JPH085794B2 - Hyperlipidemia treatment, blood lipid component lowering agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a therapeutic agent for hyperlipidemia and a blood lipid component lowering agent. The purpose of this drug is to reduce triglyceride, cholesterol and phospholipid levels in the treatment of conditions with elevated triglyceride, cholesterol and phospholipid levels.

[Prior Art] Prostaglandins (hereinafter prostaglandins are PG
Designated as) are a group of organic carboxylic acids contained in human and other mammalian tissues or organs that exhibit a wide range of physiological activities. Naturally occurring PGs have a prostanoic acid backbone as a general structural feature.

On the other hand, some synthetic analogs have modified backbones. Natural PGs have PGAs and PGBs depending on the structural characteristics of the 5-membered ring.
, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGI
And PVJs, and the chain part is also subscript 1 ... 15-OH subscript 2 ... 5,6-unsaturated-15-OH under the presence or absence of unsaturation and oxidation. Appendix 3 ... Classified as 5,6- and 17,18-diunsaturated-15-OH.

Furthermore, PGFs are classified into α (the hydroxyl group is in the alpha position) and β (the hydroxyl group is in the beta position) according to the arrangement of the hydroxyl group at the 9-position.

Native PGE ₁ , PGE ₂ and PGE ₃ are known to have vasodilatory, hypotensive, hypogastric secretion, intestinal motility, uterine contraction, diuretic, bronchodilator and antiulcer activity. Also,
Native PGF ₁ α, PGF ₂ α and PGF ₃ α are known to have blood pressure elevation, vasoconstriction, intestinal motility, uterine contraction, luteal regression and tracheal constriction activity.

In addition, some 15-keto (ie, having an oxo group at the 15-position instead of a hydroxyl group) PGs and 13,14-dihydro-15-keto-PG are naturally produced by the action of an enzyme during the metabolism of natural PG. It is known as a substance produced by
Physiologica Scandinavia (Acta Phasiologica
Scandinavica), 66, 509, 1966]. In addition, 1
It has also been reported that 5-keto-PGF ₂ α has anti-pregnancy activity.

It is also described in EP-A-0310305 that 15-keto-PGEs can be used as laxatives. However, it has not been reported so far that the 15-keto-prostaglandin compound has an action of lowering triglyceride, cholesterol or phospholipid.

[Structure of the Invention] As a result of further studies on the properties of 15-keto-prostaglandin compounds, the present inventors have surprisingly found that these compounds have an effect of lowering blood triglyceride, cholesterol or phospholipid levels. Found to have
This invention has been completed.

That is, the present invention provides a 15-keto-prostaglandin having at least one of (a) having a halogen atom at the 16-position and (b) having an α chain terminal as a carboxylic acid or a functional derivative thereof. The present invention provides a therapeutic agent for hyperlipidemia and a hypolipidemic agent in blood, which comprises as an active ingredient.

“Hyperlipidemia” is a disease characterized by a condition in which blood lipid levels are elevated. The lipid components in the blood include triglycerides, (free and total) cholesterol and phospholipids. For example, when the blood cholesterol level is elevated, the disease is also called hypercholesterolemia.

In the present invention, the term "treatment" includes the management of any disease, including prevention, treatment, alleviation, prevention of deterioration or alleviation of deterioration.

"15-keto prostaglandin compound" means the following 15-
It is abbreviated as a keto-PG compound, but any of them can be any prostaglandin derivative having an oxo group instead of a hydroxyl group at the 15-position of the prostanoic acid skeleton regardless of the presence or absence of a double bond between the 13- and 14-positions. Including.

When naming the 15-keto-PG compounds of the present invention, the prostanoic acid number shown in formula (A) is used.

The above formula (A) has a basic skeleton of C-20, but the number of carbon atoms is not limited thereto in the present invention. That is, the numbers of the carbons constituting the basic skeleton are carboxylic acid in the order of 1- and 5-membered rings, 2 to 7 in order on the α chain carbon, 8 to 12 on the 5-membered ring, and 13 to 20. Are added to the ω chain, but when the carbon number decreases on the α chain, the number is sequentially deleted from the 2-position, and when it increases on the α chain, the carboxyl group (1st position) is substituted for the 2-position. It is named as having a substituent. Similarly, if the carbon number decreases on the ω chain,
When the carbon number is sequentially reduced from the 20th position and increased on the ω chain, the 21st and subsequent carbon atoms are designated as substituents. Regarding the three-dimensional arrangement, unless otherwise specified,
It should follow the configuration of the basic skeleton.

Therefore, the 15-keto-PG with 10 carbon atoms in the ω chain
The compound is named 15-keto-20-ethyl-PGs.

Although the above formula shows a particular configuration, which is the most typical coordination,
In this specification, unless otherwise stated, compounds are
It shall have the above arrangement.

PGD, PGE or PGF generally refers to a compound having a hydroxyl group at the 9-position and / or 11-position of prostanoic acid, but the 15-keto-prostaglandin compound of the present invention includes other compounds at the 9-position and / or 11-position. It extends to and includes compounds having a group. The above compounds are referred to as 9-dehydroxy-9-substituted or 11-dehydroxy-11-substituted compounds.

As mentioned above, the nomenclature of 15-keto-PG compounds herein is based on the prostanoic acid backbone. When this is named based on IUPAC, for example, 13,14-dihydro-15-keto-16R, S-fluoro-PGE ₂ is (Z) -7-{(1R, 2R, 3
R) -3-Hydroxy-2-[(4R, S) -fluoro-3
-Oxo-1-octyl] -5-oxo-cyclopentyl} -hept-5-enoic acid; 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE ₂
The methyl ester is methyl 7-{(1R, 2S, 3S) -3-methyl-2- [3-oxo-1-decyl] -5-oxocyclopentyl} -hept-5-enoate; 13,14-dihydro-6. , 15-Diketo-19-metric-PGE ₂ ethyl ester is ethyl 7-{(1R, 2S, 3S) -3-hydroxy-2- (7
-Methyl-3-oxo-1-octyl) -5-oxo-
Cyclopentyl} -6-oxoheptanoate.
13,14-dihydro-15-keto-20-ethyl-PGF ₂ alpha isopropyl ester isopropyl (Z) -7- [1R, 2R , 3
R, 5S) -3,5-Dihydroxy-2- {3-oxo-1-
Decyl} cyclopentyl] -hept-5-enoate; 13,14-dihydro-15-keto-20-ethyl-PGF ₂ α
Methyl ester is methyl (Z) -7-[(1R, 2R, 3R, 5
S) -3,5-Dihydroxy-2- {3-oxo-1-nonyl} -cyclopentyl] -hept-5-enoate.

The 15-eth-PG compounds used in the present invention are 15
Having an oxo group instead of a hydroxyl group at the position, (a) having a halogen atom at the 16th position, and (b) having at least one of a carboxylic acid or a functional derivative thereof at the α chain end It may be a derivative of PG and additionally has one single bond (15-keto-PG type 1 compounds), 5
One double bond between position 6 and 6 (15-keto-PG type 2
Compound), or 2 between the 5th and 6th positions and the 17th and 18th positions
It may have one double bond (15-keto-PG type 3 compound).

A typical example that can be used in the present invention has at least one of the requirements that (a) has a halogen atom at the 16-position and (b) that the α terminal chain is a carboxylic acid or a functional derivative thereof. Keto-PG type 1, 15-keto-PG type 2, 15-keto-PG type 3, 13,14-dihydro-15-keto-PG type 1, 13,14-dihydro-15-keto-PG type 2, 13,14-dihydro-15-keto-PG type 3 and the like and their derivatives.

Examples of the substitution product or derivative are the α of 15-keto-PGs described above.
A compound in which the carboxyl group at the chain end is esterified, a physiologically acceptable salt, a compound in which the carbon bond at the 2-3 position has a double bond or the carbon bond at the 5-6 position has a triple bond, the 3 position, A compound having a substituent at the 6-position, 16-position, 17-position, 19-position and / or 20-position carbon, a compound having a lower alkyl group or a hydroxy (lower) alkyl group instead of the 11-position hydroxyl group, and the like.

In the present invention, examples of the substituent bonded to the carbon atom at the 3-position, 17-position and / or 19-position include, for example, 1 to 4 carbon atoms.
And an alkyl group, especially a methyl group and an ethyl group. As the substituent bonded to the carbon atom at the 16th position,
Examples thereof include lower alkyl groups such as methyl group and ethyl group, hydroxyl group, halogen atoms such as chlorine and fluorine, and aryloxy groups such as trifluoromethylphenoxy. The substituent bonded to the 20th carbon atom may be a saturated or unsaturated lower alkyl group such as C _1-4 alkyl, C
_It includes lower alkoxy groups such as _1-4 alkoxy, lower alkoxyalkyl such as C _1-4 alkoxy-C _1-4 alkyl. Substituents on the 6th carbon atom include oxo groups that form carbonyl groups. When the carbon atom at the 9- and / or 11-position has a hydroxy group, a lower alkyl or a lower (hydroxy) alkyl substituent, the configuration of these groups may be α, β or a mixture thereof.

Further, the above derivative may be one having a substituent such as an alkoxy group, a phenoxy group or a phenyl group at the ω chain end of a compound in which ω is shorter than natural PGs.

Particularly preferred compounds include a compound having a lower alkyl group such as a methyl group and an ethyl group at the 16-position carbon, a compound having a halogen atom such as chlorine and fluorine, a lower alkyl group such as a methyl group and an ethyl group at the 19-position carbon. A compound having an alkyl group, a compound having an oxo group at the 6-position carbon, a compound having a lower alkyl group such as a methyl group or an ethyl group at the 20-position carbon, and an alkyl chain after the 16-position carbon Instead, it is a compound in which a phenyl group or a phenoxy group which may have a substituent such as a halogen atom or a halogen-substituted alkyl group is bonded to the 16th carbon atom.

The preferred compounds used in this invention are of formula (I) [Wherein X and Y are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo (provided that at least one of the groups X and Y is a group other than hydrogen, and the 5-membered ring is At least one double bond), Z is hydrogen or halogen, A is —CH ₂ OH, —COH ₂ OH, —COOH or a functional derivative thereof, R ₁ is unsubstituted or halo, oxo Or an aryl-substituted, divalent saturated or unsaturated, low to intermediate aliphatic hydrocarbon residue, R ₂ is unsubstituted or oxo, hydroxy, halo,
Saturated or unsaturated, low to intermediate aliphatic hydrocarbon residue substituted with lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, aryl or aryloxy (provided that it is the third from the 5-membered ring side). A carbon atom is substituted with an oxo group) ".

In the above formula, the term “unsaturated” in R ₁ and R ₂ means at least one or more double bonds and / or triple bonds independently as a bond between carbon atoms of the main chain or side chains, It is meant to include separately or continuously. In accordance with normal nomenclature, the unsaturation between two consecutive positions is indicated by displaying the younger position number, and the unsaturation between two non-consecutive positions is indicated by displaying both position numbers. Preferred unsaturation is a double bond at the 2-position and a double or triple bond at the 5-position.

The term "low to middle aliphatic hydrocarbon" means a hydrocarbon having a straight or branched chain having 1 to 14 carbon atoms (however, the side chain preferably has 1 to 3 carbon atoms), and Is R ₁
Is a hydrocarbon having 2 to 8 carbon atoms, and R ₂ is a hydrocarbon having 6 to 12 carbon atoms.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The term “lower” is intended to include a group having 1 to 6 carbon atoms unless otherwise specified.

The term "lower alkyl" includes straight or branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl,
Includes ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

The term "lower alkoxy" means a lower alkyl-O- group in which lower alkyl is as defined above.

The term "hydroxy (lower) alkyl" means an alkyl as described above substituted with at least one hydroxy group, for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxy. It is ethyl.

The term "lower alkanoyloxy" refers to the formula RCO-O-
(Here, RCO- refers to a group represented by acyl, such as acetyl, produced by oxidation of the above lower alkyl.

The term "cyclo lower alkyl" means a group resulting from ring closure of a lower alkyl group as described above.

The term "aryl" includes optionally substituted aromatic carbocyclic or heterocyclic groups (preferably monocyclic groups) and includes, for example, phenyl, tolyl, xylyl and thienyl. The substituent includes halogen and a halogen-substituted lower alkyl group (wherein the halogen atom and the lower alkyl group have the same meanings as described above).

The term "aryloxy" means a radical of the formula ArO-, where Ar is an aryl radical as described above.

The term "functional derivative" of the carboxyl group represented by A includes salts (preferably pharmaceutically acceptable salts), esters and amides.

Suitable "pharmaceutically acceptable salts" include commonly used non-toxic salts, salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, Magnesium salt, etc.), ammonium salt, salt with organic base, for example, amine salt (eg, methylamine, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt,
Ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, procaine salt, caffeine salt, etc.), basic amino acid salt (eg, arginine salt, lysine salt, etc.) Examples thereof include tetraalkylammonium salts. These salts may be prepared, for example, from the corresponding acids and bases by conventional methods or by salt exchange.

Examples of the ester include lower alkyl ester such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isopropyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester, vinyl ester, allyl ester and the like. Lower alkenyl ester, ethynyl ester, propynyl ester, etc. lower alkynyl ester, hydroxyethyl ester such as hydroxyethyl ester, methoxymethyl ester, 1-
Aliphatic esters such as lower alkoxy (lower) alkyl esters such as methoxyethyl ester and optionally phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-dimethoxyphenyl ester, benzamide phenyl ester, etc. Substituted aryl ester, benzyl ester,
Examples thereof include aryl (lower) alkyl esters such as trityl ester and benzhydryl ester.

Examples of the amide include mono- or di-lower alkylamides such as methylamide, esylamide and dimethylamide, arylamides such as anilide and toluidide, and alkyl or arylsulfonylamides such as methylsulfonylamide, ethylsulfonylamide and tolylsulfonylamide.

Examples of preferred A _{groups, -COOH, -COOCH 3, -COOCH 2} CH
_{3, -COOCH (CH 3) 2} , a -CONHSO ₂ CH _3.

In the above formula (I), the arrangement of rings, α and / or ω chains may be the same as or different from the arrangement of natural prostaglandins. However, the invention also includes mixtures of compounds having a natural configuration and compounds having a non-natural configuration.

An example of typical compounds of this invention is 15-keto-PG
S, 13,14-dihydro-15-keto -PG acids and 6-keto derivatives, △ ² - derivative, 3R, S- methyl derivatives, 16R, S-
These are methyl derivatives, 16,16-dimethyl derivatives, 16R, S-fluoro derivatives, 16,16-difluoro derivatives, 17S-methyl derivatives, 19-methyl derivatives, 20-methyl derivatives and 16-debutyl-16-phenoxy derivatives.

In the 15-keto-PG compound used in this invention, 13,1
When the 4-position is saturated, hemiacetal formation between the hydroxy at the 11-position and the keto at the 15-position may result in a keto-hemiacetal equilibrium.

When such tautomers exist, the abundance ratios of both isomers vary depending on the structures of other moieties or the types of substituents, and in some cases, one isomer may predominantly exist. In the present invention, both of them are included, and a compound may be represented by a keto-type structural formula or a nomenclature regardless of the presence or absence of such isomers. It does not try to exclude the compound.

In the present invention, isomers such as individual tautomers, mixtures thereof or optical isomers, mixtures thereof, racemates and other stereoisomers can be used for the same purpose.

Some of the compounds used in this invention are disclosed in JP-A-64-
It can be produced by the method described in 52753. Alternatively, these compounds may be prepared by methods similar to those described herein or known.

The compound used in the present invention can be used as a drug for animals and humans, and is usually used systemically or locally by a method such as oral, intravenous injection (including drip), subcutaneous injection, and rectal administration. . The dose varies depending on the type of subject such as animal or human, age, weight, symptom to be treated, desired therapeutic effect, administration method, treatment period, etc., but usually 2 to 4 divided doses per day or When administered in a continuous form, a dose of 0.001 to 500 mg / kg usually gives a sufficient effect.

Solid compositions for oral administration according to this invention include tablets, troches, sublingual tablets, capsules, pills, powders,
Granules and the like are included. In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Acid mixed with magnesium aluminate. According to a conventional method, the composition has an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin gluconate, an α, β or γ-cyclodextrin, and dimethyl-α. -, Dimethyl-β-, trimethyl-β
-Or hydroxypropyl-β-cyclodextrin or other etherified cyclodextrin, glycosyl, branched cyclodextrin such as maltosyl-cyclodextrin, formylated cyclodextrin, sulfur-containing cyclodextrin, misoprotol, stabilizers such as phospholipids You can leave. When the above cyclodextrins are used, an inclusion compound may be formed with the cyclodextrins to increase the stability in some cases. In addition, stability may be increased by forming liposomes using phospholipids. 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, capsules made of a disintegrable substance such as gelatin may be used. When immediate action is required, a sublingual tablet may be used. Glycerin, lactose and the like may be used as a base.

Liquid compositions for oral administration include emulsions, solutions,
Suspensions, syrups, elixirs and the like are exemplified. It may contain a commonly used inert diluent such as purified water and ethanol. The composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.

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 solvates of suspensions include, for example, distilled water for injection, physiological saline and Ringer's solution.

Examples of the non-aqueous medium for liquids and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate. 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 to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

Another form is a suppository or pessary. These suppositories can be prepared by mixing an active ingredient with a base softening at body temperature such as cacao butter, and the absorbency may be improved by using a nonionic surfactant having an appropriate softening temperature.

[Effect] The agent for treating hyperlipidemia and the agent for lowering blood lipid according to the present invention have an action of reducing triglyceride, cholesterol or phospholipid in blood. Further, one mechanism of action of the agent of the present invention is through in vitro excretion of triglyceride, cholesterol or phospholipid, which promotes excretion of triglyceride, cholesterol or phospholipid in blood into the intestine or as feces. Based on the action. Therefore, the agent of the present invention, regardless of the cause of various diseases, drug administration or dietary properties, treatment of serum cholesterol abnormality, triglyceride abnormality or phospholipid abnormality, for example, prevention, treatment, reduction of deterioration, Useful for maintenance. Further, the agent of the present invention is also suitable for treating the above-mentioned abnormality when accompanied by obesity.

[Examples] Hereinafter, the present invention will be described in more detail with reference to formulation examples and test examples, but these do not limit the present invention.

Formulation Example 1 (hard gelatin capsule) 13,14-dihydro-15-keto-16R, S-fluoro PGE ₂ 500 mg lactose 200 mg The above are mixed and filled into a gelatin hard capsule.

Formulation Example 2 (powder for injection) (parts by weight) 13,14-dihydro-15-keto-16,16-difluoro PGE ₂ ^* 1 Mannitol 5 Sterile water 0.4 Mix the above components, stir and filter before Lyophilized to obtain powder for injection.

Formulation Example 3 (injection solution) (parts by weight) 13,14-dihydro-15-keto-16,16-dimethylmethyl PGE ₂ 0.2 Nonionic surfactant 2 Sterile water for injection 98 Sterilized by mixing the above components To give an injectable solution.

Formulation Example 4 13,14-Dihydro-15-keto-1 in methanol (10 ml)
6,16- difluoro-20-dissolving ethyl -PGE ₂ (50mg), further resulting solution was mixed with mannitol (18.5 g). The mixture was screened (pore size: 30 mm), dried at 30 ° C. for 90 minutes and then screened again. The resulting powder was mixed with particulate silica gel (Aerosil, 200 g) and the mixture was filled into a # 3 hard gelatin capsule (100). Capsules are enteric capsules containing 13,14-dihydro-15-keto-16,16-difluoro-20-ethyl--PGE ₂ of 0.5mg per capsule.

Formulation Example 5 (powder for oral administration) (parts by weight) 13,14-dihydro-15-keto-16,16-difluoro-PGF ₂ α-methyl ester 5 Light weight silicic anhydride 5 Avicel 20 Lactose 70 Mix the above ingredients Thus, powder for oral administration was obtained.

Formulation Example 6 (gelatin soft capsule) (parts by weight) 13,14-dihydro-15 keto-20-methyl-PGE ₂ methyl ester 1 Panasate 899 The above ingredients were mixed and filled into a gelatin soft capsule.

Formulation Example 7 (Enteric coated capsule) 16-desbutyl-13,14-dihydro-15-keto-16- (m-trifluoromethyl) phenoxy-PGF ₂ α methyl ester (50 mg) was dissolved in methanal (10 ml), The resulting solution was further mixed with mannitol (18.5g). The mixture was screened (pore size: 30 mm), dried at 30 ° C. for 90 minutes and then screened again. The resulting powder was mixed with particulate silica gel (Aerosil, 200 g) and the mixture was filled into a # 3 hard gelatin capsule (100). Capsules contain 0.5 mg of 13,14-dihydro-15-keto-16- per capsule.
An enteric-coated capsule containing desbutyl-16- (m-trifluoromethyl) phenoxy-PGF ₂ α methyl ester.

Test Example 1 Male Wistar rats (8 weeks old) were anesthetized with 40 mg / kg (intraperitoneal) pentobarbital, and the cortex of the left kidney was partially excised. The right kidney was removed after 3 to 7 days and finally 1
3/4 to 14/5 renal tissue was excised. As a test compound,
13,14-dihydro-15-keto-16R, S-fluoroprostaglandin E ₂ was added to distilled water, sonicated and homogenized, and at a rate of 3 mg / kg / ml, 2 weeks after nephrectomy Orally for 2 weeks continuously (3 animals per group). The same amount of distilled water was orally administered to the control group.

Immediately after the start of administration, 2 days and 1 week after the start of administration, feces were collected, and after 2 weeks, the abdominal contents were collected to collect triglyceride (TG), phospholipid (PL), free cholesterol (F-CHO), total cholesterol ( The total excretion amount of T-CHO) was measured.

Furthermore, one week after the start of administration, blood was collected from the jugular vein under non-anesthesia, and total protein (TP), albumin (ALB),
Glucose (GLU), triglycerides, phospholipids, free cholesterol, total cholesterol were measured.
The body weight and the amount of drinking water were measured immediately before the test period and during the test period.

 The results are shown in the table below.

* P <0.1 ** P <0.05, *** P <0.01, significant difference.

From these results, it is understood that serum phospholipid, fiber cholesterol, total cholesterol and triglyceride levels are significantly reduced in the administration group.

In addition, the effects on body weight and food intake were hardly observed in the administration group.

Furthermore, no difference was observed in the total protein, albumin and glucose concentrations in serum between the administration group and the control group,
No effect on serum nutritional status was observed in the dose group.

Test Example 2 13,14-dihydro-15-eco-16,16 as a test compound
- except difluoro-PGF ₂ using 1.0 mg / kg were tested in the same manner as in Test Example 1. Total amount in feces on day 5 after the start of administration,
The total amount in the intestinal contents on day 14 and the serum concentration on day 14 are shown below.

Test Example 3 Crj: Wister rats were used in groups of 5 and 13,14-dihydro-15-keto-20-ethyl-PGF ₂ α-isopropyl ester was dissolved as a test compound in physiological saline to give a dose of 5 m.
L / kg was subcutaneously administered to the back once a day for 14 consecutive days. The dose of the test compound was 20 mg / kg per day. In addition, only physiological saline was administered to the control group. The concentration of triglyceride (TG) in serum after 14 days is shown below.

From these results, it is clear that triglycerides, cholesterol, and phospholipids are significantly excreted in feces or intestinal contents in the administration group.

Claims (9)

[Claims] 1. A 15-keto-prostaglandin compound having at least one of the following requirements: (a) having a halogen atom at the 16-position; and (b) having an α chain terminal as a carboxylic acid or a functional derivative thereof. A therapeutic agent for hyperlipidemia, which comprises: 2. A 15-keto-prostaglandin compound having at least one of (a) having a halogen atom at the 16-position, and (b) having an α chain terminal as a carboxylic acid or a functional derivative thereof. A blood lipid component reducing agent containing as an active ingredient. 3. The agent according to claim 1, wherein the lipid component is triglyceride, cholesterol or phospholipid. 4. The agent according to claim 1, which is for treating hyperlipidemia. 5. The agent according to claim 1, which is used for treating hypercholesterolemia. 6. A 15-keto-prostaglandin compound,
The agent according to claim 1 or 2, which is a 16-mono- or dihalo-15-keto-prostaglandin compound. 7. A 15-keto-prostaglandin compound,
The agent according to claim 1 or 2, which is a 13,14-dihydro-16-mono- or difluoro-15-keto-prostaglandin compound. 8. A 15-keto-prostaglandin compound,
The agent according to claim 1 or 2, which is a 6,15-diketo-prostaglandin compound. 9. A 15-keto-prostaglandin compound,
The agent according to claim 1 or 2, which is 13,14 dihydro-16-mono or difluoro-15-keto-prostaglandin Es.