JPH07258090A - Circulatory function-improving agent - Google Patents

Abstract

PURPOSE:To obtain the circulatory function-improving agent containing a prostaglandin E represented by the specified formulae as the active component and useful for therapy of essential hypotension, symptomatic hypotension and orthostatic hypotension and as a hypertensive agent for hypotension caused by shock, a therapeutic agent for circulatory diseases and a cardiac. CONSTITUTION:This circulatory function-improving agent contains a 13,14- dihydro-15-keto-prostaglandin E represented by the formula I [Y is an (un)saturated 2 to 6C hydrocarbon chain; Z is a 1 to 10C (un)saturated hydrocarbon chain substituted with a halogen atom], preferably a 13,14-dihydro-15-keto-16-mono or difluoro-prostaglandin E or its physiologically permissible salt as the active component. In addition, production of PGE1 of the formula TV is carried out recommendably, e.g. by using Cori's lactone of the formula II as the starting material, synthesizing a 6-keto compound through tetrapyranyl ether of the formula III as an intermediate, conducting Jones oxidation and subsequently removing the protecting group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is effective for 13,14-dihydro-15-keto-prostaglandin Es (carboxylic acid type) in which the ω chain is substituted with a halogen atom or a physiologically acceptable salt thereof. It relates to a circulatory function enhancer as an ingredient.

[0002]

2. Description of the Related Art Prostaglandin E (hereinafter P
GE) has various pharmacological actions such as vasodilator action, blood pressure lowering action, inflammation action, uterine muscle stimulating action, intestinal muscle stimulating action, and antiulcer action.

On the other hand, 15-keto-prostaglandin E
(Hereinafter referred to as 15-keto-PGE) is PG in vivo.
E is known as a substance produced by a metabolic reaction by an enzyme, and 15-keto-PGE or 13,
14-Dihydro-15-keto-prostaglandin E
(Hereinafter, referred to as 13,14-dihydro-15-keto-PGE. Also, both are simply referred to as 15-keto-PGE) was considered to be a physiologically or pharmacologically inactive substance (Acta). Physiologica Scandinavica, 6
(6, 509, 1966).

The present inventor has conducted a pharmacological study on derivatives of 15-keto-PGE (hereinafter referred to as 15-keto-PGEs), and as a result, they have been PGE ₁ , PGE ₂ and metabolites thereof. , 14-Dihydro-15-keto-
PGE ₁ , 13,14-dihydro-15-keto-PGE ₂
Shows a blood pressure lowering effect, while the opposite of these,
It has been found that 13,14-dihydro-15-keto-PGEs (carboxylic acid type) in which the ω chain is substituted with a halogen atom show a blood pressure increasing action. Further, 13,14-dihydro-15-keto-PGEs (carboxylic acid type) in which these ω chains are substituted with a halogen atom have desirable pharmacological actions such as a blood flow increasing action and, in addition, low Since it is toxic, it is expected to be a useful drug as a wide-ranging agent for promoting circulatory function.

[0005]

The present invention provides 13,14-dihydro-15-keto- in which the ω chain is substituted with a halogen atom.
The present invention relates to a circulatory function enhancer containing a PGE (carboxylic acid type) or a physiologically acceptable salt thereof as an active ingredient.

In the present specification, the circulatory function promoting agent has at least one function enhancing function such as heart rate increasing effect, blood pressure increasing effect, blood flow increasing effect, etc., and preferably has two or more of them together. Especially, those having all of their actions are particularly useful as agents for promoting circulatory function, and are useful for recovery and maintenance of functions of patients requiring circulatory function promotion such as hypotension treatment, circulatory insufficiency, and heart disease. 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:

[Chemical 2] The carbon numbers constituting the α chain, ω chain and 5-membered ring of this basic skeleton are used as they are. That is, the number of carbons constituting the basic skeleton is carboxylic acid 1, and 2 to 7 are sequentially assigned to carbons on the α chain toward the 5-membered ring and 8 to 12
Up to 5 membered carbons and 13 to 20 on the ω chain, but when the carbon number decreases on the α chain, the number is sequentially deleted from the 2nd position and increases on the α chain. In this case, the compound is named as having a substituent at the 2-position in place of the carboxyl group (1-position). When the carbon number decreases on the ω chain, the carbon number is sequentially decreased from the 20th position, and when the carbon number increases on the ω chain, the 21st and subsequent carbon atoms are designated as substituents.

Regarding the stereoscopic configuration, the stereoscopic configuration having the above basic skeleton is used unless otherwise specified. Furthermore, PGEs are classified into PGE _1's and PGE ₂ 's depending on the way of bonding carbons at the 5, 6 and 7 positions.

PGE _1's refer to a group of compounds in which the carbons at the 5, 6 and 7 positions are bonded by a single bond, and PGE ₂ 's the carbons at the 5 and 6 positions are bonded by a double bond. Refers to a group of compounds. Therefore,

[Chemical 3] The compound having a bond represented by is called 6-keto-PGE _{1 group} ,

[Chemical 4] The compounds having the binding mode shown by are referred to as 5,6-dehydro-PGE ₂ classes. In the present invention, the cerebral function promoting action of 13,14-dihydro-15-keto-PGEs is particularly represented by the general formula:

[Chemical 5] [In the formula, Y represents a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms; Z represents a saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms substituted by a halogen atom, respectively] It is remarkable in 13,14-dihydro-15-keto-PGEs represented by

In the present invention, particularly preferred Z is

[Chemical 6] [R ₁ and R ₂ are each independently a hydrogen atom and a halogen atom, at least one of which is a halogen atom; Z ′ represents a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms] It is a base.

Y is saturated or unsaturated and has 2 to 6 carbon atoms
Examples of the hydrocarbon chain include a linear hydrocarbon chain such as an alkyl chain, an alkenyl chain and an alkynyl chain, and a hydrocarbon chain having 6 carbon atoms is particularly preferable.

An example of Y being an unsaturated hydrocarbon chain is the above-mentioned PGE ₂
Class, other 5,6-dehydro -PGE _2, such 2-3 positions PG such carbon bond is unsaturated are exemplified. A part of the carbon constituting the hydrocarbon chain represented by Y may form a carbonyl group, and a typical example thereof is 6-keto-PGE ₁ in which the carbon at 6-position forms 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 the like, and typical examples thereof are PGs having an alkyl group at the 3-position carbon.

Z represents a saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms, which is substituted with a halogen atom, and the hydrocarbon chain may itself form a ring.
The number of carbon atoms in the hydrocarbon chain is particularly preferably 3-7. Carbon number 5
The straight-chain type corresponds to general PGs in which the ω chain has 8 carbon atoms. Therefore, as described above, a hydrocarbon chain represented by Z having a carbon number of 6 or more is expressed as a substituent at the 20th carbon of the ω chain. (That is, hydrocarbons having 6 carbon atoms are referred to as 20-methyl-PGs.)

The unsaturated bond may be located at any position of Z, but one having no unsaturated bond is preferred.
Examples of the hydrocarbon chain in which Z forms a ring include a cyclopentyl group and a cyclohexyl group in which the carbon itself at the 16th or 17th position of the ω chain is the ring-constituting carbon.

The hydrocarbon chain represented by Z may be substituted with atoms or groups. These atoms or groups are halogen atoms, especially fluorine; alkyl groups such as methyl, ethyl, isopropyl, isopropenyl; alkoxy groups; for example methoxy, ethoxy; hydroxyl group; phenyl group; phenoxy group and the like. The position of the substituting atom or group is not limited, but is represented by the carbon number of the ω chain and is 16
Positions 17, 17, 19 and / or 20 are typical. A substituent, for example, an alkyl group such as methyl or 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 at the 16th position as a member; an alkyl group such as methyl at the 17th or 19th position; 20th position is methyl, ethyl, isopropyl, butyl,
A compound having an alkyl group such as isopropenyl and an alkoxy group such as methoxy, ethoxy, and propoxy is preferable.

The configuration of the hydroxyl group with respect to the 11th carbon may be α, β or a mixture thereof. This 11
In some cases, an equilibrium mixture of a hemiacetal which is a tautomer generated between the hydroxyl group at position 15 and the carbonyl at position 15 and a compound having a hydroxyl group at position 11 may be formed.
The 14-dihydro-15-keto-PGEs also include these tautomers. In particular, the following equilibrium mixtures are specific examples of tautomers.

[Chemical 7] It is easy to form an electron-attracting group at the 16-position, for example, one having fluorine.

Equilibrium mixtures of isomers, for example racemic, tautomeric hydroxy compounds and hemiacetal equilibrium also show the same effect as when used alone. The carboxyl group at the α chain end of the PGEs of the present invention is a free or physiologically acceptable salt.

The 13,14-dihydro-15-keto-PGEs of the present invention include various isomers such as tautomers, optical isomers and geometric isomers. In the present invention, among the compounds that promote circulatory function, compounds that are particularly effective in increasing the heart rate are 3
Compounds having 1 or 2 alkyl groups, especially methyl groups, halogen atoms, especially fluorine atoms, at the 16-, 16- and / or 19-positions, compounds having 8 to 10 carbon atoms in the main chain of the ω chain, 2-3 Compounds in which the carbon bond at the position is a double bond and the like.

Particularly effective for increasing heart rate, 13,14-dihydro-15-keto-P in which the ω chain is substituted with a halogen atom
Examples of GEs (carboxylic acid type) are 13,14-dihydro-
15-Keto-16R, S-Fluoro-PGE ₂ , 13,14
-Dihydro-15-keto-16R, S-fluoro-20-
Methyl -PGE _2, 13,14-dihydro-15-keto -
Examples are 16,16-difluoro-PGE ₂ , 13,14-dihydro-15-keto-16,16-difluoro-PGE _{1, and the} like.

The 13,14-dihydro-15-keto-PGEs of the present invention, which are effective in increasing blood pressure, are compounds in which the carbon bond at the 2-3 position is a double bond, and the carbons at the 16 and / or 19 positions. Preferable results are obtained in a compound in which one or two halogen atoms, particularly a fluorine atom, a methyl group are bonded, or a compound in which the main chain carbon number of the ω chain is 8 to 12.
The present invention 13,14-dihydro-1 particularly effective for increasing blood pressure
5-keto-PGEs are 13,14-dihydro-15-
Keto -16R, S- fluorosilicone -PGE _2, 13,14-dihydro-15-keto -16R, S- fluoroalkyl-20-methyl -PGE _2, 13,14-dihydro-15-keto -16,
16-difluoro-PGE ₂ , 13,14-dihydro-1
5-keto-16,16-difluoro-PGE _{1 and the} like are exemplified.

The present invention 13,14-dihydro-which has an overall favorable effect on the increase of heart rate and the increase of blood pressure.
The 15-keto-PGEs have 1 or 2 carbons at the 16-position.
A halogen atom, especially a fluorine atom, or a compound having an alkyl group, especially a methyl group, at the carbons at the 3-, 16- and / or 19-positions thereof. Examples of specific compounds, 13,14-dihydro-15-keto -16R, S- fluorosilicone -PGE _2, 13,14-dihydro-15-keto-16,16-difluoro -PGE _2, 1
An example is 3,14-dihydro-15-keto-16,16-difluoro-PGE ₁ .

The circulatory function enhancer of the present invention does not necessarily have a totally balanced compound suitable for all cases. In general, it is preferable to select a compound suitable for the patient's symptom, and for example, it is preferable to select a compound having a high blood pressure-increasing action for a large amount of bleeding with a severe decrease in blood pressure or a patient after surgery.

As a specific method for producing the 13,14-dihydro-15-keto compound used in the present invention, a synthetic chart is used.
As shown in (I), aldehyde (2) obtained by Collins oxidation of commercially available corey lactone (1) is reacted with dimethyl (2-oxohebutyl) phosphonate anion to obtain α,
β-unsaturated ketone (3) was obtained and reduced to give ketone (4)
And reacting the carbonyl group of the ketone with a diol to protect it as a ketal (5), then dep-phenylbenzoylating to give the alcohol (6), protecting the newly generated hydroxyl group with dihydropyran, It is tetrapyranyl ether (7). As a result, the ω chain becomes 13,14-
A precursor of prostaglandin Es which is a dihydro-15-keto-alkyl group is obtained. Also, the ω chain is 15-keto-
The precursor of the prostaglandin Es which is an alkyl group can be synthesized by advancing the reaction without reducing the α, β-unsaturated ketone (3).

Using the above tetrapyranyl ether (7) as a raw material,

[Chemical 8] Is -PGE ₁ (15) is tetrapyranyl ether
(7) is reduced with diisobutylaluminum hydride or the like to give lactol (8), which is reacted with an ylide obtained from (4-carboxybutyl) triphenylphosphonium bromide and then esterified, followed by 5-, 6- The double bond at the -position and the hydroxyl group at the 9-position are dehalogenated with NBS or iodine to obtain a 6-keto compound (13), which is obtained by Jones oxidation and then removing the protecting group.

Further

[Chemical 9] PGE ₂ (19) is a lactol (8) obtained by reducing the above tetrapyranyl ether (7) as shown in Synthesis Chart II, to which an ylide obtained from (4-carboxybutyl) triphenylphosphonium bromide. To give a carboxylic acid (16), followed by esterification (17), then Jones oxidation (18), and then removal of the protecting group.

Using the above tetrapyranyl ether (7) as a raw material,

[Chemical 10] To obtain PGE ₁

[Chemical 11] In the same manner as in PGE ₂ which is a compound (18), the compound (18) can be obtained by catalytically reducing the double bond at the 5th and 6th positions and then removing the protecting group. 5-, 6- and 7
The hydrocarbon chain at the − position is

[Chemical 12] The synthesis of 5,6-dehydro-PGE ₂ is a monoalkyl copper complex or a dialkyl copper complex as shown below.

[Chemical 13] By trapping copper enolate formed by 1,4-addition of 4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one with 6-carboalkoxy-1-iodo-2-hexyne or a derivative thereof. Can be synthesized. The 11-β form can be synthesized as shown in Synthesis Chart III.

[0028]

[Chemical 14]

[Chemical 15]

[Chemical 16]

[Chemical 17]

[0029]

[Chemical 18]

[Chemical 19]

[0030]

[Chemical 20]

[Chemical 21]

[Chemical formula 22]

1 in which the ω chain of the present invention is substituted with a halogen atom
3,14-Dihydro-15-keto-PGEs (carboxylic acid type) may be used as a drug for animals and humans, and is usually systemically or locally orally or intravenously injected.
It is used by methods such as (including drip), subcutaneous injection, and suppository. The dose varies depending on the animal, human, age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is preferably 0.001 to 500 mg / kg.

Solid compositions for oral administration according to the present invention include tablets, powders, granules and the like. In such a solid composition one or more active substances is combined with at least one inert diluent such as lactose,
It is mixed with mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate.
According to a conventional method, the composition is an additive other than an inert diluent,
For example, lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate, α-, β- or γ-cyclodextrin, dimethyl-α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-. An etherified cyclodextrin such as β-cyclodextrin, a branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin, a formylated cyclodextrin, a sulfur-containing cyclodextrin, and a stabilizer such as misoprotol may be contained. When the above cyclodextrins are used, they may form an inclusion compound with the cyclodextrins to increase the stability. In addition, the stability may be increased by using phospholipids and forming them into liposomes. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Further, it may be a capsule of an absorbable substance such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. This composition includes auxiliary agents such as wetting agents and suspending agents in addition to the inert diluent,
It may contain a sweetening agent, a flavoring agent, an aromatic agent, and a preservative.

Other compositions for oral administration include spray formulations 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.
Examples of the aqueous solution medium and suspension medium include distilled water for injection, physiological saline, and Ringer's solution.

The medium for non-aqueous solutions and suspensions includes
Examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a sterilizing agent, gas sterilization or radiation sterilization. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

Example 1 (Blood Pressure, Heart Rate, and Elevating Action by Intravenous Administration) As animals, 8-week-old Wistar male rats were used. Rats were anesthetized by intraperitoneal administration of urethane at 1.25 g / kg.
For blood pressure, insert a polyethylene tube into the femoral artery,
The measurement was performed by connecting to a pressure transducer. The heart rate was measured with a tachometer from the R wave of the second lead electrocardiogram of the extremities. The test drug was dissolved in ethanol, diluted with Ringer's solution before use, and intravenously administered to rats at 1 mg / kg. The maximum concentration of ethanol was 2%. The control was an ethanol-containing Ringer's solution containing no test drug, and the effect was confirmed in each experiment. Table 1 shows the results of the average values of the blood pressure and the heart rate in 3 to 4 cases obtained by obtaining the rate of change (%) by administration of the test drug.

[0037]

[Table 1] 1 13,14-Dihydro-15-keto-PGE ₁ 2 13,14-dihydro-6,15-diketo-PGE ₁ 3 13,14-dihydro-15-keto-PGE ₂ 4 13,14-dihydro-15- Keto-16R, S-Fluoro-PGE ₂ 5 PGE ₁ 6 PGE ₂ 7 PGE ₂ methyl ester 8 control

From the above results, 13,14-dihydro-15-keto-PGEs (carboxylic acid type) in which the ω chain is substituted with a halogen atom are PGs such as PGE ₂ and PGE ₂ methyl ester and It does not show the blood pressure lowering effect observed in carboxylic acid forms such as 13,14-dihydro-15-keto-PGE ₂ which does not have a halogen atom in the ω chain, but expresses a pressor effect. A positive chronotropic effect (cardiotonic effect) is also expressed.

[0039]

INDUSTRIAL APPLICABILITY The 13,14-dihydro-15-keto-prostaglandin Es (carboxylic acid type) in which the ω chain is substituted with a halogen atom of the present invention or a physiologically acceptable salt thereof has a low essential property. It is useful as a treatment for blood pressure, symptomatic hypotension, orthostatic hypotension and acute hypotension associated with various diseases or conditions, or as a pressor during shock, a therapeutic agent for circulatory insufficiency, and a cardiotonic agent.

Claims (6)

[Claims] 1. A general formula: [Wherein Y is a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms; Z is a saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms substituted by a halogen atom] A circulatory function enhancer containing 13,14-dihydro-15-keto-prostaglandin Es or a physiologically acceptable salt as an active ingredient. 2. The circulating function enhancer according to claim 1, wherein Z is a fluoroalkyl group. 3. The 13,14-dihydro-15-keto-prostaglandin Es are 13,14-dihydro-15-
The enhancer of circulatory function according to claim 1, which is a keto-16-mono- or difluoro-prostaglandin Es. 4. The circulatory function enhancer according to claim 1, which is intended to increase blood pressure. 5. The circulatory function promoting agent according to claim 1, which is intended to increase heart rate. 6. The circulatory function enhancer according to claim 1, which is intended to increase blood flow.