KR840000409B1 - Process for preparing cephalosporins - Google Patents

Abstract

Cephalosporins (I; R=H, Me, cyclopropyl, OH, OMe, OEt, SH, amino; A=optionally substituted Ph, cyclohexyl, 1-cyclohexenyl, 2,4-cyclohexadienyl, thienyl, furyl; Y=H, OMe; D=H, OH, OAc, O2CNH2, pyridinium, carbamoylpyridinium, heterocyclythio; E=H, protective group) were prepd. Thus, 5-amino-4-hydroxy-pyrimidine was treated with THF and triethylamine to give Na-7-{D-α-[(4-hydroxy-5-pyrimidinyl)-ureido phenylacetamido}-3-methyl-ceph-3-em-4-carboxylate.

Description

Method for preparing cephalosporin

The present invention relates to a process for the preparation of novel cephalosporins of the general formula (I) and salts thereof.

In the above formula

A is phenyl, 4-hydroxyphenyl, cyclohexyl, cyclohexen-1-yl, cyclohex-1,4-dien-1-yl, 2- or 3-thienyl, 2- or 3-furyl group, Or a phenyl group di-substituted at the 3,4-position by the same or different substituents selected from chlorine, hydroxy and methoxy groups;

Y represents a hydrogen atom or a methoxy group;

D is a hydrogen atom, hydroxy, acetoxy, aminocarbonyloxy, or S-Het group, wherein Het is 1-methyl-tetrazol-5-yl, tetrazol-5-yl, 3-methyl-1 , 2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-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-form Milamino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-oxadiazole- 5-yl, 1,2,3-triazol-4-yl, or 1,2,4-triazol-3-yl group;

의 그룹[여기에서 R₁및 R₂는 같거나 다를 수 있으며, 수소원자, 1개 또는 2개의 이중 결합 또는 3중 결합을 함유할 수 있는 탄소수 1내지 6의 직쇄 또는 측쇄 지방족 탄화수소기, 탄소수 3내지 6의 사이클로알킬기, 또는 사이클로알킬 부분에는 3개 내지 6개의 탄소원자를 함유하며 알킬 부분에는 1개 또는 2개의 탄소원자를 함유하는, 사이클로알킬기에 의해 치환된 알킬 그룹을 나타내거나, R₁및 R₂가 함께 탄소수 2내지 7의 알킬렌 체인을 형성할 수 있으며, 이때는 3-내지 8-원 헤테로사이클릭환이 형성된다], 일반식

의 그룹[여기에서 R₃는 포르밀, 아세틸 또는 에틸옥시카보닐 그룹을 나타낸다], 모르폴리노, 티오모르폴리노, 티오모르폴리노-S-옥사이드 또는 티오모르폴리노-S,S-디옥사이드 그룹, 또는 일반식 -NH-Z-X의 그룹(여기에서 Z 및 X는 이하에서 정의하는 바와 같다), 일반식 -NH(CH₂)n

의 그룹(여기에서 n, R₆, R₇및 R₈은 이하에서 정의하는 바와 같다), 또는 일반식

의 그룹[여기에서 R₉는 수소원자, 탄소수 1내지 4의 알킬그룹, 탄소수 1내지 3의 알콕시 그룹, 유리 아미노 그룹 또는 메틸 또는 디메틸아미노 그룹을 나타낸다]을 나타내고;R is a hydrogen atom, methyl group, cyclopropyl group, hydroxy group, methoxy or ethoxy group, mercapto group, general formula

[Wherein R ₁ and R ₂ may be the same or different and have a hydrogen atom, a 1 to 6 straight or branched chain aliphatic hydrocarbon group containing 3 or 2 double bonds or a triple bond, 3 carbon atoms; A cycloalkyl group of 6 to 6, or an alkyl group substituted by a cycloalkyl group containing 3 to 6 carbon atoms in the cycloalkyl moiety and 1 or 2 carbon atoms in the alkyl moiety, or R ₁ and R ₂ Together may form an alkylene chain of 2 to 7 carbon atoms, wherein a 3- to 8-membered heterocyclic ring is formed.

Where R ₃ represents a formyl, acetyl or ethyloxycarbonyl group, morpholino, thiomorpholino, thiomorpholino-S-oxide or thiomorpholino-S, S-dioxide Group, or group of general formula -NH-ZX, where Z and X are as defined below, and general formula -NH (CH ₂ ) n

Where n, R ₆ , R ₇ and R ₈ are as defined below, or a general formula

R ₉ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a free amino group or a methyl or dimethylamino group;

E represents a hydrogen atom or a protecting group that can be readily degraded in vitro or in vivo;

Z represents a straight or branched chain alkylene group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, substituted by substituent X,

-SOR₄또는 -SO₂R₄[여기에서 R₄는 탄소수 1내지 3의 직쇄 또는 측쇄알킬 그룹을 나타내고,X represents a cyano group, a hydroxy group, a mercapo group, amino, aminocarbonyl, aminosulfonyl group or aminocarbonylamino group or groups of the following general formula,

-SOR ₄ or -SO ₂ R _4, wherein R ₄ represents a straight or branched chain alkyl group having 1 to 3 carbon atoms,

R ₅ represents hydrogen or an alkyl group of 1 to 3 carbon atoms, or

R ₄ and R ₅ together may optionally form a 3- to 5-membered monocyclic heterocyclic ring containing a nitrogen atom in the middle;

n represents 0 or 1,

R ₆ , R ₇ and R ₈ may be the same or different from one another and may be hydrogen, halogen, free amino group, alkylamino or dialkylamino group, hydroxy or alkoxy group, formylamino group, aliphatic acylamino group, aminocarbo Nylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino group, nitro, alkylsulfonylamino group, formyl or alkylcarbonyl group, alkylcarbonyloxy, alkoxycarbonyl or alkoxycarbonyloxy group, amino Carbonyl, alkyl or dialkylaminocarbonyl, aminocarboxyl, alkylaminocarboxyl, dialkylaminocarboxyl or alkoxycarbonylamino groups, cyano, mercapto, alkylmercapto, alkylsulfinyl or alkylsulfonyl groups, aminosulfur Phenyl, alkyl or dialkylaminosulfonyl groups, hydroxylsulfonyl groups or straight or branched chain alkyl groups, wherein the groups mentioned above Each group may contain from 1 to 3 carbon atoms.

Wherein the carboxyl protecting group may be ones commonly used in the field of penicillin and cephalosporin, in particular ester-forming groups which may be removed under favorable conditions by hydrolysis or hydrolysis or other treatment, or bio There are ester-forming groups that can be easily decomposed and removed within. Protective groups that can be readily degraded in vitro include, for example, benzyl, diphenylmethyl, trityl, tert-butyl, 2,2,2-trichloroethyl or trimethylsilyl groups. Protective groups that can be readily degraded in vivo include, for example, alkanoyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, 2-acetoxyethyl or pivaloyloxymethyl groups, or phthalidyl or There is an indanyl group. When E represents hydrogen, it is also 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, salts with triethylamine or dicyclohexylamine. Salts to form.

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

A represents phenyl, p-hydroxyphenyl, 3,4-dihydroxyphenyl, 2 or 3-thienyl, 2 or 3-furyl group;

Y represents a hydrogen atom or a methoxy group;

D represents a hydrogen atom, hydroxy, acetoxy, aminocarbonyloxy, or a group of the general formula -S-Het, wherein Het is 3-methyl-1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol 5-yl, 1,3,4-thiadiazol-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-thiadiazole-5 -Yl, 2-acetylamino-1,3,4-thiadiazol-5-yl, 1-methyl-tetazol-5-yl, tetrazol-5-yl, 1,2,3-triazole-4 -Yl, 1,2,4-triazol-3-yl or 2-methyl-1,3,4-oxadiazol-5-yl group;

의 그룹[여기에서, R₁및 R₂는 상기 정의한 의미를 갖는다.], 일반식 -NH-Z-X의 그룹[여기에서 Z 및 X는 상기 정의한 의미를 갖는다], 또는 일반식

의 그룹[여기에서 R₆내지 R₈은 상기 정의한 의미를 갖는다]을 나타내거나 또는 포르밀아미노, 아세틸아미노 또는 아미노카보닐아미노 그룹을 나타내고;R is a hydrogen atom, a cyclopropyl group, a hydroxy or methoxy group, general formula

A group of wherein R ₁ and R ₂ have the meanings defined above, a group of the formula -NH-ZX, wherein Z and X have the meanings defined above, or a general formula

Represents a group of wherein R ₆ to R ₈ have the meanings defined above or a formylamino, acetylamino or aminocarbonylamino group;

E is a compound as defined above.

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

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

Y represents a hydrogen atom or a methoxy group;

E represents a hydrogen atom or pivaloyloxymethyl group;

D represents a hydrogen atom, an acetoxy group, an aminocarbonyl group or a group of -S-Het, wherein Het is tetrazol-5-yl, 1-methyl-tetrazol-5-yl, 1,3,4 -Thiadiazol-5-yl or 2-methyl-1,3,4-thiadiazol-5-yl group;

의 그룹[여기에서, R₁은 수소, 탄소수 1내지 4의 잭쇄 또는 측쇄, 포화 또는 불포화 아실 그룹 또는 탄소수 3내지 6의 사이클로알킬기를 나타낸다]을 나타내거나, 또는 일반식 -NH-Z-X의 그룹을 나타내며, 여기에서 -NH-Z-는 특히

또는

의 그룹을 나타내고, X는 하이드록시, 아미노, 메톡시, 에톡시, 머캅토, 아미노카보닐, 메틸아미노카보닐, 디메틸아미노카보닐, 아미노설포닐, 메틸아미노설포닐, 디메틸아미노설포닐, 아미노카보닐아미노, 메틸아미노카보닐아미노, 메톡시카브닐, 에톡시카보닐, 메틸카보닐, 에틸카보닐, 메틸머캅토, 에틸머캅토, 카복시, 메틸아미노, 디메틸아미노, 포르밀아미노, 아세틸아미노, 메틸설포닐아미노, 아세톡시, 메틸설피닐 또는 메틸설포닐 그룹을 나타내거나,

가 4'-하이드록시사이클로헥실아미노 그룹을 나타내는 화합물이다.R is a hydrogen atom, a cyclopropyl group, a hydroxy or methoxy group, a dimethylamino group or a general formula

Wherein R ₁ represents hydrogen, a jack or branched chain having 1 to 4 carbon atoms, a saturated or unsaturated acyl group or a cycloalkyl group having 3 to 6 carbon atoms, or a group of the formula -NH-ZX Wherein -NH-Z- is particularly

or

X represents hydroxy, amino, methoxy, ethoxy, mercapto, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, amino Carbonylamino, methylaminocarbonylamino, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, methylmercapto, ethylmercapto, carboxy, methylamino, dimethylamino, formylamino, acetylamino , Methylsulfonylamino, acetoxy, methylsulfinyl or methylsulfonyl group, or

Is a compound representing a 4'-hydroxycyclohexylamino group.

More particularly preferred in the sense for R is a group of the following general formula:

In the above formula,

n represents 0 or 1;

One or two of R ₆ , R ₇ and R ₈ is hydrogen, chlorine or fluorine atom, methyl, ethyl, amino, methylamino, dimethylamino, hydroxy, methoxy, ethoxy, nitro, formylamino, acetylamino, Aminocarbonylamino, methylaminocarbonylamino, methylsulfinyl, methylsulfonyl, acetyl, methylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methylmercapto , Methylsulfonylamino, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, ethylaminosulfonyl or trifuluromethyl group, and the rest of R ₆ , R ₇ and R ₈ represent a hydrogen atom .

It is also particularly preferred that R represents an acetylamino group. A very particularly preferred aspect of the present invention is directed to compounds in which R represents a group of the following general formula.

In the above,

R ₆ is hydrogen or chlorine atom, hydroxy, nitro, acetylamino, methylsulfinyl, acetyl, aminocarbonyl, aminocarbonylamino, methylsulfonylamino, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or Ethylaminosulfonyl group.

The cephalosporin compound of formula (I) may exist in two tautomeric forms (ie, lactim type and lactam form). Which form in general formula (I) or (I ') predominates depends especially on the kind of solvent and substituent R.

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

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 high pressure liquid chromatography (HPLC).

The compound of general formula (I) can be manufactured by making the compound of general formula (II) react with the pyrimidine derivative of general formula (III).

In the above formula,

A, Y, D, E and R have the same meaning as described above;

의 그룹을 나타내고, 여기에서 -NCO 및 -NHCOCl 그룹이 특히 바람직하다.B is a reactive group of group -NCO, or -NHCOOH, for example -NHCOCl, -NHCOBr or

Groups are preferred, wherein the -NCO and -NHCOCl groups are particularly preferred.

를 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 -NCO and him

Simultaneously.

When E represents a hydrogen atom, the starting material of formula (II) may be used in the form of an inorganic or organic salt such as triethylammonium salt or sodium salt. In this case, the reaction is carried out with water and ketones (e.g. acetone), cyclic ethers (e.g. tetrahydrofuran or dioxane), nitrile (e.g. acetonitrile), formamide (e.g. dimethylformamide), dimethylsulfoxide Or in any mixture with a water miscible organic solvent such as 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 pH6.5 to 8.0 with 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 may 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 ( 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 an organic or inorganic base or by adding a buffer product.

When E represents a trimethylsilyl group, i.e. using a silyl derivative of the general formula (II) compound (e.g. mono- or trimethylsilyl derivative in which amino and carboxyl groups are appropriately silylated) as starting material for the process according to the invention When these compounds are reacted with compounds of the general formula (III), the reaction is generally carried out in anhydrous solvents and solvents which do not contain hydroxyl groups, for example halogenated hydrocarbons such as methylene chloride or chloroform, benzene, tetrahydrofuran It is appropriate to carry out in 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 triethylamino or dicyclohexylamine, are suitable.

When E represents one of the protecting groups that can be readily degraded in vitro or in vivo as described above, for example diphenylmethyl group or pivaloyloxymethyl group, methylene chloride anhydrous, chloroform It is also advantageous to carry out the process in an aprotic solvent, such as 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, then 1.0 to 2.0 molar equivalents of base are used unless the silylated compound of formula (II) is present. . When the silylated compound is present, it is preferable to use 1 molar equivalent or less of base.

In general, all organic and inorganic bases commonly used in organic chemistry can be used as base additives. Such bases include alkali and alkaline earth metal hydroxides, alkaline earth metal oxides, alkali and alkaline earth metal carbonates and bicarbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines as well as heterocyclic bases. Preferred bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ethylamine, methyl-ethylamine, triethylamine, hydroxy-ethylamine, aniline, dimethylaniline, Pyridine and piperidine. However, when using a silylated starting material, limitations on the types of bases mentioned above should be considered.

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

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

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

Compounds prepared according to the invention, wherein E represents a protecting group that can be readily degraded in vitro, are free carboxylic acids of formula (I) in which E represents a hydrogen atom according to methods known in the art of cephalosporin chemistry. You can switch. Thus, the trimethylsilyl group can be easily removed by, for example, quartz hydrolysis, and the benzhydryl group can be removed by hydrolytically separating by, for example, trifluoroacetic acid. Removal of such protective groups is well known in the literature.

[여기에서 Hal은 염소, 브롬 또는 요오드이다]의 피발로일옥시메틸 할로게나이드와 반응시킴으로써, E가 피발로일옥시메틸기 -CH₂-OC-C(CH₃)₃를나타내는 아실옥시알킬 에스테르로 전환시킬 수 있다. 이외에 적합한 아실옥시알킬할로게나이드로는 또한 예를들어 클로로메틸 아세테이트, 브로모메틸 프로피오네이트 또는 1-브로모 에틸 아세테이트가 있다.In addition, the cephalosporin antibiotic of the general formula (I) in which E represents a hydrogen atom is, for example, an alkali salt (eg, sodium or potassium salt) of cephalosporin carboxylic acid.

Ac is an acyloxyalkyl ester in which E represents a pivaloyloxymethyl group -CH ₂ -OC-C (CH ₃ ) ₃ by reacting with a pivaloyloxymethyl halogenide of Hal, where Hal is chlorine, bromine or iodine Can be converted to Other suitable acyloxyalkylhalogenides are also, for example, chloromethyl acetate, bromomethyl propionate or 1-bromo ethyl acetate.

The process for preparing acyloxyalkyl esters of general formula (I) is a slightly molar excess of pivaloyloxymethyliodine at room temperature or at a temperature slightly elevated to about 40 to 45 ° C. in each alkali metal salt of the inert solvent. It is carried out by reacting with iodine, bromine or chloroalkyl esters such as id. Suitable solvents are, for example, acetone, tetrahydrofuran, dioxane dimethyl formamide or methylene chloride.

Indanyl ester of the general formula (I) in which E represents an oil of

5-indanol in an inert solvent such as dioxane or tetrahydrofuran is reacted with a compound of formula (I) in free acid form in which E represents hydrogen in the presence of a condensing agent such as diimide such as dicyclohexyl carbodiimide It can manufacture. The reaction is carried out for a reaction time of about 6 to 8 hours with stirring at a temperature of about 20 to 35 ℃. For the separation of indanyl esters the reaction mixture is first diluted with water and the insoluble dicyclohexyl urea is filtered off from the reaction mixture. Thereafter, the ester is extracted from the filtrate.

Indanyl esters may also be prepared by reacting 5-indanol with anhydrides formed from cephalosporranic acid and acetic acid of formula (I).

의 프탈리딜 그룹을 나타내는 일반식(Ⅰ)의 프탈리딜에스테르는 다음 구조식의 브로모프탈리드와 일반식(Ⅰ)의 세팔로스포란산의 염을 반응시켜 제조할 수 있다.R3 is a structural formula

The phthalidyl ester of general formula (I) which shows the phthalidyl group of can be manufactured by making the bromophthalide of the following structural formula and the salt of the cephalosporranic acid of general formula (I) react.

The esterification reaction can be carried out by slowly heating an equimolar mixture of a cephalosporin salt such as sodium or potassium salt and bromophthalide in dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran or mixtures thereof. have.

Once the reaction is complete, the reaction mixture obtained according to the mentioned process is further treated in a routine procedure for β-lactam antibiotics.

That is to say with regard to the separation and purification of the desired product, such as freeing the acid to form other salts using inorganic or organic bases. In particular, suitable methods for the preparation of the potassium or sodium salts include the addition of potassium or sodium-2-ethylhexanoate to precipitate these salts from the alcoholic-etheric solutions of the free acids, or the free acid to the corresponding amounts under pH control. After reacting with sodium bicarbonate, there is a method of freeze drying.

As representative starting materials, A represents phenyl, substituted phenyl or thienyl, and D represents 1-methyl-1H-tetrazol-5-yl or 2-methyl-1,3,4-thiadiazol-5-yl. General formula (II) This compound is known from literature such as US Pat. No. 3,641,021. Starting materials of the general formula (II) in which A represents furyl or thienyl or represents a hydrogen atom or a methoxy group are also described in [Example. J. Antibiotics 31, page 546 and page 560 (1978). Starting materials of general formula (V) are also known in the literature. For example, a 7-aminocephalosporranic acid system in which D represents a heterocyclic system can be obtained by reacting 7-amino cephalosporranic acid with the corresponding mercapto heterocycle compound in a conventional manner.

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

Wherein R is as defined above.

The reaction is preferably free of hydroxyl groups such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol at temperatures of -40 ° C to + 60 ° C, preferably -10 ° C to 20 ° C. In 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 formula (IV) is difficult to dissolve in one of the solvents mentioned above, the phosgenation reaction may be carried out in heterogeneous phase. In a particularly preferred method, aminopyrimidines of general formula (IV) are substituted with silylating agents such as hexamethyldisilazane, trimethylchlorosilane / triethylamine, trimethylsilyl diethylamine or N, O-bis-trimethylsilyl acetamide. The treatment can generally be converted to aminopyrimidines which dissolve very easily in the solvents mentioned above, which aminosilimidines are silylated once or several times depending on the substitutable hydrogen atoms present. After addition of the phosgene, the aminopyrimidine is reacted, preferably without the addition of a base, to give the corresponding compound of formula (III). Depending on the type of solvent, the temperature, and the type and amount of base actually added, the corresponding isocyanates of the carbamic acid halogenides or mixtures of these two compounds are obtained. Depending on the reaction conditions, the isocyanate of general formula (III) may also be present as dihydro-oxazolo-pyrimidine of general formula (IIIa) which is an isomeric compound of isocyanate.

Depending on the type of substituent R, the isocyanate of general formula (III) may also exist as one or several silylated homologs.

Starting materials of the general formula (III) or (IIIa) or mixtures thereof or silylated homologs obtained by the above-described phosgenation reaction are generally dissolved in the above-mentioned solvents, and after removal of excess phosgene, no further purification is performed. And directly react with the corresponding cephalosporin derivative of formula (II).

However, the intermediate product of general formula (IIIa) is also separated and optionally desilylated, purified on the basis of solubility or reacted by the above-mentioned method, using a protonic solvent such as water or methanol.

A process for the synthesis of 2-substituted 5-amino-4-hydroxy-pyrimidines of formula (IV) is described in JP-A-P28 08 153 P29 10 190.

Cephalosporin antibiotics are used extensively in the treatment of diseases caused by pathogenic bacteria in humans and animals. In particular, cephalosporin antibiotics can be used in the treatment of penicillin-sensitive patients as well as in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds. In most cases, it is desirable to use cephalosporin antibiotics that exhibit good activity against Gram-positive and Gram-negative microorganisms. For this reason, many experiments have been conducted to develop several different types of cephalosporin antibiotics with a broad spectrum of activity.

These experiments have found it difficult to develop cephalosporin antibiotics that exhibit a broad spectrum of activity and also have good activity against several strains of Pseudomonas aeruginosa. However, experiments in the field of penicillin have attempted to obtain pseudomonas-activated cephalosporins by acylation of α-aminobenzyl cephalosporins, but these compounds have generally been found to have little activity. Therefore, there is a need to develop new cephalosporins with increased activity against several strains of Pseudomonas aeruginosa in addition to exhibiting a broad spectrum of activity.

As already mentioned, generally intensive studies have been conducted on the acylation of α-aminobenzyl derivatives, whereby the heterocyclic system can be used to bind α-aminobenzyl cephalosporins via ureido bonds (-NHCONH-). Only a few compounds bound to the α-benzyl hydrogen atom have been known. Only in JP 2710979 and JP 2650826 have described cephalosporins in which pyridine or condensed pyridine is bound to the cephalosporin structure in the manner mentioned above.

However, these compounds exhibit insufficient activity against Pseudomonas. In contrast, several of the compounds which differ in the present invention have been found to exhibit very excellent activity against Pseudomonas strains with their broad spectrum of activity in their antibiotic activity.

The compounds of the present invention show high activity against a number of β-lactamase-producing Gram-negative strains, since these compounds show high stability against β-lactamases resulting from a series of Gram-negative bacteria. In addition, the active ingredients according to the invention have very good tolerance in use. Therefore, they can be used for the prevention and chemotherapy of local and systemic infections in the human and veterinary fields. Thus, these compounds are used, for example, in the treatment of diseases of the respiratory system, pharyngeal cavity and urine, in particular pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis media, cystitis, endocarditis, 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.

As already mentioned, the compounds of general formula (I) also have a wide range of antibiotics, as in vitro, because they show very potent activity against harmful microorganisms, in particular Gram-positive and Gram-negative bacteria and microorganisms similar to bacteria. Can be used as a substance.

Various local and / or systemic diseases can be treated and / or prevented by using cephalosporin derivatives composed of the compounds according to the invention. Examples of such diseases include diseases caused by the following microorganisms.

Micrococases such as Staphylococcus; Lactobacterial such as Streptococcus; Neisseria, such as Neisseria; Corynebacteria, such as corynebacteria; Enterobacteriaceae, such as Escherichia coli; Klebsiella, such as Klebsiella pneumoniae; Proteases of the proteus group such as proteus vulgaris; Salmonella such as Salmonella typhimurium; Shigella such as Shigella descenteri; 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; Brucellas such as Brucella Abbottus; Haemophilus, such as Haemophilus influenzae; Bordetella, such as Bordetella pertussis; Moraxella, such as Moraxella rakunata; Bacteroidases such as bacteroides; Pushforms such as Fusobacterium pushforms; Spherophorus, such as spherophorus necrophorus; Bacillase, an aerobic spore former such as Bacillus anthracis; Anaerobic spore-forming Clostridia, such as Clostridium perfringens; Spirohetases such as Borrelia; Treponema, such as treponema palitum; Leptospira, such as Leptospira interogans.

The above-mentioned microorganisms are only described by way of example and not by way of limitation.

Specific examples of general formula (I) compounds are shown in the following table.

TABLE 1

The activity of cephalosporins according to the invention can be explained by the following test.

1.In vitro test:

This test is performed using a serial dilution test in a microtiter system. The effect of the test compound on bacteriostatic action is tested at the following concentrations: 80,40,20,10.5,2.5,1.25,0.6,0.3,0.08 and 0.02 μg / ml. The nutrient medium is prepared by adding distilled water to 10 g of peptone, 8 g of meat extract oxoid, 3 g of sodium chloride, and 2 g of sodium diphosphate (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. The standardization of the bacterial suspension is a photometer according to the Eppendorf method using a barium sulfate suspension produced by adding 3.0 ml of a 1% barium chloride solution to 97 ml of 1% sulfuric acid as a control. 546 mm). After expression, the streptococcus aronson is further diluted to 1:15 using sodium chloride solution, and the other bacteria to 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 are expressed using distilled water or a suitable solvent.

Fill a hole in the microtiter plate with 0.2 ml of nutrient medium. 0.01 ml of the appropriate test compound solution is then added and then inoculated with 0.01 ml of the expressed bacterial suspension. The bacteria are 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 with bacteriostatic effect).

The following strains are used as test microorganisms. Staphylococcus Oreus SG511, Staphylococcus Oreus E88 (β-lactamase producing bacteria), Escherichia coli ATCC 11775, Pseudomonas aeruginosa hamgengensis and Pseudomonas aeruginosa flutter, Serratia marsesen ATCC 13880, Klebsiella pneumoniae ATCC 10031 and 272, Proteus mirabilis hamgensis, Proteus retigeri, Everella cloase ATCC 13047, Escherichia coli R + TEM (β-lactamase producing bacteria).

Table 1 shows the minimum inhibitory concentrations (MIC) measured for representative compounds according to the invention.

A, R, Y and D were tested using the sodium salt of the compound of formula (I), which has the meaning as follows.

Two representative cephalosporins already on the market are used as control compounds.

TABLE 1

MIC values of various cephalosporins (µg / ml)

As shown in Table 1 above, all test compounds according to the present invention exhibit very excellent activity against representative compounds against representative pathogenic Gram-negative bacteria. It is particularly important to show high activity against Pseudomonas strains.

Acute toxicity of the compounds is determined by oral and subcutaneous administration to the rats of increasing doses of the compounds of Table 1.

LD ₅₀ refers to the dose that kills 50% of the animals within 8 days. All the test compounds indicate the LD ₅₀ is> 4g / kg and, after subcutaneous administration of the LD ₅₀ is> 3g / kg after oral administration, that is, the capacity of 3g / kg; means that no animal died. This means that the test compound is substantially non-toxic at the actual dose used.

The compounds according to the invention were tested for their activity against experimental infection in mice. Pathogenic bacteria include Escherichia coli ATCC11775 and Pseudomonas aeruginosa Walter. Intraperitoneal infection is induced by administering 0.2 ml of a 5% mucin suspension of bacteria corresponding to about 1.4 × 10 ⁶ Escherichia coli cells and about 1.3 × 10 ⁶ Pseudomonas cells per rat. Female NMRI mice are divided into 10 groups. Group 2 is an untreated group and the remaining groups are treated with different doses of cephalosporin to be tested to determine ED ₅₀ (a dose that survives 50% of the animals). Groups infected with Escherichia coli were treated three times with test compound (1, 4 and 7 hours after infection) on the first day and twice with 2 days. 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 cephalosporins according to the present invention are shown in Table 2 below.

TABLE 2

Activity in vivo in rats:

a) Escherichia coli-infected (subcutaneous):

In this experiment also the test compound according to the invention shows very excellent activity against the control compound.

Also according to the invention, pharmaceutical compositions useful for the treatment of infectious diseases in humans and animals are provided.

Chilled forms of pharmaceutical compositions include, for example, tablets, tablets, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays. The active ingredient of formula (I) or a mixture of various other active ingredients of formula (I) can be administered to both humans and animals. The daily dose is conveniently from 5 to 500 mg, preferably from 10 to 200 mg per kg body weight at 24 hour intervals, optionally administered in several divided doses. 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, as well as the duration and interval of administration, it may be necessary to administer in an amount outside 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 dose and dosage form of the active ingredient required in each case can be readily selected by those skilled 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 this method of administration, infection by the Gram-negative or Gram-positive group can be prevented, restored and / or cured, and also can promote growth and improve feed utilization.

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

Example 1

Sodium-7- {D-α-[(4-hydroxy-5-pyrimidinyl) -ureido] phenylacetamido} -3-methyl-sef-3-m-4-carboxylate

A suspension of 2.66 g (0.0073 moles) of cephalexin monohydrate in 80 ml of tetrahydrofuran and 20 ml of water is dissolved in triethylamine with ice cooling.

800 mg (0.0073 mol) of 5-amino-4-hydroxy-pyrimidine are dissolved in tetrahydrofuran, mixed with 1 ml of triethylamine, and added dropwise to 750 mg of phosgene dissolved in 18 ml of tetrahydrofuran with ice cooling. The resulting mixture is evaporated to 40 ml in vacuo and added dropwise to the solution prepared above with ice cooling. At this time, the pH was maintained at 7.5 by adding triethylamine. The resulting solution was stirred at 5 ° C. for 1 hour, further stirred at room temperature for several hours, then tetrahydrofuran was removed in vacuo, the residue was diluted with 20 ml of water and extracted twice with ethyl acetate. Continue to treat the aqueous phase with ethyl acetate and slowly adjust the pH value to 2.5 with cooling and stirring. The ethyl acetate layer is separated and the aqueous phase is extracted again with ethyl acetate, the two organic phases are combined and the solvent is evaporated in vacuo. Sodium salt is prepared by conventional methods.

Yield: 2.49 g (68%)

IR spectrum: 1760, 1655, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ DO) 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, 5H), 8.1 (s, 1 H), 8.50 (s, 1 H).

Using cephalexin monohydrate in the method described in Example 1, the following cephalosporins were obtained.

Example 2

Sodium-7- {D-α-[(2-cyclopropyl-4-hydroxy-5-pyrimidinyl) -ureido] -fetyl-acetamido} -3-methyl-sep-3-m-4 Carboxylate

Prepared using the reaction product of 5-amino-2-cyclopropyl-4-hydroxypyrimidine and phosgene.

Yield: 81%

IR spectrum: 1760, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.0 (m, 4H), 1.9 (m, 1H), 2.0 (s, 3H), 4.4 (q, 2H), 4.95 (d, 1H), 5.45 (s, 1 H), 5.60 (d, 1 H), 7.4 (s, 5 H), 8.4 (s, 1 H).

Example 3

Sodium-7- {D-α-[(4-hydroxy-2- (4'-hydroxy-cyclohexylamino) -5-pyrimidinyl) -ureido] -phenyl-acetamido} -3- Methyl-sep-3-m-4-carboxylate

Prepared using the reaction product of 5-amino- (4'-hydroxy-cyclohexyl-amino) -pyrimidine with phosgene (after silylation). Yield: 64%

IR spectrum: 1760, 1660, 1610, 1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.8 (m, 8H), 2.05 (s, 3H), 3.4 (q, 2H), 3.6 to 4.0 (Broad m, 1H + 1H), 4.95 (d , 1H), 5.54 (s, 1H), 5.65 (d, 1H), 7.4 (s, 5H), 8.05 (s, 1H).

Example 4

Sodium-7- {D-α-[(2-p-chlorobenzylamino-4-hydroxy-5-pyrimidinyl) -ureido] -phenyl-acetamido} -3-methyl-sef-3- M-4-carboxylate

Prepared using the reaction product of 5-amino-2-p-chlorobenzyl amino-4-hydroxypyrimidine and phosgene. Yield: 71%

IR spectrum: 1760, 1655, 1610, 1545cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.0 (s, 3H), 3.35 (q, 2H), 4.95 (d, 1H), 5.4 (s, 1H), 5.65 (p, 1H), 6.8 (d, 2H), 7.4 (m, 7H), 8.0 (s, 1H).

Example 5

Sodium-7- {D-α-[(2,4-dihydroxy-5-pyrimidinyl) -ureido] -p-hydroxy phenyl-acetamido} -3-acetoxymethyl-sef-3 M-4-carboxylate

635 mg (0.005 mol) of 5-amino-2,4-dihydroxy-pyrimidine are suspended in 50 ml of tetrahydrofuran and the suspension is treated with trimethylsilyl diethylamine until a solution is formed. After the tetrahydrofuran was evaporated off in vacuo, the residue product was dissolved in 30 ml of tetrahydrofuran and the mixture was added dropwise to a solution of 500 mg of phosgene in tetrahydrofuran with ice cooling. Nitrogen is then introduced into the solution to remove unreacted phosgene. The subsequent reaction is carried out in a similar manner as in Example 1 using 7- [D-α-amino-p-hydroxyphenyl acetamido] -3-acetoxymethyl-sef-3-m-4-carboxylic acid. . Yield of sodium salt: 830 mg (29%)

IR spectrum: 1760, 1665, 1505, 1545 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.05 (s, 3H), 3.55 (q, 2H), 4.8 (m, 2 + 1H), 5.45 (s, 1H), 5.65 (d, 2H) , 6.75 (d, 2H), 7.3 (d, 2H), 8.15 (s, 1H).

Example 6

Sodium-7- {D-α-[(2-amino-p-4-hydroxy-5-pyrimidinyl) -ureido] -phenyl-acetamido} -3-methyl-sep-3-m- 4-carboxylate

The phosgene moiety of 2,5-diamino-4-hydroxy-pyrimidine is prepared from TT (after silylation as described in Example 5) and cephalexin monohydrate. The cephalosporin obtained is precipitated from water at pH3.0, dried by suction filtration and converted to sodium salt as described above. Yield: 26%

IR spectrum: 1760, 1655, 1615, 1545cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.0 (s, 3H), 3.45 (q, 2H), 4.90 (d, 1H), 5.40 (s, 1H), 5.60 (d, 2H), 7.4 (m, 5 H), 8.0 (s, 1 H).

Example 7

Sodium-7- {D-α-[(4-hydroxy-methyl amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl-acetamido} -3-[(1-methyl- Tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

7- [D-α-amino- (p-hydroxy phenyl-acetamido)]-3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4- A phosgene reaction product of 405 mg (0.001 mol) of carboxylic acid and 140 mg (0.001 mol) of 5-amino-4-hydroxy-2-methylamino-pyrimidine as a starting material was prepared in a similar manner to Example 5.

The subsequent process is carried out as follows.

The cephalosporin obtained is precipitated from water at pH2.8, dried by suction filtration and converted to sodium salt by conventional methods. Yield: 315 mg (31.5%)

IR spectrum: 1760, 1655, 1610, 1540 cm ^-1 ,

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 2.85 (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), 6.85 (d, 2H), 7.35 (d, 2H), 8.05 (s, 1H).

Example 8

Sodium-7- {D-α-[(4-hydroxy-2-methoxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl acetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Reaction product of 280 mg (0.002 mol) of 5-amino-3-hydroxy-2-methoxypyrimidine with phosgene and 7- [D-α-amino-p-hydroxy phenyl acetamido] -3-[(1 920 mg (0.002 mole) of -methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylic acid was prepared in a similar manner to Example 1.

Yield of sodium salt: 735 mg (53%)

IR spectrum: 1760, 1660, 1615, 1545cm ^-1

NMR Spectrum (DMSO + CD ₃ OD): Signal (ppm) 3.5 (q, 2H), 3.85 (s, 3H), 3.95 (s, 3H), 4.35 (q, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.35 (d, 2H), 8.1 (s, 1H).

Example 9

Sodium-7- {D-α-[(4-hydroxy-2-propyl amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl acetamido} -3-[(1-methyl -Tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

A reaction product of 1.70 g (0.01 mol) of 5-amino-3-hydroxy-2-propylamino-pyrimidine and phosgene and 4.61 g (0.01 mol) of cephalosporin used in Example 8 were used as starting materials. Prepared in a similar manner to Example 1. The subsequent process is carried out similarly to Example 6. Yield of sodium salt: 4.0 g (61%)

IR spectrum: 1760, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.0 (t, 3H), 1.65 (q, 2H), 3.2 (t, 2H), 3.50 (q, 2H), 3.9 (s, 3H), 4.35 (q, 2H), 4.85 (d, 1H), 5.50 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.35 (d, 2H), 8.0 (s, 1H).

Example 10

Sodium-7- {D-α-[(4-hydroxy-2-isopropyl amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl-acetamido} -3-acetoxymethyl -Cef-3-M-4-carboxylate

Reaction product of 505 mg (0.003 mol) of 5-amino-4-hydroxy-2-isopropyl amino-pyrimidine with trimethylsilyl diethylamine and phosgene and 1.22 g (0.003 mol) of the cephalosporin derivative of Example 98 Prepared in a similar manner to Example 5 as a starting material. The subsequent process is carried out similarly to Example 6.

Yield of sodium salt: 980 mg (61%)

IR spectrum: 1760, 1660, 1615, 1535 cm ^-1 ,

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.15 (d, 6H), 2.05 (s, 3H), 3.55 (q, 2H), 3.90 (Broad, 1H), 4.80 (m, 2 + 1H) , 5.45 (s, 1H), 5.65 (d, 1H), 6.85 (d, 2H), 7.3 (d, 2H), 8.0 (s, 1H).

Example 11

Sodium-7- {D, L-α-[(4-hydroxy-2-propyl amino-5-pyrimidinyl) -ureido] -2-thienyl-acetamido} -3-[(1- Methyltetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

1 ml of bis-trimethyl-silylacetamide was added to 7- (D, L-α-amino-2-thienyl-acetamido) -acetamido) -3-[(1-methyl-tetrazole in 10 ml of anhydrous acetonitrile. To a suspension of 436 mg (0.00093 mol) of -5-yl) -thiomethyl] -3-cef-4-carboxylic acid. After obtaining a homogeneous solution, 160 mg (0.00095 mol) of 5-amido-4-hydroxy-2-propylamino-pyrimidine, trimethylsilyldiethylamine and 950 mg of phosgene dissolved in tetrahydrofuran Drop it off. The subsequent process is carried out similarly to Example 6.

In a similar manner, sodium-7- {D-α-[(2-ethylamino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacet amido} -3- [ Prepare (2-Methylamino-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 12

Sodium-7- {D-χ-[(2-allylamino-4-hydroxy-5-pyrimidinyl) -ureido] phenyl-acetamido} -3-acetoxymethyl-sep-3-m- 4-carboxylate

A reaction product of 332 mg (0.002 mole) of 5-amino-2-allyl-amino-4-hydroxy-pyrimidine with 200 mg of phosgene and 850 mg (0.002 mole) of cephalglycine dihydrate as starting materials similar to those of Example 1 It is prepared by the method. The subsequent process is carried out similarly to 5. Yield of sodium salt: 680 mg (56.5%)

IR spectrum: 1760, 1660, 1610, 1540 cm ^-1

NMR spectrum (DMSO + CD ₃ OD) signal (ppm): 2.05 (s, 3H), 3.4 (q, 2H), 3.9 (broad signal, 2H), 4.85 (m, 2H + d, 1H), 5.0 to 5.5 (m, 3H), 5.45 (s, 1H), 5.65 (d, 1H), 6.0 (m, 1H), 7.45 (5H), 8.05 (s, 1H).

Example 13

Sodium-7- {D-α- [2-allylamino-4-hydroxy-5-pyrimidinyl) -ureido] phenylacetamido} -3-[(1-methyl-tetrazol-5-yl ) -Thiomethyl] -cep-3-m-carboxylate

Example 1 starting with 3.2 g (0.005 mol) of the corresponding cephalosporin derivative and 0.83 g (0.005 mol) of 5-amino-2-allylamino-4-hydroxy-pyrimidine reacted with 500 mg of phosgene first. Prepared in a similar manner. Yield of sodium salt: 1.52 g (48%)

IR spectrum: 1760, 1660, 1615, 1545cm ^-1

NMR spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (d, 2H), 3.95 (s, 3H + Broad, Signal 2H), 4.4 (g, 2H), 4.85 (d, 1H), 5.0 to 5.5 ( m, 4H), 5.65 (d, 1H), 5.95 (m, 1H), 7.45 (m, 5H), 8.0 (s, 1H).

In a similar manner, the following compounds are prepared.

Sodium-7- {D-α-[(2- (3'-methylallylamino) -4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3 -[(1,2,4-thiadiazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

Sodium-7- {D-α-[(4-hydroxy-2-propargyl-amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(2 -Dimethylamino-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate,

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

Sodium-7- {D-α-[(2-cyclohexyl amino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate,

Sodium-7- {D-α-[(2-cyclohexyl amino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1- Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate,

Sodium-7- {D-α-[(2-cyclohexyl amino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-[(1, 2,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate,

Example 14

Sodium-7- {D-α- [α-hydroxy-2- (4'-hydroxy-xaclohexyl amino) -5-pyrimidinyl) -ureido] -p-hydroxy phenylacetamido} 3-acetoxy-methyl-sef-3-m-4-carboxylate

810 mg (0.002 mol) of 7- (D-α-amino-p-hydroxy-phenylacetamido) -3-acetoxymethyl-sep-3-m-4-carboxylate, and 5-amino-4-hydr A reaction product of 450 mg (0.002 mol) of oxy-2- (4′-hydroxy-cyclohexylamino) -pyrimidine with 200 mg of trimethylsilindiethylamine and phosgene was prepared in a similar manner to Example 5 . The subsequent process is carried out similarly to Example 6.

Yield of sodium salt: 615 mg (44.5%)

IR spectrum: 1760, 1660, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.75 (m, 8H), 2.05 (s, 3H), 3.35 (q, 2H), 3.5 to 4.0 (m, 1 + 3H), 4.80 (m, 2 + 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6.8 (d, 2H) 7.35 (d, 2H), 8.0 (s, 1H).

Example 15

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

Example 1 was prepared using 550 mg (0.00123 mol) of cephalosporin of Example 13 and 220 mg (0.0012 mol) of 5-amino-4-hydroxy-2- (2'-methoxyethylamino) -pyrimidine as starting materials. Prepared in a similar manner. The subsequent process is carried out similarly to the sixth in the implementation. Yield of sodium salt: 450 mg (59%)

IR spectrum: 1760, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.0 to 3.5 (m, 2 + 2 + 2H), 3.55 (s, 3H), 3.9 (s, 3H), 3.9 (s, 3H), 4.35 ( q, 2H), 4.85 (d, 1H), 5.45 (s, 1H), 5.65 (d, 1H), 6,8 (d, 2H), 7.35 (d, 2H), 8.0 (s, 1H).

In a similar manner, the following compounds are prepared.

Sodium-7- {D-α- {4-hydroxy-2- (2'-methoxy-ethylamino) -5-pyrimidinyl_-ureido] -p-hydroxy-phenylacetamido]- 3-[(1,3,4-thiadiazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 16

Sodium-7- {D-α-[(4-hydroxy-2- (3'-hydroxy-propyl amino) -5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} 3-acetoxy-methyl-sef-3-m-4-carboxylate

1.84 g of 5-amino-2- (3'-hydroxy-propylamino) -4-hydroxy-5-pyrimidine and 7-D-α-amino-p- reacted with 1 g of trimethylsilyldiethylamine and phosgene 4.05 g (0.01 mol) of hydroxy-phenylacetamido-3-acetoxymethyl-cef-3-em-4-carboxylic acid was prepared in a similar manner to Example 5 as a starting material.

Yield of sodium salt: 3.56 g (50%)

IR spectrum: 1760, 1670, 1620, 1550cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.85 (m, 2H), 2.05 (s, 3H), 3.0 to 3.7 (m, 2 + 2 + 2H), 4.85 (m, 2 + 1H), 5.40 (s, 1H), 5.55 (d, 1H), 6.85 (d, 2H), 7.3 (d, 2H), 8.05 (s, 1H).

The following compounds are prepared in a similar manner using the same cephalosporin derivative as starting material.

Sodium-7- {D-α-[(2-p-hydroxybenzylamino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido} -3-ace Oxymethyl-cef-3-m-4-carboxylate,

Sodium-7- {D-α-[(4-hydroxy-2-m, p-dioxymethylene-benzylamino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido] -3-acetoxymethyl-sef-3-4-emcarboxylate,

Sodium-7- {D-α-[(2-p-dimethyl amino-anilino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido] -3- Acetoxymethyl-sef-3-m-4-carboxylate.

Example 17

Sodium-7- {D-α-[(2-p-hydroxy-2-p-hydroxy-anilino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido]- 3-[(1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

218 mg (0.001 mol) of 5-amino-4-hydroxy-2-p-hydroxy-anilino-pyrimidine as a starting material were reacted with trimethylsilyl diethylamine and phosgene, Prepared in a similar manner to Example 5 by reacting with 460 mg (0.001 mol) of the corresponding cephalosporin derivative. Yield of sodium salt: 280 mg (38.5%).

IR spectrum: 1760, 1660, 1610, 1540 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 3.5 (q, 2H), 3.9 (s, 3H), 4.35 (q, 2H), 4.85 (d, 1H), 5.40 (s, 1H), 5.60 (d, 2H), 6.8 (d, 2H), 7.4 (m, 4H), 7.7 (d, 2H), 8.30 (s, 1H).

In a manner similar to that of Example 5 or 6, the following cephalosporin derivatives were prepared.

Example 28

Pivaloyloxymethyl-7- {D-α-[(2-cyclopropyl-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido) -3- [ (1-Methyl-tetrazol-5-yl) -thiomethyl] -cell-3-m-4-carboxylate

A solution of 900 mg (0.0013 mol) of sodium salt of Example 3 and 325 mg of pivaloyloxymethyl iodide 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 hydrogen carbonate are added. The ethyl acetate layer is then washed successively with water, dilute hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is stirred with anhydrous ether and filtered off with suction. Yield: 670 mg (66%)

IR spectrum: 1770, 1735 cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 0.9 (m, 4H), 1.10 (s, 9H), 1.95 (m, 1H), 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), 6.9 (d, 2H), 7.4 (d, 2H), 8.4 ( s, 1 H).

According to the above method, the following ester is prepared.

Pivaloyloxy methyl-7- {D-α-[(4-hydroxy-2-isopropyl amino-5-pyrimidinyl-ureido-p-hydroxy-phenylacetamido} -3-[( 1-methyl-tetrazol-5-yl) -thiomethyl] -cell-3-m-4-carboxylate,

Acetyloxy methyl-7 {D-α-[(4-hydroxy-2- (4'-hydroxy-cyclohexyl-amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetami Fig. 1-3- (1-Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate,

Fibaroyloxymethyl-7- {D-α-[(4-hydroxy-2- (3'-hydroxy-propylamino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacet Amido} -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate.

Example 29

Pivaloyloxy methyl-7- {D-α-[(4-hydroxy-2- (3'-methylallyl amino-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl acetamido } -3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate

Sodium-7- {D-α-[(2- (3'-methyl allylamino) -4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl acetamido] -3 3.4 g of [[1-methyl tetrazol-5-yl) -thiomethyl] -sef-3-m-4-carboxylate is used as a starting material and reacted with 1.2 g of pivaloyloxymethyl iodide. Prepared in a similar manner to Example 28. Yield: 2.62 g (68%)

IR spectrum: 1770, 1740cm ^-1

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.10 (s, 9H), 1.75 (d, 3H), 3.55 (q, 2H), 3.85 (Broad, 2H), 3.95 (s, 3H), 4.45 (m, 2H), 4.95 (d, 1H), 5.55 (s, 1H), 5.65 (m, 2 + 1H), 5.8 (dd, 2H), 5.75 (d, 2H), 7.35 (d, 2H), 8.0 (s, 1 H).

Example 30

Pivaloyloxymethyl-7- {D-α-[(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido] -p-hydroxy-phenyl acet amido ] -3-[(1-methyl tetrazol-5-yl) -thiomethyl] -cell-3-m-4-carboxylate

Prepared in a similar manner to Example 28 by reacting pivaloyloxy methyl iodide with the corresponding sodium salt as starting material. Yield: 64%

IR spectrum: 1770, 1730 cm ^-1 .

NMR Spectrum (DMSO + CD ₃ OD) Signal (ppm): 1.10 (s, 9H), 3.50 (q, 2H), 3.95 (s, 3H), 4.40 (q, 2H), 5.0 (d, 1H), 5.60 (s, 1H), 5.65 (d, 1H), 5.80 (dd, 2H), 6.75 (d, 2H), 7.3 (d, 2H), 7.7 (d, 2H), 8.0 (d, 2H), 8.38 ( s, 1 H).

Example 31

Sodium 7- {D-[(4-hydroxy-2-p-methylsulfonyl alinino-5-pyrimidinyl) -ureido] -p-hydroxy-phenylacetamido] -3-[(1 -Methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4-carboxylate

7- [D-α-amino- (p-hydroxy-phenylacetamido)]-3-[(1-methyl-tetrazol-5-yl) -thiomethyl] -cep-3-m-4- Example 1 starting product of a reaction product of 1.0 g (2.47 mmol) of carboxylic acid and 690 mg of 5-amino-4-hydroxy-2-p-methyl sulfonylanilino-pyrimidine with trimethylsilyl diethylamine and phosgene as starting materials Prepared in a similar manner. Yield of sodium salt: 940 mg (52%)

IR spectrum: 1765,1650,1600,1150 cm ^-1

NMR spectrum (DMSO + CD ₃ OD): Signal (ppm): 3.1 (s, 3H), 3.45 (q, 2H), 3.95 (s, 3H), 4.25 (m, 2H), 4.95 (d, 1H), 5.5 (s, 1H), 5.60 (d, 1H), 6.80 (d, 2H), 7.35 (d, 2H), 7.85 (dd, 4H), 8.30 (s, 1H).

Claims (1)

The mixture of the pyrimidine derivative of the general formula (III) or the pyrimidine derivative of the general formula (III) (in this case B, the compound of general formula (II) at a temperature of -20 to + 50 ° C. at a pH of 2.0 to 9.0 Are partially the same and some are different) to prepare the salts of cephalosporins of the general formula (I) or (I ') and their esters and physiologically acceptable inorganic or organic bases. Way.

Wherein A is phenyl, 4-hydroxyphenyl, cyclohexyl, cyclohexen-1-yl, cyclohexa-1,4-dien-1-yl, 2- or 3-thienyl, 2- or 3-furyl group Or a phenyl group di-substituted by the same or different substituents selected from chlorine, hydroxy and methoxy groups at the 3,4-position; Y represents a hydrogen atom or a methoxy group; D is a hydrogen atom, hydroxy, acetoxy, aminocarbonyloxy or S-Het group, wherein Het is 1-methyl-tetrazol-5-yl, tetrazol-5-yl, 3-methyl-1, 2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4- Thiadiazol-5-yl, 2-dimethylamizo-1,3,4-thiadiazol-5-yl, 2-dimethylamino-1,3,4-thiadiazol-5-yl, 2-form Mill amino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-oxadiazole- 5-yl, 1,2,3-triazol-4-yl, or 1,2,4-triazol-3-yl group; R is a hydrogen atom, methyl group, cyclopropyl group, hydroxy group, methoxy or ethoxy group, mercapto group, general formula

[Wherein R ₁ and R ₂ may be the same or different and may be a hydrogen atom, a straight or branched chain aliphatic hydrocarbon group having 1 to 6 carbon atoms which may contain 1 or 2 double bonds or triple bonds, 3 carbon atoms; A cycloalkyl group of 6 to 6, or an alkyl group substituted by a cycloalkyl group containing 3 to 6 carbon atoms in the cycloalkyl moiety and 1 or 2 carbon atoms in the alkyl moiety, or R ₁ and R ₂ Together may form an alkylene chain having 2 to 7 carbon atoms, wherein a 3- to 8-membered heterocyclic ring is formed.

Where R ₃ represents a formyl, acetyl or ethyloxycarbonyl group, morpholino, thiomorpholino, thiomorpholino, thiomorpholino-S-oxide or thiomorpholino- S, an S-dioxide group, or a group of the formula -NH-ZX, wherein Z and X are as defined below, and

Where n, R ₆ , R ₇ and R ₈ are as defined below, or a general formula

R ₉ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a free amino group or a methyl or dimethylamino group; E represents a hydrogen atom or a protecting group that can be readily degraded in vitro or in vivo; Z represents a straight or branched chain alkylene group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, substituted by substituent X; X represents a cyano group, a hydroxy group, a mercapto group, amino, aminocarbonyl, aminosulfonyl group or aminocarbonylamino group or groups of the following general formula;

- from here, R ₄ denotes a linear or branched alkyl group having 1 to 3 carbon atoms, R ₅ represents an alkyl group of hydrogen or C 1 -C 3 or, R ₄ and R ₅ taken together with the nitrogen atom to which they are attached Optionally a 3- to 5-membered monocyclic heterocyclic ring; n represents 0 or 1, R ₆ , R ₇ and R ₈ may be the same or different from each other, hydrogen, halogen, free amino group, alkylamino or dialkyl amino group, hydroxy or alkoxy group, formylamino group , Aliphatic acylamino group, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino group, nitro, alkylsulfonylamino group, formyl or alkylcarbonyl, aminocarboxyl group, alkylcarbonyloxy, alkoxy Carbonyl or alkoxycarbonyloxy group, aminocarbonyl, alkyl or dialkylaminocarbonyl, aminocarboxyl, alkylamino carboxyl, dialkylaminocarboxyl or alkoxycarbonylamino group, cyano, mercapto, alkylmercapto, alkyl Sulfinyl or alkylsulfonyl groups, aminosulfonyl, alkyl or dialkylaminosulfonyl groups, hydroxylsulfinyl groups or straight or branched alkyl groups; Naemyeo, each alkyl group in the above-mentioned groups herein may contain from 1 to 3 carbon atoms; B represents a reactive derivative of -NCO or group-NHCOOH.