KR810001203B1 - Preparing process for prostaglandine derivatives - Google Patents

Abstract

Title compds. (I; R = H, acetyl; Z = -OR or =O; n = 1, 2; m = 0, 1, 2), showing decreased adverse reaction of a medicine, were prepd. by reacting prostaglandine or acetylated prostaglandine with OH on 17- or 21- of steroid hormone having OH, acetoxy, propionyloxy, benzoyloxy or oxo group on 3-positionor by binding prostaglandine with X(CH2)nCOOH (X = halo, n = 1, 2) or HOOC(CH2)nCOOH at room temp. in absolute solvent.

Description

Method for preparing prostaglandin derivative

1 is a graph showing the results of the binding function of estradiol and PGFE.

FIG. 2 is a graph showing cardiac arrest, breathing, and electrocardiac conduction when 0.2 ml of a 50% ethanol salt solution is administered intravenously.

FIG. 3 is a graph showing heart rate, respiratory rate, and electrocardiogram when intravenously administered 0.2 ml of 50% ethanol solution containing PGF ₂ at a dose of 15γ / mouse.

4 is a graph showing heart rate, respiratory rate and electrical depth when intravenously administered 0.2 ml of 50% ethanol salt solution containing PGFR-4AC at a dose of 30 μs / mouse.

The present invention relates to a process for the preparation of novel prostaglandin derivatives with significantly reduced side effects in order to maintain good physiological activity.

As is known, prostaglandin derivatives are synthesized in the human body and are important physiologically active substances having hypotension effect, gastric secretion inhibitory effect, bronchodilator effect, blood vessel aggregation inhibitory effect or promoting effect.

Prostaglandins are hereafter abbreviated PGS. PGE-PGFs are known to have specific physiological activities such as hysterolimus and corpus luteum degeneration, which are useful as powder promoters, agents for the treatment of placenta release and menstrual irregularities after miscarriage and postpartum in the early and middle stages of pregnancy. (Brit. Med. J. 4 , 618 (1968), Brit. Med. J., 4 621 (1968), Amr. NY Acad. SCE., 180 456 (1970).

It can also regulate sexual cycles, miscarriage and contraception in mammalian females.

Useful prostaglandins, however, cause nausea, vomiting and diarrhea and sudden changes in blood pressure, pulse and breathing when administered as a medicament. Although prostaglandins are useful agents, they are only used in certain dental applications because of significant side effects.

We have worked diligently to develop novel prostaglandin derivatives with significantly reduced side effects.

It is an object of the present invention to produce novel prostaglandin derivatives which can significantly reduce the side effects of prostaglandins and make them highly available.

The novel prostaglandin derivatives are a combination of prostaglandin-steroid hormones having hydroxyl, acetoxy propionyloxy, benzyloxy or oxo groups in the 3-position.

The combination of prostaglandin-steroid hormones reacts prostaglandins directly with hydroxyl groups at the 17- or 21-position of the steroid hormone having hydroxyl, acetoxy, propionyloxy, benzyloxy or oxo groups at the 3-position or acetyl Structural formula with or without

It can be prepared by combining with a binder selected from the group consisting of compounds having n wherein 1 is 1 or 2 and X is a halogen atom.

The novel prostaglandin derivatives of the present invention have the following general formula (I) or (I ').

Wherein R is a hydrogen atom or an acetyl group, Z is -OR or = O and 1 or 2, and m is 0.1 or 2.

In general formula (I), St is selected from the group consisting of the groups of the formulas (II) to (IX).

(Wherein R 'is selected from hydrogen atom, acetyl group, propionyl group and benzoyl group)

Typical prostaglandin derivatives (I) can be classified as follows.

[Group I]

A ₁ -B ₁ A ' ₁ -B ₁ A' ₂ -B ₁ A ₃ -B ₁ A ' ₃ -B ₁ A ₁ -B' ₁ A ₁ -B ' ₁ A ₂ -B' ₁ A ' _2- B ' ₁ A ₃ -B' ₁ A ₃ -B ' ₁ A ₁ -B ＂ ₁ A ₁ ' B＂ ₁ A ₂ -B ＂ ₁ A ' ₂ -B＂ ₁ A ₃ -B ＂ ₁ A' ₃ ' B ＂ ₁ A ₁ -B＂ ' ₁ A' ₁ -B ＂' ₁ A ₂ -B＂' ₁ A ₂ -B ＂' ₁ A ₃ -B'' ₁ A ₃ -B'' ₁ A' _1- B ₂ A ' ₁ -B ₂ A ₂ -B ₂ A' ₂ -B ₂ A ' ₃ -B ₂ A' ₃ -B ₂

[Group II]

Structural unit B ₁ may be substituted with one of the following structural units.

(Wherein R 'is selected from hydrogen atom, acetyl group, propylonyl group and benzoyl group.)

E) 또는 (PGFE), 에스트라-1,3,5(10)-트리엔-3-하이드록시-17--옥시카르보닐에틸-9α,11α,15α-트리하이드록시-5(시스)-13(트란스)-프로스타디에노에이트,에스트라-1,3,5(10)-트리엔-3-하이드록시-17-옥시카르보닐메틸-9α,11α ,15α트리아세톡시-5(시스)-13(트란시)-프로스타디에노에이트(PGFE-3AC), 에스트라, 1,3,5(10)트리엔-3-하이드록시-17-옥시카르보닐에틸-9α,11α,15α-트리아세톡시-5-(시스)-13(트란스)Compounds of group II are of particular interest. Examples of typical prostaglandin derivatives having Formula (I) include estra-1,3,5 (10) -triene-3--hydroxy-17--oxycarbonylmethyl-9α, 11α, 15α-trihydroxy -5 (cis) -13 (trans) -prostadienoate (PGF ₂

E) or (PGFE), estra-1,3,5 (10) -triene-3-hydroxy-17-oxycarbonylethyl-9α, 11α, 15α-trihydroxy-5 (cis) -13 (Trans) -prostadienoate, estra-1,3,5 (10) -triene-3-hydroxy-17-oxycarbonylmethyl-9α, 11α, 15α triacetoxy-5 (cis)- 13 (Tranci) -prostadienoate (PGFE-3AC), estra, 1,3,5 (10) triene-3-hydroxy-17-oxycarbonylethyl-9α, 11α, 15α-triace Toxy-5- (cis) -13 (trans)

Prostaglandin derivatives (I) as the main ingredient is 9α, 11α, 15α- trihydroxy-5 (cis) -13 (trans) - (hereinafter called after PGF ₂ α) acid in the pro-study and may be prepared using estradiol have.

However, if the administration of the prostaglandin derivatives (I), the characteristic side-effects of PGF ₂ α are not found, interrogating Heath tree mousse, a pharmacological effect and the I-implantation (卵着床) inhibition effects, such as lactic acid, modified LH stimulation Significantly improved. Thus, the novel prostaglandin derivative (I) is extremely effective against lactic acid, labor promotion, fertilization improvement, estrous control contraception and menstrual palpation.

The compound of the present invention, its preparation method, pharmacological test, preparation of medicament, method of administration and dosage will be described later.

Prostaglandin derivative (I) is prepared as follows. In the present invention, PGE ₁ , PGE ₂ , PGE ₃ , PGF ₁ α, PGF ₂ α and PGF ₃ can be used as prostaglandins (see Chemistry and Biology, Vol. 15, No. 2, pages 80-88, 1977). ).

Combinations of prostaglandin-steroid hormones can be prepared by directly reacting the prostaglandins and steroid hormone compounds or by using suitable binders therebetween.

Binder is a compound having the structure

X (CH ₂ ) _n COOH

(n is 1 or 2, X is a halogen atom)

Examples include α-monochloroacetic acid, α-monobromoacetic acid and β-monobromopropionic acid, compounds having the structure

X (CH ₂ ) _n COX

For example α-monochloroacetyl chloride and α-monobromoacetyl bromoamide,

Compound having the formula

HOOC (CH ₂ ) _n COOH or XOC (CH ₂ ) _n COX

Examples include malonic acid, succinic acid and dichloric acid thereof. These binders can be prepared by conventional methods.

Prostaglandin derivatives (I) are estrone, estradiol, estriol or progesterone or steroid hormone derivatives having a conjugated group. It can be prepared by reaction with a salt.

Steroid hormone derivatives having a linking group can be easily obtained by reacting a steroid hormone such as estradiol with the binder described above. This binder must react with the OH group at position 17 or 21 of the selected steroid hormone.

The reaction of a steroid hormone such as estradiol with a binder is preferably performed in anhydrous tetrahydrofran, preferably in a non-aqueous solvent. The reaction temperature is usually not very high and is often at or below room temperature.

Prostaglandins are usually used in the form of their salts, in particular silver salts. Prostaglandins may be acetylated prior to reacting with steroid hormones or derivatives thereof. The reaction of metal salts of prostaglandins with steroid hormone derivatives is carried out by mixing them in a solvent such as DMSO in the dark. In acetylation, acetic anhydride is added in an inert solvent such as pyridine. The reaction temperature can change this, but at room temperature. The product is column chromatographed with silica gel filled with several organic solvents.

Some examples for preparing prostaglandin derivative (I) are described below.

(1) PGFE reacted BrCH ₂ COBr with the OH group at the 17 position of estradiol in the first step reaction to obtain estra-1,3,5 (10) -trien-3-ol-17-bromoacetate, It is then prepared as an oil by reacting the product of the metal salt of the carboxyl group (the silver salt) of PGF ₂ α in a solvent such as a DMS in a dark room in the final reaction.

(2) PGFE-3AC reacted BrCH ₂ COBr with the OH group at the 17-position of estradiol in the first step reaction to estra-1,3,5 (10) -trien-3-ol-17-bromoacetate In the second step reaction, the product was reacted with a metal salt (silver salt) of the carboxyl group of PGF ₂ α in a solvent such as DMSO in the dark, and then the second reaction product was separated with acetic anhydride in a solvent such as pyridine. It is made to react as an oily substance.

의 금속염(은염)으로 전환시킨 다음에 수득된 아세틸화 PGF₂α의 금속염을 에스트라-1,3,5(10)-트리엔-3-올-17-브로모아세테이트와 반응시켜 유상물로서 제조한다.(3) PGFE-3AC is acetylated the acid portion of the sum acetylated with acetic anhydride in an inert solvent such as pyridine to PGF ₂ α, PGF ₂ α and _2-acetyl-PGF

A switch to which the metal salt (silver salt), and then a metal salt of acetylated PGF ₂ α to obtain estradiol -1,3,5 (10) -triene prepared as an oil by reaction with 3-ol-17-bromoacetate do.

(4) estra-1,3,5 (10) -trie-3-ol-17-bromorph instead of estra-1,3,5 (10) -trien-3-ol-17-bromoacetate When using ropionate, the corresponding product is obtained.

(5) PGF ₂ α with fold-polymer of estradiol is estradiol, PBr ₅ and bromination was carried out in an inert solvent such as tetrahydro Francisco OH group at the 17-position, the product metal salt of prostaglandin in an inert solvent such as DMSO (silver salt It is prepared by reacting with).

Other derivatives are prepared in the same manner. The structure of these products was confirmed by IR spectrum, elemental analysis and NMR. The side effects of these products are described later.

The acute toxicity of PGFE, PGFE-4AC and PGFE-3A (LD ₅₀ ) was determined by intravenous injection of 10 mg of ICR-JCL mouse females (4 weeks) at a dose of 400 mg / kg. Mice (10) all survived. In the fact that LD of PGF ₂ α is ₅₆ mg / kg, PGFE. It is clear that PGFE-4AC and PGFE-3A are remarkably safe.

PGF ₂ α. PGFE. Before and after administration of PGFE-4AC and PGFE-3AC, the heart rate metal, respiration, and electrocardiogram of mice during pregnancy were tested with Biopiggiograph 180-4 (4ch) (manufactured by San-A-Sokuki Co., Ltd.).

의 투여에서 명백히 관찰되는 것과 대조적으로, 비정상 조건은 PGFE. PGFE-4AC 및 PGFE-3AC의 경우에 확인되지 않았다.As a result, the normal condition is PGF ₂

In contrast to what is apparently observed at the administration of PGFE. It was not confirmed for PGFE-4AC and PGFE-3AC.

By these side effects tests, PGFE. It was found that PGFE-4AC and PGFE-3AC had sufficiently low toxicity and reduced side effects.

PGFE. Lactose rates of PGFE-4AC and PGFE-3A were tested as pharmacological effects using appropriate dosing methods and dosages using ICR-JCL pregnant mice.

의 것과 비교하여 우수한 효과를 나타냈다.As a result, PGFE. PGFE-4AC and PGFE-3AC are PGF ₂

Compared with that of the excellent effect was shown.

(4.24x10^-8몰)의 복용량으로 PGF₂α를 계속해서 투약했을 경우 유산은 불완전했으나, 만족한 결과는 이 복용량과 같거나 또는 그 이하인 PGFE. PGFE-4AC 및 PGFE-3AC의 경우에 나타났다.15 to mouse for 4 days

Continued administration of PGF ₂ α at a dose of (4.24x10 ^-8 moles) resulted in incomplete abortion, but a satisfactory result was PGFE at or below this dose. In the case of PGFE-4AC and PGFE-3AC.

The hydroxyl group in the 9, 11 and 15-position of the PGF ₂ α has an active group, in the case of acetyl hwahal a hydroxyl group, which is inert to the normal.

PGFE. In the case of PGFE-4AC and PGFE-3AC, hydroxyl groups are acetylated but they have surprisingly good effects.

The prostaglandin derivative (I) of the present invention can be prepared in the required form such as injection, oral administration, intravaginal administration or coating agent. For example, the compound may be formulated in a solid form such as tablets, powders, granules and capsules, and liquids such as syrups for oral administration. For example, only in the solid phase, starch, gallium carbonate and lactose can be combined as excipients and lubricants can be combined with the product of the present invention. In the case of solutions for oral administration, the products of the present invention may be mixed with pharmaceutically acceptable excipients such as emulsifiers, suspending and syrup additives, water, alcohols, liquid paraffins and olive oils, and also sweetening and flavoring agents. . Gelatin can be used to formulate capsules.

In the case of solids for intravenous administration, the product of the present invention may be mixed with wax higher fatty acids or higher alcohols having a suitable melting point dissolved in the vagina and a disintegrant with an appropriate composition as needed.

In the case of injectables, the product of the present invention is dissolved in the vagina and an appropriate addition of 2 첨가 of ethanol, surfactant, emulsifier, salinity stabilizer, pH adjuster and nutrient is added as necessary.

The concentration of the product of the invention in the formulation is at least 0.0025% by weight for injectables and at least 0.1% by weight for oral preparations.

The dose of the product of the present invention is only 0.1 μg to 500 μg / day of pregnant women, preferably 0.001 to 50 mg / day, and the suitable dosage is determined by the method of administration and the state of pregnancy.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

[Estra-1,3,5 (10) -triene-3-hydroxy-17-oxycarbonylmethyl-9α, 11α, 15α-trihydroxy-5 (cis) -13 (trans) -prostadie Preparation of potassium or silver salts of noate (PGFE) and 9α, 11α, 15α-trihydroxy-5 (cis) -13 (trans) -prostadieenoic acid (hereafter PGF ₂ ).]

(a) Preparation of potassium salt of PGF ₂ α

1 ml of water was added to 0.1053 g (2.97 × 10 ⁻⁴ mol) of PGF ₂ , the mixture was stirred at + 1-2 ° C., and 4 ml of an aqueous solution containing 0.0205 g of KOH was slowly added to the mixture. The slurry became a clear solution after stirring for about 1 hour and the pH was between 7.5 and 8.5.

의 은염의 제조(b) PGF ₂

Preparation of silver salt

의 칼륨염의 수용액에 부가했다.0.05301 g of AgNO ₃ is dissolved in a small amount of water and the solution is dissolved in PGF ₂ in the dark.

It added to the aqueous solution of potassium salt of.

The solution was stirred for about 15 minutes to precipitate the white silver salt of PGF ₂ α. After the white precipitate was filtered off, the precipitated precipitate was washed with water and then washed with ether. 0.1085 g of white silver salt was then obtained by drying at room temperature under reduced pressure (yield 79.14%).

[Preparation of Estra-1,3,5 (10) -triene-3β-ol-17β-bromoacetate]

10 g of estradiol was dissolved in 400 ml of anhydrous tetrahydrofuran (THF), followed by addition of 8.8 g of anhydrous pyridine.

A solution containing 74 g of carbon tetrachloride in 22.5 g of α-bromoacetyl bromide was added dropwise to a solution of estradiol at -5 to 7 ° C. This mixture was allowed to react overnight. After the reaction, the additive was filtered off, and the solvent was distilled off from the filtrate.

The residue was dissolved in ether and recrystallized to give estra-1,3,5 (10) -triene-3.17β-dibromoacetate. Subsequently, 2 g of product was dissolved in 900 ml of methanol, cooled to −5 ° C., and 20 ml of an aqueous solution containing 0.2 g of K ₂ CO ₃ was added dropwise.

After 30 minutes, 1000 ml of water was added to this solution, and the resulting precipitate was separated and dried. This product was identified as estra-1,3,5 (10) -triene-3β-17β-bromoacetate by elemental analysis and IR spectrum.

[Reaction of Silver Salt of PGF ₂ α with Estra-1,3,5 (10) -Triene-3β-10-17β-Bromoacetate]

-브로모아세테이트 0.1000g을 부가하고, 이 혼합물을 실온에서 2일동안 교반했다. 침전된 취화은을 제거하고, 잔류 용액을 물 20ml를 부가하여 냉각 상태에서 유화제로 제제했다. 유화액을 원심 분리시켜 담황색 유상물을 얻었다.PGF (DM SO) dimethyl sulfoxide a silver salt 0.1085g (2.35 × 10 ^-3 mol) of ₂ α in the dark room were dissolved in 2cc, followed by estradiol here -1,3,5 (10) -triene -17

0.1000 g of bromoacetate was added and the mixture was stirred at room temperature for 2 days. The precipitated silver embrittlement was removed and the residual solution was formulated with emulsifier under cooling by adding 20 ml of water. The emulsion was centrifuged to give a pale yellow oil.

와 다음과 같은 구조식을 갖는 에스트라디올과의 배합체로 확인되었다.The reaction product was chromatographed with 42 g of silica gel using a mixed solvent (cyclohexane, ethyl acetate and ethanol 45: 45: 10 volume ratio) to obtain a substance which was purified to 68.95%. This product is PGF ₂

And estradiol having the following structural formula.

와 에스트라디올의 배합체PGF ₂

And a combination of estradiol

Elemental analysis: Calculated value (%): C 71.07 H 8.71

Found (%): C 71.60 H 8.00

IR spectrum (cm ^-1 ): 3400, 2920, 1735, 1650, 1580, 1495, 1440, 1378, 1350, 1280, 1215, 1140, 1075, 1040, 1040, 1020, 1000, 960, 920, 915, 865, 810, 7801 720

Example 2

[Preparation of PGF ₂ times the lattice of the α and estradiol;

1 g of estradiol was dissolved in 65 ml of tetrahydrofuran containing 5 g of CaCO ₃ , and 5.0 g of PBR ₅ was added thereto for 30 minutes under stirring at −4 ° C., and the mixture was further stirred at −4 ° C. for 30 minutes. The reaction was further stirred at 0 ° C. for 20 minutes and at 20 ° C. for 3.5 hours. The reaction mixture was decanted into an aqueous solution of NaHCO 3 (at ° C.). This product was extracted with ether and purified with acetone (0.7 g of tablet).

The purified product (bleach) was reacted with PGF ₂ α-Ag prepared in Example 1 to obtain the following formulation.

IR spectrum (cm ^-1 ): 3400, 2920, 2850, 1735, 1600, 1570, 1500,, 1440, 1378, 1350, 1280,, 1215, 1140,, 1080, 1040, 1020, 1000, 955, 918, 910 , 870, 810, 780, 712

The physiological effect was measured by the method of Example 1 except using the resultant blend. As a result, it was confirmed that the combination was bound to the estrogen receptor causing hysterolitrimus.

Example 3

[Combination of PGE ₂ and Progesterone]

As progesterone derivatives, 3.2 g of 11-desoxicodycosterone was dissolved in a mixture of 200 ml of anhydrous THF and 10 ml of anhydrous pyridine, and the solution was kept at -5 ° to 7 ° C.

-브로모아세틸브로마이드 0.3g의 용액을 11-데속시코르티코스테론의 용액에 적가했다.ccl _{4 in} 80 g

A solution of 0.3 g bromoacetylbromide was added dropwise to a solution of 11-desoxycorticosterone.

This mixture was stirred and left overnight at room temperature.

After the reaction, the precipitate was filtered off, the solvent was distilled off from the filtrate, and the residue was recrystallized from ether.

In the spectra, no absorption based on OH groups at the 21-position was found, and the characteristic wet water of ester bonding was found at 1735 cm ⁻¹ .

As a result of IR spectra and elemental analysis, it was confirmed that the α-bromoacetyl group was introduced into the OH group at the 21-position of 11-decoxycortisosterone.

Is reacted with a PGE ₂ -Ag manufacture the product in Example 1 to obtain a ship-polymer of PGE ₂ and progesterone (PGE ₂ P).

In the UV absorption spectrum, the characteristic absorption of the blended carbonyl group was confirmed at 241 nm.

The physiological effect was measured by the method of Example 1, except for the use of the resulting formulation. As a result, it was confirmed that the dimer was bound to the estrogen receptor causing the hysterolimus.

Example 4

[Estra-1,3,5 (10) -triene-3-hydroxy-17-oxycarbonylmethyl-9α, 11α, 15α-trihydroxy-5 (cis) -13 (trans) -prostadie Manufacturing of No Eight]

PGF ₂ α and estradiol -1,3,5 (10) -17-bromo-3-ol to prepare a potassium salt and a silver salt of the parent acetate by the method of Example 1, GF ₂ α and estradiol -1,3,5 The reaction with (10) -3-ol-17-bromoacetate was carried out by the method of Example 1.

PGF ₂ α and the estradiol incorporated into the fold times 0.0290g of acetylation of the polymer of a diol, where in addition to a 0.5ml anhydrous pyridine was dissolved the ship incorporated, then add 0.15ml of acetic anhydride, and the mixture at room temperature Stir overnight. After the reaction, the solvent was removed at 45 ° C. under reduced pressure to obtain 0.0351 g of an acetylated combination of PGF ₂ α as an oil and estradiol (PGFE-4AC).

This product was confirmed to have the following structural formula by elemental analysis and IR spectrum.

Elemental analysis: Calculated value (%): C 69.06 H 7.91

Found (%): C 68.8 H 8.0

IR spectrum (cm ^-1 ): 2920, 2850, 1735, 1610, 1593, 1580, 1490, 1430,, 1375, 1230, 1150, 1010, 960, 890, 865, 820, 793, 780, 750, 705, 676 .

Example 5

[Estra-1,3,5 (10) -triene-3-hydroxy-17-oxycarbonylmethyl-9α, 11α, 15α-trihydroxy-5 (cis) -13 (trans) -prostadie Manufacturing of No Eight]

0.1008 g of PGF ₂ alpha was dissolved in 1.0 ml of anhydrous pyridine, and then 0.3 ml of pentoxide anhydride was added thereto, and the mixture was left overnight. After the reaction, pyridine and acetic anhydride were removed under reduced pressure at 40 占 폚, the residue was washed with water and the oily substance was separated. Then adding a silver nitrate solution was prepared by dissolving in water, 2ml and 3ml ethanol (0.1515g AgNO3) to the reaction mixture, followed by further 1 h in this dark room to obtain a silver salt of 0.1140g acetylated PGF ₂ α.

To 2 ml of KMSO, 0.11 g of a silver salt of acetylated PGF ₂ α was dissolved, followed by addition of 0.10 g of estra-1,3,5 (10) -triene-3-hydroxy-17-bromoacetate, This was reacted for 48 hours in the cow. After the reaction, AgBr was filtered through a G-4 filter. The filtrate was mixed with 20 ml of cold water and the resulting oil was separated by centrifugation. The product was chromatographed with 42 g of silica gel using a mixed solvent (cyclohexane, ethyl acetate and ethanol 45:45:10 volume ratio). The purified product is an oil.

The product was confirmed to have the following structural formula by elemental analysis and IR spectrum.

Elemental analysis: Calculated value (%): C 69.70 H 8.08

Found (%): C 68.90 H 8.0

IR spectrum (cm ^-1 ): 3400, 2920, 2850, 1735, 1610, 1580, 1500, 1440, 1370, 1230, 1145, 1080, 1020, 960, 915, 865, 812, 790, 780, 725

Example 6

-모노브로모아세테이트 0.13g(2.60×10^-4몰)을 암소에서 부가하여 이것을 실온에서 반응시켰다.0.1 (2.17 × 10 ⁻⁴ mol) of PGF ₂ α · Ag salt was dissolved in 1 ml of anhydrous pyridine, and 3-benzyloxy-1,3,5 (10) -triene-17

0.13 g (2.60 × 10 ⁻⁴ mol) of monobromoacetate was added in the dark and reacted at room temperature.

AgBr was separated, the filtrate was cooled, mixed with water, and the product was separated as an oil at the bottom by centrifugation.

The oil was dried in a desiccator in vacuo, dissolved in a mixed solvent of ethyl acetate, cyclohexane and ethanol (45:45:10 volume ratio), and the solution passed through a column of silica gel to give PGFE-BA (yield 71.8%). ) Was obtained.

Molecular Weight 770

Elemental analysis: Calculated value (%): C 73.25 H 8.05

Found (%): C 73.31 H 7.98

IR spectrum (cm ^-1 ): 3400, 2920, 2840, 1735, 1600, 1580, 1490, 1450, 1418, 1380, 1350, 1260, 1208, 1170, 1145, 1078, 1060, 1020, 1000, 960, 910, 890, 874, 812, 796, 780, 698, 680, 610

Example 7

21.0 mg (2.73 x 10 ^-5 mol) of PGFE-BA was dissolved in 0.5 ml of anhydrous pyridine, acetic anhydride was added thereto, the mixture was allowed to react by ice cooling, and the reaction mixture was left overnight. After the reaction, the solvent was distilled off in a vacuum at 40 ° C., and the residue was dissolved in a mixed solvent of ethyl acetate and cyclohexane (50 to 30% by volume). This solution was passed through a silica gel column to give 23.5 mg (96.31%) of PGFE-3AC-BA.

Elemental analysis: Calculated value (%): C 71.0 H 7.59

Found (%): C 71.0 H 7.62

IR spectrum (cm ^-1 ): 2920, 2850, 1735, 1600, 1580, 1490, 1450, 1425, 1370, 1240, 1170, 1145, 1078, 1060, 965, 915, 890, 705, 680

Example 8

0.1 (2.17 × 10 ⁻⁴ mol) of PGF ₂ α · Ag salt was dissolved in 1 ml of anhydrous DMSO, and 3-propionyloxy-1,3,5 (10) -triene-17β-monobromoacetate 0.114 g (2.6 × 10 ⁻⁴ moles) was added in the dark and allowed to react at room temperature for 3 days. After the reaction, AgBr was separated, the filtrate was mixed with water and the product was centrifuged to separate as an oil at room temperature.

The oil was dissolved in a mixed solvent of ethyl acetate, cyclohexane and ethanol (45:45:10 volume ratio) and the solution was passed through a silica gel collection to yield 0.12 g of oil, which was analyzed by DGFE by elemental analysis and IR spectrum. -PR was identified as the target compound.

Molecular Weight 722

Elemental analysis: Calculated value (%): C 71.47 H 8.59

Found (%): C 71.30 H 8.55

IR spectrum (cm ^-1 ): 3400, 2920, 2840, 1735, 1600, 1590, 1580, 1490, 1430, 1373, 1230, 1150, 1010, 960, 890, 820, 793, 780, 750

Example 9

11-deoxy corticosterone -21- bromoacetate 0.145g (2.60 × 10 ^-4 mol) of PGF ₂ α · reaction in anhydrous DMSO 1ml for Ag salt 0.1 (2.17 × 10 ^-4 mol) in a cow 3 days This gave 1.3 g of oil, which was identified as the target compound of PGR-P by elemental analysis and IRF spectrum.

C ₄₃ H ₆₄ 0 ₉

Molecular Weight 724

Elemental analysis: Calculated value (%): C 71.27 H 8.84

Found (%): C 71.50 H 8.62

IR spectrum (cm ^-1 ): 3420, 2950, 2920, 2850, 1750, 1725, 1665,1612, 1450, 1420, 1385, 1320, 1270, 1230, 1190,, 1145, 1080,, 1050, 965, 940, 910, 860, 780, 760, 720, 680

In addition to using PGR-P as a raw material, partial esterification was carried out to obtain an oily product by the method of Example 7, which was identified as the target compound of PGF-P-3AC by elemental analysis and IR spectrum.

Elemental analysis: Calculated value (%): C 68.77 H 8.77

Found (%): C 69.00 H 8.52

IR spectrum (cm ^-1 ): 3000, 2950, 2920, 1750, 1735, 1705, 1610, 1580, 1430, 1405, 1385, 1368, 1320, 1270, 1230, 1270,, 12,30, 1190, 1,145, 1080 , 1050, 965, 940, 910, 860, 780, 760, 720, 680

Example 10

0.1 g (2.17 × 10 ⁻⁴ mol) of PGE ₂ Ag salt is dissolved in 1 m of anhydrous DMSO, followed by 3-benzoyl-oxy-1,3,5 (10) -triene-17β-monobromoacetate 0.13 g was added in the dark, which was reacted for 3 days at room temperature. After the reaction, the product was purified to give 0.12 g of a colorless oil, which was identified as the PGEE-BA target compound by elemental analysis and IR spectrum.

C ₄₇ H ₆₁ O ₉

Elemental analysis: Calculated value (%): C 73.43 H 7.81

Found (%): C 73.12 H 7.89

IR spectrum (cm ^-1 ): 3420, 2000, 2950, 2920, 2850, 1735, 1705, 1585, 1490, 1450, 1418, 1380, 1368, 1350, 1235, 1145, 1090, 1018, 965, 890, 780, 720, 700, 680

Except for using PGE ₂ E-3A as a raw material, by the method of Example 7, partial acetylation was carried out at room temperature to obtain an oily product, which was analyzed by elemental analysis and IR spectrum to give PGE ₂ E-2AC-BA. It was identified as the target compound of.

C ₅₁ H ₆₄ O ₁₁

Molecular Weight 852

Elemental analysis: Calculated value (%): C 73.43 H 7.81

Found (%): C 73.12 H 7.89

IR spectrum (cm ^-1 ): 2950, 2920, 2850, 1735, 1705, 1583, 1490, 1448, 1415, 1381, 1368, 1350, 1235, 1143, 1090, 1020, 970, 890, 780, 720, 698, 6801

Example 11

0.1 g of PGE ₁ Ag salt is dissolved in 1 ml of anhydrous DMSO, and then 0.13 g of 3-benzoyloxy-1,3,5 (10) -triene-17β-monobromoacetate is added in the dark, which is 3 The reaction was at room temperature for days. After the reaction, the product was purified to give 0.12 g of a colorless oil, which was identified as the PGEE-BA target compound by elemental analysis and IR spectrum.

C ₃₇ H ₆₂ O ₉

Molecular Weight 770

Elemental analysis: Calculated value (%): C 73.43 H 7.81

Found (%): C 73.12 H 7.89

IR spectrum (cm ^-1 ): 2950, 2920, 2850, 1735, 1705, 1583, 1490, 1448, 1415, 1381, 1368, 1350, 1235, 1143, 1090, 1020, 970, 890, 780, 720, 698, 680

Except for using PGE ₁ E-3A as a raw material, partial acetylation was carried out at room temperature by the method of Example 7 to obtain an oily product, which was analyzed by elemental analysis and IR spectrum to give PGE ₁ E-2AC-BA. It was identified as the target compound of.

C ₅₁ H ₆₆ O ₁₁

Molecular Weight 854

Elemental analysis: Calculated value (%) C 71.66 H 7.73

Found (%) C 72.03 H 7.59

IR spectrum (cm ^-1 ): 2950, 2920, 2850, 1735, 1705, 1583, 1490, 1448, 1415, 1381, 1368, 1350, 1235, 1143, 1090, 1020, 970, 890, 780, 698, 680

[Measurement of Physiological Activity of PGFE]

The binding action of estradiol and PGFE on each uterus of the rabbits was measured by the competition sink test.

Estradiol, expressed as tritium (3H), was inoculated and bound to the uterus of the rabbit, and then estradiol and PGFE were added to this system to measure the amount of free 3H-estradiol, which was then added by adding PGFE or estradiol. Replaced. The result is shown in FIG.

As is apparent from FIG. 1, PGFE binds to the estrogen receptor in the same way as estradiol itself.

Hysterolitris of the drug was observed in the same pieces used for oxytocin. 5-50γ of 5γ or PGFE of PGFE α ₂ are shown the results for interrogating Heath tree mousse a positive maetnae injection in rats.

In the former case, a cardiac arrest occurred, and in the latter case, the cardiac activity was normal even when the formulation was administered 50γ, and thus had no side effects.

PGFE had a brief delay the erection of Heath Tero tree mousse when compared to the α ₂ PGFE itself. This fact is the heumsu with intrauterine selective PGFE represents a hydrolyzed glass PGFE ₂ α.

The miscarriage of ICR-JCL pregnant rats was tested by continuous dosing of the drug for 4 days and the side effects of dosing were also tested.

Ethanol salt after intravenous administration of 2 ml of 50% ethanol-salt solution containing PGFE ₂ α (PGFE 30γ in animals) at 4 and 10 γ doses per mouse or 15 γ dose per mouse for 4 days daily The abortion of the group that received the drug was confirmed by feeding continuously until the control group administered with the solution alone gave birth. The results were as follows.

TABLE 1

[Side Effects Test of PGFE-3AC and PGFE-4AC]

Acute toxicity (LD ₅₀ ) and abnormal heart rate, respiratory rate, and electrocardiogram by Biofiggiograph were tested.

In the measurement of LD ₆ , 101 CR-JCL mouse females (4 weeks old) were used as the first group. Mice were injected intravenously into mice by taking 0.2 ml of 50% ethanol-salt solution containing the medicinal agent several times for 7 days to obtain its LD ₅₀ value by the Litchfieldwilcoxon graph method.

As a result, all mice survived, and no abnormality was observed even with 400 mg / kg of PGFE-3AC, which is about 7 times PGFE ₂ αLD ₅₀ (56 mg / kg). Thus, their LD ₅₀ was too high to measure directly. This fact indicates that the products of PGFE-3AC and PGFE-4AC have markedly low readings.

Three minutes after each sample was administered, the electrocardiogram was measured with Biopiggiograph 180-4 (4ch) (manufactured by San-A-Sokuki Co., Ltd.) on ICR-JCL pregnant mice (day 6).

의 복용량으로 마우스에 정맥내로 주입했다. 참조로서 PGF₂α를 또한 사료로서 사용했다. (마우스당 15

의 투여량).In this test, 0.2 ml of 50% ethanol-salt solution was added per 30 mice.

The mice were injected intravenously at a dose of. PGF ₂ α was also used as feed as reference. (15 per mouse

Dosage).

The measurement results are shown in Figs. 2 to 5, where mV is shown in ordinate and time in seconds, and the car art speed was 250 mm / sec.

From the measurement results, PGF ₂ α rapid heart rate after the administration (FIG. 3), respiratory rate and electro electrocardiogram; is ideally different from those of the control (FIG. 2) to turn. However, after administration of PGFE-3AC or 4AC (4th and 5th degrees), heart rate, respiratory rate and electrocardiogram were substantially the same as those of the control.

[Lactic acid test of PGFE-3AC or PGFE-4AC]

Continuously dosing in to day 6 of the ICR-JCL mouse (one per group 5) as compared to that of pregnancy PGF ₂ α tested the abortion rate obtained by the medicaments of the present invention. 5% ethanol containing PGFE-3AC - after adding the salt solution 0.2ml, PGFE-3AC or PGF ₂ α and a daily dosage in the mice for four days at a constant dose by injection and subcutaneous injection into the vein, and continues to feed The abortion rate of the group administered with the drug was confirmed until the control group administered with ethanol salt solution only gave birth.

The results are shown in the table. Test Results As is apparent from, PGFE-4AC and abortion rate of PGFE-3AC was significantly superior to those of known compounds PGF ₂ α.

TABLE 2

TABLE 3

Lactic acid test of other prostaglandin derivatives of the present invention

The drug of the present invention was dissolved in olive oil at several concentrations to obtain an effective lactic acid (100% hyoda) dose. 0.2 ml of the solution was injected subcutaneously into ICR-JCL pregnant rats (5 per group).

ICR-JCL A single subcutaneous injection of 0.2 ml solution was given to pregnant rats (day 4 of pregnancy), followed by feeding until the birth of the oil-only control group confirmed the abortion rate of the group dosed with the medicinal agent. .

Example 12

TABLE 4

[Pharmaceutical]

[Example 1]

These components were heated, mixed and sterilized to prepare injection solutions.

[Example 2]

These ingredients were mixed, milled and compressed to form tablets with a diameter of 10 ml.

[Example 3]

These components were mixed and sterilized to prepare an injection solution.

Claims (1)

Prostaglandin or Acetylation; The prostaglandin is reacted directly with a hydroxyl, acetoxy, propionyloxy, benzoyloxy or hydroxyl group at the 17- or 21-position of the steroid hormone having a 3-position at the 3-position or acetyl; With or without

Wherein n is 1 or 2 and X is a halogen atom, and has a hydroxyl, acetoxy, propionyloxy, benzoyloxy or oxo group in the 3-position by bonding with a binder selected from the group A combination of prostaglandin-steroid hormones A method for producing a novel prostaglandin derivative represented by (I) or (I ').

(Meal,

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