Title of Invention	"2-(ALPHA-HYDROXYPENTYL) BENZOATE AND ITS PREPARATION"
Abstract	The present invention relates to a new compound of 2-(α-hydroxypentyl) benzoate, its preparation and the pharmaceutical composition in which the compound is used as active ingredient; the invention also relates to the use of the compound for preventing and treating cardioischemia, cerbroischemia and cardiac or cerebral arterial embolism etc.

Full Text

NEW 2-(α-HYDROXYPENTYL) BENZOATES THEIR PREPARATIONS AND THEIR USES TECHNICAL FIELD This invention relates to new chemically synthetic 2-(α-hydroxypentyl) benzoates, their preparations and pharmaceutical compositions containing the salts as active ingredients. This invention also relates to the uses ol' the compounds in the prevention and treatment of the diseases such as cardioischemia, cerebroischemia, heart and brain arterial occlusions, etc. BACKGROUND OF THE INVENTION Acute ischemic cerebral apoplexy is a common disease with high incidence (12-18 cases per ten thousands) and high death rate (6-12 cases per ten thousands) which seriously endangers human's health, which often leaves sequela in the survivals and imposes a heavy burden on the patients' family and society. Therefore, it is very valuable of developing drug for the prevention and treatment of the disease. Many researchers have been studying the mechanism of the disease (acute ischemic cerebral apoplexy) since the 1980's, and have proposed theories such as energy metabolism,'excitatory poison, oxidative injury, calcium overload and many other theories for the .purpose of developing high effective and low toxic drugs. However, an ideal therapeutic drug is still under developing. Drugs such as calcium antagonists, excitatory receptor antagonists, free radical scavengers are' being clinically used, but the effects are uncertain. Thrombolytic drugs such as t-PA are being used to treat acute ischemic cerebral apoplexy (within 6 hrs from incidence), and is effective, but the hazard of hemorrhage has not been solved. Thus it is still a focus of developing new drugs to treat ischemic cerebial apoplexy. Coronary heart disease is also a severe disease which hat ins human's health. Due to the coronary atherosclerosis and the formation of thrombus, ischemic cardiac muscle trauma is induced. For this reason, it has been being a leading work of developing new drugs to prevent and treat coronary atherosclerosis, prevent thrombus formation and dilatate coronary artery. SUMMARY OF THE INVENTION The object of the present invention is to provide new 2-(a-hydu>xy-pentyl)benzoates which can significantly inhibit platelet aggregation and ameliorate cerebral microcirculation and effective to cardioischemiu. cercbio-ischemia, heart and brain arterial occlusions. Another object of the present invention is to provide a synthetic method of 2-(α-hydroxypentyl) benzoates. Yet another object of the present invention is lo provide a pharmaceutical composition which can prevent and treat cardioischcmia, cerbroischemia, heart and brain arterial occlusions, The fourth object of the present invention is to provide use of the above compounds and pharmaceutical compositions in the prevention and treatment of cardioischemia, cerbroischemia, heart and brain arterial occlusions, and amelioration of cerebral microcirculation. The present invention provides a compound of the following formula (I): (Formula Removed) wherein n-1,2; M is a monovalent metal ion. such as 1C, Na', Li", a divalent metal ion, such as Ca2"", Mg2*, Zn2+; or an organic basic gioup, such as anilino. benzyl amino, morpholinyl or diethylamino. The preparation method of present invention is as following 1. Preparation of 2-(α-hydroxypentyl)benzoates of general formula (1) wherein M is a monovalent metal ion: Solving an equivalent racemic 3-n-butyl-isoben/,ufuran-l-(3H)-Ofie in a hydrolysis and ring-opening reaction solvent medium, adding an equivalent or slightly excess amount of monovalent base. After that hydiolysis and ring-opening reaction is conducted under the temperature of 10-100"C, for 0.5-6 hours, to afford the 2-(α-hydroxypentyl)benzoates of general tbimula (I) wherein M is a monovalent metal ion. The solvent for the hydrolysis and ring-opening reaction may be any one of methanol, ethanol, acetone, isopropanol, water 01 mixture ol' ffcO-alcohol (or ketone). The crystallization solvent may be any one of meihunoi, ctrumol, propanol, isopropanol, acetone, acetyl acetate, chloroform, ether, • dichloromethane, benzene, toluene, petroleum ether, or a mixture of iwo or three above solvents with different proportions; monovalent base may be an inorganic base, such as a chemically pure inorganic base, for example sodium hydroxide, potassium hydroxide, or lithium hydroxide, etc; or a chemically pure organic base, such as sodium (or potassium) methoxidc, sodium (or potassium) ethoxide, etc. 2. Preparation of 2-(α-hydroxypentyl) benzoates of general formula (I) wherein M is a divalent metal ion: 2-(α-Hydroxypentyl)benzoate of general formula (1) wherein M is a monovalent metal ion (e.g., sodium or potassium) is solved in a solvent, then an equivalent or slightly excess amount of chemically pure divalent metal salt • is added and an ion-exchange reaction is conducted under the lempciauire of 10-100°C for 0.5-10 hours to afford the 2-(α-hydroxypenty|)ben/oaics of general formula (I) wherein M is a divalent metal ion. The reaction solvent medium is methanol, ethanol, acetone, isopropanol, water or a mixture of water-alcohol (or ketone), divalent metal salt may be magnesium chloride, calcium chloride, or zinc chloride; the crystallization solvent may be methanol, ethanol, isopiopanol, acetyl acetate, chloroform, ether, dichloromethane, or a mixture or' two or three above solvents with different proportions. 3. Preparation ofthe2-(α-hydroxypeniyl)benoates oi'genera I Ibnuula (1) wherein M is an organic base: (l)2-(α-hydroxypentyl)benzoate of general formula (I) wherein M is a monovalent metal ion (e.g., sodium or potassium) is solved in a solveot. then a inorganic acid is added to the solution to adjust pH value to 6.0-2.0 at the temperature of -20-20°C, preferably -20-0°C, to acidify the 2-(u-hydroxy pentyl)benzoate and 2-(α-hydroxypentyl)berizoic acid is obtained. (2) After the reaction is completed, an organic extraction solvent is added to the solution and the free acid 2-(α-hydroxypentyl)benzoic acid is extracted with common extraction method at a temperature of 20-0°C. An organic solution containing 2-(a-hydroxypentyl) ben/oic acid is obtained and the solution is kept for use under the temperature of-20-IO°C, preferably -20~0°C. (3) To the solution obtained in the above step,' a solution which contains an equivalent or slightly excess amount of monovalent base to the 2-(a-hydroxypentyI)ben/oic acid, for example an alcohol solution of potassium hydroxide, is added, at the temperature of-l0-0°C. lo al'fbid the 2-(α-hydroxylpentyl)benzoate of present invention wherein M is a monovalent metal ion, such as potassium. After the reaction is sullicicntly conducted, with a same purification method with mat of preparation method 1, the compound of present invention, i.e., 2-(α-hydroxylpcntyl)ben/oatc wherein M is a monovalent metal ion is prepared. (4) To the solution obtained in step (2), a solution which contains an equivalent or slightly excess amount of divalent base or a divalent metal salt to the 2-(α-hydroxypentyl) benzoic acid, for instance an alcohol solution of calcium hydroxide, is added, under the temperature of ~10~0°C. to allbrd the 2-(α-hydroxypentyl)benzoate of present invention wherein M is a divalent metal ion, such as calcium. After the reaction is sufficiently conducted, with a same purification method with that of preparation method 2, the compound of present invention, i.e., 2-(α-hydroxylpentyl)benzoate wherein M is divalent metal ion is prepared. (5) To the solution obtained in step (2), a solution which contains an equivalent or slightly excess amount of organic base to the 2-(u-hydroxy-pentyl) benzoic acid, for instance chemically pure aniline, is added, under the temperature of-10~0°C, to afford the 2-(α-hydroxypemyl)bcn/oatc ofpresent invention wherein M is an organic base, such as aniline. Alter the re-action is sufficiently conducted, with a same purification method with that of preparation method 2, the compound of present invention., i.e., ?-(u-hydroxyl-pentyl)benzoate wherein M is divalent metal ion is prepared The acid used in the acidity reaction may be any one of concentrated or diluted hydrochloric acid or sulfuric acid; the temperature should lie controlled within the range of -20~+20°C; the organic solvent to extract 2-(α-hydroxypentyl) benzoic acid may be any one of ether ethyl acetate, chloroform, dichlorornethane, benzene, toluene, petroleum ether n hexane. or cyclohexane; the monovalent base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium (or potassium) metlioxidc, or sodium (or potassium) ethoxide, the divalent inorganic metal salt or divalent inorganic base is selected from MgCl2, MgCO3, CaCI2, CaCO3. 2nd:. /nCX)-,. MgSO4, Zn(OH)2, Mg(OH)2 or Ca(OH)2; the organic base is selected from aniline, benzyl amine, rnorpholine or diethylamme, the solvent 10 solve the 2-(a-hydroxylpentyl) benzoate wherein M is a monovalent meial salt may be any one of H2O7 MeOH-H20, EtOH-H20, acetone-! I2O; isopropanol-J I2O It has been found that the present compounds show good effects on prevention and therapeutics to cardioischemia and cerebrouschemui. further, the present compounds also have pharmacological effects of anti-platelet aggregation, arterial occlusion of heart and brain therapeutic effect, and cerebral microcirculation amelioration effect, etc. The present compounds have shown from animal tests excellent effects on protecting ischemic injury of heart, anti-platelet aggregation and alleviation of injury due to cerebral-arterial occlusion, moreover, no side effects such as exciting or hemorrhage have not been found. The pharmaceutical composition of the prevent invention comprises an treatment effective amount of the compound of the present invention as active ingredient and a phannaceutically acceptable earner. The compounds and pharmaceutical compositions of the prevent invention can be used for the preparation of drugs which can pi event and treat cardioischemia and cerebroischemia, arterial occlusion of heart and bruin, amelioration of cardiac-cerebral microcirculations. The above mentioned "phannaceutically acceptable earner" means the ordinary drug carriers such as diluents, excipicnts. fillers such as starch, saccharide; binders such as cellulose derivatives, alp.inates. gelatin, arid polyvinylpyrrolidone; moisturizing agents such as glycerol, disintegrating agents such as agar, calcium carbonate arid sodium bicarbonate, lesorption accelerators such as quaternary ammonium compounds, surface active agents such as cetyl -alcohol, adsorptive carriers such as kaolin and bentonite: lubricants such as talc, calcium or magnesium stearate. and polyethyleneglycols; further, other assistants such as flavors and sweeieneis can also be added. The compounds of this invention can be administered orally and intravenously to the patients in need of such treatment in a form of pharmaceutical formulation. When administrated orally, it can be administrated in the dosage form such as tablets,, panicles. 01 capsules. And it can be in the form of solutions or oily/aqueous suspensions for injection. Preferred dosage forms are tablet, capsule and injection. The dosage forms of present pharmaceutical compositions can bo prepared by common procedures in the art. For example, the compounds of this invention can be admixed with one or more earners and formed into a desired dosage form. The present pharmaceutical composition preferably contains active ingredients in a weight ratio of 3:2, most preferably 1.1. The dose of present compound may vary based on administration route, age, weight, disease type and severeness of disease of the patient being treated. A typical daily dose may be from 50 nig to 600 mp. pei day. preferably 100~200mg per day, which can be administered once or more times DETAILED DESCRIPTION OF THE INVENTION The following examples are only illusU'ative and arc not intended to limit the scope of the present invention. Example 1 Preparation of racemic potassium 2-(a-hydroxypentyl) benzoutc (herein after also referred as potassium /-2-(u-hydroxypcrityl) bcuzoute, or dl-PRPB) Dissolving dl-3-n-Butyl-isobenzofuran-l-(3H)-one (8.5g. 0 04.5mol) in 20rnl methanol and a 10ml methanol solution of KOI 1 (2.611, 0046mol) was added. The reaction solution was stirred under reflux for one hour. After that, TLC analysis (petroleum ether-acetone=10:l) and l2 vapor coloration showed mat the starting material was disappeared. The reaction solution was concentrated under reduced pressure to afford a sticky yellow residue-, which was allowed to crystallize in the refrigerator after addition of 20 ml of chloroform. The crude product was recrystallized in MeOH-CHC13 and a white granular crystal (10.07g, yield=91.50%) was obtained. Example 2 Preparation of potassium dl-2-(α-hydroxypcntyl)bcn/oate Dissolving dl-3-n-Butyl-isobenzofuran-l-(3H)-one (0 63g, 3.3mmol) in 10ml methanol and a 10ml methanol solution of KOH (0.19g, 3.4mmol) was added. The reaction solution was stirred under rcilux tor one hour, A Pier that, TLC analysis (petroleum ether-acetone=10:l) and lz vapor coloration showed that the starting material was disappeared. The reaction solution was concentrated under reduced pressure to afford a sticky yellow residue, which was allowed to crystallize in the refrigerator alter addition of 5 ml of chloroform. The crude product was recrystallized in MeOU-CUCl-; and a white granular crystal (0.6g, yield=73.56%) was obtained. Example 3 Preparation of potassium dl-2-(α-hydroxypcntyl)b(>nxoaie Dissolving sodium dl2-(α-hydroxypentyl) bcn/oute (1.96g. 8 5mmol) in 10ml of H2O and the solution was cooled to about 0°C in an ice-salt bath. The pH was adjusted to 2.0~3.0 with IN HC1 and the solution was extracted quickly with cold ether (3x20ml). The ether extract was combined arid dried with anhydrous Na2SO4 at a low temperature for 3 hours and then filtered quickly under the low temperature. To the filtrate a 20ml methanol solution of anhydrous K2CO3 (0.58g, 4.2mmol) was added and the mixture was stirred fastly to ambient temperature. A white solid appeared in the ether solution and the solution was kept for over 24 hours, then the white solid was filtered and dried (1.4g,yield=66.67%). Example 4 Preparation of potassium dl-2-(α-hydroxypentyl)benzoate Dissolving sodium dl-2-(α-hydroxypentyl) ben/oate (l.78g, 7 7mmol) in about 10ml of H2O and the solution was cooled to about 0°C in'an ice-salt bath. The pH was adjusted to 2.0-3.0 with IN HC1 and the solution was extracted quickly with cold ether (3x20ml). The ether layer was combined and dried with anhydrous Na2SO4 at a low temperature for 2 hours and then filtered quickly under the low temperature. To the filtrate a I Oml methanol solution of KOH (0.43g, 7.7mmol) was dropped in and the mixture was kept in the ice-salt bath to ambient temperature. After concentration imdci reduced pressure, the residue was recrystallized with MeOH-ether. A \\hitc .solid was obtained (1.3g, yield=68.42%). The potassium dl-2-(α-hydroxypentyl)benzoate as prepared in the above Examples 1 till 4 procedures is a white granular crystal mp. 151-152°C IR(KBr) 3198 cm-1(voH), 2933 cm-1 (VCH3) 1577, 1561(VCOO) 1H-NMR (300MHz, DMSO) δ (ppm) 7,65 (dd, J==6.3Hz, 2.7Hz, 1H),7. 17-7.05 (in, 3H), 4.32 (t, 111), 3.40 (j>? 111), 1 .80-1.55 (m, 2H), 1.38-1.04 (m, 4H)5 0.81 (t, 311) Elemental Analysis C12H150.-3K(FW246.35) Calculated 58.51 6.14 1587 Found 58.24 6.01 15.84 MS (El) m/z 133(50, (Formula Removed) Example 5 Preparation of sodium ^/-2-(a-hydroxypcntyl)bcn/,oate Dissolving ^/-3-n-Butyl-isobenzofuran-l-(311)-one (4.6". 0.024mol) in 20ml methanol and a 10ml aqueous solution of NaOK (0.86g, 0.022mol) was added. The reaction solution was stirred under rellux lor 2 hours Alter that, TLC analysis (petroleum ether aceton.e=10:l) and I2 vapor coloration showed mat the starting material was disappeared. The reaction solution was concentrated under reduced pressure to afford a sticks yellow residue. which did not crystallize in the solvents such as chloroform, acetone etliei or methanol, etc. A small amount of residue was solidified with ether-ethyl acetate (10:1) to afford a white solid, which was very hydroscopic and became sticky over filtration. The yellow residue was washed with ether for several times and dehydrated with anhydrous benzene, dried under reduced pressure to afford a white foamed solid (3.67g, yield1 65.91%). Example 6 Preparation of sodium dl-2-(α-hydroxypciiiyl)beiizoatc Dissolving dl3-n-Butyl-isobenzofuran-l-(3H)-onc (7.6g 0.04mol) in 20ml methanol and a fresh methanol solution (20ml) of sodium methoxide (0.92g, 0.04mol of Na) was added. The reaction solution was stirred under reflux for 2 hours. After that, TLC analysis (petroleum ether-acetone -10:1) arid b vapor coloration showed that the starting material was disappeared. The reaction solution was concentrated under reduced pressure to afford a sticky yellow residue, which did not crystallize in the solvents such as chloroform, acetone, ether or methanol, etc. The yellow residue was washed with ether for several times and dehydrated with anhydrous benzene, dried under reduced pressure to afford a white foamed solid (6.4g. yield~69 56%). Example7 Preparation of sodium dl/-2-(α-hydroxypcntyl)bcn/oatc Dissolving dl-PHPB (l.0g, 0.004 mol) in 10ml of l12O and the solution was cooled to about 0°C in an ice-salt bath. The pll was adjusted to 2.0-3.0 with IN HC1 and the solution was extracted quickly with cold ether (3x20ml). The ether extract was combined and diiecl with anhydrous Na2SO4 at a low temperature for 2 hours and then filtered quickly under the low temperature. To the filtrate a 20ml methanol solution of anhydious NcbGO? (0.58g, 4.2mmol) was added and the solution became turbid and return clear after 3 hours of standing with ice-salt bath. The reaction solution was concentrated under reduced pressure to afford a sticky yellow residue which was washed with ether for several times and dehydrated with anhydrous benzene, dried under reduced pressure to afford a white foamed solid (0.4g, yield-42.78%). Example 8 Preparation of dl-sodium-2-(α-li) droxpentyl)benzoatc Dissolving dl-Pl-IPE (2.4g, O.Olmol) in 20ml ol"H2O and the solution was cooled to about 0°C in an ice-salt bath. The pHwas adjusted to 20-30 with IN HC1 and the solution was extracted quickly with eold ether (3*20ml). The ether extract was combined then a 20rnl methanol solution of NaOJI (0.39g, O.Olmol), the resulted solution was kept over night- in the ice-salt bath. After concentration under reduced pressure, a sticky yellow icsiduc was afforded, which was processed as above, and a white fomned solid (1.2g, yield=53.48%) was afforded. The sodium dL-2-(α-hydroxypentyl)benzoate as prepared in the above Examples 5 till 8 procedures is a foamed white solid. IR (film) 3398 cM-1'(VoH),2969 cm-1(VCH3), 1558, 1394 cm-1(vcoo) 1H-NM R(300MI-Iz,l)MSO) 5(ppm) 7.70(dd,J=6.9Hz, l.SHz, IH), 7.17-7.07 (rn, 3H), 4.39 (t, 1H), 1.05-1 48 (m. 2H), 1.39-1.10(m, 4H)r 0.83(t, 3H) Exam Die 9 Preparation oflithium dl-2-(α-hydroxypentyl)ben/onte Dissolving dl-3-n-Butyl-isobenzofuran-l-(3H)-one (1.2g. 0.006mol) in 15ml methanol and LiOH'H20 (0.26g, 0.006mol) was added. The leaction solution was stirred under reflux for 2 hours. After that. TLC analysis (petroleum ether-acetone=10:l) and I2 vapor coloration showed that the starting material was disappeared. The reaction solution was concentrated under reduced pressure to afford a white crystal (1.1 g. yield=81 38%) mp. 134-136°C IR(KBr) 3323 cm-l(KoH),2931 cnfl(vtH3),1604, 1414 cm-1(vcoo) lH-NMR(300MHz,DMSO) δ(ppm) 7.66(dd, 1H), 7.17-7.l6(m, 3H), 4.32(t, 1H), 1.78-1.54(in, 2IJ): 1.27-1.02(m, 4H), 0.84(t, 3H) Elemental Analysis C12H1503Li(FW214.19) C(%) H(%) Li(%) Calculated 67.29 7.06 324 ' Found 67.34 6.87 3.26 Example 10 Preparation of calcium dl-2-(α-hydro\ypcrttyl)bcn/oatc Dissolving dl-3-n-Butyl-isobenzofura.n-l-(3H)-one (I -1g. 7 1mmol) in 15 ml methanol and a 20ml aqueous solution of NaOll (0.28g: 7.0mmol) was added. The reaction solution was stirred under reflux for 2 hours After that. TLC analysis (petroleum ether-acetone=l0:1) and l2 vapor coloration showed that the starting material was disappeared. Calcium chloride (0,4g 4.5mmol) was solved in 40ml of H20, and the solution was dropped into the above reaction solution. The reaction was carried out in a 60°C water bath foi 2 hours, and the pH was adjusted to about 7 with IN 1ICT and then leaciion • solution was filtered. The filtrate was concentrated to 10ml under reduced pressure and a white solid appeared. The solution with the white .solid appeared was kept for 30 minutes and then filtered. The filter cake was washed several times with water and HzO-MeOH (1:1). respectively, until no chloride ion can be detected. Heating the filter cake to dry to al'foicl a while solid (1.08g,yield=33.23%). Example 11 Preparation of calcium dl-2-(α-liydroxypcnlyl)beiizoale Dissolving dl-3-n-Butyl-isobenzofuran-l-(31 l)-ouc (l.lg. 5.8mmol) in 20 ml anhydrous ethanol and a 10ml aqueous solution of NaOH (O.?9ji? 9.8 mmol) was added. The reaction solution was stirred under reflux for 2 hours After that, TLC analysis (petroleum ether-acetone-r-l0:l) and I? vapor coloration showed that the starting material was disappeared. The r.oaction solution was cooled to about 0°C in an ice-salt bath, and acidified to pi I 5.0-6.0 with 1N HC1, additional 20ml ethanol was added to solve the precipitated white solid. Calcium carbonate powder (0.33g, 3,3mmol) was added and the reaction solution was stirred vigorously under low temperature and kept over night. A white solid appeared from the reaction solution and the reaction solution was filtered. The filter cake was washed several times with H20-MeOH. Heating the filter cake to dry to afford a white solid (0.65g, yield= 24.73%). Example 12 Preparation of calcium tf/-2-(tt-hydro\ypeu'tyl)l>en/.oalc Calcium chloride (0.12g, 0.002mmol) was dissolved in 20rr.il ll.-O. and heated to about 60°C. To the solution a 10ml aqueous solution of dl-PHPB (0.5g, 0.001 mol) was added. After a while, a white solid appeared arid the reaction was continued for another 3 hours. After that, the reaction solution was filtered and the filter cake was washed with hot water and dried under heating to obtain a white solid (0.21g) and the filtrate was concentrated under reduced pressure arid washed with hot water and heated to dry, additional 0.15g of white solid was obtained. The combined total white solid was 0.36g (yield=78.02%). Calcium dl-2-(α-hydroxypentyl)benzoate as prepared in the above hxarnples 9 till 12 procedures is a white solid, which decomposes above a temperature of252°C. IU(KBr) coo 3323 crn-1 (voH), 2931 cnVl(vCH3), 1604, 1401 cm-1(Vcoo) 1H-NMR (300MHz,DMSO) δ(ppm) 7.56 (d, 1H), 7.24-7.05 (m,3H), 4.55 (t, 1H), 1.71-1.52 (rn. 21 [). 1.26-1.04 (UK 4H), 0.80(t, 3H) Elemental Analysis C24H3006Ca (FW454.57) C(%) H(%) Ca(%) Calculated 63.41 6.65 8.82 Found 63.20 6.61 902 Example 13 Preparation of af/-2-(δ-hydroxypentlyl) benzoic acid benzyl amine salt Dissolving dl-3-n-Butyl-isobenzofuran-l-(3H)-onc (1 4g7.1 mmol) in 15ml methanol and a 20ml aqueous solution ofNaOH (0 28g. 7.0mmol) was added. The reaction solution was stirred continuously under rellux lor 2 hours. After that, TLC analysis (petroleum ether-acetone 10.1) and J2vapor coloration showed that the starting material was disappcaicd. The icactiou solution was cooled to about 0°C in an ice-salt bath and acidified with 1N 1 IC1 to pH 3.0-4.0, and the solution was extracted quickly with cold ether (3> IK (KBr) 3396 cm-1(VNH), 2927 cm-1(VON) 1637 cm(vcc) 1515 cm"'(vcoo) 1HNMR (300MHz, DMSO) δ (ppm) 7.65-7.13(m, 9H,), 4.67(t, 1H, CH), 3.95(d, 2H,CH2), 1.58-1.66(m, 2H, CH2), 1.14-1.34(m, 4H, CH2CH2,)s 0.82(.t, 3H. CI-L) Elemental Analysis C19H25NO3(FW315.41) (Table Removed) Example 14 Preparation of Pharmaceutical Compositions (Table Removed) The active ingredient, starch, microcrystalline cellulose and sodium carboxymethyl cellulose were crushed and mixed. The mixture was moisturized homogenously and powdered, which were then sieved and dried and then sieved again. Magnesium stearate and talc were' mixed with the above mixture and the mixture was compressed to tablets, and the tablets were coated with a film coating (which may be hydroxypropy]methyl cellulose and the like). Each tablet contains 50~200mg ofaciivc ingredient. Exuinule 15 Preparation of Pharmaceutical Compositions Capsules (Table Removed) The active ingredient arid excipients were mixed and sieved The so-obtained mixture was filled into stomach-soluble hard capsules with determine amounts. Each capsule contains 50-200mg of active ingredient Example 16 Preparation of Pharmaceutical Compositions Intravenous solution (Table Removed) The active ingredient was dissolved in an appropriate amount ol'water for injection or isotonic saline and then filtered. Adjusting pH I to 10 5'(which may vary from 9.0 to 10.5) with appropriate amount of NaOH The intravenous solution was filled into bottles under sterilizing condition. Example 17 Preparation of Pharmaceutical Compositions Lyophihzed intravenous injection (Table Removed) The active ingredient was dissolved in an appropriate amount of water for injection and the pH was adjusted to 9.0-10.0 with NaOH The solution was filtered and freeze-dned to afford a cake or powder The lyopliili/.cd injection can be injected and transfused intravenously a tier it is solved in the 0.9% NaCl solution for injection or 5% glucose injection. lest Example 1: Effeet of the present compounds on the infarction area after local cerebral ischemia in rats (1) Materials and Methods Animal: male Wistar rats (250 - 280g), from the Animal Center of the Chinese Academy of Medical Sciences. Drugs: dl-PilPB was dissolved in double distilled watci. 2,3,5-triphenyltctrazolium chloride (TIC) was purchased I torn Beijing Chemical Plant. Methods: Middle cerebral artery ocelusion(MCAO) the rats were anesthetized by trichloroacetaldehyde monohydrate (350ing/kg. ip). 'I lie left CCA was exposed through a middle neck incision and was carefully dissected free from surrounding nerves. The ICA and 1;CA were isolated. Then a '1cm long 0.26mm diameter nylon suture was inserted through pioxima! l-X'A into ICA for a length of 2.0mm from the bifurcation. The wounds were 'sutiucd and the rats were released. The room temperature was kept 24-25°C during the test. Groups: Animals were divided into two groups. 1) adminisitation gioup: dl-PHPB (200mg / kg) and HC1 (pH 1.6) 0.5ml (to mimic the acidic condition of the human stomach) were administrated per os (p.o) 30 minutes prior to ischemia; 2) Control group: double-distilled water and IICI (pH 1.6) O.Mnl were administrated per os (p.o) 30 minutes prior to ischemia. Infarction measurement: The anaesthetized animals were decapitated 24 houis alter VK'AO Each brain were rapidly removed and kept in ice-cold saline (0-4 '(.') After 10 minutes, the coronal section was sliced into five pieces alter the removal of bulbus olfactus, cerebellum, and low brain stem Upon cutting, the first cut was at the center point of the connection line of the polus anterior of cerebrum and the optic chiasrn, the second cut was at the site of optic chiasm. the third was at the site of infundibulum stalk, and the fourth was between the infundibulum stalk and the caudal pole of posterior lobe. The sliced brain was kept in a 5ml solution of TTC (4%) and K2HPO4(1 ML .shaded and incubated at 37°C for 30 minutes. During the incubation, slices were turned ovei cvciy 7 - 8 minutes. After staining, the normal cerebral tissue showed rosy color, but the infarcted tissue showed white color. The infaicted tissue was separated from the normal tissue and weighed. The infarction area is calculated from the weight percentage of the infarct tissue to the total ceiel.ua] tissue. (2) Result : Effect of dl-PHBP to the cerebral infarct areas in the rats of permanent MCAO. Table 1 showes the infarct area, the area of the dl-PIJBP treated group is 1.9.83±3.53%, and that of the control is 26.99±351%. The mtarclion is significantly reduced (PO.01) in the treated group compared to the control. Table 1. (Table Removed) ** PO.01 vs control group (3) Conclusion: Potassium 2-(α-hydroxypentyl)-benzoak\ dl-PlIPB) sip.niliumtly reduced the cerebral tissue injury induced by MCAO and decreased ilic infarction areas. Test Example 2: The effect of the present compounds on platelet aggregation (I) Materials and Methods Animal: male Wistar rats (260-280g), from the Animal Center ol' the Chinese Academy of Medical Sciences. Drugs: Potassium 2-( 1 -hydroxypentyl)-benzoatc, dl-Pl IPU) ADP, obtained from Shanghai Institute of Biochemist!v Aceckmia Sinica. Equipment: Platelet Aggregometer (type: PAT-1A MI-GUKO KU, TOKYO, JAPAN. Groups: Animals were divided into four groups 1) Control group: double-distilled water (400mg/kg) was adirnistrcitcd per os (p.o) 30 minutes prior blood sampling; 2)Dl-PHPB (400mg/kg) was administrated per os (p.o) .>0 minutes prior to the blood sampling; 3)Dl-PHPB (400mg/kg) was administrated per os (p.o) 60 minutes prior to the blood sampling; 4)D/-PHPB (200mg/kg) was administiated per os (p.o) 30 minutes prior to ti»e blood sampling; Method: After oral administration of dl-PHPB. blood was drawn from the carotid of rats at the tune points of 30 and 60 minutes, lespectively. Platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared upon common procedure. According to the method described by of Bom. PRP (200µl) was put on the Platelet Aggregometer and prc-incubated at 37- (' Ibi 5 minutes and then ADP with the final concentration of 5µrnol/L was added to induce platelet aggregation. The maximum aggregation was measured 5 minutes after the addition of ADP. (2) Results Table 2 shows the inhibitory effect on platelet aggregation induced by ADP. Table 2 (Table Removed) **P (3) Conclusion: Potassium 2-(l-hydroxypentyl)-benzoaic. /-PHPB) significantly inhibits platelet aggregation compared to the control group. Test Examlpe 3: The protective effects of dl/-PlIPB on cardiac arrythmia induced by ischemia-reperfusioii in isolated hearts on rats (1) Materials and Methods Animals: male Wistar rats, 250-300 g, from the Animal Center of the Chinese Academy of Medical Sciences, randomly grouped Drugs: af/-PHPB, NaCl, from the Beijing Chemical Reagent Factory No 2 KC1 and MgSCV, Beijing Shuanghuan Chemical Reagents J-'actoiy. KH2PO4, Beijing Yili Fine Chemicals Co., Ltd NaHCO3, Beijing Chemical Reagents Company Glucose, Beijing Guohua Chemical Reagents Factory CaCl2, Sigma. Apparatus: Langendoff perfusion system; XD-7100 ECG Shanghai Medical Electronic Devices I-'actory Methods: (1) remove me rat heart quickly after decapitation and put it into K-JJ solution at 4 °C, fix the aorta to the perfusion system, (2) perfuse the heart with K-H solution, 6-8 ml/mm, 37-i:0.5'C. under the pressure of about 60 mmRkO; (3) connect the two copper electrodes to the cardiac apex and the bottom of the right atria and record the cardiogram; (4) perporate under the left anterior descending branch of'thc coronary artery with 3/0 line; (5) perfuse the heart for 10 minutes and record the normal caidiogiam, (6) ligate the left anterior descending branch of the coronary ailciy to make myocardial ischemia for 15 minutes; (7) nip the line and resume the perfusion, rccoid the change of cardiogram for 30 minutes (mainly on VF and Spasmic VT.), (8) dissolve the dl/-PHPB at pH 1.5 to a desired concentration, add it into K-H solution to do the experiments. (2)Results: Table 3 shows the protective effects of dl-PJ.IPB on cardiac arrylJimia induced by ischemia-reperfusion in isolated hearts on rats Table 3 (Table Removed) VT; ventricular tachycardia VF: ventricular fibrillation VE: ventricular ectopic beats *P (3) Conclusion: Dl-PHPB can significantly shorten the duration of arrhythmia and VI' induced by ishchemia-reperfusion in isolated hearts on rats, decreases the accidence of spasmic ventricular tachycardia, and shows significant protections on the ischemic injuries of hearts at the concentration of l0-4mol/L. INDUSTRIAL AVALABILIT Y The novel 2-(α-hydroxypentyl) benzoates can be used lor the preparation of pharmaceutical compositions, which is used for the prevention and treatment of the diseases such as cardiac ischemia, cerebral ischemia, arterial occlusion (obstruction) of heart and brain, etc. WE CLAIM: 1. A compound of the following general formula (1): (Formula Removed) wherein M is a monovalent metal ion, a divalent metal ion, or an organic base group selected from aniline group, benzyl amino group, morpholinyl group and diethylamino group, and n-1 or 2. 2. The compound as claimed in claim 1, wherein M is a potassium ion, a sodium ion, or a lithium ion. 3. The compound as claimed in claim 1, wherein M is a calcium ion, magnesium ion or zinc ion. 4. A method of preparation of the compound of general formula (1) as claimed in claim 1, comprising either one of th« following A to C; A. in case that M is a monovalent metal ion, dissolving an equivalent racemic 3-n-butyl-isobenzofuran-l-(3H)-one in a hydrolysis and ring-opening reaction solvent medium, adding an equivalent or slightly excess amount of a respective monovalent base, conducting hydrolysis and ring-opening reaction under the temperature of 10 ~ 100 °C to afford the 2-(cx-hydroxypentyl)benzoate of general formula (I), wherein M is a monovalent ion; or B. in case that M is a divalent metal ion, dissolving 2-(a-hydroxypentyl) benzoate of general formula (1), wherein M is a monovalent metal ion in a solvent medium, adding an equivalent or slightly excess amount of divalent metal salt, and conducting an ion-exchange reaction under the temperature of 10 ~ 100 °C to afford the 2-(α-hydroxypentyl)benzoate of general formula (1), wherein M is a divalent metal ion; or C. in case that M is an ion 01 an alkali or alkaline earth metal, (1) dissolving 2-(α-hydroxypentyl) benzoate of general formula (I), wherein M is a monovalent metal ion different from the product, in a solvent medium, adding an inorganic acid to the solution and adjusting the pH value to 6.0-2.0, allowing the 2-(a-hydroxypentyl) benzoate to react with the acid to afford 2~(a-hydroxypentyl) benzoic acid at a temperature of-20 ~ 20 °C; (2) adding an organic extraction solvent to the so-obtained benzoic acid solution and extracting free 2-(a-hydroxypentyl) benzoic acid to obtain an organic solution containing 2-(α-hydroxypentyl) benzoic acid which solution is kept for subsequent use under the temperature of-20 ~ 10 °C; (3) adding a solution which contains an equivalent or slightly excess amount of base of a correspondent monovalent metal ion, where in M is different from that of the starting material, to the 2-(a-hydroxypentyl) benzoic acid solution obtained in the previous step under the temperature of -10 ~ 0 °C to afford a 2-(α-hydroxypentyl) benzoate of general formula (I), wherein M is a monovelent metal ion; or, alternatively adding a solution which contains an equivalent or slightly excess amount of base containing a divalent metal ion, or a salt of a divalent n metal to the 2-(a-hydroxypentyl) benzoic acid solution obtained in step (2) under the temperature of-10 ~ 0 °C to afford a 2-(a-hydroxypentyl) benzoate of general formula (I), wherein M is a divalent metal ion; or adding a solution which contains an equivalent or slightly excess amount of an organic base corresponding to the group selected from an aniline group, a benzyl amino group, a morpholinyl group and a diethylamino group, to the 2-(a-hydroxypentyl)benzoic acid solution obtained in step (2) under the temperature of -10 ~ 0 °C to afford a 2-(α-hydroxypentyl) benzoate of general formula (I), wherein M is an organic base group selected from anilino group, benzyl amino group, morpholinyl group and diethylamino group. 5. The method as claimed in claim 4, wherein in A, the solvent medium for the hydrolysis and ring-opening reaction is any one of methanol, ethanol, acetone, isopropanol, water or a mixture of water-alcohol or water-ketone; and the respective monovalent base is an inorganic base selected from a group including sodium hydroxide, potassium hydroxide or lithium hydroxide, or an organic base selected from a group including sodium or potassium methoxide, and sodium or potassium ethoxide. 6. The method as claimed in claim 4, wherein in B, the reaction solvent medium is a solvent selected from a group including methanol, ethanol, acetone, isopropanol, water or a mixture of water-alcohol or water-ketone; and the divalent metal salt is selected from a group including magnesium chloride, calcium chloride, and zinc chloride. 7. The method as claimed in claim 4, wherein in C, the temperature for carrying out the reaction in step (1) and keeping the solution in step (2) is -20 ~ 0 °C. 8. The method as claimed in claim 7, wherein for the reaction at step (1), a concentrated or diluted hydrochloric acid or sulfuric acid is used; for the extraction of the 2-(a-hydroxypentyl) benzoic acid at step (2), as the organic solvent, a solvent selected from the group including ether, ethyl acetate, chloroform, dichloromethane, benzene, toluene, petroleum ether, n-hexane or cyclohexane, is used; the monovalent base at step (2) is a base selected from the group including sodium hydroxide, potassium hydroxide or lithium hydroxide, sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide; the divalent inorganic metal salt or the divalent inorganic metal base is selected from the group including magnesium chloride, magnesium carbonate, calcium chloride, calcium carbonate, zinc chloride, zinc carbonate, magnesium sulfate or magnesium hydroxide or calcium hydroxide; the solvent medium at step (1) is a solvent selected from the group including methanol, ethanol, acetone, isopropanol, water or mixture of water-alcohol, or ether, acetyl acetate, chloroform, dichloromethane, benzene, toluene, petroleum ether, n-hexane or cyclohexane. 9. A pharmaceutical composition comprising an effective amount of the compound of general formula (1) in a daily dosage of50-600mg and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition as claimed in claim 9, wherein M is a sodium ion or a potassium ion. 11. The pharmaceutical composition as claimed in claim 9, which is in the form of tablets, capsules, injections and lyophilized injections.

Documents:

8323-delnp-2007-abstract.pdf

8323-delnp-2007-Claims-(07-12-2012).pdf

8323-delnp-2007-claims.pdf

8323-delnp-2007-Correspondence Others-(20-05-2013).pdf

8323-delnp-2007-Correspondence Others-(03-12-2012).pdf

8323-delnp-2007-Correspondence Others-(07-12-2012).pdf

8323-delnp-2007-Correspondence Others-(21-04-2014).pdf

8323-delnp-2007-correspondence others.pdf

8323-delnp-2007-description (complete).pdf

8323-delnp-2007-form-1.pdf

8323-delnp-2007-form-2.pdf

8323-delnp-2007-Form-3-(03-12-2012).pdf

8323-delnp-2007-Form-3-(07-12-2012).pdf

8323-delnp-2007-form-3.pdf

8323-delnp-2007-form-5.pdf

8323-delnp-2007-GPA-(03-12-2012).pdf

8323-delnp-2007-Petition-137-(07-12-2012).pdf