is obtained by formulating a compound which has a partial structure of formula I (R<1> is an alkyl) and shows vitamin B1 effect, preferably a compound (salt) of formula II [R<2> is a (substituted) hydrocarbon group which may be linked through thio groups]. In the formula II, R<1> is preferably methyl group and R<3> is preferably a (phenyl) 1-7C alkyl or a (phenyl) 2-7C alkenyl. As the compound of formula II, e.g. N-(4- amino-2-methyl-5-pyrimidinyl) methyl-N-(2-allyldithio-4-hydroxy-1-methyl-1-butenyl) formamide is favorable. The compound of formula I is usually contained in the promotive agent in a proportion of 0.01-100 wt.%. The promotive agent is low in toxicity, high in safety and excellent in absorbency and stability and possesses catecholamine secretory effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a body heat production enhancer containing a compound having a vitamin B ₁ action.

[0002]

BACKGROUND OF THE INVENTION Obesity is associated with diabetes, hypertension, hyperlipidemia,
It is a major risk factor for arteriosclerosis and ischemic heart disease. Therapy has been diet therapy, exercise therapy, surgery and drug therapy (appetite suppressants, drugs that inhibit intestinal absorption of dietary components, hormones that increase metabolism).
Has been done. Recently, along with the progress of research on brown adipose tissue having a high thermogenic function, it has been revealed that the present tissue plays an important role in the pathogenesis or control of obesity. Iwai and colleagues focused on the body heat-producing effect of the pungent component and found that capsicin, a pepper component (J. Nutr., 11).
6, 1272-1278, (1986), Proc.Soc.Exp.Biol.Med.,
183, 250-256, (1986), Argic. Biol. Chem., 51, 75-7.
9, (1987)) and the garlic component diallyl disulfide (J. Nutr. Biochem., 6, 250-255, (1995)) activates the sympathetic nervous system and promotes the secretion of catecholamines, resulting in energy metabolism. And promotes lipid metabolism. On the other hand, vitamin B ₁ derivatives JP-B-29-1287, JP-B-29-1484, JP-B-29-1840, JP-B-29-2186, JP-B 2
9-2187, JP-B-29-7728, JP-B-35
-13023, JP-B-43-19549, JP-B-4
Nos. 4-18864 and JP-B-49-6911 disclose that these derivatives have an effect of enhancing body heat production or are useful as agents for preventing or treating obesity or diabetes. Not.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a preventive or therapeutic agent having an effect of enhancing body heat production and useful for obesity or diabetes.

[0004]

The present inventors Means for Solving the Problems] As a result of extensive research per prophylactic or therapeutic agent for body heat production promoting agent or obesity or diabetes, surprisingly allyl thiamine sulfide compound is a compound having vitamin B ₁ activity The present invention was also found to be effective. That is, the present invention relates to (1) Formula (I)

Embedded image [Wherein, R ¹ represents an alkyl group. And (2) a vitamin, which comprises a compound having a partial structure represented by the following formula (1) and having a vitamin B ₁ action (hereinafter sometimes abbreviated as compound (I)): The compound having B ₁ action is represented by the formula (II)

Embedded image [In the formula, R ¹ represents an alkyl group, and R ² represents a hydrocarbon group which may be substituted via thio and may be substituted. (1) wherein R ¹ is a methyl group, or a salt thereof (hereinafter may be abbreviated as compound (II)); (4) The body heat production enhancer according to the above (1), wherein R ² is an alkyl group or an alkenyl group which may be thio and may be substituted. ) R ²
Is a C _1-7 alkyl group or a C _2-7 alkenyl group which may be via a thio group and may be substituted with a phenyl group;

Equation (6)

Embedded image [Wherein, R ¹ represents an alkyl group. It has a partial structure represented by], and to a prophylactic or therapeutic agent for obesity or diabetes, characterized by containing a compound having vitamin B ₁ activity. Here, as the compound (I), for example, a compound represented by the formula (Ia)

Embedded image Wherein R ³ is a protecting group for a hydrogen atom or a hydroxyl group, R ⁴ is a protecting group for a hydroxyl group, a mercapto group or a formula —SR ² (the symbols in the formula have the same meanings as described above) And the other symbols have the same meanings as described above, and R ³ and R ⁴ may be bonded to each other. Or a salt thereof (hereinafter may be abbreviated as compound (Ia));

Embedded image [The symbols in the formula are as defined above. Or a salt thereof (hereinafter may be abbreviated as compound (Ib)). In the above formula, R ¹ represents an alkyl group.

The “alkyl group” represented by R ¹ includes:
For example, a C _1-7 alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl and the like are used, and among them, methyl is preferable. In the above formula, R ² may be a thio-substituted or optionally substituted hydrocarbon group. As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R ² , for example, a C _1-7 alkyl group (eg, methyl, ethyl, n-propyl, iso
-Propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, etc.),
A C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _{3-8
A 2-7} alkenyl group (eg, vinyl, allyl, 2-butenyl, 3-butenyl, etc.), a C _2-7 alkynyl group (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.), C _3-8
A cycloalkenyl group (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.), a C _6-10 aryl group (eg, phenyl, naphthyl, etc.), a C _7-13 aralkyl group (eg, phenyl-C _1-6 alkyl such as benzyl, phenethyl, etc.) Etc.) are used.

Such a hydrocarbon group can be substituted at a substitutable position, for example, (1) nitro group, (2) hydroxyl group, (3) oxo group, (4)
Thioxo group, (5) cyano group, (6) carbamoyl group, (7) carboxyl group, (8) _C1-7 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), (9) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (1
0) a C _1-7 alkoxy group (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, etc.), (11) phenoxy group, (12) halogenophenoxy group (for example, 1 to 3 such as o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy) pieces halogen substituted phenoxy, etc.), (13) C _1-7 alkylthio group (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert- butylthio, etc.), (14) phenylthio group, (15) C _{1 A -7} acylthio group (eg, C _1-7 alkanoylthio such as acetylthio), (16) a C _1-7 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.),

(17) C _1-7 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc., propylsulfonyl, butylsulfonyl, etc.), (18) amino group, (19) C
_1-7 acylamino group (such as acetylamino, C _{1 -7} alkanoylamino such as propionylamino), (20) mono- - or di -C _1-7 alkylamino group (e.g. methylamino, ethylamino, propylamino, isopropyl Amino, butylamino, dimethylamino, diethylamino and the like), (21) C _1-7 acyl group (for example, C _1-7 alkanoyl such as formyl and acetyl, benzoyl and the like), (22) (a) halogen atom (for example, fluorine, Chlorine, bromine, iodine, etc.),
(b) a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and (c) a halogenophenoxy group (eg, o-, m- or p-chlorophenoxy, o-,
phenoxy substituted with 1 to 3 halogens such as m- or p-bromophenoxy, etc.), and may have 1 to 4 substituents. A 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from atoms and oxygen atoms (for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, thienyl, thiazolyl, Isothiazolyl, thiadiazolyl, furyl,
Oxazolyl, isoxazolyl, oxadiazolyl,
Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,
Triazinyl, piperidyl, piperazinyl, pyridazinyl, pyrazinyl, thiazinyl, thiomorpholinyl, morpholinyl, pyranyl, furyl, tetrahydrofuryl, oxazinyl and the like, and (23) a halogeno-C _1-7 alkyl group (for example, difluoromethyl, trifluoromethyl, trifluoromethyl) And 1 to 5 substituents selected from 1 to 3 halogen-substituted C _1-6 alkyl such as ethyl and trichloroethyl.

The hydrocarbon group may also be a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.)
A C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-8
6-10 aryl group (eg phenyl, naphthyl, etc.) or C
_{A 7-12} aralkyl group (for example, phenyl-C _1-6 alkyl such as benzyl and phenethyl) is substituted with 1 to 4
You may have one. As R ² , a thio group may be used, and an alkyl group or an alkenyl group which may be substituted is preferable. Among them, C _1-7 which may be thio and may be substituted with a phenyl group An alkyl group or a C _2-7 alkenyl group is preferred. In the above formula, R ³
The hydrogen atom or a hydroxyl protecting group, the R ⁴ is a hydroxyl group, a mercapto-protecting group, or the formula -S-R ² (R ² may be the through thio, optionally substituted hydrocarbon group )
Wherein R ³ and R ⁴ may be bonded to each other.

[0010] "hydroxyl protecting group" represented by R ³ and R ⁴
Examples of the "protecting group for a mercapto group" include a _C1-7 alkyl group (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-
Butyl, n-pentyl, n-hexyl, n-heptyl, etc.), C _1-7 acyl group (eg, C _1-7 alkanoyl such as formyl, acetyl, benzoyl, etc.), phosphono group, mono- or di-C _{1-. 7} alkoxyphosphoryl groups (for example, diethoxyphosphoryl and the like) and the like. R ³ and R ⁴ are bonded to each other to form

Embedded image [The symbols in the formula are as defined above. Represented by the formula

Embedded image May be formed.

The compound (I) which is an active ingredient of the present invention is preferably a compound (Ia) or (Ib), particularly preferably a compound having a disulfide or trisulfide bond as a partial structure (eg, a compound (II)). In particular, an allylthiamine disulfide compound having a disulfide bond is preferable. Specific examples of compound (II) include compound 1: N- (4-amino-2-methyl-5-pyrimidinyl) methyl-N- (2-allyldithio-4-hydroxy-1-methyl-1-butenyl) formamide, Compound 2: N- (4-amino-2-methyl-5-pyrimidinyl) methyl-N- (4-hydroxy-2-isopropyldithio-1-methyl-1-butenyl) formamide, Compound 3: N- (4- Amino-2-methyl-5-pyrimidinyl) methyl-N- (2-propyltrithio-4-hydroxy-1-methyl-1-butenyl) formamide, Compound 4: N- (4-amino-2-methyl-5) -Pyrimidinyl) methyl-N- (2-benzyldithio-4-hydroxy-1-methyl-1-butenyl) formamide, Compound 5: N- (4-amino-2-methyl-5) Pyrimidinyl) methyl -N- (4- hydroxy-1-methyl -
2-propyldithio-1-butenyl) formamide, compound 6: N- (4-amino-2-methyl-5-pyrimidinyl) methyl-N- [4-hydroxy-2- (2-hydroxyethyldithio) -1- Methyl-1-butenyl]
Formamide, compound 7: N- (4-amino-2-methyl-5-pyrimidinyl) methyl-N- (2-ethyldithio-4-hydroxy-1-methyl-1-butenyl) formamide, compound 8: N- (4 -Amino-2-methyl-5-pyrimidinyl) methyl-N- [4-hydroxy-1-methyl-
2- (2-phenylethyldithio) -1-butenyl] formamide, compound 9: N- (4-amino-2-methyl-5-pyrimidinyl) methyl-N- [4-hydroxy-1-methyl-
2- (3-phenylpropyldithio) -1-butenyl]
Formamide and the like are preferred.

The compound (I) which is an active ingredient of the present invention comprises
Methods known per se, for example, JP-B-29-1287, JP-B-29-1484, JP-B-29-1840, JP-B-29-2186, JP-B-29-2187, and JP-B-29
No. 9-7728, Japanese Patent Publication No. 35-13023, Japanese Patent Publication No. 4
It can be produced by the method described in, for example, JP-A-3-19549, JP-B-44-18864, JP-B-49-6911, and JP-B-49-9471, or according to the method. Compound (I) is usually a salt with an acid such as an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
For example, salts with organic acids such as acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, toluenesulfonic acid and methanesulfonic acid, or salts with bases such as salts with alkali metals such as sodium and potassium, For example, it may be used in the form of a pharmacologically acceptable salt such as a salt with an alkaline earth metal such as calcium and magnesium.
When stereoisomers may exist in compound (I), these individual isomers and mixtures thereof are, of course, included in the scope of the present invention. If desired, these isomers may be produced individually. Can also. The compound (I) may be a hydrate, and both a hydrate and a non-hydrate are included in the scope of the present invention. The body heat production enhancer of the present invention containing the compound (I) has low toxicity, high safety, excellent absorption and stability, secretes catecholamine, and has an action of promoting body heat production. Therefore, it promotes energy metabolism and lipid metabolism and lowers plasma lipids, thereby preventing obesity in mammals including humans (eg, mice, rats, guinea pigs, dogs, monkeys, cats, horses, rabbits, humans, etc.) or Diseases that can be used for treatment and are associated with obesity (eg, diabetes, hypertension, hyperlipidemia,
It is also effective in preventing or treating arteriosclerosis, adult diseases such as ischemic heart disease, etc.). It is also useful for chills.

In the present invention, together with compound (I),
Other pharmaceutically active ingredients effective for obesity or diseases associated with obesity may be used in combination. Such pharmaceutically active ingredients include, for example, insulin sensitivity enhancers, α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrate compounds, LDL catabolism promoters, angiotensin conversion Examples include an enzyme inhibitor, an insulin secretagogue, an insulin preparation and the like. When compound (I) is used in combination with a drug having the same or different pharmacological action, two or more drugs may be blended in the same preparation, and the same preparation (eg, powder, injection, etc.) at the time of administration It can also be compounded inside. Further, separately formulated drugs may be administered to the same subject separately, simultaneously or at staggered times. The dosage of the preparation of the present invention varies depending on the target disease, symptoms, administration target, administration method, patient condition and weight, administration route, and the like.
For example, when administered as a therapeutic agent for obesity or diabetes in an adult (body weight: about 60 kg), 5 to 5000 mg / person, preferably 5 to 5000 mg / day as compound (I) as an active ingredient by oral administration.
0 to 500 mg / person, intravenously 0.5 to 500 mg / person
Human, preferably 5 to 200 mg / person once or twice daily
It is preferable to administer the drug in three or three divided doses. The preparation of the present invention comprises compound (I) alone or in combination with a pharmaceutically acceptable carrier, and as an oral preparation, for example, a liquid preparation, an extract preparation, an elixir, a suspension / emulsion, a syrup, a capsule, Parenteral preparations such as granules, pills, powders, tablets (including sugar-coated tablets and film-coated tablets), for example, injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), infusions And external preparations (eg, transnasal preparations, transdermal preparations, ointments, etc.) and suppositories (eg, rectal suppositories, vaginal suppositories, etc.).

The content of the compound (I) in the preparation of the present invention is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight. Pharmaceutically acceptable carriers that may be included in the formulation of the present invention include:
For example, excipients (eg, calcium carbonate, kaolin, sodium bicarbonate, lactose, starches (eg, corn starch), crystalline cellulose (eg, microcrystalline cellulose), talc, sucrose, light silicic anhydride, etc.), coloring agents (eg, Tar dyes, caramel, iron sesquioxide, titanium oxide, riboflavins, etc., lubricants (eg, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), binders (eg, dextrin, rubbers (gum arabic) ), Pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrants (eg, carboxymethylcellulose calcium, croscarmellose sodium, crospopidone, low-substituted hydroxypropylcellulose, Far starch, etc.), coating agents (such as talc, gum arabic, titanium oxide, white sugar (sucrose), precipitated calcium carbonate, etc.), solvents (such as purified water, distilled water, saline, aqueous solvents Ringer's solution or the like,
For example, vegetable oils such as olive oil, sesame oil, cottonseed oil and corn oil, oily solvents such as propylene glycol, etc.), stabilizers (eg, sodium sulfite), preservatives (eg, parabens, sorbic acid, etc.), flavoring agents (eg, DL-apple) Acid, citric acid, sodium citrate, lactic acid, honey,
Tartaric acid, sucrose (sucrose), fructose, sodium chloride, L-
Sodium glutamate, etc.), flavoring agents (eg, cherry flavor), preservatives (eg, butyl paraoxybenzoate, benzoic acid), solubilizing agents (eg, sodium salicylate, sodium acetate, etc.), soothing agents (eg, benzalco chloride) , Procaine hydrochloride, etc.), dispersants (eg, Tween 60, polyethylene glycol, carboxymethyl cellulose, etc.), tonicity agents (eg, sodium chloride,
Glycerin, sorbitol, glucose, invert sugar, etc.) and the like. For example, an oral preparation is produced by adding a carrier such as an excipient, a disintegrant, a binder, a lubricant and the like to an active ingredient and formulating the preparation by a method known per se.
If necessary, it may be coated by a method known in the art of autonomy for the purpose of taste masking, enteric coating or sustainability.
For example, injections are produced by dissolving, suspending and emulsifying the active ingredient in a solvent together with a dispersing agent, a preservative, an isotonic agent and the like. If necessary, a solubilizer, a stabilizer, a soothing agent and the like may be added. For example, sustained release agents include tablets, granules, fine granules, capsules, etc. by means known per se using, for example, fats and oils (eg, triglycerides and the like), fatty acid esters such as polyglycerin, hydroxypropylcellulose and the like. It can be manufactured by coating. For example, suppositories and external preparations are produced by a method known per se by converting the active ingredient into a solid, semi-solid or liquid composition.

The thermogenesis enhancer of the present invention comprises the compound (I)
In addition to, it may have other active ingredients, as such active ingredients, for example vitamin A (retinol palmitate, etretinate, etc.), vitamin B ₁ class (oct thiamine, prosultiamine, full Suruchiamin, fursultiamine hydrochloride, bisbentiamine, benfotiamine, Shikochiamin, hydrochloric dicethiamine, cocarboxylase, etc.), vitamin B ₂ compounds (riboflavin, riboflavin butyrate, riboflavin sodium phosphate, flavin adenine dinucleotide sodium, etc.), nicotine acids (nicotinamide, etc.), pantothenic acid (B ₅₎ compounds (calcium pantothenate, pantothenol, pantethine, etc.), vitamin B ₆ compound (pyridoxine hydrochloride, pyridoxal phosphate, etc.), vitamin B ₁₂ compound (hydroxocobalamin acetate Hidorokisoko Ramin, cyanocobalamin,
Mecobalamin, cobalamide, etc.), folic acid, vitamin Cs (ascorbic acid, etc.), vitamin Ds (ergocalciferol, alfacalcidol, calcitriol,
Dihydrotaxerol), vitamin Es (tocopherol acetate), vitamin Ks (phytonadione, menatrenone, etc.), vitamin Hs (biotin, etc.), gamma-oryzanol, caffeine anhydride, sodium L-aspartate, aminoethylsulfonic acid, Sodium chondroitin sulfate;

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Experimental Example 1 Effect of Compound (I) on Catecholamine Secretion Method: Rats (SD male, 7 weeks old) were anesthetized with urethane α-chloralose, and control solutions (2% ethanol and 1% Tw) were used.
1 ml of 0.9% NaCl solution containing een 80) or 1 of compound 1
0, 20, or 30 mmol / ml solution (dissolved in control solution) 1 ml
Was administered from the right femoral vein of rats. Ten minutes after administration, blood was collected from the abdominal vena cava, and blood catecholamines (plasma norepinephrine and epinephrine concentrations) were measured by HPLC. Results: As shown below, Compound 1 administration increased plasma norepinephrine and epinephrine concentrations in a dose-dependent manner.

[Table 1] From these results, it is clear that Compound (I) increases catecholamine secretion in a dose-dependent manner.

Experimental Example 2 Effect of Compound (I) on Catecholamine Secretion Method: A rat (SD male, 7 weeks old) was anesthetized with urethane α-chloralose, and a control solution (2% ethanol and 1% Tw) was used.
1 ml of a 0.9% NaCl solution containing een 80) or 1 ml of a 10 mmol / ml solution of each of compounds 1, 3, 5, 6 or 7 (dissolved in a control solution) was administered from the right femoral vein of the rat. Administration 1
0 minutes later, blood was collected from the abdominal vena cava, and blood catecholamines (plasma norepinephrine and epinephrine concentrations) were analyzed by HP
It was measured by the LC method. Results: As shown below, administration of compound 1, 3, 5, 6, or 7 increased plasma norepinephrine and epinephrine concentrations.

[Table 2] From these results, it is clear that various compounds (I) increase catecholamine secretion.

Experimental Example 3 Effect of Compound (I) on Body Thermogenesis Method: Rats (SD male, 7 weeks old) were anesthetized with urethane α-chloralose. The tip of the temperature sensor was fixed to the interscapular brown adipose tissue and rectum of the rat, and after the body temperature was kept constant, a 10 mmol / L solution of Compound 1 (dissolved in the control solution)
100 μl was administered intramuscularly on the back. One minute after the administration, the temperature change at two sites was measured for 120 minutes, and the temperature before administration (about 37 ° C. for brown adipose tissue between the scapula and 37 ° C. for the rectum).
5 to 38 ° C.) and the temperature at the time of the highest increase after administration. Physite for temperature measurement of interscapular brown adipose tissue
mp Model BAT-12, rectum temperature measurement using Techno Seven Thermister C510.
It was set at 8 ° C. Results: As shown below, Compound 1 administration increased the temperature of the interscapular brown adipose tissue and rectum.

[Table 3] From these results, it is clear that compound (I) enhances body heat production.

Experimental Example 4 Effect of Compound (I) on Mesenteric Adipose Tissue and Interscapular Brown Adipose Tissue Weight or Plasma Glucose Method: Spontaneously Obese Diabetic Mice (KKA ^y mice: 1)
A 3-week-old female) was allowed to freely take a commercially available powdered feed (CE-2, CLEA Japan) containing 0.2% of compound 1 (compound 1 dose: 252 mg / kg body weight / day). Compound 1 in the control group
An unfed feed was given. After breeding for 2 weeks, the animals were sacrificed by decapitation, and the weight of mesenteric adipose tissue or interscapular brown adipose tissue was measured. Plasma glucose was measured with an automatic biochemical analyzer (Hitachi 7070). Results: There was no difference in the amount of food consumed between the mice in the administration group and the control group, but as shown below, administration of compound 1 increased the weight of interscapular brown adipose tissue and decreased the weight of mesenteric adipose tissue as shown below. did. In addition, administration of Compound 1 reduced plasma glucose (KKA ^y mice show characteristic hyperglycemia).

[Table 4] These results indicate that compound (I) increases interscapular brown adipose tissue weight associated with body heat production, decreases mesenteric adipose tissue weight associated with the onset of adult disease, and lowers plasma glucose. It is clear. From the above results, it is clear that the preparation of the present invention containing compound (I) as an active ingredient has a catecholamine secretion action and is useful as a thermogenesis enhancer or an agent for preventing or treating obesity or diabetes. .

Formulation Examples A thermogenesis enhancer or an agent for preventing or treating obesity or diabetes containing the compound of the present invention as an active ingredient can be produced, for example, by the following formulation. Production Method Take 4 components from compound 1 to lactose in the column of "Components and Amounts" and prepare tablets according to the section of Japanese Pharmacopoeia General Formulation Tablets.

[0021]

Industrial Applicability According to the present invention, there is provided a preventive or therapeutic agent having an effect of enhancing body heat production and useful for obesity or diabetes.

Claims (6)

[Claims] (1) Formula (1) [Wherein, R ¹ represents an alkyl group. ] A thermogenesis enhancer comprising a compound having a partial structure represented by the formula ( ₁ ) and having a vitamin B1 action. 2. A compound having a vitamin B ₁ action is represented by the formula: [In the formula, R ¹ represents an alkyl group, and R ² represents a hydrocarbon group which may be substituted via thio and may be substituted. The body heat production enhancer according to claim 1, which is a compound represented by the formula: or a salt thereof. 3. The agent for enhancing body heat production according to claim 1, wherein R ¹ is a methyl group. 4. R ² may each be through a thio,
The body heat production enhancer according to claim 1, which is an alkyl group or an alkenyl group which may be substituted. 5. The body thermogenesis enhancer according to claim 1, wherein R ² is a C _1-7 alkyl group or a C _2-7 alkenyl group _optionally substituted with thio group. . 6. A compound of the formula [Wherein, R ¹ represents an alkyl group. Prophylactic or therapeutic agent for obesity or diabetes mellitus, characterized in that has a partial structure, and contains a compound having vitamin B ₁ activity represented by].