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EP0056408A1 - Guanylated aminoglycosides, a process for their production and their use as pharmaceuticals - Google Patents

Guanylated aminoglycosides, a process for their production and their use as pharmaceuticals

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Publication number
EP0056408A1
EP0056408A1 EP81902303A EP81902303A EP0056408A1 EP 0056408 A1 EP0056408 A1 EP 0056408A1 EP 81902303 A EP81902303 A EP 81902303A EP 81902303 A EP81902303 A EP 81902303A EP 0056408 A1 EP0056408 A1 EP 0056408A1
Authority
EP
European Patent Office
Prior art keywords
group
compound
formula
amino groups
represents hydrogen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP81902303A
Other languages
German (de)
French (fr)
Inventor
Hans Loibner
Wolfgang Streicher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
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Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Publication of EP0056408A1 publication Critical patent/EP0056408A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234—Cyclohexane 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234—Cyclohexane 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
    • C07H15/236—Cyclohexane 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 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin

Definitions

  • the present invention concerns guanylated aminoglycosides a process for their production, pharmaceutical composition containing them and their use as pharmaceuticals.
  • guanylated as used herein denotes substitution by at least. one amidino group.
  • the invention concerns more particularly a compound of formula I (as shown hereinafter together with all other formulae) wherein R 1 represents hydrogen or a group of the formulae II , Ila , lIb , Hc , lId ; R 2 represents hydrogen or a group of the formula III or IlIa, whereby at least one of R 1 or R 2 represents hydrogen; R 3 represents hydroxy or the group -NHR 8 ; either R 4 and R 5 represent independently hydrogen or hydroxy and R and R' represent hydrogen or
  • R 4 and R 5 represent hydrogen and R and R' represent an additional bond
  • R6 represents hydroxy, the group -NHR 8 or the group -N(CH 3 )R 8 ;
  • R 7 represents hydrogen or methyl;
  • R 8 represents hydrogen or amidino;
  • R 9 represents hydrogen, amidino or the group
  • R 10 represents hydrogen or a group of formula
  • the present invention also provides a process for preparing the compounds of the invention which comprises guanylating an aminoglycoside which contains at least one free amino group optionally together with potential or protected amino groups and if required converting in a compound thus obtained any potential amino groups present to amino groups and deprotecting protected amino groups present.
  • the present invention provides more particularly a process for preparing a compound of formula I as defined above which comprises guanylating a corresponding compound of formula VII wherein represents hydroxy or ammo; represents hydroxy, amino or methylamino; represents hydrogen or the group
  • Z represents an amino group or a potential amino group
  • R, R', R 1 , R 2 , R 4 , R 5 , R 7 , X and n have the meanings given above whereby one or more of the amino groups can be protected with a suitable amino protecting group and if required converting in the product obtained any potential amino groups present to amino groups and deprotecting any protected amino groups present.
  • the process can be effected in conventional manner for the introduction of an amidino group for example as described in Houben-Weyl, Methoden der organischen Chemie, Bd. XV/1, S. 531 ff.
  • suitable guanylating agents are S-alkylisothioureas,
  • reaction may be carried out in solvent inert under the reaction conditions such as pyridine, dimethylformamide, chloroform or mixtures thereof.
  • Suitable protecting groups for use in the process are those known for this purpose in the art such as benzyloxycarbonyl, tert.butyloxycarbonyl, or trichloro ethyloxycarbonyl. 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 potential amino groups such as those represented by Z in the formula VII are azido, benzyl oxycarbonylamino, tert.butyloxycarbonylamino, phthalimido and succinimido which can be converted into the free amine in conventional manner such as herein after described in the examples.
  • the starting materials of formula VII wherein represents a group of the formula are in part new and can be prepared for example by reacting the corresponding compound of formula VII wherein represents hydrogen and the amino groups are protected with an appropriate protecting group with a compound of formula or wherein X, Z and n are as defined above and Y represents a leaving group such as halogen particularly chlorine or bromine N-succini-midoxy, N-phthalimidoxy, P-nitrophenoxy, 1-benzotriazolyloxy or imidazolyl.
  • This reaction can be carried out in conventional manner for example in an inert solvent such as chloro form, dimethylformamide or tetrahydrofurane at room temperature or raised temperature preferably at room temperature.
  • an inert solvent such as chloro form, dimethylformamide or tetrahydrofurane at room temperature or raised temperature preferably at room temperature.
  • the remaining starting materials are either known or can be prepared according to known methods.
  • the compounds can be isolated and purified by conventional methods.
  • the compounds of formula I exhibit chemotherapeutic activity.
  • they exhibit 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. epidermis, Strept.
  • the effective dosage will, of course, vary depending on the particular compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results can be obtained when the compounds are administered at a daily dosage of from about 2 to 30 mg/kg of animal body weight, suitably given in divided doses two to four times daily. For most large mammals, the total daily dosage is from about 0.1 to 2 g and dosage forms suitable for internal administration comprise about 25 to 1500 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.
  • the compounds may be used in free base form or in the form of chemotherapautically acceptable acid addition salts e.g. as the hydrochloride. Such salt forms exhibit the same order of activity as the free base forms.
  • R 1 a group of formula lI or Ila
  • R 3 guanidino
  • R 6 NH 2 , NHCH 3
  • R 4 , R 5 H or OH
  • R 1 a group of formula Ila
  • R 3 guanidino
  • R 6 NH 2 , NHCH 3
  • R 6 guanidino
  • preferred compound groups for the indicated use are those derived from gentamycin or kanamycin, particularly gentamycin C 1 , C 1a and C 2 and kanamycin A, whereby compounds are particularly preferred wherein one amidino group is in the 1-, 2'- or 6'-N-pcsition in the molecule or in the exposition of a side chain when present as R 9 ; and chemotherapeutically acceptable acid addition salts thereof.
  • X Chloroform/methanol/25% ammonia 2/1/1
  • XI Chloroform/methanol/conc. ammonia 9/1/0.2
  • XII Chloroform/metha ⁇ ol/conc. ammonia 17/3/0.4
  • XIII Chloroform/methanol/25% ammonia 9/1/0.2
  • XIV Chloroform/methancl/25% ammonia 17/3/0.4
  • 0.65 g of this product are dissolved in 5 ml of methanol mixed with 20 ml of a 20% solution of ammonium formate in methanol/water (8/2) and 100 mg of Pd/C and the solution boiled for 5 mins .
  • the methanolic solution is concentrated on a rotary evaporator and the residue dissolved in 7 ml of trifluoroacetic acid and after 7 minutes treated with 200 ml ether.
  • the resulting precipitate is dissolved in methanol and filtered over a ion-exchanger column (Amberlite IRA 401S , Cl--form). The filtrate is concentrated to about 10 ml and treated with 200 ml ether.
  • the required starting materials can be prepared for example as follows: A) 1,3,6',3"-tetra-N-tert.butoxy carbonylgentamycin C 1 (for Example 1)
  • the solution is then treated with 50 ml of a 20% ammonium formate solution and 500 mg 10% Pd/active charcoal added.
  • reaction mixture is boiled for 3 minutes, filtered, the solvent removed in vacuo and the residue dissolved in water.
  • This solution is extracted three times with ethylacetate and the combined extracts dried over sodium sulphate and the solvent removed in vacuo. A TLC-pure product is obtained.
  • the solution obtained as described under d) is mixed at 20° with 23 g of di-tert.butyldicarbonate and stirred for 4 hrs. The solution is then diluted with one litre 25% ammonia and stirred for 20 hrs. at 20°.
  • reaction mixture is then diluted further with water, the methanol removed in vacuo and the aqueous phase repeatedly extracted with ethylacetate. After washing with saturated NaHCO, solution and 0.5 N-hydrochloric acid the solution is rotary evaporated and the residue chromatographed over Kieselgel (eluant XIII) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Nouveaux glycosides guanyles de desoxystreptamine eventuellement substitues par un second radical d'hydrate de carbone et/ou par un radical acyle ou un amidino sur l'un des groupes amines, utiles comme antibiotiques a action antibacterienne.New guanyl glycosides of deoxystreptamine optionally substituted by a second carbohydrate radical and/or by an acyl radical or an amidino on one of the amine groups, useful as antibiotics with antibacterial action.

Description

GUANYLATED AMINOGLYCOSIDES A PROCESS FOR THIER PRODUCTION AND THEIR USE AS PHARMACEUTICALS
The present invention concerns guanylated aminoglycosides a process for their production, pharmaceutical composition containing them and their use as pharmaceuticals. The term "guanylated" as used herein denotes substitution by at least. one amidino group.
The invention concerns more particularly a compound of formula I (as shown hereinafter together with all other formulae) wherein R1 represents hydrogen or a group of the formulae II , Ila , lIb , Hc , lId ; R2 represents hydrogen or a group of the formula III or IlIa, whereby at least one of R1 or R2 represents hydrogen; R3 represents hydroxy or the group -NHR8; either R4 and R5 represent independently hydrogen or hydroxy and R and R' represent hydrogen or
R4 and R5 represent hydrogen and R and R' represent an additional bond;
R6 represents hydroxy, the group -NHR8 or the group -N(CH3)R8; R7 represents hydrogen or methyl; R8 represents hydrogen or amidino; R9 represents hydrogen, amidino or the group R10 represents hydrogen or a group of formula
IV or IVa; R11 represents hydrogen or a group of formula V; X represents oxygen or imino and n represents a whole number from 2 to 5 whereby at least one and not more than two amidino groups are present in the molecule, or an acid addition salt thereof. The present invention also provides a process for preparing the compounds of the invention which comprises guanylating an aminoglycoside which contains at least one free amino group optionally together with potential or protected amino groups and if required converting in a compound thus obtained any potential amino groups present to amino groups and deprotecting protected amino groups present.
The present invention provides more particularly a process for preparing a compound of formula I as defined above which comprises guanylating a corresponding compound of formula VII wherein represents hydroxy or ammo; represents hydroxy, amino or methylamino; represents hydrogen or the group
Z represents an amino group or a potential amino group and
R, R', R1, R2, R4 , R5, R7, X and n have the meanings given above whereby one or more of the amino groups can be protected with a suitable amino protecting group and if required converting in the product obtained any potential amino groups present to amino groups and deprotecting any protected amino groups present.
It is well established that the reactivity of amino groups present in aminoglycosides such as for example those of the formula VII differs widely depending on their position cf. e.g. T. Naito et.al., J.Antibiot. 26 ,
297 (1973); J.J. Wright et.al., J.Antibiot. 29.
714, (1976). In order to obtain the desired product which will be guanylated on one or two particular amino groups it will only be necessary to protect amino groups of higher reactivity than that or those to be guanylated. Molecules containing two amino groups of approximately equal reactivity can thus correspondingly yield disubstituted products. When guanylation on the most reactive amino group is desired it is clear that it is not necessary to protect the other amino groups. However, protection of these groups can in certain circumstances minimize the risk of obtaining undesirable side products and can thus increase yield.
The process can be effected in conventional manner for the introduction of an amidino group for example as described in Houben-Weyl, Methoden der organischen Chemie, Bd. XV/1, S. 531 ff. Examples of suitable guanylating agents are S-alkylisothioureas,
1-pyrazolecarboxamidino(hydrochloride),
1-amidino-3,5-dimethylpyrazole. The reaction may be carried out in solvent inert under the reaction conditions such as pyridine, dimethylformamide, chloroform or mixtures thereof.
Temperatures lie for example between room temperature and elevated temperature e.g. 65° to 80°C. Suitable protecting groups for use in the process are those known for this purpose in the art such as benzyloxycarbonyl, tert.butyloxycarbonyl, or trichloro ethyloxycarbonyl. 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 potential amino groups such as those represented by Z in the formula VII are azido, benzyl oxycarbonylamino, tert.butyloxycarbonylamino, phthalimido and succinimido which can be converted into the free amine in conventional manner such as herein after described in the examples.
The starting materials of formula VII wherein represents a group of the formula are in part new and can be prepared for example by reacting the corresponding compound of formula VII wherein represents hydrogen and the amino groups are protected with an appropriate protecting group with a compound of formula or wherein X, Z and n are as defined above and Y represents a leaving group such as halogen particularly chlorine or bromine N-succini-midoxy, N-phthalimidoxy, P-nitrophenoxy, 1-benzotriazolyloxy or imidazolyl.
This reaction can be carried out in conventional manner for example in an inert solvent such as chloro form, dimethylformamide or tetrahydrofurane at room temperature or raised temperature preferably at room temperature.
The remaining starting materials are either known or can be prepared according to known methods.
The compounds can be isolated and purified by conventional methods.
Compounds of the formula I may be converted in conventional manner into their acid addition salts and vice versa.
The compounds of formula I exhibit chemotherapeutic activity. In particular they exhibit 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. epidermis, Strept. faecalis, Pseudomonas aeruginosa, E.coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Shigella dysenteriae, Shigella sonnei, Shigella flexneri, Enterobacter verogenes, Enterobacter cloacal, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneumonias, Serratia marcescens, Salmonella typhimurium and Salmonella heidelberg. This activity is observed in vitro at concentrations between ca. 0.1 to 50 μg/ml and in vivo at between ca. 0.4 and 100 mg/kg animal body weight. The compounds may therefore be used as anti bacterially active antibiotics.
For this use, the effective dosage will, of course, vary depending on the particular compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results can be obtained when the compounds are administered at a daily dosage of from about 2 to 30 mg/kg of animal body weight, suitably given in divided doses two to four times daily. For most large mammals, the total daily dosage is from about 0.1 to 2 g and dosage forms suitable for internal administration comprise about 25 to 1500 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.
The compounds may be used in free base form or in the form of chemotherapautically acceptable acid addition salts e.g. as the hydrochloride. 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 comnositions also form part of the invention. Examples of particular compound groups are those wherein a) when R = R' = H
R1 = a group of formula lI or Ila
R3 = guanidino
R6 = NH2, NHCH3
R2 = R8 = R9 = H
R4, R5 = H or OH
or when R + R' = additional bond
R1 = a group of formula Ila
R3 = guanidino
R6 = NH2, NHCH3 R4 = R5 = R8 = R9 = H;
or b) when R = R' = H
R3 = OH, NH2 R4 , R5 = H , OH
R6 = NH2 , NHCH3
or when R + R' = additional bond in addition
R2 = H
R4 = R5 = H; or c) when R = R ' = H R3 = OH, NH2 R4, R5 = H , OH
R6 = guanidino
R7 = R8 = R9 = H or when R + R ' = additional bond in addition R2 = H
R4 = R5 = Η ; and acid addition salts thereof. Examples of preferred compound groups for the indicated use are those derived from gentamycin or kanamycin, particularly gentamycin C1, C1a and C2 and kanamycin A, whereby compounds are particularly preferred wherein one amidino group is in the 1-, 2'- or 6'-N-pcsition in the molecule or in the exposition of a side chain when present as R9; and chemotherapeutically acceptable acid addition salts thereof.
Preferred single compounds are
2'-N-amidinogentamycin C1 and 2'-N-amidinogentamycin C1a or a chemotherapeutically acceptable acid addition salt thereof in particular e.g. the hydrochloride thereof.
The following examples illustrate the invention. All temperatures are in degrees centigrade. The following eluants are used: I = Chloroform/methanol/conc.ammonia 15/4/1 II = Chloroform/methanol/conc.ammonia 1/1/1 III = Chloroform/methanol/25% ammonia 1/2/2 IV = Chloroform/methanol/25% ammonia 2/2/1 V = Chloroform/methanol/25% ammonia 1/1/1 VI = Chloroform/methanol/33% ammonia 1/2/2 VII = Chloroform/methanol/25% ammonia 15/4/1 VIII = Chloroform/methanol/25% ammonia 70/21/9 IX = Chloroform/methanol/33% ammonia 15/4/1
X = Chloroform/methanol/25% ammonia 2/1/1 XI = Chloroform/methanol/conc. ammonia 9/1/0.2 XII = Chloroform/methaήol/conc. ammonia 17/3/0.4 XIII = Chloroform/methanol/25% ammonia 9/1/0.2 XIV = Chloroform/methancl/25% ammonia 17/3/0.4
XV = Chloroform/methanol 8/2
XVI = Chloroform/methanol/33% ammonia 17/3/0.4
EXAMPLE 1 : 2' -N-amidinogentamycin C1 (hydrochloride)
2.2 g. of 1,3,6',3"-tetra-N-tert.butoxy carbonyl gentamycin C1 and 0.73 g of 1-pyrazolecarboxamidino hydrochloride are dissolved in 50 ml of pyridine and heated for 15 hours at 75°. The resulting solution is concentrated to dryness on a rotary evaporator and the residue chromatographed over Kieselgel (eluant I) . A thin-layer chromatographically (TLC) pure product RF = 0.37 (eluant I) is obtained. This is dissolved in 5 ml of trifluoroacetic acid and after 5 minutes treated with 200 ml of ether. The precipitated trifluoroacetate is converted to the hydrochloride in a basic ion-exchanger (Amberlite IRA 400, Cl--form). A TLC-pure product is obtained. RF = 0.15 (eluant II - lower phase) compound No. 1. C-13-NMR: 157,3 101,7 (1"); 97,1 (1'); 84,5
(6); 77.8 (4); 75,5 (5) ; 70,7 (4"); 70,0 (5'); 68,7
(5"); 67,0 (2"); 64,3 (3"); 58,8 (6'); 50,8, 50,4,
49,9 (1,3,2'); 35,4 (7") ; 32,1 (8'); 28,5 (2); 23,8 (4'); 22,9 (3'); 21,9 (6"); 11,0 (7'). EXAMPLE 2 : 6'-N-amidinoσentamycin Cla (hydrochloride)
1.7 g of 1,3,2',3"-tetra-N-tert.butoxy carbonylgentamycin C1a are dissolved in 20 ml of absolute pyridine, added to 590 mg of 1-pyrazolecarboxamidinohydrochloride and the resulting solution heated to 75°. After 2 hrs. the pyridine is evaporated in vacuo and the residue chromatographed over Kieselgel (eluant VII) .
The product thus obtained is reacted with 5 ml of trifluoroacetic acid and after 7 minutes diluted with 20 ml ether. The resulting precipitate is dissolved in methanol and converted to the hydrochloride in an ion-exchanger (Amberlite 401S, Cl--form). RF = 0.37 (eluant III) compound No. 2. EXAMPLE 3 : 6'-N-amidinokanamvoin A (hydrochloride)
0.7 g of 1,3,3"-tri-N-tert.butoxycarbonyl kanamycin A and 0.26 g 1-pyrazoϊecarbcxamidine hydrochloride are dissolved in 30 ml of pyridine and heated at 70° for 18 hrs. The solvent is removed in a rotary evaporator and the residue chromatographed on Kieselgel (eluant VII). A TLC-pure amorphous product is obtained RF = 0.48 (eluant IV).
This is dissolved in 10 ml of trifluoroacetic acid and after 7 minutes treated with 100 ml ether. The resulting precipitate is dissolved in methanol and converted to the hydrochloride in an ion-exchanger (Amberlite 401S, Cl--form). RF = 0.13 (eluant III) compound No. 3. EXAMPLE 4 : 1-N-amidinogentamycin C1a (hydrochloride)
1.88 g of 3,2',6'-tri-N-tert.butoxy carbonyl gentamycin C1a and 730 mg of 1-pyrazolecarboxamidino hydrochloride are dissolved in 30 ml of pyridine and the solution heated for 3 hrs. at 75°.
The solvent is removed in vacuo and the resulting residue chromatographed over Kieselgel (eluant VIII) . A TLC-pure product is obtained. RF = 0.28 (eluant V - lower phase).
950 mg of this product are dissolved in 3 ml trifluoroacetic acid. After 7 minutes 50 ml ether are added and the resulting precipitate filtered off. This is dissolved in methanol and filtered over a column containing a basic ion-exchanger (Amberlite IRA 401S, Cl--form). Evaporation of the solvent yields the hydrochloride as a white amorphous powder. RF = 0.33 (eluant III) compound No. 4.
C-13-NMR: 157,8 (N-C=N) ; 99,4 (l"); 95,7 (l'); 82,4 (6); 78,2 (4); 75,1 (5) ; 70,7 (4"); 68,2 (5") ; 66,8 (2" ); 66,7 (5'); 65,0 (3"); 51,6 (2'); 49,7 (1,3);
43,5 (6'); 36,0 (7"); 31,3 (2); 26,1 (4'); 22,0 (6"); 21,4 (3'). EXAMPLE 5 : 1-N-amidinogentamycin C2 (hydrochloride)
1.9 g of 3,2',6'-tri-N-tert.butoxy carbonylgentamycin C2 and 730 g of 1-pyrazolecarboxamidinohydrochloride are reacted analogously to Example 4. RF = 0.48 (eluant V - lower phase).
The resulting product is de-protected analogously to Example 4 and converted into its hydrochloride. The compound is TLC-pure. RF = 0.47 (eluant III) compound No. 5. C-13-NMR: 157.8 (N-C=N) ; 99,4 (l"); 96,3 (I'); 82,4 (6); 78,7 (4); 75,1 (5); 70,6 (4") ; 70,0 (5'); 68,2 (5"); 67,0 (2"); 66 , 6 (3"); 51,6, 50,5, 49,7 (6,,1,3,2,); 35,8 (7"); 31,3 (2); 23,0 (4'); 21,9 (6"); 21,4 (3') ; 13,5 (7'). EXAMPLE 6 : 1-N-amidinogentamycin C1 (hydrochloride)
1.95 g of 3,2',6'-tri-N-tert.butoxy carbonylgentamycin C1 and 730 mg of 1-pyrazolecarboxamidinohydrochloride are reacted analogously to Example 4 to yield on chromatography a TLC-pure product. RF = 0.28 (eluant V-lower phase).
The product thus obtained is reacted as described in example 4. The TLC-pure hydrochloride thus obtained has RF = 0.43 (eluant III). C-13-NMR: 157,8 (N-C=N) ; 99,3 (l"), 96,2 (l'); 82,4
(6); 78.4 (4); 75,1 (5) ; 70,6 (4"); 70,1 (5'); 68,2
(5"); 66 , 6 (2"); 64,9 (3"); 58,6 (6'); 51,6 (2'); 49,7
(1,3); 35,9 (7"); 32,1 (8'); 31,3 (2); 23,2, 21,4 (4' ,3'6"); 10,9 (7').
EXAMPLE 7 : 1-N-(2-guanidinoethoxycarbonyl)-gentamvcin C 1a (base and hydrochloride)
1.9 g of 1-N-(2-aminoethoxycarbonyl)-3,2',6',3"- tetra-N-tert.butoxy carbonylgentamycin C1a are dissolved in 60 ml of absolute pyridine and the solution reacted with 0.6 g 1-pyrazolecarboxamidinohydrochloride. After heating for 15 hrs. at 75° the pyridine is distilled off and the residue purified by column chromatography. A TLC-pure amorphous product is obtained. RF = 0.39 (eluant IX) .
1.3 g of the 1-N-(2-guanidinoethoxy carbonyl)-3,2',6',3"-tetra-N-tert.butoxy carbonylgentamycin C1a thus obtained are dissolved in 5 ml of trifluoro acetic acid and after 7 mins. poured into 50 ml ether. The precipitate is filtered under suction, dissolved in methanol and converted to the hydrochloride in a basic ion-exchanger (Amberlite IRA 401S , C1--form). The product is TLC-pure. RF = 0.47 (eluant VI). 93.6° (c = 1.3 in water) compound No. 7. C-13-NMR (free base) : 158,25 (CO, C=NH) ; 99,03 (1') ;
98.73 (1") ; 84,65 (4) ; 81,89 (6) ; 75,54 (5) ; 72,12 (4"); 68,53, 68,29, 67,69 (2" ,5' ,5") ; 64,57 (3") ; 64,27 (CH2O) ; 51,80 (2') ; 50,19, 49,89 (1,3) ; 44,37 (6'); 41,38 (CH2N) ; 36,95 (7") ; 35,62 (2); 27,41 (4') ;
24,47 (3') ; 22,38 (6") .
C-13-NKR (hydrochloride) : 158,07 (CO, C=NH) ; 98,79 (l"); 95,56 (l'); 81,ll (6); 78,18 (4); 75,18 (5);
70.74 (4"); 67,81, 66,79 (5" ,2" ,5') ; 64,93 (3"); 64,27 (CH2O) ; 50,97 (2'); 49,83, 49,59 (1,3); 43,47 (6');
41,31 (CH2N) ; 35,86 (7"); 31,67 (2); 26,15 (4');
21,90, 21, 30 (6", 3').
EXAMPLE 8 : 1-N-(2-guanidincethoxycarbonyl)-gentamycin C2 (hydrochloride)
The title product may be obtained analogously to
Example 7 as a TLC-pure substance. RF = 0.53 (eluant
VI). = 96.4° (c = 1.2 in water) compound No. 8.
EXAMPLE 9 : 1-N-(2-aminoethowcarbonvl)-2'-N-amidino gentamycin C1 (hydrochloride)
1 g of 1-N-[2-(benzyloxycarbonylamino)-ethoxycarbonyl]-3,6',3"-tri-N-tert.butoxy carbonylgentamycin C1 and 0.6 g of 1-pyrazolecarboxamidinohydrochloride are dissolved in 5 ml of pyridine and heated for 50 hrs. at 70°. The solvent is then removed on a rotary evaporator and the residue chromatographed over Kieselgel (eluent VII) . A TLC-pure product is obtained. RF = 0.20 (eluant VII).
0.65 g of this product are dissolved in 5 ml of methanol mixed with 20 ml of a 20% solution of ammonium formate in methanol/water (8/2) and 100 mg of Pd/C and the solution boiled for 5 mins . The methanolic solution is concentrated on a rotary evaporator and the residue dissolved in 7 ml of trifluoroacetic acid and after 7 minutes treated with 200 ml ether. The resulting precipitate is dissolved in methanol and filtered over a ion-exchanger column (Amberlite IRA 401S , Cl--form). The filtrate is concentrated to about 10 ml and treated with 200 ml ether. The product is obtained as a TLC-pure amorphous powder. RF = 0.34 (eluant IV) compound No. 9. EXAMPLE 10 : 1-N-(2-guanidinoethoxycarbonyl)-2'-N- amidinogentamycin C1 (hydrochloride)
1.38 g of 1-N-(2-aminoethoxycarbonyl)-3,6',3"—tri-N-tert.butoxycarbonylgentamycin C1 and 1.38 g of pyrazolecarboxamidinohydrochloride are dissolved in 50 ml of pyridine and heated for 40 hrs. at 70°. After evaporation of the solvent on a rotary evaporator the residue is chromatographed over Kieselgel (eluant VIII) . RF = 0.40 (eluant VIII). 0.83 g of this product are dissolved in 10 ml of trifluoroacetic acid and worked up analogously to Example 9 to yield a TLC-pure product. RF = 0.12 (eluant III) compound No. 10.
EXAMPLE II : 2'-N-amidinogentamycin C1a (hydrochloride)
2.3 g of 6'-N-benzyloxycarbonylgentamycin C1a and 1.16 g of 1-pyrazolεcarboxamidinohydrochloride are dissolved in 50 ml of pyridine. After heating for 50 hrs. at 70° the solvent is removed by distillation and the residue chromatographed over Kieselgel (eluant VIII). A TLC-pure amorphous product is obtained. RF = 0.47 (eluant IV) .
0.52 g of the 6'-N-benzyloxycarbonyl-2'-amidinogentamycin Cla are dissolved in 30 ml methanol and 10 ml 10% aqueous acetic acid and hydrated over palladium black at 20° and 3 atmospheres. After filtering off the catalyst the solvent is removed by distillation, the residue dissolved in methanolic hydrochloric acid (pH = 3) and filtered over an ion-exchanger column (Amberlite IRA 401S. Cl--form).
The filtrate is concentrated to 5 ml and the product precipitated by addition of ether. The product is TLC-pure. RF = 0.11 (eluant IV) compound No. 11. C-13-NMR : 157,4 101,9 (1") ; 96,6 (l') ; 84,6
(6); 77,4 (4) ; 75,5 (5) ; 70,8 (4") ; 68,8 (5") ; 67,1 (2") ; 66,6 (5') ; 64,2 (3") ; 50,6 (1,2') ; 49,8 (3) ; 43,7 (6'); 35,6 (7") ; 28,6 (2) ; 26,9 (4') ; 22,9 (3') ; 21.9 (6").
EXAMPLE 12 : 6'-N-amidinogentamycin Cla
5.4 g of gentamycin Cla and 3.6 g of 1-pyrazole carboxamidinohydrochloride are dissolved in 120 ml of chloroform and 30 ml of pyridine. This solution is heated for 20 hrs. at 70°. After cooling the precipitate is filtered off, dissolved in methanol and again precipitated by the addition of ether. This precipitate is chromatographed over Kieselgel v:ith 5% aqueous acetic acid. A product is obtained which is TLC-pure, the same as that in Example 2 and which can be converted to its hydrochloride as described therein. EXAMPLE 13 : 2'-N-amidinogentamycin Cl
0,48 g of gentamycin C1 and 0.3 g 1-pyrazolecarboxamidinohydrochloride are dissolved in 5 ml of chloroform and 5 ml of pyridine and the solution refluxed for 40 hrs. After cooling the precipitate is filtered and chromatographed over Kieselgel with 5% aqueous acetic acid. A product is obtained which is TLC-pure the same as that in Example 1 and which can be converted to its hydrochloride as described therein.
The required starting materials can be prepared for example as follows: A) 1,3,6',3"-tetra-N-tert.butoxy carbonylgentamycin C1 (for Example 1)
8.5 g of gentamycin C1 are dissolved in 100 ml methanol cooled to 40° and slowly reacted with a solution of 2.9 g of in 20 ml of methanol. After three hrs. a solution of 17.3 g di-tert.butyldicarbonate in 20 ml of methanol is added dropwise. After 35 hrs. at 20° an equal volume of 3.3 % ammonia is added and after 15 hrs. the solution evaporated to dryness on a rotary evaporator. Column chromatography over Kieselgel (eluant XI) yields a TLC-pure product. RF = 0.26 (eluant XII).
B) 1,3,2',3"-tetra-N-tert.butoxy carbonylgentamycin C1a
(for Example 2) a) 6'-N-benzybxycarbonylgentamcyin C1a
4.5 g of gentamycin Cla are dissolved in 100 ml methanol and cooled to -10°. To this solution 3.1 g of N-benzylcarbonyl-5-norbornene-2,3-dicarbonic acid imide in 50 ml methanol and 10 ml chloroform are slowly added dropwise. After 1/2 hour the solvent is removed in vacuo and the residue chromatographed over Kieselgel. RF = 0.37 (eluant VII). b) 1,3,2 ,3"-tetra-N-tert.butoxy carbonylgentamycin C1a
2.3 g of 6'-N-benzykxycarbonylgentamycin C1aare dissolved in 50 ml of methanol and 3.6 g of di-tert. butyldicarbonate in 30 ml methanol added. After 4 hrs. the reaction, which is checked by TLC , is completed.
RF = 0.58 (eluant XIII).
The solution is then treated with 50 ml of a 20% ammonium formate solution and 500 mg 10% Pd/active charcoal added.
The reaction mixture is boiled for 3 minutes, filtered, the solvent removed in vacuo and the residue dissolved in water. This solution is extracted three times with ethylacetate and the combined extracts dried over sodium sulphate and the solvent removed in vacuo. A TLC-pure product is obtained.
RF = 0.25 (eluant XIII).
C) 1,3,3"-tri-N-tert.butoxycarbonylkanamycin A (for Example 3) a) 6'-N-benzyloxycarbonyl-1,3,3"-tri-N-tert.butoxy carbonylkanamycin A
1 g of 6 ' -N-benzylcarbonylkanamycin A is dissolved in 50 ml methanol water (1/1) and reacted with 1. 27 g of di-tert.butyldicarbonate and 1 ml of triethylamine. Stirring is carried out for 20 hrs. at room temperature during which time white jelly-like precipitate forms. After dilution with water the TLC-pure precipitate is filtered off. RF = 0.42 (eluant XV) .
b) 1,3,3"-tri-N-tert.butoxycarbonylkanamycin A
1 g of the product obtained as des cribed under a) is dissolved in methanol/10% aqueous acetic acid (5/1) and hydrated at 20° and 3 atmospheres with Pd/C. The TLC-pure product obtained after filtration and evaporation has an RF of 0.77 (eluant III).
D) 1-N-(2-aminoethoxycarbonyl)-3,2',6',3"-tetr-a-N- tert.butoxy carbonylgentamycin C1a (for Example 7)
a) N-(2-Azidoethoxycarbonyloxy)phthalimide
5.41 g of N-(chlorocarbonyioxy)phthalimide are added to a solution of 1,74 g of 2-azidoethanol in 100 ml of ethanol-free chloroform and 10 ml of pyridine. The solution stirred overnight and then extracted with NaHCO3 solution, dried over Na2SO4 and the solvent distilled off. A crystalline residue is obtained which can be employed directly in the next step. b) 3,2',6'-tri-N-tert.butoxy carbonylgentamycin Cla
Is obtained analogously to Example E/a) (q.v.) m.p. 215-217° RF = 0.31 (eluant XIV).
c) 1-N-(2-azidoethoxycarbonyl)-3,2',6'-tri-N- tert.butoxy carbonylgentamycin Cla
A solution of 4,56g of N-(2-azidoethoxycarbonyloxy)- phthalimide in 50 ml of chloroform is added dropwise at room temperature to a solution of 11.23 g of 3,2',6'- tri-N-tert.butoxy carbonylgentamycin Clain 200 ml of ethanol-free chloroform. After 7 hrs. the solution is extracted with NaHCO3 solution and after evaporation on a rotary evaporator the amorphous residue is purified by column chromatography. A TLC-pure product is obtained. RF = 0.35 (eluant XV). d) 1-N-(2-aminoethoxycarbonyl)-3,2',6',3"-tetra- N-tert.butoxy carbonylgentamycin Cla
1.85 g Di-tert.butyldicarbonate dissolved in 20 ml of methanol are added dropwise at room temperature to 7.3 g of 1-N-(azidoethoxycarbonyl)-3,2',6'-tri-N-tert.butoxy carbonylgentamycin Cla. After reaction is complete [RF = 0,45 in chloroform/methanol (10/1)] 200 mg of 10% Pd/active charcoal are added and the suspension reduced at room temperature with hydrogen. After completion of the reduction the catalyst is filtered off and the residue obtained after evaporation on a rotary evaporator is purified by column chromatography on Kieselgel. A TLC-pure product is obtained. RF = 0.2 (eluant XV).
E) 1-N-(2-aminoethoxycarbonyl)-3,2',6',3"-tetra-N-tert.- butoxy carbonylgentamycin C2 (for Example 8)
a) 3,2',6'-tri-N-tert.-butoxy carbonylgentamycin C2
232 g of gentamycin C2 and 439 g of Zn (OCOCH3) 2.H2O are dissolved in 8 litres of isopropanol. After one hour 392 g of di-tert.butyldicarbonate dissolved in isopropanol are added and the reaction mixture heated for 20 hrs at 50°. The solution is then evaporated on a rotary evaporator and the residue taken up in 10 litres of 2N-ammonia. The aqueous phase is extracted six times with 1.5 litres of ethylacetate each. The combined organic phases are washed with saturated NaHCO3 solution,
10% KHSO4 solution and water and dried over Na2SO4.
After evaporation of the solvent the residue is digested with acetonitrile to produce a crystalline product m.p. 254-256°. The product is TLC-pure. RF= 0.34 (eluant XIV) . Further product can be obtained from the mother liquor by chromatography over Kieselgel (eluant XIII). b) 1-N-(2-azidoethoxycarbonyl)-3,2',6'-tri-N-tert. butoxy carbonylgentamycin C2
38.2 g of 3,2',6'-tri-N-tert.butoxy carbonylgentamycin C2 are dissolved in 300 ml of chloroform and after addition of 5.6 g of triethylamine 7.5 g of azidoethoxycarbonylchloride are dissolved in 100 ml chloroform and slowly dropped in at 0° . After 15 hrs. at 20° the solution is evaporated in vacuo. A colourless foam is obtained (RF = 0.27 - eluant XV) which can be used directly in the next step. c) 1-N-(2-azidoethoxycarbonyl)-3,2',6',3"-tetra-N- tert.butoxy carbonylgentamycin C2
The product obtained as described under b) is dissolved in 100 ml of chloroform and diluted to one litre with methanol. After addition of a strongly basic ion-exchanger (Merck III, OH--form) the solution is reacted with 13 g of di-tert.butyldicarbonate and the suspension stirred for 15 hrs. After filtering the solvent is evaporated off to yield a colourless foam. RF = 0.9 (eluant XV) which can be used directly in the next step. d) 1-(2-aminoethoxy carbonyl)-3,2',6',3"-tetra-N- tert.butoxy carbonylgentamycin C2
3 g of the product obtained as described under c) are dissolved in 100 ml of a solution of 200 g ammonium formate in 200 ml of water and 800 ml methanol, mixed with 300 mg Pd-C (10%) and refluxed for 1.5 hrs. After filtration the solvent is evaporated off and the residue chromatographed over Kieselgel (eluant XVI). A
TLC-pure foam is obtained. RF = 0.2 (eluant XV) . F) 1-N-[2-(benzyloxycarbonylamino)-ethoxycarbonyl]- 3,6',3"-tri-N-tert.butoxy carbonylgentamycin C1 (for Example 9)
a) 3,2',6'-tri-N-tert.butoxy carbonylgentamycin C1
Analogous to E/a) TLC-pure amorphous product RF = 0.3 (eluant XIV). b) 3,2',6'-tri-N-tert.butoxycarbonyl-1-N-[benzyloxycarbonylamino)-ethoxycarbonyl]-gentamycin C1
31.1 g 3,2',6'-tri-N-tert.butoxy carbonylgentamycin C1 and 5 g of triethylamine are dissolved in 200 ml of chloroform and slowly mixed with a solution of 15.4 g of N-[2-(benzyloxycarbonylamino) ethoxycarbonyloxy]phthaiimide in 100 ml of chloroform. After 20 hrs. at 20° the mixture is repeatedly washed with NaHCO3 solution. The product obtained on rotary evaporation can be purified by chromatography over Kieselgel (chloroform/methanol - 10/1). RF = 0.42 (eluant XV) .
c) 1-N-[2-(benzyloxycarbonylamino)ethoxycarbonyl]- gentamycin C1
31.1 g of 3,2',6'-tri-N-tert.butoxycarbonyl-1-N- [benzyloxycarbonylamino) ethoxycarbonyl] gentamycin C1 are dissolved in 60 ml of trifluoroacetic acid and after 10 minutes mixed with one litre ether. The resulting precipitate is sucked off, dissolved in water and chromatographed over a column (Amberlite CG-50(NH4 +)) with water and 0.3 N-ammonia. The fractions reacting positively to ninhydrine are combined and lypholised. A TLC-pure amorphous foam is obtained. RF = 0.73 (eluant V) .
d) 1-N-[2-(benzyloxycarbonylamino) ethoxycarbonyl]- 2'-N-trifluoroacetylgentamycin C1
22.6 g of 1-N-[2-(benzyloxycarbonylamino)ethoxycarbonyl]gentamycin C1 are dissolved in 1.2 litres of methanol and slowly mixed at -10° with a solution of 4.1 ml of CF3COSC2H5 in 15 ml of methanol. The solution is kept at 20° for 20 hrs. the reaction being followed by TLC. The reaction product has an RF = 0.57, (eluant VII) . The resulting solution can be used directly in the next step. e) 1-N-[2-(benzyloxycarbonylamino)ethoxycarbonyl]- 3,6',3"-tri-N-tert.butoxy carbonylgentamycin C1
The solution obtained as described under d) is mixed at 20° with 23 g of di-tert.butyldicarbonate and stirred for 4 hrs. The solution is then diluted with one litre 25% ammonia and stirred for 20 hrs. at 20°.
The reaction mixture is then diluted further with water, the methanol removed in vacuo and the aqueous phase repeatedly extracted with ethylacetate. After washing with saturated NaHCO, solution and 0.5 N-hydrochloric acid the solution is rotary evaporated and the residue chromatographed over Kieselgel (eluant XIII) .
The product is TLC-pure. RF = 0.40 (eluant XIV). G) 1-N-(2-aminoethoxycarbonyl)-3,6',3"-tri-N-tert.- butoxy carbonylgentamycin C1 (for Example 10)
1.5 g of 1-N-[2-(benzyloxycarbonylammo) ethoxycarbonyl]-3,6',3"-tri-n-tert.butoxy carbonyl gentamycin C1 are dissolved in 10 ml of methanol, mixed with 20 ml of 20% ammonium formate solution in methanol/water (8/2) and 200 mg Pd-C and boiled for 5 minutes.
After filtration the solution is rotary evaporated, the residue taken in water and neutralised to pH 9 with ammonia. Extraction with ethylacetate produces a TLC-pure product. RF = 0.23 (eluant XIV).
Formulae as referred to in the specification and claims (examples of numbering given).

Claims

We claim:
1. A guanylated aminoglycoside.
2. A guanylated aminoglycoside of formula I
(as hereinbefore shown with all other formulae) wherein
R1 represents hydrogen or a group of the formulae II, Ila, lIb, lIe, lId;
R2 represents hydrogen or a group of the formula III or IlIa, whereby at least one of R1 or R2 represents hydrogen; R3 represents hydroxy or the group -NHR8; either R4 and R5 represent independently hydrogen or hydroxy and R and R' represent hydrogen or R4 and R5 represent hydrogen and R and R' represent
an additional bond; R6 represents hydroxy, the group -NHR8 or the group -N(CH3)R8; R7 represents hydrogen or methyl; R8 represents hydrogen or amidino; R9 represents hydrogen, amidino or the group
R10 represents hydrogen or a group of formula
IV or IVa; R11 represents hydrogen or a group of formula V; X represents oxygen or imino and n represents a whole number from 2 to 5 whereby at least one and not more than two amidino groups are present in the molecule, or an acid addition salt thereof.
3. A compound as claimed in Claim 1 wherein
when R = R' H R1 = a group of formula II or Ila R3 = - guanidino R6 = NH2, NHCH3
R2 = R8 = R9 = H R4, R5 = H or OH
or when R + R' = additional bond R1 = a group of formula Ila R3 = guanidino R6 = NH2, NHCH3
R4 = R5 = R8 = R9 = H
4. A compound as claimed in Claim 1 wherein when R = R' = H R3 = OH, NH2
R4, R5 = H, OH R6 = NH2, NHCH3
or when R + R' = additional bond in addition
R2 = H R4 = R5 = H
5. A compound as claimed in Claim 1 wherein
when R = R' = H
R3 = OH, NH2
R4, R5 = H, OH R6 = guanidino R7 = R8 = R9 = H or when R + R' = additional bond in addition
R2 = H
R4 = R5 = H
6. A compound as claimed in Claim 1 which is derived from a gentamycin or a kanamycin.
7. A compound as claimed in Claim 6 which is derived from gentamycin C1, C1a or C2 or kanamycin A.
8. A compound as claimed in Claim 6 or 7 wherein the amidino group is in the 1-,2'-or 6'-N-position or in the w-position of a side chain when present as R9.
9. 2'-N-amidinogentamycin C1 or the hydrochloride thereof.
10. 2'-N-amidinoσentamycin C1a or the hydrochloride thereof.
11. A method of combatting bacteria comprising administering to a subject in need of such treatment an effective amount of a compound of formula I stated in
Claim 1, or a chemotherapeutically acceptable acid addition salt thereof.
12. A pharmaceutical composition comprising a compound of formula I, stated in Claim 1, or a chemotherapeutically acceptable acid addition salt thereof, in association with a chemotherapeutically acceptable diluent or carrier.
13. A process for preparing a compound as claimed in Claimlwhich comprises guanylating an aminoglycoside which contains at least one free amino group optionally together with potential or protected amino groups and if required converting in a compound thus obtained any potential amino groups present to amino groups and deprotecting protected amino groups present.
14. A process for preparing a compound of formula I as defined above which comprises guanylating a corresponding compound of formula VII wherein
represents hydroxy or amino; represents hydroxy, amino or methylamino; represents hydrogen or the group Z represents an amino group or a potential amino group and R, R', R1 , R2, R4, R5, R7, X and n have the meanings given above whereby one or more of the amino groups can be protected with a suitable amino protecting group and if required converting in the product obtained any potential amino groups present to amino groups and deprotecting any protected amino groups present.
EP81902303A 1980-07-28 1981-07-16 Guanylated aminoglycosides, a process for their production and their use as pharmaceuticals Withdrawn EP0056408A1 (en)

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WO2011044501A2 (en) 2009-10-09 2011-04-14 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8318685B2 (en) 2010-11-17 2012-11-27 Achaogen, Inc. Antibacterial aminoglycoside analogs
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