KR900018118A - New cephalosporin antibiotics and preparation method thereof - Google Patents

Abstract

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Description

New cephalosporin antibiotics and preparation method thereof

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Claims (22)

A cephalosporin compound represented by the following general formula (I), a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof. Wherein R ¹ is a C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) R ^b ) CO ₂ H. Here, when R ¹ is represented by -C (R ^a ) R ^b ) CO ₂ H, R ^a , R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a And R ^b represents a C _3-7 cycloalkyl group together with the carbon atom to which they are attached. R ² represents a C _1-4 alkyl group, C _3-4 alkenyl group or C _3-7 cycloalkyl group. A compound according to claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (4, 6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester, hydrate or solvate thereof Phosphorus compound of general formula (I). A compound according to claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (4, 6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester, hydrate or solvate thereof Phosphorus compound of general formula (I). A compound according to claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (4, 6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester, hydrate or solvate thereof Phosphorus compound of general formula (I). The compound according to claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido ] -3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable A compound of formula (I) which is an ester, hydrate or solvate thereof. The method of claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetimido ] -3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable A compound of formula (I) which is an ester, hydrate or solvate thereof. The compound of claim 1, wherein (6R, 7R) -3- (1-allyl-4,6-diamino pyrimidin-2-yl) thiomethyl-7-[(Z) -2- (2-aminothia Zol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable A compound of formula (I) which is an ester, hydrate or solvate thereof. The method of claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-1-oxyimino) acetimido] -3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolyzable thereof A compound of formula (I) which is an ester, hydrate or solvate. The compound according to claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxyl-1-oxyimino) acetimido] -3- (4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolyzable thereof A compound of formula (I) which is an ester, hydrate or solvate. The compound of claim 1, wherein (6R, 7R) -3- (1-allyl-4,6-diamino pyrimidin-2-yl) thiomethyl-7-[(Z) -2- (2-aminothia Zol-4-yl) -2- (1-carboxyate-1-oxyimino) acetimido] carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable ester, hydrate or solvate thereof Compound of general formula (I). The compound of claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxymethoxyimino) acetimido] -3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester thereof, hydrate Or a solvate of formula (I). The compound of claim 1, wherein (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxymethoxyimino) acetimido] -3- (4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester thereof, hydrate Or a solvate of formula (I). The compound of claim 1, wherein (6R, 7R) -3- (1-allyl-4,6-diamino pyrimidin-2-yl) thiomethyl-7-[(Z) -2- (2-aminothia Zol-4-yl) -2- (1-carboxyethoxyimino) acetimido] -3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt thereof, physiologically hydrolysable ester thereof, hydrate Or a solvate of formula (I). A compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable, characterized by reacting a compound of formula (II) with a compound of formula (III) in the presence of a solvent Process for preparing esters, hydrates or solvates thereof. In the above formula, R ¹ , R ² are as described above, n is 0 or 1, and R ⁵ is a C _1-4 alkyl group, C _3-4 alkenyl group, or -C (R ^a ) (R ^b ) CO ₂ (R ^c ) group. R ^a , R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a , R ^b represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, R ^c Is hydrogen or a carboxyl protecting group. R ³ is hydrogen or an aminoprotecting group, and R ⁴ is hydrogen or a carboxyl protecting group. L is a leaving group, for example, halogens such as chlorine and fluorine, (lower) alkanoyloxy groups such as acetoxy, (lower) alkanesulfonyloxy of methanesulfonyl oxide, and arenesul such as paratoluenesulfonyloxy Phonyloxy or alkoxycarbonyloxy and the like. The method according to claim 14, wherein the solvent used is water or a mixed aqueous solution of water and a water miscible solvent. The method of claim 15 wherein the water miscible solvent is acetonitrile, acetone. 15. The method of claim 14, wherein the amount of the compound of formula (III) is 1 to 2 equivalents based on the compound of formula (II). 15. The method of claim 14, wherein the pH of the reaction solvent is 5-8. The method of claim 14, wherein the reaction is carried out in the presence of a stabilizer. 20. The method of claim 19, wherein the stabilizing agent is one or more selected from among sodium iodide, potassium iodide, bromonatium, bromopotassium or potassium thiocyanate. The method according to claim 14, wherein the amino protecting group or acid protecting group is removed or the S-oxide is reduced before or after reacting the compound of formula (II) with the compound of formula (III). As an active ingredient, a therapeutically effective amount of a compound as defined in claims 1 to 13, a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof, and a pharmaceutically effective amount Pharmaceutical composition, characterized in that consisting of acceptable carriers, excipients or other additives. ※ Note: The disclosure is based on the initial application.