KR890000497A - Acyl derivatives - Google Patents

Abstract

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Description

Acyl derivatives

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

Claims (36)

Acyl derivatives of formula (I), easily hydrolyzable esters and pharmaceutically acceptable salts thereof, and hydrates of compounds of formula (I), esters thereof or salts thereof. Wherein X is -OCO-, -SCO-, -NHCO- or -OCONH-; R ₁ is an acyl group; R ₂ is hydrogen or lower alkoxy; R ₃ is [Wherein R ₄ , R ₄ ′ and R ₄ ″ are independently hydrogen or —COR ₂₀₀ where R ₂₀₀ is straight or branched lower alkyl; A and B are halogen; a, b, X, Y and Z are independently O (in this case a hydrogen atom is at its ring position) or 1 provided that at least two of X, Y and Z are always 1 and m is 0 or 1 to 8 Is an integer of]. The compound of claim 1, wherein m is 0 or 1. _3. A compound according to claim 1 or 2, wherein R ₄ , R ₄ ′ and R ₄ ″, if present, are independently hydrogen or —COCH ₃ . The compound of any of claims 1-3, wherein A and B are chlorine. The compound of any one of claims 1-4, wherein R is hydrogen. 6. The compound of claim 1, wherein X is —OCO—. The compound of any one of claims 1-5, wherein X is -SCO-. 6. The compound of claim 1, wherein X is —NHCO—. The compound of any one of claims 1-5 wherein X is -OCONH-. 10. The compound of claim 1, wherein the acyl group R ₁ is an aliphatic group of the general formula R ₅ CO—, wherein R ₅ is lower alkyl, lower cycloalkyl, lower alkoxy, lower alkenyl, C ₃ -C ₇ -cycloalkenyl or cyclohexadienyl or from a group consisting of lower alkyl or lower alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio or cyano methylthio groups Is selected). The compound according to any one of claims 1 to 9, wherein the acyl group R ₁ is a carbocyclic aromatic group selected from the group consisting of the following general formula. Wherein n is 0, 1, 2 or 3; R ₆ , R ₇ and R ₈ are independently from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl Is selected; R ₉₀ is selected from the group consisting of amino, acylamino, hydroxy, carboxy salts, protected carboxy, azido and sulfo salts. The compound according to any one of claims 1 to 9, wherein the acyl group R ₁ is a heteroaromatic group selected from the group consisting of the following general formula. Wherein n is 0, 1, 2 or 3; R ₉₀ is selected from the group consisting of amino, acylamino, hydroxy, carboxy salts, protected carboxy, azido and sulfo salts; R ₁₀₁ is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 nitrogen, oxygen and / or sulfur atoms. 10. The compound of any one of claims 1 to 9, wherein the acyl group R ₁ is a [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl group of the following general formula: compound. In which R ₁₁₁ is lower alkyl, hydroxy-lower alkyl; Substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 nitrogen, oxygen or sulfur atoms or a general formula Aromatic groups of wherein R ₆ , R ₇ and R ₈ are independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms Or aminomethyl); R ₁₂₀ is lower alkyl or substituted alkyl, wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups. The compound according to any one of claims 1 to 9, wherein the acyl group R ₁ is a (acylamino) arylacetyl group of the following general formula. Wherein R ₁₁₁ is lower alkyl, hydroxy-lower alkyl or a general formula Aromatic groups of wherein R ₆ , R ₇ and R ₈ are independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms Or aminomethyl), or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 nitrogen, oxygen or sulfur atoms; Wherein R ₆ , R ₇ , R ₈ are as defined above and n is 0, 1, 2 or 3), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower -Alkylamino, (cyano-lower alkyl) amino, hydrazino, lower alkyl-hydrazino, aryl-hydrazino, or acyl-hydrazino. 10. The compound of any one of claims 1 to 9, wherein the acyl group R ₁ is a (substituted acyl amino) arylacetyl group of the general formula: Wherein R ₁₁₁ is lower alkyl, hydroxy-lower alkyl or a general formula Aromatic groups of wherein R ₆ , R ₇ and R ₈ are independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms Or aminomethyl), or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 nitrogen, oxygen or sulfur atoms; R ₁₄₀ is Wherein R ₆ , R ₇ , R ₈ are as defined above and n is 0, 1, 2 or 3), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower -Alkylamino, (cyano-lower alkyl) amino, hydrazino, lower alkyl-hydrazino, aryl-hydrazino, or acyl-hydrazino; R ₂₂ or R ₂₃ are independently selected from the group consisting of hydrogen and lower alkyl, or R ₂₂ and R ₂₃ together with the carbon atom to which they are attached form a C ₃ -C ₇ carbocyclic ring. The compound according to any one of claims 1 to 9, wherein the acyl group R ₁ is a [[[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl group of the following general formula. Wherein R ₁₁₁ is lower alkyl, hydroxy-lower alkyl or a general formula Aromatic groups of wherein R ₆ , R ₇ and R ₈ are independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms Or aminomethyl) or a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or 4 nitrogen, oxygen and / or sulfur atoms; R ₁₅ is hydrogen, lower alkylsulfonyl, arylmethyleneamino (ie, -N = CHR ₁₁₁ (where R ₁₁₁ is as defined above)), -COR ₁₆ (where R ₁₆ is hydrogen, lower alkyl Or alkyl substituted with halogen, aromatic group (as defined in R ₁₁₁ above), lower alkyl or substituted alkyl, wherein the lower alkyl group is one or more halogen, cyano, nitro, amino and / or mer Is substituted with a capto group). The compound according to any one of claims 1 to 9, wherein the acyl group R ₁ is a group of the following general formula. Wherein R ₁₀₁ contains 1,2,3 or 4 nitrogen, oxygen or sulfur atoms, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, 1 to 4 carbon atoms A 5-, 6- or 7-membered heterocyclic ring unsubstituted or substituted with 4 alkoxy; R ₁₃₀ is hydrogen, lower alkyl, C ₃ -C ₇ cycloalkyl, carboxy-C ₃ -C ₇ -cycloalkyl or substituted lower alkyl, wherein the lower alkyl group is at least one halogen, cyano, nitro, amino, Mercapto, lower alkylthio, aromatic group (as defined in R ₁₁₁ ), carboxy (including salts thereof), carbamoyl, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy- Lower-alkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, di-lower-alkoxyphosphinyl substituents. 18. The compound of claim 17, wherein acyl group R ₁₀₁ is represented by the following general formula. Wherein R ₂₀ is hydrogen or an amino protecting group and R ₁₃₀ is hydrogen, lower alkyl or a general formula Wherein R ₂₂ and R ₂₃ are selected from the group consisting of hydrogen and lower alkyl or together with the carbon atom to which they are attached form a C ₃ -C ₇ carbocyclic ring, P is hydroxy or NHR ₁₉ Wherein R ₁₉ is hydrogen or lower alkyl, amino, lower alkylamino, arylamino or acylamino. 19. The compound of claim 18, wherein R ₂₀ is hydrogen or triphenylmethyl. The compound of claim 1, wherein [6R- [6 alpha, 7beta (Z)]]-3-[[[3,4-bis (acetyloxy) benzoyl] oxy] methyl] -7-[[[2-amino -4-thiazolyl] [(2-amino-2-oxoethoxy)] amino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 Carboxylic acids, salts thereof, and hydrates of such compounds and salts thereof. The compound of claim 1, wherein [6R- [6 alpha, 7 beta (Z)]]-3-[[(3,4-dihydroxybenzoyl] oxy] methyl] -7-[[[2-amino-4 -Thiazolyl] [(2-amino-2-oxoethoxy)] amino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid , Salts thereof, and hydrates of the compounds and salts thereof. 2. The compound of claim 1, wherein [6R- [6 alpha, 7 beta (Z)]]-7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3-[[3 , 4-dihydroxybenzoyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta ( Z)]]-7-[[[(2-amino-4-thiazolyl)-[carboxy-1-methylethoxy] imino] acetyl] amino] -3-[[3,4-dihydroxybenzoyl ] Oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] -oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (S *)]]- 7-[[ -[[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -3-[[[(3,4-dihydroxy) benzoyl] oxy] Methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-7-[[( 2-amino-4-thiazolyl)-(methoxyimino) acetyl] amino] -3-[[[((3,4-bis (acetyloxy) benzoyl)]-oxy] methyl] -8-oxo-5- Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7beta (Z)]]-7-[[2-amino-4-thiazolyl)- (Methoxyamino) acetyl] amino] -3-[[[2,3-dihydroxyphenyl) carbonyl] -oxy] methyl] -8-oxothia-1-azabicyclo [4.2.0] -oct- 2-ene-carboxylic acid, [6R-trans] -3-[[3,4-bis (acetyloxy) benzoyl] oxy] methyl] -8-oxo-7-[(phenoxyacetyl) amino] -5-thia -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-7-[[[3,4,5-tris (acetyloxy ) -Benzoyl] oxy] methyl] -7-[[(2-amino-4-thiazole Reyl) (methoxyimino) -acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta ( Z)]]-7-[[(2-amino-4-thiazolyl)-(methoxyimino) acetyl] amino] -3-[[2- (3,4-dihydroxyphenyl) -acetoxy] Methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-3-[[[ (3,4-bis (acetyloxy) benzoyl)]-oxy] methyl] -7-[[(2-amino-4-thiazolyl) [(1-carboxy-1-methyl-ethoxy) imino] acetyl ] Amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (S *)]]-3- [ [[3,4-bis (acetyloxy) -benzoyl] oxy] methyl] -7-[[ -[[4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-ene-2-carboxylic acid, [6R-cis] -3-[[[3,4-bis (acetyloxy) -benzoyl] oxy] methyl] 7-methoxy-8-oxo-7-[(2- Thienylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R-cis] -3-[[(3,4-dihydroxybenzoyl) Oxy] methyl] -7-methoxy-8-oxo-7-[(2-thienylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-7-[[(2-amino-4-thiazolyl)-(methoxyimino) acetyl] amino] -3-[[[(3,4- Bis (acetyloxy) -2,5-dichlorobenzoyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 Alpha, 7 beta (Z)]]-3-[[[[[[(3,4-bis (acetyloxy) -phenyl] amino] carbonyl] oxy] methyl] -7-[[2-amino-4- Thiazolyl)-(methoxyimino) acetyl] amino] -8-oxo-5-ti A-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-3-[[[[[(3,4-bis ( Acetyloxy) -phenyl] amino] carbonyl] oxy] methyl] -7-[[[[2-amino [2-amino-2-oxoethoxy] imino] -4-thiazolyl] acetyl] amino]- 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-7-[[(2-amino -4-thiazolyl)-(methoxyimino) acetyl] amino] -3-[[(3,4-dihadihydroxybenzoyl) thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-7-[[(2-amino-4-thiazolyl)-(methoxyimino) Acetyl] amino] -3-[[[(3,4-bis (acetyloxy) benzoyl] -thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid, [6R- [6 alpha, 7 beta (Z)]]-3-[[(3,4-bis (acetyloxy) benzoyl)] amino] methyl] -7-[[(2-amino -4-thiazolyl)-(methoxy-imino) acetyl] amino] -5-thia-1-aza Cyclo [4.2.0] oct-2-ene-2-carboxylic acid, [6R- [6alpha, 7beta (Z)]]-3-[[[3,4-dihydroxy-benzoyl] amino] methyl] -7-[[(2-amino-4-thiazolyl) (methoxy-amino) acetyl] amino] -5-thia-1-azabicyclo [4.2.0] octo-2-ene-2-carboxylic acid A compound selected from the group consisting of: a salt thereof, and a hydrate of the compound and salts thereof. 2. The compound of claim 1, wherein [6R- [6 alpha, 7 beta (Z)]]-7-[[[(2-amino [2-amino-2-oxoethoxy] imino] -4-thiazolyl] Acetyl] amino] -3-[[3,4-dihydroxybenzoyl] thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid , [6R- [6 alpha, 7 beta (Z)]]-7-[[(2-amino-2-thiazolyl) (carboxy-methoxy) imino] acetyl] amino] -3-[[3, 4-dihydroxybenzoyl] oxy] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, (6R-trans) -7-[[ (2-amino-4-thiazolyl) [[1-aminocarbonyl) -1-methylethoxy] imino] acetyl] amino] -3-[[(3,4-dihydroxybenzoyl) oxy] methyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, a compound thereof, and a salt thereof, and a compound which is a hydrate of the compound and its salt. Compounds of formula (XVIII) and salts thereof. Wherein R is hydrogen or a carboxylic acid protecting group; R ₂ is hydrogen or lower alkoxy; R ₃ is Or wherein R ₄ , R ₄ ′ and R ₄ ″ are independently hydrogen or COR ₂₀₀ , wherein R ₂₀₀ is straight or branched lower alkyl; A and B are halogen; a, b, x, y and Z are independently 0 (in this case the hydrogen atom is at its ring position) or 1 provided that at least two of x, y and z are always 1 and m is 0 or 1 to Is an integer of 8]. The method of claim 24, wherein (6R-trans) -7-amino-3-[[[3,4-bis (acetyloxy) benzoyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester and acid addition salts thereof. The method of claim 24, wherein (6R-trans) -7-amino-3-[[[3,4-bis (acetyloxy) benzoyl] thio] methyl] -8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester and acid addition salts thereof. 24. A compound according to any one of claims 1 to 23 as a pharmaceutically active substance. 24. A compound according to any one of claims 1 to 23 as pharmaceutically active substance for treating and preventing infectious diseases. (a) reacting a compound of formula (XVIII) with an acid of formula R ₁ COOH, wherein R ₁ is as defined above, or a reactive functional derivative thereof; (b) when preparing the carboxylic acid of general formula (I), converting the ester of general formula (XIX) to the carboxylic acid of general formula (I); (c) when R ₁ produces a compound of formula (I) or an ester or salt thereof containing an amino substituent, the amino-protecting group in substituent R ₁₀ in the compound of formula (XX) or ester or salt thereof Remove or; (d) if X is to prepare a compound of formula (Ⅰ) -OCO- or -SCO-, a compound represented by the general formula (XXI) or a carboxylic acid ester thereof or a salt thereof, R ₃ COOH (where R ₃ is the And Q is O or S); (e) When preparing a compound of formula (I) wherein X is -OCO- or -OCONH-, the compound of formula (XXII) or its ester or salt thereof is prepared by the formula R ₃ COZ, R ₃ NHCOZ or R Or react with a compound of ₃ NCO, wherein R ₃ is as defined above and Z is an acyl activation group; (f) When X is prepared a compound of formula (Ⅰ) -NHCO-, formula (XXIII) to the compound or its esters or salts in the general formula R ₃ acid (here of the -COOH, R ₃ is As defined above; (g) when preparing an easily hydrolyzable ester of the compound of general formula (I), reacting the carboxylic acid of general formula (I) with the corresponding esterification reaction; Or (h) when preparing a salt or hydrate of a compound of formula (I) or a hydrate of said salt, converting the compound of formula (I) to a salt or hydrate thereof, or a hydrate of said salt, wherein A process for preparing a compound according to any one of claims 1 to 23. Wherein R ₁ , R ₂ , R ₃ and X are as defined above; R is a carboxylic acid protecting group; R ₁₀ is an acyl group containing a protected amino group; Y is a leaving group; A is an anion of an acid; In formula (XVIII), the carboxy group and / or amino group may be present in protected form. A pharmaceutical formulation containing the final product according to any one of claims 1 to 23. A pharmaceutical formulation for treating and preventing an infectious disease, comprising the final product according to any one of claims 1 to 23. Use of the end product according to any one of claims 1 to 23 for the treatment and prevention of illness. Use of the end product according to any one of claims 1 to 23 for the treatment and prevention of infectious diseases. Use of the final product according to any one of claims 1 to 23 for the manufacture of a medicament for treating and preventing an infectious disease. A final product according to any one of claims 1 to 23 prepared according to the method as claimed in claim 29 or by a method which is clearly chemically equivalent thereto. Novel compounds, formulations, processes and methods substantially described herein. ※ Note: The disclosure is based on the initial application.