WO1982000464A1 - 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 Download PDF

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Publication number
WO1982000464A1
WO1982000464A1 PCT/EP1981/000100 EP8100100W WO8200464A1 WO 1982000464 A1 WO1982000464 A1 WO 1982000464A1 EP 8100100 W EP8100100 W EP 8100100W WO 8200464 A1 WO8200464 A1 WO 8200464A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
amino groups
represents hydrogen
Prior art date
Application number
PCT/EP1981/000100
Other languages
English (en)
French (fr)
Inventor
Ag Sandoz
Original Assignee
Loibner H
Streicher W
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Loibner H, Streicher W filed Critical Loibner H
Publication of WO1982000464A1 publication Critical patent/WO1982000464A1/en

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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)
PCT/EP1981/000100 1980-07-28 1981-07-16 Guanylated aminoglycosides,a process for their production and their use as pharmaceuticals WO1982000464A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CH5756/80 1980-07-28
CH575680 1980-07-28
CH7778/80801017 1980-10-17
CH777880 1980-10-17
CH184281 1981-03-18
CH1842/81 1981-03-18

Publications (1)

Publication Number Publication Date
WO1982000464A1 true WO1982000464A1 (en) 1982-02-18

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PCT/EP1981/000100 WO1982000464A1 (en) 1980-07-28 1981-07-16 Guanylated aminoglycosides,a process for their production and their use as pharmaceuticals

Country Status (9)

Country Link
EP (1) EP0056408A1 (enrdf_load_stackoverflow)
JP (1) JPS57501084A (enrdf_load_stackoverflow)
CS (1) CS228516B2 (enrdf_load_stackoverflow)
GR (1) GR74312B (enrdf_load_stackoverflow)
IL (1) IL63429A0 (enrdf_load_stackoverflow)
IT (1) IT1171411B (enrdf_load_stackoverflow)
PT (1) PT73428B (enrdf_load_stackoverflow)
WO (1) WO1982000464A1 (enrdf_load_stackoverflow)
YU (1) YU184481A (enrdf_load_stackoverflow)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7893039B2 (en) 2005-12-02 2011-02-22 Isis Pharmaceuticals, Inc. Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
EP2315802A4 (en) * 2008-07-31 2012-04-18 3M Innovative Properties Co AZIUM COMPOSITIONS AND METHOD FOR THEIR PREPARATION AND USE
US8288005B2 (en) 2008-07-31 2012-10-16 3M Innovative Properties Company Fluoropolymer compositions and method of making and using thereof
US8318685B2 (en) 2010-11-17 2012-11-27 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8367625B2 (en) 2008-10-09 2013-02-05 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8372813B2 (en) 2008-10-09 2013-02-12 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8377896B2 (en) 2008-09-10 2013-02-19 Isis Pharmaceuticals, Inc Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs
US8399419B2 (en) 2008-09-10 2013-03-19 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8481502B2 (en) 2009-10-09 2013-07-09 Achaogen, Inc. Antibacterial aminoglycoside analogs
CN116462721A (zh) * 2023-04-18 2023-07-21 江南大学 抗菌性氨基糖苷衍生物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2321296A1 (fr) * 1975-08-21 1977-03-18 American Cyanamid Co Nouveaux antibiotiques denommes bm-123 et leur procede de preparation
FR2412560A1 (fr) * 1977-12-21 1979-07-20 Kyowa Hakko Kogyo Kk Nouveaux derives de la fortimicine a et procede pour les preparer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2321296A1 (fr) * 1975-08-21 1977-03-18 American Cyanamid Co Nouveaux antibiotiques denommes bm-123 et leur procede de preparation
FR2412560A1 (fr) * 1977-12-21 1979-07-20 Kyowa Hakko Kogyo Kk Nouveaux derives de la fortimicine a et procede pour les preparer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 83, No. 21, issued November 24, 1975, (Columbus, Ohio, US), see page 622, Abstract No. 179513h, JP A, 7513789, 22nd May 1975, Institute of Microbial Chemistry *
The Merck Index, ninth edition, edited by MARTHA WINDHOLZ, published by Merck & Co. Inc., 1976 (Rahway, N.J., US), see page 1140, 8607 "Streptobiosamine" *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8114856B2 (en) 2005-12-02 2012-02-14 Isis Pharmaceuticals, Inc. Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
US8569264B2 (en) 2005-12-02 2013-10-29 Isis Pharmaceuticals, Inc. Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
US7893039B2 (en) 2005-12-02 2011-02-22 Isis Pharmaceuticals, Inc. Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
EP2315802A4 (en) * 2008-07-31 2012-04-18 3M Innovative Properties Co AZIUM COMPOSITIONS AND METHOD FOR THEIR PREPARATION AND USE
US8288005B2 (en) 2008-07-31 2012-10-16 3M Innovative Properties Company Fluoropolymer compositions and method of making and using thereof
US8399419B2 (en) 2008-09-10 2013-03-19 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8742078B2 (en) 2008-09-10 2014-06-03 Isis Pharmaceuticals, Inc. Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs
US8377896B2 (en) 2008-09-10 2013-02-19 Isis Pharmaceuticals, Inc Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs
US8372813B2 (en) 2008-10-09 2013-02-12 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8367625B2 (en) 2008-10-09 2013-02-05 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8481502B2 (en) 2009-10-09 2013-07-09 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8653041B2 (en) 2010-11-17 2014-02-18 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8318685B2 (en) 2010-11-17 2012-11-27 Achaogen, Inc. Antibacterial aminoglycoside analogs
CN116462721A (zh) * 2023-04-18 2023-07-21 江南大学 抗菌性氨基糖苷衍生物
CN116462721B (zh) * 2023-04-18 2024-02-02 江南大学 抗菌性氨基糖苷衍生物

Also Published As

Publication number Publication date
IT8148952A0 (it) 1981-07-22
YU184481A (en) 1983-09-30
PT73428B (en) 1983-01-13
GR74312B (enrdf_load_stackoverflow) 1984-06-22
IT1171411B (it) 1987-06-10
EP0056408A1 (en) 1982-07-28
CS228516B2 (en) 1984-05-14
JPS57501084A (enrdf_load_stackoverflow) 1982-06-24
PT73428A (en) 1981-08-01
IL63429A0 (en) 1981-10-30

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