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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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Definitions

• the present invention relates to a method and composition for treating a central nervous system disorder in a mammalian subj ect .
• the invention also relates to a novel prostaglandin compound. BACKGROUND ART
• junctional complexes mediate adhesion and communication between adj oining endothelial and epithelial cells .
• junctional complexes comprise tight junctions , adherens junctions, and gap junctions .
• the expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs .
• Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells . Tight j unctions serve the major functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity.
• Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes . In addition, they are required for a correct organization of new vessels in angiogenesis (Physiol . Rev. 84 ( 3) , 869-901 , 2004) .
• the blood-brain barrier is a specialized structure in the central nervous system (CNS) , which participates in 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 underlying the vasculature plays a critical role in maintaining the integrity of the BBB by providing structural support to the endothelial cell wall
• 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 .
• CNS central nervous system
• a wide range of central nervous system (CNS) disorders associated with disruption of the BBB are known .
• disorders include multiple sclerosis, experimental allergic encephalomyelitis, bacterial meningitis, ischemia, brain edema, Alzheimer ' s disease, acquired immune deficiency syndrome dementia complex (Helga),
• the neuronal tissue becomes infracted as a result of these events, with contributions from excitotoxicity, enzyme activation, edema, and inflammation (Trends Pharmacol Sci . 1996; 17 : 227-233, Crit Care Med. 1988 ; 16 : 954-963 ) .
• BBB BBB tight junctional disruption
• paracellular permeability The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment .
• Prostaglandins are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity.
• PGs found in nature primary PGs
• primary PGs generally have a prostanoic acid skeleton as shown in the formula (A) :
• the primary PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five- membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety: Subscript 1 : 13, 14-unsaturated-l5-OH Subscript 2 : 5, 6- and 13 , 14-diunsaturated-15-OH Subscript 3 : 5, 6- , 13, 14-, and 17 , 18-triunsaturated-15- OH .
• the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into a type (the hydroxyl group is of an a -configuration) and ⁇ -type (the hydroxyl group is of a ⁇ -configuration) .
• PGEi and PGE 2 and PGE 3 are known to have vasodilation, hypotension, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, bronchodilation and anti ulcer activities .
• PGFi ⁇ , PGF2 ⁇ and PGF 3C have been known to have hypertension, vasoconstriction, intestinal tract movement enhancement, uterine contraction, lutein body atrophy and bronchoconstriction activities .
• U. S . Patent No . 5, 290, 811 to Ueno et al . describes that some 15-keto-PG compounds are useful for improvement of encephalic function .
• U. S . Patent No . 5, 290, 811 indicates that when the bond between 13- and 14-positions is saturated, a keto-hemiacetal equilibrium may sometimes be formed by the formation of a hemiacetal between the hydroxy group at 11-position and the keto group at 15-position .
• U . S . Patent No . 5, 317 , 032 to Ueno et al . describes prostaglandin compound cathartics, including the existence of bicyclic tautomers and U . S . Patent No . 6, 414 , 016 to Ueno describes the bicyclic tautomers as having pronounced activity as anti-constipation agents .
• the bicyclic tautomers substituted by one or more halogen atoms can be employed in small doses for relieving constipation . At the C-16 position, especially, fluorine atoms can be employed in small doses for relieving constipation .
• the present inventor conducted an intensive study and found that 11-deoxy-prostaglandin compounds possessed significant effects on the central nervous system disorders, which resulted in the completion of the present invention .
• 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 11-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 subj ect, which comprises an effective amount of a 11-deoxy-prostaglandin compound.
• the present invention relates to a use of
• 11-deoxy-prostaglandin compound for manufacturing a composition for treating a central nervous system disorder in a mammalian subj ect, which comprises 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 subj ect, which comprises administering an effective amount of a 11-deoxy-prostaglandin compound to a subj ect in need thereof .
• 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;
• Z is
• R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, wherein R 4 and R5 are not hydroxy and lower alkoxy at the same time;
• Xi ' and X 2 ' are same or different halogen atoms ;
• Ri is a saturated or unsaturated bivalent lower or medium 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;
• R 2 is a single bond or lower alkylene; and R 3 is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl , cyclo ( lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-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 11-deoxy- 13, 14-dihydro-15-keto-16, 16-difluoro-PGEi is provided.
• l is a graph showing the effect of Compound A on Recovery of 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 deprived of oxygen for 30 minutes by incubation in a nitrogen atmosphere .
• the cells were then either 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 IO cells .
• Fig.2 is a graph showing the effect of Compound A on Recovery of ATP Level .
• Fig . 3 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 6) obtained in Synthesis Example 2 below.
• Fig . 4 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound ( 6) obtained in Synthesis Example 2 below.
• Fig. 5 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 9) obtained in Synthesis Example 3 below.
• Fig. 6 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound ( 9) obtained in Synthesis Example 3 below.
• Fig . 7 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 12 ) obtained in Synthesis Example 4 below .
• Fig. 8 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound ( 12 ) obtained in Synthesis Example 4 below.
• Fig . 9 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 15) obtained in Synthesis Example 5 below.
• Fig . 10 is a 13 C-NMR (50MHz, CDCl 3 ) chart of the compound ( 15) obtained in Synthesis Example 5 below.
• Fig . 11 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 18 ) obtained in Synthesis Example 6 below.
• Fig. 12 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound ( 18 ) obtained in Synthesis Example 6 below.
• Fig . 13 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound (21 ) obtained in Synthesis Example 7 below.
• Fig. 14 is a 13 C-NMR (50MHz, CDCl 3 ) chart of the compound (21 ) obtained in Synthesis Example 7 below.
• Fig. 15 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound (23 ) obtained in Synthesis Example 8 below .
• Fig . 16 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound (23 ) obtained in Synthesis Example 8 below.
• Fig . 17 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound (25) obtained in Synthesis Example 9 below.
• Fig . 18 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound (25) obtained in Synthesis Example 9 below.
• Fig . 19 is a 1 H-NMR (200MHz, CDCl 3 ) chart of the compound ( 34 ) obtained in Synthesis Example 10 below.
• Fig . 20 is a 13 C-NMR ( 50MHz, CDCl 3 ) chart of the compound ( 34 ) obtained in Synthesis Example 10 below.
• the "11-deoxy- prostaglandin compound” may include any derivatives or analogs (including substituted derivatives) of a compound having no substituent at 11-position of the prostanoic acid skeleton, irrespective of the configuration of the five-membered ring, the number of double bonds, presence or absence of a substituent, or any other modification in the ⁇ or ⁇ chain .
• the formula (A) shows a basic skeleton of the C-20 carbon atoms, but the present invention is not limited to those having the same number of carbon atoms .
• the numbering of the carbon atoms which constitute the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1 ) , and carbon atoms in the ⁇ -chain are numbered 2 to 7 towards the five-membered ring, those in the ring are 8 to 12, and those in the ⁇ -chain are 13 to 20.
• the nomenclature of the 11-deoxy-PG compounds is based on the prostanoic acid skeleton .
• PG partial structure as a prostaglandin
• the abbreviation of "PG” may be used .
• a 11-deoxy-PG compound of which ⁇ -chain is extended by two carbon atoms, that is, having 9 carbon atoms in the ⁇ -chain is named as 2-decarboxy-2- (2- carboxyethyl ) -11-deoxy-PG compound.
• 11-deoxy-PG compound having 11 carbon atoms in the ⁇ -chain is named as 2-decarboxy-2- ( 4-carboxybutyl ) -11-deoxy-PG compound.
• 11-deoxy-PG compound of which ⁇ -chain is extended by two carbon atoms that is, having 10 carbon atoms in the ⁇ -chain is named as ll-deoxy-20-ethyl-PG compound.
• These compounds may also be named according to the IUPAC nomenclatures .
• Examples of the analogs (including substituted derivatives) or derivatives include a 11-deoxy-PG compound of which carboxy group at the end of ⁇ -chain is esterified; a compound of which ⁇ -chain is extended; physiologically acceptable salt thereof; a compound having a double bond at
• preferred substituents at position 3, 17 , 18 and/or 19 include alkyl having 1-4 carbon atoms, especially methyl and ethyl .
• Preferred substituents at position 16 include lower alkyl such as methyl and ethyl, hydroxy, halogen atoms such as chlorine and fluorine, and aryloxy such as trifluoromethylphenoxy .
• Preferred substituents at position 17 include lower alkyl such as methyl and ethyl, hydroxy, halogen atoms such as chlorine and fluorine, aryloxy such as trifluoromethylphenoxy .
• Preferred substituents at position 20 include saturated or unsaturated lower alkyl such as Cl-4 alkyl, lower alkoxy such as Cl-4 alkoxy, and lower alkoxy alkyl such as Cl-4 alkoxy-Cl-4 alkyl .
• Preferred substuents at position 5 include halogen atoms such as chlorine and fluorine .
• Preferred substituents at position 6 include an oxo group forming a carbonyl group .
• Stereochemistry of PGs having hydroxy, lower alkyl or hydroxy (lower) alkyl substituent at position 9 may be ⁇ , ⁇ or a mixture thereof .
• analogs or derivatives may 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 PGs .
• a preferred compound used in the present invention is represented by the formula ( I ) :
• 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 saturated or unsaturated bivalent lower or medium 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
• R 0 is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo ( lower) alkyl, cyclo ( lower) alkyloxy, aryl, aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cyclo (lower) alkyl ; cyclo (lower) alkyloxy; aryl ; 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 .
• a more preferred compound used in the present invention is represented by the formula ( II ) :
• 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;
• Z is
• 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;
• Ri is a saturated or unsaturated bivalent lower or medium 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
• Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo ( lower) alkyloxy, aryl, aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cyclo ( lower) alkyl ; cyclo (lower) alkyloxy; aryl ; 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 .
• a group of particularly preferable compounds among the above-described compounds is represented by the formula ( III ) :
• L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy or oxo, wherein, and 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;
• Z is
• R 4 and R 5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy ( lower) alkyl, wherein R 4 and R5 are not hydroxy and lower alkoxy at the same time;
• Xi and X 2 are hydrogen, lower alkyl, or halogen
• Ri is a saturated or unsaturated bivalent lower or medium 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
• R 2 is a single bond or lower alkylene;
• R 3 is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo ( lower) alkyl, cyclo ( lower) alkyloxy, 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 further relates to a compound represented by the formula (IV) :
• 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;
• R 4 and R5 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;
• Ri is a saturated or unsaturated bivalent lower or medium 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 ;
• R 2 is a single bond or lower alkylene; and R 3 is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo ( lower) alkyl, cyclo ( lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-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 11-deoxy- 13, 14-dihydro-15-keto-16, 16-difluoro-PGEi, and a method for producing the same .
• the term "unsaturated" in the definitions for R 1 and Ra is intended to include at least one or more double bonds and/or triple bonds that are iso'latedly, separately or serially present between carbon atoms of the main and/or side chains .
• an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both of the positions .
• lower or medium 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 R a .
• halogen covers fluorine, chlorine, bromine and iodine .
• lower alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1 to
• lower alkoxy refers to a group of lower alkyl-O-, wherein lower alkyl is as defined above .
• 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-l-hydroxyethyl .
• 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 .
• cyclo (lower) alkyl refers to a cyclic group formed by 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 .
• cyclo ( lower) alkyloxy refers to the group of cyclo ( lower) alkyl-O-, wherein cyclo ( lower) alkyl is as defined above .
• aryl may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups) , for example, phenyl, tolyl, xylyl .
• substituents are halogen atom and halo ( lower) alkyl, wherein halogen atom and lower alkyl are as defined above .
• aryloxy refers to a group represented by the formula ArO-, wherein Ar is aryl as defined above .
• heterocyclic group may include mono- to tri-cyclic, preferably monocyclic heterocyclic group which is 5 to 14 , preferably 5 to 10 membered ring having optionally substituted carbon atom and 1 to 4 , preferably 1 to 3 of 1 or 2 type of hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom.
• heterocyclic group examples 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, phenothiazo
• heterocyclic-oxy group means a group represented by the formula HcO- , wherein Hc 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 calcium salt 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 salt) , tetraalkyl ammonium salt and the like .
• an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt) , an alkaline earth metal salt (
• 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-cyclopropyl ethyl ether; and medium, 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
• esters examples 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, 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; hydroxy (lower) alkyl ester such as hydroxyethyl ester; lower alkoxy ( lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters such as, for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicyl ester, 3, 4-di-methoxyphenyl ester and
• the amide of A mean 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 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 which has a 5-membered ring structure of, so called, especially PGF or PGE type .
• Preferred example A is -COOH, its pharmaceutically acceptable salt, ester or amide thereof .
• Preferred example B is -CH 2 -CH 2 - , which provide the structure of so-called, 13, 14-dihydro type .
• Xi and X2 is hydrogen, or that at least one of them is halogen, more preferably, both of them are halogen, especially, fluorine that provides a structure of, so called 16, 16-difluoro type .
• Preferred Xi 1 and X 2 ' are difluoro atoms .
• Preferred Ri is a hydrocarbon containing 1-10 carbon atoms, preferably, 6-10 carbon atoms . Further, at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur .
• Ri examples include, for example, the following groups :
• Ra is a hydrocarbon containing 1-10 carbon atoms, more preferably, 1-8 carbon atoms . Ra may have one or two side chains having one carbon atom. Preferred R 2 is single bond, and preferred R3 is lower alkyl . R3 may have one or two side chains having one carbon atom.
• the configuration of the ring and the ⁇ - and/or ⁇ chains in the above formula (I ) , (II) , (III) and (IV) may be the same as or different from that of the primary PGs .
• 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 present compound is a 11- deoxy-13, 14-dihydro-16, 16-difluoro-PGE or PGF compound, ll-deoxy-13, 14-dihydro-15-keto-16, 16-difluoro-PGE or PGF compound, 2-decarboxy-2- (2-carboxyethyl ) - ll-deoxy-13, 14- dihydro-15-keto-l ⁇ , 16-difluoro-PGE or PGF compound, or ll- deoxy-13, 14-dihydro-15-keto-16, 16-difluoro- 20-methyl or ethyl-PGE or PGF compound and its derivative or analogue .
• the preferred example of the present compound is 11- deoxy-13, 14-dihydro-15-keto-16 / 16-difluoro-PGEi, 11-deoxy- 13, 14-dihydro-l ⁇ , 16-difluoro-PGEi, ll-deoxy-13, 14-dihydro- 15-keto-16, 16-difluoro-PGEi isopropyl ester, 2-decarboxy-2- (2-carboxyethyl ) -ll-deoxy- 13, 14-dihydro-15-keto-16, 16- difluoro-PGEi isopropyl ester, 2-decarboxy-2- (2- carboxyethyl) -ll-deoxy-13, 14-dihydro-15- keto-16, 16- difluoro-PGEi, ll-deoxy-13 , 14-dihydro-15-keto- 16, 16- difluoro-20-methyl-PGEi isopropyl ester, 11-deoxy-
• any of isomers such as the individual tautomeric isomers, the mixture thereof, or optical isomers, the mixture thereof, a racemic mixture, and other steric isomers may be used in the same purpose .
• Some of the compounds used in the present invention may be prepared by the method disclosed in USP Nos . 5, 073, 569, 5, 166, 174, 5, 221, 763, 5, 212, 324, 5, 739, 161 and 6, 242, 485 (these cited references are herein incorporated by reference) .
• a mammalian subject may be treated by the instant invention by administering the compound used in the present invention .
• the subj ect may be any mammalian subject including a human.
• the compound may be applied systemically or topically .
• the compound may be administered by oral administration, intravenous inj ection (including infusion) , subcutaneous inj ection, intra rectal administration, intra vaginal administration, transdermal administration and the like .
• the dose may vary depending on the strain of the animal, age, body weight, symptom to be treated, desired therapeutic effect, administration route, 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 0.00001-500mg/kg per day, more preferably 0.0001-lOOmg/kg .
• the compound may preferably be formulated 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 it may be an external preparation, suppository or pessary .
• composition of the present invention may further contain physiologically acceptable additives .
• Said additives may include the ingredients used with the present compounds such as excipient, diluent, filler, resolvent, lubricant, adjuvant, binder, disintegrator, coating agent, cupsulating agent, ointment base, suppository base, aerozoling agent, emulsifier, dispersing agent, suspending agent, thickener, tonicity agent, buffering agent, soothing agent, preservative, antioxidant, corrigent, flavor, colorant, a functional material such as cyclodextrin, and biodegradable polymer, stabilizer .
• the additives are well known to the art and may be selected from those described in general reference books of pharmaceutics .
• the amount of the above-defined compound in the composition of the invention may vary depending on the formulation of the composition, and may generally be 0.000001-10.0%, more preferablyO .00001-5.0%, most preferably 0.0001-1% .
• solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like .
• the solid composition may be prepared by mixing one or more active ingredients with at least one inactive diluent .
• the composition may further contain additives other than the inactive diluents, for example, a lubricant, a disintegrator and a stabilizer . Tablets and pills may be coated with an enteric or gastroenteric film, if necessary.
• compositions may be covered with two or more layers . They may also be adsorbed to a sustained release material, or microcapsulated. Additionally, the compositions may be capsulated by means of an easily degradable material such gelatin . They may be further dissolved in an appropriate solvent such as fatty acid or its mono, di or triglyceride to be a soft capsule . Sublingual tablet may be used in need of fast-acting property.
• liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs and the like .
• Said composition may further contain a conventionally used inactive diluentseg . purified water or ethyl alcohol .
• the composition may contain additives other than the inactive diluents such as adjuvant e . g . wetting agents and suspending agents, sweeteners , flavors , fragrance and preservatives .
• the composition of the present invention may be in the" form of spraying composition, which contains one or more active ingredients and may be prepared according to a known method.
• compositions of the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions .
• Diluents for the aqueous solution or suspension may include, for example, distilled water for inj ection, physiological saline and Ringer ' s solution .
• Non-aqueous diluents for 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 further comprise additives such as preservatives, wetting agents, emulsifying agents, dispersing agents and the like . They may be sterilized by filtration through, e . g . a bacteria- retaining filter, compounding with a sterilizer, or by means of gas or radioisotope irradiation sterilization .
• the inj ectable composition may also be provided as a sterilized powder composition to be dissolved in a sterilized solvent for inj ection before use .
• the external preparation of the invention may be any form of the external preparations used in the fields of dermatology and otolaryngology, which includes ointment, cream, lotion and spray.
• compositionsuppository or pessary which may be prepared by mixing active ingredients into a conventional base such as cacao butter that softens at body temperature, and nonionic surfactants having suitable softening temperatures may be used to improve absorbability.
• treatment used herein includes any means of control such as prevention, care, relief of the condition,- attenuation of the condition, arrest of progression, etc .
• central nervous system disorder used herein includes any central nervous system disorder involved or being 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) , arteriosclerosis , metabolic disorder, degeneration, aging, drugs, medications or surgical procedures .
• central nervous system disorder examples include, but 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 disease , Parkinson ' s disease, Huntington ' s chorea, dementia, Pick disease, spino-cerebellar degeneration, chorea, AIDS encephalopathy, hepatic encephalopathy, amyotrophic lateral sclerosis, anticancer drug-induced peripheral neuropathy, diabetic neuropathy, traumatic neurological disorder and multiple sclerosis ; cerebral edema, hypernatremic cerebral disorder and brain tumor; ischemic diseases such as cerebral ischemia caused by vascular disorders , transient ischemic attack (TIA) , reversible ischemic neurological deficit
• the compounds used herein have a significant effect on recovery of barrier function of cerebrovascular endothelial cells, especially blood brain barrier, so it is also useful for protecting cerebrovascular endothelial cells .
• the pharmaceutical composition of the present invention may further contain other pharmacological ingredients as far as they do not contradict the purpose of the present invention .
• the present formulations may contain a single active ingredient or a combination of two or more active ingredients .
• their respective contents may be suitably increased or decreased in consideration of their therapeutic effects and safety.
• present formulations may contain other pharmacologically active ingredients, as far as they are not contrary to the obj ects of the present invention .
• the control group received an equal amount of the vehicle in the same manner .
• the animals were decapitated at 30 minutes after the administration, and the persistent time of gasping movements was measured.
• Compound A at 10, 30, 100 and 300 ⁇ g/kg produced a dose-dependent prolongation of the persistent time of gasping 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 .
• Compound A 300 S . C . 10 23.6 ⁇ 0.6** s . c subcutaneous, **p ⁇ 0.01 , *p ⁇ 0.05 compared to vehicle-treated control group (Dunnett' s multiple comparison test ) .
• mice Four-week-old male ddY mice were housed in aluminum cages in an animal room controlled for temperature (24 ⁇ 3 0 C) / relative humidity ( 55 ⁇ 10% ) , ventilation rate (-12 times/hour) and light-dark cycle ( fluorescent lighting: 8 : 00 to 20 : 00 ) for at least 7days .
• the animals were allowed free access to pellet diet and tap water from water bottles . Healthy animals without abnormalities in general signs were used in this study. The animals were fasted for 20 hours or longer with free access to water before use .
• Compound A and ll-deoxy-13, 14-dihydro- 15-keto-16, 16- difluoro-PGEi methyl ester (hereinafter, "Compound B” ) were dissolved in a vehicle (physiologic saline containing 0.01% polysorbate 80 and 0.5% ethanol) , and was administered orally to the animals .
• the control group received an equal amount of the vehicle in the same manner .
• the control group received an equal amount of the vehicle in the same manner .
• the animals were decapitated at 30 minutes after the administration, and the persistent time of gasping movements was measured.
• Example 4 Seven-week-old Crj : CD (SD) male rats were housed in polymethylpentene cages in an animal room controlled for room temperature (22-26°C) , relative humidity ( 47-60% ) , ventilation rate ( 10-20 times/hour) and light-dark cycle
• the animals were monitored for rectal temperature using a temperature probe during the period of the surgical operation . When a fall in body temperature was observed, an incandescent lamp was used to maintain the temperature at around 37 0 C .
• the right common carotid artery, external carotid artery, and internal carotid artery were exposed for occluding the middle cerebral artery (hereafter, MCA) .
• the right common carotid artery and the external carotid artery were ligatured using sutures ( 5-0) , and a 19 mi ⁇ i-long segment of No . 4-0 nylon suture which were precoated with silicone was inserted into the MCA through the bifurcation of the external and internal carotid arteries to occlude the MCA. At '2 hours after the MCA occlusion, the suture was removed and the blood flow in the MCA was restored .
• Compound A was dissolved in a vehicle (physiological saline containing 1 % polysorbate 80 ) , and was administered intravenously to the animals at a volume of 2 mL/kg immediately after the MCA occlusion-reperfusion and 30 minutes after the MCA occlusion-reperfusion.
• the control group received an equal volume of the vehicle in the same manner .
• the animals were decapitated and the brains were immediately isolated. Using a tissue chopper (Micro-3D; The Mickle Laboratory Engineering Co . , Ltd. ) , sequential brain sections 2 mm in thickness were prepared .
• the brain tissue sections were positioned following the brain atlas of Paxinos and Watson to include the coronal plane at 4 mm anterior to the bregma, at 2 mm anterior to the bregma, at the bregma, at 2 mm posterior to the bregma, at 4 mm posterior to the bregma, and at 6 mm posterior to the bregma .
• the brain sections were stained in 1% TTC solution and photographed. Graphic analysis (Adobe PhotoshopTM, version 3.0 J; Adobe Systems Incorporated, Color Count 0.3b; K&M Software Corporation) was applied to the photographs, and the infarct area was measured. Based on these results, the infarct volume (4 mm anterior to the bregma - 6 mm posterior to the bregma) was 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
• Alzheimer ' s disease model animals were prepared by bilateral ibotenic acid lesions of basal ganglia in rats . Briefly, rats were anesthetized with pentobarbital sodium and placed in a small animal stereotaxic apparatus . Bilateral infusions of 5 ⁇ g/0.5 ⁇ L of ibotenic acid into the basal ganglia were made at a rate of 0.1 ⁇ L/min via a syringe pump and a stainless steel cannula (outer diameter : 0 , 5 mm) . Stereotaxic coordinates were as follows : -0.8 mm posterior from bregma, 2.6 mm lateral (both sides) from midline, and 7.4 mm depth from the bone surface . Animals in sham group received only anesthesia . Animals were then housed with free access to food and water for the rest of the study.
• Compound A was orally administered for 14 days after surgery to the model animals .
• Control group received the same amount of the vehicle .
• the Morris water maze test was performed to evaluate the effect of test compound.
• the water maze was a circular pool (painted gray, 1.48 m in diameter, 0.33 m high) .
• the pool contained water that was maintained at a temperature of 17-18 0 C .
• a platform 12 cm in diameter, was located 2 cm below the water in one of four locations ( zone 4 ) in the pool, approximately 38 cm from the sidewall .
• a light bulb was placed around the pool as a cue external to the maze .
• the animals received 2 trials per day from 10 days after the initiation of the administration with Compound A or the vehicle .
• the rats were trained to locate the hidden escape platform, which remained in a fixed location throughout testing . Trials lasted a maximum of 90 sec .
• the latency to find the submerged platform was recorded and used as a measure of acquisition of the task .
• the animals were tested in this way for 4 days (total 8 trials ) , and then they received a probe trial on the 5th day.
• the platform was removed from the pool and then the animal was released from the quadrant opposite to where the platform would have been located.
• the length of the trial was 90 sec, after which the rat was removed from the pool .
• the time the rat spent searching for the platform in the training quadrant ( zone 4) ; i . e . , the previous location of the platform was recorded and used as an index of memory.
• TEER transendothelial electrical resistance
• the DMSO-treated cells showed very little recovery of TEER.
• the Compound A-treated cells showed immediate recovery of TEER.
• HMVEC-AD Human microvascular endothelial cells (adult) (HMVEC-AD) were grown to confluence . The cells were then treated for 30 minutes with a nitrogen atmosphere and returned to normal oxygen. ATP levels were monitored at the indicated time points using a luciferin-luciferase assay system (ATPlite, Perkin Elmer) . ⁇ Results>
• 16-Difluoro-PGEi benzyl ester (1 ) ( 457.8 mg, 0.95 mmol) was dissolved in acetic acid ( 13.7 ⁇ iL, 0.24 i ⁇ ol) , 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 removed acetic acid.
• BusSnH ( 11.21g, 38.5mmol ) was dissolved in toluene (224mL) , and refluxed by heating .
• the crude compound (28) (19.2mmol) was dissolved in THF ( 52mL) and TBAF solution ( 1.0M in THF, 38.5mL, 38.5mmol ) was dropped for 10 minutes . After an hour, TBAF solution ( 1.0M in THF, 19.2mL, 19.2mmol ) was dropped to the solution. After stirring for total 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) , Fuj i Silysia, hexane/ethyl acetate ( 1 : 1 ) ) to obtain compound (29) as yellow oil (4.01g, 69.3% ) .
• Compound (31 ) was obtained from compound (29) by Swern oxidation and introduction of ⁇ -chain .
• Compound (31 ) ( 807.4mg, 1.88mmol ) was hydrogenated in ethyl acetate ( 8mL) under the presence of 10% palladium- carbon at room temperature for 2 hours .
• the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain crude compound ( 32 ) as the light brown oil .
• the crude compound ( 32 ) ( 1.88mmol ) was dissolved in EtOH ( 8mL) .
• IN-NaOH solution 7.4mL, 7.4mol
• the reaction mixture was stirred at room temperature for 10 hours, and then cooled with ice .
• IN-HCl 7. ImL
• the reaction mixture was extracted with TBME ( 3OmL) .
• the organic layer was washed with water ( 1OmL) and brine ( 1OmL) , dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure .

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