JP3005275B2 - Quinuclidine derivative and method for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel quinuclidine derivative or a salt thereof, which is effective for treating a disease of the central nervous system, and a method for producing the same.

(Prior Art) As quinuclidine derivatives, for example, JP-A-61-28
No. 0497 discloses 2-substituted spiro (1,3-oxathiolane-
5,3 ′) Quinuclidine is disclosed to be effective in treating diseases of the central nervous system. However, there is no description of a spiro (1,3-oxathiolane-5,3 ') quinuclidine derivative in which a cycloalkyl is spiro-bonded at the 2-position of the 1,3-oxathiolane ring as in the compound of the present invention.

(Disclosure of the Invention) The present invention provides a compound represented by the general formula (I): Wherein n is an integer of 3 to 11, and a quinuclidine derivative or a salt thereof and a method for producing the same.

The compound of the present invention represented by the general formula (I) includes 5,3 ′
Since the (spiro) carbon is an asymmetric carbon, there are optical isomers (R-form or S-form), and the compound of the present invention includes these optical isomers and racemic forms.

Examples of the salt of the compound represented by the general formula (I) include an addition salt with an organic acid or an inorganic acid.

The compound represented by the general formula (I) can be produced, for example, by the following method.

(Where n is an integer from 3 to 11).

The above reaction is usually performed in the presence of a solvent and an acid catalyst, if necessary, with the addition of a dehydrating agent.

Examples of the solvent include benzene, toluene, xylene, aromatic hydrocarbons such as chlorobenzene, chloroform, carbon tetrachloride, methylene chloride, dichloroethane,
Examples include halogenated hydrocarbons such as trichloroethane, and ethers such as diethyl ether, dioxane, and tetrahydrofuran.

Examples of the acid catalyst include boron trifluoride or a complex compound thereof (for example, an ether complex compound), and sulfonic acids such as paratoluenesulfonic acid.

 Examples of the dehydrating agent include zeolite.

The reaction temperature of the above reaction is usually 0 to 50 ° C, and the reaction time is 0.1 to 24 hours.

The racemic form of the compound represented by formula (I) can be separated into (+) form and (-) form by optical resolution. For example, when optically active tartaric acid is used as the resolving agent, the compound represented by the general formula (I) is converted into (+)-form and (-)-form optically active tartaric acid salts. Alternatively, one salt is selectively crystallized in a solvent and separated.

The obtained optically active tartrate salt can be converted into its free form by a conventional method, for example, by adding an alkali such as sodium hydroxide or potassium hydroxide for neutralization.

In the above optical resolution method, it is necessary to use a specific solvent. As the solvent, (+) L (+) tartrate and (−) L of the compound represented by the general formula (I) may be used.
One capable of selectively crystallizing only one of (+) tartrate, or only one of (+)-form D (-) tartrate and (-)-form D (-) tartrate, For example, alcohols such as methanol, ethanol, and isopropyl alcohol can be mentioned, and among them, ethanol is desirable.

It is desirable that tartaric acid is gradually added dropwise to the racemic form of the compound represented by formula (I).

Crystallization of the optically active tartrate salt can be promoted by cooling the reaction solution. In addition, the optical purity can be improved by heating and refluxing after crystal deposition to dissolve the crystallized easily soluble salt.

 Next, specific synthesis examples of the compound of the present invention will be described.

Synthesis Example 1. Racemic cyclohexane spiro-2 '-(1,3-oxathiolane) -5'-spiro-3 "-quinuclidine,
Synthesis of (+)-form 1 / 2D (-) tartrate and its free form and (-)-form 1 / 2L (+) tartrate and its free form (1) 3-Hydroxy-3-mercaptomethylquinucuri To a chloroform solution containing 34.6 g (0.2 mol) of gin, 58.9 g (0.6 mol) of cyclohexanone was added dropwise at 18 ° C. under a nitrogen stream. After the addition, the mixture was stirred at the same temperature for 3 hours and 20 minutes. Then 19-
47% Boron trifluoride etherate 12 over 3.5 hours at 20 ° C
0.8 g (0.4 mol) was added dropwise and stirred overnight. After adding 20% aqueous sodium hydroxide solution at 15 ° C to make it alkaline,
The mixture was filtered and separated. The aqueous layer was extracted again with chloroform, and the chloroform layers were combined and washed with water. It was back-extracted with 5% dilute sulfuric acid, made alkaline with a 10% aqueous sodium hydroxide solution, and extracted four times with 115 ml of n-hexane. The n-hexane layers were combined, dried over sodium sulfate and filtered, and n-hexane was distilled off to give cyclohexane spiro-2 '-(1,3-oxathiolane) -5'-spiro-3 "-quinuclidine (racemic compound: 20.27 g of compound No. 1) was obtained.

(2) 20.27 g of the above racemate (Compound No. 1) was added to ethanol
Dissolved in 75 ml and heated to 50 ° C. 2.82 g of D (-) tartaric acid
Was dissolved in 75 ml of ethanol, and this was added dropwise over 30 minutes. After heating and refluxing for 30 minutes after the dropwise addition, the mixture was allowed to cool naturally, and the precipitated crystals were separated by filtration and separated into crystals and crystal mother liquors. The crystals were washed three times with 5 ml of ethanol, twice with 10 ml of ether, dried in vacuo, and treated with (+) cyclohexanespiro-
2 '-(1,3-oxathiolane) -5'-spiro-3 "
-Quinuclidine 1 / 2D (-) tartrate (melting point 242 to 244
° C: 8.65 g of compound No. 2).

This salt was dissolved in water, made alkaline with sodium hydroxide, and extracted with n-hexane. n-Hexane was distilled off to obtain a free form (Compound No. 3), and the optical rotation was measured. As a result, 〔[α] ²⁵ _D ▼ = + 26.5 (C4.75, CH ₃ OH).

(3) The crystal mother liquor obtained in the above (2) was dissolved in 80 ml of water, adjusted to pH 11 with 20 ml of a 20% aqueous sodium hydroxide solution, and extracted three times with 100 ml of ether. The ether layer was dried over sodium sulfate and filtered to remove the ether. 75 ml of this
After heating to 50 ° C., a solution of 2.82 g of L (+) tartaric acid in 75 ml of ethanol was added dropwise over 75 minutes. After dripping
The mixture was heated under reflux for 30 minutes and allowed to cool naturally. The precipitated crystals are collected by filtration, washed three times with 3 ml of ethanol and twice with 5 ml of ether,
After drying in vacuo, (-) cyclohexane spiro-2'-
9.76 g of (1,3-oxathiolane) -5′-spiro-3 ″ -quinuclidine · 1 / 2L (+) tartrate (melting point: 244 to 247 ° C., compound No. 4) were obtained.

This salt is converted into a free form (compound) in the same manner as in the above (2).
No.5), and the optical rotation was measured, and it was ▲ [α] ²⁵ _D ▼
_{= -24.7 (C4.65, CH 3 OH} ) was. The NMR values and mass spectrum values were as follows. ¹ H-NMR (CDCl ₃ ) (see FIG. 1) δ: 1.253 to 2.047 ppm (H, Hd, He of cyclohexyl) 2.684 to 3.332 ppm (Ha, Hf, Hg) ¹³ C-NMR (CDCl ₃ ) Mass spectrum m / e = 253 The positions of the above a to g are as follows.

Synthesis Example 2. (1) In the same manner as in Synthesis Example 1 (2), (+) cyclopentane spiro-2 '-(1,3-oxathiolane)-
There was obtained 5'-spiro-3 "-quinuclidine 1 / 2D (-) tartrate (melting point: 223-226 ° C: compound No. 7).

This salt was used as a free form (Compound No. 8), and the optical rotation was measured. As a result, 〔[α] ²⁵ _D ▼ was +30.1 (C3.75, CH ₃ OH).

(2) In the same manner as in Synthesis Example 1 (3), (-) cyclopentane spiro-2 '-(1,3-oxathiolane)-
5′-Spiro-3 ″ -quinuclidine 1 / 2L (+) tartrate (mp 224-226 ° C .: compound No. 9) was obtained.

This salt was used as a free form (Compound No. 10), and the optical rotation was measured. As a result, 〔[α] ²⁵ _D ▼ = -36.9 (C3.60, CH ₃ OH).

Next, Table 1 shows typical examples of the compound of the present invention represented by the general formula (I).

The compound of the present invention represented by the above general formula (I) has central nervous system activity. That is, the compound of the present invention is a muscarinic drug having an excellent effect for the central nervous system,
Can be used to activate central cholinergic function.

Accordingly, the compounds of the present invention may be associated with some disorders of central cholinergic hyperactivity, such as Alzheimer's-type senile dementia, tardive dyskinesia, Pick's disease, Huntington's disease, Jill de la. It can be used for treatment of Tourette's syndrome, Friedrich's ataxia, chromosomal aberration syndrome, and the like.

In addition, it may act on the peripheral nervous system, and can be used for treatment of Sjogren's syndrome and the like.

Test Example 1 [Muscarinic binding analysis] The cerebrum was excised from male Wistar rats (250 g to 350 g), and a rat cerebral membrane fraction was prepared. The membrane fraction, the present invention compound and 0.08 nM L-[N- methyl - ³ H] Kinukurijineiru Benjireto methyl chloride (hereinafter
QNB and abbreviated) or 1nM [N- methyl - ³ H] pirenzepine (hereinafter abbreviated as pirenzepine) was present in 50mM phosphate buffer pH 7.2, and they 1 hour incubation at 25 ° C. (incubation) And then filtered through a glass fiber paper treated with a 0.01% ethyleneimine solution. The amount of non-specific binding was measured in the presence of 10 ^-6 M atropine sulfate. The amount of QNB or pirenzepine bound to the membrane fraction was determined by measuring the amount of RI by the liquid scintillation counter method, and the concentration (IC ₅₀ ) at which binding was inhibited by 50% was calculated to obtain the results shown in Table 2.

As a result, all the compounds inhibited the binding to QNB and pirenzepine, and particularly inhibited the binding to pirenzepine at a very low concentration.

Test Example 2 [Effect on Normal Body Temperature] After oral administration of each drug to ddy male mice, the rectal body temperature was measured 30 minutes and 60 minutes later, and the decrease in rectal body temperature was examined to obtain the results shown in Table 3. Was.

As a result, it was confirmed that all compounds reduced body temperature and had muscarinic activity.

Test Example 3 using [Mouse Acute Toxicity] ddy male mice, various drugs were administered in a route, LD ₅₀ values from the cumulative mortality 3 days after administration (mg / kg)
And the results in Table 4 were obtained.

When the compound of the present invention is administered for treating the above-mentioned conditions related to the central nervous system, it may be orally, parenterally, topically or rectally, alone or in combination with a pharmaceutically acceptable carrier. It is administered in the form of a pharmaceutical composition suitable for use, for example, tablets, powder packaging, capsules, granules, injections, ointments, suppositories and the like.

Formulations suitable for oral use include, for example, solid compositions such as tablets, capsules, powders, granules, troches, and liquid compositions such as syrups and suspensions.

Solid compositions include binders such as microcrystalline cellulose, gum arabic, tragacanth, gelatin, polyvinyl pyrrolidone; excipients such as starch, lactose, carboxymethyl cellulose; disintegrants such as alginic acid, corn starch, carboxymethyl cellulose; Lubricants such as magnesium acid, soft silicic anhydride, colloidal silicon dioxide; dispersants such as sucrose fatty acid esters;
It may contain a sweetening agent such as sucrose; a flavoring agent such as peppermint and methyl salicylate; and various solubilizing agents such as a surfactant.

Liquid compositions include sorbitol, gelatin, methylcellulose, carboxymethylcellulose, vegetable oils such as peanut oil, emulsifiers such as lecithin, and, if necessary, sweeteners, preservatives, dyes, flavoring agents, solubilizing agents, and the like. And they can also be provided as dry preparations.

These preparations preferably contain 1 to 95% by weight of the active ingredient compound.

Formulations suitable for parenteral use include, for example, injections.

As an injection, for example, it may be dissolved in normal injection water or the like in the form of a salt, or in a form of an injectable form such as a suspension or emulsion in a mixture of medically acceptable oils or liquids. Can be. In this case, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid,
It may contain a buffer, a reagent for adjusting osmotic pressure, a solubilizing agent, and the like. This injection preferably contains 0.1 to 5% by weight of the active ingredient compound.

Formulations suitable for topical or rectal use include, for example, ointments, suppositories and the like.

The ointment is prepared by adding a commonly used base and the like and by a conventional method. 0.1-30% by weight of active ingredient compound
It is desirable to include.

Suppositories may contain formulation carriers well known in the art, for example, polyethylene glycol, lanolin, cocoa oil, fatty acid triglyceride, and the like. It is desirable to contain 1 to 95% by weight of the active ingredient compound.

The above-mentioned oral, parenteral, pharmaceutical composition suitable for topical or rectal use, after administration to a patient by a known method,
The active ingredient can be formulated to be released rapidly, sustainedly, or delayed.

The dose of the compound of the present invention depends on the type of the compound, the method of administration,
Of course, it depends on the condition of the patient or the animal to be treated.The appropriate amount and the number of administrations under certain conditions must be determined by the judgment of a specialist, but about 1 mg to about 1 g per adult per day. It will usually be administered.

Next, specific examples of preparations when the compound of the present invention is used for the treatment of conditions related to the central nervous system will be described.

Formulation Example 1 (tablet) (1) Compound No. 4 20mg (2) Lactose 150mg (3) Starch 30mg (4) Magnesium stearate 6mg More than one tablet of (1) to (4) Mold.

Formulation Example 2 (powder / fine granule) Surfactant Deca Green 1-L (manufactured by Nikko Chemicals Co., Ltd.) in a 5% aqueous solution containing 15 mg, wet-pulverize 200 mg of compound No. 7 and add sugar ester (DK ester) F-
160: manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) and freeze-dried. The dried product is pulverized and mixed with 25 mg of light anhydrous silicic acid to obtain a powder or fine granules.

These can be encapsulated in a capsule to form a capsule.

Formulation Example 3 (Hard gelatin capsule) (1) Compound No. 4 10 mg (2) Starch 200 mg (3) Magnesium stearate 10 mg More than one component (1) to (3) is packed in a hard gelatin capsule as one tablet. And hard gelatin capsules.

Formulation Example 4 (Injection) (1) Compound No. 7 1 g (2) Glucose 10 g (3) Distilled water for injection A total of 200 ml or more Inject the components of (1) to (3) according to the general preparation method of injection. Agent.

[Brief description of the drawings]

FIG. 1 is an NMR (400 MHz) spectrum of Compound No. 5.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-61-280497 (JP, A) JP-A-2-62883 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 497/20 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The compound of the general formula (I) (Wherein, n is an integer of 3 to 11) or a quinuclidine derivative or a salt thereof. 2. A compound of the formula: 3-hydroxy-3-mercaptomethylquinuclidine; Wherein n is an integer of 3 to 11; and a compound represented by the general formula (I): Wherein n is as described above, or a quinuclidine derivative or a salt thereof.