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Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient
RE44872 Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient
Patent Drawings:

Inventor: Takasu, et al.
Date Issued: April 29, 2014
Application:
Filed:
Inventors:
Assignee:
Primary Examiner: Klinkel; Kortney L
Assistant Examiner:
Attorney Or Agent: Fitzpatrick, Cella, Harper & Scinto
U.S. Class: 514/370
Field Of Search: ;514/370
International Class: A61K 31/426; A61P 13/10
U.S Patent Documents:
Foreign Patent Documents: 715216; 731391; 0 420 120; 97/15549; 0 958 835; 1258253; 1028111; 2356197; 06-293664; 07-228543; 2001-114736; 92/18461; 93/15041; 94/25427; 98/07445; 99/20607; WO 99/20607; 99/31045; 99/52856; 00/02846; 01/54728; 01/62705; 02/00622
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Nathalie Blin, et al., "Structural And Conformational Features Determining Selective Signal Transduction In The .beta.3-Adrenergic Receptor", The American Society for Pharmacology and Experimental Therapeutics, 1993, vol. 44, pp. 1094-1104. cited byapplicant.
Takashi Morita, et al., The Japanese Journal of Urology, 88 (2), p. 119, (p. 183) 1997. cited by applicant.
Yasuhiko Igawa, et al., The Japanese Journal of Urology, 88 (2), p. 119, (p. 183) 1997. cited by applicant.
Penelope A. Longhurst et al., "Pharmacological characterization of .beta.-adrenoceptors mediating relaxation of the rat urinary bladder in vitro" (1999), British Journal of Pharmacology, vol. 127, pp. 1744-1750. cited by applicant.
Yasuhiko Igawa et al., "Relaxant Effects of Isoproterenol and Selective .beta.-3Adreenoceptor Agonists On Normal Low Compliant and Hyperreflexic Human Bladders" (2001), The Journal of Urology, vol. 165, pp. 240-244. cited by applicant.
Paul Abrams et al., "The Standardisation of Terminology of Lower Urinary Tract Functions: Report from the Standardisation Sub-committee of the International Continence Society" (2002), Neurourology and Urodynamics, 21: pp. 167-178. cited byapplicant.
Jeffrey P. Weiss and Jerry G. Blaivas, "Nocturia", Journal of Urology, Jan. 2000, pp. 5-12, vol. 163, No. 1, XP005556162, ISSN: 0022-5347, American Urological Association, Inc. cited by applicant.
Martin C. Michel, et al., "Effect of Diabetes on Lower Urinary Tract Symptoms in Patients with Benign Prostatic Hyperplasia", Journal of Urology, Jun. 2000, pp. 1725-1729, vol. 163, No. 6, XP005555510, ISSN: 0022-5347, American UrologicalAssociation, Inc. cited by applicant.
Jens T. Andersen and William E. Bradley, "Abnormalities of Bladder Innervation in Diabetes Mellitus", Urology, Apr. 1976, pp. 442-448, vol. 7, No. 4, XP002430159. cited by applicant.
Guo-Ming Zhao, et al., "Advance on the Research on and Development of Beta-sub3-Adrenoceptor Agonists", Chinese Jornal of Medicinal Chemistry, Jun. 2001, pp. 177-181, vol. 11, No. 3, China Academic Journal Electronic Publishing House. cited byapplicant.
Takashi Morita, et al., "Function and Distribution of Beta-sub3-Adrenoceptors in Rat, Rabbit and Human Urinary Bladder and External Urethral Sphincter", J. Smooth Muscle Res., 2000, pp. 21-32, vol. 36. cited by applicant.
Osamu Yamaguchi, ".beta..sub.3-Anrenoceptors In Human Detrusor Muscle", Urology, 2002, 59 (Supplement 5A): 25-29. cited by applicant.









Abstract: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or its salt shows a potent bladder relaxation effect in "isolated rat bladder smooth muscle relaxation test", dose-dependently lowers the contraction frequency of rhythmic bladder contractions in "rat rhythmic bladder contraction measurement test" and, moreover, prolongs the urination intervals in "urination functions measurement test on cyclophosphamide-induced overactive bladder model rat". Owing to these effects, the above compound is useful as a remedy for ovaractive bladder.
Claim: The invention claimed is:

1. A method for treating overactive bladder comprising administering to a subject in need thereof, a pharmaceutically effective amount of(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or a salt thereof as an active ingredient, wherein the subject is not suffering from diabetes.

2. The method according to claim 1, wherein the overactive bladder is a result of benign prostatic hyperplasia.

3. The method according to claim 1, wherein the subject has urinary urgency.

4. The method according to claim 1, wherein the subject has urinary urge incontinence.

5. The method according to claim 1, wherein the subject has pollakiuria.

6. A method for treating overactive bladder comprising administering to a subject in need thereof, a pharmaceutically effective amount of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide, in its freebase form, as an active ingredient, wherein the subject is not suffering from diabetes.

7. The method according to claim 6, wherein the overactive bladder is a result of benign prostatic hyperplasia.

8. The method according to claim 6, wherein the subject has urinary urgency.

9. The method according to claim 6, wherein the subject has urinary urge incontinence.

10. The method according to claim 6, wherein the subject has pollakiuria.

11. The method according to claim 1, wherein the subject is human.

12. The method according to claim 6, wherein the subject is human.

.Iadd.13. A method for treating overactive bladder comprising administering to a subject in need thereof, a pharmaceutically effective amount of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)ami- no]ethyl]acetic acid anilide or asalt thereof as an active ingredient, wherein when the subject is not an adult, the subject is not suffering from diabetes..Iaddend.

.Iadd.14. A method for treating overactive bladder comprising administering to a subject in need thereof, a pharmaceutically effective amount of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)ami- no]ethyl]acetic acid anilide, inits free base form, as an active ingredient, wherein when the subject is not an adult, the subject is not suffering from diabetes..Iaddend.
Description: TECHNICAL FIELD

This invention relates to a remedy for overactive bladder comprising (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or a salt thereof as an active ingredient.

BACKGROUND

Bladder of mammals is under a dual control of autonomic nerve and detrusor relaxes via an adrenaline .beta. receptor by stimulation of sympathetic nerve upon urination while, upon excretion of urine, it contracts via a muscarine receptor bystimulation of parasympathetic nerve. As a remedy for overactive bladder resulted when the dual control as such is unbalanced, anticholinergic agents such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, there are intractable cases showing resistance to such compounds and there are side effects caused by anticholinergic agents such as urinary dysfunction and dry mouth and, therefore, it is the current status that satisfactory clinical resultsare not always achieved.

Further, as a result of increase in population of aged people in recent years, numbers of patients suffering from overactive bladder are increasing year by year and, in view of QOL (quality of life) of patients, there has been a brisk demand forthe development of new drugs.

The present inventors reported in Example 41 of a pamphlet of International Laid-Open WO 99/20607 that (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]- acetic acid anilide dihydrochloride has both promotion action forinsulin secretion and enhancing action for insulin sensitivity and further has anti-obese and anti-hyperlipemic actions whereby it is a useful compound for the treatment of diabetes mellitus but there is neither suggestion nor disclosure for thetherapeutic use for overactive bladder (refer to Patent Document 1).

##STR00001##

In the meanwhile, in a pamphlet of International Laid-Open WO 98/07445, as an agent for prevention and treatment of urinary frequency and urinary incontinence containing a drug having stimulating action to a .beta..sub.3-adrenaline receptor asan active ingredient, there is mentioned that CGP-12,177A represented by the following chemical structural formula has a relaxation action for bladder (refer to Patent Document 2). CGP-12,177A has been known as a selective drug having stimulating actionto a .beta..sub.3-adrenaline receptor (refer to Non-Patent Documents 1 and 2)

##STR00002##

In a pamphlet of International Laid-Open WO 99/31045, compounds represented by the following formula are mentioned as having a stimulating action to a .beta..sub.3-adrenaline receptor and as an agent for prevention or treatment of diseasescaused by obesity, hyperglycemia and acceleration of movement of intestinal tract and diseases caused by urinary frequency or urinary incontinence, melancholia, biliary calculus or acceleration of bile duct movement (refer to Patent Document 3).

##STR00003##

(In the formula, R.sup.1 is hydroxyl group, a lower alkyl group, an aralkoxy group, amino group, etc.; R.sup.2 is hydroxyl group or a lower alkyl group; R.sup.3 is hydrogen atom or halogen atom; R.sup.4 and R.sup.5 each is hydrogen atom, halogenatom or a lower alkyl group; and A is a lower alkylene group.)

In a pamphlet of International Laid-Open WO 99/52856, compounds represented by the following formula are mentioned as having a stimulating action to a .beta..sub.3-adrenaline receptor and as an agent for prevention or treatment of diseasescaused by obesity, hyperglycemia and acceleration of movement of intestinal tract and diseases caused by urinary frequency or urinary incontinence, melancholia, biliary calculus or acceleration of bile duct movement (refer to Patent Document 4).

##STR00004##

(In the formula, R.sup.1 is hydrogen atom, a lower alkyl group or an aralkyl group; R.sup.2 is hydrogen atom, a lower alkyl group or halogen atom; and A is oxygen atom or imino group.)

In a pamphlet of International Laid-Open WO 00/02846, compounds represented by the following formula are mentioned as having a stimulating action to a .beta..sub.3-adrenaline receptor and as an agent for prevention or treatment of diseasescaused by obesity, hyperglycemia and acceleration of movement of intestinal tract and diseases caused by urinary frequency or urinary incontinence, melancholia, biliary calculus or acceleration of bile duct movement (refer to Patent Document 5).

##STR00005##

(In the formula, R.sup.1 is hydroxyl group, etc.; one of R.sup.2 and R.sup.3 is hydrogen atom, halogen atom, etc. and another is hydrogen atom; and R.sup.4 is halogen atom, etc.)

Patent Document 1: Pamphlet of International Laid-Open WO 99/20607

Patent Document 2: Pamphlet of International Laid-Open WO 98/07445

Patent Document 3: Pamphlet of International Laid-Open WO 99/31045

Patent Document 4: Pamphlet of International Laid-Open WO 99/52856

Patent Document 5: Pamphlet of International Laid-Open WO 00/02846

Non-Patent Document 1: Drugs of the Future, 1993, volume 18, no. 6, page 542

Non-Patent Document 2: The American Society for Pharmacology and Experimental Therapeutics, 1993, volume 44, page 1100

DISCLOSURE OF THE INVENTION

The present inventors have carried out intensive studies for finding new pharmacological effects of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]- acetic acid anilide or a salt thereof (hereinafter, referred to as"the active ingredient of the present invention") which is useful as a remedy for diabetes mellitus and, as a result, they have found that the active ingredient of the present invention is useful as a remedy particularly for overactive bladder. In thepresent invention, overactive bladder is defined as a disease by which urinary urgency is frequently resulted. Although benign prostatic hyperplasia is exemplified as one of the causes for overactive bladder, there are many cases where the cause isambiguous and they are called idiopathic overactive bladder. Although overactive bladder is sometimes accompanied by urinary frequency and urinary incontinence, it is not limited to the disease which is always accompanied by urinary frequency andurinary incontinence. Thus, in the case of mild overactive bladder, a patient is sensitive to the sense of wishing to urinate and frequently has a sense of wishing to urinate but, actually, he/she is able to hold his/her urine for a while. However,even in the case of a mild overactive bladder, its improvement has been strongly demanded in view of QOL (quality of life) of a patient. On the other hand, a severe overactive bladder is sometimes accompanied by urinary frequency and urinaryincontinence. Urinary frequency is a state where number of times of urination is more than the normal one and is said to be not less than about two times at night and not less than about 8 times during 24 hours. In urinary incontinence, there is aninvoluntary leakage of urine and that is defined as a state where there is a problem socially or hygienically and is classified into stress urinary incontinence which occurs when abdominal pressure is applied such as cough and sneeze, urinary urgeincontinence where a desire to urinate suddenly occurs and urine leaks before arriving at the toilet and urinary incontinence of a mixed type where both stress urinary incontinence and urinary urge incontinence are present.

The characteristic feature of the present invention is that the active ingredient of the present invention mitigates especially the frequent occurrence of urinary urgency of a patient and number of times of urination and state of urination aremade into a more normal state. It goes without saying that overactive bladder in the present invention includes not only that as a result of benign prostatic hyperplasia but also that accompanied with urinary urgency, urinary incontinence andpollakiuria.

In Patent Document 1, the active ingredient of the present invention is useful, in addition to treatment of diabetes, as an agent for prevention and treatment of other diseases where an improvement in symptom is able to be achieved by reducingthe symptom of obesity and hyperlipemia such as arteriosclerosis, ischemic cardiac disease such as cardiac infarction and angina pectoris, brain artery sclerosis such as cerebral infarction, aneurysm, etc. However, there is neither description norsuggestion at all to the effect that the active ingredient of the present invention is useful as a remedy for overactive bladder.

In Patent Document 2, use for overactive bladder is not mentioned as well. In Patent Document 2, there is a description that only CGP-12,177A has a relaxation action to bladder as a compound having a selective stimulating action to a.beta..sub.3-adrenaline receptor. However, as compared with CGP-12,177A, the active ingredient of the present invention has far stronger relaxation action for bladder. In addition, in Patent Document 2, there is no description for in vivo tests showingthe usefulness for the treatment of overactive bladder such as "rat rhythmic bladder contraction measurement test" and "urination function measurement test on cyclophosphamide-induced overactive bladder model rat".

Further, use for overactive bladder is not mentioned in Patent Documents 3 to 5 as well. Compounds mentioned in Patent Documents 3 to 5 and the active ingredient of the present invention are different in their fundamental structures in suchrespects that the compounds mentioned in the documents always have a phenol ring but have no thiazole ring and also have no amide bond. In addition, in Patent Documents 3 to 5, there is no description for in vivo tests showing the usefulness for thetreatment of over active bladder such as "rat rhythmic bladder contraction measurement test" and "urination function measurement test on cyclophosphamide-induced overactive bladder model rat".

The present invention will now be illustrated in detail as hereunder.

In the present invention, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or a salt thereof is an active ingredient. The characteristic feature of the present invention is that the active ingredientof the present invention has been found to be useful as a remedy for overactive bladder which is a new use.

It is particularly preferred that the active ingredient of the present invention is a free substance having no salt. However, it may form a salt with an acid and examples of the salt are acid addition salts with a mineral acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid and an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. The active ingredient of the present invention having a salt may be easily manufactured from a free substance by a commonsalt-forming reaction. The active ingredient of the present invention further includes hydrate, solvate and polymorphism. The active ingredient of the present invention still further includes pharmacologically acceptable prodrug. With regard to agroup for forming the prodrug, that mentioned in Prog. Med. 5, 2157-2161 (1985) and "Iyakuhin no Kaihatsu" (Development of Drugs) (Hirokawa Shoten, 1990), volume 7, Molecule Design, 163-198 may be exemplified.

The drug containing the active ingredient of the present invention may be in any of forms of oral administration by tablets, pills, capsules, granules, diluted powder, etc. and parenteral administration by inhalant, etc. As to a solidcomposition for oral administration, tablets, diluted powder, granules, etc. are used. In the solid composition as such, one or more active ingredient(s) is/are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and magnesium metasilicate aluminate. The composition may contain an inert additive such as lubricant (e.g., magnesium stearate), disintegrating agent (e.g., carboxymethyl starchsodium), solubilizing agent, etc. by a common method. Tablets and pills may, if necessary, be coated with sugar coat or with an intragastric or enteric coating agent. Dose may be appropriately decided for each case taking symptom, age and sex of thesubject to be administered, etc. into consideration. Usually, it is about 0.01 mg/kg to 100 mg/kg per day for an adult in the case of oral administration and is administered either at one time or by dividing into two to four.

The active ingredient of the present invention is able to be easily manufactured by a method mentioned in Patent Document 1 but, since method for the manufacture of a free substance which is preferred as the active ingredient of the presentinvention is not specifically mentioned therein, such a manufacturing method is shown in Manufacturing Examples. Route for the manufacture is illustrated as follows.

##STR00006##

MANUFACTURING EXAMPLES

Manufacturing Method for the Active Ingredient of the Present Invention

Step 1

To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 liters of N, N-dimethylformamide were added 3.93 kg of hydroxybenztriazole and 5.58 kg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) followed by stirring at about room temperature for 2 hours. EDC (0.28 kg) was further added thereto and the mixture was stirred at about room temperature throughout one night. Thereaction solution was diluted with 110 liters of water and extracted with ethyl acetate (60 liters, 30 liters). The organic layer was successively washed with 60 liters of 1M aqueous hydrochloric acid, 60 liters of 20% aqueous solution of potassiumcarbonate and water (60 liters, 60 liters) and concentrated in vacuo at 10 to 19.degree. C. The residue was dissolved in 35 liters of toluene with heating at 87.degree. C., cooled and stirred at 20.degree. C. throughout one night. The resultingcrystals were filtered and washed with 10 liters of toluene. This was dried in vacuo to give 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as light yellow crystals.

.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm)=2.87 (2H, t, J=7.2 Hz), 3.30-3.46 (2H, m), 4.85 (1H, d, J=4.8 Hz), 6.12 (1H, d, J=4.8 Hz), 7.20-7.33 (5H, m), 7.40 (2H, d, J=8.0 Hz), 8.04-8.12 (3H, m). FAB-MS m/z: 301 (M+H).sup.+.

Step 2

A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 23 liters of 1,3-dimethyl-2-imidazolidinone and 23 liters of tetrahydrofuran was cooled at -18.degree. C. and 49.4 kg of 1M boran-tetrahydrofuran solution wasdropped there into at not higher than -7.degree. C. After that, temperature of the mixture was raised to 70.degree. C. followed by stirring for 5 hours. The reaction mixture was cooled at -12.degree. C. and 2.9 kg of methanol and 5.9 kg ofconcentrated hydrochloric acid were added thereto at not higher than 5.degree. C. After stirring at 68.degree. C. for 1 hour, the mixture was concentrated in vacuo until the amount became 50 liters. A 30% aqueous solution (60 kg) of K.sub.2CO.sub.3and 6 liters of water were added thereto followed by extracting with 75 liters of ethyl acetate. The organic layer was washed with 75 liters of water and concentrated in vacuo. Isopropanol (75 liters) was added to the residue, the mixture was dissolvedat 40.degree. C. and 2.46 kg of concentrated hydrochloric acid was added to crystallize followed by stirring at 23.degree. C. throughout one night. The crystals were filtered and washed with 38 liters of isopropanol. They were dried in vacuo to give7.29 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride.

.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm)=3.00-3.08 (1H, m), 3.15-3.30 (5H, m), 5.00-5.05 (1H, m), 6.23 (1H, d, J=4.0 Hz), 7.29-7.35 (1H, m), 7.36-7.43 (4H. m), 7.57 (2H, d, J=8.4 Hz), 8.21 (2H, d, J=8.4 Hz), 9.12 (2H, br). FAB-MSm/z: 287 (M+H).sup.+.

Step 3

A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 110 liters of methanol and 1.20 kg of wet 10% palladium-carbon (wetting rate: 54.2%) was stirred in a hydrogen atmosphere until absorption ofhydrogen stopped. The reaction solution was filtered and the filtrate was concentrated in vacuo. Methanol (40 liters) was added to the residue to dissolve at 40.degree. C. and crystallization was conducted by addition of 220 liters of diisopropylether thereto followed by stirring at 20.degree. C. throughout one night. The crystals were filtered and washed with 30 liters of diisopropyl ether. They were dried in vacuo to give 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanolmonohydrochloride.

.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm)=2.76-2.90 (2H, m), 2.95-3.16 (4H, m), 4.95-5.11 (3H, m), 6.20 (1H, d, J=4.0 Hz), 6.53 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.28-7.43 (5H, m), 8.97 (1H, br), 9.29 (1H, br). FAB-MS m/z: 257(M+H).sup.+.

Step 4

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) (5.76 g) was added to a mixture of 8.00 g of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 4.32 g of 2-aminothiazol-4-yl acetic acid, 2.64 g ofconcentrated hydrochloric acid and 120 ml of water at room temperature followed by stirring for 1 hour. A mixed solution of 2.40 g of sodium hydroxide and 40 ml of water was dropped into the reaction solution to crystallize. The resulting crystals werefiltered, washed with water and dried in vacuo to give 9.93 g of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]- acetic acid anilide (hereinafter, referred to as "compound A").

.sup.1H-NMR (DMSO-d.sub.6, 500 MHz) .delta. (ppm)=1.60 (1H, s), 2.59-2.66 (4H, m), 2.68-2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J=8.5 Hz), 7.19-7.23 (1H, m), 7.27-7.33 (4H, m), 7.49(2H, d, J=8.5 Hz), 9.99 (1H, s). FAB-MS m/z: 397 (M+H).sup.+.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be specifically illustrated by way of the following Examples but the present invention is not limited to the content thereof.

Example 1

Isolated Rat Bladder Smooth Muscle Relaxation Test

Test Method

The test was conducted by referring to The Journal of Urology, 1999, volume 161, page 680.

Male rats of Wistar strain of 10 to 11 weeks age were sacrificed by depletion, whole bladder was isolated by laparotomy and bladder sections each being in a size of about 3.times.10 mm were prepared in a nutrient solution which was welloxygenated with 95% O.sub.2 and 5% CO.sub.2 (Krebs-Henseleit solution (118.4 mM NaCl, 4.7 mM KCl, 1.2 mM KH.sub.2PO.sub.4; 1.2 mM MgSO.sub.4, 2.5 mM CaCl.sub.2, 25.0 mM NaHCO.sub.3 and 11.1 mM glucose)). The section was hung in a Magnus tube in which anutrient solution (Krebs-Henseleit solution) of 37.degree. C. into which 95% O.sub.2 and 5% CO.sub.2 were aerated, stabilized for 30 to 60 minutes with a load of 1 g and 10.sup.-6 M carbachol (CCh) or 40 mM potassium chloride (KCl) was repeatedlyapplied thereto whereupon it was confirmed that reactivity to CCh or KCl became almost constant. After contraction by 10.sup.-6 M CCh or 40 mM KCl was induced and the generated tension was stabilized, a test drug (compound A or CGP-12,177A) wascumulatively administered in 10-fold ratio with intervals of about 10 minutes and the relaxation reaction was observed. After completion of observation of relaxation reaction at maximum concentration of the test drug, 10.sup.-4 M papaverine was added toinduce the maximum relaxation and a relaxation rate was calculated where the relaxation reaction was defined as 100%.

Results

As a result of the above test, the compound A which is the active ingredient of the present invention showed a strong relaxation action in antagonism test to contraction by carbachol and antagonism test to contraction by potassium chloride in anisolated rat bladder smooth muscle relaxation test. In addition, the compound A showed a significantly strong relaxation action as compared with CGP-12,177A (control compound).

Relaxation rates to drug concentration of the compound A which is the active ingredient of the present invention and the control compound are shown in FIG. 1 (antagonism test to contraction by carbachol) and FIG. 2 (antagonism test tocontraction by potassium chloride), respectively. Further, EC.sub.50 and maximum relaxation rate of the test drug in the antagonism test to contraction by carbachol are shown in Table 1 while concentration comparison of the compound A expressing themaximum relaxation rate of CGP-12,177A is shown in Table 2. The compound A showed an action strength of 270-fold as compared with the CGP-12,177A (control compound). Similarly, EC.sub.50 and maximum relaxation rate of the test drug in the antagonismtest to contraction by potassium chloride are shown in Table 3 while concentration comparison of the compound A expressing the maximum relaxation rate of CGP-12,177A is shown in Table 4. The compound A showed an action strength of 383-fold as comparedwith the CGP-12,177A (control compound).

TABLE-US-00001 TABLE 1 EC.sub.50 and maximum relaxation rate of the test drug in the antagonism test to contraction by carbachol Test Drug EC.sub.50 (M) Maximum Relaxation Rate (%) Compound A 5.2 .times. 10.sup.-6 94.0 (Active Ingredient of thePresent Invention) CGP-12, 177A >10.sup.-4 15.7 (Control Compound)

TABLE-US-00002 TABLE 2 Concentration comparison of the compound A expressing the maximum relaxation rate of CGP-12, 177A in antagonism test to contraction by carbachol Comparison of Action Test Drug Concentration (M) Strength* Compound A 3.7.times. 10.sup.-7 270 (Active Ingredient of the Present Invention) CGP-12, 177A 10.sup.-4 1 (Control Compound) *Compared in the concentration where the compound showed a relaxation rate of 15.7%

TABLE-US-00003 TABLE 3 EC.sub.50 and maximum relaxation rate of the test drug in the antagonism test to contraction by potassium chloride Test Drug EC.sub.50 (M) Maximum Relaxation Rate (%) Compound A 1.1 .times. 10.sup.-5 69.1 (ActiveIngredient of the Present Invention) CGP-12, 177A >10.sup.-4 17.4 (Control Compound)

TABLE-US-00004 TABLE 4 Concentration comparison of the compound A expressing the maximum relaxation rate of CGP-12, 177A in antagonism test to contraction by potassium chloride Comparison of Action Test Drug Concentration (M) Strength* CompoundA 2.6 .times. 10.sup.-7 383 (Active Ingredient of the Present Invention) CGP-12, 177A 10.sup.-4 1 (Control Compound) *Compared in the concentration where the compound showed a relaxation rate of 17.4%

Example 2

Rat Rhythmic Bladder Contraction Measurement Test

Test Method

The test was conducted by referring to European Journal of Pharmacology, 2000, volume 407, page 175.

1. Measuring Method

Female rats (225 to 290 g) of Wistar strain was used for the test. Under anesthetization with urethane, right and left ureters were ligated and cut and, after that, a polyethylene cannula was inserted from external urinary meatus and fixed. One end of the fixed cannula was connected to a pressure transducer via a three-way cock and pressure in the bladder was measured. Another end thereof was connected to a syringe pump and a physiological saline solution was continuously infused at aconstant rate into bladder whereupon rhythmic bladder contraction was induced. The continuous infusion of a physiological saline solution was stopped after a rhythmic bladder contraction was noted. After the rhythmic bladder contraction was stabilized,drug or vehicle was administered from a catheter for administration of drug inserted into femoral vein.

2. Drug

The compound A was intravenously administered in increased doses where the ratio was 3 (0.03, 0.1, 0.3, 1 and 3 mg/kg). A group to which vehicle was administered was used as a control group.

3. Evaluated Items and Statistical Analysis

Parameters for evaluation were number of times and contraction pressure of bladder contraction during 10 minutes from 5 to 15 minutes after the administration of the drug and each group was conducted in n=5. The result is shown in terms of meanvalue .+-. standard error and Student t-test was conducted for comparison between the two groups.

Results

By intravenous administration of the compound A, contraction frequency of rhythmic bladder contraction decreased on a dose-dependent manner (FIG. 3). An action of decreasing the contraction frequency by intravenous injection (i.v.) of 3 mg/kgof the compound A was significant as compared with the control group. On the other hand, the compound A did not affect the contraction pressure until intravenous administration of 3 mg/kg (FIG. 4). The fact of no influence on the contraction pressureis a preferred property from the viewpoint that urinary retention is not induced or that residual urine is not resulted upon urination.

A suppressive effect for contraction frequency by the compound A is presumed to be due to an increase in bladder volume by stimulation of the compound A for a .beta..sub.3 receptor existing in the bladder. It has been believed that an increasein functional bladder volume showing the urine volume which is able to be stored in the bladder is clinically useful for the treatment of patients suffering from overactive bladder and, therefore, the compound A is believed to be clinically effective asa remedy for overactive bladder.

Example 3

Test for Measurement of Urination Function of Model Rat Suffering from Overactive Bladder Induced by Cyclophosphamide

Overactive bladder model rats induced by cyclophosphamide were prepared by referring to British Journal of Pharmacology, 2000, volume 130, page 331 and the following test was conducted.

Test Method

1. Measuring Method

Female rats (220 to 230 g) of Wistar strain were used for the test. Under anesthetization with pentobarbital sodium, a catheter for infusion of physiological saline solution and for measurement of pressure in bladder was inserted into bladderfrom the top of the bladder and fixed while a catheter for administration of a drug was inserted into carotid vein and fixed. Cyclophosphamide (CYP) was administered into abdominal cavity and, after being recovered, the rats were returned to a feedingcage. On the next day of the operation, one end of the catheter inserted into bladder of the rat was connected to a syringe pump via a three-way cock and a physiological saline solution was continuously infused whereby micturition reflex was induced. Another end was connected to a pressure transducer and pressure in the bladder was measured. After the micturition reflex was stabilized, 1 mg/kg of the compound A was administered from a catheter for administration of drug which was inserted intocarotid vein.

2. Evaluated Items and Statistical Analysis

Parameter for the evaluation was an average interval for urination from administration of the drug until 30 minutes thereafter. The result was shown in terms of an average urination interval after administration of the drug to the averageurination interval before administration of the drug where an average urination interval during 30 minutes before administration of the drug was defined 100% and was shown in a mean value of n=3.

Results

As a result of intravenous administration of the compound A (1 mg/kg), micturition interval of overactive bladder model rats induced by cyclophosphamide was elongated to an extent of 17.3% (FIG. 5). From such a fact, the compound A whichprolongs the micturition interval of the present model rats is believed to be clinically effective as a remedy for overactive bladder.

Thus, the active ingredient of the present invention shows a strong bladder relaxation action in "isolated rat bladder smooth muscle relaxation test", decreases the contraction frequency of rhythmic bladder contraction on a dose-depending mannerin "rat rhythmic bladder contraction measurement test" and prolongs the micturition interval in "micturition function measurement test on cyclophosphamide-induced overactive bladder model rat" whereby it is clinically useful as a remedy for overactivebladder. In addition to overactive bladder as a result of benign prostatic hyperplasia, it is also able to be used as a remedy for overactive bladder accompanied with urinary urgency, urinary incontinence and pollakiuria.

Example 4

Formulation Example

Formulation Example for Oral Agent

TABLE-US-00005 TABLE 5 Composition Tablet Active ingredient of the present invention 100.0 mg Lactose 199.5 mg Corn starch 40.0 mg Hydroxypropyl cellulose 9.0 mg Magnesium stearate 1.5 mg Subtotal 350 mg Coat Hydroxypropyl methyl cellulose 29108.7 mg Polyethylene glycol 6000 1.2 mg Titanium oxide 4.8 mg Talc 0.3 mg Subtotal 15 mg Grand total 365 mg

100-mg Tablet

The active ingredient of the present invention (200.0 g) and 399.0 g of lactose were mixed in a polyethylene bag. The mixture was mixed and disintegrated in a sample mill (manufactured by Hosokawa Micron). The disintegrated mixture (450.0 g)and 60.1 g of corn starch were uniformly mixed in a fluidized granulation coating apparatus (manufactured by Ogawara Seisakusho). A 10% hydroxypropyl cellulose solution (192 g) was sprayed thereon to granulate. After being dried, the above was passedthrough a sieve of 20 meshes, 2.3 g of magnesium stearate was added thereto and the mixture was made into tablets each comprising 350 mg by a rotary tabletting machine (manufactured by Hata Tekkosho) using a pounder of c/9.0 mm.times.10.8 R. The tabletswere sprayed with 150 g of a coating solution containing 8.7 g of hydroxypropyl methyl cellulose, 1.2 g of polyethylene glycol 6000, 4.8 g of titanium oxide and 0.3 g of talc in a coating apparatus (manufactured by Freund Sangyo) to give film-coatedtablets each being coated with 15 mg.

INDUSTRIAL APPLICABILITY

As mentioned hereinabove, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or a salt thereof which is an active ingredient of the present invention showed a significantly strong relaxation action ascompared with the control compound in "isolated rat bladder smooth muscle relaxation test". Further, it decreased the contraction frequency of rhythmic bladder contraction on a dose-dependent manner in "rat rhythmic bladder contraction measurementtest". Still further, it prolonged the micturition interval of cyclophosphamide-induced overactive bladder model rat in "micturition function measurement test on cyclophosphamide-induced overactive bladder model rat".

Accordingly, (R)-2-(2-Aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]a- cetic acid anilide or a salt thereof which is an active ingredient of the present invention is able to be used as a remedy for overactive bladder. Inaddition to overactive bladder as a result of benign prostatic hyperplasia, it is also able to be used as a remedy for overactive bladder accompanied with urinary urgency, urinary incontinence and pollakiuria.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Effects of the compound A and the control compound to isolated rat bladder smooth muscle relaxation test (antagonism test to contraction by carbachol)

FIG. 2: Effects of the compound A and the control compound to isolated rat bladder smooth muscle relaxation test (antagonism test to contraction by potassium chloride)

FIG. 3: Effect of the compound A to rat rhythmic bladder contraction (effect to contraction frequency (.star-solid.: p<0.05))

FIG. 4: Effect of the compound A to rat rhythmic bladder contraction (effect to contraction pressure)

FIG. 5: Effect of the compound A to micturition function of cyclophosphamide-induced overactive bladder model rat (showing the urination interval after administration of a drug where the urination interval before administration of the drug wasdefined as 100%)

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