JPH09268162A - Isoprene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new isoprene derivative, useful as an action enhancer for a carcinostatic agent, e.g. taxol. SOLUTION: This compound is represented by formal I (m) is 0-3; (n) is 5-12; A is a cyclo (3-6C) alkyl, etc.; R1 and R2 are each benzyl, etc.; X is a single bond or (CH2 )p NH [(p) is 0-3], etc.} and its pharmaceutically permissible salt, e.g. trans-N,N-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane. The compound represented by formula I is produced by reacting a compound represented by formula II with a computer represented by formula III (L is a halogen, etc.). The compound represented by formula III in an amount of 0.1-10mol equiv. based on the compound represented by formula II is used at this time and the reaction is carried out in, e.g. an ether solvent at 10-30 deg.C temperature for 5-6hr.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention overcomes the novel isoprene derivatives, a process for their production, and pharmaceutical compositions containing them as active ingredients, and in particular, the multidrug resistance of cancers containing them as active ingredients. The present invention relates to a multidrug resistance overcoming agent and a potentiating agent for anticancer drug.

[0002]

2. Description of the Related Art Overcoming cancer is a problem common to all human beings, and many anticancer agents have been developed to this end. On the other hand, however, the clinical development of multidrug resistance has become a problem. Multidrug resistance means that a cancer cell becomes resistant to an anticancer drug not only with respect to that anticancer drug but also with another anticancer drug due to the administration of a certain anticancer drug or the resistance to the anticancer drug originally possessed by the cancer cells (cross resistance. ) It is a phenomenon. Approximately 50% of newly diagnosed cancer patients are resistant to anticancer drug treatment, and 90% or more of cancer death patients have some relationship with the resistance of anticancer drug to anticancer drug treatment. It is said that he was exhibiting the behavior that he had. Therefore, in cancer chemotherapy, overcoming multidrug resistance of cancer cells to anticancer agents has become extremely important.

There are many unclear points about the mechanism by which cancer cells develop multidrug resistance, but basically, when cancer cells acquire multidrug resistance, the concentration of anticancer drug is reduced in cells. It is thought to be due to the mechanism working. On the other hand, many multidrug-resistant cancer cells overproduce P-glycoprotein, and
-Glycoproteins are thought to be responsible for the transport of anticancer agents out of the cell.

[0004] P-glycoprotein is encoded by a gene called MDR1 in humans, and therefore expression of the MDR1 gene in human cancer cells is considered to contribute to the acquisition of resistance (MDR1 resistance). P-glycoprotein has a low substrate specificity and can bind to a wide variety of compounds to transport the drug to the outside of the cell. Therefore, once P-glycoprotein is expressed in cancer cells, it can be used against many anticancer agents. Will also gain resistance.

In fact, it is known that many structurally different anticancer agents such as adriamycin, vinblastine, vincristine, actinomycin D and colchicine serve as substrates for extracellular transport by P-glycoprotein. Therefore, P
-Inhibition of glycoprotein function is thought to lead to overcoming multidrug resistance. About 30% of multidrug resistance
Is said to be due to P-glycoprotein.

On the other hand, the messenger RNA of the MDR1 gene encoding P-glycoprotein is known to be expressed in normal tissues such as kidney, adrenal gland, large intestine, small intestine, colon, lung, liver, pancreas and lymphocyte. Has been. And in the kidney, P-glycoprotein is responsible for excreting the drug out of the body,
The weak effect of the anticancer drug in renal cancer in which renal cells have become cancer is considered to be because the anticancer drug is excreted extracellularly by the P-glycoprotein expressed in the kidney. Recently, it has been considered that the main body of the blood-brain barrier that controls the transfer of drugs into the brain is P-glycoprotein. This means that by inhibiting P-glycoprotein, the brain, kidney, adrenal gland,
It means that it is possible to increase the concentration of an anticancer agent in the large intestine, small intestine, colon, lung, liver, pancreas, leukemia lymphocytes, etc.,
The P-glycoprotein inhibitor is expected to enhance the effect of an anticancer agent in brain tumor, kidney cancer, adrenal cancer, colon cancer, small intestine cancer, colon cancer, lung cancer, liver cancer, pancreatic cancer, leukemia and the like.

In the area of cancer chemotherapy, mitomycin, cyclophosphamide, melphalan, nidran, carbocon, vincristine, vinblastine, vindesine, bleomycin, 5-fluorouracil, adriamycin, cisplatin, actinomycin D,
Many anticancer agents such as methotrexate, aclarubicin, toyomycin, neocarzinostatin, ifosfamide, etoposide, camptothecin, doxorvidin, irinotecan are used, and each of these anticancer agents has its own anticancer spectrum. However, it is known that some of these anti-cancer agents make the cancer cells resistant by continuous or long-term administration, and there is a problem of cross resistance. Therefore, in chemotherapy for cancer, it is required to activate or enhance the sensitivity of resistant cancer cells to anticancer agents. In addition, most of the anticancer agents have side effects such as hair loss, diarrhea, nausea, and vomiting, in addition to the main effects such as the anticancer effect, and the side effects sometimes impede the treatment by the anticancer agent for cancer patients. Therefore, for the purpose of reducing the side effects of anticancer drugs not only in resistant cancer patients but also in nonresistant cancer patients, there is a demand for an anticancer drug action enhancer capable of exerting an equivalent anticancer drug action with a small dose.

In recent years, taxol and its derivative taxotere have been approved in the United States and are expected to be approved in Japan. Taxol and taxotere have a high response rate particularly in the solid cancer area, and are expected to become one of the centers of solid cancer chemotherapy in the future. However, taxol is known to serve as a substrate for extracellular transport by P-glycoprotein, and its effect is considered to be diminished by resistance to MDR1. By the way, recently
It has been reported that P-glycoprotein inhibitors overcome taxol resistance in DR1-resistant cells (Cancer Re
s., 55, p.1086, 1995). This suggests that P-glycoprotein inhibitors are effective for taxol resistance.

As a drug for overcoming multidrug resistance, Tsuruo et al.

Embedded image Verapamil inhibits P-glycoprotein and causes MDR1
Reported to overcome tolerance (Cancer Res., 41
Vol., P. 1967, 1981).

Nakagawa et al.
(V)

[Chemical 6] And a pharmaceutically acceptable salt thereof. This compound has a resistance overcoming action against resistance to adriamycin (ADM), which is a type of anticancer agent. Also, Ogawa et al.
It is disclosed that the malate salt of the compound represented by the formula (1) has an anticancer activity enhancing action. Further, there is no particular report that the compound represented by the formula (V) enhances the effect of taxol in MDR1-resistant cells.

[0011]

[Problems to be Solved by the Invention] P-glycoprotein inhibitors are effective in overcoming multidrug resistance of cancer. However, existing P-glycoprotein inhibitors have strong side effects due to cytotoxicity or calcium antagonism and are clinically problematic. Therefore, there is a demand for the development of a drug that does not have these side effects and that clinically enhances the activity of an anticancer drug or overcomes multidrug resistance. Furthermore, in recent years, it has been desired to enhance the carcinostatic effect of taxol and its derivatives such as taxotere. Therefore, it has no cytotoxicity or calcium antagonism,
It is desired to develop a novel compound useful as a drug for overcoming multidrug resistance with less side effects, or as a potentiator of various cancer drugs such as taxol and taxotere.

[0012]

[Means for Solving the Problems] The present inventors have conducted diligent research aiming at elucidation and acquisition of a compound having no calcium antagonistic activity, low cytotoxicity, and potentiating the effects of taxol and its derivatives. As a result, they have found that a novel isoprene derivative having a structure represented by the formula (I) solves the above problems, and completed the present invention. That is, the novel isoprene derivative of the present invention overcomes multidrug resistance in cells resistant to anticancer agents, and the present compound enhances the antitumor effect of taxol and its derivatives in MDR1-resistant cells. The inventors have completed the present invention by discovering that they have no calcium antagonistic effect and have low cytotoxicity.

That is, the present invention has the formula (I)

Embedded image(In the formula, m represents an integer of 0 to 3, and n is an integer of 5 to 12.
And A is cyclo (C _Three~ C₆) Alkylene groups, phenyl
Ren group, fluorenylene group, pyrrolidinylene group, pipera
Dinylene group, 9-aza-3-oxabicyclo [3.3.
1] represents a nonylene group, R₁, R_TwoBen independently
Represents a dil group, and the phenyl ring of this benzyl group is
Hydroxyl group, C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group
And substituted with 1 to 5 substituents selected from halogen atoms
X may represent a single bond, or-
(CH_Two)_pIt is a divalent group represented by NH-, and p is 0 to 3.
And the pharmaceutically acceptable form thereof.
Related to salt.

The present invention also relates to a pharmaceutical composition containing the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, more specifically, the above formula (I). Containing a compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient, an agent for overcoming multidrug resistance of cancer cells to an anticancer agent, and brain tumor, kidney cancer, adrenal cancer, colon cancer, small intestine cancer, colon cancer, The present invention relates to an agent for enhancing the action of an anticancer agent used in combination with an anticancer agent in the treatment of cancer such as lung cancer, liver cancer, pancreatic cancer and leukemia. Further, the present invention relates to a taxol and its derivative, which are used in combination with taxol and its derivative, and which comprise the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. Examples of taxol derivatives include taxotere.

The present invention also has the following formula (II)

Embedded image (Wherein m, A, X, R ₁ and R ₂ are as defined in the above formula (I)) and the following formula (III)

Embedded image (Wherein n is as defined in formula (I) above, L is a leaving group selected from a halogen atom, a C ₁ -C ₄ alkylsulfonyloxy group, and an arylsulfonyloxy group) Also relates to a method for producing a compound of the above formula (I).

The above-mentioned compounds of the formula (I) of the present invention and the starting compounds for producing the compounds of the formulas (II) and (III)
In the compound of, specific examples of the cyclo (C ₃ -C ₆ ) alkylene group include cyclopropylene, cyclobutylene,
Cyclopentylene, cyclohexylene group, C
Specific examples of the _{1 to} C ₄ alkyl group include linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl, and C ₁ -C ₄ straight or methoxy branched chain alkoxy groups as specific examples of the alkoxy group, ethoxy,
n-propoxy, isopropoxy, n-butoxy, sec
-Butoxy and t-butoxy groups are mentioned, and the halogen atom includes fluorine, chlorine, bromine and iodine, and C
Specific examples of the ₁ -C ₄ alkylsulfonyloxy group,
Examples thereof include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, and isopropylsulfonyloxy, and specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, p-toluenesulfonyloxy, and naphthalenesulfonyloxy.

In the above formulas (I) and (III), formula (VI)

Embedded image Specific examples of the polyisoprene group represented by the formula (wherein n is as defined in the above formula (I)) include geranyl farnesyl group (n = 5), farnesyl farnesyl group (n = 6), and farnesyl. Geranylgeranyl group (n =
7), farnesyl farnesyl geranyl group (n =
8), solanesyl group (n = 9), decaprenyl group (n =
10), undecaprenyl group (n = 11), dodecaprenyl group (n = 12) and the like.

The pharmaceutically acceptable salt of the compound of the present invention includes, for example, hydrochloride, hydrobromide, sulfate, nitrate,
Inorganic acid salts such as phosphate, acetate, propionate, butyrate, fumarate, citrate, lactate, maleate,
Organic acid salts such as phthalates, malates and tartrates can be mentioned. The compounds of the present invention include geometrical isomers, optical isomers and racemates which are possible in the compounds represented by the above formula (I), and metabolites and metabolic precursors of these compounds.

The compounds of the invention may be resolved into their individual enantiomers by a variety of conventional methods, for example using an optically active acid as a resolving agent. Alternatively, any enantiomer of a compound of the invention may be produced by stereospecific synthesis using optically pure starting materials of known absolute configuration.

The compound of the above formula (I) of the present invention can be produced by the following method. That is, the following formula (II)

Embedded image (Wherein, m, A, X, R ₁ and R ₂ are as defined in the above formula (I)), and a compound of the following formula (III)

Embedded image (In the formula, n is as defined in the above formula (I), and L is a leaving group selected from a halogen atom, a C ₁ -C ₄ alkylsulfonyloxy group, and an arylsulfonyloxy group). A compound of formula (I) above can be prepared by reacting with a compound.

This reaction is carried out with a compound of formula (II)
It is carried out in the presence or absence of a solvent using 1 to 10 molar equivalents of the compound represented by formula (III), but this reaction can be carried out in the presence of a base as the case may be. Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, triethylamine, diethylamine, diisopropylethylamine, tributylamine and diisopropyl. Amines, amines such as trimethylamine, pyridine, 4-
Examples thereof include pyridines such as dimethylaminopyridine, and diisopropylamine is preferably used.

Specific examples of the compound represented by the formula (III) include geranyl farnesyl chloride, farnesyl farnesyl chloride, farnesyl geranyl geranyl chloride, farnesyl farnesyl geranyl chloride, solanesyl chloride, decaprenyl chloride, undecaprenyl chloride, dodecaprenyl chloride, Geranyl farnesyl bromide, farnesyl farnesyl bromide, farnesyl geranyl geranyl bromide, farnesyl farnesyl geranyl bromide, solanesyl bromide, decaprenyl bromide, undecaprenyl bromide, dodecaprenyl bromide, geranyl iodide farnesyl bromide, farnesyl farnesyl iodide, iodo Farnesyl geranyl geranyl iodide, farnesyl farnesyl farnesyl geranyl iodide, solanesyl iodide, decaprenyl iodide,
Undecaprenyl iodide, dodecaprenyl iodide, geranyl farnesyl methanesulfonate, farnesyl farnesyl methanesulfonate, farnesyl geranyl geranyl methane sulfonate, farnesyl farnesyl geranyl methane sulfonate, solanesyl methane sulfonate, decaprenyl methane sulfonate, undecaprenyl methane sulfonate, dodecaprenyl Methane sulfonate, geranyl farnesyl ethane sulfonate, farnesyl farnesyl ethane sulfonate, farnesyl geranyl geranyl ethane sulfonate, farnesyl farnesyl geranyl ethane sulfonate, solanesyl ruethane sulfonate, decaprenyl ethane sulfonate, undecaprenyl ethane sulfonate, dodecaprenyl ethane Rufonate, geranyl farnesyl propane sulfonate, farnesyl farnesyl propane sulfonate, farnesyl geranyl geranyl propane sulfonate, farnesyl farnesyl geranyl propane sulfonate, solanesyl propane sulfonate, decaprenyl propane sulfonate, undecaprenyl propane sulfonate, dodecaprenyl propane sulfonate, geranyl farnesyl butane sulfonate, Farnesyl farnesyl butane sulfonate, farnesyl geranyl geranyl butane sulfonate, farnesyl farnesyl geranyl butane sulfonate, solanesyl butane sulfonate, decaprenyl butane sulfonate, undecaprenyl butane sulfonate, dodecaprenyl butane sulfonate, gela Rufarnesyl isopropyl sulfonate, farnesyl farnesyl isopropyl sulfonate, farnesyl geranyl geranyl isopropyl sulfonate, farnesyl farnesyl geranyl isopropyl sulfonate, solanesyl isopropyl sulfonate, decaprenyl isopropyl sulfonate, undecaprenyl isopropyl sulfonate, dodecaprenyl isopropyl sulfonate, geranyl farnesyl p-toluene sulfonate, Farnesyl farnesyl p-toluene sulfonate, farnesyl geranyl geranyl p-toluene sulfonate, farnesyl farnesyl geranyl p-toluene sulfonate, solanesyl p-toluene sulfonate, decaprenonyl p-toluene sulfonate, undecaprenyl p-
Examples thereof include toluene sulfonate and dodecaprenyl p-toluene sulfonate.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, carbon tetrachloride. Halogenated hydrocarbons such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; methanol, ethanol, isopropanol, etc. Alcohols; Sulfoxides such as dimethyl sulfoxide; Sulfolane; Pyridine;
Pyridines such as 4-dimethylaminopyridine; water; or a mixed solvent thereof is preferably used.

This reaction is carried out in the temperature range from ice-cooling to heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 36 hours. Preferably in ether solvents for 5 hours to 3
It is carried out at 10 ° C to 30 ° C for 6 hours. More preferably, in tetrahydrofuran for 12 to 24 hours, 1
It is carried out at 0 ° C to 25 ° C.

The compound represented by the above formula (II) can be produced by various conventional methods, for example, the following methods. Formula (VII)

Embedded image (In the formula, m, A, X and R ₂ are as defined in the above formula (I)) and the formula (VIII) R ₃ CHO (VIII) (In the formula, R ₃ is a hydroxyl group, (C ₁ -C ₄ ) alkyl group, (C ₁
-C ₄₎ alkoxy group, and 1 to 5 substituents phenyl group which may be substituted by a group selected from a halogen atom. ) Is reacted with a compound of formula (IX)

Embedded image (Wherein m, A, X and R ₂ are as defined in the above formula (I) and R ₃ is as defined in the above formula (VIII)) (step A) Then, the compound represented by the formula (II) can be produced by reduction (step B).

Step A is a step for producing the compound having the above formula (IX), and is usually suitably carried out in the presence of a solvent. Depending on the case, the reaction is carried out while removing water produced by a Dean-Stark device or the like, or in the presence of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, molecular sieve as a dehydrating agent. Done in. The solvent to be used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethylene. Halogenated hydrocarbons such as diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent of these. Used for. The reaction is carried out under ice cooling or heating to reflux. The reaction time is the reaction reagent,
It depends on the reaction temperature and the like, but it is usually 0.5 to 24 hours. It is preferably carried out in a solvent of hydrocarbons or alcohols for 1 to 12 hours at 0 ° C. or under heating under reflux. More preferably 3 to 1 in methanol
It is carried out for 2 hours at 0 ° C to 30 ° C.

Step B is a step of producing the above formula (II), and is a step of reducing the compound having the above formula (IX).
The reaction is usually performed in the presence of a reducing agent. Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride. The reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, chloride Methylene, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol, etc. Sulfoxides such as dimethylsulfoxide; water; or a mixed solvent thereof is preferably used. The reaction is carried out under ice cooling or heating to reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. It is preferably carried out in the presence of sodium borohydride or sodium cyanoborohydride in an alcohol solvent for 1 hour to 5 hours and under ice cooling to 50 ° C.

The above step B is also optionally carried out by catalytic hydrogenation. When carrying out catalytic hydrogenation, the reaction is preferably carried out in the presence of a solvent. The reaction is usually performed in the presence of a catalyst. As the catalyst used, a catalytic hydrogenation catalyst such as palladium-carbon, platinum dioxide or palladium hydroxide is preferably used. The solvent used is not particularly limited as long as it does not affect the reaction, for example, benzene, toluene,
Hydrocarbons such as xylene, hexane, heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and methyl acetate; water or a mixed solvent thereof. The reaction is carried out under hydrogen gas at atmospheric pressure or hydrogen gas at medium to high pressure, or is carried out using formic acid or a formate salt such as sodium formate or ammonium formate as a hydrogen donor. In the reaction, an acid can optionally be added. Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, organic acids such as acetic acid and propionic acid, methanesulfonic acid, toluenesulfonic acid, camphor. Examples include sulfonic acid, or a mixture thereof. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours.
Suitably for 1 to 12 hours under hydrogen gas at atmospheric pressure using a palladium-carbon catalyst in a solvent of alcohols.
It is carried out at a temperature of 0 ° C to 50 ° C.

The above steps A and B can be carried out in the same container as the case may be. That is, the compound of formula (VII) and the formula
The compound of formula (VIII) is reacted in a solvent to produce a compound of formula (IX), which is then reduced with a reducing agent in the same vessel to give a compound of formula (I)
The compounds of I) can be prepared. Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethyl. Formamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol;
Organic acid esters such as methyl acetate and ethyl acetate; organic acids such as acetic acid; or a mixed solvent thereof is preferably used. The reaction is preferably carried out at 0 ° C. to 30 ° C. in an alcohol solvent, more preferably methanol or ethanol at 1 ° C.
After the compound of formula (IX) is prepared by reacting the compound of formula (VII) with the compound of formula (VIII) for 12 hours, it is stored in the same vessel at 0 ° C to 30 ° C.
It is carried out by adding sodium borohydride or sodium cyanoborohydride at 0 ° C. and reacting for 1 to 5 hours.

The above reduction is optionally carried out also by catalytic hydrogenation. When carrying out catalytic hydrogenation, the reaction is preferably carried out in the presence of a solvent. The reaction is usually performed in the presence of a catalyst. As the catalyst used, a catalytic hydrogenation catalyst such as palladium-carbon, platinum dioxide or palladium hydroxide is preferably used. The solvent used is not particularly limited as long as it does not affect the reaction, for example, benzene, toluene,
Hydrocarbons such as xylene, hexane, heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and methyl acetate; water or a mixed solvent thereof. The reaction is carried out under hydrogen gas at atmospheric pressure or hydrogen gas at medium to high pressure, or is carried out using formic acid or a formate salt such as sodium formate or ammonium formate as a hydrogen donor. In the reaction, an acid can optionally be added. Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, organic acids such as acetic acid and propionic acid, methanesulfonic acid, toluenesulfonic acid, camphor. Examples include sulfonic acid, or a mixture thereof. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours.
Suitably in a solvent of alcohols using a palladium-carbon catalyst under hydrogen gas at atmospheric pressure for 1 to 12 hours,
It is carried out at a temperature of 0 ° C to 50 ° C.

Among the compounds represented by the above formula (II), X is-
(CH ₂ ) _p NH— and R ₁ and R ₂ are benzyl groups each having the same substituent can also be produced by the following method. Formula (X)

Embedded image (In the formula, m, A and p are as defined in the above formula (I)) and the compound represented by the formula (VIII) is reacted with the compound of the formula (XI)

Embedded image (Wherein, m, A and p are as defined in the above formula (I), and R ₃ is as defined in the above formula (VIII)), after producing a compound (step C), Reduce (D process) formula
In (II), the formula (XII) in which X =-(CH ₂ ) _p NH

Embedded image (In the formula, m, A, p, R ₁ and R ₂ are as defined in the above formula (I), but R ₁ and R ₂ are each a benzyl group having the same substituent) Compounds can be prepared.

Step C is a step for producing a compound having the above formula (XI), and is usually suitably carried out in the presence of a solvent. The reaction is carried out while removing water produced by a Dean-Stark device or the like, or in the presence of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, and molecular sieves. . The solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; chloroform, methylene chloride, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol, etc. Sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent thereof is preferably used. The reaction is carried out under ice cooling or heating to reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. 1 in a solvent of hydrocarbons and alcohols
It is carried out at 0 ° C. or under heating under reflux for 1 hour to 12 hours. More preferably in methanol for 3 to 12 hours
It is carried out at a temperature between 30 ° C and 30 ° C.

The step D is carried out by the above formula (II) (wherein m,
A, p, R ₁ and R ₂ are as defined in the above formula (I), but R ₁ and R ₂ are benzyl groups each having the same substituent). In this step, the compound having (XI) is reduced. The reaction is usually carried out by reduction in the presence of a reducing agent or hydrogenation in the presence of a catalyst. Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride. The reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, chloride Halogenated hydrocarbons such as methylene, carbon tetrachloride, 1,2-dichloroethylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; methanol, Alcohols such as ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; water; or a mixed solvent thereof is preferably used.
The reaction is carried out under ice cooling or heating to reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. It is preferably carried out in the presence of sodium borohydride or sodium cyanoborohydride in a solvent of alcohols for 1 hour to 5 hours under ice cooling to 50 ° C.

When carrying out catalytic hydrogenation, the reaction is carried out in the presence of a catalyst. As the catalyst used, a catalytic hydrogenation catalyst such as palladium-carbon, platinum oxide, or palladium hydroxide is preferably used. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc .;
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, isopropanol; organic acid esters such as methyl acetate and ethyl acetate; or a mixed solvent thereof is preferably used. In the reaction, hydrogen gas at atmospheric pressure, or hydrogen gas at medium or high pressure, preferably hydrogen gas at atmospheric pressure is used. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 0.5 hours to 2 hours.
4 hours. The reaction is preferably carried out in an alcoholic solvent, especially methanol or ethanol, using platinum oxide under hydrogen gas at atmospheric pressure at 0 ° C. to 50 ° C. for 0.5 to 12 hours.

The above steps C and D can be carried out in the same container as the case may be. That is, the compound of formula (X) and the compound of formula (V
The compound of (III) is reacted in a solvent to produce a compound represented by formula (XI), and the compound of formula (II) ( However,
In the formula, m, A, p, R ₁ and R ₂ are as defined in the above formula (I), but R ₁ and R ₂ are each a benzyl group having the same substituent). can do.
Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
The reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, chloride Halogenated hydrocarbon such as methylene, carbon tetrachloride, 1,2-dichloroethylene; diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; sulfoxides such as dimethyl sulfoxide; water; or a mixed solvent thereof is preferable. Used for. The reaction is carried out under ice cooling or heating to reflux. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but it is usually 0.5 to 24 hours. The reaction is preferably carried out in an alcohol solvent, more preferably methanol or ethanol, at 0 ° C to 30 ° C.
Then, after the compound of formula (XI) is reacted with the compound of formula (VIII) for 1 to 12 hours to prepare the compound of formula (XI), sodium borohydride or sodium cyanoborohydride is prepared at 0 ° C to 30 ° C in the same vessel. Is added and the reaction is carried out for 1 to 5 hours. When the reduction is carried out by catalytic hydrogenation, the catalyst used is preferably a catalytic hydrogenation catalyst such as palladium-carbon, platinum oxide or palladium hydroxide. The solvent used is not particularly limited as long as it does not affect the reaction, and for example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethyl. Amides such as formamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; organic acid esters such as methyl acetate and ethyl acetate; organic acids such as acetic acid; or mixed solvents thereof are preferable. Used for. The reaction is carried out using hydrogen gas at atmospheric pressure, or hydrogen gas at medium to high pressure, preferably
Atmospheric pressure hydrogen gas is used. The reaction time is the reaction reagent,
It depends on the reaction temperature and the like, but it is usually 0.5 to 24 hours. The reaction is preferably carried out in an alcoholic solvent, especially methanol or ethanol, using platinum oxide or palladium-carbon as a catalyst in the presence of acetic acid and hydrogen gas at atmospheric pressure at 0 ° C. to 50 ° C. for 3 hours to 12 hours.
It is carried out by reacting the compound of formula (X) with the compound of formula (VIII) for a period of time.

The compounds of formula (I) of the present invention may be administered in various forms. Examples of the dosage form include oral administration such as tablets, capsules, granules, powders, syrups, and elixirs, and injections (intravenous, intramuscular, subcutaneous,
Intraperitoneal), parenteral administration by drip and suppository. These various preparations are usually used in the technical field of pharmaceutical preparation such as excipients, binders, disintegrating agents, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, etc. It is possible to formulate with known auxiliary agents. The dose varies depending on symptoms, age, weight and administration method, but is usually 0.1 m per day for adults.
g to 600 mg can be administered. No toxicity was observed within this dose range.

The present invention is described below with reference to Examples for the production of the compound of the present invention, Production Examples for the production of synthetic intermediates of the compound of the present invention, Test Examples for the pharmacological effect of the compound of the present invention, and the efficacy of the compound of the present invention. Formulations as the components will be described with reference to formulation examples, but these merely illustrate the present invention and do not limit the present invention.

Example 1 Trans-N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane 10.36 g (2
To a solution of 5 mmol) of tetrahydrofuran in 50 ml of solanesyl bromide 3.47 g (5 mmol) of tetrahydrofuran 1
A 0 ml solution was added dropwise at room temperature, the mixture was stirred at room temperature for 24 hours, and then the solvent was distilled off under reduced pressure. Hexane 30 in the residue
After adding 0 ml and washing with acetonitrile (50 ml × 3), the solvent was distilled off from the taken out hexane layer under reduced pressure. The residue was subjected to silica gel column chromatography to give trans-N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane (3.0 g). Yield: 29%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.25
(m, 4H), 1.60 (s, 27H), 1.68 (s, 3H), 1.50-1.85 (m, 5
H), 1.88-2.18 (m, 32H), 2.42-2.56 (m, 2H), 3.01 (d, J
= 6.5 Hz, 2H), 3.29 (d, J = 13.5 Hz, 1H), 3.49 (d, J = 1
2.5 Hz, 1H), 3.62 (s, 3H), 3.68 (d, J = 12.5 Hz, 1H),
3.81 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 3.80-3.86 (d,
J = 13.5 Hz, 1H), 5.06-5.15 (m, 8H), 5.17 (t, J = 6.5 H
z, 1H), 6.72-6.85 (m, 6H) Further, the dihydrochloride was obtained by a conventional method.

Example 2 Trans-N, N'-bis (3,4,5-trimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (3,4,5-trimethoxybenzyl) -1,2- The same procedure as in Example 1 was carried out using diaminocyclohexane to give trans-N-solanesyl-N,
N'-bis (3,4,5-trimethoxybenzyl) -1,
2-Diaminocyclohexane was obtained. Yield: 67%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.25
(m, 4H), 1.60 (s, 27H), 1.68 (s, 3H), 1.50-1.85 (m, 5
H), 1.90-2.15 (m, 32H), 2.43-2.57 (m, 2H), 3.05 (d, J
= 6.5 Hz, 2H), 3.30 (d, J = 14.0 Hz, 1H), 3.48 (d, J = 1
2.6 Hz, 1H), 3.64 (s, 6H), 3.70 (d, J = 14.0 Hz, 1H),
3.78 (s, 6H), 3.79 (s, 3H), 3.82 (s, 3H), 3.82 (d, J =
12.6 Hz, 1H), 5.06-5.15 (m, 8H), 5.22 (t, J = 6.5 Hz,
1H), 6.47 (s, 2H), 6.52 (s, 2H) Further, dihydrochloride was obtained according to a conventional method.

Example 3 cis-N, N'-bis (3,4-dimethoxybenzyl)-
N-Solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, cis-N, N'-bis (3,4-dimethoxybenzyl) -1,
The same procedure as in Example 1 was carried out using 2-diaminocyclohexane to obtain cis-N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 39%; Free base: ¹ H NMR (CDCl ₃ ) δ1.15-1.35
(m, 4H), 1.44 (s, 3H), 1.60 (s, 24H), 1.68 (s, 3H),
1.50-1.82 (m, 5H), 1.85-2.11 (m, 32H), 2.55-2.63 (m,
1H), 2.98-3.04 (m, 1H), 3.12 (d, J = 6.5 Hz, 2H), 3.45
(d, J = 13.0 Hz, 1H), 3.60 (s, 3H), 3.73 (s, 3H), 3.76
(d, J = 13.0 Hz, 1H), 3.80 (s, 3H), 3.84 (s, 3H), 3.85
(s, 3H), 5.06-5.15 (m, 8H), 5.26 (t, J = 6.5 Hz, 1H),
6.73-6.87 (m, 6H) Further, dihydrochloride was obtained according to a conventional method.

Example 4 1- (3,4-dimethoxybenzyl) -3- [N, N-
(3,4-Dimethoxybenzyl) solanesylamino] pyrrolidine

[Chemical 21] 1-instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane
(3,4-dimethoxybenzyl) -3- [N- (3,4-
The same procedure as in Example 1 was carried out using dimethoxybenzyl) amino] pyrrolidine to give 1- (3,4-dimethoxybenzyl) -3- [N, N- (3,4-dimethoxybenzyl) solanesylamino] pyrrolidine. Yield: 35%; Free base: ¹ H NMR (CDCl ₃ ) δ1.60 (s,
27H), 1.68 (s, 3H), 1.85-2.10 (m, 34H), 2.45-2.67 (m,
4H), 3.05 (d, J = 6.5 Hz, 2H), 3.40-3.64 (m, 5H), 3.86
(s, 6H), 3.87 (s, 3H), 5.05-5.15 (m, 8H), 5.25 (t, J =
6.5 Hz, 1H), 6.75-6.91 (m, 6H) Further, dihydrochloride was obtained according to a conventional method.

Example 5 End-9-aza-9-benzyl-7- [N, N- (3,
4-dimethoxybenzyl) soranesyl] amino-3-oxabicyclo [3.3.1] nonane

Embedded image Endo-9-aza-9-benzyl-7- [N- (3,4
-Dimethoxybenzyl)] amino-3-oxabicyclo [3.3.1] nonane 1.27 g of tetrahydrofuran 5
Solanesyl bromide (2.99 g, 4.31 mmol) was added dropwise to the 0 ml solution at room temperature, and the mixture was stirred for 1.5 hours. A 1% (w / v) aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in hexane and washed with acetonitrile, the solvent was distilled off from the taken out hexane layer under reduced pressure, the residue was subjected to silica gel column chromatography, and endo-9-aza-
360 mg of 9-benzyl-7- [N- (3,4-dimethoxybenzyl) -N-solanesyl] amino-3-oxabicyclo [3.3.1] nonane were obtained. Free base: IR (film) ν _max cm ^-1 2928, 2846, 1593, 1
515, 1453, 1383, 1265, 1235, 1155, 1134, 1035; ¹ H
NMR (CDCl ₃ ) δ 1.60 (s, 27H), 1.64 (s, 3H), 1.68 (s, 3
H), 1.73-1.76 (m, 2H), 1.97-2.06 (m, 34H), 2.80-2.83
(m, 2H), 3.14 (d, J = 6 Hz, 2H), 3.27 (d, J = 11 Hz, 2
H), 3.62 (s, 2H), 3.86-3.93 (m, 4H), 3.87 (s, 3H), 3.
88 (s, 3H), 5.09-5.13 (m, 9H), 5.27-5.29 (m, 1H), 6.8
1 (d, J = 8Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 6.97 (d, J = 2
Hz, 1H), 7.22-7.29 (m, 5H) Further, a pale yellow amorphous dihydrochloride was obtained according to a conventional method.

Example 6 N-{[N- (3,4-dimethoxybenzyl)]-3-
Aminopropyl} -N '-{[N- (3,4-dimethoxybenzyl) -N-solanesyl] -3-aminopropyl} piperazine

Embedded image Endo-9-aza-9-benzyl-7- [N- (3,4
-Dimethoxybenzyl)] amino-3-oxabicyclo [3.3.1] nonane instead of N, N'-bis {[N-
(3,4-dimethoxybenzyl)]-3-aminopropyl} piperazine was carried out in the same manner as in Example 5 to obtain crude N
-{[N- (3,4-dimethoxybenzyl)]-3-aminopropyl} -N '-{[N- (3,4-dimethoxybenzyl) -N-solanesyl] -3-aminopropyl}
1.03 g (37%) of piperazine was obtained. Further, it was converted into tetrahydrochloride by a conventional method, and then recrystallized from acetone to obtain yellow crystals of N-{[N- (3,4-dimethoxybenzyl)]-3.
1.13 g of -aminopropyl} -N '-{[N- (3,4-dimethoxybenzyl) -N-solanesyl] -3-aminopropyl} piperazine tetrahydrochloride were obtained. Free base: ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 24H), 1.68 (s, 3
H), 1.90-2.10 (m, 32H), 2.25-2.78 (m, 12H), 3.03 (d,
J = 6.4 Hz, 2H), 3.47 (s, 2H), 3.74 (s, 2H), 3.86 (s, 6
H), 3.87 (s, 3H), 3.89 (s, 3H), 5.10-5.13 (m, 8H), 5.
28 (t, J = 6.4 Hz, 1H), 6.77-6.91 (m, 6H) tetrahydrochloride: mp 163-171 ° C.

Example 7 N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,3-xylylenediamine

Embedded image N, N'-bis (3,4-dimethoxybenzyl) -1,3
-1.55 g (10.4 mmol) of xylylenediamine in 50 ml of tetrahydrofuran, 1.81 g of solanesyl bromide
A solution of (2.61 mmol) in 15 ml of tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred for 19 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, the organic layer was dried over anhydrous potassium carbonate, and the solvent was evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography,
Light yellow oily N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,3-xylylenediamine 2.
10 g were obtained. Yield: 77%; Free base: ¹ H NMR (CDCl ₃ ) δ1.57 (s,
3H), 1.60 (s, 27H), 1.89-2.11 (m, 32H), 3.02 (d, J = 6.
3 Hz, 2H), 3.50 (s, 2H), 3.54 (s, 2H), 3.74 (s, 2H),
3.79 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3
H), 3.88 (s, 3H), 5.01-5.19 (m, 8H), 5.34 (brt, J = 6.8
Hz, 1H), 6.72-6.97 (m, 7H), 7.16-7.32 (m, 3H) Further, dihydrochloride was obtained according to a conventional method.

Example 8 N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-2,7-diaminofluorene

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, N,
Using N'-bis (3,4-dimethoxybenzyl) -2,7-diaminofluorene, the same procedure as in Example 1 was carried out.
N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-2,7-diaminofluorene was obtained. Yield: 25%; Free base: ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 2
4H), 1.68 (s, 6H), 1.93-2.13 (m, 32H), 3.70-4.05 (m,
16H), 4.45-4.55 (m, 2H), 5.05-5.15 (m, 8H), 5.27-5.35
(m, 1H), 6.55-7.05 (m, 7H), 7.15-7.65 (m, 5H) Further, a dihydrochloride was obtained according to a conventional method.

Example 9 (1R, 2R) -N, N'-bis (3,4-dimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane (1
R, 2R) -N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane was used in the same manner as in Example 1 to obtain (1R, 2R) -N, N'-bis ( Three,
4-dimethoxybenzyl) -N-solanesyl-1,2-
Diaminocyclohexane was obtained. Yield: 46%; Free base: [α] _D ²⁷ = −5.0 ° (c 1.01,
Ethanol); Other spectral data were in agreement with those of Example 1. Further, dihydrochloride was obtained according to a conventional method. [α] _D ²⁷ = + 20.1 ° (c 1.00, ethanol)

Example 10 (1S, 2S) -N, N'-Bis (3,4-dimethoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane (1
S, 2S) -N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane was used as in Example 1 to obtain (1S, 2S) -N, N'-bis ( Three,
4-dimethoxybenzyl) -N-solanesyl-1,2-
Diaminocyclohexane was obtained. Yield: 47%; Free base: [α] _D ²⁷ = + 5.4 ° (c 1.00,
Ethanol); other spectral data were in agreement with Example 1. Further, dihydrochloride was obtained according to a conventional method. [α] _D ²⁷ = −20.6 ° (c 1.03, ethanol)

Example 11 trans-N, N'-bis (3,4-dimethoxybenzyl) -N-geranylfarnesyl-1,2-diaminocyclohexane

Embedded image Geranyl farnesyl bromide was used in place of solanesyl bromide and the procedure was as in Example 1, trans-N, N'-
Bis (3,4-dimethoxybenzyl) -N-geranylfarnesyl-1,2-diaminocyclohexane was obtained. Yield: 41%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.40
(m, 4H), 1.54-1.83 (m, 21H), 1.88-2.15 (m, 18H), 2.4
1-2.55 (m, 2H), 3.01 (d, J = 6.3 Hz, 2H), 3.28 (d, J = 1
4.1 Hz, 1H), 3.49 (d, J = 13.0 Hz, 1H), 3.62 (s, 3H),
3.69 (d, J = 13.0Hz, 1H), 3.80 (s, 3H), 3.84 (s, 3H),
3.85 (s, 3H), 3.80-3.85 (m, 1H), 5.05-5.13 (m, 4H),
5.16-5.22 (m, 1H), 6.71-6.83 (m, 6H) Furthermore, the dihydrochloride was obtained according to a conventional method. Dihydrochloride: ¹ H NMR (CDCl ₃ ) δ 0.80-1.40 (m, 4H), 1.45-
1.74 (m, 20H), 1.75-2.40 (m, 18H), 3.25-3.38 (m, 1H),
3.50-3.65 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 3.99
(s, 6H), 3.80-4.00 (m, 1H), 4.20-4.90 (m, 4H), 4.95-
5.22 (m, 4H), 5.70-5.90 (m, 1H), 6.70-7.15 (m, 4H),
7.50-7.80 (m, 2H), 10.48 (brs, 1H), 11.64 (brs, 1H),
11.88 (brs, 1H)

Example 12 Trans-N, N'-bis (3,4-dimethoxybenzyl) -N-farnesylgeranylgeranyl-1,2-diaminocyclohexane

Embedded image Substituting farnesylgeranylgeranyl bromide in place of solanesyl bromide was carried out as in Example 1, trans-
N, N'-bis (3,4-dimethoxybenzyl) -N-farnesylgeranylgeranyl-1,2-diaminocyclohexane was obtained. Yield: 76%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.
40 (m, 4H), 1.54-1.83 (m, 27H), 1.88-2.15 (m, 26H),
2.41-2.55 (m, 2H), 3.01 (d, J = 6.3 Hz, 2H), 3.28 (d, J
= 14.1 Hz, 1H), 3.49 (d, J = 13.0 Hz, 1H), 3.62 (s, 3
H), 3.69 (d, J = 13.0 Hz, 1H), 3.80 (s, 3H), 3.84 (s, 3
H), 3.85 (s, 3H), 3.80-3.85 (m, 1H), 5.05-5.13 (m, 6
H), 5.16-5.22 (m, 1H), 6.71-6.83 (m, 6H) Further, dihydrochloride was obtained according to a conventional method. Dihydrochloride: ¹ H NMR (CDCl ₃ ) δ 0.80-1.40 (m, 4H), 1.45-
1.74 (m, 26H), 1.75-2.40 (m, 26H), 3.25-3.38 (m, 1H),
3.50-3.65 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 3.99
(s, 6H), 3.80-4.00 (m, 1H), 4.20-4.90 (m, 4H), 4.95-
5.22 (m, 6H), 5.70-5.90 (m, 1H), 6.70-7.15 (m, 4H),
7.50-7.80 (m, 2H), 10.48 (brs, 1H), 11.64 (brs, 1H),
11.88 (brs, 1H)

Example 13 trans-N, N'-bis (3,4-dimethoxybenzyl) -N-farnesyl farnesylgeranyl-1,2
-Diaminocyclohexane

Embedded image Subsequent to Example 1 using farnesyl farnesylgeranyl bromide instead of solanesyl bromide, trans-N, N'-bis (3,4-dimethoxybenzyl) -N-
Farnesyl farnesyl geranyl-1,2-diaminocyclohexane was obtained. Yield: 39%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.40
(m, 4H), 1.54-1.83 (m, 30H), 1.88-2.15 (m, 30H), 2.4
1-2.55 (m, 2H), 3.01 (d, J = 6.3 Hz, 2H), 3.28 (d, J = 1
4.1 Hz, 1H), 3.49 (d, J = 13.0 Hz, 1H), 3.62 (s, 3H),
3.69 (d, J = 13.0Hz, 1H), 3.80 (s, 3H), 3.84 (s, 3H),
3.85 (s, 3H), 3.80-3.85 (m, 1H), 5.05-5.13 (m, 7H),
5.16-5.22 (m, 1H), 6.71-6.83 (m, 6H) Furthermore, the dihydrochloride was obtained according to a conventional method. Dihydrochloride: ¹ H NMR (CDCl ₃ ) δ 0.80-1.40 (m, 4H), 1.45-
1.74 (m, 29H), 1.75-2.40 (m, 30H), 3.25-3.38 (m, 1H),
3.50-3.65 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 3.99
(s, 6H), 3.80-4.00 (m, 1H), 4.20-4.90 (m, 4H), 4.95-
5.22 (m, 7H), 5.70-5.90 (m, 1H), 6.70-7.15 (m, 4H),
7.50-7.80 (m, 2H), 10.48 (brs, 1H), 11.64 (brs, 1H),
11.88 (brs, 1H)

Example 14 trans-N, N'-bis (3,4-dimethoxybenzyl) -N-decaprenyl-1,2-diaminocyclohexane

Embedded image The same procedure as in Example 1 was carried out using decaprenyl bromide instead of solanesyl bromide, and trans-N, N'-bis (3,
4-dimethoxybenzyl) -N-decaprenyl-1,2
-Diaminocyclohexane was obtained. Yield: 65%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.26
(m, 5H), 1.50-1.85 (m, 4H), 1.60 (s, 30H), 1.68 (s, 3
H), 1.90-2.13 (m, 36H), 2.45-2.50 (m, 2H), 3.01 (d, J
= 6.4 Hz, 2H), 3.29 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 1
2.7 Hz, 1H), 3.62 (s, 3H), 3.68 (d, J = 13.7 Hz, 1H),
3.81 (s, 3H), 3.81 (d, J = 12.7 Hz, 1H), 3.84 (s, 3H),
3.85 (s, 3H), 5.07-5.13 (m, 9H), 5.18 (t, J = 6.4 Hz, 1
H), 6.72-6.82 (m, 6H) Further, the dihydrochloride was obtained according to a conventional method.

Example 15 trans-N, N'-bis (3,4-dimethoxybenzyl) -N-dodecaprenyl-1,2-diaminocyclohexane

Embedded image Dodecaprenyl bromide was used instead of solanesyl bromide in the same manner as in Example 1 to obtain trans-N, N'-bis (3,4-dimethoxybenzyl) -N-dodecaprenyl-1,2-diaminocyclohexane. . Yield: 71%; Free base: ¹ H NMR (CDCl ₃ ) δ1.00-1.26
(m, 5H), 1.50-1.85 (m, 4H), 1.60 (s, 36H), 1.68 (s, 3
H), 1.90-2.13 (m, 44H), 2.45-2.50 (m, 2H), 3.01 (d, J
= 6.4 Hz, 2H), 3.29 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 1
2.7 Hz, 1H), 3.62 (s, 3H), 3.69 (d, J = 13.7 Hz, 1H),
3.81 (s, 3H), 3.81 (d, J = 12.7 Hz, 1H), 3.84 (s, 3H),
3.85 (s, 3H), 5.08-5.13 (m, 11H), 5.19 (t, J = 6.4 Hz,
1H), 6.72-6.82 (m, 6H) Further, the dihydrochloride was obtained according to a conventional method.

Example 16 trans-N, N'-bis (4-methylbenzyl) -N
-Solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (4-methylbenzyl) -1,2-
The same procedure as in Example 1 was carried out using diaminocyclohexane to give trans-N, N'-bis (4-methylbenzyl).
-N-Solanesyl-1,2-diaminocyclohexane was obtained. Yield: 83%; Free base: ¹ H NMR (CDCl ₃ ) δ0.99-1.23
(m, 4H), 1.53 (s, 3H), 1.68 (s, 3H), 1.49-1.69 (m, 28
H), 1.73-1.79 (m, 1H), 1.87-2.14 (m, 32H), 2.31 (s, 3
H), 2.32 (s, 3H), 2.34-2.49 (m, 2H), 2.90-3.03 (m, 2
H), 3.27 (d, J = 14 Hz, 1H), 3.50 (d, J = 13 Hz, 1H), 3.
68 (d, J = 14 Hz, 1H), 3.81 (d, J = 13 Hz, 1H), 5.06-5.18
(m, 9H), 7.03-7.17 (m, 8H) Further, dihydrochloride was obtained according to a conventional method.

Example 17 trans-N, N'-bis (4-isopropylbenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (4-isopropylbenzyl)-
The same procedure as in Example 1 was carried out using 1,2-diaminocyclohexane to give trans-N, N'-bis (4-isopropylbenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 73%; Free base: ¹ H NMR (CDCl ₃ ) δ1.10-1.27
(m, 4H), 1.23 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.8 Hz,
6H), 1.52 (s, 3H), 1.68 (s, 3H), 1.50-1.70 (m, 28 H),
1.73-1.80 (m, 1H), 1.87-2.17 (m, 32 H), 2.41-2.58
(m, 2H), 2.82-3.04 (m, 4H), 3.17 (d, J = 14 Hz, 1H),
3.53 (d, J = 13 Hz, 1H), 3.65 (d, J = 14 Hz, 1H), 3.85 (d,
J = 11 Hz, 1H), 5.06-5.21 (m, 9H), 7.08-7.20 (m, 8H) Furthermore, the dihydrochloride was obtained according to the conventional method.

Example 18 trans-N, N'-bis (4-fluorobenzyl)-
N-Solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (4-fluorobenzyl) -1,2 is used.
The same procedure as in Example 1 was carried out using -diaminocyclohexane to obtain trans-N, N'-bis (4-fluorobenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 68%; Free base: ¹ H NMR (CDCl ₃ ) δ1.07-1.24
(m, 4H), 1.53 (s, 3H), 1.68 (s, 3H), 1.51-1.84 (m, 29
H), 1.86-2.14 (m, 32H), 2.38-2.55 (m, 2H), 2.88-3.03
(m, 2H), 3.32 (d, J = 14 Hz, 1H), 3.52 (d, J = 13 Hz, 1
H), 3.64 (d, J = 14 Hz, 1H), 3.86 (d, J = 11 Hz, 1H), 5.
06-5.15 (m, 9H), 6.92 (d, J = 8.3 Hz, 2H), 6.97 (d, J =
8.8 Hz, 2H), 7.14-7.24 (m, 4H) Further, dihydrochloride was obtained according to a conventional method.

Example 19 trans-N, N'-bis (2,3-dichlorobenzyl)
-N-Solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (2,3-dichlorobenzyl)-
The same procedure as in Example 1 was carried out using 1,2-diaminocyclohexane to obtain trans-N, N'-bis (2,3-dichlorobenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 71%; Free base: ¹ H NMR (CDCl ₃ ) δ1.05-1.27
(m, 4H), 1.55-1.81 (m, 32H), 1.93-2.17 (m, 34H), 2.3
5-2.45 (m, 2H), 2.87 (dd, J = 4, 14 Hz, 1H), 3.03 (dd,
J = 8, 14 Hz, 1H), 3.58 (d, J = 15 Hz, 1H), 3.68 (t, J = 1
4 Hz, 2H), 3.89 (d, J = 15 Hz, 1H), 5.09-5.17 (m, 9H),
7.02-7.19 (m, 3H), 7.29-7.36 (m, 3H) Further, the dihydrochloride was obtained according to a conventional method.

Example 20 trans-N, N'-bis (4-hydroxy-3-methoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane

Embedded image Trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane instead of trans-N, N'-bis (4-hydroxy-3-methoxybenzyl) -1,2-diamino The same procedure as in Example 1 was carried out using cyclohexane to obtain trans-N, N'-bis (4-hydroxy-3-methoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 62%; Free base: ¹ H NMR (CDCl ₃ ) δ1.09-1.23
(m, 4H), 1.56-1.78 (m, 32H), 1.83-2.06 (m, 34H), 2.4
5-2.55 (m, 2H), 3.00 (d, J = 7 Hz, 2H), 3.27 (d, J = 14 H
z, 1H), 3.45 (d, J = 12 Hz, 1H), 3.56 (s, 3H), 3.64-3.
70 (m, 1H), 3.77 (s, 3H), 3.83 (d, J = 12 Hz, 1H), 5.07
-5.13 (m, 8H), 5.16-5.19 (m, 1H), 6.65-6.82 (m, 6H) Further, dihydrochloride was obtained according to a conventional method.

Example 21 trans-N, N'-bis (4-methoxybenzyl)-
N-Solanesyl-1,2-diaminocyclohexane

Embedded image Trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane instead of trans-N, N'-bis (4-methoxybenzyl) -1,2
The same procedure as in Example 1 was carried out using -diaminocyclohexane to obtain trans-N, N'-bis (4-methoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 72%; Free base: ¹ H NMR (CDCl ₃ ) δ1.12-1.17
(m, 4H), 1.53 (s, 3H), 1.60 (s, 24H), 1.68 (s, 3H),
1.75-2.10 (m, 36H), 2.39-2.47 (m, 2H), 2.95-2.97 (m,
2H), 3.25 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 12.7 Hz, 1
H), 3.64 (d, J = 13.7 Hz, 1H), 3.81 (d, J = 13.2 Hz, 1
H), 3.78 (s, 6H), 5.08-5.17 (m, 9H), 6.78-6.82 (m, 4
H), 7.11-7.19 (m, 4H) Further, dihydrochloride was obtained according to a conventional method. ¹ H NMR (CDCl ₃ ) δ1.24-1.49 (m, 4H), 1.59 (s, 3H), 1.
60 (s, 24H), 1.67 (s, 3H), 1.74-2.29 (m, 38H), 3.60 (br
s, 2H), 3.79 (s, 3H), 3.83 (s, 3H), 4.31 (d, J = 13.2 H
z, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.63 (d, J = 12.7 Hz,
1H), 4.83 (br, 1H), 5.08-5.12 (m, 8H), 5.81 (brs, 1
H), 6.92-6.96 (m, 4H), 7.61-7.73 (m, 4H), 10.49 (br,
1H), 11.65 (br, 1H), 11.81 (br, 1H)

Example 22 trans-N, N'-bis (4-butoxybenzyl)-
N-Solanesyl-1,2-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (4-butoxybenzyl) -1,2
The same procedure as in Example 1 was carried out using -diaminocyclohexane to obtain trans-N, N'-bis (4-butoxybenzyl) -N-solanesyl-1,2-diaminocyclohexane. Yield: 82%; Free base: ¹ H NMR (CDCl ₃ ) δ 0.98 (t, J
= 7.6 Hz, 6H), 0.99-1.17 (m, 4H), 1.44-.52 (m, 4H),
1.53 (s, 3H), 1.60 (s, 24H), 1.68 (s, 3H), 1.72-1.79
(m, 4H), 1.88-2.06 (m, 36H), 2.41-2.44 (m, 2H), 2.94
-2.96 (m, 2H), 3.24 (d, J = 13.7 Hz, 1H), 3.48 (d, J = 1
2.7 Hz, 1H), 3.63 (d, J = 13.7 Hz, 1H), 3.81 (d, J = 12.
7 Hz, 1H), 3.93 (t, J = 6.4 Hz, 4H), 5.10-5.13 (m, 9
H), 6.77-6.81 (m, 4H), 7.10 (d, J = 8.3 Hz, 2H), 7.16
(d, J = 8.3 Hz, 2H) Further, a dihydrochloride was obtained according to a conventional method. ¹ H NMR (CDCl ₃ ) δ0.95-1.00 (m, 6H), 1.20-1.44 (m, 4
H), 1.45-1.84 (m, 38H), 1.96-2.29 (m, 38H), 3.58 (br
s, 2H), 3.92-3.99 (m, 4H), 4.29 (d, J = 13.2 Hz, 1H),
4.46 (d, J = 12.2 Hz, 1H), 4.63 (d, J = 13.2 Hz, 1H), 4.
85 (br, 1H), 5.07-5.13 (m, 8H), 5.83 (brs, 1H), 6.91-
6.94 (m, 4H), 7.58-7.71 (m, 4H), 10.49 (br, 1H), 11.6
4 (br, 1H), 11.83 (br, 1H)

Example 23 trans-N, N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl-1,2-
Diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (2,3,4,5-tetramethoxy-
6-Methylbenzyl) -1,2-diaminocyclohexane was used as in Example 1 to give trans-N,
N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl-1,2-diaminocyclohexane was obtained. Yield: 51%; free base: ¹ H NMR (CDCl ₃ ) δ1.15-1.1
6 (m, 4H), 1.60 (s, 24H), 1.62 (s, 3H), 1.68 (s, 3H),
1.95-2.18 (m, 36H), 2.13 (s, 3H), 2.21 (s, 3H), 2.34-
2.40 (m, 2H), 2.90-2.95 (m, 2H), 3.44 (d, J = 12.2 Hz,
1H), 3.52 (d, J = 11.7 Hz, 1H), 3.57 (d, J = 12.2 Hz, 1
H), 3.60 (s, 3H), 3.61 (d, J = 11.7 Hz, 1H), 3.75 (s, 3
H), 3.76 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.88 (s,
6H), 3.89 (s, 3H), 5.08-5.17 (m, 9H) Further, dihydrochloride was obtained according to a conventional method. ¹ H NMR (CDCl ₃ ) δ 0.90-1.75 (m, 34H), 1.88-2.45 (m, 4
4H), 3.48-4.99 (m, 30H), 5.09-5.13 (m, 9H), 10.27 (b
r, 1H), 10.71 (br, 1H), 11.08 (br, 1H)

Example 24 trans-N, N'-bis (3,4-diethoxybenzyl) -N-solanesyl-1,4-diaminocyclohexane

Embedded image Instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane, trans-N, N'-bis (3,4-diethoxybenzyl)-
The same procedure as in Example 1 was carried out using 1,4-diaminocyclohexane to obtain trans-N, N'-bis (3,4-diethoxybenzyl) -N-solanesyl-1,4-diaminocyclohexane. Yield: 56%; Free base: ¹ H NMR (CDCl ₃ ) δ1.07-1.13
(m, 2H), 1.31-1.37 (m, 2H), 1.41-1.45 (m, 12H), 1.53
-1.58 (m, 27H), 1.68 (s, 3H), 1.83 (d, J = 11 Hz, 2H),
1.97-2.06 (m, 32H), 2.41 (t, J = 10 Hz, 1H), 2.55 (t, J
= 8 Hz, 1H), 3.05 (d, J = 7 Hz, 2H), 3.49 (s, 2H), 3.7
0 (s, 2H), 4.04-4.15 (m, 8H), 5.10-5.12 (m, 8H), 5.21
(t, J = 6 Hz, 1H), 6.78-6.92 (m, 6H) Further, dihydrochloride was obtained according to a conventional method.

Example 25 1- (2,3,4,5-tetramethoxy-6-methylbenzyl) -3- [N, N- (2,3,4,5-tetramethoxy-6-methylbenzyl) Solanesylamino] pyrrolidine

Embedded image 1-instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane
(2,3,4,5-Tetramethoxy-6-methylbenzyl) -3- [N- (2,3,4,5-tetramethoxy-6
-Methylbenzyl) amino] pyrrolidine was used as in Example 1 to give 1- (2,3,4,5-tetramethoxy-6-methylbenzyl) -3- [N, N- (2,3, 4,
5-Tetramethoxy-6-methylbenzyl) solanesylamino] pyrrolidine was obtained. Yield: 24%; Free base: ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 2
7H), 1.68 (s, 3H), 1.75-1.90 (m, 2H), 1.90-2.10 (m, 3
2H), 2.21 (s, 3H), 2.25 (s, 3H), 2.32-2.38 (m, 1H),
2.42-2.48 (m, 1H), 2.64-2.67 (m, 1H), 2.74-2.77 (m, 1
H), 2.99 (d, J = 6.4 Hz, 2H), 3.35-3.42 (m, 1H), 3.45-
3.55 (m, 4H), 3.75 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3
H), 3.81 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s,
3H), 3.91 (s, 3H), 5.05-5.15 (m, 8H), 5.21 (t, J = 6.4
(Hz, 1H) Further, dihydrochloride was obtained according to a conventional method.

Example 26 1- (3,4-diethoxybenzyl) -3- [N, N-
(3,4-diethoxybenzyl) solanesylamino] pyrrolidine

Embedded image 1-instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane
(3,4-diethoxybenzyl) -3- [N- (3,4-
Diethoxybenzyl) amino] pyrrolidine was used as in Example 1 to give 1- (3,4-diethoxybenzyl) -3- [N, N- (3,4-diethoxybenzyl) solanesylamino] pyrrolidine. Obtained. Yield: 40%; Free base: ¹ H NMR (CDCl ₃ ) δ1.41-1.45
(m, 12H), 1.60 (s, 3H), 1.68 (s, 3H), 1.83-1.85 (m, 2
H), 1.98-2.06 (m, 32H), 2.45-2.61 (m, 4H), 3.03 (d, J
= 7 Hz, 2H), 3.40 (d, J = 13 Hz, 1H), 3.48 (d, J = 14 Hz,
1H), 3.57 (dd, J = 6 Hz, 15 Hz, 2H), 4.06-4.11 (m, 8
H), 5.09-5.12 (m, 8H), 5.24 (t, J = 7 Hz, 1H), 6.78 (d,
J = 2 Hz, 3H), 6.87 (d, J = 7 Hz, 3H) According to a conventional method, dihydrochloride was obtained.

Example 27 1- (3,4-difluorobenzyl) -3- [N, N-
(3,4-Difluorobenzyl) solanesylamino] pyrrolidine

Embedded image 1-instead of trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane
(3,4-difluorobenzyl) -3- [N- (3,4-
The same procedure as in Example 1 was carried out using difluorobenzyl) amino] pyrrolidine to obtain 1- (3,4-difluorobenzyl) -3- [N, N- (3,4-difluorobenzyl) solanesylamino] pyrrolidine. Yield: 12%; Free base: ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 2
7H), 1.68 (s, 3H), 1.80 (m, 1H), 1.95-2.10 (m, 33H),
2.40-2.70 (m, 4H), 3.03 (d, J = 5.8 Hz, 2H), 3.35-3.60
(m, 5H), 5.00-5.15 (m, 8H), 5.19 (t, J = 5.8 Hz), 6.90
-7.20 (m, 6H) Further, a dihydrochloride was obtained according to a conventional method. ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 27H), 1.68 (s, 3H), 1.80-
2.20 (m, 32H), 2.50-3.10 (m, 2H), 3.50-4.60 (m, 11H),
5.11 (m, 8H), 5.36 (m, 1H), 7.25 (m, 2H), 7.49 (m, 2
H), 7.68 (m, 2H), 13.22 (m, 2H)

Example 28 N-{[N- (2,3,4,5-tetramethoxy-6-methylbenzyl)]-3-aminopropyl} -N'-
{[(N-2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl] -3-aminopropyl}
Piperazine

Embedded image Endo-9-aza-9-benzyl-7- [N- (3,4
-Dimethoxybenzyl)] amino-3-oxabicyclo [3.3.1] nonane instead of N, N'-bis {[N- (2,3,4,5-tetramethoxy-6-methylbenzyl) ] -3-Aminopropyl} piperazine was used in the same manner as in Example 5 to give N-{[N- (2,3,4,
5-Tetramethoxy-6-methylbenzyl)]-3-aminopropyl} -N '-{[N- (2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl]
-3-Aminopropyl} piperazine was obtained. Yield: 56
% Further, tetrahydrochloride was obtained according to a conventional method. Tetrahydrochloride: mp 118-122 ° C

Example 29 N-{[N- (3,4-diethoxybenzyl)]-3-
Aminopropyl} -N '-{[N- (3,4-diethoxybenzyl) -N-solanesyl] -3-aminopropyl} piperazine

Embedded image Endo-9-aza-9-benzyl-7- [N- (3,4
-Dimethoxybenzyl)] amino-3-oxabicyclo [3.3.1] nonane instead of N, N'-bis {[N
-(3,4-Diethoxybenzyl)]-3-aminopropyl} piperazine was carried out as in Example 5, except that N
-{[N- (3,4-diethoxybenzyl)]-3-aminopropyl} -N '-{[N- (3,4-diethoxybenzyl) -N-solanesyl] -3-aminopropyl}
I got piperazine. Yield: 56%; Free base: ¹ H NMR (CDCl ₃ ) δ1.42-1.45
(m, 12H), 1.58 (s, 27H), 1.58-1.72 (m, 4H), 1.68 (s,
3H), 1.97-2.08 (m, 32H), 2.30 (t, J = 5 Hz, 2H), 2.38-
2.68 (m, 10H), 2.68 (bs, 2H), 3.02 (d, J = 6 Hz, 2H),
3.45 (s, 2H), 3.71 (s, 2H), 4.04-4.10 (m, 8H), 5.09-
5.13 (m, 8H), 5.27 (t, J = 4 Hz, 1H), 6.78 (s, 2H), 6.8
2 (s, 2H), 6.88 (s, 2H) Further, tetrahydrochloride was obtained by a conventional method.

Example 30 N, N'-bis (3,4-difluorobenzyl) -N-solanesyl-1,3-xylylenediamine

Embedded image N, N'-bis (3,4-dimethoxybenzyl) -1,3
-N, N'-bis (3, instead of xylylenediamine
4-Difluorobenzyl) -1,3-xylylenediamine was carried out in the same manner as in Example 7 to give N, N′-bis (3,4-difluorobenzyl) -N-solanesyl-1,
3-Xylylenediamine was obtained. Yield: 17%; Free base: ¹ H NMR (CDCl ₃ ) δ1.55-1.59
(m, 27H), 1.67 (s, 3H), 1.92-2.07 (m, 32H), 2.99 (d,
J = 6.8 Hz, 2H), 3.47 (s, 2H), 3.53 (s, 2H), 3.75 (s, 2
H), 3.77 (s, 2H), 5.05-5.12 (m, 8H), 5.29 (t, J = 6.8 H
z, 1H), 7.02-7.12 (m, 4H), 7.18-7.27 (m, 6H) Furthermore, the dihydrochloride was obtained according to the conventional method.

Example 31 N, N'-bis (3,4-diethoxybenzyl) -N-solanesyl-1,3-xylylenediamine

Embedded image N, N'-bis (3,4-dimethoxybenzyl) -1,3
-N, N'-bis (3, instead of xylylenediamine
4-diethoxybenzyl) -1,3-xylylenediamine was carried out in the same manner as in Example 7 to obtain N, N'-bis (3,4-diethoxybenzyl) -N-solanesyl-1,
3-Xylylenediamine was obtained. Yield: 11%; Free base: ¹ H NMR (CDCl ₃ ) δ1.40-1.45
(m, 12H), 1.55-1.62 (m, 27H), 1.68 (s, 3H), 1.92-2.0
9 (m, 32H), 3.01 (d, J = 6.8 Hz, 2H), 3.47 (s, 2H), 3.52
(s, 2H), 3.72 (s, 2H), 3.77 (s, 2H), 4.03-4.09 (m, 8
H), 5.06-5.13 (m, 8H), 5.33 (t, J = 6.8 Hz, 1H), 6.77-
6.83 (m, 4H), 6.89 (s, 1H), 6.92-6.93 (m, 1H), 7.16-
7.20 (m, 1H), 7.25-7.26 (m, 2H), 7.29 (s, 1H) Furthermore, the dihydrochloride was obtained according to a conventional method. ¹ H NMR (DMSO-d ₆ ) δ1.30-1.35 (m, 12H), 3.99-4.09 (m,
16H), 6.93-6.96 (m, 2H), 7.00-7.02 (m, 2H), 7.28 (d,
J = 1.9 Hz, 2H), 7.47-7.51 (m, 1H), 7.61 (d, J = 7.3 Hz,
2H), 7.66 (s, 1H), 9.70 (brs, 4H)

Example 32 N, N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl-1,3-xylylenediamine

Embedded image N, N'-bis (3,4-dimethoxybenzyl) -1,3
Instead of xylylenediamine, N, N'-bis (2,
3,4,5-Tetramethoxy-6-methylbenzyl)-
N-N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -N-solanesyl-1,3-was carried out as in Example 7 using 1,3-xylylenediamine. Xylylenediamine was obtained. Yield: 14%; Free base: ¹ H NMR (CDCl ₃ ) δ1.51-1.61
(m, 27H), 1.67 (s, 3H), 1.95-2.09 (m, 32H), 2.17 (s,
3H), 2.23 (s, 3H), 2.94 (d, J = 6.8 Hz, 2H), 3.44 (s, 2
H), 3.53 (s, 2H), 3.72 (s, 2H), 3.74 (s, 3H), 3.76 (s,
3H), 3.77-3.82 (m, 2H), 3.79 (s, 3H), 3.81 (s, 3H),
3.85 (s, 3H), 3.87 (s, 3H), 3.895 (s, 3H), 3.899 (s, 3
H), 5.09-5.12 (m, 8H), 5.35 (t, J = 6.8 Hz, 1H), 7.17-
7.27 (m, 4H) Further, dihydrochloride was obtained according to a conventional method.

Production Example 1 trans-N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane

Embedded image To a solution of 16.6 g (0.10 mol) of veratraldehyde in 100 ml of methanol was added at room temperature 5.71 g (0.05 mol) of trans-1,2-cyclohexanediamine,
After stirring for 12 hours, sodium borohydride 7.60
g (0.20 mol) was added little by little, and then at room temperature, 5
Stirred for hours. Methanol was concentrated under reduced pressure, water was added to the concentrate, and the mixture was extracted with chloroform. The chloroform layer was washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily trans-
N, N'-bis (3,4-dimethoxybenzyl) -1,2
-Diaminocyclohexane was obtained and used in the next reaction without purification.

Production Example 2 trans-N, N'-bis (3,4,5-trimethoxybenzyl) -1,2-diaminocyclohexane

Embedded image Using 3,4,5-trimethoxybenzaldehyde instead of veratraldehyde, the same procedure as in Production Example 1 was performed,
Trans-N, N'-bis (3,4,5-trimethoxybenzyl) -1,2-diaminocyclohexane was obtained.

Production Example 3 cis-N, N'-bis (3,4-dimethoxybenzyl)-
1,2-diaminocyclohexane

Embedded image Using cis-1,2-cyclohexanediamine instead of trans-1,2-cyclohexanediamine, the same procedure as in Preparation Example 1 was repeated to obtain cis-N, N′-bis (3,4-dimethoxybenzyl) -1, 2-Diaminocyclohexane was obtained.

Production Example 4 1- (3,4-dimethoxybenzyl) -3- [N- (3,
4-dimethoxybenzyl) amino] pyrrolidine

Embedded image Using 3-aminopyrrolidine in place of trans-1,2-cyclohexanediamine, the same procedure as in Preparation Example 1 was repeated to obtain 1- (3,4-dimethoxybenzyl) -3- [N-
(3,4-dimethoxybenzyl) amino] pyrrolidine was obtained.

Production Example 5 End-9-aza-9-benzyl-7- [N- (3,4
-Dimethoxybenzyl)] amino-3-oxabicyclo [3.3.1] nonane

Embedded image Instead of trans-1,2-cyclohexanediamine, endo-7-amino-9-aza-9-benzyl-3-oxabicyclo [3.3.1] nonane (JP-A-7-1088).
In the same manner as in Production Example 1, using the same procedure as in Preparation Example 1, using endo-9-aza-9-benzyl-7- [N- (3,4-dimethoxybenzyl)] amino-3-oxabicyclo [3.
3.1] I got Nonan.

Production Example 6 N, N'-bis {[N- (3,4-dimethoxybenzyl)]-3-aminopropyl} piperazine

Embedded image Using 1,4-bis (3-aminopropyl) piperazine instead of trans-1,2-cyclohexanediamine, the same procedure as in Preparation Example 1 was repeated to obtain N, N'-bis {[N-
(3,4-dimethoxybenzyl)]-3-aminopropyl} piperazine was obtained.

Production Example 7 N, N'-bis (3,4-dimethoxybenzyl) -2,7
-Diaminofluorene

Embedded image Using 2,7-diaminofluorene instead of trans-1,2-cyclohexanediamine, the same procedure as in Preparation Example 1 was repeated to obtain N, N'-bis (3,4-dimethoxybenzyl) -2,7-diaminofluorene. Got

Production Example 8 N, N'-bis (3,4-dimethoxybenzyl) -1,3
-Xylylenediamine

Embedded image A solution of 10.0 g (73.42 mmol) of m-xylylenediamine in 300 ml of methanol was added with veratraldehyde 25.0.
g (150.50 mmol) was added, the mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. Dissolve the residue in benzene,
The solvent was distilled off under reduced pressure, and this operation was repeated twice. The residue was dissolved in 200 ml of methanol, and under ice cooling, sodium borohydride (5.83 g, 154.20 mmol) was added little by little over 15 minutes, and the mixture was added for 30 minutes. After stirring, the mixture was further stirred at room temperature for 18 hours. 10 ml of acetone was added to the reaction solution, the solvent was distilled off under reduced pressure, 150 ml of water was added to the residue, 20 ml of concentrated hydrochloric acid was further added to acidify, and the mixture was stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration and recrystallized from water to give colorless crystals of N, N'-bis (3,4-dimethoxybenzyl) -1,3.
-Xylylenediamine (dihydrochloride) 23.05 g (62
%). Part of the solution was dissolved in 10% (w / v) sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous potassium carbonate and the solvent was distilled off under reduced pressure to obtain N, N'-bis (3,4- Dimethoxybenzyl) -1,3-xylylenediamine (free base) was obtained. Dihydrochloride: ¹ H NMR (DMSO-d ₆ ) δ3.76 (s, 6H), 3.77 (s,
6H), 4.07 (s, 4H), 4.09 (s, 4H), 6.95 (d, J = 8.3 Hz, 2
H), 7.05 (dd, J = 1.0 Hz, 6.8 Hz, 2H), 7.35 (s, 2H),
7.49 (t, J = 7.3 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.69
(s, 1H), 9.82 (brs, 4H, replaced by heavy water). Free base: ¹ H NMR (CDCl ₃ ) δ 1.60 (s, 2H, replaced with heavy water), 3.76 (s, 4H), 3.80 (s, 4H), 3.87 (s, 6H), 3.88
(s, 6H), 6.81 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.3Hz, 2
H), 6.90 (s, 1H), 7.23 (d, J = 7.3 Hz, 2H), 7.27-7.40
(m, 2H)

Production Example 9 (1S, 2S) -N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane

Embedded image Instead of trans-1,2-cyclohexanediamine, (1S, 2S) -1,2-diaminocyclohexane was used and the same procedure as in Production Example 1 was carried out to obtain (1S, 2S) -N,
N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane was obtained. Yield: 87%; ¹ H NMR was consistent with Preparation Example 1.

Production Example 10 (1R, 2R) -N, N'-bis (3,4-dimethoxybenzyl) -1,2-diaminocyclohexane

Embedded image Instead of trans-1,2-cyclohexanediamine, (1R, 2R) -1,2-diaminocyclohexane was used and the same procedure as in Production Example 1 was carried out to obtain (1R, 2R) -N,
N'-bis (3,4-dimethoxybenzyl) -1,2-
Diaminocyclohexane was obtained. Yield: 100%; ¹ H NMR was consistent with Preparation Example 1.

Production Example 11 trans-N, N'-bis (4-methylbenzyl) -1,
2-diaminocyclohexane

Embedded image Using 4-methylbenzaldehyde instead of veratraldehyde, the procedure of Production Example 1 was repeated.
N, N'-bis (4-methylbenzyl) -1,2-diaminocyclohexane was obtained.

Production Example 12 trans-N, N'-bis (4-isopropylbenzyl) -1,2-diaminocyclohexane

Embedded image Using 4-isopropylbenzaldehyde in place of veratraldehyde, the same procedure as in Preparation Example 1 was carried out to obtain trans-N, N′-bis (4-isopropylbenzyl)-
1,2-diaminocyclohexane was obtained.

Production Example 13 trans-N, N'-bis (4-fluorobenzyl)-
1,2-diaminocyclohexane

Embedded image 4-Fluorobenzaldehyde was used in place of veratraldehyde and the same procedure as in Preparation Example 1 was carried out to obtain trans-N, N'-bis (4-fluorobenzyl) -1,2-diaminocyclohexane.

Production Example 14 trans-N, N'-bis (2,3-dichlorobenzyl)
-1,2-diaminocyclohexane

Embedded image 2,3-Dichlorobenzaldehyde was used in place of veratraldehyde, and the same procedure as in Preparation Example 1 was carried out to obtain trans-N, N'-bis (2,3-dichlorobenzyl)-
1,2-diaminocyclohexane was obtained. ¹ H NMR (CDCl ₃ ) δ1.04-1.09 (m, 2H), 1.18-1.30 (m, 2
H), 1.72-1.74 (m, 2H), 2.02-2.04 (m, 2H), 2.16 (d, J = 1
4 Hz, 2H), 2.21-2.28 (m, 2H), 3.77 (d, J = 14Hz, 2H),
3.97 (d, J = 14 Hz, 2H), 7.15 (t, J = 8 Hz, 2H), 7.30-7.
35 (m, 4H)

Production Example 15 trans-N, N'-bis (4-hydroxy-3-methoxybenzyl) -1,2-diaminocyclohexane

Embedded image The same procedure as in Production Example 1 was carried out using vanillin in place of veratraldehyde to give trans-N, N'-bis (4
-Hydroxy-3-methoxybenzyl) -1,2-diaminocyclohexane was obtained. ¹ H NMR (CDCl ₃ ) δ1.15-1.27 (m, 4H), 1.74-1.76 (m, 2
H), 2.16-2.19 (m, 2H), 2.35-2.38 (m, 2H), 3.56 (d, J = 1
3 Hz, 2H), 3.72 (s, 6H), 3.87 (d, J = 13 Hz, 2H), 6.72
(dd, J = 1, 8 Hz, 2H), 6.77 (d, J = 8 Hz, 2H), 6.85 (d,
(J = 1 Hz, 2H)

Production Example 16 trans-N, N'-bis (4-methoxybenzyl)-
1,2-diaminocyclohexane

Embedded image Using 4-methoxybenzaldehyde instead of veratraldehyde, the same procedure as in Preparation Example 1 was carried out to obtain colorless needle crystals of trans-N, N′-bis (4-methoxybenzyl) -1,2-diaminocyclohexane. Obtained. Yield: 67%; mp 110-112 ° C; ¹ H NMR (CDCl ₃ ) δ1.0
1-1.03 (m, 2H), 1.19-1.24 (m, 2H), 1.70-1.72 (m, 2H),
1.81 (brs, 2H, replaced by heavy water), 2.13-2.16 (m, 2H), 2.22
-2.24 (m, 2H), 3.58 (d, J = 12.7 Hz, 2H), 3.79 (s, 6H),
3.83 (d, J = 12.7 Hz, 2H), 6.84 (d, J = 8.3 Hz, 4H), 7.
22 (d, J = 8.3 Hz, 4H)

Production Example 17 trans-N, N'-bis (4-butoxybenzyl)-
1,2-diaminocyclohexane

Embedded image Using 4-butoxybenzaldehyde instead of veratraldehyde, the same procedure as in Preparation Example 1 was carried out to obtain trans-N, N′-bis (4-butoxybenzyl) -1,2-diaminocyclohexane. Yield: 81%; ¹ H NMR (CDCl ₃ ) δ 0.97 (t, J = 7.3 Hz, 6
H), 0.99-1.03 (m, 2H), 1.15-1.23 (m, 2H), 1.44-1.54
(m, 4H), 1.70-1.79 (m, 6H), 2.11-2.15 (m, 2H), 2.20-
2.25 (m, 2H), 3.55 (d, J = 12.7 Hz, 2H), 3.81 (d, J = 12.
7 Hz, 2H), 3.94 (t, J = 6.4 Hz, 4H), 6.83 (d, J = 8.3 H
z, 4H), 7.19 (d, J = 8.3 Hz, 4H)

Production Example 18 trans-N, N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -1,2-diaminocyclohexane

Embedded image 2,3,4,5-Tetramethoxy-6-methylbenzaldehyde was used in place of veratraldehyde and the same procedure as in Preparation Example 1 was carried out to obtain trans-N, N'-bis (4-
Butoxybenzyl) -1,2-diaminocyclohexane was obtained. Yield: 100%; ¹ H NMR (CDCl ₃ ) δ1.06-1.08 (m, 2H),
1.23-1.33 (m, 2H), 1.75-1.78 (m, 2H), 2.16-2.19 (m,
2H), 2.18 (s, 6H), 2.28-2.31 (m, 2H), 3.51 (d, J = 11.7
Hz, 2H), 3.74 (s, 6H), 3.76 (s, 6H), 3.84 (d, J = 11.2
Hz, 2H), 3.84 (s, 6H), 3.90 (s, 6H)

Production Example 19 trans-N, N'-bis (3,4-diethoxybenzyl) -1,4-diaminocyclohexane

Embedded image Trans-1,4-cyclohexanediamine is used in place of trans-1,2-cyclohexanediamine, and 3,4-diethoxybenzaldehyde is used in place of veratraldehyde. Trans-N, N'-bis (3,4-diethoxybenzyl) -1,4-diaminocyclohexane was obtained. Yield: 47%: ¹ H NMR (CDCl ₃ ) δ1.15 (t, J = 10 Hz, 4
H), 1.41-1.48 (m, 12H), 1.96 (d, J = 6 Hz, 4H), 2.49 (b
s, 2H), 3.72 (s, 4H), 4.07 (q, J = 7 Hz, 4H), 4.08 (q,
J = 7 Hz, 4H), 6.79-6.86 (m, 6H)

Production Example 20 N, N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -3-aminopyrrolidine

Embedded image 100 ml of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde 12.7 g (52.9 mmol) of methanol
To the solution was added 3-aminopyrrolidine (2.0 g, 23.2 mmol), and the mixture was stirred with heating under reflux for 4 hours. After cooling to room temperature, 2.0 g (52.6 mmol) of sodium borohydride was added little by little and stirred for 3 hours. After adding a 5 (w / v)% sodium hydroxide aqueous solution to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the methanol / chloroform (1/19) fraction, N, N'-bis (2,
3,4,5-Tetramethoxy-6-methylbenzyl) -3
-6.34 g of aminopyrrolidine were obtained. Yield: 51%

Production Example 21 N, N'-bis (3,4-diethoxybenzyl) -3-aminopyrrolidine

Embedded image Using 3-aminopyrrolidine in place of trans-1,2-cyclohexanediamine and 3,4-diethoxybenzaldehyde in place of veratraldehyde, the same procedure as in Production Example 1 was repeated. -Bis (3,
4-diethoxybenzyl) -3-aminopyrrolidine was obtained. Yield: 76%; ¹ H NMR (CDCl ₃ ) δ1.41-1.45 (m, 12H),
1.60-1.61 (m, 1H), 2.10-2.15 (m, 1H), 2.38 (dd, J = 5 H
z, 10 Hz, 1H), 2.50 (dd, J = 8 Hz, 15 Hz, 1H), 2.62 (d
d, J = 8 Hz, 15 Hz, 1H), 2.72 (dd, J = 7 Hz, 9 Hz, 1H),
3.30-3.35 (m, 1H), 3.49 (d, J = 12 Hz, 1H), 3.55 (d, J =
11 Hz, 1H), 3.64 (s, 2H), 4.03-4.10 (m, 8H), 6.80-6.
90 (m, 6H)

Production Example 22 N, N'-bis (3,4-difluorobenzyl) -3-
Aminopyrrolidine-trans

Embedded image The same procedure as in Production Example 1 was carried out using 3-aminopyrrolidine instead of trans-1,2-cyclohexanediamine and 3,4-difluorobenzaldehyde instead of veratraldehyde. (3,4
-Difluorobenzyl) -3-aminopyrrolidine was obtained. Yield: 95%; Free base: ¹ H NMR (CDCl ₃ ) δ1.61 (m, 1
H), 2.13 (m, 1H), 2.39 (m, 1H), 2.47 (m, 1H), 2.60-2.
70 (m, 2H), 3.31 (m, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.5
6 (d, J = 13.2 Hz, 1H), 3.66 (d, J = 13.7 Hz, 1H), 3.70
(d, J = 13.7 Hz, 1H), 6.90-7.20 (m, 6H)

Production Example 23 N, N'-bis {[N- (2,3,4,5-tetramethoxy-6-methylbenzyl)]-3-aminopropyl} piperazine

Embedded image 1,4-bis (3-aminopropyl) piperazine was used instead of trans-1,2-cyclohexanediamine, and 2,3,4,5 was used instead of veratraldehyde.
-Tetramethoxy-6-methylbenzaldehyde was used and the same procedure as in Preparation Example 1 was repeated to obtain N, N'-bis {[N-
(2,3,4,5-Tetramethoxy-6-methylbenzyl)]-3-aminopropyl} piperazine was obtained. ¹ H NMR (CDCl ₃ ) δ1.67-1.74 (m, 4H), 2.23 (s, 6H), 2.
36-2.64 (m, 12H), 2.68 (t, J = 6.8 Hz, 4H), 3.70 (s, 4
H), 3.78 (s, 6H), 3.84 (s, 6H), 3.89 (s, 6H), 3.90 (s,
6H)

Production Example 24 N, N'-bis {[N- (3,4-diethoxybenzyl)]-3-aminopropyl} piperazine

Embedded image 1,4-bis (3-aminopropyl) piperazine was used in place of trans-1,2-cyclohexanediamine, and 3,4-diethoxybenzaldehyde was used in place of veratraldehyde. In the same manner, N, N'-bis {[N- (3,4-diethoxybenzyl)]-3-aminopropyl} piperazine was obtained. Yield: 80%; Free base: ¹ H NMR (CDCl ₃ ) δ1.41-1.46
(m, 12H), 1.70 (sept, J = 7 Hz, 4H), 2.38 (t, J = 7 Hz, 4
H), 2.35-2.58 (m, 4H), 2.66 (t, J = 7 Hz, 4H), 3.70 (s,
4H), 4.05-4.12 (m, 4H), 6.81 (d, J = 1 Hz, 4H), 6.87
(s, 2H)

Production Example 25 N, N'-bis (3,4-difluorobenzyl) -1,3
-Xylylenediamine

Embedded image Using 3,4-difluorobenzaldehyde instead of veratraldehyde, the procedure of Production Example 8 was repeated.
N'-bis (3,4-difluorobenzyl) -1,3-xylylenediamine was obtained. ¹ H NMR (CDCl ₃ ) δ 3.76-3.81 (m, 8H), 7.04-7.13 (m, 4
H), 7.16-7.36 (m, 6H)

Production Example 26 N, N'-bis (3,4-diethoxybenzyl) -1,3
-Xylylenediamine

Embedded image Using 3,4-diethoxybenzaldehyde instead of veratraldehyde, the same procedure as in Preparation Example 8 was repeated.
N'-bis (3,4-diethoxybenzyl) -1,3-xylylenediamine was obtained.

Production Example 27 N, N'-bis (2,3,4,5-tetramethoxy-6-methylbenzyl) -1,3-xylylenediamine

Embedded image Using 2,3,4,5-tetramethoxy-6-methylbenzaldehyde instead of veratraldehyde, the same procedure as in Preparation Example 8 was repeated to obtain N, N'-bis (2,3,4,5-tetramethoxy -6-Methylbenzyl) -1,3-xylylenediamine was obtained.

Production Example 28 2,3,4,5-tetramethoxy-6-methylbenzaldehyde

Embedded image 34.3 g of 1,2,3,4-methoxy-5-methylbenzene
Hexamethylenetetramine (25.0 g, 178 mmol) was added to a solution of (162 mmol) in trifluoroacetic acid (200 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was evaporated under reduced pressure,
200 ml of water was added to the residue and heated under reflux for 1 hour. Neutralized with 3N sodium hydroxide. The mixture was extracted with 200 ml of ethyl acetate × 3, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 34.9 g of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde. Yield: 90%; ¹ H NMR (CDCl ₃ ) δ2.46 (s, 3H), 3.76
(s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 10.43 (s, 1H)

Next, a multidrug resistance overcoming agent of the compound of the present invention,
The effect as a carcinostatic agent will be described. Test Example 1 Human breast cancer-derived adriamycin (ADM) resistant cells (M
Colony formation test in CF7 / ADM) In a 12-well plate, 1 of human breast cancer-derived adriamycin resistant cells (MCF7 / ADM) prepared at 750 cells / ml was prepared.
MEM (minimal) containing 0% fetal bovine serum and glutamine (2 μg / ml) and kanamycin (50 μg / ml)
Essential medium) Culture solution (Nissui Pharmaceutical Co., Ltd.) is dispensed at 1500 cells / well and placed in a 5% carbon dioxide gas atmosphere for 3
It was cultured at 7 ° C for 24 hours. A 0.50 mmol solution of the test compound in dimethyl sulfoxide was added cumulatively, and the mixture was incubated at 37 ° C. for 1 week in 5% carbon dioxide gas. After staining with a 0.1% methylene blue / methanol solution for 30 minutes, it was dried and microscopically examined to count the number of colonies. IC ₃₀ (concentration of compound that inhibits 30% colony formation) was calculated from the number.

[0099]

[Table 1] As is clear from Table 1 above, the compounds of the present invention have lower cytotoxicity than known compounds.

Test Example 2 Combined effect on human breast cancer-derived adriamycin (ADM) non-resistant cells (MCF7 / WT) In a 12-well plate, human breast cancer-derived adriamycin non-resistant cells (MCF7 / WT) containing 10% fetal calf serum and glutamine ( 2 μg / ml) and kanamycin (50 μg
/ Ml) containing MEM (minimal essential medium) culture solution (Nissui Pharmaceutical Co., Ltd.) was dispensed at 1000 cells / well and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide gas atmosphere. Adriamycin was added cumulatively to the culture solution in the range of 0 to 50 ng / ml, and further a dimethylsulfoxide solution of the test compound was added so that the final concentration reached the IC ₃₀ value determined in Test Example 1, and 5% carbonic acid was added. The cells were cultured under gas at 37 ° C for 1 week. As a control, adriamycin alone was added. After staining with a 0.1% methylene blue / methanol solution for 30 minutes, it was dried and microscopically examined to count the number of colonies. From the number, the IC ₅₀ (concentration of the compound that inhibits 50% colony formation) was calculated, and the enhancement factor (relative value when the IC ₅₀ value obtained for the control example (adriamachine alone administration) was set to 1) I asked. This test consisted of two series of experiments, ie, the addition of doriamycin alone as a control and either Example 1 (dihydrochloride) or Example 6
About the one in which the compound of (dihydrochloride) was used in combination (first experiment), and the one in which only doriamycin was added as a control, and the one in which the compound of Example 4 (dihydrochloride) was used in combination ( Second experiment)

[0101]

[Table 2] As is clear from Table 2 above, the compound of the present invention enhances the antitumor effect of adriamycin in human breast cancer-derived ADM non-resistant cells.

Test Example 3 Human breast cancer-derived adriamycin resistant cells (MCF7 / A
Combined effect on DM) In a 12-well plate, 10% fetal bovine serum of human breast cancer-derived adriamycin resistant cells (MCF7 / ADM), glutamine (2 μg / ml) and kanamycin (50 μg)
/ Ml) containing MEM (minimal essential medium) culture solution (Nissui Pharmaceutical Co., Ltd.) was dispensed at 1500 cells / well and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide atmosphere. Adriamycin was added cumulatively to the culture medium in the range of 0 to 5000 ng / ml, and a dimethylsulfoxide solution of the test compound was added to give a final concentration of IC ₃₀ determined in Test Example 1.
It was added so that the value became a value, and the cells were cultured in 5% carbon dioxide at 37 ° C. for 1 week. As a control, adriamycin alone was added. 3 with 0.1% methylene blue / methanol solution
After staining for 0 minutes, it was dried and microscopically examined to count the number of colonies. The IC ₅₀ (concentration of compound that suppresses 50% colony formation) was calculated from the number, and the relative value when the IC ₅₀ value of the fold resistance (control example of Test Example 2 (administration of Adriamachine alone) was set to 1) ) Was asked. This test is similar to Test Example 2
As a series of experiments, that is, as a control example, only doriamycin was added, and to this, Example 1 (dihydrochloride)
Alternatively, for the combination of the compounds of Example 6 (dihydrochloride) (first experiment), and the one to which only doriamycin was added as a control, and to Example 4 (dihydrochloride) or Example 7 The experiment using the compound of (dihydrochloride) in combination (second experiment) was conducted.

[0103]

[Table 3] As is clear from the above table, the compound of the present invention has a resistance overcoming action in human breast cancer-derived adriamycin resistant strain (MCF7 / ADM).

As described above, the compound represented by the above formula (I) of the present invention or a salt thereof has low cytotoxicity and enhances the action of an anticancer agent in non-resistant cancer cells. In addition, it has an action of overcoming resistance in multidrug-resistant cancer cells. Therefore, the compound represented by the above formula (I) of the present invention, or a salt thereof, is useful as a multidrug resistance overcoming agent and an anticancer agent enhancer.

Finally, examples of pharmaceutical preparations containing the compound of the present invention or its hydrochloride as an active ingredient will be shown. Formulation Example 1 Oral Hard Capsule 25 g of the compound of Example 1 and 7.5 g of polyoxyethylene castor oil were dissolved in methanol, and then 25 g of silicic anhydride was mixed. After evaporation of methanol, 5 g of carboxymethyl cellulose calcium, 5 g of corn starch and 7.5 g of hydroxypropyl cellulose.
And 20 g of microcrystalline cellulose are mixed, 30 ml of water are added, kneaded and granulated. This was granulated with a granulator equipped with a No. 24 mesh (BS) screen. The granules were dried to a water content of less than 5% and processed through a No. 16 mesh (BS) sieve. Next, 200 mg per capsule was filled with the particles using a capsule filling machine.

Formulation Example 2 Oral Soft Capsule 30 g of the compound of Example 1 and 130 g of polyethylene glycol (Macrogol 400) were mixed to prepare a uniform solution. Separately, 93 g of gelatin, 19 g of glycerin, D
-Sorbitol 10 g, ethyl paraoxybenzoate 0.
A gelatin solution having the composition of 4 g, propyl paraoxybenzoate 0.2 g and titanium oxide 0.4 g was prepared,
Using this as a capsule film agent, a soft capsule containing 190 mg of the content was manufactured by a manual flat plate punching method.

Formulation Example 3 Oral Soft Capsule Agent 40 g of the compound of Example 1 and 120 g of polyethylene glycol (Macrogol 400) were mixed to prepare a uniform solution. Separately 90 g of gelatin, 16 g of glycerin, D
-Sorbitol 8g, ethyl paraoxybenzoate 0.3
A gelatin solution having a composition of 5 g, propyl paraoxybenzoate 0.2 g and titanium oxide 0.3 g was prepared,
Using this as a capsule film agent, a soft capsule containing 180 mg of the content was manufactured by a manual flat plate punching method.

Formulation Example 4 Injectable Solution 5 g of the hydrochloride of the compound of Example 1, 5 parts of peanut oil and 1 g of benzyl alcohol were mixed, and the total amount was 100 ml using peanut oil. By aseptic operation, 1 ml of this solution was poured into an ampoule and melted.

Formulation Example 5 Injectable Compound 9 g of the hydrochloride of the compound of Example 1, hydrogenated castor oil polyoxyethylene (60 mol) ether (Nikkor HC
O 60) 5.0 g, propylene glycol 20 g, glycerin 10 g and ethanol 5.0 g were mixed, and 100 ml of distilled water was added and stirred. By aseptic operation, 2 ml of this solution was poured into an ampoule and melt-closed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 209/08 8828-4H C07C 209/08 211/29 8828-4H 211/29 211/40 8828- 4H 211/40 213/02 7457-4H 213/02 215/50 7457-4H 215/50 215/54 7457-4H 215/54 215/64 7457-4H 215/64 217/58 7457-4H 217/58 217 / 62 7457-4H 217/62 217/74 7457-4H 217/74 C07D 207/14 C07D 207/14 241/04 241/04 295/12 295/12 A 491/08 491/08 (72) Inventor Taniuchi Makoto 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Drug Discovery Laboratory (72) Inventor Hiroyuki Yamazaki 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Fine Chemicals Research Institute (72) Inventor Masashi Suzuki 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Milling Co., Ltd. Drug Discovery Laboratory (72) Inventor Tsutomu Takazawa 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Flour Milling Co., Ltd. (72) Kenji Kawamura Iruma-gun, Saitama Prefecture Ichimachi Tsurugaoka 5-3-1, Nisshin Seifun Co., Ltd. Drug Discovery Laboratory (72) Inventor Norio Oshida 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. (72) Inventor Hiroyuki Ikemoto 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Fine Chemical Research Center (72) Takao Kishie 5-chome Tsurugaoka, Oi-cho, Iruma-gun, Saitama Prefecture No. 1 within the drug discovery laboratory of Nisshin Seifun Co., Ltd.

Claims (10)

[Claims] 1. The following formula (I):(In the formula, m represents an integer of 0 to 3, and n is an integer of 5 to 12.
And A is cyclo (C _Three~ C₆) Alkylene groups, phenyl
Ren group, fluorenylene group, pyrrolidinylene group, pipera
Dinylene group, 9-aza-3-oxabicyclo [3.3.
1] represents a nonylene group, R₁, R_TwoBen independently
Represents a dil group, and the phenyl ring of this benzyl group is
Hydroxyl group, C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group
And substituted with 1 to 5 substituents selected from halogen atoms
X may represent a single bond, or-(C
H_Two)_pIt is a divalent group represented by NH-, and p is 0 to 3
Representing an integer) and its pharmaceutically acceptable
Salt. 2. The compound according to claim 1, wherein A is a cyclo (C ₃ -C ₆ ) alkylene group. 3. The compound according to claim 1 or 2, wherein A is cyclohexylene. 4. A pharmaceutical composition containing the compound according to any one of claims 1 to 3 as an active ingredient. 5. An agent for overcoming multidrug resistance of a cancer cell resistant to an anticancer agent, which comprises the compound according to any one of claims 1 to 3 as an active ingredient. 6. An antitumor agent action enhancer comprising the compound according to any one of claims 1 to 3 as an active ingredient. 7. An anticancer agent for brain tumor, kidney cancer, adrenal cancer, colon cancer, small intestine cancer, colon cancer, lung cancer, liver cancer, pancreatic cancer and leukemia, which comprises the compound according to claim 1 as an active ingredient. Action enhancer. 8. The agent for overcoming multidrug resistance according to claim 5, wherein the anticancer agent is taxol or a derivative thereof. 9. The action-enhancing agent for a carcinostatic agent according to claim 6, wherein the carcinostatic agent is taxol or a derivative thereof. 10. The following formula (II): (In the formula, m represents an integer of 0 to 3, and A represents cyclo (C ₃ to
C ₆₎ alkylene group, a phenylene group, a fluorenylene group, pyrrolidinylene group, piperazinylene group, 9-aza -
R represents a 3-oxabicyclo [3.3.1] nonylene group, R
₁ and R ₂ each independently represent a benzyl group, and the phenyl ring of this benzyl group has ₁ to 5 groups selected from a hydroxyl group, a C _{1 to} C ₄ alkyl group, a C _{1 to} C ₄ alkoxy group and a halogen atom. Table in (CH ₂₎ a bivalent group represented by _p NH-, p is an integer of 0 to 3) - may be substituted with a substituent, or X represents a single bond, or Compound represented by the following formula (III): (Wherein, n represents an integer of 5 to 12, L is a leaving group selected from a halogen atom, a C _{1 to} C ₄ alkylsulfonyloxy group, and an arylsulfonyloxy group). After reaction, the following formula (I): (In the formula, m, n, A, R ₁ , R ₂ , and X are respectively as defined in the above formula (I)).