RU2481841C2 - Method and composition for treating diseases of peripheral vessels - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to angiology, and deals with treatment of diseases of peripheral vessels. For this purpose pharmaceutical composition, containing efficient amount of 11-deoxy-prostaglandin compound, characterised by general formula III, is introduced.

EFFECT: introduction of said composition ensures enhancement of peripheral blood flow, reduction of intraocular pressure, recovery of barrier function and increase of ATP level in endothelial cells with absence of impact on arterial pressure and heart rate.

17 cl, 8 ex, 5 tbl, 22 dwg

Description

FIELD OF THE INVENTION

The present invention relates to a method for treating peripheral vascular disease in a mammalian subject using a specific prostaglandin compound. The invention also relates to a composition useful for this method.

State of the art

Vascular diseases are often the result of reduced perfusion in the vascular system or physical or biochemical damage to blood vessels.

By peripheral vascular disease (PVD) is understood a blood vessel disease, often found in the form of narrowing of the vessels of the limbs. There are two main types of these diseases, a functional disease that does not include defects in blood vessels, but rather is due to stimuli such as cold, stress or smoking, and organic disease that occurs due to structural defects of the vascular system, such as atherosclerotic lesions, local inflammation or traumatic injury. This can lead to vessel occlusion, impaired blood flow and, ultimately, to tissue ischemia.

One of the most clinically significant forms is peripheral artery disease (PAD). PAD is often treated with angioplasty and stent implantation or with artery bypass surgery. The clinical manifestation depends on the location of the occluded vessel. For example, narrowing of an artery that supplies blood to the intestines can lead to severe pain that occurs after eating in the lower abdomen, due to the inability of the occluded vessel to provide the tissue with increased oxygen concentrations, which are necessary for digestion and absorption. Severe forms of ischemia can lead to intestinal necrosis. Similarly, PAD in the legs can lead to periodic pain, usually in the calf, which appears with active movement and accompanies it. This disorder is known as intermittent claudication (IC) and can progress to constant pain even during rest, ischemic ulcer, and even amputation.

Peripheral vascular disease also occurs in atherosclerotic stenosis of the renal artery, which can lead to renal ischemia and renal dysfunction.

One of the diseases in which vascular diseases and their complications are very common is diabetes.

Diabetes mellitus causes many physiological and anatomical disorders, the most noticeable of which is the inability of the body to properly utilize glucose, which leads to hyperglycemia. Chronic diabetes can lead to complications of the vascular system, which include atherosclerosis, abnormalities, including large and medium sized blood vessels (macroangiopathy), and abnormalities, including small blood vessels (microangiopathy), such as arterioles and capillaries.

Diabetic patients are at increased risk of developing one or more ulcers, which is the result of established long-term complications of the disease, which include weakened nervous activity (neuropathy) and / or ischemia.

Local tissue ischemia is a key factor that contributes to the development of diabetic ulceration on the legs. In addition to large vessel disease, patients with diabetes also suffer from a possible complication in the blood supply to the skin, which occurs in at least two ways. Firstly, by including non-main arteries, which are adversely affected by the process of atherosclerosis. The second and most important way involves disrupting the mechanisms that control microcirculation (small vessel disease). Usually, if any part of the body suffers from some form of damage, then within the framework of the healing mechanism of the body, it will undergo increased blood circulation. In the case of small vessel disease and ischemia, as well as in many patients with diabetes, this natural response in the form of increased blood circulation is significantly reduced. It is believed that this fact, together with the tendency in patients with diabetes to form blood clots (thrombosis) in the microcirculatory system with a low level of blood flow, is an important factor in the mechanism of development of ulcerative lesions.

Neuropathy is a general term that describes the disease process leading to dysfunction of the nervous system, and is one of the main complications of diabetes mellitus, for which there is no reliable therapy, both in case of symptomatic treatment, and to prevent progressive deterioration of nervous function.

The thickening and leakage of capillaries caused by diabetes primarily affects the eyes (retinopathy) and the kidneys (nephropathy). The thickening and leakage of capillaries caused by diabetes is also associated with skin lesions and disorders in the nervous system (neuropathy). Eye diseases associated with diabetes include non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy, glaucoma, cataract, and the like.

Other diseases, for which, although not shown to be related to diabetes, are similar in their physiological effects to the peripheral vascular system. These diseases include Raynaud's syndrome, CREST syndrome, autoimmune diseases such as erythematosis, rheumatoid disease, and the like.

Prostaglandins (hereinafter referred to as PG (s)) are representatives of the class of organic carboxylic acids that are found in tissues and organs of humans or other mammals and which exhibit a wide range of physiological activity. Naturally occurring PGs (primary PGs) typically contain a skeleton consisting of prostanoic acid, as shown in formula (A):

On the other hand, some synthetic analogues of primary PGs have modified skeletons. Primary PGs are divided into classes of PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs in accordance with the structure of the five-membered ring part of the molecule and, in addition, are divided into the following three types according to the number and position of the unsaturated bond in the hydrocarbon part of the molecule:

Subscript 1: 13.14-unsaturated-15-OH.

Lower subscript 2: 5,6- and 13,14-unsaturated-15-OH.

Subscript 3: 5,6-, 13,14- and 17,18-trisaturated-15-OH.

In addition, PGFs are classified according to the configuration of the hydroxyl group in the 9th position on the α-type (the hydroxyl group is in the α-configuration) and β-type (the hydroxyl group is in the β-configuration).

It is known that PGE ₁ and PGE ₂ and PGE ₃ have vasodilation, hypotensive activity, reduce gastric secretion, increase intestinal motility, contractile activity of the uterus, have diuretic, bronchodilation and antiulcer activity. It is known that PGF _1α , PGF _2α and PGF _3α have hypertensive, vasoconstrictive activities, enhance intestinal motility, uterine contractility, corpus luteum atrophy and have bronchoconstriction activity.

Some 15-keto-PGs (for example, those at the 15th position instead of the hydroxyl group have an oxo group) and 13,14-dihydro-15-keto-PGs (for example, those that have a single bond between positions 13 and 14) are known as compounds formed in nature by enzymes during the metabolism of primary PGs.

U.S. Patent No. 6197821 to Ueno et al. describes some 15-keto-PGE compounds that are an antagonist of endothelin, which is believed to be related to hypertension, Buerger's disease, asthma, fundus diseases, etc. (cited sources are included here by reference).

US Patent No. 6197821 suggests that if the bond between the 13th and 14th positions is saturated, a keto-semi-acetal balance can sometimes occur by forming a half-acetal between the hydroxyl group at the 11th position and the keto group at the 15th position (cited source included here by reference).

U.S. Patent No. 5317032 to Ueno et al. describes laxatives of a prostaglandin nature, including existing bicyclic tautomers, and US Patent No. 6414016 to Ueno describes bicyclic tautomers having pronounced activity as anti-constipation agents (cited sources are incorporated herein by reference). Bicyclic tautomers substituted with one or more halogen atoms can be used in small doses to relieve constipation. In particular, to relieve constipation in small doses, compounds with fluorine atoms in position C-16 can be used.

Currently used oral medications for treating peripheral vascular disease include cilostazol (commercial name: Pletaal) and prostaglandin preparations (PG) (commercial name: Dorner, Opalmon, etc.), which have a vasodilation effect as well as an antiplatelet effect, ticlopidine mainly antiplatelet effect (commercial name: Panaldine), sarpogrelate (commercial name: Anplag) and eicosapentaenoic acid ethyl ester (commercial name: Epadel), which is also adapted hyperlipemia. They have different mechanisms of action, therefore, depending on the pathology, it may be necessary to use two or three drugs in combination. In particular, with a disease of moderate severity, the use of multidrugs is more likely. Injectable preparations include prostaglandin E1 preparations, antithrombin preparations (commercial name: Argatroban). They are, in principle, used for a moderate disease or for more serious diseases requiring hospitalization.

The effectiveness of existing drugs is not completely satisfactory. In particular, antiplatelet agents, such as ticlopidine or ethyl ester of eicosapentaenoic acid, are less effective, because it is not clear how much platelets are involved in each pathology, or whether the vasodilation effect is sufficient if the drug has such an effect, or whether blood circulation in the areas ischemia to be selectively and sufficiently provided.

Disclosure of invention

The author of the present invention conducted an intensive study and found that in peripheral vascular disease 11-deoxy-prostaglandin compounds have significant selective effects, which led to the creation of the present invention.

Namely, the present invention relates to a method for treating peripheral vascular disease in a mammalian subject, which comprises administering an effective amount of an 11-deoxy-prostaglandin compound to a subject in need thereof.

The present invention also relates to a composition for treating peripheral vascular disease in a mammalian subject, which comprises an effective amount of an 11-deoxy-prostaglandin compound.

Furthermore, the present invention relates to the use of an 11-deoxy-prostaglandin compound for the manufacture of a composition for treating peripheral vascular disease in a mammalian subject, wherein the composition comprises an effective amount of the 11-deoxy-prostaglandin compound.

Another embodiment of the present invention relates to a method for treating a damaged wall of peripheral vessels and / or endothelial cells of the peripheral vessels of a mammalian subject, which comprises administering an effective amount of an 11-deoxy-prostaglandin compound to a subject in need thereof.

Brief Description of the Figures

Figa is a graph showing the effect of compound A (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ) on reduced peripheral microcirculation in rats induced by ET-1. On the graph, the data are presented as mean values ± standard. Osh., * p <0.05 compared with the solvent-treated control. CTBF: blood flow in the skin tissue.

FIG. 1B is a graph showing the effect of compound B (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ether) on ET-1-induced reduced peripheral microcirculation in rats. Data are presented as mean ± ST. Osh., * p <0.05 compared with the solvent-treated control. CTBF: blood flow in the skin tissue.

2A is a graph showing the effect of compound A on the restoration of transendothelial electrical resistance (TEER). Human vascular endothelial cell cultures were grown to confluency, as measured by transendothelial electrical resistance (TEER). Cell cultures were then deprived of oxygen for 30 minutes by incubation in a nitrogen atmosphere. Cells were then treated with either 0.1% DMSO or 5 nM Compound A and 0.1% DMSO. In all time points measured after drug administration, statistical significance is indicated. N = 10 cells.

2B is a graph showing the effect of compound A on the restoration of ATP level. Human capillary endothelial cells (adult) (HMVEC-AD) were grown to confluence. Then the cells were kept for 30 minutes in a nitrogen atmosphere and returned to the normal atmosphere of air. At the indicated time points, the ATP level was monitored using a luciferin-luciferase measurement system (ATPlite, Perkin Elmer). ATP level is presented as relative luminescence. N = 6 cells at each point.

Figure 3 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (6) obtained in Synthesis Example 2 below.

Figure 4 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (6) obtained in Synthesis Example 2 below.

Figure 5 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (9) obtained in Synthesis Example 3 below.

6 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (9) obtained in Synthesis Example 3 below.

7 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (12) obtained in Synthesis Example 4 below.

Fig. 8 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (12) obtained in Synthesis Example 4 below.

Fig.9 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (15) obtained in Synthesis Example 5 below.

Figure 10 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (15) obtained in Synthesis Example 5 below.

11 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (18) obtained in Synthesis Example 6 below.

12 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (18) obtained in Synthesis Example 6 below.

13 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (21) obtained in Synthesis Example 7 below.

Fig. 14 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (21) obtained in Synthesis Example 7 below.

FIG. 15 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (23) obtained in Synthesis Example 8 below.

Fig. 16 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (23) obtained in Synthesis Example 8 below.

17 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (25) obtained in Synthesis Example 9 below.

Fig. 18 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (25) obtained in Synthesis Example 9 below.

Fig. 19 is a ¹ H-NMR spectrum (200 MHz, CDCl ₃ ) of compound (34) obtained in Synthesis Example 10 below.

FIG. 20 is a ¹³ C-NMR spectrum (50 MHz, CDCl ₃ ) of compound (34) obtained in Synthesis Example 10 below.

The implementation of the invention

In the present invention, the “11-deoxy-prostaglandin compound” (hereinafter “the 11-deoxy-PG compound”) may include any of the derivatives or analogs (including substituted derivatives) of a compound having no substituent in the 11th position of the skeleton of prostanoic acid , regardless of the configuration of the five-membered ring, the number of double bonds, the presence or absence of a substituent, or any other modifications in the α or ω chain.

Formula (A) shows a skeleton consisting of C-20 carbon atoms, but the present invention is not limited to the aforementioned number of carbon atoms. In formula (A), the numbering of carbon atoms that make up the basic skeleton of PG compounds begins with carboxylic acid (numbered 1) and the carbon atoms in the α chain are numbered from 2 to 7 towards the five-membered ring, the atoms in the ring are numbered from 8 to 12, and the atoms in the ω-chain - from 13 to 20. If the number of carbon atoms in the α-chain decreases, the number is excluded in the order starting from position 2; and if the number of carbon atoms in the α chain increases, the compounds are called substituted compounds having corresponding substituents at position 2 instead of the carboxyl group (C-1). Similarly, if the number of carbon atoms in the ω chain decreases, the number is deleted in the order starting at position 20; and if the number of carbon atoms in the ω-chain increases, carbon atoms above position 20 are called substituents. The stereochemistry of the compounds is the same as in the above formula (A), unless otherwise indicated.

As indicated above, the nomenclature of 11-deoxy-PG compounds is based on the skeleton of prostanoic acid. However, in the case where the compounds have a similar partial structure as in prostaglandin, the abbreviation "PG" may be used. So, an 11-deoxy-PG compound in which the α chain is extended by two carbon atoms, i.e. has 9 carbon atoms in the α chain, is called 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-PG -connection. Similarly, an 11-deoxy-PG compound having 11 carbon atoms in the α chain is called a 2-decarboxy-2- (4-carboxybutyl) -11-deoxy-PG compound. In addition, the 11-deoxy-PG compound in which the ω chain is extended by two carbon atoms, i.e., which has 10 carbon atoms in the ω chain, is called the 11-deoxy-20-ethyl-PG compound. These compounds, however, may also be referred to in accordance with the IUPAC nomenclature.

Examples of analogs (including substituted derivatives) or derivatives include the 11-deoxy-PG compound in which the carboxy group at the end of the chain is esterified; a compound in which the α chain is extended; their physiologically acceptable salt; a compound having a double bond in position 2-3 or a triple bond in position 5-6, a compound having a substituent (s) in position 3, 5, 6, 16, 17, 18, 19 and / or 20; and a compound having a lower alkyl or hydroxy (lower) alkyl group at position 9 instead of a hydroxy group.

In accordance with the present invention, preferred substituents at position 3, 17, 18 and / or 19 include alkyl having 1-4 carbon atoms, in particular methyl and ethyl. Preferred substituents at position 16 include lower alkyl, such as methyl and ethyl, hydroxy, halogen atoms, such as chlorine and fluorine, and aryloxy, such as trifluoromethylphenoxy. Preferred substituents at position 17 include lower alkyl, such as methyl and ethyl, hydroxy, halogen atoms, such as chlorine and fluorine, and aryloxy, such as trifluoromethylphenoxy. Preferred substituents at position 20 include saturated or unsaturated lower alkyl, such as C1-4 alkyl, lower alkoxy, such as C1-4 alkoxy, and lower alkoxy alkyl, such as C1-4 alkoxy-C1-4 alkyl . Preferred substituents at position 5 include halogen atoms such as chlorine and fluorine. Preferred substituents at position 6 include an oxo group forming a carbonyl group. The stereochemistry of PGs having a hydroxy, lower alkyl or hydroxy (lower) alkyl substituent at position 9 may be of the α, β type, or a mixture thereof.

In addition, the above analogs or derivatives may be compounds having an alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl group at the end of the ω chain, where the chain is shorter than that of the primary PGs.

The nomenclature of 11-deoxy-PG compounds used herein is based on the numbering system of prostanoic acid represented by the above formula (A).

A preferred compound used in the present invention is represented by formula (I):

,

,

where L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, where the five-membered ring may optionally have at least one double bond;

A is —CH ₃ , —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof;

R ₁ is a saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon which is unsubstituted or substituted with a halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or gray; and

R ₀ is a saturated or unsaturated lower or middle aliphatic hydrocarbon residue that is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic a group or heterocyclic oxy group; lower alkoxy; lower alkanoyloxy; cyclo (lower) alkyl; cyclo (lower) alkyloxy; aryl; aryloxy; a heterocyclic group; a heterocyclic oxy group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur.

A more preferred compound used in the present invention is represented by formula (II):

,

,

where L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, where the five-membered ring may optionally have at least one double bond, where the five-membered ring may optionally have at least at least one double bond;

A is —CH ₃ , —CH ₂ OH, —COCH ₂ OH, —COOH, or a functional derivative thereof;

B is a single bond, —CH ₂ —CH ₂ -, —CH = CH—, —CH≡C—, —CH ₂ —CH ₂ —CH ₂ -, —CH = CH — CH ₂ -, —CH ₂ —CH = CH-, -C≡C-CH ₂ - or -CH ₂ -C≡C-;

Z is

,

или

,

,

or

,

where R ₄ and R ₅ are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, where R ₄ and R _{5 are} simultaneously not hydroxy and lower alkoxy;

R ₁ is a saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon which is unsubstituted or substituted with a halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or gray; and

Ra is a saturated or unsaturated lower or middle aliphatic hydrocarbon residue that is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or a heterocyclic hydroxy group; lower alkoxy; lower alkanoyloxy; cyclo (lower) alkyl; cyclo (lower) alkyloxy; aryl; aryloxy; a heterocyclic group; a heterocyclic oxy group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur.

A group of compounds particularly preferred among the above substances is represented by formula (III):

,

,

where L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, and where the five-membered ring may optionally have one double bond;

A is —CH ₃ , —CH ₂ OH, —COCH ₂ OH, —COOH, or a functional derivative thereof;

B is a single bond, —CH ₂ —CH ₂ ; -CH = CH-, -C≡C-, -CH ₂ -CH ₂ -CH ₂ -, -CH = CH-CH ₂ -, -CH ₂ -CH = CH-, -C≡C-CH ₂ - or -CH ₂ -C≡C-;

Z is

,

или

,

,

or

,

where R ₄ and R ₅ are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, where R ₄ and R _{5 are} simultaneously not hydroxy and lower alkoxy;

X ₁ and X ₂ are hydrogen, lower alkyl, or halogen;

R ₁ is a saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon which is unsubstituted or substituted with a halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or gray; and

R ₂ is a single bond or lower alkylene; and

R ₃ is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic hydroxy group, and at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen nitrogen or sulfur.

In the above formula, the designation "unsaturated" in the definitions of R ₁ and Ra is intended to include at least one or more double and / or triple bonds that are isolated, separate or sequentially located between the carbon atoms of the main and / or side chains. According to traditional nomenclature, an unsaturated bond between two consecutive positions is represented by indicating the number of the lowest of the two positions, and a unsaturated bond between two distal positions is represented by indicating both positions.

The term "lower or middle aliphatic hydrocarbon" refers to a linear or branched chain hydrocarbon group having from 1 to 14 hydrocarbon atoms (for the side chain, preferably from 1 to 3 carbon atoms) and preferably from 1 to 10, in particular from 6 to 10 carbon atoms for R ₁ , and from 1 to 10, in particular 1 to 8 carbon atoms for Ra.

The term “halogen” includes fluoro, chloro, bromo and iodo.

The term "lower" throughout the text is intended to include a group having from 1 to 6 carbon atoms, unless otherwise specified.

The term “lower alkyl” refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "lower alkylene" refers to a linear or branched chain bivalent saturated hydrocarbon group containing from 1 to 6 carbon atoms, and includes, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butalene, pentylene and hexylene.

The term "lower alkoxy" refers to the group of lower alkyl-O-, where lower alkyl is defined above.

The term "hydroxy (lower) alkyl" refers to lower alkyl, as defined above, which is substituted by at least one hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.

The term "lower alkanoyloxy" refers to a group represented by the formula RCO-O-, where RCO- is an acyl group formed by the oxidation of a lower alkyl group as defined above, such as acetyl.

The term “cyclo (lower) alkyl” refers to a cyclic group formed by cyclization of a lower alkyl group as defined above, but which contains three or more carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "cyclo (lower) alkyloxy" refers to the group cyclo (lower) alkyl-O-, where cyclo (lower) alkyl is defined above.

The term “aryl” may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups), for example phenyl, tolyl, xylyl. Examples of substituents are a halogen atom and halo (lower) alkyl, where a halogen atom and lower alkyl are defined above.

The term “aryloxy” refers to a group represented by the formula ArO—, where Ar is aryl, as defined above.

The term “heterocyclic group” may include from a mono to tricyclic group, preferably a monocyclic heterocyclic group represented by a 5-14, preferably 5-10 membered ring having an optionally substituted carbon atom and from 1 to 4, preferably from 1 to 3 heteroatoms of one or two types selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinylidene, pyrrolidinylidene, pyrrolidinylidene pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include a halogen and a lower alkyl group substituted with a halogen, and where a halogen atom and a lower alkyl group are described above.

The term “heterocyclic oxy group” means a group represented by the formula Hco-, where Hc is a heterocyclic group as described above.

The term “functional derivative” of Group A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.

Suitable “pharmaceutically acceptable salts” include conventionally used non-toxic salts, for example, an inorganic base salt such as an alkali metal salt (eg, sodium salt and potassium salt), alkaline earth metal salt (eg, calcium salt and magnesium salt), ammonium salt; or an organic base salt, for example, an amine salt (e.g. methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylene diamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tri (hydroxymethylamino) ethane salt, monomethyl monoethanol salt procaine and caffeine salt), a salt of a basic amino acid (e.g., an arginine salt and a lysine salt), a tetraalkylammonium salt, and the like. These salts can be obtained using conventional methods, for example, from the corresponding acid and base, or by means of salt exchange.

Examples of ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and simple 1-cyclopropylethyl ether; and middle or higher alkyl ethers, such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether; lower alkenyl ethers, such as vinyl ether, allyl ether; lower alkynyl ethers, such as ethynyl ether and propynyl ether; hydroxy (lower) alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy (lower) alkyl ethers such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, tert-butylphenyl ether, salicylic ether, 3,4-dimethoxyphenyl ether and benzamidophenyl ether; and aryl (lower) alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.

Examples of esters include aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters, such as ethinyl ester and propynyl ester; hydroxy (lower) alkyl esters such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters, such as, for example, phenyl ester, tolyl ester, tert-butyl phenyl ester, salicylic ester, 3,4-dimethoxyphenyl ester and benzamidophenyl ester; and aryl (lower) alkyl ester such as benzyl ester, trityl ester and benzhydryl ester.

The amide of group A denotes a group represented by the formula —CONR′R ″, where each of R ′ and R ″ is a hydrogen atom, lower alkyl, aryl, alkyl or aryl sulfonyl, lower alkenyl and lower alkynyl, and include, for example lower alkyl amides such as methylamide, ethylamide, dimethylamide and diethylamide; arylamides such as anilide and toluidide; and alkyl or aryl sulfonylamides such as methylsulfonylamide, ethylsulfonylamide and tolylsulfonylamide.

Preferred examples of the L group include hydroxy or oxo, which have a 5 membered ring structure in particular of the so-called PGF or PGE type.

A preferred example of group A is —COOH, a pharmaceutically acceptable salt thereof, an ester or amide thereof.

A preferred example of group B is —CH ₂ —CH ₂ -, which provides a structure of the so-called 13,14-dihydro type.

A preferred example of the groups X ₁ and X ₂ is hydrogen, or at least one of them is halogen, more preferably both of them are halogen, in particular fluorine, which provides the structure of the so-called 16.16-difluoro type.

Preferred R ₁ is a hydrocarbon containing 1-10 carbon atoms, preferably 6-10 carbon atoms. In addition, at least one of the carbon atoms in the aliphatic hydrocarbon is optionally substituted with oxygen, nitrogen or sulfur.

Examples of R ₁ include, for example, the following groups:

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-,

-CH ₂ -C≡C-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -O-CH ₂ -,

—CH ₂ —CH = CH — CH ₂ —O — CH ₂ -,

-CH ₂ -C≡C-CH ₂ -O-CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-.

—CH ₂ —CH — CH ₂ —CH ₂ —CH ₂ —CH ₂ -.

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-,

-CH ₂ -CH≡CH-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -

A preferred Ra group is a hydrocarbon containing 1-10 carbon atoms, more preferably 1-8 carbon atoms. Ra may be one or two side chains having one carbon atom.

A preferred R ₂ group is a single bond, and a preferred R ₃ group is lower alkyl. R ₃ may be one or two side chains having one carbon atom.

The configuration of the ring and the α and / or ω chains in the above formulas (I), (II) and (III) may be the same or different from the configuration in the primary PGs. However, the present invention also includes a mixture of a compound having a primary type configuration and a compound with a non-primary type configuration.

A typical example of the present compound is the compound 11-deoxy-13,14-dihydro-16,16-difluoro-PGE or -PGF, the compound 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE or -PGF, compound 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE or -PGF, or compound 11-deoxy-13,14 -dihydro-15-keto-16,16-difluoro-20-ethyl-PGE or -PGF and their derivatives or analogues. A preferred example of the present compound is 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ , 11-deoxy-13,14-dihydro-16,16-difluoro-PGE ₁ , isopropyl ester 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ , 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15- isopropyl ester keto-16,16-difluoro-PGE ₁ , 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ , isopropyl ester 11 -deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE ₁ , 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl- PGE _1, 11-deoxy-13,14-dihydro-15-keto-16,16-difto -20-ethyl-PGE ₁ methyl ester 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester 11-deoxy-13,14-dihydro-15-keto -16,16-difluoro-20-ethyl-PGE ₁ or 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGF _1α isopropyl ester.

In the present invention, for the same purpose, any isomers, such as individual tautomeric isomers, a mixture thereof or optical isomers, a mixture thereof, a racemic mixture and other steric isomers can be used.

Some compounds used in the present invention can be obtained using the method disclosed in USP Nos. 5073569, 5166174, 5221763, 5212324 and 5739161 and 6242485 (these cited sources are included here by reference).

In accordance with the present invention, a mammalian subject can be treated with the present invention by administering a compound described above. The subject may be any mammal, including humans. The compound can be applied systemically or topically. Typically, the compound can be administered by oral administration, intranasal administration, administration by inhalation, intravenous injection (including infusion), subcutaneous injection, intrarectal administration, intravaginal administration, transdermal administration, local injection into the eyes (e.g., periocular (e.g., subtenon space) ), subconjunctival, intraocular, intravitreal, intracameral, subretinal, suprachoroidal and retrobulbar methods of administration), etc.

The dose may vary depending on the breed of the animal, age, body weight, the symptom to which the treatment is directed, the desired therapeutic effect, route of administration, duration of treatment, etc. A satisfactory effect can be obtained by systemic administration 1-4 times per day or by continuous administration in an amount of 0.000001-500 mg / kg, more preferably 0.00001-100 mg / kg per day.

The compound can preferably be formulated in a pharmaceutical composition suitable for administration in a suitable manner. The composition may be in a form suitable for oral administration, injection or perfusion, and it may also be an external agent, suppository or pessary.

The composition of the present invention may further comprise physiologically acceptable additives. These additives may include ingredients used with the compounds of the present invention, such as an excipient, diluent, filler, solvent, lubricant, adjuvant, binder, disintegrant, coating agent, encapsulating agent, ointment base, suppository base, aerosol agent , emulsifier, dispersing agent, suspending agent, thickening agent, tonicity agent, buffering agent, analgesic agent, con ervant, antioxidant, corrigent, flavor, colorant, a functional material such as cyclodextrin and biodegradable polymer, stabilizer. Additives are well known in the art and can be selected from those described in generally accepted pharmaceutical manuals.

The amount of the above compound in the composition of the present invention may vary depending on the composition of the composition and can usually be 0.000001-10.0%, more preferably 0.00001-5.0%, most preferably 0.0001-1%.

Examples of solid compositions for oral administration include tablets, lozenges, sublingual tablets, capsules, pills, powders, granules, and the like. Solid compositions can be prepared by mixing one or more active ingredients with at least one inert diluent. The composition, in addition, may contain additives that are not an inert diluent, for example, a lubricant, disintegrant and stabilizer. Tablets and pills, if necessary, may be coated with an enteric film or a film soluble in the gastrointestinal tract.

They may be coated with two or more layers. They can also be adsorbed on sustained release material or microencapsulated. In addition, the compositions can be encapsulated using easily degradable material such as gelatin. They can also be dissolved in a suitable solvent, such as a fatty acid or its mono-, di- or triglyceride, to form a soft capsule. If there is a need for high-speed properties, a sublingual tablet can be used.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs and the like. The specified composition, in addition, contains traditionally used inert diluents, for example, purified water or ethyl alcohol. The composition may contain additives that are not inert diluents, such as an auxiliary agent, for example, moisturizers and suspending agents, sweeteners, flavorings, fragrance and preservatives.

The composition of the present invention may be in the form of a sprayable composition that contains one or more active ingredients and can be prepared in accordance with a known method.

Examples for injectable compositions of the present invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions and emulsions.

Diluents for an aqueous solution or suspension may include, for example, distilled water for injection, saline and Ringer's solution.

Non-aqueous diluents for the solution and suspension may include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and polysorbate. The composition may also include additives such as preservatives, moisturizers, emulsifiers, dispersants, and the like. They can be sterilized by filtration, for example through a filter that traps bacteria, mixed with autoclaving, or by gas sterilization or sterilization with exposure to a radioisotope.

The injectable composition may also be provided in the form of a sterile powder composition, which is dissolved in a sterile solvent before use.

Examples of topical agents include topical preparations known in the field of dermatology and otolaryngology, which include ointment, cream, lotion and aerosol.

The present compound is also used with an ophthalmic solution, eye drops, eye ointment, and the like. The form includes all formulations for topical administration to the eyes known in the field of ophthalmology.

An ophthalmic solution or eye drops are prepared by dissolving the active ingredients in a sterile aqueous solution, such as physiological and buffered saline, or by combining powdered compositions that are dissolved before use. Eye ointments are obtained by mixing the active ingredient with the base of the ointment. Compositions can be obtained in accordance with any conventional methods.

Modifiers that regulate osmolarity can be any of those that are traditionally used in the field of ophthalmology. Examples of osmolarity modifiers include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, boric acid, borax, sodium hydroxide, hydrochloric acid, mannitol, isosorbite, propylene glycol, glucose and glycerins.

In addition, if desired, additional agents commonly used in the field of ophthalmology may be added to the present composition. Such additives include, for example, a buffering agent (e.g. boric acid, sodium monohydrogen phosphate and sodium dihydrogen phosphate), preservatives (e.g. benzalkonium chloride, benzetonium chloride and chlorobutanol), thickeners (e.g. saccharide such as lactose and mannitol, maltose; e.g. hyaluronic acid or its salts, such as sodium hyaluronate and potassium hyaluronate; for example, a mucopolysaccharide such as chondroitin sulfate; for example, sodium polyacrylate, carboxyvinyl polymer and crosslinked polyacrylate), all of which are incorporated herein by reference .

Upon receipt of the present composition in the form of an ophthalmic ointment, the composition may contain a commonly used ointment base different from the above additional funds. Such an ointment base includes, but is not limited to, an oil base, for example, petroleum jelly, liquid paraffin, polyethylene, selenium 50, dispersed polyethylene (Plastibase), macrogol, or a combination thereof; an emulsion base having an oil phase and an aqueous phase emulsified with a surfactant; and a water soluble base such as hydroxypropyl methyl cellulose, carboxypropyl methyl cellulose and polyethylene glycol.

The present composition can be formulated in a sterile unit dosage form containing no preservatives.

Another form of the present invention is a suppository or pessary, which can be obtained by mixing the active ingredient with a conventional base, such as cocoa butter, which softens at body temperature, and non-ionic surfactants having suitable softening temperatures can be used to improve absorption.

The term “treatment,” as used herein, includes any means of controlling a disease or condition, such as prevention, care, alleviation of the condition, mitigation of the condition, and suspension of progression.

The compounds used in the present invention have a significant effect on the restoration of insufficient peripheral blood circulation, damaged peripheral vascular wall and / or peripheral vascular endothelial cells.

Thus, the compounds are useful for the treatment of peripheral vascular diseases, in particular for the treatment of peripheral vascular diseases and capillary diseases. Vascular and capillary diseases in this specification and claims may include diseases of the retina, skin, general blood circulation, kidneys, or the peripheral or autonomic nervous system. All of these diseases are often associated with diabetes and can occur in the form of symptoms associated with acute or chronic complications of diabetes. In addition, other diseases, which, although it is not known that they are related to diabetes, have similar physiological effects on the peripheral vascular system, and such diseases can also be effectively treated using the method of the present invention.

The present invention would be useful in peripheral and autonomic neuropathies or any other diseases that lead to the disease of small vessels and the disease of large vessels directly. It is believed that this beneficial effect is due to increased blood flow in small vessels and the protection of vascular endothelial cells.

The term "peripheral vascular disease" as used herein includes any peripheral vascular disease, including peripheral and autonomic neuropathies. Examples of “peripheral vascular disease” include peripheral arterial disease, such as chronic arterial vascular occlusion, including arteriosclerosis, arteriosclerosis obliterans and thromboangiitis obliterans (Burger’s disease), macroangiopathy, microangiopathy, diabetes mellitus, thrombophlebitis, phlebotrombosis, Raynaud’s syndrome, Raynaud’s syndrome, Raynaud’s syndrome, Raynaud’s syndrome , health hazard due to vibration, Sudeck syndrome, intermittent claudication, feeling of coldness in limbs, atypical sensation in limbs, sensitivity to cold, b Meniere’s disease, Meniere’s syndrome, numbness, loss of sensation, lack of sensitivity, pain at rest, causalgia (burning pain), impaired peripheral circulation, impaired nerve function, impaired motor function, motor paralysis, impaired peripheral circulation in diabetes, lumbar spinal stenosis channel, diabetic neuropathy, shock, autoimmune disease such as erythematosis, rheumatoid disease and rheumatoid arthritis, autoimmune neuropathy, diabetic veg native neuropathy, autonomic regulation disorder, orthostatic hypotension, erectile dysfunction, female sexual dysfunction, retrograde ejaculation, cystopathy, neurogenic bladder, vaginal lubrication impairment, lack of endurance during physical exertion, cardiac denervation, intolerance to high temperature, ear-and-ear complication diabetes, hyperglycemia, lack of perception of symptoms of hypoglycemia, hypoglycemic immunity; glaucoma, neovascular glaucoma, cataracts, retinopathy, diabetic retinopathy, diabetic maculopathy, occlusion of the retinal arteries, occlusion of the central retinal artery, occlusion of the retinal vein, macular edema, age-related macular degeneration, age-related disk-shaped macular degeneration, edema, cystic edema, edema , chorioretinopathy, neovascular maculopathy, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment ent epithelitis, conjunctivitis, cyclitis, scleritis, episiscleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative exfoliation of the retina, corneal ulcer, conjunctival ulcer, chronic coin-like keratitiseritis, progressive tuberculosis, tuberculosis, tuberculosis skin, including foot ulcer, diabetic ulcer, burn ulcer, lower leg ulcer, postoperative ulcer, traumatic ulcer, ulcer after herpes zoster, radiation ulcer, drug ulcer, cooling (cold injury), frostbite, gangrene and sudden gangrene, bronchial ulcer, variant angiitis, coronary arteriosclerosis (chronic coronary heart disease, asymptomatic coronary heart disease, arteriosclerotic cardiovascular disease), myocardial infarction, heart failure, congestive heart failure and congestive heart failure coronary heart disease, pulmonary edema, hypertension, pulmonary hypertension; portal hypertension; diabetic nephropathy; bedsore, renal failure.

The present composition may contain a single active ingredient or a combination of two or more active ingredients. In a combination of multiple active ingredients, their respective proportion may suitably be increased or decreased, taking into account their therapeutic effect and safety.

The pharmaceutical composition of the present invention, in addition, may contain other pharmacological ingredients, if they do not contradict the purpose of the present invention.

The present invention will be described in detail with reference to the corresponding examples, which, however, do not limit the scope of the present invention.

Example 1

Test compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁

Test compound B: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester

Male Wistar rats (7 weeks old) were used in this study. Animals were anesthetized with an intraperitoneal injection of sodium thiobutabarbital (80 mg / kg). During the experiment, the body temperature (rectal temperature) of the animals, approximately equal to 37 ° C, was maintained using a heating pad. After removing wool from the right hind limb foot lift using a depilatory cream, blood flow in skin tissues was continuously measured using a non-contact laser Doppler flowmeter (FLO-N1, Omegawave Inc., Japan). To measure the average arterial blood pressure, a polyethylene catheter placed in the left femoral artery was connected to a blood pressure sensor (TP-400T, Nihon Koden Inc., Japan) coupled to an amplifier (AP-641G, Nihon Koden Inc., Japan). Blood flow in skin tissue and blood pressure were recorded and analyzed using a computer system (HEM Ver. 3.5, Notocord Systems, France). Endothelin-1 (ET-1) was injected into the femoral artery for 15 minutes at a rate of 200 pmol / kg / min using a syringe pump through a polyethylene catheter retrogradely inserted into the caudal epigastric artery branching from the right femoral artery. After the end of the infusion at 200 pmol / kg / min, the ET-1 infusion rate was reduced to 20 pmol / kg / min and the infusion of a reduced amount of ET-1 was maintained until the end of the study. Cutaneous tissue blood flow was reduced by infusion of ET-1 into the femoral artery. When the blood flow in the skin tissues reached a new stationary level (25 to 50 minutes after the start of ET-1 infusion), animals were injected with a solvent or each test compound for 2 minutes in a volume of 1 ml / kg through a polyethylene catheter placed in the left femoral vein. The amount of test compound administered was 100 μg / kg. Skin blood flow and blood pressure were continuously measured and recorded every 5 minutes for 60 minutes after administration of the solvent or each test compound.

As shown in FIGS. 1A and 1B, by infusion of ET-1 into the femoral artery, blood flow in the skin tissue was reduced to approximately 37% of the baseline between 25 and 50 minutes after the start of ET-1 infusion. There were no differences in blood flow in skin tissues after treatment with a solvent (Figs. 1A and 1B).

In the group, which was administered 100 μg / kg of compound A (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ), blood flow in the skin tissues, which decreased to approximately 35% of the baseline after infusion, ET-1 increased significantly after administration of compound A (Fig. 1A).

In the group that was injected with 100 μg / kg of compound B (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester), blood flow in the skin tissue decreased to approximately 38% from the baseline after ET-1 infusion, increased significantly after administration of compound B (FIG. 1B).

ET-1 infusion did not affect blood pressure. Compound A and compound B in an amount of 100 μg / kg did not significantly affect blood pressure.

Example 2

Test compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ Eight male white Japanese rabbits (Std: JW / CSK) weighing approximately 2.5-3 were used in this study 5 kg. During the study, one eye in each animal was treated with the test compound, and the other eye was continuously treated with a solvent with a washing period between each treatment. Using a micropipette (Pipetman, Gilson, Inc., France), thirty microliters of each test compound solution were topically applied to one eye of each animal. The opposite eye was treated with an equal volume of solvent. Animals were treated with drugs at approximately the same time each morning. After the animals were fixed on a stand, one drop of a local anesthetic (0.4% oxybuprocaine hydrochloride) was injected into each eye and IOP was measured using an appliance pneumotonometer (Model 30 Classic ™, Mentor O&O, Inc., USA) until administration of the drug and at 1, 2, 4, 6 and 8 hours after administration.

As shown in table 1, compound A significantly reduced intraocular pressure.

Table 1 Intraocular pressure (IOP) after treatment with test compound Treatment Concentration,% n IOP (mm Hg) Time after administration (hour) Before introduction one 2 four 6 8 Solvent - 8 16.4 ± 0.9 18.3 ± 1.6 18.9 ± 1.6 18.4 ± 1.3 19.5 ± 1.7 19.0 ± 1.1 Compound A 0.0016 8 17.0 ± 0.8 13.1 ± 0.6 ** 14.5 ± 0.6 * 13.8 ± 0.8 * 15.1 ± 1.0 * 17.5 ± 1.3

Results are presented as mean ± ST. er., * p <0.05, ** p <0.01 compared to control eyes treated with solvent (paired Student's t-test).

Compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ .

Example 3

Diabetes was induced by a single intravenous injection of 50 mg / kg streptozotocin (STZ) in 7-week-old male Crl rats: CD (SD). In this study, animals with a plasma glucose level of 400 mg / dl or more were used on day 19 after STZ treatment. Three weeks after the STZ injection, the animals were anesthetized with an intraperitoneal injection of sodium thiobutabarbital. During the experiment, the body temperature (rectal temperature) of the animals, approximately equal to 37 ° C, was maintained using a heating pad. After removing wool from the right hind limb foot lift using a depilatory cream, the blood flow in skin tissues (CTBF) was continuously measured using a non-contact type laser Doppler flowmeter (FLO-N1, Omegawave Inc., Japan). At the same time, blood pressure and heart rate were monitored. Compound A or a solvent was administered intravenously to animals for 10 minutes.

As shown in table 2, compound a significantly increased blood flow in the skin tissue compared with the solvent. Compound A did not affect blood pressure (BP) and heart rate.

Results are presented as mean ± ST. Osh., * p <0.05, ** p <0.01 compared with the control group treated with the solvent.

Compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ .

Example 4

Four month old male Kbs rabbits: J.W. placed in aluminum cages in a vivarium with controlled room temperature (23-24 ° C), relative humidity (55-74%), ventilation rate (10-20 times / hour) and a 12-hour light / dark cycle (lighting: 7: 00 am - 7:00 pm). The animals were fed dry rabbit food (120 g / animal / day) and water was fed unlimitedly from an automatic feeding system. Animals were subjected to at least 6 days of quarantine and acclimatization. During this period, their body weight was measured and observations were made according to the main characteristics, and animals recognized as healthy were used in the study.

The cannula was inserted into the common carotid artery of the rabbit under isoflurane inhalation anesthesia. Nine parts of blood samples obtained through the cannula were mixed with one part of 3.8 percent (w / v) sodium citrate. After centrifuging blood samples for 10 minutes at 1000 rpm, platelet-rich plasma (PRP) was collected from the upper layer. Then, the lower layer was centrifuged for 15 min at 3000 rpm and platelet depleted plasma (PPP) was collected from the upper layer. Platelet counts in PRP and PPP fractions were performed using the ADVIA120 Hematology system (ADVIA120, Bayer Medical Ltd.). The PRP fraction was diluted with the PPP fraction so that the platelet count was adjusted to approximately 30 × 10 ⁴ cells / μl. The PRP fraction thus obtained (0.178 ml) was placed in a cuvette and incubated in a warm bath at 37 ° C for about 5 minutes. A test solution (0.022 ml) containing prostaglandin E1 or compound A was added to PRP. After one minute, 25 μM ADP solution (0.022 ml) was added and platelet aggregation (NBS hematolaser, Nikko Bioscience Inc.) was measured to measure platelet aggregation . On blood samples taken from three animals, a double analysis was performed for each test solution. The inhibition rate (in%) was estimated by comparing aggregation in the group to which the test substance was administered with the control group to which the solvent was introduced (100%).

As shown in table 3, prostaglandin E ₁ (PGE ₁ ) inhibited platelet aggregation by 20.9%, 91.2% and 89.0% at a concentration of 1 × 10 ^-8 , 1 × 10 ^-7 and 1 × 10 ^-6 g / ml, respectively. On the other hand, compound A had no effect on platelet aggregation up to the highest concentrations studied (1 × 10 ^-5 g / ml). The results show that compound A does not affect platelet aggregation.

Table 3 Group Concentration (g / ml) n Maximum aggregation (%) Inhibition (%) Control (saline) - 3 37.5 + 3.1 - Control (solvent) - 3 36.3 ± 2.8 - Compound A 1 × 10 ^-7 3 35.2 ± 3.9 3.0 1 × 10 ^-6 3 36.2 ± 4.0 0.3 1 × 10 ^-5 3 36.8 ± 3.1 -1.4 PGE ₁ 1 × 10 ^-8 3 28.7 ± 3.6 20.9 1 × 10 ^-7 3 3.2 ± 0.6 ** 91.2 1 × 10 ^-6 3 4.0 ± 0.7 ** 89.0

The maximum aggregation (in%) is the mean ± ST. osh for 3 rabbits.

** P <0.01; Significant difference from control (solvent) (Dunnett's multiple comparative test).

Example 5

Male Crl: CD (SD) rats were anesthetized by intraperitoneal injection of sodium thiobutabarbital. During the experiment, the body temperature (rectal temperature) of the animals, approximately equal to 37 ° C, was maintained using a heating pad. After removing hair from raising the foot of the right hind limb using a depilatory cream, the blood flow in the skin tissues (CTBF) was continuously measured before administration and 30 minutes after intravenous administration of compound C (11-deoxy-13,14-dihydro-16,16- difluoro-PGE ₁ ) or solvent using a non-contact type laser Doppler flowmeter (FLO-N1, Omegawave Inc., Japan). At the same time, blood pressure and heart rate were monitored.

As shown in table 4, unlike the solvent, compound B significantly increased blood flow in the skin tissue. Compound B did not affect blood pressure and heart rate.

Table 4 The effect of compound B on blood flow in the skin tissue of rats Group Dose mcg / kg, i.v. n Blood flow in skin tissues (ml / min / 100 g of tissue) Before introduction After introduction Solvent (control) 0 5 11.4 ± 1.1 10.4 ± 0.8 Compound B 10 5 11.6 ± 0.3 13.0 ± 0.2 *

Data are presented as mean ± ST. Osh., * p <0.05; compared with the control group (solvent treatment).

Example 6

Human vascular endothelial cell cultures were grown to confluency, as measured by transendothelial electrical resistance (TEER). Cell cultures were then deprived of oxygen for 30 minutes by incubation in a nitrogen atmosphere. Cells were then treated with either 0.1% DMSO or 5 nM Compound A and 0.1% DMSO. Cell density at the indicated time points was determined using TEER.

As shown in FIG. 2A, DMSO-treated cells showed very little TEER recovery. Compound A treated cells showed immediate TEER reduction.

The results show that impaired TEER, which measures the barrier function of endothelial cells, is quickly restored after treatment with compound A.

Example 7

Human capillary endothelial cells (adult) (HMVEC-AD) were grown to confluence. Then the cells were kept for 30 minutes in a nitrogen atmosphere and returned to the normal atmosphere of air. At the indicated time points, the ATP level was monitored using a luciferin-luciferase measurement system (ATPlite, Perkin Elmer).

As shown in FIG. 2B, ATP levels decreased if cells were exposed to a nitrogen atmosphere. The ATP level returned to its initial value more rapidly in cells treated with 5 nM compound A than in cells treated with only 0.01% DMSO.

Example 8

Male rats GK / Jcl, a spontaneous non-insulin-dependent diabetes model, were anesthetized by intraperitoneal injection of sodium thiobutabarbital. During the experiment, the body temperature (rectal temperature) of the animals, approximately equal to 37 ° C, was maintained using a heating pad. After removing wool from the right hind limb foot lift using a depilatory cream, the blood flow in the skin tissue (CTBF) was continuously measured before administration (baseline) and 20 minutes after the intravenous administration of compound A or solvent using a laser Doppler flowmeter (FLO-N1 , Omegawave Inc., Japan) non-contact type. The results were expressed as a percentage compared to the baseline blood flow in the skin tissues.

As shown in table 5, unlike the solvent, compound A significantly increased blood flow in the skin tissue of rats with spontaneous diabetes.

Table 5 The effect of compound A on blood flow in the skin tissue of rats with spontaneous diabetes Group Dose, mcg / kg, i.v. n Blood flow in skin tissue compared to baseline (%) Solvent (Control) 0 5 103 ± 2 Compound A twenty 5 122 ± 1 *

Data are presented as mean ± ST. Osh., * p <0.05; compared with the control group (solvent treatment).

Synthesis Example 1

Synthesis of benzyl ester 16.16-difluoro-PGA ₁ (2)

16.16-difluoro-PGE ₁ (1) benzyl ester (457.8 mg, 0.95 mmol) was dissolved in acetic acid (13.7 ml, 0.24 mol) and the solution was stirred at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature. 10 ml of toluene was added to the solution and concentrated under reduced pressure. This operation was repeated five times to remove acetic acid. The residue was purified by silica gel column chromatography (silica gel: FL60D (70 g), Fuji Silysia, hexane / ethyl acetate (2: 1)) to obtain compound (2) as a yellow oil. Yield: 391.6 mg (88.9%).

Synthesis of 11-deoxy-13,14-dihydro-16,16-difluoro-PGE ₁ (3)

16.16-difluoro-PGA ₁ benzyl ester (compound (2)) (382.5 mg, 0.83 mmol) was hydrogenated in ethyl acetate (10 ml) in the presence of 10% palladium carbon (57.4 mg, moistened with 50 % wt./wt. water) at room temperature, at atmospheric pressure for 2 hours. The reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel BW-300SP (50 g, moistened with 15% w / w water), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain the crude compound (3) (298, 5 mg, 95.7%).

The crude compound (3) was combined with another portion of the crude compound. And then, a total of about 350 mg of the crude compound was purified using preparative HPLC (YMC-Pack D-SIL-5-06 20 × 250 mm, hexane / 2-propanol / acetic acid (250: 5: 1), 20 ml / min) to obtain compound (3) as a colorless oil. Yield: 297.3 mg (recovery by purification by HPLC: 83.5%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ

0.94 (3H, t, J = 7.1 Hz), 1.22-2.29 (28H, m), 2.34 (2H, t, J = 7.3 Hz), 3.65-3 81 (1H, m)

¹³ C-NMR (50 MHz, CDCl ₃ ) δ

13.70, 22.40, 23.25, 24.32, 26.28, 26.63, 27.18, 27.58, 28.49, 29.09, 30.39, 31.77 (t, J = 24.4 Hz), 33.67, 37.63, 41.05, 54.76, 72.73 (t, J = 29.0 Hz), 124.09 (t, J = 244.3 Hz ), 179.07, 220.79.

Synthesis Example 2

According to the method described for Synthesis Example 1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester (compound (6)) was obtained as a colorless oil using the above above a two-stage reaction. Yield: 0.285 g (stage 1: 96.2%, stage 2: 97.6%, HPLC purification: recovery: 81.0%). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (6) are shown in figures 3 and 4, respectively.

Synthesis Example 3

According to the method described for Synthesis Example 1, 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester (compound (9)) was obtained as a colorless oil. Yield: 0.402 g (1st stage: 94.9%, 2nd stage: 92.2%, HPLC purification: 83.1% recovery). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (9) are shown in figures 5 and 6, respectively.

Synthesis Example 4

According to the method described for Synthesis Example 1, 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ (compound (12) ) was obtained as a colorless oil. Yield: 0.696 g (stage 1: 95.6%, stage 2: 99.3%, HPLC purification: 87.4% recovery). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (12) are shown in figures 7 and 8, respectively.

Synthesis Example 5

According to the method described for Synthesis Example 1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE ₁ isopropyl ester (compound (15)) was obtained as a colorless oils. Yield: 0.271 g (stage 1: 91.4%, stage 2: 97.3%, HPLC purification: recovery: 79.0%) ¹ H-NMR spectra (200 MHz, CDCl ₃ ) and ¹³ C NMR (50 MHz, CDCl ₃ ) for compound (15) are shown in figures 9 and 10, respectively.

Synthesis Example 6

According to the method described for Synthesis Example 1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE ₁ (compound (18)) was obtained as a colorless oil. Yield: 0.637 g (stage 1: 93.3%, stage 2: 96.6%, HPLC purification: recovery: 73.9%). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (18) are shown in figures 11 and 12, respectively.

Synthesis Example 7

According to the method described for Synthesis Example 1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE ₁ (compound (21)) was obtained as a colorless oil. Yield: 0.401 g (1st stage 90.6%, 2nd stage: 92.7%, HPLC purification: recovery: 29.2%). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (21) are shown in figures 13 and 14, respectively.

Synthesis Example 8

The 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ methyl ester (compound (23)) was obtained as a colorless oil by esterification of the compound (22) with diazomethane. Yield: 0.860 g (72.9%, after purification by silica gel column chromatography). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (23) are shown in figures 15 and 16.

Synthesis Example 9

Compound (24) (0.67 g, 1.66 mmol) was dissolved in DMF (13 ml) and K ₂ CO ₃ (460.1 mg, 3.33 mmol) and isopropyl iodide (831 μl, 8.32 mmol) were added. . The solution was stirred at room temperature for 2 hours. The reaction mixture was cooled with ice, water (10 ml) and brine were added, and extracted with ethyl acetate (30 ml). The organic layer was washed with brine (10 ml), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The precipitate was purified by silica gel column chromatography (silica gel FL60D (50 g), Fuji Silysia, hexane / ethyl acetate (5: 1)) to obtain the crude crude isopropyl ester 11-deoxy-13,14-dihydro-15-keto-16. 16-difluoro-20-ethyl-PGE ₁ (compound (25)) (0.70 g, 94.6%). The crude compound (25) was purified using preparative HPLC to obtain compound (25) as a colorless oil. Yield 245.8 mg (35.1%). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (25) are shown in figures 17 and 18, respectively.

Synthesis Example 10

Compound (26) (8.71 g, 20.2 mmol) was dissolved in 1,2-dichloroethane (70 ml) and 1,1'-thiocarbonyldiimidazole (5.41 g, 30.3 mmol) was added. The solution was stirred at 70 ° C. for one hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The precipitate was purified by silica gel column chromatography (silica gel BW-300SP (650 g), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain compound (27) as a light yellow oil (10.61 g, 97, 0%).

Bu ₃ SnH (11.21 g, 38.5 mmol) was dissolved in toluene (224 ml) and heated in a flask under reflux. A solution of compound (27) (10.41 g, 19.2 mmol) in toluene (208 ml) was added dropwise to the reaction mixture at reflux for 70 minutes. And then the reaction mixture was cooled to room temperature, concentrated under reduced pressure to obtain the crude compound (28) as a pale yellow oil.

The crude compound (28) (19.2 mmol) was dissolved in THF (52 ml) and a solution of TBAF (1.0 M in THF, 38.5 ml, 38.5 mmol) was added dropwise over 10 minutes. After one hour, a TBAF solution (1.0 M in THF, 19.2 ml, 19.2 mmol) was added dropwise to the solution. After stirring for a total of 3.5 hours, the reaction mixture was concentrated under reduced pressure. The precipitate was purified by silica gel column chromatography (silica gel BW-300SP (1000 g), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain compound (29) as a light yellow oil (4.01 g, 69, 3%).

Compound (31) was prepared from compound (29) by oxidizing Fern and introducing an ω chain.

Compound (31) (807.4 mg, 1.88 mmol) was hydrogenated in ethyl acetate (8 ml) in the presence of 10% palladium carbon at room temperature for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude compound (32) as a light brown oil.

The crude compound (32) (1.88 mmol) was dissolved in EtOH (8 ml). A 1 N NaOH solution (7.4 ml, 7.4 mol) was added dropwise to the solution at room temperature over 10 minutes. The reaction mixture was stirred at room temperature for 10 hours and then cooled with ice. 1 N HCl (7.1 ml) was added dropwise to the reaction mixture to adjust the pH to about 3-4. Then the reaction mixture was extracted with TBME (30 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The precipitate was purified by silica gel column chromatography (silica gel comprising 15% water, FL-60D (80 g), Fuji Silysia, hexane / ethyl acetate (2: 1)) to obtain compound (33) as a light yellow oil (481 4 mg, 68.8%).

According to the method described in synthesis example 9, isopropyl ester 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGF _1α (compound (34)) was obtained from compound (33) as colorless oil. Yield: 166.6 mg (reaction stage 91.9%: HPLC purification: recovery: 55.4%). Spectra ¹ H-NMR (200 MHz, CDCl ₃ ) and ¹³ C-NMR (50 MHz, CDCl ₃ ) for compound (34) are shown in figures 19 and 20, respectively.

Claims (17)

1. The use of an 11-deoxy-prostaglandin compound in the manufacture of a composition for treating peripheral vascular disease in a mammalian subject, wherein said composition comprises an effective amount of an 11-deoxy-prostaglandin compound and said compound is a compound represented by formula (III)

where L is hydroxy or oxo;
A is —COOH, or a salt, or an ester;
B is —CH ₂ —CH ₂ -;
Z is

,

or

,
R ₄ and R ₅ are hydrogen or hydroxy, wherein R ₄ and R _{5 are} simultaneously not hydroxy;
X ₁ and X ₂ are both F;
R ₁ is an unsubstituted saturated or unsaturated bivalent simple or branched hydrocarbon group having from 1 to 8 carbon atoms;
R ₂ is simple C _1-6 alkylene; and
R ₃ is a straight or branched C _1-6 alkyl. 2. The use according to claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-13,14-dihydro-prostaglandin compound. 3. The use of claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-15-keto-prostaglandin compound. 4. The use according to claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-16-mono- or dihalo-prostaglandin compound. 5. The use according to claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-13,14-dihydro-16-mono- or dihalo-prostaglandin compound. 6. The use according to claim 1, where the specified 11-deoxy-prostaglandin compound is an 11-deoxy-15-keto-16-mono- or dihalo-prostaglandin compound. 7. The use according to claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-13,14-dihydro-15-keto-16-mono or dihalo-prostaglandin compound. 8. The use according to claim 1, wherein said 11-deoxy-prostaglandin compound is an 11-deoxy-13,14-dihydro-15-keto-16-mono- or difluoro-prostaglandin compound. 9. The use of claim 1, wherein said 11-deoxy-prostaglandin compound is 11-deoxy-13,14-dihydro-15-keto-16-mono- or dihalo-prostaglandin E or F. 10. The use according to claim 1, where the specified prostaglandin compound is 11-deoxy-13,14-dihydro-15-keto-16-mono - or difluoro-prostaglandin E or F. 11. The use according to claim 1, where the specified prostaglandin compound is 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E ₁ . 12. The use according to claim 1, where the specified disease of the peripheral vessels is a disease of the peripheral arteries. 13. The use of claim 13, wherein said peripheral vascular disease is arteriosclerosis. 14. The use according to claim 1, wherein said 11-deoxyprostaglandin compound is selected from the group consisting of:
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ,
11-deoxy-13,14-dihydro-16,16-difluoro-PGE ₁ ,
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ isopropyl ester,
isopropyl ester 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ,
2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ,
isopropyl ester 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE ₁ ,
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PCE ₁ ,
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE ₁ ,
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ methyl ester,
isopropyl ester 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PCE ₁ ,
11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGF _1α isopropyl ester. 15. A composition for treating peripheral vascular disease in a mammalian subject, which comprises an effective amount of an 11-deoxy-prostaglandin compound represented by the formula (III)

where L is hydroxy or oxo;
A is —COOH, or a salt, or an ester;
B is —CH ₂ —CH ₂ -;
Z is

,

or

,
R ₄ and R ₅ are hydrogen or hydroxy, wherein R ₄ and R _{5 are} simultaneously not hydroxy;
X ₁ and X ₂ are both F;
R ₁ is an unsubstituted saturated or unsaturated bivalent simple or branched hydrocarbon group having from 1 to 8 carbon atoms;
R ₂ is simple C _1-6 alkylene; and
R ₃ is a straight or branched C _1-6 alkyl. 16. The use of an 11-deoxy-prostaglandin compound in the manufacture of a composition for treating an injured peripheral vessel wall in a mammalian subject, wherein said composition contains an effective amount of an 11-deoxy-prostaglandin compound and said compound is a compound represented by formula (III)

where L is hydroxy or oxo;
A is —COOH, or salt, or ester;
B is —CH ₂ —CH ₂ -;
Z is

,

or

,
R ₁ and R ₅ are hydrogen or hydroxy, wherein R ₄ and R _{5 are} simultaneously not hydroxy;
X ₁ and X ₂ are both F;
R ₁ is an unsubstituted saturated or unsaturated bivalent simple or branched hydrocarbon group having from 1 to 8 carbon atoms;
R ₂ is simple C _1-6 alkylene; and
R ₃ is a straight or branched C _1-6 alkyl. 17. The use of an 11-deoxy-prostaglandin compound in the manufacture of a composition for treating damaged peripheral vascular endothelial cells in a mammalian subject, wherein said composition contains an effective amount of an 11-deoxy-prostaglandin compound and said compound is a compound represented by formula (III)

where L is hydroxy or oxo;
A is —COOH, or a salt, or an ester;
B is —CH ₂ —CH ₂ -;
Z is

,

or

,
R ₁ and R ₅ are hydrogen or hydroxy, wherein R ₄ and R _{5 are} simultaneously not hydroxy;
X ₁ and X ₂ are both F;
R ₁ is an unsubstituted saturated or unsaturated bivalent simple or branched hydrocarbon group having from 1 to 8 carbon atoms;
R ₂ is simple C _1-6 alkylene; and
R ₃ is a straight or branched C _1-6 alkyl.

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