WO2001083487A1 - Froindazole derivative - Google Patents

Abstract

A froindazole derivative represented by the following formula (I), which has an aminoalkyl in the 1-position and an alkyl in the 7-position, or a pharmaceutically acceptable salt thereof. The derivative has high selectivity for 5-HT2C receptors and excellent agonistic activity. (In the formula, R?1, R2, R4, and R5¿ each is hydrogen or alkyl; and R3 is an alkyl.) Also provided: are a medicinal composition comprising the froindazole derivative or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, especially a medicinal composition for the treatment of central nervous system diseases such as sexual function disorders; a process for industrially producing the froindazole derivative or pharmaceutically acceptable salt; and an intermediate for use in the process. (I)

Description

 Specification

 Freindazole derivative

Technical field

The present invention relates to a novel Freindazole derivative having an aminoalkyl at the 1-position and an alkyl at the 7-position having high selectivity for 5-HT _2C receptor and excellent agonist activity, or a pharmaceutically acceptable product. , A salt thereof, and a pharmaceutical composition comprising the Freindazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, particularly a medicament for treating central nervous system diseases such as sexual dysfunction Composition.

 Furthermore, the present invention relates to an industrial production method of the furindazole derivative or a pharmaceutically acceptable salt thereof, or an intermediate for producing the production method. Background art

5—HT _2C receptors are mainly distributed in the central nervous system and their role is poorly understood, but central nervous system disorders such as sexual dysfunction, anxiety, depression, and sleep disorders Invest. Drugs 2 (4) 317 (1993). Therefore, the 5-HT _2C receptor agonist is useful for preventing or treating the above diseases.

As a 5-HT _2C receptor agonist, an indazole derivative (W098 / 56768) having an aminoalkyl at the 1-position and having an unsaturated heterocyclic ring fused thereto is disclosed. These indazole derivatives are useful for treating central nervous system diseases, for example, sexual dysfunction such as impotence, anxiety, depression, and sleep disorders.

However, the compounds specifically described in W098 / 56768 also have an affinity for 5-HT _2A receptor, and there are concerns about side effects associated therewith, such as a blood pressure increasing effect. Therefore, there is a need for a drug having a low affinity for the 5-HT _2A receptor and a higher selectivity for the 5-HT _2C receptor.

In addition, W098 / 56768 has a production method, for example, in which an aminoalkyl having an asymmetric carbon at the 1-position is bonded (S) —2- (7-ethyl-1H-thieno [2 ', 3-glindazole- 1-yl) — 1-Methylethylamine is disclosed to be the following production method.

発明の開示

Disclosure of the invention

The present inventors have diligently searched for an indazole derivative having a fused heteroaromatic ring having high selectivity for 5-HT _2C receptor and excellent agonist activity. As a result, a Freundazol derivative having an aminoalkyl at the 1-position and an alkyl at the 7-position represented by the following formula (is represented by the general formula in W098 / 56768, but is not specifically described. It is a novel compound that has remarkably low action on 5-HT _2A receptor, has high selectivity for 5-HT _2C receptor and excellent agonist activity, and is used as a drug for central nervous system diseases such as sexual dysfunction. The present inventors have found that the present invention is useful as a therapeutic agent for the present invention and completed the present invention.

 That is, the present invention relates to a furoindazole derivative represented by the following formula (I) having an aminoalkyl at position 1 and an alkyl at position 7, or an optically active compound thereof, or a pharmaceutically acceptable salt thereof.

(式中の記号は、 以下の意味を示す。

(The symbols in the formula have the following meanings.

RR ² , R ⁴ and R ⁵ : identical or different, 1 H or alkyl

R ³ : alkyl)

The compound (I) of the present invention is preferably the compound (I) of the present invention, wherein R ¹ R ² , R ⁴ and R ⁵ are the same or different and are 1 H, methyl or ethyl, more preferably R ³ is methyl, ethyl, propyl or isobutyl; R ¹ R ² and R ⁵ are the same or different and are 1 H, methyl or ethyl; R ⁴ is methyl and R ⁴ is substituted carbon; The compound of the present invention (I) having a (S) configuration, and more preferably (S) -2- (7-ethyl-1 W-flow [2,3-g] indazolu-yl) ) 1-methylethylamine, (S) — 2— (7-ethyl-3—methyl-1 / ■ / —Flo [2,3-g] indazole—1-yl) (S) — 2— (3, 7—Jetil—1 H—FΏ [2,3-g] indazo 1/11) — 1—Methylethylamine, (S) —1— Methyl-2- (7-propyl-1H-furo [2,3-g] indazole-1yl) ethylamine,

(S)-V-ethyl-2 _ (7-ethyl-1 H-flow [2,3-si indazol-1-ethyl])-1-methylethylamine, (S)-2-(4, 7—Jetyl—1H—Flo [2,3-g] indazole—11-yl) —1-Methylethylamine, (S) —2— (7-butyl—1 »—Flo [2,3 — G] indazo 1-yl) 1-methylethylamine or (S) — 2— (7-isopentyl— 1 H—f mouth [2,3—g] indazo 1—yl 1) -Methylethylamine or a pharmaceutically acceptable salt thereof, particularly preferably (S) -2- (7-ethyl-1W-furo [2,3-g] indazolone. 1-Methylethylamine or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to a pharmaceutical composition comprising the compound (I) of the present invention or an optically active compound thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention is preferably a pharmaceutical composition for treating impotence. Furthermore, the present inventors have conducted intensive studies on the industrial production method of the furoindazole derivative which is the compound (I) of the present invention, and as a result, have found the following production method. The production method of the present invention is similar to the production method of the above-mentioned chenoindazole derivative (W098 / 56768). Solving industrial manufacturing problems. In the production method of the present invention, a less expensive aminoalkylating agent can be used without using expensive (R) -propylene oxide, an azide compound which is difficult to handle, and lithium aluminum hydride. Further, the intermediates of the present invention and the compound of the present invention (I) can be obtained with high purity without performing silica gel column chromatography purification.

 Further, the following alcohol derivative (IV) obtained by reducing the following ketone derivative (III) can be dehydrated and aromatized by simply reacting it under acidic conditions without isolation and purification, and the compound of the present invention ( The production method of the following intermediate (V) of I) is a production method which has not been known for this type of compound, and can be carried out without using DDQ. Is the law.

 That is, the present invention also includes an industrial production method of the following compound (I) of the present invention. The production method of the present invention comprises:

 1) The compound (III) is acylated under acidic conditions to produce the compound (III),

 2) By reducing the compound (III) obtained in 1), a ligated compound (IV) is produced,

 3) The compound (IV) obtained in 2) is reacted under acidic conditions to produce a compound (V),

4) reacting the compound (V) obtained in 3) with an amino-protected aminoalkylating agent under basic conditions to produce a compound (VI);

 5) This is a method for producing a compound of the present invention (Fruindazole derivative, which is a compound of the present invention, by deprotecting the compound (VI) obtained in 4).

Vapour

 (The symbols in the formula have the following meanings.

RR ² , R ⁴ and R ⁵ : same or different—H or alkyl

R ³ : alkyl

R ⁶ : protecting group for amino. The same applies hereinafter. )

 The present invention also relates to the use of the following formula (11), (III), (IV), (V) or (VI) or a salt thereof as a production intermediate for the production of the compound (I) of the present invention. .

(II)

(VI)

(VI)

The present invention also provides a compound of the following formula (II, (IV) or (V) or a compound thereof useful as an intermediate for producing the compound (I) of the present invention, which is useful as a medicament, particularly as a therapeutic agent for central nervous system diseases such as sexual dysfunction. The intermediate (III), (IV) or (V.) of the present invention can be produced by the following production method or the method shown in the Examples, and the intermediate (III) of the present invention can be produced. Compound (I) of the present invention can be produced from (IV), (IV) or (V).

The intermediate (111), (IV) or (V) according to the present invention is preferably such that R ³ is methyl, ethyl, propyl or isobutyl, and R ¹ and R ² are the same or different and 1 H, The intermediate (11 1), (IV) or (V) of the present invention, which is methyl or ethyl, and particularly preferably the present invention wherein R ³ is methyl and R ¹ and R ² are —H. It is a production intermediate (111), (IV) or (V).

The present invention also provides the following formula (VI) or a salt thereof, which is useful as an intermediate for the production of the compound (I) of the present invention, which is useful as a medicament, particularly as a therapeutic agent for central nervous system diseases such as sexual dysfunction. . The intermediate (VI) of the present invention can be produced, and the compound (I) of the present invention can be produced from the intermediate (VI) of the present invention by the following production methods or the methods described in Examples.

The intermediate (VI) of the present invention is preferably the intermediate (VI) of the present invention wherein RR ² , R ⁴ and R ⁵ are the same or different and are 1 H, methyl or ethyl, and more preferably, R ³ is methyl, ethyl, propyl or isobutyl; R ¹ R ² and R ⁵ are the same or different and are 1 H, methyl or ethyl; RS is tert-butoxycarbonyl; R ⁴ is methyl And the configuration of the carbon substituted by R ⁴ is the intermediate (VI) of the present invention in which the configuration is (^ configuration). Particularly preferably, R ³ and R ⁴ are methyl, and RR ² and R ⁵ is —H, R ^{6 is} ίerί-butoxycarbonyl, and the configuration of the carbon substituted with R ⁴ is the intermediate (VI) of the present invention.

 Hereinafter, the compound of the present invention (and the production method of the present invention and the intermediate for the production method of the present invention) will be described in detail.

 "Alkyl" means a linear or branched carbon chain having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , Isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, heptyl, nonyl, decyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and more preferably Is methyl or ethyl, particularly preferably methyl.

 "Amino protecting group" means an amino protecting group that can be used industrially, and includes, for example, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzyl or P-toluenesulfonyl. And preferably tert-butoxycarbonyl.

The compound (I) of the present invention may have an asymmetric carbon atom depending on the type of the substituent. is there. Therefore, the compound (I) of the present invention includes a mixture of optical isomers and an isolated one.

 Further, the compound (I) of the present invention can form a salt with an acid. Such salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Organic acid such as maleic acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid. Preferably, it is succinic acid.

 Furthermore, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as various solvates such as hydrates and ethanol solvates, or as crystalline polymorphs thereof. The compound of the present invention (or a pharmaceutically acceptable salt thereof) also includes various hydrates, solvates and polymorphic substances.

 Furthermore, the compound (I) of the present invention also includes all compounds that are metabolized in vivo and converted into the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, so-called prodrugs. Examples of the group that forms a prodrug of the compound (I) of the present invention include those described in Prog. Med. 5: 2157-1161 (1985), and Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. Groups described in Designs 163-198. Specifically, it is a group which can be converted back into the primary or secondary amine of the compound (I) of the present invention by hydrolysis, solvolysis or under physiological conditions. Monoalkyl, monoNH—C (0) —O—alkyl, —NH—C (O) —NH—alkyl or —NH—CH, -0-C (O) —alkyl.

 In addition, the intermediate (II), (III), (IV), (V) or (VI) of the present invention, which is a useful intermediate for the production method of the present invention, is obtained by subjecting it to a usual salt-forming treatment. Lithic acid addition salts can be produced. Such salts include, for example, acid addition salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid and the like.

 (Manufacturing method)

The compound (I) of the present invention can be produced industrially by the following production method of the present invention. 1st step

 Compound (II) or a salt thereof can be produced by acylating compound (II). The reaction is carried out by reacting the compound (II) with an excess of an appropriate acylating agent and an acid, such as acetic acid, propinoic acid or butyric acid, the acid chloride, the acid bromide or the acid anhydride as the acylating agent. Can be carried out using methanesulfonic acid, P-toluenesulfonic acid, trifluroic anhydride or the like as an acid, and preferably a compound (I

It can be carried out using an excess amount of acetic anhydride and methanesulfonic acid with respect to I). Examples of the reaction solvent include acetic acid, acetic anhydride, acetate nitrile or ethers such as diisopropyl ether, tetrahydrofuran or dioxane, and preferably acetic acid or no solvent. The reaction temperature is from cooling to heating, preferably from room temperature to heating. If desired, the reaction product is followed by the addition of alcohols such as methanol, ethanol or 2-propanol or water, preferably 2-propanol, optionally with a suitable base such as sodium hydroxide, potassium hydroxide. The reaction is carried out at room temperature or under heating in the presence of calcium, sodium carbonate, potassium carbonate, sodium ethoxide or sodium methoxide.

 Compound (II) can be produced by a known method (Heterocycles, 22, 2313, 1984; W098 / 56768).

The second king

化合物 （ I V ) は、 化合物 （ I I 又はその塩のケ卜ン基を還元することで 製造できる。 反応は、 適当な還元剤、 例えば、 水素化ホウ素ナトリウム、 卜リア セトキシ水素化ホウ素ナトリウム、 ジイソブチルアルミニウムヒドリド、 ボラン 又は酸化白金（I V)若しくはパラジウム-炭素存在下の水素等を用いて行うことが でき、 好ましくは水素化ホウ素ナトリウムを当量乃至過剰量用いて行うことがで きる。 反応溶媒としては、 メタノール、 エタノール若しくは 2—プロパノール等 のアルコール類、 ベンゼン、 トルエン若しくはキシレン等の芳香族炭化水素類、 ジイソプロピルエーテル、 テ卜ラヒド Dフラン若しくはジ才キサン等のエーテル 類又は水等が挙げられ、 好ましくはエタノールである。 反応温度は、 冷却乃至室 温下、 好ましくは氷冷乃至室温下である。 ィ匕合物 （ I I I ) の塩が反応に用いら れる場合、 当量の適当な塩基、 例えば、 ナトリウムェ卜キシド、 ナトリウムメト キシド、 水酸化ナトリウム、 水酸化カリウム、 炭酸ナトリウム又は炭酸カリウム、 好ましくはナ卜リウ厶ェ卜キシド又は水酸化ナ卜リウ厶にて中和後、 反応を行つ ても良い。 化合物 （ I V ) は、 単離精製することなく次の反応に用いることもで きる。

The compound (IV) can be produced by reducing the ketone group of the compound (II or a salt thereof. The reaction is carried out by using a suitable reducing agent such as sodium borohydride, sodium triethoxy borohydride, diisobutylaluminum. The reaction can be performed using hydride, borane, platinum (IV) oxide, hydrogen in the presence of palladium-carbon, or the like, preferably using an equivalent to excess amount of sodium borohydride. Alcohols such as methanol, ethanol or 2-propanol; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diisopropyl ether, tetrahydrofuran or dioxane; water; and the like. The reaction temperature is preferably from cooling to room temperature. When a salt of the compound (III) is used in the reaction, an equivalent amount of a suitable base, for example, sodium ethoxide, sodium methoxide, sodium hydroxide, or hydroxide is used. The reaction may be carried out after neutralization with potassium, sodium carbonate or potassium carbonate, preferably sodium ureaoxide or sodium hydroxide. It can also be used for the next reaction.

3rd step

The compound (V) or a salt thereof can be produced by subjecting the compound (IV) to dehydration and aromatization under acidic conditions. The reaction can be carried out using an equivalent to excess amount of a suitable acid, for example, hydrochloric acid, acetic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, or the like, relative to compound (IV). Preferably, an equivalent amount of hydrochloric acid is used. It can be performed using: Examples of the reaction solvent include alcohols such as methanol, ethanol and 2-propanol, aromatic hydrocarbons such as benzene, toluene and xylene, water and acetic acid, and preferably ethanol. The reaction temperature is from room temperature to under heating, preferably Or under heating reflux

4th step

The compound (VI) can be produced by a condensation reaction between the compound (V) or a salt thereof and an amino-protected aminoalkylating agent. Examples of amino-protected amino alkylating agents include, for example, (S)-(1-methyl-2-tosyl-kisechil) rubamic acid i "ert-butyl ester, (S)-(1-methyl-2-mesyl-kisechil) ) Potassium tertiary butyl ester, (S)-(1-Methyl-12-butyl bromide) Potassium tertiary butyl ester or (S) — (1-Methyl-2- cisyl) Acid benzyl ester, etc., and preferably (S)-(1-methyl-2-tosylkisechyl) terfamine terf-butyl ester The reaction is equivalent to compound (V) or a salt thereof. It can be carried out using an excess amount of a suitable base, for example, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium ί-butoxide. Preferably, the reaction can be carried out using 2 equivalents of cesium carbonate with respect to the compound (V) Examples of the reaction solvent include aromatic hydrocarbons such as benzene, toluene and xylene, acetone and 2-butynone. , Such as ketones, ethers such as diisopropyl ether, tetrahydrofuran, or dioxane; alcohols such as methanol, ethanol, or 2-propanol; acetate nitrile or Ν, Ν "" dimethylformamide (DM F) and the like, and is preferably DM. The reaction temperature is from cooling to heating, and preferably from room temperature to heating. It can also be used for the reaction.

 Compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be produced by deprotecting the amino of compound (VI). The reaction can be performed using a known method (Theodora. Greene and Peter G. Ulluts, Protective Groups in Organic Synthesis, John Wiley & Sons, INC., 199L) or a method similar thereto, and preferably vinegar. The reaction can be carried out at an ice-cooled temperature to room temperature by using an excess amount of hydrochloric acid with respect to compound (VI) in an ethyl acetate solvent. If desired, the reaction product is subsequently neutralized with a suitable base in a solvent such as water or alcohols, preferably in an aqueous solution of potassium carbonate, under cooling to room temperature, preferably under ice cooling to room temperature. The compound (I) of the present invention can be obtained. The compound (I) of the present invention thus produced is isolated as it is or as a pharmaceutically acceptable salt thereof. The salt of the compound (I) of the present invention can be produced by subjecting the compound (I) of the present invention, which is a free base, to a usual salt-forming reaction.

 The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is isolated and purified as a hydrate, solvate, or polymorphic substance thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, and recrystallization.

 Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, an optical isomer can be obtained by selecting an appropriate raw material or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer with a general optically active acid). It can lead to stereochemically pure isomers. Industrial applicability

The compound (I) of the present invention is a novel compound not specifically described in W098 / 56768, which has excellent agonist activity for 5-HT _{2 C} receptor, and has 5-HT _2A receptor activity. It showed over 90 times higher selectivity to the body. Furthermore, it has a penile erection evoking effect in rats, and is useful for treating central nervous system diseases, for example, sexual dysfunction such as impotence, anxiety, depression and sleep disorders.

 Pharmaceutical compositions containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared using tablets, excipients and other additives commonly used in the preparation of tablets, tablets and tablets. It is prepared into powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., and is administered orally (including sublingually) or parenterally.

 The clinical dose of the compound (I) of the present invention to humans is appropriately determined depending on the individual case in consideration of the symptoms, body weight, age, sex, administration route and the like of the patient to which the compound is applied. It is orally administered once to several times a day in the range of 10 mg to 100 mg, preferably 50 mg to 200 mg per person, or 1 adult per day. 1 mg to 500 mg per day, preferably 5 mg to 100 mg administered intravenously once to several times a day, or 1 hour to 24 hours a day It is administered intravenously over a period of time. Of course, as described above, the dosage varies under various conditions, so that a smaller amount may be sufficient in some cases.

 Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrole. Ridone is mixed with magnesium aluminate metasilicate. In accordance with the usual methods, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stable materials such as lactose. It may contain a solubilizing agent such as an agent, glutamic acid or aspartic acid. If necessary, tablets or pills may be coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose or a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, For example, it contains purified water and ethanol. This composition f may contain, in addition to the inert diluent, solubilizing agents, solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavoring agents, fragrances, and preservatives. .

 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as crude oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. . Such compositions further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. But it is good. These are sterilized, for example, by filtration through a bacterial retention filter, blending of a bactericide or irradiation. They can also be used in the manufacture of a sterile solid composition which is dissolved in sterile water or a sterile injection solvent before use.

 As described above, the compound (I) of the present invention, which is useful for central nervous system diseases such as sexual dysfunction, is industrially advantageously produced by the production method of the present invention as compared with the production method described in W098 / 56768.

 In the production method of the present invention, the compound (V) can be prepared by using a less expensive aminoalkyliylide without using expensive (R) -propylene oxide, difficult-to-handle azide compound and lithium aluminum hydride. Aminoalkyl can be easily introduced at the first position.

 Furthermore, each of the intermediates and the compound of the present invention (门) can be obtained with high purity without purification by chromatography in any of the steps. Not using Holm.

In particular, the alcohol derivative (IV) obtained by reducing the ketone derivative (III) is dehydrated and aromatized by simply reacting it under acidic conditions without isolation and purification, and the compound of the present invention (I) The production method for obtaining the intermediate (V) is a production method that has not been known for this kind of compound, and is a highly useful production method because it can be carried out without using DDQ.

 As described above, the production method of the present invention has solved the problems in the conventional industrial production, and can now industrially produce the compound (I) of the present invention for the first time. BEST MODE FOR CARRYING OUT THE INVENTION

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

 (Production example)

 Hereinafter, the method for producing the compound (I) of the present invention will be described in detail. The starting compounds used in the examples will be described as reference examples. The purity of each compound was determined by HPLC.

The symbols in the examples have the following meanings.

 Boc: t e r t-butoxycarbonyl

Jour R: - Nuclear magnetic resonance Supekubokuru (DMS0 - d _6, TMS internal standard) [delta]:

Reference example 1

 6, 7—dihydrobenzofuran 1 4 (5 Η) 1 year old

λ, 3-cyclohexanedione 32.0 kg, sodium hydroxide Ί0.3 kg, sodium bicarbonate 7.Ί8 kg, water 220, 41.5% chloroacetate An aqueous aldehyde solution (64.6 kg) was added, and the mixture was stirred at 0 ° C or lower for 2 hours. To the reaction solution was added toluene 160, concentrated sulfuric acid 18.7 kg, and the mixture was stirred at 0 ° C or lower for 16 hours. Precipitated crystals were removed by filtration, and the reaction solution was allowed to stand to separate. The aqueous layer was extracted with 64 L of toluene. The organic layer was washed successively with aqueous sodium bicarbonate (8.3 kg of sodium bicarbonate / 90 L of water) and brine (24 kg of sodium chloride / 74 L of water). The organic layer was concentrated under reduced pressure to give 6,7-dihydrobenzofuran-1,4 having a purity of 98.4%. 〃;) 24.8 kg of a toluene solution was obtained. .

Seki R: 2.09 (2H, q), 2.42 (2H, t), 2.88 (2H, t), 6 · 66 (1Η, d), 7.69 (1H, d) Reference Example 2

 5-Hydroxymethylidene-1,6,7-dihydrobenzofuran-4 (5H) 1 year old 6,7-dihydrobenzofuran-4 (5H) 1 year old 24.8 kg, ethyl formate 54.0 kg To a solution of 120 L of toluene was added a suspension of 40.9 kg of potassium / butoxide in 150 L of tetrahydrofuran, and the mixture was stirred at 0 ° C or lower for 0.5 hours. After adding 20 L of water to the reaction solution, concentrated hydrochloric acid was added until the pH of the aqueous layer became 5 or less. The reaction solution was allowed to stand and separated. 50 L of toluene was added to the aqueous layer and extracted. The organic layers were combined and washed with 98 L of water. Again, the organic layer was washed with 98 L of water. The organic layer was concentrated under reduced pressure to give a toluene solution of 30.1 kg of 5-hydroxymethylidene-6,7-dihydrobenzofuran-14 (5H) -butane having a purity of 99.0%. NMR: 2.76 (2H, t), 2.86 (2H, t), 6.67 (1H, d), 7.57 (1H, s), 7.66 (1H, d), 10.67 (1H, s)

Reference example 3

 4,5-dihydro-1 W-furo [2,3-indazole

 5-Hydroxymethylidene-6,7-dihydrobenzofuran-1 4 (5H) 1 30.1 kg of toluene 60 L, ethanol 190 L, 80.35% hydrazine monohydrate The product (12.6 kg) was added, and the mixture was stirred at 45 ° C or lower for 22 hours. To the solution obtained by concentrating the reaction solution under reduced pressure, 180 L of water was added with stirring, followed by cooling. The precipitated crystals were collected by filtration and dried to obtain brownish crystals having a purity of 99.0%.

5-Dihydro-1furo [2,3-g] indazole 23.67 kg was obtained. NMR: 2.85 (4H, s), 6.63 (1H, s), 7.44 (1H, s), 7.58 (1H, s), 12.28 (1H, s) Reference Example 4

 (S)-(〗 -Methyl-2-tosyloxyshetyl) dirubramic acid tert-butyl ester

B 0 c—L-alaninol 26.0 kg, p-toluenesulfonyl chloride 29.6 kg of isopropyl ether 260 L was added to a solution of sodium hydroxide aqueous solution (sodium hydroxide 17 3 kg / water 26), and stir at 30 ° C or less for ₂₁ hours. Stirred. 100 L of water was added to the reaction suspension, followed by cooling and stirring. The precipitated crystals were collected by filtration to obtain crude crystals. 43.5 kg of acetonitrile 180 was prepared under cooling with crude crystals, and 350 L of water was added to a solution of 22 L of water and stirred under cooling. The precipitated crystals were collected by filtration and dried to give 99.9% pure white crystals of (S)-(1-methyl-2-tosyl-kisechil) -potassium rubbamate t β t-butyl ester 40.70 kg I got

 NR: 0.97 (3H, d), 1.34 (9Η, s), 2.42 (3H, s), 3.66 (1H, m), 3.86 (2H, m), 6.86 (1H, d), 7.480H, d ), 7.78 (1H, d)

Example 1

 1-one (4,5-dihydro-1-fluoro [2,3-g] indazolone 7-yl) ethanone

 4,5-dihydro-1H-furo [2,3-g] indazole 23.6 kg of acetic acid 49 kg solution, methanesulfonic acid 70.6 kg and acetic anhydride 45.0 kg are added. The mixture was stirred at 50 ° C for 1 hour. To the reaction solution, 120 L of 2-propanol was added, and the mixture was stirred at 20 to 40 ° C for 1 hour. After cooling, the precipitated crystals were collected by filtration. After suspending the crystals in 230 L of water, an aqueous sodium hydroxide solution (5.88 kg of sodium hydroxide / water 54) was added under cooling and stirring. The precipitated crystals were collected by filtration and dried to give a brown crystalline 1- (4,5-dihydro-1-fluoro [2,3-g] indazolone 7-purity with a purity of 98.1%. Le) 23. 79 kg of ethanone was obtained. NMR: 2.42 (3H, s), 2.88-3.00 (4H, m), 7.52 (1H, s), 7.61 (1H, s), 12.5 (1H, s) Example 2

 (±) _ 1 — (4,5-dihydro-1-furo [2,3-g] indazole-7-yl) Ethanol

1 — (4,5-Dihydro-1-furo [2,3-indazole-7-yl) Ethanone 5.50 g dissolved in methanol (11 Oml), sodium borohydride, 1. 03 g was added, and the mixture was stirred at room temperature for 30 minutes. After adding water and 50 ml, the solvent was concentrated under reduced pressure to a total amount of about 5 OmI. After stirring at room temperature for further 30 minutes under ice-cooling for 1 hour, the crystals were filtered, and (Sat) -1-1 (4,5-dihydro-1H-furo [2,0.3-g indazole-7-yl) ethanol 5. 19 g were obtained. NMR: 1.39 (3H, d), 2.83 (4H, s), 4.64-4.71 (1H _; m), 5.22 (1H, d), 6.37 (1H, s), 7.43 (1H, s), 12.23 (1H, s).

Example 3

 7—Ethyl—1 safe mouth [2,3—g] indazole

 (±) — 1 — (4,5-dihydro-1-furo [2,3-g] indazole-7-yl) To 6.18 g of ethanol, add ethanol, 62 ml, concentrated hydrochloric acid, 2.5 ml In addition, the mixture was heated under reflux for 7 hours. After cooling to room temperature, 10% aqueous sodium hydroxide solution, 12.7 ml, water and 5 OmI were added, and the solvent was distilled off under reduced pressure. 6 M hydrochloric acid and 15 ml were added, and the mixture was stirred at room temperature for 30 minutes. Then, the crystals were filtered and washed with 1 M hydrochloric acid and water in that order. The obtained crystals were dissolved in 25 ml of methanol, 13.3 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 15 minutes. After adding 40 ml of water and stirring for 1 hour under ice-cooling, the crystals were filtered, washed with water and dried to obtain 5.26 g of 7-ethyl-1H-furo [2,3-g] indazole.

 NMR: 1.31 (3H, t), 2.85 (2H, q), 6.77 (1H, s), 7.32 (1H, d), 7.56 (1H, d), 8.09 (1H, s), 13.29 (1H, s)

Example 4

 7—Engineering 1 H—H D [2,3—g] Indazole

 1- (4,5-dihydro_1-furo [2,3-g] indazole-7-yl) ethanone 2 3.6 kg of ethanol 2 40 L of suspension was added to sodium borohydride 21 kg was added, and the mixture was stirred at 20 to 30 ° C for 4 hours. To the reaction solution was added 16.5 kg of 38.9% hydrochloric acid, and the mixture was heated under reflux for 7 hours. To the suspension obtained by concentrating the reaction solution under reduced pressure, 33.2 kg of hydrochloric acid (33.2 kg) and 90 L of water were added, followed by stirring. The precipitated crystals were collected by filtration. The crystals were dissolved in 180 L of methanol, and an aqueous solution of sodium hydroxide (5.16 kg of sodium hydroxide / 47 L of water) was added. Under stirring, 310 L of water was added, and the mixture was cooled, and the precipitated crystals were collected by filtration and dried to give 7-ethyl- 1H-flow [9, 76.5%] as pale yellow crystals having a purity of 96.5%. 3—g] indazole 1 9.74 kg was obtained.

N: 1.31 (3H, t), 2.85 (2H, q), 6.77 (1H, s), 7.32 (1H, d), 7.56 (1H, d), 8.09 (1H, s), 13.29 (1H, s) ' Example 5

 (S) — 2— (7-ethyl-1—furo [2,3— g] indazole—1—yl) 1-methylethylamine 1/2 succinate

 7—Ethyru 1 W—Flo [2,3—Indazole 1 8.0 kg, (S) −

(1-Methyl-2-cysylkisechyl) Potassium tert-butyl ester 35.0 kg Ν, Ν-dimethylformamide 270 L solution, add 63.0 kg of cesium carbonate, 60-70 ° The mixture was stirred at C for 25 hours. To the reaction suspension, 270 ml of water and 80 L of ethyl acetate were added. The reaction solution was allowed to stand and separated. 180 L of ethyl acetate was added to the aqueous layer and extracted. Again, ェ 80 L of ethyl acetate was added to the aqueous layer for extraction. The organic layers were combined and washed with a saline solution (sodium chloride 59 kg gZ aqueous solution). The organic layer was concentrated under reduced pressure to obtain [(S) -2- (7-ethyl-H-F).

 [2,3—g] indazole-1 —yl) — dimethylethyl] potassium tert-butyl ester ethyl acetate (27 ml), add 4 kg of 4 M hydrogen chloride monoethyl acetate solution (182 kg) at 26 ° C The mixture was stirred for 3 hours below. To the reaction suspension was added a potassium carbonate aqueous solution (potassium carbonate 56.1 <8 / water 180 L). The reaction solution was allowed to stand and separated. The organic layer was washed with saline (22 kg of sodium chloride // 68 L of water). The organic layer was concentrated under reduced pressure, to a solution of the remaining 180 L of ethanol, 5.7 kg of succinic acid was added with stirring, and the mixture was cooled. The precipitated crystals were collected by filtration to obtain crude crystals. To 9.23 kg of the crude crystals, 180 L of ethanol and 3.5 L of water were added. The mixture was heated to around the reflux temperature with stirring to dissolve the crude crystals. After filtration, the mixture was filtered with ethanol 9.2 and washed with 0.18 L of water. The filtrate was cooled with stirring. The precipitated crystals were collected by filtration and dried to give a yellow-brown crystal (S) with a purity of 99.5%.

(7-Ethyl-furo [2., 3-g] indazoyl 1-yl) — 1—Methyllueluamine 1/2 succinate 7.83 kg was obtained.

 The compounds of Examples 6 to 12 were obtained in the same manner as in Examples 1, 4 and 5. Example 6: (S) —2— (7-ethyl-3—methyl-1H—furo [2,3-g] indazolu-1-yl) —1-methylethylethylamine hydrochloride

Example 7: (S) -2- (3-, 7-Jetyl-1H-furo [2,3-g] indazol-vinyl) 1-methylethylethylamine hydrochloride Example 8: (S) -1-methyl-2- (7-propyl-1H-furo [2,3-g] indazole-1-yl) ethylamine hydrochloride

Example 9: (S) -Λ / —ethyl-2— (7-ethyl-1H—furo [2,3-g] indazol-1-yl) -1-methylethylethylamine fumarate

Example 10: (S) —2— (4,7—Jetyl-1H—furo [2,3—g] indazo-vinyl) 1-1-methylethylamine hydrochloride

Example 11 1: (S) —2— (7-butyl—1H—F. [2,3—g] indazolu-1-yl) 1-1-methylethylamine hydrochloride

Example 12: (S) —2- (7-Isopentyl-1H—furo [2,3-g] indazole-1-yl) -1-methylethylamine hydrochloride

 The chemical structural formulas and physicochemical properties of the compounds obtained in Examples 5 and 2 are shown in Table 1 below.

 The symbols in the table have the following meanings.

Ex .: Example number

Me: Methyl

Et: Ethil

Pr: propyl

Bu: butyl

iBu: isobutyl

Pen: Pentyl

Hex: Hexyl

Hep: heptyl

Oct: Talented Kutil

Non: Nonyl

Dec: Tenjire

MS: Mass Sector (ηι / ζ) ([(thin) +], FAB)

In the following, in addition to those described in the examples, the above-mentioned production methods, the production methods of the reference examples and examples, the production methods known to those skilled in the art, and modifications thereof are required, and special experiments are required. The compounds shown in Table 2 can be obtained without using the same.

Table 2

(Pharmacological test example)

Hereinafter, measurement of the agonist activity of the compound (I) of the present invention for the 5-HT _2C receptor and animal experiments using rats will be described in detail.

Example 13

Measurement of agonist activity

 j

A P-hydrolysis assay was performed using CH0 cells expressing human 5-HT _2C and 5-HT _2A receptors. EC ₅ . Values were calculated by non-linear regression analysis. Table 3 shows the results.

Table 3 Agonist activity (EC ₅ , nM)

Target compound: Example 1 of W098 / 56768 1 ((5) — 2— (1 ^ —furo [2, 3 g] indazole—1 yl) 1—1—Methylethylamine hydrochloride) The agonist activity of the compound of the present invention was 1.5 times higher than that of the target compound, and the selectivity was 93 times higher than that of the target compound, which was 93 times higher than that of the target compound. Example 14

Rat penis erecting action

5 — It is known that stimulation of HT _{2 C} receptor induces penile erection (Berendsen & Broekkamp, Eur. J. Pharmacol., 135, 179-184 (1987)). The test compound was administered to the rat, and immediately after the administration, the number of penile erections for 30 minutes was measured to determine the minimum effective dose at which a statistically significant response was observed.

 As a result, the compound of Example 5 showed strong activity with a minimum effective dose of 0.3 mg / kg, po.

Claims

The scope of the claims  1. A furindazole derivative represented by the following formula (I), an optically active compound thereof, or a pharmaceutically acceptable salt thereof.

 (The symbols in the formula have the following meanings. RR ² , R ⁴ and R ⁵ : identical or different, 1 H or alkyl R ³ : alkyl) 2. The compound according to claim 1, wherein RR ² , R ⁴ and R ⁵ are the same or different—H, methyl or ethyl. 3. The compound according to claim 2, wherein R ³ is methyl, ethyl, propyl or isobutyl, R ⁴ is methyl, and the configuration of the carbon substituted by R ⁴ is a configuration.  4. (S) — 2— (7-ethyl) 1-fluoro [2,3-g] indazole-1 — yl) 1-methylethylamine, (S) — 2— (7-ethyl) 3-Methyl J- 1 H-Flo [2,3-g] Indazole — Ί-yl) — 1 —Methylethylamine, (S) 1 2— (3, 7—Jethyl-1H—Flo [2,3—g] indazole-1—yl) — 1-methylethylamine, (S) —1-methyl-2- (7—propyl — 1 H—Flo [2,3—g] Indazo 1-yl) Ethylamine, (S) -Λ / —Ethyl—2- (7—Ethyl 1-Flo [2,3-g] Indazole—1 1-Methylethylamine, (S) -2- (4,7-Jetyl—1H—H- [2,3-g] indazole—Pyryl) —1-Methylethylamine Min, (S) —2— (7-butyl—1H—furo [2,3-g] indazole—1-1yl) 1 1—methylethylamine or (S) -2- (7-isopentyl) 1 H-Flo [2,3_g] indazole-1yl) — 1—Methylethylamine or pharmaceutically acceptable 4. The compound according to claim 3, which is a salt thereof.  5. (S) —2- (7-ethyl-1H-furo [2,3-g] indazol-1-yl) 1-methylethylamine or a pharmaceutically acceptable salt thereof 4. The compound according to item 3, wherein  6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 7. 5-HT _2C Agonisu Bok a is a pharmaceutical composition in the range 6 claim of claim.  8. The pharmaceutical composition according to claim 7, which is a therapeutic agent for impotence.  9. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of impotence.  10. A method for treating impotence, comprising administering to a patient a therapeutically effective amount of the compound of claim 1.  11.1) A compound represented by the following formula (V):

 (The symbols in the formula have the following meanings. R ¹ and R ^{2 are the} same or different and 1 H or alkyl R ³ : alkyl) A compound represented by the following formula (VI) is produced by reacting the amino with a protected amino alkylating agent under basic conditions.

(The symbols in the formula have the following meanings. R ¹ , R ² , R ⁴ and R ⁵ : same or different, 1 H or alkyl R ³ : alkyl R ⁶ : protecting group for amino  2) A process for producing a furindazole derivative represented by the following formula (I), comprising deprotecting the compound (V) obtained in 1).

(R ¹ , R ² , R ⁴ and R ⁵ : — or different — H or alkyl R ³ : alkyl)  12.1) A compound represented by the following formula (IV)

 (The symbols in the formula have the following meanings. (^ And ^{1 2:!?} The same or different and one H or alkyl R ³ : alkyl) By reacting under acidic conditions, a compound represented by the following formula (V) is produced,

 (The symbols in the formula have the following meanings. R ^ iXR ² : same or different 1H or alkyl R ³ : alkyl)  2) reacting the compound (V) obtained in 1) with an amino-protected aminoalkylating agent under basic conditions to produce a compound represented by the following formula (VI);

 (The symbols in the formula have the following meanings. RR ² , R ⁴ and R ⁵ : identical or different, 1 H or alkyl R ³ : alkyl R ⁶ : protecting group for amino  3) deprotecting the compound (VI) obtained in 2), A process for producing a furindazole derivative represented by the following formula (I): (0

R \ RR ⁴ and R ⁵ : same or different, 1 H or alkyl R ³ : alkyl) 13.1) A compound represented by the following formula () is

 (The symbols in the formula have the following meanings. R ^ r R ² : same or different one H or alkyl R ³ : alkyl) By reduction, a compound represented by the following formula (IV) is produced,

 (The symbols in the formula have the following meanings. R ¹ and R ^{2 are the} same or different and 1 H or alkyl R ³ : alkyl)  2) reacting the compound (IV) obtained in 1) under acidic conditions to produce a compound represented by the following formula (V);

(The symbols in the formula have the following meanings. [^ And 1 ^ ² : same or different 1 H or alkyl R ³ : alkyl)  3) reacting the compound (V) obtained in 2) with an aminoalkylide-protected amino-protected compound under basic conditions to produce a compound represented by the following formula (VI);

 (The symbols in the formula have the following meanings. R \ R ² , R ⁴ and R ⁵ : same or different — H or alkyl R ³ : alkyl R ⁶ : protecting group for amino  4) A method for producing a Freundazole derivative represented by the following formula (I), comprising deprotecting the compound (V) obtained in 3).

RR ² , R ⁴ and R ⁵ : same or different—H or alkyl R ³ : alkyl)  14.1) A compound represented by the following formula (II)

(The symbols in the formula have the following meanings. R ^ t / R ² : same or different — H or alkyl) The compound represented by the following formula (III) is produced by acylation under acidic conditions,

 (The symbols in the formula have the following meanings. R ¹ and R, ^{2 are the} same or different and are 1 H or alkyl R ³ : alkyl)  2) By reducing the compound (III) obtained in 1), a compound represented by the following formula (IV) is produced,

 (The symbols in the formula have the following meanings. 1 and 1 ^ ² : same or different 1 H or alkyl R ³ : alkyl) 3) reacting the compound (IV) obtained in 2) under acidic conditions to produce a compound represented by the following formula (V);

 (The symbols in the formula have the following meanings. 1 ^ ¹ and ² : same or different 1H or alkyl R ³ : alkyl)  4) reacting the compound (V) obtained in 3) with an amino-protected aminoalkylating agent under basic conditions to produce a compound represented by the following formula (VI);

 (The symbols in the formula have the following meanings. RR ² , R ⁴ and R ⁵ : same or different—H or alkyl R ^3: Arukizore R ⁶ : protecting group for amino  5) A method for producing a furoindazole derivative represented by the following formula (I), comprising deprotecting the compound (VI) obtained in 4).

RR ² , R ⁴ and R ⁵ : same or different _H or alkyl R ³ : alkyl)  1 5. The following formula (II), (IV), (V) or (VI) or a salt thereof.

 (The symbols in the formula have the following meanings. RR ² , R ⁴ and R ⁵ : same or different—H or alkyl R ³ : alkyl R ⁶ : protecting group for amino