KR940003960A - Novel cephalosporin antibiotics and preparation method thereof (Ⅱ) - Google Patents

Abstract

The present invention relates to novel cephalosporin compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof and physiologically hydrolysable esters, hydrates or solvates, methods for their preparation and pharmaceutical compositions containing them .

Wherein R ¹ , R ² , R ³ , R ⁴ and Q are as defined in claim 1.

Description

Novel cephalosporin antibiotics and preparation method thereof (Ⅱ)

Since this is an open matter, no full text was included.

Claims (8)

The cephalosporin compound represented by the following general formula (I), a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof and an isomer thereof. Wherein R ¹ is a C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkylyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and R ^b may be the same or different Each represents hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached represent a C _3-7 cycloalkyl group), and R ² is hydrogen, C _1-4 An alkyl group, an amino group, a hydroxyl group, a carboxyl group or CH ₂ Y, wherein Y is an amino group, a hydroxyl group or a carboxyl group, and R ₃ is hydrogen, a C _1-4 alkyl group, an amino group, a hydroxyl group, acetamide or CH ₂ Y '(Y' is a hydroxyl group, a carboxyl group, a hydroxy or methoxy is kilgi nilke sulfo group), R ⁴ is hydrogen, C _1-4 alkyl group, an amino group or a hydroxyl group, Q is CH or N. The compound of claim 1, wherein R ¹ is a methyl group, an ethyl group, an allyl group, a propargyl group, or —C (R ^a ) (R ^b ) COOH, wherein R ^a and R ^b may be the same or different, and each hydrogen, represent a methyl or ethyl group, or to form a cyclopentyl together with the carbon atom to which they are attached.), and an R ² is hydrogen, methyl or amino group, and R ³ is a methyl group, an ethyl group, an amino group or a carboxymethyl group, R ⁴ is A compound of formula (I) wherein Q is carbon or nitrogen, a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolysable ester thereof, a hydrate or solvation thereof, and a hydrogen or methyl group, an amino group or a hydroxyl group Isomers. The compound of formula (I) selected from the group consisting of the following compounds, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof and isomers 7- [ (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (7-amino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazole- 4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (2,7-diamino-1-methyl [1, 2, 4] triazolo [1, 5 -c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2- Carboxyprop-2-oxyimino) acetamido] -3- (7-amino-1,8-dimethyl [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-5-yl) Thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-amino Azol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (2, 7-amino-1, 8-dimethyl [1, 2, 4] triazolo [ 1, 5-c] pyrimidin-5-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido [-3- (7-amino-1,8-dimethyl [1, 2, 4] triazolo-3-one [1, 5-c] pyrid Midin-5-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2-((S) -carboxylate -1-oxyimino) acetamido] -3- (7-amino-1-methyl [1,2,4] triazolo [1,5-c] pyrimidinium-5-yl) thiomethyl-3- Cefem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (7-amino-1- Methyl [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2- Aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- (2,7-diamino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazole-4- Yl) -2- (methoxyimino) acetamido] -3- (7-amino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-5-yl) thio Methyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (7- Amino-1-carboxymethyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z)- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (2,7-diamino-1-methyl [1, 2, 4] triazolo [1 , 5-c] pyrimidin-5-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- ( Methoxyimino) acetamido] -3- (2,7-diamino-1-carboxymethyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl- 3-cefe-4-carboxylate 7-[(Z) -2- (5-amino-1,2, 4-thiadiazol-3-yl) -2- ( Ethoxyimino) acetamido] -3- (7-amino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem- 4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2-((R) -1-carboxylate-1-oxyimino) acetamido] -3 -(7-amino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[( Z) -2- (2-aminothiazol-4-yl) -2-[(R) -1-carboxylate-1-oxyimino) acetamido] -3- (2, 7-diamino-1 -Methyl [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2 -Aminothiazol-4-yl) -2-((R) -1-carboxylate-1-oxyimino) acetamido] -3- (7-amino-1, 8-dimethyl [1, 2, 4 ] Triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl ) -2-((R) -1-carboxy-1-oxyimino) acetamido] -3- (2,7-diamino-1,8-dimethyl [1 , 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazole -4-yl) -2- (1-carboxycyclopentoxyamino) acetamido] -3- (7-amino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidy Nium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyamino ) Acetamido] -3- (2,7-diamino-1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem- 4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2-((R) -1-carboxyprop-1-oxyimino) acetamido]- 3- (7-amino-1-methyl [1, 2,4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7- [ (Z) -2- (2-aminothiazol-4-yl) -2-((R) -1-carboxyprop-1-oxyimino) acetamido] -3- (2,7-diamino -1-methyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3- Cefem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl) -2-((R) -1-carboxyprop-1-oxyimino) acetamido ] -3- (7-amino-1, 8-dimethyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate , 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxybut-2-oxyimino) acetamido] -3- (7-amino-1-methyl [1, 2, 4] triazolo [1, 5- (2-carboxybut-2-oxyimino) acetamido] -3- (2, 7-amino-1-methyl [1, 2, 4] tria Zolo [1,5-c] parimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate, 7-[(Z) -2- (2-aminothiazol-4-yl)- 2- (2-carboxybut-2-oxyimino) (acetamido] -3- (7-amino-1,8-dimethyl [1, 2, 4] triazolo [1, 5-c] pyrimidinium -5-yl) thiomethyl-3-cepem-4-carboxylate. A compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiological hydrolysis, characterized by reacting a compound of formula (I) with a compound of formula (III) in the presence of a solvent Methods of preparing possible ester hydrates or solvates thereof and isomers thereof. Wherein R ¹ , R ² , R ³ , and R ⁴ are as defined in claim 1, n is 0 or 1, R ⁵ is hydrogen or an aminoprotecting group, R ⁶ is a C _1-4 alkyl group, A C _3-4 alkenyl group, a C _3-4 alkynyl group, or a —C (R ^a ) (R ^b R) CO ₂ (R ^c ) group, where R ^a and R ^b may be the same or different, respectively Hydrogen or a C _1-4 alkyl group or R ^a and R ^b together with the carbon atom to which they are attached represent a C _3-7 cycloalkyl group, R ^c is hydrogen or a carboxyl protecting group, L is a leaving group, halogen, A lower (alkanolyloxy group), a (lower) alkanesulfonyloxy group, a arenesulfonyloxy group, or an alkoxycarbonyloxy group. The method of claim 4 wherein the solvent is N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide or methanol. The method according to claim 4, wherein the compound of general formula (III) is used in an amount of 0.5 to 2 equivalents based on the compound of general formula (II). The method according to claim 4, 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 compound of formula (III). A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound of any one of claims 1 to 3 and a pharmaceutically acceptable carrier, excipient or other additive. ※ Note: The disclosure is based on the initial application.