JP2760514B2 - Circulatory function enhancer - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a circulating agent comprising a 15-keto-prostaglandin E ester as an active ingredient.

2. Prior Art and Problems Plastaglandin E (hereinafter referred to as PGE) has various pharmacological actions such as vasodilatory action, hypotensive action, inflammatory action, uterine muscle stimulating action, intestinal muscle stimulating action, anti-ulcer action and the like. Have been.

On the other hand, 15-keto-prostaglandin E (hereinafter referred to as 15-keto-PGE) is known as a substance produced by metabolic reaction of PGE in an organism.
-Keto-PGE or 13,14-dihydro-15-keto-plastaglandin E (hereinafter 13,14-dihydro-15-keto-P
GE. In addition, the term “15-keto-PGE” which includes both is no longer considered a physiologically and pharmacologically inactive substance (Acta Physiologica Scandinavica, 66).
Vol. 509, 1966).

The present inventors conducted a pharmacological study on a derivative of 15-keto-PGE (hereinafter referred to as 15-keto-PGEs), and as a result, found that PGE ₁ , PGE ₂ and their metabolites 13,14-
Dihydro-15-keto-PGE ₁ and 13,14-dihydro-15-keto-PGE ₂ exhibit a blood pressure lowering effect, whereas, in contrast, esters of 15-keto-PGEs increase blood pressure. It has been found to work. In addition, these 15-keto-PGE
The compounds have desirable pharmacological effects such as a blood flow increasing effect, and have low toxicity, and thus are expected to be useful drugs as a broad-range circulatory function promoting agent. JP
Certain prostaglandins are described in AR 60-208917 as AR
Treatment of DS (Acute Respiratory Disorder Syndrome) and various multi-organ failures resulting therefrom (eg, decreased heart rate, acute circulatory failure,
Although it is described as useful for the prevention of blood pressure lowering, the mechanism of action is to treat ARDS itself, that is, to improve the oxygen gas exchange function of the lungs and eliminate oxygen deficiency in other organs. This does not mean that the circulatory function itself is advanced.

Means for Solving the Problems The present invention has a general formula: [Wherein, R ₁ is a hydroxyl group, a hydroxyalkyl group or an alkyl group; Y is a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (a part of carbon atoms constituting the hydrocarbon chain is a carbonyl group; And the hydrocarbon chain may be substituted by an atom or a group); Z is a group having 1 to 1 carbon atoms substituted by a group or an atom selected from a hydroxyl group, a halogen atom, an alkyl group and an alkoxy group. 10 saturated or unsaturated hydrocarbon groups constituting a straight or ring; R ₂ represents a group forming an ester; However,
The 13-14 position indicates a saturated or double bond]. From the increase in heart rate, blood pressure and blood flow, a physiologically acceptable ester of a 15-keto-prostaglandin E represented by the following formula: The present invention relates to a circulatory function subcutaneous agent having one or more actions selected from the group consisting of, except for those used for treating ARDS or preventing multi-organ failure resulting therefrom.

In the present specification, the circulatory function promoting agent has at least one of the functions of increasing the heart rate, increasing the blood pressure, increasing the blood flow, and the like, preferably having at least two of these functions. In particular, those having all of their actions are particularly useful as circulatory function subcutaneous agents, and restore or maintain the function of patients who require circulatory function subcutaneous treatment such as hypotension treatment, circulatory insufficiency, heart disease, etc. An effective drug.

In the present specification, 15-keto-PGEs are represented by the following nomenclature. That is, 15-keto-PGE has the following basic skeleton: However, the numbers of carbons constituting the α-chain, the ω-chain and the 5-membered ring of the basic skeleton are used as they are. That is, the number of carbons constituting the basic skeleton is 1 with carboxylic acid as the number of carbon atoms in the 5-membered ring. Are added on the ω chain, but when the number of carbon atoms decreases on the α chain, the numbers are deleted sequentially from the second position, and when the number of carbon atoms increases on the α chain, the carboxyl group (1 position) is substituted for the second position. Are named as having a substituent. When the carbon number decreases on the ω chain, the carbon number is sequentially reduced from the 20th position, and when the carbon number increases on the ω chain, the carbon atoms after the 21st are named as substituents.

Unless otherwise specified, the configuration is assumed to be the configuration having the above basic skeleton.

In general, PGE refers to a compound having a hydroxyl group at the carbon at the 11th position.In the present specification, PGEs include those having another substituent in place of the hydroxyl group at the 11th position, and are referred to as PGEs.
Named in the form of a dehydroxy-11 substitution.

Furthermore PGE compound is classified into PGE ₁ compounds and PGE ₂ compounds by 5,6 and 7 positions of how carbon bond.

Group and PGE ₁ such carbon of 5,6 and 7 refers to a group of compounds that bound a single bond, and the PGE ₂ compound, carbon of 5 and 6-positions are bonded by a double bond Of the compound. Therefore, A compound having a bond represented by is referred to as 6-keto-PGE ₁ class, The compound having the bonding mode shown is 5,6-dehydro-P
GE class ₂ .

In the present invention, 15-keto-PGEs have the general formula: [Wherein, R ₁ is a hydroxyl group, a hydroxyalkyl group or an alkyl group; Y is a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (a part of carbon atoms constituting the hydrocarbon chain is a carbonyl group; Z may be substituted by a group or atom selected from a hydroxyl group, a halogen atom, an alkyl group, a phenyl group, an alkoxy group and a phenoxy group. A saturated or unsaturated hydrocarbon group constituting a saturated or unsaturated straight-chain or ring having 1 to 10 carbon atoms; R ₂ represents a group forming an ester (provided that the 13-14 position represents a saturated or double bond; )].

Examples of the hydrocarbon chain having 2 to 6 carbon atoms wherein Y is saturated or unsaturated include straight-chain hydrocarbon chains such as alkyl chains, alkenyl chains, and alkynyl chains. Particularly preferred are hydrocarbon chains having 6 carbon atoms. It is.

Y is an example of the unsaturated hydrocarbon chain wherein the PGE ₂ compound, 5,6-other-dehydro -PGE _2, such 2-3-position carbon bond of PG compounds is unsaturated are exemplified.

Part of carbon constituting the hydrocarbon chain represented by Y may form a carbonyl group, a typical example is the 6-position carbon 6-keto -PGE ₁ such that form a carbonyl group .

The hydrocarbon chain represented by Y may be substituted by another atom or group. Examples of such atoms or groups are halogen atoms such as fluorine and chlorine; alkyl groups such as methyl and ethyl; hydroxyl groups; and typical examples thereof are PGs having an alkyl group at the 3-position carbon.

Z represents a saturated or unsaturated hydrocarbon group having 1 to 10 carbon atoms, and the hydrocarbon group may itself form a ring. The carbon number of the hydrocarbon group is particularly preferably 3 to 7. The straight chain having 5 carbon atoms corresponds to general PGs having 8 carbon atoms in the ω chain. Therefore, as described above, a hydrocarbon group represented by Z having 6 or more carbon atoms is represented as a substituent of the carbon at position 20 of the ω chain. (That is, a hydrocarbon having 6 carbon atoms in Z is referred to as 20-methyl-PGs.) The unsaturated bond may be in any position of Z.
Those having no unsaturated bond are preferred. Examples of the hydrocarbon group in which Z forms a ring include a cyclopentyl group and a cyclohexyl group in which the carbon at position 16 or 17 of the ω chain is a ring-constituting carbon.

The hydrocarbon groups represented by Z are substituted by atoms or groups, which are halogen atoms, especially fluorine; alkyl groups such as methyl, ethyl, isopropyl, isopropenyl; alkoxy groups; such as methoxy, ethoxy; A hydroxyl group; a phenyl group; a phenoxy group. The position of the atom or group to be substituted is not limited, but ω
Positions 16, 17, 19 and / or 20 are typical, as represented by the carbon number of the chain. In particular at position 16 one or two identical or different atoms, for example halogen atoms such as fluorine or substituents, for example alkyl groups such as methyl, ethyl,
A hydroxyl group, a phenyl group which may have a substituent, a benzyl group, a phenoxy group, or a cycloalkyl group such as cyclopentyl or cyclohexyl having a carbon atom at position 16; an alkyl group such as methyl at position 17 or 19; Compounds having an alkyl group such as methyl, ethyl, isopropyl, butyl and isopropenyl at the 20-position and an alkoxy group such as methoxy, ethoxy and propoxy are preferred.

PGEs generally have a carbonyl group at the 9-position carbon,
Compounds having a prostanoic acid skeleton having a hydroxyl group at the carbon at the 1-position are collectively referred to, but in this specification, compounds having, for example, a hydroxyalkyl group or an alkyl group instead of the hydroxyl group at the 11-position are also included in the PGEs. Treat as
Therefore, the 15-keto-PGEs of the present invention contain R _{1 of the} general formula [I].
Is a hydroxyl group, a hydroxyalkyl group or an alkyl group. The hydroxyalkyl group is preferably a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-methyl-1-hydroxyethyl group, and the alkyl group is preferably a lower alkyl group, particularly a methyl group, an ethyl group, and the like. .

The configuration of R ₁ with respect to the carbon at position 11 may be α, β or a mixture thereof.

Further, when R ₁ is a hydroxyl group, a hemiacetal which is a tautomer generated between the hydroxyl group and the carbonyl at the 15-position.
The 15-keto-PGEs of the present invention also include these tautomers, although an equilibrium mixture with the compound in which R ₁ is a hydroxyl group may occur. Tautomers between the hydroxyl group at the 11th position and the carbonyl group at the 15th position are found in the 13,14-dihydro form in which the carbons at the 13th and 14th positions are saturated.In particular, an electron withdrawing group at the 16th position, for example, It is easy to be formed in those having fluorine.
Specific examples of tautomers include, for example, the following equilibrium mixtures.

A parallel mixture of isomers, for example, an equilibrium mixture of a racemic or tautomeric hydroxy compound and hemiacetal, also exhibits the same effect as when used alone.

Further, in PGEs, the bond at the 13-14 position of the prostanoic acid skeleton is a double bond.In the present invention, in addition to such PGEs, the 13,14-dihydro form in which the 13-14 position is saturated is also used. Good results are obtained. Rather, the 13,14-dihydro form is preferred.

The carboxyl group at the terminal of the α chain of the PGEs of the present invention is esterified.

The ester moiety R _2, such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl,
Straight-chain or side-chain alkyl groups which may have an unsaturated bond such as 2-ethyl-hexyl and allyl; alicyclic groups such as cyclopropyl, cyclopentyl and cyclohexyl; Aromatic group (aromatic group may have a substituent); for example, hydroxyalkyl such as hydroxyethyl, hydroxyisopropyl, hydroxypropyl, polyhydroxyethyl, polyhydroxyisopropyl, methoxyethyl, ethoxyethyl, methoxyisopropyl, etc. Examples thereof include a group or an alkoxyalkyl group, an alkylsilyl group such as trimethylsilyl and triethylsilyl, and a tetrahydropyranyl group.

Lower alkyl esters preferably R ₂ is having a linear or side chain, such as methyl, ethyl, propyl, n- butyl, isopropyl, alkyl groups such as tertiary butyl; cycloalkyl group; a benzyl group; such as hydroxyethyl ester, hydroxypropyl And hydroxyalkyl groups such as isopropyl. Particularly, an alkyl group generally gives good results in both heart rate increase and blood pressure increase.

The 15-keto-PGEs of the present invention include various isomers, for example, tautomers, optical isomers, geometric isomers and the like.

In the present invention, among the circulatory functions, the compounds that are particularly effective in increasing the heart rate are those in the 3rd, 16th and / or 19th positions.
A compound having one or two alkyl groups, particularly a methyl group, a halogen atom, particularly a fluorine atom, a compound wherein R ₁ is a methyl group, a compound having 8 to 10 carbon atoms in the main chain of the ω chain, 2-3
And the like, in which the carbon bond at the 2-position is a double bond.

Examples of 15-keto-PGEs that are particularly effective in increasing heart rate are 13,14
-Dihydro-6,15-diketo-16,16-dimethyl-PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16
R, S-fluoro-PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16R, S-fluoro-11-dehydroxy-1
1R-methyl-PGE ₁ -alkyl ester, 13,14-dihydro-15-keto-16R, S-methyl-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-3R, S, 16R, S-dimethyl -PGE ₂ alkyl ester, 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-16R, S-fluoro-20-methyl-PGE ₂
Alkyl ester, 13,14-dihydro-15-keto-19-
Methyl-PGE ₂ alkyl ester, 13,14-dihydro-15
-Keto-20-methoxy-16,16-dimethyl-PGE ₂ alkyl ester, 15-keto-16R, S-fluoro-PGE ₂ alkyl ester and the like.

The 15-keto-PGEs effective for increasing blood pressure include compounds in which R ₁ is methyl, compounds in which the carbon-carbon bond at position 2-3 is a double bond, one at the carbon at position 16 and / or 19 or Preferred results are obtained in a compound having two halogen atoms, particularly a fluorine atom and a methyl group, and in a compound having 8 to 12 carbon atoms in the main chain of the ω chain. 15- Particularly effective for increasing blood pressure
Keto-PGEs are 13,14-dihydro-6,15-diketo-16,1
6-dimethyl-PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16R, S-methyl-PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16R, S-fluoro-
PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16R, S-fluoro-11-dehydroxy-11R-methyl-
PGE ₁ alkyl ester, 13,14-dihydro-15-keto-1
6,16-dimethyl-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-16R, S-fluoro-11-dehydroxy-1
1R-methyl-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-16R, S-hydroxy-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂
Alkyl ester, 13,14-dihydro-15-keto-16R, S
-Fluoro-20-methyl-PGE ₂ alkyl ester, 13,14
-Dihydro-15-keto-19-methyl-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-20-methoxy-16,
16- dimethyl -PGE ₂ - alkyl esters, etc. are exemplified.

15-Keto-PGEs, which have overall favorable effects on increasing heart rate and increasing blood pressure, are ranked 3rd, 16th and / or
Or a compound having one or two alkyl groups, particularly a methyl group, at the carbon at position 19 or a compound having one or two halogen atoms, particularly a fluorine atom, at the carbon at position 16. Examples of specific compounds are 13,14-dihydro-6,15-diketo-16R, S-methyl-PG
E ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16,16-dimethyl-
PGE ₁ alkyl ester, 13,14-dihydro-6,15-diketo-16R, S-fluoro-PG
E ₁ alkyl ester, 13,14-dihydro-15-keto-16R, S-methyl-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-3R, S-16R, S-dimethyl-PGE ₂ alkyl ester , 13,14-dihydro-15-keto-16,16-dimethyl-PGE ₂
Alkyl ester, 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ alkyl ester, 13,14-dihydro-15-keto-19-methyl-PGE ₂ alkyl ester, especially a methyl group at position 16 Compounds having a lower alkyl group such as an ethyl group or an ethyl group, or a hydroxyl group are preferable because they exhibit high blood pressure increasing action and positive chronotropic action (cardiotonic action).

As for the circulatory function subcutaneous agent of the present invention, an overall well-balanced compound is not necessarily suitable for all cases. In general, it is preferable to select an appropriate compound in accordance with the patient's condition. For example, it is preferable to select a compound having a high blood pressure increasing effect for a patient with a large amount of bleeding with a severe decrease in blood pressure or a postoperative patient.

15-Keto-prostaglandin E used in the present invention
The compounds can be produced, for example, by the method described in Japanese Patent Application No. 63-18326. These descriptions are incorporated herein by reference.

As a specific method for producing the 13,14-dihydro-15-keto compound, as shown in the synthesis chart (I), the aldehyde compound (2) obtained by performing the oxidation oxidation on a commercially available corey lactone (I) is converted into dimethyl (2). -Oxohexyl) phosphonate anion to give an α, β-unsaturated ketone (3), which is reduced to give a ketone (4), and the carbonyl group of the ketone is reacted with a diol to give a ketal (5) And then de-p-phenylbenzoylation to give alcohol (6), and the newly generated hydroxyl group is protected with dihydropyran to give tetrapyranyl ether (7). This gives a precursor of prostaglandins E in which the ω chain is a 13,14-dihydro-15-keto-alkyl group. Further, by proceeding the reaction of a precursor of prostaglandins E in which the ω chain is a 15-keto-alkyl group without reducing the above α, β-unsaturated ketone (3),
Can be synthesized.

Using the above tetrapyranyl ether (7) as a raw material, 6-keto-PGE _1's (15) are reduced from tetrapyranyl ether (7) using diisobutylaluminum hydride or the like to obtain lactol (8), which is obtained from (4-carboxybutyl) triphenylphosphonium bromide. After reacting the resulting ylide and then esterifying, 5-,
The 6-position double bond and the 9-position hydroxyl group are dehalogenated using NBS or iodine to obtain a 6-keto form (13), which can be obtained by removing the protecting group after Jones oxidation.

Further Ylide PGE ₂ compound is (19), as shown in the synthetic chart II by reducing the tetra pyranyl ether (7) to give the lactol (8), obtained from this (4-carboxybutyl) triphenylphosphonium bromide To give a carboxylic acid (16), followed by esterification (17), followed by Jones oxidation (18), followed by removal of the protecting group.

Using the above tetrapyranyl ether (7) as a raw material, To get the PGE ₁ class In analogy to the PGE ₂ compound is a double bond at the 5 -6-position of the resulting compound (18) was catalytically reduced and then, can be obtained by removing the protecting group. The 5-, 6- and 7-position hydrocarbon chains are The synthesis of 5,6-dehydro-PGE ₂ is a monoalkyl copper complex or a dialkyl copper complex as shown below. To a 4R-tert-butyldimethylsilyloxy-2-cyclopenten-1-one by trapping the resulting copper enolate with 6-carboalkoxy-1-iodo-2-hexyne or a derivative thereof. Can be synthesized.

The l1-β form can be synthesized as shown in Synthesis Chart III. PGs having a methyl group instead of the hydroxyl group at the l1-position can be synthesized by reacting a dimethyl copper complex with a PGA type obtained by Jones oxidation of the hydroxyl group at the 9-position of the l1-tosylate. PGs having a hydroxymethyl group instead of the hydroxyl group at the l1 position can be synthesized by adding methanol to the PGA type obtained above using benzophenone as a photosensitizer.

The 15-keto-PGEs of the present invention may be used as drugs for animals and humans, and are usually used systemically or locally by oral, intravenous injection (including infusion), subcutaneous injection, suppository and the like. used. Dosage may be animal, human, age, body weight,
It is preferably 0.001 to 500 mg / kg, although it varies depending on symptoms, therapeutic effect, administration method, treatment time and the like.

Solid compositions for oral administration according to the present invention include:
Tablets, powders, granules and the like are included. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate. The composition may be prepared in a conventional manner using additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose gluconate, α-, β- or γ-cyclodextrin, or dimethyl. -Α-, dimethyl-β-,
Etherified cyclodextrins such as trimethyl-β- or hydroxypropyl-β-cyclodextrin, glucosyl-, branched cyclodextrins such as mantosyl-cyclodextrin, formylated cyclodextrins,
A stabilizer such as sulfur-containing cyclodextrin or misoprotol may be contained. When the above cyclodextrins are used, an inclusion compound may be formed with the cyclodextrins to increase the stability in some cases. In addition, the use of phospholipids to form liposomes may increase the stability in some cases. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary, or with two or more layers. Further, capsules made of an absorbable substance such as gelatin may be used.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Containing ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspension media include, for example, distilled water for injection, physiological saline and Ringer's solution.

Non-aqueous solutions and suspension media include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol,
Polysorbate and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide, gas sterilization or radiation sterilization. They can also be used as a sterile solid composition prepared by dissolving in sterile water or a sterile solvent for injection before use.

Example 1 Blood Pressure, Heart Rate, and Elevating Effect by Intravenous Administration Wistar male rats 8 weeks old were used. Rats were anesthetized by intraperitoneal administration of urethane at 1.25 g / kg. Blood pressure was measured by inserting a polyethylene tube into the femoral artery and connecting to a pressure transducer. The heart rate was measured with a tachometer from the R wave of the second lead electrocardiogram of the limb. The test drug was dissolved in ethanol, diluted with Ringer's solution at the time of use, and intravenously administered to rats at 1 mg / kg. The maximum concentration of ethanol was 2%. A control was a Ringer solution containing ethanol containing no test drug, and the effect was always confirmed in each experiment.
The change in blood pressure and heart rate due to administration of the test drug (%) was determined,
Table 1 shows the results of the average values of 3 to 4 examples.

1 13,14-dihydro-15-keto-PGE ₁ 2 13,14-dihydro-15-keto-PGE ₁ ethyl ester 3 13,14-dihydro-15-keto- △ ^2- PGE ₁ methyl ester 4 13,14 - dihydro-15-keto-20-ethyl -PGE ₁ methyl ester 5 13,14-dihydro-6,15-diketo -PGE ₁ 6 13,14-dihydro-6,15-diketo -PGE ₁ methyl ester 7 13, 14-dihydro-6,15-diketo-PGE ₁ ethyl ester 8 (±) 13,14-dihydro-6,15-diketo-PGE ₁ ethyl ester 9 13,14-dihydro-6,15-diketo-PGE _1n − Butyl ester 10 13,14-dihydro-6,15-diketo-16R, S-methyl-
PGE ₁ methyl ester 11 13,14-dihydro-6,15-diketo-16R, S-methyl-
PGE ₁ ethyl ester 12 13,14-dihydro-6,15-diketo-16,16-dimethyl-PGE ₁ ethyl ester 13 13,14-dihydro-6,15-diketo-16R, S-fluoro-
PGE ₁ ethyl ester 14 13,14-dihydro-6,15-diketo-19-methyl-PGE
₁ methyl ester 15 13,14-dihydro-6,15-diketo-19-methyl-PGE
₁ ethyl ester 16 13,14-dihydro-6,15-diketo-11-dehydroxy-11R-hydroxymethyl-19-methyl-PGE ₁ ethyl ester 17 13,14-dihydro-6,15-diketo-11-de Hydroxy-11R-methyl-PGE ₁ methyl ester 18 13,14-dihydro-6,15-diketo-11-dehydroxy-11R-methyl-PGE ₁ ethyl ester 19 13,14-dihydro-6,15-diketo-16R , S-Fluoro
11-dehydroxy-11R-methyl-PGE ₁ ethyl ester 20 13,14-dihydro-15-keto-PGE ₂ 21 13,14-dihydro-15-keto-PGE ₂ methyl ester 22 13,14-dihydro-15- Keto-PGE ₂ ethyl ester 23 13,14-dihydro-15-keto-PGE ₂ propyl ester 24 13,14-dihydro-15-keto-PGE ₂ n-butyl ester 25 13,14-dihydro-15-keto-PGE ₂ benzyl ester 26 13,14-dihydro-15-keto-PGE ₂ hydroxyethyl ester 27 13,14-dihydro-15-keto- △ ^2- PGE ₂ methyl ester 28 13,14-dihydro-15-keto-3R, S-methyl-PGE ₂
Methyl ester 29 13,14-dihydro-15-keto-3R, S-methyl-PGE ₂
Ethyl ester 30 13,14-dihydro-15-keto-16R, S-methyl-PGE ₂
Methyl ester 31 13,14-dihydro-15-keto-16R, S-methyl-PGE ₂
Ethyl ester 32 13,14-dihydro-15-keto-3R, S-16R, S-dimethyl-PGE _2- methyl ester 33 13,14-dihydro-15-keto-16,16-dimethyl-PG
E ₂ methyl ester 34 13,14-dihydro-15-keto-16,16-dimethyl-PG
E ₂ ethyl ester 35 13,14-dihydro-15-keto-16R, S-hydroxy-
PGE ₂ ethyl ester 36 13,14-dihydro-15-keto -16R, S- fluorosilicone -PGE ₂ 37 13,14-dihydro-15-keto -16R, S- fluorosilicone -PGE ₂
Methyl ester 38 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂
Ethyl ester 39 13,14-dihydro-15-keto-16R, S-fluoro-20-
PGE ₂ methyl ester 40 13,14-dihydro-15-keto-16R, S-fluoro-11-
Dehydroxy-11R-methyl-PGE ₂ ethyl ester 41 13,14-dihydro-15-keto-11-dehydroxy-1
1R-methyl-PGE ₂ ethyl ester 42 13,14-dihydro-15-keto-17S-methyl-PGE ₂ methyl ester 43 13,14-dihydro-15-keto-19-methyl-PGE ₂ methyl ester 44 13,14 - dihydro-15-keto-19-methyl -PGE ₂ ethyl ester 45 13,14-dihydro-15-keto-20-methoxy -PGE ₂
Methyl ester 46 13,14-dihydro-15-keto-20-methoxy- △ ²
-PGE ₂ methyl ester 47 13,14-dihydro-15-keto-20-methoxy-3R, S
-Methyl-PGE ₂ methyl ester 48 13,14-dihydro-15-keto-20-methoxy-16,16
-Dimethyl-PGE ₂ methyl ester 49 13,14-dihydro-15-keto-20-isopropenyl-PGE ₂ 50 13,14-dihydro-15-keto-20-isopropenyl-PGE ₂ methyl ester 51 13,14- Dihydro-15-keto-20-ethyl-PGE ₂ methyl ester 52 13,14-dihydro-15-keto-20-ethyl-PGE ₂ ethyl ester 53 13,14-dihydro-15-keto-20-ethyl-11R- Methyl-PGE ₂ methyl ester 54 13,14-dihydro-15-keto-20-n-propyl-P
GE ₂ methyl ester 55 15-keto-16R, S-fluoro-PGE ₂ methyl ester 56 PGE ₁ 57 PGE ₂ 58 PGE ₂ methyl ester 59 control 60 15-keto-17S-methyl-PGE ₂ ethyl ester 61 15-keto- 20-ethyl-PGE ₂ isopropyl ester 62 15-keto-19-methyl-PGE ₂ ethyl ester 63 15-keto-PGE ₂ isopropyl ester From the above results, the ester form of 15-keto-PGE is PGE ₂ PGs such as _2- methyl ester and carboxylate such as 13,14-dihydro-15-keto-PGE ₂ do not exhibit the blood pressure lowering effect observed in the carboxylate type, and conversely express a blood pressure effect. In addition, a positive chronotropic effect (inotropic effect) also appears.

Example 2 Wistar male rats 9 weeks old were used as animals. Rats were anesthetized by intraperitoneal administration of urethane at 1.25 g / kg.
Carotid artery blood flow was measured with a blood flow meter. Blood pressure and heart rate were measured in the same manner as in Example 1.

13,14-dihydro-6,15-diketo-19-methyl-PGE ₁
Ethyl ester (Compound No. 16) was dissolved in a small amount of ethanol, diluted 50 times or more with Ringer's solution, and then 0.1 ml from polyethylene chirbe inserted into femoral vein in advance.
At 1 mg / kg. Thereafter, changes in blood flow (BF), blood pressure (BP), and heart rate (HR) were measured over time. The results are shown in FIG. 1 as the average value of four cases.

As shown in FIG. 1, blood flow, blood pressure, and heart rate all greatly increased.

Example 3 Recovery action of hypotension and low heart rate during blood loss (hemorrhagic shock model) Wistar male rats 8 weeks old were treated with urethane at 1.5 g / k
g Anesthetized by subcutaneous back injection. Blood pressure and heart rate were measured in the same manner as in Example 1. 1.Weight than rat
A 5% equivalent of blood was collected from the heart and allowed to stand at room temperature for 60 minutes, after which 13,14-dihydro-6,15 was added to 0.1 ml of Ringer's solution.
-Diketo-19-methyl-PGE ₁ ethyl ester (Compound No. 16) was dissolved and administered intravenously. Ringer's solution was administered to the control group.

For both the blood pressure and the heart rate, the recovery rate was determined by taking the value 60 minutes after blood removal as 0% and the value before blood removal as 100%. The results are shown in Table 2 with the average value of 5 cases. FIG. 2 shows a temporal change of blood pressure of a representative example, and FIG. 3 shows a temporal change of a heart rate. In the figure, (1) shows a dose of 1 mg / kg, and (2) shows a dose of 0.5 mg / kg. (3) shows a control group.

As is clear from Table 2 and FIGS. 2 and 3, remarkable recovery of blood pressure and heart rate was observed by administration of the test drug.

Example 4 Slc-ddy male and female mice (5 weeks old) were examined for acute toxicity upon oral administration, subcutaneous administration, intraperitoneal administration and intravenous administration.

 The experimental results are shown in Table-3.

Esters of 15-keto-prostaglandins E are found to be low toxins.

EFFECT OF THE INVENTION The treatment of essential hypotension, symptomatic hypotension, orthostatic hypotension, and acute hypotension associated with various diseases or conditions, or shock, in the case of esters of 15-keto-prostaglandins E of the present invention It is useful as a vasopressor, a therapeutic agent for circulatory insufficiency and an inotropic agent.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the effect of 13,14-dihydro-6,15-diketo-19-methyl-PGE ₁ ethyl ester on blood flow (BF), blood pressure (BP) and heart rate (HR). FIGS. 2 and 3 show the effects of 13,14-dihydro-6,15-diketo-19-methyl-PGE _1- ethyl ester on blood pressure and heart rate recovery during blood removal.

Claims (10)

(57) [Claims] (1) a general formula: [Wherein, R ₁ is a hydroxyl group, a hydroxyalkyl group or an alkyl group; Y is a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (a part of carbon atoms constituting the hydrocarbon chain is a carbonyl group; And the hydrocarbon chain may be substituted by an atom or a group); Z is a group having 1 to 1 carbon atoms substituted by a group or an atom selected from a hydroxyl group, a halogen atom, an alkyl group and an alkoxy group. 10 saturated or unsaturated hydrocarbon groups constituting a straight or ring; R ₂ represents a group forming an ester; However,
The 13-14 position indicates a saturated or double bond]. From the increase in heart rate, blood pressure and blood flow, a physiologically acceptable ester of a 15-keto-prostaglandin E represented by the following formula: A circulatory function subcutaneous agent having one or more actions selected from the group consisting of, except for those used for treating ARDS or preventing multi-organ failure resulting therefrom. 2. The circulating agent according to claim 1, wherein the ester is a lower alkyl ester. 3. The circulating agent according to claim 1, wherein Z is a fluoroalkyl group. 4. The method according to claim 1, wherein the 15-keto-prostaglandin E is 13,1
2. A circulatory function promoting agent according to claim 1, which is a 4-dihydro-15-ketoprostaglandin E. 5. The method according to claim 5, wherein the 15-keto-prostaglandin E is 13,1
4-dihydro-15-keto-16-mono or difluoro-
2. The circulatory function promoting agent according to item 1, which is a prostaglandin E. 6. The method according to claim 6, wherein the 15-keto-prostaglandin E is 13,1
2. A circulatory function enhancer according to claim 1, which is 4-dihydro-15-keto-16-mono or dimethyl-prostaglandin E. 7. The method according to claim 1, wherein the 15-keto-prostaglandin E is 13,1
2. The circulatory function promoting agent according to claim 1, which is a 4-dihydro-15-keto-19-methyl-prostaglandin E. 8. The circulatory function subcutaneous agent according to claim 1, which is intended to increase blood pressure. 9. The circulatory function promoting agent according to claim 1, which is intended to increase the heart rate. 10. A first method for increasing blood flow.
The circulatory agent described in the item.