Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to new quinolone compounds useful as antibacterial agents.
• Various quinolone type structures are known for their antibacterial properties, however new antibacterials are continually sought especially those which exhibit both gram positive and gram negative activity.
• 1-tertiary-alkyl substituents disclosed include 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-methyl-1- phenylethyl, 1-phenylcyclopropyl, 2-methyl-1-phenylcyclopropyl, 1- methylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methylcyclobutyl, 1- methylethenyl and 1-adamantyl.
• N- heterocyclic ring substitutents in the 7-position including piperazinyl, piperidinyl, 3-amino-1-pyrrolidinyl, 3-aminoalkyl-1-pyrrolid- inyl, 2-aminoalkyl-morpholin-4-yl, 2-aminoalkyl-thimorpholin-4-yl, and diazabicycloalkyl groups containing 7-9 atoms in the diazobicyc- loalkyl ring system.
• amines and intermediates used in the preparation of the naphthyridine- and quinoline-carboxylic acids are also disclosed.
• the present invention is directed toward new compounds, generi cally represented by Formula I, useful as antibacterials or in the preparation of antibacterial compositions.
• Formula I is defined where X is nitrogen, a carbon substituted with a hydrogen, hydroxyl, cyano, nitro, halogen C 1 -C 4 alkyl or an amine; R 3 is H, halogen, amine or hydroxyl; Y is
• R 13 is independently hydrogen, methyl, halogen substituted methyl or joined to form a cyclopropyl and R 14 is hydrogen, fluorine, chlorine, bromine, C 1 -C 6 alkyl or phenyl; or
• bicyclo (1.1.1) pent-1-yl which can be substituted at C-3 with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoro, bromo, chloro, nitro, amino, hydroxy, COOH, COO(C 1 -C 6 alkyl) and phenyl optionally substituted with one or two C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, trifluromethyl, C 2 - Cg dialkylamino, C 1 -C 3 alkylthio or nitro;
• Z is nitrogen, or a fluorine substituted carbon; wherein R 1 is hydrogen or hydroxyl; wherein R 7 is selcted from the Formula A'- H'; wherein R 2 is independently selected from H, C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, -Q-N(R 10 )-C(R 9 )H-CH 2 -C(R 8 )O, -Q-N(R 10 )-C(R 9 )-CH(R 12 )- C(R 8 )O, R 8 is hydrogen, hydroxyl, amine, C 1 -C 4 alkoxy or aryloxy,- SH, C 1 -C 6 thioalkyl or thioaryl; R 9 is C 1 -C 4 alkyl, C 6 -C 12 aryl, alkylaryl, heteroaryl, -(CH 2 ) n -CO 2 -(CH 2 ) m -R 11 , R
• R 1 is hydrogen or hydroxyl
• Y is C 1 -C 10 alkyls, C 3 -C 10 cycloalkyl or heterocycloalkyl, a phenyl, or a substituted phenyl wherein the substituent on the phenyl group is one or more of C 1 -C 10 alkyl, halogen, hydroxyl, hydrogen or a combination thereof, or C 2 -C 4 alkylene wherein each carbon atom may be substituted with fluorine;
• R 3 is hydrogen, halogen, amine or hydroxyl
• A, B, C, D are independently hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, ethenyl, ethynyl, C 3 -C 6 cycloalkyl, fluoromethyl, difluoro- methyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C 1 -C 18 alkoxy methyl, phenoxymethyl, C 1 -C 3 alkyl aminomethyl, C 1 -C 3 dialkyl aminomethyl, C 6 -C 12 aryl, substituted aryl, heteroaryl or substituted heteroaryl containing at least one O, N or S;
• R 8 is hydrogen, hydroxyl, amine, C 1 -C 4 alkoxy or aryloxy, -SH, C 1 -C 6 thioalkyl or thioaryl;
• R 9 is C 1 -C 4 alkyl, C 6 -C 12 aryl, alkylaryl, heteroaryl, -(CH 2 ) n - CO 2 -(CH 2 ) m -R 11 , wherein R 11 is hydrogen, hydroxyl, methyl alkyloxy, aryloxy or an amine, n is 0-4 and m is 0-4;
• R 10 is hydrogen, -(CH3) O, C 2 -C 4 alkyl, C 6 -C 12 aryl, alkylaryl, heteroaryl, or acetyl, where o is 0 or 1;
• R 12 is hydrogen CN, halogen, or R 9 ;
• Z is nitrogen or carbon substituted by fluorine
• X is nitrogen, a carbon substituted with hydrogen, hydroxyl, cyano, nitro, halogen, C 1 -C 4 alkyl, or an amine;
• Q is (CH 2 ) q where q is 0-2, CH-CH 3 or C(CH3) 2 .
• R 10 is -(CH 3 ) 0 where o is 0 and preferably, Q is (CH 2 ) q where q is 0.
• Preferred compounds of the Formula IA structure can include 2- [4-(1-Cyclopropyl-3-carboxy-6,8-difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl]2-butenedioic acid, dimethyl ester; 2-[4-(1-Ethyl- 3-carboxy-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperizinyl]2- butenedioic acid, dimethyl ester; 2-[4-(1-Cyclopropyl-3-carboxy- 5,6,8-trifluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl]2- butenedioic acid, dimethyl ester; 2-[4-(1-Cyclopropyl-3-carboxy-6- fluoro-1,4-dihydro-4-oxo-7-quinoliny
• the present invention is as shown in Formula IB which are novel 4-oxo-naphthyridine- and 4-oxo-quinoline-3- carboxylic acids derivatives having a 1-bicyclo[1.1.1]pent-1-yl substituent, to compositions containing the same, and their use in treating bacterial infections in warm-blooded animals and man. Also disclosed are novel amines and intermediates used in the preparation of the same.
• the subject invention is novel naphthyridine- and quinoline-carboxylic acids derivatives having a propargyl moiety (RC ⁇ C-CR' 2 -) at the Y position according to Formula I, as structurally depicted in Formula IC and to compositions containing the same.
• the present invention is a pharmaceutical composition containing an antibacterially effective amount of a compound or therapeutically acceptable salts thereof according to Formula I in admixture with a pharmaceutical carrier.
• the composition can contain from about 0.5 to about 90% by weight of such compound.
• the composition can be present in unit dose form of tablets, pills, dragees, capsules, ampules or suppositories.
• the present invention is method for treating bacterial infection in animals including humans which comprises administering an antibacterially effective amount of a compound or therapeutically acceptable salts thereof according to Formula I.
• the compound can be administered orally or parenterally.
• the present invention relates to quinolone compounds and antibacterial agents containing these compounds.
• the quinolone compounds are structurally represented by Formula I, shown on the Formula Sheet, and includes therapeutically acceptable salts thereof.
• Formula I is further broken down into Formula IA, IB and IC where each structure encompasses a similar heterocyclic riig structure each with a particular Y substituent.
• Formula IA has a group of alkyl, alkylene, cycloalkyl, heterocycloalkyl phenyl and substituted phenyls at the Y position
• Formula IB has a bicyclo (1.1.1) pent-1-yl substituent at the Y position
• Formula IC has a propargyl substituent at the Y position.
• Formula IA is defined wherein R 1 is hydrogen or hydroxyl; Y is G 1 -C 10 alkyls, C 3 -C 10 cycloalkyl or heterocycloalkyl, a phenyl, or a substituted phenyl wherein the substituent on the phenyl group is one or more of C 1 -C 10 alkyl, halogen, hydroxyl, hydrogen or a combination thereof, or C 2 -C 4 alkylene wherein each carbon atom may be substituted with fluorine (known substituents for the Y group are described by Domagala et al., J. Med.
• R 3 is hydrogen, halogen, amine or hydroxyl
• A, B, C, D are independently hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, ethenyl, ethynyl, C 3 -C 6 cycloalkyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C 1 -C 18 alkoxy methyl, phenoxy-methyl, C 1 -C 3 alkyl aminomethyl, C 1 -C 3 dialkyl aminomethyl, C 6 -C 12 aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• R 8 is hydrogen, hydroxyl, amine, C 1 -C 4 alkoxy or aryloxy, -SH, C 1 -C 6 thioalkyl or thioaryl;
• R 9 is C 1 -C 4 alkyl, C 6
• R 10 is -(CH 3 ) o where o is 0 and preferably, Q is (CH 2 ) q where q is 0.
• Preferred quinolone compounds of Formula IAa are where R 1 is hydroxy, Y is cyclopropane or ethyl, R 3 is hydrogen or fluorine, Z and X are carbon or fluorine substituted carbon, A, B, C and D are hydrogen, R 8 is methoxyl, R 9 is a carbomethoxyl ester so as to form either the dimethylester of maleic or fumaric acid and R 10 is (CH 3 ) o where o is 0.
• Preferred quinolone compounds of Formula IAb are when R 1 is hydroxyl and Y is cyclopropyl and R 3 , A, B, C, D and R 11 are hydrogen, R 8 is O-CH 3 , R 9 is C(O)OCH 3 , Z and X are C(F) and Q is (CH 2 ) q where q is zero.
• C 1 -C 10 alkyl are one to ten carbon atoms such as methyl, ethyl, propyl, butyl, etc. and isomerlc forms thereof.
• the "C 2 -C 4 alkylenes” are ethylene, propylene and 1 or 2-butylene and isomeric forms thereof.
• Examples of "C 3 -C 10 cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. and "heterocyclo- alkyl”are cycloalkyl ring which contain at least one heteroatom such as oxygen, sulfur or nitrogen.
• C 6 -C 12 aryl are compounds such as phenyl, ⁇ - naphthyl, ⁇ -naphthyl, m-methylphenyl, p-trifluoromethylphenyl and the like.
• the aryl groups can also be substituted with one to 3 hydroxy, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, trifluoromethyl, fluoro, chloro or bromo groups.
• alkylaryl are alkyl chains of one to eight carbon atoms and isomeric forms thereof which are substituted with aryl groups of 6 to 12 carbon atoms.
• heteroaryls are 6 to 12 carbon atom aryls which contain at least one heteroatom such as nitrogen, sulfur and oxygen.
• amine is meant to include primary, secondary and tertiary amines.
• Halogen is meant to include F, C1, Br and I.
• Therapeutically acceptable salts are those compounds of Formula I wherein a carboxyl group is substituted with a counter ion such as Li, Na, K, Ca or other acceptable counter ions for carboxylic acids.
• the effectiveness of the subject compounds on bacteria were obtained by performing a dip disk assay.
• the antibacterial activity of the compounds was determined by the disk-diffusion method. Paper disks (12.7 mm) were loaded with 0.05 ml of drug solution prepared at a concentration of 0.1 mcg/ml; the disks were allowed to air dry. They were then applied to the surface of microorganism-seeded agar assay trays, which contained the bacterial strain Pseudomonas aeruginosa UC 95 (PA), Escherichia coli UC 51 (EC), Klebsiella pneumoniae UC 57 (KP), or Staphylococcus aureus UC 80 (SA). The assay trays were incubated overnight under aerobic condition to allow for the growth of the organisms. Zones of growth inhibition due to the action of the antibiotic were then measured to the nearest millimeter.
• PA bacterial strain Pseudomonas aeruginosa UC 95
• EC Escherichia
• Ciprofloxacin 29 38 27 31 The results show that compounds 1-4, all of Formula IAa, corresponding to Examples 1-4, below, have potent gram negative and positive activity as compared to the commercially available antibacteria Ciprofloxacin, from Miles Pharm. Div., West Haven, CT.
• Ciprofloxacin Compound 10 Staphylococcus Aureus 0.25 0.03
• Formula IB is defined wherein X is selected from N, CH, CF, CCl, CBr, and CCH 3 ;
• R 3 is selected from H, F and NH 2 ;
• R is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoro, bromo, chloro, nitro, amino, hydroxy, COOH, COO(C 1 -C 6 alkyl) and phenyl optionally substituted with one or two C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, trifluoromethyl, C 1 -C 6 dialkylamino, C 1 -C 3 alkylthio or nitro;
• R 7 is selected from Formula A', B', C', D', E', F', G' and H' (see GENERAL FORMULA sheet) wherein R 2 is independently selected from H, C 3 -C 5 cycloalkyl, C 5 -C 6 cycloalkenyl, -Q-N(R 10 )- C(R 9 )H-CH 2 -C(R 8 )O (see GENERAL FORMULA sheet), -Q-N(R 10 )-C(R 9 )-CH- C(R 8 )O and C 1 -C 6 alkyl optionally substituted with 1, 2 or 3 hydroxy, fluoro, chloro, amino, C 1 -C 4 alkylamino, trifluoroacetylamino and phenyl; wherein A, B, C, and D are independently selected from H, amino, hydroxy, fluoro, chloro, C 1 -C 4 alkyl optionally substituted with 1, 2 or 3 hydroxy,
• R 8 is hydrogen or methyl
• R 9 is C 1 -C 4 alkyl or -(CH 2 ) m -CO 2 -(CH 2 ) p -R 13 , wherein R 13 is hydrogen, methyl or an amine, m is 0-4 and p is 0-4;
• R 10 is hydroxy, amine, C 1 -C 4 alkoxy or aryloxy
• Q is (CH 2 ) q where q is 0-2, CH-CH 3 or C(CH 3 ) 2 ;
• R is preferably hydrogen.
• R 3 is preferably hydrogen or NH 2 .
• X is preferably CH, CF and N.
• R 7 is preferably 1-piperazinyl, 4-methyl-1-piperazinyl, 3- methyl-1-piperazinyl, 3,5-dimethyl-1-piperazinyl, 2,5-diazabicyclo [2,2,1]heptan-2-yl, 3-amino-1-pyrrolidinyl, 3-amino-4-methyl-1- pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl and 3-(ethylamino)methyl-1- pyrrolidinyl.
• R 10 is preferably hydrogen.
• R 9 is preferably a carbomethoxy ester and R 8 is methoxy so as to form either the dimethyl ester of succinic, maleic and/or fumaric acid.
• C 1 -C 4 alkyl are one to four carbon atoms such as methyl, ethyl, propyl, butyl and isomeric forms thereof.
• C 1 -C 6 alkoxy Include methoxy, ethoxy, propoxy, butoxy, heptoxy and isomeric forms thereof.
• C 3 -C 6 cycloalkyl are cyclopropyl, cyclobutyl, eyc lopentyl and cyclohexyl.
• Examples of “C 5 -C 5 cycloalkenyl” include cyclopenten-3-yl and cyclohexen-3-yl.
• Formula IB compounds of this invention include:
• the compounds of Formula IB according to this invention may be provided as pharmaceutically acceptable acid addition and base salts wherein. the anion or cation, respectively, does not contribute significantly to the toxicity of the salt and which salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuvants and excipients customarily employed in producing pharmaceutical compositions adapted for oral or parenteral administration.
• the acid addition salts are formed by conventional techniques involving reaction of compounds of Formula I with mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and with organic carboxyllc and sulfonic acids such as, for example, aspartic acid, glutamic acid, galacturonic acid, gluconic acid, acetic acid, citric acid, maleic acid, succinic acid, benzole acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, and the like.
• mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid
• organic carboxyllc and sulfonic acids such as, for example, aspartic acid, glutamic acid, galacturonic acid, gluconic acid, acetic acid, citric acid, maleic
• esters 5 are treated with an appropriate heterocyclic amine in a suitable solvent such as acetonitrile in the presence of a suitable base such as diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to provide the penultimate naphthyridine- or quinoline-esters 6.
• a suitable base such as diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene
• a second route to compounds of Formula I involves the saponification of esters 5 with, for example, aqueous sodium hydroxi de, to provide the penultimate naphthyridine- or quinoline-carboxylic acids 7.
• the compounds 7 are then reacted with an appropriate heterocyclic amine in a suitable solvent such as pyridine, which acts as its own base, or in an aprotic solvent such as DMSO (dimethylsulfoxide) in the presence of a suitable added base such as diisopropylethylamine, to afford the targeted naphthyridine- or quinolinecarboxylic acids of Formula I (R 3 -H,F).
• the present invention also provides new naphthyridine- and quinoline-carboxylic acids of Formula I (see GENERAL FORMULA sheet) .
• X is N, CH, CF, CC1, CBr, or CCH 3 and R 3 is H, F or NH 2 .
• the R 23 groups are independently hydrogen, methyl, a methyl substituted with one or more halogens (fluorine, cholorine, bromine or iodide, preferably, fluorine) such as, for example, -CH 2 F or are joined to form a cyclopropyl.
• R 24 is hydrogen, fluorine, chlorine, bromine, C 1 -C 6 alkyl, or phenyl.
• R 7 is as defined above for Formula I or selected from various piperazinyl and pyrrolidinyl structures as depicted in Formula J', K', L', M', N', O', P', Q' and R' (see GENERAL FORMULA sheet) wherein R 26 is independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with one or more hydroxy, fluoro, chloro, amino, C 1 -C 4 alkylamino, trifluoroacetylamino and phenyl groups and R 27 is hydrogen, hydroxyl or a C 1 -C 6 alkyl optionally substituted with one or more hydroxy, or halogens (fluorine, chlorine, bromine or iodide, preferably, fluorine).
• R 26 is independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with one or more hydroxy, fluoro, chloro, amino, C 1 -C 4 alkylamino, trifluoroacet
• R 7 can be 1-piperazinyl (Formula J'), 4- methyl-1-piperazinyl (Formula K'), 3-methyl-1-piperazinyl (Formula L'), 3,5-dimethyl-1-piperazinyl (Formula M'), 2,5-diazabicyclo [2.2.1]hept-2-yl (Formula N'), 3-hydroxy-1-pyrrolidinyl (Formula 0' where Rg is hydrogen), 3-amino-1-pyrrolidinyl (Formula P' where R 6 is hydrogen), 3-amino-4-methyl-1-pyrrolidinyl (Formula Q'), 4-amino- methyl-3-hydroxy-1-pyrrolidinyl (Formula R' where R 26 is hydrogen and R 27 is hydroxyl) and 3-(ethylamino)methyl-1-pyrrolidinyl (Formula R' where R 26 is ethyl and R 27 is hydrogen).
• C 1 -C 6 alkyl are one to six carbon atoms such as methyl, ethyl, propyl, butyl, etc. and isomeric forms thereof.
• Formula IC compounds of this invention include:
• the compounds of Formula I according to this invention may be provided as pharmaceutically acceptable acid addition and base salts wherein the anion or cation, respectively, does not contribute significantly to the toxicity of the salt and which salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuvants and excipients customarily employed in producing pharmaceutical compositions adapted for oral or parenteral administration.
• the acid addition salts are formed by conventional techniques involving reaction of compounds of Formula I with mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and with organic carboxylic and sulfonic acids such as, for example, aspartic acid, glutamic acid, galacturonic acid, gluconic acid, acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, and the like.
• mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid
• organic carboxylic and sulfonic acids such as, for example, aspartic acid, glutamic acid, galacturonic acid, gluconic acid, acetic acid, citric acid, maleic acid,
• the compounds of Formula IC can be prepared according to the general reaction Scheme 16, below.
• the first step involves the coupling of a propargyl moiety with a vinyl ether 1 to form compound 2, followed by base induced cyclization to produce the quinolone 3.
• heterocycles such as piperidine or trifluoroacetamidopyr- rolidine
• the coupling reaction of heterocycle was achieved in dimethylsulfoxide solvent in the presence of potassium dibasic phosphate buffer.
• Compound 4 is then hydrolyzed to the final product 5 by running the reaction at room temperature.
• this invention is a pharmaceutical composition
• a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula IC above.
• this invention is a method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a compound of Formula IC or of a pharmaceutical composition thereof.
• Pharmaceutically acceptable base salts are formed by conventional techniques involving reaction of the compounds of Formula IC with alkali (Na,K) and alkaline earth (Ca, Ba, Zn, Mn) metal bases, more preferably with alkali metal bases such as, for example, dilute solutions of sodium hydroxide and potassium carbonate.
• pharmaceutically acceptable base salts are formed by conventional techniques involving reaction with amines such as, for example, triethyl- amine, dibenzylamine, triethanolamine, ethanolamine, N,N'-dibenzyl- ethylenediamine, procaine and equivalent amines.
• the antibacterial activity of the compounds of Formula IC was determined by using standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically" (MFT) published January 1983 by the National Committee for Clinical Laboratory Standards, 771 East Lancaster Avenue, Villanova, PA 19084, USA. Briefly, MIC values are determined in unsupplemented Mueller Hinton Agar (MHA). The compounds tested are diluted serially into molten MHA at 47°C. The agar is poured into petri dishes and allowed to harden.
• MHA Mueller Hinton Agar
• the various bacteria used for testing are grown overnight on MHA at 35oC and transferred to Trypticase soy broth (TSB) until a turbidity of 0.5 McFarland standard is obtained.
• the bacteria are diluted one to 20 in TSB and inoculated on the plates (1 ⁇ l using a Steers replicator). The plates are incubated at 35oC for 20 hours and the MIC is read to be the lowest concentration of drug that completely inhibits visible growth of the bacteria.
• Ciprofloxacin was used as a control and the results of the compounds of the subject invention are shown in Table CI where A is
• C is (+,-)- 6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-(2-propynyl)-3- quinolinecarboxylic acid methanesulfonate
• D is (+,-)-7-(amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-1-(2-propynyl)-3-quinoline- carboxylic acid
• E is (+,-)-7-(3-amino-1-pyrrolidinyl)-1,4- dihydro-1-(1,1-dimethyl-2-propynyl)-6-fluoro-4-
• this invention is a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula I above.
• this invention is a method of combatting bacterial infection in warm-blooded animals comprising adminis- tering to said animals an antibacterially effective amount of a compound of Formula I or of a pharmaceutical composition thereof.
• Pharmaceutically acceptable base salts are formed by conventional techniques involving reaction of the compounds of Formula I with alkali (Na,K) and alkaline earth (Ca, Ba, Zn, Mn) metal bases, more preferably with alkali metal bases such as, for example, dilute solutions of sodium hydroxide and potassium carbonate.
• pharmaceutically acceptable base salts are formed by conventional techniques involving reaction with amines such as, for example, triethyl amine, dibenzylamine, triethanolamine, ethanolamine, N,N'-dibenzyl- ethylenediamine, procaine and equivalent amines.
• compositions of this invention may be prepared by combining the compounds of Formula I of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
• Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
• Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
• Liquid form compositions include solutions, suspensions and emulsions.
• solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
• the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing appropriate amounts of the active component, that is, the compound of Formula I according to this invention.
• the quantity of active component that is the compound of Formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
• the compounds according to the invention have a potent and broad antimicrobial efficacy. These properties make it possible to use them as chemotherapeutic active compounds in medicine and as substances for preserving inorganic and organic materials, in particular organic materials of all types, for example polymers, lubricants, dyes, fibers, leather, paper and wood, foodstuffs and water.
• the compounds according to the invention are active against Gram-negative and Gram-positive bacteria and bacterioid microorganisms. Thus, diseases caused by these pathogens can be treated.
• the compounds according to the invention are particularly active against bacteria and bacterioid microorganisms. Thus, they are particularly well suited for the chemotherapy of local and systemic Infections caused by these pathogens in medicine.
• pseudomonadaceae such as pseudomonas bacteria, for example Pseudomonas aeruginosa
• mycoplasma for example Mycoplasma pneumonia.
• the present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutically suitable excepients contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the production of these preparations.
• the present invention also includes pharmaceutical preparations in dosage units.
• the preparations are in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampoules, of which the content of active substance corresponds to a fraction or a multiple of an individual dose.
• An individual dose preferably contains the amount of active compound which is given in one administration and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
• non-toxic, inert pharmaceutically suitable excipients there are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
• Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
• Tablets, dragees, capsules, pills and granules can contain the active compound or compounds alongside the customary excipients such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerine, (d) disintegrating agents, for exampl agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary ammonium compound (g) wetting agents, for example cetyl alcohol or glycerine monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols
• the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release the active compound or compounds only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.
• the active compound or compounds can also be in a micro- encapsulated form.
• Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C 14 -alcohol with C 16 -fatty acid) or mixtures of these substances.
• the customary water-soluble or water-insoluble excipients for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C 14 -alcohol with C 16 -fatty acid) or mixtures of these substances.
• Ointments, pastes, creams and gels can contain the customary excipients in addition to the active compound or compounds, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
• Powders and sprays can contain the customary excipients in addition to the active compound or compounds, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these substances.
• Sprays can additionally contain the customary propellents, for example chlorofluorohydrocarbons.
• Solutions and emulsions can contain the customary excipients in addition to the active compound or compounds, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyIformamide, oils, especially cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerine, glycerine- formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
• solvents such as solvents, solubilising agents and emulsifiers
• solubilising agents and emulsifiers for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate
• the solutions and emulsions can be in a sterile form which is isotonic with blood.
• Suspensions can contain the customary excipients in addition to the active compound or compounds, such as liquid diluents, for exampie water, ethyl alcohol or propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
• liquid diluents for exampie water, ethyl alcohol or propylene glycol
• suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
• the formulation forms mentioned can also contain dyestuffs, preservatives and additives which improve the odour and flavour, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
• the therapeutically active compounds should preferably be present in the above mentioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95, percent by weight of the total mixture.
• compositions can also contain other pharmaceutical active compounds in addition to the active compounds according to the invention.
• the above mentioned pharmaceutical preparations are manufactured in the usual manner according to known methods, such as by mixing the active compound or compounds with the excipient or excipients.
• the active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and/or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.
• the active compound or compounds in total amounts of about 0.5 to about 50, preferably 1 to 30, especially preferably 1-20 mg/kg of body weight, orally or parenterally, every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results.
• An individual administration contains the active compound or the active compounds preferably in amounts of about 1 to about 250, especially of 3 to 60, mg/kg of body weight.
• the new compounds can be utilized as feedstuff.
• the amino ester B (500 mg, 1.32 mmol) was dissolved in 20 ml of chloroform and 163 ⁇ L (1.32 mmol of dimethyl acetylene dicarboxylate was added. The product C was then obtained by evaporating off the solvent. Product C (250 mg, 0.48 mmol) was dissolved in 2.0 ml of THF and 1.0 ml (2.0 mmol) of potassium hydroxide and stirred at 23o C for 24 hours. The THF was then removed by vacuum and the residue dissolved in 25 ml of water and washed with 25 ml of ethyl acetate. The acidity was adjusted to pH 6 and a white participate formed. The participate D was filtered, air dried and washed with ethyl alcohol to yield 180 mg of the subject product In 81% yield.
• the starting material A (1 g, 37 mmol) was admixed with 14 ml of pyridine and 1.58 g (18.5 mmol) of piperazine at 60o C for about 4 hours.
• the solvent was removed under nitrogen and the product B recrystallized from ethyl alcohol.
• the piperazine product B yield was 72%, 0.85 g, melting point 195-201o C.
• Product B (0.4 g, 1.25 mmol) was admixed with 10 ml. of DMF and 154 ⁇ (1.25 mmol) of acetylene dicarboxylate at room temperature for about 2 hours. The solvent was then evaporated under nitrogen and the residue recrystallized from DMF and ethyl alcohol. The product C was dried in an oven at 60o C to obtain 265 mg, 235-239o C melting point, in 46% yield.
• the starting material A (500 mg, 1.45 mmol) was dissolved in 10 ml chloroform and added to 178 ⁇ L (1.45 mmol) dimethylacetylene dicarboxylate. The mixture was stirred overnight at room temperature and then chromatographed over 150 g of silica dioxide and flushed with chloroform and ethyl alcohol (96:4). The product B was recrystallized in ethyl acetate to yield 727 mg of white solid.
• the ester product B (200 mg, 0.41 mmol) was added to 1 ml of THF, 2 ml of 2N potassium hydroxide and stirred at 30° C for about 4 hours. After all material had dissolved the THF was evaporated and the remaining mixture was diluted with 10 ml of water. The pH was adjusted to 7 and a white participate formed. The participate was filtered and dried to yield 141 mg of a white solid product C, melting point 225-226o C. 73% yield.
• the starting material A (27.46 g, 97.4 mmol) was admixed with 41 ml of acetic anhydride and 17.4 g (117.4 mmol) triethylor- thoformate and refluxed for about 3 hours. The mixture was evaporated at 60°C and azeotroped with toluene three times to yield 32.98 g of product B.
• the enol ether B (12 g, 35.5 mmol) was added to 2.05 g, 36 mmol of cyclopropylamine in 50 ml of methylene chloride and stirred at room temperature. This mixture was evaporated under vacuum and the product added to 600 g silica gel packed and eluted with methylene chloride. Approximately 11.43 g of the product C was obtained in a 92% yield and had a melting point of 88-92°C.
• the benzylamine E (1.85 g, 4.45 mmol) was dissolved in 17 ml ethanol and 11 ml acetic acid with 10% palladium on carbon (0.28 g) and shaked for 1.5 hours under 12 pounds hydrogen pressure. The mixture was filtered rinsing with chloroform. The filtrate was evaporated and the residue triturated with ethanol to give 1.23 g of the product F in 85% yield, melting point 228-232°C.
• Ester G (0.24 g, 0.62 mmol) was stirred for 1 day in 6 ml of tetrahydrofuran and 3 ml of 2 N aqueous potassium hydroxide.
• Ester B (0.5 g) was refluxed in 36 ml of 6N hydrochloric acid for 7 hours. Evaporation of the solvent under nitrogen and recrystallization of the residue from ethanol afforded 0.296 g (64%) of product C, mp 310-328°C.
• Product D was prepared as B in example 2.
• the amino acid C (0.27 g) was converted to 0.214 g (57% yield) of D after recrystallization from ethanol (mp 215-221°C).
• Product B was prepared as B in example 2.
• the amino acid A (0.4 g) was converted to 0.35 g (64% yield) of B after recrystallization from dimethyl formamide/ethanol (mp 244-251°C).
• Product B was prepared as B in example 2.
• the amino acid A (0.23 g) was converted to 85 mg (27% yield) of B after chromatography over 80g silanized silica gel packed and eluted with chloroform and recrystallization from methylene chloride/hexane (mp 176-182°C).
• Example 9 Preparation of 2-[4-(3-carboxy-1-cyclopropyl-6,8- difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-(3-amino- pyrrolidinyl)]-3-butenoic acid- (E)-1-methyl ester.
• the preparation of this compound is illustrated in Scheme 11.
• the preparation of the starting material A is described as "B" in example 10, scheme 2.
• the amino acid A (200 mg, 0.57 mmol) was dissolved in DMF (1.0 mL) and heated to 150°C for 4 h with methylacetoacetate (108 uL, 1.0 mmol). The mixture was then cooled and DMF removed under a stream of dry nitrogen. The residue was extracted with methylene chloride and concentrated, then chromatographed over silanized silica gel, eluting with 3 % ethanol in methylene chloride, giving the product B (159 mg, 63 %) as a pale yellow powder. MP - 189-91°C, dec.
• the product A (2.0 g, 4.8 mmol) was then dissolved in 2 N KOH (14 mL) and heated to reflux for 6 h, then neutralized under heating with acetic acid. On cooling the mixture was filtered and the filtrate discarded. The product was then dissolved in 2.5 % acetic acid in water (2.5 mL / 100 mL) and filtered thru a medium frit. The filtrate was made to pH 10 with 50 % sodium hydroxide and neutralized with acetic acid to give a white powder which was filtered and washed with methanol and ether to give B as a white powder (809 mg, 48 %).
• the product B (400 mg, 1.2 mmol) was dissolved in a mixture of chloroform (3.0 mL) and DMF (0.5 mL) and dimethylacetylenedicarboxy- late (141 uL, 1.2 mmol) was added. the mixture was stirred for 24 h at 23°C, then the solvent was removed under a stream of dry nitrogen gas and the residue was chromatographed over silanized silica gel, eluting with chloroform to give the product C (354 mg, 63 %) as an off white solid. MP - 173-5°C, dec.
• the tetrafluoro ester A (0.44 g) was admixed with 5 ml of pyridine and 0.12 g of piperazine for about 1 day. The pyridine was then evaporated off under nitrogen and the residue chromatographed over silica gel (5-10% methanol/methylene chloride) to afford 0.166 g (31% yield) of the product B which was recrystallized from methylene chloride/hexane. mp 227oC.
• the product C was prepared as C in example 1.
• the amino ester B (0.23 g, 0.58 mmol) was converted to 0.21 g (67% yield) of C after chromatography over 20 g silica gel packed and eluted with 3% methanol/methylene chloride and recrystallization from ethanol/ethyl acetate (mp 224-7oC).
• ester C (0.15 g) was admixed with 5 ml of methylene
• ester D (2 g, 6.08 mmol) was refluxed in 6N (150 ml) hydrochloric acid for about seven hours and evaporated at 70o C. The residue was recrystallized from ethyl alcohol to yield 0.59 g of product E, melting point 169-177oC.
• the tetrafluoro acid E (0.4 g, 1.33 mmol) was admixed with 5.5 ml of pyridine and 0.42 g (4.8 mmol) of piperazine and heated to 60° C for about 1.5 hours. The pyridine was then evaporated off under nitrogen and the product recrystallized from ethyl alcohol with ethyl acetate to yield 0.34 g of product F, melting point 230-238°C, in 70% yield.
• a 50 ml one-neck round bottom flask Is equipped with a magnetic stirring bar condenser and gas inlet.
• ethyl 2,3,4,5-tetrafluorobenzoyl acetate 2.8 g, 10.6 mmol
• acetic anhydride 6.5 g, 63.6 mmol
• triethyl orthoformate 2.4 g, 15.9 mmol
• TLC of the mixture at this time shows complete consumption of starting material.
• the reaction mixture is concentrated to leave behind an orange waxy solid.
• the mixture is chromatographed on silica gel. Elution with 5:1 hexane/EtOAc gives 470 mg of the enamino keto ester as a light yellow gummy solid.
• a 25 ml flame dried round bottom flask is equipped with a reflux condenser, magnetic stirring bar, and gas inlet.
• the system is purged with nitrogen and the trifluoroquinolone obtained above (150 mg, 0.445 mmol) is added along with 10 ml dry CH 3 CN.
• piperazine (191 mg, 2.22 mmol) is added.
• the resultant red solution is brought to reflux. As reflux begins the solution becomes yellow.
• the mixture is left to reflux overnight.
• a 250 ml flame dried round bottom flask is equipped with a pressure equalizing addition funnel, magnetic stirring bar, and gas inlet.
• the flask is charged with a 50% sodium hydride-in-oil suspen- sion (3.74 g, 78.0 mmol) along with 20 ml of dry THF.
• the quinolone ester obtained in the previous step (349 mg, 1.04 mmol) is slurried in 3 ml of H 2 O. Next 5 ml of IN NaOH is added and the mixture is brought to reflux. After one hour reflux, TLC shows starting material to be consumed and a low Rf material forms. The mixture is cooled to 0°C and acidified to pH 7. The solids are filtered, washed with water, cold ethanol, and ether. Drying under vacuum gives 290 mg of an off-white solid (mp>250oC).
• the compounds according to the invention have good actions against Gram-positive and Gram-negative bacteria.
• the effectiveness of the subject compounds on some bacteria were obtained by performing a dipped disk assay.
• the antibacterial activ ⁇ - ity of the compounds is determined by the disk-diffusion method. Paper disks (12.7 mm) were loaded with 0.10 ml of drug solution prepared at a concentration of 1 and 0.1 mcg/ml; the disks were allowed to air dry. They were then applied to the surface of microorganism- seeded agar assay trays, which contained the bacterial strain Pseudomonas aeruginosa UC 95 (PA) , Escherichia coli UC 51 (EC) or Staphylococcus aureus UC 80 (SA). The assay trays were incubated overnigjht under aerobic condition to allow for the growth of the organisms. Zones of growth inhibition due to the action of the antibiotic were then measured to the nearest millimeter.
• PA bacterial strain Pseudomonas aeruginosa UC 95
• EC Escherichia
• MIC minimum inhibitory concentration
• MFT Method for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically
• the various bacteria used for testing are grown overnight on MHA at 35°C and transferred to Trypticase soy broth (TSB) until a turbidity of 0.5 McFarland standard is obtained.
• the bacteria are diluted one to 20 in TSB and inoculated on the plates (1 ⁇ l using a Steers replicator). The plates are incubated at 35°C for 20 hours and the MIC is read to be the lowest concentration of drug that completely inhibits visible growth of the bacteria.
• the MIC test results of selected of Formula B compounds of this invention are found in Tables B2-B9.
• the compounds according to the invention have a potent and broad antimicrobial efficacy.
• chemotherapeutic active compounds in medicine and as substances for preserving inorganic and organic materials, in particular organic materials of all types, for example polymers, lubricants, dyes, fibres, leather, paper and wood, foodstuffs and water.
• the compounds according to the invention are active against Gram-negative and Gram-positive bacteria and bacterioid microorganisms. Thus, diseases caused by these pathogens can be treated.
• the compounds according to the invention are particularly active against bacteria and bacterioid microorganisms. Thus, they are particularly well suited for the chemotherapy of local and systemic infections caused by these pathogens in medicine.
• pseudomonadaceae such as pseudomonas bacteria, for example Pseudomonas aeruginosa
• mycoplasma for example Mycoplasma pneumonia.
• Naphthridine ester 9 (650 mg, 1.35 mM) was dissolved in DMSO (20 ml) containing aq. NaOH (240 mg of 50% NaOH in 3 ml H2O by heating briefly at 75°C). The mixture was allowed to cool to room temperature over 1 hour and then left at room temperature overnight. The DMSO was removed in vacuo and the residue was dissolved in 15 ml of H 2 O whose pH was 9.8 at this point. The pH of the solution was adjusted to 7 by use of IN HCl.
• the carboxylic acid product was precipitated out of the solution which was filtered, washed with H 2 O and dried to obtain 360 mg of solid which was found to be the acid 10 with trifluoroacetyl group of the pyrrolidine ring intact.
• the filtrate solution was concentrated again in vacuo and the residue was redissolved in H 2 O (5 ml).
• the pH of the solution was readjusted to 7 to induce the additional solid precipitation.
• the solid precipitate was filtered, washed with H 2 O followed by Et 2 O and dried to obtain 135 mg of solid.
• Example 16 Preparation of E-2-(4-(3-carbosy-1-(bicyclo(1.1.1.)- pent-1-yl)-6-fluoro-1,4-dihydro-4-oxo-7-(1,8-naphthyridine))-1-(N-(3-aminopyrrolidinyl)))-2-butenoic acid, dimethyl ester Dimethyl acetylenedicarboxylate (71 mg) was added to a DMF (3 mL) suspension of the amino acid (165 mg) and the resulting reaction stirred at 55oC for 2 hours. The reaction was cooled to room temperature and the DMF removed under a stream of N2. The resulting solid was dissolved in CH 2 CI 2 and filtered. The filtrate was evaporated and the resulting product recrystallized from isopropyl alcohol/ether to yield 152 mg of a white solid. MP 157-61oC.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (10)

Publications (1)

Family

ID=27540650

Family Applications (1)

Country Status (5)

Families Citing this family (11)

Family Cites Families (3)

• 1989
  • 1989-11-24 JP JP50126989A patent/JPH04502317A/ja active Pending
  • 1989-11-24 AU AU47438/90A patent/AU4743890A/en not_active Abandoned
  • 1989-11-24 WO PCT/US1989/005213 patent/WO1990006307A2/en not_active Application Discontinuation
  • 1989-11-24 EP EP19900901236 patent/EP0447484A1/de not_active Withdrawn
  • 1989-12-06 CA CA 2004693 patent/CA2004693A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events