JPS6236003B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to thio-prostaglandin I ₁ (hereinafter referred to _as thio-PGI ₁ ) or _thio-
This invention relates to pharmaceuticals that use compounds similar to PGI ₁ to induce menstruation, terminate pregnancy, and induce labor. PGI ₂ is known as a natural physiologically active substance and has the following structural formula (), and its chemical name is (5Z,
13E)-(9α, 11α, 15S)-6,9-epoxy-
11,15-dihydroxyprosta-5,13-dienoic acid. [Nature, 263 , 663 (1976),
Prostaglandins, 12 ,
685 (1976), same magazine, 12 , 915 (1976), same magazine, 13 ,
3 (1977), same magazine, 13 , 375 (1977) and Chemical and Engineering News, December 20 issue, 17 (1976)]. PGI ₂ is produced by injecting prostaglandin G ₂ (hereinafter referred to as PGG ₂ ) or prostaglandin H ₂ (hereinafter referred to as PGH ₂ ) into microsomes such as porcine aorta, porcine mesenteric artery, rabbit aorta, or rat stomach fundus. It is known to be formed when incubated with PGI ₂
has a strong arterial-relaxing effect, and its action is specific to arteries and does not relax other smooth muscles. Furthermore, PGI ₂ strongly inhibits human platelet aggregation induced by arachidonic acid. Thromboxane A ₂ is also produced by incubating PGG ₂ or PGH ₂ with platelet microsomes.
Considering that (thromboxane A ₂ ) has an arterial constriction effect and a platelet aggregation effect, the above-mentioned PGI ₂
The properties of PGI ₂ indicate that PGI 2 plays an extremely important physiological role in the circulatory system in living organisms. Therefore, PGI ₂ is considered effective in treating arteriosclerosis, heart failure, thrombosis, and the like. The present inventors have conducted extensive research to use prostaglandins for the purpose of inducing menstruation, abortion, and inducing labor in humans. As a result, the present compound has been found to be effective in inducing menstruation, inducing pregnancy termination, and inducing labor in humans. It has only strong myometrial contractile activity, which is considered
We discovered that it is a very specific compound that hardly has some of the pharmacological properties that PGI ₂ has and many of the pharmacological properties that other prostaglandins have, and further developed the compound of the present invention. When actually used for inducing menstruation, abortion, and labor induction in humans, the present invention has been completed by proving that it is very effective with almost no side effects. (1) The extremely strong myometrial contractile activity of the compound of the present invention, which was discovered in the present invention, is an activity that cannot be imagined from _the pharmacological properties of PGI ₂ described above. (2) The excellent selectivity of the pharmacological properties of the compound of the present invention is due to the fact that prostaglandins are well known for their excellent selectivity. In other words, the pharmacological properties of prostaglandins themselves (e.g., hypotensive action, action to stimulate smooth muscle contraction, diuretic action, action to inhibit platelet aggregation, action to inhibit gastric acid secretion and gastrointestinal ulcers, bronchial Because it has a wide variety of effects, such as diastolic effect, lipolysis inhibition effect, and diarrhea effect, if one effect is taken up, the other effects may become side effects.)
This is completely unexpected and unique (as shown in the table below). According to the invention, the general formula [Wherein, Y is an ethylene group (i.e. -CH ₂ CH ₂
-) or trans-vinylene group (i.e.

[Formula], R ¹ is a hydrogen atom, a straight or branched alkyl group having 1 to 12 carbon atoms, or an unsubstituted or at least one chlorine atom, or a trifluoromethyl group, or a trifluoromethyl group having 1 to 12 carbon atoms.
-C _o H _2o OR ⁶ (in the group,
R ⁶ represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 2 to 12. ), R ² represents a hydrogen atom, a methyl group, or an ethyl group, R ³ represents a single bond or a straight or branched alkylene group having 1 to 4 carbon atoms, R ⁴ represents a hydrogen atom, or carbon number 1-8
or a C4-C7 cycloalkyl group which is unsubstituted or substituted with at least one C1-C8 straight-chain or branched alkyl group, or Represents a phenyl or phenoxy group that is unsubstituted or substituted with at least one chlorine atom, trifluoromethyl group, or alkyl group having 1 to 4 carbon atoms, and is attached to the carbon atoms at the 11th and 15th positions.
represents α-configuration or β-configuration (i.e. S-configuration or R-configuration) or a mixture thereof, and the configuration of the carbon atom at position 6 is S-configuration or R-configuration or a mixture thereof (i.e. RS) represents. ] In animal experiments, the compounds shown or their cyclodextrin clathrates, or the non-toxic salts of their acids when R ¹ represents a hydrogen atom, showed strong uterine muscle contractility, but no platelet aggregation. Effects such as suppressive action, antihypertensive action, antiulcer action, and diarrheal action were almost absent or very weak. These characteristics suggest that the compound of the present invention is an excellent compound that has excellent efficacy for the purpose of inducing menstruation, abortion, and labor induction in humans, and has no side effects. Furthermore, when the compound of the present application was administered to actual humans for the purpose of inducing menstruation, abortion, and labor induction, it was extremely effective and had no side effects, such as various symptoms caused by fluctuations in blood pressure, diarrhea, and vomiting. I had no abdominal pain. These results demonstrate that the compound of the present invention is an epoch-making compound that does not require any pretreatment for the purpose of reducing side effects, and is therefore an ideal drug. The results of the animal experiments are shown in the table.

【table】

[Table] In the table, myometrial contractile activity is the contractile activity of myometrium when the compound is intravenously administered to female rats on the 20th day of pregnancy, and prostaglandin E ₁ (hereinafter PGE ₁
It is written as ) is expressed as a relative activity, taking the activity of PGE 1 as 1, and the hypotensive activity is the blood pressure-lowering activity when the compound is intravenously administered to dogs anesthetized with allobarbital, and is a relative activity, taking the activity of PGE ₁ as 1. The platelet aggregation inhibitory activity is the inhibitory activity against platelet aggregation induced by adenosine diphosphate using rat blood, and is expressed as a relative activity with the activity of PGE ₁ as 1. This is the inhibitory activity on gastric acid secretion when the compound was continuously injected intravenously into gastrin-treated rats, and the pH of gastric acid was 2.0 to 2.0 in 50% of the rats used in the test.
It is considered effective when the value increases from 2.5 to at least 4.0, and is expressed as a relative activity with the activity of PGE ₁ as 1. Anti-ulcer activity is determined by the method by Takagi and Okabe [Jap.J.
Pharmac., 18 , 9-18 (1968)], the compound was orally administered to rats with stress ulcers generated by soaking in a 19°C water bath for ₆ hours. The activity is expressed as a relative activity with the activity as 1, and the diarrhea activity is the diarrhea-inducing activity when the compound is subcutaneously administered to rats, and the activity is expressed as a relative activity with the activity of PGE ₁ as 1. Effective administration methods for the present invention include oral, intravaginal, intrarectal, intrauterine, intravenous, intramuscular and extra-amniotic administration, preferably oral and intravaginal administration. The dosage varies depending on the administration method, but a single dose ranges from 5 μg to 5 μg.
Preferably, the dose is administered orally or intravaginally in one or several doses. 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 inert diluents, the formulations may also contain auxiliary agents, such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or preservatives. Preparations for oral administration according to the invention also include capsules of absorbable materials such as gelatin with or without one or more active substances and diluents or excipients. Solid preparations or ointments for intravaginal administration include:
Petsari, silicone rubber, which consists of at least one inert base containing one or more active substances, such as cocoa butter, macrogold, Uiteepsol, silicone rubber or petrolatum, formulated by methods known per se. Includes petals and ointments. Acute toxicity tests for the compound of the present application were conducted by intravenous administration using mice, and it was confirmed that the compound could be sufficiently used as a pharmaceutical. For example, (13E)−
(6RS, 9α, 11α, 15S)-6,9-epithio-
11,15-dihydroxyprost-13-enoic acid methyl ester (thio-PGI ₂ methyl ester) and (13E)-(6RS,9α,11α,15R)-6,9-epithio-11,15-dihydroxy-16, 16-dimethylprost-13-enoic acid methyl ester (16,16
-dimethyl-thio-PGI ₁ methyl ester)
LD ₅₀ was 100 mg and 25 mg, respectively. Among the compounds of the present application, only thio-PGI ₁ , its sodium salt, and its methyl ester are certified by JCS.
It is a known compound described in Chem.Comm., 375 (1978). However, the same document only states that thio-PGI ₁ methyl ester had a weak platelet aggregation inhibitory effect in human blood and a coronary artery constriction effect in isolated cats, and the main purpose of the present invention is not stated. There is no mention of some of the findings that lead to
The gist of the present invention regarding PGI ₁ and its analogous compounds was discovered for the first time by the present inventors. Further, the compounds of the present invention other than those mentioned above are new compounds, but they are compounds described in JP-A-55-73678, which has already been filed. Next, the present invention will be explained in more detail with reference to the following examples. Example 1 Thio-PGI ₁ methyl ester 500 mg, carboxymethyl cellulose calcium 2 g, silicon dioxide
Add 0.2g of magnesium stearate, 2g of magnesium stearate, and dry mannite to make 100g, mix well until homogeneous, and then directly compress into tablets using a mortar with a diameter of 6.5mm using a conventional method to obtain tablets containing 0.5mg of active substance in each tablet. Got 1000 tablets. Example 2 In the same manner as in Example 1 using 250 mg of 16,16-dimethyl-thio-PGI ₁ methyl ester in one tablet.
1000 tablets containing 0.25 mg of active substance were obtained. Example 3 50 mg of thio-PGI ₁ methyl ester, 0.03 g of silicon dioxide, 0.1 g of magnesium stearate and 10 g of semi-digested starch were added, mixed well until homogeneous, and then directly mixed using a mortar with a diameter of 6.5 mm using a conventional method. The tablets were compressed to give 100 Patukal tablets containing 0.5 mg of active substance in each tablet. Example 4 Add lactose to 50 mg of thio-PGI ₁ methyl ester
100 g of powder containing 0.5 mg of active substance in 1 unit by a conventional method after mixing well until homogeneous.
I got credit. Example 5 50 mg of thio-PGI ₁ methyl ester, 0.23 g of magnesium stearate and 23 g of lactose
Mix well until homogeneous, then fill into No. 3 gelatin capsules using the usual method.
100 capsules containing 0.5 mg of active substance were obtained. Example 6 100 capsules containing 0.25 mg of active substance in each capsule were obtained in the same manner as in Example 5 using 2.5 mg of 16,16-dimethyl-thio-PGI ₁ methyl ester. Example 7 A solution of 100 mg of thio-PGI ₁ methyl ester dissolved in 2 ml of ethanol was added to 80 g of Uiteepsol S-52 that had been melted at low temperature, mixed well until homogeneous, and then filled into a 0.9 ml container using a conventional method. Petsari containing 1mg of active substance in 1 tablet
Got 100 pieces. Example 8 Using 20 mg of thio-PGI ₁ methyl ester, 100 petals containing 0.2 mg of active substance in each tablet were obtained in the same manner as in Example 7. Example 9 Using 50 mg of 16,16-dimethyl-thio-PGI ₁ methyl ester, 0.5 mg of 16,16-dimethyl-thio-PGI was prepared in the same manner as in Example 7 in one tablet.
100 petusari containing mg of active substance were obtained. Example 10 A solution of 50 mg of thio-PGI ₁ methyl ester dissolved in 10 ml of ethanol was impregnated in 0.1 ml portions onto 100 pieces of silicone rubber with a thickness of 0.25 mm and an area of 10 cm ² , dried under reduced pressure, and an appropriate gelatin was used as an adhesive. After pasting the sheets one by one, metal pack them using the usual method.
50 silicone rubber pettu saris containing 1 mg of active substance each were obtained. Example 11 One pettu sari manufactured in Example 8 was given to five pregnant women between the ages of 20 and 40 at one time.
The drug was administered vaginally 1 to 3 times every 3 hours, and induction of labor was confirmed in all cases. Example 12 The petusari manufactured in Example 7 was administered vaginally to 15 women aged 20 to 40 years old, 1 to 5 times every 1 to 3 hours, 2 to 3 days before the expected menstrual date. Induction of menstruation was confirmed in all cases. Example 13 The petusari produced in Example 9 was administered vaginally to three women between the ages of 20 and 21, 1 to 3 times every 1 to 3 hours, 2 to 3 days before the expected menstrual date. Induction of menstruation was confirmed in all cases. Example 14 The tablets manufactured in Example 1 were orally administered to five women aged 20 to 22, 1 to 3 tablets at a time, 2 to 3 days before the expected menstrual date to induce menstruation in all women. confirmed. Example 15 One pettu saree manufactured in Example 7 was given to 15 women aged 20 to 40 who were in early pregnancy.
The drug was administered vaginally 2 to 5 times every 3 hours, and all cases were successfully terminated. Example 16 Seven women between the ages of 25 and 31 who were in early stages of pregnancy were given 1 to 3 tablets of the tablets manufactured in Example 2 at a time.
After 5 oral administrations, all cases were successfully terminated.

Claims (1)

[Claims] 1. General formula [Wherein, Y is an ethylene group (i.e. -CH ₂ CH ₂
-) or a trans-vinylene group (i.e. [Formula]), R ₁ is a hydrogen atom, or a straight or branched alkyl group having 1 to 12 carbon atoms,
or a phenyl group which is unsubstituted or substituted with at least one chlorine atom or a trifluoromethyl group or an alkyl group having 1 to 4 carbon atoms or a phenyl group, or a -C _o H _2o OR ⁶ group (basic, R ⁶ represents a hydrogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 2 to 12), and R ² represents a hydrogen atom, a methyl group, or an ethyl group. , R ³ represents a single bond or a straight chain or branched alkylene group having 1 to 4 carbon atoms, R ₄ represents a hydrogen atom, or a straight chain or branched alkyl group having 1 to 8 carbon atoms, or Unsubstituted or at least one carbon number 1-8
a cycloalkyl group having 4 to 7 carbon atoms substituted with a straight-chain or branched alkyl group, or unsubstituted or having at least one chlorine atom or trifluoromethyl group, or an alkyl group having 1 to 4 carbon atoms; represents a phenyl or phenoxy group substituted with , 〓 on the 11th and 15th carbon atoms represents an α-configuration or a β-configuration (i.e. S-configuration or R-configuration) or a mixture thereof;
The configuration of the carbon atom at position 6 is S-configuration or R-
configuration or a mixture thereof (i.e. RS). ] An agent for inducing menstruation, abortion, and labor, characterized in that it contains a compound represented by the above, a cyclodextrin clathrate thereof, or a non-toxic salt of the acid when R ¹ represents a hydrogen atom. 2 The compound is (13E)-(6RS, 9α, 11α,
The agent for inducing menstruation, abortion and labor according to claim 1, which is 15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid or its methyl ester. 3 The compound is (13E)-(6RS, 9α, 11α,
15R)-6,9-epithio-11,15-dihydroxy-15-(1-butylcyclobutyl)-16,17,
Claim 1 which is 18,19,20-pentanolprost-13-enoic acid or its methyl ester
Agents for inducing menstruation, abortion and labor as described in Section 1. 4 The compound is (13E)-(6RS, 9α, 11α,
15R)-6,9-epithio-11,15-dihydroxy-16,16-dimethylprost-13-enoic acid or its methyl ester, the agent for inducing menstruation, abortion, and labor according to claim 1 . 5 The compound is (13E)-(6RS, 9α, 11α,
15S,16S)-6,9-epithio-11,15-dihydroxy-16-methylprost-13-enoic acid or its methyl ester, the agent for inducing menstruation, abortion and labor according to claim 1 . 6 The compound is (13E)-(6RS, 9α, 11α,
15R)-6,9-epithio-11,15-dihydroxy-16-(4-chlorophenoxy)-17,18,19,
The agent for inducing menstruation, abortion, and labor according to claim 1, which is 20-tetranorprost-13-enoic acid or its methyl ester.