MX2007009094A - Method and composition for treating central nervous system disorders. - Google Patents

Abstract

The present invention provides a method and composition for treating a central nervous system disorder in a mammalian subject, which comprises administering an effective amount of a 11-deoxy-prostaglandin compound to a subject in need thereof. The invention also provide novel 11-deoxy-prostaglandin compound.

Description

METHOD AND COMPOSITION FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM TECHNICAL FIELD The present invention relates to a method and composition for the treatment of a disorder of the central nervous system in a mammalian subject. The invention also relates to a novel prostaglandin compound.

BACKGROUND OF THE INVENTION The intercellular junctions mediate adhesion and communication between joining endothelial and epileptic cells. In the endothelium, complex junctions comprise occluding junctions, adherent junctions, and communicating junctions. The expression and organization of these complexes depends on the type of vessels and the permeability requirements of preformed organs. The communicating junctions are communication structures, which allow the passage of low molecular weight solutes between surrounding cells. Occlusive junctions serve the main functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherent junctions play an important role in inhibiting growth contact endothelial cell, paracellular permeability to circulating leukocytes and solutes. In addition, they require the correct organization of new vessels in angiogenesis (Physiol, Rev. 84 (3), 869-901, 2004). The mechanism by which epithelial and endothelial cells interact to form polarized tissue is of fundamental importance for multicellular organisms. The deregulation of these barriers occurs in a variety of diseases, destroying normal cellular environments and leading to organ malfunction. The brain microvascular endothelial cells that form the blood-brain barrier (BBB) have occluding junctions that are critical for the maintenance of brain homeostasis and low permeability. The blood-brain barrier (BBB) is a specialized structure in the central nervous system (CNS), which participates in the maintenance of a state of cerebrospinal fluid homeostasis by controlling the access of nutrients and toxic substances to the central nervous system ( CNS). The base membrane that supports the vasculature performs a critical function in maintaining the integrity of the BBB by providing structural support to the endothelial cell wall (Trends Neurosci 1990, 13 (5): 1 74-178). The BBB serves to protect the central nervous system (CNS) from invasive agents, such as inflammatory cells and bacteria, as well as from chemical agents. A wide variety of central nervous system (CNS) disorders associated with the breakdown of the BBB are known. Examples of disorders include multiple sclerosis, experimental allergic encephalomyelitis, bacterial meningitis, ischemia, cerebral edema, Alzheimer's disease, demential complex of acquired immune deficiency syndrome (Helga E. DE Vries et al, Pharmacological reviews, 49 (2): 143-155, 1997), brain tumors (Davies DC et al., J Anat., 200 (6): 639-46, 2002), traumatic brain injury (Hartl R et al., Acta Neurochir Suppl. 70: 240-242, 1997) . It has also been reported that, after focal apoplexy, there is a breakdown of the BBB with an associated increase in vascular permeability. BBB damage sometimes results in hemorrhage and edema, resulting in neuronal cell death (Biomedicine, 1974; 21: 36-39, Stroke, 1998; 29 (5): 1020-1030, Stroke, 2003; 34 ( 3): 806-812, J Neurotrauma, 1995; 12: 833-842). Brain damage after focal strokes is mainly a result of decreased blood flow and energy consumption due to the occlusion of a cerebral blood vessel. Neuronal tissue begins to rupture as a result of these events, with contributions of excitoxicity, enzymatic activation, edema, and inflammation (Trends Pharmacol Sci. 1996; 17: 227-233, Crit Care Med. 1988; 954-963). In addition, systemic-derived inflammation has recently been shown to cause rupture of the occluding junction of BBB and increased paracellular permeability. The BBB has the capacity for rapid modulation in response to physiological stimuli at the cytoskeletal level, which allows to protect cerebral parenchyma and maintain a homeostatic environment. Research has shown that the destruction of BBB is associated with CNS diseases. However, there is little research on how the BBB could be protected. Prostaglandins (hereinafter, referred to as PG (s)) are members of the class of organic carboxylic acids, which are contained in tissues or organs of the human being or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid structure as shown in formula (A): (chain a) On the other hand, some of the synthetic analogs of primary PGs have modified the major structures. Primary PGs are classified into PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI and PGJ according to the structure of the five-member ring radical, and are further classified into the following three types by number and position of the unsaturated bond in the radical of the carbon chain: Subindex 1: 13,14-unsaturated-1 5-OH Subindex 2: 5,6- and 13,14-di-unsaturated-15-OH Subindex 3: 5, 6-, 13,14-, and 17,18 tri-unsaturated-15-OH. In addition, PGFs are classified, according to the configuration of the hydroxyl group in the 9-position, in a type a (the hydroxyl group is of a configuration a) and type β (the hydroxyl group is of a β-configuration). PG ET and PGE2 and PGE3 are known to have vasodilation, hypotension, gastric diminution of secretion, increased movement of the intestinal tract, uterine contraction, diuretic, bronchodilation and anti-ulcer activities. PGF1 A, PGF2A and PGF3"have been known to have hypertension, vasoconstriction, increased movement of the intestinal tract, uterine contraction, atrophy of the lutein body and bronchoconstriction activities. Some 15-ketoes (that is, they have oxo at position 15 instead of hydroxy) - PG and 13, 14-dihydro (ie, having a single bond between the position 1 3 and 14) -15-keto- PG are known as substances produced naturally by the action of enzymes during the metabolism of primary PGs. The Patent of E.U.A. No. 5,290.8 1 to Ueno et al., Discloses that keto-PG compounds are useful for the improvement of brain function. The patent of E.U.A. No. 5,290.8 1 indicates that when the bond between positions 13- and 14- is saturated, a keto-hemiacetal balance can sometimes be formed by the formation of a hemiacetal between the hydroxy group in the 1 1 position and the group keto in position 1 5. The US Patent No. 5,31 7,032 for Ueno et al., Describes cathartics of prostaglandin compound, including the existence of bicyclic tautomers and the U.S. Patent. No. 6,414,016 for Ueno describes bicyclic tautomers having a pronounced activity as agents against constipation. Bicyclic tautomers, substituted by one or more halogen atoms, can be used in small doses to decrease constipation. In the C-16 position, especially, fluorine atoms can be used in small doses to decrease constipation.

BRIEF DESCRIPTION OF THE INVENTION The current inventor conducted an intensive study and found that the deoxy-prostaglandin compounds have significant effects on central nervous system disorders, which resulted in the termination of the present invention. Namely, the present invention relates to a method for treating a central nervous system disorder in a mammalian subject, which comprises administering an effective amount of a 1-deoxy-prostaglandin compound to a subject in need thereof. The present invention further relates to a composition for treating a central nervous system disorder in a mammalian subject, comprising an effective amount of a 1-deoxy-prostaglandin compound. In addition, the present invention relates to a use of the 1-deoxy-prostaglandin compound to make a composition for treating a Central nervous system disorder in a mammalian subject, comprising an effective amount of a 11-deoxy-prostaglandin compound. Another embodiment of the present invention relates to a method for protecting cerebrovascular endothelial cells in a mammalian subject, comprising administering an effective amount of a 11-deoxy-prostaglandin compound to a subject in need thereof. In another aspect of the present invention, a novel compound represented by the formula (IV): wherein L is hydrogen, hydroxy, halogen, a lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo; wherein the five-membered ring may optionally have at least one double bond; A is -CH3, -CH2OH, -COCH2OH, -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 , R / 4 R5 or O 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; ? G and X2 'are the same or different halogen atoms; Ri is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; R2 is a single bond or lower alkylene; and R3 is lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyoxy (lower), aryl, aryloxy, heterocyclic group or heterocyclic-oxy group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; Provided that the formula (IV) is not 1 1-deoxy-13, 14-dihydro-1-keto-16,6-difluoro-PGE,.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the effect of Compound A on the recovery of the Transendothelial Electrical Resistance (TEER). Vascular endothelial cell cultures of human were taken to the confluence, as measured by the transendothelial electrical resistance (TEER). The cell cultures were then deprived of oxygen for 30 minutes by incubation in a nitrogen atmosphere. The cells were then treated with 0.1% DMSO or with 5 nM Compound A with 0.1% DMSO. Statistical significance is indicated at all data points after drug treatment. N = 10 cells. Figure 2 is a graph showing the effect of Compound A on the recovery of the ATP level. Human (adult) microvascular endothelial cells (HMVEC-AD) develop for confluence. The cells are then treated for 30 minutes under a nitrogen atmosphere and back to normal oxygen. ATP levels are monitored at the indicated time points using a luciferin-luciferase assay system (ATPIite, Perkin Elmer). ATP levels are given as relative luminescence. N = 6 cells at each time point. Figure 3 is a 1 H-NMR chart (200MHz, CDCI3) of the compound (6) obtained in the synthesis example 2 below. Figure 4 is a 13C-NMR chart (50MHz, CDCI3) of the compound (6) obtained in the synthesis example 2 below. Figure 5 is a 1H-NMR chart (200MHz, CDCI3) of compound (9) obtained in synthesis example 3 below. Figure 6 is a 13C-NMR chart (50MHz, CDCI3) of compound (9) obtained in synthesis example 3 below. Figure 7 is a chart of ^ -RMN (200MHz, CDCI3) of the compound (12) obtained in synthesis example 4 below. Figure 8 is a 13C-NMR chart (50MHz, CDCI3) of the compound (12) obtained in the synthesis example 4 below. Figure 9 is a 1 H-NMR chart (200MHz, CDCl 3) of the compound (15) obtained in the synthesis example 5 below. Figure 10 is a 13C-NMR chart (50MHz, CDCl 3) of the compound (15) obtained in the synthesis example 5 below. Figure 11 is a 1 H-NMR chart (200 MHz, CDCl 3) of the compound (18) obtained in the synthesis example 6 below. Figure 12 is a 13C-NMR chart (50MHz, CDCI3) of the compound (18) obtained in the synthesis example 6 below. Figure 13 is a 1 H-NMR chart (200 MHz, CDCl 3) of the compound (21) obtained in the synthesis example 7 below. Figure 14 is a 13C-NMR chart (50MHz, CDCI3) of the compound (21) obtained in the synthesis example 7 below. Figure 15 is a 1 H-NMR chart (200 MHz, CDCl 3) of the compound (23) obtained in the synthesis example 8 below. Figure 16 is a 13C-NMR chart (50MHz, CDCI3) of the compound (23) obtained in the synthesis example 8 below. Figure 17 is a 1 H-NMR chart (200MHz, CDCl 3) of compound (25) obtained in synthesis example 9 below. Figure 18 is a 13C-NMR chart (50MHz, CDCI3) of compound (25) obtained in synthesis example 9 below.

Figure 19 is a 1 H-NMR chart (200MHz, CDCl 3) of the compound (34) obtained in the synthesis example 10 below. Figure 20 is a 13C-NMR chart (50MHz, CDCI3) of the compound (34) obtained in the synthesis example 10 below.

DETAILED DESCRIPTION OF THE INVENTION In the present invention, "1-deoxy-prostaglandin compound" (hereinafter, referred to as "1-deoxy-PG compound") can include any of the derivatives or analogues (including substituted derivatives) of a compound that does not have no substitute at the 1-position of the main structure of the prostanoic acid, irrespective of the configuration of the five-membered ring, the number of double bonds, the presence or absence of a substitute, or any other modification in the α or α chain. Formula (A) shows a basic structure of 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 2 to 7 towards the ring of five members, those in the ring are 8 to 12, and those in the chain "are 13 to 20. When the number of carbon atoms decreases in the a chain, the number is suppressed in the order starting at the position inside 2; and when the number of carbon atoms increases in the α-chain, the compounds are referred to as substitution compounds having respective substituents in the 2-position instead of the carboxy (C-1) group. Similarly, when the number of carbon atoms is decreased in the chain a, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the α chain, the carbon atoms beyond the 20 position are referred to as substituents. The stereochemistry of the compounds is the same as that of the previous formula (A) unless otherwise specified. As stated above, the nomenclature of the 1-deoxy-PG compounds is based on the base structure of prostanoic acid. However, in case the compound has a similar partial structure as a prostaglandin, the abbreviation of "PG" can be used. Thus, a compound 1-deoxy-PG of which the chain a is extended by two carbon atoms, that is, having 9 carbon atoms in the chain a is referred to as 2-decarboxy-2- (2-carboxyethyl) compound -1 1 -deoxi-PG. Similarly, the compound 1 1-deoxy PG having 1 1 carbon atoms in the a chain is named as the compound 2-decarboxy-2- (4-carboxybutyl) -1 1 -deoxy-PG. In addition, the compound 1 1-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 the compound of 1-deoxy-20-ethyl-PG. These compounds, however, may also be referred to as IUPAC nomenclatures. Examples of the analogues (including the substituted derivatives) or derivatives include a 1-deoxy-PG compound from which the carboxy group is esterified at the end of the a chain; a compound from which the chain extends; 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 position and / o 20; and a compound having a lower alkyl or a hydroxy (lower) alkyl group in the 9-position in place of the hydroxy group. According to the present invention, preferred substituents at the 3,1,7,18 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 alkoxy alkyl such as C 1-4 alkoxy of 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 PG having a hydroxy, lower alkyl or hydroxy-lower alkyl substituent in position 9 it can be a, ß or a mixture thereof. In addition, the aforementioned analogues or derivatives can be compounds having an alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl group at the end of the chain? where the chain is shorter than the primary PG. The nomenclature of the compounds 1 1-deoxy-PG used in this document is based on the numbering system of prostanoic acid represented in the aforementioned formula (A). A preferred compound used in the present invention is represented by the 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 -CH3, -CH2OH, -COCH2OH, -COOH or a functional derivative thereof; Ri is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by a halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of the carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and R0 is a lower or middle aliphatic hydrocarbon residue, saturated or unsaturated, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy ( lower), aryl, aryloxy, a heterocyclic group or a heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one of the 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 -CH3, -CH2OH, -COCH2OH, -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; R! is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of a carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and Ra is a lower or middle aliphatic hydrocarbon residue, saturated or unsaturated, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy ( lower), aryl, aryloxy, a heterocyclic group or a heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one of the 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 -CH3, -CH2OH, -COCH2OH, -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; Xi and X2 are hydrogen, lower alkyl, or halogen; R1 is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of 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 of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. The present invention also relates to a compound represented by the formula (IV): wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy-alkyl (lower), lower alkanoyloxy or oxo; wherein the five-membered ring may optionally have at least one double bond; A is -CH3, -CH2OH, -COCH2OH, -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 and R5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R and R5 are not hydroxy and lower alkoxy at the same time; ? and X2 'are the same or different halogen atoms; RT is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; 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 of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; Provided that formula (IV) is not 1 1-deoxy-3, 4-dihydro-1-keto-6,16-difluoro-PGEi, and a method for the production thereof. In the aforementioned formula, the term "unsaturated" in the definitions for and Ra is intended to include at least one or more double bonds and / or triple bonds that are present in an isolated, separate or serial manner between the carbon atoms of the main and / or side chains. According to the general nomenclature, an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between the 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" includes fluorine, chlorine, bromine and iodine. The term "lower" throughout the entire 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 include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. 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, -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 the oxidation of a lower alkyl group as defined above, for example acetyl. The term "(lower) alkyl cycle" refers to a cyclic group formed by the cyclization of a lower alkyl group as defined above but contains three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "(lower alkyloxy) cycle" refers to the group of cycloalkyl-O- (lower), wherein cyclo-lower alkyl 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 halo (lower) alkyl, wherein the halogen atom and a 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 from 5 to 10 members optionally having a substituted carbon atom and 1 to 4, preferably 1 to 3 of type 1 or 2 heteroatoms selected from the nitrogen atom, oxygen atom and sulfur atom. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, sotiazolilo, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2 -imidazolinilo, 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 a lower alkyl group substituted with halogen, 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 salt magnesium), 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, salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl- monoethanolamine salt, procaine salt and caffeine), a basic amino acid salt (such as arginine salt and lysine salt), salt and tetra-alkyl ammonium the similar. These salts can be prepared by means of a conventional process, for example of the corresponding acid and base or by exchange of the salt. Examples of the ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl and 1-cyclopropyl ethyl 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; alkoxy-lower alkyl ethers such as methoxymethyl ether and 1-methoxyethyol ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether; and aryl-lower alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.

Examples of the esters include the aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; hydroxyalkyl ester (lower), such as hydroxyethyl ester; alkoxy-alkyl (lower) esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters, for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicylic ester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; and aryl-alkyl ester (lower) such as benzyl ester, trityl ester and benzhydril ester. The amide of A refers to a group represented by the formula - CONR'R ", wherein each of R 'and R" is a hydrogen atom, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl, lower alkynyl, and includes, 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, ethylsulfonyl-amide and tolylsulfonylamide. Preferred examples of L include hydroxy or oxo having a 5-membered ring structure, called, especially of the PGF or PGE type. A preferred example A is -COOH, its pharmaceutically acceptable salt, ester or amide thereof.

A preferred example B is -CH2-CH2-, which provides the so-called structure, type 13,14-dihydro. A preferred example of Xi and X2 is hydrogen, or that at least one of them is halogen, more preferably both of them are halogen, especially fluorine which provides a structure of the so-called 16,16-difluoro type. ?? and X2 'preferred are difluoro atoms. preferred 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 Ri include, for example, the following groups: - CH2-CH2-CH2-CH2-CH2-CH2-, -CH2-CH = CH-CH2-CH2-CH2-, - CH2-CH2-CH2-CH2-CH = CH-, -CH2-CsC-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH- (CH3) -CH2-, -CH2-CH2-CH2-CH2-0-CH2-, -CH2 -CH = CH-CH2-0-CH2-, -CH2-C = C-CH2-0-CH2-, -CH-CH2-CH2-CH2-CH2-CH2-CH2-, -CH2-CH = CH-CH2 -CH2-CH2-CH2-, - CH2-CH2-CH2-CH2-CH2-CH = 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, 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 α- and / or α-chains in the above formula (I), (II), (III) and (IV) may be the same as or different from that of the primary PG. However, the present invention also includes a mixture of a compound having a primary type configuration and a compound of a non-primary type configuration. The typical example of the compound herein is a compound 1 1-deoxy-13,14-dihydro-16,16-difluoro-PGE or a compound PGF, 1-deoxy-3,14-dihydro-15-keto-16, 16-difluoro-PGE or PGF, 2-decarboxy-2- (2-carboxyethyl) -1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE or PGF, or a compound 1 1 -deoxy-13, 14-dihydro-1-keto-16,16-difluoro-20-methyl or ethyl-PGE or PGF and its derivative or analog. The preferred example of the compound herein is 1-deoxy-1,3-dihydro-15-keto-16,16-difluoro-PGEi., 1-deoxy-13,14-dihydro-1 6,16-difluoro-PGET, isopropyl ester of 1-deoxy-13, 14-dihydro-15-keto-16,16-difluoro-PGEi, isopropyl ester of 2-Decarboxy-2- (2-carboxyethyl) -1 1 -deoxi-13,14-dihydro-15-keto-16,16-difluoro-PGE! , 2-decarboxy-2- (2-carboxyethyl) -1,1-deoxy-13,14-dihydro-15-keto-16,16 -difluoro-PGE-i, isopropyl ester of 1-deoxy-13,14- dihydro-15-keto-16,16-difluoro-20-methyl-PGE! , -deoxy- 13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE 1, 1-deoxy-13,14-dihydro-5-keto-l ei e-difluoro-O-ethyl -PGEL 1,1-methyl ester-deoxy-13,14-dihydro-15-keto-6,16-difluoro-PGE! , isopropyl ester of 1 1 -deoxi-13,14 dihydro-15-keto-l ei e-difluoro ^ 0-ethyl-PGFL or isopropyl ester of 1 1-deoxy-13,14-dihydro-1 5-keto-16 , 16-difluoro-PGF1a. In the present invention, any of the isomers such as the individual tautomeric isomers, the mixture thereof, or the optical isomers, the mixture thereof, a racemic mixture, and other spherical isomers can be used for the same purpose. Some of the compounds used in the present invention can be prepared by the method disclosed in USP Nos. 5,073,569, 5, 166, 1 74, 5,221, 763, 5,212,324, 5,739, 161 and 6,242,485 (these references are incorporated herein by reference) . According to the present invention, a mammalian subject can be treated by the present invention when administering the compound used in the present invention. The subject can be any mammalian subject including a human being. The compound can be applied systemically or topically. Generally, the compound can be administered by oral administration, intravenous injection (including infusion), subcutaneous injection, intrarectal administration, intra vaginal administration, transdermal administration and the like. The dose may vary depending on the breed of the animal, age, body weight, the symptom to be treated, the desired therapeutic effect, the route of administration, the term of treatment and the like. A satisfactory effect can be obtained by means of systemic administration 1 -4 times per day or continuous administration in the amount of 0.00001 -500 mg / kg per day, more preferably 0.0001 -100 mg / kg. The compound can be formulated preferably in a pharmaceutical composition suitable for administration in a conventional manner. The composition may be those suitable for oral administration, injection or perfusion as well as may be an external preparation, suppository or pessary. The composition of the present invention may further contain physiologically acceptable additives. Such additives may include the ingredients used with the present compounds such as excipient, diluent, filler, resolvent, lubricant, adjuvant, binding agent, disintegrator, coating agent, encapsulating agent, ointment base, suppository base, forming agent, spray agent emulsifier, dispersing agent, suspending agent, thickener, tonicity agent, pH regulating agent, soothing 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 pharmacy reference 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 -10.0%, more preferably 0.00001 -5.0%, still more preferably 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 disintegrator and a stabilizer. The tablets and pills can be covered with an enteric or gastroenteric film, if necessary. These can be covered with two or more layers. They can also be adsorbed to a sustained release, or microencapsular material. In addition, the compositions can be encapsulated by means of an easily degradable material such as gelatin. They can be further dissolved in an appropriate solvent such as fatty acid or its mono, di or triglyceride to be a soft capsule. A sublingual tablet can be used in need of a fast acting property. Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs and the like. The aforementioned composition may further contain a conventionally used inactive diluent, for example purified water or ethyl alcohol. The composition may contain additives other than inactive diluents such as adjuvants, for example, 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 may be prepared according to a known method. Examples of the injectable compositions of the present invention for parenteral administration include sterile solutions, aqueous or non-aqueous suspensions and emulsions. 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, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and polysorbate. The composition may comprise additives such as preservatives, wetting agents, emulsifying agents, dispersing agents and Similar. They can be sterilized by filtration through, for example, a filter that retains bacteria, composed with a sterilizer, or by means of sterilization by irradiation with gas or radioisotope. The injectable composition can also be provided as a sterilized powder composition which is dissolved in a sterilized solvent for injection before use. The external preparation of the invention can be any form of external preparations used in the fields of dermatology and otolaryngology, which includes an ointment, cream, lotion and aerosol. Another form of the composition is the suppository or pessary, which can be prepared by mixing the active ingredients on a conventional basis such as cocoa butter which softens at body temperature, and nonionic surfactants having suitable softening temperatures can be prepared. Use to improve absorption capacity. The term "treatment" used herein includes any means of control such as prevention, care, relief of the condition, attenuation of the condition, arrest of progress, etc. The term "central nervous system disorder" used herein includes any disorder of the central nervous system involved or that is associated with any type of condition and / or diseases, or caused by ischemia, trauma, infection, inflammation, tumor, edema , hypotension, hypoxemia, blood clot (thrombus), enzyme activation, arterial obstruction (embolus), arteriesclerosis, metabolic disorder, degeneration, aging, drugs, medications or surgical procedures. Examples of "central nervous system disorder" include, but are not limited to, cerebrovascular disorders such as stroke and cerebral infarction (e.g., cerebral thrombosis, cerebral embolism, lacunar cerebral infarction, asymptomatic cerebral infarction); vasospasm due to intracerebral hemorrhage or subarachnoid hemorrhage; cerebrovascular dementia; neuronal disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, Pick's disease, spino-cerebellar degeneration, chorea, encephalopathy of AIDS, hepatic encephalopathy, amyotrophic lateral sclerosis, peripheral neuropathy induced by anticancer drug, diabetic neuropathy , traumatic neurological disorder and multiple sclerosis; cerebral edema, hypernatremic brain disorder and brain tumor; ischemic diseases such as cerebral ischemia caused by vascular disorders, transient ischemic attack (TIA), reversible ischemic neurological deficit (RIND), cerebrovascular ischemia caused by migraine or cocaine abuse, cerebral ischemia including epilepsy or psychiatric epileptic symptoms, cerebral ischemia during the operation surgical (ischemic tissue injury), cerebral ischemia caused by head injury, cerebral ischemia due to hypotension, hypoxemia or dyspnea and cerebral ischemia due to heart failure; inflammatory brain disorders such as relapsing multiple sclerosis chronic, encephalomyelitis, meningitis, traumatic brain injury; Neonatal asphyxia and secondary complications of these diseases. According to the present invention, the compounds used herein have a significant effect on the recovery of the barrier function of cerebrovascular endothelial cells, especially brain-blood barrier, so it is also useful for protecting cerebrovascular endothelial cells. The pharmaceutical composition of the present invention may further contain other pharmacological ingredients so that they do not contradict the purpose of the present invention. The formulations herein may contain a single active ingredient or a combination of two or more active ingredients. In a combination of plural active ingredients, their respective contents can increase or decrease conveniently considering their therapeutic effects and safety. In addition, the present formulations may contain other pharmacologically active ingredients, so they are not contrary to the objectives of the present invention. The present invention will be described in detail with reference to the following examples, which, however, are not intended to limit the scope of the present invention.

EXAMPLE 1 Method Four-week old male ddY mice are housed in aluminum cages in an animal room with temperature control (24 ± 3 ° C), relative humidity (55 ± 10%), ventilation rate (-12 times / hour) ) and a light-dark cycle (fluorescent lighting: 8:00 a.m. to 8:00 p.m.) for at least 7 days. The animals are allowed free access to the diet of pellets and tap water from the water bottles. Healthy animals without abnormalities in general signs are used in this study. 1-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGET (hereinafter, "compound A") is dissolved in a vehicle (physiological saline solution containing 0.01% polysorbate 80 and 0.5% ethanol), and are administered subcutaneously to the animals. The control group received an equal amount of the vehicle in the same way. The animals are decapitated at 30 minutes after administration, and the persistent time of panting movements is measured.

Results As shown in table 1, compound A in 10, 30, 100 and 300} _ig / kg produces a dose-dependent prolongation of persistent time of panting movement after decapitation. The results indicate that compound A has a neuroprotective activity and that compound A is useful for the treatment of ischemic disease.

TABLE 1 Effects of compound A in persistent time of panting movements after decapitation of mice s. c: subcutaneous, ** p < 0.01, * p > 0.05 compared to the control group treated with vehicle (Dunnett's multiple comparison test).

EXAMPLE 2 Method Four-week old male ddY mice are housed in aluminum cages in an animal room with temperature control (24 ± 3 ° C), relative humidity (55 ± 10%), ventilation rate (-12 times / hour) ) and a light-dark cycle (fluorescent lighting: 8:00 a.m. to 8:00 p.m.) for at least 7 days. Animals are allowed to have free access to the diet of pellets and tap water from water bottles. Healthy animals without abnormalities in general signs are used in this study. Animals fast for 20 hours or more with free access to water before use. Compound A and 1 1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGEi (hereinafter "compound B") are dissolved in a vehicle (physiological saline containing 0.01% polysorbate) 80 and 0.5% ethanol), and administered subcutaneously to the animals. The control group received an equal amount of the vehicle in the same way. The animals were decapitated at 30 minutes after administration, and the persistent time of panting movements is measured.

Results As shown in table 2, oral administration of compound A and compound B in 100, 300 and 1000 produces a dose-dependent prolongation of persistent time of panting movement after decapitation. The results indicate that compound A and compound B have a neuroprotective activity and by oral administration and that compound A and compound B are useful for the treatment of ischemic disease.

TABLE 2 Effects of oral administration of compound A and B on persistent time of panting movements after decapitation of mice Decapitation in mice p. o .: for os, ** p < 0.01, * p < 0.05 compared to the control group treated with vehicle (Dunnett's multiple comparison test).

EXAMPLE 3 Method Four-week old male ddY mice are housed in aluminum cages in an animal room with temperature control (24 ± 3 ° C), relative humidity (55 ± 10%), ventilation rate (-12 times / hour) ) and a light-dark cycle (fluorescent lighting: 8:00 a.m. to 8:00 p.m.) for at least 7 days. The animals are allowed free access to the diet of pellets and tap water from the water bottles. Healthy animals without abnormalities in general signs are used in this study. 1-deoxy-13, 14-dihydro-15-keto-16,16-difluoro-PGEi (hereinafter, "Compound C") are dissolved in a vehicle (physiological saline solution containing 0.01% polysorbate 80 and 0.5% of ethanol), and administered subcutaneously to the animals. The control group received an equal amount of the vehicle in the same way. The animals were decapitated at 30 minutes after administration, and the persistent time of panting movements is measured.

Results As shown in table 3, compound C in 300 it produces a significant prolongation of the persistent time of the panting movement after decapitation. The results indicate that compound C has a neuroprotective activity.

TABLE 3 Effect of compound C on persistent time of panting movements after decapitation of mice s. c: subcutaneous, ** p < 0.01 compared to the control group treated with vehicle.

EXAMPLE 4 Method Male Crj: CD (SD) mice of seven weeks of age are housed in polymethylpentene cages in an animal room with control at room temperature (22-26 ° C), relative humidity (47 ± 60%), proportion of ventilation (10-20 times / hour) and a light-dark cycle (lighting: 7:00 a.m. to 1:00 p.m.) for at least 6 days. The animals are allowed to have free access to the diet of pellets and water from the water bottles. Healthy animals are used in this study. The rats are anesthetized by inhalation of a gas mixture of 2% isoflurane and N20: 02 (= 7: 3), stabilized at the position supine, and remain in the anesthetized state by inhalation of the above gas mixture. The animals are monitored to verify the rectal temperature using a temperature probe during the time period of the surgical operation. When a drop in body temperature is observed, an incandescent lamp is used to maintain the temperature at approximately 37 ° C. The right common carotid artery, the external carotid artery, and the internal carotid artery are exposed to occlude the middle cerebral artery (hereafter, MCA). The right common carotid artery and the external carotid artery are ligatures that use sutures (5-0), and a length segment of 19 mm nylon suture No. 4-0 that is pre-covered with silicone is inserted into the MCA through the bifurcation of the external and internal carotid arteries to occlude the MCA. 2 hours after the occlusion of the MCA, the suture is removed and the blood flow in the MCA is restored. Compound A is dissolved in a vehicle (physiological saline containing 1% polysorbate 80), and administered intravenously to the animals in a volume of 2 ml / kg immediately after the occlusion-reperfusion of the CAM and 30 minutes after of the MCA occlusion-reperfusion. The control group receives an equal volume of the vehicle in a similar manner. At 24 hours after occlusion of the MCA, the animals are decapitated and the brains are isolated immediately. Using a tissue cutter (Micro-3D, The Mickle Laboratory Engi- neering Co., Ltd.), the sections sequential brain 2 mm thick, are prepared. Sections of the brain tissue are placed after the brain atlas of Paxinos and Watson to include the coronal plane at 4 mm anterior to the bregma, 2 mm anterior to the bregma, on the bregma, 2 mm posterior to the bregma, at 4 mm posterior bregma, and 6 mm after the bregma. Sections of the brain are stained in 1% TTC solution and photographed. Graphical analysis (Adobe Photoshop ™, version 3.0 J, Adobe Systems Incorporated, color counter 0.3b, K &M Software Corporation) is applied to photographs, and the infarct area is measured. According to these results, the infarct volume (4 mm anterior to the bregma - 6 mm posterior to the bregma) is calculated using the following formula. V = 2 (a + b) / 2 + 2 (b + c) / 2 + 2 (c + d) / 2 + 2 (d + e) / 2 + 2 (e + f) / 2 = a + 2 (b + c + d + e) + f V: infarct volume to infarct area in the cross section 4 mm before bregma b: infarct area in the cross section 2 mm before bregma c: infarct area in the cross section just in the bregma d: infarct area in the cross section 2 mm behind the bregma e: infarct area in the cross section 4 mm behind the bregma f: infarct area in the cross section 6 mm behind the bregma Results As shown in Table 4, Compound A at 0.05 and 0.5 mg / kg significantly reduces the volume of cerebral infarction after ischemia in a dose-dependent manner compared to that of the vehicle group. The results indicate that compound A is useful for the treatment of cerebrovascular disorders such as cerebral infarction.

TABLE 4 Effects of Compound A on cerebral infarct volume after transient focal cerebral ischemia in rats The brain is removed 24 hours after the occlusion of the MCA. Each value represents the mean ± S.E. of 10 rats. The compounds are administered intravenously immediately after the occlusion-reperfusion of the CAM and 30 minutes after the occlusion-reperfusion of the CAM. * P < 0.05, ** P < 0.01; The significant difference of the vehicle group and compound A group (Dunnett's multiple comparison test) EXAMPLE 5 Method Animals of the Alzheimer's disease model are prepared by bilateral ibotenic acid lesions of basal ganglia in rats. Briefly, the rats are anesthetized with pentobarbital sodium and placed in a small animal stereotaxic apparatus. The bilateral infusions of 5 μ? /0.5 μ? of ibotenic acid in the basal ganglia are performed at a rate of 0.1 μm / min via a syringe pump and a stainless steel cannula (external diameter: 0.5 mm). The stereotaxic coordinates are as follows: -0.8 mm posterior of the bregma, 2.6 mm lateral (both sides) of the midline, and 7.4 mm of depth of the bone surface. The animals in false group receive only anesthesia. The animals are then housed with free access to food and water for the remainder of the study. Compound A is administered orally for 14 days after surgery to the model animals. The control group receives the same amount of the vehicle. The Morris water maze test is performed to evaluate the effect of the test compound. The water labyrinth is a circular pool (painted in gray, 1.48 m in diameter, 0.33 m in height). The pool contains water that is maintained at a temperature of 17-18 ° C. During the test in the water maze, a platform, 12 centimeters diameter, it is placed 2 centimeters below the water in one of four sites (zone 4) in the pool, approximately 38 centimeters from the side wall. A focus is placed around the pool as an external signal to the labyrinth. The animals receive 2 tests per day starting 10 days after the initiation of administration with compound A or the vehicle. The rats are trained to locate the hidden escape platform, which remains at a fixed location through the test. The trials last a maximum of 90 seconds. The latency to find the submerged platform is recorded and used as a measure of task acquisition. The animals are analyzed in this way for 4 days (8 total trials), and then receive a trial by tube on the 5th day. For the probe test, the platform is removed from the pool and then the animal is released from the opposite quadrant where the platform should have been located. The length of the test is 90 seconds, after which the rat is removed from the pool. The time the rat spends in looking for the platform in the training quadrant (zone 4); i. e., the previous site of the platform is registered and used as a memory index.

Results As shown in tables 5 and 6, the vehicle group shows spatial cognition seriously deteriorated. Treatment with compound A produces significant investments of the deficit in learning and memory. These results suggest that compound A is useful for the treatment of neuronal disorders such as Alzheimer's disease.

TABLE 5 Effect of compound A in target latent in Morris water maze learning test ## p < 0.01 compared to the false group, ** p < 0.01 compared to the vehicle group.

TABLE 6 Effect of compound A on the time spent in the quadrant (zone 4) on the anterior platform site in the Morris water maze learning test ## p < 0.01 compared to the false group, ** p < 0.05 compared to the vehicle group.

EXAMPLE 6 Method Vascular endothelial cell cultures of human are brought to confluence, as measured by transendothelial electrical resistance (TEER). The cell cultures are then deprived of oxygen for 30 minutes by incubation in a nitrogen atmosphere. The cells are then treated with 0.1% DMSO or 5nM Compound A with final 0.1% DMSO.

Results As shown in Figure 1, cells treated with DMSO show very little recovery from TEER. Cells treated with compound A show an immediate recovery of TEER. The results demonstrate that TEER, a measured barrier function of endothelial cells, rapidly recovers from damage after treatment with compound A.

EXAMPLE 7 Method Human microvascular endothelial cells (adult) (HMVEC-AD) are grown for confluence. The cells are then treated for 30 minutes with a nitrogen atmosphere and return to normal oxygen. ATP levels are monitored at the indicated time points using a luciferin-luciferase assay system (ATPIita, Perkin Elmer).

Results As shown in Figure 2, ATP levels decrease when cells are exposed to a nitrogen atmosphere for 30 minutes. ATP levels return more rapidly in cells treated with compound 5nM compared to cells treated with 0.01% DMSO alone. The results indicate that compound A is useful for the treatment of disorders of the central nervous system.

EXAMPLE OF SYNTHESIS 1 Compound 1 Compound Compound (3 í Synthesis of benzyl ester of 16,16-difluoro-PGE (2) benzyl ester of 16,16-difluoro-PGET (1) (457.8 mg, 0.95 mmol) is dissolved in acetic acid (1 3.7 ml, 0.24 mol), and the solution is stirred at 80 ° C for 18 hours. The reaction mixture is cooled to room temperature. 10 ml of toluene are added to the solution and concentrated under reduced pressure. This operation is repeated five times to remove the acetic acid. The residue is purified by column chromatography on silica gel (silica gel: FL60D (70 g), Fuji Silysia, hexane / ethyl acetate (2: 1)) to obtain the compound (2) as a yellow oil. Performance 391.6 (88.9%).

Synthesis of 1-deoxy-13, 14-dihydro-6,16-difluoro-PGE1 (3) benzyl ester of 16,16-difluoro-PGAT (compound (2)) (382.5 mg, 0.83 mmol) is hydrogenated in ethyl acetate (10 ml), under the presence of 10% palladium-carbon (57.4 mg, wet with 50% w / w of water) at room temperature, at atmospheric pressure for 2 hours. The reaction mixture is filtered through a pad of Celite, the filtered cake is washed with ethyl acetate, and then the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (silica gel BW-300SP (50 g, wet with 15% w / w of water), Fuji Silysia, hexane / ethyl acetate (1:)) to obtain the crude compound (3) (298.5 mg, 95.7%). The crude compound (3) is combined with another batch of the crude compound. And then, approximately 350 mg of the crude compound is 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 of purification by HPLC: 83.5%). 1 H-NMR (200 MHz, CDCl 3) d 0.94 (3 H, t, J = 7.1 Hz), 1.22-2.29 (28 H, m), 2.34 (2 H, t, J = 7.3 Hz), 3.65-3.81 (1 H , m) 13 C-NMR (50 MHz, CDCl 3) 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), 1 79.07, 220.79.

EXAMPLE OF SYNTHESIS 2 According to the similar manner described in Synthesis Example 1, isopropyl ester of 1-deoxy-1,3,1-dihydro-1-keto-16,16-difluoro-PGE-i (compound (6)) is obtained as a colorless oil by the previous two-stage reaction. Yield: 0.285g (1 st stage: 96.2%, 2nd stage: 97.6%, purification by HPLC, recovery 81 .0%). 1 H-NMR (200MHz, CDCl 3) and 13 C-NMR (50MHz, CDCl 3) of the compound (6) is shown in Figures 3 and 4 respectively.

EXAMPLE OF SYNTHESIS 3 COO- According to the similar manner described in Synthesis Example 1, 2-decarboxy-2- (2-carboxyethyl) -1 1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGEi isopropyl ester. (compound (9)) are obtained as a colorless oil. Yield: 0.402 g (1st stage: 94.9%, 2nd stage: 92.2%, purification by HPLC: recovery 83.1%). 1 H-R N (200MHz, CDCl 3) and 13 C-NMR (50MHz, CDCl 3) of the compound (9) is shown in Figures 5 and 6 respectively.

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

EXAMPLE OF SYNTHESIS 5 (13) (14) HF \ C rop. 0 COO ~ < w K, P P < < UuC YMC (Sil) 20 * 250mm, - ..., .-- .., -, ..., 000 - F. f (6Pr n n - Hneexx..tmnoo A «cceett..int oo d oee e etmiloo - '¿"' (100: 7) (H) 87.3 * ecu ei .wi 70.0 °.

According to the similar way described in the synthesis example 1, isopropyl ester of 1-deoxy-13,14-dihydro-15-keto-16,16-d-fluoro-20-methyl-PGE-i (compound (5)) is obtained as a colorless oil.

Performance: 0.271g (1st stage: 91.4%, 2nd stage: 97.3%, HPLC purification: recovery: 79.0%). 1 H-NMR (200MHz, CDCl 3) and 13 C-NMR (50MHz, CDCl 3) of the compound (15) are shown in Figures 9 and 10 respectively.

EXAMPLE OF SYNTHESIS 6 According to the similar manner described in synthesis example 1,1,1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE 1 (compound (18)) is obtained as an oil colorless. Yield: 0.637g (1st stage: 93.3%, 2nd stage: 96.6%, HPLC purification: recovery: 73.9%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of compound (18) are shown in Figures 1 and 12 respectively.

EXAMPLE OF SYNTHESIS 7 According to the similar manner described in synthesis example 1,1,1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE! (compound (21)) was obtained as a colorless oil. Yield: 0.401 g (1st step: 90.6%, 2nd step: 92.7%, HPLC purification: 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 1 1-Deoxy-13,14-dihydro-15-keto-6,16-difluoro-16 methyl ester (compound (23)) is obtained as a colorless oil by esterification of the compound (22) with diazomethane. Yield: 0.860 g (72.9%, after purification chromatography on silica gel column). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (23) are shown in Figures 15 and 16.

EXAMPLE OF SYNTHESIS 9 Compound (24) (0.67g, 1.66 mmol) is dissolved in DMF (13 mL), and K2C03 (460.1 mg, 3.33 mmol) and isopropyl iodide (831 μ ?, 8.32 mmol) are added. The solution is stirred at room temperature for 2 hours. The reaction mixture is cooled with ice, water (10 mL) and saline are added, and it is extracted with ethyl acetate (30 mL). The organic phase is washed with saline (10 mL), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel FL60D (50 g), Fuji Silysia, hexane / ethyl acetate (5: 1)) to obtain isopropyl ester of 1-deoxy-3,14 dihydro Crude -1 5-keto-16,16-difluoro-20-ethyl-PGE1 (compound (25)) (0.70 g, 94.6%). The crude compound (25) is purified by preparative HPLC to obtain the compound (25) as a colorless oil. Yield 245.8 mg (35.1%). 1 H-NMR (200MHz, CDCl 3) and 13 C-NMR (50MHz, 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) is dissolved in 1,2-dichloroethane (70 mL) and 1'-thiocarbonyldiimidazole (5.41 g, 30.3 mmol) is added.

The solution is stirred at 70 ° C for one hour. The reaction mixture is cooled to room temperature, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel BW-300SP (650 g), Fuj i Silysia, hexane / ethyl acetate (1: 1)) to obtain compound (27) as a yellow oil. clear (10.61 g, 97.0%). Bu3SnH (11.21 g, 38.5 mmol) is dissolved in toluene (224 mL), and refluxed by heating. The solution of compound (27) (10.41 g, 19.2 mmol) in toluene (208 mL) is added dropwise to the reaction mixture at a reflux temperature for 70 minutes. And then, the reaction mixture is cooled to room temperature, concentrated under reduced pressure to obtain the crude compound (28) as light yellow oil. The crude compound (28) (19.2 mmol) is dissolved in THF (52 mL) and TBAF solution (1.0 M in THF, 38.5 mL, 38.5 mmol) is added dropwise for 10 minutes. After one hour, TBAF solution (1.0 M in THF, 19.2 mL, 9.2 mmol) is added dropwise to the solution. After stirring for a total of 3.5 hours, the reaction mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel BW-300SP (1000 g), Fuji Silysia, hexane / ethyl acetate (1: 1)) to obtain the compound (29) as a yellow oil (4.01 g, 69.3%). The compound (31) is obtained from the compound (29) by oxidation of Swem and the introduction of the chain- ?. Compound (31) (807.4 mg, 1.88 mmol) is hydrogenated in ethyl acetate (8 mL) under the presence of 10% palladium-carbon at room temperature. environment for 2 hours. The reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated under reduced pressure to obtain the crude compound (32) as the light brown oil. The crude compound (32) (1.88 mmol) is dissolved in EtOH (8 mL). Solution 1 N-NaOH (7.4 mL, 7.4 mol) is dripped into the solution at room temperature for 10 minutes. The reaction mixture is stirred at room temperature for 10 hours, and then cooled with ice. 1 N-HCl (7.1 mL) is added dropwise to the reaction mixture to adjust the pH around 3-4. Then the reaction mixture is extracted with TBME (30 mL). The organic phase is washed with water (10 mL) and saline (10 mL), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (15% silica gel in water including FL-60D (80 g), Fuji Silysia, hexane / ethyl acetate (2: 1)) to obtain the compound (33). ) as a light yellow oil (48 .4 mg, 68.8%). According to the similar manner described in Synthesis Example 9, isopropyl ester of 1-deoxy-13,14 dihydro-15-keto-16,16 difluoro-PGF 1a, (compound (34)) is obtained from the compound (33). ) as a colorless oil. Yield: 166.6 mg (reaction step 91.9%: Purification with HPLC: recovery: 55.4%). 1 H-NMR (200 MHz, CDCl 3) and 13 C-NMR (50 MHz, CDCl 3) of the compound (34) are shown in Figures 19 and 20 respectively.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- Use of a 1-deoxy-prostaglandin compound for the preparation of a pharmaceutical composition useful for the treatment of central nervous system disorder in a mammalian subject. 2. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound represented by the following general 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 -CH3, -CH2OH, -COCH2OH, -COOH or a functional derivative thereof; is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by a halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of the carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and R0 is a lower or middle aliphatic hydrocarbon residue, saturated or unsaturated, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cycloalkyl (lower), cycloalkyloxy (lower), aryl, aryloxy, a heterocyclic group or a heterocyclic group -oxi; lower alkoxy; lower alkanoyloxy; cycloalkyl (lower); cycloalkyloxy (lower); aril; aryloxy; heterocyclic group; heterocyclic-oxy group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur. 3. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1 l-deoxy-13,14-dihydro-prostaglandin. 4. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 11-deoxy-15-keto-prostaglandin. 5. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1-deoxy-mono or dihalogen-prostaglandin. 6. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1-deoxy-13,14-16-mono or dihalogen-prostaglandin. 7. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1-deoxy-15-keto-16-mono or dihalogen-prostaglandin. 8. The use claimed in claim 1, wherein said compound of 1-deoxy-prostaglandin is a compound of 1-deoxy-13,14-dihydro-15-keto-16-mono or dihalogen-prostaglandin. 9. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1-deoxy-13,14-dihydro-15-keto-16-mono or difluoro-prostaglandin. . 10. The use claimed in claim 1, wherein said 1-deoxy-prostaglandin compound is a compound of 1 1-deoxy-13,14-dihydro-5-keto-16-mono or dihalogen-prostaglandin E or F. 1 1. - The use claimed in claim 1, wherein said prostaglandin compound is a compound of 1-deoxy-13,14-dihydro-15-keto-16-mono or difluoro-prostaglandin E or F. 12. The use claimed in claim 1, wherein said prostaglandin compound is a compound of 1-deoxy-13,14-dihydro-15-keto-16,16-difluoro-prostaglandin Ei. 13.- The use claimed in any of the claims 1 - . 1-12, where the central nervous system disorder is a cerebrovascular disorder. 14. A composition useful for the treatment of a central nervous system disorder in a mammalian subject, comprising an effective amount of a 1-deoxy-prostaglandin compound. 15. Use of a 1-deoxy-prostaglandin compound for the preparation of a pharmaceutical composition useful for protecting cerebrovascular endothelial cells in a mammalian subject. 16. - The use claimed in claim 15, wherein the cerebrovascular endothelial is that of a blood-brain barrier. 1 7. - A compound represented by the formula (IV): wherein L is hydrogen, hydroxy, halogen, a lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo; wherein the five-membered ring may optionally have at least one double bond; A is -CH3, -CH2OH, -COCH2OH, -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 and R 5 are not hydroxy and lower alkoxy at the same time; ? - and X2 'are the same or different halogen atoms; R is a lower or middle, bivalent, saturated or unsaturated aliphatic hydrocarbon, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon 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 of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; as long as the compound is not 11-deoxy-13,14-dihydro-15-keto-16, 16-difluoro-PGEi. 18. The compound according to claim 17, further characterized in that it is selected from the group consisting of: 11-deoxy-3,14-dihydro-15-keto-16,16-difluoro-PGEi, isopropyl ester of 11- deoxi-IS. -dihydro-IS-keto-ie.ie-difluoro-PGE !, isopropyl ester of 2-decarboxi-2- (2-carboxyethyl) -11-deoxy-13,4-dihydro-15-keto-1,6,6-difluoro -PGE! , 2-decarboxy-2- (2-carboxyethyl) -11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGEL 11-deoxy-13,14-dihydro-15-keto isopropyl ester -16,16 -difluoro-20-methyl-PGE !, 1-deoxy-3,14-dihydro-15-keto-16,1 e-difluoro ^ 0-methyl-PGE !, 11-deoxy-SM-dihydro- IS-keto-ie.ie-difluoro ^ O-ethyl-PGE!, 11-deoxy-IS.M-dihydro-IS-keto-ie.-difluoro-PGE! Methyl ester, 11-deoxy-isopropyl ester 13,14 dihydro-IS-keto-e.i-difluoro-O-ethyl-PGF! and isopropyl ester of 11-deoxy-13, 14-dihydro-15-keto-16,16-difluoro-PGF1a.