JPH10503508A - Benzoxazole and pyridine derivatives useful in the treatment of type II diabetes - Google Patents

Abstract

(57) A compound represented by the formula (I) wherein R ⁰ represents 2-benzoxazolyl or 2-pyridyl, and R ¹ represents CH ₂ OCH ₃ or CF _3. Pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable solvates thereof; methods for producing such compounds, pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION   Benzoxazole and pyridine derivatives useful in the treatment of type II diabetes   The present invention relates to a novel compound, a method for producing such a compound, and a medical device containing such a compound. It relates to pharmaceutical compositions and the use of such compounds and compositions in medicine.   International patent application, publication number WO94 / 01420, has formula (A):         A¹'-X'-(CH_Two)_n'-OA^Two'-A^Three'-Y.R^Two'(A) [Where,   A¹'Represents a substituted or unsubstituted aromatic heterocyclyl group;   A^Two'Represents a benzene ring having three optional substituents;   A^Three'Is the formula-(CH_Two)_m-CH (OR¹')-(Where R¹'Is substituted or unsubstituted Represents an alkyl, aryl, aralkyl or alkylcarbonyl, and m is 1 Represents an integer of from 5 to 5), or A^Three'Is the formula-(C H_Two)_m'_-1-CH = C (OR¹')-(Where R¹'And m' are the same as defined above Represents a part)   R^Two'Is OR^Three'(Where R^Three'Is hydrogen, alkyl, aryl or aralkyl Represents R) or R^Two'Is an aromatic heterocyclyl group or -NR^Four 'R^Five'(Where R^Four'And R^Five'Are each independently hydrogen, alkyl or alk Represents carbonyl, or R^Four'And R^Five'The nitrogen they are binding Represents a heterocyclic ring together with an element atom, provided that R^Two'Is below Represents an aromatic heterocyclyl group only when Y ′ to be defined represents a bond);   X ′ represents NR ′ (where R ′ represents a hydrogen atom, an alkyl group, an acyl group, An aralkyl group or a substituted or unsubstituted reel moiety Or an unsubstituted aryl group);   Y ′ represents C ＝ O or C ＝ S or a bond (provided that Y ′ is R^Two'Is the above Represents a bond only when it represents an aromatic heterocyclyl group as defined);   n 'represents an integer in the range of 2 to 6] Or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable salt thereof. Are disclosed.   These compounds are disclosed to have, inter alia, good hypoglycemic activity. And therefore useful for the treatment and / or prevention of hyperglycemia, It is particularly useful for treating urine.   Here, surprisingly, compounds within the general scope of compounds of formula (A) Certain groups, especially when combined with no hematological and cardiac side effects, Have good blood glucose lowering activity. Therefore, these Compounds are particularly useful in treating and / or preventing hyperglycemia and Type II Consider retaining potential to be particularly useful in the treatment of diabetes available.   These compounds may be used to treat and / or treat other diseases, including hyperlipidemia and hypertension. It is also shown to be useful for prevention or prevention. They also include cardiovascular disease, In particular, those useful in the treatment and / or prevention of atherosclerosis It is also shown that there is. In addition, these compounds are useful in treating certain eating disorders, In addition, disorders associated with inadequate eating, such as anorexia nervosa, and obesity and nervousness For patients with disorders associated with overeating, such as anorexia bulimia It appears to be useful for the control of appetite and food intake.   These compounds are also useful for kidney diseases, especially diabetic nephropathy, glomerulonephritis, glomeruli Type II diabetes including sclerosis, nephrotic syndrome, hypertensive renal sclerosis and end-stage renal disease It is useful in treating and / or preventing kidney disease associated with the occurrence of the disease It is also shown. The preventive effect of insulin sensitizers on nephropathy is also Phosphorus sensitizing drug prevents progression from microalbuminuria to albuminuria, reverse Can be expected to roll, stabilize or delay. This is because microalbuminuria In particular, clinical evidence of prediabetic insulin resistance syndrome (also called syndrome X) May be a predictor of future nephropathy in eligible patients. You.   Accordingly, the present invention provides a compound of formula (I): [Wherein, R⁰Represents 2-benzoxazolyl or 2-pyridyl;¹Is C H_TwoOCH_ThreeOr CF_ThreeRepresents] Or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable salt thereof. To provide a solvate acceptable to   Preferably, R⁰Represents 2-benzoxazolyl.   Preferably, R¹Is CH_TwoOCH_ThreeRepresents   Preferably, R¹Is CF_ThreeRepresents   As described above, the compound represented by the formula (I) and a pharmaceutically acceptable salt thereof are: It may exist as one of several tautomeric forms, all of which are individually Of the present invention or as a mixture thereof.   Suitable pharmaceutically acceptable salts include carboxy group salts and acid addition salts. I can do it.   Suitable pharmaceutically acceptable salts of the carboxy group include, for example, aluminum Which metal salts, alkali metal salts such as lithium, sodium or potassium, Alkaline earth metal salts such as calcium or magnesium and ammonium salts Or substituted ammonium salts, for example, lower alkylamines such as triethylamine , 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or Hydroxyalkylamines such as l- (2-hydroxyethyl) amine, bicyclo With cycloalkylamines such as hexylamine, procaine, dibenzine Lupiperidine, N-benzyl-β-phenethylamine, dehydroabiethylamido , N, N'-bisdehydroabiethylamine, glucamine, N-methylglucamine Or pyridine, collidine, quinine or quinoline And those based on unsymmetrical bases.   Suitable acid addition salts include sulfates, nitrates, phosphates, borates, hydrochlorides and the like. And pharmaceutically acceptable inorganic salts such as hydrobromide and, where appropriate, acetate and liquor. Citrate, maleate, citrate, succinate, benzoate, ascorbic acid Salts, methanesulfonate, α-ketoglutarate and α-glycerophosphate Any pharmaceutically acceptable organic acid addition salts are included.   Suitable pharmaceutically acceptable solvates include hydrates.   Salts and / or solvates of the compounds of formula (I) may be prepared according to conventional methods. Made and isolated, for example, sodium salt is sodium methoxy in methanol It is prepared by using   In a further aspect, the present invention provides a compound of formula (II): [Wherein, R⁰And R¹Is the same as defined in formula (I),¹Is the hydrolysis Represents a possible group] Is hydrolyzed, and then, if desired, a compound of formula (I) A pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof Or a pharmaceutically acceptable salt thereof. And / or a method for producing a pharmaceutically acceptable hydrate thereof. is there.   Suitable hydrolyzable groups L¹Is the formula (a): Or an epimer thereof.   Suitable hydrolyzable groups L¹Is an Evans chiral auxiliary, for example of the formula (b): Or an epimer thereof.   Suitable hydrolyzable groups L¹Is C_1-6It is an alkyl group.   Hydrolysis of the compound of formula (II) is carried out with the selected specific group L¹Hydrolyze This is done using conditions that are suitable for¹Is a group represented by the formula (a): Is C_1-6When it is an alkoxy group, the hydrolysis is carried out under acidic conditions, for example, using dilute sulfuric acid. And conveniently in a water / dioxane mixture (eg, a 1: 1 mixture) At a temperature that provides a suitable rate of formation of the product, generally in the range of 50 ° C to 120 ° C. It is preferably carried out at such an elevated temperature, for example at 90 ° C .;¹Is the formula ( In the case of the group represented by b), the hydrolysis is generally carried out in an aqueous tetrahydrofuran solution. The use of lithium hydroperoxide in an aqueous solvent such as At a temperature that provides a high rate of formation, typically at a low temperature such as in the range of -10C to 0C. For example, it is performed at 0 ° C. Alternatively, L¹Is a group represented by the formula (b), The hydrolysis is usually carried out at room temperature in an appropriate solvent such as an aqueous tetrahydrofuran solution. The reaction is performed under basic conditions, for example, using an aqueous solution of sodium hydroxide.   L¹Is a moiety represented by formula (a) or (b) as defined above, The compound has the formula (III): [Wherein, R⁰And R¹Is the same as defined in formula (I),^TwoRepresents a leaving group Represent] (I) L¹Is a moiety represented by the formula (a) as defined above, The compound represented by ()) is obtained by the reaction with (S) -phenylglycinol. Or (ii) L¹Is a portion represented by the formula (b) as defined above, represented by the formula (II) (S) -4-benzyloxazolidin-2-one, preferably Is prepared by reaction with its active form and then the resulting diastereoisomer Separate the desired isomer from the body.   Suitable leaving group L^TwoIs a halogen atom, for example, a chlorine atom.   The reaction between the compound of formula (III) and (S) -phenylglycinol is conventionally carried out. Desired amidation conditions, for example in an inert solvent such as dichloromethane. At a temperature that provides a suitable rate of formation of the product, suitably at room temperature, preferably The reaction is performed in the presence of a base such as ruamine.   The preferred active form of (S) -4-benzyloxazolidin-2-one is the salt form For example, an alkali metal salt form, preferably a lithium salt.   The active form of (S) -4-benzyloxazolidin-2-one can be prepared by any suitable conventional method. Therefore, it is manufactured. Thus, when the active form is a lithium salt, the (S) -4-beta Ndiloxazolidine-2-one is usually treated at low temperature, for example, at -78 ° to 0 ° C. To the extent that lithium in an aprotic solvent such as tetrahydrofuran in the presence of a base. A source of muons (preferably provided by n-butyllithium) Manufactured by processing.   Compound of Formula (III) and (S) -4-benzyloxazolidin-2-one The reaction between the active form and the desired form is carried out in an aprotic solvent such as tetrahydrofuran. The reaction mixture is conveniently brought to -78 ° C at a temperature that provides a suitable rate of product formation. From 0 to 0 ° C.   Preferably, the active form of (S) -4-benzyloxazolidin-2-one is prepared. Then, it is reacted in-situ with the compound of the formula (III).   Compounds of formula (III) are represented by formula (IV): [Wherein, R⁰And R¹Is the same as defined in formula (I),^TwoIs an alkyl Represents a group] The carboxylic acid ester COOR of the compound represented by^TwoHydrolyze and then form CO.L^TwoManufactured by converting into parts.   A suitable alkyl group R^TwoIs C_1-6An alkyl group, especially a methyl group.   Hydrolysis of the carboxylic acid ester is carried out with alkali metal such as sodium hydroxide. This is done by using a conventional hydrolyzing agent such as a hydroxide.   The hydrolysis of the compound of formula (IV) is carried out in a methanol / water mixture (conveniently, A suitable rate of formation of the desired product in a suitable solvent such as a 1: 1 mixture). The reaction is carried out at a temperature, preferably at an elevated temperature, conveniently at the reflux temperature of the solvent.   CO.L of carboxylic acid group^TwoThe conversion to a moiety is performed by selecting the selected group L^TwoDepends on the specific nature of And performed using any suitable conventional method,^TwoIs a halogen If so, a suitable method is to convert the carboxylic acid with an oxalyl halide,^TwoIs chlorine And treating with oxalyl chloride.   CO.L of carboxylic acid^TwoThe reaction conditions for the conversion to the moiety are L^TwoSpecific properties of And selected L^TwoWill be dictated by the source. For example, L^TwoIs haloge And L^TwoWhen the source of is oxalyl chloride, the reaction is Provides a suitable rate of formation of the desired product in an inert solvent such as benzene or benzene. At room temperature, preferably at room temperature, or at an elevated temperature, such as the reflux temperature of the solvent. .   L¹Is an epimer of the moiety (a) or (b) as defined above. Compounds of formula (I) by production and separation of the product and subsequent hydrolysis To get L¹Represents a moiety (a) or (b) as defined above, Use the same method for the preparation, separation and hydrolysis of the compound as described above. And can be done by   L¹Is a moiety represented by the formula (b), a compound represented by the formula (II): [Wherein, R⁰And R¹Is the same as defined in formula (I), and X is Is the part indicated by It is also produced by dehydroxylation of the compound represented by   The dehydroxylation of the compound of formula (V) can be performed by using a trialkylsilane, for example, , Triethylsilane, preferably in the presence of trifluoroacetic acid, conveniently in a solvent Using trifluoroacetic acid as a temperature at which to provide a suitable rate of formation of the product, For example, it is conveniently carried out by treating at a temperature in the range of 0 ° C. to room temperature. is there.   L¹Is a moiety represented by the formula (b), a compound represented by the formula (II) Dehydroxylation of a compound represented by formula (V) in which a stereocenter having the compound is epimerized It will be clear that this may be obtained by:   The compound represented by the formula (V) has the formula (VIA): [Wherein, R⁰Is the same as defined in formula (I)] A compound represented by the formula (VIB): [Wherein, R¹Is the same as defined in formula (I)] And then reacting the resulting mixture of diastereoisomers From the desired isomer.   Suitably, in the reaction, the compound represented by the formula (VIB) is preferably a compound represented by the formula: A compound represented by the formula (VIB) is converted to an alkyl boron triflate such as dibutyl borohydride Triflate, preferably in the presence of an amine such as triethylamine. It is an active form obtained by   The active form of the compound of formula (VIB) will depend on the particular nature of the active form chosen. And manufactured by a suitable conventional method. For example, a compound represented by the formula (VIB) In an inert solvent such as dichloromethane at a temperature in the range of -78 ° to 0 ° C. React with ruvolon triflate and triethylamine.   The reaction between the compound of formula (VIA) and the compound of formula (VIB) A temperature that provides a suitable rate of formation of the desired product in an inert solvent such as dichloromethane. And, advantageously, allowing the reaction mixture to slowly warm from −78 ° to 0 ° C. Done by   Preferably, an active form of the compound of formula (VIB) is prepared and then in-situ To react with the compound represented by the formula (VIA).   R⁰Is a compound represented by the formula (I), which represents 2-benzoxazolyl, A suitable compound represented by VIA) is 4- [2- [N- (2-benzoxazolyl)- N-methylamino] ethoxy] benzaldehyde.   Suitable for separating the desired single isomer from a mixture of diastereoisomers The means is preparative high-performance liquid chromatography or silica gel column chromatography. It is chromatography such as Raffy.   L¹Is C_1-6One for producing a compound represented by the formula (II) which is an alkoxy group Is a convenient method for L¹Is a moiety of the formula (b) Is a basic alcoholysis.   Suitable bases are alkali metal alkoxides, for example L¹Is methoxy If so, L¹Is a compound of the formula (II) in which Treat with thorium methoxide.   Compounds of formula (I) have the formula (VII): [Wherein, R⁰And R¹Is the same as defined in formula (I)] Is resolved and then, if desired, a compound of formula (I) A pharmaceutically acceptable salt of the product and / or a pharmaceutically acceptable solvate thereof. It is also manufactured by manufacturing.   Resolution of the compound represented by the formula (VII) is performed using a known resolution method. example For example, the compound represented by the formula (VII) is reacted with a resolving agent such as an optically active acid or base. To give a mixture of diastereoisomeric salts which are then separated by fractional crystallization. And then separated from the separated diastereoisomeric salts by conventional means such as hydrolysis. To regenerate the compound of formula (I).   The compound represented by the formula (VII) is mixed with other optical isomers to form a compound represented by the formula (I) It will be clear that the compounds constitute. The compound represented by the formula (VII) or a compound thereof Pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates thereof are described in the present invention. It forms another aspect of the invention. In addition to the compound of formula (I), the compound of formula (VII) Isolated isomer of the compound, or a pharmaceutically acceptable salt thereof and / or Pharmaceutically acceptable solvates also constitute the present invention.   Suitable acids or bases for resolving compounds of formula (VII) are Enantiom ers, Racemates and Resolution, J Jaques et al., 1981, Willy Inters. and, in particular, pages 255 and 256. For splitting A preferred method is also disclosed by Jaques et al.   The compounds of the formulas (II) and (III) form a further aspect of the invention.   Compounds represented by formulas (IV) and (VIA), for example, 4- [2- [N- (2-benzo Oxazolyl) -N-methylamino] ethoxy] benzaldehyde is a known compound Or they are the methods used to produce the known compounds Similar methods are disclosed in, for example, International Patent Application Publication No. WO 94/01420. It is manufactured using the method which is.   The compound represented by the formula (VIB) is a known compound, or Methods similar to those used to produce the compounds, for example, Organic Synt hesis Vol. 68, p83, 1990 Ed. JD White; Or using a method analogous to it and combining it with conventional methods for the production of acid chlorides. Manufactured   In any of the above reactions, any reactive groups on the substrate molecule are converted to conventional Obviously, it may be protected according to chemical practice. The reaction Suitable protecting groups for any of the above are those commonly used in the art. is there. Methods for the formation and removal of such protecting groups are those suitable for the molecule being protected. It is an idiomatic method.   A compound of formula (I), or a pharmaceutically acceptable salt thereof and / or Said production of a pharmaceutically acceptable solvate of is a stereoselective method; and It will be apparent that the compounds of formula (I) are the single stereoisomers. Departure The clarification is that the compound of formula (I) is mixed with less than 50% w / w of its racemic isomer. If present, ie, the compound has an optical purity of greater than 50%, preferably 80-100%, preferably 90-100% purity, e.g. 90-95%, most Also preferably, 95 to 100%, for example, 95%, 96%, 97%, 98%, 99% % Or 99.9% of the optical purity.   In one preferred embodiment, the compound of formula (I) or the compound of formula (I) is provided in optically pure form. Or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. Is provided.   The absolute stereochemistry of a compound is determined using conventional methods, such as X-ray crystallography.   As mentioned above, the compounds of the invention are shown to have useful therapeutic properties. Accordingly, the present invention provides compounds of formula (I) useful as active therapeutic substances. Or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvent thereof. Offers Japanese food.   Thus, the present invention provides a compound of the formula useful in the treatment and / or prevention of hyperglycemia. The compound represented by (I), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable salt thereof. It provides a pharmaceutically acceptable solvate.   In another aspect, the invention also relates to the treatment and / or prevention of hyperlipidemia. Useful compounds of formula (I), or pharmaceutically acceptable salts and / or salts thereof, Or a pharmaceutically acceptable solvate thereof.   As mentioned above, the invention also relates to hypertension, cardiovascular disease, certain eating disorders. Formulas useful in the treatment of harm and / or the treatment and / or prevention of kidney disease, A compound represented by I), or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable salt thereof; It also provides a pharmaceutically acceptable solvate.   Furthermore, the present invention also relates to the progression of microalbuminuria to albuminuria. A compound of formula (I) useful for preventing, reversing, stabilizing or delaying Or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. It also provides.   Cardiovascular diseases include, inter alia, atherosclerosis.   Certain eating disorders, especially those associated with inadequate eating, such as anorexia nervosa. And disorders associated with overeating, such as obesity and nervous gluttony Regulation of appetite and food intake in certain patients.   Kidney disease includes diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome Group, kidneys associated with the development of type II diabetes, including hypertensive renal sclerosis and end-stage renal disease Disease.   A compound of formula (I), or a pharmaceutically acceptable salt thereof and / or Of the pharmaceutically acceptable solvates may be administered neat or preferably Alternatively, it may be administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.   Therefore, the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable compound thereof. Or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising a carrier.   As used herein, the term "pharmaceutically acceptable" refers to human and veterinary medicine. Encompasses compounds, compositions and components for scientific use: for example, The term "acceptable salts" includes veterinarily acceptable salts.   The composition may, if desired, be in the form of a pack with instructions for use. No.   Usually, the pharmaceutical compositions of this invention will be adapted for oral administration, but will be suitable for injection or And compositions for administration by other routes, such as by transdermal absorption.   Particularly preferred compositions for oral administration are unit dosages such as tablets and capsules. It is a form. Use other immobilized unit dosage forms such as powders present in sachets May be.   In accordance with conventional pharmaceutical practice, carriers may include diluents, fillers, disintegrants, wetting agents , Lubricating agents, coloring agents, flavoring agents or other customary auxiliaries.   Typical carriers include, for example, microcrystalline cellulose, starch, starch Sodium recholate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, Mention may be made of magnesium stearate or sodium lauryl sulfate.   Most preferably, the compositions will be formulated in a unit dosage form. Take Unit doses will generally be between 0.1 and 1000 mg, more usually between 0.1 and 500 mg, especially between 0.1 and 500 mg. It will contain amounts of active ingredient in the range of 1-250 mg.   The invention further relates to a hyperglycemic human or human in need of treatment and / or prevention. Is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in a non-human mammal: Administering an effective non-toxic amount of a salt and / or a pharmaceutically acceptable solvate. Treating and / or treating hyperglycemia in a human or non-human mammal comprising It provides a prevention method.   The invention further relates to human or non-human mammals in need of treatment and / or prevention. In a milk animal, the compound of the formula (I) or a pharmaceutically acceptable salt thereof and / or Or an effective non-toxic amount of a pharmaceutically acceptable solvate thereof. Hyperlipidemia, hypertension, cardiovascular disease, in a human or non-human mammal, Treatment of certain eating disorders, treatment and / or prevention of kidney disease, and / or Preventing, reversing, stabilizing or slowing the progression of chloralbuminuria to albuminuria It provides a method for postponement.   Conveniently, the active ingredient may be administered as a pharmaceutical composition as defined above, It forms a particular aspect of the present invention.   Treatment and / or prevention of hyperglycemic humans, and / or In the treatment and / or prevention, a compound represented by the general formula (I) A pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof is 70 kg The total daily dose for an adult is generally in the range of 0.1 to 6000 mg, more commonly In a manner such that the dose is in the range of about 1 to 1500 mg, 1 to 6 times a day Administered in doses.   In the treatment and / or prevention of non-human mammals, especially dogs, with hyperglycemia, The sexual component may be taken orally, usually once or twice daily, from about 0.025 mg / kg to 25 mg / kg. For example, in an amount ranging from 0.1 mg / kg to 20 mg / kg. Similar dosing schedule Is suitable for treating and / or preventing hyperlipidemia in a non-human mammal.   Treatment of hypertension, cardiovascular disease and eating disorders, treatment of kidney disease and / or Prevention and / or prevention of progression from microalbuminuria to albuminuria, Dosage regimes for reversal, stabilization or delay are generally described above for hyperglycemia. Would have done.   In a further aspect, the present invention relates to a medicament for treating and / or preventing hyperglycemia. A compound of formula (I) or a pharmaceutically acceptable salt thereof for the production of a product And / or the use of a pharmaceutically acceptable solvate thereof.   The invention also relates to hyperlipidemia, hypertension, cardiovascular disease or certain eating disorders. For the treatment and / or prevention of and / or from microalbuminuria. Drug manufacture in preventing, reversing, stabilizing, or delaying progression to albuminuria A compound of formula (I), or a pharmaceutically acceptable salt thereof, and / or Or the use of a pharmaceutically acceptable solvate thereof.   Within the above-mentioned administration range, the compound of the formula (I) or a pharmaceutically acceptable salt thereof. And / or its pharmaceutically acceptable solvents have no toxicological effects Was established.   The present invention will be described with reference to the following production examples and examples. It does not limit the light.   Example 1   (S) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] e Toxy] phenyl] -2- (2-methoxyethoxy) propanoic acid   In a mixture of 1 M sulfuric acid (45 mL) and dioxane / water (1: 1, 150 mL) [2S, N (1S)]-3- [4- [2- [N- (2-benzoxazolyl) -N-methyl] [Amino] ethoxy] phenyl] -2- (2-methoxyethoxy) -N- (2-hydro A solution of (xy-1-phenylethyl) propanamide (1.846 g) was added at 90 DEG C. for 5 minutes. Heat for 6 hours and then add the aqueous solution of sodium bicarbonate to The pH was adjusted to pH3. The mixture was extracted with ethyl acetate, and the organic extract was extracted with water, brine Wash with water, dry (MgSO 4_Four), Evaporated to an oil. Dilute as eluent Chromatography on silica gel using a gradient of 1-5% methanol in chloromethane Purification by luffing gave a foam with 88% ee (by HPLC). The product is reacted with (S) -α-methylbenzylamine in acetone to give The salt was recrystallized several times from ethyl acetate-hexane, dissolved in water, and diluted with dilute hydrochloric acid. Acidify and extract with ethyl acetate, which is added to MgSO 4_FourAnd dried. Ethyl acetate solution Was evaporated to give the enantiomerically enriched title compound; [α]_D ^{twenty five}-28 ° (C = 0.625, CHCl_Three); E.e 94% (by HPLC);⁺ 414.1791. C_{twenty two}H₂₆N_TwoO₆Theoretical value of M⁺414.1791];¹1 H NMR The spectrum is identical to that described in Example 5.   Example 2   (S) -3- [4- [2- [N- (2-benzoxazolyl) by hydrolysis of amide ) -N-Methylamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy Xy) propanoic acid   [2S, N (1S)]-3- [4- [2- [N- (2-benzoxazolyl) -N-methyl] Amino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) -N- (2 -Hydroxy-1-phenylethyl) propanamide (from Production Example 3) Hydrolysis was carried out in the same manner as described in 1. Dichlorometa as eluent Chromatography on silica gel using a gradient of 0-5% methanol in silica gel And triturated with diethyl ether-hexane to give the title compound. Obtained. Melting point 116-7 ° C; [α]_D ^{twenty five}−24.6 ° (c = 0.24, CHCl_Three); E.e .95% (by HPLC). [Measured value C, 57.9; H, 4.7; N, 6.8%; M]⁺ 438.1403. C_{twenty one}H_{twenty one}F_ThreeN_TwoO_FiveH, 4.8; N, 6.4. %; M⁺438.1403]; δ_H(DMSO-d₆) 2.96 (2H, m), 3.22 ( 3H, s), 3.88 (2H, m), 3.95-4.18 (2H, m), 4.27 (3H, m) 6.8-7.37 (8H, m) and 12.9 (1H, brs, D_TwoO).   Example 3   (S) -3- [4- [2- [N- (2-benzoxazo) by direct hydrolysis of imide Ryl) -N-methylamino] ethoxy] phenyl-2- (2,2,2-trifluoroe Toxic) propanoic acid   [3 (2S), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl) -N -Methylamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) Propanoyl] -4-benzyloxazolidin-2-one (from Production Example 10) Stirring in 42.5 g (0.071 mol) of THF (500 mL) and water (125 mL) An aqueous solution of sodium hydroxide (2.5 M, 65 mL, 0.163 mol, 2.3 equivalents) was added to the solution. ) Was added. The mixture is stirred for 20 minutes, the reaction is diluted with water (1 L) and Extracted with chloromethane (3 × 700 mL). Steam these dichloromethane solutions And elute the residue with 5% methanol in dichloromethane as eluent. Purified by chromatography on Kagel, (S) -4-benzyloxazo Lysin-2-one was obtained. The initial aqueous solution was acidified to pH 3.5 with dilute hydrochloric acid, Re-extract with methane (3 × 700 mL). Dichloromethane solution from acidic extract Is dried (MgSO 4_Four), Evaporated to give a solid. This is dichloromethane-di Recrystallization from ethyl ether gave the title compound. 119.5-120.5 ° C. [α]_D ^{twenty five}= -31 ° (c = 2.50, CHCl_Three); E.e. 99.6% (HPL C.); [Measurement C, 57.7; H, 4.7; N, 6.25%; M⁺(EI) 438 .1412. C_{twenty one}H_{twenty one}F_ThreeN_TwoO_FiveOf C, 57.5; H, 4.8; N, 6.4%; M⁺ 438.1403]; δ_H(CDCl_Three) 3.05 (1H, dd), 3.13 (1H, dd) 3.31 (3H, s), 3.72 (1H, m), 3.89 (2H, m), 4.04-4.14 (3H, m), 4.21 (1H, dd), 6.78 (2H, d), 7.03-7.40 (6H, m) and 11.20 (1H, br, D_TwoO); δ_F(DMSO-d₆) = − 72 .7 (3F, t,^ThreeJ_HF9.3Hz, CF_Three).   Example 4   (S) -3- [4- [2- [N- (2-benzoxy) by hydrolysis of methyl ester Sazolyl) -N-methylamino] ethoxy] phenyl-2- (2,2,2-trifluoro (Roethoxy) propanoic acid   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (S) -methyl (1.256g, 2.8 × 10^-3mol), aqueous hydrochloric acid (2.0 M, 50 mL) and A mixture of oxane (50 mL) was heated at reflux for 7 hours, then cooled. , Concentrated in vacuo. The residue was suspended in saline (200 mL) and ethyl acetate (3 × 300 mL). Dry the combined ethyl acetate solution (MgSO 4_Four), Steam Departure This gave a waxy solid. This solid was triturated with hexane, filtered, Vacuum drying at 65 ° C. gave the desired product. 113-5 [deg.] C. [α]_D ^{twenty five}= −32 ° (c = 1.02, CHCl_Three); E.e. 99.4% (by HPLC); Found C, 57.25; H, 4.8; N, 6.3%. C_{twenty one}H_{twenty one}F_ThreeN_TwoO_FiveTheoretical value of C5 7.5; H, 4.8; N, 6.4%]. Of this substance¹1 H NMR spectrum was obtained in Example 3. Was the same as that produced in   Example 5   (S) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] e Toxy] phenyl-2- (2-methoxyethoxy) propanoic acid   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2-methoxyethoxy) propanoate (S) -methyl Hydrolysis was carried out in the same manner as described. Use the crude reaction mixture as eluent Chromatography on silica gel using 5% methanol in dichloromethane This gave the title compound as a gum. [α]_D ^{twenty five}= -27 ° (c = 0.73, CHCl_Three) Ee 99.8% (by HPLC); [Measurement M⁺(EI) 414.1779. C_{twenty two}H₂₆N_TwoO₆Theoretical value of M⁺414.1791]; δ_H(CDCl_Three) 2.90 (1H, dd), 3.15 (1H, dd), 3.33 (3H, s), 3.37 (3H, s), 3.40 − 3.70 (4H, m), 3.93 (2H, t), 4.05 (1H, dd), 4.21 (2H, t) , 6.81 (2H, d) and 6.95-7.40 (6H, m).   Production Example 1   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d Toxy] phenyl] -2- (2-methoxyethoxy] propanoic acid   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy Methyl [phenyl] -2- (2-methoxyethoxy) propanoate (1.08 g, international Patent application, publication number WO94001420) and sodium hydroxide (253 mg) Of methanol in water (1: 1, 10 mL) was heated under reflux for 2 hours. After evaporating the resulting mixture in vacuo, the residue is diluted with water and brought to pH 5 with 2M hydrochloric acid. Acidified and then extracted with ethyl acetate. Wash the ethyl acetate extract with water and dry Let dry (MgSO 4_Four), Evaporated to give the title compound as an oil, which was Crystallized by trituration with ether / hexane. [Measured value C, 63.8; H, 6.5; N, 7.0%; M⁺414.1791. C_{twenty two}H₂₆N_TwoO₆Theoretical value of C, 63.8 H, 6.3; N, 6.8%; M⁺414.1791]; δ_H(CDCl_Three) 2.91 (1H , dd), 3.15 (1H, dd), 3.34 (3H, s), 3.38 (3H, s), 3.41 -3.69 (4H, m), 3.93 (2H, t), 4.05 (1H, dd), 4.21 (2H, t), 6.80 (2H, d) and 6.83-7.38 (6H, m).   Production Example 2   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d [Toxi] phenyl] -2- (2-methoxyethoxy) propanoyl chloride   (±) -3- [4- [2- [N- (2-benzoxa) in dichloromethane (2 mL) Zolyl) -N-methyl-amino] ethoxy] phenyl] -2- (2-methoxyethoxy B) Oxalyl chloride (92 mg) was added to propanoic acid (100 mg). The mixture Was stirred at room temperature for 16 hours and evaporated to dryness to give the title compound as a gum, which was They were used without purification.   Production Example 3   [2S, N (1S)]-3- [4- [2- [N- (2-benzoxazolyl) -N-methyl] Amino] ethoxy] phenyl] -2- (2-methoxyethoxy) -N- (2-hydroxy (S--1-phenylethyl) propanamide   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d Toxi] phenyl] -2- (2-methoxyethoxy) propanoyl chloride (S) -2-phenylglycinol (33 mg) and methanol (2 mL). And a mixture of dried triethylamine (37 mg) in dichloromethane (1 mL) was added. Added. After stirring for 5 minutes, water was added and the mixture was extracted with dichloromethane. . The organic extract was washed with water, brine, dried (MgSO 4)_Four), Evaporated. Residual The silica gel was eluted using a gradient of 10-50% acetone in hexane as eluent. And [2R, N (1S)]-3- [4- [2- [ N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- ( 2-methoxyethoxy) -N- (2-hydroxy-1-phenylethyl) propane The amide is obtained and then the desired title compound [2S, N (1S)]-propa Amide was obtained. [α]_D ^{twenty five}−33 ° (c = 1.1, CHCl_Three); 92.6% de. (By HPLC); [Measured value M⁺533.2526. C₃₀H₃₅N_ThreeO_FiveTheoretical value of M⁺ 533.2526]; δ_H(CDCl_Three) 2.81 (1H, dd), 3.07 (1H, dd), 3.35 (3H, s), 3.36 (3H, s), 3.48-3.58 (2H, m), 3.52- 3.62 (2H, m), 3.71 (1H, dd), 3.82 (1H, dd), 3.94 (1H, dd), 3.93 (2H, t), 4.22 (3H, t), 5.05 (1H, dt), 6.75- 7.35 (13H, complex), 7.54 (1H, br, D_TwoO).   Production Example 4   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d [Toxi] phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Methyl] phenyl] -2- (2,2,2-trifluoroethoxy) propanoate (International Patent Application, Publication No. WO94001420) by the same method as described in Production Example 1. To give the title compound as a solid. Melting point 116-117 ° C; [Measured value C, 57.4; H, 4.9; N, 6.4%. C_{twenty one}H_{twenty one}F_ThreeN_TwoO_FiveTheoretical value of C, 5 7.5; H, 4.8; N, 6.4%];_H(CDCl_Three) 3.03-3.17 (2H, m), 3.29 (3H, s), 3.73-3.83 (1H, m), 3.85 (2H, m), 4.02 ( 2H, m), 4.04-4.30 (2H, m) and 6.74-7.40 (8H, m).   Production Example 5   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d [Toxi] phenyl] -2- (2,2,2-trifluoroethoxy) propanoyl chloride   (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] d [Toxi] phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (1.7 Oxalyl chloride (1.1 mL) was added to a solution of 2 g) in dry benzene (30 mL). Was. The mixture was heated at reflux for 2 hours, then cooled and evaporated to dryness This gave the title compound as a gum, which was used without further purification.   Production Example 6   [2S, N (1S)]-3- [4- [2- [N- (2-benzoxazolyl) -N-methyl] Ruamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) -N- ( 2-hydroxy-1-phenylethyl) propanamide   By a method similar to that described in Production Example 3, (±) -3- [4- [2- [N- (2 -Benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2, 2-trifluoroethoxy) propanoyl chloride was converted to (S) -2-phenyliglyci Reacted with phenol. Gradient 10-70% ethyl acetate in hexane as eluent And then chromatographed on silica gel, first [2R, N (1S)] -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2,2,2-trifluoroethoxy) -N- (2-hydroxy- 1-phenylethyl) propanamide to give the desired title compound as a foam The compound [2S, N (1S)]-propanamide was obtained; [α]_D ^{twenty five}+ 14 ° (c = 0.5, MeOH); 99% de (by HPLC);⁺557.2136. C₂₉ H₃₀F_ThreeN_ThreeO_FiveTheoretical value of M⁺557.2138]; δ_H(CDCl_Three) 2.35 (1H, br, D_TwoO) 2.91 (1H, dd), 3.13 (1H, dd), 3.36 (3H, dd) s), 3.70-3.87 (2H, m), 3.84 (2H, d), 3.95 (2H, t), 4. 12 (1H, dd), 4.22 (2H, t), 5.01 (1H, m), 6.75 (2H, d), 6.97 (1H, brs, D_TwoO) and 7.01-7.36 (11H, complex Box).   Production Example 7   (2,2,2-trifluoroethoxy) ethanoyl chloride   (2,2,2-trifluoroethoxy) ethanoic acid (international patent application, publication number WO8 7/07270, 31.6 g, 0.2 mol) and N, N-dimethylformamide ( 5 drops) in dry dichloromethane (400 mL) at room temperature with stirring. Oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichloromethane ( (50 mL). The mixture is stirred for a further hour and then at reflux Heat for 2 hours then cool and remove most of the solvent by distillation (bp 4 0-45 ° C / 760 mmHg). Transfer the residue to a Claisen distillation flask, The medium and oxalyl chloride were removed by distillation (boiling point 45-60 ° C / 760 mmH g). The residue was then vacuum distilled to give the product. Boiling point 50-55 ° / 25- 32 mmHg. δ_H(CDCl_Three) 4.00 (2H, q,^ThreeJ_HF8.3) and 4.57 (2H, s).   Production Example 8   (4S) -4-benzyl-3- [2- (2,2,2-trifluoroethoxy) ethano Yl] oxazolidin-2-one   (4S) -4-Benzyloxazolidine-2-one (5.21 g, 0.029 mol) Was dissolved in dry THF (60 mL) and cooled to -70 ° C under argon. n- Butyl lithium (18.4 mL, 1.6 M solution in hexane, 1.1 eq.) For 10 minutes And the resulting mixture was stirred at -70 <0> C for 20 minutes. (2,2,2-g (Fluoroethoxy) ethanoyl chloride (5.19 g, 1 equivalent) in dry THF ( 60 mL) in 10 minutes and the mixture is allowed to stand at -70 ° C for another 30 minutes. And allowed to warm to room temperature overnight. The reaction was quenched by the addition of saline (20 mL). Allowed to cool and concentrated in vacuo. The residue was diluted with brine (300 mL) and ethyl acetate ( (3 × 300 mL). The combined organic extracts were dried (MgSO 4_Four), Steam And the residue obtained is purified on silica gel using dichloromethane as eluent. To afford the product as an oil. [α]_D ^{twenty five}= + 48 ° (c = 2.55, CHCl_ThreeEe) 100% (by HPLC); [measured value (CI, ammonia) MH⁺318.0934. C₁₄H₁₄NO_FourF_ThreeTheoretical value MH⁺3 18.0953]; δ_H(CDCl_Three) 2.82 (1H, dd), 3.34 (1H, dd), 4.02 (2H, q,^ThreeJ_HF8.6), 4.30 (2H, m), 4.69 (1H, m), 4.84 (2H, s) and 7.15-7.40 (5H, m);_F(CDCl_Three) =-74.8 (3 F, t,^ThreeJ_HF8.6, CF_Three).   Production Example 9   [3 (2S, 3R), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl)] -N-methylamino] ethoxy] phenyl] -3-hydroxy-2- (2,2,2-li Fluoroethoxy) propanoyl] -4-benzyloxazolidin-2-one   (4S) -4-benzyl-3 in dry dichloromethane (300 mL) under argon. -[2- (2,2,2-trifluoroethoxy) ethanoyl] oxazolidine-2-o (31.7 g, 0.1 mol) dissolved in liquid nitrogen / acetone as a cooling medium And cooled to −78 ° C. (the internal temperature of the solution). Triethylamine (16.72m L, 1.2 eq.) And then di-n-butylboron triflate (O Aldrich Chemical Company, Dichloro (1.0 M solution in methane, 110 mL, 1.1 eq.) Add slowly over about 10 minutes to maintain. The mixture at -78 ° C Stir for 50 minutes, replace the cooling bath with an ice bath, and stir the mixture at 0 ° C. for another 50 minutes. After stirring, the mixture was recooled to -78 ° C. 4- [2- [N- (2-benzoxazolyl)- Drying of N-methylamino] ethoxy] benzaldehyde (29.6 g, 1.0 equivalent) The solution in dichloromethane (220 mL) was previously cooled to −50 ° C. and the solution was reacted. The addition was done over about 12 hours to keep the temperature below -70 ° C. The resulting blend The mixture was stirred at −78 ° C. for 30 minutes and then along a linear gradient from −78 ° C. to 0 ° C. For 60 minutes (heating rate-1.3 ° C./min) and stir at 0 ° C. for another 75 minutes. Stirred. The reaction mixture was mixed with methanol (500 mL), pH 7 phosphate buffer (25 mL). 0 mL) and hydrogen peroxide (27.5% w / v, 110 mL). For 30 minutes. Water (4 L) is added, the layers are separated and the aqueous layer is Extracted with dichloromethane (3 × 1 L). The dichloromethane solution is first added to the reaction mixture. Organic layer, then combine the organic solution with water (2 L) and brine (2 L), dried (MgSO 4)_Four), Evaporated to give a foam. This coarse Reaction mixture¹1 H NMR indicates the desired aldol product (95% major diastereomer). A mixture of the three diastereoisomers consisting of the reo isomers) and the starting material. Indicates that The crude mixture is prepared by first adding 15% ethyl acetate in dichloromethane (desired Until the product begins to elute) to 50% ethyl acetate in dichloromethane The desired product is chromatographed on silica gel using a gradient eluent Elution of the product was completed. Unreacted imides and aldehydes from initial fractions Recovery, then a large amount of product containing impurities, then the title compound (NM Consisting of two diastereoisomers whose ratio by R is 97.8: 2.2) Collected. [α]_D ^{twenty five}= + 45 ° (c = 2.82, CHCl_Three). [Measurement value (EI) M⁺ 613.2042. C₃₁H₃₀F_ThreeN_ThreeO₇Theoretical value of M⁺613.2036]; δ_H(CD Cl_Three, The major diastereoisomer only) 2.75 (1H, dd), 2. 90 (1H, d, D_TwoO) 3.25 (1H, dd), 3.34 (3H, s), 3.80 -4.00 (5H, m), 4.07 (1H, dd), 4.24 (2H, t), 4.45 (1H, m), 4.99 (1H, parent t), 5.48 (1H, d), 6.85 (2H, d), and And 6.95-7.40 (11H, m);_F(CDCl_Three) =-74.7 (3F, t,^ThreeJ_HF 8.5, CF_Three). The minor diastereoisomer in the purified product is [3 (2 [S, 3S), 4S] -diastereoisomer.   Production Example 10   [3 (2S), 4S] -3- [3- [4- [2- [N- (2-be) Benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2,2- Trifluoroethoxy) propanoyl] -4-benzyloxazolidin-2-one Manufacturing of   [3 (2S, 3R), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl)] -N-methylamino] ethoxy] phenyl] -3-hydroxy-2- (2,2,2-li Fluoroethoxy) propanoyl] -4-benzyloxazolidin-2-one (4 6.23 g, 7.5 × 10^-2mol) of trifluoroacetic acid (650 mL) Triethylsilane (120 mL, 0.75 mol) was added to the solution over 5 minutes. The The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for another 60 hours. Solvent and residue Most of the triethylsilane present is reduced to 40 mmHg first and finally to Removed by tally evaporation. The residue was diluted with dichloromethane (800 mL). ) And water (800 mL) and then until the pH of the aqueous layer is pH7 Stir vigorously while cautiously adding (foaming) solid sodium bicarbonate (~ 29 g). Stirred. The layers were separated, and the aqueous layer was extracted with dichloromethane (800mL). Match The dried dichloromethane layer was washed with water (600 mL), dried (MgSO 4)._Four), Steam Fired. Triturate the residue with hot hexane and collect the resulting solids by filtration did. Recrystallization from diethyl ether-hexane gave the title compound. Melting point 107-109 ° C.¹Single diastereoisomer by 1 H NMR spectroscopy. [α]_D ^{Two Five} = + 38 ° (c = 1.51, CHCl_Three[Measurement value C, 62.1; H, 4.9; N, 7] .2%; M⁺(EI) 597.2089. C₃₁H₃₀N_ThreeO₆F_ThreeTheoretical value of C, 62.3; H, 5.1; N, 7.0%; M⁺597.2087]; δ_H(CDCl_Three) 2.82 (1H, dd), 2.96 (1H, dd), 3.04 (1H, dd), 3.32 (1H, dd), 3.3 4 (3H, s), 3.70 (1H, m), 3.88 (1H, m), 3.94 (2H, t), 4.1 2 (1H, m), 4.18 (1H, m), 4.25 (2H, t), 4.57 (1H, m), 5.3 4 (1H, dd), 6.82 (2H, d) and 7.00-7.35 (11H, m);_F( CDCl_Three) =-74.8 (3F, t,^ThreeJ_HF8.6, CF_Three).   Production Example 11   [3 (2S), 4S] -3- [3- [4- [2- [N- ( 2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2 , 2-Trifluoroethoxy) propanoyl] -4-benzyloxazolidine-2 -On production   (S) -4-Benzyloxazolidin-2-one (0.1 mL) was added to dry THF (10 mL). 291 g, 1.64 × 10^-3mol) was dissolved and the resulting solution was dissolved under argon under − Cooled to 70 ° C. n-Butyl lithium (1.6 M in hexane, 1.03 mL, 1. 64 × 10^-3mol) was added and the mixture was stirred at −70 ° C. for 10 minutes, after which (±) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2,2,2-trifluoroethoxy) propanoyl chloride (previous A solution of 0.36 g of the acid according to Preparation Example 5) in dry THF (15 mL) was prepared. Was added. The reaction was stirred, warmed to room temperature overnight, and diluted with water (200 mL). And extracted with ethyl acetate (2 × 200 mL). The combined ethyl acetate layers were washed with water (2 00 mL) and brine (200 mL), dried (MgSO 4)._Four), Evaporated To give a brown gum. This is eluted with 35% to 50% in hexane Initial chromatography on silica gel using a gradient of ethyl acetate To give the (R, S) -diastereoisomer followed by the title compound as a foam. This substance Is spectroscopically identical to the material prepared by the aldol route (Preparation Example 10). Was.   Production Example 12   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (S) -methyl   [3 (2S), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl) -N -Methylamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) Propanoyl] -4-benzyloxazolidin-2-one (1.879 g, 3.1 × 10^-3mol) of dry methanol (100 mL) in ice-cooled stirred suspension. Oxide solution [Sodium hydride (mineral) dissolved in dry methanol (3.5 mL) 60% dispersion in oil, 138 mg, 3.41 × 10^-3mol) was added. . The mixture was stirred at 0 ° C. for a total of 20 minutes, then the reaction was diluted with dilute aqueous hydrochloric acid (2. (0 M, 1.75 mL) and concentrated in vacuo. The residue was washed with water (100 mL), extracted with ethyl acetate (3 × 200 mL) and combined ethyl acetate The solution was washed with brine (500 mL), dried (MgSO4)_Four), Evaporated. Profit The resulting gum was silylated using 4% ethyl acetate in dichloromethane as eluent. Chromatography on Kagel gave the product as a clear gum. [α]_D ^{twenty five}= -17 ° (c = 1.24, CHCl_Three); [Measured value (EI) M⁺452.15 61, C_{twenty two}H_{twenty three}N_TwoO_FiveF_ThreeTheoretical value of M⁺452.1559]; ee 100% (HP LC); δ_H(CDCl_Three) 3.02 (2H, m), 3.34 (3H, s), 3.65 (1H, m), 3.72 (3H, s), 3.94 (2H, t), 4.00 (1H, m), 4.13 (1H, dd), 4.24 (2H, t), 6.80 (2H, d) and 6.96-7.40 (6 H, m).   Production Example 13   (4S) -4-benzyl-3- [2- (2-methoxyethoxy) ethanoyl] oxa Zolidine-2-one   By a method similar to that described in Production Example 8, 2- (2-methoxyethoxy) e The title compound was prepared from tanoyl chloride. 70-8 in hexane as eluent Chromatography on silica gel using a gradient of 0% diethyl ether To give the product as a gum. [α]_D ^{twenty five}= + 54 ° (c = 2.70, CH Cl_Three); [Measured value (EI) M⁺293.1263, C_FifteenH₁₉NO_FiveTheoretical value of M⁺29 3.1264]; δ_H(CDCl_Three) 2.81 (1H, dd), 3.33 (1H, dd), 3. 41 (3H, s), 3.63 (2H, t), 3.78 (2H, t), 4.25 (2H, m), 4. 70 (1H, m), 4.74 (1H, d), 4.76 (1H, d) and 7.10-7.40 ( 5H, m).   Production Example 14   [3 (2S, 3R), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl)] -N-methylamino] ethoxy] phenyl] -3-hydroxy-2- (2-methoxy Ethoxy) propanoyl] -4-benzyloxazolidin-2-one   By a method similar to that described in Production Example 9, (4S) -4-benzyl-3- [ 2- (2-methoxyethoxy) ethanoyl] oxazolidine-2-one A compound was produced. The crude reaction mixture is treated with 15-40% ethyl acetate in dichloromethane. Chromatography on silica gel using a gradient of Product (¹From two diastereoisomers in a ratio> 99: 1 by 1 H NMR. ). [α]_D ^{twenty five}= + 49 ° (c = 1.14, CHCl_Three). Measured value (FAB, N OBA / Na) MH⁺590.2472. C₃₂H₃₅N_ThreeO₈Theoretical value MH⁺590.2 502]; δ_H(CDCl_Three, Only the major diastereoisomer is recorded) 2.71 (1 H, dd), 3.25 (1H, dd), 3.31 (3H, s), 3.35 (3H, s), 3.5 6 (2H, m), 3.72 (2H, m), 3.78 (1H, d, D_Two3.85-4 .00 (4H, m), 4.22 (2H, t), 4.31 (1H, m), 4.89 (1H, dd), 5.42 (1H, d), 6.83 (2H, d) and 6.95-7.40 (11H, m); The minor diastereoisomer in the product prepared is [3 (2S, 3S), 4S] -di- Identified as an astereoisomer.   Production Example 15   [3 (2S), 4S] -3- [3- [4- [2- [N- (2-benzoxazolyl) -N -Methylamino] ethoxy] phenyl] -2- (2-methoxyethoxy) propanoy Ru] -4-benzyloxazolidin-2-one   [3 (2S, 3R), 4S] -3 by a method similar to that described for Production Example 10. -[3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] [S] phenyl] -3-hydroxy-2- (2-methoxyethoxy) propanoyl]- 4-Benzyloxazolidine-2-one (0.561 g) is mixed with triethylsilane and 6 The reaction was performed for .25 hours. The reaction mixture was washed with water (200 mL) and dichloromethane (2 00 mL) and the solid sodium bicarbonate was added until the aqueous layer showed a pH of 6.5. Added cautiously. Separate the layers and wash the aqueous layer with dichloromethane (2 × 300 mL). The extracted and combined dichloromethane solution was washed with brine (400 mL) and dried. S (MgSO_Four), Evaporated. The residue is 35% in dichloromethane as eluent Chromatography on silica gel using ethyl acetate,¹H NMR The gummy title compound was obtained as a single diastereoisomer. [α]_D ^{twenty five}= + 45 ° (c = 1.39, CHCl_Three); [Measured value M⁺(EI) 573.2473. C₃₂ H₃₅N_ThreeO₇Theoretical value of M⁺573.2475]; δ_H(CDCl_Three) 2.76 (1H, dd) 2.94 (2H, m), 3.30 (3H, s), 3.33 (4H, m), 3.40-3.70 (4H, m), 3.93 (2H, t), 4.00 (1H, dd), 4.12 (1H, dd), 4. 22 (2H, t), 4.52 (1H, m), 5.31 (1H, dd), 6.79 (2H, d) And 6.90-7.40 (11H, m).   Production Example 16   3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy ] Phenyl] -2- (2-methoxyethoxy) propanoate (S) -methyl   [3 (2S), 4S] -3- [3- [4- [ 2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl]- 2- (2-methoxyethoxy) propanoyl] -4-benzyloxazolidine-2 The -one was reacted with sodium methoxide. Use the crude reaction mixture as eluent Chromatography on silica gel using 20% isohexane in diethyl ether The title compound was obtained in the form of a gum. [α]_D ^{twenty five}= -12 ° (c = 1.26, CHCl_Three); [Measured value (EI) M⁺428.1974. C_{twenty three}H₂₈N_TwoO₆Theoretical value of M⁺ 428.1948]: ee> 99.8% (by HPLC);_H(CDCl_Three) 2 .95 (2H, m), 3.29 (3H, s), 3.34 (3H, s), 3.35 (3H, m), 3 .69 (4H, m), 3.93 (2H, t), 4.05 (1H, dd), 4.23 (2H, t) And 6.75-7.40 (8H, m).   Demonstration of compound potency   Obese mice, oral glucose tolerance test   Feeding C57b11 / 6 obese (ob / ob) mice with powdered oxoid diet did. After at least one week, the mice are maintained on a powdered oxoid diet, or Was fed a powdered oxoid diet containing the test compound. 8 of supplemented diet After a day, all the mice were fasted for 5 hours, and then glucose (3 g / kg) was orally administered. Gave. 0, 45, 90 and 135 minutes after glucose administration, glucose analysis Blood samples were collected for the test group and the results By comparison, the percentage reduction in area under the blood glucose curve is shown below. For each treatment, eight mice were used.   Effects on erythrocyte sediment volume and heart weight:   These were repeated oral doses of the compound for 14 days in female Sprague Dawley rats. (1 day at a dose of 3 μmol / kg body weight for 14 days by gavage) 1)). The changes shown are percentage changes from the control. Statistical comparisons were made by Student's t-test on unpaired data; p <0.05, p <0.001 vs. control. No effect means significant difference from control group Absent. Results were obtained from 8 rats per treatment group.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI A61K 31/42 ADN A61K 31/42 ADN ADP 9454-4C ADP 31/44 9454-4C 31/44 C07D 263/58 9639-4C C07D 263/58 // C07M 7:00 (31) Priority number 9509923.0 (32) Priority date May 17, 1995 (33) Priority country United Kingdom (GB) (31) Priority Claim number PCT / GB95 / 01323 (32) Priority date June 7, 1995 (33) Priority claiming country United Kingdom (GB) (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, D, TG), AP (KE, MW, SD, SZ, UG), AM, AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI , GB, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TT, UA, UG, US, UZ, VN (72) Inventor Rami, Harshad Cantilal United Kingdom, Katy 18.5 Xcu, Sally , Epsom, You Tree Bottom Road, Great Burgh (not shown) SmithKline Beecham Pharmaceuticals

Claims (1)

[Claims] 1. Formula (I): [Wherein R ⁰ represents 2-benzoxazolyl or 2-pyridyl, and R ¹ represents CH ₂ OCH ₃ or CF ₃ ], or a pharmaceutically acceptable salt thereof; And / or a pharmaceutically acceptable solvate thereof. 2. The compound according to claim 1, wherein ^R0 represents 2-benzoxazolyl. 3. _3. The compound according to claim ^{1, wherein} R ¹ represents CF ₃ . 4. (S) -3- [4- [3- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2-methoxyethoxy) propanoic acid; or (S)- 3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid; 2. The compound according to claim 1, which is a salt acceptable for the compound (I) and / or a pharmaceutically acceptable solvate thereof. 5. A compound according to any one of claims 1 to 4 when present as a mixture with less than 50% w / w of the racemic isomer. 6. The compound according to any one of claims 1 to 5, wherein the compound has an optical purity of 90 to 100%. 7. 7. The compound according to claim 1, which is in optically pure form. 8. (a) Formula (II): [Wherein R ⁰ and R ¹ are the same as defined in formula (I), and L ¹ represents a hydrolyzable group] or a compound represented by the formula (b) (VII): Wherein R ⁰ and R ¹ are the same as defined in formula (I); and then, optionally, pharmaceutically acceptable compounds of formula (I) A compound of formula (I), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable salt thereof, comprising producing a salt thereof and / or a pharmaceutically acceptable solvate thereof. Method for producing hydrate. 9. A pharmaceutical composition comprising the compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier. 10. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof in a hyperglycemic human or non-human mammal in need of treatment and / or prevention A method for treating and / or preventing hyperglycemia in a human or non-human mammal comprising administering an effective non-toxic amount of a substance. 11. Administering to a human or non-human mammal in need thereof an effective non-toxic amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof. Treating hyperlipidemia, hypertension, cardiovascular disease, certain eating disorders, treating and / or preventing kidney disease, preventing the progression of microalbuminuria to albuminuria, Method for stabilization or delay. 12. A compound of formula (I), or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof, useful as an active therapeutic substance. 13. Treatment and / or prevention of hyperglycemia, hyperlipidemia, hypertension, cardiovascular disease, certain eating disorders, treatment and / or prevention of kidney disease, and / or from microalbuminuria to albuminuria A compound of formula (I), or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, useful in preventing, reversing, stabilizing or delaying the progress of the compound. 14． Treatment and / or prevention of hyperlipidemia, hypertension, cardiovascular disease or certain eating disorders, prevention of kidney disease, and / or prevention, reversal, stabilization of the progression from microalbuminuria to albuminuria Use of a compound of formula (I), or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for treatment or delay. 15. An intermediate compound represented by the formula (II) or (III).