GB2127818A - Aminoglycoside derivatives processes for their production and their use - Google Patents

Aminoglycoside derivatives processes for their production and their use Download PDF

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GB2127818A
GB2127818A GB08325758A GB8325758A GB2127818A GB 2127818 A GB2127818 A GB 2127818A GB 08325758 A GB08325758 A GB 08325758A GB 8325758 A GB8325758 A GB 8325758A GB 2127818 A GB2127818 A GB 2127818A
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compound
formula
amino
acid addition
addition salt
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Hans Loibner
Wolfgang Streicher
Peter Stutz
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Sandoz AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20Carbocyclic rings
    • C07H15/22Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/224Cyclohexane rings substituted by at least two nitrogen atoms with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20Carbocyclic rings
    • C07H15/22Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

New amine glucoside derivatives having the formula (I), wherein R1 is hydrogen or a group having the formula (II, IIa, IIb, IIc), R2 is OH or NH2, R3 is hydrogen or OH, R4 is hydrogen or OH, R5 is an amino, methyl amino, dimethylamino group or, when R2 is the amino group, a hydroxyl group and R6 is hydrogen or a methyl group, and their acid addition salts; method for producing bonds having the formula (I) and their acid addition salts, as well as a utilization thereof.

Description

SPECIFICATION Aminoglycoside derivatives, processes for their production and their use The present invention concerns aminoglycoside derivatives, processes for their production, pharmaceutical compositions containing them and such derivatives for use as pharmaceuticals.
In particular the invention concerns compounds of formula I
wherein R1 represents hydrogen or a group of formula
R2 represents hydroxy or amino, R3 represents hydrogen or hydroxy, R4 represents hydrogen or hydroxy, R6 represents amino, methylamino, dimethylamino or, when R2 represents amino also hydroxy and R6 represents hydrogen or methyl in free base form or in the form of an acid addition salt.
According tithe invention these compounds can be prepared a) by reducing a compound of formula villa or Illb
wherein X is a leaving group and R1 to R6 are as defined above, and amino and hydroxy groups, where present. may be protected, and if required deprotecting any protected groups still present in the compound thus obtained, or b) to produce a compound wherein R5 represents methylamino or dimethylamino, mono- or dimethylating a corresponding compound of formula I wherein R5 represents amino or mono-methylating a corresponding compound wherein R5 represents methylamino, whereby other amino groups, where present may be protected, and if required deprotecting any protected amino groups in the compound thus obtained;; and recovering the compound of formula I thus obtained in free form or in the form of an acid addition salt as required.
Process a) can be carried out in a manner conventional for such reductions such as known for hydrogenolytic cleavage of an aziridine ring for example, using Raney-Nickel and hydrogen in an inert solvent such as an alcohol e.g. methanol. Raised pressure can be advantageous.
Process b) can be effected using conventional methylating agents. For example for introduction of a single methyl group in a compound containing a 6'-NH2 group this is first reacted selectively with a carbonic acid derivative of formula Y-COOR9wherein Y represents a reactive group and R9 represents alkyl or aralkyl to produce the corresponding NHCOORg derivative which is then reduced in conventional manner, e.g. with a complex metal hydride e.g. LiAIH4. Introduction of two methyl groups in compounds containing a 6'-NH2 group can four example be carried out by protecting all amino groups except that at 6'-, introducing methyl groups in conventional manner e.g. by reaction with formaldehyde in the presence of a reducing agent or of NaH2PO3 and then deprotecting the end product.Introduction of a further methyl group in a 6'-methylamino compound may be effected analogously in conventional manner.
Suitable protecting groups are for example benzyloxycarbonyl, tert.butoxycarbonyl or trichlorethoxycarbonyl. These groups can be introduced and removed in conventional manner such as for example analogously to the methods described hereinafter in the examples.
Examples of leaving groups (X) are mesyloxy, tosyloxy, trifluoromethanesulphonyloxy, chlorine, bromine or iodine.
The compounds of the formula I may be converted in conventional manner into their acid addition salts and vice versa.
The starting materials of formula villa may be obtained by introducing in conventional manner a group X into a compound of formula VI
wherein R to R6 are as defined above.
The starting materials of formula Illb may-be obtained by cyclising a compound of formula IV
wherein R, to R6 are as defined above, amino and hydroxy groups may be protected except in the case of the amino group at position I in formula IV.
Cyclisation is carried out in conventional manner or using triphenylphosphane and an azodicarboxylic acid ester (e.g. azodicarboxylic acid di-isopropylester) in an inert solvent such as a chlorinated hydrocarbon e.g. chloroform.
The compounds of formula III are new and also form part of the invention.
The compounds of formulae IV and VI and methods for their preparation are described in published European Patent Application No.0072351.
The intermediates can be employed in the form of mixtures such as those obtained when preparation is by fermentative methods. Reaction of these compounds will lead in turn to corresponding mixtures of intermediates or end-products. Such mixtures can be separated into their individual components at any stage of the preparative chain, but this is preferably carried out on deprotected end products of formula I. The methods employed in separation are conventional such as described in USP 3,984,395 or K. Byrne et. al. J. Chromatogr. 1311191(1977).
The compounds of formula I exhibit chemotherapeutic, in particular antimicrobial activity as indicated in vitro in series dilution tests and in vivo in tests on mice using various bacterial strains such as e.g. Staph. aureus, Staph. epidermidis, Pseudomonas aeruginosa, E. coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Enterobacter cloacae, Klebsiella pneumonia and Serratia marcescens. This activity is observed in vitro at concentrations between ca. 0.05 to 50 fg/ml and in vivo at between ca.
0.4 and 100 mg/kg animal body weight. They are particularly effective in aminoglycoside resistant strains and have thus a broad spectrum of activity.
The compounds are thus indicated for use as chemotherapeutics in particular anti bacterially active antibiotics.
An indicated suitable daily dosage for use as anti-bacterially active antibiotic is from about 0.1 to 2 g. If desired this may be administered in divided doses 2 to 4 times a day in unit dosage form containing about 25 to 1 500 mg of the compound or in sustained release form.
The compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts e.g. as the penta hydrochloride or sulphate. Such salt forms exhibit the same order of activity as the free base forms.
The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally, other excipients and administered in such forms as tablets, capsules or injectable preparations.
Such compositions also form part of the invention.
The invention therefore also concerns a method of combatting bacteria comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof and such compounds for use as chemotherapeutic agents, in particular anti-bacterially active antibiotics.
Preferred meanings for the substituents are R1 = a) formula Ila b) formula II R2 = a) hydroxy or amino b) amino R3 + R4 = a) hydrogen b) hydroxy R5 = a) amino, methylamino, dimethylamino b) amino R6 = a) hydrogen or methyl b) hydrogen; as well as combinations of these.
A particular group of compounds according to the invention is that wherein R1 represents a group of formula Ila, R2 represents amino, R3 and R4 represent hydrogen and R6 represents hydrogen or methyl and R5 represents amino, methylamino or dimethylamino.
Another interesting group covers those compounds wherein R1 represents a group of formula 11, R2 represents hydroxy or amino, R3 and R4 represent hydroxy, R5 represents amino and R6 represents hydrogen.
A further interesting group covers those compounds wherein R1 represents a group of formula II or Ia, R2 represents hydroxy or amino, R3 and R4 represent hydrogen or hydroxy, R5 represents amino, methylamino or dimethylamino, R6 represents hydrogen or methyl.
A particularly preferred single compound is 1 -C-methylgentamicin C1 in free base form or acid addition salt form preferably pentahydrochloride salt form.
The following examples illustrate the invention. All temperatures are in degrees centigrade.
EXAMPLE 1 1-C-Methylgentamicin C2. Pentahydrochloride (Process a)) 1 g of 3.2',6',3"-Tetra-N-tert.butoxycarbonyl-1 -desamino- 1 -nitro- 1 -C- methanesulfonyloxymethylgentamicin C2 (compound of formula Illa) is dissolved in 30 ml of methanol and reduced with hydrogen in the presence of a Raney-nickel suspension at 4 atm. After filtering off the catalyst an amorphous foam is obtained which is taken up in chloroform, shaken three times with dilute ammonia and washed neutral. Removal of solvent on a rotary evaporator yields a residue which is dissolved in 10 ml of trifluoracetic acid and after 7 minutes diluted with 200 ml of diethylether. The precipitate is filtered under suction, dissolved in methanol and converted to the pentahydrochjloride over IRA 401 S (chloride form).
Rf = 0.17 (in dichloromethane/methanol/25% ammonia = 70/26/9) H-NMR, characteristic signals: 1.29 (d, J = 7, 3H); 1.38 (s, 3H); 1.52 (s, 3H); 2.44 (dd, J1 = 13, J2 =3.6, lah); 2.96 (s, 3H); 5.10 (d, J = 3.6, 1 H); 5.86 (d, J = 3.6, 1 H).
EXAMPLE 2 1-C-Methylgentamicin C1. P entahydrochloride (Process a)) 0.5 g of 1 -C-hydroxymethyl-3,2',6',3"-tetra N-tert.butoxycarbonylgentamicin C1 and 0.26 g of triphenylphosphane are dissolved in 10 ml of abs. chloroform, 0.2 g of azodicarboxylic acid diisopropylester added and the mixture refluxed for 5 minutes. The residue obtained after evaporation of the solvent can be purified by chromatography over silica gel with dichloromethane/methanol (15/1) or further used directly without purification. This residue is taken up in 10 ml of trifluoroacetic acid and after 7 minutes diluted with 200 ml of diethylether.Chromatography of the filtered precipitate over silica gel (dichloromethane/methanol/30% ammonia = 15/4/1) yields fractions containing the desired product which are concentrated, dissolved in 1 N methanolic hydrochloric acid and precipitated with diethylether. An amorphous white powder is obtained.
Rf = 0.6 (in chloroform/methanol/33% ammonia = 1/1/1, lower phase).
H-NMR (characteristic signals): 1.32 (d, J = 7, 3H); 1.38 (s, 3H); 1.53 (s, 3H); 2.43 (dd, J1 = 13, J2 = 4.2, 1 H); 2.76 (s, 3H); 2.95 (s, 3H); 5.13 (d, J = 3.8, 1 H); 5.87 (d, J = 3.7, 1 H).
EXAMPLE 3 1 -C-Methylgentamicin C1,,. pentahydrochloride Obtained analogously to Example 1 or 2.
H-NMR (characteristic signals): 1.37 (s, 3H); 1.53 (s, 3H); 2.44 (dd, J1 = 13, 13,J2=4,1H);2.95(s, 3H); 5.13 (d, J = 3.6, 1 H); 5.84 (d, J = 3.5, 1 H).
EXAMPLE 4 1-C-Methyl-6'-N-methylgentamicin C1,, . pentahydrochloride (Process b)) 220 mg of 1-C-Methyl-6'-N-benzyloxycarbonylgentamicin C1,, are dissolved in 50 ml abs.
tetrahydrofuran, 500 mg of lithiumaluminium hydride added and the mixture refluxed for 3 hours. 10 ml of methanol are then carefully added and the mixture acidified with 1 ml acetic acid and filtered over celit. The organic phase is evaporated and chromatographed over chloroform/methanol/30% ammonia (15/4/1). Fractions having an Rf value of 0.2t in chloroform/methånol/30% ammonia (70/21/9) are collected, dissolved in 4 ml of 1N methanol hydrochloric acid and precipitated by addition of 100 ml of diethylether. A white powder is obtained.
H-NMR (characteristic signals): 1.36 (s, 3H); 1.52 (s, 3H); 2.45 (dd, J1 = 12.5 Hz, J2=4Hz,1H); 2.76 (s, 3H); 2.94 (s, 3H); 5.12 (d, J = 3.6 Hz, 1 H); 5.85 (d, J = 3.6 Hz, 1 H).
The required starting materials may be prepared as follows.
A) 3,2',6',3"-Tetra-N-tert.butoxycarbonyl- -desa mino- 1 -nitro-1 -Cmethanesulfonyloxymethylgentamicin Cz a) 3,2 ',6',3"-Tetra-N-tert.butoxycarbonyl- 1 -desamino- 1 -nitrogentamicin C2 A mixture of 50 g potassium permanganate and 125 g potassium dihydrogenphosphate in 0.5 litre of water is brought to 75 and 25 g of 3,2',6',3"-tetra-N-tert.-butoxycarbonylgentamicin C2 dissolved in 0.5 litre of acetone added in one gush. The mixture is refluxed for 3 minutes and poured into ice-water containing 1 50 g of sodium hydrogensulphite. The manganese dioxide is filtered off and the solution extracted with chloroform.After drying, the organic phase is concentrated on a rotary evaporator and the residue chromatographed over silica gel with ethylacetate/hexane = 3/2. A colourless foam is obtained Rf = 0.17 (dichloromethane/methanol = 20/1).
b) 3,2 ',6',3 "-Tetra-N-tert. butoxycarbonyl- 1 -desamino- 1 -nitro- 1 -C-hydroxymethylgentamicin C2 0.64 g of 3,2',6',3"-Tetra-N-tert.-butoxycarbonyl-1 -desamino-1 -nitrogentamicin C2 are dissolved in 5 ml of methanol and after cooling to --70 reacted with 0.3 ml of triethylamine. After 5 mins the solution is poured into 10 ml of 37% formaldehyde solution and raised to room temperature. After dilution with water and acidification with 0.1 N HCI the solution is extracted with dichloromethane and the organic phase concentrated on a rotary evaporator. The substance having Rf = 0.56 (in dichloromethane/methanol = 10/1) is isolated by chromatography on silica gel with dichloromethane/methanol (100/2-4).
c) 3,2 ',6',3 "-Tetra-N-tertbutoxycarbonyl- 1 -desamino- 1 -nitro- 1-C- methanesulfonyloxymethylgentamicin C2 1.82 g of 3,2',6',3"-Tetra-N-tert.butoxycarbonyl-1 -desamino-1 -nitro-1 -C- hydroxymethylgentamicin C2 and 0.6 ml of diisopropylethyl amine are dissolved in 60 ml of dichloromethane, 0.16 ml of methane sulphonic acid chloride added and the mixture refluxed for 1 hour.
The residue obtained after evaporation is chromatographed over silica gel with chloroform to yield an amorphous foam.
Rf = 0.43 (in dichloromethane/methanol/33% ammonia = 9/1/0.2).
B) 1 -C-Hydroxymethyl-3,2',6',3"-tetra-N-tert.butoxycarbonylgentamicin C1 a) 3,2', 6 ',3 "-Tetra-N-tert. butoxycarbonyl- 1 -desamino- 1 -nitrogentamicin C1 To a solution of 1 7 g of 3,2',6',3"-tetra-N-tert.-butoxycarbonylgentamicin C1 and 3.4 g 3-tert.butyl-4-hydroxy-5-methylenephenylsulphide in 750 ml of 1,2-dichloroethane are added whilst boiling 34 g of 3-chloroperbenzoic acid in solid form. After 30 minutes the solution is concentrated on a rotary.
evaporator and the residue triturated with 20% KHSO3, saturated NaHCO3 and water and chromatographed over silica gel (ethylacetate/hexane = 3/2). The substance with Rf = 0.74 (dichloromethane/methanol = 9/1) is isolated.
b) 1 -C-Hydroxymethyl-3,2 ',6 ',3 "-tetra-N-tert.butoxycarbonylgentamicin C1 0.8 g of 3,2',6',3"-Tetra-N-tert.-butoxycarbonyl -desamino-l -nitrogenta micin C1 are dissolved in 20 ml of chloroform, reacted with 10 g of paraformaldehyde and 1 ml of triethylamine and refluxed for 30 minutes. The resulting mixture is filtered under suction and the mother liquor chromatographed over silica gel with ethylacetate/hexane (2/1). Rf = 0.62 (in dichloromethane/methanol = 9/1). The resulting product is reduced with hydrogen at 4 atm. using a Raney-Nickel suspension in 30 ml of methanol. Filtration of the cataiyst yields an amorphous foam which is directly further reacted.
C) 1 -C-Hydrnxymethyl-3,2',6',3"etra-Nqert.butoxycarbonylgentamicin C1,, The compound is obtained analogously to Example B)b) via 3,2',6',3"-tetra-N- tert.butoxycarbonyl-1 -desamino- 1 -nitrogentamicin C1,, [Rf 0.16 in dichloromethane/methanol = 20/1 analogous to Example A)a)j.
Rf value = 0.5 (dichloromethane/methanol = 9/1) prior to reaction with Raney-Nickel.
D) 1 -C-Methyl-6'-N-benzyloxycarbonylgentamicin C Ia 740 mg 1 -C-Methylgentamicin C la are dissolved in 30 ml of methanol and a solution of 500 mg of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarboxylic acid imide in 5 ml of methanol and 5 ml of chloroform added dropwise at --150. After one hour the temperature is raised to ambient. After a further two hours the mixture is concentrated on a rotary evaporator and the residue chromatographed on silica gel with chloroform/methanol/30% ammonia (15/4/1). The product with Rf = 0.66 (chloroform/methanol/30% ammonia (70/21/9) is collected.
E) l-N,1 -C-Methylenegentamicin C 0.5 g of 1-C-Hydroxymethyl-3,2',6',3"-tetra-N-tert.butoxyCarbonylgentamicin C1,, and 0.269 of triphenylphosphane are dissolved in 10 ml of abs. chloroform, 0.2 g of azodicarboxylic acid diisopropylester added and the whole refluxed for 5 minutes. Evaporation of solvent yields a residue which is chromatographed over silica gel (dichloromethane/methanol = 15/1). The product with Rf = 0.49 (dichloromethane/methanol = 9/1) is collected. 0.2 g of 1-N,1-C-methylene-3,2',6',3"-tetra- N-tert.-butoxycarbonylgentamicin C1a are dissolved in 5 ml of trifluoracetic acid and after 5 minutes diluted with 100 ml of diethylether.The residue is chromatographed on silica gel (dichloromethane/methanol/30% ammonia = 1 5/4/1) to obtain an amorphous powder.
Rf = 0.3 (in chloroform/methanol/33% NH3 = 1/1/1, lower phase).
H-NMR (characteristic signals): 1.2 (s, 3H); 1.37 (dd, J1 = 13.8, J2 = 4.5, 1 H); 1.56 (s, 1 H); 2.01(s, 1 H); 2.51(s, 3H); 4.91 (d, J = 3.6, 1 H); 5.23 (d, J = 3.6, 1 H).
F) 1-N,1-C-Methylenegentamicin C1 Analogous to E) via 1-N,1-C-Methylene-3,2',6',3"-tetra-N-tert.-butoxycarbonylgentamicin C1: Rf = 0.47 (in dichloromethane/methanol = 9/1).
Title compound: Rf = 0.36 (in chloroform/methanol/33% NH3 = 1/1/1, lower phase).
H-NMR (characteristic signals): 1.25 (s, 3H); 1.27 (d, J = 7, 3H); 1.39 (dd, J1 = 13.5, ,J3=4.6, 1 H); 1.59 (s, 1 H); 2.01(s, 1 H); 2.67 (s, 3H); 2.69 (s, 3H); 4.96 (d, J = 3.6, 1 H); 5.33 (d, J = 3.6, 1 H).

Claims (9)

1. Compounds of formula I
wherein R1 represents hydrogen or a group of formula
R2 represents hydroxy or amino, R3 represents hydrogen or hydroxy, R4 represents hydrogen or hydroxy, R5 represents amino, methylamino, dimethylamino or, when R2 represents amino also hydroxy and R6 represents hydrogen or methyl in free base form or in the form of an acid addition salt.
2. 1 -C-methylgentamicin C2 in free base form or in the form of an acid addition salt.
3. A compound according to Claim 1 or 2 in the form of its pentahydrochloride.
4. A process for the preparation of compounds according to Claim 1 which comprises: a) reducing a compound of formula Ills or Illb
wherein X is a leaving group and R1 to R6 are as defined above and amino and hydroxy groups, where present, may be protected, and if required deprotecting any protected groups still present in the compound thus obtained, or b) to produce a compound wherein R5 represents methylamino or dimethylamino, mono- or dimethylating a corresponding compound of formula I wherein R5 represents amino or mono-methylating a corresponding compound wherein R5 represents methylamino, whereby other amino groups, where present may be protected, and if required deprotecting any protected amino groups in the compound thus obtained;; and recovering the compound of formula I thus obtained in free form or in the form of an acid addition salt as required.
5. A pharmaceutical composition comprising a compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable acid addition salt thereof together with a chemotherapeutically acceptable diluent or carrier.
6. A method of combatting bacteria comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof.
7. A compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable acid addition salt thereof for use as a pharmaceutical.
8. A compound of formula I as claimed in Claim 1 or a chemotherapeutically acceptable acid addition salt thereof for use as an antibacterially active antibiotic.
9. A compound of the formula III as hereinbefore defined.
GB08325758A 1982-09-30 1983-09-27 Aminoglycoside derivatives processes for their production and their use Withdrawn GB2127818A (en)

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FR2533927B1 (en) 1985-06-14
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