JPH02184667A - N-n'-di-substituted piperazyl derivative and dysuria-improving agent containing the same - Google Patents

Abstract

NEW MATERIAL:N,N'-Di-substituted piperazyl derivative expressed by formula I (A is >CH2 or >C=O; B is >C=O or >SO2; R<1> is H or halogen; R<2> is 1-3C lower alkyl; n is 2-4). EXAMPLE:2-[4-(2-Methoxyphenyl)piperazinoethyl]phthalimidine. USE:The above-mentioned derivative expressed by formula I has excellent alpha1- blocking action and is useful as a remedy for dysuria disorder. The derivative expressed by formula I is used in treatment for dysuria disorder by tension of musculus sphincter urethrae or improvement for closure of urinary tract by prostatomegaly and is effective thereto and has low toxicity. PREPARATION:For example, as shown in the reaction formula, a compound expressed by formula II (Z is halogen, alkyl, etc.) or inorganic salt thereof is subjected to condensation reaction with a compound expressed by formula III, preferably in a solvent such as dichloroethane at 20-100 deg.C to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel compound N,N'-disubstituted piperazyl derivative and an agent for improving urinary dysfunction containing the same as an active ingredient.

[Conventional technology]

Dysuria is caused by tension in the sympathetic nerves in the bladder neck.
It is a disease in which the urethra does not open and urination is not possible, and is especially common in the elderly. Kleeman (J, Llrol
.

104, 549.1970) revealed the α-receptor for bladder internal sphincter function and reported the effectiveness of reserpine (a catecholamine depleting agent) for patients with functional bladder neck passage disorder caused by neurogenic bladder. ing. Later, the α-blocker phenoxybenzamine was reported to be effective (rane and
01sson J, tlrol, village, 653.197
3>.

Furthermore, it was found that only C1-adrenergic receptors are involved in contraction in the human bladder neck (unis
awa et al, J, Llrol, 134,
396.1985), it was envisioned that α1 blockers were agents that could selectively treat functional bladder neck passage disorders.

[Problem to be solved by the invention]

Reserpine and phenoxybenzamine are effective for patients who have difficulty urinating due to tension in the sympathetic nerves present in the bladder neck, but they pose problems such as central effects and side effects such as release of catecholamines.

Since it has become clear that this disease is expressed through α,-adrenergic receptors, α, blockers such as prazosin and bunazosin have been used to treat dysuria with fewer side effects. . However, since these drugs also have a hypotensive effect, there is a desire for a compound that is highly selective to the urethra and does not have a hypotensive effect.

[Means to solve the problem]

The present inventors have developed a new general formula (1 The present invention was completed based on the discovery that the compound represented by () has an excellent effect as a therapeutic agent for dysuria.

The present invention is based on the general formula (1), where the formula is >CH2 or >C=0 group, B is >C=0 or >SO2 group I R' is a hydrogen atom or a halogen atom R
2 is a C3 to C5 alkyl group, n is an integer of 2 to 4, and an N,N'-disubstituted piperazine derivative or a pharmacologically acceptable salt thereof is used as an active ingredient to improve urinary dysfunction. It is a drug.

Examples of pharmacologically acceptable salts of the present compound include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, acetic acid,
Organic acids such as propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, benzoic acid, salicylic acid, methanesulfonic acid, aspartic acid,
Examples include salts with amino acids such as glutamic acid.

Examples of the compound represented by general formula (1) which is an active ingredient of the present invention include the following, but the present invention is not limited thereto.

2- C4-(2-methoxyphenyl)piperazinoethyl]phthalimidine 2- (4-(2-methoxyphenyl)piperazinopropyl)phthalimidine 2- (4-(2-ethoxyphenyl)piperazinoethyl)phthalimidine 2- (4- (2-Methoxyphenyl)piperazinopropyl]phthalimide 2- (4-(2-methoxyphenyl)piperazinopropyl)-4-fluorophthalimide 2- (4-(2-methoxyphenyl)biperazinopropyl) Pill]-5-chlorophthalimide 2- (4-(2-methoxyphenyl)piperazinoethylcy5-chlorophthalimidine 2- (4
-(2-methoxyphenyl)piperazinoethyl)-5-
Chlorphthalimidine 2- (1-(2-methoxyphenyl)piperazinopropyl)benzoic sulfimide Symptoms that can be treated as urinary disorders include dysuria, $1 urine, and urinary incontinence. The drug of the present invention is mainly intended for the treatment of dysuria caused by tension in the urethral sphincter, etc., or for the improvement of urinary tract obstruction caused by prostatic hyperplasia.

The compound represented by general formula (I), which is the active ingredient of the present invention, can be synthesized by any method suitable for forming and introducing its skeleton and substituents.

For example, a compound represented by the following formula (■) (wherein R1, Δ, B, and n have the same meanings as above, and Z represents a halogen atom, an alkyl or an allylsulfonyloxy group), an inorganic salt thereof, or an organic It can be synthesized by condensing a salt with a compound represented by formula (■) (wherein R2 has the same meaning as above).

The halogen atom of the compound used in this reaction is chlorine,
Bromine, iodine, etc. can be used, and as the alkyl or allylsulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. can be used. Moreover, this reaction can be performed in the presence of a base. As a base, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium hydroxide, potassium hydroxide, etc., and organic bases such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, etc. can be used.

The condensation of the compound represented by formula (I[) and the compound represented by formula (I[I)] is carried out in an inorganic or organic solvent, preferably dichloromethane, dichloroethane, or ethanol.

Dimethylformamide, dimethyl sulfoxide.

This can be carried out in dioxane, tetrahydrofuran, etc. This condensation reaction is carried out in a temperature range of 20 to 100 °C.
The reaction is completed for 4 hours. After completion of the reaction, the compound represented by formula (1) can be purified by an appropriate method such as extraction, crystallization, precipitation, silica gel chromatography, etc., and if necessary, the compound represented by formula (1) can be obtained as an addition salt with an acid.

The compound represented by the general formula (1) of the present invention has been found to have excellent α,-blocking action and low toxicity according to pharmacological and toxicological tests, and is therefore a useful compound for the treatment of dysuria.

Next, a test example showing the α1-blocking effect of the compound which is the active ingredient of the present invention will be shown.

Example 1. α1-adrenergic receptor blocking effect test method in guinea pig excised urethra specimen: The bladder and urethra were removed together from the guinea pig.
The urethra was cut and then incised to prepare a urethral smooth muscle (internal sphincter) specimen. This was suspended in a 15 ml Magnus tube filled with Taleb-Henseleit's solution. During the exam, 95%
0. A mixed gas of and 5% CO□ was continuously bubbled through. Contractions were recorded on a polygraph using an isotonic transgeniser (manufactured by Nihon Kohden). After pre-administering the test compound, noradrenaline is cumulatively administered, a dose-response curve is obtained, and the panning is determined based on the degree of shift in the dose-response curve.
van Rossum's method (^rch,
1ntern.

Pharmacodyn 143. 299.196
3), pAz was determined and the strength of action was compared. The test results are shown in Table 1.

Example 21 α,-Adrenergic receptor blocking effect in guinea pig thoracic aorta specimen Test method: The thoracic aorta was removed from a guinea pig and a spiral specimen was prepared. This is 15mj filled with Taleb-Henseleit's liquid! suspended in the Magnus tube. 95%0 during the exam. A mixed gas of 5% C02 and 5% CO2 was continuously bubbled through. Recording of contraction and calculation of pAz were performed in the same manner as in Test Example 1.

The test results are shown in Table 1.

Table 1 *Values corresponding to the dissociation constants of antagonists Test compounds 1 to 5 are compounds of the present invention, compound 1 is 2-
(4-(2-methoxyphenyl)piperazinoethyl)
Phthalimidine, Compound 2 is 2-[4-(2-methoxyphenyl)piperazinopropyl]phthalimide, Compound 3 is 2-(4-(2-methoxyphenyl)piperazinopropyl)-4-fluorophthalimide, Compound 4 is 2-
(4-(2-methoxyphenyl)piperazinoethyl)
-5-fluorophthalimidine, compound 5 is 2-[1-(
2-methoxyphenyl)piperazinoprobyl]0-benzoic sulfimide. Note that prazosin is a known α1 blocker and was used as a control in the same test.

Toxicity test Compound 4 subjected to the above test was dissolved in distilled water for injection.
00 mg/kg to 4 male acty mice (28
~29g) was orally administered and observed for one week.

The animals survived on the gold side for one week without any significant changes.

Although the compound of the present invention had a C1-adrenergic receptor blocking effect in the vascular arterial system, which reflects its antihypertensive effect, was lower than that of the control prazosin, it showed an antagonistic effect equal to or greater than that of prazosin in urethral specimens; This clearly demonstrates the effectiveness of the compound of the present invention as an agent for improving dysuria.

General formula (1) which is the active ingredient of the urinary disorder improving agent of the present invention
The compound represented by or a pharmacologically acceptable salt thereof can be used clinically by intravenous or oral administration. As mentioned above, it has an excellent α,-adrenergic receptor blocking effect and suppresses urethral contraction caused by sympathetic nervous tension, so it is effective for dysuria.

Further, the compound represented by formula (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and the dosage is determined depending on the degree of the disease, the age of the patient, Although it varies depending on body weight and condition, oral dosage is usually 0.1 to 100 a+g/kg per day, preferably 0.
．． 5 to 50 mg/kg is appropriate, and parenteral doses are usually 0.001 to 10 mg/kg per day.

Preferably, 0.05 to 5 mg/kg is appropriate.

The urinary disorder improving agent of the present invention can be used by mixing the compound represented by formula (1) or a pharmacologically acceptable salt thereof with an excipient suitable for oral or parenteral administration. As such excipients, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid, and any other commonly used excipients can be used. These pharmaceutical preparations are tablets and emulsions.

Solid preparations such as capsules and engravings, solutions, and suspensions.

Liquid preparations such as emulsions may also be used, and these preparations may be sterilized and may further contain auxiliary agents such as stabilizers, wetting agents, and emulsifiers.

Examples of the present invention and the active ingredient of the general formula (I
) The present invention will be further explained in detail by giving an example of manufacturing a compound represented by the following formula. However, the invention is not limited to this example.

〔Example〕

1-(2-methoxyphenyl)piperazine 96 mg (0
,50mmo i'), 2-(2-bromoethyl)phthalimidine 120 mg (0,50mmoJ), anhydrous sodium carbonate 105 mg (1,00mmo R
) was added to dimethylformamide 4-16 at room temperature.
Stir for an hour. After the reaction is completed, the reaction solution is diluted with 20 mA' of water, extracted with ethyl acetate, washed with water, dried, and then ethyl acetate is distilled off. The residue was subjected to silica gel column chromatography [
Elution solvent: chloroform-ethanol (20:1)) to obtain 129 ff1g (yield 73%) of the title compound as an oil.

N M R (CDCl2) δ, 2.74 (m, 6
H), 3.09 (br, 4H).

3,80 (t, 2N), 3.87 (s, 3H),
4.55 (s, 2H), 6.85 ~ 7.10 (
m, 4H), 7.42 to 7.60 (+n, 3H), 7
．． 87(d, IH).

1-(2-methoxyphenyl)piperazine 96a+g (0.50 mmoJ) in dimethylformamide 4,
2(3-bromopropyl)phthalimidine 127 m
g (0,50 mmol>, anhydrous sodium carbonate 105
mg (1,00 mmol) was added and stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was diluted with 20 mm of water, extracted with ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography [elution Solvent: Chloroform-methanol (20:l)) to purify the title compound 1.
42 mg (yield 78%) of an oil was obtained.

N M R (CDC1,) δ, 1.94 (m,
2H), 2.52 (m, 2H).

2,67 (br, LH), 3.08 (br,
2H), 3.71 (m, 2H), 3.87.
(s, 3H).

4, 42 (s, 2N), 6.8-7.1 (m, 4
tl), 7.4-7.65 (m, 311).

7.85(d,1)1).

192 mg of 1-(2-methoxyphenyl)piperazine (1,00 mmol) in dimethylformamide
2-(3-bromopropyl)phthalimide 268 a
+g (1,00 mmo 1 ), anhydrous sodium carbonate 2
Add 10 mg (2,00 mm) and cool at room temperature for 16 minutes.
Stir for an hour. The reaction solution was diluted with 30 rnl of water, extracted with ethyl acetate, and washed with water.

Concentrate after drying. The residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (200
: 1)) to obtain 350 mg (yield 92%) of the title compound as an oil.

NMR (CDCI3) δ, 1.92
(quin, 2H).

2,50 (t, 2t() , 2.59 (br,
4H), 3.93 (br, 4N).

3.80 (t, 2H), 3.83 (s, 3H), 6.
75-7.1 (m, 4H).

7, TO (dd, 2H), 7.86 (dd,
28).

1-(2-methoxyphenyl)piperazine 115 (0,60 mmo 1
).

86 mg (0.30 mmol) of 2-(3-bromopropyl)-4-fluorophthalimide and 53 mg (0.50 mmol) of anhydrous sodium carbonate are added, and the mixture is stirred at room temperature for 16 hours.

Add the reaction solution to 30ml of water! The mixture was diluted with water, extracted with ethyl acetate, washed with water, dried, and condensed with -a. The residue was purified by silica gel column chromatography [elution solvent: chloroform-methanol (
200:1)) to obtain 69 mg (yield 58%) of the title compound as an oil.

NMR (CDCI, ) δ, 1.83 (Qu
in, 2H).

2,41(t, 2H), 2.52(br, 4H)
, 2.84 (br, 4H).

3,74 (t, 3H), 3.77 (s, 3H),
6.7-6.95 (m, 4H).

7, 28 (dd, IH), 7.55-7.70
(m, 2H).

Luimidine (Step 1) 2.49 g of 5-fluorophthalic anhydride in 50-toluene
(15,0 mmol), ethanolamine 916
mg (15.0 ml 1 oi) is suspended and refluxed for 24 hours while continuously removing water. After cooling at room temperature, the solvent was distilled off under reduced pressure, the crystalline residue was collected, and 2.89 g of 2-(2-hydroxyethyl)5-fluorophthalimide (yield: 9
2%).

(Step 2) 1.50 g (7,2
0 mmo Il), 4.5 g of zinc powder was added, and 10
Reflux with stirring for an hour. After cooling to room temperature, the solids are filtered off and the filtrate is concentrated under reduced pressure. The residue was made alkaline with IN sodium hydroxide solution, extracted with ethyl acetate, washed with water,
After drying, the solvent is distilled off. The residue was purified by silica gel column chromatography [Elution solvent: ethyl acetate-hexane (1:
1) Purified by ), 2-(2-acetoxyethyl)-
1.30 g (yield 76%) of 5-fluorophthalimidine crystals were obtained.

NMR (CDC13) δ, 2.07 (s, 3H)
, 3.86 (m, 2H).

4, 34 (m, 2H), 4.48 (s, 2H),
7.17 (m, 2H).

7,85 (m, 1) 1) (Step 3) 2-(2-acetoxyethyl)-5- obtained in Step 2
Fluorophthalimidine 1.30g (5.49mmol)
is dissolved in 30 mf of methanol and 10 mf of IN sodium hydroxide solution and heated at 40°C for 3 hours. After cooling, concentrate under reduced pressure and extract the precipitated oil with chloroform. The organic layer was washed with saturated brine, dried, and condensed to obtain 931 mg of pure alcohol (yield: 87%).

This alcohol body 390 mg (2,00 mmol
) was dissolved in pyridine 3rR1, and 419 mg (2.2 mmo
After stirring for 30 minutes at θ°C, leave it in the refrigerator for 4 days. After cooling with water and acidifying with IN hydrochloric acid,
Extract with ethyl acetate, wash with water, dry, and then evaporate the solvent. The residue was subjected to silica gel column chromatography [elution solvent:
The mixture was purified with chloroform-methanol (200:1) to obtain 381 mg (yield: 55%) of 2-(2-tosyloxyethyl)-5-fluorophthalimidine.

NMR (CDC1,) δ, 2.37 (S, :
E), 3.85 (m, 28).

4.30 (m, 2H), 4.43 (s, 2H),
7.0-7.3 (m, 4H).

7, 6~? , 8 (m, 3H) (Step 4) 2-(2-)yloxyethyl)-5 obtained in Step 3
-Florophthalimidine 105 mg (OJOn+n+
o1), 115 mg (0.60 mmoi) of l-(2-methoxyphenyl)piperazine, and 64 g (0.60 mmoi) of anhydrous sodium carbonate were added to dimethylformamide, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with 20% water, extracted with ethyl acetate, washed with water, dried, and then the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography [Elution solvent: chloroform-methanol (1
00: 1)) to produce the title compound 88■ (yield 7).
9%) of an oil was obtained.

NMR (CDC13) δ. 2.67 (m, 6
H), 3.03 (br, 4H).

3, 75 (t, 2H), 3. 84 (s.
3H), 4. 49 (s, 2N).

6, 7-7. 2 (dd. 18), 7. 80
(dd. IH) <Step 1) Saccharin sodium 1.0Hg (4.87 mmo
i') suspended in 1,3-dibromopropane,
Heat at 140°C for 10 hours. After cooling, add 30% water to the reaction solution.
．． Add 40 mj' of ethyl acetate and separate the organic layer. Wash with water. After drying, concentrate under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: chloroform] to obtain 693 mg (yield 47%) of 2-(3-bromopropyl)0-benzoic sulfide as a solid.

NMR (CDCI+1) δ. 2.42
(Quin, 2H).

3, 51 (t. 2H), 3. 99(t, 2H
), 7. 8-7. 95 (m, 3H).

8, 06 (d. IH).

(Step 2) 304 mg (1.00 mmo) of 2-(3-bromopropyl)-benzoic sulfide obtained in Step 1
i') 1-(2-methoxyphenyl)piperazine 384
(2.00 mmol) and 159 g (1.5 mIIloJ) of sodium carbonate were added to dimethylformamide 5IR1 and stirred at room temperature for 16 hours. The reaction solution was diluted with 30 ml of water and extracted with ethyl acetate. Organic layer was washed with water, dried and concentrated, and the residue was subjected to silica gel column chromatography [elution solvent: toluene-ethyl acetate (4
:1)) to obtain the title compound (88 mg<yield 71%)
crystals were obtained.

N M R (CDCl2) δ, 2.07 (qu
in, 2H).

2, 55 (t, 2H), 2.67 (br, 4H
), 3. 07 (hr. 4H).

3, 86 (s. 3H), 3. 88 (t.
2H), 6. 8-7. 05 (m, 4
H).

7, 75-8. 1 (a. 41 ().

Example 2 - (4-(2-methoxyphenyl)piperazinoethyl)phthalimidine 10.0mg and lactose 86.8m
L Corn starch 37. Add On+g,
After stirring well, add polyvinylpyrrolidone5. A solution of On+g dissolved in purified water is added, kneaded, and granulated. After drying the obtained granules, magnesium stearate 1, 2
mg is added and compressed to obtain tablets.

〔Effect of the invention〕

The present invention is an agent for improving urinary dysfunction containing as an active ingredient a compound having a novel α1 blocking action that has a strong affinity for α1 receptors in the urethral region and has low toxicity. Therefore, this invention is extremely useful as a drug for treating patients with dysuria with few side effects.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, A is ■CH_2 or ■C=O group, B is ■C=O or ■SO_2 group, and R^1 is hydrogen atom or halogen atom,
R^2 is a lower alkyl group of C_1 to C_3, n is 2 to 4
An N,N'-disubstituted piperazyl derivative represented by the following integer: 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, A is ■CH_2 or ■C=O group, B is ■C=O or ■SO_2 group, R^1 is hydrogen atom or halogen atom,
R^2 is a lower alkyl group of C_1 to C_3, n is 2 to 4
An agent for improving urinary dysfunction characterized by containing as an active ingredient an N,N'-disubstituted piperazyl derivative represented by the following integer: or a pharmacologically acceptable salt thereof.