KR100500760B1 - Process for preparation of the propiverine hydrochloride - Google Patents

Abstract

The present invention comprises the steps of preparing O-n-propylbenzylic acid from benzylic acid; And reacting the O-n-propylbenzylic acid with 4-hydroxy-1-methylpiperidine to produce propiberine, and to prepare propiberine hydrochloride using hydrochloric acid.

Description

Process for preparation of the propiverine hydrochloride

The present invention is directed to bladder stimulating conditions such as neurogenic bladder disease, neuronal urinary disease, unstable bladder disease, chronic cystitis and chronic prostatitis, as well as neurogenic bladder disease, neuronal urinary disease, unstable bladder disease, chronic cystitis and chronic prostatitis. The present invention relates to a method for preparing propiberine hydrochloride, which is useful as an agent for preventing and treating urinary incontinence and urinary incontinence caused by bladder irritant conditions.

More specifically, the present invention comprises the steps of preparing O-n-propylbenzylic acid from benzylic acid; And reacting the O-n-propylbenzylic acid with 4-hydroxy-1-methylpiperidine to produce propiberine, and to prepare propiberine hydrochloride using hydrochloric acid.

Propyberine hydrochloride is a therapeutic agent for overactive bladder disease. Irritable (overactive) bladder that causes urinary incontinence (urgery incontinence) irrespective of one's will or activity if urine is frequent (urinary) or urine is urgent (urgency urinary) is the most researched in the field of urination disorder It is an ongoing and developing field. At present, etiology is active, but the exact cause is not known. Symptoms of overactive bladder disease include frequent urine, urgency and urge incontinence more than eight times a day. According to the World Urinary Incontinence Society, it can be diagnosed by urinadynamic test, especially hypotonic bladder pressure measurement, and the patient himself attempts to suppress it, but involuntary decay muscle contraction is caused by objective or causal factor. If a neurological abnormality is found, it is called "detrusor hyperreflection", otherwise it is called "detrusor root instability".

There is still considerable debate about the etiology of overactive detrusors. The main types of anaphylactic detrusors include detrusor hyperreflection, detrusor instability associated with bladder outlet obstruction, and idiopathic detrusor instability. This cannot be distinguished by bladder filling test and the pathology is different. It appears that the different forms are the result of neuronal and muscular toughness alone or in combination. The exact mechanism of overactive detrusor is currently being studied using the physiology of nerves and muscles, the microstructure of detrusor smooth muscle, and cell biochemistry.

The bladder pressure test is very important in the diagnosis of detrusor hyperactivity. Previously, urinary muscle contraction pressure of 15cmH ₂ O or more should be required. In recent years, patients have suppressed urination. Cold water tests have been used to distinguish between detrusor overreflection and instability, but they have been used to distinguish between various forms of neurogenic lower urinary tract dysfunction.

The goal of treatment of overactive bladder is to effectively improve symptoms such as frequent urination, nocturia, urgency and urinary incontinence. There are various methods of treatment, and it can be divided into medical treatment and surgical treatment. Medical treatment includes behavioral therapy, pharmacotherapy and electro-stimulation therapy.

As behavior therapy, voluntary control of bladder function is done in early childhood, and urea medicine is a combination of normal physiological function with social behavior acquired through learning. Behavioral therapy is widely used for the treatment of lower urinary tract dysfunction, and is particularly effective for urinary incontinence and primary sensory urgency of urinary sphincter or detrusor dysfunction. A variety of behavioral therapies have been studied in the meantime, but the results of long-term follow-up on improving subjective and objective symptoms have not been reported.

Bladder training or drill is a type of biofeedback therapy that corrects poor urination habits and has three components: education, scheduled voiding, and positive reinforcement. Explain the normal urination mechanism and interval to the patient to understand the type of urination that is formed incorrectly by the patient and explain the effect of bladder training. Bladder training is a training that gradually extends the urination interval. We aim at extension to four hours. Patient education is important because the critical factor predicting success in this treatment is patient compliance with the treatment method.

As pharmacological therapy, the direct suppression of the detrusor itself and the regulation of cholinergic and adrenergic neuronal functions reflect most of the drug treatment of overactive bladder. Drugs that can inhibit or reduce physiological mechanisms associated with detrusor muscle contraction include anticholinergic drugs, smooth muscle relaxants, calcium antagonists, beta sympathetic agents, tricyclic antidepressants, and K channel openers. Can be divided.

Anticholinergic drugs (Anticholinergics), the main nerve stimulation of physiological bladder contraction is cholinergic, so anticholinergic drugs are the main treatment of overactive bladder. Anticholinergic drugs are competitive inhibitors that interfere with the muscarinic effect of acetylcholine. They inhibit normal bladder contractions and involuntary detrusor contractions. Dry mouth, decreased sweating, emotional disorders, constipation, pupil dilatation, visual field disorders, tachycardia, severe cardiac arrhythmias, angular glaucoma, gastrointestinal obstruction, severe myasthenia gravis are contraindicated. Anticholinergic medication alone is difficult to treat and can be combined with other mechanisms.

As musculotropic relaxants, there have been efforts to find other drugs due to unsafe reactions and side effects of bladder muscle to Atropine-like drugs. Smooth muscle relaxant acts directly on the distal portion of cholinergic receptors and inhibits smooth muscle activity, resulting in various anticholinergic and local anesthetic effects. Drugs include oxybutynin chloride, dicyclomine HCl, flavoxate HCl, propiverine HCl, and side effects are similar to other anticholinergic drugs. Recently, tolterodine (Detrol) and oxybutynin ER (Ditropan XL), which have significantly reduced anticholinergic side effects, have been developed and used. Intracavitary infusions of oxybutynin were initiated due to the possibility of obtaining high concentrations of drugs in the detrusor muscle and avoiding systemic side effects and are effective when oral administration is difficult.

As calcium antagonists, calcium is a necessary element for muscle contraction. Therefore, calcium channel blockers that prevent the inflow of calcium into myocytes can be used to inhibit bladder contraction. Drugs include terodiline, HCl, and nifedifine. Terodiline is a representative drug with calcium antagonism and antimuscarinic action. Common side effects of calcium antagonists include hypotension, headache, constipation, tachycardia and abdominal pain.

As a beta-adrenergic agonists, there is a study to treat hyperactive bladder by stimulating the presence of beta-sympathetic receptors in the detrusor muscle, and it has been reported that terbutaline was effective in some patients.

Tricyclic antidepressants have been used for a long time to increase bladder volume and urethral resistance in children with nocturnal enuresis and urinary incontinence. Inhibition results in alpha-sympathetic nerve stimulation. The mechanism of action on the bladder is controversial, but there is a dual action that promotes urinary storage in the lower urinary tract, which reduces bladder contractility and enhances sphincter resistance. Drugs include imipramine-HCl, amitriptyline-HCl, and doxepin.

K channel openers, as potassium channel openers, increase K excretion in smooth muscle, thereby relaxing membrane muscle hypermembrane (membrane yperpolarization). Although it does not affect the contractile force involved in normal urination, there are no objective data on clinical efficiency, proper dose, and side effects.

Alpha sympathetic blockers (alpha-adrenergic antagonists) are widely used as a drug for the treatment of prostate hyperplasia and have a good effect on urinary incontinence. In particular, when the bladder is decentralized due to nerve damage, the beta-sympathetic nerve receptor in the bladder gradually changes to the alpha-sympathetic nerve receptor, which decreases the elasticity of the bladder and increases the pressure in the bladder, resulting in an urinary incontinence. Increase the risk of kidney damage.

As other drugs, capsaicin, resiniferatoxin, and lidocaine may be used for intra- bladder administration. Capsaicin is a pungent ingredient of red pepper, which reversibly inhibits sensory nerve activity after desensitizing C-fibers that stimulate detrusor hyperactivity. It has been used topically for the treatment of skin pain disorders and increases the bladder volume and reduces bladder irritation symptoms by eliminating systemic side effects.

As electrical stimulation therapy, Caldwell reported a success rate of about 50% in 1963 by placing electrodes around the urethra and applying chronic electrical stimulation for the purpose of treating urinary incontinence, but the success rate was relatively lower than the risk of planting electrodes around the urethra. It has changed into a non-invasive way of electrical stimulation through the anus, anus and skin. Electrical stimulation has two effects: contraction of pelvic muscles and relaxation or inhibition of bladder activity. Only at low currents below 35 mA, only the pelvic muscles are affected. Pelvic muscle contractions for high currents of 65 mA or more and 40 mA or more And bladder relaxation have two effects. When the electrical stimulation is fixed at 20Hz and only the current intensity is changed, pelvic muscle contraction and bladder relaxation effect can be obtained. have. In an overactive bladder, intravaginal or intravaginal electrical stimulation strengthens the urethral muscles, increasing exit resistance and inhibiting the detrusor muscles, thereby reducing the overactive activity of the detrusor muscles. Reflexive suppression of the detrusor muscle is stimulated by the genital afferent nerves by electrical stimulation, and depressive muscle suppression is induced by pudendal-hypogastric and pudendal-pelvic spinal reflex through the shallow water. These findings indicate that bladder contractions during bladder pressure test in hypersensitive bladder patients disappear or decrease during electrostimulation treatment and the bladder volume increases by 2 to 5 times. However, it is reported that electrostimulation therapy is effective and long lasting for idiopathic causes, but only for a short period of time in neurogenic causes.

Intestinal cystoplasty with surgery is generally considered as a last resort before urinary tract surgery in patients with idiopathic urinary incontinence. The results are good in terms of postoperative symptoms, but cystoplasty is associated with severe complications. Bladder self-expansion using detrusor partial resection is less than cystoplasty, but there is improvement in symptoms and significant improvement in urodynamic parameters. The success rate was clearly higher in patients with idiopathic detrusor instability than in hyperreflective patients. Although less effective than using the intestine, intestinal complications can be avoided and intestinal cystoplasty may be performed later.

Prior to the present application, there is known a method for preparing propiberine hydrochloride in the prior literature, the synthesis process of which is as follows (see Chinese Patent No. 1285348 A).

The synthesis process comprises the steps of adding sodium hydroxide to diphenyl hydroxyacetic acid to prepare a sodium salt of diphenyl hydroxyacetic acid; Adding 4-chloro-1-methylpiperidine to the sodium salt of diphenylhydroxyacetic acid to prepare hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester; Thionylchloride was added to the hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester to prepare chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride. ; It is known to prepare propiberine hydrochloride, which comprises adding propyl alcohol to the chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride to produce propiberine hydrochloride.

However, the main drawback in the above-described method of preparing propiberine hydrochloride is that 4-chloro-1-methylpiperidine is added to the sodium salt of diphenylhydroxyacetic acid to give 1-methyl hydroxy-diphenyl-acetic acid. In the step of preparing piperidin-4-yl ester, the reaction must be carried out under strong basic conditions, so that the ring of piperidine may be decomposed, and thus 4-chloro-1 in the sodium salt of diphenylhydroxyacetic acid. In the preparation of the hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester by addition of -methylpiperidine, the yield is actually only 30% or less. In addition, thionyl chloride was added to the conventional hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester described above to give chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester. In the step of preparing hydrochloride, the reaction must be carried out using strong acid thionyl chloride, and thus the ring of piperidine may be decomposed, which causes chloro-diphenyl-acetic acid 1 from the sodium salt of diphenylhydroxyacetic acid. The yield in the preparation of -methyl-piperidin-4-yl ester hydrochloride is only 28%. Therefore, the above conventional method is inefficient in the manufacturing process and unsuitable for the industrial mass production method. In addition, the method of preparing propiberine hydrochloride by adding propyl alcohol to chloro-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester hydrochloride does not proceed well and yields poor results. A problem occurred.

The present inventors have made a lot of research and efforts to solve the above-mentioned problems in the conventional method and found a novel manufacturing method which is simpler, safer and higher in yield, and completed the present invention. The present invention relates to a method for producing propiberine hydrochloride, which has an anticholinergic action and calcium antagonistic action, and has an urinary tract disorder such as urinary insufficiency, urinary incontinence, and the like in diseases such as neuropathy, neurogenic bladder, enuresis, unstable bladder, and chronic cystitis. The present invention relates to a method for producing propiberine hydrochloride, which is a raw material of a pharmaceutical preparation for prophylaxis and treatment. Drugs that inhibit reflex bladder contraction are useful for preventing and treating urinary disorders such as anemia, neurogenic bladder, nocturnal enuresis, unstable bladder, anemia caused by chronic cystitis, and urinary incontinence. Oxyvintin hydrochloride with anticholinergic activity, propiberine hydrochloride, bamicamide, tolterodine and Japanese Patent Laid-Open No. 2-262548, Japanese Patent Laid-Open No. 6-92921, Japanese Patent Laid-Open No. 6-135958, Japanese Patent Laid-Open Compounds described in Japanese Patent Application Laid-Open No. 7-258250, Japanese Patent Application Laid-Open No. 8-291141, Japanese Patent Application Laid-Open No. 9-71563, WO93 / 16048, WO95 / 06635, WO96 / 33973, WO97 / 13766, and WO97 / 45414. This is being reported. However, these conventional compounds have insufficient effect of inhibiting reflex bladder contraction or, if sufficient, thirst (saliva secretion inhibitory effect), which is a side effect of anticholinergic action, appears as an effective amount, and the separation of main action and side effects is insufficient. It is a problem. An object of the present invention is to provide a compound that inhibits reflex bladder contraction, has a low side effect of thirst (saliva secretion inhibitory effect), has high safety, and is useful as a medicament for preventing and treating urinary tract disorders. In view of the above facts, the present inventors synthesized various compounds and studied intensively thereof, and found that they have excellent anticholinergic and calcium antagonistic effects, have little side effects such as thirst, are safe, and useful as preventive and therapeutic agents for urinary disorders. The present invention has been completed.

Profiberine hydrochloride preparation method of the present invention comprises the steps of preparing O-n-propylbenzylic acid from benzyl acid; And reacting the O-n-propylbenzylic acid with 4-hydroxy-1-methylpiperidine to produce propibelin, and using hydrochloric acid to prepare propiberine hydrochloride.

O-n-propylbenzylic acid in the method for preparing propiberine hydrochloride of the present invention is to oxidize benzylic acid to phosphorus pentachloride and react with 1-propanol to prepare O-n-propylbenzylic acid. In addition, another method of preparing O-n-propylbenzylic acid in the method of preparing propiberine hydrochloride of the present invention is a method of producing O-n-propylbenzylic acid by reacting benzylic acid with propyl chloride.

In the present invention, after reacting benzylic acid with phosphorus pentachloride added to benzene, the reactant is concentrated under reduced pressure, 1-propanol is added to the concentrated reactant, refluxed and cooled, and caustic soda and purified water are refluxed in the cooled reactant. After the reaction, cooling, washing and drying to obtain On-propylbenzylic acid; And tetrahydrofuran, triphenylphosphine, and 4-hydroxy-1-methylpiperidine were added and stirred in a nitrogen atmosphere, and 40% by weight of ethylazodicarboxylate was slowly added to the reaction solution at room temperature. After slowly adding the solution of On-propylbenzylic acid dissolved in tetrahydrofuran and reacting at room temperature, the reaction precipitate was filtered and the filtrate was distilled into dichloromethane, washed with water and anhydrous sodium sulfate, and concentrated under reduced pressure. When the propiberine base is obtained, acetone and 35% hydrochloric acid are added thereto to reflux, and then cooled to prepare propiberine hydrochloride.

In addition, as another synthesis method for preparing intermediate product On-propylbenzylic acid for preparing propiberine hydrochloride of the present invention, benzylic acid, dioxane and potassium anhydrous potassium are sequentially added and stirred, followed by slowly adding propyl chloride to the reaction to reflux. Reacting, cooling the reaction product, filtration, concentrating the filtrate under reduced pressure, extracting with petroleum ether, washing with purified water and drying with anhydrous sodium sulfate, and then filtering and distilling the filtrate to crystallize to prepare On-propylbenzylic acid; And tetrahydrofuran, triphenylphosphine, and 4-hydroxy-1-methylpiperidine were added sequentially under a nitrogen atmosphere, followed by stirring. Then, 40 wt% diezaazodicarboxylate was slowly added to the reaction solution at room temperature. After slowly adding On-propylbenzylic acid in tetrahydrofuran, the solution was slowly added, and then reacted at room temperature. The reaction precipitate was filtered and the filtrate was distilled into dichloromethane, washed with water and anhydrous sodium sulfate, and then decompressed. When concentrated, to obtain a propiberine base, acetone and 35% hydrochloric acid is added to the reflux reaction, and then cooled to produce propiberine hydrochloride, comprising a step of producing a propiberine hydrochloride.

Referring to the synthesis method for synthesizing propiberine hydrochloride according to the present invention in detail. In order to prepare propiberine hydrochloride of the present invention, O-n-propylbenzylic acid should be prepared first. The method for preparing the intermediate product is as follows.

In order to prepare propiberine hydrochloride of the present invention, on-propylbenzylic acid should be prepared first. To prepare on-propylbenzylic acid, the reaction product was concentrated under reduced pressure after reacting with benzylic acid added phosphorus pentachloride to benzene. 1-propanol was added to the reactant to reflux, followed by cooling. Caustic soda and purified water were refluxed in the cooled reaction, cooled, filtered and washed to obtain On-propylbenzylic acid. Purification of the product can prepare a high yield and high purity of the intermediate product O-n-propylbenzylic acid.

In addition, the synthesis process of synthesizing propiberine hydrochloride of the present invention using the intermediate product On-propylbenzylic acid is as follows.

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In order to synthesize propiber hydrochloride of the present invention using on-propylbenzylic acid, tetrahydrofuran, triphenylphosphine, and 4-hydroxy-1-methylpiperidine are sequentially added under a nitrogen atmosphere, followed by stirring. After slowly adding 40 wt% diezaazodicarboxylate to the reaction solution at room temperature, the solution obtained by dissolving On-propylbenzylic acid in tetrahydrofuran was added slowly, followed by reaction at room temperature, and filtering the reaction precipitate. Distillate is added to dichloromethane, washed with water and treated with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain propiberine base. Acetone and 35% hydrochloric acid were added thereto, refluxed, and cooled to obtain propiberine hydrochloride. Purification of the product can produce high yield and high purity of the final product, propiber hydrochloride.

In addition, other synthetic methods may be used to prepare the intermediate product O-n-propylbenzylic acid for preparing propiberine hydrochloride of the present invention.

Another synthetic method for preparing the intermediate product On-propylbenzylic acid for preparing propiberine hydrochloride of the present invention is to first add benzylic acid, dioxane and anhydrous potassium carbonate one by one and stir and then slowly add propyl chloride to the reaction to reflux. After the reaction, the reaction product is cooled and filtered, and the filtrate is concentrated under reduced pressure, extracted with petroleum ether, washed with purified water and dried over anhydrous sodium sulfate, and then filtered and the filtrate is distilled to crystallize to obtain On-propylbenzylic acid.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Example 1

(First Step) Preparation of O-n-propylbenzylic Acid

Benzylic acid 107.27g (0.47mol), benzene 500g, phosphorus pentachloride 212.4g (1.02mol) was added to the 2L reactor for 2 hours and the reaction was concentrated under reduced pressure. 306 g (5.1 mol) of 1-propanol was added to the concentrated reaction mixture, refluxed for 6 hours, and cooled. 22.56 g (0.56 mol) of caustic soda and 200 mL of purified water were added to the cooled reaction mixture, and the mixture was refluxed for 1 hour, filtered, washed, and dried to obtain 117.91 g of O-n-propylbenzylic acid (yield: 92.84%).

(2nd process) Preparation of propiberine hydrochloride

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700 ml of tetrahydrofuran, 81.30 g (0.31 mol) of triphenylphosphine and 53.55 g (0.47 mol) of 4-hydroxy-1-methylpiperidine were added and stirred in a 2 L reactor under a nitrogen atmosphere. After stirring for 1 hour, 135 g (54 g, 0.31 mol) of 40 wt% diezaazodicarboxylate was slowly added to the reaction solution at room temperature, and 83.77 g (0.31 mol) of On-propylbenzylic acid was dissolved in 700 ml of tetrahydrofuran. The solution is added for 2 hours and then reacted at room temperature for 24 hours. The precipitate was filtered off, and the filtrate was distilled into 700 g of dichloromethane. The mixture was washed with water and treated with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain propibelin base. 500 g of acetone and 32 g of 35% hydrochloric acid (11.2 g, 0.31 mol) were added thereto, refluxed for 2 hours, and cooled to obtain 100 g of propiberine hydrochloride. (Yield: 79.86%)

Example 2

(First Step) Preparation of O-n-propylbenzylic Acid

107.27 g (0.47 mol) of benzylic acid, 640 g of dioxane, and 162.4 g (1.18 mol) of anhydrous potassium carbonate were sequentially added to the 2 L reactor and stirred. After stirring for 1 hour, 71.45 g (0.52 mol) of propyl chloride was slowly added to the reaction, followed by reflux for 24 hours. After the reaction was cooled and filtered, the filtrate was concentrated under reduced pressure and extracted with petroleum ether. After washing with purified water and drying over anhydrous sodium sulfate, and the filtrate was distilled and crystallized, 83.77 g of O-n-propylbenzylic acid was obtained. (Yield 92.84%)

(2nd process) Preparation of propiberine hydrochloride

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700 ml of tetrahydrofuran, 81.30 g (0.31 mol) of triphenylphosphine and 53.55 g (0.47 mol) of 4-hydroxy-1-methylpiperidine were added and stirred in a 2 L reactor under a nitrogen atmosphere. After stirring for 1 hour, 135 g (54 g, 0.31 mol) of 40 wt% diezaazodicarboxylate was slowly added to the reaction solution at room temperature, and 83.77 g (0.31 mol) of On-propylbenzylic acid was dissolved in 700 ml of tetrahydrofuran. The solution was added for 2 hours and then reacted at room temperature for 24 hours. The precipitate was filtered off, and the filtrate was distilled into 700 g of dichloromethane. The mixture was washed with water and treated with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain propibelin base. 500 g of acetone and 32 g (11.2 g, 0.31 mol) of 35% hydrochloric acid were added thereto, and the mixture was refluxed for 2 hours and then cooled to obtain 100 g of propibel hydrochloride. (Yield: 79.86%)

Test Example 1 Effect of Propyberine Hydrochloride on Acetylcholine-Induced Bladder Contraction

SD male rats weighing 230-390 g were intraperitoneally administered urethane 500 mg / kg and ??-chlorarose 50 mg / kg. After rats were fixed, the rats were fixed in the middle of the abdomen and the bladder was exposed. A polyethylene tube filled with physiological saline was inserted into the bladder government, and the bladder internal pressure was measured. An intravenous cannula for drug administration was inserted into the femoral vein, and 10 g / kg of acetylcholine was used to cause bladder contraction, followed by acetylcholine at 10 minute intervals. After bladder contraction by acetylcholine was stabilized, the center of the test compound was dissected and administered using a needle in the duodenum, and then the action on bladder contraction reaction was observed for 120 minutes.

Bladder contraction response was measured by the difference in bladder pressure before and after the administration of acetylcholine. In addition, the bladder contraction before administration of the test compound was taken as the pre-administration value, and the 50% inhibitory dose (ID50) was calculated from the contraction response after administration of each test compound. The results are shown in the table below.

Experimental Example 2 Effect of Propyberine Hydrochloride on Carbacol-Induced Saliva Secretion Hyperactivity

The test compound was orally administered to SD male rats weighing 100 to 150 g, and carbacol 0.1 mg / kg was intraperitoneally administered 30 minutes later. Immediately after this carbacol administration, the rat was anesthetized and fixed by hand, and the saliva was wiped off with a cotton ball for 10 minutes in that state. The weight of this saliva was measured, and the saliva secretion inhibitory dose (ID50) of 50% was computed as 100% of the saliva secretion amount of the group which administered only the excipient. The results are shown in the table below.

Compound number Bladder contraction Saliva secretion Saliva secretion inhibitory bladder contraction Selectivity 3  9.4 33.9 3.6 4.0 4  9.8 56.6 5.8 6.2 12 10.0 22.5 2.3 2.4 Oxybutynin hydrochloride  3.4  3.5 1.0 1.1 Hydrochloric acid  9.9  9.2 0.9 1.0

From the above results, the compound of the present invention showed better bladder selectivity than the comparative control oxybutynin hydrochloride and the other company's commercially available propiberine hydrochloride, and showed diseases such as anemia, neurogenic bladder, enuresis, unstable bladder, and chronic cystitis. It can be confirmed that it is useful as an agent for the prevention and treatment of urinary disorders such as urinary frequency and urinary incontinence.

Profiberine hydrochloride preparation method of the present invention can be easily synthesized by using the intermediate product On-propylbenzylic acid, propiberine hydrochloride of the present invention has excellent anticholine action and calcium antagonism action and various bladder urination It has an excellent effect as an agent for preventing or treating an obstacle.

Claims (5)

Preparing O-n-propylbenzylic acid from benzylic acid; And reacting the on-propylbenzylic acid with 4-hydroxy-1-methylpiperidine to produce propiberine and to prepare propiberine hydrochloride using hydrochloric acid. . The method of claim 1, wherein the O-n-propylbenzylic acid is prepared by oxidizing benzylic acid to phosphorus pentachloride and reacting with 1-propanol. The method of claim 1, wherein the O-n-propylbenzylic acid is prepared by reacting benzylic acid with propyl chloride. The method of claim 1, wherein the O-n-propylbenzylic acid comprises reacting benzylic acid with phosphorus pentachloride and reacting 1-propanol with the reactant to produce O-n-propylbenzylic acid; And Propyl hydrochloride was added with tetrahydrofuran, triphenylphosphine and 4-hydroxy-1-methylpiperidine under a nitrogen atmosphere, followed by stirring. Then, 40 wt% diezaazodicarboxylate was slowly added to the reaction solution. A method for preparing propiberine hydrochloride, comprising the steps of adding propylene and reacting with on-propylbenzylic acid to produce propiberine and adding hydrochloric acid to produce propiberine hydrochloride. The method of claim 1, wherein the O-n-propylbenzylic acid is prepared by sequentially adding benzylic acid, dioxane and anhydrous potassium carbonate, and then reacting the propyl chloride with the reactant.