JP2824381B2 - N- (cycloalkyl) alkylazepine derivatives and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention is novel azepine induction bodies and their having an activity of specifically binding to the sigma receptor
A method for producing the same .

[0002]

2. Description of the Related Art The sigma (σ) receptor is originally μ,
It was defined as one of the opioid receptors together with the δ, κ, and ε receptors. However, since naloxone, an opioid antagonist, has no affinity for the σ receptor, it has recently been classified as an independent receptor rather than an opioid receptor.

[0003] The pharmacological action via the sigma receptor has not yet been elucidated. However, the fact that phencyclidine, which has a psychiatric manifestation effect, has an affinity not only for the NMDA receptor but also for the σ receptor, and that the antischizophrenic drug haloperidol is used for the σ receptor in addition to the dopamine receptor It has also been found that they bind strongly. These facts suggest that the σ receptor may be involved in mental functions. However, few drugs specific to the sigma receptor have been reported.

[0004] British Patent 852971 (1959), Acta Pharmacol. et toxic
ol. , 17, 277-287 (1960) and Ac
taChemica Scandinavica, 1
7, 2069 to 2078 (1963) have the general formula

[0005]

Embedded image (Wherein R ₁ , R ₂ , R ₃ and R ₄ are H, Cl, -N
_{O 2, -NH 2, -CH 3} , shows a -OCH ₃ or -OH group, m is an integer of 1-3. N-substituted phenylalkyl camfidine derivatives represented by the following formulas are disclosed, and depressor activators
y upon the centralnervous
systems) and tranquilizers.

Also, Pharmaceutical Magazine, 84 (10), 918-
929 (1964) has the general formula

Embedded image

Wherein R ′ is H, Cl or —NH ₂ group and m is 1 or 2. An N-substituted phenylalkylcamphidine derivative represented by the formula: It was considered but reportedly not effective. However, none of the above-mentioned prior art documents describes the usefulness of these known compounds in an apomorphine-induced climbing model widely used as an animal model of schizophrenia.

[0008]

DISCLOSURE OF THE INVENTION A drug specific to a sigma receptor has been found, and the discovery of its efficacy is important in developing a new type of drug.

[0009]

Means for Solving the Problems The present inventors have synthesized various compounds and searched widely for their pharmacological actions. As a result, the azepine derivative represented by the following general formula (1) was converted to a sigma receptor. Showed high affinity for other receptors and showed little effect on the inhibitory effect of apomorphine-induced climbing used in the evaluation of anti-schizophrenia. The present invention has been completed based on the above findings.

That is, the present invention provides a compound represented by the general formula

Embedded image [Wherein R is a formula

Embedded image (Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a phenyl group which may have a substituent, and n represents 0 or 1) a lower alkyl group substituted with an optionally several 5-8 cycloalkyl group having a carbon also shows a norbornyl group or a bicyclo [3.3.1] nonyl group, m represents an integer of 0 to 4, C ^* Represents an asymmetric carbon atom], or a salt thereof.

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

Embedded image Wherein C ^* represents an asymmetric carbon atom, p represents an integer of 0 to 3, and R has the same meaning as described above. Or the general formula

[0012]

Embedded image (Wherein, C ^* is an asymmetric carbon atom) amine of the general formula _{X- (CH 2) m-R} (5) ( wherein, represented by, X is a reactive organic sulfonyloxy group or a halogen atom Wherein m is an integer of 0 to 4, and R has the same meaning as described above), wherein the reactive derivative represented by the general formula is reacted in an inert organic solvent in the presence of a base. An object of the present invention is to provide an azepine derivative represented by (1) or a salt thereof.

Further , the present invention provides an azepine derivative represented by the general formula (3) and a salt thereof useful as an intermediate of the azepine derivative represented by the general formula (1) or a salt thereof. is there.

The group R defined in the general formula (1)
Examples thereof include a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an adamantyl group or a noradamantyl group substituted with a halogen atom or a phenyl group which may have a substituent. The above substituent may be substituted on a carbon atom at any position in the adamantane ring and the noradamantane ring. A lower alkyl group means an alkyl group which may have a branched chain having 1 to 4 carbon atoms, and a lower alkoxy group means an alkoxy group which may have a branched chain having 1 to 4 carbon atoms. And a halogen atom means a chlorine atom, a bromine atom, a fluorine atom and the like, and a phenyl group which may have a substituent means 1 to 3 lower alkyl groups, lower alkoxy groups, hydroxyl groups or halogens. A phenyl group which may be substituted with an atom is meant. Group adamantane group and noradamantane group - (CH ₂₎ m
The bonding position with-may be bonded to a carbon atom at any position in the ring.

Examples of the other group R include a cycloalkyl group having 5 to 8 carbon atoms which may be substituted with a lower alkyl group, a norbornyl group, and a bicyclo [3.3.1] nonyl group. Norbornyl group and bicyclo [3.3.1]
Nonyl group and a - (CH ₂₎ bonding site to the m- may be attached to a carbon atom of any position in the ring. Carbon number 5
8 pieces of cyclopentyl Examples of cycloalkyl groups include cyclohexyl, include cycloheptyl and cyclooctyl groups cycloheteroalkyl, a lower alkyl group and the alkyl group which may have 1 to 4 branched chain atoms means.

The azepine derivative (1) of the present invention and a salt thereof are produced by the following method. A). Compound (3)
Target compound (1) wherein m in the general formula (1) is 1 to 4 by reduction of a carbonyl group of

Embedded image (C ^* represents an asymmetric carbon atom, p represents an integer of 0 to 3, and R has the same meaning as described above).

The compound (3) is obtained by converting the amine represented by the general formula (4) into a general formula R- (CH ₂ ) p-COOH (6) (where p represents an integer of 0 to 3, R has the same meaning as described above) or a acyl derivative thereof, or a reactive derivative thereof.

Of the above starting materials, the amine represented by the general formula (4), that is, 1,8,8-trimethyl-3-
Since azabicyclo [3.2.1] octane has an asymmetric carbon atom as represented by the general formula (4), 1 R, or
It is used as an optically active substance of the 1 S form. The 1R-form is a known compound described in the literature, for example, Acta. Che
m. Scand. , 17, 2069 (1963), Te
Trahedron Letters, 21, 4593
(1980). The 1 S form is a compound not described in the literature, and is (1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane-2.
-One is reduced by a reducing agent such as lithium aluminum hydride in an inert organic solvent.

On the other hand, preferred examples of the carboxylic acid represented by the general formula (6) include 1-adamantyl acetic acid, 2-adamantyl acetic acid, 3-methyl-1-adamantyl acetic acid,
-Adamantanecarboxylic acid, 2-adamantyl-3-propionic acid, 2-adamantyl-4-butyric acid, 3-noradamantancarboxylic acid, 2-norbornylacetic acid, 9-bicyclo [3.3.1] nonylacetic acid, cyclohexanecarboxylic acid , Cyclopentanecarboxylic acid, cyclopentylacetic acid, cyclohexylacetic acid, cycloheptylacetic acid, cyclooctylacetic acid, 3-cyclohexylpropionic acid, 4-
Cyclohexyl butyric acid, 4-methyl-cyclo-hexyl acetate,
5-hydroxy-2-adamantyl acetic acid, 5-methoxy-2-adamantyl acetic acid, 5-phenyl-2-adamantyl acetic acid, 4-hydroxy-2-adamantyl acetic acid, 4
-Phenyl-2-adamantylacetic acid and the like.
These In many are known compounds, it is readily available by the respective commercially or synthesized.

The above-mentioned acylation reaction can be carried out according to a known amidation reaction. When the carboxylic acid (6) 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'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3
Carbodiimide compounds such as-(3'-dimethylaminopropyl) carbodiimide (WSC), N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, diphenylphosphoryl azide, benzotriazolyl-N-hydroxytris (dimethylamino) Reagents such as phosphonium hexafluorophosphide salts and carbonyldiimidazole, and reagents for producing amide compounds such as N-methylformamide and N, N-dimethylformamide by reaction with halides such as thionyl chloride, phosphorus oxychloride and phosgene ( So-called Vilsmeier reagent). Other known condensing agents can also be used.

Examples of the reactive derivative of the carboxylic acid (6) include acid halides, acid anhydrides, acid azides, active esters, and active amides. Preferred examples thereof include acid chloride, acid bromide, acetic acid, and the like. Pivalic acid,
Mixed acid anhydrides with isovaleric acid, trichloroacetic acid, monoalkyl carbonate, etc., p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, 1-
Active esters such as hydroxy-1H-pyridone, N-hydroxysuccinimide ester and N-hydroxyphthalimide ester, and active amides such as pyrazole, imidazole, dimethylpyrazole and benzotriazole are exemplified.

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

The quantitative ratio of the amine (4) to the carboxylic acid (6) or its reactive derivative may theoretically be equimolar, but usually the carboxylic acid (6) or its reactive derivative is in excess. Used.

The above-mentioned acylation reaction is carried out in an organic solvent which does not adversely affect the reaction.
Chloroform, methylene chloride, tetrahydrofuran,
1,4-dioxane, N, N-dimethylformamide,
N, N-dimethylacetamide, acetone or a mixed solvent 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 type of the carboxylic acid (6) or a reactive derivative thereof, and cannot be generally specified.
It is up to about an hour.

In order to collect the compound (3) obtained by the acylation reaction from the reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is treated with an alkaline aqueous solution.
After washing with an acidic aqueous solution or a saturated saline solution, the organic solvent layer is concentrated, and 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 compound (3). The compound (3) is further, for example,
It can be purified by a known purification method such as column chromatography and recrystallization.

In the present invention, the compound (3a) is reduced by reducing the carbonyl group of the compound (3) to obtain the compound (1a) of the present invention. , Sodium aluminum hydride, borohydride and the like. Examples of the inert organic solvent include tetrahydrofuran, diethyl ether, 1,4-dioxane, pyridine and the like. The reaction is usually carried out with heating, preferably at reflux. The reaction time depends on the reaction temperature and the type of the reducing agent, but the progress of the reaction can be monitored by thin-layer chromatography, high performance liquid chromatography, etc. It should just end. Although it cannot be specified in general,
It takes about 10 hours.

In order to collect the target compound (1a) obtained by the above reduction reaction from the reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is treated with an acidic aqueous solution, an alkaline aqueous solution, or a saturated saline solution. After washing with water, the organic solvent layer is concentrated, and when the reaction solvent is a hydrophilic organic solvent, the solvent is distilled off and, if necessary, the residue is dissolved in a non-hydrophilic organic solvent. Compound (1a) can be obtained by treating in the same manner as described above. The compound (1
a) is further treated, for example, by column chromatography,
It can be purified by a known purification method such as recrystallization.

B). Production of target compound (1) by N-alkylation of amine (4) The target compound (1) is represented by the general formula

Embedded image ( Wherein C ^* represents an asymmetric carbon atom)
And X- (CH ₂ ) _m -R (5) (wherein, X represents a reactive organic sulfonyloxy group or a halogen atom, m represents an integer of 0 to 4, and R has the same meaning as described above.) ) In an inert organic solvent in the presence of a base.

Among the reactive derivatives (5), the sulfonyloxy derivative is obtained by converting an alcohol represented by the general formula HO— (CH ₂ ) m—R (7) (m is an integer of 0 to 4) into methylene chloride drying reaction inert solvent such as, methanesulfonyl chloride, Ru obtained by sulfonylating the like p- toluenesulfonyl chloride. The example above alcohol (7), 1-adamantyl ethanone nor, 1-adamantyl methanol, 2-adamantyl eth-nor, 2-norbornyl ethanol, 3-noradamantyl methanol, 9-bicyclo [3. 3.1] Nonylethanol, cyclopentyl alcohol, cyclohexyl alcohol, cyclopentylmethanol, cyclohexylmethanol, cycloheptylmethanol, cyclooctylmethanol, cyclopentylethanol, cyclohexylethanol, cyclopentylethanol,
3-cyclohexyl-1-propanol, 4-cyclohexyl-1-butanol, 5-methoxy-2-adamantylethanol, 5-chloro-2-adamantylethanol, 5-phenyl-2-adamantylethanol , 4
-Phenyl-2-adamantylethanol and the like. These are known compounds, each of which is commercially available or easily available by synthesis.

Examples of the halide in the reactive derivative (5) include cyclohexyl bromide, cyclohexylmethyl bromide, 1-adamantyl bromide and 2-adamantyl bromide. These are known compounds and are listed in the catalogs of reagent manufacturers and are readily available.

Examples of the base used in the reaction of the amine (4) with the reactive derivative (5) include, for example, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, pyridine, N , N
Tertiary organic bases such as dimethylaminopyridine and inorganic bases such as carbonates, bicarbonates, hydroxides or hydrides of alkali or alkaline earth metals.

Examples of the inert organic solvent used in the above reaction include acetonitrile, benzene, acetone, tetrahydrofuran and the like, and acetonitrile is 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. It should just end. Although it cannot be generally specified, it is usually about 2 to 72 hours.

In order to obtain the desired compound (1) from the above reaction mixture, insoluble substances are removed by filtration, the solvent is concentrated, and the residue is subjected to silica gel column chromatography using, for example, a mixture of chloroform, acetone and methanol as an eluent. It can be purified by a known purification method such as In the present invention, as long as 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 salt, and if necessary, a pharmaceutically acceptable non-toxic salt. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acid, Examples thereof include acid addition salts with organic acids such as methanesulfonic acid, mandelic acid, p-toluenesulfonic acid, and maleic acid.

As is clear from the fact that no death was observed when the compound (1) of the present invention or a non-toxic salt thereof was intravenously administered to rats at 30 mg / kg.
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 non-toxic salt thereof as a medicament, it may be prepared into a pharmaceutical preparation and usually administered orally or parenterally by injection including infusion. Dosage form, age, weight,
In general, the dose is about 0.1 mg to 100 mg per day for an adult, although it varies depending on symptoms and the like.

The dosage forms for the above formulation include tablets,
Pills, powders, granules, capsules, injections and the like are mentioned. For the production thereof, various carriers according to these preparations, for example, tablets, granules, oral preparations such as capsules include starch. Excipients such as lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts,
Binders such as starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropylstarch, carboxypropylcellulose, carboxymethylcellulose Disintegrants such as sodium and hydroxypropylcellulose; surfactants such as sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester and polysorbate 80; lubricating agents such as talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate and calcium stearate. Lubricants, glidants, flavoring agents, coloring agents, flavors and the like can be used.

The compound (1) of the present invention or a non-toxic salt thereof can also be used as a suspension, emulsion, syrup or elixir. As the parenteral agent, 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, a bactericide, preservative, stabilizer, tonicity agent, soothing agent and the like may be added.

[0039]

The ability of the target compound (1) or a non-toxic salt thereof to bind to the sigma receptor was measured by the following method. The results are shown in Table 1. (A) Reference (Proc. Natl. Acad. Sci.
USA, vol. 83, 8784-8788 (198
6), E. The binding ability of the compound of the present invention to the sigma receptor was measured according to the method described by Weber et al.

The spray dolly (Sprague-Da)
wley) male rats (7 weeks old, Charles River)
After decapitation, remove the brain immediately and remove 5
After homogenization with 0 mM Tris / HCl buffer (pH 8.0, TH buffer), the mixture was centrifuged at 700 × g for 10 minutes. The supernatant was centrifuged at 48,000 × g for 15 minutes, and the obtained precipitate was resuspended in TH buffer and incubated at 37 ° C. for 20 minutes. This was centrifuged at 48,000 × g for 15 minutes, and the resulting precipitate was suspended in a TH buffer to prepare a membrane preparation.

The membrane sample (about 600 μg protein) and [ ³
H] 1,3-di (2-tolyl) guanidine (DTG, N
ew England Nuclear) (final concentration: 3 nM) was reacted at 25 ° C. for 60 minutes, the reaction was stopped by suction filtration with a Wattman GF / C filter, and the radioactivity adsorbed on the filter was measured by scintillation. > Measured with a ration counter, and the obtained value was used as the total binding amount. The amount of nonspecific binding (NB) was determined by adding 10 μM of haloperidol and measuring in the same manner. In order to measure the binding amount of the sample, an appropriate concentration of the sample was added in place of haloperidol, and the same measurement was performed to obtain a measured value (DTB) in the sample.

(B) Calculation Method of Ki Value (Affinity of Drug for Receptor) The binding inhibition rate of a sample at a certain concentration was calculated by the following calculation method. Binding inhibition rate (%) = [1- (DTB-NB)
{(TB-NB)] × 100 The binding inhibition rate at an appropriate concentration (from high concentration to low concentration) was determined for each sample, and the logarithmic value of the concentration was plotted on the horizontal axis, and the binding inhibition rate was plotted on the vertical axis, and the nonlinearity was plotted. A curve was drawn by the least squares method, and an IC50 value was determined.

The Ki value was calculated by the following equation. Ki = (IC50) ÷ [1+ (L) / Kd] where (L) is the concentration of the radioligand used in the experiment (3 nM), and Kd is the concentration (10.6 nM) representing the affinity of the radioligand for the receptor. ), IC50 is the drug concentration that inhibits the binding between the receptor and the radioligand by 50%. Table 1 shows the binding ability to the sigma receptor.

[0044]

[Table 1]

As is apparent from the test examples, the present compound (1) or its non-toxic salts have a high affinity for the sigma receptor, it had little affinity for other receptors.

Next, the pharmacological action of the compound (1) of the present invention will be described. Inhibitory effect of apomorphine-induced climbing When apomorphine, a dopamine agonist, is administered to mice, various abnormal behaviors are observed, and it is known that climbing behavior in the cage (climbing) is closely related to schizophrenia in humans. Have been. That is, if a certain 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 was orally administered to male ICR mice (Charles River), and 30 minutes later, 2 mg / kg of apomorphine was subcutaneously administered. Climbing behavior for 3 minutes from 20 to 23 minutes after administration of apomorphine was observed. Climbing was performed by placing the mouse in a stainless steel wire mesh cage.
The time of staying two or more at the top was measured. Assuming that the climbing time of the apomorphine alone group was 100%, the time reduction by the test drug was shown by the inhibition rate. Table 2 shows the inhibitory effect of apomorphine-induced climbing.

[0048]

[Table 2]

Compound (1) of the present invention inhibited apomorphine-induced climbing behavior. From these results, it was confirmed that the compound (1) of the present invention has a very strong antischizophrenic effect.

As is apparent from the test examples, the present compound (1) or its non-toxic salts have a high affinity for sigma receptors, hardly exhibit affinity for other receptors, also Effective against the apomorphine-induced climbing that has been used in the evaluation of anti-schizophrenia, and can be advantageously used in the treatment of sigma receptor-related diseases such as schizophrenia .

[0051]

EXAMPLES Next, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The mass spectrometry (MS) and nuclear magnetic resonance spectrum of the compound obtained in the Reference Examples and Examples ⁽¹ H-NMR) are shown in Table 3-4.

Reference Example 1 (1S) -1,8,8-trimethyl-3-azabicyclo
[ 3.2.1 ] Octane-2-one (1S) -camphor (8.31 g) and hydroxylamine-O-
9.25 g of sulfonic acid was heated and refluxed in 200 ml of acetic acid for 7 hours. After the reaction, the reaction mixture 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 desiccant, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wako gel, C200, chloroform) to obtain the title compound. 5.57 g (yield 56
%) [Α] _D ²⁵ = + 25.0 ° (c 1, methanol)

Reference Example 2 (1S) -1,8,8-Trimethyl-3-azabicyclo
[ 3.2.1 ] octane (1S) -1,8,8 was added to a solution of 0.88 g of lithium aluminum hydride in 20 ml of tetrahydrofuran (THF).
1.93 g of -trimethyl-3-azabicyclo [3.2.1] octan-2-one was added, and the mixture was refluxed for 22 hours.
After the reaction, the mixture was cooled, and 6N hydrochloric acid and then 5N sodium hydroxide were added to make the mixture alkaline. The insoluble material was separated by filtration, the filtrate was extracted with diethyl ether (ether), dried over anhydrous sodium sulfate, and after filtering the desiccant, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 1.70 g (97% yield) [α] _D ²⁵ = -17.2 ° (c 1, methanol)

Example 1 (1S) -3- [2- (1-adamantyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [ 3.2.
1 ] octane (1S) -1,8,8-trimethyl-3-azabicyclo
To a solution of [ 3.2.1 ] octane hydrochloride (490 mg) in methylene chloride (20 ml) was added triethylamine (0.43 ml), and the mixture was stirred at 0 ° C for 1 hour. There, 552 mg of 1-adamantyl acetic acid, followed by 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC).
After adding 595 mg, the mixture was gradually returned to room temperature and stirred for 23 hours. After the reaction, it was washed with 10% sodium hydroxide and dried over anhydrous sodium sulfate. After filtration of the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3- (1-adamantylacetyl).
-1,8,8-Trimethyl-3-azabicyclo [ 3.
2.1 ] Octane was obtained.

This was added without isolation to a solution of 196 mg of lithium aluminum hydride in 25 ml of THF,
The mixture was refluxed for 1 hour. After the reaction, the reaction mixture was cooled, ether, water and a 10% aqueous sodium hydroxide solution were added thereto, and the insolubles were filtered off. The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform) to obtain the title compound. Yield 737mg
A 2-fold molar amount of a methanol solution of hydrogen chloride was added to the obtained title compound, and the mixture was concentrated and crystallized from diethyl ether to obtain a hydrochloride. [Α] _D ²⁵ = −8.6 ° (c = 0.5, methanol)

Example 2 (1S) -3- [2- (2-norbornyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [ 3.2.
1 ] octane (1S) -1,8,8-trimethyl-3-azabicyclo
To a solution of [ 3.2.1 ] octane hydrochloride (485 mg) in methylene chloride (20 ml) was added triethylamine (0.43 ml), and the mixture was stirred at 0 ° C for 40 minutes. Thereto was added 0.41 ml of 2-norbornylacetic acid, and subsequently 588 mg of WSC, and the mixture was gradually returned to room temperature and stirred for 23 hours. After the reaction, concentration under reduced pressure,
It was made into an ether solution, washed with 5N sodium hydroxide, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3- (2-norbornylacetyl) -1,8,8-trimethyl-3-azabicyclo.
[ 3.2.1 ] Octane was obtained.

This was added without isolation to a solution of 194 mg of lithium aluminum hydride in 20 ml of THF,
The mixture was refluxed for 1 hour. After the reaction, the reaction mixture was cooled, ether, water and a 10% aqueous sodium hydroxide solution were added thereto, and the insolubles were filtered off. The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was purified by flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-chloroform: acetone = 20: 1) to obtain the title compound. I got something. Yield: 618 mg (88% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -11.3 ° (c = 0.5, methanol)

Example 3 (1S) -3- (2-cyclopentylethyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane (1S) -1,8,8-trimethyl-3-azabicyclo
[ 3.2.1 ] 0.43 ml of triethylamine was added to a solution of 0.49 g of octane hydrochloride in 20 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 45 minutes. Thereto, 0.36 ml of cyclopentylacetic acid and 0.59 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 24 hours. The reaction solution was washed with 10% sodium hydroxide and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3.
-Cyclopentylacetyl-1,8,8-trimethyl-
3-Azabicyclo [ 3.2.1 ] octane was obtained.

This was added without isolation to a solution of 0.19 g of lithium aluminum hydride in 30 ml of THF.
The mixture was refluxed for half an hour. The reaction solution was cooled, ether, water and 10% sodium hydroxide were added, and the insolubles were filtered off. The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was purified by flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-chloroform: acetone = 20: 1), and the title compound was obtained. I got Yield: 0.58 g (yield: 91%) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -11.8 ° (c 0.5, methanol)

Example 4 (1S) -3- (2-cyclohexylethyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane (1S) -1,8,8-trimethyl-3-azabicyclo
To a solution of [ 3.2.1 ] octane hydrochloride (0.95 g) in methylene chloride (20 ml) was added triethylamine (0.84 ml), and the mixture was stirred at 0 ° C. for 30 minutes. 0.72 g of cyclohexylacetic acid and 1.35 g of WSC were added thereto, and the mixture was gradually returned to room temperature and stirred for 25 hours. The reaction solution was washed with a saturated saline solution and dried over anhydrous sodium sulfate. After filtering the desiccant,
The filtrate was concentrated under reduced pressure to give crude (1S) -3-cyclohexylacetyl-1,8,8-trimethyl-3-azabicyclo.
[ 3.2.1 ] Octane was obtained.

This was added without isolation to a solution of 0.38 g of lithium aluminum hydride in 30 ml of THF.
Heated to reflux for an hour. The reaction solution was cooled, 6N hydrochloric acid and then 1N sodium hydroxide were added, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wakogel, C200, chloroform: acetone: methanol = 10: 1: 0.1) to give the title compound. Yield: 1.01 g (yield: 77%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -11.5 ° (c 0.5, methanol)

Example 5 (1R) -3-cyclohexylacetyl-1,8,8-
Trimethyl-3-azabicyclo [3.2.1] octane (1R) -1,8,8-trimethyl-3-azabicyclo
To a solution of [ 3.2.1 ] octane hydrochloride (0.95 g) in methylene chloride (20 ml) was added triethylamine (0.84 ml), and the mixture was stirred at 0 ° C. for 30 minutes. 0.72 g of cyclohexylacetic acid and 1.35 g of WSC were added thereto, and the mixture was gradually returned to room temperature and stirred for 24 hours. 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, and the residue obtained was purified by silica gel column chromatography (Wako gel, C200, chloroform: methanol = 50: 1) to obtain the title compound. Yield 0.52 g (37% yield)

Example 6 (1R) -3- (2-cyclohexylethyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane Lithium aluminum hydride 0.15g THF 20m
1 solution to (1R) -3-cyclohexylacetyl-1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
0.52 g of octane was added, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled, water was added, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wakogel, C200, chloroform: acetone:
Purification with methanol (5: 1: 0.1) gave the title compound. Yield: 0.30 g (61% yield) Treatment was carried out in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = + 11.6 ° (c 0.5, methanol)

Reference Example 3 Methylcycloheptylidene acetate 1.18 ml of cycloheptanone and 2.21 ml of methyl diethylphosphonoacetate were dissolved in 10 ml of benzene, and 0.08 g of sodium hydride (60%, oil dispersion) was dissolved.
Was added, and the mixture was heated and refluxed at room temperature for 15 hours and then for 6 hours. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wako gel, C200, chloroform) to obtain the title compound. Yield 1.20 g (yield 71
%)

Reference Example 4 Cycloheptylethyl alcohol Lithium aluminum hydride 0.81 g of THF 35 m
1 solution of methylcycloheptylidene acetate 1.20
g was added and heated under reflux for 4 hours. Cool the reaction and add 1
0% sodium hydroxide was added and the insolubles were filtered off. The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. This is methanol 5
The mixture was dissolved in 0 ml, and 0.12 g of 10% Pd-C was added thereto, followed by catalytic reduction at room temperature and normal pressure for 4 hours under a hydrogen stream. After the reaction, Pd-C was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.45 g (Yield 45%)

Example 7 (1S) -3- (2-Cycloheptylethyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane cycloheptylethyl alcohol (0.45 g) was dissolved in methylene chloride (20 ml), cooled to 0 ° C., added with methanesulfonyl chloride (0.30 ml), and then triethylamine (0.62 ml).

The reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound.
0.51 g of (1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 1.10 g of potassium carbonate were added thereto, and the mixture was heated under reflux for 24 hours as a 20 ml solution of acetonitrile. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (Merck, silica gel 60:
Purification with 230-600 mesh, chloroform) gave the title compound. Yield: 0.61 g (yield: 82%) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -11.7 ° (c 0.5, methanol)

Reference Example 5 Methylcyclooctylidene acetate 2.00 g of cyclooctanone and 3.50 ml of methyl diethylphosphonoacetate were dissolved in 20 ml of THF.
2.67 g of potassium tertiary butoxide
Was added dropwise over 20 minutes. The mixture was gradually returned to room temperature and stirred for 12 hours. Water was added to the reaction solution, and only THF was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wakogel,
(C200, chloroform) to give the title compound. 1.33 g (46% yield)

Reference Example 6 Cyclooctyl acetic acid methyl ester 0.50 g of methyl cyclooctylidene acetate was dissolved in 5 ml of methanol, 0.10 g of 10% Pd-C was added, and catalytic reduction was carried out for 3 hours at room temperature and normal pressure under a hydrogen stream. Was.
After the reaction, Pd-C was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.45 g (88% yield)

Reference Example 7 Cyclooctylacetic acid 0.45 g of cyclooctylacetic acid methyl ester was dissolved in 10 ml of methanol, and 4.0 ml of 1N sodium hydroxide was added thereto, followed by stirring at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was washed with ether.
The aqueous layer was cooled, acidified with 6N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.
28 g (67% yield)

Example 8 (1S) -3- (2-Cyclooctylethyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane (1S) -1,8,8-trimethyl-3-azabicyclo
To a solution of 0.28 g of [ 3.2.1 ] octane hydrochloride in 10 ml of methylene chloride was added 0.24 ml of triethylamine, and the mixture was stirred at 0 ° C. for 30 minutes. Thereto was added 0.25 g of cyclooctylacetic acid, followed by 0.40 g of WSC, and the mixture was gradually returned to room temperature and stirred for 21 hours. 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 crude (1S) -3-cyclooctylacetyl-1,8,8-trimethyl-3-azabicyclo [3.2.1] octane.

This was added without isolation to a solution of 0.12 g of lithium aluminum hydride in 15 ml of THF.
Heated to reflux for an hour. The reaction solution was cooled, water was added, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wakogel, C200,
Purification with chloroform: acetone = 10: 1) gave the title compound. Yield: 0.26 g (61% yield) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -12.9 ° (c 0.5, methanol)

Example 9 (1S) -3- (4-Cyclohexyl-1-butyl)-
1,8,8-Trimethyl-3-azabicyclo [ 3.2.
1 ] Octane 4-cyclohexyl-1-butanol (0.52 ml) was dissolved in methylene chloride (20 ml), cooled to 0 ° C., added with methanesulfonyl chloride (0.28 ml), and then triethylamine (0.50 ml). Half agitated. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl form.

To this was added (1S) -1,8,8-trimethyl-3-azabicyclo [ 3.2.1 ] octane hydrochloride.
47 g and potassium carbonate (1.04 g) were added, and the mixture was heated under reflux for 15 hours as a 20 ml solution of acetonitrile. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform).
And the title compound was obtained. Yield 0.55 g (yield 75%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -13.1 ° (c 0.5, methanol)

Example 10 (1S) -3- (3-Cyclohexylpropyl) -1,
8,8-Trimethyl-3-azabicyclo [ 3.2.1 ]
Octane (1S) -1,8,8-trimethyl-3-azabicyclo
[ 3.2.1 ] 0.43 ml of triethylamine was added to a solution of 0.49 g of octane hydrochloride in 20 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 40 minutes. Thereto, 3-cyclohexyl propionic acid 0.44 ml, followed by WSC0.59g
, And the mixture was gradually returned to room temperature and stirred for 45 hours. The reaction solution was concentrated under reduced pressure, the residue was converted to an ether solution, washed with 10% sodium hydroxide, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3- (3
-Cyclohexylpropionyl) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane was obtained.

This was added without isolation to a solution of 0.19 g of lithium aluminum hydride in 20 ml of THF.
The mixture was refluxed for half an hour. The reaction solution was cooled, ether, water and 10% sodium hydroxide were added, and the insolubles were filtered off.
The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-
Purification with chloroform: acetone = 20: 1) gave the title compound. Yield: 0.56 g (79% yield) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = 11.3 ° (c 0.5, methanol)

Example 11 (1S) -3-cyclohexylmethyl-1,8,8-trimethyl-3-azabicyclo [ 3.2.1 ] octane (1S) -1,8,8-trimethyl-3-azabicyclo
[ 3.2.1 ] Octane hydrochloride (0.50 g) and cyclohexylmethyl bromide (0.44 ml) were mixed with acetonitrile 2
The mixture was dissolved in 5 ml, and potassium carbonate (1.10 g) was added thereto, followed by heating under reflux for 26 hours. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (Merck, silica gel 60: 230-
Purification was performed using 600 mesh, chloroform-chloroform: acetone = 20: 1) to obtain the title compound. Yield: 0.66 g (100% yield) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -11.0 ° (c 0.5, methanol)

Example 12 (1R) -3-cyclohexylmethyl-1,8,8-trimethyl-3-azabicyclo [ 3.2.1 ] octane (1R) -1,8,8-trimethyl-3-azabicyclo
[ 3.2.1 ] 3.00 g of octane and 5.48 ml of cyclohexylmethyl bromide were added to 50 ml of acetonitrile.
, And 6.78 g of potassium carbonate was added thereto, followed by heating under reflux for 39 hours. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wako gel, C200, chloroform) to obtain the title compound. 4.62 g (yield 9)
5%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 13.0 ° (c 0.5, methanol).

Example 13 (1S) -3-cyclohexyl-1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S) -1,8,8-trimethyl-3-azabicyclo [3 2.2.1] Octane hydrochloride 0.12 g and cyclohexyl bromide 0.092 ml were mixed with acetonitrile 5 ml
And 0.26 g of potassium carbonate was added thereto, followed by heating under reflux for 51 hours. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to flash column chromatography (Merck, silica gel 60: 230-600).
Mesh, chloroform to chloroform: acetone = 2
0: 1) to give the title compound. Yield 32.0
mg (yield: 22%) The same treatment as in Example 1 was carried out to obtain a hydrochloride.

Example 14 (1R) -3- [2- (1-adamantyl) ethyl]-
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 (5.0 mmol) and 1-adamantyl acetic acid 1.17 g (6.0 mmol) In the same manner as in the synthesis of the compound of Example 1 and silica gel column chromatography (Wako-gel, C2
00, chloroform: acetone = 20: 1),
The title product was obtained. Yield: 1.21 g (yield: 77%) Treatment was carried out in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = + 9.2 ° (c 0.5, methanol).

Reference Example 8 Methyl 2-adamantylidene acetate 115.00 g (0.77 mol) of 2-adamantanone and 210.78 ml of methyl diethylphosphonoacetate
A solution (1.15 mol) of methanol in 500 ml was cooled to 0 ° C., 371.7 g of a 28% methanol solution of sodium methylate was added dropwise, and the mixture was gradually returned to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate.
After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (Wako-gel, C20
0, normal hexane: ethyl acetate = 20: 1) to obtain the title compound. Yield 157.70 g (Yield 1
00%)

Reference Example 9 2-adamantyl acetic acid methyl ester methyl 2-adamantylidene acetate 145 g
(0.74 mol) in 1150 ml of methanol
% Palladium on carbon 2.90 g and ammonium formate 178
g (2.8 mol) was added and the mixture was stirred at room temperature for 3 hours. Palladium carbon was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 146.41 g (100% yield)

Reference Example 10 2-adamantyl acetic acid 2-adamantyl acetic acid methyl ester 150 g (0.7 g)
433 ml of 2.5 N sodium hydroxide was added to a solution of 2 mol) in methanol (1125 ml), and the mixture was stirred at room temperature for 6 hours.
The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 12N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield: 129.39 g (93% yield)

Example 15 (1S) -3- [2- (2-adamantyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] Octane (1S) -1,8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (0.78 g, 4.1 mmol) in methylene chloride (20 ml) was treated with 0.69 ml (5. (0 mmol) and stirred at 0 ° C. for 30 minutes. There, 0.80 g of 2-adamantyl acetic acid
(4.1 mmol), followed by 1.11 g of WSC (5.7
9 mmol), and the mixture was gradually returned to room temperature and stirred for 23 hours. The reaction solution was washed with a saturated saline solution and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3- (2-adamantylacetyl) -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane obtained.

Without isolation, 0.47 g (12 mmol) of lithium aluminum hydride in THF 50
The mixture was added to the resulting solution and heated under reflux for 2 hours. Cool the reaction solution,
Water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wako-
Gel, C200, chloroform: acetone = 10: 1 to 1
5: 1) to give the title compound. 1.26 yield
g (yield 97%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -10.2 ° (c 0.5, methanol)

Example 16 (1R) -3- [2- (2-adamantyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] Octane (1R) -1,8,8-trimethyl-3-
0.38 g of azabicyclo [3.2.1] octane hydrochloride
(2.0 mmol) and 0.43 g of 2-adamantyl acetic acid
(2.2 mmol), and reacted in the same manner as in the synthesis of the compound of Example 15; silica gel column chromatography (Wako-gel, C200, chloroform: acetone = 10:
Purification in 1) gave the title compound. Yield 0.57g
(Yield: 91%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 10.5 ° (c 0.5, methanol)

Reference Example 11 2-adamantylethanol To a solution of lithium aluminum hydride (0.16 g, 4.2 mmol) in diethyl ether (20 ml) was added 2-adamantylacetic acid methyl ester (0.57 g, 2.7 mmol). Heated to reflux for an hour. The reaction solution was cooled, water was added, and insolubles were removed by filtration. The filtrate was extracted with ether and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure,
The title product was obtained. Yield 0.23 g (47% yield)

Example 17 (1S) -3- [2- (2-adamantyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] A solution of 0.64 g (3.6 mmol) of octane 2-adamantyl ethanol in 10 ml of methylene chloride was cooled to 0 ° C., and 0.42 ml (5.4 mmol) of methanesulfonyl chloride was added, followed by 1.00 ml of triethylamine (7 ml). .17 mmol) and gradually returned to room temperature and stirred for 15 hours. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl form.

To this was added ( 1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride.
68 g (3.6 mmol) and potassium carbonate 1.49 g
(10.8 mmol) and 30 ml of acetonitrile
It was made into a solution and heated under reflux for 18 hours. The insoluble matter of the reaction solution was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wako-gel, C200, chloroform: acetone = 20: 1 to 5: 1),
The title product was obtained. Yield: 0.59 g (53% yield) The same treatment as in Example 1 was carried out to obtain a hydrochloride.

Example 18 (1S) -3- [2- (4-Methylcyclohexyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S) -1,8 To a solution of 0.95 g of 8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 20 ml of methylene chloride was added 0.84 ml of triethylamine, followed by stirring at 0 ° C for 30 minutes. There, 0.94 g of 4-methylcyclohexyl acetic acid and subsequently 1.35 g of WSC were added,
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 obtain crude (1S) -3- (4-methylcyclohexylacetyl) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane.

This was added without isolation to a solution of 0.39 g of lithium aluminum hydride in 30 ml of THF.
Heated to reflux for an hour. After the reaction, the reaction mixture was cooled, water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wako-gel, C200,
Purification with chloroform: acetone = 10: 1) gave the title compound. Yield: 1.37 g (100% yield) The same treatment as in Example 1 was performed to obtain a hydrochloride. [Α] _D ²⁵ = -11.0 ゜ (c 0.5, methanol)

Example 19 (1S) -3- [2- (3-Methyl-1-adamantyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S)- 0.53 ml of triethylamine was added to a solution of 0.51 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 15 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 30 minutes. Thereto, 0.68 g of 3-methyl-1-adamantylacetic acid and subsequently 0.73 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 23.5 hours. After the reaction,
The extract 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 crude (1S) -3-.
(3-methyl-1-adamantylacetyl) -1,8,
8-Trimethyl-3-azabicyclo [3.2.1] octane was obtained.

This was added without isolation to a solution of 0.21 g of lithium aluminum hydride in 15 ml of THF.
Heated to reflux for an hour. After the reaction, the reaction mixture was cooled, water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography (Merck, silica gel 6).
0: 230-600 mesh, chloroform) to give the title compound. Yield 0.63 g (yield 71
%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -9.4 ゜ (c 0.5, methanol)

Example 20 (1S) -3- (3-Noradamantylmethyl) -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane (1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] 0.096 ml of triethylamine was added to a solution of 100 mg of octane hydrochloride in 5 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 30 minutes. There, WSC 0.132g,
Subsequently, 96.5 mg of 3-noradamantanecarboxylic acid was added, and the mixture was gradually returned to room temperature and stirred for 15.5 hours. 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 crude (1S) -3.
-(3-noradamantylcarbonyl) -1,8,8-
Trimethyl-3-azabicyclo [3.2.1] octane was obtained.

Without isolation, this was added to a solution of 24.0 mg of lithium aluminum hydride in 10 ml of THF, and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Wakogel, C2
00, chloroform) to give the title compound.
Yield: 118.2 mg (yield: 78%) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = −9.4 ゜ (c 0.5, methanol)

Reference Example 12 Methyl 9-bicyclo [3.3.1] nonylidene acetate 0.50 g of bicyclo [3.3.1] nonan-9-one and 1.00 ml of methyl diethylphosphonoacetate
0.30 g of sodium hydride (60%, oil dispersion) was added to 10 ml of 2-dimethoxyethane (DME) solution, and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction solution to decompose unreacted sodium hydride, DME was concentrated under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate. After filtration of the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Wakogel, C
200, normal hexane: ethyl acetate = 20: 1) to obtain the title compound. Yield 0.70 g (Yield 1
00%)

Reference Example 13 9-Bicyclo [3.3.1] nonylacetic acid methyl ester 10% Pd was added to a solution of 0.70 g of methyl 9-bicyclo [3.3.1] nonylidene acetate in 10 ml of methanol.
0.07 g of -C was added, and catalytic reduction was performed at room temperature and normal pressure for 2 hours under a hydrogen stream. The Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.67g
(94% yield)

Reference Example 14 9-Bicyclo [3.3.1] nonylacetic acid To a solution of 0.67 g of 9-bicyclo [3.3.1] nonylacetic acid methyl ester in 15 ml of methanol was added 5.2 ml of a 1N aqueous sodium hydroxide solution. Stir at room temperature for 5 hours.
The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 12N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound.
Yield 0.44 g (71% yield)

Example 21 (1S) -3- [2- (Bicyclo [3.3.1] nonan-9-yl ) ethyl ] -1,8,8-trimethyl-3-
Azabicyclo [3.2.1] octane (1S) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (100 mg) was added to a solution of 100 mg of methylene chloride in 0.12 ml of triethylamine. Stir for 30 minutes. There, 9-bicyclo [3.
3.1] Nonylacetic acid 97.0 mg, followed by WSC 0.1
5 g was added, and the mixture was gradually returned to room temperature and stirred for 19 hours. 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 crude (1S) -3.
-(Bicyclo [3.3.1] nonan-9-yl) acetyl-1,8,8-trimethyl-3-azabicyclo [3.
2.1] Octane was obtained.

This was added without isolation to a solution of 41 mg of lithium aluminum hydride in 10 ml of THF and heated under reflux for 1 hour. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wakogel, C200, chloroform: acetone = 10: 1 to 5: 1) to obtain the title compound. Yield: 110 mg (69% yield) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = −17.9 ° (c 0.5, methanol)

Example 22 (1S) -3- (1-adamantylmethyl) -1,8,
8-Trimethyl-3-azabicyclo [3.2.1] octane (1S) -1,8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (100 mg) was added to a solution of 100 mg of triethylamine in 5 ml of methylene chloride. 096 ml was added and the mixture was stirred at 0 ° C for 30 minutes. Thereto, 0.13 g of WSC and subsequently 0.11 g of 1-adamantanecarboxylic acid were added, and the mixture was gradually returned to room temperature and stirred for 15 hours. 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 crude (1S) -3- (1-adamantylcarbonyl) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane.

Without isolation, this was added to a solution of lithium aluminum hydride (24.0 mg) in THF (10 ml), and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Wakogel, C2
00, chloroform) to give the title compound.
Yield: 71.2 mg (yield: 45%) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -10.5 ゜ (c 0.5, methanol)

Reference Example 15 Methyl 5-hydroxy-2-adamantylidene acetate Methyl diethylphosphonoacetate 0.200 ml of D
The ME 5 ml solution was cooled to −10 ° C., 54.3 mg of sodium hydride (60%, oil dispersion) was added, and the mixture was stirred at the same temperature for 1 hour. Thereto was added a solution of 5-hydroxy-2-adamantanone (150 mg) in DME (5 ml) and the mixture was heated at the same temperature for 1.5
Stirred for hours. There, water was added, and DME was concentrated under reduced pressure.
The residue was extracted with chloroform and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (Wakogel, C
(200, chloroform) to give the title compound. 180 mg (90% yield)

REFERENCE EXAMPLE 16 Methyl 5-hydroxy-2-adamantyl acetic acid methyl ester 17% of methyl 5-hydroxy-2-adamantylidene acetate was added to a solution of 179.9 mg of 10% P in 5 ml of methanol.
18.0 mg of d-C was added, and the mixture was subjected to catalytic reduction under a hydrogen stream at normal temperature and normal pressure for 2.5 hours. Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the desired product as a colorless oil.
Yield 166.3 mg (92% yield)

Reference Example 17 5-Hydroxy-2-adamantyl acetic acid To a solution of 181.5 mg of methyl 5-hydroxy-2-adamantyl acetic acid in 10 ml of methanol was added 0.49 ml of a 2.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 14 hours. . The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer is p
H1, extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 150 mg (88% yield)

[0106] Example 23 (1S) -3- [2 - (5- hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1S) - 0.38 ml of triethylamine was added to a solution of 0.44 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 15 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 30 minutes. There, 0.53 g of WSC, followed by 0.44 g of 5-hydroxy-2-adamantyl acetic acid.
Was gradually added to room temperature and stirred for 14.5 hours. 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 crude (1S) -3.
-(5-hydroxy-2-adamantylacetyl)-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] Octane was obtained.

This was added without isolation to a solution of 95.5 mg of lithium aluminum hydride in 30 ml of THF, and the mixture was refluxed for 1.5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Wakogel, C2
00, chloroform: methanol = 150: 1) to give the title compound. Yield 556 mg (yield 79
%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -10.9 ゜ (c 0.5, methanol)

Reference Example 18 5-methoxy-2-adamantanone A solution of 100 mg of 5-hydroxy-2-adamantanone and 0.113 ml of methyl iodide in 5 ml of THF was cooled to 0 ° C., and sodium hydride (60%, oil dispersion 48.2)
mg was gradually added, and the mixture was gradually returned to room temperature and stirred for 25 hours. Water was added to the reaction solution, and only THF was concentrated under reduced pressure. The obtained residue was extracted with chloroform and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (Wakogel, C
200, normal hexane: ethyl acetate = 10: 1) to obtain the title compound. Yield 57.7 mg (54% yield)

Reference Example 19 DME2 containing 57.7 mg of methyl 5-methoxyadamantylidene acetate 5-methoxy-2-adamantanone and 70.6 μl of methyl diethylphosphonoacetate
ml solution was cooled to 0 ° C. and sodium hydride (60%,
2. Oil dispersion (25.6 mg) was added and gradually returned to room temperature.
Stir for 5 hours. After water was added to the reaction solution to decompose unreacted sodium hydride, DME was concentrated under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate.
After filtration of the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Wakogel, C20).
0, normal hexane: ethyl acetate = 10: 1) to obtain the title compound. Yield 53.2 mg (yield 70
%)

Reference Example 20 methyl 5-methoxy-2-adamantyl acetic acid methyl ester methyl 5-methoxy-2-adamantylidene acete
10% Pd- in 5 ml solution of 53.2 mg of methanol
C. 5.3 mg was added, and catalytic reduction was carried out at room temperature and normal pressure for 1.5 hours under a hydrogen stream. The Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 50.0m
g (93% yield)

Reference Example 21 5-methoxy-2-adamantyl acetic acid methyl 5-methoxy-2-adamantyl acetic acid 5
To a 2 mg solution of 0.0 mg of methanol was added 0.13 ml of 2.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 12N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 36.2 m g (77% yield)

[0112] Example 24 (1S) -3- [2 - (5- methoxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1S) - To a solution of 33.7 mg of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 1 ml of methylene chloride was added 29.3 μl of triethylamine, and the mixture was stirred at 0 ° C. for 30 minutes. There, 36.2 mg of 5-methoxy-2-adamantylacetic acid, followed by WSC40.3m
g was added, and the mixture was gradually returned to room temperature and stirred for 20.5 hours.
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 a crude (1S)
-3- (5-Methoxy-2-adamantylacetyl)-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] Octane was obtained.

Without isolation, this was added to a solution of 7.4 mg of lithium aluminum hydride in 3 ml of THF.
The mixture was refluxed for 5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wako gel, C20).
0, chloroform: acetone = 20: 1 to 10: 1) to obtain the title compound. Yield: 32.1 mg (58% yield) Treatment was conducted in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -22.5 ° (c 0.1, methanol)

[0114] Example 25 (1S) -3- [2 - (5- chloro-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1S) - 3- [2 - (5-hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane 80.3mg in thionyl chloride 5ml was added, 4.5 hours Heated to reflux. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide was added to the obtained residue to make it alkaline, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered off with a desiccant, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Wako gel, C200, chloroform: acetone = 20: 1) to give the title. Was obtained. Yield: 44.8 mg (53% yield) The same treatment as in Example 1 was performed to obtain a hydrochloride. [Α] _D ²⁵ = 12.2 ゜ (c 0.5, methanol)

Reference Example 22 Methyl 5-phenyl-2-adamantylideneacete
86.1 mg of 5-phenyl-2-adamantanone and 84.0 μl of methyl diethylphosphonoacetate in DME2
ml solution was cooled to 0 ° C. and sodium hydride (60%,
(Oil dispersion) 22.9 mg and stirred at 0 ° C. for 1.5 hours. After water was added to the reaction solution to decompose unreacted sodium hydride, DME was concentrated under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (Wako gel, C200, normal hexane: ethyl acetate = 30: 1) to obtain the title compound. Yield 55.3 mg (52% yield)

Reference Example 23 5-phenyl-2-adamantyl acetic acid methyl ester methyl 5-phenyl-2-adamantylidene acete
55.3 mg of 10% Pd-
C. 5.3 mg was added, and catalytic reduction was performed at room temperature and normal pressure for 2.5 hours under a hydrogen stream. The Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 55.7m
g (100% yield)

Reference Example 24 5-Phenyl-2-adamantyl acetic acid methyl 5-phenyl-2-adamantyl acetic acid 5
To a solution of 5.7 mg in 3 ml of methanol was added 0.12 ml of a 2.5 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 14.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. PH of aqueous layer with 12N hydrochloric acid
The extract was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 22.6 m g (43% yield)

[0118] Example 26 (1S) -3- [2 - (5- phenyl-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1S) - To a solution of 15.9 mg of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 1 ml of methylene chloride was added 14.0 μl of triethylamine, and the mixture was stirred at 0 ° C. for 30 minutes. There, 22.6 mg of 5-phenyl-2-adamantylacetic acid, followed by 19.3 m of WSC
g was added, and the mixture was gradually returned to room temperature and stirred for 64 hours. 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 crude (1S) -3.
-(5-phenyl-2-adamantylacetyl) -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane obtained.

Without isolation, 3.8 mg of lithium aluminum hydride was added to a solution of 3.8 mg of THF.
The mixture was refluxed for 5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wako gel, C20).
0, chloroform: acetone = 20: 1) to give the title compound. Yield: 7.0 mg (Yield: 21%) Treatment was carried out in the same manner as in Example 1 to obtain a hydrochloride.

Reference Example 25 Methyl 4-hydroxy-2-adamantylidene acetate 536.1 mg of 4-hydroxy-2-adamantanone and 0.72 ml of methyl diethylphosphonoacetate in DM
E20 ml solution was cooled to −10 ° C., 259 mg of sodium hydride (60% oil dispersion) was added, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution to decompose unreacted sodium hydride, and then DME was concentrated under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate. After filtration of the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Wakogel, C20).
0, chloroform) to give the title compound. 0.51 g (71% yield)

Reference Example 26 4-Hydroxy-2-adamantyl acetic acid methyl ester 10% Pd was added to a solution of 0.51 g of methyl 4-hydroxy-2-adamantylidene acetate in 20 ml of methanol.
-C 51 mg was added, and catalytic reduction was performed at room temperature and normal pressure for 1 hour under a hydrogen stream. The Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.47 g (92% yield)

Reference Example 27 4-Hydroxy-2-adamantyl acetic acid To a solution of 0.47 g of 4-hydroxy-2-adamantyl acetic acid methyl ester in 15 ml of methanol was added 1.26 ml of a 2.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5.5 hours. Stirred. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. PH of aqueous layer with 12N hydrochloric acid
The extract was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 0.26 g (59% yield)

[0123] Example 27 (1S) -3- [2 - (4- hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1S) - To a solution of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (0.26 g) in methylene chloride (5 ml) was added triethylamine (0.23 ml).
Stirred at 30 ° C for 30 minutes. Thereto, 0.26 g of 4-hydroxy-2-adamantylacetic acid and subsequently 0.31 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 25 hours. 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 crude (1S) -3-.
(4-hydroxy-2-adamantylacetyl) -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane obtained.

Without isolation, this was added to a solution of 70.5 mg of lithium aluminum hydride in 25 ml of THF, and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Wakogel, C2
00, chloroform: methanol = 150: 1) to give the title compound. Yield 160.5 mg (Yield 3
9%) The product was treated in the same manner as in Example 1 to obtain a hydrochloride.

Reference Example 28 Methyl 4-phenyl-2-adamantylideneacete
DME50 of 1.43 g of 4-phenyl-2-adamantanone and 1.74 ml of methyldiethylphosphonoacetate
sodium hydride (60%, oil dispersion) 50 ml solution
6 mg was added, and the mixture was stirred at room temperature for 23.5 hours. Ether was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the residue obtained by concentrating the filtrate under reduced pressure was purified by flash silica gel column chromatography (Merck, silica gel 60, 230-400 mesh, normal hexane: ethyl acetate = 8: 1) to obtain the title compound. I got something. Yield 866 mg (49% yield)

REFERENCE EXAMPLE 29 4-Phenyl-2-adamantylacetic acid methyl ester methyl 4-phenyl-2-adamantylideneacetate
10% Pd- in a solution of 838 mg of methanol in 15 ml of methanol
100 mg of C was added, and catalytic reduction was performed at room temperature and normal pressure for 1 hour under a hydrogen stream. The Pd-C was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain the title compound. 838 mg (96% yield)

Reference Example 30 4-phenyl-2-adamantyl acetic acid methyl 4-phenyl-2-adamantyl acetic acid 8
6 ml of a 1N aqueous sodium hydroxide solution was added to a solution of 38 mg of methanol in 20 ml, and the mixture was stirred at room temperature for 13.5 hours.
The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 12N hydrochloric acid, extracted with methylene chloride, and dried over anhydrous sodium sulfate.
After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 774 mg (97% yield)

Example 28 (1S) -3- [2- (4-Phenyl-2-adamantyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S)- Triethylamine (1.00 ml) was added to a solution of 815 mg of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 30 ml of methylene chloride, and the mixture was stirred at 0 ° C. for 30 minutes. Thereto, 774 mg of 4-phenyl-2-adamantylacetic acid and subsequently 1.65 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 16.5 hours. The reaction solution was washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3.
-(4-phenyl-2-adamantylacetyl) -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane obtained.

Without isolation, this was added to a solution of 229 mg of lithium aluminum hydride in 30 ml of THF, and 1
Heated to reflux for an hour. The reaction solution was cooled, water and 2.5N sodium hydroxide were added, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure. The obtained residue is subjected to flash silica gel column chromatography (Merck, silica gel 60, 230 to 40).
(0 mesh, chloroform) to give the title compound. Yield 878 mg (yield 78%) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = -8.9 ゜ (c 0.5, methanol)

Example 29 (1R) -3- [2- (4-Phenyl-2-adamantyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1R)- Reaction was conducted in the same manner as in the synthesis of the compound of Example 28 from 0.48 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 0.59 g of 4-phenyl-2-adamantylacetic acid, Silica gel column chromatography (Wako gel, C200, chloroform)
And the title compound was obtained. Yield: 0.69 g (82% yield) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 9.5 ゜ (c 0.5, methanol)

[0131] Example 30 (1R) -3- [2 - (5- methoxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1R) - Example 2 from 28.4 mg of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 36.9 mg of 5-methoxy-2-adamantylacetic acid
The reaction was carried out in the same manner as in the synthesis of the compound No. 4 and purified by silica gel column chromatography (Wako gel, C200, chloroform: acetone = 10: 1) to obtain the title compound. Yield: 34.1 mg (66% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = + 18.7 ° (c 0.5, methanol)

[0132] Example 31 (1R) -3- [2 - (5- hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1R) - Example 23 was prepared from 0.15 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 0.15 g of 5-hydroxy-2-adamantyl acetic acid.
And purified by silica gel column chromatography (Wakogel, C200, chloroform: methanol = 100: 1) to obtain the title compound. Yield: 0.16 g (66% yield) The same treatment as in Example 1 was performed to obtain a hydrochloride. [Α] _D ²⁵ = + 11.2 ゜ (c 0.5, methanol)

[0133] Example 32 (1R) -3- [2 - (5- chloro-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1R) - 3- [2 - (5-hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane 82.8mg in thionyl chloride 5ml was added, heated under reflux for 5 hours did. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide was added to the obtained residue to make it alkaline, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered off with a desiccant, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Wako gel, C200, chloroform: acetone = 20: 1) to give the title. Was obtained. Yield: 48.1 mg (55% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = + 13.6 ° (c 0.5, methanol)

[0134] Example 33 (1R) -3- [2 - (5- phenyl-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1R) - Example 2 from 37.2 mg of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 53.0 mg of 5-phenyl-2-adamantylacetic acid
The reaction was carried out in the same manner as in the synthesis of the compound No. 6 and purified by silica gel column chromatography (Wako gel, C200, chloroform: acetone = 20: 1) to obtain the title compound. Yield 11.0 m g (13% yield) was treated in the same manner as in Example 1 to obtain the hydrochloride.

[0135] Example 34 (1R) -3- [2 - (4- hydroxy-2-adamantyl) ethyl] -1,8,8- trimethyl-3-azabicyclo [3.2.1] octane (1R) - Example 27 was prepared from 0.22 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 0.37 g of 4-hydroxy-2-adamantyl acetic acid.
And purified by silica gel column chromatography (Wakogel, C200, chloroform: methanol = 150: 1) to give the title compound. Yield: 74 mg (19% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride.

Example 35 (1R) -3- [2- (3-Methyl-1-adamantyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1R)- Reaction was conducted in the same manner as in the synthesis of the compound of Example 19 from 0.50 g of 1,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride and 0.65 g of 3-methyl-1-adamantylacetic acid, Purification by silica gel column chromatography (Wako gel, C200, chloroform) gave the title compound. 0.74 g (yield 8
5%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 10.6 ゜ (c 0.5, methanol)

Example 36 (1S) -3- [3- (2-Adamantyl) -1-propyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S) -1 To a solution of 50.0 mg of 5,8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 3 ml of methylene chloride was added 44.1 μl of triethylamine, and the mixture was stirred at 0 ° C. for 30 minutes. There, 60.4 mg of 3- (2-adamantyl) propionic acid, followed by WSC65.7
mg was added, and the mixture was gradually returned to room temperature and stirred for 13 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 crude (1S) -3.
-[3- (2-adamantyl) propionyl] -1,
8,8-Trimethyl-3-azabicyclo [3.2.1]
Octane obtained.

This was added to a solution of 12.0 mg of lithium aluminum hydride in 5 ml of THF without isolation, and
Heated to reflux for an hour. After the reaction, the reaction mixture was cooled, water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Wako-gel, C200,
Purification with chloroform) gave the title compound. Yield 6
1.6 mg (yield 71%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = -9.8 ゜ (c 0.5, methanol)

Example 37 (1R) -3- [3- (2-Adamantyl) -1-propyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1R) -1 , 8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (50.0 mg) and 3- (2
The reaction was carried out in the same manner as in the synthesis of the compound of Example 36 from 60.4 mg of -adamantyl) propionic acid, followed by purification by silica gel column chromatography (Wako-gel, C200, chloroform) to obtain the title compound. Yield 59.0m
g (yield: 68%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 9.6 ゜ (c 0.5, methanol)

Example 38 (1S) -3- [2- (3-Noradamantyl) ethyl] -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane (1S) -1,8 To a solution of 50.0 mg of 8,8-trimethyl-3-azabicyclo [3.2.1] octane hydrochloride in 3 ml of methylene chloride was added 44.1 µl of triethylamine, and the mixture was stirred at 0 ° C for 30 minutes. There, WSC65.7mg,
Subsequently, 52.2 mg of 3-noradamantyl acetic acid was added,
The mixture was gradually returned to room temperature and stirred for 18 hours. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration of the drying agent, the filtrate was concentrated under reduced pressure to give crude (1S) -3- (3-noradamantylacetyl) -1,8,8-trimethyl-3.
-Azabicyclo [3.2.1] octane was obtained.

This was added without isolation to a solution of 12.0 mg of lithium aluminum hydride in 5 ml of THF.
Heated to reflux for an hour. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wakogel, C200,
Purification with chloroform) gave the title compound. Yield 6
5.9 mg (83% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = −9.8 ゜ (c 0.5, methanol)

Example 39 (1S) -3- (2-Adamantylmethyl) -1,8,
8-Trimethyl-3-azabicyclo [3.2.1] octane (1S) -1,8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (100 mg) was added to a solution of 100 mg of triethylamine in 5 ml of methylene chloride. 096 ml was added and the mixture was stirred at 0 ° C for 30 minutes. Thereto, 0.11 g of 2-adamantanecarboxylic acid and subsequently 0.13 g of WSC were added, and the mixture was gradually returned to room temperature and stirred for 17 hours. 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 crude (1S) -3- (2-adamantylcarbonyl) -1,8,8-trimethyl-3-azabicyclo [3.2.1] octane.

This was added without isolation to a solution of lithium aluminum hydride (24.0 mg) in THF (10 ml) and heated under reflux for 2 hours. The reaction solution was cooled, water was added, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Wakogel, C200,
Purification with chloroform) gave the title compound. Yield 5
3.0 mg (yield: 33%) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. [Α] _D ²⁵ = −9.7 ゜ (c 0.5, methanol)

Example 40 (1R) -3- (2-Adamantylmethyl) -1,8,
8-Trimethyl-3-azabicyclo [3.2.1] octane (1R) -1,8,8-Trimethyl-3-azabicyclo [3.2.1] octane hydrochloride (100 mg) and 2-adamantanecarboxylic acid (0.11 g) And purified by silica gel column chromatography (Wako gel, C200, chloroform) to give the title compound. Yield 55.2 mg (yield 34
%) The same treatment as in Example 1 was carried out to obtain a hydrochloride. [Α] _D ²⁵ = + 10.3 ゜ (c 0.5, methanol)

Example 41 Production of Injection (1S) -3- [2- (2-Adamantyl) ethyl]-
1,8,8-Trimethyl-3-azabicyclo [3.2.
1] 1.0 g of octane hydrochloride was dissolved in 1 L of distilled water for injection, adjusted to pH 6-7 with a 1N aqueous solution of sodium hydroxide, sterilized, and filled into ampoules in 5 ml portions to obtain injections.

Example 42 Preparation of tablet (1S) -3- [2- (2-adamantyl) ethyl]-
1,8,8 - trimethylene-3-azabicyclo [3.2.1] 1 having a composition of octane hydrochloride 50.0mg Corn starch 40.0mg crystalline cellulose 80.0mg Magnesium stearate 0.5mg Talc 29.5mg Tablets 200 mg tablets were obtained by dry tableting.

[0147]

[Table 3]

[0148]

[Table 4]

Claims (8)

(57) [Claims] 1. A compound of the general formula [Wherein R is a compound of the formula: (Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a phenyl group which may have a substituent, and n represents 0 or 1) a lower alkyl group substituted with an optionally several 5-8 cycloalkyl group having a carbon also shows a norbornyl group or a bicyclo [3.3.1] nonyl group, m represents an integer of 0 to 4, C ^* Represents an asymmetric carbon atom], or a salt thereof . 2. The method according to claim ¹ , wherein R ¹ is a hydrogen atom.
Zepin derivatives or salts thereof . 3. ( 1S) -3- [2- (2-adamanche)
Ru) ethyl] -1,8,8-trimethyl-3-azabisi
3. The method according to claim 1, wherein the compound is black [3.2.1] octane.
Azepine derivatives or salts thereof . 4. A compound of the general formula [ Wherein R is a compound of the formula : ( Wherein R ¹ is a hydrogen atom, a lower alkyl group, a lower alcohol
Having a xy group, a hydroxyl group, a halogen atom or a substituent
And n represents 0 or 1).
Carbon represented by the group represented by the lower alkyl group
5 to 8 cycloalkyl groups, norbornyl groups or
A bicyclo [3.3.1] nonyl group;
Represents an integer, and C ^* represents an asymmetric carbon atom.]
A general formula characterized by reducing the carbonyl group of the compound (In the formula, m is an integer of 0 to 4, C ^* represents an asymmetric carbon atom.
And R has the same meaning as described above )
Method for producing derivative or salt thereof 5. A compound of the general formula ( Wherein C ^* represents an asymmetric carbon atom)
And the general formula X- (CH ₂ ) m—R wherein R is ( Wherein R ¹ is a hydrogen atom, a lower alkyl group, a lower alcohol
Having a xy group, a hydroxyl group, a halogen atom or a substituent
And n represents 0 or 1).
Carbon represented by the group represented by the lower alkyl group
5 to 8 cycloalkyl groups, norbornyl groups or
X represents a bicyclo [3.3.1] nonyl group;
A sulfonyloxy group or a halogen atom, and m is
Inactive reactive derivative represented by 0 to 4)
It is characterized by reacting in the presence of a base in an organic solvent.
The general formula (In the formula, m is an integer of 0 to 4, C ^* represents an asymmetric carbon atom.
And R has the same meaning as described above)
A method for producing a derivative or a salt thereof . 6. A compound of the general formula [Wherein R is a compound of the formula: (Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a phenyl group which may have a substituent, and n represents 0 or 1) A cycloalkyl group having 5 to 8 carbon atoms, a norbornyl group or a bicyclo [3.3.1] nonyl group which may be substituted with a lower alkyl group, p represents an integer of 0 to 3, and C ^* Represents an asymmetric carbon atom], or a salt thereof. 7. The method according to claim 6, wherein R ¹ is a hydrogen atom.
Zepin derivatives or salts thereof . 8. ( 1S) -3- (2-adamantyl acetyl
Tyl) -1,8,8-trimethyl-3-azabicyclo
[3.2.1] The method according to claim 6 or 7, which is octane.
An azepine derivative or a salt thereof .