JPH06321829A - Alpha,alpha-dimethylcyclohexanecarbinol derivative or its salt - Google Patents

Abstract

PURPOSE:To obtain a new alpha, alpha-dimethylcyclohexanecarbinol derivative or its salt, having myoneural blocking and arterialization inhibiting actions and useful as a medicine. CONSTITUTION:This alpha,alpha-dimethylcyclohexanecarbinol derivative or its salt is expressed by formula 1 [R is amino, lower alkenyl, lower acyl, exo-methylene, OH, oxo, lower alkoxy or 1,3-dioxane forming a spiro ring; (m) is 0-3, except the case where (m) is 0-1 and R is lower alkoxy substituted at the 2-position; (m) is 0-1 and R is lower acyl substituted at the 4-position; (m) is 0-1 and R is amino substituted at the 2- or 3-position and (m) is 0-1 and R is exo- methylene,0H or oxo[, e.g. 3-(4-hydroxy-4-methylpentyl)cyclohexanol. The compound expressed by formula 1 is obtained by starting from, e.g. a compound expressed by formula 2 (R<2> is alkoxycarbonyl, etc.) through a compound expressed by formula 3 (X is alkylene, etc.) or a compound expressed by formula 4.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel α, α-dimethylcyclohexanecarbinol derivative or a salt thereof. INDUSTRIAL APPLICABILITY The α, α-dimethylcyclohexanecarbinol derivative of the present invention has a neuromuscular blocking action and angiogenesis inhibiting action and is useful as a pharmaceutical.

[0002]

2. Description of the Related Art Currently, as an α, α-dimethylcyclohexanecarbinol derivative, Aust. J. Chem., 3
7 , 629 (1984), JP-A-58-187158 and JP-A-55-23977, and the like, but the biological behavior of these compounds is not described. Further, compounds described in JP-A-55-92349 include α, α-dimethylcyclohexanecarbinol derivatives having antiallergic action, antitumor action, antirheumatic action and antiinflammatory action, but they are at the 4-position of the cyclohexane ring. Is substituted with a methyl group, a cyano group or a carbamoyl group, which is different from the substituent of the compound of the present invention.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to treat rheumatoid arthritis, chronic nephritis, as a therapeutic agent for neuromuscular blockade and as a therapeutic agent for motor paralysis, and also for angiogenesis inhibition.
It is intended to provide a novel α, α-dimethylcyclohexanecarbinol derivative or a salt thereof useful as a therapeutic drug for chronic inflammation such as chronic hepatitis, psoriasis, cancer, diabetic retinopathy, arteriosclerosis and the like.

[0004]

The present invention has the general formula [Chemical formula 2]
The α, α-dimethylcyclohexanecarbinol derivative represented by or a salt thereof.

[0005]

[Chemical 2]

[In the formula, R is an amino group, a lower alkenyl group, a lower acyl group, an exomethylene group, a hydroxyl group, an oxo group, a lower alkoxy group or 1,3-forming a spiro ring.
Dioxane and m are 0 to 3. However, m is 0 to 1 and R
Is a lower alkoxy group substituted at the 2-position, m is 0 to 1 and R
Is a lower acyl group substituted at the 4-position, m is 0 to 1 and R is 2
Amino group substituted at the 3-position or 3-position, or m is 0 to 1
Except when R is an exomethylene group, a hydroxyl group or an oxo group. ]

In the present invention, the lower alkenyl group represented by R is, for example, vinyl, allyl, isopropenyl, 1-butenyl, 1-but-2-enyl, 1-bute-3.
-2, 4-, 2-butenyl, 2-but-2-enyl, 2-but-3-yl, 1-isobutenyl, 2-isobutenyl and the like straight-chain or branched alkenyl groups having 2 to 4 carbon atoms. Can be illustrated.

The lower acyl group has 2 to 4 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl groups.
The linear or branched acyl group can be exemplified.

Examples of the lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy and n.
Examples thereof include linear or branched alkoxy groups having 1 to 4 carbon atoms such as -butoxy, isobutoxy and t-butoxy groups.

Specific compounds of the present invention include 3-
(4-Hydroxy-4-methylpentyl) cyclohexanol, 3- (4-hydroxy-4-methylpentyl)
Methoxycyclohexane, 3- (3-hydroxy-3-
Methylbutyl) cyclohexanol, 2- (3-hydroxy-3-methylbutyl) cyclohexanol, 3-
(4-hydroxy-4-methylpentyl) cyclohexanone, 3- (3-hydroxy-3-methylbutyl) cyclohexanone, 3- (1-hydroxy-1-methylethyl) acetylcyclohexane, 3- (4-hydroxy-
4-methylpentyl) cyclohexylidene, 3- (3-
Hydroxy-3-methylbutyl) cyclohexylidene,
3- (1-hydroxy-1-methylethyl) isopropenylcyclohexane, 4- (1-hydroxy-1-methylethyl) cyclohexylamine, 2- (3-hydroxy-3-methylbutyl) cyclohexylidene, 7-
An example is (3'-hydroxy-3'-methylbutyl) -1,5-dioxospiro [5,5] undecane.

The compound of the present invention represented by the general formula (1) is
It has a neuromuscular blocking effect and a therapeutic drug for motor paralysis, and also has an angiogenesis inhibiting effect, chronic inflammation such as rheumatoid arthritis, chronic nephritis, chronic hepatitis, psoriasis, cancer, diabetic retinopathy, arteriosclerosis, etc. It is useful as a remedy for.

The compound of the present invention represented by the general formula (1) is
It is produced by the reaction process formulas shown in [Chemical Formula 3] to [Chemical Formula 7] below. The compounds represented by the general formulas (2), (4) and (5), which are used as raw materials in the reaction process formulas of [Chemical Formula 3] and [Chemical Formula 4], are publicly known and readily available compounds, or conventionally publicly known compounds. It can also be produced by the synthetic method of. Here, as a known and easily available compound, or a conventionally known synthetic method,
J. Med. Chem., 35 , 958 (1992),
J. Am. Chem. Soc., 86 , 5626 (1964), but not limited thereto.

[0013]

[Chemical 3]

[In the formula, R and m are the same as above. R ¹ is an amino group, a lower alkenyl group, a lower acyl group, an exomethylene group, a hydroxyl group, a lower alkyl group having a hydroxyl group, an oxo group, a lower alkoxy group, a benzyloxy group or 1,3-dioxane forming a spiro ring. Show. R ² represents a lower alkoxycarbonyl group, a cyano group or an acetyl group. X
Represents a linear lower alkylene group and a linear lower alkenylene group, or represents a direct bond. ]

A lower alkenyl group represented by R ¹ above,
The lower acyl group and the lower alkoxy group are each R
The same lower alkenyl group, lower acyl group, and lower alkoxy group as mentioned above can be mentioned. Examples of the lower alkyl group having a hydroxyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-2-propyl, 2-hydroxy. −
2-propyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxy-2-butyl, 2-hydroxy-2
1 to 4 carbon atoms having one hydroxyl group such as -butyl, 3-hydroxy-2-butyl, 4-hydroxy-2-butyl
The straight-chain or branched alkyl group can be exemplified.

The lower alkoxycarbonyl group represented by R ² is carbon number such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl. 2 to 5 linear or branched alkoxycarbonyl groups can be exemplified.

Examples of the linear lower alkylene group represented by X above include linear lower alkylene groups having 1 to 4 carbon atoms such as methylene, ethylene, propylene and butylene. Examples of linear lower alkenylene groups include vinylene, 1-propenylene, 2-propenylene,
Examples thereof include linear alkenylene groups having 2 to 4 carbon atoms such as 1-butenylene, 2-butenylene and 3-butenylene.

Details of each step will be described below.

Step A The compound represented by the general formula (3) or (1) is obtained by reacting the compound represented by the general formula (2) or (4) with a methyl anion in a suitable solvent under a nitrogen atmosphere. To get
However, when R ² is a cyano group, the compound represented by the general formula (3) or (1) can be obtained by once isolating it as a methyl ketone body and then performing the same reaction. Examples of the counter cation of methyl anion include lithium cation and magnesium cation. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene and toluene. It can be illustrated. In the reaction, the methyl anion is 2 relative to the compound represented by the general formula (2) or (4).
It is preferable to use about 10 to 10 equivalents. The reaction proceeds from -78 ° C to room temperature, and the reaction time proceeds advantageously for about 30 minutes to 48 hours.

Step B The compound represented by the general formula (4) or (1) is obtained by reacting the compound represented by the general formula (2) or (3) at room temperature in a suitable solvent with a metal catalyst and reacting under hydrogen pressure. To obtain the compound. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, N, N-dimethylformamide, water, acetic acid and the like. The metal catalyst is not particularly limited, but rhodium / alumina, platinum, platinum dioxide, nickel, palladium / carbon and the like can be exemplified. The metal catalyst has the general formula (2)
Alternatively, it is preferable to use about 0.05 to 0.5 times the weight ratio of the compound represented by (3). Reaction time is 12 to 72 hours
It progresses in an advantageous manner in about time. The hydrogen pressure is preferably about 1 to 200 atm.

[0021]

[Chemical 4]

[In the formula, m is the same as above. R ³ represents a hydroxyl group or a lower alkyl group having a hydroxyl group. R ⁴ represents an oxo group or a lower acyl group. R ⁵ represents an exomethylene group or a lower alkenyl group. Examples of the lower alkyl group having a hydroxyl group represented by R ³ include the lower alkyl group having a hydroxyl group similar to R ¹ . R ⁴ above
Examples of the lower acyl group represented by and the lower alkenyl group represented by R ⁵ include the same lower acyl groups and lower alkenyl groups as R. ]

Details of each step will be described below.

Step C The compound represented by the general formula (5) obtained by the reaction formula of the chemical formula [3] is reacted with an oxidizing agent in an appropriate solvent to form an α represented by the general formula (1a). , Α-Dimethylcyclohexanecarbinol derivative is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, for example, methylene chloride, halogenated hydrocarbons such as chloroform,
Aromatic hydrocarbons such as benzene and toluene, acetone,
Examples thereof include alkyl ketones such as methyl ethyl ketone. The oxidizing agent is not particularly limited, and examples thereof include Diones reagent, pyridinium chlorochromate, pyridinium dichromate, and dimethyl sulfoxide-oxalyl chloride. The oxidizing agent is preferably used in an amount of about 1 to 5 times the equivalent amount of the compound represented by the general formula (5). The reaction time is advantageously about 10 minutes to 24 hours. The reaction temperature is preferably from -20 ° C to the boiling point of the solvent.

Step D By reacting the compound represented by the general formula (1a) with a methyltriphenylphosphonium halide and a phosphonium ylide prepared by a base in an appropriate solvent in an inert gas atmosphere, Α represented by the formula (1b),
An α-dimethylcyclohexane carbinol derivative is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, and aromatic hydrocarbons such as benzene and toluene.
The inert gas is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrogen and argon. Examples of the base include organic lithium compounds such as methyllithium and n-butyllithium, metal halides such as sodium hydride and potassium hydride, and the like. As the halogen of methyltriphenylphosphonium halide,
Examples thereof include chlorine, bromine and iodine. It is preferable to use the methyltriphenylphosphonium halide and the base in an amount of about 1 to 10 times equivalent to that of the compound represented by the general formula (1a). The reaction time is advantageously about 1 to 24 hours. The reaction temperature is preferably about -78 ° C to room temperature.

Step E The compound represented by the general formula (5) is reacted with a sulfonic acid halide in the presence of a base to form a sulfonic acid ester body, and then reacted with sodium azide to synthesize an azide body. . Further, the azide is reduced to obtain an α, α-dimethylcyclohexanecarbinol derivative represented by the general formula (1c).

The sulfonate ester compound is obtained by reacting the hydroxyl group present in the substituent R ³ of the compound represented by the general formula (5) with a sulfonate halide in an inert gas atmosphere in the presence of a base in a suitable solvent. It can be synthesized by The inert gas is not particularly limited as long as it does not participate in the reaction, and examples thereof include nitrogen and argon. Examples of the sulfonic acid halide include toluenesulfonic acid chloride and methylsulfonic acid chloride. Examples of the base include metal halides such as sodium hydride and potassium hydride, and organic amines such as pyridine, triethylamine and piperidine. As the solvent,
There is no particular limitation as long as it does not participate in the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, N, N-dimethylformamide. Examples thereof include aprotic polar solvents such as dimethyl sulfoxide and acetonitrile, and the base may be used as the solvent as it is. Except when the base is used as a solvent, it is desirable to use the base and the sulfonic acid halide in an amount of about 1 to 2 times the equivalent of the compound of the general formula (5). The reaction temperature is from under ice-cooling to about the boiling point of the solvent, and the reaction time is about 2 to 72 hours, and the reaction proceeds advantageously. Furthermore, add 0.1% of dimethylaminopyridine to the reaction solution.
The reaction can be advantageously carried out by adding about 1 to 1 equivalent.

The azide form can be synthesized by reacting the sulfonate form with sodium azide in a suitable solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, and aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile. It is desirable to use sodium azide in an amount of 1 to 10 equivalents relative to the sulfonate ester. The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is advantageously from 2 hours to 24 hours.

The azide is represented by B in the reaction formula of the above [Chemical formula 3].
By reduction in the same manner as in the step, general formula (1
An α, α-dimethylcyclohexanecarbinol derivative represented by c) is obtained.

The compound of the general formula (2) in which the substituent R ² is a cyano group used as a raw material in the reaction formula of the above [Chemical Formula 3] is produced according to the reaction formula of the following [Chemical Formula 5]. You can also Further, the substituent R in the general formula (4) is
^A compound in which ¹ is 1,3-dioxane forming a spiro ring, or a compound having a lower acyl group or an oxo group can also be produced according to the following reaction schemes of [Chemical Formula 6] and [Chemical Formula 7], respectively. .

[0031]

[Chemical 5]

[In the formula, m, R ¹ and X are the same as defined above. R ³ represents a carboxyl group or a lower alkoxycarbonyl group. ]

Examples of the lower alkoxycarbonyl group represented by R ³ include the same alkoxycarbonyl groups as R ² .

Step F: A known compound represented by the general formula (6) is added to a suitable solvent,
A compound represented by the general formula (7) is obtained by reacting with a reducing agent. The solvent is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol,
Alcohols such as tert-butanol, ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, and aliphatic hydrocarbons such as hexane and heptane. Can be illustrated. Examples of the reducing agent include lithium aluminum hydride and sodium borohydride. It is preferable to use the reducing agent in an amount of about 2 to 10 times equivalent to the compound represented by the general formula (6). Further, the reaction temperature is from under ice cooling to about the boiling point of the solvent, and the reaction time is about 10 minutes to 24 hours, and the reaction proceeds advantageously.

Step G: A sulfonate ester compound is synthesized by the same method as the step E in the reaction formula of [Chemical Formula 4], and the sulfonate ester compound is reacted with potassium cyanide or sodium cyanide in a suitable solvent. Thus, the compound represented by the general formula (2a) is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include alkyl ketones such as acetone and methyl ethyl ketone, and aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile. In the reaction, it is preferable to use potassium cyanide or sodium cyanide in an amount of about 1 to 2 equivalents relative to the sulfonate ester. The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is advantageously about 1 to 24 hours.

[0036]

[Chemical 6]

[In the formula, m and R ² are the same as defined above. ]

Step H The compound represented by the general formula (4b) is obtained by reacting the known compound represented by the general formula (4a) with trimethylene glycol in an appropriate solvent using an acid. Examples of the acid include sulfonic acids such as paratoluenesulfonic acid and phenylsulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene. It can be illustrated. The acid is preferably added in an amount of 0.05 to 0.2 times the equivalent amount of the compound represented by the general formula (4a). It is preferable to use trimethylene glycol in an amount of 1 to 5 times equivalent to that of the compound represented by the general formula (4a). The reaction temperature is from under ice cooling to the boiling point of the solvent,
The reaction time is advantageously about 1 to 24 hours. The reaction proceeds particularly advantageously if the reaction is allowed to proceed while removing water from the system. Examples of the dehydration operation include a method of azeotropically removing with a solvent such as benzene and toluene, and a method of adding a dehydrating agent such as molecular sieves into the system.

[0039]

[Chemical 7]

[In the formula, m and R ² are the same as defined above. R ⁴ represents a lower acyl group or oxo group, and R ⁵ represents a lower alkenyl group or exomethylene group. ]

The reaction is carried out in the same manner as in the step D of the reaction formula of [Chemical formula 4] to obtain the compound represented by the general formula (4d). Each compound obtained by the reaction schemes of [Chemical Formula 3] to [Chemical Formula 7] is isolated and purified by means usually used in the art such as concentration, filtration, recrystallization, various chromatographies and the like.
Further, the compound thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt by adding a suitable acidic compound thereto according to a conventional method.
It has the same pharmacological activity as the present compound in free form, and the present invention also includes such an acid addition salt. Examples of the acidic compound forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid and benzenesulfonic acid. Examples thereof include organic acids.

[0042]

EXAMPLES The present invention will be described in more detail with reference to the following examples. In the table, DST indicates diastereomer.

Example 1 9.62 g of lithium aluminum hydride was added to 600 ml of a dry tetrahydrofuran solution of 42.92 g of m-benzyloxycinnamic acid under ice cooling, and the mixture was stirred for 12 hours. After the reaction, 3N sulfuric acid was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give an oily residue. Next, under a nitrogen gas atmosphere, 13.1 ml of methylsulfonic acid chloride was added to 90 ml of a pyridine solution of this residue under ice cooling, and the mixture was stirred for 30 minutes. After the reaction, 3N sulfuric acid was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 32.1 g of mesyl derivative (yield 59%).

To 200 ml of a solution of 32.1 g of the above mesyl derivative in 200 ml of dimethyl sulfoxide, 7.35 g of sodium cyanide was added, and the mixture was kept at 90 ° C.
The mixture was heated and stirred for 1 hour. After the reaction, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with methylene chloride, washed with saturated saline, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to give 23.53 g of 3-benzyloxy-3′-cyanopropylbenzene (yield 94 %)Obtained.

Under a nitrogen gas atmosphere, 14.5 ml of methyl iodide and 5.24 g of magnesium were reacted in 200 ml of ether to prepare methyl magnesium iodide. Under ice-cooling the solution 3-
Benzyloxy-3'-cyanopropylbenzene 23.53g
100 ml of an ether solution of was added, and the mixture was stirred at room temperature for 12 hours, and heated under reflux for 1 hour. After the reaction, a mixed solution of dioxane and 6N sulfuric acid was added under ice cooling, and the mixture was stirred for 10 minutes, extracted with ether, washed successively with aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane), and 5- (3-benzyloxyphenyl) -2-
15.47 g of pentanone (yield 62%) was obtained.

Further, under ice cooling in a nitrogen gas atmosphere, ether was used.
Methyl iodide (9 ml) and magnesium (3.22 g) in 100 ml were reacted to prepare methyl magnesium iodide. Under ice cooling 5
-(3-Benzyloxyphenyl) -2-pentanone 1
5.47 g of ether solution (100 ml) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, a solution of 2N hydrochloric acid was added under ice cooling, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) and 3-benzyloxy- (4-hydroxy-4-methylpentyl) benzene 13.67g. (Yield 83%) was obtained.

3-benzyloxy- (4-hydroxy-
0.7 g of 5% rhodium-alumina was added to 30 ml of an ethanol solution of 13.67 g of 4-methylpentyl) benzene, and hydrogen was pressurized to 5 atm at room temperature and reacted for 3 hours. Furthermore, 3.5 g of 5% rhodium-alumina was added, and the reaction was conducted for 12 hours in the same manner. Rhodium-alumina was filtered off, ethanol was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane).
6.87 g (yield 88%) of Compound 1 shown in Table 1 was obtained.

Example 2 Using 2-methoxycinnamic acid as a starting material, compound 2 shown in Table 1 was synthesized in the same manner as in Example 1.

Example 3 Methyl 3-hydroxycinnamate (15.8 g) and 5% rhodium-alumina (2.5 g) were added to ethanol (60 ml), and hydrogen was added at room temperature to 5%.
It was pressurized to atmospheric pressure and reacted for 5 hours. Rhodium-alumina was filtered off and ethanol was concentrated under reduced pressure to give 16.5 g of oily compound.
Got Under a nitrogen gas atmosphere, 15.06 ml of methyl iodide and 5.23 g of magnesium were reacted in 200 ml of ether to prepare methyl magnesium iodide.
50 ml of an ether solution of g was added dropwise and the mixture was stirred for 12 hours. After the reaction, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent, ethyl acetate: n
-Hexane) was used for separation and purification, and compound 3 shown in Table 1 was used in 4.
9 g (yield 98%) was obtained.

Example 4 Using 4-hydroxycinnamic acid as a raw material, compound 4 shown in Table 1 was synthesized in the same manner as in Example 3.

Example 5 Pyridinium chlorochromate 9 in 50 ml of methylene chloride
g, 3.42 g of sodium acetate and 5 g of celite were added, and 30 ml of a methylene chloride solution of 4.17 g of 3- (4-hydroxy-4-methylpentyl) cyclohexanol obtained in Example 1 was added dropwise and stirred for 2 hours. Ether was added, celite was filtered off, ether was further concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 4.05 g of compound 5 shown in Table 2 ( Yield 98%).

Example 6 Using the 3- (1-hydroxy-3-methylbutyl) cyclohexanol obtained in Example 3 as a starting material, Compound 6 shown in Table 2 was synthesized in the same manner as in Example 5.

Example 7 1- (1-hydroxyethyl) -3- (1-hydroxy-1-methylethyl) cyclohexane was used as a starting material and compound 7 shown in Table 2 was synthesized in the same manner as in Example 5.

Example 8 An ylide was prepared by adding 6.5 ml of a hexane solution of 2.5 M n-butyllithium to 100 ml of a tetrahydrofuran solution containing 5.82 g of methyltriphenylphosphonium bromide in an ice atmosphere while cooling with ice. 3 obtained in Example 7 in this solution
20 ml of a tetrahydrofuran solution containing 1.5 g of-(1-hydroxy-1-methylethyl) acetylcyclohexane was added dropwise, and the mixture was stirred at room temperature for 5 hours. After the reaction, water was added, the mixture was extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 0.61 g (yield 41%) of compound 8 shown in Table 2.

Example 9 Using the 3- (3-hydroxy-3-methylbutyl) cyclohexanone obtained in Example 6 as a starting material, compound 9 shown in Table 3 was synthesized in the same manner as in Example 8.

Example 10 Using the 3- (4-hydroxy-4-methylpentyl) cyclohexanone obtained in Example 5 as a starting material, compound 10 shown in Table 3 was synthesized in the same manner as in Example 8.

Example 11 Under a nitrogen gas atmosphere, 1.6 g of 4- (1-hydroxy-1-methylethyl) cyclohexanol was dissolved in 8 ml of pyridine, and 2.03 g of paratoluenesulfonic acid chloride and 0.25 g of dimethylaminopyridine were sequentially added. Stir for 3 days at room temperature. After the reaction, the mixture was diluted with ether, washed successively with water, 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 2.7 g of tosyl compound (yield 88%).

10.18 g of the tosyl compound obtained by repeating the above operation several times was added to 100 ml of N, N-dimethylformamide.
30 ml of an aqueous solution of 11.78 g of sodium azide was added dropwise to this solution, and the mixture was heated with stirring at 80 ° C. for 1 hour. After the reaction
It was diluted with ether, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure,
The residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 2.58 g (yield 43%) of an azide compound.

1 g of azide and 0.1 g of platinum dioxide were added to 20 ml of 95% ethanol, and the reaction was carried out at room temperature for 3 hours under hydrogen pressure of 5 atm using an autoclave. Platinum dioxide was removed by filtration, ethanol was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, chloroform: methanol: 28% aqueous ammonia) and further converted into maleic acid salt. Compound 11 as described in 0.
61 g (yield 41%) was obtained.

Example 12 Ylide was prepared by adding 15.2 ml of a 1.6 M n-butyllithium hexane solution to 100 ml of an ether solution of 8.66 g of methyltriphenylphosphonium bromide in an ice-cooled argon atmosphere. To this solution, 20 ml of an ether solution of 4.0 g of ethyl 3- (2-oxocyclohexyl) propionate was added dropwise,
It was stirred at room temperature for 12 hours. After the reaction, water was added, the mixture was extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent, ethyl acetate: n
-Hexane) was separated and purified, and 2.01 g of ethyl 3- (2-ethylenecyclohexyl) propionate (yield 51%)
Obtained.

100 ml of ether under nitrogen atmosphere under ice cooling
Methyl methyl iodide (2.2 ml) was reacted with magnesium (0.84 g) to prepare methyl magnesium iodide. 3- (2
-Ethylenecyclohexyl) ethyl propionate 1.7 g
Was added dropwise and the mixture was stirred for 12 hours. After the reaction, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 1.15 g of compound 12 shown in Table 3 (yield 73%).

Example 13 Ethyl 3- (2-oxocyclohexyl) propionate
2.0 g, trimethylene glycol 1.1 ml, and paratoluenesulfonic acid monohydrate 0.17 g were added to benzene 40 ml, and the mixture was heated under reflux for 12 hours while removing water using a Dean-Stark apparatus. After the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium carbonate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane) to obtain 1.47 g of dioxane (yield 57%).

100 ml of ether under a nitrogen gas atmosphere under ice cooling
Methyl methyl iodide (1.5 ml) was reacted with magnesium (0.53 g) to prepare methyl magnesium iodide. An ether solution of 1.4 g of dioxane was added dropwise to this and stirred for 12 hours. After the reaction, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent, ethyl acetate: n
-Hexane) was used for separation and purification, and compound 13 in Table 4 was added to 1.
11 g (yield 84%) was obtained.

[0064]

[Table 1]

[0065]

[Table 2]

[0066]

[Table 3]

[0067]

[Table 4]

Pharmacological test The neuromuscular blocking effect on skeletal muscle was analyzed by Japan J. et al. Pharmaco
According to the method described in L., 50 , 69 (1989), the effect of enhancing the action of succinylcholine (SuCh) was examined as an index. Krebs-Henseleit solution (118 mM sodium chloride, 5.4 mM potassium chloride, 0.57 mM magnesium sulfate, 2.5 mM calcium chloride, 1.2 mM sodium dihydrogen phosphate, 11.1 mM) was used at 36 to 37 ° C. using an isolated mouse diaphragm neuromuscular specimen.
Glucose, 12 to 15.5 mM sodium hydrogen carbonate; pH =
Experiments were carried out in 7.2-7.4). SuCh was cumulatively administered at 2-minute intervals, and the tension of the twitch generated by electrically stimulating the nerve was measured to obtain a concentration-response curve and IC.
₅₀ (control) was calculated. In addition, the compound of the present invention (80 μ
M) was pretreated for 1 hour and the concentration-reaction curve of SuCh was obtained in the same manner to calculate the IC ₅₀ (drug). The enhancing effect was determined from these IC ₅₀ values using the following formula. The results are shown in Table 5. (Enhancing effect) = IC ₅₀ (control) / IC ₅₀ (drug)

[0069]

[Table 5]

[0070]

INDUSTRIAL APPLICABILITY The α, α-dimethylcyclohexanecarbinol derivative or a salt thereof of the present invention has a neuromuscular blocking action and a therapeutic drug for motor paralysis, and also has an angiogenesis inhibiting action, rheumatoid arthritis, chronic It is useful as a therapeutic drug for nephritis, chronic inflammation such as chronic hepatitis, psoriasis, cancer, diabetic retinopathy, arteriosclerosis and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 215/42 7457-4H C07D 319/08 // A61K 31/045 ABG 9454-4C 31/12 ACV 9454-4C 31/13 AAT 9454-4C ABL ABX ADA ADU 31/335 ACS 9454-4C

Claims (3)

[Claims] 1. An α, α-dimethylcyclohexanecarbinol derivative represented by the general formula [Chemical Formula 1] or a salt thereof. [Chemical 1] [In the formula, R represents an amino group, a lower alkenyl group, a lower acyl group, an exomethylene group, a hydroxyl group, an oxo group, a lower alkoxy group or 1,3-dioxane forming a spiro ring,
m shows 0-3. However, a lower alkoxy group in which m is 0 to 1 and R is substituted at the 2 position, a lower acyl group in which m is 0 to 1 and R is substituted at the 4 position, m is 0 to 1 and R is at the 2 or 3 position Or an amino group substituted by, or m is 0 to 1 and R is an exomethylene group, a hydroxyl group or an oxo group. ] 2. R is an amino group, isopropenyl group, acetyl group, exomethylene group, hydroxyl group, oxo group, methoxy group or 1,3-dioxane forming a spiro ring, and m is 0 to 3. An α, α-dimethylcyclohexanecarbinol derivative or a salt thereof. 3. 3- (4-Hydroxy-4-methylpentyl) cyclohexanol, 3- (4-hydroxy-4)
-Methylpentyl) methoxycyclohexane, 3- (3
-Hydroxy-3-methylbutyl) cyclohexanol, 2- (3-hydroxy-3-methylbutyl) cyclohexanol, 3- (4-hydroxy-4-methylpentyl) cyclohexanone, 3- (3-hydroxy-3-)
Methylbutyl) cyclohexanone, 3- (1-hydroxy-1-methylethyl) acetylcyclohexane, 3-
(4-Hydroxy-4-methylpentyl) cyclohexylidene, 3- (3-hydroxy-3-methylbutyl) cyclohexylidene, 3- (1-hydroxy-1-methylethyl) isopropenylcyclohexane, 4- (1- Hydroxy-1-methylethyl) cyclohexylamine,
The α, α- of claim 1, which is 2- (3-hydroxy-3-methylbutyl) cyclohexylidene and 7- (3′-hydroxy-3′-methylbutyl) -1,5-dioxospiro [5,5] undecane. A dimethylcyclohexane carbinol derivative or a salt thereof.