KR20060014373A - Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists - Google Patents

Abstract

This invention generally relates to derivatives of substituted azabicyclo hexanes of formula I. The compounds of this invention can function as muscarinic receptor antagonists, and can be used for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to a process for the preparation of the compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention and the methods of treating the diseases mediated through muscarinic receptors.

Description

SUBSTITUTED AZABICYCLO HEXANE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS As a muscarinic receptor antagonist

The present invention relates to derivatives of substituted azabicyclo hexanes.

The compounds of the present invention can function as muscarinic receptor antagonists and can be used to treat various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.

The invention also relates to methods of making the compounds of the invention, pharmaceutical compositions containing the compounds of the invention and methods of treating diseases mediated through muscarinic receptors.

Muscarinic receptors in the absence of receptors (GPCRs) bound to G protein consist of five receptor sub-type groups (M ₁ , M ₂ , M ₃ , M ₄ and M ₅ ) and the neurotransmitter acetylcholine Is activated by These receptors are widely distributed in a plurality of organs and tissues and are important for the maintenance of central and peripheral cholinergic neurotransmission. Local distribution of these receptor sub-types in the brain and other organs has been demonstrated. For example, the M ₁ subtype is originally located in neural tissues such as the cerebral cortex and autonomic ganglia, and the M ₂ subtype is primarily present in the heart (which in the heart mediates cholinergic bradycardia), and M ₃ Subtypes are primarily located in smooth muscle and salivary glands ( Nature , 1986; 323: 411 ; Science, 1987; 237: 527).

Trends in Pharmacological Sciences, 2001 by Eglen et al .; 22: 409 as well as in Current opinions in Chemical Biology, 1999; The 3: 426 study describes the biological potential of modulating muscarinic receptor subtypes by ligands in other disease states such as Alzheimer's disease, pain, urinary disease states, chronic obstructive pulmonary disease, and the like.

Christian C. Felder et al. J. Med. Chem., 2000; 43: 4333's study describes the therapeutic opportunities for muscarinic receptors in the central nervous system and describes muscarinic receptor structures and actions, pharmaceuticals and their therapeutic use.

The pharmaceutical and medical aspects of the muscarinic class of acetylcholinergic and antagonists are described in the study of Molecules, 2001, 6: 142.

Trends in Pharmacological Sciences, 2001; 22: 215 to N.J.M. Birdsall et al. Also summarize recent developments on the role of other muscarinic receptor subtypes using other muscarinic receptors in knocked out mice.

Muscarinic agonists such as muscarin and pilocarpin, and antagonists such as atropine have been known for 100 years, but no progress has been made in the development of receptor subtype-selective compounds that make it difficult to assign specific actions to individual receptors. Traditional muscarinic antagonists such as atropine are effective in bronchodilating, but their clinical utility is limited because of the high incidence of peripheral and central adverse effects such as tachycardia, decreased vision, dry mouth, constipation, and dementia. Subsequent development of quadrant derivatives of atropine, such as ipratropium bromide, is more resistant than the parenteral dosing option, but most of them are anti-cholinergic because they lack selectivity for muscarinic receptor subtypes. Not ideal as a bronchodilator. Existing compounds offer limited treatment benefits due to their lack of selectivity, which limits their administration to adverse effects such as thirst, nausea, Shandong, and heart related diseases such as tachycardia mediated by the M ₂ receptor.

Pharmacological Toxicol., 2001; 41: 691's annual study describes the pharmacology of low urinary tract infections. Anti-muscarinic agents, such as oxybutynin and tolterodine, which are non-selectively active at the muscarinic receptor, have been used to treat bladder hyperactivity for many years, but the clinical efficacy of the Limited due to adverse effects such as dry mouth, poor vision and constipation. Tolterodine is generally thought to be more resistant than oxybutynin (WDSteers et. Al. In Curr. Opin. Invest.Drugs, 2: 268, CR Chapple et. Al. In Urology, 55: 33), Steers WD, Barrot DM, Wein AJ, 1996, Voiding dysfunction: diagnosis classification and management. In "Adult and Pediatric Urology," ed. JY Gillenwatter, JT Gravhack, SS Howards, JW Duckett, pp 1220-1325, St. Louis, MO; Mosby. 3 ^rd edition.)

Despite the above advantages, there is a need for the development of new highly selective muscarinic antagonists that can interact with certain subtypes and avoid the occurrence of adverse effects.

Compounds with antagonistic activity against muscarinic receptors are described in Japanese patent application Laid, Open Number 92921/1994 and 135958-1994; WO 93/16048; U.S. Patent No. 3,176,019; GB 940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054; WO 9109013; U.S. Patent No. 5,281,601. U.S. Patent Nos. 6,174,900, 6,130,232, and 5,948,792; WO 97/45414 relates to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstituted piperidine derivatives; WO 93/16018 and WO 96/33973 are other close references.

J. Med. Chem., 2002; 44: 984 describes a cyclohexylmethyl piperidinyl triphenylpropioamide derivative as a selective M ₃ antagonist that is discernible to other receptor subtypes.

Summary of the Invention

The present invention relates to substituted azabicyclohexane as a muscarinic receptor antagonist which can be used as a safe and effective therapeutic or prophylactic agent for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems, and methods of synthesizing these compounds. It is about.

The present invention also provides pharmaceutical compositions containing these compounds and also containing water-soluble carriers, excipients or diluents useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.

The invention also relates to enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates, esters of these compounds having the same type of activity and Metabolite (metabolite).

The invention is further combined with a pharmaceutically acceptable carrier and optionally included excipients to provide compounds of the invention, their metabolites, esters, enantiomers, diastereomers, N-oxides, polymorphs, or pharmaceuticals thereof Pharmaceutical compositions comprising an acceptable salt or pharmaceutically acceptable solvate.

Other advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be identified in the experiments of the invention.

According to one embodiment of the invention, a compound having a structure of formula (I) and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester, enantiomer, diastereomer, N-oxide, polymorph, or Metabolites are provided:

[In Formula 1,

Ar is an aryl ring or a heteroaryl ring having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhalo alkyl, cyano, hydroxy, nitro, halogen (eg F, Cl, Br, I), lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) One to three substituents independently selected from the group consisting of perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkyl amino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl May be substituted or unsubstituted by;

R ₁ is hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoyl or halogen (eg fluorine, chlorine, bromine and iodine);

R ₂ is an aryl ring having 1 to 2 heteroatoms selected from the group consisting of hydrogen, alkyl, C ₃ -C ₇ cycloalkyl rings, C ₃ -C ₇ cycloalkenyl rings, oxygen, sulfur and nitrogen atoms Or heteroaryl ring [aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) ₁ independently selected from the group consisting of perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl To optionally substituted by from 3 to 3 substituents;

W is (CH ₂ ) _p (p is 0 to 1);

X is oxygen, sulfur, -NR (R is H or alkyl) or nitrogen, or is no atom;

Y is (CH ₂ ) _q (q is 0 to 1);

R ₃ , R ₅ and R ₆ are independently selected from the group consisting of H, lower alkyl, COOH, CONH ₂ , NH ₂ and CH ₂ NH ₂ ;

R ₄ is hydrogen, one to six hydrogen atoms are halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl (heteroarylalkyl and heteroarylalkenyl are selected from the group consisting of nitrogen, oxygen and sulfur atoms Aryl in the arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl group optionally selected from C ₁ -C ₁₅ saturated or unsaturated aliphatic hydrocarbon groups which may be substituted with one or two hetero atoms selected One to three hydrogen atoms on the ring or heteroaryl ring are lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhaloalkyl, cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen , Lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino or N-lower (C _1- C ₄ ) may be substituted with alkylamino carbonyl]

According to a second embodiment of the present invention, there is provided a method of preventing or treating an animal or human suffering from a disease or condition of the digestive, urinary and gastrointestinal system, wherein the disease or condition is mediated by muscarinic receptors.

According to a third embodiment of the invention, an animal or human suffering from a disease or condition associated with a muscarinic receptor, comprising a method of administering to a patient an effective amount of a muscarinic receptor antagonist compound as described above Provide a method of prevention or treatment.

According to a fourth embodiment of the invention, a disease or condition of the urinary tract system inducing a urinary tract disease such as urinary incontinence, lower urinary tract symptoms (LUTS), and the like; Diseases or conditions of the digestive system such as bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and the like; And methods of treating or preventing animals or humans suffering from diseases or disorders of the gastrointestinal system such as irritable bowel symptoms, obesity, diabetes and gastrointestinal hyperactivity, and the compounds as described above, wherein the disease or disorder is a muscarinic receptor The method comprises administering to a patient an effective amount of such a compound as needed.

According to a fifth embodiment of the invention, there is provided a process for preparing the compound described above.

The compounds of the present invention show remarkable efficacy in view of their activity, which was determined by ex vivo receptor binding assays and functional assays. Some compounds of the present invention have been found to be efficacious as muscarinic receptor antagonists with high affinity for the M ₃ receptor. Accordingly, the present invention provides a pharmaceutical composition capable of treating a disease or condition associated with a muscarinic receptor. In addition, the compounds of the present invention can be administered orally or parenterally.

The compounds of the present invention can be prepared by techniques well known to those skilled in the art and average synthetic organic chemists. In addition, the compounds of the present invention can be prepared by the reaction sequence represented by Scheme 1:

Compound of formula 1 of the present invention can be prepared according to the reaction sequence shown in Scheme 1. The preparation method includes the step of condensing a compound of Formula 2 and a compound of Formula 3, wherein,

Ar is an aryl ring or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl , Lower (C ₁ -C ₄ ) perhalo alkyl, cyano, hydroxy, nitro, halogen (eg F, Cl, Br, I), lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) 1 to 3 independently selected from the group consisting of perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkyl amino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl May or may not be substituted by a substituent;

R ₁ is hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoyl or halogen (eg fluorine, chlorine, bromine and iodine);

R ₂ is an aryl ring having 1 to 2 heteroatoms selected from the group consisting of hydrogen, alkyl, C ₃ -C ₇ cycloalkyl rings, C ₃ -C ₇ cycloalkenyl rings, oxygen, sulfur and nitrogen atoms Or heteroaryl ring [aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) ₁ independently selected from the group consisting of perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl To optionally substituted by from 3 to 3 substituents;

W is (CH ₂ ) _p (p is 0 to 1);

X is oxygen, sulfur, -NR (R is H or alkyl) or nitrogen, or is no atom;

Y is (CH ₂ ) _q (q is 0 to 1);

R ₃ , R ₅ and R ₆ are independently selected from the group consisting of H, lower alkyl, COOH, CONH ₂ , NH ₂ and CH ₂ NH ₂ ;

R ₄ is hydrogen, one to six hydrogen atoms are halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl (heteroarylalkyl and heteroarylalkenyl are selected from the group consisting of nitrogen, oxygen and sulfur atoms C ₁ -C ₁₅ saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a group consisting of 1 to 2 hetero atoms selected from (optionally the arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalke One to three hydrogen atoms on the aryl ring or heteroaryl ring in the alkyl group are lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhaloalkyl, cyano, hydroxy, nitro, lower alkoxycar Carbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino or N-lower ( C ₁ -C ₄ ) alkylamino carbonyl;

P is a group usable for protecting amino groups, for example benzyl, t-butyloxy carbonyl, which provides a protected compound of formula 4 in the presence of a condensing agent, and reacts with a deprotecting agent in an organic solvent to When protected, an unprotected intermediate represented by Formula 5 is provided, wherein Formula 5 is finally N-alkylated or benzylated with a suitable alkylation or benzylating agent LR ₄ , where Formula 1 is where L is any leaving group and R ₄ is the same as defined above.

Reacting a compound of Formula 2 with a compound of Formula 3 to give a compound of Formula 4 comprises 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and 1,8-diazabi It may be carried out in the presence of a condensing agent selected from the group consisting of cyclo [5.4.0] undec-7-ene (DBU).

The reaction of the compound of Formula 2 with the compound of Formula 3 to give the compound of Formula 4 is from about 0 ° C. in a suitable solvent selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, toluene and xylene. It may be carried out at a temperature of about 140 ℃.

Deprotecting the compound of formula 4 to provide a compound of formula 5 can be carried out by a deprotecting agent selected from the group consisting of palladium on carbon, trifluoroacetic acid (TFA) and hydrochloro acid. have.

Deprotecting the compound of formula 4 to produce the compound of formula 5 is carried out at a temperature of about 10 ° C. to about 50 ° C. in a suitable organic solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran and acetonitrile. Can be.

N-alkylated or benzylated compounds of formula 5 to give compounds of formula 1 are suitable alkylated or benzylating agents LR ₄ (L is any leaving group, known in the art, halogen, O-meth Steel group and O-tosyl group).

N-alkylated or benzylated compounds of formula 5 to give compounds of formula 1 are reactions of about 25 ° C. in suitable organic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and acetonitrile. It may be carried out at a temperature of about 100 ℃.

In Scheme 1, specific bases, condensing agents, protecting groups, deprotecting agents, N-alkylated / benzylating agents, solvents, catalysts, and the like are mentioned, and other bases, condensing agents known to those skilled in the art. It is understood that protecting groups, deprotecting agents, N-alkylating / benzylating agents, solvents, catalysts and the like can be used. Similarly, reaction temperature and duration can be adjusted according to the required needs.

A suitable salt of the compound of formula 1 is prepared to dissolve the compound in an aqueous medium for biological evaluation. Examples of such salts include inorganic acid salts (eg hydrochloride, hydrobromide, sulfates, nitrates and phosphorates), organic acid salts (eg acetate, tartarate, citrate, fumarate, malate, Pharmaceutically acceptable salts), such as tolunesulfonate and metanesulfonate). When the carboxyl group is included in Formula 1 as a substituent, it may be an alkali metal salt (eg, sodium, potassium, calcium, magnesium, etc.). The salts can be prepared by conventional conventional techniques such as treating the compound with an equivalent amount of an inorganic acid or an inorganic base, organic acid or organic base in a suitable solvent.

Preferred compounds according to the invention, which may be prepared by Scheme 1 as shown in Table 1, include:

Compound Number Chemical Name

1. (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2,2-diphenylcarboxylic ester.

2. (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclohexyl-2-phenylcarboxyl ester .

3. (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclopentyl-2-phenylcarboxyl ester .

4. (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxymethyl-2-phenylacetamide.

5. (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxy-2,2-diphenylacetamide.

6. (1α, 5α)-[3- (2-methyl-2-pentenyl) -3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2- Cyclohexyl-2-phenylcarboxyl esters.

7. (1α, 5α)-[3- (3,4-methylenedioxyphenyl) ethyl] -3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy- 2-cyclohexyl-2-phenylcarboxyl ester.

Various solvents such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexane and dichloromethane were dried using various drying reagents according to the procedures described in the literature. IR spectra were recorded on a Perkin Elmer Paragon device as a thin neat film or nujol mull, and nuclear magnetic resonance (NMR) was used as tetramethylsilane as an internal control. Were recorded on a Varian XL-300 MHz device.

Example 1

(1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2,2-diphenylcarboxylic ester (first compound Manufacturing

Step-a: Preparation of 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid ethyl ester.

Concentrated H in suspension of 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid (8.5 gm, 0.0390 mole) in ethyl alcohol (250 ml) (prepared as described in EP 0413455A2) ₂ SO ₄ (10 mL) was added. The resulting pale yellow solution was heated to reflux for 2 hours, cooled to 0 ° C. and neutralized with aqueous ammonia. The neutralized solution was concentrated and dissolved in dichloromethane. The organic layer was washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product, which was further purified by column chromatography (100-200 mesh, silica gel) and eluting the compound by 5% ethyl acetate in hexanes. To give the pure product as a yellow oil.

Step-b: Preparation of 3-benzyl-1-hydroxymethyl-3-azabicyclo [3.1.0] hexane

A solution of 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid ethyl ester in tetrahydrofuran (20 mL) (2.5 gm, 0.0108 mole) was added to lithium aluminum in tetrahydrofuran (50 mL). To a suspension of hydride (0.966 gm, 0.026 mole) was added. The resulting mixture was heated to reflux for 2 hours. The reaction mixture was carefully quenched with saturated aqueous NH ₄ Cl (1 mL), treated with ethyl acetate (50 mL) and stirred for 1 h. The solution was filtered to remove the solution from the filtrate to give the crude title product which was purified by column chromatography (100-200 mesh, silica gel) and eluted the compound with 15% ethyl acetate in hexane to give a colorless oil. Pure product as obtained.

Step-c: Preparation of 3-benzyl-1-methanesulfonyl-3-azabicyclo [3.1.0] hexane

To a solution of 3-benzyl-1-hydroxymethyl-3-azabicyclo [3.1.0] hexane in ethyl acetate was added triethylamine (2.15 gm, 0.02125 mole) and methane sulfonylchloride (1.947 gm, 0.017 mole) did. The mixture was stirred at 0 ° C for 1 h. Saturated NaHCO ₃ was added to quench the reaction. The saturated organic layer was washed with water, brine, dried and evaporated to afford the crude product which was used for further reaction.

Step-d: (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2,2-diphenylcarboxylic ester Manufacture

Diphenylglycolic acid (commercially available) (0.389 gm, 0.0017 mole), 3-benzyl-1-methane sulfonyl-3-azabicyclo [3.1.0] hexane (0.40 gm, 0.0014 mole) in toluene (50 mL) ) And 1,8-diazabicyclo [5.4.0] undec-7-ene (0.323 gm, 0.00213 mole) were refluxed for 2 hours. The solution was cooled to room temperature. The solution was dried on a rotary evaporator. The oil obtained was purified on column chromatography (100-200 mesh, silica gel) and eluting the compound with 5% ethyl acetate in hexanes gave the pure product as a white solid.

Example 2

(1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclohexyl-2-phenylcarboxylic acid ester ( Preparation of the second compound)

2-cyclohexyl-2-hydroxy-2-phenylacetic acid (prepared as described in J. Amer. Chem. Soc., 75, 2654, 1953) (0.398 g, 0.0017 mole), 3-benzyl-1- A solution of methanesulfonyl-5-azabicyclo [3.1.0] hexane (0.40 gm, 0.0014 mole) and 1,8-diazabicyclo [5.4.0] undec-7-ene (323 mg, 0.002 mole) Reflux for 1 hour. The solution was cooled to room temperature and stripped with solvent to afford the crude product, which was further purified by column chromatography (100-200 mesh, silica gel) and eluting the compound with 5% ethyl acetate in hexanes. The desired product was obtained.

Example 3

(1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclopentyl-2-phenylcarboxylic acid ester ( Preparation of the third compound)

2-cyclopentyl-2-hydroxy-2-phenyl acetic acid (prepared as described in J. Amer. Chem. Soc., 75, 2654, 1953) in toluene (50 mL) (375 mg, 0.0017 mole), 3-benzyl-1-methanesulfonyl-3-azabicyclo [3.1.0] hexane (400 mg, 0.00142 mole) and 1,8-diazabicyclo [5.4.0] undec-7-ene (323 mg, 0.00213 mole) of the solution was refluxed for 2 hours. The solution was cooled to room temperature and stripped with solvent to afford crude oil product. The crude product was further purified by column chromatography (100-200 mesh, silica gel) and eluting the compound with 5% ethyl acetate in hexanes gave the desired product.

Example 4

Preparation of (1α, 5α) -N- [3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxymethyl-2-phenylacetamide (fourth compound)

3-hydroxy-2-phenylpropionic acid (353 mg, 0.0021 mole, commercially available) and 1-amino-3-benzyl-3-azabicyclo [3.1.0] hexane (400 mg, 0.00212 mole, in DMF (50 mL) To a cold solution of EP 0413455A2) is added N-methylmorpholine (536 mg, 0.0053 mole), hydroxybenzotriazole (286 mg and 0.002 mole), at 1 ° C. Stir for time. And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (400 mg, 0.002 mole) is added. The solution is brought to room temperature and stirred for a further 24 hours. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated on a rotary evaporator to give a crude product, which was further purified by column chromatography (100-200 mesh, silica gel) and 30% ethyl in hexane The compound was eluted with acetate to give a yellow oil.

Example 5

Preparation of (1α, 5α) -N- [3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxy-2,2-diphenylacetamide (5th compound)

Diphenylglycolic acid (269.5 mg, 0.001 mole) and 1-amino-3-benzyl-3-azabicyclo [3.1.0] hexane (222 mg, 0.0011 mole, as described in EP 0413455A2) in DMF (50 mL). N-methyl morpholine (298 mg, 0.003 mole) is added to the cold solution of (prepared), 1-hydroxybenzotriazole (159 mg and 0.0011 mole) is added and stirred at 0 ° C. for 1 hour. And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (225 mg, 0.0011 mole) is added. The solution is brought to room temperature and stirred for 1 day. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford the crude product, which was further purified by column chromatography (100-200 mesh, silica gel) and 30% ethyl acetate in hexane The compound was eluted to give a pale yellow powder.

Example 6

(1α, 5α) -N- [3- (2-methyl-2-pentenyl) -3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2- Preparation of cyclohexyl-2-phenylcarboxylic acid ester (sixth compound)

Step-a: Preparation of (1α, 5α)-[3-azabicyclo [3.1.0] hex-1- (methyl) -yl] -2-hydroxy-2-cyclohexyl-2-phenylcarboxylic acid ester .

A par bottle is placed in a solution of a second compound (2.25 g, 0.005 mole) in methanol. To this is added 10% Pd (dry) on carbon (C). The solution is hydrogenated for 4 hours at 60 psi pressure in a par hydrogenation apparatus. And the reaction mixture is filtered. The filtrate is concentrated to give the desired product as off-white semisolid material.

Step-b: (1α, 5α) -N- [3- (2-methyl-2-pentenyl) -3-azabicyclo [3.1.0] hex-1- (methyl) -yl] -2-hydroxy Preparation of 2-cyclohexyl-2-phenylcarboxylic acid ester

3-azabicyclo [3.1.0] hexane-1-methylene-2-hydroxy-2-cyclohexyl-2-phenyl carboxylic acid ester (250 mg, 0.000760 mole) in acetonitrile, 5-bromo-2 To a solution of methyl-2-pentene (148.6 mg, 0.000911 mole) were added potassium carbonate (210.0 mg, 0.0015 mole) and potassium iodide (252 mg, 0.0015 mole). The reaction mixture is refluxed for 12 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. The organic layer is dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh, silica gel) and eluted with 15% ethyl acetate in hexanes to afford the desired product.

Example 7

(1α, 5α)-[3- (3,4-methylenedioxyphenyl) ethyl] -3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2- Preparation of cyclohexyl-2-phenylcarboxylic acid ester (seventh compound)

3-azabicyclo [3.1.0] -hex-1- (methyl) -yl-2-hydroxy-2-cyclohexyl-2-phenyl carboxylic acid ester (250 mg, 0.0007 mole) in acetonitrile and 3, To a solution of 4-methylenedioxyphenethyl bromite (207.8 mg, 0.00091 mole) was added potassium carbonate (210 mg, 0.0051 mole) and potassium iodide (252.0 mg, 0.0051 mole). The reaction mixture is refluxed for 12 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in ethyl acetate, washed with water and washed with brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh, silica gel) and eluting the compound with 15% ethyl acetate in hexanes gave the desired product.

Biological activity

Radioligand binding assays:

The affinity of the test compounds for the M ₂ and M ₃ muscarinic receptor subtypes was determined in Moriya et al. (Life Sci, 1999, 64 (25): 2351-2358) with slight modifications to the rat heart and submandibular gland. Each was measured by [ ³ H] -N-methylscopolamine binding study.

Membrane Preparation: Immediately after sacrifice, the submandibular gland and heart were removed and placed in ice cold homogenization buffer (HEPES 20 mM, 10 mM EDTA, pH 7.4). The tissues were homogenized in 10 volumes of homogenization buffer, the homogenate was filtered through two wet gauze layers and the filtrate was centrifuged at 500 g for 10 minutes. The supernatant was subsequently centrifuged at 40,000 g for 20 minutes. The pellets obtained were then resuspended in the same volume of assay buffer (HEPES 20 mM, EDTA 5 mM, pH 7.4) and stored at −70 ° C. until analysis time.

Ligand Binding Assay: Compounds were dissolved and diluted in DMSO. Membrane homozinate (150 μg-250 μg protein) was incubated in 250 μl of assay buffer (HEPES 20 mM, pH 7.4) for 3 hours at 24 ° C.-25 ° C. Non-specific binding was measured in the presence of 1 μM atropine. Cultures were terminated by vacuum filtration on GF / B fiber filters (Wallac). The filter was then washed with ice cold 50 mM Tris HCl buffer, pH 7.4. The filter mat was dried and the bound radioactivity remaining on the filter was counted. IC ₅₀ & Kd was measured using a non-linear curve fitting program using G Pad Prism software. The inhibition constant value (Ki) is given by the Cheng & Prusoff equation (Biochem Pharmacol, 1973, 22: 3099-3108), Ki = IC ₅₀ / (1 + L / Kd), where L is the value of [ ³ H [Concentration of NMS] was calculated from competitive binding studies. pKi =-(Log Ki)

Functional experiments with extracted mouse bladder:

Way:

Overdose urethane to euthanize the animals, remove the entire bladder, remove it quickly, and place in ice cold Tyrode buffer with the following composition (mMol / L), 95% O ₂ and 5% CO ₂ Successively gasified with: NaCl 137; KCl 2.7; CaCl ₂ 1.8; MgCl ₂ 0.1; NaHCO ₃ 11.9; NaH ₂ PO ₄ 0.4; Glucose 5.55.

The bladder is cut into longitudinal strips (3 mm wide and 5 mm to 6 mm long), placed in a 10 ml organ bath at 30 ° C., one end connected to the base of the tissue holder, and the other end The polygraph was connected via a force displacement transducer. Each tissue was maintained at a constant base tension of 2 g and equilibrated for 1 hour while the PSS changed every 15 minutes. At the end of equilibration, the stabilization of the tissue contraction response was assessed at 1 μmol / L Carbachol continuously for 2-3 times. Thereafter, cumulative concentrated reaction curves for carbacol (10 ⁻⁹ mol / L to 3 × 10 ⁻⁵ mol / L) were obtained. After several washes, once a baseline was obtained, a cumulative concentrated reaction curve was obtained in the presence of NCE (addition of NCE 20 minutes before the second CRC).

Shrinkage results are expressed as% of control E max. ED50 values were calculated by fitting a non-linear regression curve (graph pad prism). The pKB values were calculated by the formula pKB = -log [(molar concentration of antagonist / (dose rate-1))] (wherein dosing rate = ED50 in the presence of the antagonist / ED50 in the absence of the antagonist).

In vivo test results are shown in Table 2.

In vivo testing

Although the present invention has been described in terms of specific embodiments, specific modifications and equivalents will be apparent to those skilled in the art, and such modifications and equivalents are considered to be within the scope of the present invention.

Claims (17)

A compound represented by Formula 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester, enantiomer, diastereomer, N-oxide, polymorph, or metabolite thereof ): (Formula 1)

{In Formula 1, Ar is an aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [The aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) Perhaloalkyl, cyano, hydroxy, nitro, halogen (eg F, Cl, Br, I), lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted Unsubstituted or substituted by one to three substituents independently selected from the group consisting of amino, N-lower (C ₁ -C ₄ ) alkylamino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl Can be; R ₁ is hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoyl or halogen (eg fluorine, chlorine, bromine and iodine); R ₂ is hydrogen; Alkyl; C ₃ -C ₇ cycloalkyl ring; C ₃ -C ₇ cycloalkenyl ring; Aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [aryl ring or heteroaryl ring may be selected from lower (C ₁ -C ₄ ) alkyl, cyano, hydroxy, Nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino and N- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower (C ₁ -C ₄ ) alkyl amino carbonyl; W is (CH ₂ ) _p (p is 0 to 1); X is not oxygen, sulfur, —NR where R is H or alkyl or no atom; Y is (CH ₂ ) _q (q is 0 to 1); R ₃ , R ₅ and R ₆ are independently selected from the group consisting of H, lower alkyl, COOH, CONH ₂ , NH ₂ and CH ₂ NH ₂ ; R ₄ is hydrogen; 1 to 6 hydrogen atoms are halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl (heteroarylalkyl and heteroarylalkenyl are 1 to 6 selected from the group consisting of nitrogen, oxygen and sulfur atoms C ₁ -C ₁₅ saturated or unsaturated aliphatic hydrocarbons (straight chain or branched chain) which may be substituted with a group independently selected from the group consisting of two hetero atoms (optionally the arylalkyl, arylalkenyl, One to three hydrogen atoms on the ring in the heteroarylalkyl or heteroarylalkenyl group are lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhaloalkyl, cyano, hydroxy, nitro, lower Alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino or N-lower (C ₁ -C ₄₎ alkyl substituted by aminocarbonyl Be that] a} A compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, an ester, an enantiomer, a diastereomer, an N-oxide, or a polymorph thereof, selected from the group consisting of the following compounds: polymorph or metabolite: (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2,2-diphenylcarboxylic ester (first compound ); (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclohexyl-2-phenylcarboxyl ester 2 compound); (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclopentyl-2-phenylcarboxy ester 3 compound); (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxymethyl-2-phenylacetamide (fourth compound); (1α, 5α)-[3-benzyl-3-azabicyclo [3.1.0] -hex-1-yl] -2-hydroxy-2,2-diphenylylacetamide (5th compound); (1α, 5α)-[3- (2-methyl-2-pentenyl) -3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclohexyl 2-phenylcarboxylic ester (sixth compound); (1α, 5α)-[3- (3,4-methylenedioxyphen) ethyl-3-azabicyclo [3.1.0] -hex-1- (methyl) -yl] -2-hydroxy-2-cyclo Hexyl-2-phenylcarboxyl ester (seventh compound). A therapeutically effective amount of a compound as defined in claim 1 or 2, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester, enantiomer, diastereomer, N-oxide, polymorphic form thereof ( polymorphs or metabolites; Or a therapeutically effective amount of a compound as defined in claim 1 or 2, and a pharmaceutically acceptable carrier, excipient or diluent. A method of treating or preventing a disease or disorder of the respiratory, urinary or gastrointestinal tract mediated through an animal or human muscarinic receptor, Administering to the animal or human a therapeutically effective amount of a compound represented by Formula 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester, enantiomer, diastereomer, N-oxide, polymorph, and metabolite thereof Method comprising the: (Formula 1)

{In Formula 1, Ar is an aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [The aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) Perhaloalkyl, cyano, hydroxy, nitro, halogen (eg F, Cl, Br, I), lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted Unsubstituted or substituted by one to three substituents independently selected from the group consisting of amino, N-lower (C ₁ -C ₄ ) alkylamino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl Can be); R ₁ is hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoyl or halogen (eg fluorine, chlorine, bromine and iodine); R ₂ is hydrogen; Alkyl; C ₃ -C ₇ cycloalkyl ring; C ₃ -C ₇ cycloalkenyl ring; Aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [aryl ring or heteroaryl ring may be selected from lower (C ₁ -C ₄ ) alkyl, cyano, hydroxy, Nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino and N- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower (C ₁ -C ₄ ) alkyl amino carbonyl; W is (CH ₂ ) _p (p is 0 to 1); X is not oxygen, sulfur, —NR where R is H or alkyl or no atom; Y is (CH ₂ ) _q (q is 0 to 1); R ₃ , R ₅ and R ₆ are independently selected from the group consisting of H, lower alkyl, COOH, CONH ₂ , NH ₂ and CH ₂ NH ₂ ; R ₄ is hydrogen; 1 to 6 hydrogen atoms are halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl (heteroarylalkyl and heteroarylalkenyl are 1 to 6 selected from the group consisting of nitrogen, oxygen and sulfur atoms C ₁ -C ₁₅ saturated or unsaturated aliphatic hydrocarbons (straight chain or branched chain) which may be substituted with a group independently selected from the group consisting of two hetero atoms (optionally the arylalkyl, arylalkenyl, One to three hydrogen atoms on the aryl or heteroaryl ring in the heteroarylalkyl or heteroarylalkenyl group are lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhaloalkyl, cyano, hydroxy , Nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino or N -lower (C ₁ -C ₄₎ alkyl, O Furnace is carbonyl may be substituted; a} The method of claim 4, wherein The disease or condition is urinary incontinence, lower urinary tract symptoms (LUTS), bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes or gastrointestinal dyskinesia. A method of treating or preventing a disease or disorder of the respiratory, urinary or gastrointestinal tract mediated through an animal or human muscarinic receptor, A method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 3 to an animal or human. The method of claim 6, The disease or condition is urinary incontinence, lower urinary tract symptoms (LUTS), bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes or gastrointestinal dyskinesia. As a compound represented by the following formula (1), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, ester, enantiomer, diastereomer, N-oxide, polymorphic or metabolite thereof (a) reacting the compound represented by the following formula (2) with the compound represented by the following formula (3) in the presence of a condensing agent to produce a compound represented by the following formula (4); (b) deprotecting the compound represented by Formula 4 with a deprotecting agent to produce a compound represented by Formula 5; And (c) N-alkylating or benzylating the compound represented by Formula 5 with the compound represented by Formula LR ₄ to produce a compound represented by Formula 1 below: (Formula 1)

{In Formula 1, Ar is an aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [The aryl ring or heteroaryl ring is lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) Perhaloalkyl, cyano, hydroxy, nitro, halogen (eg F, Cl, Br, I), lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted Unsubstituted or substituted by one to three substituents independently selected from the group consisting of amino, N-lower (C ₁ -C ₄ ) alkylamino and N-lower (C ₁ -C ₄ ) alkylamino carbonyl Can be; R ₁ is hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoyl or halogen (eg fluorine, chlorine, bromine and iodine); R ₂ is hydrogen; Alkyl; C ₃ -C ₇ cycloalkyl ring; C ₃ -C ₇ cycloalkenyl ring; Aryl ring; Or a heteroaryl ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms [aryl ring or heteroaryl ring may be selected from lower (C ₁ -C ₄ ) alkyl, cyano, hydroxy, Nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhaloalkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino and N- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower (C ₁ -C ₄ ) alkyl amino carbonyl; W is (CH ₂ ) _p (p is 0 to 1); X is not oxygen, sulfur, —NR where R is H or alkyl or no atom; Y is (CH ₂ ) _q (q is 0 to 1); R ₃ , R ₅ and R ₆ are independently selected from the group consisting of H, lower alkyl, COOH, CONH ₂ , NH ₂ and CH ₂ NH ₂ ; R ₄ is hydrogen; One to six hydrogen atoms are halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl (heteroarylalkyl and heteroarylalkenyl is one selected from the group consisting of nitrogen, oxygen and sulfur atoms C ₁ -C ₁₅ saturated or unsaturated aliphatic hydrocarbons (linear chain or branched chain) which may be substituted with a group independently selected from the group consisting of from 2 hetero atoms) (optionally, the arylalkyl, arylalkenyl 1 to 3 hydrogen atoms on the aryl or heteroaryl ring in the heteroarylalkyl or heteroarylalkenyl group are lower (C ₁ -C ₄ ) alkyl, lower (C ₁ -C ₄ ) perhaloalkyl, cyano, hydroxide Roxy, nitro, lower alkoxycarbonyl, halogen, lower (C ₁ -C ₄ ) alkoxy, lower (C ₁ -C ₄ ) perhalo alkoxy, unsubstituted amino, N-lower (C ₁ -C ₄ ) alkylamino or N-lower (C ₁ -C ₄ ) alkylamimi May be substituted with no carbonyl]

The method of claim 8, P is selected from the group consisting of benzyl and t-butyloxy carbonyl groups. The method of claim 8, The process of reacting the compound represented by the formula (2) with the compound represented by the formula (3) to produce the compound represented by the formula (4) includes 1- (3-dimethyl aminopropyl) -3-ethyl carbodiimide hydrochloric acid (EDC) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). A process characterized in that it is carried out in the presence of a condensing agent selected from the group consisting of. The method of claim 8, The process of reacting the compound represented by the formula (2) with the compound represented by the formula (3) to produce the compound represented by the formula (4) is a suitable solvent selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, toluene and xylene The method characterized in that the execution. The method of claim 8, The reaction process of the compound represented by the formula (2) and the compound represented by the formula (3) is carried out at a temperature of about 0 ℃ to about 140 ℃. The method of claim 8, Deprotecting the compound represented by the formula (4) to produce the compound represented by the formula (5) is carried out with a deprotection agent selected from the group consisting of palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid Characterized in that the method. The method of claim 8, Deprotecting the compound represented by the formula (4) to produce the compound represented by the formula (5), wherein the process is performed in a suitable organic solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran and acetonitrile. The method of claim 8, A process for producing a compound represented by Formula 1 by N-alkylating or benzylating a compound represented by Formula 5 is a suitable alkylating agent or benzylating agent, LR ₄ [where L is a leaving group, and R ₄ is As defined in the following. The method of claim 15, Leaving group L is selected from the group consisting of halogen, O-methyl and O-tosyl groups. The method of claim 15, The process of N-alkylating or benzylating the compound represented by Formula 5 to produce the compound represented by Formula 1 is appropriately selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile. Characterized in that it is carried out in an organic solvent.