CS792A3 - tRIFLUOROMETHYL-1-CARBA-(1-DETHIA)CEPHEM, PROCESS OF ITS PREPARATION AND APHARMACEUTICAL COMPRISING THEREOF - Google Patents

Description

Trifluoromethyl-1-carb-1-dethia / cefem and the pharmaceutical composition containing it

Technical field

BACKGROUND OF THE INVENTION The present invention relates to 1-carba- / 1-dethia / Cafalosporin anti-biotics, intermediates for their preparation, pharmaceutical compositions containing the antibiotic and methods of treating infectious diseases in humans and animals.

BACKGROUND OF THE INVENTION 1-Carba-1-dethia / cephalosporin antibiotics have a bicyclic ring system of the following structural formula with the numbered positions commonly used in the cephem nomenclature system

1-Carba- (1-dethium) cephalosporins are referred to herein as 1-carbacephalosporins or as 1-carba- (1-de-thia) for simplicity. -3-cephem-4-carboxylic acid or as a derivative thereof

The process for the preparation of 1-carbacephalosporins and their carbon-substituted 3-substituted derivatives is broadly described in U.S. Pat. No. 4,268,666 (Ghristensen et al.), Which discloses Hirataa et al. and 3-halo 1-carbo-cephalosporins, while Hatanaka et al., Tetrahedron Letters, 24, 44, pp. 4837-4838 (1983) discloses the preparation of 3-hydroxy- 1-carbacephalosporins.

Although numerous, safe and effective β-lactam class antibiotics are known and clinically used, intensive research on the search for new antibiotics with improved efficacy, especially with regard to micro-organisms insensitive or resistant to numerous known antibiotics, continues.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention relates to 7-acyl-amino-1-carboxamido-3-cephem-4-carboxylic acid antibiotics substituted at the 3-position with a trifluoromethyl group. The position 7 of these antibiotics is substituted by an acylamino group, for example, by D-aryl glycylamide or by an oxo amino acetylamino group substituted by a heterocycle. The invention also relates to pharmaceutical compositions comprising antibiotics, antibiotic intermediates, and processes for their preparation. Examples of such anti-biotics include 7-β-D-phenylglycylamido-1-carba- [1-dethia] -3-trifluoromethyl-4-cephem-4-carboxylic acid, 7- β-Dp-hydroxyphenylglycyldimethyl-1-carbohydrate. - [1-dimethia] -3-trifluoromethyl-3-cephem-4-carboxylic acid, 7- (3-Dm-methylsulfonylaminophenylglycylamido-1-carb-1-dethia) -3-trifluoromethyl-3- cefem-4-carboxylic acid and 7β- (2-aminothiazol-4-yl) - N -methoxyiminoacetyl-7-amino-1-carbox-1-dethia / 3-trifluoromethyl-4-3-cephem-4 carboxylic acid.

Accordingly, the present invention provides compounds of formula I wherein RCONH1 ·

(1) R, hydrogen, (C1-C4) -alkyl-C1-4-alkoxy or -NHCHO-carbon, -al-formamido-R2-hydrogen or carboxy-protecting group, R (1) hydrogen, hydroxy, alkyl of 1 C 5 -C 5 alkyl, halogen substituted halogen, halogen C 1 -C 5 alkoxy, C 5 -C 5 acyloxy, C 1 -C 5 acyloxy, C 1 -C 5 acyl, alkylthio and R is a carboxylic acid moiety of RCOOH, and where hydrogen is a pharmaceutically acceptable acid salt.

The term "carboxylic acid moiety" includes at the 7-position the side chains known in the cephalosporin and carbocephalo-spore chemistry and the 6-position side chain known from penicillin chemistry. The colorants are side chains of carboxylic acid residues of 1 to 2 carbon atoms, for example, when R is hydrogen: alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with cyano, carboxy, atom halogen, amino, C 1 -C 4 alkoxy, C 1-4 alkylthio, trifluoromethyl or trifluoromethylthio; a naphthyl group, a phenyl group or a substituted phenyl group of the formula

wherein aaa * independently of one another is hydrogen, halo, hydroxy, cyano, nitro, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkylthio group of 1 to (C-C,), (C 1-C alkyl alkyl) alkylsulfonylamino, (Cbox ,y), carbamoyl, hydroxymethyl, aminomethyl, carboxymethyl, (C 4-C halogen) haloalkyl or perhaloalkyl C 1 -C 4; a group of the formula - 4 - Λ / z / m - = ¾ where a and a * are as defined above and wherein Z is an oxygen atom or a sulfur atom and m is 0 or 1; aryimethyl of formula E3 - CIL, - wherein R5 is naphthyl, thienyl, furyl, benzothienyl, benzoaminothiazolyl, benzofuryl, pyridyl, 4-pyridylthio, pyrimidyl, pyridazinyl, indolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and the like 1 'aryl groups substituted with amino, hydroxy, cyanospine, nitro, halogen, C1-4 alkyl, C1-4 alkoxy, phenyl, substituted phenyl or alkyl Isulfonyl & a substituted methyl group of the formula wherein R 1 is cyclohex-1,4-dienyl, phenyl or substituted phenyl having the formula

wherein a and a * are as defined above and wherein R 1 is as defined above for R 1 and Q is a hydroxy group, alkanoyloxy group. C 1 -C 4, carboxy, sulfo, amino, sulfoamino or substituted amino of the formula -NE-GNG-R yn R x O-5 - wherein R is hydrogen or alkyl having 1 to 3 carbon atoms, R 4 is (C 1 -C 4) alkyl, furyl, thienyl, phenyl, halophenyl, nitrophenyl, styryl, halo, aryl, nitrostyl or a general formula

R 2 wherein R X represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R 2 represents a hydrogen atom, a C 1 -C 3 alkylsulfonyl group, a C 1 -C 3 alkyl group or a C 1 -C 4 alkyl group; or Q represents a substituted amino group of formula a.

NH-C

Q t »

R 2 wherein R 2 is as defined above and q is 3 or 2; or Q is a substituted amino group of formula

-HNC (= O) - and n - (C 1-6 W) or Q represents a benzamido group of the formula

Q where x is 1 to 3; or Q is pyridone or hydroxy substituted pyridonylcarbonylamino

X wherein R is as defined above; or Q is pyrxylcarbonyl amino;

wherein the group is optionally substituted with an alkyl group. with 1 to 4 carbon atoms, amino, carboxy, hydroxy or halogen; or Q is imidazolyl or pyrazolyl

wherein said imidazolyl or pyrazolyl group is optionally substituted by C 1-4 alkyl, carboxy, amino or halogen; or Q represents a benzpyridazin-4-one group or a general formula tautomer thereof

or

Η Ν where R is as defined above and where t 1 is 3; or Q represents a benzpyranone group of formula * 5. -C. o or R means

and c - t ΝΓ j ÓR ^ or ÍL · - C -

5 M R. 12

R 2 in which R 4 is the same as R 4 or R 6, as defined above, R 4 represents a hydrogen atom or a halogen atom and R 8 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms substituted by an atom halo, carboxy-substituted alkyl or cycloalkyl of formula bi-C-γΕγ b * where n and n are independently hydrogen or C 1 -C 3 alkyl, n 0, 1, 2 or 3 aba bspol together with the carbon atom to which they are attached form a 3 to 6 membered carbocyclic ring and R? is hydroxy, amino, C1 -C4 alkylamino, or C1 -C4 dialkylamino, or R8 is C1-4 alkyl - 8-substituted phenyl or phenyl a group substituted by one or two identical or different groups of a group comprising a C 1 -C 4 alkyl group, a hydroxy group, a halogen atom, a carboxy group or a protected carboxy group; or R 8 represents an alkyl group having 1 to 4 carbon atoms substituted by an amino group or a protected amino group; or R 8 represents an alkenyl group having 1 to 4 carbon atoms; or R 8 is a cyclic lactam group of the general formula

Wherein R 2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms or R 8 is an arylmethyl group of the general formula S 1 - CH 2 - wherein R 1 is as defined above. The compounds of formula (I) wherein R @ 1 is hydrogen or a pharmaceutically acceptable salt thereof can inhibit the growth of microorganisms pathogenic to humans and animals and can be used to combat disease. The compounds of the formula I are obtained in the same manner as in the same stereochemical form as the semisynthetic cephalosporin antibiotics as described below. As used herein, the term "carboxy protecting group" refers to ester derivatives of the carboxylic acid group commonly used to block or protect the carboxylic acid group during reactions carried out on other functional groups of the compound. Examples of such carboxyl protecting groups are 4-nitrobenzyl, 4-methylbenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4, d-trimethoxybenzyl, 2,4,6- trimethylbenzyl, penta-methylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, -9,4'-dimethoxybenzhydryl, 2,2 ', 4,4'-tetramethylbenzhydryl, tert-butyl, tert-amyl, trityl , 4-methoxytriethyl, 4,4'-dimethoxytrityl, 4,4 ', 4 "-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl , β - (di / n-butyl) methylsilyl / ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) prop-1-en-3-yl and the like. is not critical if the derivatized carboxylic acid is stable under the conditions of the following reaction or subsequent reactions elsewhere in the ring system and can be removed at the appropriate moment without disrupting the residual moiety. A preferred carboxylic acid protecting group is an allyl group. Similar carboxyl-protecting groups used in the chemicephalosporin, penicillin, and peptides can also be used to protect the carboxy group of any substituent on the azetidinone. Further examples of such protecting groups are given in E. Halsam " Protectives Groups in Organic Chemistry " (J.G.W.). McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5 and T.W. Greene, " Protective Groups in Organic Synthesis " by John Wiley & Sons, " Protective Groups in Organic Synthesis ", New York, NY, 1981, Chapter 5 " Related " Protected Carboxy " means that carboxy is substituted by one of the aforementioned protecting groups . The term "amino protecting group" refers to a substituent of the amino group commonly used to block or protect an amino group in the reaction of other functional groups of the compound. Examples of such amino protecting groups are formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl and iodoacetyl, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl; -cyano-benzyloxycarbonyl, 2- (4-xenyl) isopropoxycarbonyl, 1,1-di-phenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- / p-toluyl (prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyl-oxycarbonyl) , 2-methylcyclohexanyloxycarbonyl, 2- / 4-toluylsulfonyl / ethoxycarbonyl, 2- / methylsulfonyl / ethoxycarbonyl, 2- / triphenylphosphino / ethoxycarbonyl, 9-fluorenylmethoxycarbonyl / "PMOC", 2- / trimethylsilyl / ethoxycarbonyl, allyloxy carbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1 piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2- (nitro) phenylsulfonyl group, diphenylphosphine oxide group and the like amino protecting group Preferred amino protecting groups include allyloxycarbonyl, tert-butoxycarbonyl and trityl groups. The term includes such similar groups as those used for this purpose in chemicephalosporin, penicillins and peptides. For example, other such amino-protecting groups are those disclosed in J.W. Protecting Groups in Organic Chemistry (J.G.7). McCmie, 3d., Plein Press, New York, N.Y., 1973, Chapter 2 and T.W. Greene ' ' ' ' ' ' s in Grouge in Crganic " " John V ' and Sons, New York, N.Y., 1981, Chapter 7 (Organic Synthesis Protecting Groups). Similarly, the term "protected amino" means that it is an amino group substituted with the aforementioned protecting group.

In the above definition of compounds of formula (I) with a C 1 -C 6 -alkyl group, a straight-chain or branched-chain alkyl group, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n -pentyl, n-hexyl, 3-ethylpentyl and the like alkyl groups; cyano-substituted C1-6 alkyl means, for example, cyanomethyl, cyanoethyl, 4-cyanobutyl; C 1-6 alkyl substituted by carboxy means, for example, carboxymethyl, 2-carboxyethyl, 2-carboxy-propyl, 4-carboxybutyl, 5-carboxypentyl; Halogen-substituted C1-6alkyl is, for example, chloromethyl, bromomethyl, 2-chloroethyl, 1-bromo, thyl, 4-chlorobutyl, 4-bromopentyl, 6-chlorohexyl, 4-fluorobutyl, 3- fluoropropyl, fluoromethyl. C1 -C6 alkyl substituted with an amino group means, for example, 2-aminoethyl, aminomethyl, 3-aminopropyl and 4-aminobutyl; C 1 -C 6 -alkyl substituted by C 1 -C 4 -alkoxy means, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, ethoxymethyl, 3-propoxypropyl, 3-ethoxybutyl, 4-tert-butyl, -butyloxybutyl, 3-methoxypentyl, 6-methoxyhexyl; C 1 -C 6 alkyl substituted with C 3 -C 4 alkylthio refers to, for example, methylthiomethyl, 2-methylthioethyl, 2-ethylthiopropyl, 4-methylthiobutyl, 5-ethylthiohexyl, 3-tert-butyl, 3-tert- C 1 -C 6 alkyl substituted by trifluoromethyl means, for example, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl; C1-6 alkyl substituted with trifluoromethyl means, for example, trifluoromethylthiomethyl, 2-trifluoromethylthioethyl, 2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl and 5-trifluoromethylthiohexyl.

When R is a substituted phenyl group in the compound of formula (I) wherein the substituent is optionally aaa and / or is a substituent, a halogenophenyl group such as 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 2,4 -dichlorophenyl and 3,5-dichlorophenyl. hydroxyphenyl, for example 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl and 3,4-dihydroxyphenyl; an alkylphenyl group such as 2,6-dimethoxyphenyl, 4-tert-butoxyphenyl, 4-methoxy-3-ethoxy phenyl and 4-n-propoxyphenyl; alkanoyloxy-phenyl, for example 2-acetoxyphenyl, 4-propionoxyphenyl, 4-formyloxyphenyl, 4-acetoxyphenyl, 3-butyryloxyphenyl and 3 acetoxyphenyl; an alkylphenyl group such as 4-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-ethylphenyl, 4-ethyl-3-methylphenyl and 3,5-dimethylphenyl; alkylthiophenyl, for example, 4-methylthiophenyl, 3-n-butylthio-phenyl, 2-methylthiophenyl, 3,4-dimethylthiophenyl and 3-n-propylthiophenyl; aminophenyl, for example, 2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl and 3-aminophenyl; alkanoylamino, for example 2-acetylamino, 4-acetylamino, 3-propynylamino and 4-butylamino; alkylsulfonylamino such as 3-methyl-sulfonylamino, 4-methylsulfonylamino, 3,5- (dimethylsulfonylamino) phenyl, 4-n-butylsulfonylaminophenyl and 3-ethylsulfonylaminophenyl; carboxyphenyl 3,4-dicarboxyphenyl, 2,4-dicarboxyphenyl; carbamoyl-phenyl, for example 2-carbamoylphenyl, 2,4-dicarbamoylphenyl and 4-carbamoylphenyl; for example, hydroxymethylphenyl is 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenyl such as 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxyphenyl, for example, 2-carboxymethylphenyl, 3-carboxymethylphenyl, and 3,4-dicarboxymethylphenyl; and substituted phenyl groups having various substituents, for example, 4-chloro-3-methylphenyl, 4-fluoro-3-hydroxyphenyl, 3,5-dichloro-4-hydroxy-phenyl, 4-hydroxy-3-chlorophenyl, 4-hydroxy-3 -methylphenyl, 4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl, 4-tert-butoxy-2-hydroxyphenyl, 4-acetylamino-3-methoxyphenyl, 3-amino-4-ethylphenyl, 2- aminomethyl-4-chlorophenyl, 2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethyl-4-fluorophenyl, 2-acetoxy-4-aminophenyl, 4-acetoxy-3-methoxyphenyl, 3-iso-propylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl, 4-carboxy-3-hydroxyphenyl, 4-ethoxy-3-hydroxyphenyl, 4-methylsulfonylamino-2-carboxyphenyl, 4-amino-3-chlorophenyl-13 and 2-carboxymethyl-4 -hydroxyphenyl group.

When R is a substituted phenyl group or a C 1 -C 4 haloalkyl group or a C 1 -C 4 haloalkyl group, chloromethyl, iodomethyl, trichloromethyl, trichloroethyl groups are exemplified. , 2-bromo-2-methylpropyl, chloropropyl and fluoromethyl.

By way of example, where R in formula X is a general formula a

when m is zero, phenylacetyl, 4-hydroxy-f. 3-ethoxyphenylacetyl, 3-carboxyphenylacetyl, 4-acetoxyphenylacetic, 3-ethoxyphenylacetyl, 3-carboxyphenylacetyl, 4-acetoxyphenylacetyl, 3-carboxyphenylacetyl, 4-chlorophenylacetyl, 3-ethoxyphenylacetyl, 3-carboxyphenylacetyl, 4-acetoxyphenylacetyl; aminophenylacyl and 4-acetylaminophenylacetyl; and wherein m 1 and Z are alkyl, and include phenoxyacetyl, 4-chlorophenoxyacetyl, 4-fluorophenoxyacyl, 3-aminophenoxyacetyl, 3-hydroxyphenoxyacetyl, 2-methoxyphenoxyacetyl, 2-methylthiophenoxyacetyl, 4-acetylaminophenoxyacetyl, 3, 4-dimethylphenoxyacetyl and 3-hydroxymethylphenoxyacetyl; and wherein m 1 and Z are sulfur, phenylthioacetyl, 4-chlorophenylthioacetyl, 3,4-dichlorophenylthioacetyl, 2-fluorophenylthioacetyl, 3-hydroxyphenylthioacetyl, and 4-ethoxyphenylthioacetyl.

Examples of R in formula I are those of the general formula R3CH2 - wherein R1 is aryl, are naphthyl, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl, 2-benzothienylacetyl, 2-benzofurylacetyl, indole-2- ylacetyl, 1H-tetrazol-1-ylacetyl, oxazol-2-ylacetyl, oxazol-4-ylacetyl, thiazol-4-ylacetyl, 2-aminothiazol-4-ylacetyl, 1,3,4-oxadiazole-2-one; ylacetyl, 1,3,4-thiadiazol-2-ylacetyl-14-yl, 5-ethyl-1,3,4-thiadiazol-2-ylacetyl and benzoamico-thiazoyl and the like groups optionally substituted by amino, alkylsulfonylamino having 1 to 4 atoms carbon, hydroxy, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

Examples of those in which R in formula I is a substituted methyl group of the formula R 4 -CH / Q / - where Q is amino, carboxy, hydroxy or sulfo include, for example, 2-carboxy-2-phenylacetyl, 2-carboxy-2- (4-oxyphenyl) acetyl, 2-amino-2-phenylacetyl, 2-amino-2- (4-hydroxyphenyl) acetyl, 2-amino-2- (3-chlorophenyl) acetyl; 4-hydroxyphenyl / acetyl, 2-amino-2- (3-chloro-4-hydroxyphenyl) acetyl, 2-amino-2- / cyclohex-1,4-diene-1 -yl / acetyl, 2-hydroxy-2-phenylacetyl, 2-formyloxy-2-phenylacetyl, 2-sulfo-2-phenylacetic, 2-sulfo-2- (4-methylphenyl) acetyl and 2-acetyloxy-2 - / 3-hydroxyphenyl-acetyl, 2-amino-2- (2-thienyl) -acetyl, 2-amino-2- (3-benzothienyl) acetyl, 2-amino-2- (1H-tetrazol-1-yl) (acetyl, 2-hydroxy-2- [1,3,4-thiadiazol-2-yl] acetyl, 2-amino-2- (2-aminothiazol-4-yl) acetyl, 2-carboxy-2- [2- thienyl / acetyl, 2-carboxy-2- / benzothien-2-yl / acetyl and 2-hydroxy-2- / ben zofur-2-yl / acetyl; and when Q is a substituted amino group of formula

Rx! in -NK-C0 / -NC (O) -Ry, examples of such acyl groups are the 2- (N-methyl-N-benzoylcarbamoylamino) -2-phenylactyl, 2- (N-methyl-N-benzoylcarbamoylamino) 2-phenylacetyl, 2- (R-methyl-N-inaminoylcarbamoylamino) -2- (2-furyl) acetyl, 2- (N, N-dimethylcarbamoylureido) -2- (4-chlorophenyl) acetyl; [N-methyl-N- [2-chloro-inamoyl] carbamoylamino-7-2- (2-thienyl) acetyl and 2- [N-ethyl-N-acetylcarbamoylamino] -2- (4-hydroxyphenyl) acetyl] ; and when Q is a substituted amino group of Formula 15

C

examples of such groups include the group 2 - "" (3-methylimidazolidin-2-on-1-yl) carbonylamino-7-phenylacetylalkyl, 2- (3-acetylimidazolidin-2-one-1-yl). carbonylamino-7-2-phenylacetylamino, 2- [3-methylsulfonylimidazolidin-2-on-1-yl] -2- (2-thienyl) acetyl, and 2- [3-acetylhexahydropyrimidin-2-on-1-yl] carbonylamino-7-2-phenylacetyl; and when Q represents a hydroxy-substituted benzamido group of the general formula;

Examples of such acyl groups include, but are not limited to, 2- (2,4-dihydroxybenzamido) -2-phenylacetyl, 2- (4-hydroxybenzamido) -2- (4-hydroxyphenyl) acetyl, 2- (3,4-dihydroxy). -benzamido / -2- (2-aminothiazol-4-yl) acetyl, 2- [3,5-dihydroxy-benzamido] -2- (3-thienyl) acetyl and 2- (2-hydroxybenzamido) -2- / 2 -benzofuryl / acetyl group.

When Q is a hydroxy-substituted pyridine-carbonylamino group, 2-hydroxypyridin-4-on-6-ylcarbonylamino and 3-hydroxypyridin-4-on-6-ylcarbonylamino are exemplified as examples. When Q is a pyridylcarbonylamino group, examples include pyridin-3-ylcarbonylamino, 4-aminopyridin-3-ylcarbonylamino, 5-chloropyridin-2-ylcarbonylamino, 3-carboxypyridin-4-ylcarbonylamino and 4-aminopyridinyl. n-2-ylcarbonylamino. When Q is an imidazole or pyrazole group, 2-aminoimidazol-4-ylcarbonylamino, 5-carboxy-2-methylimidazol-4-ylcarbonylamino, 5-carboxypyrazol-3-ylcarbonylamino, 3-aminoprazol-4- and carbonylamino and 4-hydroxypyrazol-5-ylcarbonylamino. When Q is a benzpyridazin-4-one-3-ylcarbonylamino group, examples of group Q are given in the formula.

NH -

NH -

Examples of when R in the compound of formula I is a keto group or an oximino-substituted group of the formula RK - C - and Re - G - 5h 5µ

N 1 is the 2-oxo-2-phenylacetyl, 2-oxo-2- (2-thienyl) acetyl, 2-oxo-2- (2-aminothiazol-4-yl) acetyl group and oximino-substituted groups; , for example, 2-phenyl-2-methoxyiminoacetyl, 2- (2-thienyl) 2-ethoxyiminoacetyl, 2- (2-furyl) -2-methoxyiminoacetyl, 2- (2-benzothienyl) -2-carboxymethoxyiminoacetyl, 2- (2-thienyl) -2- (2-carboxyethoxy) iminoacetyl, 2- (2-amino-1, 2,4-thiadiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) 2-methoxyiminoacetyl, 2- (2-chlorothiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (2-carboxy-prop-2-yl) oxyiminoacetyl, 2- [2-aminothiazol-4-yl] -2- (2-carbamoylprop-2-yl) oxyiminoacetyl, 2- (5'-smino-1,3,4-thia-17-diazol-2-yl) -2-methoxyiminoacetyl 2- (2-Aminothiazol-4-yl) -2- (pyrrolidin-2-one-yl) oxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (1-methylpyrrolidin-2-one-3) -yl / oxyiminoacetyl, 2-phenyl-2- [pyrrolidin-2-on-3-yl] oxyiminoacetyl, 2 - [2-Amino-oxy-zol-4-yl] -2- (1-ethyl-pyrrolidin-2-on-3-yl) oxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2- (1-ethylpiperidine-2) -on-3-yl / -2-oxyiminoacetyl; and 2- (2-furyl) -2- (pyrrolidin-2-on-3-yl) oxyiminoacetyl.

By way of example, where R in the compound of formula (1) represents a group of the formula

Rc - G - 5 «,

.G

R, 2 'SS are referred to in U.S. Pat. No. 4,634,617 to Hamashima. Examples of the substituent R @ 1 are hydrogen and, as examples of R @ 4, phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionally protected aminothiazolyl, thiadiazolyl and aminothiazolyl groups, and as examples R @ 9 alkenyl of 1 to 1. 3 carbon atoms and a group of formula

When R @ 1 in formula (1) is C1 -C4 alkyl substituted with phenyl or substituted phenyl, benzyl, 4-hydroxybenzyl, 4-chloro-benzyl, 3-carboxybenzyl, 3-chloro- 4-hydroxybenzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-hydroxy-2-phenylpropyl, 3-phenylbutyl and the like phenylalkyl groups.

When R 8 is an alkyl group having 1 to 4 carbons, substituted with an amino group or protected with an amino group, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-aminopropyl and the like are exemplified, the amino group being protected by protecting the amino group.

18

When R8 is an alkenyl group having 2 to 4 carbon atoms, examples include groups of allyl, butene-2, butene-3, butene-1 and the like. R1 may be a side-chain substituent 2 known from carbacephalosporin chemistry, such as hydrogen, C1-C5 alkyl, halogen-substituted C1-C5 alkyl, halo, hydroxy, 1 to 5-alkoxy carbon, acyloxy of 1 to 5 carbon atoms, acyl of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms, and nitrile group These substituents and others are exemplified in U.S. Pat. No. 4,302540 (Hirata et al., 4, 291164- (Hiraat et al.) and 4,744,494 to Hirata et al. Examples of the 1-carbacephalosporins defined above are shown in Table I below, wherein the individual compounds are represented by the general formula (I) - 19 -

Table I

2-thienylmethyl-2-thienylmethyl-2-furylmethyl-4-pyridylthiomethyl-4-chloro-methyl-4-chloro-thienylmethyl-2-thienylmethyl-2-thienylmethyl- aminobenzyl α-carboxybenzyl α-hydroxybenzyl 2-aminothiazol-4-ylmethyl (2-aminothiazol-4-yl) methoxyiminomethyl (1H) tetrazolylmethyl- (2-aminothiazol-4-yl) (2-carboxyprop-2-yl) oxyiminomethyl- -amino-1,4-cyclodienyl-methyl-4-aminopyridin-3-ylmethyl-α-sulfoaminobenzyl α-sulfoaminothien-2-ylmethyl 4-aminopyridazin-3-ylmethyl

Ri R2

Η H

Η H

Η H

Η H

Η H

Η H

Η H

0CH3 H

Η H

Η H

Η H

Η H

Η H

Η H

Η H

Η H

Η H

Η H

H H

Η H

Η H

Η H

- H - 20

Table I / continued /

R 1, R 2 (2-aminothiazol-4-yl)

Cyclo-thoxyimino-methyl-H Na + (2-aminothiazol-4-yl) (2-, carboxyprop-2-yl) oxyiminomethyl-K +

2-thienylmethyl-1H-2-aminothiazol-4-yl

(syn-methoxyimino) methyl-H

Li +

H

H ch3-ncch2-C1-CH2-cis3-2,6-dimethoxy. phenyl 14-methylphenyl-4-chlorophenyl-3-hydroxyphenylphenoxymethylphenoxymethyl-4-chloro-phenoxymethyl-4-hydroxy-phenyloxymethyl-benzyl-benzyl-4-fluoro-phenylthiomethyl-4-chlorobenzyl-2-aminomethyl-benzyl

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H benzyl benzyl benzyl

pMB

H

Na +

pMB benzyl benzyl benzyl

pNB

H

H

H benzyl

H

H

H 21

Table I / continued /

Ri r2

3-carboxymethylbenzyl H

2-thienylmethyl H

2-thienylmethyl H

2-benzothienylmethyl H

2-benzofurylmethyl H

1,3,4-thiadiazol-2-ylmethyl H

1,3,4-oxadiazol-2-ylmethyl H

α-aminobenzyl H

t-aminobenzyl H

α-amino- (4-hydroxybenzyl) H

? -amino- (3-methylsulfonylaminobenzyl) H

α-formyloxybenzyl H

α-carboxy- (4-hydroxybenzyl) H

α-sulfobenzyl H

[alpha] - [[beta] -3-methyl-3-H (2-chlorobenzoyl) ureido] benzyl

N 6 - [N 3 - (methylaminocarbonyl) N 3 - H methylureido] -4-hydroxybenzyl

α- (3-acetylimidazolidin-2-one-1-yl-H-carbonylamino) benzyl

α- (3-methylsulfonylimidazolidin-2-H-1-ylcarbonylamino) benzyl

α- (4-ethylpiperizin-2-dione-1-yl H carbonylamino) benzyl

α- (4-hydroxybenzamido) benzyl H

α- (3,4-dihydroxybenzamido) benzyl

H benzyl

pNB

H

H

H

H

pMB 2,2,2-trichloroethyl

H

H

H

H

H

H

H

H

H

H

H

The compounds of formula (I) may be prepared according to the process of Scheme 1 below according to the invention.

Scheme 1

t-BocNH

5) TFA 4) 23-3-Trifluoromethanesulfonyloxy ("triflate") or "Ti" / carbabefem starting material according to Scheme 1 can be prepared as described by Evans et al., U.S. Pat. The triflate starting material is first reacted with thiophenol under nitrogen in the presence of an amine and preferably a tertiary amine such as, for example, triethylamine or diisopropylethylamine to give benzhydryl-7-β-phenoxyacetylamino-1-carbonic acid. The 3-phenylthio-3-phenylthio-3-cephem-4-carboxylate is then reacted under nitrogen with tributyltin hydride in the presence of a free radical initiator such as 2,2-azo / bis / isobutyl. with ethylene nitrile (AIBN), with heating, preferably at 120 ° C, to give 3- (tri-n-butyl) stannane intermediate product as indicated, this tin intermediate being allowed to react with a positive halogenating agent and preferably with bromo to give benzhydryl-7-phenoxyacetylamino-1-carba- [1-dethione] -3-bromo-3-cephem-4-carboxylate. The 3-bromo product was then heated to 70 ° C and then treated with a mixture of cadmium, copper (I) chloride, dibromodifluoromethane and dimethylformamide to give benzhydryl-7-phenoxyacetylamino-1-carba- (1-de-thia). 3-trifluoromethyl-3-cephem-4-carboxylate. While dimethylformamide may be preferred, other suitable compounds may be used in the general formula

wherein R @ 1 is hydrogen or C1 -C4 alkyl, R @ 1 and R @ 4 are independently C1 -C4 alkyl or, together with the nitrogen atom to which they are attached, form a saturated ring, such as a pyrrolidine or piperidine. This intermediate is then acylated with di-tert-butyl dicarbonate (T-BOC) (20%) and worked up.

butyloxycarbonylamino (intermediate) (not shown). Other changes to the t-butoxycarbonyl protecting group for the phenoxyacetyl protecting group are described in European Patent Application No. 24 / 8836996.5, Publication No. G30 877, Cocket No.X-6913./ t-Butoxycarbonyl group / t-BOC / and benzhydryl ester group they can be removed in a manner known per se by, for example, trifluoroacetic acid (TFA) in the presence of snisol. The 7-emino-3-trifluoromethyl nucleic acid obtained is then acetylated on the nitrogen-activated form of the desired 7-acyl group. According to Scheme 1, the D-phenylglycyl group is introduced by reacting the 7-amino nucleic intermediate (7-amino nucleus intermediate). -boc protected with D-phenylglycine anhydride, formed with t-protected biphenylglycine and isobutylchromate as follows: 0

t-boc NO

Any remaining t-butoxycarbonyl protecting groups are removed by treatment with trifluoroacetic acid. Anyway, phenoxyacetyl and t-butoxycarbonyl groups are used as amino-protecting groups and benzhydryl groups as carboxy-protecting groups, O-lactam chemists. it is clear that other amino or carboxy protecting groups may be used as functional equivalents.

The process of Scheme 1 is carried out under substantially anhydrous conditions, meaning that substantially no water is present. Therefore, the solvents are dried in the reaction before use. Suitable solvents include methylene chloride, chloroform, methanol, toluene and dichloroethane or trichloroethane, tetrahydrofuran (TEF), dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (ELiPA), dimethylacetamide, tetrahydropyran, dioxane, acetonitrile, diethyl ether, dimethyl acetamide, dimethyl sulfoxide, dimethyl ethane and mixtures thereof. free radical initiators are described in - 25 -

Laird with Jcrgensen, "Eree Radical Chain Reaction", J. Crg. Chem., Vol. 55, No. 1, pp. 9-27 (1990). Suitable free radical initiators include AIBN, Bu4 SnH, Cl4 CBr, benzoyl peroxide and the like in the above-cited article on page 19 and in Table VI. Other initiators include a photolysis, where X is chlorine, bromine and iodine (Schlecker, Henkel, Seebach, Chem.). games. 110, p.2880 (1977), O2 / Russell, Kaup, J.A.C.S. 91, 3851 (1967), metal salts (Toong, Yates, J. Chem. Soc., Chem. Commun., P.205, 1978) and thiohydroxamic acid esters / Barton, Crich, Kretzachman, Tetra. Flight. 25, 1955 (1984). By "positive halogenating agent" is meant a compound having an electrophilic halogen or, in other words, a halogen-carrying compound with a positive charge. Examples which may be mentioned are SbE5, F2, JE5, BrE4, SE4, Cl2, HOC1, CH3 CO / gNCl, N-cis-L-succinamide, Me2CQCl, NOgCl, SO2C12, Br2, 1,3-dibromohydro- toin, Ν, Ν-dibromobenzenesulfonamide, HOBr, N-bromosuccinimide, C ^ EEEgQgEfcg, JC1, JBR, J2, N-iodosuccinamide and 1,3-diiodo-5,5-di-methylhydroxide in ·

Scheme 2 illustrates a process for preparing compounds of Formula X using the method of Scheme 1 together with the use of a p-nitrobenzyl group protecting a carboxy group instead of benzhydryl. - 26

Scheme-2

The intermediate trifluoroacetate salt is then treated with a mixture of N-methylmorpholine / NMM, N-tert-butoxycarbonylemino / 3-fluorophenylacetic acid (NH 4 -Boc-FPAA) and 1-chloro-3,5-dimethoxytriazine (CDMT). to prepare a t-Boc protected intermediate. The intermediate is then treated with zinc and hydrochloric acid followed by treatment with trifluoroacetic acid.

In general, the 3-trifluoromethylcarbacefems of the formula I can be prepared as shown in Scheme 3. 27

Schemes 3

3) TFA CO 2 CO 2 CH 2 CH 2 CH 2

2S

In Scheme 3, the 3-triflate intermediate in the anhydrous organic solvent is converted to the 3-bromo intermediate by a displacement reaction using a bromide containing salt, preferably lithium bromide, in the presence of a hindered amine base. Bromide containing salts include alkali metal bromide, tetraalkyl ammonium bromide, and tetraalkyl phosphonium bromide. A preferred hindered amine base is 2,6-lutidine. This 3-bromo intermediate is then converted directly to the 3-trifluoromethyl intermediate by treatment with a mixture of zinc and dibromodiormomethane in the presence of bromobutyl and dimethylformamide. p-Nitrobenzyl-7 f? The -phenoxyacetyl-amino-1-carbamoyl-3-trifluoromethyl-3-cephem-4-carboxylate intermediate is then treated with zinc / hydrochloric acid to remove the p-nitrobenzyl ester group and then esterified with allyl bromide. The phenoxyacetyl group is removed in a manner known per se using, for example, phosphorus pentachloride / pyridine / isobutyl alcohol to give 7-amino-1-carba- [1-dethia] -3-trifluoromethyl-3-cephem-4-carboxylic acid hydrochloride. This intermediate is then treated with an activated form of the desired carboxylic acid to form the 7-acyl substituent as shown in Scheme 1. The 4-Allyl carboxy protecting group can then be removed by a known deprotection method, for example, using tetrakiatrifenylphosphine palladium (0), followed by removal of the t-boc protecting group with trifluoroacetic acid to give the compound of formula (I). As shown in Scheme 1, the amino and carboxy protecting groups are used, for example, in the lactam chemistry industry, which other protecting groups may be used.

According to both Schemes 1 and 3, the 3-bromo intermediate is subjected to a mixture of a copper halide / bromide, chloride or iodide /, dihalodifluoromethane, either camel or zinc, and dimethylformamide or a compound of formula

Wherein R, R "and R *" are as defined above. Obviously, in the case of this mixture, in situ, trifluoromethyl copper. It is preferably reacted with a 3-bromo intermediate to form a 3-trifluoromethyl intermediate. Preferably, at least one molar equivalent of trifluoromethylcadmium or trifluoromethylzinc with copper is used to provide at least theoretically at least one equimolar amount of trifluoromethyl copper.

The reaction in which 3-triflate is converted to the 3-bromo meoproduct is illustrated in Scheme 4:

Scheme 4

Ve. in Scheme 4, R 4 and R 6 are as defined above, wherein A represents an amino or acylamino group protecting the compound of formula (F) - R - CNH - wherein R is as defined above. The reaction is carried out in aprotic solvents as defined above. 3-Triflat is combined with lithium bromide and preferably with 2,6-lutidine. The mixture is maintained at a temperature of about 60 ° C to 70 ° C and preferably at about 65 ° C for a sufficient period of time to form the 3-bromo compound. This heating time is preferably longer than 16 hours and is preferably about 48 hours. Generally arisen

- 3C products include a mixture of »2 / Δ3 isomers. Then, the isomer can be isomerized to the 3 3 isomer by contacting the 2 2 isomer with a cross-linking base such as 1,8-diazabicyclo [·5.0 < 4 > As noted above, the 3-bromo compound is a useful intermediate for the preparation of compounds of Formula I. However, it is noted that the 3-bromo compound itself is a useful anti-biotic. Accordingly, the 3-bromo intermediate can be converted similarly to 3-trifluoromethyl to 1-carba- [1-dethia] -3-cephem-3-bromo-4-carboxylic acids or their pharmaceutically acceptable salts. For example, according to Scheme 3, the step of converting the 3-bromo compound to 3-trifluoromethyl may be omitted for the preparation of (3-bromo / cefems).

The term "hindered amine base" encompasses both aromatized tosaliphatic hindered amines. Aromatic hindered amines include amines with alkyl substituents attached to the aromatic carbon atom adjacent to the nitrogen atom. Preferred substituents are larger than methyl, such as ethyl, isopropyl, tert. Preferred aromatic amines are hindered amines with at least two aromatic carbons adjacent to the nitrogen, substituted substituents such as alkyl groups having from 1 to 6 carbon atoms, and alkoxy groups having from 1 to 4 carbon atoms. At least one nitrogen atom has a suitable substituent, and aliphatic hindered amines, including tertiary amines such as diisopropylethylamine, ethyldiphenylamine, may also be used.

The invention also relates to 7-amino-1-carbacephalosporin compounds and their salts and esters useful as intermediates in the preparation of antibiotics of formula X. These intermediates have the general formula IIR &

wherein S 1, R 2 and R 3 are as defined above for Formula I The invention also relates to acid addition salts of the compounds of Formula II, and when R 2 is hydrogen as well as their alkali metal salts with alkali metals. earth and amines. The 7-amine compounds of formula (II) form salts with conventional acids such as mineral acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and such as ganosulfonic acids, for example methanesulfonic acid, n-butanesulfonic acid, benzenesulfonic acid , p-toluenesulfonic acid, and naphthalenesulfonic acid. Such salts are used to isolate and purify 7-amino acids and their salts. The compounds of formula II may also form alkali metal and alkali metal salts in the form of hydroxides, carbonates and bicarbonates. Examples of such salts are the sodium, potassium, calcium and magnesium salts. Salts can also be formed by 3 amines such as dibenzylamine, cyclohexylamine, triethylamine, ethanolamine and diethanolamine. 7 (ω-Amino-1-carba-3-cephem compounds of general formula IIse, acylate at the nitrogen atom with a carboxylic acid of the general formula)

RCOOH wherein R is as defined above, or a reactive derivative thereof for the compound of formula I. N-acylation can be carried out by generally known acylation methods using N-acylation of the cephalosporin core, for example, 7-ACA and 7-ADCA. For example, the core (2) is coupled with an acid of the formula RCOOH in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, exemplified as carbodiimides. Alternatively, the carboxylic acid can be converted to a reactive derivative of the carboxy group and then used in the N-acylation to react it. The reactive derivatives of the carboxy group which may be used are acid halides, acid azides, acid anhydrides, as well as active esters formed with ethyl fluoroformate and isobutyl chloroformate; phenylcarbamates; N-hydroxyimides, such as those formed with N-hydroxysuccinimide and N-hydroxyphthalimide; further with hydroxy-32-benzotriazole (HBT) and other similar active carboxy derivatives. During the N-acylation it is desirable to protect all free amino or carboxy groups in the carboxylic acid of the general formula RCOOH.

The invention further relates to an intermediate of formula III

wherein R i, R e R * are as defined above, R 1 is C 1 -C 6 alkyl or aryl and W is a protecting amino or carboxylic acid acyl group. The term aryl refers to a monocyclic arene group in which it is possible to remove a hydrogen atom from a carbon atom of a core such as phenyl, tolyl and dimethylphenyl and also includes aryl-substituted alkyl groups having 1 to 6 carbon atoms. The term " carboxylic acid-derived anyl group " includes groups in the 7-position side chain, known in the cephalosporin and in the carbacephalosporin chemistry, and the 6-position of the side chain known from penicillin chemistry, and may have the general formula

O

N R - C - wherein R is as defined above.

The invention also relates to compounds of formula IV, which are preferred embodiments 33 - (IV).

wherein R 6, R 6 are as defined above, and pharmaceutically acceptable salts thereof. Particularly preferred compounds are those wherein R 1 is as defined above for R 1 and are thienyl, furyl, benzofuryl, benzothienyl, benzoaminothiazolyl, phenyl, substituted phenyl and cyclohexadienyl groups. a phenyl, 4-hydroxyphenyl or 2-aminothiazole compound.

The invention also relates to a process for the preparation of a compound of formula V

with a mixture of ammonium halide, cadmium or zinc, dihalodifluoromethane and either with dimethylformamide or with a compound of formula

Wherein R *, R "and R * H are as defined above, or with trifluoromethyl-copper in a substantially anhydrous organic solvent, wherein X is a halogen atom, R 2, R *, and R 1 are as defined above and R 1 R is is a protected amino group or R5 is a hydrogen atom and R6 is an acyl group derived from carboxylic acid. The process can be carried out at a temperature of about 10 to about 90 DEG C. and preferably at about 60 DEG C.

The invention also relates to a process for the preparation of a general compound

/ VII /

wherein the compound of formula (VIII) is reacted

(VIII) in an inorganic organic solvent or in the absence of a solvent with at least one equivalent of the compound of general formula HSn / R1 in the presence of a free radical initiator, wherein R1, R2, R4, R8, R8 and R6 are as defined above and R 6 is a hydrocarbylthio radical having 1 to 10 carbon atoms or a hydrocarbyl phenyl group having 1 to 10 carbon atoms. The reaction mixture is preferably heated to about 120 ° C. The terms "hydrocarbylthiol residue" and "hydrocarbyl-ethyl radical" each having from 1 to 0 carbon atoms are represented by - 35 - R 5 's - and R 5' s -, wherein R p is an alkyl group having 1 to 10 carbon atoms; C 1 -C 10 alkyl substituted by hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, trifluoromethyl, carboxy, carboxyl, amino, alkylamino of 1 to 4 carbon atoms; 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms in the alkyl moiety, a halogen atom, a cyano group, a phenyl group or a substituted phenyl group, as set forth above for the E symbol; (C 2 -C 10) alkenyl; C 3-7 cycloalkyl; a 5- or 6-membered heterocycle of the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, benzoaminothiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, triazinyl and pyrazinyl; benzheterocycles, benzothienyl, benzofuryl, indolyl, benzimidazolyl or benztriazolyl; wherein said five-membered or six-membered heterocyclic groups and benheterocyclic groups are optionally substituted with C 1 -C 4 alkyl, halo, hydroxy, C 1 -C 4 alkoxy, amino, carboxy, cyano or carbamoyl; if the heterocyclic group or the benzheterocyclic group contains a basic nitrogen atom in the ring, it also has a C1 -C4 alkyl quaternary salt »

The invention also relates to a process for the preparation of compounds of general formula VI

in which the compound of general formula I - 36 - / VII / is reacted

in an inert organic solvent with a positive halogenating agent, preferably in an amount of about 1.0 to 1.2 equivalents, wherein R 2, and R 1 are as defined above, and X is a fluorine, chlorine, bromine or iodine atom. The reaction mixture temperature is about -78 ° C to room temperature (21 ° C) and is preferably -78 to -40 ° C.

The invention also relates to a process for preparing a compound of general formula IX

wherein, R 1, R 6 and R 6 are as defined above, and wherein A is an amino group, a protected amino group or a group of formula I - R - C - NE 2 -

where is tt. as defined above, by reacting a compound of formula X

in the presence of a bromide-containing salt, such as the bromide-alkaline metal tetrahydro-bromide and tetraalkylphosphonium bromide -37-, and preferably lithium bromide and hindered amine base, such as 2,6'-lutidine for and at the temperature required to prepare the compound of Formula 1X1. for the preparation, 21 to -70 ° C, the most preferred being 65 ° C.

The invention also relates to the aforementioned process including isomeric reaction, wherein the isomer is converted to 3 isomertane such that the isomer is treated with a strong base such as DBU or DBN.

In addition, the invention relates to compounds of formula IX as such. When, in the compound of formula (IX), A 1 is NH 4, the compound of formula (IX) forms a salt, as shown for compound (II), and the compound may similarly acylate.

The invention also relates to a method of treating infectious diseases and other animals and pharmaceutical compositions for such purposes. The therapeutic method of the invention is based on administering to humans and animals an antibiotic and effective amount of a compound of formula (I) in a non-toxic dose or compound of formula (IX), wherein it is a hydrogen atom or a pharmaceutically acceptable salt thereof. The 1-carbacephalosporins prepared by the process of the invention form salts with suitable bases, especially pharmaceutically acceptable non-toxic salts. The carboxy group in 1-carbacephalosporin may form salts with hydroxides, with carbonates or with bicarbonate of alkali metals or alkaline earth metals. Examples of suitable salts include the pharmaceutically acceptable salts of sodium, potassium, calcium and magnesium. Salts can also be formed by amines such as dibenzylamine, dicyclohexylamine, triethylamine, ethanolamine, diethanolamine. Similarly, when 1-carbacephalosporin is substituted with two or more carboxy groups, double salts or trisodium salts are obtained by conventional salt preparation methods. The 1-carbacephalosporin compounds of the present invention having an amino group as a substituent at the 7-position of the side chain form salts with suitable acids to provide the antibiotic in the form of pharmaceutically acceptable salts. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Carbeeephalosporins of the invention of the general formula wherein the hydrogen atom may form an inner salt when the 7-position substituent includes a free amino group.

An antibiotic effective amount is about 25 mg to about 2 g. The compound, salt or ester thereof may be administered in a single dose or in multiple doses throughout the day. Treating possible for week to 10 days. or longer depending on the duration of the infection. The appropriate dose and regimen will be determined by the physician depending upon the factors of the body, such as weight and age of the treated, condition being treated, severity of the disease, and individual tolerability of the antibiotic. 1-Carba / 1-dethia / cefem can be administered orally, parenterally or subcutaneously or rectally. As with other β-lactam antibiotics, it is possible to administer for the purpose of treatment or prevention, to prevent infection or to prevent infection, for example, prior to surgery. The 1-carba-1-dethia / cefem antibiotic can be administered by methods known per se, for example in the form of capsules, tablets, suppositories, syringes or intravenously.

The pharmaceutical compositions of the present invention comprise an antibiotic effective amount of a non-toxic 1-carba- / dethium / cephem of formula I or IX when it is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable salts are conveniently formulated into antibiotic agents. Formulations for oral administration include capsules, tablets, lozenges, and liquid suspensions. Antibiotics or their dry powder esters or salts are encapsulated in gelatin capsules for oral administration. The antibiotic may be mixed with an excipient, for example a stabilizer, prior to filling. The capsules contain from about 100 mg to about 500 mg to form a unit dosage form.

Tablets containing about 100 to about 500 mg of the antibiotic or salt or ester thereof are formulated in a manner well known in the art and may contain a binder, disintegrant, stabilizer, antioxidant and the like. - 39 -

Liquid antibiotic agents can be prepared for children and for geriatric purposes. Pediatric suspensions are formulated with antibiotic oral excipients such as suspending agents, flavoring agents, stabilizers, and the like. Similarly, antibiotic solutions can be formulated with solubilizing, flavoring and similar additives, sugar, water, and the like.

Parenteral antibiotics for injection are formulated as aqueous compositions, Binger solutions, physiological solutions, or glucose solutions. Antibiotics may also be administered as an intravenous fluid in a capacity manner.

For parenteral administration of the antibiotic salt or derivatives thereof, the active ingredient is preferably produced in the form of a dry crystalline powder, or in the form of a lyophilized powder, and is filled with dofiol. Such vials contain about 100 mg to 2 g of antibiotic. The following abbreviations are used in the following examples: t-boc = t-butoxycarbonyl or t-butyloxycarbonyl: HPLC = high performance liquid chromatography; THF = tetrahydrofuran, < RTI ID = 0.0 > J ' = < / RTI > DMF = Ν, β-dimethylformamide; DMAP = dimethylpropyleneurea; BSU-bis- (trimethylsilyl) urea; BSA bis- (trimethylsilyl) acetimide-DMAP with dimethylaminopyridine-DBU = 1,8-diazabicyclo [75.0] 7-undec-7-ene; AIBK = azo / bis / iso-butyryl trii; DCC = dicyclohexylcarbodiimide; TFA = trifluoroacetic acid; HMPA = triaxidehexamethylphosphoric acids; DMSO = dimethylsulfoxide. The following examples illustrate the invention without limiting it. Percentages and parts are by weight unless otherwise indicated. EXAMPLES Preparation 1

Diphenylmethyl / 7S, 6R7-7-phenoxyacetamido-3-phenylthio-1-carba- [1-dethia] -3-cephem-4-carboxylate - 40 -

Diphenylmethyl / 7S, 6R-7-7-phenoxyacetamido-3-trifluoromethylsulfonyloxy-1-carba [1-dethium] -3-cephem-4-carboxy-drug solution (40.0 g, 63.00 mmol / v 180) ml of anhydrous acetonitrile is treated under nitrogen with diisopropylethylamine (15.4 ml, 88.0 mmol) and thiophenol (7.1 ml, 69.0 mmol). The reaction mixture is stirred overnight at ambient temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluting with 35:65 ethyl acetate / hexane) to give 33.45 g (90% of theory) of a pale yellow solid. 1 H NMR (CDCl 3): δ 7.2-7.6 (m, 19H), 7.08 (t, J 7Hz, 1H), 7.05 (s, 1H), 6.90 / d, J = 8Hz, 2H /, 5.44 (m, 1H), 4.54 (s, 2H), 3.81 (dt, J = 12.12 Hz, 1H), 2.0-2.3 / m, 2H 1.7-1.8 (m, 1H), and 1.3-1.5 (m, 1H). Preparation 2

Diphenylmethyl 6R17-7-phenoxyacetamido-3-bromo-1-carba [1-de thia] -3-ee-4-carboxylate

Diphenylmethyl (7S, 6R-7-7-phenoxyacetamido-3 'trifluoromethylsulfonyl-1-carba [1-de thia] -3-cephem-4-carboxylate (150 g, 0.238 mol) is dissolved in 1600 ml of anhydrous tetrahydrofuran was treated with 2,6-lutidine (63.8 g, 0.595 mol) and lithium bromide (121.1 g, 1.43 mol). The reaction mixture was heated to 65 ° C over 30 minutes and held at this temperature for 64 hours. The reaction mixture was then cooled to ambient temperature and 75% of the solvent was removed under reduced pressure at 50 ° C. The suspension was diluted with ethyl acetate / ether, washed with sodium bicarbonate (3 times), 1N hydrochloric acid (3 times) and brine. and dried over magnesium sulfate, filtered through silicagel, washed with 10% ethyl acetate / dichloromethane and evaporated under reduced pressure until solids precipitate and precipitate. The beige solid (34.4 g) was separated and the mother liquors were further evaporated to give an additional 10.6 g of a solid. Both batches of solid are combined because both the desired 3-isomers / desired product / · The residual liquid is evaporated to dryness, yielding 64.7 g of a /2 / Δ3 isomer mixture. The olefin-41-isomer mixture was worked up as follows: A mixture (64.7 g, 0.115 mol) was dissolved in 675 ml of anhydrous dichloromethane and treated with DBU (4.7 g, 0.031 mol). The reaction mixture was filtered through silica gel, washed with 10% ethyl acetate / dichloromethane and evaporated. The residue was dissolved in a small amount of ethyl acetate, diluted with hexane and cooled to 0 ° C. This gives 17.6 g of pure Δ 3isomer and the remaining 39.4 g (from mother liquor) is chromatographed on silica gel (eluted with a gradient of toluene to 30/70 ethyl acetate in toluene) to give 31.5 g. mixtures of /2 / Δ3, which are dissolved in ethyl acetate, diluted with hexanes, seeded with the product and cooled rapidly to 0 ° C. Thus, 18.2 gA 3 of the isomer is obtained in addition to the 14 * 2 g of A 2 / A 3 mixture. A total of 80.8 g of the desired product was isolated in a yield of 61% of theory. Preparation 3

Allyl (7S, 6R7) 7-phenoxyacetylamino-1-bromo-1-carba [l-dethium] -3-cephem-4-carboxylate (a) Allyl (7S, 6R7-7-phenoxy) thylamino-3-trifluoromethyl -sulfonyloxy-1-carba [1-dethium] -3-cephem-4-carboxylate (1.0 g, 1.9826 mmol) of dried lithium bromide (0.689 g, 7.9302 mmol) was mixed with dimethylformamide. After dissolving all the solids, the mixture was slowly warmed to approximately 67 ° C and stirred for 16 hours, then cooled to room temperature and treated with 75 mL of EtOAe, 50 mL of water, and sat. The organic fractions were separated, washed with 50 ml of 1N hydrochloric acid, dried over sodium sulfate, filtered and evaporated to give a reddish brown oil, eluting with 7% EtOAc. 87 mg of the product are obtained in a yield of approximately 10% of theory. (B) 3-Triflate of the compound according to paragraph (a) (200 mg, 0.3965) is mixed with dried lithium bromide. (138 mg, 1.566 mmol) and DMPU (2 ml) and the mixture is maintained at 65-67 ° C for 6 hours. To the mixture was added 2,6-lutidine (0.4362-42 - mmol) and the mixture was stirred at 67 ° C overnight (14 hours). The mixture was poured into 50 ml of ethyl acetate and 20 ml of saturated sodium bicarbonate solution. The organic layer was washed with 25 ml of 1N hydrochloric acid, separated and dried over sodium sulfate, filtered and concentrated to give a brownish-yellow oil. Chromatography eluting with 7% ethyl acetate / dichloromethane gave 45 mg / 26% of theory / 60/40 of a mixture of 42 to 3% of the solvents. (c) The procedure is as in (b), but 2,6-lutidine adds heat to the mixture at the beginning of the process instead of starting. The following amounts are used: 3-triflate starting material: 200 mg, 0.3965 mmol 2,6-lutidine: 0.793 mmol, 92 µL lithium bromide: 138 mg, 1.566 mmol DUPU: 2 ml 55 mg / 31% 2% is obtained theory / product 60/40 Δ2 / Δ3 / d / Proceeds as in (c) but adds DME instead of DMPU. The following amounts are used: 3-triflate starting material: 145 mg, 0.2875 mmol 2,6-lutidine: 0.5749 mmol, 67 µL lithium bromide: 100 mg, 1.15 mmol DMF: 1.5 mL , 2 mg / 49% t & QTie / 70/30 mixture of 2 2 / Δ 3 isomers. (e) The procedure is as in (d), but the mixture is heated 2.5 times or 48 hours. The following amounts are used: 3-triflate starting material: 11 g: 21.808 mmol 2,6-lutidine: 43,616 mmol, 5.08 ml lithium bromide: 7.6 g, 87.232 mmol DME: 120 ml e hc. 4.6 g of the desired product are obtained or 48.5% of the theory of the mixture Δ2 / is3 isomers in a ratio of> 95/5 · Values for Δ2 isomer: NMR / 300 MHz, CDCl-/ δ 7.32 / t, J = Hz, 2H, 7.10 (d, J = 43 = 9 Hz, 1H), 7.05 (t, J = 6 Hz, 1H), 6.92 (d, J = 8 Hz, 2H / 6) , 50 (a, 1H), 5.95 (m, 1H), 5.35 (m, 3H, 4.90 (s, 1H), 4.68 (m, 2H), 4.55 (s), 2H (4.15 (m, 1H); 2.35 (m, 1H); and 2.15 (m, 1H). IR (CHCl3 / 3019, 1771, 1747, 1691, 1517, 1495, 1236, and 1182 cm @ -1MS, m / e 434 / M @ + /, 436 / M ++ 2)

H, 4.40; N, 6.44. Found: C, 52.23; H, 4.36; N, 6.37.

Diphenylmethyl / "7S, 6R- 7 -7-phenoxyacetamido-3-tributylstannyl-1-carba / 1-dethium] -3-cephem-4-carboxylate

A suspension of diphenylmethyl ("7S, 6R" -7-phenoxyacetamido-3-phenyl-thio-1-carba / 1-dethium) -3-cephem-4-carboxylate (37.0 g, 62.7 mmol) in 32 ml of anhydrous diglyme The reaction mixture was treated under nitrogen with tributyltin hydride (42.1 mL, 157.0 mmol) and azo / bis / isobuturyl nitrile (AIBH) (12.4 mL, 75.2 mmol) and maintained at 120 ° C. The residue was purified by silica gel chromatography (eluting with <0:60 ethyl acetate / hexane) to give 37.1 g of a clear viscous oil (77% of theory). NMR / CDCl3 7.55 (d, J = 7 Hz, 2H), 7.44 (d, J = 7 Hz, 2H), 7.2-7.4 (m, 7H), 7.0-7; 1 (m, 2H), 6.9 (m, 3H), 5.48 (m, 1H), 4.56 (s, 2H), 3.87 (m, 1H), 2.6 - 2.7 (m, 1H), 2.3-2.45 (m, 1H), 1.9-2.0 (m, 1H), 1.2-1.4 (m, 12H), and 0.8 - 0.85 (m, 15H) IR / CH 2 O 2: 2958.2, 2923.7, 1766.2, 1689.9, 1523.0, 1496.2, 1374.4, and 1239.5 cm -1; (PAB /: m / e / M + / 771} UV / EtOH /: λ max 275 nm / E 9960); analysis: C ^ HH ^ gN ^O ^ Sn; Example 2

Diphenylmethyl-7S, 6R-7-7-phenoxyacetamido-3 "bromo-1-carba / 1-dethium / 3-cephem-4-carboxylate

Ciničitan. according to Example 1 / 8.58 gt > 13 mmol / in 400 ml of anhydrous tetrahydrofuran was cooled in a dry ice bath and acetone and treated dropwise with a solution of bromine (1.78 g, 11.13 mmol) in 100 ml of tetrahydrofuran over 30 minutes. The solvent was then removed under reduced pressure and the residue was chromatographed on silica using a 40:60 ethyl acetate / hexane system to give 5% g / 80% of theory / white solid. 7.26-7.5 (m, 12H), 7.0-7.1 (m, 2H), 6.98 (s, 1H), 6.9 / d, J = 8Hz, 2H /, 5.40 (m, 1H), 4.54 (s, 2H), 3.95 (m, 1H), 2.7-2.8 (a, 2H) > 1 , 9-2.0 (t, 1H), 1.5-1.7 (m, 1H), and 1.3-1.4 (m, 1H); IR (CHCl 3): 3025.2, 1787.0, 1742.2, 1692.7, 1600.6, 1518.9, 1496.0, 1302.3 and 1242.7 cm -1; MS / FAB /: m / e / M + 561; UV / EtOH (λ max 275 nm; δ 4870) analysis: Cg ^HggBrNNO ^; C, Η, N. Example 3

Diphenylmethyl (7S, 6,6) -7-phenoxylation tamido-3-trifluoromethyl-1-carba [1-de thia] -3-ee-4-carboxylate

The cadmium suspension (20.0 g, 178 mmol) in 100 mL of anhydrous tetrahydrofuran was cooled in an ice bath under nitrogen and treated dropwise with difluorodibromomethane. Periodic removal of the ice bath is necessary to maintain a smooth flow. When the addition is complete, the bath is removed and the reaction mixture is stirred at ambient temperature for one hour. In a separate flask, 3-bromo intermediate (10.0 g, 17.8 mmol) was dissolved in 18 mL of anhydrous THF and heated to 70 ° C. The cadmium solution was treated with copper (I) chloride (17.6 g, 178 mmol) and added to the 3-bromo intermediate via cannula over one hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered through celite, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to give a brown oil. This oil was chromatographed on silica gel using ethyl acetate / hexane (40:60) to give 4.7 g (49%) of the desired product as a foam. NMS / CDCl3: δ 7.3-7.4 (m, 12H), 7.0-7.2 (m, 3H), 6.9 / d, J = 8Hz, 2H / 5, 49 (m, 1H), 4.58 (s, 2H), 3.96 (m, 1H), 2.3-2.5 (m, 2H), 2.0-2.1 (m, 1H) , and 1.4-1.5 A, 1H); IB / CHCl 3: 1787.0, 1742.2, 1692.7, 1600.6, 1518.9, 1496.0, 1302.3, and 1242.7 cm -1; MS (PAB): m / e (M + +1) 517; UV / StOH (λ max 264 nm) (δ 8946); Analysis: C 30 H 25 F 3 N 2 O 5 · C · H ’N * Example 4

Diphenylmethyl-7S, 6R- 7-t-butoxycarboxamido-3-trifluoromethyl-1-carba / 1-dethium / 3-ee-4-carboxylate

Difluoromethyl-1,6R-7-phenoxylation tamido-3-trifluoromethyl-1-carba [1-dethium] -3-cephem-4-carboxylate (4.7 g, 8.5 mmol) is dissolved in 85 ° C. 1 anhydrous dichloromethane in the middle! nitrogen, cooled in an ice bath, and treated with di-t-butyl dicarbonate (2.04 g, 9.35 mmol) and dimethylaminopyridine (DMAP) / 0) 52 g, 4.3 mmol / 0.5 mol. minutes, the reaction mixture is warmed to room temperature and maintained for 4 hours at this temperature. The solution is filtered through a silica system. 20: 80e thylate thaw / dichloromethane. The solvent is then removed in vacuo and the residue is taken up in 85 ml of anhydrous tetrahydrofuran and cooled rapidly in an ice bath. Hydrochloride (9.7 ml of a 1M solution) is added dropwise and the solution is then allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness in vacuo to give 4.2 g of crude orange foam. NMR (CDCl3). : 7.3, 7.4 (m, 10H), 6.95 (s, 1H), 5.98 (broad d, J = 11Hz, 1H), 5.22 / m, 1H / 3, 87 (m, 1H), 2.3-2.5 (m, 2H), 2.0-2.1 (m, 1H), and 1.6-1.7 (m, 1H), 1.21 (s, 9H); M.p. 1785.3, 1740.0, 1718.5, 1497.3, 1301.7 and 1243.3 cm -1; MS (FAB): m / e / M ++ 1/517; UV / EtOH /: λ max 264 nm (δ 8946); analysis: C27H27P3N2O5 * C, Η, N. Example 5

6H-7-Amino-3-trifluoromethyl-1-carba / 1-dethium / 3-cephem-4-carboxylic acid trifluoroacetate salt

The product of Example 4 (2.00 g, 3.87 mmol) was dissolved in cold trifluoroacetic acid (TFA) (40 mL) and in triethylsilane (13 mL) under nitrogen at 0 ° C. The reaction mixture was kept at 0 ° C for 30 minutes in an ice bath, whereupon the ice bath was removed and the mixture was stirred for 20 minutes. Anhydrous CH 2 Cl 2 and toluene were added and evaporated in vacuo. This process was repeated and stripped to dryness. The residue was suspended in GH 2 CN and filtered. The solids were washed with CH 2 Cl 2 / diethyl ether and then twice with diethyl ether to give 925 mg (66%) of the desired product as a white solid. HMR / DMSO-dg / TEA /: δ 8.0 - 8.2 / broad s, 1H /, 4.92 / d, J = 6 Hz, 1H /, 3.97 / m, 1H /, 2.0 2.1 (m, 2H), and 1.7-1.8 (m, 2H). Example 6 7S, 6R7-7-2SD-alpha-t-butoxycarbonylamino / phenylacetylamino-3-trifluoromethyl-1-carba [1-dethia] -3-cephem-4-carboxylic acid

The trifluoroacetate salt of Example 5 (0.90 g, 2.47 mmol) was suspended in 25 mL of ethyl acetate under nitrogen and treated with monosilyl trifluoroacetamide (1.51 mL, 8.15 mmol) and then maintained at 35 ° C. until the solids are dissolved. The t-BOC phenylglycine is dissolved in a separate flask. in 25 ml of ethyl acetate under nitrogen, cooled to -45 DEG C. and treated sequentially with isobutyl chloroformate (0.32 ml, 2.47 mmol) and N-methylmorpholine (0.326 ml, 2.96 mmol). After 30 minutes in the course of 5 minutes, the amine solution is cooled to 0 and then added via cannula and stirred for 30 minutes while raising the temperature to -45 ° C to -35 ° C and then one time. and half an hour, with the temperature rising to 0 ° C. At this point, 2.0 mL of methanol was added, the ice bath was removed, and the solution was stirred for 10 minutes while warming to room temperature. Filtration, evaporation and chromatography on silica using 3% acetic acid in ethyl acetate afforded the desired product as a beige foam (1.03 g, 87% of theory). NMR (CDd 3): δ 7.1-7.4 / m, 5H /, 6.1 / wide s, 1H /, 5.4 / wide s, 1H /, 3.8 / wide m, 1H /, 2 , 2 - 2.4 (broad m, 2H), and 1.2 - 1.5 (broad m, 11H). Example 7 7 (3-D-amino-phenylation-thiamine-7-3-trifluoromethyl-1-carba- / l-dethium) -3-cephem-4-carboxylic acid t-BOC protected according to Example 6 was introduced into flasks at 0 ° C and treated with a mixture of trifluoroacetic acid / TFA / 20 mL / and triethylsilane (7 mL). Stir for 15 min at 0 ° C, then remove the ice bath and stir the reaction mixture for 5 min. for 10 minutes at ambient temperature, diluted with CH 2 Cl 2 and evaporated, further diluted with CH 2 Cl 2, evaporated to dryness, suspended in ethyl ether and filtered and the solid obtained is repeatedly washed with ethyl ether. and dried in a vacuum to give 0.74 g of crude product with a purity of about 85%, followed by chromatography on C-18 with a gradient of 10% CH 3 CN / H 2 O to 30% CH 3 CN / HgO to give 0.39 g. 50% of theory / product as a white solid 1 H NMR (D 10): δ 7.5-7.6 (m, 5H), 5.44 / d, J = 7 Hz, 1H / 5, 21 (s, 1H), 3.95 A, 1H), 2.25 (broad m, 2H), 1.7-1.8 (m, 1H), and 1.0-1.1 / m, ΙΗ (IR) / CHCl3: 1776.7, 1740.0, 1693.7, 1561.6, 1300, 21 and 1166.1 cm -1; MS (FAB): m / e / M @ + + 1/384; UV / EtOH (λ max 257 nm) (8,9190). Example 8 2TYS, 6R7-7- [2- (tert-Butoxycarbonyl) amino-4-thiazolyl-7-methoxyimino] acetyl] -amido-3-trifluoromethyl-1-carba [l-de thia] -3- cefem-4-carboxylic acid

7S, 6R- 7-Amino-3-trifluoromethyl-1-carba / 1-dethium / 3-cephem-4-carboxylic acid trifluoroacetate salt (0.10 g, 0.275 mmol) was treated under nitrogen with bis / trimethyl -silyl / urea (0.281 g, 1.38 mmol) and 1.4 mL of anhydrous dimethylformamide. The solids dissolved after suspension are heated to 45 ° C and the solution is maintained at this temperature for one hour. In a separate flask, 2-t-butoxycarbonyl / amino-4-thiazolyl-7-methoxyimino / octaic acid (0.083 g, 0.275 mmol) was dissolved in 1.4 ml of BMP cooled to -5 ° C, treated with with oxalyl chloride (0.035 g, 0.275 mmol) and warm the room temperature over 30 minutes. The nuclea solution is cooled to ambient temperature, treated with pyridine (0.067 ml, 0.825 mmol) and then with the acid chloride solution. After stirring for one hour, the solution was cooled in an ice bath and treated with water (2 mL), diluted with ethyl acetate and partitioned. The organic layer was washed twice with 1N hydrochloric acid, water, brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude solid (0.101 g) was chromatographed on silica with 4% HOAc in ethyl acetate to give 0.087 g (59% of theory) of the desired product. EXAMPLE 9 (7S, 6R7) 7- (2-Amino-4-thiazolyl) methoxyimino (acetyl-7-amido) -3-trifluoromethyl-1-carba [1-de-thia] -3-cephem-4- a carboxylic acid

A mixture of trifluoroacetic acid (1.5 ml) and triethylsilane (0.5 ml) was cooled in an ice / ethanol bath and treated with diphenylmethyl ("7S, 6R, 7'-7- (2-t-butoxycarbonyl)). amino-4-thiazolyl-7-methoxyimino / acetylJ-amido-3-trifluoromethyl-1-carba [1-dethium] -3-cephem-4-carboxylate After 30 min. Evaporate to dryness. The crude product (0.055 g) was chromatographed on a preparative HPLC on a 15: 84: 1 to 20: 79: 1 step gradient of CH 2 Cl 2 / H 2 O 2 OAc to give 0.021 g of the final product. (DMSO-d6): 9.25 (d, J = 11Hz, 1H), 7.18 (broad s, 2H), 6.70 (s, 1H), 5.48 / m, 1H /, 3, 9 (a, 1H), 3.80 (s, 3H), 2.37 (broad m, 2H), 1.95 (a, 1H), and 1.6 (m, 1H). -7-tert-butoxycarbonylamino-4-hydroxyphenyl-amino-7-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylic acid

A solution of (D-O-t-butoxycarbonylamino) -4-hydroxyphenylacetic acid (0.214 g, 0.799 µl) in 2.4 µl of anhydrous tetrahydrofuran was treated with 1-hydroxybenzotriazole (0.108 g, 0.799 mM) and DCC / 0, 19 ® g, 0.959 mM (at 0 ° C) The precipitate formed after five minutes and the suspension was warmed to room temperature and stirred for two hours before the solution was filtered and cooled to 0 ° C. C. Carbacephemic zwitterion is suspended in 2.4 L of anhydrous tetrahydrofuran and treated with bistrimethylsilylacetimide (BSA) (0.8 mL) to give a solution which is concentrated to a thick oil, diluted with 0.8 mL of tetrahydrofuran, cooled to After 30 minutes at 0 ° C the bath was removed and the reaction mixture was stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. the layer is extracted with one aqueous one the sodium bicarbonate solution and the aqueous layers are treated with ethyl acetate and the pHL is reduced to 2.5 with hydrochloric acid. The aqueous layer is washed with ethyl acetate and the combined organic layers are dried (MgSO4), filtered and concentrated to give 0.20 g of the title compound. 271 g (67%) of the desired product which is not further purified. 5Q - Example 11 / 6R, 7S-7-7- (amino) -4-hydroxyphenylacetylamino-7-trifluoromethyl-1-carba-1-dethia-3-cephem-4-carboxylic acid

The product of Example 10 was charged to a flask at 0 ° C and treated with a mixture of cold trifluoroacetic acid (TFA / 2, 2 mL) and triethylsilane (0.5 mL). The flask is placed immediately on the rotary; The residue was concentrated to an oil which was triturated with diethyl ether to give a solid which was collected by filtration and washed with diethyl ether. The solid was dried under vacuum for three hours to give 0.132 g of crude product. Reverse phase chromatography on a gradient of 99/1 HgO / HOAc to 5/94/1 CH 2 Cl 2/0 / acetic acid yielded 0.05 after lyophilization. g (25%) of the desired product as a white solid. 4 NMR (D 2 O): δ 7.35 (m, 2H), 6.97 (m, 2H), 5.40 (d, J = 7Hz, 1H), 5.13 (s, 1H), 3.90 (m, 1H), 2.1-2.3 (broad m, 2H), 1.73 (m, 1H), and 1.1 (m, 1H); IR (KBr): 1768.0, 1688.9, 1613.6, 1519.1 and 1300.21 cm -1; MS (FAB): m / e / M @ + +1 / 400; UV / ethanol (λ max 234, 257 nm) (λ 12800, 9030).

Calc &apos; d: G 51.13; H, 4.04; N, 10.52; Found: C, 51.25; H 4.21; N 10.29 · Example 12 / ”6R, 7S-7-7- (3-D) -amino] -4-fluorophenylacetylamino-7-3“ trifluoromethyl-1-carba-1-dethia-3 ”Cefea-4-carboxylic acid acid

A solution of racemic t-BOC protected 4-fluorophenylglycine (0.216 g, 0.80 mM) in 8.0 mL of ethyl acetate is cooled to -45 ° C, treated with isobutyl chloroformate / 0.104 mL, 0.80 mM / and N-methylmorpholine / 0.097 ml, 0.88 mM), stirred for 30 minutes. dissolved in 8.0 mL of ethyl acetate after addition of monosilyl trifluoroacetamide (0.341 mL, 1.84 mM) and added to the stirred anhydride at -45 ° C. After 30-51 minutes, the solution was warmed to 0 ° C for 1 hour and then treated with 0.5 mL of methanol, warmed to ambient temperature, filtered with celite, and concentrated at 30 ° C. The product is chromatographed on silica gel with 3/87/10 HOAc / ethyl acetate / hexane. Both diesteromers are evident in 1 H-NMR together with a smaller amount of impurities. The crude product (0.228 g) is processed

NoutTPA (1.8 ml) and Et 2 O SiHL (0.6 ml), concentrated, triturated with ethyl ether, collected by filtration and washed with diethyl ether. The crude IPA salt (0.209 g) was chromatographed on 18 column with two step gradients from 15% CH 2 CN / H 2 O to 20% CH 2 CN / HgO to give 0.030 g (10%) of product after lyophilization. from L-amino acid and 0.046 g (14%) of the product resulting from the Dramino acid. HPLC retention time: CH 2 Cl 2, 1/20/79 HOAc / CH 2 Cl 2 / H 2 O, 2 mL / ain. L = 4.11 min D → 5.38 min. L-diastereoisomer: NMR (CDCl 3): δ 9.1 (m, 1H), 7.50 (m, 2H), 7.22 (t, J = 10 Hz, 2H), 5.17 (broad s, 1H) 4.89 (broad s, 1H); 3.76 (m, 1H); 2.17 (m, 2H); 1.73 (m, 1H); 1.60: (m, 1H); IR (CHCl 3): cm -1; MS (PAB): m / e (M @ +); EXAMPLE 13 ("7S, 6R, 7-7- [2- (Triphenylmethyl) amino-4-thiazolyl-7] tri-phenylmeoxyimino] acetyl] -amido-3-trifluoromethyl-1-carboxamide; dethia [3-cephem-4-carboxylic acid

7-Amino-3-trifluoromethyl-1-carba (1-dethia) -3-cephem-4-carboxylic acid (0.300 g, 1.20 mM) (carbaceous zwitterion) was dissolved in 6.0 ml of dry dimethylformamide with bis- trimentylsilyl urea (BSU) (1.23 g, 6.0 mM) at 50 ° C for one hour and then at room temperature for 30 minutes. In a separate flask, 2-trimethylamino-4-thiazolyl-7 / trityloxyimino / acetic acid (0.806 g, 1.20mM) was dissolved in 6.0 mL of dry BMP and cooled to 0 ° C, treated dropwise; oxalyl chloride (0.105 ml, 1.20 mM) and warm the ambient temperature · The nucleus is then cooled to 0 ° C, treated with pyridine (0.194 ml, 2.4 mM) and acid chloride, warmed to room temperature and stir for two hours. Dilute with 2.0 mL of water and then treat the reaction mixture with 1N hydrochloric acid and extract with ethyl acetate. The ethyl acetate layer was washed with water, 1N hydrochloric acid, water and brine, dried over magnesium sulfate, and concentrated. The crude product (1.12 g) was chromatographed through silica gel with 3% HOAc / ethyl acetate to give 0.95 &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; (88% of theory) of the desired product as a white powder. EXAMPLE 14 Z "7S, 6F-7-7- (Z)" 2-Amino-4-thiazolyl / oximino / acetyl] -7-amido] -3-trifluoromethyl-1-carba / 1-dethia [-3-cephem-4-carboxylic acid

A solution of bis-tritycarbacephem according to Example 13 in 4 ml of tetrahydrofuran was treated with 7.6 ml of 75% aqueous acid and slowly warmed to 40 ° C under nitrogen for 2 hours. After cooling, 20 ml of CHCl 3 was added and then the mixture was concentrated and this process was repeated to give a brown residue. The solid was washed with 3/1 ethyl ether / CH2Cl2 and the solids were collected by centrifugation. After further ethyl ether washing, the solid is chromatographed on HP-20ss with 1% HOAc / water over CH 2 Cl 2. The solid obtained was chromatographed on C18 with 1/10/89 HOAc / CH2Cl2 / HgO to give 0.027 g of a cream colored solid. 4 NMR. (DMSO-d6): 9.13 (&amp;amp; J = 9 Hz, 1H), 7.07 (s, 2H), 6.64 (s, 1H), 5.50 (m, 1H), 3, 89 A, 1H, 2.25 (a, 2H), 1.95 (m, 1H), 1.60 (m), IR (CHCl3) cm @ -1, MS (m / e): m / e [.alpha.] @ 21D / EtOH / .lambda.max 257 .mu.m. Example 15

DiphenylmethylZ-7S, 6S, 7-7-phenoxyacetamido-3-trifluoromethyl-1-carba / 1-dethium / 3-cephem-4-carboxylate

A suspension of zinc-washed acid (58.2 g, 0.89 mol) in 1780 ml of anhydrous tetrahydrofuran under nitrogen was treated dropwise with 205.4 g (0.98 mmol) of difluordibromomethane. The di-fluoribromomethane is added to maintain the reaction temperature of the mixture at 45-50 ° C. When the addition is complete, stir the reaction mixture at room temperature for 1.5 hours, returning the temperature of the mixture to room temperature. The zinc reagent solution is then cooled to -30 ° C and treated with BMPU / 100 mL / CHCl 3. (88.1 g, 0.89 mmol). After 15 minutes, the reaction mixture was warmed to 0 ° C over 30 minutes. In a separate flask dissolve diphenylmethyl (6R, 7S) -7-phenoxyacetamido-3-bromo-1-carba (l-dethium) -3-cephem-4-carboxylate (50.0 g, 0.089 mol) in anhydrous 100 ml DMPTT and 100 ml of dimethylformamide. in the environment! and the mixture was heated to 65 ° C. Changing solution: the bromide cannula is added over one hour to maintain! temperature of 65 ° C. After an additional hour, the reaction mixture was cooled to 50 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, poured into saturated sodium bicarbonate solution, filtered through celite, washed twice with bicarbonate solution. sodium, water, twice 1N. hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo to give a brown oil. This oil was filtered through silica gel. with ethyl acetate / hexane (60:40) and recrystallized from systemic ethyl acetate / hexane to give 28.4 g (58% of theory) of a white solid.

Allyl / 7R, 6S-7-7-phenoxyation tamide-3-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylate

After dissolution of the product of Example 15 (26.00 g, 0.050 mol) in 375 ml of Ν-dimethylformide and 750 ml of tetrahydrofuran in nitrogen, add 375 ml of 1N hydrochloric acid and then zinc powder (19.61 g, 0.30 mol). . The solution became warm and stirred for 90 minutes and then filtered through celite. The tetrahydrofuran was then evaporated. The mixture was diluted with ethyl acetate and washed four times with 1N hydrochloric acid, water and brine, dried over sodium sulfate and evaporated under reduced pressure. pressure to give a crude orange solid. The solid dissolved in ethyl acetate, 50% aqueous solution, sodium bicarbonate was added, and the biphasic solution was treated with tetrabutylammonium hydrogen sulfate (17.83 g, 0.052 mol). After stirring for 15 minutes, the layers were separated and the ethyl acetate layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a viscous oil. The oil was dissolved in 110 ml of chloroform and treated with allyl bromide (7.26 g, 0.060 mol) dissolved in 35 ml of chloroform using a funnel over 30 minutes. The solution was stirred overnight at room temperature, evaporated to give a solid and chromatographed on silica gel with 70% hexane / 30% ethyl acetate to give 14.35 g of the desired product after evaporation under reduced pressure (68% of theory). . H NMR (CDCl 3): 7.45 (d, J = 8, 1H), 7.30 (t, J = 7, 2H), 7.00 (t, a = 7, 1H), 6.87 / d, J = 10, 2H (6.0 - 5.8 / m, J = 1H), 5.45 (dd, 9, 1H), 5.4 - 5.2 (m, 2H), 5 , 72 / t, = = 6, 2H /, 5.43 (s, 2H), 3.95-3.85 (m, 1H), 2.55-2.4 / m, 1H / 2, 4 -2.25 (m, 1H), 2.1-1.95 (m, 1H), 1.6-1.4 (m, 1H). Example 17

Diphenylmethyl-7S, 6R7-7-phenol-thiido-3-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylate

A suspension of freshly washed zinc dust (58.2 g, 0.89 mol) is suspended in 1780 ml of anhydrous tetrahydrofuran in a three-liter three-liter flask equipped with a whisper, a thermometer, a nitrogen inlet, a funnel and a condenser. ice. Approximately 20% of ice-cold dibromodifluoromethane (205.4 g, 0.98 mol) is added dropwise via the left side and, after 15 minutes of initiating the exothermic reaction, causes an increase in temperature to 50 ° C. The dibromodifluoromethane residue is added while the internal temperature of the reaction mixture is maintained. 45-50 ° C, then the reaction mixture is stirred for 90 minutes after the addition is complete. After cooling the solution to -30 [deg.] C., 150 ml of DMF and then copper (I) chloride (88.1 g, 0.89 mol) were added, the mixture was stirred for 20 minutes and then the bath was replaced with an ice bath and stirred for 20 minutes. In a separate flask, the starting vinyl bromide (50.0 g, 0.089 mL) was dissolved in 100 mL of anhydrous DMPU and 100 mL of anhydrous dimethylformamide and heated to 65-70 ° C. Cold copper reagent was added to the bromide over a period of about one hour while maintaining the temperature at 65-70 ° C during the addition, and then the mixture was stirred at 70 ° C for 1 hour. After cooling to room temperature, it is diluted with ethyl acetate, poured slowly into 50% aqueous bicarbonate solution, partitioned, washed twice with 50% aqueous bicarbonate solution, water, twice with 1N hydrochloric acid, water, brine, dried over magnesium sulfate and evaporated. The oil was chromatographed on silica gel with 60:40 hexane / ethyl acetate and recrystallized from ethyl acetate / hexane to give 28.4 g of a beige solid (58% of theory). Example 18 p-Nitrobenzyl / "7S, 6R- 7 -7-phenoxyacetamido-3-trifluoromethyl-1-carba / 1-thia] -3-cephem-4-carboxylate The desired compound is prepared in analogy to Example 177 (used). however, the bromide is measured in place of copper chloride to give a beige solid in 64% yield. 1H NMB (CDd3): δ 8.19 / d, J = 9, 2H /, 7.63 / d, J = 9, 2H, 7.30 (tr, J = 6, 3H), 7.03 (tr, J = 8, 1H), 6.86 (d, J = 9, 2H), 5.45 / tr, J = 5, 1H, 5.37 (quartet, J = 15, 2H), 4.457 (s, 2H), 4.0-3.9 A, 1H, 2.6-2.35 A, 1H / 2 4 - 2.3 A, 1H), 2.1-2.0 A, 1H /, 2.6-2.4 A, 1H /

7-Amino-3-trifluoromethyl-1-carba (1-dethium) -3-cephem-4-carboxylate hydrochloride salt

The product of Example 16 (10.53 g, 0.0248 mol) was dissolved in 83 mL of dry methylene chloride under nitrogen and cooled to 0 ° C. The solution was treated with pyridine (2.41 g, 0.0305 mol) using a syringe and platinum chloride (56-, 5.84 g, 0.0280 mol) was then added portionwise over 20 minutes. after 30 minutes and the solution was stirred for 1.5 hours, the solution was again cooled to ice-ice and treated with isobutyl alcohol (18.4 g, 0.248 mol) dissolved in 20 ml of diethyl ether using a syringe in the course of time. five minutes. After 30 minutes, the ice bath was removed and the mixture stirred for one hour. The thick, white, fluffy solid was filtered off at 0 ° C, washed twice with 50:50 methylene chloride / diethyl ether and once with diethyl ether. The solid was then dried under vacuum for three hours to give 6.49 g of the desired compound as a white solid (77% of theory). ^ Η. NMR (DMSO-d6): δ 9.20 (s, 3H), 6.0-5.8 (m, 1H), 5.35 / dar = Hz, 1H /, 5.24 / d, J = Hz (1H), 4.90 (d, J = Hz, 1H), 4.75 (t, 2H), 4.1-3.9 (m, 1H), 3.5-3.2 (a, 2H) (2.2-2.1 / m, 1H) and 1.9-1.7 (m, 1H). Example 20

Allyl- (7S, D) - t -butoxycarbonylamino / 3-fluorophenyl-amino-tert-3-trifluoromethyl-1-carba [1-thia] -3-cephem-4-carboxylate.

A solution of (t-butoxycarbonylamino) -3-fluorophenylacetic acid (1.05 g, 0.00321 mol) in 21 ml of anhydrous methylene chloride-sulfuric acid (N-methylmorpholine / 0.35 g, 0.00343 mol) and 1- chloro-3,5-dimethoxytriazine (0.58 g, 0.00321 mol) at 0 ° C under nitrogen and stir for 45 minutes. The product of Example 16 ΟΟ g (0.00306 mol) was suspended in 8 ml of methylene chloride, treated with N-methylmorpholine (0.35 g, 0.00343 mol) and added dropwise over 10 minutes to the above. activated ester solution. Leave for 20 minutes at 0 ° C, then remove the bath and stir for 90 minutes. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, the insoluble material was filtered off with suction and evaporated to give an oil. The crude product was chromatographed on silica gel using 75:25 hexane / ethyl acetate then 65:45 hexane / ethyl acetate to give 1.45 g (88%) of theory of the desired product as a beige foam. NMR (CDCl3): ξ 7.4-7.3 (a, 2H), 7.2-7.0 (m, 2H), 6.75 (d, 1H), 6.0-5.85 / m , 1H /, 5.7 - 5.5 / m, 1H /, 5.4 - 5.2 / m, 2H /, 5.2 - 5.1 / m, 1H /, 4.8 - 4.7 (m, 1H), 3.95-3.8 (a, 1H), 2.6-2.2 (m, 2H), 2.0-1.7 (m, 1H), 1.40 / s , 9H, and 1.3-1.1 (m, 1H). Example 21 Z "7S, 6rJ7-7 - /" D, L- oc - (t-Butoxycarbonylamino) -3-fluoro-phenylamino-3-trifluoromethyl-1-carboxy / l-de thia -3-cephem-4-carboxylic acid

The product of Example 20 (1.45 g, 0.00268 mol) was dissolved in 4.5 ml of ethyl acetate and 1 ml of methylene chloride in nitrogen and deoxygenated by bubbling nitrogen in the flask for five minutes. cooled in an ice bath and treated with 0.070 g of tetrakistriphenylphosphine palladium, 0.070 g of triphenylphosphine and 6.4 ml (0.00322 mol) of a 0.5 M solution of sodium 2-ethylhexanate in ethyl acetate. After 5 minutes, the ice bath is removed and the solution is stirred for 30 minutes, after which the solution is poured into 30 ml of a 50/50 mixture of diethyl ether and hexane. The precipitate was filtered off with suction, dissolved in ethyl acetate and a small amount of methylene chloride, washed with 1N hydrochloric acid and dried over magnesium sulfate, and evaporated to give 1.20 g (89% of theory) of the desired compound, no longer clean. Example 22 / 6R, 7S-7-7- (amino-4-fluorophenyl-ethylamino-7-trifluoromethyl-1-carba-1-de-thia-3-cephem-4-carboxylic acid)

The product of Example 21 (1.15 g, 0.00229 mol) was added in one portion to ice cold TTX (11.5 ml) and anisole (0.75 ml, 0.00687 mol) under nitrogen and stir for 30 minutes. The reaction mixture was diluted with acetonitrile and evaporated, again diluted with acetonitrile and evaporated to dryness at 30 ° C. The residue was triturated with diethyl ether and the resulting solid collected by filtration and washed repeatedly with diethyl ether. The crude solid was dissolved in vacuo to give 0.89 g of a mixture of diastereomers. 0.20 g of product is chromatographed by reverse phase chromatography on C-18 in 0.020 g portions with 10% acetonitrile / 1% AcOH / HgO to give 0.032 g of product after lyophilization. Example 23

Allyl (" 7S, 6R-7- t -butoxycarbonylamino) -3-ethylsulfonamido-phenylacetylamino-7-trifluoromethyl-1-carba [1-dethium] -3-ee-4-carboxylate. as described in Example 20 to give a white foam (88% of theory) .delta.E / CDCl3: δ 7.50 (s, 1H), 7.35-7.1 A, 6H / 6.0-5, 75A, 2H /, 5.4-5.1 A, 4H /, 5.8-5.7 A, 2H / 3.95-3.8 A, 1H / 3.10 / q, J = 8 2H, 2.6-2.0 (m, 3H), 1.40 (s, 9H), 1.30A, 4H). EXAMPLE 24 ^ 7S, 6R_7 " 7 - / &quot; D, L-OC- (t-Butoxycarbonylamino) -3-et &lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; fem-4-carboxylic acid

The crude desired product is prepared from the product of Example 23 by the method of Example 21 (96% of theory) and further purified. Example 25 (7 "6β, 7β-, 7-amino) -3-ethylsulfonamidophenylacetyl-aro-n-7H-trifluoromethyl-1-carba-1-de thia-3-cephem-4-carboxylic acid The desired product was prepared from the crude product of Example 24 by the method of Example 22 and chromatographed on a G18 column using 20% acetonitrile / 1% ammonium acetate / water to give the product in 14% yield after lyophilization. bHMH: (DMSO-d6), 9.85 (broad s, 1H), 9.3-9.1 (m, 1H), 7.3-7.0 (m, 4H), 5.3-5, 2 (m, 1H), 4.72 (s, 1H), 3.7-3.6 (m, 1H), 3.1-2.9 (a, 1H), 2.2-1.9 / a, 2H (1.4-1.3) (a, 1H), 1.25-0.95 (a, 4H)

Allyl - [(7S, 6B7-7 -) - (t-butoxycarbonylamino) -3-bromophenyl-acetylamino-7-trifluoromethyl-1-carba- [1-dethium] -3-cephem-4-carboxylate Prepare as in Example 20 and chromatograph on silica gel using 70 / 30hexane / ethyl acetate to give a white foam (91% of theory). NMK; / CDC! 3 /: &amp; 7.5-7.2 (a, 5H), 6.0-5.7 (a, 2H), 5.5-5.2 (m, 3H), 5.0-4.7 (a, 1H). 3.95-3.8 (m, 1H); 2.6-2.2 (a, 2H); 2.1-1.7 (a, 1H); 1.4 (s, 9H); 1.1-1.3 (a, 1H). Example 27 - tert -Butoxycarbonylamino / -3-bromophenyl-acetylamino-7-trifluoromethyl-1-carba [1-dethile] -3-ee-4-carboxylic acid

The crude yield of > 100% of the desired product is isolated by a similar reaction as in Example 21. Default! the compound is the product of Example 26. Example 28 (6R, 7S, 7-7-β-D-N-amino) -3-bromophenylacetylamino-3-trifluoromethyl-1-carba-1-dethia-3-cephem-4 -carboxylic acid - 60 -

The product was prepared as in Example 26 and chromatographed using 15% acetonitrile / 1% AcOH / HgO to give 10% product. ^ iME. (DMSO-d6): 9.20 (broad s, 1H), 7.65 (s, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.40 (d, J = 5 Hz) , 1H /, 7.30 (t, J = 5 Hz, 1H), 5.3 - 5.2 / m, 1H (> 4.75 / s, 1H), 3.7 - 3.6 / m, 1H (2.2-2.0 m, 2H), 1.4-1.2 (m, 2H). Example 29

Allyl- (7S, 68-7-7- (N-tert-butoxycarbonylamino) -3-trifluoromethyl-phenylation) 6minol 7 "trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylate Desired product, prepared / similar to Example 20? is white foam (91% of theory). 1NMS / CDCl 3: δ 7.4-7.2 / m, 4H /, 6.9-6.8 / m, 1H /, 6.0-5.85 / m, 1H / 5.7-5 , 55 (m, 1H), 5.4-5.2 (m, 4H), 4.75 / tr, J = 3 / 4.0 - 3.8 / m, 1H /, 2.5-2, 2 (m, 2H), 2.1-1.7 (m, 1H), 1.7-1.5 (m, 1H), 1.40 (s, 1H). EXAMPLE 30 3- tert -Butoxycarbonylamino (3-trifluoromethyl-phenylation) thiophene-3-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylic acid The desired product is prepared similarly to Example 21; yielding more than 100% crude, pale yellow solid. The starting material is the product of Example 29. EXAMPLE 31 (6R, 7S-7,7- (7 &apos;) - (4-Amino) -3-trifluoromethylphenylacetylamino-7-trifluoromethyl-1-carba-1-dethia-3- cefem-4-carboxylic acid The desired product is prepared similarly to Example 22 using the product of Example 30 as starting material and chromatographed on a C18 column in 0.020 g aliquots using a 15% acetonitrile / 1% AcOH system. (HgO) to give a product in 12¾ yield, ΣΝΜΕ / DMSO-dg /: δ 9.5-9.3 / m, 1H /, 8.6 / broad s, 3H /, 7.9-7.6 / m , 4H /, 5.45 - 5.35 (m, 1H), 5.16 (s, 1H), 3.85-3.7 (m, 1H), 2.3-2.1 / m, 2H), 1.35-1.25 (m, 1H), 1.25-1.1 (m, 1H) Example 32 (7S, 7 &lt; 7 &gt;) [beta] - [beta] - [Amino] -3,4-dichlorophenylacetylamino. [3-trifluoromethyl-1-carba-1-dethia-3-eefem-4-carboxylic acid]

Eacemic t-boc protected roatole 3,4-dichlorophenylglycine (0.550 g, 0.00173 mol) in 21 ml of Ν, ΐζ-dimethylformamide is cooled to -45 ° C under nitrogen, isobutyl chloroformate / 0.22 ml, 0.00173 and then N-methylmorpholine (0.15 ml, 0.00173 mol) and the solution was stirred for 30 minutes. Monosilyltrifluoroacetamide (1.53 mL, 0.00824 mol) was added to a stirred suspension of 7-amino-3-trifluoromethyl-1-carba (1-dethia) -3-defem-4-carboxylic acid (0.600 g, 0.1%). In 16 ml of Ν, β-dimethylformamide, and the solution is maintained at 40 ° C for 30 minutes. The solution of the silyl nuclea was cooled and added to the mixed anhydride at such a rate as to maintain the internal temperature of the reaction mixture at -40 ° C. The solution was slowly warmed to 0 ° C over an hour, 1.2 mL of methanol was added and the ice bath was removed. After reaching room temperature, the solution was diluted with ethyl acetate, filtered through celite, and washed four times. 1N hydrochloric acid, water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel using 2/80/18: HOAc / ethyl acetate / hexane. The crude product was taken up in a stirred solution of TFA (4.0 mL) and Et 2 Si (1.2 mL) in an ice bath and after 30 min the solution was concentrated, triturated with diethyl ether, filtered and washed. diethyl ether. Chromatography of the crude TFA salt (0.114 g) on a C18 column using a gradient to 25% CH 2 CN / HgO gave 0.021 g (3% of theory / mixture - 62) diastereomers / 90% D-side chain and 10% Lp o after lyophilization. side chain by HPLC. 1NMR (DMSO-d6): δ 9.15 (broad s, 1H), 7.7-7.6 (m, 22), 7.38 / d, J = 8Hz, 1H), 5.3-5, 25 (a, 1H), 4.75 (s, 1H), 3.8-7.7 (a, 1H), 2.2-2.1 (a, 2H), 1.4-1.2 / and, 2H). Example 33 (6R, 7S-7-β-β-N, N-CC /-amino) -3-chloro-4-hydroxyphenylacetyl-amino-17-3-trifluoromethyl-1-carba-1-dethia-3-cephem-4- the carboxylic acid desired product is prepared as in Example 32, but the pure t-boc protected D-3-chloro-4-hydroxyphenyl-glycine is used for acylation to yield a white solid in a yield of 41% 1NMR / DMSO-dg [.Alpha.] D: 7.40 (J, 1H); 7.15 (d, J = 9 Hz; 1H); 6.95 (d, J = 10.12); 5.17 (d, J = 5 W) , 4.75 (s, 12), 3.7-3.6 (a, 1H), 2.2-1.9 (a, 2H), 1.45-1.3 (a, 1H), 1 , 15-1.0 (a, 1H)

Allyl- (7S, 6R7-7 -) - 2- (triphenylmethyl) amino-4-thiazolyl-7- (tert -butoxycarbonylthio) thiocarboxylic acid (7) -aido-3-trifluoromethyl-1-carba [l-dethile] [3-Cephem-4-carboxylate] The desired product is prepared in a similar manner to that obtained in the form of a white solid (41% yield).

Example 35 L 7 S, 6 R 7 -, 7 -? - 2-Amino-4-thiazolyl / carboxymethoxyimino / acetyl-7-3-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylic acid 200 mg (0.245 mmol) of the product of Example 34 were treated with 2.5 ml of cold trifluoroacetic acid and 0.8 ml of cold triethylsilane under nitrogen in an ice bath for one hour. The bath was then removed and the solution allowed to warm to room temperature and stirred overnight. The solution is diluted with acetonitrile to a small volume in vacuo at 30 ° C, then diluted with acetonitrile twice and evaporated to dryness. The residue was triturated with diethyl ether and 73 mg of crude beige solid was obtained by filtration (57% of theory).

65 mg (0.126 mmol) of the above crude product are dissolved in 3 ml of anhydrous acetonitrile under nitrogen and 3 mg (0.126 mmol) of triphenylphosphine and 1 mg (0.00252 mmol) of palladium acetate are added. The solution was cooled in an ice bath by adding 0.036 ml (0.132 mmol) of tributyltin hydride via syringe. After one hour, the solution was treated with 0.014 ml (0.252 mmol) of acetic acid and stirred for 30 minutes. The precipitate was collected and washed with diethyl ether and then recrystallized from methanol / ethyl acetate / diethyl ether to give 21 mg of a pale yellow solid (35% yield). NMR (DMSO-d6): 9.45-9.3 (m, 1H), 7.14 (s, 2H), 6.76 (a, 1H), 5.5-5.4 - Zm, 1H / , 4.56 (s, 2H), 3.9-3.8 (m, 1H), 2.4-2.2 (m, 2H), 1.95-1.85 (a, 1B), 1 , 6 - 1.45 (m, 1H). Example 36

Allyl - (7S, 6R7-7-O-, t-butoxycarbonylamino) -3-thienyl-acetyl-amino-1-trifluoromethyl-1-carba [1-de thia] -3-cephem-4-carboxylate It is prepared similarly to Example 20 and is obtained in the form of a white, light solid in a yield of 91%. Example 37 (7S, 6R-7-7- (D, 1S) -C-t-butoxycarbonylamino) 3-Thienylethyl-amino-3- (3-trifluoromethyl-1-carba-1-thia) -3-cephem-4-carboxylic acid Prepared from the product of Example 36 by the method of Example 21 and longer with impurity. 38 / "6R, 7S_7" 7- P - / "D-O-N-amino-3-thienylacetylamino-7-3-trifluoromethyl-1-carba-1-dethia-3-cephem-4-carboxylic acid Prepared from the crude product of Example 37 according to Example 22 and chromatographed on a C18 column using methanol / acetic acid / water to yield the product in 18% yield by lyophilization. HMR (DMSO-d6): S 9.3 - 9.2 (m, 1H), 7.6 - 7.5 (m, 2H), 7.15 (d, 1H), 5.3 - 5.2 (m, 1H), 4.90 (s, 1H), 3.85-3.6 (m, 1H), 2.2-2.0 (m, 2H), 1.45-1.2 / m (2H). Example 39

Allyl / 7S, 6R7-7- [4- (7-tert-butoxycarbonylamino) -3-benzothienylamino] -7-trifluoromethyl-1-carba [1-de thia] -3-cephem; Carboxylate Prepared similar to Example 20, yielding white foam (60% of theory). EXAMPLE 40 ^ 7S, 6R_7-7- [beta] - (" D-O- (tert-Butoxycarbonylamino) -3-benzothienyl-thiamino-3-trifluoromethyl-1-carbo [l-de thia] - 3-cephem-4-carboxylic acid Prepared from the product of Example 39 by the procedure of Example 65 and not purified

Trifluoromethyl-1-carba [1-dethia] -3-ee-4-carboxylic acid Prepared according to Example 22 from the crude product of Example 40 and chromatographed on a C18 column using methanol / acetic acid / water to lyophilize. white solid in 32% yield.

1H), 1.2-1.1 (m, 1H). Example 42

Allyl 7 - ["- N-t-butyloxycarbonyl-N-phenoxyacetyl] amino-3-bromo-1-carba / 1-de thia] -2,3-cephem-4-carboxylate

The 60/40-/2 / β-3-bromo compound mixture of Preparation 3/100 mg, 0.2297 mmol) is mixed with DILAP / 29 mg, 0.2343 mmol / adi-t-butyl dicarbonate / 0.2412 mmol, 85%. 1 /. The mixture was stirred at room temperature for about one hour. The mixture was chromatographed directly on silica gel eluting with 20% ethyl acetate / methylene chloride to give 104 mg (85%) of the desired product as a 60/40 Δ2 / Δ3 isomer mixture. The values for the Δ2 isomer are as follows. ζΝΜΒ / 300 mHz, CDG1 / δ: 7.30 / t, J = 8Hz, 2H /, 7.0 / t, J * 6 Hz, 1H /, 6.90 / d, δ = 8 Hz, 2H (6.30 (m, 1H), 5.95 (m, 1H), 5.65 (m, 1H), 5.35 (m, 2H), 5.10 (m, 2H), 4.88 (s, 1H), 4.75 (m, 2H), 4.10 (m, 1H), 2.25 (m, 2H) and 1.50 (s, 9H). Example 43

Allyl-7β-N-t-butyloxycarbonyl-N-phenoxyacetyl / amino-7-3-6 &amp; - bromo-1-carba / l-dethia / 2-cephem-4-carboxylate Pure Δ2 isomer of 3-bromo compound according to Preparation 3 (4.6 g, 10.57 mmol) is mixed with di-t-butyl dicarbonate / 2, 54 g, 11.6241 mmol, 2.65 mL), then with DiaP (1.33 g, 10.88 mmol) and stir.

The mixture was treated as in Example 34 to give 5.3 g (93.6% of theory) of the desired product

Allyl27 "7S, 6R- 7-t-butyloxycarbonylamino-3-bromo-1-carba / 1-dethium] -2-cephem-4-carboxylate.

Example 42 (104 mg, 0.1947 mmol) was mixed with THF (2 mL) and the first portion of lithium hydroxide (0.1652 mL) and stirred for 40 minutes. 0295 ml) and the mixture was stirred for one hour. The mixture was poured into 40 ml of ethyl acetate and then mixed with 10 ml of water and 10 ml of saturated sodium bicarbonate solution. The organics were separated, dried over sodium sulfate, filtered and concentrated to give 79 mg (more than 100% of theory) of crude product. The values for the 2isomer are as follows: 1 H NMR (300 MHz), CDCl 3, 6.35 (m, 1H), 5.95 (m, 1H), 5.35 (m, 2H), 5.15 (m, 2H), 4.83 (s, 1H), 4.68 (m, 2H), 4.05 (m, 1H), 2.35 (m, 2H) and 1.42 (s, 9H) Example 45

Allyl - / "7S, 6H-7-7-butyloxycarbonylamino-3-bromo-1-carba / 1-dethia / 2-chloro-4-carboxylate

The product of Example 43 (5.25 g, 9.8076 mmol) was mixed with THF (95 mL) and the first portion of lithium hydroxide (8.75 mL) and stirred for about 40 minutes. A second portion of lithium hydroxide (1.55 mL) was added and the mixture was stirred for one hour. The mixture was worked up as in Example 36 to give 4.02 g (> 100% of theory) of the desired product. Example 46

Allyl - (7S, 6B-7-butyloxycarbonylamino-3-bromo-1-carba / l-dethium) 3-cephem-4-carboxylate (a) The product of Example 44 (16 mg * 0.0399 mmol) was mixed with 0.3 ml of CH 2 Cl 2 and DBU / 0.0064 mmol, 1.0 (µl). The mixture was stirred for 60 minutes at room temperature. The mixture was pipetted over 1 g of silica and then eluted with 10% ethyl acetate / methylene chloride. The desired product passes through and leaves DBU ca of silica. The mixture was concentrated to give a foam to give 15.1 mg of the product in a 15/85 ratio of isomers -Α2 / Δ3, representing 94.4% yield with respect to the theoretical maximum of 16 mg.

Allyl - "7S, 6E-7-7-butyloxycarbonylamino-3-bromo-1-carbao-1-thiazole-3-chloro-4-carboxylate

The product of Example 45 (4.0 g, 9.97 mmol) was treated according to the procedure of Example 38 except that a 6% ethyl acetate / methylene chloride system was used instead of a 10% solution to obtain a pure Λ 3 isomer. The reaction conditions are as follows: DBU: 2.5 mmol, 0.373 mL CH 2 Cl 2: 70 mL

The crude mixture was loaded directly onto a chromatography column 203.2 mm deep and 101.6 mm in diameter / silica and eluted with 6% ethyl acetate / methylene chloride to yield 1.98 g of the desired aného3 isomer and 610 mg of Δ2 / Δ3 chromatographed as above to give a further 230 mg of pure Δ 3 isomer and 360 mg of pure is isomer. The pure omer 3 isomer was combined to give a total of 2.23 g (66% of theory) of pure omer isomer. 3 isomer. or NMB / 300 mHz, CHG1 / S5.95 (m, 1H), 5.35 (m, 3H), 5.15 (m, 1H), 4.75 (m, 2H), 3.85 (m, 1H), 2.75 (m, 2H), 2.0 (m, 1H), -68-1.70 (m, 1H) and 1.42 (s, 9H). IR / CHCl 3/3019, 1775, 1718, 1504, 1369, 1206 and 105? cm 1MS, m / e 400 / M + /

Calcd for C16H21N2O5Br: C, 47.89; H, 5.28; N, 6.78; Br 19.91 found: C 47.85; H 5.05; N, 6.77; Br 19.76 Example 48 / "7S, 6R, 7-7- (Aminophenylacetyl) amino-3-broa-1-carba / 1-dethium] -3-cephem-4-carboxylic acid A / To a 25 mL flask adds 78 mg (0.1944 mmol) of allyl (7S, 6R- 7-butyloxycarbonylamino-3-bromo-1-carba / 1-dethium) -3-cephem-4-carboxylic acid in 4 ml EtOIL and 37 mg is added (0.1944 mmol) of p-toluenesulfonic acid monohydrate at 30 ° C and the mixture is evaporated to dryness, ethanol (4 ml) is added and the mixture is again evaporated to dryness, 46 mg / 0.1944 is mixed in a separate flask mmol / 2-propenyloxy / carbonylamino-D-phenylglycine and 34 mg / 0.1944 mol / chlorodimethoxytriazine in 1.5 ml methylene chloride and cooled to 0 DEG C. N-methylmorpholine (NMM) was added and the mixture was stirred After 40 minutes, another equivalent of N-methylmorpholine is added.

The mixture was allowed to warm to room temperature over 2 to 5 hours. The mixture was evaporated to near vacuum and 1 mL of methylene chloride and 1 mL of 50/50 EtOACl / hexane were added. The mixture was then loaded onto a 15 g silica column and eluted with 10% methanol / ethyl acetate to give 74 mg of allyl-7- (phenyl-p-propenyloxy) carbonylamino / acetylamino-3-bromo-1-carbo. - [1-dethium] -3-cephem-4-carboxylate «having the following physical characteristics: 1 HNMR / 300 MHz, CDCl 3 /? 7.30 (s, 5U, 7.08 (m, 1H), 5.95 (m, 3H), 5.25 (m, 6H), 4.72 (d, J = 6 Hz, 2H), 4.52 (m, 2H), 3.82 (m, 1H), 2.62 (m, 2H), 1.58 (m, 1H) and 1.25 (m, 1H). IR (CHCl3 3019, 1775, 1727, 1689, 1496, 1241, and 1052 cm @ -1MS, m / e 517-69 -

Calcd for C CH ^ NN ^O ^Cl ^: C, 53.29; H, 4.67; N, 8.11; Br 15.4 found: C 53.51; H, 4.46; N, 7.93; Br 15.4 B / 73 mg (0.1408 mmol) of the product of (A) in 2.0 ml of GHNCN and 1.0 ml of EtgO are introduced into a 25 ml flask and mixed with 7 ml. Triphenylphosphine 4 mg (0.0282 mmol) and 1.4 mg / 0.0056 mmol / palladium acetate. The mixture was cooled to 0 ° C, five minutes, and 76 µl Bu Bu Sn Sn microsyringe was added. The mixture was allowed to warm to room temperature and stirred for 45 minutes. To the mixture was added 4 µl Bu 2 Sn 2ff and 2 ml ethyl ether and stirred for an additional 30 minutes. Concentrated hydrochloric acid (23.5 µL, 1221) was added to the mixture while precipitation occurred. 10 ml of ethyl ether are then added and the mixture is transferred to a 40 ml centrifuge tube. Then 20 ml of diethyl ether was added to the mixture and the mixture was centrifuged. The solid was decanted and washed (2 x 10 mL CH 2 Cl 2/10 mL diethyl ether) and then washed twice with 15 mL diethyl ether. The mixture was dried in vacuo to give 51.5 mg of a brown solid. The brown solid was dissolved in 1.2 mL of CHOCNO 3 and 0.13 mL of 1N hydrochloric acid, centrifuged and decanted into a 15 mL centrifuge tube. While stirring, more qsl of 1 equivalent of 1.5 M ammonium hydroxide was added to adjust the pHL to about 4.0 with a white solid precipitated. The white solid was centrifuged and decanted and 8 mL of ethyl ether and 2 mL of 1/1 ethyl ether / hexane were added and then dried to give 46.5 mg of the desired product. 1 HN 2 Si / 300 2 Hz, D 8 O / δ 7.55 / m, 5H /, 5.40 / d, J = 12Hz, 1H /, 5.20 (s, 1H), 3.85 / m, 1H / 2, 50 (m, 2H), 1.55 (m, 1H and 1.25 (m, 1H)). IB / KBr / 3150, 3050, 1770, 1750, 1625, 155O "1405 and 1325 cm" 1. MS, m / e 394 / M + +1 / - 70 - Example 49 7 - [(2-Amino-4-thiazolyl) methoxyiminoacyl] amino] -3-bromo-1-carba [1-dethium] -3 -cephem-4-carboxylate A / A 240 ml (0.5981 mmol) of allyl-7-t-butyloxyamino-3-bromo-1-carba [l-dethium] -3-cephem- was introduced into a 50 ml flask. 4-carboxylate in 8 mL of EtOH. and mixing 114 mg (0.5981 mmol) of p-toluenesulfonic acid monohydrate and processing with sound. to dissipate solids. The mixture was evaporated to dryness and ethanol (8 ml) was added and the mixture was evaporated to dryness again. In a second 50 ml flask, 181 mg (0.5981 mmol) of 2-t-butoxycarbonyl / amino-4-thiazolyl-7-methoxyimino / acetic acid and 105 mg (0.5981 mmol) of chlorodimethoxytriazine are mixed in a 50 ml flask. CH 2 Cl 2 (4.5 mL) was cooled to 0 ° C and N-methylmorpholine (NMM) (69 µL, 0.628 mmol) was added to the second flask and the contents were stirred for 49 min. The contents of the second flask were allowed to warm to room temperature and stirred for 2.5 hours, and the mixture was concentrated to near dryness and 2.5 mL of methylene chloride / ethyl acetate system was added. (50 g, silica) eluted with 80/20 methylene chloride / ethyl acetate system, and the filtrate was concentrated to give 270 mg of the desired product .fwdarw.1MMB / 300 MHz, CDCl3 / 5 9.45 / 3, 1H /. 8.25 (d, J = 8Hz, 1H), 6.98 (s, 1H), 5.95 (m, 1H), 5.68 (m, 1H), 5.35 (m, 2H), 4.75 (m, 2H), 4.0 m, 1H, 3.95 (s, 3H), 2.80 (m, 2H), 2.10 (m, 1H), 1.90 (m, 1H) and 1.52 (s, 9H). MS, m / e 583 (m + +1)

Calcd for C22H25N5O7SBr: C, 45.29; H, 4.32; N 12.00; Found: C, 45.09; H, 4.52; N, 11.76. B) The product of paragraph A (270 mg, 0.4623 mmol) in 3 mL of CHCl 3 was added to a 50 mL flask with 54 mg (0.5085 mmol) of sodium ethylhexanoate with 3 mL of EtOAC. Triphenylphosphine (3.1 mg, 71%, 0.0116 mmol) and tetrakistrifluorophosphine (13.4 mg, 0.011 mmol) were added to the flask and the mixture was stirred for 1.5 hours. 30 ml of ethyl ether are added until the solid precipitates and the mixture is stirred for 1.5 hours. Ethyl ether (30 ml) was added to precipitate a solid and the mixture was stirred for a further 20 minutes and then poured into methylene chloride (200 ml) and 1N hydrochloric acid (75 ml). The solid was collected, dried over sodium sulfate, filtered and concentrated to dryness to give 250 mg of product. A 50 ml flask was charged with 251 mg (0.4591 mmol) of the product of (B) and 3 ml of methylene chloride and cooled to 0 ° C. Add 0.22 ml (1.38 mmol) of Et 2 SiH and then 3 ml of trifluoroacetic acid to the flask and allow to warm to room temperature and stir for 35 to 40 minutes. Dilute the mixture with 25 ml of acetonitrile and add 10 ml. toluene and the mixture is evaporated to dryness to give a tan solid. The solid was chromatographed on 75 g (silica) and eluted with 0.5% acetic acid / 4.5% isopropanol / 20% acetonitrile / 75% ethyl acetate to give all the desired solid. The desired fractions were concentrated to 1/2 mL and precipitated with ethyl ether. The mixture was centrifuged and the product was dried to give 60 mg of the desired product. The solid product was again chromatographed on 10 g of HP20SS eluting with 0.25% acetic acid, 10% acetonitrile, 89.75% water; 10 ml fractions were collected. (300 MHz, D 2 O / δ 7.08 / s, 1H), 5.46 (d, J = 12Hz, 1H), 4.10 (m, 1H), 4.05 (s, 3H), 2.78 (m, 2H), 2.05 (m, 1H) and 1.80 (m, 1H). MS, m / e 444 (m + +1)

The compounds of formula (I) inhibit the growth of certain pathogenic organisms, as evidenced by the agar dilution test, whereby the test compounds are diluted to a suitable range of concentrations in 0.1 M phosphate buffer, pH. is 7, Q. bring to MuellerHinton agar / Difco / supplemented with 1% additive - 72 -

Bacto-Supplement C / Difco / at 50 ° C and do not stick to petri dishes. Fresh cultures of overnight bacteria were diluted approximately 1 x / 10/4 cells / microliter and placed in a single microliter volume on the surface of the agar plate. The inoculated plates were incubated overnight at 35 ° C in ambient air. The minimum inhibitory concentration (mic) is read as the lowest antibiotic concentration in mg per ml, which inhibits the development of visible growth on the plates. The following is a summary of the test results of the compounds of the above examples. In the following Table II, the compounds are assigned the following numbers: 1. 7β- (D-β-amino) phenylacetylamino-7-trifluoromethyl-1-carba- (1-dethia) -3-cephem-4 carboxylic acid 2?, "6R, 7S-7-7? -"? - D? and? - amino-4-hydroxyphenylacetylamino-7-trifluoromethyl-carba-1-de thia-3-cephem-4-carboxylic acid (3) 6R, 7S, 7-7-β-D-cis-amino-4-fluorophenylacetylamino-7-trifluoromethyl-1-carba-1-de-thia-3-cephem-4-carboxylic acid. - 7S, 6R, 7- (7-N-2-amino-4-thiazolyl) methoxyimino (acetyl) -7-amido / 3-trifluoromethyl-1-carboxy (1-thia) -3-cephem-4-carboxamide; boxylic acid 5. Z-7S, 6R-7-7H-2-amino-4-thiazolyl / oximino / acetyl-7-amido] -3-trifluoromethyl-1-carba- [1-dethium] -3-cephem-4-carboxylic acid 6 [6R, 7S_7-7 "6 - /" D-O '- (amino) -3-ethylsulfonamidophenyl-thiamine-3-trifluoromethyl-1-carba-1-de-thia-3-cephem- 4 - carboxylic acid 7. 6R, 7S-7-7- D- / amino / 3-bromophenylation thiamine-7-3-tri-fluoromethyl-1-carb-1-de-thia-3-acetamide-4-ka rb oxylic acid 8. (6R, 7S-7-7- (3- (De) -amino) -3-fluorophenylacetylamino-7-trifluoromethyl-1-carba-1-de-thia-3-cephem-4- carboxylic acid - 73 - 9 · / 7 "6E, 7S__7" 7 * - β - D - gC- / amino / -3-trifluoromethyl acetylamino-3-trifluoromethyl-1-carba-1-dethia-3-cephem -4-carboxylic acid

The industrial utility of 7- (S-Acylamino-1-carb-1-dethia) -3-trifluoromethyl-3-cephem-4-carboxylic acid and its derivatives have antibacterial activity against gram-positive and gram-negative bacteria and can therefore be in the form of pharmaceuticals. used to prevent and treat infectious diseases.

Table II in vitro activity of compounds of formula

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Bulb II / continued /

Acin AC12

Claims (22)

PATENT'S N What is claimed is: 1. Trifluoromethyl-carba- (1-dethia / cefem) of formula (I) RCONH2 O5 (1) wherein R 1 is hydrogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio; or a fluoramido group of the formula -NHCHO, R8 hydrogen or a carboxy protecting group, R6 is hydrogen, hydroxy, C1-5 alkyl, C1-5 alkyl, halogen, C1-5 alkoxy carbon, acyloxy and 1 to 5 carbon atoms, acyl of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms or nitrile and R is carboxylic acid radical RGOOH, where Rg is hydrogen, pharmaceutically acceptable acid addition salts. 2. A compound of the formula I as claimed in claim 1, wherein R is hydrogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, cyano, carboxy, atom, halogen, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, trifluoromethyl or trifluoromethylthio, naphthyl, phenyl or substituted phenyl. where aaa * is independently hydrogen, halogen, hydroxy, cyano, nitro, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkylthio group; C 1 -C 4, amino, C 1 -C 4 alkanoylamino, C 1 -C 4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, aminomethyl, carboxymethyl, haloalkyl of 1 to 4 carbon atoms, or a perhaloalkyl group having from 1 to 4 aromatic groups of the formula wherein a and a * are as defined above and wherein Z is an oxygen atom or a sulfur atom and m is 0 or 1; or an arylmethyl group of the formula K-CH wherein the group is naphthyl, thiepyl, furyl, benzothienyl, benzoaminothiazolyl, benzofuryl, pyridyl, 4-pyridylthio, pyrimidyl, pyridazinyl, indolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, , oxadiazolyl, thiadiazolyl and the like aryl substituted with amino, hydroxy, cyano, nitro, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, substituted phenyl or alkylsulfonylamino; a substituted methyl group having the general formula - 78 - B - CH - 1 - Q where R 3 is cyclohex - 1,4 - dienyl, phenylene or substituted phenyl of formula wherein aaa * is as defined above and wherein R 1 is as defined above for R 1 and Q is hydroxy, alkanoyloxy of 1 to 4 carbon atoms, carboxy, sulfo, amino, sulfoamino or substituted amino of the formula -NH-CNC-R 7 II I II Wherein R x is hydrogen or C 1 -C 3 alkyl, R 7 is C 1 -C 4 alkyl, furyl, thienyl, phenyl, halo-phenyl, nitrophenyl, styryl, or a halostyryl group, a nitrostyryl group or a group of the formula wherein R is hydrogen or C 1 -C 3 alkyl and R 2 is hydrogen, alkylsulfonyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms or alkanoyl C 1 -C 4; or Q represents a substituted amino group of formula 0 Wherein R is as defined above and q is 3 or 2; or Q is - 79 - a less substituted amino group of formula -HNC / = O / - N - (C 1 -C 4) alkyl or Q represents a benzamido group of the formula wherein x is 1-3; or Q is a pyridone or hydroxy group of the substituted pyridonylcarbonylamino group wherein it is as defined above; or Q is pyridylcarbo- wherein the group is optionally substituted by alkyl. a C 1 -C 4 group, an amino group, a carboxy group, a hydroxy group or a halogen atom; or) Q represents an imidazolyl or pyrazolyl group of formula - 80 - wherein said imidazolyl or pyrazolyl group is optionally substituted by a C 1 -C 4 alkyl, carboxy, amino or halo group; or Q represents a benzpyridazin-4-one group or a dimer of the formula or l wherein R x is as defined above and wherein t is 1 or 3, or Q is benzpyranone of formula or R Rc - G - H N I OR, or Re - G - 5 i | Wherein R Re - has the same meaning as R ^ or R ^, as above, R 2 znamená represents a hydrogen atom or a halogen atom and Rg Ho represents a hydrogen atom, a (C 4-C alky alky) alkyl group, an alkyl group, or a hydrogen atom; C 1 -C 4 substituted by a halogen atom, a 81-carboxy substituted alkyl group or a cycloalkyl group of the formula b 1 - c. b 'where bab * is independently hydrogen or C 1 -C 3 alkyl, n 0, 1, 2 or 3 abab * together with the carbon atom to which they are attached form 3 to 6 - a membered carbonic ring and B? is hydroxy, amino, (C 1 -C 4) alkylamino or (C 1 -C 4) alkylamino; or Bg is a C 1-4 alkyl substituted phenyl or phenyl substituted by one or two identical or different groups from the group having from 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a carboxy group or a protected carboxy group; or R 8 represents an alkyl group having 1 to 4 carbon atoms substituted with an amino group or an amino group; or R 8 represents an alkenyl group having 1 to 4 carbon atoms; or Bg is a cyclic lactam. of the general formula wherein R 2 is 4 and R 4 is hydrogen or C 1 -C 3 alkyl or Bg is an arylmethyl group of formula R 1 - CH 2 - wherein R 1 is as defined above. / 11 / wherein R 2 is a hydrogen atom or a carboxy protecting group, R 1 is a hydrogen atom; hydroxy, alkyl of 1 to 5 carbon atoms, alkyl of 1 to 5 carbon atoms substituted by halogen, halogen, alkoxy of 1 to 5 carbon atoms, acyloxy of 1 to 5 carbon atoms, acyl: 1 to 5 carbon atoms, acyloxy of 1 to 5 carbon atoms, C 1 -C 5, C 1 -C 5 alkylthio or nitrile and R 1. hydrogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or formamido-NHCHQ and its acid addition salts, and when R 2 is hydrogen or alkali metal salts, with an alkaline earth metal or amine. A compound according to claim 3 wherein R 1 and R 2 are hydrogen and the other symbols are as defined in claim 3. 5. A compound according to claim 4, wherein the hydrogen atom and the other symbols are as defined in claim 4. 6. A compound according to claim 4, wherein the carboxy protecting group and other symbols are as defined in claim 4. 7. A compound of formula III - 83 - wherein R5 is hydrogen or alkoxy. C 1 -C 4, R 8 hydrogen or carboxy protecting group, R 4 hydrogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkyl, halogen, alkoxy 1 to 5 carbon atoms, acyloxy of 1 to 5 carbon atoms, acyl of 1 to 5 carbon atoms, alkylthio group of 1 to 5 carbon atoms, or nitrile group and R 6 alkyl of 1 to 6 carbon atoms or aryl group; an amino protecting group or an acyl group derived therefrom. from carboxylic acid and when R1 is hydrogen, a pharmaceutically acceptable salt of the acid. 8. A compound of formula IV wherein R @ 1 is hydrogen, C1 -C4 alkoxy, C1 -C4 alkylthio or formamido. - 84 - of formula -NHCHO, cyclohex-1,4-dienyl, phenyl or substituted phenyl of formula wherein aaa * independently of one another is hydrogen, halogen, cyano, nitro, hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoxycarbonyl of 1 to 4 carbon atoms, alkyl of up to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, (C 1 -C 4) alkylthio groups, (C 1 -C 4) alkylsulfonylamino, carbamoyl, (hydroxymethyl) carboxy groups. aminomethyl-1-carboxylic acid, C1-C4haloalkyl, C1-C4haloalkyl, or naphthyl, thienyl, furyl, or aryl. benzothienyl, benzoaminothiazolyl, benzofuryl, pyridyl, pyrimidyl, pyridazinyl, indolyl, pyrazolyl, imidazolyl, triazolyl, tetrazoyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl and the like substituted with amino, hydroxy, nitro, cyano, halogen, , (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or (C 1 -C 4) alkylsulfonylamino. 9. A compound according to claim 8 of the formula IV, wherein R1 is a substituted phenyl group of the formula Wherein a and a * are as defined in claim 8 and R 1 is as defined in claim 8. A compound of formula (IV) according to claim 9, wherein a is a hydrogen atom and a * is hydroxy and E 1 is as defined in claim 8. 11. A compound according to claim 9, wherein a, a * and R5 are hydrogen. 12. A compound according to claim 9 wherein IV is fluorine and the other symbols are as defined in claim 9. Process for preparing a compound of formula V a compound of formula VT (V) that is reacted (VI) with a mixture of copper (I) halide, cadmium or zinc, dihalo-difluoromethane and dimethylformamide, or wherein R * represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R &apos; and R * " independently of one another, an alkyl group of 86 to 1-4 carbon atoms or R " and R &quot; together with the nitrogen atom to which they are attached a saturated 5-membered or 6-membered heterocyclic group or with trifluoromethyl-copper in a substantially anhydrous organic solvent, wherein Σ represents a halogen atom, R 2 represents a hydrogen atom or a carboxy-protecting group, and R 1 represents a hydrogen atom, a hydroxy group, a C 1-5 alkyl group, an alkyl group (C 5-C), substituted by halogen, halogen, (C ac-C alko) alkoxy, (C až-C) acyl, (C až-C 5 5) acyl, (C až-C 5) alkylthio or by nitrile and R 1 is hydrogen or C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or -NHCHO and formamide acetyl is protected by amino; R6 represents a hydrogen atom and an acyl group derived from a carboxyl group. The process of claim 12 wherein at least one equivalent of trifluoromethyl-copper is reacted. 15. A process for preparing a compound of formula (VII) identifying the compound of formula (VIII) by reacting with (VIII) in an inert organic solvent with at least one equivalent of the compound of formula -87-HSn / Rt / 3 in the presence of a free radical initiator, wherein R * is alkyl of 1 to 6 carbon atoms or aryl, R 4 is hydrogen or a carboxy protecting group and R 4 is hydrogen, hydroxy, C 1 -C 5 alkyl, halogen C 1 -C 5 alkyl, halogen, C 1 -C 5 alkoxy, C 1 -C 5 acyloxy, alkyl C 1 -C 5, C 1 -C 5 alkylthio or nitrile and R 4 are hydrogen or C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or -KHCHO and is protected by or an amino group or a hydrogen atom and an acyl group derived from a carboxylic acid and a R ^ radical of a hydroxycarbylthiol having 1 to 10 carbon atoms or hyd (C 1 -C 10) -carbylselenyl group. 16. The process of claim 15 wherein the free radical initiator is azo / bis / isobutyryl nitrile. A process for preparing a compound of formula (TI) Characterized in that the compound of formula (VII) is reacted (VII) in an inert organic solvent or, in the absence of a solvent, a positive halogenating agent, wherein R 1 is C 1 -C 6 alkyl or aryl, X is bromine, iodine, chlorine or fluorine, R 4 is hydrogen, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio or formamido (-NHCHO, R 2), or a carboxyl protecting group; hydrogen, hydroxy, alkyl of 1 to 7 carbon atoms, alkyl of 1 to 5 carbon atoms substituted, halo, halogen, alkoxy of 1 to 5 carbon atoms, acyloxy of 1 to 5 atoms carbon, acyl of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms or nitrile and R 1 is hydrogen or alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, or formamido of formula -NHCHO and R ^ R ^ qN- are protected by amino or Rg is hydrogen, and R6 is an acyl group derived from a carboxylic acid. 18. The process of claim 17 wherein the positive halogenating agent is used in an amount of about 1.0 to 1.2 molar equivalents. 19. A process for preparing a compound of Formula IX wherein R 4 is hydrogen or C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or -NHCHO, R 4 is hydrogen or a carboxy-protecting group and R 1 is hydrogen, hydroxy, alkyl of 1 to 1, C 5 -C 5 alkyl, halo, halogen, C 1 -C 5 alkoxy, C 1 -C 5 acyloxy, C 1 -C 5 acyl , an alkylthio group having 1 to 5 carbon atoms or a nitrile group, an amino group or a protected amino group or a group of the general formula IIR - C - NH - wherein R is a carboxylic acid radical and when R @ 1 is an atom hydrogen of a pharmaceutically acceptable salt thereof with an acid, wherein the compound of Formula X is reacted with R 1 / X / OSO 2 CF 3 with a bromide-containing salt in the presence of a protected amine base of sufficient temperature to form a compound of formula IX for a sufficient time. 20. The process of claim 19 wherein the reaction is carried out at a temperature of about 21 ° C to about 70 ° C. The process of claim 19, wherein the reaction is carried out at a temperature of about 65 ° C. A compound of formula IX. wherein -90 is hydrogen or (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio or -NHCHO, (R 6) is hydrogen or carboxy protecting group and R * is hydrogen, hydroxy, alkyl of 1 to 1 5 carbon atoms, C 1 -C 5 alkyl, halogen, halogen, C 1 -C 5 alkoxy, C 1 -C 5 acyloxy, C 1 -C 5 acyl, alkylthio C 1 -C 5 or a nitrile group, A amino group or a protected amino group or a group of the formula NR - C - NH - wherein R is a carboxylic acid radical and, when R ^ is a hydrogen atom, a pharmaceutically acceptable salt thereof. acid. A compound according to claim 22 of formula IX wherein R is hydrogen, alkyl of 1 to 6 and tons of carbon, alkyl of 1 to 6 carbon atoms substituted, cyano, carboxy, halogen, amino, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylthio, trifluoromethyl or trifluoromethylthio furthermore denotes naphthyl, phenyl or substituted phenyl of the formula wherein aas * independently of one another is hydrogen, halogen, hydroxy, cyano, nitro, (C 1 -C 4) alkoxy, (C 1 -C 4) alkanoyloxy, (C 1 -C 4) alkyl, alkylthio (C 1 -C 4) alkyl (C 1 -C 4), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl (91), aminomethyl, carboxymethyl, (C 1 -C 4) haloalkyl or a C 1 -C 4 haloalkyl group; a general formula group wherein a and a * are as defined above and wherein Z is oxygen or sulfur and m is 0 or L; or an arylmethyl group of the formula R 3 -O 3 - wherein R 4 is naphthyl, thienyl, furyl, benzothienyl, benzoaminothiazolyl, benzofuryl, pyridyl, 4-pyridylthio, pyrimidyl, pyridazinyl, idolyl, pyrazolyl, imidazolylovir , triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl and the like aryl groups substituted with amino, hydroxy, cyano, nitro, halogen, C1-4 alkyl, alkoxy with 1 C 4 -C 4 phenyl, substituted phenyl or alkylsulfonylamino; Q wherein R 1 is cyclohex-1,4-dienyl, phenyl, or substituted phenyl of the general formula wherein aaa * are as defined above and wherein R 1 is as defined above for R 1 and Q is hydroxy, alkanoyloxy of 1 to 4 carbon atoms, carboxy, sulfo, amino-92, sulfoamino or substituted amino of general formula -NH - Wherein R x represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, a alkyl group having from 1 to 4 carbon atoms, a furyl group, a thienyl group, a phenyl group, a halophenyl group, a nitrophenyl group, a styryl group, a halostyryl group, a nitrostyryl group, or a general formula group wherein R x represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms and R 2 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms or an alkanoyl group having from 1 to 4 carbon atoms; my Q represents a substituted amino group of the formula NH - C - N wherein R 2 is as defined above and q is 3 or 2; or Q denotes a substituted amino group of the general formula -HN.C (= O) - N K - (C 1 -C 4 alkyl) or Q 1 represents a benzamido group of the general formula. Or OH represents a pyridone group or a hydroxy-substituted pyridonylcarbonylamino group of the formula wherein RX is as defined above; or Q represents a pyridylcarbonyl-amino group of the formula wherein said group is optionally substituted with an alkyl group having 1 to 4 carbon atoms, an amino group, a carboxy group, a hydroxy group or a halogen atom; or Q is imidazolyl or pyrazolyl wherein said imidazolyl or pyrazolyl group is optionally substituted by a C 1 -C 4 alkyl group, a carboxy group, an amino group or a halogen atom; or Q represents a benzpyridazin-4-one group or a tautomer of the general formula or - 94 - wherein R * is as defined above and wherein t is 1-3 or Q is a benzpyrazone group or R is a radical of formula Rc R10 where Rc is as defined for R nebo or Rj as above, R.2 is hydrogen or halogen and R 8 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by halogen, carboxy-substituted alkyl or cycloalkyl, b - C 2 - (2-b ') COR? wherein, m and n are independently hydrogen or C 1 -C 3 alkyl, n 0, 1, 2 or 3 abab * together with the carbon atom to which they are attached form a 3 to β-silane carbocyclic ring. and R ^. is hydroxy, amino, (C 1 -C 4) alkylamino, or (C 1 -C 4) alkylamino, or R 8 is C 1 -C 4 alkyl substituted by phenyl or phenyl substitution. represented by one or two identical or different groups of the group consisting of a C 1 -C 4 alkyl group, a hydroxy group, a halogen atom, a carboxy group or a protected carboxy group; or R 8 represents an alkyl group having 1 to 4 carbon atoms substituted with an amino group or a protected amino group; or R 8 represents an alkenyl group having 1 to 4 carbon atoms; or R 8 represents a cyclic lactam group of the general formula «8 where means 2 to 4 and R &amp; atom. hydrogen or alkyl of 1 to 3 carbon atoms or Rg is; wherein the compound of formula (23) of formula (IX) wherein A is phenoxyacetylamino, R (1) is hydrogen and the other radicals are as defined in claim 23 meaning. 25. A pharmaceutical composition for controlling gram-positive agram-negative bacteria comprising a compound of claim 1, 2, 8 and 22 and at least one pharmaceutically acceptable excipient or diluent carrier as active ingredient.