JP3129370B2 - Appetite suppressant - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the following formula (1)

[0002]

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N-piperonyl-1,2,3,
The present invention relates to an appetite suppressant containing, as an active ingredient, 4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-carbamide or an acid addition salt thereof.

[0004]

2. Description of the Related Art In the age of satiety, so-called obesity is not merely an apparent problem but induces diabetes, high blood pressure, and many other heart diseases, and can be said to be one modern disease. Especially for highly obese patients, there is no effective method, and at present, stomach resection, diet therapy, and tooth extraction are being performed. Further, reflecting the stressed society, the so-called bulimia nervosa continues to increase.

[0005]

The only appetite-reducing agent, generic name mazindol, which has recently been marketed, has a similar mechanism of action as the stimulant amphetamine, and therefore requires careful use. It has many problems, such as the establishment of sexuality and various side effects such as mental symptoms.
Therefore, it is very clinically significant to develop a new type of appetite suppressant that does not have such problems, and the present invention aims to solve this problem.

It is already known that the compound represented by the formula (1) is an effective substance having an anxiolytic effect and a learning improving effect (JP-A-5-163278).

[0007]

Means for Solving the Problems The present inventors have obtained the formula (1)
As a result of repeated studies on a compound represented by the formula (1), the present inventors newly found that the compound has an anorexia-suppressing effect unexpected from the anxiolytic effect and learning-improving effect in known applications, and completed the present invention. That is, the present invention provides the following formula (1)

[0008]

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N-piperonyl-1,2,3
An appetite suppressant containing 4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-carbamide or an acid addition salt thereof as an active ingredient. The appetite suppressant of the present invention is an anti-obesity drug that suppresses abnormal appetite hypertension, and thus prevents obesity increase and improves obesity, and further effectively assists in the execution and maintenance of a diet accompanying obesity treatment. Can be used. It is also promising as an effective drug for preventing and treating overeating observed in various stress-related diseases.

The compound of the present invention includes one of a racemate of the compound represented by the formula (1) or one of its optical isomers, or an acid addition salt thereof.

As specific compounds represented by the formula (1) of the present invention, the following compounds can be mentioned as preferred examples. (1) N-piperonyl-1,2,3,4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-carbamide (racemate). (2) (R) -N-piperonyl-1,2,3,4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-
3-carbamide.

A racemic N-piperonyl-1,2,3,4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-carbamide represented by the above formula (1) or one of optical properties thereof As the acid addition salt of the isomer, any pharmaceutically acceptable non-toxic salt may be used. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and acetic acid, citric acid, tartaric acid, and lactic acid , Succinic acid, fumaric acid, maleic acid,
Salts of organic acids such as methanesulfonic acid can be mentioned.

The compound of the present invention represented by the formula (1) can be synthesized by a known method, for example, a method described in JP-A-5-163278, Japanese Patent Application No. 5-6578, or the like. . A specific synthesis example is shown below. The compound of the present invention represented by the above formula (1) is synthesized by the following synthesis method 1

[0014]

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[0015] However, in the formula, R ′
Represents a lower alkyl group having 1 to 6 carbon atoms. Further, the X _1, Boc-X ₂ of HX ₁ X _2, HX
X ₃ of ₃ represents excellent as halogen atom, or not to be bonded to the acid hydrogen atoms, such as methanesulfonic acid, leaving group such as 4,6-dimethyl-pyrimidinyl mercapto group.

In this synthesis method 1, the method for obtaining the compound (3) from the compound (2) is described in Gerhardwolf, Felix Timorkowski, Artib. Bear. Fermagy (Gerhard Wolf and Fe
lix Zymalkows-ki, Arch. Pha
rm. 279, 309 (1976).

The solvent used in the method for synthesizing compound (3) from compound (2) is preferably an ether such as diethyl ether, tetrahydrofuran, dioxane and the like. This reaction is usually performed at 10 to 120 ° C., and is generally completed in about 1 to 30 hours. Acetaminomalonic acid diethyl ester is used in an amount of 1 to 3 equivalents, and an alkali metal such as lithium or potassium may be used instead of sodium metal.

The method for obtaining the compounds (4) and (5) from the compound (3) is described in Etch. Art. Shinaida, Cultus W. Smith, Journal of
American Chemistry Society (HRS
nyder and Curt-is Smith
J. Am. Chem. Soc. ,) 66, 350 (1
944) can be referred to.

The solvent used in the ester hydrolysis reaction for obtaining the compound (4) from the compound (3) is preferably water or a mixed solvent of a lower alcohol such as methanol, ethanol and propanol and water. . Usually, sodium hydroxide, potassium hydroxide, sodium carbonate and the like are used. This reaction is carried out at 10 to 100 ° C.
It is preferable that the process be completed in about 10 hours. As the acid for neutralizing the alkali, for example, citric acid and acetic acid are used.

The solvent used in the decarboxylation reaction and amide hydrolysis reaction for obtaining the compound (5) from the compound (4) is preferably water. The decarboxylation reaction is carried out at 60 to 100 ° C., and is generally preferably completed in about 1 to 30 hours. The amide hydrolysis reaction may use potassium hydroxide instead of sodium hydroxide.
This reaction is usually performed at 10 to 100 ° C.,
It ends in about 30 hours.

The method of obtaining compound (6) from compound (5) is described in Nobuo Izumiya, Tetsuo Kato, Motonori Ohno, Higashihiko Aoyagi, Synthetic Chemistry Series Peptide Synthesis (Maruzen) 66, Experimental Examples 3.2
Can be referred to. Alcohol (R'OH) used in this method includes methyl alcohol
And lower alcohols such as ethyl alcohol, propyl alcohol, hexyl alcohol and the like, and this alcohol includes the meaning as a solvent. Usually, thionyl chloride, sulfuric acid, hydrochloric acid gas, p-toluenesulfonic acid and the like are used as the acid catalyst. The reaction is carried out at a temperature of from 10 to 100 ° C, preferably from 20 to 30 ° C. Generally, it ends in 1 to 48 hours.

The solvent used in the method for obtaining the compound (7) from the compound (6) includes lower alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol and hexyl alcohol, or ethyl acetate. Preferred examples are given. As the HX ₁ usually an acid addition salt using sulfuric acid, hydrochloric acid, p- toluenesulfonic acid and the like. The reaction is carried out at a temperature of -10 to 30C, preferably 0 to 10C. Generally ends within one day.

The method for synthesizing the compound (8) from the compound (7) is described in D. Zoelens et al., Journal of
Organic Chemistry (D. Soenerse)
t. al. J. Org. Chem. ,) 44 (4), 5
35-545 (1979).
Formalin is used usually in 1 to 10 equivalents, preferably 1.5 to 2 equivalents, relative to compound (7). Solvents used in this method are water, methanol, ethanol
A mixed solvent of lower alcohols such as isopropyl, propyl and hexyl alcohols is preferred. The reaction temperature is
Usually performed at 10 to 100 ° C, preferably 50 to 70 ° C
It is. The reaction time is generally 1 to 30 hours, preferably 20 to 25 hours. Further, it is preferable to use 10 to 100 equivalents of an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or the like as a reaction catalyst.

The method for obtaining the compound (9) from the compound (8) is described in T. Nakagawa, K. Kloiwa, K. Narita, Wy. Isowa, Bullen of the Chemical Society of Japan (T. Nakagawa,
K. Kuroiwa, K .; Na-rita, Y .; Iso
wa, Bull. Chem. Soc. Japan, 12
69, 46 (1973).

The solvent used in the method for synthesizing compound (9) from compound (8) is preferably an organic solvent such as chloroform, methylene chloride, tetrahydrofuran and dimethylformamide. This reaction is usually performed at 0 to 100 ° C.
And generally ends in 1 to 48 hours. Compound HX ₁ (8) to neutralize, triethylamine,
It is preferable to use a tertiary amine such as N-methylmorpholine, and the tertiary amine is usually used in an amount of 2 to 3 equivalents. As a method for introducing a tert-butoxycarbonyl group (Boc group), a Boc-agent such as Boc-azide may be used. X ₂ is a thio-4,6 dimethyl pyrimidine, and the like. Alternatively, a protecting group for another amino group such as benzyloxycarbonyl may be used instead of the Boc group.

The method for obtaining the compound (10) from the compound (9) is described in I. Brand, B. F. Erlanga, etch. Saxophone, J. Polasuk, J. Jar
Null of American Chemistry Society (E. Brand, BF Erlanger, HS
acks, J.M. Polathick, J .; Am. Che
m. Soc. ,) 73, 3510 (1951).

In the method for synthesizing the compound (10) from the compound (9), for example, the compound is hydrolyzed with sodium hydroxide and then neutralized with an acid. In this reaction, it is preferable to use an alcohol such as methanol or ethanol or water as a solvent. This reaction is usually performed at 0 to 80 ° C, and is generally completed in 1 to 48 hours. Sodium hydroxide is usually used in an amount of 1 to 3 equivalents. Further, potassium hydroxide or the like may be used instead of sodium hydroxide. As the acid for neutralizing the alkali, for example, citric acid and acetic acid are used.

The solvent used in the method for obtaining the compound (11) from the compound (10) is preferably an aprotic polar solvent such as dimethylformamide and dimethylsulfoxide. As the condensing agent, for example, 1,3-dicyclohexylcarbodiimide (DCC), diphenylphosphoric azide (DPPA) and the like are used. This reaction is carried out at 10 to 100 ° C, preferably at 20 to 30 ° C. Generally, it ends in 1 to 10 hours.

Compound (11) is converted to N represented by the formula (1)
The solvent used in the method for obtaining the acid addition salt (1-1) of -piperonyl-1,2,3,4-tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide is ethyl acetate Or an organic solvent of an alcohol-based solvent such as methyl alcohol and ethyl alcohol. Also,
The HX ₃ sulfuric acid, hydrochloric acid, p- toluenesulfonic acid and the like are used. This reaction is carried out at 10 to 100 ° C, preferably at 40 to 60 ° C. Generally 1
It ends in 10 hours. N-piperonyl-1,2,3,
4-tetrahydro-benzo [b] thieno [2,3-c]
Pyridine-3-carbamide can be obtained by neutralizing with a base such as sodium hydroxide, potassium hydroxide, and triethylamine.

(R) -N-piperonyl-1,2,3,4
Compound (1) which is -tetrahydro-benzo [b] thieno [2,3-c] pyridine-3-carbamide hydrochloride
Is the following synthesis method 2.

[0031]

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Can be manufactured. This D-2-amino-
(Benzo [b] thiophen-3-yl) -propionic acid (13) is D-α-acetamino-α-carboxy-β
-(3-Benzo [b] thiophen-3-yl) -propionic acid (12) can be produced by hydrolyzing an acyl group using an acid without causing racemization. As the acid to be used, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid and trifluoroacetic acid can be used. The concentration is 0.1 to 18 normal, preferably 1 to 12 normal.

The amino group used in the reaction of the compound (13) with the compound (14) is protected by a urethane-type protecting group such as a t-butoxycarbonyl group or a benzyloxycarbonyl group, an acetyl group, a formyl group, a trifluoroacetyl group. An acyl-type protecting group such as a group is used. For example, when protecting with a t-butoxycarbonyl group, it can be obtained by the following synthesis method.

The method for synthesizing compound (13) from compound (13) is to dissolve optically active compound (13) in a mixed solvent of water and an ether solvent such as tetrahydrofuran and di-t-butyl-di- 1 to 12 of carbonate and triethylamine
After adding an equivalent (preferably 1-2 equivalents), the reaction is carried out at room temperature. As a method for synthesizing the compound (15) from the compound (14), an ordinary method for synthesizing an amide from a carboxylic acid and an amine can be applied. For example, a method using a condensing agent such as DCC (dicyclohexylcarbodiimide),
A method of converting a carboxylic acid into an acid chloride and condensing the acid is exemplified.

The method using DCC can be performed, for example, by the following method. Compound (14) is dissolved in a halogenated solvent such as chloroform, and 1-hydroxybenzotriazole is added. At this time, 1-hydroxybenzotriazole is used in an amount of 1 to 10 equivalents, preferably 1.1 to 2 equivalents.
Is equivalent. Further, piperonylamine and 1,3-dicyclohexylcarbodiimide are added. At this time, the amount of piperonylamine and 1,3-dicyclohexylcarbodiimide is 1 to 10 equivalents, preferably 1.1 to 2 equivalents. Finally, dicyclohexylurea formed is removed by filtration.

As a method for synthesizing the compound (16) from the compound (15), for example, a method using an acid or a method using catalytic reduction can be applied. In this case, the method using an acid is preferable since the molecule has a sulfur atom. Usually used acids such as methanesulfonic acid, hydrochloric acid and sulfuric acid can be used.
For example, a 4N hydrochloric acid 1,4-dioxane solution is added to the compound (15) and reacted. At this time, the amount of the acid is 1 to 100 equivalents, preferably 2 to 5 equivalents. Reaction temperature is 0-1
55 ° C, preferably 60-90 ° C.

The method for synthesizing the compound (1) from the compound (16) is similar to the method for preparing the compound (8) from the compound (7) in the above-mentioned synthesis method 1; Zoelens et al., Journal of Organic Chemistry (
D. soerens et. al. J. Org. Che
m. , 44 (4), 535-545 (1979)). Formalin is used usually in 1 to 10 equivalents, preferably 1.5 to 2 equivalents, relative to compound (16). The solvent used in this method is preferably a mixed solvent of water and a lower alcohol solvent such as methanol, ethanol, propyl alcohol and hexyl alcohol. The reaction is carried out at a temperature of 10 to 100 ° C, preferably 50 to 70 ° C. Reaction times are generally between 1 and 30
Hours, preferably 20 to 25 hours. Also,
As a reaction catalyst, for example, 1 to 10 equivalents of hydrochloric acid, sulfuric acid,
An acid such as p-toluenesulfonic acid is used.

When the compound of the present invention represented by the formula (1) or an acid addition salt thereof is used as an appetite suppressant, it is prepared alone or in a mixture with a pharmaceutically acceptable carrier.
The composition may be determined according to the administration route and administration schedule. The dosage is determined by the age, health, weight, severity of symptoms, type of concurrent treatment, if any, frequency of treatment, nature of the desired effect, etc., of the patient.

Therapeutic doses generally range from 0.01 to parenteral administration.
20 mg / kg / day, 0.02 to 40 mg / day by oral administration
kg.day, and can be administered once to three times a day. Regarding the toxicity value of the compound represented by the formula (1), even in a single oral administration to rats, even at 1500 mg / kg, there is no death and it can be said that the compound is extremely safe. When the compound represented by the formula (1) of the present invention is orally administered as an appetite suppressant, it is in the form of tablets, capsules, powders, granules, liquids, elixirs, and the like. It is used in the form of a sterilized liquid and may be prepared as the above-mentioned dosage as a preparation having the designed content. When used in the form as described above, solid or liquid non-toxic pharmaceutical carriers can be included in the composition.

As an example of the solid carrier, a gelatin type capsule is usually used. The active ingredient is tableted, granulated, and powder-packed with or without an auxiliary agent. The excipient used in these cases is water:
Gelatin: lactose, sugars such as glucose: corn, wheat,
Starches such as rice and corn starch: fatty acids such as stearic acid: fatty acid salts such as calcium stearate and magnesium stearate: talc: vegetable oils: alcohols such as stearyl alcohol and benzene alcohol: gums: polyalkylene glycols and the like.

These capsules, tablets, granules and powders
Generally, 1 to 80% by weight, preferably 1 to 60% by weight of the compound represented by the formula (1) can be contained as an active ingredient. As the liquid carrier, water, physiological saline, dextrose or a similar saccharide solution, and glycols such as ethylene glycol, propylene glycol and polyethylene glycol are generally preferred as the liquid carrier.

When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, the compound represented by the formula (1) and an acid addition salt thereof are added to a solution such as sodium chloride or glucose to make the solution isotonic. It is also preferable to use as a sterile solution to which other solutes are added. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection) and the like. In the case of these injections,
Usually, it is preferable to contain 0.01 to 20% by weight, preferably 0.1 to 10% by weight of the active ingredient.

In the case of solutions for oral administration, a suspension or syrup containing 0.01 to 20% by weight of the active ingredient is preferred. As the carrier in this case, for example, an aqueous excipient such as a flavor, syrup, or pharmaceutical micelle is used.

[0044]

EXAMPLES Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[0045]

EXAMPLE 1 Male SD rats (5 rats per group) weighing 300-350 g and bred under free-feeding and drinking conditions in individually bred cages were used. The experiment is from 10:00 to 3: 0 pm
0 hours 2 hours. Remove the existing feed from the breeding cage and re-weigh the new 4 blocks of fresh feed (12
g) was placed on the floor of the cage and the drug described below was administered. The control group showed about 1 g of feeding. The results are shown in Table 1 [Effect of the following compound (1) on the food intake of rats] and FIG.

[0046]

[Table 1]

In Table 1 and FIG. 1, the control is a 0.5% aqueous methylcellulose solution. (R) -N-
Piperonyl-1,2,3,4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-carbamide.hydrochloride [compound (1)] was treated with 0.5% methylcellulo-
Solution to a concentration of 1 mg / ml. 1m each
g / kg, 3 mg / kg, 10 mg / kg were used for intraperitoneal administration.

As is apparent from FIG. 1, the test was conducted 30 minutes to 2 hours after administration of the compound (1). As a result, a clear dose-dependent decrease in food intake was observed. This result clearly indicates that the compounds of the present invention can be used as appetite suppressants.

[0049]

Example 2 An appetite-suppressing effect was confirmed by administering the compound of the present invention into the brain in the following food intake increase model. Under pentobarbital anesthesia, a cannula was chronically implanted in the dorsal mesencephalic raphe nucleus of the rat, and rats (five rats per group) which passed 7 days or more after the operation were used for the experiment. The results are shown in Table 2 and FIG. In Table 2 and FIG.
vehicle1 (a 10% aqueous solution of γ-cyclodextrin was injected into the dorsal midbrain raphe nucleus), Vehicle2
[(±) -2-dipropylamino-8-hydroxy-
0.5 mg / l of 1,2,3,4-tetrahydronaphthalene hydrobromide (hereinafter abbreviated as 8-OH-DPAT).
kg, and a 10% aqueous solution of γ-cyclodextrin was injected into the dorsal midbrain raphe nucleus as a solution. ], Compound (1) [0.5 m of 8-OH-DPAT
g / kg was administered subcutaneously, and a 10% aqueous solution of γ-cyclodextrin as a solution to which compound (1) was finally administered at 10 μg was injected into the dorsal raphe nucleus. The drug was injected into the dorsal midbrain raphe nucleus at 1 μl / min using a microinfusion pump.
μl was injected. The results are shown in Table 2 and FIG. From these results, first, Veh is compared with Vehicle1.
It was confirmed that the amount of eating of ice2 was extremely increased, and it was confirmed that the model of this example was a preferable model of increasing eating. Next, it was confirmed that the compound (1) of the present invention was able to significantly reduce the amount of food consumed by intracerebral administration with respect to the above-mentioned food intake increase model. Also,
At the dose at which this effect was observed, it was also confirmed that Compound (1) did not show any muscle relaxation or sedation that would affect eating behavior. It was confirmed that the invention compound clearly has an effect as an appetite suppressant.

[0050]

[Table 2]

[0051]

Example 3 Compound (1) 1 mg Lactose 99 mg Corn starch 33 mg Carboxymethyl cellulose 4 mg Hydroxypropyl cellulose 4 mg Light anhydrous silicic acid 1 mg Magnesium stearate 1 mg or more Tablets containing 1 mg of compound (1) having a composition of 1 mg or more were prepared by a conventional method. did.

[0052]

The appetite suppressant of the present invention has been confirmed to exhibit an excellent appetite suppressing effect as described below. The compound represented by the formula (1) or an acid addition salt thereof is used in rat
The ay-time eating behavior was effectively suppressed without a decrease in so-called muscle relaxation or locomotor activity. In addition, even the experimentally enhanced food intake was effectively suppressed by intracerebral administration. Accordingly, the appetite suppressant of the present invention exhibits an excellent appetite suppressing effect, suppresses abnormal appetite increase, prevents the progression of obesity, aims to improve obesity, and enhances the diet or exercise therapy for severe obesity. Used effectively for assistance. Further, it is effectively used for suppressing overeating in stress-induced bulimia nervosa and the like.

[Brief description of the drawings]

FIG. 1 is a table showing the effects of the compounds of the present invention on the amount of food consumed in rats.

FIG. 2 is a table showing the results of direct administration of the compound of the present invention into the brain for a model of increased food intake.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 495/04 105 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] [Claim 1] The following formula (1) N-piperonyl-1,2,3,4-tetrahydrobenzo [b] thieno [2,3-c] pyridine-3-
Carbamide, or anorectic agent as an active ingredient one of the acid addition salts thereof.