MX2007010746A - Method and composition for treating peripheral vascular diseases. - Google Patents

Abstract

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

Description

METHOD AND COMPOSITION TO TREAT PERIPHERAL VASCULAR DISEASES TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for treating peripheral vascular diseases in a mammalian subject using a specific prostaglandin compound. The invention also relates to a composition that is useful for the method BACKGROUND OF THE INVENTION Vascular diseases are often the result of decreased perfusion in the vascular system or physical or biochemical damage to the blood vessel. Peripheral vascular disease (PVD) is defined as a disease of the blood vessels often found as narrowing of the vessels of the extremities. There are two main types of these disorders: functional disease that does not involve defects in the blood vessels but rather arises from stimuli such as cold, stress or smoking, and organic diseases that originate from structural defects in the vasculature such as atherosclerotic lesions, inflammation local or traumatic injury. This can lead to occlusion of the blood vessel, flow aberrant blood and usually to tissue ischemia. One of the most clinically significant forms of PVD is peripheral artery disease (PAD). PAD is often treated by angioplasty and stent implantation or by arterial bypass surgery. The clinical presentation depends on the location of the occluded vessel. For example, the narrowness of the artery supplying blood to the intestine can result in severe postprandial pain in the lower abdomen that results from the inability of the occluded vessel to satisfy the increased oxygen demand arising from the digestive and absorption processes. Severe forms of ischemia can lead to intestinal necrosis. Similarly, PAD in the leg can lead to intermittent pain, usually in the calf, which comes and goes with the activity. This disorder is known as intermittent claudication (IC) and may progress to persistent pain while at rest, ischemic ulceration and even amputation. Peripheral vascular disease also manifests in atherosclerotic stenosis of the renal artery, which can lead to renal ischemia and kidney dysfunction. A disease in which vascular diseases and their complications are very common is diabetes mellitus. Diabetes mellitus causes a variety of physiological and anatomical irregularities, the most prominent being the inability of the body to use glucose in a normal manner, resulting in hyperglycemia. Chronic diabetes can lead to complications of vascular system including atherosclerosis, abnormalities involving large and medium size blood vessels (macroangiopathy) and abnormalities involving small blood vessels (microangiopathy) such as arterioles and capillaries. Patients with diabetes mellitus are at increased risk of developing one or more foot ulcers as a result of established long-term complications of the disease, including altered nerve function (neuropathy) and / or ischemia. Local tissue ischemia is a key contributor to diabetic foot ulceration. In addition to large vessel disease, patients with diabetes have a subsequent threat to their skin perfusion in at least two additional ways. First, through the involvement of non-conductive arteries, which are detrimentally affected by the atherosclerosis process. Second, and perhaps the most important, by altering the mechanisms of microcirculatory control (diseases of small vessels). Normally, when a part of the body suffers some form of trauma, the part of the body, as part of the healing mechanism of the body, will experience increased blood flow. When small vessel disease and ischemia are present, as in the case of many diabetics, this increased blood flow response is significantly reduced. This fact, together with the tendency of diabetics to form blood clots (thrombosis) in the microcirculatory system during low levels of blood flow, is thought to be an important factor in the ulcer pathogenesis. Neuropathy is a general term that describes a disease process that leads to nervous system dysfunction, and one of the major complications of diabetes mellitus, with therapies not well established either for symptomatic treatment or for prevention of progressive decline in function nervous. The thickening and draining of capillaries caused by diabetes mainly affects the eyes (retinopathy) and kidneys (neuropathy). Thickening and draining of capillaries caused by diabetes are also associated with skin disorders and nervous system disorders (neuropathy). The eye diseases associated with diabetes are non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy, glaucoma, cataracts and the like. Others, although not known to be related to diabetes, are similar in their physiological effects on the peripheral vascular system.

Such 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 members of the class of organic carboxylic acids, which are contained in tissues or organs of humans or other mammals, and exhibit a wide range of physiological activity. The PGs found in nature (mainly PGs) generally have a basic structure of prostanoic acid as it is known in the formula (A): (string a) On the other hand, some of the synthetic analogs of the primary PGs have base structures. The primary PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-member ring portion, and are further classified into the following three types by the number and position of the unsaturated bond in the carbon chain portion: Subindex 1: 13,14-unsaturated-15-OH Subindex 2: 5,6- and 13,14-di-unsaturated-15-OH Subindex 3: 5, 6-, 13,14-, and 17,18-th-unsaturated-15-OH. In addition, the PGFs are classified, according to the configuration of the hydroxyl group at position 9, at type a (the hydroxyl group is of a configuration a) and type ß (the hydroxyl group is of a configuration P) - It is known that PGEi and PGE2 and PGE3 have activities of vasodilation, hypotension, decreased gastric secretion, increased movement of the intestinal tract, uterine contraction, diuretics, bronchodilation and anti-ulcer. It has been known that PGF1a, PGF2a and PGF3a have activity of hypertension, vasoconstriction, increased movement of the intestinal tract, uterine contraction, atrophy of luteal body and bronchoconstriction. Some 15-ketoes (ie, having oxo at position 15 instead of hydroxy), -PGs and 13,14-dihydro (ie having a double bond between positions 13 and 14) -15-keto- PGs are known as substances naturally produced by the action of enzymes during the metabolism of Primary PGs. The patent of E.U.A. No. 6,197,821 to Ueno et al., Discloses that some compounds of 15-keto-PGE are an endothelin antagonist that is considered to be related to hypertension, Buerger's disease, asthma, diseases of the base of the eyes and the like (the cited reference is incorporated herein by reference). The patent of E.U.A. No. 6,197,821 indicates that when the bond enters positions 13 and 14 is saturated, a keto-hemiacetal equilibrium can sometimes be formed by the formation of a hemiacetal between the hydroxyl group in position 11 and the keto group in the position 15 (the cited reference is incorporated herein by reference). The patent of E.U.A. No. 5,317,032 to Ueno et al., Describes prostaglandin compound cathartics, including the existence of bicyclic tautomers and the U.S. patent. No. 6,414,016 to Ueno describes bicyclic tautomers as having pronounced activity as anti-constipation agents (references cited are incorporated herein by reference). The bicyclic tautomers, substituted by one or more atoms of Halogen can be used in small doses to relieve constipation. At position C-16, especially fluorine atoms can be used in small doses to relieve constipation. Oral drugs currently used for vascular diseases include cilostazol (trade name: Pletaal) and prostaglandin (PG) preparations (trade names: Comer, Opalmon, etc.) which have a vasodilating effect as well as an antiplatelet effect, mainly ticlopidine which has a antiplatelet effect (trade name: Panaldine), sarpogrelate (trade name: Anplag) and ethyl icosapentate (trade name: Epadel) which is also adaptable to hyperlipidemia. They have different mechanisms of action, so it may be necessary to use two or three preparations in combination depending on the pathology. Particularly in median disease, multiple drugs are more likely to be applied. Injectable preparations include preparations of prostaglandin E1, preparations of antithrombin (trade name: Argatroban). In principle they are used for medium or more severe diseases that require italization. The effectiveness of existing drugs is not completely satisfactory. Particularly, antiplatelets such as ticlopidine or ethyl icosapentate are less effective, probably because it is unclear to what extent the platelets are involved in each pathology, or if the vasodilatory effect is sufficient even when a drug has such an effect, or if the bloodstream in ischemic sites can be assured selectively enough.

BRIEF DESCRIPTION OF THE INVENTION The inventor of the present invention conducted an intensive study and found that the 11-deoxy-prostaglandin compounds possessed significant selective effects on peripheral vascular diseases, which resulted in the conclusion of the present invention. Namely, the present invention relates to a method for treating a peripheral vascular disease in a mammalian subject, comprising administering an effective amount of an 11-deoxy-prostaglandin compound to the subject in need thereof. The present invention further relates to a composition for treating a peripheral vascular disease in a mammalian subject, comprising an effective amount of an 11-deoxy-prostaglandin compound. In addition, the present invention relates to the use of an 11-deoxy-prostaglandin compound for the manufacture of a composition for treating a peripheral vascular disease in a mammalian subject, wherein the composition comprises an effective amount of a 11-deoxy compound. -prostaglandin. Another embodiment of the present invention relates to a method for treating peripheral vascular wall and / or vascular endothelial cells damaged peripherals in a mammalian subject, comprising administering an effective amount of a 11-deoxy-prostaglandin compound to the subject in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A is a graph showing the effect of compound A (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE1) on the decreased peripheral microcirculation in rats induced by ET-1. In the graph, the data is shown as the mean ± D.E., * p < 0.05 compared to the control treated with vehicle. CTBF: cutaneous tissue blood flow. Figure 1B is a graph showing the effect of compound B (isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE?) On the decreased peripheral microcirculation in rats induced by ET-1. The data is presented as the mean ± D.E., * p < 0.05 compared to the control treated with vehicle. CTBF: cutaneous tissue blood flow. Figure 2A is a graph showing the effect of Compound A on the recovery of the transendothelial electrical resistance (TEER). Human vascular endothelial cell cultures were brought to confluence, as measured by transendothelial electrical resistance (TEER). The cell cultures were then devoid of oxygen for 30 minutes by incubation in a nitrogen atmosphere. The cells were then treated with either 0.1% DMSO or 5 nM Compound A in DMSO at 0. 1 %. Statistical significance is indicated at all data points after drug treatment. N = 10 cells. Figure 2B is a graph showing the effect of compound A on recovery of the ATP level. Human microvascular endothelial cells (adult) (HMVEC-AD) were grown to confluence. The cells were then exposed for 30 minutes to a nitrogen atmosphere and returned to the normal air atmosphere. ATP levels were monitored at the indicated time points using a luciferin-luciferase test system (ATPIite, Perkin Elmer). ATP levels are given as relative luminescence. N = 6 cells at each time point. Figure 3 is a diagram of 1 H-NMR (200MHz, CDCl 3) of the compound (6) obtained in the following synthesis example 2. Figure 4 is a 13C-NMR diagram (50MHz, CDCI3) of the compound (6) obtained in the following synthesis example 2. Figure 5 is a diagram of 1 H-NMR (200 MHz, CDCl 3) of the compound (9) obtained in the following synthesis example 3. Figure 6 is a 13C-NMR diagram (50MHz, CDCI3) of compound (9) obtained in synthesis example 3 below. Figure 7 is a 1 H-NMR diagram (200 MHz, CDCl 3) of the compound (12) obtained in the following synthesis example 4. Figure 8 is a 13C-NMR diagram (50MHz, CDCI3) of the compound (12) obtained in the following synthesis example 4.

Figure 9 is a 1 H-NMR diagram (200MHz, CDCl 3) of the compound (15) obtained in the following Synthesis Example 5. Figure 10 is a 3C-NMR diagram (50MHz, CDCI3) of the compound (15) obtained in the synthesis example 5 below. Figure 11 is a 1 H-NMR diagram (200 MHz, CDCl 3) of the compound (18) obtained in the following Synthesis Example 6. Figure 12 is a 13C-NMR (50MHz, CDCI3) diagram of the compound (18) obtained in the following Synthesis Example 6. Figure 13 is a H-NMR diagram (200MHz, CDCI3) of the compound (21) obtained in the following synthesis example 7. Figure 14 is a 13C-NMR diagram (50MHz, CDCI3) of the compound (21) obtained in the following synthesis example 7. Figure 15 is a 1 H-NMR diagram (200MHz, CDCl 3) of the compound (23) obtained in the synthesis example 8 below. Figure 16 is a 13C-NMR diagram (50MHz, CDCI3) of the compound (23) obtained in the synthesis example 8 below. Figure 17 is a 1 H-NMR diagram (200 MHz, CDCl 3) of the compound (25) obtained in the following Synthesis Example 9. Figure 18 is a 13C-NMR (50MHz, CDCI3) diagram of the compound (25) obtained in the following Synthesis Example 9. Figure 19 is a 1H-NMR diagram (200MHz, CDCI3) of the compound (34) obtained in the following synthesis example. Figure 20 is a 13C-NMR (50MHz, CDCI3) diagram of the compound (34) obtained in synthesis example 10 below.

DETAILED DESCRIPTION OF THE INVENTION In the present invention, the "11-deoxy-prostaglandin compound" (hereinafter referred to as "11-deoxy-PG compound") can include any of the derivatives or analogs (including substituted derivatives) of a compound that does not it has a substituent at the 11-position of the base structure of prostanoic acid, irrespective of the configuration of the five-membered ring, the number of double bonds, the presence or absence of a substituent, or any other modification in the ao chain. Formula (A) shows a basic structure of the C-20 carbon atoms, but the present invention is not limited to those having the same number of carbon atoms. In formula (A), the numbering of the carbon atoms that make up the basic structure of the PG compounds starts at the carboxylic acid (numbered 1), and the carbon atoms on the a chain are numbered from 2 to 7 towards the ring of five members, those in the ring are 8 to 12, and those in the co-chain are 13 to 20. When the number of carbon atoms decreases in the chain a, the number is deleted in the order starting from position 2; and when the number of carbon atoms increases in the a chain, the compounds are named as substitution compounds having respective substituents at position 2 instead of the carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the? Chain, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the? chain, the carbon atoms beyond position 20 are named as substituents. The stereochemistry of the compounds is the same as that of formula (A) above unless otherwise specified. As stated above, the nomenclature of the 11-deoxy-PG compounds is based on the base structure of prostanoic acid. However, in the event that the compound has a similar partial structure as a prostaglandin, the abbreviation "PG" may be used. Therefore, a compound 11-deoxy-PG of which a chain a is extended by two carbon atoms, that is, having 9 carbon atoms in the chain a is named as the compound 2-decarboxy-2- (2) -carboxyethyl) -11-deoxy-PG. Similarly, the 11-deoxy-PG compound having 11 carbon atoms in the a chain is named as 2-decarboxy-2- (4-carboxybutyl) -11-deoxy-PG compound. In addition, the compound 11-deoxy-PG of which the chain? is it extended by two carbon atoms, that is, has 10 carbon atoms in the chain? it is named as a compound of 11-deoxy-20-ethyl-PG. These compounds, however, can also be named in accordance with the lUPAC nomenclatures. Examples of analogs (including substituted derivatives) or derivatives include a 11-deoxy-PG compound from which the carboxy group at the end of the a chain is esterified; a compound of which the chain a is extended; physiologically acceptable salt thereof; a compound having a double bond in the 2-3 position or a triple bond in the 5-6 position, a compound having substituent (s) in the 3, 5, 6, 16, 17, 18, 19 and / position or 20; and a compound having lower alkyl or a hydroxy (lower) alkyl group in the 9-position in place of the hydroxy group. In accordance with the present invention, preferred substituents in the 3, 17, 18 and / or 19 position include alkyl having 1-4 carbon atoms, especially methyl and ethyl. Preferred substituents in the 16-position 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, aryloxy such as trifluoromethylphenoxy. Preferred substituents at position 20 include saturated or unsaturated lower alkyl such as C 1-4 alkyl, lower alkoxy such as C 1-4 alkoxy, and lower alkoxyalkyl such as C 1-4 alkoxy-C 1-4 alkyl. Preferred substituents in the 5-position include halogen atoms such as chlorine and fluorine. Preferred substituents in the 6-position include an oxo group that forms a carbonyl group. The stereochemistry of the PGs having hydroxy, lower alkyl or hydroxy (lower) alkyl substituent at the 9-position can be a, β or a mixture thereof.

Furthermore, the above analogs or derivatives can be compounds having alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl group at the end of the chain? where the chain is shorter than the primary PGs. The nomenclature of the 11-deoxy-PG compounds used herein is based on the numbering system of prostanoic acid represented in formula (A) above. A preferred compound used in the present invention is represented by formula (I): wherein L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein 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; Ri is a lower aliphatic hydrocarbon or saturated or unsaturated bivalent medium, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur; Y Ro is a lower aliphatic hydrocarbon residue or saturated or unsaturated medium, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy (lower), aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. A more preferred compound used in the present invention is represented by formula (II): wherein L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein 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; B is a single bond, -CH2-CH2-, -CH = CH-, -C = C-, -CH2-CH2-CH2-, -CH = CH-CH2-, -CH2-CH = CH-, -C = C-CH2- or -CH2-C = C-; Z is wherein R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R 4 and R 5 are not hydroxy and lower alkoxy at the same time; R1 is a lower aliphatic hydrocarbon or saturated or unsaturated bivalent medium, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur; and Ra is a lower aliphatic hydrocarbon residue or saturated or unsaturated medium, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy (lower), aryl, aryloxy , heterocyclic group or heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. A group of particularly preferable compounds among the compounds described above is represented by the formula (III): wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein 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; B is a single bond, -CH2-CH2-, -CH = CH-, -C = C-, -CH2-CH2-CH2-, -CH = CH-CH2-, -CH2-CH = CH-, -C = C-CH2- or -CH2-C = C-; Z is \ / R4 R5 R4 R * wherein R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R 4 and R 5 are not hydroxy and lower alkoxy at the same time; X-i and X2 are hydrogen, lower alkyl, or halogen; R- \ is a lower aliphatic hydrocarbon or saturated or unsaturated bivalent medium, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and R2 is a single bond or lower alkylene; and R3 is lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy (lower), aryl, aryloxy, heterocyclic group or heterocyclic-oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. In the previous formula, the term "unsaturated" in the definitions for R < and Ra is intended to include at least one or more double bonds and / or triple bonds that are isolated, separately or serially present between the carbon atoms of the main and / or side chains. In accordance with the usual nomenclature, an unsaturated bond between two serial positions is represented by denoting the lowest number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both positions. The term "lower or middle aliphatic hydrocarbon" refers to a straight or branched chain hydrocarbon group having 1 to 14 carbon atoms (for a side chain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10, especially 6 to 10 carbon atoms for Ri and 1 to 10, especially 1 to 8 carbon atoms for Ra. The term "halogen" covers fluorine, chlorine, bromine and iodine.

The term "lower" throughout the specification is intended to include a group having 1 to 6 carbon atoms unless otherwise specified. The term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. The term "lower alkylene" refers to a bivalent straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene and hexylene. The term "lower alkoxy" refers to a lower alkyl-O- group, wherein lower alkyl is as defined above. The term "hydroxy (lower) alkyl" refers to a lower alkyl as defined above which is substituted with 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-, wherein RCO- is an acyl group formed by oxidation of a lower alkyl group as defined above, such as acetyl. The term "(lower) cycloalkyl" refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but containing three or more carbon atoms, and includes, for example, cyclopropyl, Cyclobutyl, cyclopentyl and cyclohexyl. The term "(lower) cycloalkyloxy" refers to the (lower) cycloalkyl group -O-, wherein (lower) cycloalkyl is as defined above. The term "aryl" may include rings of unsubstituted or substituted aromatic hydrocarbon (preferably monocyclic groups), for example, phenyl, tolyl, xylyl. Examples of the substituents are halogen atom and halogenalkyl (lower), wherein the halogen atom and the lower alkyl are as 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 mono- to tricyclic, preferably monocyclic heterocyclic group which is a ring of 5 to 14, preferably 5 to 10 members having optionally substituted carbon atom and 1 to 4, preferably 1 to 3 heteroatoms of types 1 or 2 selected from nitrogen atom, oxygen atom and 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, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl. , 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 halogen, and halogen-substituted lower alkyl group, wherein the halogen atom and lower alkyl group are as described above. The term "heterocyclic-oxy group" means a group represented by the formula HcO-, wherein He is a heterocyclic group as described above. The term "functional derivative" of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides. Suitable "pharmaceutically acceptable salts" include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as salt) of calcium and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, 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 and caffeine salt), a basic amino acid salt (such as arginine salt and lysine), tetraalkylammonium salt and the like. These salts can be prepared by a conventional method, for example from the corresponding acid or base or by salt exchange. Examples of the ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 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; hydroxyalkyl (lower) ethers such as hydroxyethyl ether and hydroxyisopropyl ether; alkoxyalkyl (lower) ethers such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicylic ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether; and alkyl ethers (lower) such as benzyl, trityl and benzhydryl ether. Examples of the esters include aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentylester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; hydroxy-alkyl ester (lower) such as hydroxyethyl ester; alkoxyalkyl (lower) esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters such as, for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicylic ester, 3,4-di-methoxy-phenyl ester and benzamidophenyl ester; and arylalkyl (lower) ether such as benzyl ester, ester trityl and benzhydryl ester. The amide of A means a group represented by the formula -CONR'R ", wherein each of R 'and R" is hydrogen atom, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and include for example lower alkylamides such as methylamide, ethylamide, dimethylamide and diethylamide; arylamides such as anuide and toluidide; and alkyl- or aryl-sulfonylamides such as methylsulfonylamide, ethylsulfonylamide and tolylsulfonylamide. Preferred examples of L include hydroxy or oxo having a 5-membered ring structure of the so-called type, especially PGF or PGE. The preferred example A is -COOH, its pharmaceutically acceptable salt, ester or amide thereof. The preferred example B is -CH2-CH2-, which provides the structure of the so-called 13,14-dihydro type. Preferred example of Xi and X2 is hydrogen, or that at least one of them is halogen, most preferably, both of them are halogen, especially fluorine which provides a structure of the type, so-called 16,16-difluoro. Preferred RT is a hydrocarbon containing 1-10 carbon atoms, preferably, 6-10 carbon atoms. In addition, at least one of the carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. Examples of Rx include, for example, the following groups: -CH2-CH2-CH2-CH -CH -CH -, -CH2-CH2-CH2-CH2-CH = CH-, -CH2-C = C-CH2-CH2-CH2-? -CH2-CH2-CH2-CH2-CH (CH3) -CH2-, -CH2-CH2-CH2-CH2-O-CH2-, -CH2-CH = CH-CH2-O-CH2-, -CH2-C = C-CH2-O-CH2-, -CH2-CH2"CH2-CH2" CH2-CH -CH-, -CH2-CH = CH-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2- CH2-CH = CH-, -CH2-C = C-CH2-CH2-CH2-CH-, -CH2-CH2-CH2-CH2-CH2-CH (CH3) -CH2-, -CH2-CH2-CH2-CH2 -CH2-CH2-CH2-CH2-, -CH2-CH = CH-CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-CH = CH-, -CH2-C = C-CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-CH (CH3) -CH2- Preferred Ra is a hydrocarbon containing 1-10 carbon atoms, most preferably , 1 -8 carbon atoms. Ra can have one or two side chains that have a carbon atom. Preferred R2 is a single bond, and preferred R3 is lower alkyl. R3 may have one or two side chains having a carbon atom.

The configuration of the ring and the chains a- and / or? in the formulas (I), (II) and (III) above may be the same as or different from those of the Primary PGs. However, the present invention also includes a mixture of a compound having a primary-type configuration and a non-primary-type configuration. The typical example of the compound of the present invention is 11-deoxy-13,14-dihydro-16,16-difluoro-PGE or compound PGE, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro -PGE or compound PGE, 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE or compound PGE, or 11-deoxy-13, 14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE or compound PGE and its derivative or analog. The preferable example of the compound of the present invention is 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE1, 11-deoxy-13,14-dihydro-16,16-difluoro-PGE1, isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE1, isopropyl ester of 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro- 15-keto-16,16-difluoro-PGE1, 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE1, isopropyl ester of -deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl- PGE1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro methyl ester -PGE1, isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE1 or isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16 , 16-difluoro-PGFia. In the present invention, any of the isomers such as the individual tautomeric isomers, the mixture thereof, or optical isomers, the mixture thereof, a racemic mixture, and other steric isomers can be used in the same purpose. Some of the compounds used in the present invention can be prepared by the method described in USP Nos. 5,073,569, 5,166,174, 5,221, 763, 5,212,324 and 5,739,161 and 6,242,485 (these references are incorporated herein by reference). In accordance with the present invention, a mammalian subject can be treated by the present invention by administering the above-described compound. The subject can be any mammalian subject including a human. The compound can be applied systemically or topically. Usually, 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 administration to the eyes (e.g., periocular administrations). (e.g., subTenon), subconjunctival, intraocular, intravitreal, intracameral, subretinal, suprachoroidal and retrobulbar) and the like. The dose may vary depending on the breed of the animal, age, body weight, symptom to be treated, desired therapeutic effect, route of administration, term of treatment and the like. A satisfactory effect can be obtained by systemic administration 1-4 times per day or continuous administration at the amount of 0.000001-500 mg / kg, very preferably 0.00001 -100 mg / kg per day. The compound may preferably be formulated into a suitable pharmaceutical composition to be administered in a conventional manner. The composition may be those suitable for oral administration, injection or perfusion as well as an external agent such as suppository or pessary. The composition of the present invention may contain physiologically acceptable additives. Said additives may include the ingredients used with the compounds of the present invention such as excipient, diluent, filler, solvent, lubricant, adjuvant, binder, disintegrant, coating agent, encapsulating agent, ointment base, suppository base, aerosolizing agent. , emulsifier, dispersing agent, suspending agent, thickener, tonicity agent, pH regulating agent, softening agent, preservative, antioxidant, concealer, flavor, colorant, a functional material such as cyclodextrin, and biodegradable polymer, stabilizer. The additives are well known in the art and can be selected from those described in general reference pharmaceutical books. The amount of the compound defined above in the composition of the invention may vary depending on the formulation of the composition, and may generally be 0.000001-10%, most preferably 0.0001-5.0%, most preferably still 0.0001-1%. Examples of solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like. The solid composition can be prepared by mixing one or more active ingredients with at least one inactive diluent. The composition may also contain additives other than inactive diluents, for example, a lubricant, a disintegrant and a stabilizer. The tablets and pills can be coated with an enteric or gastroenteric layer, if necessary. They can be covered with two or more layers. They can also be adsorbed to a sustained release material, or microencapsulated. In addition, the compositions may be encapsulated by a medium of an easily degradable material such as gelatin. They can be further dissolved in an appropriate solvent such as fatty acid or their mono, di or triglyceride to be a soft capsule. A sublingual tablet can be used if a fast-acting property is needed. Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs and the like. Said composition may further contain inactive diluents conventionally used e.g., purified water or ethyl alcohol. The composition may contain additives other than active diluents such as adjuvants, wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives. The composition of the present invention may be in the form of a spray composition, which contains one or more active ingredients and it can be prepared in accordance with a known method. Examples of injectable compositions of the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The diluents for the aqueous solution or suspension may include, for example, distilled water for injection, physiological saline and Ringer's solution. Non-aqueous diluents for the solution and suspension may include, for example, propylene glycol, propylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and polysorbate. The composition may further comprise additives such as preservatives, wetting agents, emulsifying agents, dispersing agents and the like. They can be sterilized by filtration through, e.g., a bacteria retention filter, combining with a sterilizer or by means of sterilization by irradiation of radiosotopes or gas. The injectable composition can also be provided as a sterilized powder composition which is to be dissolved in a sterilized solvent to be injected before use. Examples of external agent include all external preparations used in the fields of dermatology and otolaryngology, which includes ointment, cream, lotion and spray. The compound of the present invention is also applied by means of ophthalmic solution, eye drops, eye ointment and Similar. The form includes all formulations for local administration for the eyes used in the ophthalmic fields. Ophthalmic solution or eye drops are prepared by dissolving active ingredients in a sterile aqueous solution such as saline and pH regulator, or by combining powder compositions to be dissolved before use. Eye ointments are prepared by mixing the active ingredient in the base. The formulations can be prepared according to any of the conventional methods. The osmolarity modifiers may be any of those ordinarily used in the ophthalmic field. Examples of osmolarity modifiers include but are not limited thereto, sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium acid phosphate, sodium diacid phosphate, acid phosphate of dipotassium, boric acid, borax, sodium hydroxide, hydrochloric acid, mannitol, isosorbitol, propylene glycol, glucose and glycerins. In addition, additives ordinarily used in the ophthalmic field can be added to the present composition as desired. Such additives include, for example, pH regulating agent (e.g., boric acid, mono sodium phosphate and sodium diacid phosphate), preservatives (e.g., benzalkonium chloride, benzethonium chloride and chlorobutanol), thickeners (e.g., saccharide such as lactose and mannitol, maltose; e.g., hyaluronic acid or its salt such as sodium hyaluronate and potassium hyaluronate; v.gr., mucopolysaccharide such as chondroitin sulfate; e.g., sodium polyacrylate, carboxyvinyl polymer and linked polyacrylate), all of which are included herein by reference. In preparing the present composition as an eye ointment, other than the above additives, the composition may contain an eye ointment base ordinarily used. Said eye ointment base includes but is not limited to, oil base such as petrolatum, liquid paraffin, polyethylene, selen 50, plastibase, macrogol or a combination thereof; emulsion base having oil phase and water phase emulsified with surfactant; and water-soluble base such as hydroxypropylmethylcellulose, carboxypropylmethylcellulose, and polyethylene glycol. The composition of the present invention can be formulated as a type of sterile unit dose that does not contain preservatives. Another form of the present invention is suppository or pessary, which can be prepared by mixing active ingredients in a conventional base such as cocoa butter that softens at body temperature, and nonionic surfactants having suitable softening temperatures to improve absorption capacity . The term "treatment" used herein includes any means of controlling the disease or condition, such as prevention, care, alleviation of the condition, attenuation of the condition and prevention of progression. The compounds used in the present invention have a significant effect on the recovery of peripheral circulation insufficient, damaged peripheral vascular wall and / or peripheral vascular endothelial cells. Accordingly, the compounds are useful for pretreatment of peripheral vascular diseases, especially peripheral vascular and microvascular diseases. Peripheral vascular and microvascular diseases in this specification and claims may include diseases of the retina, skin, general circulation, kidney or peripheral or autonomic nervous system. All of these diseases are often associated with diabetes mellitus and can occur as symptoms associated with the acute or chronic complications of diabetes mellitus. In addition, other diseases, although not known to be related to diabetes, are similar in their physiological effects on the peripheral vascular system and such diseases are also effectively treated by the method of the present invention. The present invention would also be beneficial in peripheral and autonomic neuropathies or any other diseases resulting from a disease of small vessels and large vessel disease directly. The beneficial effect of the method is believed to be due to increased blood flow in the small vessels and protection of vascular endothelial cells. The term "peripheral vascular diseases" used herein encompasses any peripheral vascular disease that includes autonomic peripheral neuropathies. Examples of "peripheral vascular disease" include peripheral arterial disease, such as chronic arterial occlusion including arteriosclerosis, arteriosclerosis obliterans and thromboangitis obliterans (Buerger's disease), macroangiopathy, microangiopathy, diabetes mellitus, thrombophlebitis, flebemfraxis, Raynaud's disease, Raynaud's syndrome, CREST syndrome, hazards to the health due to vibration, Sudeck syndrome, intermittent claudication, cold sensation in the extremities, abnormal sensation in the extremities, sensitivity to cold, Meniere's disease, Meniere's syndrome, numbness, numbness, lack of sensation, anesthesia, pain during the rest, causalgia (pain from burning), disturbance of peripheral circulation function, disturbance of nerve function, disturbance of motor function, motor paralysis, diabetic peripheral circulation disorder, lumbar spinal canal stenosis, diabetic neuropathy, shock, autoimmune disease such as erythematosis, rheumatoid disease and rheumatoid arthritis, autonomic neuropathy, autonomic diabetic neuropathy, autonomic imbalance, orthostatic hypotension, erectile dysfunction, female sexual dysfunction, retrograde ejaculation, cystopathy, neurogenic bladder, defective vaginal lubrication, intolerance to exercise, cardiac denervation, heat intolerance, gustatory sweating, diabetic complication, hyperglycemia, unconsciousness due to hypoglycemia, lack of response due to hypoglycemia; glaucoma, neovascular glaucoma, cataracts, retinopathy, diabetic retinopathy, diabetic maculopathy, retinal artery occlusion, central retinal artery obstruction, retinal vein occlusion, edema macular, age-related macular degeneration, disciform macular degeneration due to age, cystoid macular edema, eyelid edema, retinal edema, chorioretinopathy, neovascular maculopathy, uveitis, iritis, retinal vasculitis, endophlalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis , conjunctivitis, cielitos, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, Thygeson's keratitis, progressive Mooren's ulcer, skin, skin ulcer including foot ulcer, diabetic ulcer, burn ulcer, ulcer of the lower leg, postoperative ulcer, traumatic ulcer, ulcer after shingles, radiation ulcer, drug-induced ulcer, cold burn (cold injury), chilblain, gangrene and sudden gangrene, angina chest, variant angina, coronary arteriosclerosis (chronic ischemic heart disease, asymptomatic ischemic heart disease, arteriosclerotic cardiovascular disease), myocardial infarction, heart failure, congestive heart failure and ischemic heart disease without pain, pulmonary edema, hypertension, pulmonary hypertension; portal hypertension; diabetic neuropathy; decubitus, renal failure. The present composition may contain a single active ingredient or a combination of two or more active ingredients. In a combination of a plurality of active ingredients, their respective contents may be suitably increased or decreased in consideration of its therapeutic effects and safety. The pharmaceutical composition of the present invention may further contain the other pharmacological ingredients as long as it does not contradict the purpose of the present invention. The present invention will be described in detail with reference to the following example which, however, is not intended to limit the scope of the present invention.

EXAMPLE 1 Test compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE! Test compound B: isopropyl ester of 11-deoxy-13,14-dihydro-l-keto-i e? -difluoro-PGE! In this study, male Wistar rats (7 weeks old) were used. The animals were anesthetized by intraperitoneal injection of sodium thiobutabarbital (80 mg / kg). The body temperature (rectal temperature) of the animals was maintained at approximately 37 ° C throughout the experiment with a heating pad. After depilating the anterior aspect of the right hind limb with a depilatory cream, the blood flow of cutaneous tissue was measured continuously using a non-contact type laser Doppler flowmeter (FLO-N1, Omegawave Inc., Japan). For measurements of mean arterial blood pressure, a catheter Polyethylene placed in the left femoral artery was connected to a pressure transducer (TP-400T, Nihon Koden Inc., Japan) coupled to an amplifier (AP-641 G, Nihon Koden Inc., Japan). Blood flow of cutaneous tissue and blood pressure were recorded and analyzed using a computer system / HEM Ver. 3.5, Notocord Systems, France). Endothelin-1 (ET-1) was applied by infusion into the femoral artery at a rate of 200 pmol / kg / min with a syringe pump through the polyethylene catheter inserted retrogradely into the epigastric ramified caudal artery of the femoral artery right for 15 minutes. The infusion rate of ET-1 was decreased to 20 pmol / kg / min after finishing the infusion of 200 pmol / kg / min, and the decreased amount of ET-1 infusion was maintained until the end of this study. Blood flow of cutaneous tissue was reduced by infusion of ET-1 into the femoral artery. When the blood flow of cutaneous tissue reached a new constant level (25 to 50 minutes after the start of the ET-1 infusion), administered vehicle or each test compound solution to the animals for 2 minutes in volume of 1 ml / kg via the polyethylene catheter placed in the left femoral vein. The administered amount of the test compound was 100 μg / kg. Blood flow of cutaneous tissue and blood pressure were measured continuously and recorded every 5 minutes for 60 minutes after vehicle administration or each test solution. As shown in Figures 1A and 1B, by femoral arterial infusion of ET-1 the blood flow of cutaneous tissue was reduced to approximately 37% of the baseline value between 25 and 50 minutes after the start of ET-1 infusion. There was no alteration in cutaneous tissue blood flow by vehicle treatment (Figures 1A and 1B). In the group of 100 μg / kg of compound A (11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE?), The blood flow of cutaneous tissue, which was reduced to approximately 35% of the baseline value for the infusion of ET-1, was significantly reduced by the administration of the compound A (figure 1A). In the group of 100 μg / kg of compound B (isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE-?), The blood flow of skin tissue, which is decreased to approximately 38% of the baseline value by infusion of ET-1, was significantly increased by the administration of compound B (Figure 1B). Blood pressure was not affected by ET-1 infusion. Compound A and compound B at 100 μg / kg had no significant effects on blood pressure.

EXAMPLE 2 Test compound A: 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE! In this study eight male Japanese white rabbits (Std: JW / CSK) weighing approximately 2.5-3.5 kg were used. the same Each animal's eye was treated with the test compounds and the other eye was with the vehicle consistently throughout the study with a washout period between each treatment. Thirty microliters of each test compound solution was applied topically to one eye of each animal using a micropipette (Pipetman, Wilson, Inc., France). The contralateral control eye received an equal volume of the vehicle. The animals were dosed at about the same time each morning. After the animals were confined in a container, a drop of topical anesthetic (0.4% oxybuprocaine hydrochloride) was applied to both eyes and the IOP was measured with a applanation pneumatomometer (Model 30 Classic ™, Mentor O &O , Inc., USA) before dosing and at 1, 2, 4, 6, and 8 hours after dosing. As shown in Table 1, Compound A significantly decreased intraocular pressure.

TABLE 1 Infraocular pressure (IOP) after treatment with test compound The data is presented as the mean ± D.E., * p < 0.05, ** p < 0.01 compared with contralateral control eyes treated with vehicle (paired Student t test). Compound A: 11-deoxy-13, 14-dihydro-15-keto-16; 16-difluoro-PGET EXAMPLE 3 Diabetes was induced by individual intravenous injection of 50 mg / kg streptozotocin (STZ) in 7-week-old Crl: CD (SD) rats.

Animals with plasma glucose levels of 400 mg / dL or more per day 19 after treatment with STZ were used in this study. Three weeks after the STZ injection, the animals were anesthetized by intraperitoneal injection of sodium thiobutabarbital. The body temperature (rectal temperature) of the animals was maintained at approximately 37 ° C throughout the experiment with a heating pad. After depilating the anterior aspect of the right hind limb with a depilatory cream, the cutaneous tissue blood flow (CTBF) was continuously measured using a non-contact type laser Doppler flowmeter (FLO-N1, Omegawave Inc., Japan) . Blood pressure and heart rate were monitored simultaneously. Compound A or the vehicle was administered intravenously to the animals for 10 minutes. As shown in table 2, compound A increased significantly blood flow of skin tissue compared to the vehicle. Compound A had no effect on blood pressure (PS) and heart rate TABLE 2 Effect of SAG-017 on cutaneous tissue blood flow in diabetic rats induced by streptozotocin Blood flow of skin tissue Dose (ml / m? N / 100 g of tissue) μg / kg Time after the start of I V Pre-dosing (min) 5 10 30 Vehicle (Control) 0 5 38 38 37 36 ± 02 ± 02 ± 02 ± 02 Compound A 30 5 48 62 ** 59 ** 52 * ± 05 ± 05 ± 05 ± 05 Data are presented as mean ± D.E., * p < 0.05, ** p < 0.01 compared to the vehicle control group. Compound A: 11-deoxy? -13,14-dihydro-15-keto-16,16-difluoro-PGET EXAMPLE 4 Rabbits Kbs: J.W. Four-month-old males were housed in aluminum cages in an animal room controlled by room temperature (23-24 ° C), relative humidity (55-74%), ventilation rate (10-20 times / hour) and 12-hour dark light cycle (lighting: 7:00 a.m. - 7:00 p.m.). The animals were fed a solid diet for rabbits (120 g / animal / day) and water ad libitum from an automatic feeding system. The animals were subjected to at least 6 days of quarantine and acclimatization. During the period, measurements of body weight and observations and general signs were carried out and animals that were considered to be in good health were used in this study. A cannula was inserted into the common carotid artery of the rabbit under anesthesia by inhalation of isoflurane. Nine parts of the blood samples obtained through the cannula were mixed with 1 part of 3.8% w / v of sodium citrate. After centrifugation of the blood samples for 10 minutes at 1,000 rpm, platelet-rich plasma (PRP) was collected from the upper layer. Then the lower layer was further centrifuged for 15 minutes at 3,000 rpm, and platelet-poor plasma (PPP) was collected from the top layer. The platelet counts of the PRP and PPP fractions were performed using an ADVIA120 hematology system (ADVIA120, Bayer Medical Ltd.). The PRP fraction was diluted with the PPP fraction so that the platelet counts were adjusted to approximately 30 x 104 cells / μL. The obtained PRP (0.178 ml) was placed in a tube, and preincubated in a warm bath at 37 ° C for approximately 5 minutes. The test solution (0.022 ml) containing prostaglandin E1 or compound A was added to PRP. One minute later, a solution of 25 μM ADP (0.022 ml) was added and the degree of platelet aggregation was measured using a platelet aggregation measuring device (NBS hematolaser, Nikko Bioscience Inc.). For each test solution, a duplicate test was performed on the blood samples of 3 animals. The inhibition rate (%) was evaluated by comparing the aggregation in the group of test substance with that of the vehicle control group (100%). As shown in Table 3, prostaglandin Ei (PGEi) inhibited platelet aggregation by 20.9%, 91.2%, and 89.0% at concentrations of 1 x 10"8, 1 x 10" 7, and 1 x 10 ~ 6 g / ml, respectively. On the other hand, compound A showed no effects on platelet aggregation up to the highest concentration (1 x 10 5 g / ml) tested.The results indicate that compound A had no effect on platelet aggregation.

TABLE 3 Group Concentration n Aggregation Maximum inhibition (g / ml) (%) Control (physiological saline solution) - 3 37.5 ± 3.1 - Vehicle control 3 36-3 ± 2.8 Compound A 1 xi 0'7 3 35.2 ± 3.9 3.0 1 X 10"6 3 36.2 ± 4.0 0.3 1 x 10" 5 3 36.8 ± 3.1 -1.4 PGET ix? Cr5 3 28.7 ± 3.6 20.9 1 x 10'7 3 3.2 ± 0.6 ** 91 .2 1 x 10"6 3 4.0 ± 0.7"89.0 Maximum aggregation (%) represents the mean ± D.E. of 3 rabbits.

**: P < 0.01; Significant vehicle control difference (Dunnett's multiple comparison test).

EXAMPLE 5 Crl rats: CD (SD) males were anesthetized by an intraperitoneal injection of sodium thiobutabarbital. Body temperature (rectal temperature) of the animals was maintained at approximately 37 ° C throughout the experiment with a heating pad. After depilating the inner side of the right hind limb with a depiladotate cream, cutaneous tissue blood flow (CTBF) was measured before and 30 minutes after the intravenous administration of compound C (11-deoxy-1S. -ie.ld-difluoro-PGET) or the vehicle using a non-contact type Doppler flowmeter (FLO-N |, Omegawave Inc., Japan). Blood pressure and heart rate were also monitored. As shown in Table 4, compound B significantly increased cutaneous tissue blood flow compared to vehicle treatment. Compound B had no effect on blood pressure and heart rate.

TABLE 4 Effect of Compound B on Sanitary Flux of Skin Tissue in Rats Blood flow of skin tissue Dose (ml / m? N / 100 g of tissue) Group μg / kg n - 1 V Before the After administration administration Vehicle 0 5 11.4 ± 1 1 10.4 ± 0.8 (Control) Compound B 10 5 11 6 ± 0 3 13 0 ± 0 2 * The data is presented as the mean ± D.E., * p < 0.05 compared to the vehicle control group.

EXAMPLE 6 Culture of human vascular endothelial cells was brought to confluence, as measured by transendothelial electrical resistance (TEER). The cell culture was then devoid of oxygen for 30 minutes by incubation in a nitrogen atmosphere. The cells were then treated either with 0.1% DMSO or with the combination of compound 5 nM and 0.1% DMSO (final concentrations). The cell density was determined by TEER at the points of the indicated times. As shown in Figure 2A, cells treated with DMSO showed very little recovery of TEER. The cells treated with compound A showed immediate recovery of TEER. The results show that damaged TEER, a function of Measured endothelial cell barrier, recovers rapidly after treatment with compound A.

EXAMPLE 7 Human microvascular endothelial cells (adult) (HMVEC-AD) were grown to confluence. The cells were then exposed to a nitrogen atmosphere for 30 minutes and returned to the normal air atmosphere. ATP levels were monitored at the indicated time points using a luciferin-luciferase test system (ATPIite, Perkin Elmer). As shown in Figure 2B, ATP levels decreased when the cells were exposed to the nitrogen atmosphere. ATP levels returned very rapidly in cells treated with 5 nM Compound A compared to cells treated with DMSO at 0.01% only.

EXAMPLE 8 Rats GK / Jcl, a spontaneous model of non-insulin-dependent diabetes, were anesthetized by intraperitoneal injection of sodium thiobutabarbital. The body temperature (rectal temperature) of the animals was maintained at approximately 37 ° C throughout the experiment with a heating pad. After depilating the inner side of the right hind limb as a depiladotate cream, cutaneous tissue blood flow (CTBF) was measured before (baseline) and 20 minutes after intravenous administration of compound A or the vehicle using a Doppler flowmeter of non-contact type laser (FLO-N1, Omegawave Inc., Japan). Data were expressed as% compared to blood flow of baseline cutaneous tissue. As shown in table 5, compound A significantly increased cutaneous tissue blood flow in rats with spontaneous diabetes compared to the vehicle.

TABLE 5 Effect of Compound A on skin tissue blood flow in rats with spontaneous diabetes Group Dose n Blood flow of cutaneous tissue μg / kg compared to the baseline (%) I V Vehicle 0 5 103 ± 2 (Control) Compound B 20 5 122 ± 1 * The data is presented as the mean ± D.E., * p < 0.05 compared to the vehicle control group. ro OR Synthesis of benzyl ester of 16,16-difluoro-PGA? (2) Benzyl ester of 16,16-difluoro-PGEt (1) (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 H-deoxy-I S. ^ - dihydro-ie.i-difluoro-PGEi (3) benzyl ester of 16,16-difluoro-PGAt (compound (2)) (382.5 mg, 0.83 mmol) was hydrogenated in acetate of ethyl (10 ml) under the presence of 10% palladium-carbon (57.4 mg, moistened with 50% w / w of water) at room temperature, at atmospheric pressure for 2 hours. The reaction mixture was filtered through a pad of 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 of water), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain Crude compound (3) (298.5 mg, 95. 7%). The crude compound (3) was combined with another batch of the compound raw. And then, in its totality approximately 350 mg of the crude compound was purified by preparative HPLC (YMC-Pack D-SIL-5-06 20 X 250mm, hexane / 2-propanol / acetic acid (250: 5: 1), 20 ml / min) to obtain the compound (3) as a colorless oil. Yield: 297.3 mg (recovery by purification of HPLC: 83.5%). H-NMR (200MHz, CDCl 3) d 0.94 (3H, t, J = 7.1 Hz), 1.22-2.29 (28H, m), 2.34 (2H, t, J = 7.3Hz), 3.65-3.81 (1H, m ) 3C-NMR (50MHz, CDCI3) d 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 = 24.4Hz), 33.67, 37.63, 41.05, 54.76 , 72.73 (t, J = 29.0Hz), 124.09 (t, J = 244.3Hz), 179.07, 220.79.

EXAMPLE OF SYNTHESIS 2 In accordance with the similar manner described in Synthesis Example 1, isopropyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGEi (Compound (6)) was obtained as a colorless oil by the previous two-step reaction. Yield: 0.285 g (1st step: 96.2%, 2nd step: 97.6%, Purification by HPLC: recovery of 81.0%). 1H-NMR (200MHz, CDCI3) and 3C-NMR (50MHz, CDCI3) of the compound (6) are shown in Figures 3 and 4 respectively. EXAMPLE OF SYNTHESIS 3 In accordance with the similar manner described in the example of synthesis 1, isopropyl ester of 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE? (Compound (9)) was obtained as a colorless oil. Yield: 0.402 g (1st step: 94.9%, 2nd step: 92.2%, purification by HPLC: recovery of 83.1%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (9) are shown in Figures 5 and 6 respectively.

EXAMPLE OF SYNTHESIS 4 In accordance with the similar manner described in the synthesis example 1, 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE? (Compound (12)) was obtained as a colorless oil. Yield: 0.696 g (1st step: 95.6%, 2nd step: 99.3%, purification by HPLC: recovery: 87.4%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (12) are shown in Figures 7 and 8 respectively.

EXAMPLE OF SYNTHESIS 5 In accordance with the similar manner described in Synthesis Example 1, isopropyl ester of 11-deoxy? -13,14-d? H? Dro-15-keto-16,16-d? Fluoro-20-met? L- PGE1 (Compound (15)) was obtained as colorless oil Yield 0 271 g (1st step 91 4%, 2nd step 97 3%, purification by HPLC recovery 79 0%) 1 H-NMR (200MHz, CDCl 3) and 3 C-NMR (50MHz, CDCl 3) of the compound (15) are shown in Figures 9 and 10 respectively EXAMPLE OF SYNTHESIS 6 In accordance with the similar manner described in synthesis example 1, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-inethyl-PGE? (Compound (18)) was obtained as a colorless oil. Yield: 0.637 g (1st step: 93.3%, 2nd step: 96.6%, purification by HPLC: recovery: 73.9%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (18) are shown in Figures 11 and 12 respectively.

EXAMPLE OF SYNTHESIS 7 In accordance with the similar manner described in synthesis example 1, 11-deoxy-13,14-dihydro-15-keto-16,1-difluoro-O-ethyl-PGEn (compound (21)) was obtained as a colorless oil . Yield: 0.401 g (1st step: 90.6%, 2nd step: 92.7%, purification by HPLC: recovery: 29.2%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (21) are shown in Figures 13 and 14 respectively.

EXAMPLE OF SYNTHESIS 8 Methyl ester of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE-i (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 column chromatography on silica gel). 1 H-NMR (200MHz, CDCl 3) and 13 C-NMR (50MHz, CDCl 3) of the compound (23) are shown in Figures 15 and 16.

EXAMPLE OF SYNTHESIS 9 Compound (24) (0.67 g, 1.66 mmol) was dissolved in DMF (13 mL), and K2CO3 (460.1 mg, 3.33 mmol) and isopropyl iodide (831 μL, 8.32 mmol) was added. The solution was stirred at room temperature for 2 hours. The reaction mixture was cooled with ice ice, water (10 ml) and brine was 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 residue was purified by silica gel column chromatography (silica gel FL60D (50 g), Fuji Silysia, hexane / ethyl acetate (5: 1)) to obtain 11-deoxy-13,14-dihydro isopropyl ester -15-keto-16,16-difluoro-20-ethyl-PGE? crude (compound (25)) (EYE g, 94.6%). The crude compound (25) was purified by preparative HPLC to obtain the compound (25) as a colorless oil. Yield 245.8 mg (35.1%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) for the compound (25) are shown in Figures 17 and 18 respectively.

EXAMPLE OF SYNTHESIS 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 residue 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 light yellow oil ( 10.61 g, 97.0%). Bu3SnH (11.21 g, 38.5 mmol) was dissolved in toluene (224 ml), and refluxed by heating. The solution of compound (27) (10.41 g, 19.2 mmol) in toluene (208 ml) was dripped into the reaction mixture at a reflux temperature for 70 minutes. And then, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to obtain crude compound (28) as light yellow oil. The crude compound (28) (19.2 mmole) was dissolved in THF (52 ml) and TBAF solution (1.0M in THF, 38.5 ml, 38.5 mmole) was dripped for 10 minutes. After one hour, TBAF solution (1.0M in THF, 19.2 ml, 19.2 mmol) was dripped into the solution. After stirring for a total of 3.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel BW-300SP (1, 000 g), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain compound (29) as yellow oil (4.01 g, 69.3%). The compound (31) was obtained from the compound (29) by Swern oxidation and chain introduction?. Compound (31) (807.4 mg, 1.88 mmol) was hydrogenated in ethyl acetate (8 ml) under the presence of 10% palladium-carbon at room temperature for 2 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain crude compound (32) as light brown oil. The crude compound (32) (1.88 mmol) was dissolved in EtOH (8 mL). A solution of 1 N NaOH (7.4 ml, 7.4 moles) was added dropwise to the solution at room temperature for 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 around 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 residue was purified by silica gel column chromatography (silica gel with 15% water including FL-60D (80 g), Fuji Silysia, hexane / ethyl acetate (2: 1)) to obtain the compound (33). ) as light yellow oil (481.4 mg, 68.8%). In accordance with the similar manner described in Synthesis Example 9, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGF1a isopropyl ester (compound (34)) was obtained from of the compound (33) as a colorless oil. Yield: 166.6 mg (step of reaction step 91.9%: purification by HPLC: recovery: 55.4%). 1 H-NMR (200MHz, CDCl 3) and 13 C-NMR (50MHz, CDCl 3) of the compound (34) are shown in Figures 19 and 20 respectively.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - The use of an 11-deoxy-prostaglandin compound, to prepare a medicament useful for treating a peripheral vascular disease in a mammalian subject. 2. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound represented by the following general formula (I): wherein L and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxyalkyl (lower), lower alkanoyloxy or oxo, wherein 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; Ri is a lower aliphatic hydrocarbon or saturated or unsaturated bivalent medium, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur; and Ro is a lower aliphatic hydrocarbon residue or saturated or unsaturated medium, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy (lower), aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. 3. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-prostaglandin. 4. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-15-keto-prostaglandin. 5. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-16-mono or dihalogen-prostaglandin. 6. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-16-mono or dihalogen-prostaglandin. 7 '.- The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-15-keto-16-mono or dihalogen-prostaglandin. 8. - The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-15-keto-16-mono or dihalogen-prostaglandin. 9. The use as claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-15-keto-16-mono or difluoro- Prostaglandin 10. The use as claimed in claim 1, wherein said 11-deoxy-prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-15-keto-16-mono or dihalogen-prostaglandin. E or F. 11. The use as claimed in claim 1, wherein said prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-15-keto-16-mono or difluoro-prostaglandin. E or F. 12. The use as claimed in claim 1, wherein said prostaglandin compound is a compound of 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro- prostaglandin EL 13. The use as claimed in claim 1, wherein said peripheral vascular disease is peripheral arterial disease. 14. The use as claimed in claim 13, wherein said peripheral arterial disease is arteriosclerosis. 15. A composition for treating a peripheral vascular disease in a mammalian subject, comprising an effective amount of an 11-deoxy-prostaglandin compound. 16.- The use of an 11-deoxy-prostaglandin compound, for preparing a medicament useful for treating a damaged peripheral vascular wall in a mammalian subject. 17. The use of an 11-deoxy-prostaglandin compound, to prepare a medicament useful for treating damaged peripheral vascular endothelial cells in a mammalian subject.