JPH0733385B2 - N-alkylquinuclidinium salts as antagonists of substance P - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention relates to novel N-alkylquinuclidinium salts, pharmaceutical compositions containing such compounds, and inflammatory diseases.
It relates to the use of such compounds in the treatment and prophylaxis of gastrointestinal disorders and several other disorders. The pharmaceutically active compound of the present invention is an antagonist of substance P.

The substance P is a natural undecapeptide belonging to the tachykinin family of peptides, and is so called because it has a rapid stimulating action on smooth muscle tissue. In particular, substance P is a pharmacologically active neuropeptide produced in mammals (first isolated from the intestine) and is described in US Pat. No. 4,680,283 in DFVeb.
It has a characteristic amino acid sequence disclosed by Er et al. Extensive relationships between the pathophysiology of numerous diseases and substance P and other tachykinins have been well documented in the prior art.
For example, the substance P may carry pain or migraine (BEBSandbe
rg et al., Journal of Medicinal Chemistry, 25 , 1009 (198
2)), central nervous system diseases (eg anxiety and schizophrenia), respiratory and inflammatory diseases (eg asthma and rheumatoid arthritis), rheumatic diseases (eg fibromyalgia),
And gastrointestinal diseases and gastrointestinal tract diseases (eg ulcerative colitis and Crohn's disease), etc. ("Trends in Cluster Headache" (Elsevier Scientific edited by F. Sicuteri et al.
Publishers, Amsterdam, pp.85-95 (1987) D. Regoli
It has recently been found to be involved.

Both the quinuclidine derivative and related compounds which are active as receptor antagonists of substance P are assigned to the applicant.
PCT patent application PCT / US 89/05338 filed November 20, 1989 and
It is described in US patent application Ser. No. 557,442, filed July 23, 1990. A similar compound is a PC entitled "3-Amino-2-arylquinuclidine" filed April 25, 1991.
T patent application and PCT patent application entitled "Quinuclidine Derivatives" filed May 15, 1991. These applications are also assigned to the applicant.

In US Patent Application No. 619,361 filed on November 28, 1990 and US Patent Application No. 590,423 filed on September 28, 1990, assigned to the present applicant, piperidine derivatives effective as antagonists of substance P Related nitrogen-containing heterocycles are described.

SUMMARY OF THE INVENTION The present invention has the formula: (In the formula, R ¹ (C ₁ -C ₄ ) alkyl, allyl, phenyl-
(C ₁ -C ₆ ) alkyl, HOOC- (C ₁ -C ₁₀ ) alkyl or (C ₁ -C ₄ ) alkoxy-OOC- (C ₁ -C ₁₀ ) alkyl, R ² is phenyl, thienyl, furyl. And pyridyl, each of these groups R ² is cyano, nitro, amino, N-mono- (C ₁ -C ₃ ) alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C ₁
-C ₃₎ alkyl, (C ₁ -C ₃₎ alkoxy, Ariokishi,
_{1 to 3} substituents independently selected from the group consisting of (C ₁ -C ₃ ) alkoxy-carbonyl, carboxamide and N, N-di- (C ₁ -C ₃ ) alkyl-carboxamide. And X ⁻ is a pharmaceutically acceptable counterion (eg chloride, bromide, fluoride, iodide, mesylate, tosylate or trifluoromethanesulfonate).

Examples of pharmaceutically acceptable counterions are halides (eg fluoride, chloride, bromide or iodide), (C ₁ -C ₃ ) alkyl mono- or dicarboxylates, mesylates, tosylates, arylcarboxylates, one or more alkyl moieties. Fluorine atom, aryl sulfonate, citrate, maleate, fumarate, lactate, malate, sulfate, phosphate, nitrate, tartrate, saccharate and pamoate (C ₁ -C ₃ ) alkyl sulfonate.

As used herein, unless otherwise noted, "alkyl"
The term embraces monovalent saturated hydrocarbon radicals having or in combination with linear, branched or cyclic moieties.

Preferred compounds of formula I are those in which R ² is 2-methoxyphenyl.

The present invention further relates to inflammatory diseases of mammals (eg humans) (eg arthritis, psoriasis, asthma and inflammatory bowel disease), colitis, pain, allergies (eg eczema and rhinitis), chronic obstructive airway diseases, hypersensitivity disorders. (E.g. Urushi), vasospasm disorders (e.g. angina, migraine and Raynaud's disease), fibrotic and collagen disorders (e.g. scleroderma and eosinophilic leprosy), reflex sympathetic dystrophy (e.g. shoulder-hand syndrome), Effective in treating or preventing a condition selected from the group consisting of peripheral neuropathy, diseases associated with immune enhancement or immunosuppression (eg systemic lupus erythematosus) and rheumatic diseases (eg fibromyalgia) A pharmaceutical composition for the treatment or prevention of the aforementioned conditions, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further relates to inflammatory diseases of mammals (eg humans) (eg arthritis, psoriasis, asthma and inflammatory bowel disease), colitis, pain, allergies (eg eczema and rhinitis), chronic obstructive airway diseases, hypersensitivity disorders. (E.g. Urushi), vasospasm disorders (e.g. angina, migraine and Raynaud's disease), fibrotic and collagen disorders (e.g. scleroderma and eosinophilic leprosy), reflex sympathetic dystrophy (e.g. shoulder-hand syndrome), Effective in treating or preventing a condition selected from the group consisting of peripheral neuropathy, diseases associated with immune enhancement or immunosuppression (eg systemic lupus erythematosus) and rheumatic diseases (eg fibromyalgia) Administering an amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal,
It relates to a method of treating or preventing the above mentioned conditions.

The invention further antagonizes the action of a mammalian (eg human) substance P comprising a substance P-antagonizing amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. For pharmaceutical compositions.

The present invention further relates to a method of antagonizing the action of substance P in a mammal (eg a human), which comprises administering to the mammal a substance P-antagonizing amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The invention further provides a mammal (eg, a human) produced by an excess of substance P, which comprises a substance P-antagonizing amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention relates to a pharmaceutical composition for treating or preventing the disorders described above.

The present invention further relates to a disorder of a mammal (eg human) caused by an excess of substance P, which comprises administering to the mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof which antagonizes substance P. Treatment or prevention method.

The present invention further comprises a mammal comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to antagonize the action of substance P at the receptor site and a pharmaceutically acceptable carrier. Animal (eg, human) inflammatory diseases (eg, arthritis, psoriasis, asthma and inflammatory bowel disease), colitis, pain, allergies (eg, eczema and rhinitis), chronic obstructive airway diseases, hypersensitivity disorders (eg, boils), blood vessels Convulsive disorders (eg angina, migraine and Raynaud's disease), fibrotic and collagen disorders (eg scleroderma and eosinophilic leprosy), reflex sympathetic dystrophy (eg shoulder-hand syndrome), peripheral neuropathy, immune enhancement Alternatively, it relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of diseases related to immunosuppression (eg systemic lupus erythematosus) and rheumatic diseases (eg fibromyalgia).

The present invention further comprises administering to the mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof that is effective to antagonize the action of substance P at the receptor site. Inflammatory diseases of mammals (eg humans) (eg arthritis, psoriasis,
Asthma and inflammatory bowel disease), colitis, pain, allergies (eg eczema and rhinitis), chronic obstructive airway disease, hypersensitivity disorders (eg urushi), vasospasm diseases (eg angina,
Related to migraine and Raynaud's disease), fibrotic and collagen diseases (eg scleroderma and eosinophilic leprosy), reflex sympathetic dystrophy (eg shoulder-hand syndrome), peripheral neuropathy, immune enhancement or immunosuppression Diseases (eg systemic lupus erythematosus)
And a method for treating or preventing a condition selected from the group consisting of rheumatic diseases (for example, fibromyalgia).

The present invention further comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to antagonize the action of substance P at the receptor site, and a pharmaceutically acceptable carrier, It relates to a pharmaceutical composition for the treatment or prophylaxis of a mammalian (eg human) disorder carried out or promoted by reducing substance P mediated neurotransmission.

The present invention further provides a mediation of substance P, which comprises administering to a mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to antagonize the action of substance P at the receptor site. A method of treating or preventing a disorder in a mammal (eg, a human) carried out or promoted by reducing neurotransmission.

The present invention further provides a substance P which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in an amount effective for treating or preventing the disorders as mentioned above. It relates to a pharmaceutical composition for the treatment or prevention of disorders in mammals (eg humans) carried out or promoted by reducing mediated neurotransmission.

The present invention further relates to the mediated neurotransmission of substance P, which comprises administering to a mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent the disorders as mentioned above. A method of treating or preventing a disorder in a mammal (eg, a human) carried out or promoted by reducing

The compounds of formula I have chiral centers and therefore exist in different enantiomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of formula I and mixtures thereof.

The optically active compounds of formula I are further useful as intermediates in the synthesis of the corresponding racemic mixtures as well as the opposite enantiomers.

A compound identical to the compounds described above, except that one or more hydrogen or carbon atoms is replaced by a radioactive isotope (eg tritium, carbon-14 isotope or nitrogen-15 isotope) and is of the formula I Does include. Such radiolabeled compounds are useful as investigative / diagnostic tools in metabolic pharmacokinetic studies and binding assays. Research applications include radioligand binding assays, autoradiography studies and in vivo binding studies in particular, and diagnostic applications particularly in inflamed tissues (eg immunotype cells or Of cells directly related to inflammatory bowel disease, etc.)
Examples include studies of human substance P receptors by in vivo binding.

Detailed Description of the Invention Formula: (Wherein the meaning of R ² is as defined above), the compound represented by the formula R ¹ X (wherein, R ₁ is as defined above, X is chloro, fluoro, bromo, A compound of formula I) which is iodo, tosyloxy, methyloxy or trifluoromethanesulfonyloxy. Generally, the reaction is carried out in a polar solvent (eg ethanol, acetone, dimethylformamide or tetrahydrofuran) at about 0 ° C to about 150 ° C, preferably at about the reflux temperature of the solvent.

Pressures of about 0.5 to about 5 atmospheres are generally acceptable, with atmospheric pressure being preferred, about 1 atmosphere for convenience.

The novel compounds of formula I and their pharmaceutically acceptable salts are effective as antagonists of substance P. That is, they have the ability to antagonize the action of substance P at the receptor site in mammals and thus can function as therapeutic agents for the diseases and disorders mentioned above affecting mammals.

Since the compounds of formula I are basic, they are capable of forming a wide variety of salts with various inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but in practice once the compound of formula I is isolated from the reaction mixture as a pharmaceutically unacceptable salt and then known to those skilled in the art. It is often desirable to simply convert such salts to alternative pharmaceutically acceptable salts by standard ion sympathetic methods. Furthermore, acid addition of a compound of the invention by treatment of a suitable compound of Formula I with a selected substantially equivalent amount of a mineral or organic acid in an aqueous solvent or a suitable organic solvent (eg, methanol or ethanol). Salt is easily produced. Careful evaporation of the solvent will readily give the desired solid salt.

The compounds of formula I and their pharmaceutically acceptable salts are the substances P
, Which are useful in the treatment and prevention of a wide variety of clinical conditions that exhibit binding activity to the receptor for and thus are performed or promoted by reducing substance P-mediated neurotransmission, such conditions include: Inflammatory diseases (eg arthritis, psoriasis, asthma and inflammatory bowel disease), colitis, pain,
Allergies (eg eczema and rhinitis), chronic obstructive airway diseases, hypersensitivity disorders (eg Urushi), vasospasm diseases (eg angina, migraine and Raynaud's disease), fibrotic and cologen diseases (eg scleroderma and eosinophilic leech). Disease), reflex sympathetic dystrophy (eg shoulder-hand syndrome), peripheral neuropathy,
Diseases associated with immune enhancement or immunosuppression (eg systemic lupus erythematosus) as well as rheumatic diseases (eg fibromyalgia)
Is included. Accordingly, these compounds are readily adapted for therapeutic use as antagonists of substance P for the examination and / or treatment of clinical conditions as described above in mammals (eg humans).

The compounds of formula I and their pharmaceutically acceptable salts can be administered orally, parenterally or topically. In general, these compounds are most desirably administered at a dose of about 5.0 mg / day to about 1500 mg / day, although there will necessarily be variation depending on the weight and condition of the patient being treated and the particular mode of administration chosen. Occurs. However, it is most desirable to use a dose of about 0.07 mg to about 21 mg / kg body weight per day. However, the types of animals being treated, individual drug reactions,
Dose variation will occur depending on the type of pharmaceutical formulation selected and the time and interval of such administration. It may be appropriate for the dose to be lower than the lower limit of the stated range, or if the dose is divided into a number of smaller doses to be administered in a single day, doses above the prescribed range should be used. However, harmful side effects may not occur.

The compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the three routes previously described. Such administration may be carried out once or several times. In particular, the novel therapeutic agents of the present invention can be administered in a wide variety of forms. That is, the therapeutic agent is a tablet, capsule, sweetened tablet, troche, hard candy, powder, spray, cream,
Wax, suppository, jelly, gel, paste, lotion,
It may be combined with various pharmaceutically acceptable inert carriers in the form of ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents and the like. Furthermore, the sweetness and / or suitable for oral pharmaceutical composition
Or it can be flavored. Generally, the therapeutically effective compounds of this invention are present in a form as previously described at concentrations of about 5.0 to about 70% by weight.

For oral administration, tablets containing various excipients (e.g. microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine) are mixed with various disintegrants (e.g. starch (preferably corn, potato or Tapioca starch), alginic acid and some silicic acid double salts), and granule binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Moreover, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very effective in forming tablets. The same type of solid composition may be used as a filler for gelatin capsules. Preferred materials for such attachment further include lactose or lactose and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs for oral administration are desired, the active ingredient may be combined with various sweetening or flavoring agents, colorants or dyes, and if desired emulsifying agents and / or suspending agents, diluents ( For example, water, ethanol, propylene glycol, glycerin and various combinations thereof).

For parenteral administration, solutions of the therapeutic compounds of the invention in sesame oil, peanut oil or aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably at pH 8 or higher) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection. The oily solution is suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all these sterile solutions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

Furthermore, the compounds of the present invention may be administered topically when treating inflammatory skin conditions. this is,
Preference is given to creams, jellies, gels, pastes, waxes etc. according to standard pharmaceutical practice.

Using a radioligand to visualize the tachykinin receptor by autoradiography, the ability of the compounds of the invention as antagonists of substance P by virtue of its ability to inhibit the binding of substance P at the receptor site of bovine tail tissue. To measure. Jour
nal of Biological Chemistry (Vol.258, p.5158 (198
3)) A standard assay method by MACascieri et al. May be used to evaluate the antagonistic activity of the compounds described in the present specification against substance P. This method essentially consists of measuring the concentration of the individual compounds required to reduce the amount of radiolabeled substance P ligand at the receptor site of isolated bovine tissue by 50%. , Which gives a unique IC ₅₀ value for each compound tested.

In this method, the sea-tail tissue was removed from the -70 ° C freezer and a 50 volume ratio (w / v) of 50 mM ice-cold Tris (ie trimethamine (2-amino-2-hydroxymethyl-1,3
-Propanediol)) Homogenize in hydrochloride buffer (pH 7.7). Centrifuge the homogenate at 30,000 x G for 20 minutes. The pellet is resuspended in 50 volume ratio of Tris buffer, rehomogenized and then centrifuged at 30,000 x G for an additional 20 minutes. Then, a 40 volume ratio of 50 mM ice-cold Tris buffer (pH 7) containing 2 mM calcium chloride, 2 mM magnesium chloride, 40 g / ml bacitracin, 4 μg / ml leupeptin, 2 μg chymostatin and 200 g / ml bovine serum albumin. .7) Resuspend the pellet in This step completes the tissue preparation generation.

The radioligand binding process is then carried out as follows. That is, 100 μl of test compound at a concentration of 1 μM
Then, add 100 mM of radioligand to a final concentration of 0.5 mM.
μl is added, and finally 800 μl of the tissue preparation prepared by the above method is added to start the reaction. Therefore, the final capacity is
It is 1.0 ml. The reaction mixture is then stirred and allowed to come to room temperature (about 20
Incubate for 20 minutes. The tube is then filtered using a cell harvester and the glass fiber filter (Whatman GF / B) is washed 4 times with 50 mM Tris buffer (pH 7.7). The filter is pre-soaked for 2 hours before over-processing. The radioactivity is then measured on a beta counter with 53% counting efficiency and the IC ₅₀ is calculated by standard statistical methods.

The invention is illustrated by the following examples. However, the invention is not limited to the specific details of the examples that follow.

Example 1 (2S, 3S) -cis-1-methyl-2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-
Azabicyclo [2.2.2] octane-3-amine iodide: In a 50 mL round bottom flask equipped with a condenser and N ₂ inlet, 500 mg (1.21 mmol) of (2S, 3S) -cis-2- (diphenylmethyl) ) -N-((2-Methoxyphenyl) methyl) -1-azabicyclo [2.2.2] octane-3-amine and 6 mL of ethanol were added. The solution was heated to near boiling and 207 mg (1.46 mmol) methyl iodide was added. Continue heating for 10 minutes and then cool the solution to give a precipitate. The precipitate was passed and dried. 328 mg
A solid (yield 49%) was obtained: mp 239-244 ° C. ¹ H-NMR (δ, CDCl ₃ ): 1.8-2.0 (m, 2H), 2.1-2.3 (m, 2
H), 2.47 (s, 3H), 2.59 (m, 1H), 3.04 (dd, J = 13.84,2
H), 3.50 (m, 1H), 3.63 (s, 3H), 3.67 (s, 1H), 3.95
(M, 1H), 4.12 (m, 1H), 4.46 (d, J = 11.5,1H), 5.45 (d
d, J = 6.5,11.5,1H), 6.33,6.68 and 7.07−7.2 (multiple lines,
14H), 7.7-7.9 (wide area m, 2H). ¹³ C-NMR (δ, CDCl ₃ ): 20.0, 22.4, 23.8, 46.1, 49.4,53.
9,54.6,55.3,55.6,61.2,71.5,110.2,120.4,126.9,127.
2,127.9,128.5,129.6,141.7,143.5,157.1.

Mass spectrum (%): 426 (1, parent), 259 (31), 245 (4
6), 142 (45), 121 (100), 91 (62).

The title compounds of Examples 2-8 were prepared in the same manner as in Example 1.

Example 2 (2S, 3S) -cis-1- (4-carboethoxybutyl)
-2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-azabicyclo [2.2.2] octane-3-amine iodide: product yield 13%, melting point 85 ° C. Met.

Mass spectrum: 541 (1, parent), 373 (89), 359 (56), 121
(100), 91 (45).

Example 3 (2S, 3S) -cis-1- (4-carboethoxyphenylmethyl) -2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-azabicyclo [2.2.
2] Octane-3-amine iodide: The yield of the product was 13% and the melting point was 140 to 145 ° C.

Calculated as C ₃₈ H ₄₃ N ₂ O ₃ l ・ 1 / 3H ₂ O: C64.40, H6.21, N3.
95. Found: C64.05, H6.16, N3.38.

Example 4 (2S, 3S) -cis-1- (5-carbomethoxypentyl) -2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-azabicyclo [2.2.2] octane- 3-Amine triflate: Prepared (using acetonitrile as solvent instead of ethanol). The yield of product obtained as an oil was 5%.

Calculated as C ₃₆ H ₄₅ N ₂ O ₆ SF ₃・ HCl ・ 1 / 2H ₂ O: C57.32, H
6.55, N3.71. Found: C57.29, H6.48, N3.68.

Example 5 (2S, 3S) -cis-1- (5-carboxypentyl)-
2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-azabicyclo [2.2.2] octane-3-amine triflate: The above compound was hydrolyzed with potassium hydroxide in ethanol. Manufactured.

High resolution mass spectrum: Calculated as C ₃₄ H ₄₃ N ₂ O ₃ : 52
7.3278. Found: 527.3268.

Example 6 (2S, 3S) -cis-1-allyl-2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-
Azabicyclo [2.2.2] octane-3-amine bromide: The yield of the product was 58% and the melting point was 150-160 ° C.

Calculated as C ₃₁ H ₃₇ N ₂ OBr ・ 1.25H ₂ O: C66.96, H7.16, N
5.04. Found: C66.95, H7.06, N4.97.

Example 7 (2S, 3S) -cis-1-benzyl-2- (diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1
-Azabicyclo [2.2.2] octane-3-amine bromide: The product yield was 53% and the melting point was 206-208 ° C.

Calculated as C ₃₅ H ₃₉ N ₂ OBr ・ H ₂ O: C69.87, H6.87, N4.6
6. Found: C69.48, H6.84, N4.52.

Example 8 (2S, 3S) -cis-1- (carboethoxymethyl) -2
-(Diphenylmethyl) -N-((2-methoxyphenyl) methyl) -1-azabicyclo [2.2.2] octane-
3-Amine bromide: The product yield was 17% and the melting point was 125-135 ° C.

Calculated as C ₃₂ H ₃₉ N ₂ O ₃ Br ・ H ₂ O: C64.32, H6.92, N4.6
9. Found: C64.14, H6.88, N4.62.

Claims (9)

[Claims] 1. A formula: (In the formula, R ¹ is (C ₁ -C ₄ ) alkyl, allyl, phenyl-
(C ₁ -C ₆ ) alkyl, HOOC- (C ₁ -C ₁₀ ) alkyl or (C ₁ -C ₄ ) alkoxy-OOC- (C ₁ -C ₁₀ ) alkyl, R ² is phenyl, thienyl, furyl. And pyridyl, each of these groups R ² is cyano, nitro, amino, N-mono- (C ₁ -C ₃ ) alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C ₁
-C ₃₎ alkyl, (C ₁ -C ₃₎ alkoxy, Ariokishi,
_{1 to 3} substituents independently selected from the group consisting of (C ₁ -C ₃ ) alkoxy-carbonyl, carboxamide and N, N-di- (C ₁ -C ₃ ) alkyl-carboxamide. And X ⁻ is a pharmaceutically acceptable counterion or a pharmaceutically acceptable salt thereof). 2. R ¹ is 2-methoxyphenyl.
The compound according to. 3. The compound according to claim 2, wherein R ¹ is methyl. 4. The compound according to claim 3, wherein X ⁻ is iodide. 5. The formula: (In the formula, R ¹ is (C ₁ -C ₄ ) alkyl, allyl, phenyl-
(C ₁ -C ₆ ) alkyl, HOOC- (C ₁ -C ₁₀ ) alkyl or (C ₁ -C ₄ ) alkoxy-OOC- (C ₁ -C ₁₀ ) alkyl, R ² is phenyl, thienyl, furyl. And pyridyl, each of these groups R ² is cyano, nitro, amino, N-mono- (C ₁ -C ₃ ) alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C ₁
-C ₃₎ alkyl, (C ₁ -C ₃₎ alkoxy, Ariokishi,
_{1 to 3} substituents independently selected from the group consisting of (C ₁ -C ₃ ) alkoxy-carbonyl, carboxamide and N, N-di- (C ₁ -C ₃ ) alkyl-carboxamide. And X ⁻ is a pharmaceutically acceptable counterion). (Wherein R ^{2 has} the same meaning as previously defined), a compound represented by the formula R ¹ X (wherein R ¹ is as defined above, X is chloro, fluoro or bromo). , Iodo, tosyloxy, mesyloxy, or trifluoromethanesulfonyl)) in the presence of a polar solvent. 6. The method according to claim 5, wherein the compound of formula I produced by the above method is a compound in which R ² is 2-methoxyphenyl. 7. The method according to claim 5, wherein the compound of formula I produced by the above method is a compound in which R ¹ is methyl. 8. The method according to claim 5, wherein the compound of formula I produced by the above method is a compound in which X ⁻ is iodide. 9. The compound of formula I prepared by the above method, wherein R ¹ is selected from carboethoxybutyl, carboethoxyphenylmethyl, carbomethoxypenyl, carboxypentyl, benzyl, allyl and carboethoxymethyl. The method of claim 5, wherein: