KR840000849B1 - Process for preparing -lactam compounds - Google Patents

Abstract

Title compds. (I; A = Ph, thienyl, furyl, cyclohexyl; R = NH(CH2)nR1; R1 = thienyl, furyl, oxazolyl, etc.; n = 0-1; X = a, b; D = H, OH, etc.; E = H or protecting group)were prepd. by the reaction of II and III(B = =NCO, -NHCOC1, -NHCOBr etc.) at -20oC-50oC, pH 2.0-9.0 in solvents. Thus, 420mg amoxycillin trihydrate was treated with 100mg COCl2 and 220mg 5-amino-4-hydroxy-2-(4'-pyridylmethylamino)-pyrimidine to give 79% I which had a min. inhibitory concn. against Escherichia coli ATCC 9637 of 0.5μg/ml.

Description

[Name of invention]

Method for preparing β-lactam compound

Detailed description of the invention

The present invention relates to a novel β-lactam compound β of the following general formula (1) and a method for producing a physiologically acceptable inorganic or organic base group thereof.

In the above formula,

A represents a phenyl, 4-hydroxyphenyl, 2- or 3-thienyl, 2- or 3-furyl, cyclohexyl, cyclohexen-1-yl or cyclohexa-1,4-dien-1-yl group Or a phenyl group substituted at the 3.4 position by a chlorine atom and the same or different substituent selected from hydroxy and methoxy groups;

R represents a group of the general formula NH (CH ₂ ) _N R ₁ , wherein n is 0 or 1, and R ₁ is preferably 1 to 4 heteroatoms, such as oxygen, sulfur or nitrogen atoms And optionally substituted 5- or 6-membered heterocyclic groups containing 1 or 2, for example optionally substituted thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl , Imidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, or tetrahydro-furanyl group Halogen elements such as alkyl groups, fluorine, chlorine or bromine; nitro, cyano, amino, alkylamino or dialkylamino groups; alkylcarbonyl amino or alkoxycarbonyl amino groups; hydroxy, alkoxy, alkylthio, alkylsulfinyl Or alkylsulfonyl groups, Methylsulfonylamino, aminocarbonyl, alkylcarbonyloxy or alkoxycarbonyl groups, aminosulfonyl, alkylaminosulfonyl or dialkylaninosulfonyl groups, wherein the alkyl groups in each group are each one to four carbon sources Or a carboxylic acid or sulfonic acid group;

D represents a hydrogen atom, hydroxy, acetoxy, aminocarbonyloxy, pyridinium or 4-aminocarbonyl-pyridinium group, or group-SHet, where Het is tetrazol-5-yl, 1-methyl Tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazole- 2-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl, 2-dimethylamino-1,3, 4-thiadiazol-5-yl, 2-formylamino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4-thiadiazol-5-yl, 2 -Represents a methyl-1,3,4-oxadiazol-5-yl, 1,2,3-triazol-4-yl, or 1,2,4-triazol-3-yl group;

E represents a hydrogen atom or a protecting group that can be easily separated in vivo or in vitro.

Such carboxyl protecting groups in the present invention may be those commonly used in the field of penicillin and cephalosporin, in particular ester forming groups which can be easily removed by hydrolysis or hydrolysis or other treatment under mild conditions, or bio Ester forming groups that can be easily separated within can be used. Examples of protecting groups that can be easily separated in vitro include benzyl, diphenylmethyl, trityl, tert-butyl, 2,2,2 trichloroethyl or trimethylsilyl groups. Examples of protecting groups that can be easily separated in vivo are alkanoyloxyalkyl groups such as acetoxymethylpropionyloxymethyl, 2-acetoxyethyl or pivaloyl oxymethyl groups or phthalidyl or indanyl groups .

When E represents a hydrogen atom, or pharmaceutically acceptable such as alkali or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, organic amine salts such as ammonium salts, triethylamine or salts with dicyclohexylamine Salts to form.

When D is pyridinium or aminocarbonyl pyridinium, the compound is represented by the following general formula (Ia).

Preferred compounds of formula (I) are those in which A is phenyl, p-hydroxyphenyl, 3,4-dihydroxyphenyl, 2- or 3-thienyl or 2- or 3-furyl group, and E is hydrogen Or 2-acetoxyethyl or pivaloyloxy methyl group, D is as defined above, and (CH ₂ ) _n R ₁ has the following meaning.

3-pyridyl, 6-substituted-3-pyridyl, 2-substituted-3-pyridyl, 2-, 3- or 4-pyridylmethyl, 2-, 4- or 5-pyrimidinylmethyl, 2-substituted-5-pyrimidinylmethyl, 4-hydroxy-5-pyrimidinyl, 2-substituted-4-hydroxy-5-pyrimidinyl, 4-substituted, 2-pyrimidinyl, 4,6-disubstituted-2-pyrimidinyl, 2-substituted-4-pyrimidinyl, 2,6-disubstituted-4-pyrimidinyl, 5-substituted-2-furyl, 5-substituted -2-thienyl, 2-or 3-furylmethyl, 2-or 3-thienylmethyl, 5-substituted-2-thienylmethyl, 5-substituted-2--2-furylmethyl group or 4-substituted- 2-thiazolyl group wherein the substituents are as defined above.

Or 2-imidazoline, 2-imidazolylmethyl, 2-thiazolylmethyl, 2-oxazoline, 2-oxazolylmethyl, 1,2, 4-triazolyl, 1,2,4-triazolylmethyl, 5-methyl-2- (1,3,4) -thiadiazolyl or tetrazolylmethyl group.

Among the compounds of the general formula (I), particularly preferred compounds are

A represents phenyl, p-hydroxyphenyl, 2-thienyl or 2- or 3-furyl group;

E represents a hydrogen atom or pivaloyloxymethyl group;

D represents a hydrogen atom, acetoxy or aminocarbonyloxy group or group SHet, wherein Het is tetrazol-5-yl, 1-methyltetrazol-5-yl, 1,3,4-thiadiazole- A 5-yl or 2-methyl-1,3,4-thiadiazol-5-yl group;

(CH ₂ ) _n R ₁ is 3-pyridyl, 6-methylsulfinyl-3-pyridyl group, 6-methylsulfonyl-3-pyridyl group, 6-hydroxy-3-pyridyl group, 5- Pyrimidinylmethyl or 2-methyl-5-pyrimidinylmethyl group, 2-methyl or 2-hydroxy-5-pyrimidinyl group, 6-hydroxy-2-pyrimidinyl group, 4,6-di Hydroxy-2-pyrimidinyl group, 3-pyridylmethyl group, 2-furylmethyl group, 2-thienylmethyl group, 5-aninosulfonyl-2-thienylmethyl group, 5-aminocarbonyl- or A compound representing a 5-ethoxycarbonyl-thienyl group.

Among the compounds of the general formula (I), the most preferred compound is

A represents p-hydroxyphenyl or 2-thienyl group;

E is hydrogen;

D represents an acetoxy or 1-methyl-tetrazol-5-yl group;

(CH ₂ ) _n R ₁ is 3-pyridylmethyl, 6-methylsulfinyl-3-pyridyl, 6-methylsulfonyl-3-pyridyl or 6-hydroxy-3-pyridyl group, 2-methyl -5-pyrimidinylmethyl, 2-hydroxy-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl or 4,6-dihydroxy-2-pyrimidinyl group, 5-aminocarbonylte Enyl, 2-thienylmethyl or 5-aminosulfonyl-2-thienylmethyl or 2-furyltilyl group.

The β-lactam compound of formula (I) may exist in two tautomeric forms (ie, lactam form and lactam form). Which form of formula (I) or (I ') is dominant depends in particular on the type of solvent and substituent R:

The compounds of general formula (I) above are always considered to include two tautomeric derivatives, unless otherwise indicated.

With regard to the carbon of the chiral center, the compounds of general formula (I) may exist both in the R- and S- configuration or in mixtures thereof. Especially preferred are compounds present in the D = R configuration. Once the desired product is obtained in D, L-form, pure D- and L-diastereomers can be prepared by preparative liquid chromatography (HPLC).

The compound of general formula (I) can be manufactured by the following method.

1.A compound of the general formula (I) having the same definition as above, except that D is a pyridinium or aminocarbonyl pyridinium group, by reacting a compound of the general formula (II) with a pyrimidine derivative of the general formula (III) Manufacture.

In the above formula

A, X and R are as defined above,

D is as defined above except that it is not a pyridinium or aminocarbonyl pyridinium group;

-NO₂그룹과 같은 -NHCOOH그룹의 반응성 유도체를 나타내며, 이중 =NCO 및 -NHCOCl그룹이 특히 바람직하다.B is an = NCO group, or -NHCOCl, -NHCOBr or -NH-COO-

Reactive derivatives of the -NHCOOH group, such as the -NO ₂ group, of which = NCO and -NHCOCl groups are particularly preferred.

-COCl를 동시에 나타낸다.The pyrimidine derivatives of general formula (III) may also be used in mixtures, in which case B may in part represent one of the above meanings and in part in another of the above meanings, for example Group -NCO and-

-COCl is shown simultaneously.

When E represents a hydrogen atom, the starting material of the general formula (II) may be used in the form of an inorganic or organic salt such as triethylammonium salt or nalium salt. In this case, the reaction is carried out with water and ketones (eg acetone), cyclic ethers (eg tetrahydrofuran or dioxane), nitrile (eg acetonitrile), formamide (eg dimethylformamide). It can be carried out in a mixture with a water miscible organic solvent such as dimethylsulfoxide or an alcohol (eg isopropanol) or in hexametapol. The pH of the reaction mixture is maintained at a pH of about 2.0 to 9.0, preferably pH 6.5 to 8.0, by the addition of a base or using a buffer solution. However, the reaction may also be carried out in anhydrous organic solvents such as halogenated hydrocarbons (eg chloroform or methylene chloride) by addition of a base, preferably triethylamine, diethylamine or N-ethylpiperidine. The reaction can also be carried out with water and ethers (e.g. diethyl ether), halogenated hydrocarbons (e.g. chloroform or methylene chloride), carbon disulfide, ketones (e.g. isobutylmethylketone), esters (e.g. ethyl acetate), or aromatic solvents (e.g. Eg, benzene), in a mixture of a water-immiscible solvent, in which case it is stirred vigorously, and the pH value is adjusted to about 2.0 to 9.0, preferably 6.5 to 8.0, by adding a base or using a buffer solution. It is appropriate to keep it. However, the reaction may also be carried out only in water in the presence of organic or inorganic bases or by adding buffer.

When E represents a trimethylsilyl group, i.e., according to the present invention, a silyl derivative of the general formula (II) compound (e.g., a mono- or di-trimethylsilyl derivative in which amino and carboxyl groups are appropriately silylated) When used and reacting these compounds with compounds of the general formula (III), the reaction is generally carried out in a solvent free of anhydrous solvents and hydroxyl groups, for example halogenated hydrocarbons such as methylene chloride or chloroform, benzene, It is appropriate to carry out in trahydrofuran, acetone or dimethylformamide.

In this case no addition of base is necessary, but sometimes it may be advantageous to add a base to increase the yield or purity of the product. As the base optionally added, secondary amines which may be severely acylated by steric hindrance such as tertiary aliphatic or aromatic amines such as pyridine or triethylamine or dicyclohexylamine are suitable. When E represents one of the protecting groups which can be separated for use in vitro or in vivo as described above, for example diphenylmethyl ester group or pivaloyloxymethyl group, anhydrous, methylene chloride It is also advantageous to carry out the process in an aprotic solvent such as chloroform, tetrahydrofuran or dimethylformamide.

For example, the amount of base used is determined by the pH value desired to be maintained. If no pH measurement or adjustment is made, or if the diluent does not contain enough water to make the measurement impossible or not practical, use a non-silylated compound of general (II) to use 1.0 to 2.0 molar equivalents. It is desirable to. When using a silylated compound, it is preferable to use a base of 1 molar equivalent or less.

In general, all organic and inorganic bases commonly used in organic chemistry can be used as base additives, which include alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates and bicarbonates, ammonia, primary, secondary and tertiary. Aliphatic and aromatic amines as well as heterocyclic bases. Bases which may be mentioned are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, diethylamine, methyl-ethylamine, triethylamine, hydroxy-ethylamine , Enalin, dimethylaniline, pyridine and riperidine. However, when using silylated starting materials, limitations on the types of bases mentioned above should be considered.

Useful buffer systems include conventional buffer mixtures such as phosphate buffers, citrate buffers and tris- (hydroxymethyl) -amino-methane buffers.

The reaction temperature can vary widely. In general, the reaction can be carried out at -20 to +50 ℃, preferably 0 to +20 ℃.

The reaction of the formulas (II) and (III) can be reacted in equimolar amounts with each other at the beginning of the reaction. In some cases, however, it may be advantageous to use an excess of one of the reactant pairs to facilitate purification or increase yield in the desired product.

2. A compound of the general formula (I) having the same definition as D except for a pyridinium or aminocarbonylpyridinium group is a ureido carboxylic acid or a salt thereof or a reactive derivative of general formula (IV); Prepared by reaction with.

In the above formula

A, R and X are as defined above;

D is as defined above, but is not pyridinium or aminocarbonyl pyridinium.

Reactive derivatives of the ureidocarboxylic acid of general formula (IV) are compounds derived from acid anhydrides such as chloroformate, such as ethyl or isobutylchloroformate, or p-nitrophenylester or n-hydroxy-succinate. Reactive esters such as mid esters, or reactive amides such as N-carbonylimidazoles, and acid halides or acid azides such as the corresponding acid chlorides may also be used.

In principle, however, all binding methods known in β-lactam chemistry can be used.

It is advantageous to use 7-aminocephalosporanic acid or peniclanic acid derivatives of general formula (V) in the form of derivatives which can be easily separated in vitro or in vivo. For example, a compound of the general formula (V) in which E has the above-mentioned meaning except for a hydrogen atom may be used, and particularly preferred derivatives are diphenylmethyl ester, tert-butyl ester, trimethylsilyl ester or N, O-bis-trimethylsilyl derivatives.

For example, ureido carboxylic acid, salts thereof or reactive derivatives thereof are reacted with 7-aminocephalosporanic acid or 6-aminophenicylic acid derivative in a solvent, optionally in the presence of a base, at a temperature of -40 ° C to + 40 ° C. For example, when ureido carboxylic anhydrides such as anhydrides with ethylchloroformate are used, the reaction is in the presence of a tertiary amine such as triethylamine or N, N-dimethylaniline, acetone, tetrahydrofuran, dimethyllot It proceeds, cooling to -10 degreeC-+10 degreeC in solvents, such as imide, chloroform, dichloromethane, hexamethanol, or a mixture of these solvents. When the N-hydroxy-succinimide ester of ureido carboxylic acid is reacted with a derivative of general formula (V), a solvent such as dimethylformamido, dichloromethane, dioxane or a mixture of these solvents, such as triethylamine, In the presence of a base, the reaction proceeds preferably at 0 to 20 ° C. The reaction of the ureidocarboxylic acid itself of formula (IV) or its salt with the compound of formula (V) is advantageously carried out in the presence of a condensing agent such as N, N-dicyclohexyl-carbodiimide.

3. The cephalosporin derivative of formula (I) wherein D is -S-Het, pyridinium or 4-aminocarbonylpyridinium group is a compound of formula (VI) or a pyridine or Prepared by reaction with 4-aminocarbonylpyridine.

In the above formula

A, R and Het are as defined above;

M is a hydrogen atom or an alkali metal or alkaline earth metal.

In the above reaction, the compound of formula (VI) is mixed with water, methanol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, chloroform or a mixture of these solvents. Reaction with 5-methyl-2-mercapto-1,3,4-thiadiazole in the same solvent. Strong polar solvents such as water, acetonitrile and the like are preferably used. When water is used as the solvent, it is advantageous to maintain the pH of the reaction solution at 2 to 10, especially 4 to 8. The desired pH value can be adjusted by adding a buffer such as sodium phosphate. There are no particular restrictions on the reaction conditions. Generally, the reaction is carried out for several hours in the temperature range of 0 ° to 100 ° C.

Compounds showing a protecting group in which E can be easily separated in vitro, prepared according to the methods 1 to 3 of the present invention, are represented by the general formula (E) in which ce represents a hydrogen atom according to methods known in the art of cephalosporin or penicillin chemistry. Can be converted to the free carboxylic acid of I). Therefore, the trimethylsilyl group can be easily removed by, for example, aqueous hydrolysis, and the diphenylmethyl ester group can be removed by hydrolytically separating by, for example, trifluoroacetic acid. Methods of removing such protecting groups are generally well known in the literature.

[여기에서 Hal은 염소, 브롬 또는 요오드이다]의 피발로일옥시메틸할라이드와 반응시킴으로써, E가 피발로일옥시메틸기

를 나타내는 아실옥시알킬레이트로 전환시킬 수 있다. 이외에 적합한 아실옥시알킬 할라이드로는 또는 예를들어 클로로메틸아세데이트, 브로모메틸 프로피오네이트 또는 1-브로모에틸 아세테이트가 있다.In addition, antibiotics of the general formula (I) in which E represents a hydrogen atom include, for example, alkali salts (eg, sodium or potassium salts) of free carboxylic acids.

Where Hal is a pivaloyloxymethyl group by reacting with a pivaloyloxymethylhalide of [where Hal is chlorine, bromine or iodine]

It can be converted into an acyloxyalkylate which represents. Other suitable acyloxyalkyl halides are, for example, chloromethylacetate, bromomethyl propionate or 1-bromoethyl acetate.

The production process of acyloxy acylate of general formula (I) is a slightly molar excess of pivaloyloxymethyl iodide at room temperature or at a temperature slightly elevated to about 40 to 45 ° C. in each alkali metal salt of an inert solvent. It is carried out by reaction with iodo, bromo or chloroalkyl esters such as id. The solvent used may be, for example, acetone, tetrahydrofuran, dioxane, dimethyl formamide or methylene chloride.

Once the reaction is complete, the reaction mixture obtained according to the process mentioned is further treated in a process customary for β-lactam antibiotics. That is to say with regard to the separation and purification of the desired product, such as to liberate the acid or to convert the acid to another salt using an inorganic or organic base. In particular, a suitable method for the preparation of potassium or sodium salts is the addition of potassium quene sodium-2-ethylhexanoate to precipitate these salts from the alcoholic-etheric solutions of the free acids, or the corresponding amounts of the free acids under pH control. After reacting with sodium bicarbonate, there is a method of freeze drying.

Starting materials of general formula (II) (e.g., ampicillin, amoxicillin, epicillin, cephalglycine, (cepalaccin as well as esters thereof which can be easily separated in vivo) are known or known from known materials It can be prepared similarly according to the method, for example, acylating the known amino-lactam of general formula (IV), and optionally, subsequently, three of the resultant general formula (II) (D = -OCOCH ₃ ) Palosporaic acid derivatives are prepared by reaction with thiols of the general formula Het-SH.

Starting materials of formula (III) can be obtained, for example, by reacting the corresponding 5-aminopyrimidines of formula (III) with phosgene.

Where

R is as defined above.

The reaction preferably does not contain hydroxyl groups such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexamethapol at temperatures of -40 ° to + 60 ° C, preferably -10 ° to + 20 ° C. In a solvent. The hydrochloric acid formed is preferably added by adding an equimolar amount of an inert organic base such as triethylamine or pyridine. Excess pyridine can also be used as a solvent. If the corresponding aminopyrimidine of the general formula is difficult to dissolve in one of the solvents mentioned above, the phosgenation reaction may be carried out in heterogeneous phase. The aminopyrimidines of general formula are also treated with silylating agents such as hexamethyldisilazane, trimethylchlorosilane / triethylamine, trimethylsilin diethylamine or N, O-bis-trimethylsilin acetamide, and As mentioned above, it can be converted into aminopyrimidine which is very easily soluble in a solvent, and this aminopyrimidine is silylated one or several times depending on the substitutable hydrogen atom present, and then reacted with phosken to produce the corresponding general formula (III). To yield a compound. Depending on the type of solvent, the temperature, and the type and amount of base actually added, the corresponding isocyanates or carbamic acid halides or mixtures of these two compounds are obtained. Depending on the reaction conditions, the compound of general formula (III) may also exist, in part or in whole, as dihydro-oxazolo-pyrimidine of general formula (IIIa), which is an isomeric compound of isocyanate;

Furthermore, in the case of the above-mentioned silylation reaction, it may exist as one or several silylated homologs according to the kind of substituent R.

The starting materials of the general formula (III) or (IIIa) or mixtures thereof, obtained by the phosgenation reaction, are generally readily soluble in the solvents mentioned above, after removal of excess phosgene, without further purification and the corresponding general It can be reacted directly with the beta-lactam derivative of formula (II). However, the intermediate product of general formula (IIIa) can also be separated, desilylated, optionally using an aprotic solvent such as water or methanol, purified on the basis of solubility and then reacted in the above-mentioned manner.

The ureido carboxylic acid of general formula (IV) can be easily obtained by reacting the pyrimidine derivative of general formula (III) with the glycine derivative of the following general formula (i).

Where

A is as defined above.

The reaction is carried out in a solvent at a temperature of -20 ° to 40 ° C, preferably at a temperature of 0 ° to + 20 ° C. As a solvent, a mixture of water and a water miscible organic solvent such as acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol and dimethyl sulfoxide may be used. Optionally, the use of a hydrogen-halide-binding agent may be necessary, which is suitable for trialkylamines such as triethylamine or inorganic bases such as dilute sodium hydroxide.

Starting compounds of the general formula (VI) can be easily prepared according to the method 1. 2-substituted-5-amino-4-hydroxy-pyrimidine of formula (VII) is 2-ethylmercapto-4-hydroxy-5-natro-pyrimidine [Vorbruggen and Strehlke, Chem. Ber, 106, page 3039 (1973)] can be prepared by reacting with an amine of the general formula NH ₂ (CH ₂ ) nR ₁ and then reducing the nitro group according to known methods. Instead of the 5-nitro compound, 2-methylmercapto-4-hydroxy-5-benzoylamino-pyrimidine can also be reacted, followed by subsequent debenzoylation, and also aminopyrimidine of formula The silver 2-chloro-4-hydroxy-5-nitropyrimidine may be prepared by reacting with an amine R ₁ (CH ₂ ) n NH ₂ in an aqueous solution, followed by reduction of the nitro group. Representative starting materials thus prepared include the following compounds:

Compounds of general formula (I) have very good tolerance and have useful pharmacological properties. Therefore, the active ingredients according to the invention can be used for the prevention and chemotherapy of local and systemic infections in the human and veterinary fields.

Diseases that can be prevented or treated using the compounds according to the invention include, for example, diseases of the respiratory system, pharyngeal cavity and urinary tract, and the compounds of the invention are particularly pharyngitis, sputum, peritonitis, pyelonephritis, otitis media, cystitis, endocarditis Used for the treatment of bronchitis, arthritis and general systemic infections. These compounds can also be used for the preservation of inorganic or organic substances, in particular for the preservation of foods as well as polymers, lubricants, dyes, fibers, leather, paper and wood.

Compounds of general formula (I) can also be used as broad-spectrum antibiotics because they exhibit very potent activity against harmful microorganisms, particularly Gram-positive and Gram-negative bacteria and bacteria-like microorganisms in vitro.

By using the β-lactam compound of the present invention, it is possible to treat and / or prevent local and / or systemic diseases caused by the following microorganisms or mixed microorganisms.

Micrococases such as tasphylococcus; Lactobacterial such as Straptococcus; Neisseria, such as Neisseria; Klebsielli, such as Corynebacteria; Proteases of the proteus group such as Prodeus vulgaris; Salmonella such as Salmonella typhimurium; Shigella, such as Shigella descentere; Pseudomonas such as Pseudomonas eruginosa; Aeromonas such as aeromonas liquid faciens; Spirilases, such as the Vibrio species (eg Vibrio cholera); Parvobacterial or brucellase, such as pasteurella; Brucelles such as brucellar abotus; Haemophilus, such as Haemophilus influenzae; Bordedela, such as Bordetella pertussis; Moraxellies such as Moraxella rakunata; Bacteroideses such as Bacteroides; Pushforms such as Fusobacterium pushforms; Staphylococcus, such as Sterophorus Necrophorus; Bacillase, an aerobic spore former such as Bacillus anthracis; Nasty spore forming clostridia such as Clostridium perfringes; Spirohetases such as Borrelia; Treponemas such as treponema palidium; Leptospira, such as leptospira interogans.

The above-mentioned microorganisms are described by way of example only and are not suggested to them.

The following Tables 1 and 2 list representative penicillins and cephaloporins according to the invention with particularly excellent activity. Penicillins listed in the table can be obtained according to Method 1 or 2, and cephalosporins can be obtained according to Method 1,2 or 3.

The activity of the β-lactam antibiotics according to the invention can be explained by the following test as an example.

One.

This test is performed using the serial dilution method in microtiter systems. The compound is tested for bacteriostatic activity in liquid medium. The bacteriostatic action is tested at the following concentrations: 128,64,32,16,8,4,2,1,0.5.0.25,0.12 and 0.06 μg / ml. A nutrient medium is prepared by adding distilled water to 10 g of peptone, 8 g of juicy extract oxoid, 3 g of sodium chloride, and 2 g of sodium diphosphate to make 100 ml. (pH 7.2 to 7.4). In the experiment on Staphylococcus, only 1% of glucose is added. Primary cultures are aged for about 20 hours. Adjustment of the bacterial suspension was carried out in the Eppendorf method based on the turbidity of the barium sulfate control material produced using barium sulfate precipitation obtained by adding 3.0 ml of 1% barium chloride solution to 97 ml of 1% sulfuric acid. It is carried out using a following photometer (test tube diameter 14 mm, filter 546 mm). After expression, using a saline solution, Streptococcus aronson is further diluted to a concentration of 1:15 and other bacteria are diluted to a concentration of 1: 1500.

16 mg of each test compound is placed in a 10 ml measuring flask, and then the solvent is filled up to the marking line of the flask. Additional dilution series is expressed using distilled water or a suitable solvent.

The microtiter plate is filled with 0.2 ml of nutrient medium, 0.01 ml of diluted test compound, and 1 drop (0.01 ml) of bacterial suspension and incubated at 37 ° C. for 18-20 hours. At the same time, a control test using only a solvent is performed. Visually inspect to determine the minimum inhibitory concentration (lowest concentration that exhibits bacteriostatic effect).

The following strains were used as the test microorganisms: Staphylococcus oreus SG511, Escherichia coli TCC 11 775, A Pseudomonas aeruginosa hamgengensis and Pseudomonas aeruginosawalti Certia marcesense ATCC13 880, Clap Ciella pneumoniae ATCC10 031 and 272, Proteus mirabilis hamerdensis, Proteus retigeri, Enterobacter Cloase ATCC13 047, Yescheria coli R + TEM (β-lactamase producing bacteria) The minimum inhibitory concentrations (MIC) measured for the representative compounds according to the invention are shown:

a) penicillin,

Sodium salt of a compound of formula (I) wherein A is P-hydroxyphenyl and R has the following meaning:

TABLE 1

b) cephalosporins,

Sodium salt of compound of formula (I), wherein A, R and D have the following meanings.

TABLE 2

As shown in the table, the present invention showed excellent activity against Gram-negative pathogens compared to the control, the activity against Gram-positive bacteria was similar. The activity against Pseudomonas strains is particularly excellent.

Acute toxicity of the compounds is determined by oral and subcutaneous administration to the experimental white rats in increasing doses of the compounds of Tables 1 and 2.

LD ₅₀ refers to the dose that kills 50% of the animals within 8 days. All test compounds means that LD ₅₀ is> 4g / kg, and after subcutaneous administration is> to indicate that LD ₅₀ of 3g / kg, that is at a dose of 3g / kg is not copper died after oral administration, and therefore the test compound It is meant to be nontoxic.

The compounds according to the invention were tested for activity against experimental infection in rats in vivo. As pathogenic bacteria Escherichia coli ATCC 11775 and Pseudomonas surugino walter are used. Intraperitoneal injection starts with 0.2 ml of bacterial suspension (with 5% mucin suspension). This is equivalent to about 1.4 × 10 ⁶ Escherichia Cli and 1.3 × 10 ⁶ Pseudomonas cells per mouse. Female NMRI rats were divided into 10 groups in one group, 2 groups in the gingival group, and the other group were subcutaneously treated with various other doses of cephalosporins according to the present invention to a dose of ED ₅₀ (50% of animals survived). Measure Groups infected with Escherichia coli were treated three times on the first day (1, 4 and 7 hours post infection) and twice on day 2. Groups infected with Pseudomonas were treated with test compound 6 times on the first day (1,3,5,7,9 and 11 hours after infection) and twice from day 2.

The observation period is 7 days in both cases. The results of these experiments using representative penicillins and cephalosporins according to the present invention are shown in Table 3 below.

TABLE 3

It is also an object of the present invention to provide useful pharmaceutical formulations of infectious diseases in humans and animals.

Preferred forms of pharmaceutical preparations include, for example, tablets, tablets, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays. Preferably the active ingredient of general formula (I) or a mixture of various active ingredients of general formula (I) is administered to humans and animals at a dose of 5 to 500 mg, preferably 10 to 200 mg per kg body weight every 24 hours. It is administered in several doses, optionally divided into one dosage form. The single dosage form preferably contains the active ingredient according to the invention in an amount of 1 to 250 mg, in particular 10 to 60 mg, per kg body weight. However, depending on the type and weight of the patient to be treated, the type and severity of the disease, the form and route of administration of the pharmaceutical preparation, as well as the duration and interval of administration, it may be necessary to administer the dose beyond the dose.

Therefore, in some cases, it may be sufficient to administer an amount less than the amount of the active ingredient mentioned above, and in other cases the amount of the active ingredient mentioned above must be exceeded. The optimal dosage and dosage form of active ingredient required in each case can be readily selected by one of ordinary skill in the art.

When the novel compounds according to the invention are used as feed additives, they can be administered with the feed or feed preparation or beverage at usual concentrations and preparations. By such a method of administration, infection by Gram-negative or Gram-positive bacteria can be prevented, restored and / or cured, and the long-term or Hanjin and feed utilization can be improved.

The following non-limiting examples are provided to specifically illustrate the present invention.

Example 1

A suspension of 10.5 g (0.05 mol) of 2-methylmercapto-4-hydroxy-5-nitro-pyrimidine and 5.65 g (0.05 mol) of 2-thienylmethylamine in 250 ml of n-propanol was carried out at 100 ° C. for 8 hours. Heat. After cooling, the added solid product is suction filtered and washed with a small amount of ice cold propanol followed by ether. Thin layer chromatography (silica gel, dichloromethane / methanol 10: 1) confirmed that all starting materials had reacted.

Yield: 11.90 g (94%)

2.72 g (0.01 mol) of the nitro compound thus obtained was suspended in 40 ml of water, mixed with 10 ml of concentrated ammonia, and 7.7 g (0.05 mol) of sodium dithionite was added little by little and mixed with stirring. Then, it heats for 10 minutes in a steam bath. Thin layer chromatography of aqueous solution (silica gel, dichloromethane / methanol 10: 1) confirms that no starting material is present. The mixture is evaporated to dryness in vacuo and the residual solid product is extracted several times with 300 ml of all tetrahydrofuran. The solvent is removed in vacuo. This affords 1.65 g (74%) of the target compound.

Melting Point: 66 ~ 68 ℃

Elemental Analysis:

Calculated Value: C 48.63 H 4.53 N 25.51

Found: C 48.47 H 4.51 N 24.99

4.02 g (0.02 mol) of 2-ethylmercapto-4-hydroxy-5-nitropyrimidine is reacted with 2.0 g of 2-aminothiazole as in Example 1a). The reaction time is 24 hours, whereby 3.75 g (79%) of a nitro compound is obtained, which is dissolved in 150 ml of dimethylformamide without further purification and palladium / charcoal (at 50 ° C. under atmospheric pressure until the calculated amount of hydrogen is absorbed). 5%) to 2 g of hydrogenation. The solvent is removed in vacuo and the residue product is stirred with ethanol. Extraction yields 2.75 g (84%) of the title compound.

Melting point:> 300 ℃

Elemental Analysis:

Calculated Value: C 40.18 H 3.37 N 33.47

Found: C 40.00 H 3.37 N 32.80

The target compound in Example 1a) can also be synthesized by the following method. 169.5 g (1.5 mole) of aminomethylthiophene and 93 g of glacial acetic acid are mixed. The resulting powder is chained in moltar. To this was added 130.5 g (0.5 mol) of 2-methylmercapto-4-hydroxy-5-benzylamino-pyrimidine. The resulting mixture is heated to 180 ° C. for 6 hours with stirring in a 1 L flask.

The resulting mixture was stirred twice with 0.5 L of warmed ethyl alcohol to extract the residue solid product and washed with 150 ml of acetone.

Yield: 120 g

Melting Point: 275 ℃ (Recrystallized from Dimethylformamide)

Elemental Analysis:

Calculated Value: C 58.88 H 4.32 N 17.17

Found: C 59.00 H 4.39 N 17.21

3.26 g (0.01 mol) of the product thus obtained are refluxed with 4 g of sodium hydroxide, 0.2 g of sodium sulfite and 20 ml of water for 3 hours. The mixture is cooled, acidified to pH 0.5 by addition of concentrated hydrochloric acid and the precipitated benzoic acid is removed by shaking with ether. The pH of the aqueous phase is adjusted to 6.9 with sodium hydroxide solution and the precipitated product is extracted.

Yield: 1.9 g (85%)

1d) 2-chloro-4-hydroxy-5-nitro-pyridine, sodium monohydrate salt

A solution of 8.2 g (0.1 mol) of sodium acetate in 25 ml of water and 10 ml of glacial acetic acid is added dropwise to a solution of 9.7 (0.05 mol) of -9.2 g dichloro-5-nitropyrimidine with stirring at −10 ° C. After the addition of buffer is complete, the mixture is stirred under ice cooling for an additional hour. The precipitated concentrated lysate is extracted and dried in vacuo on calcium chloride. Thus, 2-chloro-4-hydroxy-5-nitro-pyrimidine is obtained in the form of a sodium salt having 1 molecule of crystal water.

Yield: 10.20 g (94.4%)

Melting point: No melting point, water separation at 150 ° C, decomposition at 195 ° C.

Elemental Analysis:

Calculated Value: C 22.29 H 1.40 CI 16.45 N 19.50

Found: C 22.42 H 1.50 CI 16.46 N 19.84

Moisture content (according to Karl Fischer method)

Calculated Value: 8.36%

Found: 8.4%

1e) 4-hydroxy-2- (2'-methyl-5'-pyrimidinylmethylamino) -5-nitro-pyrimidine

A solution of 0.75 g (0.0061 mol) of 2-methyl-5-methylamino-pyrimidine in 15 ml of dioxane was added to 1.4 g of sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitropyrimidine in 20 ml of water. 0.0065 mole) to a solution to obtain a homogeneous solution. The prepared solution is refluxed for 2.5 hours. The precipitated reaction product is extracted, washed with water and dried in vacuo at 50-100 ° C.

Yield: 1.05 g (65.6%)

Melting Point: 244 ~ 246 ℃ (Decomposition)

Elemental Analysis:

Calculated Value: C 45.80 H 3.84 N 32.04

Found: C 45.33 H 4.02 N 32.03

1f) 5-Amino-4-hydroxy-2- (2'-methyl-5'-pyrimidinylmethylamino) -pyrimidine

1.0 g nitropyrimidine described in Example 1e) is hydrogenated with 0.5 g palladium / charcoal (10%), 10 ml methanol 80 ml water and 5 ml concentrated hydrochloric acid in a hydrogenation vessel at atmospheric pressure and room temperature. After the water is completely absorbed, the catalyst is removed by filtration and the methanol is removed in vacuo and a small amount of water is added. The pH is adjusted to 4.5 with sodium hydroxide solution and the precipitated product is extracted.

Yield: 720 mg

Breakdown:> 250 ℃

According to one of the methods described above, the following novel pyrimidine is synthesized.

at) 4-hydroxy-2- (6'-methylsulfinyl-3'-pyridylamino) -5-nitropyrimidine

4.68 g (0.03 mol) of 2-mercapto-5-natropyridine is dissolved in a sodium hydroxide solution prepared by dissolving 1.32 g (0.033 mol) of sodium hydroxide in 60 ml of water with gentle heating. To the resulting solution is added 4.17 g (0.033 mol) of dimethylsulfate and the mixture is shaken well. The resulting precipitate is suction filtered to crystallize the wet product from ethanol. This affords 2-methylthio-5-nitropyridine.

Yield: 4.5 g (88.1%)

Melting Point: 111-112 ℃

4.5 g (0.0264 mol) of 2-methylthio-5-nitropyridine are hydrogenated using raninickel as a catalyst in ethanol at 50 ° C. and a pressure of 5 bar. After filtration to remove the catalyst and evaporate in vacuo, an oily product is obtained. To a solution of the resulting oil is added a solution of 6.84 g (0.032 mol) of sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitropyrimidine in 150 ml of water. The aqueous solution is heated in a steam bath for 30 minutes and the resulting precipitate is extracted, washed with water and dried. This gave 4-hydroxy-2- (6'-methylmercapto-3-pyridyl) -amino-5-nitropyrimidine.

Yield: 7 g (94.8%)

Melting Point: 295 ℃ (Decomposition)

The compound is dissolved in dimethyl sulfoxide and precipitated with methanol for elemental analysis.

Calculated Value: C 43.00 H 3.25 N 25.08

Found: C 43.09 H 3.36 N 24.90

5.59 g (0.02 mol) of 4-hydroxy-2- (6'-methylmercapto-3-pyridylamino) -5-nitropyrimidine is dissolved in 20 ml of formic acid and 1.87 g of 40% perhydrolol ( 0.022 mol). After standing for 3 hours at room temperature, acetone is added to complete the formation of the precipitate.

Yield: 5.4 g (91%)

Melting Point:> 300 ℃

Elemental Analysis:

Calculated Value: C 40.67 H 3.07 N 23.72

Found: C 40.36 H 3.06 N 23.50

au) 5-amino-4-hydroxy-2- (6'-methylsulfinyl-3'-pyridylamino) -pyrimidine

The reaction is carried out using dithionite according to the process described in example 1a).

Yield: 56%

l R Spectrum: 1660,1020 cm ^-1 ; NMR Spectrum (CDCL ₃ / CD ₃ OD) Signal (ppm): 2.9 (s, 3H), 7.3 (s, 1H), 7.85 and 8.4 (m, 2H), 8.8 (d, 1 H).

av) 4-hydroxy-2- (6-methylsulfonyl-3-pyridylamino) -5-nitropyrimidine

In the same manner as in Example 1au), the title 4-hydroxy-5-nitropyrimidine is prepared. Using the fruit hydrol and the reaction time is extended to 5 days.

Yield: 72.6%, melting point: 300 ° C

Deposition contains a sulphated methylsulfinyl compound, which is removed by column chromatography after reduction of the nitro group.

aw) 5-amino-4-hamidyhydroxy-2- (6'-methylsulfonyl-3'-pyridylamino) -pyrimidine

The reduction reaction is carried out using dithionite according to the process of example 1a).

Yield: 33%

lR Spectrum: 1670,1150,1355cm ^-1 ; NMR Spectrum (DMSO / CD ₃ OD) Signal (ppm): 3.1 (s, 3H), 7.15 (s, 1H), 7.9 and 8.4 (m, 2H) , 8.8 (d, 1 H).

ax) 5-amino-4-hydroxy-2- (5'-sulfonamido-2'-thienylmethylamino) -pyrimidine

4 g (0.0123 moles) of 5-benzoylamino-4-hydroxy-2- (2'-thienylmethylamino) -pyrimidine are added in portions to 14.32 g (0.12 moles) of chloro sulfoic acid while cooling. The solution was stirred at room temperature for 1.5 hours and then poured into ice water to decompose excess chlorosulfonic acid. The precipitated 5-benzoylamine-4-hydroxy-2- (5'-chlorosulfonyl-2'-thienylmethylamino) -pyrimidine is removed and dried in vacuo, over phosphorus pentoxide.

Yield: 4.6 g (88.5%)

lR Spectrum: 1170,1370cm ^-1 ; NMR Spectrum (DMSO / CD ₃ OD) Signal (ppm): 4.8 (s, 2H), 7.1 (dd, 2H), 7.5 (m, 3H), 7.9 (m , 2H), 8.4 (s, 1H).

4.6 g (0.0108 mol) of 5-phenzoylamino-4-hydroxy-2- (5'-chloro sulfonyl-2'-thienylmethylamino) -pyrimidine is suspended in 100 ml of acetone and 10 ml of concentrated aqueous ammonia solution is added. do. Heat in steam bath for 10 minutes until all compounds are dissolved. The solution is evaporated to dryness and the residue is extracted by grinding with water. The residue is suspended in 30 ml of water and 2 g of sodium hydroxide is added to reflux the mixture for 4 hours. The solution is diluted with water, treated with activated charcoal, filtered, and adjusted to pH 7 by adding 2N hydrochloric acid to stand overnight. The precipitate is extracted and recrystallized from water.

Yield: 0.85 g (26.1%)

l R Spectrum: 1150,1340 cm ^-1 ; NMR Spectrum (DMSO / CD ₃ OD) Signal (ppm): 4.55 (s, 2H), 6.95 (d, 2H), 7.35 (d, 1H).

Example 2

Preparation of ureidocarboxylic acid

-(2-(2'-푸리렘틸아미노)-4-하이드록시-5-피리미디닐)-우레이도-페닐아세트산a) D-

-(2- (2'-Puriremylamino) -4-hydroxy-5-pyrimidinyl) -ureido-phenylacetic acid

2.47 g (0.012) of 5-amino-2- (2'-furylmethylamino) -4-hydroxypyrimidine is dissolved in 80 ml of anhydrous tetrahydrofuran and mixed with 1.65 ml of triethylamine. The resulting solution is added dropwise at 0 ° C. to a solution of 1.20 g of phosgene in 25 ml of tetrahydrofuran. The mixture is stirred for about 10 minutes under ice cooling. Subsequently, nitrogen is introduced into the solution to remove unreacted phosgene.

-아미노-페닐아세트산 1.8g (0.012몰)의 현탁액을 냉각 및 교반하면서 1N수산화나트륨용액 12ml를 가하여 용해시킨다. 생성된 용액에 빙냉하에서 상기에서 제조된 현탁액을 가하여, 이때 PH는 N-수산화나트륨 용액을 가해 8.0 내지 8.5로 유지시킨다. 혼합물을 5℃에서 1시간 및 실온에서 2시간 동안 교반한다. 그후, 테트라하이드로푸란을 진공중에서 제거하고 잔유수액을 pH8.0내지 8.5에서 에틸 아세테이트와 함께 2회 진탕한다. 그후, 수용액을 냉각 및 교반하면서 묽은 염산을 가해 pH2.9로 조정한다. 침전된 고체 생성물을 추출하여 소랑의 빙냉한 물로 세척한 다음 건조시킨다.D- in 50 ml of tetrahydrofuran and 20 ml of mole

A suspension of 1.8 g (0.012 mol) of amino-phenylacetic acid is dissolved by adding 12 ml of 1N sodium hydroxide solution while cooling and stirring. To the resulting solution is added the suspension prepared above under ice cooling, where the pH is maintained at 8.0 to 8.5 by addition of N-sodium hydroxide solution. The mixture is stirred at 5 ° C. for 1 hour and at room temperature for 2 hours. Tetrahydrofuran is then removed in vacuo and the residue is shaken twice with ethyl acetate at pH 8.0-8.5. Thereafter, diluted hydrochloric acid is added to adjust the pH to 2.9 while cooling and stirring the aqueous solution. The precipitated solid product is extracted, washed with ice-cold water and dried.

Yield: 2.8 g (70%)

lR Spectrum: 3220 (Broad), 1650,1550cm ^-1 ; NMR Spectrum (CDCL ₃ + D ₂ O) Signal (ppm): 4.4 (s, 2H), 5.15 (s, 1H), 6.3 (m, 2H), 7.5 (m, 6H), 8.1 (s, 1H).

-[(2-(2'-메틸-5'-피리미디닐메틸아미노)-4-하이드록시-5-피리미디닐)-우레이도]-Pa) D-

-[(2- (2'-Methyl-5'-pyrimidinylmethylamino) -4-hydroxy-5-pyrimidinyl) -ureido] -P

2.32 g (0.01 mol) of 5-amino-2- (2'-methyl-5'-pyrimidinylmethylamino) -4-hydroxy-pyrimidine is suspended in 100 ml of anhydrous tetrahydrofuran and 4 ml of trimethylsilyldiethylamine With reflux to form a complete solution. The mixture is evaporated to dryness in vacuo. The residue solid product is dissolved in 50 ml of anhydrous tetrahydrofuran and added to a solution of 1.05 g of phosgene in 40 ml of tetrahydrofuran under ice cooling. After the excess of phosgene is removed, the reaction proceeds in a similar manner to Example 1 using 1.65 g of p-hydroxyphenylacetic acid.

Yield: 2.78 g (66%)

l Spectrum: 3330 (broad), 1650,1560 cm ^-1 ; NMR Spectrum (DMSO / CD ₃ OD) Signal (ppm): 4.4 (s, 2H), 5.05 (s, 1H), 6.7 (d, 2H), 7.20 (d, 2H), 8.05 (s, 1H), 8.6 (s, 2 H).

According to the above methods, the following ureido carboxylic acids are synthesized.

II. Preparation of Penicillin According to Formula (I) or (I ')

Example 1

[3-(4-하이드록시-2-{3'-피리딜아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {3'-pyridylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

1.02 mg (0.005 mol) of 5-amino-4-hydroxy-2- (3'-pyridyl amino) -pyrimidine is dissolved in anhydrous tetrahydrofuran and mixed with 500 mg of triarylamine. The resulting solution is added to a solution of 500 mg of phosgene in 30 ml of anhydrous tetrahydrofuran at 0 ° C.

The mixture is stirred for about 30 minutes under ice cooling. Subsequently, nitrogen is introduced into the solution to remove unreacted phosgene. 2.0 g (0.005 mol) of amoxicillin trihydrate are suspended in 80 ml of 80% aqueous 80% tetrahydrofuran and cooled to 0 ° C. Thereafter, a sufficient amount of triarylamine is added to generate a solution. To the resulting solution, the suspension prepared above is added over 5 minutes while maintaining the pH at 7.5 by adding triethylamine. Further 30 ml of water are added and the reaction mixture is kept at 0-20 占 폚 for 1 hour. Thereafter, cooling is stopped and stirred for 1 hour at room temperature.

40 ml of water are then added and the tetrahydrofuran is removed in vacuo. The remaining aqueous phase is washed twice with 50 ml of ethyl acetate. 2N hydrochloric acid was slowly added to the aqueous solution while lowering the pH to 2.9 and keeping the temperature below 5 ° C. The precipitated product is extracted and dried in a drier. To the solid product is added a solution of 700 mg sodium hexanoate in 25 ml of methanol and the resulting solution is mixed with ether. The precipitated sodium salt is extracted and dried in vacuo.

Yield: sodium salt 2.19 g (71%)

l Spectrum: 1770,1660,1610,1545cm ^-1

NMR Spectrum (DMSl + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.05 (1H), 5.45 (q, 2H +, 1H), 6.8 (d, 2H), 7.25 (d, 2H), 7.4 (m, 1H), 8.2 (m, 3H), 8.8 (s, 1H).

Example 2

[3-(4-하이드록시-2-{3'-피리딜아미노}-5-피리미디닐)-우레이도]-벤질나트륨 염D-

[3- (4-Hydroxy-2- {3'-pyridylamino} -5-pyrimidinyl) -ureido] -benzylsodium salt

2.25 g (0.006 mol) of ampicillin sodium salt and 1.22 g of 5-amino-4-hydroxy-2- (3'-pyridylamino) -pyrimidine with 600 mg of phosgene and 0.82 ml of triethylamine The title penicillin was prepared in a similar manner to Example II / I as the substance.

Yield: sodium salt 2.13 g (57.5%)

l Spectrum: 1765,1650,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.05 (s, 1H), 5.50 (q, 2H + s, 1H), 7.4 (m, 6H), 8.2 (m, 3H), 8.8 (s, 1 H).

Example 3

[3-(4-하이드록시-2-{6'-메톡시-3'-피리딜-아미노)-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {6'-methoxy-3'-pyridyl-amino) -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt

840 mg (0.002 mole) of amoxicillin trihydrate, and 470 mg (0.002 mole) of 5-amino-4-hydroxy-2- (6-methoxy-3'-pyridylamino) -pyrimidine and 200 mg of phosgene and tri Using the reaction product with 0.27 ml of ethylamine as starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 630 mg (48%) of sodium salt

l Spectrum: 1770,1650,1615,1550cm ^-1

NMR Spectrum (CD ₃ OD) Signal (ppm): 1.6 (d, 6H), 3.9 (s, 3H), 4.2 (s, 1H), 5.4 (m, 3H), 6.8 (m, 3H), 7.2 (m , 2H), 7.7-8.3 (m, 3H).

Example 4

[3-(4-하이드록시-2-{2'-피리딜메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {2'-pyridylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt

A reaction product of 4.2 g of amoxicillin trihydrate and 2.17 g (0.01 mol) of 5-amino-4-hydroxy-2- (2'-pyridylmethylamino) -pyrimidine, 1.05 g of phosgene and 1.35 mL of triethylamine As starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 4.06 g (64%) of sodium salt

l Spectrum: 1765,1650,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 3.9 (s, 1H), 4.6 (s, 2H), 5.45 (q, 2H + s, 1H), 6.85 (d, 2H), 7.85 (m, 1H), 8.2 (s, 1H), 8.7 (m, 1H).

Example 5

[3-(4-하이드록시-2-{3'-피리딜메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {3'-pyridylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylpenicillin sodium salt

2.1 g (0.005 mol) of amoxicillin trihydrate and 1.19 g (0.005 mol) of 5-amino-4-hydroxy-2- (3'-pyridylmethylamino) -pyrimidine, 500 mg of phosgene and 0.67 ml of triethylamine Using the reaction product as a starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 2.45 g (79%) of sodium salt

l Spectrum: 1765,1640,1640, 1640, 1610,1560cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (b, 6H), 3.9 (s, 1H), 4.55 (s, 2H), 5.35 (m, 3H), 6.75 (d, 2H), 7.2 (m, 3H), 7.6 (m, 1H), 8.0 (s, 1H), 8.3 (m, 2H).

Example 6

[3-(4-하이드록시-2-{4'-피리딜메틸-아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {4'-pyridylmethyl-amino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt

The reaction product of 420 mg (0.001 mol) of amoxicillin trihydrate and 220 mg of 5-amino-4-hydroxy-2- (4'-pyridylmethylamino) -pyrimidine with 100 mg of phosgene and 0.14 ml of triethylamine As starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: sodium salt 310 mg (50%)

l Spectrum: 1770,1650,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 3.9 (s, 1H), 4.5 (Broad, s, 2H), 5.4 (q, 2H + s, 1H), 6.7 ( d, 4H), 7.2 (m, 4H), 8.0 (s, 1H), 8.4 (m, 2H).

Example 7

[3-(4-하이드록시-2-{5'-피리미디닐아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {5'-pyrimidinylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylpenicillin sodium salt

410 mg (0.002 mole) of 5-amino-4-hydroxy-2- (5'-pyrimidinylamino) -pyrimidine is heated with 80 ml of triethylsilin deethylamine to 80 ° C. A homogeneous mixture is obtained and evaporated to dryness in high vacuum. The residue was dissolved in 40 ml of anhydrous tetrahydrofuran and the resulting solution was added to 200 mg of phosgene dissolved in 30 ml of tetrahydrofuran under ice cooling. The subsequent reaction is carried out similarly to Examples II / I.

Yield: Sodium salt 735 mg (64%)

l Spectrum: 1765,1655,1615,1550cm ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.55 (d, 6H), 3.95 (s, 1H), 5.40 (q, 2H + s, 1H), 6.8 (d, 2H), 7.3 (d, 2H), 8.3 (s, 1H), 8.6 (broad s, 2H), 8.9 (s, 1H).

In a similar manner, the following compounds are synthesized.

-[-(4-하이드록시-2-{5'-피리미디닐아미노}-5-피리미딜-우레이도]-벤질페니실린 나트륨염; D-

-[3-(4-하이드록시-2-{1',2',3',4',-테트라하이드로-1,3'-디메틸-2',4'-디옥소-5'-피리미디닐}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨염.D-

-[-(4-hydroxy-2- {5'-pyrimidinylamino} -5-pyrimidyl-ureido] -benzylphenicillin sodium salt;

-[3- (4-Hydroxy-2- {1 ', 2', 3 ', 4',-tetrahydro-1,3'-dimethyl-2 ', 4'-dioxo-5'-pyrimidy Nil} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt.

Example 8

[3-(4-하이드록시-2-{2'-아미노-5'-피리미디닐아미노}-5-피리미디닐-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {2'-amino-5'-pyrimidinylamino} -5-pyrimidinyl-ureido] -P-hydroxy benzylphenicillin sodium salt

660 mg (0.003 mole) of 5-amino-4-hydroxy-2- (2'-amino-5-pyrimidinyl) -pyrimidine is suspended in 50 ml of anhydrous tetrahydrofuran, and N, 0-bis-trimethyl Stir with 2 ml of silinacetamide at room temperature for 2 hours. The resulting solution is carefully dried in a water-jet vacuum and then dried at 80 ° C. in high vacuum. The product is then dissolved in 50 ml of anhydrous tetrahydrofuran and the resulting solution is added to a solution of 300 ml of phosgene in 20 ml of anhydrous tetrahydrofuran under ice cooling.

Subsequent reactions were carried out as in the above examples using 1.26 g (0.003 mol) of amoxicillin.

Yield: sodium salt 645 mg (33%)

l Spectrum: 1770,1665,1615,1550cm ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.55 (6H), 4.0 (1H), 5.40 (q, 2H + s, 1H), 6.75 (d, 2H), 7.3 (d, 2H), 8.25 (s, 1 H), 8.50 (broad s, 2 H).

Example 9

[3-(4-하이드록시-2-{5'-에톡시카보닐-2'-티에닐 아미노-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염D-

[3- (4-Hydroxy-2- {5'-ethoxycarbonyl-2'-thienyl amino-5-pyrimidinyl) -ureido] -P-hydroxy benzylpenicillin sodium salt

4.2 g (0.01 mol) of amoxicillin trihydrate and 2.8 g of 5-amino-4-hydroxy-2- (5'-ethoxycarbonyl-2'-thienylamino) -pyrimidine with 500 mg of phosgene and triethyl Using the reaction product with 0.68 ml of amine as starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 4.05 g (59.5%) sodium salt;

l Spectrum: 1770,1650,1620,1545cm ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.3 (t, 3H), 1.55 (d, 6H), 4.0 (s, 1H), 4.3 (q, 2H), 5.4 (q, 2H + s, 1H), 6.8 (s, 2H), 7.3 (d, 2H), 7.9 (m, 2H), 8.3 (s, 1H).

Example 10

[3-(4-하이드록시-2-{2'-티에닐메틸 아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염D-

[3- (4-hydroxy-2- {2'-thienylmethyl amino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

8.4 g (0.02 mol) of amoxicillin trihydrate and 4.48 g (0.02 mol) of 5-amino-4-hydroxy-2- (2'-thienylmethylamino) -pyrimidine, 2.0 g of phosgene and 2.75 ml of triethylamine Using the reaction product as a starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 9.75 g (76%) sodium salt;

l Spectrum: 1770,1660,1620,1560㎝ ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.0 (s, 1H), 4.5 (s, 2H), 5.35 (q, 2 + s, 1H), 6.7 (d, 2H), 6.85 (m, 2H), 7.25 (d, 2H), 7.35 (m, 1H), 8.1 (s, 1H).

Example 11

[3-(4-하이드록시-2-{2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-벤질페니실린 나트륨염D-

[3- (4-Hydroxy-2- {2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -benzyl penicillin sodium salt

A reaction product of 1.86 g (0.005 mol) of ampicillin sodium salt and 1.12 g of 5-amino-4-hydroxy-2- (2'-thienylmethylamino) -pyrimidine, 500 mg of phosgene and 0.86 ml of triethylamine As starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 2.20 g (70.5%) sodium salt;

l Spectrum: 1765,1655,1610,1545cm ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.55 (6H), 4.05 (s, 1H), 4.5 (s, 2H), 5.4 (q, 2 + s, 1H), 6.85 (m, 2H) , 7.4 (m, 6H), 8.05 (s, 1H).

In a similar manner, the following compounds are synthesized.

-[3-(4-하이드록시-2-{2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-m, p-디하이드록시-벤질페니실린 나트륨염; D-

-[3-(4-하이드록시-2-{2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-사이클로헥사-1,4-디엔-1-일-메틸 페니실린 나트륨염; D-

-[3-(4-하이드록시-2-{2'-티에닐메틸아미노}-5-피리미디닐)-우레이도] -2-티에닐메틸페니실린 나트륨 염; D-

-[3-(4-하이드록시-2-{2'-티에닐메틸아미노} -5-피리미디닐)-우레이도]-2-푸릴메틸페니실린 나트륨염.D-

-[3- (4-hydroxy-2- {2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -m, p-dihydroxy-benzylphenicillin sodium salt; D-

-[3- (4-Hydroxy-2- {2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -cyclohexa-1,4-dien-1-yl-methyl penicillin sodium salt ; D-

-[3- (4-hydroxy-2- {2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -2-thienylmethylphenicillin sodium salt; D-

-[3- (4-hydroxy-2- {2'-thienylmethylamino} -5 -pyrimidinyl) -ureido] -2-furylmethylpenicillin sodium salt.

Example 12

[3-(4-하이드록시-2-{3'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {3'-thienylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt

A reaction product of 840 mg (0.002 mol) of amoxicillin trihydrate and 460 mg of 5-amino-4-hydroxy-2- (3'-thienylmethylamino) -pyrimidine, 200 mg of phosgene and 0.27 mL of triethylamine As starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 860 mg (66%) sodium salt;

l Spectrum: 1765,1650,1610,1545cm ^-1

Example 13

[3-(4-하이드록시-2-{5'-메틸-2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {5'-methyl-2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

1.26 g (0.003 mole) of amoxicillin trihydrate and 700 g (0.003 mole) of 5-amino-4-hydroxy-2- (5'-methyl-2'-thienylmethylamino) -pyrimidine and 300 mg of phosgene and tri Using the reaction product with 0.41 ml of ethylamine as starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 380 mg (54.5%) of sodium salt;

l Spectrum: 1770,1645,1610,1560㎝ ^-1

NMR Spectrum (DMSO + D ₃ OD) Signal (ppm): 1.55 (6H), 2.45 (s, 3H), 4.0 (s, 1H), 4.5 (s, 2H), 5.4 (m, 3H), 6.7 (d , 2H), 6.85 (2H), 7.20 (d, 2H), 8.05 (s, 1H).

In a similar manner, the following formula is synthesized.

-[3-(4-하이드록시-2-{5'-티에닐메틸 아미노}-5-피리미디닐)-우레이도]-벤질페니실린 나트륨 염; D-

-[3-(4-하이드록시-2-{5'-메틸-2'-티에닐메틸아미노} -5-피리미디닐)-우레이도] -사이클로헥사-1,4'-디엔-1-일-매틸페니실린 나트륨 염; D-

-[3-(4-하이드록시-2-{5'-메틸}-5-피리미디닐)-우레이도]-2-푸릴메틸 나트염.D-

-[3- (4-hydroxy-2- {5'-thienylmethyl amino} -5-pyrimidinyl) -ureido] -benzylphenicillin sodium salt; D-

-[3- (4-Hydroxy-2- {5'-methyl-2'-thienylmethylamino} -5 -pyrimidinyl) -ureido] -cyclohexa-1,4'-diene-1- Mono-matylphenicillin sodium salt; D-

-[3- (4-hydroxy-2- {5'-methyl} -5-pyrimidinyl) -ureido] -2-furylmethyl nat salt.

Example 14

[3-(4-하이드록시-2-{5'-클로로-2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {5'-chloro-2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

1.0 g (0.0024 mole) of amoxicillin trihydrate and 700 mg of 5-amino-4-hydroxy-2- (5'-chloro-2'-thienylmethylamino) -pyrimidine and 250 mg of phosgene and 0.33 triethylamine Using the reaction product with ml as starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 1.1 g (67%) of sodium salt;

lR Spectrum: 1776,1655,1615,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (6H), 4.0 (1H), 4.45 (s, 2H), 5.35 (q, 2H, s, 1H), 6.7-7.0 (m, 4H) , 7.25 (d, 2 H), 8.10 (s, 1 H).

Example 15

[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

6.3 g (0.015 mol) of amoxicillin trihydrate and 3.0 g (0.015 mol) of 5-amino-4-hydroxy-2- (2'-furylmethylamino) -pyrimidine, 1.5 g of phosgene and 2.01 ml of triethylamine Using the reaction product as a starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 6.45 g (69%) sodium salt;

l Spectrum: 1770,1660,1620,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 3.9 (s, 1H), 4.4 (Broad, s, 2H), 5.4 (q, 2H + s, 1H), 6.3 ( m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.0 (s, 1H).

Example 16

[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-벤질페니실린 나트륨염D-

[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -benzyl penicillin sodium salt

1.86 g (0.005 mol) of ampicillin sodium salt, and 1.06 g of 5-amino-4-hydroxy-2- (2'-furylmethylamino) -pyrimidine, 500 mg of phosgene and 0.86 ml of triethylamine were started. As the material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 1.91 g (62%) sodium salt;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.0 (s, 1H), 4.4 (Broad, s, 2H), 5.4 (q, 2H + s, 1H), 6.3 ( m, 2H), 7.45 (m, 6H), 8.05 (s, 1H).

In a similar manner, the following compounds are synthesized.

-[3-(4-하이드록시-2-{2'-푸릴메틸 아미노}-5-피리미디닐)-우레이도]-m, p-디하이드록시-벤질페니실린 나트륨염; D-

-[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-사이클로헥사-1,4-디엔-1-일-메틸페니실린 나트륨염; D-

-[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도] -2-푸릴메-페니실린 나트륨 염; D-

-[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-2-티에닐메틸-페니실린 나이트 염; D-

-[3-(4-하이드록시-2-{2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-3-티에닐메틸-페니실린 나트륨 염.D-

-[3- (4-hydroxy-2- {2'-furylmethyl amino} -5-pyrimidinyl) -ureido] -m, p-dihydroxy-benzylphenicillin sodium salt; D-

-[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -cyclohexa-1,4-dien-1-yl-methylphenicillin sodium salt; D-

-[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -2-furyl-penicillin sodium salt; D-

-[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -2-thienylmethyl-penicillin nitrate salt; D-

-[3- (4-hydroxy-2- {2'-furylmethylamino} -5-pyrimidinyl) -ureido] -3-thienylmethyl-penicillin sodium salt.

Example 17

[3-(4-하이드록시-2-{5'-메틸-2'-티에닐-아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {5'-methyl-2'-thienyl-amino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylpenicillin sodium salt

Amoxicillin trihydrate 500 mg (0.0012 mol), and 5-amino-4-hydroxy-2- (5'-methyl-2'-thienylamino) -pyrimidine 120 mg and phosgene 120 mg and triethylamine 0.17 Using the reaction product with ml as starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 350 mg (47%) of sodium salt;

l Spectrum: 1765,1655,1610,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (6H), 2.5 (s, 3H), 4.0 (s, 1H), 5.35 (q, 2H + s, 1H), 6.5 (m, 2H) , 6.75 (d, 2H), 7.2 (d, 2H), 8.1 (s, 1H).

Example 18

[3-(4-하이드록시-2-{5'-메틸-2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {5'-methyl-2'-furylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt

840 mg (0.002 mole) of amoxicillin trihydrate, and 440 mg (0.002 mole) of 5-amino-4-hydroxy-2- (5'-methyl-2'-furylmethylamino) -pyrimidine and 200 mg and tris of phosgene Using the reaction product with 0.27 ml of ethylamine as starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 620 mg (48%) sodium salt;

l Spectrum: 1770,1655,1620,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 2.45 (s, 3H), 4.0 (s, 1H), 5.40 (q, 2H + s, 1H), 6.3 (m, 2H), 6.75 (d, 2H), 7.2 (d, 2H), 8.05 (s, 1H).

Example 19

[3-(4-하이드록시-2-{테트라하이드로-2'-푸릴메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염D-

[3- (4-hydroxy-2- {tetrahydro-2'-furylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt

A reaction product of 4.2 g (0.01 mol) of amoxicillin trihydrate and 201 g of 5-amino-4-hydroxy-2-tetrahydro-2'-furylmethylamino) -pyrimidine with 1.0 g of phosgene and 1.35 ml of triethylamine was prepared. As starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 3.62 g (58%) sodium salt;

l Spectrum: 1765,1650,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 1.9 (m, 4H), 3.5-4.0 (m, 6H), 5.4 (q, 2H + s, 1H), 6.7 ( d, 2H), 7.2 (d, 2H), 8.0 (s, 1H).

Example 20

[3-(4-하이드록시-2-{2'-피롤릴메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨 염D-

[3- (4-Hydroxy-2- {2'-pyrrolylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt

1.0 g (0.0024 mole) of amoxicillin trihydrate and 490 mg (0.0024 mole) of 5-amino-4-hydroxy-2- (2'-pyrrolylmethylamino) -pyrimidine, 250 mg of phosgene and 0.33 ml of triethylamine Using the reaction product as a starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 635 mg (42.5%) sodium salt;

l Spectrum: 1770,1650,1715,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 3.95 (s, 1H), 4.3 (s, 2H), 5.4 (m, 3H), 6.1 (m, 2H), 6.7 (m, 3H), 7.3 (d, 2H), 8.05 (s, 1H).

Example 21

[3-(4-하이드록시-2-{2'-티아졸릴아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염.D-

[3- (4-hydroxy-2- {2'-thiazolylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

2.0 g (0.005 mol) of amoxicillin trihydrate and 1.06 g of 5-amino-4-hydroxy-2- (2'-thiazolylamino) -pyrimidine were subjected to silylation with 500 mg of phosgene and 0.67 ml of triethylamine. Using the reaction product as a starting material, the title penicillin is prepared in a similar manner as in Example II / I.

Yield: 1.12 g (36%) sodium salt;

l Spectrum: 1765,1650,1610,1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (6H), 3.95 (s, 1H), 5.40 (q, 2H + s, 1H), 6.7 (m, 4H), 7.25 (d, 2H) , 8.0 (s, 1H).

Example 22

[3-(4-하이드록시-2-{4'-메틸-2'-티아졸릴-메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {4'-methyl-2'-thiazolyl-methylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

2.0 g (0.0048 mol) of amoxicillin trihydrate and 1.75 g of 5-amino-4-hydroxy-2- (4'-methyl-2'-thiazolylmethylamino) -pyrimidine, 500 mg of phosgene and 0.65 ml of triethylamine Using the reaction product as a starting material, the title penicillin was prepared in a similar manner as in Example II / I.

Yield: 1.30 mg (41%) sodium salt;

l Spectrum: 1765,1650,1615,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 2.25 (s, 3H), 4.0 (s, 1H), 4.4 (Broad s, 2H), 6.6 (s, 1H), 6.75 (d, 2H), 7.2 (d, 2H), 8.0 (s, 1H).

Example 23

[3-(4-하이드록시-2-{4'-메틸-2'-이미다졸릴}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨 염.D-

[3- (4-Hydroxy-2- {4'-methyl-2'-imidazolyl} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

Reaction of 1.5 g (0.0035 mol) of amoxicillin trihydrate and 730 mg of 5-amino-4-hydroxy-2- (2'-imidazolmelamino) -pyrimidine with 350 mg of trimethylsilyldiethylamine and phosgene As the starting material, the title penicillin was prepared in a similar manner to Examples II / 7.

Yield: 1.18 g (54%) sodium salt;

l Spectrum: 1765,1655,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 2.1 (s, 3H), 4.0 (s, 1H), 4.4 (s, 2H), 5.40 (m, 3H), 6.8 (d, 2H), 7.2 (m, 4H), 8.05 (s, 1H).

-[3-(4-하이드록시-2-{2'-옥사졸릴메틸아미노}-5-피리미디닐)-우레이도] -p-하이드록시-벨질 페니실린 나트륨.In a similar manner, the following compounds can be synthesized: D-

-[3- (4-Hydroxy-2- {2'-oxazolylmethylamino} -5-pyrimidinyl) -ureido] -p-hydroxy-belyl penicillin sodium.

Example 24

[3-(4-하이드록시-2-{5'-메틸-1',3',4'-트리아졸-2'-일-메틸아미노-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {5'-methyl-1 ', 3', 4'-triazol-2'-yl-methylamino-5-pyrimidinyl) -ureido] -P- Hydroxy benzylpenicillin sodium salt.

Amoxicillin trihydrate 840 mg (0.002 mol), and 5-amino-4-hydroxy-2- (5'-methyl-1 ', 2', 3 ', 4',-triazol-2'-ylmethylamino Using the reaction product of 440 mg (0.02 mol) of) -pyrimidine and 200 mg of phosgene as a starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: 615 mg sodium (47.5%);

l Spectrum: 1770,1660,1620,1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 2.15 (s, 3H), 3.95 (s, 1H), 4.4 (Broad s, 2H), 5.45 (m, 3H), 6.8 (d, 2H), 7.25 (d, 2H), 8.1 (s, 1H).

Example 25

[3-(4-하이드록시-2-{5'-메틸-1',3',4'-티아디아졸-2'-일아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {5'-methyl-1 ', 3', 4'-thiadiazole-2'-ylamino} -5-pyrimidinyl) -ureido] -P- Hydroxy benzylpenicillin sodium salt.

4.2 g (0.01 mol) of amoxicillin trihydrate, and 5-amino-4-hydroxy-2- (5'-methyl-1 ', 3', 4 ',-tridiazol-2'-ylamino) -pyri After silicing 2.24 g of midine, the title penicillin is prepared in a similar manner as in Example II / 7, with 1.0 g of phosgene and the reaction product as starting materials.

Yield: 2.4 g (33.5%) of sodium salt;

l Spectrum: 1765,1655,1615,1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 2.4 (s, 3H), 4.0 (s, 1H), 5.4 (q, 2H + s, 1H), 6.75 (d, 2H), 7.25 (d, 2H), 8.1 (s, 1H).

-[3-(4-하이드록시-2-{5'-메틸-1',3',4'-트리아졸-2'-일아미노]-우레이도-p-하이드록시-벤질 페니실린 나트륨.In a similar manner, the following compounds are synthesized. D-

-[3- (4-Hydroxy-2- {5'-methyl-1 ', 3', 4'-triazol-2'-ylamino] -ureido-p-hydroxy-benzyl penicillin sodium.

Example 26

[3-(4-하이드록시-2-(4'-피리미디닐메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-hydroxy-2- (4'-pyrimidinylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

Example II / The reaction product of 840 mg (0.002 mol) of amoxicillin trihydrate and 420 mg of 5-amino-4-hydroxy-2- (4'-pyrimidinylmethylamino) -pyrimidine was used as a starting material. Prepare the title penicillin in a similar manner to 7.

Yield: Sodium 780 mg (62%);

lR Spectrum: 1770,1650,1610,1555 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 3.9 (s, 1H), 4.5 (Broad s, 2H), 5.35 (q, 2H + s, 1H), 6.7 (d , 2H), 7.2 (d, 2H), 7.4 (d, 1H), 8.0 (s, 1H), 8.7 (s, 2H), 9.0 (s, 1H)

Example 27

[3-(4-하이드록시-2-(5'-아미노설포닐-2'-티에닐메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- (5'-aminosulfonyl-2'-thienylmethylamino} -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

Amoxicillin trihydrate 766 mg (0.00183 mol) and 5-amino-4-hydroxy-2- (2'-thienylmethylamino) -pyrimidine 500 mg (0.00166 mol) with N, N-diethyltrimethylsilylamine Using the reaction product of 5 ml and 164 mg (0.00166 mole) of phosgene as starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: 185 mg (16%) of sodium salt;

l Spectrum: 1600,1660,1765cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 4.1 (s, 1H), 4.6 (broad s, 2H), 5.4 (d, 1H), 6.7 (d, 2H), 7.9 (d, 1H), 7.2 (d, 2H), 7.4 (d, 1H), 8.05 (s, 1H).

Example 28

[3-(4-하이드록시-2-(2'-메틸-5'-피리미디닐메틸아미노}-5-피리미디닐)-우레이도]-P 하이드록시 벤질 페니실린 나트륨염.D-

[3- (4-hydroxy-2- (2'-methyl-5'-pyrimidinylmethylamino} -5-pyrimidinyl) -ureido] -P hydroxy benzyl penicillin sodium salt.

990 mg (0.00235 mol) of amoxicillin trihydrate, and 500 mg (0.00215 mol) of 5-amino-4-hydroxy-2- (2'-methyl-5'-pyrimidinylmethylamino) -pyrimidine and N, N-dimethyl The title penicillin is prepared in a similar manner to Examples II / 7 using 5 ml of trimethylsilylamine and 213 mg of phosgene as starting materials.

Yield: 265 mg of sodium salt (19%);

IR spectrum: 1765, 1660 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 2.5 (s, 3H), 3.95 (s, 1H), 4.4 (s, 2H), 5.4 (m, 3H), 6.7 (d, 2H), 7.15 (d, 2H), 8.05 (s, 1H), 8.6 (s, 2H).

Example 29

[3-(4-하이드록시-2-(2'-피리미아미노}-5-피리미디닐)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- (2'-pyriaminoamino) -5-pyrimidinyl) -ureido] -P-hydroxy benzylphenicillin sodium salt.

1.85 g (0.0044 mole) of amoxicillin trihydrate and 0.81 g (0.004 mole) of 5-amino-4-hydroxy-2- (2'-pyridylamino) -pyrimidine and 10 ml of N, N-dimethyl-trimethylsilylamine The title penicillin is prepared in a similar manner as in Example II / 7, using the reaction product as a starting material with 396 mg of phosgene and 0.56 ml of triethylamine.

Yield: 0.9 g (37%) of sodium salt;

IR spectrum: 1765, 1660, 1600 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 4.0 (s, 1H), 5.4 (m, 3H), 6.8 (d, 2H), 7.2 (m, 4H), 7.7 (m, 2H), 8.3 (m, 2H).

Example 30

[3-(4-하이드록시-2-(6'-하이드록시-3'-피리디닐아미노)-우레이도]-P-하이드록시 벤질페니실린 나트륨염.D-

[3- (4-hydroxy-2- (6'-hydroxy-3'-pyridinylamino) -ureido] -P-hydroxy benzylphenicillin sodium salt.

0.879 g (0.0021 mol) of amoxicillin trihydrate and 438 mg (0.002 mol) of 5-amino-4-hydroxy-2- (6'-hydroxy-3'-pyridylamino) -pyrimidine and N, N-di The title penicillin is prepared in a similar manner as in Example II / 7, using 12 ml of ethyltrimethylsilylamine and 216 mg of phosgene as starting materials.

Yield: sodium salt 0.311 g (25%);

IR spectrum: 1765, 1665, 1610 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 4.1 (s, 1H), 5.4 (Broad, m, 3H), 6.4 (d, 1H), 6.75 (d, 2H) , 7.25 (d, 2H), 7.6 (d, 1H), 7.9 (s, 1H), 8.15 (s, 1H).

Example 31

[3-(4-하이드록시-2-(6'-하이드록시-2'-피리딜아미노}-5'-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-hydroxy-2- (6'-hydroxy-2'-pyridylamino} -5'-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

420 mg (0.001 mol) of amoxicillin trihydrate and 220 mg (0.001 mol) of 5-amino-4-hydroxy-2- (6'-hydroxy-2'-pyridylamino) -pyrimidine and N, N-diethyl Using the reaction product of 2 ml of trimethylsilylamine and 100 mg of phosgene as starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: 264 mg (42%) of sodium salt;

IR spectrum: 1765, 1660, 1020 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 4.05 (s, 1H), 5.35 (q, 2H), 5.45 (s, 1H), 6.45 (d, 1H), 6.75 (d, 2H), 7.25 (d, 2H), 7.6 (d, 1H), 7.9 (s, 1H), 8.20 (s, 1H).

Example 32

[3-(4-하이드록시-2-(2'-하이드록시-5'-피리미디닐아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-Hydroxy-2- (2'-hydroxy-5'-pyrimidinylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

800 mg (0.0019 mol) of amoxicillin trihydrate, and 420 mg (0.0019 mol) of 5-amino-4-hydroxy-2- (2'-hydroxy-5'-pyrimidylamino) -pyrimidine and N, N-diethyl Using the reaction product of 4 ml of trimethylsilylamine and 190 mg of phosgene as starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: 550 mg (46%) of sodium salt;

IR spectrum: 1770, 1655, 1610 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.1 (s, 1H), 5.45 (m, 3H), 6.75 (d, 2H), 7.25 (d, 2H), 8.35 (s, 1 H), 8.75 (s, 2 H).

Example 33

[3-(4-하이드록시-2-(6'-메틸설피닐-3'-피리딜아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-Hydroxy-2- (6'-methylsulfinyl-3'-pyridylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

1 g (0.0024 mol) of amoxicillin trihydrate, and 580 mg (0.00218 mol) of 5-amino-4-hydroxy-2- (6'-methylsulfinyl-3'-pyridylamino) -pyrimidine and N, N-di Using the reaction product of 10 ml of ethyltrimethylsilylamine and 216 mg of phosgene as starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: 0.39 g (27%) sodium salt;

IR spectrum: 1770, 1650, 1020 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 2.7 (s, 3H), 4.0 (s, 1H), 5.4 (m, 3H), 6.65 (d, 2H), 7.2 (d, 2H), 7.7 (d, 1H), 8.25 (s, 1H), 8.5 (m, 1H), 8.9 (s, 1H).

Example 34

[3-(4-하이드록시-2-(6'-메틸설포닐-3'-피리딜아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-hydroxy-2- (6'-methylsulfonyl-3'-pyridylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

570 mg (0.00136 mol) of amoxicillin trihydrate, and 350 mg (0.00124 mol) of 5-amino-4-hydroxy-2- (6'-methyl-sulfonyl-3'-pyridylamino) -pyrimidine and N, N- Using the reaction product of 5 ml of diethyltrimethylsilylamine and 123 mg of phosgene as starting material, the title penicillin was prepared in a similar manner as in Example II / 7.

Yield: sodium salt 300 mg (35%);

IR spectrum: 1765, 1660, 1380, 1155 cm ⁻¹ ;

NMR Spectrum (CD ₃ OD) Signal (ppm): 1.5 (d, 6H), 3.1 (s, 3H), 4.0 (s, 1H), 5.4 (m, 3H), 6.65 (d, 2H), 7.2 (d , 2H), 7.9 (d, 1H), 8.3 (s, 1H), 8.6 (d, 1H), 8.9 (s, 1H).

Example 35

[3-(2-{5'-아미노카보닐-2'-티에닐아미노}-4-하이드록시-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (2- {5'-Aminocarbonyl-2'-thienylamino} -4-hydroxy-5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

A reaction product of 840 mg (0.001 mol) of amoxicillin trihydrate and 250 mg (0.001 mol) of pyrimidine of Example I / lao was prepared in a similar manner as in Example II / 7.

Yield: Sodium salt 340 mg (51%);

IR spectrum: 1765, 1655, 1610, 1140 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.0 (s, 1H), 5.45 (m, 3H), 6.6 (d, 1H), 6.75 (d, 2H), 7.25 (d, 2H), 7.45 (d, 1H), 8.35 (s, 1H).

Example 36

[3-(4-하이드록시-2-{5'-테트라졸릴-메틸아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {5'-tetrazolyl-methylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

Prepared in a similar manner to Example II / 7 using pyrimidine of Example I / lap).

Yield: 46%

IR spectrum: 1765, 1650, 1605 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.05 (s, 1H), 4.45 (s, 2H), 5.40 (q, 2H), 5.50 (s, 1H), 6.75 (d, 2H), 7.25 (d, 2H), 8.10 (s, 1H).

Example 37

[3-(4-하이드록시-2-{2',6'-디하이드록시-4'-피리미디닐-아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {2 ', 6'-dihydroxy-4'-pyrimidinyl-amino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin Sodium salt.

Synthesis was carried out in a similar manner to Example II / 7 using pyrimidine and amoxicillin of Example I / las).

Yield: 54.5%

IR spectrum: 1765, 1660, 1605 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.0 (s, 1H), 5.45 (q, 2H + s, 1H), 6.75 (d, 2H), 7.3 (d, 2H), 8.35 (s, 1 H), 8.55 (s, 1 H).

Example 38

[3-(4-하이드록시-2-{2',4'-디하이드록시-5'-피리미디닐아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질 페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {2 ', 4'-dihydroxy-5'-pyrimidinylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzyl penicillin sodium salt.

The pyrimidine and amoxicillin of Example I / laq) were synthesized in a similar manner as in Example II / 7.

Yield: Sodium salt 39%

IR spectrum: 1765, 1655, 1600 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.10 (s, 1H), 5.40 (q, 2H), 5.50 (s, 1H), 6.70 (d, 2H), 7.25 (d, 2H), 8.35 (s, 1H), 8.70 (s, 1H).

Example 39

[3-(4-하이드록시-2-{4',6'-디하이드록시-2'-피리미디닐아미노}-5-피리미디닐)-우레이도]-P-하이드록시-벤질페니실린 나트륨염.D-

[3- (4-Hydroxy-2- {4 ', 6'-dihydroxy-2'-pyrimidinylamino} -5-pyrimidinyl) -ureido] -P-hydroxy-benzylphenicillin sodium salt.

Amoxicillin and the aminopyrimidine of Example I / lar) are synthesized in a similar manner to Examples II / 7 using starting materials.

Yield: 42.5%

IR spectrum: 1765, 1660, 1610 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.55 (d, 6H), 4.05 (s, 1H), 5.45 (m, 3H), 6.70 (d, 2H), 7.25 (d, 2H), 8.30 (s, 1 H), 8.85 (s, 1 H).

Example 40

[3-(4-하이드록시-2-(2'-티에닐-메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시페닐아세트아미도}-페니실라네이트.Vivaloyloxymethyl 6- {D-

[3- (4-Hydroxy-2- (2'-thienyl-methylamino) -5-pyrimidinyl) -ureido] -P-hydroxyphenylacetamido} -penicilanate.

1.28 g (0.002 mol) of the compound of Example II / 10 are suspended in 10 ml of acetone. To the resulting suspension is added a solution of 340 mg (0.0022 mol) of pivaloyloxymethyl chloride in 10 ml of acetone and 0.2 ml of a 25% solution of sodium iodide in water. The mixture is cooled for 5 hours, cooled and mixed with 15 ml of ice water. After decantation, the precipitated greasy product was mixed again with 10 ml of ice water and stirred for 5 minutes. The mixture is then extracted and the colorless product is dissolved in ethyl acetate, washed with water, sodium bicarbonate solution and again with water and dried in vacuo.

Yield: 950 mg (66%);

IR spectrum: 1770, 1720, 1650 cm ⁻¹ ;

NMR Spectrum (CDl ₃ + CD ₃ OD) Signal (ppm): 1.2 (s, 9H), 1.55 (d, 6H), 4.2 (s, 1H), 4.4 (s, 2H), 5.45 (q, 2H), 5.5 (s, 1H), 5.65 (q, 2H), 6.7 (d, 2H), 6.85 (m, 2H), 7.30 (d, 2H), 7.40 (m, 1H), 8.1 (s, 1H).

In a similar manner, the following compounds are synthesized:

1'-propionyloxyethyl 6- {D-α- [3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy -Phenylacetamido} -peniclanate;

6- {D-α- [3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy- to 1'-acetoxy Phenylacetamido} -peniclanate;

Pivaloyloxymethyl 6- {D-α- [3- (4-hydroxy-2- (5'-chloro-2'-thienylmethyl amino) -5-pyrimidinyl) -ureido] -P -Hydroxy-phenylacetamido} -peniclanate.

Example 41

-[3-(4-하이드록시-2-(2'-푸릴메틸-아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-페니실라네이트.Pivaloyloxy methyl 6- {D-

-[3- (4-Hydroxy-2- (2'-furylmethyl-amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -penicilanate.

625 mg (0.001 mol) of the compound of Example II / 15 and 170 mg of pivaloyloxymethyl chloride were synthesized in a similar manner as in Example II / 40.

Yield: 420 mg (69%);

IR spectrum: 1770, 1715, 1650 cm ⁻¹ ;

NMR spectrum (CDCl ₃ + CD ₃ OD) signal (ppm): 1.2 (s, 9H), 1.55 (d, 6H), 4.3 (s, 1H), 4.5 (broad s, 2H), 5.4 (q, 2H) + s, 1H), 5.65 (q, 2H), 6.3 (m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.45 (s, 1H), 8.1 (s, 1H).

Example 42

-[3-(4-하이드록시-2-(5'-아미노설포닐)-2'-티에닐메닐아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-페니실라네이트.Pivaloyloxy methyl 6- {D-

-[3- (4-hydroxy-2- (5'-aminosulfonyl) -2'-thienylmenylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido } -Penicylanate.

The sodium salt of Example II / 27 and pivaloyloxymethyl chloride were synthesized in a similar manner to Example II / 40 using starting materials.

Yield: 74%

IR spectrum: 1770, 1700, 1660 cm ⁻¹ ;

NMR spectrum (CDCl ₃ + CD ₃ OD) Signal (ppm): 1.2 (s, 9H), 1.55 (d, 6H), 4.25 (s, 1H), 4.6 (s, 2H), 5.4 (m, 3H) , 5.70 (q, 2H), 6.7 (d, 2H), 6.9 (d, 1H), 7.45 (d, 1H), 8.05 (s, 1H).

Example 43

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-티리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-페니실라네이트.Pivaloyloxy methyl 6- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-tyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -penicilanate.

The sodium salt of Example II / 5 and pivaloyloxymethyl chloride were prepared in a similar manner to Example II / 40 using starting materials.

Yield: 58%

IR spectrum: 1770, 1710, 1650, 1600 cm ⁻¹ ;

NMR spectrum (CD ₃ OD) signal (ppm): 1.15 (s, 9H), 1.60 (d, 2H), 4.20 (s, 1H), 4.55 (s, 2H), 5.45 (m, 3H), 5.70 ( q, 2H), 6.70 (d, 2H), 7.20 (m, 3H), 7.6 (m, 1H), 8.05 (s, 1H), 8.35 (m, 2H).

III. Preparation of Cephalosporin According to Formula (I) or (I ')

Example 1

-[3-(4-하이드록시-2-(3'-피리딜 아미노)-5-피리미디닐)-우레이도]-P-하이드록시페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxyphenylacetamido} -3-acetoxymethyl-sef- 3-m-4-carboxylate

1.96 g (0.005 mole) of ureidocarboxylic acid obtained according to Example I / 2b was combined with 2.1 g (0.005 mole) of benzohydryl 7-amino-3-acetoxy-methyl-sef-3-m-4-carboxylate. Together in 50 ml of methylene chloride and 10 ml of dimethylformamide. To the solution was added 1.15 g (0.0055 mol) of dicyclohexyl carbodiamide under ice cooling and the solution was stirred at 5 ° C. for 8 hours. The urea obtained is filtered off and the mixture is evaporated to dryness in vacuo. A quick chromatography (eluent: methylene chloride / methanol 12: 1) is carried out on a silica gel column to remove small amounts of impurities. 3.4 g (82%) of benzhydryl are obtained.

The resulting product is dissolved in a small amount of methylene chloride and stirred under ice cooling with 2 ml of anisole and 10 ml of trifluoroacetic acid. Subsequently, 50 ml of toluene is added twice while the mixture is evaporated to dryness in vacuo. The obtained product is mixed with ether, suction filtered and separated. A calculated amount of sodium ethylhexanoate and ether in methanol is added to precipitate the sodium salt, extracted and dried in vacuo.

Yield of sodium salt: 2.50 g (92%);

IR spectrum: 1765, 1660, 1615, 1550 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.1 (s, 3H), 3.45 (q, 2H), 4.85 (q, 2H + d, 1H), 5.55 (s, 1H), 5.60 (d , 1H), 6.75 (d, 2H), 7.25 (d, 2H), 7.4 (m, 1H), 8.3 (m, 3H), 8.7 (s, 1H).

Example 2

-[3-(4-하이드록시-2-(3'-피리딜 아미노)-5-피리미디닐)-우레이도]-P-하이드록시 페닐아세트아미도}-3-[1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxy phenylacetamido} -3- [1-methyl-tetra Zol-5-yl) -thiomethyl] -cep-3-m-4-car-carboxylate

3.94 g (0.01 mole) of ureidocarboxylic acid of Example I / 2b) was prepared in a similar manner to that described in Example III / 1, with benzohydryl 7-amino-3-[(1 [methyl-tetrazol-5-yl React with 4.94 g (0.01 mol) of) -thiomethyl] -sef-3-m-4-carboxylate. After removal of the protecting group, 4.85 g (65%) of sodium salt are obtained.

IR spectrum: 1765, 1660, 1610, 1540 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 3.50 (q, 2H), 3.90 (s, 3H), 3.90 (s, 3H), 4.30 (partly shielded by q, 2H, LM) , 4.80 (d, 1H), 5.50 (s, 1H), 5.70 (d, 1H), 6.75 (d, 2H), 7.35 (d, 2H), 7.4 (m, 1H), 8.3 (m, 3H), 8.75 (s, 1 H).

Example 3

-[3-(4-하이드록시-2-(3'-피리딜 아미노)-5-피리미디닐)-우레이도]-P-하이드록시페닐-아세트아미도}-3-[(2-메틸-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxyphenyl-acetamido} -3-[(2-methyl -Thiadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

790 mg (0.002 mol) of ureidocarboxylic acid of Example I / 2b) and benzohydryl 7-amino-3-[(2-methyl-thiadiazol-5-yl) -thiomethyl] -3-shep-m- 1.02 g (0.002 mol) of 4-carboxylate are reacted similarly to Example III / 1. After removal of the protecting group 540 mg (39%) of sodium salt are obtained.

IR spectrum: 1760, 1655, 1615, 1540 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 2.7 (s, 3H), 3.50 (q, 2H), 4.45 (q, 2H), 4.90 (d, 1H), 5.50 (s, 1H), 5.65 (d, 1H), 6.75 (d, 2H), 7.3 (d, 2H), 7.4 (m, 1H), 8.3 (m, 3H), 8.75 (s, 1H).

Example 4

-[3-(4-하이드록시-2-(3'-피리딜 아미노)-5-피리미디닐)-우레이도]-2-티에닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D, L-

-[3- (4-Hydroxy-2- (3'-pyridyl amino) -5-pyrimidinyl) -ureido] -2-thienylacetamido} -3-[(1-methyl-tetra Zol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

The title cephalosporin was reacted in a similar manner to Example III / 1 using 1.11 g (0.0029 mol) of ureidocarboxylic acid of Example I / 2d) and benzohydryl esder used in Example III / 2 as starting materials. To obtain. After protection group removal, 920 mg (48%) of sodium salt are obtained.

IR spectrum: 1760, 1660, 1610, 1540 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 3.55 (q, 2H), 3.90 (s, 3H), 4.35 (q, 2H), 4.90 (dd, 1H), 5.5 (dd, 1H), 5.75 (broad s, 1H), 6.9 (m, 2H), 7.35 (d, 2H), 8.25 (m, 3H), 8.75 (s, 1H).

In a similar manner, the following compounds are synthesized.

Sodium 7- {D-α- [3- (4-hydroxy-2- (6'-methoxy-3'-pyridyl) -5-pyrimidinyl) -ureido-p-hydroxy-phenylacet Amido} -3-[(1-methyl-detrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Example 5

-[3-(4-하이드록시-2-(2'-티에닐 메틸)-5-피리미디닐)-우레이도]-P-하이드록시페닐-아세트아미도}-3-[(1,2,4-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienyl methyl) -5-pyrimidinyl) -ureido] -P-hydroxyphenyl-acetamido} -3-[(1,2 , 4-thiadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2g) 415 mg (0.001 mol) of ureido carboxylic acid and benzohydryl 7-amino-3-[(1,2,4-thiadiazol-5-yl) -thiomethyl] -cell-3- 500 mg (0.001 mol) of m-4-carboxylate were used as starting materials and reacted in a similar manner to Example III / 1 to obtain the title cephalosporin. After digestion of the protecting group, 410 mg (35%) of sodium salt are obtained.

IR spectrum: 1760, 1660, 1615, 1540 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 3.50 (q, 2H), 4.50 (m, 4H), 4.95 (d, 1H), 5.50 (s, 1H), 5.60 (d, 1H), 6.75 (d, 2H), 6.85 (m, 2H), 7.25 (d, 2H), 7.4 (m, 1H), 8.1 (s, 1H).

Example 6

-[3-(4-하이드록시-2-(5'-에톡시카보닐-2-티에닐아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-ethoxycarbonyl-2-thienylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido}- 3-acetoxymethyl-cep-3-m-4-carboxylate

4.70 g (0.01 mol) of the ureidocarboxylic acid of Example I / 2f) and 4.20 g (0.01 mol) of the cephalosforum derivative used in Example III / 1 were used as starting materials, in a similar manner to Example III / 1. Obtain the title cephalosporin. 3.95 g (51%) of sodium salt are obtained after protecting group separation.

l Spectrum: 1760, 1655, 1610, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.3 (t, 3H), 2.05 (s, 2H), 4.30 (q, 2H), 4.85 (m, 2 + 1H), 5.4 (s, 1H) , 5.6 (d, 1H), 6.8 (d, 1H), 7.35 (d, 2H), 7.9 (m, 2H), 8.05 (s, 1H).

Example 7

-[3-(4-하이드록시-2-(2'-티에닐메틸 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐 아세트아미도}-3-[(2-메틸-1,3,4-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenyl acetamido} -3-[(2- Methyl-1,3,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

580 mg (0.0014 mol) of ureidocarboxylic acid of Example I / 2 g) and 720 III mg (0.0014 mol) of cephalosporin used in Example III / 3 were prepared similarly to Example III / 1. 500 mg (46%) of sodium salt are obtained after separation of the benzhydryl group.

l Spectrum: 1760, 1660, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.75 (s, 3H), 3.55 (q, 2H), 4.25 (partly shielded by q, 2H, LM), 4.5 (Broad s, 2H) , 5.0 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.6-7.4 (m, 7H), 8.1 (s, 1H).

Example 8

-[3-(4-하이드록시-2-(3'-피리딜 아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-[(1-메틸-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-[(1-methyl-thiadia Zol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Prepared similarly to Example III / 1 by reacting 775 mg (0.002 mol) of ureidocarboxylic acid of Example I / 2c) with 1.0 g (0.0021 mol) of cephalosporin benzohydryl ester used in Example III / 2 do.

730 mg (46%) of sodium salt are obtained after separation of the benzhydryl group.

l Spectrum: 1770, 1655, 1615, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 3.90 (s, 3H), 4.35 (q, 2H), 4.95 (d, 1H), 5.45 (d, 1H), 5.75 (s, 1H), 6.4 (m, 2H), 7.4 (m, 1H), 7.6 (broad s, 1H), 8.25 (m, 3H), 8.8 (broad s, 1H).

Example 9

-[3-(4-하이드록시-2-(5'-에톡시 카보닐 2'-티에닐)-5-피리미디닐)-우레이도]-P-하이드록시-페닐-아세트아미도}-3-[(1-메틸-티아디아졸-5-일)-티오 메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-ethoxy carbonyl 2'-thienyl) -5-pyrimidinyl) -ureido] -P-hydroxy-phenyl-acetamido}- 3-[(1-Methyl-thiadiazol-5-yl) -thio methyl] -sef-3-m-4-carboxylate

In a similar manner in Example III / 1, 470 mg (0.001 mol) of ureidocarboxylic acid of Example I / 2f) are reacted with 500 mg (0.001 mol) of benzohydryl ester used in Example III / 2. After removal to the benzohydryl protecting group, 400 mg (53.5%) of sodium salt are obtained.

l Spectrum: 1760, 1655, 1615, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.3 (t, 3H), 3.4 (q, 2H), 3.9 (s, 3H), 4.35 (m, 4H), 4.85 (d, 1H), 5.40 (s, 1H), 5.55 (d, 1H), 6.7 (d, 2H), 7.35 (d, 2H), 7.85 (m, 2H), 8.25 (s, 1H).

Example 10

-[3-(4-하이드록시-2-(2'-푸릴메틸 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-메틸-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2-methyl -Thiadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

1.12 g (0.0028 mol) of ureidocarboxylic acid of Example I / 2j) and benzohydryl 7-amino-3-[(2-methyl-thiadiazol-5-yl) -thiomethyl] -sef-3-m 1.53 g (0.003 mol) of 4-carboxylate are synthesized in a similar manner to Example III / 1 as a starting material.

Yield of sodium salt: 760 mg (36%)

l Spectrum: 1770, 1660, 1610, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.75 (s, 3H), 3.45 (q, 2H), 4.45 (m, 4H), 4.95 (d, 1H), 5.40 (s, 1H), 5.60 (d, 1H), 6.3 (m, 2H), 6.85 (d, 2H), 7.35 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H).

Example 11

-[3-(4-하이드록시-2-(2'-푸릴메틸 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-acetoxymethyl-cef -3-m-4-carboxylate

1.21 g (0.01 mol) of N, N-dimethylaniline is added to a solution of 3.99 g (0.1 mol) of ureidocarboxylic acid of Example I / 2j) in 30 ml of anhydrous methylene chloride and 30 ml of dimethylformamide. The solution is cooled to −15 ° C. and at this temperature a solution of 1.1 g (0.01 mol) of ethyl chloroformate in 5 ml of methylene chloride is added. The resulting mixture is kept at the same temperature for 45 minutes. 3 g of N, O-bis-trimethylsilylacetamido is added to a suspension of 2.72 g (0.01 mol) of 7-aminocephalosporranic acid in 80 ml of anhydrous acetonitrile to obtain a solution. The resulting solution is cooled to -20 ° C and added to the solution. The mixture is then reacted at −10 ° C. for 60 minutes and at 10 ° C. for 60 minutes. 5 ml of ethanol are then added and the insoluble material is filtered off. After the solvent was removed in vacuo, the residue was dissolved in 100 ml of water and the pH of the solution was adjusted to 7.5. Shake twice with ethyl acetate at the same pH and discard the organic phase. The pH of the aqueous phase is adjusted to 2.9 with dilute hydrochloric acid under decay and the precipitated product is extracted, washed with a small amount of water and dried in vacuo. The aqueous solution is shaken twice with ethyl acetate, the ethyl acetate phase is dried and the solvent is distilled in vacuo. The same secondary product as the first product obtained is obtained.

The two solid products are combined and dissolved in 80 ml of absolute methanol with a calculated amount of sodium ethylhexanoate. The insoluble product is filtered off and ether is added until the precipitate is completely formed. The precipitated solid product is extracted and dried.

Yield: 3.60 g (53%)

l Spectrum: 1765, 1655, 1615, 1645 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.45 (q, 2H), 4.5 (s, 2H), 4.80 (q, 2H + d, 1H), 5.50 (s, 1H), 5.56 (d, 1H), 6.35 (m, 2H), 6.75 (d, 2H), 7.30 (d, 2H), 7.45 (s, 1H), 8.05 (s, 1H).

Example 12

-[3-(4-하이드록시-2-(2'-피리딜 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-카바모일옥시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-carbamoyloxymethyl- Sep-3-M-4-carboxylate

Example using starting material of 1.32 g (0.005 mol) of 7-amino-3-carbamoyloxymethyl-cep-3-m-4-carboxylic acid and 2.00 g (0.005 mol) of ureidocarboxylic acid of Example I / 2j) It is prepared by a method similar to III / 11.

Yield of sodium: 1.47 g (41%)

l Spectrum: 1765, 1650, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 4.45 (broad, s, 2H), 4.8 (broad, 2H + 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.25 (m, 1H), 6.85 (d, 2H), 7.35 (d, 2H), 7.45 (s, 1H), 7.45 (s, 1H), 8.0 (s, 1H).

Example 13

-[3-(4-하이드록시-2-(2'-푸릴메틸 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2j) 400 mg (0.001 mol) of ureido carboxylic acid and 7-amino [(1-methyl-detrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylic acid 334 mg (0.001 mole) is used as a starting material, and is modified in a similar manner as in Example III / 11.

Yield of sodium salt: 430 mg (58%)

l Spectrum: 1765, 1655, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.50 (q, 2H), 3.95 (s, 3H), 4.45 (q, 2H), 4.50 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H), 5.60 (s, 1H), 6.35 (m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H).

Example 14

-[3-(4-하이드록시-2-(2'-푸릴메틸 아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-메틸아미노티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2-methyl Aminothiadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2j) 800 mg (0.002 mol) of ureido carboxylic acid and 7-amino-3-[(2-methyl-damino-thiadiazol-5-yl) -thiomethyl] -sef-3-m A 720 mg (0.002 mole) of 4-carboxylic acid was used as a starting material, and was modified in a similar manner to Example III / 11.

Yield of sodium salt: 960 mg (62%)

l Spectrum: 1770, 1650, 1615, 1545 cm ^-1

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 3.0 (s, 3H), 3.65 (q, 2H), 4.15 (partially shielded by m, LM = 2H), 4.4 (s, 2H), 5.0 (d, 1H), 5.5 (s, 1H), 5.70 (d, 1H), 6.3 (m, 2H), 6.85 (d, 2H), 7.35 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1 H).

Example 15

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-카바모일옥시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-carbamoyloxymethyl -Cef-3-M-4-carboxylate

Example III using 2.64 g (0.01 mol) of 7-amino-3-carbamoyloxymethyl-ce-3-m-4-carboxylic acid and 4.10 g (0.01 mol) of ureidocarboxylic acid of Example I 2e as starting materials It is prepared by a method similar to / 11.

Yield of sodium salt: 60%

lR Spectrum: 1765, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 4.5 (s, 2H), 4.8 (Broad, 2H + 1H), 5.45 (s, 1H), 5.65 (d, 1H) 6.85 (d, 1H), 7.35 (m, 3H), 7.7 (m, 1H), 8.1 (s, 1H), 8.5 (m, 2H).

Example 16

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Ureido of 985 mg (0.003 mol) of 7-amino-3-[(1-methyl-detrazol-5-yl) -thiomethyl] -sep-3-m-4-carboxylic acid with Example I / 2e) 1.23 g (0.003 mol) of carboxylic acid was prepared in a similar manner to Examples III / 11 using starting material.

Yield of sodium salt: 1.58 g (71%)

l Spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.50 (s, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.35 (m, 3H), 7.75 (m, 1H), 8.1 (s, 1H), 8.5 (m, 2H).

Example 17

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-카바모일-옥시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-carbamoyl-oxy Methyl-sep-3-m-4-carboxylate

1.0 g (0.0038 mole) of cephalosporin derivative of Example III / 15 and 1.6 g (0.00385 mole) of ureidocarboxylic acid of Example I / 2 g were prepared in a similar manner to Example III / 11.

Yield of sodium salt: 1.33 g (50.5%);

l Spectrum: 1765, 1655, 1605, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 4.55 (Broads, 2H), 4.85 (m, 2 + 1H), 5.45 (s, 1H), 5.65 (d, 1H ), 6.65 (d, 2H), 6.80 (m, 2H), 7.30 (d, 2H), 7.45 (m, 1H), 8.05 (s, 1H).

Example 18

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(tetrazol -5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Example I / 2g) 415 mg (0.001 mol) of ureidocarboxylic acid and 315 mg (0.001 mol) of 7-amino-3- (tetrazol-5-yl) -thiomethyl-sef-3-m-4-carboxylic acid Was prepared as a starting material, in a manner similar to that of Example III / 11. 385 mg (52%) of sodium salt is obtained.

l Spectrum: 1765, 1655, 1615, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.4 (q, 2H), 4.35 (q, 2H), 4.5 (s, 2H), 4.85 (d, 1H), 5.40 (s, 1H), 5.55 (d, 1H), 6.75 (d, 2H), 6.85 (m, 2H), 7.30 (d, 2H), 7.45 (m, 1H), 8.05 (s, 1H).

Example 19

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2g) ureidocarboxylic acid 830 mg (0.002 mol) and 7-amino-3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sep-3-m-4-carboxylic acid 656 mg (0.002 mole) is used as a starting material, and is modified in a similar manner as in Example III / 11.

Yield of sodium salt: 940 mg (63%)

l Spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.50 (s, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (m, 2H), 6.95-7.4 (m, 5H), 8.05 (s, 1H).

Example 20

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-메틸-옥사디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2- Methyl-oxadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

2.08 g (0.005 mol) of ureidocarboxylic acid of Example I / 2g) and 7-amino-3-[(2-methyl-1,3,4-oxadiazol) -5-yl-thiomethyl] -sef- The title cephalosporin is prepared in a similar manner to Example III / 11, using 1.65 g (0.005 mole) of 3-m-4-carboxylate as starting material.

Yield of sodium salt: 2.22 g (59%);

IR spectrum: 1765, 1650, 1610, 1540 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 2H), 4.2 (q, (2H)), 4.45 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H) , 5.60 (d, 1 H), 6.75 (d, 2 H), 6.85 7.4 (m, 5 H), 8.05 (s, 1 H).

Example 21

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-m,P-디하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -m, P-dihydroxy-phenylacetamido} -3- [ (1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2g) of 2.15 g (0.005 mol) of ureidocarboxylic acid and 1.64 g (0.005 mol) of cephalosporin derivatives used in Examples III / 19 were prepared in a similar manner to Examples III / 11. do.

Yield of sodium salt: 2.49 g (65%);

IR spectrum: 1765, 1660, 1605, 1545 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 2.05 (q, 2H), 3.90 (q, 3H), 4.30 (q, 2H, partially shielded by LM), 4.50 (s, 2H), 4.80 (d, 1H), 5.50 (s, 1H), 5.70 (d, 1H), 6.7 (d, 1H), 7.0 (m, 4H), 7.35 (m, 1H), 8.1 (s, 1H).

Example 22

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴-아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -2-furyl-acetamido} -3-acetoxymethyl-sef- 3-m-4-carboxylate

Example I / 2L) of ureidocarboxylic acid 390 mg (0.001 mol) and 7-aminocephalosporanic acid 272 mg (0.001 mol) were prepared in a similar manner as in Example III / 11.

Yield of sodium salt: 390 mg (54%);

IR spectrum: 1765, 1660, 1610, 1540 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.1 (s, 3H), 3.45 (q, 2H), 4.5 (s, 2H), 4.85 (d, 1H + q, 2H), 5.5 (d, 1H), 5.85 (s, 1H), (.3 (m, 2H), 7.0 (m, 2H), 7.3 (m, 1H), 7.5 (s, 1H), 8.1 (s, 1H).

Example 23

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴-아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -2-furyl-acetamido} -3-[(1-methyl- Tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

780 mg (0.002 mol) of ureidocarboxylic acid of Example I / 2 L) and 655 mg (0.002 mol) of cephalosporan derivative used in Examples III / 19 were prepared in a similar manner to Examples III / 11.

Yield of sodium salt: 650 mg (46%);

IR spectrum: 1770, 1665, 1620, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.45 (q, 2H), 3.90 (s, 3H), 4.35 (q, 2H), 4.50 (s, 2H), 4.9 (d, 1H), 5.5 (d, 1H), 5.75 (s, 1H), 6.3 (m, 2H), 7.0 (m, 2H), 7.3 (m, 1H), 7.5 (s, 1H), 8.1 (s, 1H).

In a similar manner, the following compounds are synthesized:

Sodium-7- {D, L-α- [3- (4-hydroxy-2-) 2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetamido } -3-acetoxy-methyl-sef-3-m-4-carboxylate

Example 24

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-2-티에닐아세트아미도-3-아세톡시-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetamido-3-acetoxy-3-m- 4-carboxylate

Example I / 2 m) was prepared in a similar manner to Example III / 11, using 1.21 g (0.003 mol) of ureidocarboxylic acid and 815 mg (0.003 mol) of 7-aminocephalosporanic acid as starting materials.

Yield of sodium salt: 1.44 g (61%);

IR spectrum: 1770, 1665, 1620, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.55 (q, 2H), 4.50 (s, 2H), 4.80 (m, 2 + 1H), 5.45 (d, 1H) , 5.75 (s, 1H), 7.0 (m, 4H), 7.25 (m, 2H), 8.1 (s, 1H).

Example 25

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-2-티에닐아세트아미도}-3-[(1-메틸테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium 7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetamido} -3-[(1-methyltetra Zol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Example 1 / 2m) of ureidocarboxylic acid 1.20 g (0.0029 mol) and 980 mg (0.003 mol) of cephalosporin derivatives used in Examples III / 19 were reacted in a similar manner as in Example III / 11. Obtain the title cephalosporin. 1.28 g (57.5%) of sodium salt are obtained.

IR spectrum: 1770, 1660, 1610, 1540 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 3.90 (s, 3H), 4.35 (q, 2H), 4.50 (s, 2H), 4.90 (d, 1H), 5.5 (d, 1H), 5.75 (s, 1H), 7.0 (m, 4H), 7.25 (m, 2H), 8.10 (s, 1H).

In a similar manner, the following compounds are prepared: Sodium-7- {D-α- [3- (4-hydroxy-2- (3'-thienylmethylamino) -5-pyrimidinyl) -ureido]- P-hydroxy-phenylylacetamido} -3-[(1-phenyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 26

-[3-(4-하이드록시-2-(5'-메틸-2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-methyl-2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3 Acetoxymethyl-sep-3-m-4-carboxylate

Example I / 2h) was prepared in a similar manner to Example III / 11 using 1.72 g (0.004 mol) of ureidocarboxylic acid and 1.09 mg (0.004 mol) of 7-amino cephalosporin as starting materials.

Yield of sodium: 1.55 g (46%);

IR spectrum: 1765, 1655, 1605, 1545 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.1 (s, 3H), 2.4 (s, 2H), 3.55 (q, 3H), 4.50 (s, 2H), 4.80 (m, 2 + 1H) , 5.45 (s, 1H), 5.65 (d, 1H), 6.7 (d, 2H), 6.8 (broth s, 2H), 7.20 (d, 2H), 8.10 (s, 1H).

In a similar manner, the following compounds are prepared: Sodium-7- {D-α- [3- (4-hydroxy-2- (5'-chloro-2'-thienylmethylamino) -5-pyrimidinyl- 3-yl) -ureido] -P-hydroxy-phenylylacetamido} -3-acetoxyphenyl-sef-3-m-4-carboxylate.

Example 27

-[2-(4-하이드록시-2-(5'메틸-2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[2- (4-hydroxy-2- (5'methyl-2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

430 g (0.001 mol) of ureidocarboxylic acid of Example I / 2h) and 328 mg (0.001 mol) of 7-amino-[(1-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid Prepared in a similar manner to Examples III / 11 as starting materials.

Yield of sodium salt: 410 mg (53.5%) is obtained.

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.4 (s, 3H), 3.5 (s, 3H), 4.40 (q, 2H), 4.50 (s, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.7 (d, 2H), 6.8 (broth s, 2H), 7.25 (d, 2H), 8.10 (s, 1H).

Example 28

-[3-(4-하이드록시-2-(5'-클로로-2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-chloro-2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3 -[(1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

450 g (0.001 mol) of ureidocarboxylic acid of Example I / 2i) and 328 mg (0.001 mol) of 7-amino-[(1-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid Prepared in a similar manner to Examples III / 11 as starting materials.

Yield of sodium salt: 540 mg (61.5%) is obtained.

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.50 (s, 2H), 4.85 (q, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.7-7.0 (m, 2H), 7.25 (d, 2H), 8.10 (s, 1H).

Example 29

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,2,3-트리아졸-4-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1,2 , 3-triazol-4-yl) -thiomethyl] -cep-3-m-4-carboxylate

3.99 g (0.01 mol) of ureidocarboxylic acid of Example I / 2j) was prepared in the same manner as in Example III / 11 7-amino-3-[(1,2,3-triazol-4-yl) thiomethyl] React with 3.12 mg (0.01 mol) of cef-3-em-4-carboxylic acid.

4.05 g (57%) of sodium salt are obtained.

IR spectrum: 1770, 1660, 1610, 1540 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.55 (q, 2H), 4.30 (q, 2H), 4.4 (partly shielded by s, 2H LM), 4.85 (d, 1H), 5.50 (s, 1H), 5.70 (d, 1H), 6.3 (m, 2H), 6.75 (d, 2H), 7.25 (d, 2H), 7.5 (s, 1H), 7.75 (s, 1H), 8.10 ( s, 1 H).

Example 30

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,3,4-메틸-티아디아졸-2-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1,3 , 4-Methyl-thiadiazol-2-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example 1 / 2j) 800 g (0.002 mol) of ureidocarboxylic acid and 7-amino-3-[(1,2,3-thiadiazol-2-yl) -thiomethyl] sef-3-m-4- 660 mg (0.002 mol) of carboxylic acid are prepared as starting materials. 810 mg (55%) of sodium salt are obtained.

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.50 (q, 2H), 4.45 (m, 4H), 4.90 (d, 1H), 5.50 (s, 2H), 5.65 (d, 1H), 6.35 (m, 2H), 6.70 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H), 8.55 (s, 1H).

Example 31

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-acetoxymethyl-sep-3- M-4-carboxylate

1.86 g (0.005 mol) of ureidocarboxylic acid of Example I / 2n) and 1.36 g of 7-amino-cephalosporanic acid were reacted in a similar manner to Example III / 11.

1.76 g (54.5%) of sodium salt are obtained.

IR spectrum: 1765, 1650, 1605, 1545 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.55 (q, 2H), 4.4 (s, 2H), 4.85 (m, 2 + 1H), 5.45 (d, 1H) , 5.75 (s, 1H), 6.3 (m, 2H), 8.1 (s, 1H).

Example 32

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-[(1-methyl-tetrazole -5-yl) -thiomethyl] -sef-3-m-4-carboxylate

373 mg (0.001 mol) of ureidocarboxylic acid of Example I / 2n) and 328 mg (0.001 mol) of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ) Is prepared in a similar manner to Example III / 11 using the starting material.

Yield of sodium salt: 420 mg (60%);

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (m, 4H), 4.95 (d, 1H), 5.70 (s, 1H), 6.35 (m, 4H), 7.45 (m, 2H), 8.1 (s, 1H).

Example 33

Sodium-7- {D- -[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetamido} -3-acetoxy-methyl-sef- 3-m-4-carboxylate

1.890 g (0.003 mol) of ureidocarboxylic acid of Example I / 2o) was reacted with 815 g of 7-amino-cephalosfranic acid in a similar manner to Example III / 11 to give 890 mg (45%) of sodium salt.

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.50 (q, 2H), 4.50 (s, 2H), 4.48 (m, 3H), 5.5 (q, 1H), 5.7 (s, 1H), 6.3 (m, 2H), 7.0 (m, 2H), 7.35 (m, 1H), 7.5 (m, 1H), 8.1 (s, 1H).

Example 34

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-2-티에닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetamido} -3-[(1-methyl-tetra Zol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

385 ml (0.001 mol) of ureidocarboxylic acid of Example I / 2o) and 328 mg (0.001 mol) of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ) Is prepared as a starting material, in a similar manner to Examples III / 11.

Yield of sodium salt: 405 mg (53.5%);

IR spectrum: 1765, 1655, 1610, 1550 cm ⁻¹ ;

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 3H), 3.9 (s, 3H), 4.40 (m, 4H), 4.95 (d, 1H), 5.45 (d, 1H), 5.70 (s, 1H), 6.3 (m, 2H), 7.0 (m, 2H), 7.4 (m, 2H), 8.1 (s, 1H).

Example 35

-[3-(4-하이드록시-2-(5'-메틸-2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-methyl-2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

1.65 g (0.004 mol) of ureidocarboxylic acid of Example I / 2p) and 1.32 mg of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ( 0.004 mole) in a similar manner to Examples III / 11 as a starting material.

Yield of sodium salt: 1.82 g (60.5%)

IR spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.5 (s, 3H), 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (m, 4H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.3 (m, 2H), 6.80 (d, 2H), 7.30 (d, 2H), 8.1 (s, 1H).

Similarly, the following compounds are synthesized.

Sodium 7- {D-α- [3- (4-hydroxy-2- (5'-methyl-2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-thienylacetami FIG.}-3-[(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Sodium 7- {D-α- [3- (4-hydroxy-2- (5'-methyl-2'-furylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido } -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 36

-[3-(4-하이드록시-2-(2'-테트라피리딜-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-tetrapyridyl-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [ (1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

403 g (0.001 mol) of ureidocarboxylic acid of Example I / 2q) and 328 mg (0.001 mol) of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ) Is prepared in a similar manner to Example III / 11 using the starting material.

Yield of sodium salt: 426 g (58%)

IR spectrum: 1770, 1655, 1610, 1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.9 (m, 4H), 3.5-4.0 (m, 7H), 3.9 (s, 3H), 4.40 (q, 2H), 4.85 (d, 1H) , 5.45 (s, 1H), 5.65 (d, 1H), 6.70 (d, 2H), 7.20 (d, 2H), 8.0 (s, 1H).

Example 37

-[3-(4-하이드록시-2-(2'-피롤릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-pyrrolylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

800 mg (0.002 mol) of ureidocarboxylic acid of Example I / 2r) and 656 mg (0.002 mol) of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ) Is prepared as a starting material, in a similar manner to Examples III / 11.

Yield of sodium salt: 650 mg (44.5%)

IR spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (m, 4H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.1 (m, 2H), 5.75 (d, 2H), 7.25 (d, 2H), 8.1 (s, 1H).

Similar methods produce the following compounds.

Sodium 7- {D-α- [3- (4-hydroxy-2- (2'-pyrrolinemethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy} -3-acetoxy Methyl-sef-3-m-4-carboxylate.

Example 38

-[3-(4-하이드록시-2-(4'-메틸-2'-아미다졸릴-메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (4'-methyl-2'-amidazolyl-methylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Example I / 2s) of 1.6 g (0.004 mol) of ureidocarboxylic acid and 1.32 g of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ( 0.004 mole) in a similar manner to Examples III / 11 as a starting material.

Yield of sodium salt: 1.55 g (51%)

IR spectrum: 1770, 1655, 1610, 1555 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.1 (s, 3H), 3.5 (s, 3H), 4.40 (m, 4H), 4.90 (d, 1H), 5.45 (s, 1H), 5.70 (d, 1H), 6.85 (d, 2H), 7.35 (m, 4H), 8.05 (s, 1H).

A similar method produces the following compounds.

Sodium 7- {D-α- [3- (4-hydroxy-2- (2'-oxazolylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate;

Sodium 7- {D-α- [3- (4-hydroxy-2- (5'-methyl-2'-triazolyl-methylamino) -5-pyrimidinyl) -ureido] -p-hydroxy -Phenylacetamido} -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 39

-[3-(4-하이드록시-2-(5'-메틸-2'-티에닐아미)-3-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (5'-methyl-2'-thienylami) -3-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- Acetoxymethyl-sef-3-m-4-carboxylate.

2.72 g (0.01 mol) of 7-aminocephalosporranic acid and 4.15 g (0.01 mol) of ureidocarboxylic acid of Example I / 2u were prepared in a similar manner as in Example III / 11.

Yield of sodium salt: 3.73 g (53.5%)

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 2.5 (s, 3H), 3.45 (q, 2H), 4.8 (m, 3H), 5.4 (s, 1H), 5.65 (d, 1H), 6.5 (m, 2H), 6.8 (d, 2H), 7.25 (d, 2H), 8.15 (s, 1H).

Example 40

-[3-(4-하이드록시-2-(5'-메틸-2'-티에닐아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-methyl-2'-thienylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [(1-Methyltetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 1 / 2u) of 2.07 g (0.005 mol) of ureidocarboxylic acid and 1.64 g of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] cep-3-m-4-carboxylic acid ( 0.005 mole) is prepared as a starting material in a similar manner to Examples III / 11.

Yield of sodium salt: 2.2 g (59%)

l Spectrum: 1765, 1655, 1615, 1555 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 3H), 3.45 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.55 (m, 2H), 6.85 (d, 2H), 7.35 (d, 2H), 8.1 (s, 1H).

Example 41

-[3-(4-하이드록시-2-(4'-메틸-2'-티아졸릴아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (4'-methyl-2'-thiazolylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Example I / 2u) 1.0g (0.0024 mol) of ureidocarboxylic acid and 7 mg of 7-amino-[(1-methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylic acid (0.0025 mol) is used as a starting material, and is modified in a similar manner as in Example III / 11.

Yield of sodium salt: 630 mg (35.5%)

l Spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.5 (s, 3H), 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.85 (d, 1H), 5.45 (d, 1H), 6.45 (s, 1H), 6.80 (d, 2H), 7.25 (d, 2H), 8.05 (s, 1H).

In a similar manner, the following compounds are prepared.

-[3-(4-하이드록시-2-(2'-타이졸릴아미노)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트라미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium 7- {D-

-[3- (4-Hydroxy-2- (2'-Tazolylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 42

-[3-(4-하이드록시-2-(6'-메틸설피닐-3'-피리딜아미)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (6'-methylsulfinyl-3'-pyridylami) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido}- 3-acetoxymethyl-cep-3-m-4-carboxylate

The procedure is similar to that of Example III / 11, using 7-aminocephalosporranic acid and the ureidocarboxylic acid of Example I / 2v) as starting materials.

Yield of sodium salt: 440%

l Spectrum: 1760, 1655, 1605, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 2.7 (s, 3H), 3.40 (q, 2H), 4.65 (m, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.60 (d, 1H), 6.70 (d, 2H), 7.2 (d, 2H), 7.7 (d, 1H), 8.25 (s, 1H), 8.45 (m, 1H), 8.85 ( s, 1H).

The cephalosporins of the following table are synthesized according to the method of Example III / 11 using the corresponding cephalosporin derivatives (sodium salt).

Example 71

-[3-(4-하이드록시-2-(3'-피리딜아미노)-5-피리딜아미)-우레이도]-페닐아세트아미도}-3-메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -5-pyridylami) -ureido] -phenylacetamido} -3-methyl-sep-3-m-4- Carboxylate

A suspension of 2.66 g (0.0073 mol) of cephalexin monohydrate in 80 ml of tetrahydrofuran and 20 ml of water is dissolved in triethylamine under ice cooling. 1.48 g (0.0073 mol) of 5-amino-4-hydroxy-2- (3'-pyridylamino) -pyrimidine is dissolved in tetrahydrofuran and mixed with 1 ml of triethylamine, 18 ml of tetrahydrofuran in ice-cold water. To 750 mg of phosgene dissolved in is added. The pH is maintained at 7.5 using triethylamine. The resulting solution is stirred at 5 ° C. for 1 hour and further at room temperature for 1 hour. The tetrahydrofuran is then removed in vacuo, the residue is diluted with 20 ml of water and shaken twice with ethyl acetate. The aqueous phase is then covered with ethyl acetate and slowly adjusted to pH 2.9 with cooling and stirring. The ethyl acetate layer is separated, shaken once again with ethyl acetate in aqueous phase, the two aqueous phases combined and the solvent distilled in vacuo. Sodium salt is prepared according to conventional methods.

Yield: 2.94 (68%)

l Spectrum: 1765, 1655, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.0 (s, 3H), 3.40 (q, 2H), 5.05 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 7.45 (m, 6H), 8.3 (m, 3H), 8.75 (s, 1H).

Using the p-hydroxy analogs of cephalexin as described in Examples III / 71, the following cephalosporins were obtained.

Example 72

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시 페닐 아세트아미도}-3-메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy phenyl acetamido} -3-methyl-sef-3 M-4-carboxylate

Prepared using the reaction product of 5-amino-4-hydroxy-2- (3'-pyridylmethylamino) -pyrimidine with phosgene.

Yield: 71%

lR Spectrum: 1765, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.0 (s, 3H), 3.4 (q, 2H), 4.5 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H), 5.60 (d, 1H), 6.8 (d, 2H), 7.3 (m, 3H), 7.7 (m, 1H), 8.1 (s, 1H), 8.5 (m, 2H).

Example 73

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노-5-피리딜아미)-우레이도]-p-하이드록시페닐아세트아미도}-3-메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino-5-pyridylami) -ureido] -p-hydroxyphenylacetamido} -3-methyl-sep-3-m -4-carboxylate

Prepared using the reaction product of 5-amino-4-hydroxy-2- (3'-pyridylmethylamino) -pyrimidine with phosgene.

Yield: 64%

l Spectrum: 1770, 1660, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.4 (q, 2H), 4.5 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.70 (d, 2H), 6.85 (m, 2H), 7.25 (d, 2H), 7.35 (m, 1H), 8.05 (s, 1H).

Example 74

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시페닐아세트아미도}-3-메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxyphenylacetamido} -3-methyl-sep-3- M-4-carboxylate

Prepared using the reaction product of 5-amino-4-hydroxy-2- (3'-furylmethylamino) -pyrimidine with phosgene.

Yield: 71%

l Spectrum: 1765, 1655, 1610, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.0 (s, 3H), 3.35 (q, 2H), 4.4 (s, 2H), 4.95 (d, 1H), 5.4 (s, 1H), 5.65 (d, 1H), 6.3 (d, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H).

Example 75

-[3-(4-하이드록시-2-(3'-피리딜아미노)-5-피리미디닐)-우레이도]-페닐아세트아미도-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -phenylacetamido-3-acetoxymethyl-sep-3-m-4 Carboxylate

2.03 g (0.01 mol) of 5-amino-4-hydroxy-2- (3'-pyridylamino) -pyrimidine is dissolved in tetrahydrofuran, mixed with 1.35 ml of triethylamine, and then dissolved in tetrahydrofuran under ice-cooling. To a solution of 1.0 g of phosgene. The resulting mixture is reacted with 4.25 g (0.01 mol) of cephaloglycine dihydrate as described in Examples III / 71. The reaction proceeds similarly to Examples III / 71, except that the final desired product is precipitated from water at pH3.0.

Yield: sodium salt 3.16 g (48.5%)

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.45 (q, 2H), 4.85 (m, 3H), 5.45 (s, 1H), 5.65 (d, 1H), 7.45 (m, 6H), 8.25 (m, 3H), 8.75 (s, 1H).

Cephaloglycine dihydrate is used as described in Examples III / 75 to yield the following cephalosporins.

Example 76

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium 7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -phenylacetamido} -3-acetoxymethyl-sep-3-m -4-carboxylate

Prepared using the reaction product of 5-amino-4-hydroxy-2- (2'-thienylmethylamino) -pyrimidine with phosgene.

Yield: 62.5%

l Spectrum: 1765, 1655, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.4 (q, 2H), 4.45 (s, 2H), 4.85 (m, 3H), 5.45 (s, 1H), 5.60 (d, 1H), 6.85 (m, 2H), 7.45 (m, 6H), 8.1 (s, 1H).

Example 77

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium 7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -phenylacetamido} -3-acetoxymethyl-sep-3-m- 4-carboxylate

Prepared using the reaction product of 5-amino-4-hydroxy-2- (2'-furylmethylamino) -pyrimidine with phosgene.

Yield: 64%

l Spectrum: 1770, 1660, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.45 (q, 2H), 4.55 (s, 2H), 4.85 (m, 2 + 1H), 5.45 (s, 1H) , 5.65 (d, 1H), 6.3 (m, 2H), 7.5 (m, 6H), 8.05 (s, 1H).

Example 78

-[3-(4-하이드록시-2-(4'-메틸설피닐-2'-티아졸릴메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트 아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸-세프-3-일-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (4'-methylsulfinyl-2'-thiazolylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacet amido} -3-[(1-Methyl-tetrazol-5-yl) -thiomethyl-sef-3-yl-4-carboxylate

-아미노(p-하이드록시페닐 아세트아미도)]-3-[(1-페틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실산 405㎎(0.001몰) 및 5-아미노-4-하이드록시-2-(4'-페틸-2'-티아졸릴 메틸아미노)-피리미딘 240㎎(0.001몰)의 포스겐 반응 생성물을 출발물질로 하여 실시예 Ⅲ/71과 유사한 방법으로 제조한다. 반응 진행중에 생성된 세팔로스포린은 p2H 2.9에서 물로 부터 침전되며 추추랗여 건조시킨 후, 공지의 방법에 따라 나트륨 염으로 전환시킨다.7- [D-

405 mg (0.001 mol) of -amino (p-hydroxyphenyl acetamido)]-3-[(1-fetyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylic acid and Similar to Example III / 71 with starting product of 240 mg (0.001 mol) of 5-amino-4-hydroxy-2- (4'-petyl-2'-thiazolyl methylamino) -pyrimidine as a starting material It is prepared by the method. The cephalosporin produced during the reaction is precipitated from water in p2H 2.9 and dried in the dark, and then converted to the sodium salt according to a known method.

Yield: 315 mg (45.5%)

l Spectrum: 1765, 1655, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 3H), 3.5 (q, 2H), 3.9 (s, 3H), 4.35 (q, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.15 (s, 1H), 6.85 (d, 2H), 7.35 (d, 2H), 8.05 (s, 1H).

In a similar manner, the following compounds are synthesized.

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-아세톡시-메틸-세프-3-엠-4-카복실레이트;Sodium 7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-acetoxy-methyl-sef- 3-m-4-carboxylate;

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-아세톡시-메틸-세프-3-엠-4-카복실레이트;나트륨 7-{D-

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-3-푸릴아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트; 나트륨 7-{D-

[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-3-아세톡시메틸-세프-3-엠-4-카복-4-카복실레이트.Sodium 7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-acetoxy-methyl-sef- 3-m-4-carboxylate; sodium 7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -3-furylacetamido} -3-acetoxymethyl-ce-3 -M-4-carboxylates; Sodium 7- {D-

[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -3-acetoxymethyl-sef-3-m-4-carboxy-4- Carboxylates.

Example 79

-[3-(4-하이드록시-2-(5'-메틸-2'-티아디아졸릴아미노)5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (5'-methyl-2'-thiadiazolylamino) 5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- [(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

-아미노-P-하이드록시페닐-아세트 아미도]-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실산과 반응시킨다.1.14 g (0.005 mole) of 5-amino-4-hydroxy-2- (5'-methyl-2'-thiadiazolylamino) -pyrimidine is suspended in 50 ml of tetrahydrofuran and trimethylsilyldi until dissolved. Treat with ethylamine. The insoluble material is filtered off under nitrogen, the tetrahydrofuran is distilled off and then evaporated to dryness in high vacuum. The residue product is dissolved in 30 ml of tetrahydrofuran and added to a solution of 500 mg of phosgene in tetrahydrofuran under ice cooling. Subsequently, nitrogen is introduced into the solution to remove unreacted phosgene. Then, 7- [D- in a similar manner to Example III / 49.

React with -amino-P-hydroxyphenyl-acetamido] -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylic acid.

Yield: sodium salt 980 mg (28.5%)

l Spectrum: 1765, 1665, 1605, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 3H), 3.5 (q, 2H), 3.9 (s, 3H), 4.35 (q, 2H), 4.85 (d, 1H), 5.40 (s, 1H), 5.60 (d, 1H), 6.80 (d, 2H), 7.25 (d, 2H), 8.05 (s, 1H).

-[3-(4-하이드럭시-2-(5'-메틸-2'-트리아졸릴아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-데트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.In a similar manner, the following compounds are prepared. Sodium 7- {D-

-[3- (4-Hydroxy-2- (5'-methyl-2'-triazolylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3 -[(1-Methyl-detrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 80

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-acetoxymethyl- Sep-3-M-4-carboxylate

-아미노-P-하이드록시-페닐아세트아미도)-3-아세톡시메틸-세프-3-엠-4-카복실레이트 810㎎(0.002몰) 및 5-아미노-4-하이드록시-2-(2'-티에닐메틸아미노)-피리미딘 440㎎(0.002몰)과 포스겐 200㎎의 반응 생성물을 출발물질로 하여 실시예Ⅲ/71과 유사한 방법으로 표제 세팔로스포린을 제조한다. 이 후의 반응 진행은 실시예 Ⅲ/49와 유사하게 수행한다.Sodium 7- (D-

-Amino-P-hydroxy-phenylacetamido) -3-acetoxymethyl-sef-3-m-4-carboxylate 810 mg (0.002 mol) and 5-amino-4-hydroxy-2- (2 The title cephalosporin is prepared in a similar manner as in Example III / 71 using a reaction product of 440 mg (0.002 mol) of '-thienylmethylamino) -pyrimidine and 200 mg of phosgene as a starting material. Subsequent reaction runs were performed similarly to Examples III / 49.

Yield: 615 mg (44.5%) of sodium salt

l Spectrum: 1765, 1660, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.35 (q, 2H), 4.45 (s, 2H), 4.80 (m, 2 + 1H), 5.45 (s, 1H) , 5.65 (d, 1H), 6.7 (d, 2H), 6.8 (m, 2H), 7.30 (d, 2H), 7.45 (m, 1H), 8.05 (s, 1H).

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-m,p-디하이드록시-페닐아세트아미도]-3-아세톡시메틸-세프-3-엠-4-카복실레이트; 나트륨 7-{D-

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-m,p-디하이드록시-페닐아세트아미도]-3-카바모일옥시메틸-세프-3-엠-4-카복실레이트; 나트륨 7-{D-

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-m,p-디하이드록시-페닐아세트아미도]-3-[(1-메틸-테트라졸-5-일)-테오메틸]-세프-3-엠 4-카복실레이트; 나트륨 7-{D-

-[3-(4-하이드록시-2-(3'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-디하이드록시-페닐아세트아미도]-3-카바모일옥시메틸-세프-3-엠-4-카복실레이트; 나트륨 7-{D-

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-m,p-디하이드록시-페닐아세트아미도]-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트; 나트륨 7-{D-

-[3-(4-하이드록시-2-(5'-니트로-2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도]-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트;In a similar manner, the following compounds are synthesized: Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -m, p-dihydroxy-phenylacetamido] -3-acetoxy Methyl-sef-3-m-4-carboxylate; Sodium 7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -m, p-dihydroxy-phenylacetamido] -3-carbamoyl Oxymethyl-sef-3-m-4-carboxylate; Sodium 7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -m, p-dihydroxy-phenylacetamido] -3-[( 1-methyl-tetrazol-5-yl) -theomethyl] -sef-3-m 4-carboxylate; Sodium 7- {D-

-[3- (4-hydroxy-2- (3'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-dihydroxy-phenylacetamido] -3-carbamoyloxymethyl -Cep-3-m-4-carboxylate; Sodium 7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -m, p-dihydroxy-phenylacetamido] -3-[( 1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate; Sodium 7- {D-

-[3- (4-Hydroxy-2- (5'-nitro-2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido] -3- [(1-Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate;

Example 81

-[3-(4-하이드록시-2-(5'-피리미디닐-아미노)-5-피리미디닐)우레이도]-p-하이드록시-페닐아세트아미도}-3-[(1-메틸테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (5'-pyrimidinyl-amino) -5-pyrimidinyl) ureido] -p-hydroxy-phenylacetamido} -3-[(1- Methyltetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

5-amino-4-hydroxy-2- (5'-thienylmethylamino) -pyrimidine and the cephalosporin derivatives of Examples III / 50 are prepared in a similar manner to Examples III / 42 as starting materials. .

Yield of sodium salt: 260 mg (35.5%)

l Spectrum: 1765, 1655, 1610, 1550 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.40 (q, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.35 (d, 2H), 8.0 (d, 1H), 8.3 (broad s, 2H), 8.8 (s, 1H).

Example 82

-[3-(4-하이드록시-2-(3'-피리딜아미노)-피리미디닐)-우레이도]-p-하이드록시-페닐아세트아미도}-3-[(1,2,3-트리아졸-4-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylamino) -pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1,2,3 -Triazol-4-yl) -thiomethyl] -cep-3-m-4-carboxylate

680 mg of the cephalosporin derivative obtained in Example III / 1 are dissolved in 10 ml of phosphate buffer at pH 6.3. 100 mg of 4-mercapto-1,2,3-triazole is added to the resulting solution, and the mixture is heated to 70 ° C. under nitrogen for 6 hours while maintaining the pH at 6.0 to 6.5. The reaction mixture is then cooled and shaken twice with ethyl acetate. Subsequently, adjust the pH to 2.9 by adding 2N hydrochloric acid while cold red. The precipitated product is extracted, washed with a small amount of water and dried. The residue is converted to sodium salt according to a conventional method to give 460 mg (64%) of sodium salt.

l Spectrum: 1765, 1660, 1615, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 4.25 (q, 2H), 4.90 (d, 1H), 5.45 (s, 1H), 5.60 (d, 1H), 6.8 (d, 2H), 7.25 (d, 2H), 7.4 (m, 1H), 7.95 (s, 1H), 8.25 (m, 2H), 8.75 (s, 1H).

Example 83

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트아미도}-3-[(2-메틸-1,3,4-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(2- Methyl-1,3,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

A method similar to Example III / 82 by reacting 685 mg (0.001 mol) of the corresponding acetoxy cephalosporin derivative with 135 mg of 5-mercapto-2-methyl-1,3,4-thiadiazole as starting material To manufacture.

lR Spectrum: 1765, 1670, 1615, 1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.7 (s, 3H), 3.55 (q, 2H), 4.45 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.35 (m, 3H), 7.7 (m, 1H), 8.1 (s, 1H), 8.45 (m, 2H).

Example 84

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-2-푸릴아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -2-furylacetamido} -3-[(1-methyl-tetra Zol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노-5-피리미디닐)-우레이도]-2-푸릴아세트아미도]-3-아세톡시메틸-세프-3-엠-4-카복실레이트와 1-메틸-5-머캅토-테트라졸과의 반응으로부터 실시예Ⅲ/82와 유사한 방법에 의한 66.5% 수율로 제조한다.Sodium-7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino-5-pyrimidinyl) -ureido] -2-furylacetamido] -3-acetoxymethyl-sep-3- Prepared in a 66.5% yield by a method similar to Example III / 82 from the reaction of m-4-carboxylate with 1-methyl-5-mercapto-tetrazole.

Example 85

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,3,4-티아디아졸-2-일)-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1, 3,4-thiadiazol-2-yl) -thiomethyl] -cep-3-m-4-carboxylate

From the reaction of the cephalosporin derivative obtained in Example III / 80 with 2-mercapto-1,3,4-thiadiazole, it was prepared in a 71% yield by a method similar to that of Example III / 82.

Example 86

-[3-(4-하이드록시-2-(2'-티에닐 메틸 아미노)-5-피리미디닐) -우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-아세틸 아미노-티아디아졸-5-일 )-티오메틸]-세프-3-엠-4-카복실레이트Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienyl methyl amino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2- Acetyl amino-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Prepared in a similar manner to Example III / 82 from the cephalosporin derivative of Example III / 80 and 690 mg (0.001 mole) and 2-acetylamino-5-mercapto-1,3,4-thiadiazole 175 mg do.

Yield: 480 mg (59%) of sodium salt

l Spectrum: 1765, 1655, 1620, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.4 (s, 3H), 3.70 (q, 2H), 4.25 (q, 2H), 4.45 (s, 2H), 4.95 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.7-7.45 (m, 7H), 8.05 (s, 1H).

Example 87

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-메틸아미노-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2- Methylamino-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

The corresponding cephalosporin derivatives are reacted with 2-methylamino-5-mercapto-1,3,4-thiadiazole to prepare 61% yield by a method similar to III / 53.

Example 88

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,2,3-트리아졸-4-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1, 2,3-triazol-4-yl) -thiomethyl] -sef-3-m-4-carboxylate.

The corresponding cephalospoin derivative is reacted with 4-mercapto-1,2,3-triazol to prepare 68% yield by a similar method as in Example III / 53.

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노-5-피리미디닐)-우레이도]-P-하이드록시-페닐-아세트아미도]-3-아세톡시메틸-세프-3-엠-4-카복실레이트와 출발물질로 하여 다음과 같은 세팔로 스포린을 제조한다.In a manner similar to Example III / 53, sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino-5-pyrimidinyl) -ureido] -P-hydroxy-phenyl-acetamido] -3-acetoxymethyl-cef The following cephalosporins were prepared using -3-m-4-carboxylate and starting materials.

Example 89

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(tetrazol- 5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Prepared in 57% yield using 5-mercapto-tetrazole.

l Spectrum: 1770, 1655, 1615, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.45 (q, 2H), 4.45 (m, 4H), 4.90 (d, 1H), 4.45 (s, 1H), 5.60 (d, 1H), 6.3 (m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H).

Example 90

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,2,4-티아디아졸-2-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1,2 , 4-thiadiazol-2-yl) -thiomethyl] -cep-3-m-4-carboxylate.

Prepared in 64.5% yield by reaction with 5-mercapto-1,2,4-thiadiazole.

Example 91

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-아세틸아미노-1,3,4-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2-acetyl Amino-1,3,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Prepared in 56% yield by reaction with 2-acetylamino-1,3,4-thiadiazole.

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 3H), 3.70 (q, 2H), 4.3-4.4 (m, 4H, partially shielded by solvent), 4.95 (d, 1H ), 5.45 (s, 1H), 5.60 (d, 1H), 6.3 (m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.5 (s, 1H), 8.05 (s, 1H) .

Example 92

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1,3,4-트리아졸-2-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1,3 , 4-triazol-2-yl) -thiomethyl] -cep-3-m-4-carboxylate.

Prepared in 66% yield by reaction with 2-mercapto-1,3,4-triazole.

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.50 (q, 2H), 4.4 (m, 4H), 4.90 (d, 1H), 5.40 (s, 1H), 5.65 (d, 1H), 6.35 (m, 2H), 7.2 (d, 2H), 7.55 (s, 1H), 8.05 (s, 1H), 8.35 (s, 1H).

Example 93

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-디메틸아미노-1,3,4-티아디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2-dimethyl Amino-1,3,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Prepared in 60% yield by reaction with 2-dimethylamino-5-mercapto-1,3,4-thiadiazole.

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.05 (d, 6H), 3.50 (q, 2H), 4.35 (q, 2H), 4.45 (s, 2H), 5.0 (d, 1H), 5.70 (d, 1H), 6.30 (m, 2H), 6.7 (d, 2H), 7.2 (d, 2H), 7.55 (s, 1H), 8.05 (s, 1H).

Example 94

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(2-메틸-1,3,4-옥사디아졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(2-methyl -1,3,4-oxadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate.

Prepared in 63.5% yield by reaction with 2-methyl-5-mercapto-1,3,4-oxadiazole.

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.45 (s, 3H), 3.6 (q, 2H), 4.20 (2H), 4.45 (s, 2H), 4.95 (d, 1H), 5.45 (s , 1H), 5.60 (d, 1H), 6.35 (m, 2H), 7.25 (d, 2H), 7.5 (s, 1H), 8.054 (s, 1H).

Example 95

-[3-(4-하이드록시-2-(3'-피리딜아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

A solution of 965 mg (0.0013 mol) of sodium salt of Example III / 2 and 325 mg of pivaloyloxy methyl iodiside in 15 ml of dimethylformamide is stirred at room temperature for 1 hour. Then, 50 ml of ethyl acetate and 50 ml of 0.1 mol sodium bicarbonate solution were added thereto. The ethyl acetate layer is then washed successively with water, diluted hydrochloric acid, dried over magnesium sulfate, and evaporated to dryness in vacuo. The residue is extracted by stirring with anhydrous ether.

Yield: 710 mg (66%)

l Spectrum: 1775, 1735 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.10 (s, 9H), 3.6 (m, 2H), 4.0 (s, 3H), 4.5 (m, 2H), 4.95 (d, 1H), 5.5 (s, 1H), 5.75 (d, 1H), 5.85 (dd, 2H), 6.85 (d, 2H), 7.3 (d, 2H), 7.45 (m, 1H), 8.3 (m, 3H), 8.75 ( s, 1H).

In a similar manner, the following compounds are prepared:

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도]-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세포-3-엠-4-카복실레이트.Pivaloyloxymethyl 7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido] -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cell-3-m-4-carboxylate.

Example 96

-[3-(4-하이드록시-2-(3'-피리딜아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

3.75 g of sodium salt of Example III / 19 was reacted with 1.2 g of pivaloyloxymethyl iodide to prepare a method similar to that of Example III / 66.

Yield: 2.79 mg (68%)

l Spectrum: 1770, 1740 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.10 (s, 9H), 3.55 (q, 2H), 3.95 (s, 3H), 4.45 (m, 2H), 4.95 (d, 1H), 5.55 (s, 1H), 5.65 (d, 1H), 5.85 (dd, 2H), 6.65-7.35 (m, 7H), 8.05 (s, 1H).

In a similar manner, the following compounds are prepared.

-[3-(4-하이드록시-2-(2'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메칠]-세프-3-엠-1-카복실레이트.Pivaloyloxy-1-ethyl-1- (7- {D-

-[3- (4-hydroxy-2- (2'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-1-carboxylate.

Example 97

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

735 mg of sodium of Example III / 21 and 220 mg of pivaloyl oxymethyl iodide were reacted to prepare a method similar to Example III / 66.

Yield: 500 mg (61%)

l Spectrum: 1770, 1740 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.05 (s, 9H), 3.55 (q, 2H), 3.95 (s, 3H), 4.45 (m, 4H), 4.95 (d, 1H), 5.55 (s, 1H), 5.65 (d, 1H), 5.75 (dd, 2H), 6.3 (m, 2H), 6.75 (d, 2H), 7.35 (d, 2H), 7.45 (s, 1H), 8.05 ( s, 1H).

In a similar manner the following compounds are prepared:

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메칠]-세프-3-엠-4-카복실레이트;Propionyloxy-1-ethyl-1- (7- {D-

-[3- (4-hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate;

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-아세톡시메틸-세프-3-엠-4-카복실레이트.Pivaloyloxymethyl-7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino-5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-acetoxymethyl-sef- 3-m-4-carboxylate.

Example 98

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(4'-아미노카보닐피리디노)-메틸]-세프-3-엠-4-카복실레이트.7- {D-

-[3- (4-Hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(4 ' -Aminocarbonylpyridino) -methyl] -cep-3-m-4-carboxylate.

A mixture of 2 millimoles of cephalosporin of Example 47, 2.5 mmol of pyridine carboxamide, 4 g of potassium thiocyanate and 10 ml of water is heated to 50 ° C. for 8 hours. The resulting solution is introduced into a column packed with ion exchange resin Amberlite XAD-2 and eluted, of course, first, followed by a 7: 3 mixture of water and methanol. Methanol is distilled off in vacuo from the desired product containing fractions to freeze-dry the solution.

NMR spectrum (D ₂ O): 3.55 (m, 2H), 4.5 (s, 2H), 5.1 (d, 1H), 5.4 (q, 2H), 5.7 (s, 1H), 5.8 (d, 1H), 6.8 (d, 2H), 7.4 (m, 2 + 1H), 7.7 (m, 1H), 8.15 (s, 1H), 8.3 (m, 2H), 8.5 (m, 2H), 9.0 (m, 2H) .

In a similar manner, the following compounds are prepared.

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-(피리디노 메틸)-세프-3-엠-4-카복실레이트;7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3- (pyridino methyl ) -Cep-3-m-4-carboxylate;

-[3-(4-하이드록시-2-(2'-티에닐메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(4'-아미노카보닐피리디노)-메틸]-세프-3-엠-4-카복실레이트;7- {D-

-[3- (4-Hydroxy-2- (2'-thienylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(4 ' -Aminocarbonylpyridino) -methyl] -sef-3-m-4-carboxylate;

-[3-(4-하이드록시-2-(2'-푸릴메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(4'-아미노카보닐피리디노)-메틸]-세프-3-엠-4-카복실레이트;7- {D-

-[3- (4-Hydroxy-2- (2'-furylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(4'- Aminocarbonylpyridino) -methyl] -sef-3-m-4-carboxylate;

Example 99

-[3-(4-하이드록시-2-(2'-메틸)-5'-피리미디닐-메틸아미노-5-피리미디닐)-우레이도]-P-하이드록시페닐아세트아미도}-아세톡시메틸-세프-3-엠-4-카복실레이트.Sodium 7- {D-

-[3- (4-Hydroxy-2- (2'-methyl) -5'-pyrimidinyl-methylamino-5-pyrimidinyl) -ureido] -P-hydroxyphenylacetamido}- Acetoxymethyl-sef-3-m-4-carboxylate.

Benzhydrim 7-amino-3-acetoxymethyl-sef-3-m-4-carboxylate and the ureidocarboxylic acid of Example I / 2am) as starting materials were used in the method described in Example III / 1. To produce accordingly.

Yield: 52% (sodium salt);

IR spectrum: 1760, 1660, 1610, 1540 cm ⁻¹ ;

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 2.05 (s, 3H); 3.45 (q, 2 H); 4.40 (s, 2 H); 4.80 (m, 3 H); 5.55 (s, 1 H); 5.60 (d, 1 H); 6.70 (d, 2 H); 7.25 (d, 2 H); 8.05 (s, 1 H); 8.65 (s, 2 H).

Example 100

-[(4-하이드록시-2-(2'-피리미디닐아미노-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트.Sodium 7- {D-

-[(4-hydroxy-2- (2'-pyrimidinylamino-5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1-methyl-tetra Sol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 1 / 2am) of ureidocarboxylic acid and benzhydryl 7-amino-3-[(1-methyl-detrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate Prepared according to the method described in Example III / 1 as a starting material.

Yield: 58% (sodium salt)

IR Spectrum: 1760, 1660, 1615cm ^-1

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 3.50 (q, 2H); 3.90 (s, 3 H); 4.2-4.5 (m, 2 + 2H); 4.90 (d, 1 H); 5.50 (s, 1 H); 5.60 (d, 1 H); 6.75 (d, 2 H); 7.30 (d, 2 H); 8.05 (s, 1 H); 8.65 (s, 2 H).

Ⅳ. Pharmaceutical preparations according to the mode of administration

The compounds of formulas (I) and (I ') may be formulated in conventional pharmaceutical preparations such as tablets, capsules, capsules or ampoules. Single doses for adults are generally from 100 to 1000 mg, preferably from 200 to 500 mg, and the daily dose is from 150 to 5000 mg, preferably from 500 to 2500 mg.

Example I

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트함유 정제.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate containing tablets.

A mixture consisting of 2 kg of active ingredient, 5 kg of lactose, 1.8 kg of potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is compressed in a conventional manner so that each tablet contains 200 mg of the active ingredient.

Example II

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-P-하이드록시페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트 함유 제피환제.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -P-hydroxyphenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate-containing epidermal pill.

Tablets are tableted in a similar manner to Example I and subsequently coated with a coating agent consisting of sugar, potato starch, talc, and toragagant rubber in a conventional manner.

Example III

-[3-(4-하이드록시-2-(3'-피리elf메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시-페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실 레이트 함유 캅셀제.Pivaloyloxymethyl-7- {D-

-[3- (4-hydroxy-2- (3'-pyrielfmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate containing capsule agent.

5 kg of the active ingredient is filled in hard gelatin capsules in a conventional manner to contain 500 mg of active ingredient per capsule.

Example IV

-[3-(4-하이드록시-2-(3'-피리딜메틸아미노)-5-피리미디닐)-우레이도]-p-하이드록시페닐아세트아미도}-3-[(1-메틸-테트라졸-5-일)-티오메틸]-세프-3-엠-4-카복실레이트 함유건조 앰플제.Sodium 7- {D-

-[3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxyphenylacetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate-containing dry ampoule.

In a clean room, 251 kg of active ingredient is dissolved in 2008 ml of distilled water for injection. The solution is filtered through a Millipore filter (pore size 0.22 μm, manufactured by Millipore Corporation, Bedford, USA). The solution is placed in 1000 glass tubes (10 ml in volume) in 2.0 ml aliquots and lyophilized. The glass tube is then sealed with a rubber stopper and an aluminum cap. In this way, glass tubes A containing 250 mg of each active ingredient are obtained.

Fill the ampoule with 2.0 ml aliquots of injectable physiological saline solution and seal the ampoule. In this way, the ampoule B is obtained. The physiological salt solution in the ampoule (B) is poured into the glass tube (A), thereby obtaining an injectable preparation for intravenous administration.

Distilled water for injection is added to the glass tube (A) in aliquots of 20 ml each and the solution is filled into 5% injectable glucose urine solution (250 ml). In this way, a solution for continuous infusion is prepared.

In a similar manner, tablets, peeling pills, capsules and ampoules containing one or more other active ingredients of formula (I) or physiologically acceptable salts of these compounds can be prepared.

Claims (1)

Compound (II) is a mixture of pyrimidine derivatives of general formula (III) or pyrimidine derivatives of general formula (III) in a solvent at a pH of 2.0 to 9.0 at -20 ° C to + 50 ° C, wherein B is partially identical and partially different); The ureidocarboxylic acid or salt or reactive derivative thereof of formula (IV) is reacted with a compound of formula (V) at −40 ° C. to + 40 ° C., in the presence of a solvent and in the presence or absence of a base; Compound (py) of the formula (VI) at 0 to 100 DEG C while maintaining the pH of the reaction solution in a mixture of an organic solvent, water or a solvent at 2 to 10, preferably 4 to 8 Or reacted with 4-aminocarbonylpyridine; A method for producing a salt of β-lactam compound of general formula (I) or (I ') and its physiologically acceptable inorganic or organic base group, characterized by removing the protecting group from the compound thus produced.

Het-S-M (Ⅶ) In the above formula, A represents a phenyl, 4-hydroxyphenyl, 2- or 3-thienyl, 2- or 3-furyl, cyclohexyl, cyclohexyl-1-yl or cyclohexa-1,4-dien-1-yl group Or a phenyl group disubstituted at positions 3 and 4 by a chlorine atom and the same or different substituents selected from hydroxy and methoxy groups; R represents a group of the general formula NH (CH ₂ ) _n R ₁ ; n represents 0 or 1; R ₁ represents an optionally substituted 5- or 6-membered heterocyclic ring containing preferably 1 to 4, in particular 1 or 2 heteroatoms, such as oxygen, sulfur or nitrogen, For example optionally substituted thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyri Dill, pizzaninil, pyridazinyl, pyrimidinyl or tetrahydrofuranyl groups, these groups being alkyl groups; Halogen atoms such as fluorine, chlorine or bromine; Nitro, cyano, amino, alkylamino, or dialkylamino groups; Alkylcarbonylamino or alkoxycarbonylamino groups; Hydroxy, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl groups; Methylsulfonylamino, aminocarbonyl, alkylcarbonyloxy or alkoxycarbonyl groups; Aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl groups; Or may be substituted by a carboxylic acid or sulfonic acid group, wherein the alkali groups in these substituents may each contain 1 to 4 carbon atoms;

Selected from the group; D represents a hydrogen atom, hydroxy, acetoxy, aminocarbonyloxy, pyridinium or 4-aminocarbonylpyridinium group, or group-S-Het [here, Het is tetrazol-5-yl, 1 -Methyl-tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadia Zol-2-yl, 2-methyl-1,3,4-thiadiazol--5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl, 2-dimethylamino-1 , 3,4-thiadiazol-5-yl, 2-formylamino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4-thiadiazole-5- Day, 2-methyl-1,3,4-oxadiazol-5-yl, 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl group; Provided that in Formulas (II) and (V) it cannot be pyridinium or aminocarbonylpyridinium; E represents a hydrogen atom or a protecting group that can be easily separated in vitro or in vivo; B is a group = NCO, -NHCOCl, -NHCOBr or

; M represents a hydrogen atom or an alkali metal or alkaline earth metal.