WO1994006772A1

WO1994006772A1 - 3-azabicyclo[3.2.1]octane derivative, production thereof, and use thereof

Info

Publication number: WO1994006772A1
Application number: PCT/JP1993/001280
Authority: WO
Inventors: Nobuyuki Takahashi; Daisuke Mochizuki
Original assignee: Asahi Kasei Kogyo Kabushiki Kaisha
Priority date: 1992-09-11
Filing date: 1993-09-09
Publication date: 1994-03-31

Abstract

An optically active 3-azabicyclo[3.2.1]octane derivative represented by general formula (1), wherein C* represents an asymmetric carbon atom, or a pharmacologically active acid-addition salt thereof, and an antischizophrenic agent containing the same as the active ingredient. The derivative and the salt have not only an antischizophrenic effect without accompanied by any extra-pyramidal side effect but also the effect of relieving the side effects caused by the existing antischizophrenic agents, thus being useful as an antischizophrenic agent free from side effects.

Description

Azabicyclo [3.2.1] octane derivative,

Manufacturing method and its use Industrial application field

The present invention relates to optically active 3- [2- (fluorophenyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane derivatives or pharmacologically acceptable acid addition salts and The present invention relates to an anti-schizophrenic drug characterized by containing as an active ingredient.

Conventional technology

UK Patent 852971 (1959), Acta Pharmacol, ettox icol., 17, 277-287. (1960) and Acta Chemica Scandin av ica, 17 20 69 -2078 (1963) has the general formula

CH ₃ .

H R

(Wherein, R,, R ₂ , R ₃ and R ₄ represent the same or different hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups, hydroxyl groups, nitro groups or amino groups, and n is an integer of 1-3. An N-arylalkylcamphidine derivative represented by the following formula is disclosed. Specifically, the only derivatives having a fluorine group in which an aryl group is substituted with a halogen atom are chlorinated compounds such as N- (p-cyclobenzyl) camphidine and N- (m-cyclobenzyl). ) Kanfijin, Only chlorinated compounds such as N- (o-chloro-benzyl) canthidine, N- (8-0-chloro-phenylethyl) camphidine and N- (α-chloro-phenylpropyl) camphidine are disclosed. ing.

The compounds described in the above-mentioned prior art documents are useful as a depressor activity inhibitor on the centralner voucher and a tranquilizer, and preferably an N-monochloroarylalkylcamfidine derivative, more specifically, N - _(m - black port benzyl) Kanfijin are described as particularly preferred.

Also, some N-arylalkylcamphidine derivatives are disclosed in Pharmaceutical Journal, 84 (10), 918-929 (1964). Specifically, only N- (p-chlorobenzyl) camphidine is disclosed as a derivative having a phenyl group substituted with a halogen atom. In this prior document, the analgesic effect was examined, but it was reported that the compounds specifically mentioned above had no effect.

Among the N-arylalkylcamphidine compounds specifically disclosed in any of the above-mentioned prior documents, the compound having a phenyl group substituted with a halogen atom is only a chlorinated compound, and a fluorinated compound is not yet known. . Moreover, none of the above-mentioned prior art documents described the effectiveness of these known compounds in an apomorphine-induced climbing model that is widely used as an animal model for schizophrenia.

Problems to be solved by the invention

It is known that dopamine nervous system function in the brain is overactive in psychiatric patients. Therefore, conventional anti-schizophrenia drugs have been developed to block dopamine receptors, and typical examples include haloperidol and chlorpromazine. However, these conventional anti-schizophrenia drugs frequently cause extrapyramidal side effects such as parkinsonism, akathisia, and acute dystonia, and chronic intractable late-onset dyskinesia. It is known. Furthermore, there are many cases in which these conventional anti-schizophrenia drugs do not improve.

For these reasons, there is a demand for the development of a new generation of anti-schizophrenic drugs without extrapyramidal side effects. It is possible to predict the occurrence of this extrapyramidal side effect in animal experiments. When cats are given anti-schizophrenic drugs, catalepsy is observed. It is known that the strength of this catalepsy correlates well with the incidence of extrapyramidal side effects in humans. Therefore, it is considered that extracorporeal side effects do not occur even when administered to humans, unless hepatic erythema occurs.

In addition, drugs that improve the strength of leprosy induced by conventional anti-schizophrenia drugs can be therapeutic drugs for these extrapyramidal side effects. However, there are still no anti-schizophrenia drugs other than dopamine receptor blockers, and currently used anti-schizophrenia drugs cause more or less extrapyramidal side effects. Means for solving the problem

Thus, the present inventors have eagerly sought to create a drug that antagonizes apomorphine-induced climbing behavior, does not have a stimulatory effect on potency, and further improves the power induced by conventional antischizophrenic drugs. As a result of an effort and search, they have surprisingly found that a compound represented by the following general formula (1) or a pharmacologically acceptable acid addition salt thereof satisfies these conditions, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1):

CH ₃

CH: CH:

H ₃ CC-CH N— CH ₂ CH ₂

CH: CH:

H (1) (Wherein C * represents an asymmetric carbon atom) or a pharmacologically acceptable acid addition salt thereof.

Further, the present invention provides a compound represented by the following general formula (2):

CH ₃

CH CH:

H ₃ CC-CH3 N-CO-CH2

CH C * CH

H (2)

(Wherein C * represents an asymmetric carbon atom), or reducing the carbonyl group of the compound represented by the general formula (3)

CH ₃

CH: C CH:

CH: C * CH:

H

(Wherein C * represents an asymmetric carbon atom) and the general formula (5)

X-CH ₂ CH ₂ (5)

Wherein X represents a reactive organic sulfonyloxy group, wherein the sulfonyl-inducing pair represented by the general formula (1) is reacted in an inert organic solvent in the presence of a base. Or a pharmacologically acceptable acid addition salt thereof represented by the formula:

Furthermore, the present invention provides an anti-schizophrenic drug comprising, as an active ingredient, an optically active compound represented by the general formula (1) or a pharmacologically acceptable acid addition salt thereof. Is provided.

Examples of the compound of the present invention (1) include the following compounds. (1 R) — 3- [2- (2-Fluorophenyl) ethyl] 1, 8,8-trimethyl-13-azabicyclo [3.2.1] octane,

(1 R) — 3— [2- (3-fluorophenyl) ethyl] 1, 8,8—trimethyl-13-azabicyclo [3.2.1] octane,

(1 R) -3-[2- (4-Monofluorophenyl) ethyl] — 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane,

(1 S) — 3 -— [2- (2-Fluorophenyl) ethyl] 1, 8,8-trimethyl-3-azabicyclo [3.2.1] octane,

(1S) — 3- [2- (3-Fluorophenyl) ethyl] — 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane,

(1 S) — 3— [2- (4-Fluorophenyl) ethyl] — 1,8,8—Trimethyl-3-azabicyclo [3.2.1] octane,

The compound (1) of the present invention can be produced, for example, by the following method. That is, the compound (1) of the present invention can be obtained by reducing the carbonyl group of the compound represented by the general formula (2).

The compound (2) is obtained by converting the amine (3) into a compound of the general formula (4)

HO〇C-I CH. One (4)

Obtained by acylation with the carboxylic acid represented by

Of the above starting materials, amide (3), ie, 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane has an asymmetric carbon atom as shown by the general formula (3), It is used as an R-form or S-form optically active form. The R-form is a known compound described in the literature, for example, Acta. Chem. Scand., 17,269 (1963), Te trahedron Letters, 21, .4 It is described in the literature such as 593 (1980). The S-isomer is a compound that has not been described in the literature, and is prepared by adding (IS) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane-2-one to lithium aluminum hydride in an inert organic solvent. It is obtained by reduction with a reducing agent such as pum.

Examples of the carboxylic acid (4) used in the above acylation reaction include 0-fluorophenylacetic acid, m-fluorophenylacetic acid and ρ-fluorophenylacetic acid.

The above acylation reaction can be carried out according to a known acylation reaction. For example, when the carboxylic acid (4) is used in a free form, the reaction is carried out in the presence of a condensing agent. Examples of the condensing agent include N, N'-dicyclohexylcar positimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl N '-(4-ethylethylamino Cyclohexyl) force Carbodiimide compounds such as rubodiimid, diphenylphosphoryl azide, benzotriabryl N-hydroquinetris (dimethylamino) phosphonidine hexafluorophosphoride, reagents such as carbonyldiimidavour, N-methylformamide, N, Reagents (so-called Vilsmeier reagents) that generate amides such as N-dimethylformamide by reaction with halides such as titanium chloride, phosphorus oxychloride, and phosgene are also included. Other known condensing agents can also be used.

Reactive derivatives of carboxylic acid (4) include acid halides, acid anhydrides, and acids. Preferred are azides, active esters, active amides, and the like. Preferred examples thereof include acid halides such as acid chloride, acid promide, acetic acid, pivalic acid, isovaleric acid, trichloroacetic acid, and monoalkyl carbonate. Mixed anhydride with p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, 1-hydroxyl 1H-pyridone, N-hydroxysuccinine Examples include active esters such as imido and N-hydroxyphthalimidester, and active amides with pyrazole, imidabul, dimethylvirazole, benzotoriabul and the like.

The reaction using an acid halide or acid anhydride among the reactive derivatives in the above acylation reaction is preferably performed in the presence of a deoxidizing agent. Examples of the deoxidizing agent include tertiary organic bases such as triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, and known tertiary organic bases. Inorganic bases are used.

The above acylation reaction is performed in an organic solvent that does not adversely affect the reaction. Examples of the organic solvent include chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane, and N, N-dimethylformamide. , N, N-dimethylacetamide, acetone or a mixture thereof is used. The reaction temperature is not particularly limited, but usually proceeds sufficiently at room temperature. The reaction time depends on the reaction temperature and the reaction solvent and cannot be generally specified, but is about 2 to 30 hours.

In order to collect the compound (2) obtained by the above acylation reaction from the reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is washed with an alkaline aqueous solution, an acidic aqueous solution or a saturated saline solution. After that, the organic layer is concentrated.If the reaction solvent is a hydrophilic organic solvent, the solvent is distilled off, and the residue is dissolved in a non-hydrophilic organic solvent. Compound (2) can be obtained. The compound (2) can be further purified by a known purification method such as silica gel column chromatography.

The carbonyl group of the compound (2) thus obtained is reduced to give the compound of the present invention. The above reaction is carried out by reducing compound (2) with a reducing agent such as lithium aluminum hydride, sodium aluminum hydride or borohydride in an inert organic solvent. Examples of inert organic solvents include tetrahydrofuran, getyl ether, 1,4-dioxane, pyridine and the like.

The above reaction is usually carried out under heating, preferably under reflux. The reaction time depends on the reaction temperature and the type of reducing agent, but the progress of the reaction can be monitored by thin-layer chromatography, high-performance liquid chromatography, etc., and the reaction is performed after the disappearance of compound (2). Should be terminated. Although it cannot be generally specified, it is about 15 minutes to 10 hours.

In order to obtain the desired compound (1) from the obtained reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is washed with an alkaline aqueous solution, an acidic aqueous solution or a saturated saline solution, and then the organic layer is washed. When the reaction solvent is a hydrophilic organic solvent, the solvent is distilled off, the residue is dissolved in a non-hydrophilic organic solvent, and the mixture is treated in the same manner as described above to obtain the desired compound (1). Obtainable. The compound (1) can be further purified by a known purification method such as silica gel column chromatography.

In addition, compound (1) of the present invention can also be obtained by the following alternative method. That is, the present invention compound (1) is obtained by reacting the amine (3) with the sulfonyl derivative represented by the general formula (5) in an inert organic solvent in the presence of a base. The above sulfonyl derivative (5) is obtained by sulfonylation of fluorophenylethyl alcohol with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in a dry inert organic solvent such as methylene chloride. Can be Examples of the base used in the reaction of the amine (3) with the sulfonyl derivative (5) include, for example, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, pyridine, Tertiary organic bases such as N, N-dimethylaminopyridine, and carbonates and coals of alkaline and alkaline earth metals Inorganic bases such as oxyhydrogen salts, hydroxides and hydrides.

Examples of the above-mentioned inert organic solvents include acetonitrile, benzene, acetone, tetrahydrofuran and the like, with acetonitrile being particularly preferred. The above reaction is usually performed appropriately at the reflux temperature of the reaction solvent used. The reaction time depends on the reaction temperature and the type of base, but the progress of the reaction can be monitored by thin-layer chromatography, high-performance liquid chromatography, etc., and the reaction is waited for after the disappearance of amine (3). It should just end. Although it cannot be generally specified, it is about 2 to 24 hours.

In order to obtain the desired compound (1) from the above reaction solution, insoluble substances are removed by filtration, the solvent is concentrated, and the residue is purified by a known method such as silica gel column chromatography using a mixture of chloroform and acetone as an eluent. It can be purified by the purification method described above.

In the present invention, if the compound (1) of the present invention is disclosed, it is easy to produce by combining known reactions, not limited to the production method described above. The compound (1) of the present invention thus obtained can be converted into a pharmacologically acceptable acid addition salt thereof, if necessary. Examples of such salts include salts with inorganic acids such as hydrochloric, sulfuric, and phosphoric acids, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, and aspartic acid. And acid addition salts with organic acids such as methanesulfonic acid, mandelic acid, ρ-toluenesulfonic acid, and maleic acid.

It is clear from the fact that no mortality was observed when 3 OmgZkg of the compound of the present invention (1) or any of its pharmacologically acceptable acid addition salts was intravenously administered to the rat. It can be said that the compound is safe even when used as a medicine. In order to use the compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof as a medicament, it is necessary to formulate the compound and administer it orally or parenterally, for example, by injection including infusion. The dosage varies depending on the dosage form, age, weight, and symptoms of the recipient, but is generally 0.1 mg-l O Omg per adult per day. It is about.

Examples of the dosage form for the formulation include tablets, pills, powders, granules, capsules, and injections. For the production thereof, various carriers corresponding to these formulations, for example, Oral preparations such as tablets, granules and capsules include excipients such as starch, lactose, sucrose, mannite, carboxymethylcellulose, corn starch, inorganic salts, starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, Binders such as sodium carboxymethylcellulose, hydroxypropyl cellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroquinine propyl starch, carboxypropylcellulose, sodium carboxymethylcellulose, Disintegrators such as droxypropyl cellulose, sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, surfactants such as polysorbate 80, talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate A lubricant such as calcium stearate, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, and the like can be used.

The compound (1) of the present invention or a pharmacologically acceptable acid addition salt thereof can also be used as a suspending agent, emulsion, syrup, and elixir.

As the parenteral preparation, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like can be generally used as a diluent. If necessary, bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like may be added.

The invention's effect

Next, the pharmacological action of the compound (1) of the present invention and a pharmacologically acceptable acid addition salt thereof (hereinafter, may be simply referred to as “the compound of the present invention”) will be described. 1. Inhibitory effect of apomorphine-induced climbing

When apomorphine, a dopamine agonist, was administered to mice, various abnormal behaviors were observed, and climbing up the cage was particularly related to schizophrenia in humans. It is known that there is a clerk. That is, if a drug has an inhibitory effect on apomorphine-induced climbing in mice, it can be predicted that the drug has an anti-schizophrenic effect in humans.

The compound of the present invention and a control product were administered intraperitoneally to ICR male mice (Charles' River), and 30 minutes later, 2 mg of apomorphine was subcutaneously administered c. 20 to 23 minutes after administration of apomorphine We observed the climbing behavior for 3 minutes before. For the climbing behavior, mice were placed in a stainless steel wire mesh cage, and the time during which the mouse stayed at the top of the cage at least 12 times during the observation was measured. Assuming that the climbing time of the apomorphine alone group was 100%, the time shortening by the test drug was shown by the inhibition rate. The results are as shown in Table 1.

Table 1 Inhibitory effect of apomorphine-induced climbing

Based on the above results, the compound of the present invention was found to be effective in administration of apomorphine at a very low dose. It inhibited evoked climbing behavior and was as effective or better than the antischizophrenic drug chlorpromazine. In addition, the control compounds N- (m-chloro-benzyl) camphidine hydrochloride and N- (yS-0-clo-phenylphenyl) camphidine hydrochloride did not suppress the apomorphine-induced climbing behavior by administration of 1 OmgZkg. From these results, the compound of the present invention (hydrochloride) is very strong anti-schizophrenic unlike N- (m-chlorobenzyl) camphidine hydrochloride and N- (S-0-chlorophenylethyl) camphidine hydrochloride. It was found to have a disease effect.

2. Catalepsy expression

The compound of the present invention and a control product were each intraperitoneally administered to a Wistar male rat (about 180 g, Cirrus River), and the force talpe was measured 30 minutes later. The measurement of force tare was performed as follows.

A 2 mm diameter iron rod wrapped with a thin thread was placed horizontally at a height of 12 cm, and the rat's forelimb was forcibly hung on it, and the time until the rat lowered the forelimb was measured. . The points are 0 points up to 30 seconds, 1 point up to 60 seconds, 2 points up to 120 seconds, 3 points up to 180 seconds, and 4 points over 180 seconds. If it is less than 1 point, it is indicated as 1; if it is 1 or more, it is +; if it is 2 or more, it is +10; if it is 3 or more, it is +++. The results are shown in Table 2.

Table 2 Effect of expression of lepsi-leptic test drug Catalepsi-I (mg / kg intraperitoneal administration) Example No. 1 (hydrochloride) of the present invention (30)

Compound 2 (hydrochloride)-(30)

3 (hydrochloride) 1 (3 0)

4 (hydrochloride)-(30) 5 (Hydrochloride) I (30)

6 (Hydrochloride)-(30) Control haloperidol + + + (2) Many anti-schizophrenic drugs, including haloperidol, can cause severe side effects, mainly extrapyramidal symptoms. Are known. It has been shown that leptospira observed when rats were given antischizophrenic drugs reflects extrapyramidal side effects in humans.

Haloperidol caused significant leptoceptin at a dose of 2 mg / kg, whereas the compound of the present invention did not cause leptoleptic. This indicates that the compound of the present invention exerts a potent therapeutic effect on schizophrenia and is useful as a new type of antischizophrenic drug which does not cause extrapyramidal side effects.

3. Antagonistic action

The compound of the present invention and a control product were each intraperitoneally administered to a Wister male male rat (about 180 g, Cirrus River), and 30 minutes later, 2 mgZ kg of haloperidol was intraperitoneally administered. Thirty minutes later the force talpe was measured. The measurement of leptophora was carried out in the same manner as in the above-mentioned method of measuring catalepsy expression. If the average score is less than 1 point, it is indicated as +++, if not less than 2 points, it is indicated as +10; The results are shown in Table 3.

Table 3 Antagonistic effects on the potency of the test compound Catalepsy

(mgZkg intraperitoneal administration) Example No. 1 (hydrochloride) of the present invention + (0.1) Byebye

3 (hydrochloride) + + (0.1)

4 (hydrochloride) (0.1)

丄

Byon U, 1

Π 1,

Control product Ν— (m—benzyl benzyl) camphor — (10)

Idine hydrochloride

N— (S—0—clofen phenyl (10)) camfidine hydrochloride From the above results, the compounds of the present invention (hydrochloride) described in Examples 1 to 6 are haloperidol-induced catalepsy. It shows antagonism to one. This effect was not observed with the control products N- (m-cloral benzyl) camfidine hydrochloride and N-(/ 9-10-cloral phenylethyl) camfidine hydrochloride.

From the above experimental results, the compound of the present invention does not cause extrapyramidal side effects and exerts an anti-schizophrenic effect, but also has an effect of reducing the side effects caused by existing anti-schizophrenia drugs. It shows that. In contrast, the known N- (m-clo-benzyl) camphidine hydrochloride and N-(/ 5-0-clo-phenylphenyl) camphidine hydrochloride did not show an anti-schizophrenic effect.

From the above, the pharmacological action of the compound (1) of the present invention and the pharmacologically acceptable acid addition salt thereof shows utility as a medicament which could not be expected at all from the known literature. Example

Next, the present invention will be specifically described with reference to Reference Examples and Examples.

The mass fractionation spectrum (MS) of the target product obtained in each Reference Example and each Example And 'Η nuclear magnetic resonance spectra (' Η-NMR) are shown in Tables 4 and 5

Reference example 1

(1 S)-1,8,8-Trimethyl-1-azabicyclo [3.2.1]

(1S) -Camphor 1¾8.3 1 g (54.6 mimol) and hydroquinamine 10-sulfonic acid 9.25 g (81.9 mimol) were heated in acetic acid (20 Om 1) for 7 hours. Refluxed. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was washed with saturated aqueous sodium hydrogen carbonate as a chloroform solution. The organic layer was dried over anhydrous sodium sulfate, and after filtering off the drying agent, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Peco-gel, C200, black form) to give the title compound as white needles. Yield 5.5 7 ^ (55.6% yield)

[H] D ⁵ = +25.0 ° (c 1, methanol) Reference Example 2

(1 S) — 1,8,8—trimethyl-3-azabicyclo [3.2.1.1]

Lithium aluminum hydride 0.88 g (23 mimol) in tetrahydrofuran (2 Om 1) solution (1 S) — 1,8,8-trimethyl-3-azabisik mouth [3.2.1] octane 93 g (ll. 6 mimol) of 2-one was added, and the mixture was refluxed for 22 hours. After the reaction, the reaction product was cooled, and 6N hydrochloric acid and then 5N sodium hydroxide were added thereto to make it alkaline. The insolubles were removed by filtration, and the filtrate was extracted with ethyl ether. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white powder. 70 g (Yield 96.6%)

[H] D ²⁵ = — 17.2 ° (c 1, methanol) Example 1

(1 R) — 3— [2- (2-Fluorophenyl) ethyl] 1, 8,8—trimethyl-3-azabicyclo [3.2.1] octane

A solution of 0.47 ml of 2-fluorophenylethyl alcohol in 1 Oml of methylene chloride was cooled to 0 ° C, 0.3 ml of methanesulfonyl chloride was added, and 0.74 ml of triethylamine was added. And stirred for 7 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this was added 0.67 g of (1R) -1, 8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 1.21 g of lithium carbonate, and 10 m of acetonitrile was added. The solution was heated and refluxed for 14 hours. After the reaction, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (form: black form) to give the title compound. Yield 0.1 3 g

To the obtained title compound, a 2-fold molar amount of a hydrogen chloride methanol solution was added, and the mixture was concentrated and crystallized from diethyl ether to obtain a hydrochloride.

[H]. ²⁵ = + 7.7 ° (c 0.5, methanol) Example 2

(1R) _3— [2- (3-Fluorophenyl) ethyl] 1,1,8,8-trimethyl-3-azabicyclo [3.2.1] octane

(1R) -1, 8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride 0.95 g of methylene chloride 2.0 ml solution was added with 0.84 ml of triethylamine. Stirred at ° C for 30 minutes. To this was added 0.77 g of 3-fluorophenylacetic acid, followed by 1.35 g of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (WSC). Stirred for hours. After the reaction, the reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give (1R) -3- (3-fluorophenylacetyl) -11,8,8-trimethyl-3-azabicyclo [3.2.1] octane. Obtained. Without isolation, the solution was added to a solution of lithium aluminum hydride (0.38 g) in tetrahydrofuran (2Om1) and heated under reflux for 1 hour. After the reaction, the reaction product was cooled, water was added thereto, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (form on mouth) to give the title compound. Yield 1.0 3 g

The product was treated in the same manner as in Example 1 to obtain a hydrochloride.

[] D ²⁵ = + 6.4 ° (c 0.5, methanol) Example 3

(1 R) — 3— [2- (4-Fluorophenyl) ethyl] 1, 8,8-trimethyl-13-azabicyclo [3.2.1] octane

(4) A solution of 1.88 ml of monofluorophenylethyl alcohol in 3 Oml of methylene chloride was cooled to 0 ° C, and 1.4 Oml of methanesulfonyl chloride was added thereto, followed by 2.60 ml of triethylamine. The mixture was gradually returned to room temperature and stirred for 17 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this was added 2.85 g of (1R) -1, 8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 6.22 g of potassium carbonate to make a 4 Oml solution of acetonitrile, and Heated to reflux for hours. After the reaction, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (black-mouthed form) to obtain the title compound. Yield 3.46 g

[H] D ²⁵ = + 7.9 ° (c 0.5, methanol) Example 4

(1 S) — 3 -— [2- (2-Fluorophenyl) ethyl] 1, 8,8—trimethyl-13-azabicyclo [3.2.1] octane

2-fluorophenylethyl alcohol 1.0 1 ml methylene chloride 15 ml The solution was cooled to 0 ° C, 0.7 Oml of methanesulfonyl chloride was added thereto, followed by 1.26 ml of triethylamine, and the mixture was gradually returned to room temperature and stirred for 7 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this was added 43 g of (1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 3.11 g of potassium carbonate, to give a solution of acetonitrile 20m1. The mixture was refluxed while heating. After the reaction, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (form on mouth) to give the title compound. Yield 1.70 g

[H] D ²⁵ = -6.6 ° (c 0.5, methanol) Example 5

(1 S) — 3- [2- (3-Fluorophenyl) ethyl] 1, 8,8-trimethyl-3-azabicyclo [3.2.1] octane

(1S) -1,8,8-Trimethyl-13-azabicyclo [3.2.1] octane hydrochloride 0.95 g of methylene chloride 2 Om 1 solution was added with 0.84 ml of triethylamine. The mixture was stirred at 0 ° C for 30 minutes. 0.77 g of 3-fluorophenylacetic acid and then 1.35 g of WSC were added thereto, and the mixture was gradually returned to room temperature and stirred for 24 hours. After the reaction, the reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give (1S) -3- (3-fluorophenylacetyl) -11,8,8-trimethyl-3-azabicyclo [3.2: 1] octane. Obtained. Without isolation, the solution was added to a solution of lithium aluminum hydride (0.38 g) in tetrahydrofuran (2Om1) and heated under reflux for 1 hour. After the reaction, the reaction product was cooled, water was added thereto, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (form on mouth) to give the title compound. Yield 1.25 g

The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [H] D ² = -7.0 ° (c 0.5, methanol) Example 6

(1 S) — 3 _ [2- (4-fluorophenyl) ethyl] 1, 8,8—trimethyl-1-azabicyclo [3.2.1] octane

(IS) — 1,8,8—, trimethyl-3-azabicyclo [3.2.1] octane hydrochloride 0.95 g of methylene chloride 20 ml of triethylamine 0.84 m 1. The mixture was stirred at 0 ° C for 30 minutes. To this, 0.78 g of 4-fluorophenylacetic acid and then 1.35 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 23 hours. After the reaction, the reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain (1S) -3- (4-fluorophenylacetyl) -11,8,8-trimethyl-13-azabicyclo [3.2.1] octane. Was. Without isolation, the solution was added to a solution of lithium aluminum hydride (0.38 g) in tetrahydrofuran (2Om1) and heated under reflux for 1 hour. After the reaction, the reaction product was cooled, 6 N hydrochloric acid and then 1 N sodium hydroxide were added thereto, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (cloth form: acetone = 20: 1 to 10: 1) to obtain the title compound. Yield 1.10 g.

[] D ²⁵ = —7.4 ° (c 0.5, methanol) Example 7

Production of injections

(1 S) — 3 -— [2- (4-Fluorophenyl) ethyl] 1,1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride 1. Inject Og distilled water After dissolving in 1 L, the pH was adjusted to 6-7 with a 1 N aqueous sodium hydroxide solution, and then sterilized, and this was filled into ampoules in 5 ml increments to obtain an injection. Example 8

Tablet manufacturing

(IS) -3- [2- (4-Fluorophenyl) ethyl] 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride

50.0 mg corn starch 40. Omg crystal. Cellulose 80. Omg magnesium stearate 0.5 mg talc 29.5 mg. One tablet of 20 Omg was obtained by dry tableting.

Table 4 Reference ExamplesH-NMR (CDC 13) δ (p pm) MS

1 0.95 (3 H, s, CH ₃ ), 1.04 (3 H, s (FAB)

, CH ₃ ), 1.10 (3H, s, CH ₃ ), 1.5 1 68

-1.7 (1 H, m, CH ₂ ), 1.7-1.8 (1 (H ⁺ )

Η, m, CH ₂ ), 1.8-1.9 (1 H, m, CH

), 2.0 -2.2 (2 Η, m, CH ₂ ), 3.00

_{(1 Η, d, CH 2} , J = 1 0. 9 Hz), 3. 48

(1 Η, dd, CH ₂ , J = 3.0, 1 0.9 Hz)

, 5.50 (1H, bs, NH)

2 0.75 (3 H, s,, CH ₃ ), 0.86 (3 H, (EI) s, CH ₃ ), 1.03 (3 H, s, CH ₃ ), 1. 1 53 4—1.7 (4 H, m, CH ₂ x 2), 1.8— 2. (M +) 0 (1 H, m, CH), 2.13 (1 H, d, CH ₂

, J = 1 2.9 Hz), 2.42 (1 H, d d, CH

2, J = 3.0, 12.9 Hz), 2.86 (1H,

d, CH ₂ , J = 13.2 Hz), 3.16 (1 H,

d, CH ₂ , J = 1 2.9 Hz)

Example ^J H—NMR (CDC 13) <5 (p pm) MS number

1

1 U. / 0 丄 1, S no, U · 0 kil, s no ヽ u. Γ i D J

9 1 (3 H, s), 1.4-1.8 (5 H, m), 2 27 6.24 (1 H, d, J = 10 .2), 2.38 (1 H ( MH ⁺ ), d, J = 10.2), 2.5-2.7 (2H, m)

, 2.63 (2H, t, J = 7.9), 2.79 (2

H, t, J = 7. 9), 6. 9-7. 3 (4 H, m)

2 0.78 (3 H, s), 0.85 (3H, s), 0. (FAB) 9 1 (3 H, s), 1.4-1.8 (5 H, m), 2 2 76.2 3 (1H, d, J = 10.2), 2.35 (1H (MH ⁺ ), d, J = 10.6), 2.5-2.8 (6 H, m)

, 6.8-7.1 (3 H, m), 7.1-7. 3 (1

H, m) 0.78 (3 H, s), 0.85 (3 H, s), 0. (FAB)

9 1 (3 H, s), 1.5-1.8 (5 H, m), 2 2 7 6

. 2 3 (1 H, d, J = 10. 2), 2.35 (1 Η (ΜΗ +)

, D, J = 1 0.6), 2, 5-2.7 (4 Η, m)

, 2.72 (2H, d d, J = 6.3, 7.6), 6

. 9 5 (2 H, d d, J = 8.6, 8.9), 7.1

7 (2H, d d, J = 5. 6, 8. 6)

0.78 (3H, s), 0.85 (3Η, s), 0. (FAB)

9 1 (3 H, s), 1. 4 1 1.8 (5 Η, m), 2 2 7 6

. 2 3 (1 H, d, J = 1 0.6), 2.38 (1 Η (ΜΗ ⁺ )

, d, J = 1 0.6), 2.5 2 (1 Η, d d, J =

3.3, 10.6.), 2.6-1.2.8 (3Η, m),

2.79 (2H, dd, J = 6.3, 8.6), 6.

9-7.3 (4 H, m)

0.78 (3H, s), 0 • 8 5 (3Η, s), 0. (FAB)

9 1 (3 H, s), 1.5-1.8 .5 (5 Η, m), 2 27 6

. 2 3 (1 H, d, J = 10. ² ), 2.36 (1 Η (ΜΗ ⁺ )

, d, J = 1 0.2), 2 5 1 2.7 (4 Η, m)

, 2.75 (2 H, d d, J = 6.3, 7.3), 6

8-7.0 (3 H, m), 7 1-7.2 (1 Η,

m)

0.78 (3 H, s), 0.85 (3Η, s), 0. (FAB)

9 1 (3 H, s), 1.5--1.8 (5 Η, m), 2 2 7 6 . 2 3 (1 H, d, J = 1 0.6), 2.35 (1 H (MH ⁺ ), d, J = 1 0.6), 2.5-2.7 (4 H, m)

, 2.72 (2H, d d, J = 6. 3, 7.3), 6

. 9 5 (2H, t, J = 8.6), 7.17 (2 H,

d d, J = 5. 6, 8. 6)

Claims

1. General formula (1)

CH:

CH; CH:

of

CH; CH

Bandits

H (1)

(Wherein C * represents an asymmetric carbon atom) or a pharmacologically acceptable acid addition salt thereof.

2. General formula (2)

CH ₃

CH C * CH

H ₃ CC- CH ₃ N-C0-CH ₂

CH: C * CH:

H (2)

Wherein C * represents an asymmetric carbon atom, wherein the carboxy group of the compound represented by the formula is reduced. CH:

CH: C CH:

CH. CH:

H (1)

3. General formula (3)

CH ₃

CH: C * CH:

CH: CH

H

(Wherein C * represents an asymmetric carbon atom) and the general formula (5)

X-CH ₂ CH ₂

(Five)

(Wherein, X represents a reactive organic sulfonyloxy group), wherein a sulfonyl-inducing pair represented by the formula is reacted in an inert organic solvent in the presence of a base.

(1)

CH:

CH: CH:

H ₃ CC-CH ₃ N-CH ₂ CH ₂

CH: CH:

H (1)

(Wherein c * represents an asymmetric carbon atom) or a method for producing a pharmacologically acceptable acid addition salt thereof.

4. General formula (1)

CH ₃

CH: C * CH:

H ₃ C-1 C-1 CH ₃ N-CH ₂ CH ₂

CH: C * CH:

H (1)

(Wherein represents an asymmetric carbon atom) or an pharmaceutically acceptable acid addition salt thereof as an active ingredient.