WO1992008721A1 - Nouveaux composes de cephalosporine et procedes de preparation de ceux-ci - Google Patents

Nouveaux composes de cephalosporine et procedes de preparation de ceux-ci Download PDF

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Publication number
WO1992008721A1
WO1992008721A1 PCT/KR1990/000018 KR9000018W WO9208721A1 WO 1992008721 A1 WO1992008721 A1 WO 1992008721A1 KR 9000018 W KR9000018 W KR 9000018W WO 9208721 A1 WO9208721 A1 WO 9208721A1
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WIPO (PCT)
Prior art keywords
cephem
carboxylate
acetamido
aminothiazol
thiomethyl
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PCT/KR1990/000018
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English (en)
Inventor
Yong Zu Kim
Hun Seung Oh
Jae Hong Yeo
Jong Chan Lim
Won Sup Kim
Chan Sik Bang
Hyeon Joo Yim
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Lucky, Ltd.
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Application filed by Lucky, Ltd. filed Critical Lucky, Ltd.
Priority to AU66315/90A priority Critical patent/AU656886B2/en
Priority to CA002072883A priority patent/CA2072883A1/fr
Priority to PCT/KR1990/000018 priority patent/WO1992008721A1/fr
Publication of WO1992008721A1 publication Critical patent/WO1992008721A1/fr
Priority to NO92922608A priority patent/NO922608L/no
Priority to FI923156A priority patent/FI923156A/fi

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms

Definitions

  • the present invention relates to novel cephalosporin compounds, pharmaceutically acceptable non-toxic salts thereof, and physiologically hydrolyzable esters, hydrates and solvates thereof, which possess potent and broad antibacterial activities.
  • the invention also relates to processes for preparing the sane, and to pharmaceutical compositions containing the sane as active ingredients.
  • Antibiotics of cephalosporin series are widely used in therapy for treatment of diseases which are caused by general pathogenic bacteria in human beings and animals. It has been known that such antibiotics are useful for the treatment of diseases caused by bacteria exhibiting the resistance to other antibiotics, e.g. penicillin - resistant bacteria, and for treatment of penicillin - sensitive patients.
  • R is hydrogen or an organic group
  • R a is an etherifying monovalent organic group linked to the
  • B is -S- or
  • P is an organic group.
  • GB patent No. 1,522,140 discloses cephalosporin antibiotic compounds of the formula(B) which exist as syn isomers, or as a mixture of syn and anti isomers wherein the syn isomers are present in at least 90%,
  • R' is a furyl or thienyl group
  • R" is a C 1 ⁇ 4 alkyl, C 5 ⁇ 7 cycloalkyl, furylnethyl or thienylmethyl group ;
  • R''' is hydrogen or a carbamoyl, carboxymethyl, sulfonyl or methyl group.
  • an acylamido group has been introduced into the 7-position of the cephem nucleus as shown in the foregoing formula(B) and certain groups have been introduced into the 3-position thereof.
  • R 1 is amino or a protected amino group
  • R 2 is hydrogen, acyl, substituted or unsubstituted aryl, substituted alkyl, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, or a O- or S-containing 5-membered hetero cyclic group ;
  • R 3 is hydrogen or alkyl
  • R 4 is an acyloxyalkyl, acylthioalkyl, substituted or unsubstituted pyridiniumalkyl, substituted or unsubstituted heterocyclic thioalkyl, alkyl, hydroxy, or a substituted or unsubstitued thiazoliumalkyl group, or halogen ;
  • R 5 is carboxy or a protected carboxy group, wherein R 5 is COO- when R 4 is a substituted or unsubstituted pyridiniumalkyl group or a substituted or unsubstituted thiazoliunalkyl group ; and the dotted line "- - - - - - " represents a single bond or a double bond.
  • R 1 is amino or a protected amino group
  • R 2 is a substituted or unsubstituted lower aliphatic hydrocarbon group, or a cycloalkenyl group ;
  • R 1 and R 2 are the same as defined in the formula(D), respectively ;
  • R 4 is a protected carboxyl group ;
  • X- is an acid residue
  • R 1 is amino or a protected amino group
  • R 2 is a protected or unprotected lower aliphatic hydrocarbon group, cyclo(lower)alkyl, or eyelo(lower)alkenyl group ;
  • R 3 is (lower)alkylamino, N-protected(lower)alkylamino, di(lower) alkylamino, sulfo(lower)alkyla ⁇ ino, hydroxy(lower)alkylamino, N-protected hydroxy(lower)alkylanino, acyloxy(lower)alkyl, (lower)alkoxy(lower)alkoxy(lower)alkyl, di(lower)alkylamino (lower)alkyl, (lower)alkylthio(lower)alkyl, (lower)alkylthio, (lower)alkoxy(lower)alkoxy, (lower)alkoxy, hydroxy(lower)alkoxy, acyl(lower)alkyl, hydroxy(lower)alkylthio, di(lower)alkylamino (lower)alkylthio, N-containing unsaturated 5-me ⁇ bered heterocyclic group
  • R 4 is hydrogen or a (lower)alkyl group.
  • cephem compounds of the formula(F) and their salts in European patent application No.47,977
  • n is an integer of 0 or 1 ;
  • An is amino or a substituted amino group ;
  • R 2 is hydrogen, a substituted or unsubstituted carbamoyl group, a
  • R 1 is a substituted or. unsubstituted thiazolium group, a substituted or unsubstituted pyrazolium group, a tri(lower)alkyl ammonium group or a pyridinium group of the following formula
  • R a is (lower)alkyl [which is substituted with a substituent selected from the group consisting of cycloalkyl, nethyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl and sulfonyl], (lower)alkenyl or carboxy-substituted (lower)alkenyl, (lower) alkylthio or carboxy-substituted (lower)alkylthio, amino or mono-substituted amino [wherein the substituent is selected from the group consisting of (lower) alkyl, (lower)alkanoyl or aminobenzenesulfonyl], di(lower)alkylamino, carbamoyl [which is substituted by (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy, hydroxy or cyano], di(lower)alkylcarbamoyl, thiocar
  • R b is hydrogen, a carbamoyl group, or a group selected from the groups defined for R a ;
  • R c is hydrogen or a group selected from the groups as defined in the R a .
  • R c is hydrogen or a group selected from the groups as defined in the R a .
  • An objective of the present invention is to provide new antibiotic cephalosporin compounds of the formula(I), pharmaceutically acceptable non-toxic salts thereof, and metabolically labile esters and solvates thereof
  • R 1 is a C 1 ⁇ 4 alkyl (preferably methyl or ethyl), C 3 ⁇ 4 alkenyl (preferably allyl), C 3 ⁇ 4 alkynyl (perferably propargyl) group, or -C(R a )(R b )CO 2 H, wherein R a and R b , same or different, are a hydrogen atom or a C 1 ⁇ 4 alkyl group, or R a and R b form a C 3 ⁇ 7 cycloalkyl group with the carbon atom to which they are linked ;
  • R 2 is a C 1 ⁇ 4 alkyl (perferably a straight alkyl group such as methyl, ethyl, n-propyl or n-butyl), C 3 ⁇ 4 alkenyl (preferably allyl), C 3 ⁇ 7 cycloalkyl, substituted or unsubstituted anino or a substituted or unsubstituted phenyl (preferably phenyl, 4- hydroxyphenyl, 4-chlorophenyl, 3,4-dimethylphenyl, 2,4- dimethylphenyl or 2,6-dimethyoxyphenyl) group ;
  • C 1 ⁇ 4 alkyl perferably a straight alkyl group such as methyl, ethyl, n-propyl or n-butyl
  • C 3 ⁇ 4 alkenyl preferably allyl
  • C 3 ⁇ 7 cycloalkyl substituted or unsubstituted anino or a substituted or unsubstituted pheny
  • R 3 is hydrogen or a C 1 ⁇ 4 alkyl group(preferably methyl or ethyl) ; and Q is N or CH.
  • Another objective of the present invention is to provide processes for preparing the cephalosporin compounds of formula(I).
  • a further objective of the present invention is to provide pharmaceutical compositions comprising one or more of the cephalosporin compounds of formula(I) as active ingredients.
  • the new cephalosporin compounds of the present invention are either syn isomers or mixtures of syn and anti isomers which contain at least 90% of the syn isomer and not more than 10% of the anti isomer. Also, when the R 1 group of formula(I) compounds is -C(R a )(R b )CO 2 H, wherein R a and R b are diffierent, the carbon atom to which R a and R b are linked becomes an asymmetrical center, these compounds being diastereoisomers. Therefore, the present invention also includes such diastereoisomers of cephalosporin compounds of fornula (I), and mixtures thereof.
  • the solvates including hydrates of the compounds(I) are included within the scope of the invention.
  • the compounds of the formula(I) according to the present invention may exist in tautomeric forms and such tautomers are also included within the scope of the invention. Namely, when Q of the formula (I) is a carbon atom, the a ⁇ inothiazolyl group undergoes tautomerism to fon a iminothiazolinyl group, its tautomer, as follows :
  • the aainothiadiazolyl group forms iainothiadiazolinyl groups, its tautomers by tautomerism as follows :
  • the compounds of the fonula (I) also include the following resonance structures (I') and (I'') :
  • Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, a metal salt such as an alkali metal salt(e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt(e.g., calcium salt, magnesium salt, etc.), ammonium salt, etc.; an organic salt, for example, an organic amine salt(e.g., trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N.N'-dibenzylethylene-diamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino) methane salt, phenylethylbenzylamine salt ; dibenzylethylenediamine salt, etc.) etc.; organic carboxylic or sulfonic acid salt(e.g., formate, acetate, maleate,
  • the physiologicall hydrolyzable esters of the compounds (I) may include, for example, indanyl, phthalidyl, methoxynethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 5-methyl-2-oxo-1,3-dioxolan-4-yl esters, and other physiologically hydrolyzable esters which have been widely used in the technical fields of penicillin and cephalosporin antibiotics. These esters can be prepared in accordance with known methods.
  • cephalosporin compounds of the formula(I) exhibit high antibacterial activities against both Gram-positive and Gram-negative bacteria, and are especially useful in the therapheutic and prophylactic treatment of bacterial infections in human beings and animals.
  • the present invention also includes within its scope pharmaceutical compositions comprising one or more of the compounds ( I ) according to the present invention as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives.
  • the antibiotic compounds(I) of the invention may be formulated for administration, which nay be presented in unit dose form or in multidose containers.
  • the compositions may take various forms such as solutions, suspensions or emulsions in oily or aqueous vehicles, which can contain conventional additives such as dispersing agents, suspending agents, stabilizing agents, and the like.
  • the active ingredient may be formed into a dried powder that can be normally dissolved in an aqueous solution of sterile, pyrogen-free water, before use.
  • the compounds(I) may be also formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides.
  • compositions in unit dose form preferably comprise about from 50 to 1,500 mg of the active ingredient, depending on the age and body weight of the patient, the nature and the severity of the illness, and so on.
  • active compounds in general it has proved advantageous to administer the active compounds in an amount of about 500 to 5,000 mg per day in order to achieve the desired results, depending on the routes and frequency of administration.
  • dose of about 150 to 3,000 mg per day is thought sufficient, but it may be increased in case of treatment for specific infections caused by some strains.
  • the compounds(I) can be administered in combination with other antibiotics such as penicillins or other cephalosporins.
  • the compounds of the present invention as described above exhibit potent and broad antibacterial activities against Gram-positive bacteria and a variety of Gram-negative bacteria as well, particulary against Pseudomonas. Also, these compounds have high stability to ⁇ -lactanases produced by a number of Gram-negative bcteria.
  • Examples of especially preferred compounds (I) are the compounds (I-1) and (I-15) of the formula(I) wherein R 1 is -C(CH 3 ) 2 CO 2 H, R 2 is methyl or amino, R 3 is hydrogen, and Q is CH, and their pharmaceutically acceptable non-toxic salts. These compounds (I-1) and (1-15) posseses excellent antibacterial activities, especially against Pseudomonas.
  • cephalosporin compounds (I), pharmaceutically acceptable non-toxic salts thereof, or physiologically hydrolyzable esters or solvates (including hydrates) thereof may be prepared by reacting the compounds of the formula (II) with the compounds of the formula(HI) in the presence of a solvent, and then, if necessary, removing the amino protecting group and/or the carboxyl protecting group and/or reducing the S-oxide [that is, S ⁇ (O) n ] by a known method, before or after said reaction.
  • This process also constitutes a further aspect of the invention.
  • R 1 , R 2 , R 3 and Q are the sane as defined above ;
  • n is an integer of 0 or 1 ;
  • R 4 is hydrogen or an amino protecting group
  • R 5 is a C 1 ⁇ 4 alkyl, C 3 ⁇ 4 alkenyl or C 3 ⁇ 4 alkynl group, or -C(R a )(R b )CO 2 (R c ), wherein R a and R b , same or different, are a hydrogen atom or a C 1 ⁇ 4 alkyl group, or R a and R b may form a C 3 ⁇ 7 cycloalkyl group with the carbon atom to which they are linked ; and R c is hydrogen or a carboxyl protecting group ;
  • R 3 is a hydrogen atom or a carboxyl protecting group
  • L is a leaving group
  • the amino protecting group may include acyl, substituted or unsubstituted aryl(lower)alkyl(e.g. benzyl, diphenylaethyl, triphenylnethyl and 4-nethoxybenzyl), halo(lower)alkyl(e.g. trichloronethyl and trichloroethyl), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene or substituted cyclolidene.
  • the acyl group as an amino protecting group may include, for example, C 1 ⁇ 5 (lower) alkanoyl (e.g.
  • the acyl group can be substituted by 1 ⁇ 3 substituent(s) such as halogen, hydroxy, cyano or nitro.
  • the amino protecting group may include reaction products obtained fron amino groups and silane, boron or phosphorus compounds.
  • the carboxyl protecting group as R c of R 5 or R 5 may include for exanple, (lower) alkylesters (e.g. methylester and t-butylester), (lower) alkenylesters (e.g. vinylester and allylester), (lower) alkoxy (lower) alkylesters (e.g. methoxymethylester), (lower) alkylthio (lower) alkylesters (e.g. lethylthiomethylester), halo(lower)alkylesters (e.g. 2,2,2- trichloroethylester), substituted or unsubstituted aralkylesters (e.g.
  • benzylester and p-nitrobenzylester or silylesters, which can be selected after consideration of the chemical property of the desired compounds(I). It is desired that the aforementioned amino or carboxyl protecting groups may be readily removed under mild reaction conditions by a known method.
  • the leaving group L may include, for examples, halogen such as chlorine or fluorine, an (lower)alkanoyloxy group such as acetoxy, a
  • (lower)alkanesulfonyloxy group such as aethanesulfonyloxy, an arenesulfonyloxy group such as p-toluenesulfonyloxy, an alkoxycarbonyloxy groups and the like.
  • the starting laterials of the compounds(II) are known as intermediates conventionally employed for the preparation of cephalosporin compounds.
  • the dotted line of the formula(II) represents a single bond or a double bond, and therefore, the compounds of the formula(II) may be the compounds of the formula(II-a), or compounds of the formula (Il-b), or mixtures thereof :
  • the compounds of the formula(II) can be prepared by activating the compounds of the fonula(IV) or their salts with an acylating agent, and reacting with the compounds of the formula(V), as follows :
  • n, R 4 , R 5 , R 6 , Q and L are the same as defined above ; and the dotted line of the formula(V) presents a single bond or a double bond, so that the compounds of the formula(V) may be the compounds of the formula(V-a), or compounds of the fonuIa(V-b), or lixtures thereof
  • the compounds of the formula(II) are used preferably in an amount of from 1 to 2 equivalent(s) based on 1 equivalent of the compounds of the fornula(III).
  • Amino or acid protecting groups can be readily removed by a conventional deprotection methods which are well known in the field of cephalosporin antibiotics.
  • acid- or base-hydrolysis or reduction are generally applicable.
  • the protecting group is an amido group
  • Acid hydrolysis is preferable applicable to removal of such groups as tri(di)phenylmethyl or alkoxycarbonyl, and is carried out in the presence of an organic acid such as formic acid, trifluoroacetic acid, or p-tolueneacetic acid or an inorganic acid such as hydrochloric acid or the like.
  • the reaction for introducing the compounds(III) into the 3-position of compounds(II) to prepare compounds(I) is carried out in the presence of a solvent such as water, or a mixed aqueous solvent of water and a water-mixable solvent.
  • a solvent such as water, or a mixed aqueous solvent of water and a water-mixable solvent.
  • the pH of the solvent should range from 5 to 8, but preferably from 6 to 7.5.
  • An appropriate water-mixable solvent is acetonitrile or acetone.
  • reaction may be carried out at 40° to 100oC, preferably 60o to 80oC.
  • one or more salts selected from the group consisting of sodium iodide, potassiun iodide, sodium bromide, potassium bromide and potassiun thiocyanate can be used as stabilizing agents.
  • the separation and purification of the compounds(I) can be carried out using a known method such as recrystallization, column chromatography over silica gel or ion-exchange chromatography.
  • cephalosporin compounds(I) of the present invention show potent antibacterial activities against a variety of general pathogenic bacteria including Gram-negative and Gram-positive bacteria, therefore, they are especially useful in theraphy for treatment of bacterial infections in human beings and animals.
  • the minimal inhibitory concentrations(MIC) thereof against standard strains and against clinically isolated-strains were determined and compared with Ceftazidime of a known compound.
  • the in vitro antibacterial activity was determined by a twofold dilution method as described below :
  • I - 1 7-[ (Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxylprop-2-oxyimino) acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl)thiomethyl-3- cephem-4-carboxylate
  • In-vivo absorbency of the invented compounds( I ) was studied in SD rat(S) weighing 220 ⁇ 340g, as follows : The test compound was intravenously administered in a dose of 20mg/kf respectively to 2 ⁇ 5 rats. The blood samples from the femoral vein of the rats were taken every hour after administration, and analyzed by bio-assay(agar well method). The results were shown in Table 3.
  • reaction mixture was cooled to room temperature and neutralized with cone. hydrochloric acid.
  • the precipitates were filtered, washed with water (20ml) and ethyl alcohol (50ml) and dried in vacuo to give the above-indicated compound (8.1g) in pale yellow solid.
  • Preparation 6 Preparation of 1.4,6-triamino-2(1H)-pyrimidinethione Sodium metal (4.6g) was added to dried ethyl alcohol (100ml), and refluxed by heating for an hour. After malononitrile (6.6g) and thiosemicarbazide(9.1g) were added thereto, the reaction mixture was refluxed for 24 hours, cooled to room temperature. The precipitates were filtered, washed with ethyl alcohol (50ml), and dried under reduced pressure to give the above-indicated compound (8.3g) in white solid.
  • N-ethylthiourea (50ml), N-ethylthiourea (5.20g) was added and refluxed for an hour.
  • ethyl ( ⁇ )-2-cyanobutyrate 49.90g was added ethyl alcohol (40ml). After cone, aqueous ammonia solution(200ml) was added thereto over 10 minutes, the solution was stirred at 30 ⁇ 40oC for 30 minutes. Ether(500ml) was added to the solution and stirred for 10 minutes.
  • Preparation 13 Preparation of 1-(4-chlorophenyl)-4,6-diamino-2(1H)- pyrimidinethione N-(4-Chlorophenyl)-thiourea (llg) and malononitrile ( ⁇ .6g) were reacted in the same method as described in Preparation 12 to give the above-indicated compound (5.3g).
  • N-(2,4-Dimethylphenyl)-thiourea (10.8g) and malononitrile (6.6g) were reacted in the same method as described in Preparation 12 to give the above-indicated compound (5.7g).
  • N-(2,6-Dimethoxy ⁇ henyl)-thiourea (11.5g) and malononitrile (6.6g) were reacted in the same method as described in Preparation 12 to give the above-indicated compound (6.2g).
  • N-(4-hydroxyphenyl)-thiourea (9.3g) and malononitrile (6.6g) were reacted in the same method as described in Preparation 12 to give the above-indicated compound (4.1g).
  • N-cyclopropylthiourea (6.2g) and malononitrile(6.6g) were reacted in the same method as described in Preparation 12 to give the pale yellow above-indicated compound(3.7g) .
  • the compound(4.4g) prepared in (B) was dissolved in N,N-dimethyl acetamide(30ml). To the solution were added triethylamine (3.5m ⁇ ) and mesithylene sulfonyl chloride(2.3g) at 0oC, and stirred for 20 minutes. After adding 7-aminocephalosporanic acid (2.9g), the reaction mixture was stirred again for 2 hours. To the mixture was added ethyl acetate (300ml), and it was washed with 1%-hydrochloric acid (100ml), sodium chloride solution(l ⁇ ml) and distilled water(200ml). The separated organic layer was dehydrated, and concentrated. Formic acid (40ml) was added to the residue. After the solution was stirred for 2 hours at room temperature, the recipitates were filtered off.
  • the compound (24.3g) prepared in (A) was dissolved in a mixed solvent of ethyl alcohol(100ml) and tetrahydrofuran (50ml). After aqueous 5N-sodium hydroxide solution(20ml) was added thereto, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was neutralized with 5N-hydrochloric acid, and the organic solvent was removed under reduced pressure. To the residue was added ethyl acetate(1l), and it was washed twice with distilled water(500mfl). The separated organic layer was dehydrated, and concentrated to give the above-indicated compound(19.8g) in white solid.
  • the compound(27.9g) prepared in (A) was dissolved in a mixed solvent of ethyl alcohol(100ml) and tetrahydrofuran(50ml). Afterwards, a 5N-sodium hydroxide aqueous solution (40ml) was added thereto, and the solution was stirred for 2 hours at room temperature. The reaction mixture was neutralized with 5N-hydroehioric acid (40ml) , and the organic solvent was removed under reduced pressure. To the residue was added ethyl acetate(1l), and it was washed twice with distilled water (500ml). The separated organic layer was dehydrated and dried to give the above-indicated compound(23.1g) in a pale yellow solid.
  • the reaction mixture was washed twice with 1% hydrochloric acid(200ml), saline solution(200ml) and distilled water (200ml). The separated organic layer was dehydrated, and concentrated. To the residue was added formic acid (50ml). The solution was stirred for 2 hours at room temperature and the formed solid was filtered off. The filtrate was concentrated under reduced pressure, and then triturated with ethyl ether. The solid was filtered, washed, and dried to give the above-indicated compound (3.32g) in a yellow solid.
  • bromine (12.9g) was added slowly in small portions at -15oC, and the mixture was stirred for 5 minutes at -15 ⁇ -10oC.
  • Potassium thiocyanate(3.7g) dissolved in methanol(55ml) was then added dropwise to the mixture at temperatures of -10 to -5oC, and the mixture was stirred for 2 hours at 0oC.
  • the reaction mixture was poured into ice water (1.2-5), and stirred for 30 minutes. The precipitates were filtered and dired to give the above-indicated compound (12.2g) in pale brown.
  • 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid (2.0g) was dissolved in dried dimethylacetamide(20ml), and then cooled to -10oC. Triethylamine(1.5ml) and mesithylene sulfonyl chloride(2.3g) was added therein, and the mixture was stirred for an hour at -10oC. After addition of 7-amino-cephalosporanic acid(3.26g) and triethylamine (3ml), the mixture was stirred for 2 hours at room temperature. Water (100ml) was added to the reaction mixture.
  • Preparation 26 Preparation of 3-acethoxymethyl-7-[(Z)-2-(5-amino- 1,2,4,-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino) acetamido]-3-cephem-4-carboxylic acid A. Preparation of 2-(ethoxyiminp)malononitrile
  • Preparation 27 Preparation of 3-acethoxymethyl-7-[(Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino) acetamido]-3-cephem-4-carboxylic acid A. Preparation of 2-(tert-buthoxycarbonylprop-2-oxyimino)malononitrile 2-(hydroxyimino)malononitrile (95g) and tert-butyl-2-bromo-2-methyl propionate (240g) were reacted in the same method as described in (B) of Preparation 25 to give the above-indicated compound (176g).
  • Example 3 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino) acetamido]-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl -3-cephem-4-carboxylate
  • the pH of the mixture was adjusted to 7.1 ⁇ 7.2 with a sodium carbonate solution, and acetonitrile (1ml) . was added thereto. After stirring for 4 hours at 75oC, the mixture was cooled to room temperature. The pH was adjusted to 3 ⁇ 3.5 with 2N hydrochloric acid, and the precipitates were filtered, washed with distilled water (5ml), and chromatographed over silica gel. Elution with a 5 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound(300mg) in a white solid.
  • Example 7 Synthesis of 3-(1-allyl-4,6-diaminopyrimidinium-2-yl)thiometl ⁇ yl -7-[(Z)-2-(2-aminothiazol-4-yl)-2-(propen-1-oxyimino)acetamido] -3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propene-1-oxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 1-allyl-4,6-diamino-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 1 to give the above-indicated compound (310mg).
  • Example 11 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop- 2-oxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate
  • Example 14 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop -2-oxyimino)acetamido]-3-(1-butyl-4,6-diaminopyrimidinium-2- yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxylic acid dihydrochloride (500mg) and 1-butyl-4,6-diamino-1-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 13 to give the above indicated-compound (230mg).
  • Example 20 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxymethoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate
  • Example 25 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino) acetamido]-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3- cephem-4-carboxylate
  • Example 28 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (ethoxyimino)acetamido)-3-(1,4,6-triaminopyrimidinium-2-yl) thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) was reacted in the same manner as described in Example 25 to give the above-indicated compound (280mg) in a yellow solid.
  • Example 32 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- ( ⁇ ethoxyimino)acetamido]-3-(4,6-diamino-1-methylpyrimidiniua -2-yl)thiomethyl-3-cephem-4-carboxylate
  • Example 33 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (methoxyimino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium -2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diaraino-1-ethyl- 2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 32 to give the above-indicated compound (230rag).
  • Example 35 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl ⁇ -2- (methoxyimino)acetamido]-3-(1-allyl-4,6-diaminopyrimidiniuB -2-yl)thiomethyl-3-cephera-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (methoxyimino)acetamido]-3-cephem-4-carboxylic acid (500mg) and 1-allyl-4, 6-diamino-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 32 to give the above-indicated compound(170mg).
  • Example 37 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (ethoxyiraino)acetamido]-3-(4,6-diamino-1-ethylpyrimidinium -2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-1-ethyl-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 32 to give the above-indicated compound(270rog).
  • reaction mixture After adjusting the pH of the reaction mixture to 7.3 ⁇ 7.5 with a sodium bicarbonate solution, the reaction mixture was stirred for 4 hours at 70oC. The mixture was cooled to room temperature, and insoluble materials were filtered off, and pll of the filtrate was adjusted to 4. After concentration under reduced pressure, the residue was chromatographed over silica gel. Elution with a 4 : 1 (v/v) mixture of acetonitrile/distilled water gave the above-indicated compound (200mg) in a pale white solid.
  • Example 41 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazo]-3-yl)-2- (carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1- ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate
  • Example 42 Synthesis of 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (2-carboxyprop-2-oxyimino)acetamido]-3-(4,6-diamino-1- propylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-cephera-4-carboxylic acid(500mg) and 4,6-diamino-1-propyl-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 40 to give the above-indicated compound(190mg).
  • Example 43 Synthesis of 7- ⁇ (Z)-2-(5-araino-1,2,4-thiadiazol-3-yl)-2- (2-carboxyprop-2-oxyimino)acetamido]-3-(l-butyl-4,6-diamino pyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate 3-acetoxymethyl-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2- carboxyprop-2-oxyimino)acetamido]-3-cephem-4-carboxylic acid(500mg) and l-butyl-4,6-diamino-2(lH)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 40 to give the above-indicated compound(160mg).
  • the above-indicated compound (150mg) in a yellow solid was prepared in the same method as described in Example 45 except for using 4,6-diamino-1-ethyl-5-methyl-2(lH)-pyrimidinethione (200rag) obtained in Preparation 8 in place of 4,6-diamino-l,5-dimethyl-2(1H)-pyriraidinethione.
  • Example 52 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxymethoxyimino)acetamidol-3-(4,6-diamino-1-phenylpyrimidinium-2- yl)thiomethyl-3-cephem-4-carboxylate 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxymethoxyimino) acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diaraino-1-phenyl-2(1H) -pyrimidinethione (200mg) were reacted in the same manner as described in Example 60 to give the above-indicated compound (190ng).
  • Example 54 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino) acetamido]-3-(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl -3-cephem-4-carboxylate
  • Example 55 Synthesis of 7-[(Z)-2-(2-arainothiazol-4-yl)-2-(ethoxyimino) acetamido]-3-[1-(4-chlorophenyl)-4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate
  • Example 56 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop- 2-oxyimino)acetamido]-3-[4,6-diamino-1-(2,4-dimethylphenyl)- pyrimidinium-2-yl]thiomethyl-3-cephem-4-carboxylate
  • Example 58 Synthesis of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop -2-oxyimino)acetamido]-3-[4,6-diamino-1-(2,6-dimethoxyphenyl) -pyrimidiniura-2-yl]thiomethyl-3-cephem-4-carboxylate 3-Acetoxy ⁇ ethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carbo ⁇ yprop-2-oxyimino)acetamido]-3-cephem-4-carboxylic acid (500mg) and 4,6-diamino-1-(2, 6-dimethoxyphenyl)-2(1H)-pyrimidinethione (200mg) were reacted in the same manner as described in Example 50

Abstract

Nouveaux composés de céphalosporine répondant à la formule (I), leurs sels non toxiques pharmaceutiquement acceptables, et leurs esters et solvates physiologiquement hydrolysables. Dans ladite formule, R1 représente un groupe alkyle C¿1-4?, alcényle C3-4, alcynyle C3-4, ou -C(R?a)(Rb)CO¿2H, où Ra et Rb sont identiques ou différents et chacun représente un atome d'hydrogène ou un groupe alkyle C¿1-4?, ou R?a et Rb¿ ensemble forment un groupe cylcloalkyle C¿3-7? avec l'atome de carbone auquel ils sont liés; R?2¿ représente un groupe alkyle C¿1-4?, alcényle C3-4 ou cylcoalkyle C3-4, un groupe amino substitué ou non, ou un groupe phényle substitué ou non; R?3¿ représente hydrogène ou un groupe alkyle C¿1-4?; et Q représente N ou CH. On a également prévu un procédé de préparation desdits composés, ainsi que des compositions pharmaceutiques qui les contiennent.
PCT/KR1990/000018 1990-11-09 1990-11-09 Nouveaux composes de cephalosporine et procedes de preparation de ceux-ci WO1992008721A1 (fr)

Priority Applications (5)

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AU66315/90A AU656886B2 (en) 1990-11-09 1990-11-09 Novel cephalosporin compounds and processes for preparation thereof
CA002072883A CA2072883A1 (fr) 1990-11-09 1990-11-09 Composes de cephalosporine et methodes de preparation de ces composes
PCT/KR1990/000018 WO1992008721A1 (fr) 1990-11-09 1990-11-09 Nouveaux composes de cephalosporine et procedes de preparation de ceux-ci
NO92922608A NO922608L (no) 1990-11-09 1992-07-01 Nye cefalosporinforbindelser og fremgangsmaater til deres fremstillin
FI923156A FI923156A (fi) 1990-11-09 1992-07-08 Nya kefalosporinfoereningar och foerfaranden foer framstaellning av dem.

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CA002072883A CA2072883A1 (fr) 1990-11-09 1990-11-09 Composes de cephalosporine et methodes de preparation de ces composes
PCT/KR1990/000018 WO1992008721A1 (fr) 1990-11-09 1990-11-09 Nouveaux composes de cephalosporine et procedes de preparation de ceux-ci

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0584797A2 (fr) * 1992-08-24 1994-03-02 Lucky Ltd. Dérivés de céphalosporine et des procédés pour leur préparation
EP0635509A2 (fr) * 1993-07-23 1995-01-25 Lucky Ltd. Dérivés de céphalosporine et procédés pour leur préparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR930007264B1 (ko) * 1990-08-17 1993-08-04 주식회사 럭키 신규한 세팔로스포린 화합물과 그의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034760A1 (fr) * 1980-02-23 1981-09-02 Hoechst Aktiengesellschaft Dérivés de céphalosporine, des compositions pharmaceutiques les contenant et procédé pour leur préparation
AT369748B (de) * 1978-05-26 1983-01-25 Glaxo Group Ltd Verfahren zur herstellung von neuen cephalosporinantibiotika

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2005787A1 (fr) * 1988-12-29 1990-06-29 Masao Wada Composes de cephalosporine
KR930007264B1 (ko) * 1990-08-17 1993-08-04 주식회사 럭키 신규한 세팔로스포린 화합물과 그의 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT369748B (de) * 1978-05-26 1983-01-25 Glaxo Group Ltd Verfahren zur herstellung von neuen cephalosporinantibiotika
EP0034760A1 (fr) * 1980-02-23 1981-09-02 Hoechst Aktiengesellschaft Dérivés de céphalosporine, des compositions pharmaceutiques les contenant et procédé pour leur préparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0584797A2 (fr) * 1992-08-24 1994-03-02 Lucky Ltd. Dérivés de céphalosporine et des procédés pour leur préparation
EP0584797A3 (en) * 1992-08-24 1994-06-08 Lucky Ltd Novel cephalosporin compounds and processes for the preparation thereof
EP0635509A2 (fr) * 1993-07-23 1995-01-25 Lucky Ltd. Dérivés de céphalosporine et procédés pour leur préparation
EP0635509A3 (fr) * 1993-07-23 1995-03-15 Lucky Ltd Dérivés de céphalosporine et procédés pour leur préparation.

Also Published As

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AU656886B2 (en) 1995-02-23
AU6631590A (en) 1992-06-11
FI923156A0 (fi) 1992-07-08
CA2072883A1 (fr) 1992-05-10
NO922608L (no) 1992-09-01
FI923156A (fi) 1992-07-08
NO922608D0 (no) 1992-07-01

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