IE61434B1 - Acyl derivatives - Google Patents

Acyl derivatives

Info

Publication number
IE61434B1
IE61434B1 IE176587A IE176587A IE61434B1 IE 61434 B1 IE61434 B1 IE 61434B1 IE 176587 A IE176587 A IE 176587A IE 176587 A IE176587 A IE 176587A IE 61434 B1 IE61434 B1 IE 61434B1
Authority
IE
Ireland
Prior art keywords
amino
compounds according
salts
compound
alkyl
Prior art date
Application number
IE176587A
Other versions
IE871765L (en
Inventor
Harry Allen Albrecht
Ka-Kong Chan
Dennis Dalton Keith
Rudolf Ludwig Then
Manfred Weigele
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of IE871765L publication Critical patent/IE871765L/en
Publication of IE61434B1 publication Critical patent/IE61434B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Nanotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Cephalosporin derivatives of the formula <IMAGE> in which m represents 0, 1 or 2, R<1> represents hydrogen or an acyl group, R<2> represents hydrogen, lower alkoxy, amino, lower alkylthio or lower alkanoylamino, R<3><1> represents hydrogen, lower alkyl, lower alkenyl, C3-C7-cycloalkyl, halogen-lower alkyl or halophenyl; Z represents R<3><0>-C or nitrogen, R<3><0> represents hydrogen or halogen, or R<3><0> and R<3><1> together represent a C3-C5-alkylene group, a C2-C4-alkylene- monooxy group or a C1-C2-alkylenedioxy group, R<3><2> represents hydrogen, halogen, lower alkyl or an optionally substituted 5- or 6-membered heterocyclic ring having one, two or three oxygen, nitrogen and/or sulphur atoms and R<3><3> represents hydrogen or halogen or R<3><2> and R<3><3> together represent a C1-C4-alkylenedioxy group, and easily hydrolysable esters and salts of these compounds and hydrates of the compounds of the formula I or of their esters and salts are described. The products have antimicrobial activity.

Description

The present invention relates to acyl general formula R33 R32 wherein m represents 0, 1 or 2, R1 represents hydrogen or an acyl group, R2 represents hydrogen, Ci-Cs-alkoxy, amino, Ci-Ce-alkylthio or Ci-Cs-alkanoylamino, R31 represents hydrogen, CrCg-alkyl, Gg-Cg-alkenyl, Ga-Cy-cvcIoalkyl, haloi-Cg-alkyl or halo-phenyl; Z represents R30-C or nitrogen; R30 represents hydrogen or halogen, or A30 and R31 together represent a Cg-Gs-alkylene group, a C2-C4 alkylenemonooxy group or a Ci-Gg-alkylenedioxy group; R32 represents hydrogen, halogen, Ci-Gg-alkyl or a 5- or 6membered heterocyclic ring which contains one, two or three oxygen, nitrogen and/or sulphur atoms and which is optionally substituted by C?-Ce-alkyl, Gi-Cg-alkoxv, halogen, halo-Ci-Cg-alkyl, amino, mercapto, hydroxy, carbamoyl or carboxy and R33 represents hydrogen or halogen or R32 and R33 together represent a C1-C420 alkylenedioxy group, and readily hydrolyzable esters or salts of these compounds and hydrates of the compounds of formula I or of their esters or salts The term Ci-Ce-alkyl refers to straight- and branchedchain hydrocarbon groups having 1-8, preferably 1-4, carbon atoms, e.g. methyl ethyl, n-propyl, isopropyl or t-butyl.
The term Ci-Cg-alkoxy refers to straight- or branchedchain hydrocarbvloxy groups in which the alkyl moiety has the significance given above. Examples are methoxy, ethoxy or npropoxy.
The term halogen refers to chlorine, bromine, iodine or fluorine unless defined otherwise.
The term Ci-C7-alkanoyl refers to a residue of the general formula R25-COin which R25 represents hydrogen or Ci-Cg-alkyl.
Examples of these groups are acetyl, formyl, propionyl or n-buivl. o The term substituted phenyl signifies a mono- or disubstituted phenyl group, with halogen (e.g. chlorine, bromine, fluorine), C-i-Cg-alkyl, amino, nitro or trifluoromethyl coming into consideration as substituents.
The term substituted alkyl signifies a Ci-Cg-alkyl group which can be substituted e.g. by halogen (e.g. chlorine, fluorine, bromine), trifluoromethvl, amino or cyano.
The term Cg-Cg-alkenyl signifies straight- or branchedchain hydrocarbon groups having an olefinic double bond and 2-6 carbon atoms, i.e. the residue of compounds of the formula CnH2n in which n is 2-6, e.g. allyl or vinyl.
The term 5-, 6- or 7-membered heterocyclic ring with 1-4 oxygen, nitrogen and/or sulphur atoms signifies e.g. the following groups: 6-membered nitrogen-containing heterocyclic ring such as pyridyl, piperidyl, piperidino, N-oxidopyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxidopyridazinyl, etc.; a 5-membered nitrogen-containing heterocyclic ring, e.g. pyrrolidinyl, pyrazolyl, imidazolyi, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 H-tetrazolyl or 2H-tetrazolyl. These heterocyclic rings may be further substituted, whereby e.g. the following substituents come into consideration: C-j-Ce-alkyl such as methyl, ethyl or n-propyl, lower alkoxy, e.g. methoxy or ethoxy, halogen such as chlorine or bromine, halo-Ci-Cs-alkyl such as trifluoromethvl or trichloroethvl, amino, mercapto, hydroxy, carbamoyl or carboxy.
The term Cs-Cy-cycloalkvl signifies a 3-7-membered saturated carbocyclic residue, e.g. cyclopropyl, cvclobutyl or cyclohexyl.
R30 and R31 can together signify C3-C5 alkenylene, e.g. -(CH2)3-, "(CH2)4-, -(CH2)5 or -CH(CH3)-(CH2)2- or also C2-C4 alkylenemonooxv, e.g. -(CH2)2-O-,~(CH2)3-O-, -(CH2)4-O- or -CH(CH3)-CH2-O-; or also Ci-C2-alkylenedioxy, e.g. -O-CH2-O-, -O-(CH2)2-O- or -O-CH(CH3)-O-. Preferably, a 5- or 6-membered condensed ring is formed. R32 and R33 can together signify C1-C4 alkylenedioxy, e.g. -O-CH2-O-, -O-CH(CH2)2-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-CH(CH3)-O- or -O-CH(CH3)-CH(CH3)-O-.
Preferably a 5- or 6-membered condensed ring is formed in these cases.
The term acyl (substituent R1) stands for all organic radicals which are formed by removing the hydroxy group from an organic acid. Certain acyl residues are preferred. Examples of such preferred acyl groups are those which have hitherto been used for the acylation of β-lactam antibiotics, including 6aminopenicillanic acid and derivatives thereof and 7-aminocephalosporanic acid and derivatives thereof; see, e.g. Ceohalosoorins and Penicillins, edited by Flynn, Academic Press (1972), Belgian Patent 866,038, published October 17, 1978, Belgian Patent 867,994, published December 11, 1978, U.S. Patent 4,152,432, published May 1, 1979, U.S. Patent 3,971,778, published July 27, 1976, and U.S. patent 4,173,199, published October 23, 1979. Various acyl groups which are useful in the present instance are mentioned in these publications. The acyl residues set forth hereinafter illustrate the term acyl in more detail. Examples of acyl residues are: (a) aliphatic groups of the formula R5-C0in which R5 represents Ci-Ce-alkyl, Gs-Cy-cycloalkyl, Ci-Gs-alkoxy, Cg-Cg-alkylene, C3-C7=cycloalkenyl or cyclohexadienyl; or Ci-Cs-alkyl or Cg-Cg-alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, G-t-Cs-alkylihio or cyanomethylthio residues. (b) A carbocyclic aromatic group of the general formulae r7 R8 (Ci-C R7R\/TXR8 S -CH—c- R7 Rs SO3’M* R7 SO3M* in which n represents 0, 1,2 or 3: R5, R7 and R8 each represent hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethvl, Ci-C4-alkyl, C-i-C4-alkoxy or aminomeihyl, A90 represents amino, hydroxy, a carboxy salt, protected carboxy, such as e.g. henzyloxycarbonyl, formyloxv or azido and M represents a cation; Preferred carbocyclic aromatic acyl groups are those of the general formula R7 rs CH—C— in which Rs0 represents amino, hydroxy, a carboxy salt, henzyloxycarbonyl, formvloxy or azido and R6, R7 and R8 represent hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethvl, Ci-C4-alkyl, Ci-C4-alkoxy or aminomethyl, as well as those in which Rs, R7 and R8 represent hydrogen and Rs0 represents hydrogen or hydroxy, and those of the formulae c·—' il QCH,-C R9° is preferably an amino group, a hydroxy group or a carboxy or sulpho salt.
Examples of other acyl groups which can be used in accordance with the invention are: sulphonylacetvl, hydroxysulphonyloxyphenvlacetyl, sulphamoylphenvlacetyl, (phenoxycarbonyl)phenylacetyl, o (p-tolyloxycarbonyl)phenvlacetyl, formvloxyphenylacetyl, carboxyphenylacetvl, formylaminophenylacetyl, benzyloxycarbonylphenylacetyl, 2-(N,N-dimethylsulphamoyl)-2-phenylacetyl or 2-bromo-2-thienylacetyl. (c) Heteroaromatic groups of the general formulae R101-(CH2)n-COR101-CH-COI RSO R101_o_ch2-COR101-S-CH2-COor PJ θ1 -CO-COin which R90 has the significance given above, n represents 0, 1, 2 or 3 and R101 represents a 5-, 6- or 7-membered heterocyclic ring which contains 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and/or sulphur atoms and which is optionally substituted by Ci-Cs-alkyl, CvCs-alkoxv, halogen, halo-Ci-Ce-alkyl, amino, mercapto, hydroxy, carbamoyl or carboxy.
Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl and tetrazolvl. Examples of substituents on heterocyclic rings are halogen, hydroxy, nitro, amino, cyano, trifluoromethvl, Ci-C4-alkyl as well as Ci-C4-alkoxv.
Preferred heteroaromatic acyl groups are those in which R101 signifies 2-amino-4-thiazolyl, 2-amino-5-halo~4-thiazolyl, 4-aminopyridin-2-yl, 2-amino-1,3,4-thiadiazol-5-yl, 2-thienvl, 2-furanyl, 4-pyridinyl or 2,6-dichloro-4-pyridinyl. (d) [[(4-Substituted-2,3--dioxo-1 -piperazinyl)carbonyl]amino]arvlacetvl groups of the formula in which R111 represents CrCQ-alkvl, hydroxy-CvCg-alkyl or an aromatic group of the general formula (in which R6, R7 and P.8 have the above significance) or a heterocyclic ring defined for R101 and R120 represents CiCs-alkvl optionally substituted with one or more halogen, cyano, nitro, amino and/or mercapto residues, e.g. 4-(Ci-Csalkyl) (preferably ethyl or methyl)-2,3-dioxo-1piperazinecarbonvI-D-phenylglvcyl. (e) (Substituted oxyimino)-arylacetyl groups of the general formula r130—o—n=c—coin which R101 has the above significance and R130 represents hydrogen, Ci-Cs-alkyl, Cs-Cj-cycloalkyl, carboxvCs-Cy-cvcIoalkyl or substituted Ci-Cs-alkyl, wherein the Ci-Cs-alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, Cj-Cs-alkylthio, aromatic group defined above by R111, carboxy (including salts thereof), CrCyalkanoylamino, C2-Cg-alkoxycarbonyl, phenylmethoxycarbonvl, diphenylmethoxycarbonvl, hydroxy(Ci-Cs-alkoxy)phosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or di(Ci-Cs-alkoxy)phosphinyl residues.
R130—O-—NC—CO— Examples of residues ί’101 are: 2-[(2-chloroacetamidoihiazol-4-yl)]-2-[(p-nitrobenzyloxycarbonyl)methoxyimino]acetvl, 2-(2-chloroacetamidothiazol-4-vl)2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl, 2(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl, 2-thienyl-2methoxyiminoacetyl, 2-furyl-2-rnethoxyiminoacetyl, 2-(4hydroxyphenyl)-2-methoxyiminoacetyl, 2-pheny l-2-methoxyiminoacetvl, 2-phenyl-2-hydroxyiminoacetyl, 2-thienyl-2hydroxyi mi noacetyl, 2-thienyl-2-(dichloroacetyloxyimino)acetyl, 2-[4-(γ-D-g lutamyloxy)pheny l]-2-hydroxy iminoacetyl, 2-(4-(3amino-3-carboxypropoxy)phenyl]-2-hydroxy iminoacetyl, 2-(5chloro-2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetyl, 2-(5-chloro-2-aminothiazol-4-yl)-2-methoxyiminoaceiyl, 2-(2(t-butoxycarbonyl)isopropoxyimino]-2-(2-sulphonaminothiazol· 4-yl)acetyl, 2-[2-(t-butoxycarbonyl)isopropoxyimino]-2-(2-triphenylmethylamino-thiazol-4-yl)acetyl, 2-(2-chloroacetamidothiazol-4-yl)-2-isopropoxv iminoacetyl, 2-methoxy imino-2-(2sulphonaminothiazol-4-yl)acetyl, 2-(2-aminothiazol-4-yl)-2(carboxv methoxy i mi no)acetv I, 2-(2-mesylaminothiazol-4-yl)-2isopropoxy iminoacetyl, 2-(2-irnino-3-mesyl-4-thiazolin-4-yl)2-isopropoxy iminoacetyl or 2-(2-aminothiazol-4-vl)-2-(carboxyisopropoxyimino)acetyl. (f) (Acylamino)arylaceiyl groups of the general formula R1^0—CO—MH—CH —CO— R111 in which R111 has the above significance and R140 represents a group of the general formula (wherein Rs, R7, R8 and n have the above significance), hydrogen, Ci-Ce-alkyl, substituted Ci-Ce-alkyl, amino, Gi-G8-alkylamino or Ci-Ce-cyanoalkylamino.
Preferred (acylamino)arylacetyl groups of the above formula are those in which R140 represents amino. Also preferred are those groups in which R111 represents phenyl or 2-thienyl. ο (g) [[[3-Substituted-2-oxo-1 - i midazoI idiny l]carbony l]am ino]arvlacetyl groups of the general formula o II c I I I ch2—’CH2 rw in which R111 has the significance given above and R15 5 represents hydrogen, Ci-Cs-alkylsulphonyl, -N=CHR111 (wherein A111 has the above significance), R1SCO- (wherein Α1δ represents hydrogen or Ci-Cs-alkyl optionally substituted by halogen), an aromatic group as defined above under R111, or Ci-Cs-alkyl optionally substituted with one 0 or more halogen, cyano, nitro, amino and/or mercapto residues.
Preferred [[[3-substituted-2-oxo-1 -imidazolidinyl]carbonvl]amino]arylacetyl groups of the above formula are those in which R111 represents phenyl or 2-thienvl. Also preferred are those groups in which R15 represents hydrogen, methvlsulphonyl, phenylmethyleneamino or 2-furylmethyleneamino.
In a preferred embodiment of the quinolonyl or azaquinolonyl substituents in the 3-position, Z is R30-C in which R30 represents hydrogen, chlorine or fluorine, preferably hydrogen or fluorine; R31 preferably Ci-Cg-alkyl, particularly ethyl, or haloCi-C8-alkyl, especially fluoroethvl, or C3-C7-cvcloalkyl, particularly cyclopropyl; R32 is preferably Ci-Cg-alkyl, especially methyl, or 25 piperazinyl which may be substituted on the nitrogen atom in the 4-position by Ci-Gg-alkvl group, particularly by methyl; R33 is preferably hydrogen, chlorine or fluorine, especially hydrogen or fluorine, particularly fluorine. 1 The quinolonyl or azaquinolonyl substituent in the 3position includes, inter alia, residues of the following formulae o 2 Ο Ο 3 Ο ο 4 Ο ο Ν ,α—C(Ch3)3 Ο F Ν» .0CH,CCI, XX 2 3 Ο Ο ο . 1 X Ν,.. ...QCH3 - CH - CH2 \χ \ζ \,.. /\ ^χ / w F δ <' ο Preferred compounds of formula I are those in which rn represents 0 and R2 represents hydrogen. Further preferred compounds of formula I are those in which Z represents R30-C, wherein R30 represents hydrogen or halogen, R31 represents Cj-Co-alkyl, halo-Ci-Cs-alkyl or Ca-Cy-cycloalkyl, A32 represents Ci-Ce-alkyl, piperazinyl or (Ci-C8-alkyl)-piperazinyl and R33 represents hydrogen or halogen. In particular, R30 is hydrogen or fluorine, R31 is ethyl, fluoroethyl or cyclopropyl, R32 is piperazinyl or 4-methylpiperazinyl and R33 is hydrogen or fluorine.
A preferred class of compounds in accordance with the invention comprises of the general formula 7 R^NH Ib wherein R31, R32, R33 and Z have the significances given above, R20 represents an amino protecting group, e.g. trityl or chloroacetyl, or, preferably, hydrogen, and R21 represents hydrogen, C-j-Cs-alkyl or a group of the general formula IA22 I -C—COOH R23 wherein R22 and R23 represent hydrogen or C-j-Ce-alkyl or R22 and R23 together with the carbon atom to which they are attached represent a 3-7-membered carbocyclic ring, e.g. io cyclopropvl, cvclobutyl or cyclopentyl.
Especially preferred are compounds of formula la in which R20 represents hydrogen, R21 represents methyl or a group of the general formula R22 COOH Ί 5 R22 and R23 represent hydrogen or methyl, Z represents the group R30-C, A30 represents hydrogen or halogen, R31 represents Ci-Csalkyl, halo-Ci-Cs-alkvl or C3-C7-cycloalkvl, R32 represents CvCg-alkyl, piperazinyl or (Ci-C8-alkvl)-piperazinyl and A33 represents hydrogen or halogen. In particular, R30 is hydrogen or 2o fluorine, R31 is ethyl, fluoroethyl or cyclopropvl, R32 is methyl, 4-methyl-piperazinyl or piperazinyl and R33 is hydrogen or fluorine. Further preferred embodiments of compounds of formula I are: 8 1) [6R-[6-alpha,7-beta(Z)]]-7-[[(2-amino-4-thiazolyl)(R21oxyimino)acetyl]amino]-3-[[[[6-R33,8-R31 -1,4-dihydro-7-(4-R341 -piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-8-oxo5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R33 and R30 signify hydrogen or halogen, R31 signifies hydrogen, Ci-Cs-alkyl or 2-halo-Gi-Ce-alkyl, R34 signifies hydrogen or Ci-Cs-alkyl and R21 signifies hydrogen, C-j-Cs-alkyl or a group of the general formula R22 I -C —COOH and R22 and R23 signify hydrogen or Ci-Ce-alkyl. In particular, A21 is methyl, R33 and R30 are hydrogen or fluorine, R31 is ethyl or 2-fluoroethyl and R34 is methyl, R33 and R30 are fluorine and R31 is 2-fluoroethyl, R33 is fluorine, R30 is hydrogen, R31 is 2fluoroethyl and R34 is methyl, R33 is fluorine, R30 is hydrogen, R31 is ethyl and R34 is methyl, R33 is fluorine, R31 is 2-fluoroethyl, R30 is hydrogen and R34 is methyl. 2) [6R-[6-alpha,7-beta]]-3-[[[[6-R33,8-R30, 1-R3i-1,4-dihydro7-(4-R34-1-piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R33 and R30 represent hydrogen or halogen, R31 represents hydrogen, CrCsalkyl or 2-halo-Ci-Ge-alkyl and R34 represents hydrogen or C1 -Ce-alkyl. In particular, R33 and R30 are hydrogen or fluorine, R31 is ethyl or 2-fluoroethyl and R34 is methyl, R33 and R30 are fluorine and R31 is 2-fluoroethyl, R33 is fluorine, R30 is hydrogen, R31 is 2-fluoroethyl and R34 is methyl, R33 is fluorine, R30 is hydrogen, R31 is ethyl and R34 is methyl, R33 is fluorine, R31 is 2fluoroethyl, R30 is hydrogen and R34 is methyl. 3) [6R-[6-alpha,7-beia]]-7~(formylamino)-3~[[[[6-R33,8-R30, 1-R31 -1,4-dihydro-7-(4-R34-l -piperazinyl)-4-oxo-3-quinolinyl]1 9 carbonyl]oxy]methyl-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene2-carboxvlic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R33 and R30 represent hydrogen or halogen, R31 represents hydrogen, Ci-Cs-alkyl or 2-halo5 Ci-Ce-alkyl and R34 represents hydrogen or Ci-Cs-alkyl. In particular, R33 and R30 are hydrogen or fluorine, R31 is ethyl or 2 fluoroethyl and R34 is methyl, R33 and R30 are fluorine and A31 is 2-fluoroethyl, R33 is fluorine, R30 is hydrogen, R31 is 2-fluoroethyl and R34 is methyl, R33 is fluorine, R30 is hydrogen, R31 is ethyl and R34 is methyl, R33 is fluorine, R31 is 2-fluoroethyl, A30 is hydrogen and A34 is methyl. 4) [6R-[6-alpha,7-beta(Z)]]-7-[[(2-amino-4-thiazolyl)(R21oxyimino)acetyl]amino]-3-[[[[6-R33,8-R30, 1 -R31 -1,4-dihvdro-7(4-R34_i -piperazinyl)-4-oxo-3-quinolinyl]carbonyl}oxy]methyl1 5 8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R33 and R30 represent hydrogen or halogen, R31 represents hydrogen, Ci-Cs-alkyl or 2-halo-Ci-Cs-alkyl, R34 represents hydrogen or Ci-Ce-alkyl, R21 represents the group R22 I -C—COOH and R22 and R23 represent hydrogen or Ci-Cs-alkyl. In particular, R22 and R23 are both methyl, R33 and R30 are hydrogen or fluorine, R31 is ethyl or 2-fluoroethyl and R34 is methyl, R33 and R30 are fluorine and R31 is 2-fluoroethyl, R33 is fluorine, R30 is hydrogen, R31 is 2-fluoroethyl and R34 is methyl, R33 is fluorine, R30 is hydrogen, R31 is ethyl and R34 is methyl, R33 is fluorine, R31 is 2fluoroethyl, R30 is hydrogen and R34 is methyl.
Preferably the groups Ν—O—R130 O—R21 are preseni in the svn form, i.e. in the Z form, or as mixtures in which the svn form predominates.
As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group or carboxy groups of which is/are present in the form of readily hydrolyzable ester groups. Example of such esters, which can be of the conventional type, are the CvCy-alkanoyloxyCi-Cs-sIkyl esters, e.g. the acetoxymethyl, pivaloyloxymethyl, 1acetoxyethyl and 1-pivaloyloxyethyl ester; the C2-Co-alkoxycarbonyloxy-Ci-Cs-alkyl esters, e.g. the methoxycarbonyloxymethyl, -ethoxycarbonyloxyethyl and 1 -isopropoxycarbonyloxyethyl ester; the lactonyl esters, e.g. the phthalidyl and thiophthalidyl ester; the Ca-Cg-alkoxymethyl esters, e.g. the methoxymethyl ester, and the (Ci-C7-alkanoyl)-aminomethyl esters, e.g. the aceiamidomethyl ester. Other esters, e.g. the benzyl and cvanomeihvl esters, can also be used.
Examples of salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salt; ammonium salts; alkaline earth metal salts such as the calcium salt; salts with amines, e.g. salts with N-ethvl-piperidine, procaine, dibenzylamine, Ν,Ν'-dibenzylethylenediamine, alkylamines or dialkvlamines, as well as salts with amino acids such as e.g. salts with arginine or lysine.
The compounds of formula I, insofar as they have a basic functional group such as e.g. an amino group, also form addition salts with organic or inorganic acids. Examples of such salts are hvdrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkyl- and monoarylsulphonates such as ethanesulphonates, toluenesulphonates, benzenesulphonates and the like and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates or ascorbates.
The compound of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
The above acyl derivatives are manufactured in accordance with the present invention by (a) for the manufacture of a readily hydrolyzable ester of a carboxylic acid of formula I, reacting a compound of the general formula |O|m CH2HSI II in which m, R1 and R2 have the above significance, Hal represents halogen and R' represents the residue of a readily hydrolyzable ester, with a salt of a carboxylic acid of the general formula HGGO in which R31, R32 and R33 have the above significance, or (b) for the manufacture of a carboxylic acid of formula I, converting an ester of the general formula IV in which m, R1, R2, R31, R32 and R33 have the above significance and R represents an ester protecting group, into the carboxylic acid of formula I, or (c) for the represents 0 manufacture of a compound of formula I in which m reducing a compound of the general formula in which R1, A2, R3V R32 and R33 have the above significance, (d) for the manufacture of a compound of formula I in which m represents 1 or 2, or of an ester of salt thereof, oxidizing a compound of the general formula in which R1, R2, R31, R32 and R33 have the above significance and the dotted lines indicate the presence of a Δ2- or A3-double bond, or an ester or salt thereof, or (e) for the manufacture of a compound of formula I in which R1 signifies the group R130_Q_^ = C„CO = r102 and R102 signifies an amino-substituted 5-, 6- or 7-membered heterocyclic ring having 1, 2, 3 or 4 nitrogen, oxygen and/or sulphur atoms and R130 has the above significance, or an ester or salt thereof, cleaving off the amino-protecting group in the substituent R103 of a compound of the formula VH in which m, R2, R31, R32, R33 and R130 have the above significance and R103 has the significance given for R102 except that the amino substituent is protected, or of an ester or salt thereof, or (f) for the manufacture of a readily hydrolyzable ester of a compound of formula I, subjecting a carboxylic acid of formula I to a corresponding esterification, or (g) for the manufacture of salts or hydrates of a compound of formula I or of hydrates of said salts, converting a compound of formula I into a salt or hydrate or into a hydrate of said salt.
The reaction in accordance with the invention of the halide of formula II with a salt of the carboxylic acid of formula III according to variant a) of the process in accordance with the invention is preferably carried out in a non-hydroxvlated solvent such as e.g. in dimethylformamide, methylene chloride or N,N'dimethylacetamide. Suitable salts of the carboxylic acid of formula SSI are e.g. the sodium, potassium, caesium, t-butylammonium or tetrameihylammonium salts. Hal in formula II signifies halogen, especially bromine or iodine. This reaction is preferably carried out at about 0-80°C, especially at room temperature.
Ester protecting groups R in the esters of formula IV used in variant b) of the process in accordance with the invention are preferably those which can be converted into the free carboxy group under mild conditions, e.g. t-butyl, p-nitrobenzyl, benzhydryl or allyl. Also, the residues of a readily hydrolyzable ester mentioned above can be used. The ester protecting groups are cleaved off e.g. as follows: p-nitrobenzyl by hydrolysis in the presence of sodium sulphide at (or below) 0°C to room temperature in a solvent such as e.g. dimethylformamide (preferably aqueous); t-butyl by reaction with trifluoroacetic acid in the presence of anisole at about 0°C to room temperature, with or without an additional solvent such as e.g. methylene chloride; allyl by palladium(O)catalyzed trans-allylation in the presence of a sodium or potassium salt of 2-ethylcaprcate, see e.g. J. Org. Chem. 1982. 47, 587.
The reduction of the sulphoxides of general formula V according to variant c) of the process in accordance with the invention can be effected according to a variety of reactions, e.g. by treatment with phosphorus trichloride in dimethylformamide or with trifluoroacetic anhydride in the presence of sodium iodide in acetone/methvlene chloride. The temperature of these reactions preferably lies at about 0 io -20°C, especially at 0°C.
Any Δ2 isomer of formula VI is converted into the corres35 ponding 4,3 isomer of formula I in which m represents 1 or 2 by oxidizing compounds of formula VI in accordance with variant d) of the process in accordance with the invention. This oxidation is carried out by treatment with an organic or inorganic oxidizing agent. As oxidizing agents there serve various compounds which readily yield oxygen, such as e.g. organic peroxides, e.g. monosubstituted organic peroxides such as Ci-4-alkyl- or alkanoylhvdroperoxides, such as t-butylhydroperoxide, performic acid or peracetic acid; as well as phenyl-substituted derivatives of these hydroperoxides such as cumenehvdroperoxide or perbenzoic acid. io The phenyl substituent can, if desired, carry a further lower group, e.g. Ci-C4-alkvl or Ci-C4-alkoxy, or halogen or a carboxy group, e.g. 4-methvlperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid or monoperphthalic acid. Various inorganic oxidizing agents can also be used as the oxidizing agent, e.g. hydrogen peroxide; ozone; permanganates such as potassium or sodium permanganate; hypochlorites such as sodium, potassium or ammonium hypochlorite, peroxymono- and peroxvdisulphuric acid. The use of 3-chloroperbenzoic acid is preferred. The oxidation is advantageously carried out in an inert solvent, e.g. in 2o an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene chloride, chloroform, ethyl acetate or acetone; or in a protic solvent such as water, a lower alkanol, e.g. methanol or ethanol, or a lower alkanecarboxvlic acid which may be halogenated, e.g. formic acid, acetic acid or trifluoroacetic acid.
The reaction temperature generally varies in the range of -20°C io +50°C.
When using equimolar amount or slight excess of oxidizing agent in relation io the starting material there is mainly obtained the corresponding sulphoxide, i.e. a compound of formula I in which m represents the number 1. When the amount of oxidizing agent is increased to double the stoichiometric ratio or more, there is formed the corresponding sulphone, i.e. a compound of formula I in which m represents the number 2. It is also possible fo obtain the sulphone from the corresponding sulphoxide by treatment with equimolar or greater amount of oxidizing agent. The process conditions are essentially the same as in the manufacture of the sulphoxides.
By cleaving the amino-protecting group in the substituent R103 of a compound VII according to variant e) of the process in accordance with the invention there are obtained corresponding compounds of formula I having a free amino group. Possible amino5 protecting groups are those used in peptide chemistry, e.g. alkoxycarbonyl groups, e.g., t-butoxycarbonvl, substituted alkoxycarbonyl groups, e.g. trichloroethoxycarbonyl, substituted aralkvloxvcarbonyl groups, e.g. p-nitrobenzvloxycarbonyl, aralkyl groups, e.g. trityl or benzhydryl, or haloalkanoyl groups such as e.g. chloro10 acetyl, bromoacetyl, iodoacetvl or trifluoroacetvl.
Preferred protecting groups are t-butoxycarbonvl (t-BOC) and trityl.
The amino protecting groups are cleavable, for example, by acid hydrolysis (e.g. ΐ-butoxycarbonyl or trityl) or by basic hydrolysis (e.g. trifluoroacetvl). The chloro-, bromo- and iodoacetyl groups can be cleaved off by treatment with thiourea.
Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is generally at room temperature, although slightly higher or slightly lower temperatures, e.g. in the range of about 0°C to +40°C can also be used. Protecting groups which are cleavable alkalinically are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to °C. The chloro-, bromo- and iodoacetvl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C to -s-30°C.
In order to manufacture the readily hydrolyzable esters of the carboxylic acids of formula I in accordance with variant f) of the process in accordance with the invention, the carboxylic acid is preferably reacted with the corresponding halide, preferably with the iodide, containing the ester group. The reaction can be accelerated with the aid of a base, e.g. an alkali metal hydroxide or carbonate or an organic amine such as triethylamine. The esterification reaction is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide or, especially, dimethylformamide. The temperature preferably lies in the range of about 0-40°C.
The manufacture of the salts and hydrates of the compounds of formula I or of the hydrates of these salts in accordance with variant g) of the process in accordance with the invention can be effected in a manner known per se, e.g. by reacting a carboxylic acid of formula I with an equimolar amount of the desired base, conveniently in a solvent such as water of in an organic solvent such as ethanol, methanol or acetone. The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, it generally lies at room temperature but can also lie slightly thereover or thereunder, for example in the range of 0°C to +50°C.
The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous product (carboxylic acid of formula I or salt thereof) can be exposed to a moist atmosphere, e.g. at about +10°C to ~40°C.
Reaction Scheme hereinafter illustrates the process for the manufacture of the products in accordance with the invention: rW R2 H Ik Scheme I ,s.
O' ^οΗ,οοο^γγ15' COOR ^N^Z^r: R31 VIII s33 R2 R’NH-f- I COOH V R1, R2, R31, R32 r33 r and the doited bonds all have ihe significance given above.
Depending on the choice of ihe ester protecting group R and of the halogen Hal there is obtained, with respect to the double bond in the cephem ring, a Δ3- or A2-isomer of formula VIII. A Δ3/Δ2 mixture obtained can be purified, if necessary, to the desired A3-isomers by production of the sulphoxide of formula V and subsequent reduction of this compound or separation of the two components.
Explanations of Scheme. I: IIsl^VIU The compound of formula Ila is a known compound or is obtained in an analogous manner (see, e.g. U.S. Patent Nos. 4,406,899 and 4,265,049). li is reacted with a salt of the chosen quinolone of formula III. The reaction is effected as described above for process alternative a).
VIII la or Via The ester protecting group R in the compound of formula VIII is subsequently cleaved off as described above for process alternative b), there being obtained a carboxylic acid of formula la or a mixture thereof with the A3-isomer of formula Via. via v Where the double bond is isomerized with the formation of the A3-isomer, the thus-obtained compound of formula Via is oxidized as described above for process alternative d), e.g. with a peracid such as e.g. 3-chloroperbenzoic acid in a solvent such as e.g. methylene chloride at a reaction temperature of about -20°C to 40°C, preferably at about 0°C.
V -d I9 The thus-obtained compound of formula V is itself an end product falling under formula I. It can, however, be reduced to the end product la as described above for process variant c).
Compounds of formula I with the groups n-or130 n-o-r2181 SI t , -C- or -O (see above) preferably exist as syn forms. Such syn forms can be obtained using starting material in which this syn form is already present. Alternatively, a svn/anti mixture of a compound of formula I obtained can be separated into the corresponding syn and anti forms in the usual manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
In accordance with the invention there have been combined for the first time the two antibiotic components cephalosporin and quinolone/napthvridinone (the latter are known e.g. from DEA-23 62 553, 30 31 767 and 31 06 013), whereby novel products having outstanding antibiotic properties are obtained.
The compounds of formula I as well as the corresponding salts and hydrates of these products and esters have antibiotic, especially bactericidal, activity. They can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammals, e.g. dogs, cats, horses, etc., and humans. These cephalosporins are active against a broad range of both Gram-negative and Gram-positive bacteria.
The in vitro activity of the compounds in accordance with the invention against a variety of Gram-positive and Gramnegative microorganisms, expressed as Minimum Inhibitory Concentration in microgram/ml and determined using the serial dilution method (liquid medium), is as follows: Compound A: [6R-(6«.7p)]-3-[[[(1-Ethyl-1,4-dihvdro-7meihvl-4-oxo-1,8-naphthyridin-3-yl)carbonyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate Compound B: [6R-(6a,7P)]-3~[[[(5-Ethyl-5,8-dihydro-8-oxo1,3-dioxolo[4,5-g]quinolin-7-yl)carbonyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl]amino]-5thia-1 -azabicyclo[4.2.0]oci-2=ene-2~carboxylic acid monosodium salt Compound C: [6R-(6a^)(Z)]-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(1 -ethyl-1,4di hydro-7-met hyl-4-oxo-1,8-naphthyridin-3yl)-carbonyl]oxv]methyl-8-oxo-5-thia-1 -azabicvclo[4.2.0]oct-2-ene-carboxylic acid sodium salt Compound D: [6R-(6a,7p)(Z)]-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[(5-ethyl-5,8di hydro-ox o-1,3-dioxolo[4,S-g]quinolin-7-yl)carbonyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt Compound E: [61R-(6 Compound F; [6Α-(6α.7β)]-3-[[[(5-ΕίΙ^Ι~518^ΐΙ^Γθ-8-οχο1,3-dioxolo[4,5-g]quinolin-7-yl)carbonyl]oxy]meihyl]-8-oxo-7-[(2-thienylacetyl)amino]-5thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt Compound G: [6R-(6«^)]-3-[[[[(1-Ethyl-6-fluoro-1,4dihydro-7-(4-formyl-1 - piperazinyl)-4-oxoqu inolin-3-y IJcarbonyl] oxy] meth y I]-7-[(2thienylacetyl)amino]-8-oxo-5-thia-1 -azabi5 cyclo[4.2.0]-oct-2-ena-2-carboxylic acid sodium salt Compound Η: [6Α-(6α,7β)]-3-[[[[(1 - Ethy l-6-f I uo ro-1,4dihydro-7-(1 -pyrrol idin y 1)-4-0 xo-qui noli n-3yl]carbonyl]oxy]methyl]-8-oxo-7-[(phenoxy10 acetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2ene-2-carboxylic acid sodium salt Compound I: [6R-(6a,7p)(Z)]-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[1 -ethyl-6fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-4-oxoquinolin-3-yl]carbonyl]oxy]methyl]-8-oxo-5ihia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt In vitro MiC (uo/mi) Cfimpsimds Organism A B C D E F G Η 1 E. coli 48 32 2 0.5 0.25 8 2 8 32 0.5 5 K. pneumoniae A 18 1 0.5 0.25 2 1 4 32 0.5 E. cloacae 9570A 64 2 2 1 8 2 8 32 2 E. cloacae 948-1 — 2 8 1 8 1 8 32 4 E. cloacae 2387-2 ... 1 16 2 4 1 32 32 4 E. cloacae 7099 16 0.5 8 0.5 2 0.5 2 2 2 10 E. cloacae 214 1 28 2 8 0.5 8 2 64 32 4 P. vulgaris ATCC 6380 8 0.5 0.25 0.063 4 0.5 4 32 0.5 P. mirabtlis 190 8 0.5 0.18 0.008 0.5 0.5 4 0.5 0.031 S. marcescens SM 16 1 1 0.5 4 1 4 32 1 P. aeruginosa Stone 130 1 28 32 128 16 16 32 32 32 8 15 P. aeruginosa 503-58 1 28 84 128 32 32 64 64 64 32 S. aureus Smith 0.25 0.25 2 2 0.063 0.25 0.25 0.25 0.25 S. aureus 95 . . 4 8 4 2 4 4 0.5 0.5 In order ΐο combat a bacterial infection in a mammal, a compound in accordance with the invention can be used in a daily dosage of about 5 to about 500 mg/kg, preferably about 10100 mg/kg especially about 10-55 mg/kg. All modes of administration which hitherto come into consideration for penicillin and cephalosporin therapy can also be used for the cephalosporins in accordance with the invention. Modes of administration are accordingly e.g. intraveneous, intramuscular and enteral administrations.
The products in accordance with the invention can be used as medicaments, e.g. in the form of pharmacetuical preparations which contain them or their salts in admixture with a pharmaceutical organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as e.g. water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols or Vaseline. The pharmaceutical preparations can be made up in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. as solution, suspensions or emulsions. They may be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics of buffers. They can also contain other therapeutically valuable substances. The carboxylic acids of formula I and their salts and hydrates preferably come into consideration for parenteral administration and for this purpose are preferably made up in the form of lyophilizates or dry powders for dilution with customary agents such as water or isotonic sdoium chloride solution. The readily hydrolyzable esters or ethers of formula I also come into consideration for enteral administration.
ExsniQlaJL carboxylic acid (4-nitrophenyl)methyl ester and [2R-(2g_x6g,71UL· 3-f ίί(1 -ethy 1-1.4-dihvdro-7-methyl-4-oxo-1,8-naohthyridin-3yl)carbonyl1oxv1methyl1-8-oxo-7-f(phenoxvacetyl)amino]-5-tbia^ -azabicyclor4.2.03oct-3-ene-2-carbO-xy.lig—.apid (4-nitrophenyIE methvl ester.
A solution of 22.4 g (0.040 mol) of [6R-(6a,7p)]-3-(bromomethyl)-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester and 10.1 g (0.040 mol) of 1-ethyl-1,4-dihydro-7-methyl-4-oxo1,8-naphthyridine-3-carboxylic acid sodium salt in 200 ml of dry dimethylformamide is stirred in an argon atmosphere for 5 hours. The solvent is evaporated under reduced pressure. A solution of the residue in ethyl acetate is washed with brine, decolorized with active charcoal, dried over sodium sulphate and evaporated to a small volume under reduced pressure, whereupon the above end products crystallize out. The mother liquor is purified by column chromatography on 800 g of neutral silica gel (particle size 0.063-0.200 mm) using ethyl acetate as the eluent. The appropriate fractions are combined and crystallized from ethyl acetate to give additional end product. The mixture of isomers obtained is used for the subsequent reaction. Pure Δ3ester is obtained by fractional crystallization from ethyl acetate and the A2-ester is isolated by preparative thin-layer chromatography of the mother liquor on silica gel plates Characterizing data of the two isomers: A3-lsomer: IR(KBr) 3405, 1785, 1735, 1697, 1637, 1520, 1348 cm-1; mass spectrum m/z 714 (M+ + H), 736 (M+4-Na).
A2-lsomer: IR(KBr) 3560, 3480, 3415, 1780, 1745, 1693, 1620, 1520 cm-1; mass spectrum m/z 713 (M+).
Example 2 f2R-(2a.6a.7B)1-3-iff(1-Ethyl-1 .4-dihydrp-7-methvl-4-oxo-l .8naphthyrLdin-.3-vl)carbonvnoxv1methyl1-8-oxo-7-r(ohenoxy36 a£&.Wamin&^ 1 -a^bipy.C.lQflJ^ anid A solution of 2.80 g (0.0116 mol) of sodium sulphide hydrate in 20 ml of water is added dropwise to a solution of 6.11 g (0.00856 mol) of a mixture of the two isomers from Example 1 in 45 ml of dimethylformamide at -5 to -10°C. After 35 minutes, the mixture is acidified to pH 3.5 by the addition of IN aqueous hydrochloric acid, whereby a gum precipitates. The gum solidifies after the addition of 50 ml of ethyl acetate and 50 ml of ether. After filtration, washing with water and ether and drying at 50°C under reduced pressure over phosphorus pentoxide the end product is obtained. Addition of more ether to the filtrate gives additional precipitate which is filtered and dissolved in aqueous sodium bicarbonate soluton. The aqueous solution is washed with ethyl acetate and acidified to pH 3.5. A solution of the precipitated gum in methylene chloride is filtered, washed with water, dried over sodium sulphate and evaporated under reduced pressure. Additional end product is obtained; IR(KBr) 3420, 3300, 1773, 1720 cm·1; mass spectrum m/z 579 (M+ + H).
Examnle_a f6R-(6jx J8)1-3Tff(1-EthyJ-1 ,4-dihvd.ro-7-m_e_thyl-4-oxo-1.8naphthyridin-a^dk;arbonvl]oxvlmethyl1-8-Qxo-7^fIphenaxyas&tyJMm in o x y jig A solution of 0.986 g (85% pure, 0.00486 mol) of mchloroperbenzoic acid in 15 ml of methylene chloride is added dropwise while stirring to a suspension of 2.55 g (0.00442 mol) of the end product of Example 2 in 60 ml of methylene chloride at 0°C. The mixture is stirred for 4 hours at 0°C and then filtered. The solid obtained is washed with methylene chloride and dried under reduced pressure. The thus-obtained end product has the following characterizing data; IR(KBr) 3360, 1794, 1723, 1684, 1637, 1017 cm-·*; mass spectrum m/z 595 (M* + H).
Examole_4 [6 R:.(, 7 β)] - 3- ί f ί ί 1 - EthyJ -1 .4-dihyd ro -7.-m eihy I -4 -px0-J_, 85 n aoh t h v rid i n-3 - v I )ca rbo n y 11 o x vl methvlEazWin^fLQfianoxyz acetyhamino]-5-thia-1-azabicvclof4.2.0]QCt-2-ene-_2-carboxylic acid hydrate To a solution of 1.64 g (0.0109 mol) of sodium iodide in 40 ml of dry acetone and 20 ml of methylene chloride are added 10 1.30 g (0.00219 mol) of the end product of Example 3. The suspension obtained is cooled while stirring and 1.75 ml (0.0124 mol) of trifluoroacetic anhydride are added at 0°C. After 30 minutes, the pH is adjusted to 6.0 with aqueous sodium bicarbonate solution. Subsequently, the pH is adjusted to 3.5 15 with aqueous 1N hydrochloric acid and a small insoluble portion is removed by filtration. The organic phase is washed with aqueous sodium sulphide solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is washed with ether, taken up in methylene chloride and precipitated by the 20 addition of ether to give end product.
Alternatively, a mixture of 0.435 g (0.73 mmol) of the end product of Example 3 and 7 ml of dry dimethylformamide is cooled to -12°C while stirring and 0.128 ml (1.4 mmol) of phosphorus trichloride is added. After 7 minutes, an additional 0.027 ml of phosphorus trichloride is added. The mixture is stirred for 6.5 minutes and then a cold solution of 0.428 g (5.1 mmol) of sodium bicarbonate in 70 ml of water is added.
The precipitate obtained is filtered off, washed with water and dried under reduced pressure over phosphorus pentoxide to give 30 end product. Additional end product separates form the filtrate.
Characterizing data: IR (KBr) 3420, 1785, 1708, 1620 cm'1; mass spectrum m/z 579 (M+ H). £xampie_J h yd rQ.-.8rO^:.Q/1^jjiflxaLQX4^ σ 1 a u i η ο I i n - 7 - v I) car bo ay I j oxy Tm et h v I1 -8.--Q,x o._7Jlabajao-xyacaly IIamino.Hrlhia£L^Zflbj^ai^^^ lddlImathM^tbyJL_as^ A solution of 5-ethyl-5,8-dihydro-8-oxo~1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid sodium salt (1 mmol) in 12 ml of dimethylformamide is stirred in a nitrogen atmosphere with 1.5 g of a 4A molecular sieve for 1 hour, subsequently treated with a soluton of [6R-(6a,78)]-3-(iodomethyl)-8-oxo-7[(phenoxy acetyl) ami no]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid 1,1-dimethylethyl ester (1 mmol) in 6 ml of dry dimethylformamide and stirred for 5 hours. The mixture is evaporated to dryness. The residue is taken up in ethyl acetate or ethyl acetate/methylene chloride, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated to dryness. The residue is purified either by preparative layer chromatography or by flash chromatography using an 8:2 solvent mixture of ethyl acetate and methylene chloride.
ExgrnplQ Ι&ΒΛ/^,ΣβΙίΖΙΑΓίίίυΞϊΙινΜ ,47dihvdro-7rmethyl-4-nxns1^8n ap h t hyrkUrb3.-:,v ncaxbnn vJloxy Lm elb.y 11 - 7-f H met h ox v- i m i η o 1-(2(triphenylTOeihyl)jamino-4-thiarolyHacetvnamiPol-8-oxo-5-t.hia-_ L^zahicydofA^eJlMcl-g-en^^C-arboxvIic acid. 1/L· dimaihyigthyi_^sipr The title compound is obtained by repeating the reaction of Example 5 using 1 -ethyl-1,4-dihdyro-7-methyl-4-oxo-1,8naphthyridine-3-carboxylic acid sodium salt and [6Α-(6α,7β)(Ζ)]30 3-iodomethyl-7-[[(methoxyimino)[2-(triphenylmethyl)amino-4thiazolyl]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2ene-2-carboxylic acid 1,1-dimethylethyl ester. The residue is purified by flash chromatography using a 9:1 mixure of ethyl aeetate/methylene chloride as the solvent.
Example 7 -r^.S^glauinoliri-Z-vncarbonvIloxvlmethyll^-rrfmefhoxv-iminQ)l2zU£iahanyJiiifilhvlI^^ Ihiaa^asaifegha^ acid.. J-, dimethvlethyl ester The title compound is obtained by repeating the reaction of Example 5 using 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5gjquinoline-7-carboxylic acid sodium salt and [6Α~(6α,7β)(Ζ)]-3iodomethyl-7-[[(methoxyimino)[2-(triphenylmethyl)arnino-4thiazGlyl]acetyl]amino]-8-oxo~5"thia-1 -azabicyclo[4.2.0]oct-2ene-2-carboxylic acid 1,1-dimethylethyl ester. The residue is purifed by flash chromatography using a mixture of 9:1 ethyl aeetate/methylene chloride as the solvent.
Examp-Le-B [6Η-(6α.7ΒΗΖ)-3-Γί[Γ(1-Ethvl-6-fluoro-1.4-dihydro-7-i4-forrn_yl1- - P i P e r a 7 j py 1)-4-jix Qrgjui np li n^3^y Ugaibo n vJlPxyl methyl] -fi,J3X£L· 7-ί(ρΚ6ηοχν3€3ΐνΙ^ίποΐ-5-ΐΜ3--1-3Ζ&^ονοΙοΓ4,2.01οοΐ-2Γ-Θη82- carboxytjc acid i_.Udjmethylethyl ester The title compound is obtained by repeating the reaction of Example 5 using 1-ethyl-6-fluoro-1 s4~dihdyro-7-(4-f©rmyl"1piperazinyl)-4-oxo-3-quinolinecarboxylic acid monosodium salt and [6R-(Sa,7$)]-3-(iodomethyl)-8-oxo-7[(phe noxyacety I )ami no]-5-th ia-1 -azabicyclo [4.2.0]oct-2-ene-2carboxylic acid 1,1-dimethylethyl ester. The residue is purified by flash chromatography using a 20:1 mixture of methylene chloride/methanol as the solvent.
Jin -L·v LtcamaaiiUflxy 3 met.b vllβζΔ&0ζΖ4£αά e na&Mx acetyl) -am i n_ol- ariMa-Va^jAi£yxtbJAXJllQjsi^^-es2^c^ boxylic_jacid scdium-jsalt A solution of 3.00 g (4.52 mmol) of the end product of Example 5 in 15 ml of anisole is treated at room temperature while stirring with 10.6 ml of trifluoroacetic acid. The mixture is stirred for 4 hours and evaporated to dryness under reduced o pressure. The oil obtained as the residue is dissolved in methylene chloride and water is added. The pH value is adjusted to 7.5 with sodium bicarbonate. The mixture is stirred for 20 minutes and then the aqueous phase is removed. The addition of water and the adjustment of the pH value to 7.5 with sodium bicarbonate while stirring is repeated twice. The three aqueous extracts obtained are combined and freeze-dried. The residue is purified on a non-polar stationary phase (Cig reverse phase) using 50% aqueous methanol as the solvent. There is obtained, after evaporation and freeze drying, the title compound; IR(KBr) 3410, 1765, 1692, 1635, 1528 cm-1; mass spectrum m/z 630 (M+ + H), 652 (M+ + Na).
.Example i_q aruiitp] -3 - [ fj /1 _elhy LL 4ς4ϊ b y^r-Q^Z .-.amih yL.4^x q J^a^naph tkA suspension of 0.31 mmol of the end product of Example 6 in 0.66 ml of anisole is cooled to 0°C in a nitrogen atmosphere and 3.3 ml of trifluoroacetic acid is added. The resulting solution is held at 0°C for 18 hours and then evaporated under reduced pressure at room temperature. After the addition of methylene chloride, the evaporation under reduced pressure is repeated. The residue is triturated with ethyl acetate in order to obtain, if possible, a solid before conversion into the sodium salt. If it is not possible to obtain a solid, the residue is converted directly into the sodium salt. In either case, the solid or the oil obtained is dissolved in 9 ml of methylene chloride, whereafter an aqueous sodium bicarbonate solution containing sufficient sodium bicarbonate to maintain a final pH value of 7.2 to 7.4 is added dropwise at 0 to 3°C to the thus-prepared methylene chloride solution. The aqueous phase is freeze-dried and subsequently purified by analytical high pressure liquid chromatography using a reverse phase column and elution with a water-methanol gradient (0-100% methanol, 20 minutes). After evaporation and freeze drying, there is obtained the end product: IR (KBr) 3405, 3300, 3200, 1766, 1716, 1681, 1617, 1537 cm*1. £xaomis_ll r6R-(Oa.7BHZ))-7-ir(2-Amino-4-thiazolylHmethoxvimino)acetvlIamino1-3-rrf(5Tethyl-5.8-dihydro-8-oxo-1 .S-dioxoloiA^S-qlo jiincJin-- 7 - y J) c a r b ο n v 11 ο x y 1 m e t h y 11 - 8 - ο χ o hia^l -ja_zab icvclof4 2.QTQciLZ-e.ne-2-carboxyii The title compound is obtained according to the procedure of Example 10, but using the end product of Example 7: IR (KBr) 3400-3200, 1767, 1715, 1685, 1635, 1616, 1533 cm1; mass spectrum m/z 679 (M+ + H), 701 (M+ + Na).
Example. 12 f£B--J(-6α.7ΰ}l·.3-fffΠEthvl-6-fluoro-1 4-dihydro-7-i4-formvl-1olO-Qra.zirLyJ.)^-o_X-O--quinQlin-3T-yl1carbonvllQxv]methyl1-7f(Qheooxyacetvl)amino1-S-Qxo-5-thja-i-azabicyclo[A_2,Q-lo_ct-2According to the procedure of Example 10 using the end produci of Example 8 there is obtained the title compound; IR (KBr) 3420, 1768, 1668, 1620 cm·1; mass spectrum m/z 716 (M+ + H), 738 (M+ + Na).
Example 13 R -16κ.7βχί3 g1auinolin-7-yl)carbonvnoxv1methyn-8-oxo-7-f(2-thienylacetvl)amin_Ql-5-thia-1-azabicvclor4.2.0]oct-2-ene-2-carboxvlic_acid 1.1-dimethylethyl ester According to the procedure of Example 5, but using [6R(6 Example 14 g1auinolin-7-yl)carbonvl]oxylmethvn-8-oxo-7-f(2-thienvlacetvl)aminoj-5-thia-1 -azabicyclo[4.2.01oct-2-ene-2-carboxylic acid sodium salt The title compound is obtained according to the procedure of Example 10, but using the end product of Example 13: IR (KBr) 3410, 1763, 1682, 1632, 1608, cm’1; mass spectrum m/z 620 (M+ + H), 642 (MJ- + Na).
Example 1_5 f8R-X6.gvBn-6rL[JLVEthyl-6-fluoro-1.4-όΐην0Γθ-7-(4-ίο^νΙτν piperazinyn-4-oxo-auinolin-3-yncarbonyn-Qxy1methyl]-7-r(2thienylacetyl)amin-Ol-8-oxo-5-thia-1 -azablC-yclof4.2.0]oct-2ene-2-carboxylic acid 1-1-dimethylethyl ester According to the procedure of Example 5, but using [6R(6α,7β)]-3-(iodo methy I )-8-oxo-7-[(2-th ienylacetyl)am ino]-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-(4formyl-1 -piperazinyl)-4-oxo-3-quinolinecarboxylic acid sodium salt as reagents, there is obtained the title compound.
ExsmpfOS T8R~ (8_a .7 3)1-3-((((1 -EthyliMJ uo ro-1,4-dih vdro-7-(4-formyl-1 oioerazinvl)-4-oxo-auinolin-3-vl1carbonvlloxy1methvl1.-7-f(2thienylacetyl)aminol-8-oxo-5-ihia-l-azabicycJ_o_(4j?.01oct-2ene-2-carboxylic acid sodium salt.
According to the procedure of Example 10, but using the end product of Example 15, there is obtained the title compound: IR (KBr) 3430, 1765, 1715, 1662, 1623 cm1; mass spectrum m/z 70S (M- + H).
Examnis_17 (6R-(6a .7B) (2)1-3-((((1-Ethvl-6-f I uoro-1.4-dihvdro-7-(4-formvl1. - Pip eraz_i n y IL4 - Q x J_- Quinolin-3-vl1carbonvl]oxy]methylj-7[ [im^t h According io the procedure of Example 5, but using [6R(6a,7p)(Z)]-3-(iodomeihyl)-7-[[(rnethoxyimino)-[2-(iriphenylmethyl)amino-4-thiazolylJacetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1 -dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1 -piperazinvl)-4-oxo-3-quinoline-carboxylic acid sodium salt as reagents, there is obtained the title compound.
ExamQl£_l£ ί6Λ-ϊ6α.7β)(Ζ^7-[[(2-Ατηπτ£^4:ίΗ8^ amino]-3-rUI1-ethyl J3rfluoro-1.4-dihydro-7-f4-formyl-1piDerazinyfM--oxo-Qu»oQUn‘-3-vl1car-bDJ.yilQxylm.ethyl]-8-QxO"5-. to.isdLazabiCKCifiIto2. oiocto^e n e-2°carb-Q χ y 1 ic_ acid._sfidiwaj_ssto The title compound is obtained according to the procedure of Example 10, but using the end product of Example 17: IR (KBr) 3420, 1765, 1712, 1622 cm'1; mass spectrum m/z 764 (M+ + H). io ExamoifLAH Ι^Α-_ί^Ζ£Ι3^ί[π I r p -1.4 ,-d i h ydw^XvoyxLalL·· d i n y I )-4 - o x o_- on i η ο I i n - 3 - y llc a r b ο η v I l o x v 1 m e t h v II - 7 - f (o h e η o x y r. acelv l ).a rnirLQk8 -ox o-5tob j.a - toazab icy c Lo-fA .2.0loot- 2^6ΰ3.-2-. carboxYlic_acid 1.1 -dim.e.thy)athyl_esi&r The title compound is obtained according to the procedure of Example 5, but using [6R-(6a,7p)]-3-(iodomethyl)-8-oxo-7[(phenoxyacetyl)-amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxvlic acid 1,1-dimethylethyl ester and 1-ethyl-6-fluoro1,4-dihydro-4-oxo-7-(1 -pyrrolidinyl)-3-quinolinecarboxylic acid 2o sodium salt as reagents.
Examals_2Q 3θ6ίν»)Αοηο1^-οχο-5^^-ΐτ3235ίθ·νο.Ιο[4·2^1θ3ΐ-2-3ΰβ-2·2 5 GBXhQX ylS£L_S£iit3Qdmm_saJj, The title compound is obtained according to the procedure of Example 10, but using the end product of Example 19: IR (KBr) 3410, 1770, 1695, 1628 cm-1; mass spectrum m/z 673 (M+ + H), 695 (M+ + Na).
Example 21 d i n v I) -4- o x o -q u i η ο I i n - 3 - v IlcaiboiiylLo x vTm.et h y H - 7- f ί (m et h qxvL· imino)f2-(triphenylmethyl)amino-4-thiazolyllacetyLlaminflli8L·· oxo-5_-thia-1-azabicyclof4.2.0loct-2-ene-2-carboxylic acid 1 JL· dimethylethyl ester According to the procedure of Example 5, but using [6R(6a,7p)]-3-(iodomethyl)-7-[[(methoxyimino)[2-(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester and 1 - ethy I-6-f luoro-1,4-dihydro-4-oxo-7-(1 -pyrrol idi nyl)-3quinolinecarboxvlic acid sodium salt as reagents, there is obtained the title compound.
Exampje_22 [6R-(6a.7B)(Z)]-7-r[(2-Amino-4-thiazolvl)(methoxvimino)acetyllaminol-3-frrri-ethy l-6-f luoro-1,4-dihydro-7-(1-oyrrolidinvl)-4oxo-quinolin-3-yl1carbonyl1oxy]methylj-8-oxo-5-thia-1-azabicyclof4.2.01oct-2-ene-2-carboxylic acid sodium salt The title compound is obtained according to the procedure of Example 10, but using the end product of Example 21; IR (KBr) 3455, 3430, 1768, 1682, 1630 cm1; mass spectrum m/z 722 (k* + H).
Example 23 f6R-(6«.7e)1-3-fffM-Ethyl_-_6:llnqiar-1_.-4--dihvdro-7-i4-(1.1dirnethylethoxv)carbonyl-1-oioerazinvn-4-oxo-quinolin-3νΙ1ε8ή3οηνΗοχνΤηηΘΐΙιν1]-8-οχο-7-[ΐρΐΊ3ηοχν3θΘϊνΙ)3Γηΐηο1-52;1ΐΉ&46 sihyL^sigr According to the procedure of Example 5, but using [6R(δα17β)3-3-^θΓη©ΙΚνΙ·’8-οχο-7-[(ρΐΊθηοχνΒθθΐνΙ)-3πηΐηο]-5-ίΙ·υ®5 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1dimethylethyl ester and 1 -ethyl-5-fluoro-1 ,4-dihydro-7-[4-(1,1 di methylethoxy)carbonyl-1-piperaziny l]-4-oxo-3-qu i noli necarboxylic acid potassium salt as reagents, there is obtained the title compound.
IR 3420, 1787, 1730, 1698, 1510 cm1; mass spectrum m/z 822 (M+ ~ H).
Examolg_24 yl l£^rba.Qv!Tflx vJLm^ih d KSs-O X O--.7 4/p h&nax yagelyl lamin o.E5--ihia-.
According to the procedure of Example 5, but using [6R(6a^)]-3-iodomethyl-8-oxo-7-[(phenoxyaceiyl)-amino]-5-ihia1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-propenvl ester 2o and 1 -ethyl-6-fluoro-1,4-dihydro-7-[4-(1,1 -dimeihyleihoxy)carbonyl-1 -piperazinyl]-4-oxo-3-quinolinecarboxylic acid potassium salt as reagents, there is obtained the title compound.
IR (KBr) 3415, 3300, 1789, 1729m 1594, 1522 cm’1; mass spectrum m/z 806 (M++ H).
ExamalS-25 3-4JIL1 rEih y L6 - fluo rrk l^i hydrorZ^i 1 J.< d-img/Lky-IpjJmx y.1x9JlLQ-n y I i p e r az i n y 11 - 4 - o x.o - g u i n ol i n_r3 yllcadK)nyllOLXv1meihvl]-8:Oxo-7-f(ohenoxvaQetyl)amjno1r5-thia4 7 According ίο the procedure of Example 5, but using F6R(6a,78)]-3-iodomethyl-8-oxo-7-[(phenoxyacetyl)-amino]-5-ihia1-azabicyclo[4.2.0]oct-2"ene"2-carboxylic acid 2-propenyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-propenoxy)carbonyl1-piperazinyl]-4-oxoquinoline-3-carboxyiic acid sodium salt as reagents, there is obtained the title compound: IR (KBr) 3410, 1789, 1725, 1699, 1622 cm-1; mass spectrum m/z 790 (M+ + H).
Example 26 f6R-(6aJ'eil-S-fiiiS-Ethyl-S.S-dihydro-Ji^xo-l ..3j^jix^LQ±O_JA._5--fl-L· q u i no I i n - 7 - y I Ic ar b o n.y 11 o x y ] m e t h y 11 - 8 - ο χ o - 7 - f (.ph e n q xyacelylL· am i n.o.1-_8 --ο.χ 0.--5.-th i ad - azab icyclo[4J2JUflgfc22.e n,e.:.2^carImxyliG a£i±=2xaraagnyLgstar According to the procedure of Example 5, but using [6R(6α, 7β)]-3-iodo methy l-8-o xo-7-[( phe noxyacetv I)-ami no]-5-th ia1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-propenyl ester and 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7carboxylic acid sodium salt as reagents, there is obtained the title compound.
Example 27 oxq°1,3:dioxolor4_.5-q1qjiinctlLn^7-yl)carbPJLvJOXvJm_eihvi;i^firPx.Q^ 7-r(phenoxvaceiyl)amino]-5-thia-1-azabicvcloi4,2.Qloct-2-ene2jsari3oxyiic- acid sodium,salt A solution of 337 mg of the end product of Example 26, 0.03 ml of triethyl phosphite, 5.6 mg of palladium(ll) acetate, 3.9 ml of ethyl acetate and 5.6 rnl of methylene chloride is treated dropwise while stirring within 15 minutes with 1.68 ml of a 0.5 molar solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture is then stirred for 30 minutes and 11 ml of acetone are added, whereafter the stirring is continued for 10 minutes. The product is filtered off, washed with ether and air dried. After purification by Cis reverse phase high pressure liquid chromatography, the title compound is obtained. The spectra of this product are identical with those of the product of Example 9.
I M.Q ro -1., 4 -d i b yd-rJL·?,^ thiomorpholipyJ)-4-oxo-Quinolin-3-ul)carbonvl1oxy]ni£iliyll-.8·ene-2-carboxylic acid sodium salt A solution of 0.187 g of 1 -ethyl-6-rluoro-1,4-dihvdro-4oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid sodium salt in 8 ml of dimethylformamide is stirred with 4A molecular sieve for 1 hour. After the addition of 0.257 g of [SR-(6a,7p)]3-(iodomethyl)-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-propenyl ester in 8 ml of dimethylformamide, the mixture is stirred for 5 hours and then evaporated under reduced pressure. A solution of the residue in ethyl acetate is washed in succession with aqueous sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by preparative layer chromatography to give as the intermediate the allyl ester corresponding to the title compound.
To a solution of 63.5 mg of this allyl ester in 1.1 rnl of methylene chloride and 0.75 ml of ethyl acetate are added 5.1 μΙ of triethyl phosphite, 1 mg of palladium(ll) acetate and 0.28 ml of 0.5M sodium 2-ethylhexanoate solution in ethyl acetate. The mixture is stirred for 1 hour, treated with 2 ml of acetone and then evaporated to dryness under reduced pressure. The residue is triturated with ether to give a solid. After purification by reverse phase high pressure liquid chromatography, there is obtained the title compound: IR (KBr) 3420, 1768, 1695, 1622 cm-1; mass spectrum m/z 705 (M+ + H), 727 (M+ + Na).
Example 29 16R-_(6&, 76)1-3 - Γ ffjf-J - El hj/Ke-dLimrad-. 4,-d i.h vd.r.o - 4- q x q-ZJJIL pyrroM-yliguinolin-a-vIlcarbonylloxylmethyll-S-oxo^r(phenoxvaceiynamino1-5-thia-1-azabicyclo[4.2.01oct-2-ene-2carb-Qxyljg- acid sodium salt A solution of 0.845 g of 1-ethyl-6-fluoro-1,4-dihydro-4oxo-7-(1 H-pyrrol-1 -vl)-3-quinolinecarboxylic acid potassium 10 salt in 30 ml of methylformamide is stirred for 1 hour with 4A molecular sieve. Subsequently, 1-54g of [6R-(6a,7P)]-3-iodomethv l-8-oxo-7-[(phenoxy acetyl) am ino]-5-thai-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxvlic acid 2-propenvl ester is added and the mixture is stirred for 2.5 hours. The mixture is evaporated 5 under reduced pressure, ethyl acetate is added and the mixture is washed in succession with aqueous sodium bicarbonate solution and brine. After drying over sodium sulphate, the ethyl acetate is evaporated under reduced pressure and the residue is purified by flash chromatography to give as the intermediate the allyl ester 20 corresponding to the above title compound.
A solution of 69 mg of this allyl ester in 1 ml of methylene chloride is treated with 0.3 mg of palladium(ll) acetate, 1 μΙ of triethyl phosphite, 0.2 ml of 0.5M sodium 2©thylhexanoate solution in ethyl acetate and 0.3 ml of ethyl acetate. After stirring for 30 minutes, the mixture is evaporated under reduced pressure. The residue is triturated with ether io give a solid. After purification by reverse phase high pressure liquid chromatography, there is obtained the title compound: IR (KBr) 3420, 1765, 1695, 1620 cm-1; mass spectrum m/z 669 (M+ + H). 691 (M+ + Na).
Example 30 Γ6 R -L8aJ aikaJULS-i n^dhp-J^-riikYdlit-ΟλΏχΡ-τΧ^ Ii£iiajn&&va£^JUajTunflJ^J^ c.e/J3PxylLC_aGid-^adiuiP_sali A solution of 0.183 g of 5-(4-fluorophenyl)-5,8-dihydro-8oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid potassium salt in 8 ml of dimethylformamide is stirred for 1 hour with 4A molecular sieve. After the addition of a solution of 0.308 g of [6 Α-(δα,7β)]-3-iodo methy l-8-oxo-7-[(ph enoxv acetyl) am ino]-5thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-propenyl ester, the mixture is stirred for 5 hours, then evaporated under reduced pressure and ethyl acetate is added. The mixture is washed in succession with aqueous sodium bicarbonate solution and brine. After drying over sodium sulphate, the ethyl acetate is evaporated under reduced pressure and the residue is purified by preparative layer chromatography to give as the intermediate the allyl ester corresponding to the title compound.
A solution of 0.122 g of this allyl ester in 2.1 ml of methylene chloride and 1.5 ml of ethyl acetate is treated with 9.9 μΙ of triethyl phosphite, 1.94 mg of palladium(ll) acetate and 0.51 ml of a 0.5M sodium 2-ethylhexanoate solution in ethyl acetate. The mixture obtained is stirred for 1 hour, diluted with acetone and evaporated under reduced pressure. The residue is triturated with ether to give a solid. After purification by reverse phase high pressure liquid chromatography, the title substance is obtained: BR (KBr) 3420, 1765, 1695, 1632 cm1; mass spectrum m/z 696 (M- + H), 718 (M+ + Na). aminoM-frif 1 -ethyi.-6-fluoro-l ^-dihp/j-jrpjjHfArihjojm^ linvl)-4-oxo-guinolin-3-to}aarbQnxlloxylmethvn-8-I>xp-5,-ijliadjL A solution of 0.374 g of 1-ethyl-6-fluoro-1,4-dihydro-4oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid potassium salt in 16 ml of dimethylformamide is stirred for 1 hour with 1.5 g of 4A molecular sieve. After the addition of a solution of 1.07 g of [6R-(6a,78)]-3-iodomethyl-7-[[(methoxyimino)[(2triphenylmethyl)amino-4-thiazolyl]acetyl]amino]-8-oxo-5-thia1 -azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1 -dimethylethyl ester in 16 ml of dimethylformamide, the mixture is stirred for 5 hours. The mixture is evaporated under reduced pressure, the residue is taken up in ethyl acetate and the thusobtained mixture is washed with aqueous sodium bicarbonate solution and brine. After drying over sodium sulphate, the ethyl acetate solution is evaporated under reduced pressure. The residue is purified by flash chromatography to give as the intermediate the t-butyl ester corresponding to the above title compound. 0.103 g of this t-butyl ester is dissolved in a mixture of 0.21 ml of anisole and 1.06 ml of trifluoroacetic acid and held at 0°C for 18 hours. The mixture is evaporated under reduced pressure and the residue is dissolved in methylene chloride. The pH value is adjusted to 7.5 by the addition of water and sodium bicarbonate solution. The aqueous phase is freeze-dried. The title compound is obtained after purification of the residue by reverse-phase high pressure liquid chromatography: IR (KBr) 3410, 1768, 1715, 1682, 1622 cm-1; mass spectrum m/z 754 (M+ + H).
Exam.Qia_52. rg R - (7β 2^AmjiLQ^4jhjazaWCmfijtotxyJito am i n O-Utof f [ [6 JSbri ilLu o r o_-1 -(2- flimrogih y 1,)-1 A-diky£kiL-7--i.4m,etbyJALa.iaexa^iayJJ - 4 -g χ o - 3 -q.uio-9 i-m y llc.a rbanyi-lQ-O-lm.g-l-h y π 52 - οχ ο - 5 -1 h ia -1 - a z a b i c v c I (if4 _a£id monosodium.-sa.lt jdihvdrale A solution of 10 g of [6R-(6a,7p)]-3-(iodomethyl)-7[[(methoxyimino)[2-(triphenylmethyl)amino]-4-thiazolylacetyl]amino]-8-oxo-5-thia-1 -azabicyelo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 40 ml of dimethylformamide is added to a suspension of 5g of 6,8-difluoro-1-(2-fluoroethyl)~ 1,4-di hydro-7-(4-methy 1-1 - piperazinv I )-4-oxo-3-quino linecarboxylic acid potassium salt in 40 ml of dimethylformamide within 5 minutes. The mixture is stirred for 2 hours and then evaporated under reduced pressure. The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase is washed in succession with aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give a brown foam. Purification by flash chromatography on 500 g of silica gel (0.04-0.08 mm) using methanol-chloroform (gradient from 0-8% methanol) gives as the intermediate the 1,1-dimethylethyl ester corresponding to the above title compound.
A solution of 2.30 g of this 1,1-dimethylethyl ester in 25 ml of methylene chloride is treated at 0°C with 2 ml of anisole, 0.2 ml of 1,2-ethanedithiol and 25 ml of trifluoroacetic acid. The mixture is stirred at 0°C for 3.5 hours and then evaporated under reduced pressure at 0°C. Methylene chloride is added to the residue and the evaporation is repeated. To the * residue are added 5 ml of cold ethyl acetate and then 25 ml of ether to precipitate a solid. After filtration, washing with ether and air-drying, a tan solid is obtained. This is dissolved in 100 ml of 1:4 methanol-chloroform and, while cooling with ice, 100 ml of water and 35 ml of 5% aqueous sodium bicarbonate solution are added io pH 7.8. The gum which separates is dissolved in 10 ml of dimethylformamide and treated with 20 ml of chloroform and then water and aqueous sodium bicarbonate solution to pH 7.8. The combined aqueous extracts containing the end product are washed with chloroform and purified by Cisreverse-phase chromatography using a water-acetonitrile gradient as the solvent. The fractions containing the end product are evaporated under reduced pressure and freeze-dried to give the title compound: Mass spectrum m/z 787 (M+ + H), The following compounds can be manufactured by the methods illustrated in the Examples: [SR-[6 X *·» ,N, *F NH COOH O [6Ρ-(6α,7β)]-3-[[[[1 -ethy l-6-f luoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3-quinolinyl]carbonvl]oxy]methyl]-8-oxo-7[(phenoxyacetyl)amino]-5-thia-1 -azabicvclo[4.2.03oct-2-ene-2- [6R-(6a,7P)]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1 -piperazinvl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicvclo20 [4.2.0]oct-2-ene-2-carboxylic acid [6R-(6a,7p)3(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[1 -ethy l-S-i luoro-1,4-di hydro-7-(4-methyl1 -piperazi nyl)-4-oxo-3-qu ino liny l]carbonyl]oxo] methyl]-8-oxo5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [8R-(8a,7P)]-3-[[[[1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxymethyl]-3-oxo-7[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid COOH O [SR- (8 α, 7β)]-3-[[[[1-cyclopropyl-6-f luoro-1,4-dihydro-7-(1piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-8-oxo-7[(phenoxyaceiyl)amino]-5-lhia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid [6R-(6a,7p)(Z)]]-7-[[(2-amino-4-ihiazolyl)methoxyimino]acetylJamino]-3-[[[[1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1 p iperazi n y l)-3-qui no linyl]carbonyl]oxy] meth yl]-8-oxo-5-th ia-1 5 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Η H X COOH [5R-(6a,7P)]-7-[(cyanoaceiyl)amino]-3-[[[[6,8-diiluoro-1-(2Tlu oro ethy 1)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3qu i nol inyl]carboxy]oxy] meth yl]-8-oxo-5-th ia-1 -azabicyclo [4.2.0]10 oct-2-ene-2-carboxylic acid [6 R - (Sa, 7 β)]-7-(formy lam ino)-3-((((6,8-difluoro-1 - (2-f luoroethyl)-1,4-dihydro-7-(4-rnethy 1-1 - piperazinyl)-4-oxo-3quinolinyl]carbonyl]oxy]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid F Ο [6R-(6a,7p)]-7-[f[[4-ethyl-2,4-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyljamino]-3-[[[[6,8-diTluoro-1 -(2-fluoroethyl]1,4-dihydro-4-oxo-3-qui noli nyljcarbonv l]oxv] methy l]-8-oxo-55 thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [6 R-[6a,75(Z)]]-7~[[2-amino-4-thiazoly 1)(((1-carbo xy-1 methyl)ethoxy]imino]acetyl]amino]-3-[[[[6,8-difluoro-1-(2fluoroethyl)-1,4-di hydro-7-(4-methyl-1 -piperaz inyl)-4-oxo-3qu i nol in yl]carbonyl]oxy] meth yl]-8-oxo-5-th ia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [6R-[6a,7p(Z)]]-7-[[[(2-amino-4-thiazolyl)(carboxymethoxy)i mi nojacetv l]amino]-3-[[[[6,8-d if luo ro-1 -(2-f luoroethy 1)-1,4di hydro-7-(4-met hy 1-1 - pi perazinv 1)-4-0 xo-3-qui no liny l]car5 bonyl]oxv]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oci-2-ene-2carboxylic acid F COOH 0 [6R-[6a,7P)]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-qu inolinyl]carbony l]oxy]io methyl]-8-oxo-7-[(phenylacetyl)amino]-5-ihia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [6R-[6ct,7p)]-3-[[[[6,8-d if luoro-1 - (2-f luoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]58 methyl]-8-oxo-7-[2-thienylaceiyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid F COOH O [6R-[6a,7P(Z)]]-7-[[(2-amino-4-thiazoly I) (methoxy imino)acetyl]5 am i no]-3-[[[[6,8-d if luo ro-1 -(4-f luorophenyl)-'! ,4-dihydro-7-(4methyl-1 -pipe razinyl)-4-oxo-3-quinol iny l]carbonvl]oxy]methyl]8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [6R-[6a,7p)]-3-[[[[6-fluoro-1 -(4-f luo ropheny 1)-1,4-dihydro-7-(4methyl-1 -piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct2-ene-2-carboxylic acid F COOH 0 [6R-[6a,7p)]-3-[[[[9-fluoro-3,7-dihydro-3-methyl-10-(4-methyl1-piperazinyl)-7-oxo-2H-pyrido[1,2,3-de]-1,4-benzoxazin-Syl]carbonyl]oxy]methyl]-3-oxo-7-[(phenoxyacetyl)amino]-5-thia5 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [6R-[6a,7p(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[I[9-fluoro-3,7-dihydro-3-methyl-10-(4-methy I-1 piperazinyl)-7-oxo-2H~pyrido[1,2,3-de]-1,4-benzoxazin-6yl]carbonyl]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-Z-carboxylic acid COOH O [6R-(6a,7p)]-a-[[[2-carboxy-3-[[[[6,8-dif luoro-1 -(2-fluoroethyl)1,4-dihydro-7-(4-methyl-1 -piperazinyl)-4-oxo-3-qui no liny I]60 carbonyl]oxy]methyl]-8-oxo-5-ihia-1 -azabicyclo[4.2.0]oet-2-©n7-yl]amino]carbonyl]benzoic acid CHg I COOH Hi EH IW 9 9 <5 COOH O [6R-[6a,7p(Z)]]-3-[[[[7-(3-amino-1 -pyrrolidinyl)-8-chloro-25 cyclopropyl-S-iluoro-1,4-dihydro-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)[(carboxym©thoxy)imino]aceiyl]amino]-8-oxo-5-ihia-1 -azabicyclo[4.2.0]oci-2-ene-2-carboxylic acid [6R-[6a,7p(Z)]]-3"[[[[7-(3-amino-1 -pyrrolidinyl)~8-chloro-1cyclopropyl-6-iluoro-1,4-dihydrO"4-oxo-3~quinolinyl]~ carbonyl]oxy]methyl]-7-[[(2'amino-4-thia2olyl)[(1 -carboxy-1methylethoxy)imino)acetyl]amino]-8oxo-5thia-1 -azabicyclo[4.2.0]oet-2~ene’2-carboxylic acid COOH Ο O [6R-[6a,7p(Z)]]-3-[[[[7-(3-amino-1 -pyrrolidinyl)-8-chloro-1 cyclopropy I-6-f luoro-1,4-dihydro-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene2-carboxvlic acid The following Example illustrates pharmaceutical preparations containing the cephalosporin derivatives in accordance with the invention: Example A Production of dry ampoules for intramuscular administration: A lyophilizate of 1 g of {6R-(6a,7p)(Z)]-7-[[(2-amino-4~ thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[6,8-difluoro-1-(2fluoroethyl)-1,4-dihydro-7-(4 - methy 1-1 -piperazinvl)-4-oxo-3quinolinyl]-carbonyi]oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0Joct-2-ene-2-cart?oxylic acid monosodium salt dihydrate is prepared in the usual manner and filled into an ampoule. The sterile water ampoule contains 10% propylene glycol. Prior to administration, the lyophilizate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Claims (68)

Claims
1. Acyl derivatives of the general formula wherein m represents 0, 1 or 2, R 1 represents hydrogen or an acyl group, R 2 represents hydrogen, CrCg-alkoxy, amino, CrCg-alkylthio or CrCg-alkanoylamino, R 31 represents hydrogen, Ci-Ce-alkyl, C2-C6-alkenvl, Ce-Cy-cycloalkyl, haloi-Ce-alkyl or halo-phenyl; Z represents R 30 -C or nitrogen; R 30 represents hydrogen or halogen, or R 30 and R 31 together represent a Cg-Cs-alkylene group, a C2-C4 alkvlenemonooxy group or a CrC2-alkylenedioxy group; R 32 represents hydrogen, halogen, Cr Cg-alkyl or a 5- or 6membered heterocyclic ring which contains one, two or three oxygen, nitrogen and/or sulphur atoms and which is optionally substituted by Cr Cg-alkyl, Ci-Cg-alkoxy, halogen, halo-Cr Cg-alkyl, amino, mercapto, hydroxy, carbamoyl or carboxy and R 33 represents hydrogen or halogen or R 33 and R 33 together represent a C1-C4alkylenedioxy group, and readily hydrolyzable esters and salts of these compounds and hydrates of the compounds of formula ί or of their esters and sails.
2. Compounds according to claim 1, characterized in that m represents 0 and R 2 represents hydrogen.
3. Compounds according to claim 1 or 2, characterized in that Z represents R 30 -C in which R 30 represents hydrogen or halogen, R 31 represents Cr Ce-alkyl, halo-Cr Ce-alkyl or C3-C7cycloalkyl, R 32 represents CrC8-alkyl, piperazinyl or (CrCealkyl)-piperazinyl and R 33 represents hydrogen or halogen.
4. Compounds according to claim 3, characterized in that R 30 represents hydrogen or fluorine, R 31 represents ethyl, fluoroethyl or cyclopropyl, R 32 represents piperazinyl or 4methylpiperazinyl and R 33 represents hydrogen or fluorine.
5. As hereinbefore described aad exemplified» 5 1 -piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]meihyl]-8-oxo7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-enecarboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R 33 and R 30 represent hydrogen or halogen, R 31 represents hydrogen, Ci-Cs-alkyl or 210 halo-Ci-Cs-alkyl and R 34 represents hydrogen or Ci-Cs-alkyl. 5 and R 22 and R 23 signify hydrogen or Ci-Ce-alkyl. 5 5. Compounds according to any one of claims 1-4, characterized in that R 1 represents one of the following acyl groups: (a) an aliphatic group of the formula R5-CO10 in which R 5 represents Ci-Cs-alkyl, C3-C7-cycloalkyl, Ci-Cs-alkoxy, Cg-Ce-alkenyl, C3-C7-cycloalkenyl or cyclohexadienyl or Ci-Cs-alkyl or C2-Cs-alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, C1 -Ce-alkyIthio or cyanomethylthio residues:
6. Compounds according to any one of claims 1-5, characterized in that R 1 represents a carbocyclic aromatic group of the general formula in which R 90 represents amino, hydroxy, a carboxy salt, benzyloxycarbonyl, formyloxy or azido and Αθ, A 7 and R 8 represent hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, Ci-C4-alkyl, Ci-C4-alkoxy or arninomethyl.
7. Compounds according to claim 6, characterized in that R6, A 7 and R 8 represent hydrogen and R 90 represents hydrogen or hydroxy.
8. Compounds according to any one of claims 1-5, characterized in that R 1 represents an acyl group of the general formula R 130 —Ο—N—C —CO— R 101 in which R 101 represents a 5-, 6- or 7-membered heterocyclic ring which contains 1, 2, 3 or 4 nitrogen, oxygen and/or sulphur atoms and which is optionally substituted by halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, Ci-C4-alkyl or Ci-Ca-alkoxy and R 130 represents hydrogen Ci-Ce-alkyl, Cg-Cy-cycloalkyl, carboxy-Cg-Cy-eycloalkyl or Ci-Cg-alkyl substituted with one or more halogen, cyano, nitro, amino, mercapto, Ci-Cs-alkylthio, aromatic group defined by R 111 in claim 5, carboxy (including salts thereof), Ci-Cy-alkanoylamino, C2-Cg-alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy(Ci-Ce-alkoxy)phosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl and/or di(CrC8-alkoxy)phosphinyl residues.
9. Compounds according to any one of claims 1-5 and 8, characterized in that R 1 represents an acyl group of the general formula in which R 20 represents hydrogen or an amino protecting group and R 21 represents hydrogen, Ci-Ce-alkyl or a group of the general formula R 22 -C—COOH a 23 wherein R 22 and R 23 represent hydrogen, Cj-Cg-alkyl or together with the linking carbon atoms represent a 3-7membered carbocyclic ring. (9) a [[[3-substituted-2-oxo-1 -imidazolidinyl]carbonyl]amino]arvlacetyl group of the general formula o il R 13 —N N—CO—NH—CH—CO— i S I H 2 c-CHg R ni in which RH 1 has the significance given above and R 15 represents hydrogen, Ci-Cs-alkylsulphonyl, -N=GHR 111 (wherein R 111 has the significance given above), R 16 CO(wherein R 1S represents hydrogen or Ci-Cs-alkyl optionally substituted with halogen), an aromatic group as defined under R 111 above or C^-Cs-alkyl optionally substituted with one or more halogen, cyano, nitro, amino and/or mercapto residues. 10. Ethyl or 2-fluoroeihyl and R 34 represents methyl.
10. Compounds according to claim 9, characterized in that R 20 represents hydrogen and R 21 represents methyl or C—COOH
11. Compounds according to claim 1 of the general formula NOR 21 in which R 21 has the significance given in claim 9 and Z, R 31 , R 32 and R 33 have the significance given in claim 1.
12. Compounds according to any one of claims 1-11, characterized in that R 21 represents methyl or a group of the general formula R 22 I -c — COOH R 22 and R 23 represent hydrogen or methyl, Z represents the group R 3 0-C, R 30 represents hydrogen or halogen, R 31 represents C1-C310 alkyl, halo-Ci-Ce-alkyl or Ca-Cy-cycloalkvl, R 32 represents Ci-Ce-alkvl, piperazinyl or (Ci-C8-alkvl)piperazinyl and R 33 represents hydrogen or halogen.
13. Compounds according to claim 12, characterized in that R 30 represents hydrogen or fluorine, R 312 represents ethyl,
14. Compounds according to claim 1, characterized as [6R-[6-alpha,7-beta(Z)]]-7-[[(2-arnino-4-thiazolyl)(R 21 -oxy20 imino)acetyl]aminoJ-3-[[[[6-R 33 ,3-R 30 , 1-R 31 -1,4-dihydro-7-(4r34„i -pjpefazinyl)-4-oxo-3-quinolinyl]carbonyl]oxyjmethvl]-8oxo-5-thia-1 -azabicycl[4.2.0]oct-2-ene-2-carboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R 33 and R 30 signify hydrogen or halogen, R 31 signifies hydrogen, Ci-Ce-alkyl or 2-halo-Ci-Ce-alkyl, R 34 signifies hydrogen or Ci-Ce-alkyl and R 21 signifies hydrogen, C-ι-Ce-alkyl or a group of the general formula R22 I -C—COOH
15. Compounds according to claim 14, characterized in that R 21 represents methyl. 15 fluoroethyl or cyclopropyl, R 32 represents methyl, 4-methylpiperazinyl or piperazinyl and A 33 represents hydrogen or fluorine. 15 wherein R 22 and R 23 signify hydrogen or methyl. 15 (b) a carbocyclic aromatic group of the general formula o II ch 2 —c- SO 3 -M* in which n represents 0, 1, 2 or 3; R 6 and R 7 and R 8 represent hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, Ci-C4-alkyl, Ci-C4-alkoxy or aminornethyl, R 90 represents amino, hydroxy, a carboxy salt, protected carboxy, formvloxy or azido and M represents a cation; (c) a heteroaromatic group of the general formulae Ri0i.(CH 2 )rrCO~ R101-O-CH2-COR101.S-CH2-CO- or R101-CO-CO10 in which R 90 has the significances given above, n represents 0, 1, 2 or 3 and R 101 represents a 5-, 6- or 7-membered heterocyclie ring which contains 1, 2, 3 or 4 nitrogen, oxygen and/or sulphur atoms and which is optionally substituted by Ci-Ce-alkyl, Ci-Cs-alkoxy, halogen, halo-Ci Ce-alkyl, amino, mercapto, hydroxy, carbamoyl or carboxy; (d) a [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl group of the formula m 23 — INI—CO—MH—CH - CO — in which R 111 represents Ci-Ce-alkyl, hydroxy-Ci-Cs-alkvl or an aromatic group of the general formula (in which R 6 , R 7 and R 8 have the significance give above) or a heterocyclic ring as defined for R 101 and R 120 represents Ci-C8-alkvl optionally substituted with one or more halogen, cyano, nitro, amino and/or mercapto residues; (e) a (substituted oxyimino)arylacetyl group of the general formula in which R 101 has the significance given above and R 130 represents hydrogen, Ci-Cs-alkyl, Cs-Cz-cycloalkyl, carboxy-C3-C7-cycloalkyl or substituted C-j-Cs-alkyl wherein the C-j-Cg-alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, C-j-Cs-alkylthio, aromatic group defined above by Ri 11 , carboxy (including salts thereof), Ci-C7-alkanoylamino, C2-C9alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy (Ci-C8-alkoxy)phosphinyl, dihydroxyphos phinvl, hvdroxy(phenylmethoxy)phosphinyl and/or di(Ci-Csalkoxv)phosphinyl residues: (f) an (acylamino)arylacetyl group of the general formula R 1 *®—CO—NH—CH—CO— ( in which R 111 has the significances given above and R 140 represents a group of the general formula (wherein R 6 , R 7 , R 8 and n have the above significance), hydrogen, C-j-Cs-alkyl, substituted Ci-Cs-alkyl, amino, Ci-C8-alkvlamino or cyano-CrCs-alkylamino;
16. Compounds according to claim 15, characterized in that R 33 and R 30 represent hydrogen or fluorine, R 31 represents
17. Compounds according to claim 16, characterized in that R 33 and R 30 represent fluorine and R 31 represents 2fluoroethyl.
18. Compounds according to claim 15, characterized in 15 that R 33 represents fluorine, R 30 represents hydrogen, R 31 represents 2-fluoroethyl and R 34 represents methyl.
19. Compounds according to claim 15, characterized in that R 33 represents fluorine, R 30 represents hydrogen, A 31 represents ethyl and R 34 represents methyl.
20. 20. Compounds according to claim 15, characterized in that R 33 represents fluorine, R 31 represents 2-fluoroethyl, R 30 represents hydrogen and R 34 represents methyl.
21. Compounds according to any one of claims 8-20, characterized in that the groups of the general formulae N—O—-A 130 Si N—©“Ft 21 and are present in the syn-isomeric form or as mixtures in which the syn-isomeric form predominates.
22. Compounds according to claim , characterized as [6R[6-alpha-7-beta]]-3-[[[[6-R 33 ,8-R 28 * 30 ,1-R 31 -1,4-dihydro-7-(4-R 34
23. Compounds according to claim 22, characterized in that R 33 and R 30 represent hydrogen or fluorine, R 31 represents ethyl or 2-fluoroethyl and R 34 represents methyl.
24. Compounds according to claim 23, characterized in 15 that R 33 and R 30 represent fluorine and R 31 represents 2f I uoroethv I. 25. Represents hydrogen and R 34 represents methyl.
25. Compounds according to claim 22, characterized in that R 33 represents fluorine, R 30 represents hydrogen, R 31 represents 2-fluoroethyl and R 34 represents methyl. 20
26. Compounds according to claim 22, characterized in that R 33 represents fluorine, R 30 represents hydrogen, R 31 represents ethyl and R 34 represents methyl.
27. Compounds according to claim 22, characterized in that R 33 represents fluorine, R 31 represents 2-fluoroethyl, R 30
28. Compounds according to claim 1, characterized as [6R-[6-alpha,7-beta]]-7-(formylamino)-3-[[[[6-R 33 ,8-R 30 , 1-R 31 1,4-d i hydro-7-(4-R 34 -1 -piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-23 0 carboxylic acids and salts thereof and hydrates of these car72 boxylic acids and salts, wherein R 33 and R 30 represent hydrogen or halogen, R 31 represents hydrogen, Ci-Cs-alkyl or 2-haloCi-Cs-alkyl and R 34 represents hydrogen or Ci-Cs-alkyl.
29. Compounds according to claim 28, characterized in that R 33 and R 30 represent hydrogen or fluorine, R 31 represents ethyl or 2-fluoroethyl and R 34 represents methyl.
30. Compounds according to claim 29, characterized in that R 33 and R 30 represent fluorine, and R 31 represents 2fluoroethyl.
31. Compounds according to claim 28, characterized in that R 33 represents fluorine, R 30 represent hydrogen, R 31 represents 2-fluoroethyl and R 34 represents methyl.
32. Compounds according to claim 28, characterized in that R 33 represents fluorine, R 30 represent hydrogen, R 31 represents ethyl and R 34 represents methyl.
33. Compounds according to claim 28, characterized in that R 33 represents fluorine, R 30 represent 2-fluoroethyl, R 30 represents hydrogen and R 34 represents methyl.
34. Compounds according to claim 28, characterized as [6R-[6-alpha,7-beta(2)]]-7-[[(2-amino-4-thiazolyl)(R 21 -oxyimino)acetyl]amino]-3-[[[[6-R 33 ,8-R 30 ,1 -R 31 -1,4-dihydro-7-(4R 34 -1 -piperazinyl)-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-8oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acids and salts thereof and hydrates of these carboxylic acids and salts, wherein R 33 and R 30 represent hydrogen or halogen, R 31 represents hydrogen, Ci-Cs-alkyl or 2-halo-Ci-Cs-alkyl, R 34 represents hydrogen or Ci-Cs-alkyl, R 21 represents the group R 22 -C—COOH and R 22 and R 23 represent hydrogen or Ci-Ce-alkyl.
35. Compounds according to claim 34, characterized in that R 22 and R 23 both represent methyl.
36. Compounds according to claim 35, characterized in that A 33 and R 30 represent hydrogen or fluorine, R 31 represents ethyl or 2-fluoroethyl and R 34 represents methyl.
37. Compounds according to claim 36, characterized in that R 33 and R 30 represent fluorine and R 31 represents 2fluoroethyl.
38. Compounds according to claim 35, characterized in that R 33 represents fluorine, R 30 represent hydrogen, R 31 represents 2-fluoroethyl and R 34 represents methyl.
39. Compounds according to claim 35, characterized in that R 33 represents fluorine, R 30 represent hydrogen, R 31 represents ethyl and R 34 represents methyl.
40. Compounds according to claim 35, characterized in that R 33 represents fluorine, R 31 represent 2-fluoroethyl, R 30 represents hydrogen and R 34 represents methyl.
41. Compounds according to claim 1, [6Α-(6α,7β)]-3-[[[(1 -ethyl-1,4-dihydro-7-methyl-4oxo-1,8-naphthyridin-3-yl)carbonyl]oxy]methyl]-8-oxo-7[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid as well as salts of this compound and hydrates of this compound and salts. 42
42. Compounds according to claim 1, [6R-(6aJ^)]-3-[[[(5-ethyl-5,8-dihydro-8-oxo-1,3dioxolo[4,5-gjquinolin-7-yl)carbonyl]oxy]methyl]-8-oxo-7[(phenoxyacetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-@ne-274 carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
43. Compounds according to claim 1, [6R-(6a,7p)(Z)]-7-[[(2-amino-4-ihiazolyl)(methoxyimino)acetyl]amino]-3-[[[(1 - ethyl-1,4-d ihdyro-7-methyl-4-oxo1,8-naphthyridin-3’yl)carbonyl]oxy]methyl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
44. Compounds according to claim 1, [6R-(6a,7p)(Z)-7-[[(2-amino-4-thiazolyl)(methoxyimino)aceiyl]amino]-3-[[[(5-ethyl-5,8-dihydro-8-oxo-1,3dioxolo[4.5-g]quinolin-7-yl)carbonyl]oxy]methyl]-8-oxo-5-thia1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
45. Compounds according to claim 1, [6 R-(6α, 7β)]-3-[[[(1 -ethy l-6-f luoro-1,4-dihydro-7(4-formyl-1-piperazinyl)-4-oxoquinolin-3-yl]carbonyl]oxy]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
46. Compounds according to claim 1, [6R-(6a,7^)]-3-[[[(5-ethyl-5,8-dihdyro-8-oxo-1,3dioxolo[4,5-g]quinolin-7-yl)carbonyl]oxy]methyl]-7-[(2-thienyl· acetyl)amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2~ene-2carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
47. Compounds according to claim 1, [6R-(6
48. Compounds according to claim 1, [6R-(6a,7p)]-3-[[[(1-ethyl-6-fluoro-1,4-dihydro-7(1 -pyrrol idi nyl)-4-oxoqui noli n-3-yl]earbo nyl] oxy] methy l]-8-oxo7- [(phenoxy acetyl)ami no]-5-th ia-1 -azabicyclo [4.2.0]oct-2-ene2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
49. Compounds according to claim 1, [6R-(6a,7p)(Z)-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[1 -ethyl-6-fluoro-1,4-dihydro-7-(1pv rrol idi nyl)-4-oxoqui no lin-3-yl]carbonyl]oxy] methy I]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
50. Compounds according to claim 1, [6R-(6a,7p)(Z)]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[1 -ethyl-6-fluoro-1,4-di hydro-7-(4formyl-1 -piperazinyl)-4-oxoquinolin-3-yl]carbonyl]oxy]methyl]8- oxo-5-thia-1-azabicyclo[4.2.0]oct~2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
51. Compounds according to claim 1, [6Α-(6α,7β)]-3-[[[(1 -eth yl-6-f luoro-1,4-dihydro-7(4-thiomorpholinyl)-4-oxoquinolin-3-yl]carbonyl]oxy]methyl]-8oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-earboxylic acid as well as salts of this compound and hydrates of this compound and salts.
52. Compounds according ίο claim 1, [6Α-(δα,7β)]-3-[[[(1-ethyl-6-f luoro-1,4-dihydro-4oxo-7-(1 H-pyrrol-1 -yl)quinolin-3-yl]carbonyl]oxy]methyl]-8oxo-7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.3.0]oct-2ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
53. Compounds according to claim 1, [6Α-(δα,7β)]-3-[[[(1 -(4-fluorophenyl)-5,8-dihydro-8oxo-1,3-dioxolo[4,5-g]quinolin-7-yl]carbonyl]oxy]methyl]-8-oxo7-[(phenoxyacetyl)amino]-5-thia-1 -azabicyclo[4.2.0]oct-2-ene2-carbonxylic acid as well as salts of this compound and hydrates of this compound and salts.
54. Compounds according to claim 1, [6R-(6a,7p)(Z)-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[1 - ethyl-6-f luoro-1,4-dihydro-7-(4thiomorpholinyl)-4-oxo-qui noli n-3-vl]carbonyl]oxy] methy l]-8οχο-5-thia-i-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
55. Compounds according to claim 1, [6R-(6a,7p)(Z)]]-7-[[(2-amino“4-ihiazolyl)(methoxyimi no)acetyl]amino]-3-[[[[6,8-dif luoro-1 -(2-f luoroethyl)-1,4d i hyd ro-7-(4-methy I-1 -piperazinyl)-4-oxo-qui noli n-3-yl]-carbonyl]oxy]meihyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
56. Compounds according to claim 1, [6R-(6a,78)(Z)]]-3-[[[[7-(3-amino-1 -pyrrolidinvl)-8ch lo ro-1 -eye lop ropy l-6-fl uoro-1,4-dihvdro-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)[(carboxvmethoxv)-imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
57. Compounds according to claim 1, [6R-(6a,7p)(Z)]]-3-[[[[7-(3-amino-1-pyrrolidinyl)-8chloro-1 -eye lop ropy I-6-f I uoro-1,4-dihydro-4-oxo-3-quinolinyl]carbonyl]oxy]meihyl]-7-[[(2-amino-4-thiazolyl)[(1 -carboxy-1 methylethoxy)imino]aceiyl]amino]-8-oxo-5-ihia-1 -aza b icy cl o[4.2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
58. Compounds according to claim 1, [6R-(6cc,78)(2)]]-3-[[[[7-(3-amino-1 -pyrrolidinyl)-8chlo ro-1 -cyclo propyl-6-f I uoro-1,4-dihydro-4-oxo-3-quinolinyl]carbonyl]oxy]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid as well as salts of this compound and hydrates of this compound and salts.
59. Compounds according to any one of claims 1-58 as pharmaceutically active substances.
60. Compounds according to any one of claims 1-58 as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases.
61. A pharmaceutical preparation, characterized in that it contains a compound according to any one of claims 1-58.
62. A pharmaceutical preparation for the treatment and prophylaxis of infectious diseases, characterized in that it contains a compound according to any one of claims 1-58.
63. A process for the manufacture of the compounds according to any one of claims 1-58, characterized by (a) for the manufacture of a readily hydrolyzable ester of a carboxylic acid of formula I, reacting a compound of the general formula in which m, R 1 and R 2 have the significance given in claim 1, Hal represents halogen and R' represents the residue of a readily hydrolyzable ester, with a salt of a carboxylic acid of the formula o R 33 ΙΪΙ R 32 .A in which R 31 , R 32 and R 33 have the significance give in claim 1, or (b) for the manufacture of a carboxylic acid of formula I, converting an ester of the general formula lOJm ί R 2 Η I in which rn, R 1 , R 2 , R 31 , R 32 and R 33 have the significance given in claim 1 and R represents an ester protecting group, into the carboxylic acid of formula I, or (c) for the manufacture of a compound of formula I in which m represents 0, reducing a compound of the general formula in which R 1 , R 2 , R 31 , R 32 and R 33 have the significance given in claim 1, (d) for the manufacture of a compound of formula I in which m represents 1 or 2, or an ester of salt thereof, oxidizing a compound of the general formula R 2 H COOH R 31 wherein R 1 , R 2 , R 31 , R 32 and R 33 have the significance given in claim 1 and the dotted lines indicate the presence of a Δ2- or A3-double bond, or an ester or salt thereof, or (e) for the manufacture of a compound of formula I in which R 1 signifies the group R 13O—o—N=C—CQ— R 102 and R 102 signifies an amino-substituted 5-, 6- or 7-membered heterocyclic ring having 1, 2, 3 or 4 nitrogen, oxygen and/or sulphur atoms and R 130 has the significance given in claim 8, or an ester as salt thereof, cleaving off the amino-protecting group in the substituent R 103 of a compound of the general formula R 33 R33 VII in which rn, R 2 , R 31 , R 32 , R 33 have the significance given in claim 1 and R 130 has the significance given in claim 8 and R 103 has the significance given for R 102 except that the amino substituent is protected, or of an ester or salt thereof, or (f) for the manufacture of a readily hydrolyzable ester of a compound of formula I, subjecting a carboxylic acid of formula I to a corresponding esterification, or (g) for the manufacture of salts or hydrates of a compound of formula J or hydrates of said salts, converting a compound of formula S into a salt or hydrate or into a hydrate of said salt.
64. The use of the compounds according to any one of claims 1-58 for the manufacture of medicaments for the treatment or prophylaxis of infectious diseases.
65. A compound according to claim 1, substantially
66. » according described A process for the manufacture of a compound to claim 1, substantially as hereinbefore and exemplified.
67. A compound according to claim 1, whenever 10 manufactured by a process claimed in a preceding claim.
68. A pharmaceutical preparation according to claim 61, substantially as hereinbefore described with particular reference to Example A of the accompanying Examples.
IE176587A 1986-07-03 1987-07-02 Acyl derivatives IE61434B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US88155586A 1986-07-03 1986-07-03

Publications (2)

Publication Number Publication Date
IE871765L IE871765L (en) 1988-01-03
IE61434B1 true IE61434B1 (en) 1994-11-02

Family

ID=25378717

Family Applications (1)

Application Number Title Priority Date Filing Date
IE176587A IE61434B1 (en) 1986-07-03 1987-07-02 Acyl derivatives

Country Status (22)

Country Link
EP (1) EP0251330B1 (en)
JP (1) JPH0730083B2 (en)
KR (1) KR880001675A (en)
CN (1) CN1021226C (en)
AT (2) ATE97901T1 (en)
AU (1) AU603364B2 (en)
CS (2) CS270227B2 (en)
DE (1) DE3788306D1 (en)
DK (1) DK340387A (en)
ES (1) ES2060583T3 (en)
FI (1) FI88392C (en)
HU (1) HU200185B (en)
IE (1) IE61434B1 (en)
IL (1) IL83046A (en)
MC (1) MC1833A1 (en)
MX (1) MX7189A (en)
NO (1) NO168890C (en)
NZ (1) NZ220914A (en)
PH (1) PH23940A (en)
PT (1) PT85246B (en)
ZA (1) ZA874696B (en)
ZW (1) ZW12787A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ227470A (en) * 1987-12-28 1991-06-25 Hoffmann La Roche Acyl derivatives of substituted cephem compounds; pharmaceutical compositions and methods for preparation and treatment
HUT49889A (en) * 1988-03-31 1989-11-28 Hoffmann La Roche Process for producing acyl derivatives
CA2001203C (en) * 1988-10-24 2001-02-13 Thomas P. Demuth, Jr. Novel antimicrobial dithiocarbamoyl quinolones
SG54293A1 (en) * 1988-10-24 1998-11-16 Procter & Gamble Pharma Novel antimicrobial fluoroquinolonyl cephems
EP0997466A1 (en) * 1988-10-24 2000-05-03 PROCTER &amp; GAMBLE PHARMACEUTICALS, INC. Novel antimicrobial lactam-quinolones
US5328908A (en) * 1988-10-24 1994-07-12 Procter & Gamble Pharmaceuticals, Inc. Antimicrobial quinolone thioureas
ES2148135T3 (en) * 1988-10-24 2000-10-16 Norwich Eaton Pharma NEW ANTIMICROBIAL ESTERS OF QUINOLONYL LACTAMS.
EP0366193A3 (en) * 1988-10-24 1992-01-08 Norwich Eaton Pharmaceuticals, Inc. Novel antimicrobial quinolonyl lactams
AU633867B2 (en) * 1989-02-02 1993-02-11 Eli Lilly And Company Delivery of cytotoxic agents
GB8907617D0 (en) * 1989-04-05 1989-05-17 Celltech Ltd Drug delivery system
EP0525057B1 (en) * 1990-04-18 2000-06-14 Procter &amp; Gamble Pharmaceuticals, Inc. Antimicrobial quinolonyl lactams
US5066800A (en) * 1990-04-27 1991-11-19 Hoffmann-La Roche Inc. Qunoline intermediates useful therein for synthesizing antibacterial compounds
US5244892A (en) * 1990-10-16 1993-09-14 Kyorin Pharmaceutical Co., Ltd. Cephem compounds, and antibacterial agents
GB9216759D0 (en) * 1992-08-07 1992-09-23 Finpael Spa Process for the production of 7-amino thiazolyl cephalosporins
DE4234330A1 (en) * 1992-10-12 1994-04-14 Bayer Ag Quinolonecarboxylic acids
US5728691A (en) * 1994-02-25 1998-03-17 Laboratorios Aranda S.A. De C.V. Quinolonylcarboxamidocephalosporin derivatives and pharmaceutical compositions containing them
MX9505113A (en) * 1995-12-07 1997-06-28 Aranda Lab Sa De Cv Cephalosporine-fluoroquinolonates derivatives and pharmaceutical compositions containing them.
AU2015212312A1 (en) 2014-01-29 2016-08-18 Vyome Therapeutics Limited Treatments for resistant acne

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3971778A (en) 1972-05-12 1976-07-27 Glaxo Laboratories Limited Cephalosporins having (α-etherified oximino)acylamido groups at the 7-position
DE2362553A1 (en) * 1972-12-18 1974-06-20 Dainippon Pharmaceutical Co NEW PIPERAZINE DERIVATIVES
US4173199A (en) 1974-12-02 1979-11-06 Codama Holding S.A. Apparatus for reinforcing a fabric by applying a fluid reinforcing material thereto
DE2760123C2 (en) 1976-01-23 1986-04-30 Roussel-Uclaf, Paris 7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporanic acids, their preparation and pharmaceutical compositions containing them
DE2716677C2 (en) 1977-04-15 1985-10-10 Hoechst Ag, 6230 Frankfurt Cephem derivatives and processes for their preparation
JPS5854157B2 (en) 1977-06-10 1983-12-02 山之内製薬株式会社 New derivatives of cephalosporin compounds and their production method
JPS5630964A (en) * 1979-08-22 1981-03-28 Kyorin Pharmaceut Co Ltd Novel substituted quinolinecarboxylic acid and its preparation
US4266049A (en) 1980-02-20 1981-05-05 Eli Lilly And Company Process for 3-iodomethyl cephalosporins
FR2501209B1 (en) * 1981-03-03 1986-07-04 Sanofi Sa NOVEL CEPHALOSPORIN DERIVATIVES AND ANTIBIOTIC DRUGS CONTAINING THE SAME
SE440354B (en) * 1981-02-19 1985-07-29 Kyorin Seiyaku Kk quinolinecarboxylic
FR2570702B1 (en) * 1984-09-27 1987-01-09 Sanofi Sa CEPHALOSPORIN DERIVATIVES, PROCESSES FOR OBTAINING THEM AND THEIR APPLICATION AS ANTIBIOTICS
DE3687279T2 (en) * 1985-01-21 1993-05-13 Nippon Pharma Dev Inst BETA LACTAM ANTIBIOTICS.
NZ227470A (en) * 1987-12-28 1991-06-25 Hoffmann La Roche Acyl derivatives of substituted cephem compounds; pharmaceutical compositions and methods for preparation and treatment

Also Published As

Publication number Publication date
FI88392C (en) 1993-05-10
ZA874696B (en) 1988-01-04
ATA264587A (en) 1990-02-15
PT85246B (en) 1990-03-30
CS395091A3 (en) 1992-12-16
EP0251330A3 (en) 1989-06-28
EP0251330A2 (en) 1988-01-07
DK340387D0 (en) 1987-07-02
JPS6322586A (en) 1988-01-30
ZW12787A1 (en) 1988-02-03
AU603364B2 (en) 1990-11-15
MC1833A1 (en) 1988-06-03
AT391137B (en) 1990-08-27
IL83046A0 (en) 1987-12-31
MX7189A (en) 1993-08-01
JPH0730083B2 (en) 1995-04-05
CS496787A2 (en) 1989-10-13
NO168890B (en) 1992-01-06
IE871765L (en) 1988-01-03
PT85246A (en) 1987-08-01
NZ220914A (en) 1990-09-26
FI872951A0 (en) 1987-07-03
IL83046A (en) 1992-07-15
DE3788306D1 (en) 1994-01-13
KR880001675A (en) 1988-04-26
HU200185B (en) 1990-04-28
NO872770L (en) 1988-01-04
PH23940A (en) 1990-01-23
CS270227B2 (en) 1990-06-13
EP0251330B1 (en) 1993-12-01
NO168890C (en) 1992-04-15
CN87105204A (en) 1988-06-29
FI88392B (en) 1993-01-29
DK340387A (en) 1988-01-04
NO872770D0 (en) 1987-07-02
AU7500987A (en) 1988-01-07
CN1021226C (en) 1993-06-16
FI872951A (en) 1988-01-04
ATE97901T1 (en) 1993-12-15
ES2060583T3 (en) 1994-12-01
HUT44258A (en) 1988-02-29

Similar Documents

Publication Publication Date Title
IE61434B1 (en) Acyl derivatives
US5336768A (en) Antibacterial cephalosporin compounds
AU624810B2 (en) Acyl derivatives
CA2001201C (en) Antimicrobial quinolonyl lactams esters
JPH05502884A (en) Novel 3-substituted cephem compounds and methods for producing the same
EP0525057B1 (en) Antimicrobial quinolonyl lactams
HUT57769A (en) Process for producing coarbapenem compounds and pharmaceutical compositions comprising same
US5329002A (en) Antibacterial cephalosporin compounds
AU621328B2 (en) 3(heterocyclyc carbonyl thio methyl)cephalosporin derivatives
JPH0242071A (en) Selenium azolyl derivative
EP0128536B1 (en) Fluoromethylthiooxacephalosporin derivatives
US5147871A (en) Anti-bacterial cephalosporin compounds
US4645769A (en) 1-oxa-1-dethia-cephalosporin compounds and antibacterial agent comprising the same
EP0188781B1 (en) 1-oxa-1-dethia-cephalosporin compounds and antibacterial agent comprising the same
FI73442B (en) PROCEDURE FOR FRAMSTATION OF THERAPY, THERAPEUTIC ANVAENDBARA (6R, 7R) -7- / 2- (2-AMINO-4-THIAZOLYL) -2-HYDROXYIMINO) ACETAMIDO / -3 - // (SUBSTITUERAD-AS-TRIAZIN-3-Y ) TIO / METHYL / -8-OXO-5-THIA-1-AZABICYCLO / 4.2.0 / OCT-2-EN-2-CARBOXYL SYROR.
Morita et al. An approach to broad-spectrum cephalosporins
BG60385B2 (en) Antibacterial cephalosporin compounds
GB2061276A (en) Imidazole and tetrazole derivatives of 7-[(2-amino-4-thiazolyl)- oximino] cephalosporins
CS270245B2 (en) Method of new acyl derivatives production
JPH0517915B2 (en)
IL92091A (en) Quinolonyl lactam esters and pharmaceutical compositions containing them
IL92031A (en) Quinolonyl lactams and pharmaceutical compositions containing them
JPS62175489A (en) Novel cephalosporin derivative, salt, production thereof and remedy for infectious diseases comprising same as active ingredient
PH26648A (en) Acyl derivatives

Legal Events

Date Code Title Description
MM4A Patent lapsed