JPS629091B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to prostaglandin F ₂ 〓 (PGF ₂ 〓)
Concerning the use of similar compounds for diuresis. Prostaglandin is a prostanoic acid derivative represented by the following structural formula (). Various types of prostaglandins are known, and the type depends on the structure and substituents of the alicyclic ring. For example, the alicyclic ring of prostaglandin F is represented by the following structural formula (). Dotted lines in the foregoing structural formulas or in other structural formulas herein indicate that the attached group is behind the ring plane or in the α-configuration, in accordance with generally accepted nomenclature rules. , the thick line indicates that the group attached to it is in front of the ring plane, that is, the β-configuration, and the wavy line indicates that the group attached to it is α- or β-configuration.
Indicates that it is a placement. These compounds are subclassified according to the position of the double bond on the side chain at the 8th and 12th positions of the alicyclic ring. PG-1 compound has _{a trans-}
The PG-2 compound has a cis-double bond between _C5 and ^C6 and a trans-double bond between _C13 and _C14 ( _cis - ^Δ5 , trans- Δ
¹³ ). For example, PGF ₂ 〓 is represented by the following structural formula (). Prostaglandin is a fat-soluble substance that exists in very small amounts in each tissue that secretes prostaglandin into the living body of an animal, and generally has many pharmacological properties. For example, PGF ₂ 〓 has the effect of stimulating smooth muscle contraction, corpus luteum involution, and inhibiting egg implantation. It is known to be effective in expelling the placenta, improving fertilization in female mammals, regulating estrus, contraception, and normalizing menstruation. The present inventors have conducted extensive research to discover completely unknown superior pharmacological properties of PGF ₂ They discovered that it has an unknown activity, that is, a strong diuretic and urinary effect, and found that it has an excellent diuretic or urinary effect when administered to humans for diuresis or urination, thereby completing the present invention. According to the invention, the general formula () (In the formula, X is −(CH ₂ ) ₃ −, −CH=CH−CH ₂ −
or trans-CH ₂ -CH=CH-, R ¹ represents a hydrogen atom, a straight or branched alkyl group having 1 to 12 carbon atoms, or a non-toxic cation, R ² represents a hydrogen atom, trifluoromethyl Represents a group or a chlorine atom. ) A PGF ₂ 〓 analogous compound and its cyclodextrin clathrate exhibited strong diuretic and urinary activity in animal experiments, and did not show an increase in excreted potassium ions due to an increase in excreted urine volume. This suggests that the compound of the present invention is an excellent drug as a diuretic or urinary agent for humans without causing a decrease in potassium ions in the body. Furthermore, the compound of the present invention is very effective when administered to humans for the purpose of diuresis or urination, and at the same time exhibits almost no side effects such as diarrhea and vomiting that are commonly seen with prostaglandins, making it an excellent diuretic or urinary agent. It has been demonstrated that the drug is a highly effective drug. The results of the animal experiments are shown in the table.

【table】

【table】

【table】

[Table] Animal experiments were conducted using (1) normal male Wistar rats weighing 150 to 190 g and (2) spontaneously hypertensive male rats weighing 300 to 380 g. Dissolve in water (0.5:0.05:99.45), add 3.0ml per 100g of animal weight for (1), animal weight for (2).
2 ml per 100 g of each drug was orally administered, and the amounts of sodium ion and potassium ion excreted in the urine from administration to 3 hours after administration were measured. In addition, only the solvent containing no compound was similarly administered to the control group. In addition, the animals were fasted for 18 to 20 hours before the experiment (administration) and were kept under food and water deprivation conditions during the experiment (after administration). Examples of the compound of general formula () included in the present invention include 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranol-PGF ₂ 〓
and its methyl ester, 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ and its methyl ester, 16-(3-trifluoromethylphenoxy) enoxy)-17,18,19,20-tetranol- ^Δ3-
PGF ₂ 〓 and its methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranol-
PGF ₂ 〓 or its methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-
trans-Δ ² -PGF ₂ 〓 or its methyl ester, 16-(3-chlorophenoxy)-17, 18, 19,
20-tetranol- ^{Δ 3} -PGF ₂ 〓 or its methyl ester, 16-(3-chlorophenoxy)-17,
18,19,20-tetranor-trans- ^Δ3-
PGF ₂ 〓 or its methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-
cis-Δ ³ -PGF ₂ 〓 or its methyl ester,
16-phenoxy-17,18,19,20-tetranol-
PGF ₂ 〓 or its methyl ester, 16-phenoxy-17,18,19,20-tetranor-trans-Δ
² -PGF ₂ 〓 or its methyl ester, 16-phenoxy-17,18,19,20-tetranol- ^{Δ 3} -
PGF ₂ 〓 or its methyl ester, 16-phenoxy-17,18,19,20-tetranor-trans-Δ
³ -PGF ₂ 〓 or its methyl ester, 16-phenoxy-17,18,19,20-tetranor-cis-Δ
³ -PGF ₂ 〓 or its methyl ester, among which 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓 methyl ester is particularly preferred. preferable. An effective administration method for diuresis or urination for the treatment of hypertensive patients, edema patients, patients with bladder dysfunction, patients with prostatic hypertrophy, etc. is oral, rectal or parenteral administration, with a single dose of 1 μg to 1 mg. It is advisable to administer it once or several times. However, the exact dosage will depend on the patient's age, weight, symptoms, route of administration, and frequency of administration. Solid formulations for oral administration include tablets, pills, powders and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as semidigested starch, potato starch, alginic acid, mannite or lactose. The formulations may contain additives other than diluents in a conventional manner, such as lubricants such as magnesium stearate. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, supplemented with commonly used inert diluents such as water or liquid paraffin. include. In addition to an inert diluent, this preparation contains adjuvants,
These include, for example, wetting agents, suspending agents, sweetening agents, flavoring agents, aromatic agents, or preservatives. Also included as oral preparations are capsules of absorbable materials such as gelatin with or without one or more active substances and diluents or excipients. Solid preparations for rectal administration include suppositories, which consist of at least one inert base containing one or more active substances, such as cocoa butter, Macrogold, Uiteepsol, processed in a manner known per se. is included. Products for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
Non-aqueous solvents or suspending agents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through sterile filters, by incorporation with sterilizing agents, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in a sterile injection solvent immediately before use. The acute toxicity of the compounds of the present invention was determined by intravenous administration to mice, including 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF ₂ methyl ester, 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF methylphenoxy)-17,18,19,20-tetranor-trans- ^Δ2 _- PGF2
chlorophenoxy)-17,18,19,20-tetranor-PGF ₂ 〓methyl ester, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ 〓methyl Ester, 16-phenoxy-17,18,19,20-tetranol-PGF ₂
Methyl ester and 16-phenoxy-17, 18,
19,20-tetranor-trans-Δ ² -PGF ₂ 〓
The methyl ester LD ₅₀ was approximately 60 mg/Kg animal body weight, approximately 120 mg/Kg animal body weight, 8 mg/Kg animal body weight, 14 mg/Kg animal body weight, approximately 0.2 mg/Kg animal body weight, and 0.35 mg/Kg animal body weight, respectively. Compounds of general formula () are already known, and compounds where X represents -(CH ₂ ) ₃ - are described in JP-A No. 48-450, and compounds where X represents trans -CH ₂ CH=CH- Each can be manufactured by the method described in JP-A-52-25745. Also, if X is -
The compound representing CH=CHCH ₂ - is JP-A-52-
It can be produced by the method described in No. 111547. Next, the present invention will be explained in more detail with reference to the following examples. Example 1 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester 5ft, carboxymethylcellulose calcium dissolved in 5ml ethanol
0.2 g, silicon dioxide 20 mg, magnesium stearate 0.2 g, and 5 g of mannitrate were mixed and dried using a conventional method. After drying, mannite was added to make 10 g. After mixing well until homogeneous, the mixture was directly compressed into tablets using a mortar with a diameter of 6.5 mm using a conventional method. 100 tablets containing 50 μg of active substance in each tablet were obtained. Example 2 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ = Tablets containing 100 μg of active substance per tablet in the same manner as in Example 1 using 10 mg of methyl ester.
Got 100 tablets. Example 3 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ 70 mg of β-cyclodextrin clathrate of methyl ester [16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranol-
trans-Δ ² -PGF ₂ methyl ester content 5 mg], carboxymethyl cellulose calcium
Add 0.2 g, silicon dioxide 20 mg, magnesium stearate 0.2 g, and mannitrate to 10 g, mix well until homogeneous, and then make a diameter of 6.5 mm using the usual method.
100 tablets containing 50 μg of active substance in each tablet were obtained by direct compression using a mortar. Example 4 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
Using 140 mg of the β-cyclodextrin clathrate of PGF ₂ methyl ester, 100 tablets each containing 100 μg of the active substance were obtained in the same manner as in Example 3. Example 5 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ = 140 mg of β-cyclodextrin clathrate compound of methyl ester, 30 mg of silicon dioxide, 100 mg of magnesium stearate and half-digested starch were added to make 10 g, mixed well until homogeneous, and then milled using a mortar with a diameter of 6.5 mm using a conventional method. 100 Vatukar tablets containing 100 μg of active substance in each tablet were obtained by direct compression using the same method. Example 6 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ 〓 Add lactose to 140 mg of β-cyclodextrin clathrate compound of methyl ester to make 100 g, mix well until homogeneous, and then add it to one package using the usual method.
100 packets of powder containing 100 μg of active substance were obtained. Example 7 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ 70mg β-cyclodextrin clathrate of methyl ester, magnesium stearate
0.23 g and lactose were added to make 23 g, mixed well until homogeneous, and then filled into No. 3 gelatin capsules by a conventional method to obtain 100 capsules each containing 50 μg of active substance. Example 8 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
Using 140 mg of the β-cyclodextrin clathrate of PGF ₂ methyl ester, 100 capsules each containing 100 μg of the active substance were obtained in the same manner as in Example 7. Example 9 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
PGF ₂ = Methyl ester 5mg and citric acid fine powder
30mg of Uiteepsol S-52 dissolved at low temperature
Add to 80g, mix well and then use the usual method.
Filled into 0.9 ml containers, 100 suppositories containing 50 μg of active substance in each tablet were obtained. Example 10 16-(3-trifluoromethylphenoxy)-
17,18,19,20-tetranor-trans- ^Δ2-
Dissolve 14 mg of β-cyclodextrin clathrate compound of PGF ₂ methyl ester in 100 ml of distilled water for injection, sterilize the solution using a conventional method, and inject 1 ml into a 5 ml ampoule to obtain 10 μg of activity in each ampoule. Obtained 100 injections containing the substance. Example 11 Two capsules manufactured in Example 8 were orally administered to 7 normal people aged 25 to 32 years, and the amount of urine excreted and the amount of electrolytes excreted was measured over time for up to 3 hours after administration. However, the urine volume was approximately twice that of the non-administration state.
Sodium and chlorine excretion amount increased approximately 1.5 times.
In addition, the amount of potassium excreted was almost unchanged, and other substances such as calcium and inorganic phosphorus were also unchanged. Example 12 Example 7 or 8 was administered to seven patients aged 22 to 73 with dysuria after prostatectomy or hysterectomy.
Daily dose of capsules manufactured by 150μg to 400μg
(Amount of active substance, 2 to 3 minute doses) was administered orally continuously for one month, and a marked improvement in urination was observed. Example 13 Patient 11 aged 42 to 68 years after total cervical cancer removal
Daily dose of capsules prepared in Example 7 or 8 for humans
When 400 μg (amount of active substance, dosed over 2 to 3 minutes) was orally administered continuously for one week, a reduction in the number of days in which the residual urine volume reached 40 ml or less was observed.

Claims (1)

[Claims] 1. General formula (In the formula, X is −(CH ₂ ) ₃ −, −CH=CH−CH ₂ −
or trans-CH ₂ -CH=CH-, R ¹ represents a hydrogen atom, a straight or branched alkyl group having 1 to 12 carbon atoms, or a non-toxic cation, R ² represents a hydrogen atom, trifluoromethyl Represents a group or a chlorine atom. ) A diuretic or urinary agent containing a prostaglandin F ₂ analogous compound or its cyclodextrin clathrate. 2 Prostaglandin F ₂ 〓Similar compound is 16-
(3-trifluoromethylphenoxy)-17, 18,
The diuretic or urinary agent according to claim 1, which is 19,20-tetranor-PGF ₂ 〓, a nontoxic salt thereof, or a cyclodextrin clathrate compound. 3 Prostaglandin F ₂ = Similar compounds are 16-
(3-trifluoromethylphenoxy)-17, 18,
The diuretic or urinary agent according to claim 1, which is 19,20-tetranor-PGF ₂ methyl ester or a cyclodextrin inclusion compound thereof. 4 Prostaglandin F ₂ = Similar compounds are 16-
(3-trifluoromethylphenoxy)-17, 18,
19,20-tetranor-trans-Δ ² -PGF ₂ 〓
The diuretic or urinary agent according to claim 1, which is a methyl ester or a cyclodextrin clathrate thereof. 5 Prostaglandin F ₂ = Similar compounds are 16-
(3-trifluoromethylphenoxy)-17, 18,
The diuretic or urinary agent according to claim 1, which is 19,20-tetranor-Δ ³ -PGF ₂ methyl ester or a cyclodextrin inclusion compound thereof. 6 Prostaglandin F ₂ = Similar compounds are 16-
The diuretic or urinary agent according to claim 1, which is (3-chlorophenoxy)-17,18,19,20-tetranor-PGF ₂ , or a nontoxic salt thereof, or a cyclodextrin clathrate compound. 7 Prostaglandin F ₂ = Similar compounds are 16-
The diuretic or urinary agent according to claim 1, which is (3-chlorophenoxy)-17,18,19,20-tetranor-PGF ₂ methyl ester or a cyclodextrin inclusion compound thereof. 8 Prostaglandin F ₂ = Similar compounds are 16-
The diuretic or urinary agent according to claim 1, which is (3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester or its cyclodextrin clathrate compound. . 9 Prostaglandin F ₂ = Similar compounds are 16-
The diuretic or urinary agent according to claim 1, which is (3-chlorophenoxy)-17,18,19,20-tetranor-Δ ³ -PGF ₂ methyl ester or a cyclodextrin clathrate thereof. 10 Prostaglandin F ₂ = 16 similar compounds
-(3-chlorophenoxy)-17,18,19,20-tetranor-trans-Δ ³ -PGF ₂ methyl ester or its cyclodextrin clathrate, the diuresis or urination according to claim 1 agent. 11 Prostaglandin F ₂ = 16 similar compounds
-(3-chlorophenoxy)-17,18,19,20-tetranor-cis- ^Δ3 - _PGF2 = diuresis or urination according to claim 1, which is methyl ester or its cyclodextrin inclusion compound agent. 12 Prostaglandin F ₂ = 16 similar compounds
-Phenoxy-17,18,19,20-tetranol-
The diuretic or urinary agent according to claim 1, which is PGF ₂ 〓, or a non-toxic salt thereof, or a cyclodextrin clathrate compound. 13 Prostaglandin F ₂ = 16 similar compounds
-Phenoxy-17,18,19,20-tetranol-
The diuretic or urinary agent according to claim 1, which is PGF ₂ methyl ester or a cyclodextrin inclusion compound thereof. 14 Prostaglandin F ₂ = 16 similar compounds
-Phenoxy-17,18,19,20-tetranor-trans-Δ ² -PGF ₂ methyl ester or its cyclodextrin inclusion compound, the diuretic or urinary agent according to claim 1. 15 Prostaglandin F ₂ = 16 similar compounds
-Phenoxy-17,18,19,20-tetranol-Δ
³ -PGF ₂ The diuretic or urinary agent according to claim 1, which is a methyl ester or a cyclodextrin inclusion compound thereof. 16 Prostaglandin F ₂ = Similar compounds are 16
-Phenoxy-17,18,19,20-tetranor-trans- ^Δ3 - _PGF2〓 methyl ester or its cyclodextrin inclusion compound, the diuretic or urinary agent according to claim 1. 17 Prostaglandin F ₂ = 16 similar compounds
-Phenoxy-17,18,19,20-tetranor-cis- ^Δ3 - _PGF2〓 methyl ester or its cyclodextrin inclusion compound, the diuretic or urinary agent according to claim 1.