IE43582B1

IE43582B1 - A new desoxystreptamine derivative and its salts, processes for preparing these compounds and pharmaceutical compositions containing them

Info

Publication number: IE43582B1
Application number: IE1639/76A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1975-07-23
Filing date: 1976-07-23
Publication date: 1981-04-08
Also published as: DK329876A; IL49900A; SE7606795L; LU75266A1; AU503819B2; DD126770A5; DE2630590C2; SE427461B; DK149186C; IE43582L; ATA545176A; ZA763895B; GB1502537A; AT344902B; JPS619318B2; ES450028A1; FR2318648B1; CH598281A5; SU656528A3; IL49900A0

Abstract

1502537 2 - Desoxy - streptamine derivatives ROUSSEL-UCLAF 23 July 1976 [23 July 1975] 30746/76 Heading C2C Novel N 1 - [L(-) - 2 - hydroxy - 4 - aminobutyryl] - 4 - O - [21,61 - diamino - 21,61 - didesoxy - α,D - glucopyranosyl] - 6 - O - [311- methylamino - 311,411,611 - tridesoxy - α,D- xylohexopyranosyl] - 2 - desoxystreptamine (I) and addition salts thereof with mineral or organic acids are prepared by reacting 4-O- [21,61 - diamino - 21,61 - didesoxy - α,D - glucopyranosyl] - 6 - O - [311 - methylamino - 311,411, 611 - tridesoxy - α,D - xylohexopyranosyl] - 2- desoxystreptamine with N - benzyloxycarbonyloxy-succinimide, reacting the resulting novel 4 - O - [21 - amino - 61 - benzyloxycarbonylamino - 21,61 - didesoxy - α,D - glucopyranosyl] - 6 - O - [311 - methylamino - 311,411, 611 - tridesoxy - α,D - xylohexopyranosyl] - 2- desoxystreptamine with the N-hydroxysuccinimide ester of L-(-)-γ-benzyloxycarbonylamino - α - hydroxy - butyric acid and catalytically hydrogenating the resulting novel N 1 - [L - (-) - 2 - hydroxy - 4 - benzyloxycarbonylamino - butyryl] - 4 - O - [21 - amino- 61 - benzyloxycarbonylamino - 21,61 - didesoxy- α,D - glucopyranosyl] - 6 - O - [311 - methylamino - 311,411,611 - tridesoxy - α,D - xylohexopyranosyl] - 2 - desoxystreptamine, followed optionally by salification with an appropriate acid. Pharmaceutical compositions having antibiotic activity comprise, as active ingredient, the compound (I) or a pharmaceutically acceptable mineral or organic acid addition salt thereof, in association with a suitable pharmaceutical vehicle.

Description

This invention relates to a new desoxystreptamine derivative and its salts, processes for preparing these compounds and pharmaceutical compositions containing them.

In one aspect this invention provides a new derivative of the aminoglycoside family - namely, - |T(-) - 2 - hydroxy - 4 - amino - butyryTJ- 4 - 0- {?,6' diamino - 2'.6 - didesoxy - a,D - glucopyranosylj - 6 - 0 - methylamino 3,4,6 - tridesoxy - a,D - xylohexopyranosyT| - 2 - desoxystreptamine of the formula: and acid addition salts thereof formed with mineral or organic acids.

The salts of the compound of formula I may be those obtained by either total or partial neutralisation of the five basic amino functions of the compound of formula I.

The preferred salts of the compound of formula I include the hydrochlorides, hydrobromides, nitrates, sulphates, phosphates, acetates, formates, benzoates, maleates, fumarates, succinates, tartrates, citrates, oxalates, benzilates, glyoxylates, aspartates, alkanesulphonates and aryisuiphonates.

This invention also provides a process for preparing the compounds of formula 5 I, in which the L(-)-compound of the formula OH (which also forms part of the present invention) is treated with hydrogen in the presence of a catalyst to obtain the desired compound of formula I.

The treatment of the compound of formula II with hydrogen is preferably 10 carried out in the presence of a metal catalyst and this catalyst is most preferably palladium, although platinum, Raney nickel, rhodium, nickel or ruthenium catalysts may also be used. The reaction is desirably carried out in a solvent, and the particularly preferred solvent is a mixture of water and a water-miscible solvent such as dioxan, although tetrahydrofuran, 1,2-dimethoxyethane or the dimethyl ether of propylene glycol may also be used.

The starting material of formula II is conveniently prepared by a precess in which the compound of the formula: -3>533 (III) (which also forms part of the present invention) is reacted with the L(-)-compound of the formula: to obtain the desired compound of general formula II.

The reaction of the compound of formulae III and IV is preferably carried out in a solvent. The solvent desirably comprises one or more of water, 1,2dimethoxyethane, dioxan, dimethylacetamide, dimethylformamide, tetrahydrofuran and the dimethyl ether of propylene glycol. A particularly preferred solvent system is a mixture of 1,2-dimethoxyethane and water.

The compound of formula III may in turn be prepared by a process in which the -410 compound of the formula: (VI) to obtain the desired compound of formula III, In a preferred method of preparing the compound of formula III the compounds of formulae V and VI are reacted in a solvent. The solvent desirably comprises one or more of dimethylformamide, water, dimethylacetamide, dioxan, tetrahydrofuran, pyridine, acetone, ethanol, methanol, and 1,2-dimethoxyethane and a particularly preferred solvent system is a mixture of dimethylformamide and water.

The compound of formula V is known and is described, together with its sulphate, in Patent Specification No. 40384.

This invention further provides a process for the preparation of acid addition salts of the compound of formula I in which the compound of formula I is reacted with an appropriate mineral or organic acid to form the desired acid addition salt.

This salification of the compound of formula I can be carried out by the usual methods as would be appreciated by one skilled in the art. Naturally the acid used is chosen having regard to the salt which is to be formed, but by way -515 3 5 3^ of illustration typical acids which may be used to form their corresponding salts include hydrochloric, hydrobromic, nitric, sulphuric, phosphonic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, benzilic, glyoxylic and aspartic acid, the alkanesulphonic acids and the arylsulphinic acids. The salification is also preferably carried out in one or more solvents, preferred solvents being water, and/or ethyl ether and/or methanol and/or acetone.

Naturally, the compound of formula I used in the salification is preferably prepared by a process as described and claimed herein.

The compound of formula I and its acid addition salts possess very interesting antibiotic activity, on the one hand against Gram-positive bacteria such as Staphylococci-especially the oenicillino-resistant Staphylococci-and StreDtoccocci, and on the other hand against Gram-negative bacteria-especially the coliform bacteria. These properties may make the compound of formula I, and its oharmaceutically-acceptable acid addition salts, suitable for use as medicaments especially in the treatment of staphyloccal infections such as staphylococcal septicaemia, malignant facial staphylococcal infections, staphyloccal skin infections pyodermatitis, septic and suppurating sores, anthrax , phlegmons, erysiplas, acute primary or post-influenza staphylcoccal infections, bronchopneumonia, pulmonary suppurations and colon-bacillus infections. The compounds may also be useful in the treatment of infections caused by Klebsiella, by Pseudomonas and by Enterobacter.

Before any of the compounds of this invention are used in medicine, they should preferably be formed into pharmaceutical compositions by association with suitable pharmaceutical vehicles. tl It is pointed out that the terms pharmaceutical and pharmaceuticaliyacceptable are used herein to exclude any possibility that the nature of the vehicle or acid addition salt, as appropriate, considered of course in relation to the route by which the compositions are intended to be administered, could be harmful.

Accordingly, in another aspect this invention provides pharmaceutical compositions containing, as active material, the compound of formula I and/or one or nore pharmaceuticaliy-acceptable mineral or organic acid addition salts thereof in association with a suitable pharmaceutical vehicle. -64 3 5 8 2 The choice of a suitable mode of presentation of the compositions, together with an appropriate vehicle, is believed to be within the comoetence of those accustomed to the preparation of pharmaceutical formulations.

However, by way of illustration, the compositions of this invention may be administered orally, topically (to the skin or mucous membranes), parenterally, transcutaneously or rectally, and in respect of these modes, the pharmaceutical vehicle is preferably:a) the ingestible excepient of a tablet, coated tablet, sublingual tablet or pill; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of granules or a powder; or the ingestible liquid medium of a syrup, solution, suspension or elixir, b) the solid or liquid medium of a naste, lotion, salve, ointment, cream, gel or unguent. c) a sterile injectable liquid solution or suspension medium, or d) a base material of low melting point capable of releasing the active ingredient to perform its pharmacological function, which base material when appropriately shaped forms a suppository.

The pharmaceutical vehicle may conveniently be or include one or more of the excipients conventionally employed in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives and glycols. The compositions may also contain one or more wetting, dispersing or emulsifying agents, and/or one or more preservatives.

The compounds of this invention may preferably be administered in the form of plain or sugar-coated tablets, gelatin capsules, granules, ointments, creams, gels, injectable solutions or suspensions disoensed in single-dose ampoules or multi-dose phials, or suppositories.

Whilst the dosages of the pharmacologically active ingredient to a certain degree depend upon the route by which the compositions are to be administered the complaint being treated and the subject concerned, nevertheless by way of general indication it may be said that the useful dose ranges from 100 mg to 1 g -743532 active material per day for an adult, when administered parenterally.

The compounds of formulae II and III are themselves new and in another aspect this invention provides these useful new intermediates per se. Thus, this invention provides the compounds of the general formula: wherein R represents a hydrogen atom or the L-(-)-radical The invention also provides processes for preparing the compounds of general formula VII as described herein, as well as the compounds when thus prepared.

The following Example and Formulation are now given, though only byway of illustration, to show details of certain aspects of this invention.

Example. ^1 - JT - - 2 - hydroxy -4- amino -butyrylj- 4 - 0 - (Τ',6' - diainino-2',6' didesoxy - a,D - glucopyrahosyl] - 6 - 0 - JT - methylamino - 3,46 tridesoxy · - a,D - xylohexopyranosylj - 2 - desoxystreptamine: Stage A: 4-0- ]?'-amino-6'-benzyl oxycarbonylamino -2',6'-didesoxy - a,D- glucopyranoxyl] - 6 - 0 - JT - methylamino - 3,4,6 - tridesoxy - a,D - xylohexopyranosyTJ - 2 - desoxystreptamine. -84 S 3 2 To 5.5 g of 4-0-J2*,6'-diamino-21 s61-didesoxy-asD-glucopyranosjj) methyl ami no-3,4,6-tri desoxy-a,D-xylohexopyranosyTJ-2-desoxystreptami ne dissolved in 58 cm of distilled water, 60 cnr of dimethylformamide were added at 20-25°C, The mixture was cooled to -5°C and 30.1 g of n-(benzyloxycarbonyloxy) succinimide in solution in 60 cm of dimethylformamide were slowly added, followed by agitation for 20 hours at -5°C, then for 24 hours at 20-25°C. The reaction mixture was then evaporated to dryness, taken up with water saturated with n-butanol, and washed with butanol saturated with water. The phases were evaporated to dryness-aqueous phase = 6.21 g; butanol phase = 2.82 g.

By chromatography on a layer of silica, eluting with a 4:4:1 chloroform: methanol:ammonia mixture, it was established that the aqueous phase was rich in expected product. This phase was purified using an ion exchange resin of the carboxylic type in NH4 form.

The crude product was fixed in aqueous solution, then eluted with 0.1 N dilute ammonia to yield 1.72 g of the desired product.

Stage B:N^}T-(-)-2-hydroxy-4-benzyloxycarbonylamino-butyryjJ -4-P-[2'-anrino-6'benzyl oxycarbony! ami no -2',6' - didesoxy - a,D - glucoxylohexopyranas^lj - 6 -O-jTmethylamino -3,4,6 - tridesoxy - a,D-xy1ohexopyranosylJ -2-desoxystreptamine.

A solution of 1.8 g of the product obtained in stage A in 14 cm of distilled water and 14 cm3 of 1,2-dimethoxyethane was cooled to +5°C and over a period of 1 hour a solution of 1.1 g of N-hydroxysuccinimide ester of L-(-)^-benzyloxy3 carbonyl amino-a-hydroxy-butyric acid in 28 cm of 1,2-dimethoxyethane was added.

The reaction mixture was agitated for 15 hours, between 5 and 10°C, and then evaporated to dryness under vacuum. The dry extract was chromatographed on silica, eluting with a 75:25:5 chloroform: methanol:ammonia mixture.

The expected product (Rf - 0.45) was obtained and characterised by chromatography on silica gel, eluting with a 2:2:1 methanol: chloroform:ammonia mixture. Stage 6: N-| '|T;()-2-hydroxy-4-amino-butyryl}-4-P-JT',6'-diamino-2; 6'- didesoxya.D-glucopyranosyjJ -6-0- |3-methyl ami no-3,4,6-tri desoxy- a,D-xylohexopyranosy[ -2-desoxystreptamine. q To a solution of 473 mg of the product obtained in stage B in 6 cm of a 3 distilled water, 6 cm of dioxan and 0.15 cm of acetic acid, there were added, at -943S82 -25°C, 90 mg of catalyst consisting of 10% of palladium on charcoal, Hydrogen was bubbled-in, and after 5 hours' reaction, 30 mg more catalyst were added, After a further hour's bubbling-in of hydrogen, the agitation was stopped and the reaction mixture was kept overnight in an atmosphere of hydrogen. The catalyst was then filtered off, and the filtrate was evaporated to dryness under vacuum.

The formed residue was chromatographed on silica with a 2:2:1 methanol; chioroform:ammonia mixture, and 115 mg of the expected product were obtained.

The product was purified by passage over an ion exchange resin of the carboxylic type in NH^ form (eluting with 0.5 N ammonia). The purification yield was 82.2%.

NMR spectrum, (in DpO).

A. -CHyl .2 ppm doublet; J = 6 cps 8. -CHg-2.54 ppm C. -H-4.28 pm multiplet 0. H anomer-2.25 ,ppm doublet; J = 4 cps Formulation: An injectable preparation was made up as follows: Compound of formula I 50 mg Ό Sterile aqueous excipient 1 cm

Claims

1. CLAIMS «32

1. N^-|T(-)-2-Hydroxy-4-amino-butyrvJ’4-0- ^J,6'-diamino-2',6'-didesoxy- a ? DglucopyranosyT] -6-0-[3i'-methylamino-3,4,6 -tridesoxy-a.D-xylohexopyranos/iJ -2-desoxystreptamine of the formula: or an acid addition salt thereof formed with a mineral or organic acid,

2. An acid addition salt of the compound of formula I, being a hydrochloride, hydrobromide, nitrate, sulphate, phosphate, acetate, formate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, benzilate, glyoxylate, aspartate or an alkanesulphonate or aryl sulphonate.

3. A process for preparing the compound of formula I as designed in claim 1, in which the L(-)-compound of the formula: ill) is treated with hydrogen in the presence of a catalyst to obtain the desired compound of formula I, -114. A process as claimed in claim 3 S in which the treatment of the compound of formula II with hydrogen is carried out in the presence of a metal catalyst.

4. 5. A process as claimed in claim 4, in which the catalyst is palladium.

5. 6. A process as claimed in any of claims 3 to 5, in which the reaction is carried out in a mixture of water and a water-misicible solvent.

6. 7. A process as claimed in claim 6, in which the water-misicible solvent is dioxan.

7. 8. A process as claimed in claim 6, in which the water-misicible solvent is tetrahydrofuran, 1,2-dimethoxyethane or the dimethyl ether of propylene glycol.

8. 9. A process as claimed in any of claims 3 to 8, in which the starting material of formula II is prepared by a process in which the compound of the formula: CH ,NH 1-0h (III) '2 CH. '3 H OH is reacted with the L(-)-compound of the formula: 0 —C—CH —(ch 2 ) 2 nb— C-0- ch 2 OH (IV) to obtain the desired compound of general formula II. -1210. A process as claimed in claim 9, in which the reaction of the compounds of formula III and IV is carried out in a solvent.

9. 11. A process as claimed in claim 10, in which the solvent comprises one or more of water, 1,2-dimethoxyethane, dioxan, dimethylacetamide dimethylformamide, tetra 5 hydrofuran and the dimethyl ether of prooylene glycol.

10. 12. A process as claimed in claim 11, in which the solvent is a mixture of 1,2dimethoxyethane and water.

11. 13. A process as claimed in any of claims 9 to 12, in which the compound of formula III is in turn prepared by a process in which the compound of the formula: is reacted with the compound of the formula: to obtain the desired compound of formula III.

12. 14. A process as claimed in claim 13, in which the comnounds of formulae V and 15 VI are reacted in a solvent.

13. 15. A process as claimed in claim 14, in which the solvent comnrises one or more of dimethylformamide, water, dimethylacetamide, dioxan, tetrahydrofuran, pyridine, acetone, ethanol, methanol, and 1,2-dimethoxyethane. -13Λ V εϊ Q π . *

14. 16. A process as claimed in claim 15, in which the solvent is a mixture of dimethylformamide and water.

15. 17. A process as claimed in any of claims 3 to 16, and substantially as described herein with reference to the Example.

16. 18. A process for the preDaration of an acid addition salt of the comoound of formula I, as defined in claim 1, in which the compound of formula I is reacted with an appropriate mineral or organic acid to form the desired acid addition salt.

17. 19. A process as claimed in claim 18, in which the salification is carried out in water and/or ethyl ether and/or methanol and/or acetone.

18. 20. A process as claimed in claim 18 or claim 19, in which the compound of formula I used in the salification is prepared by a process as claimed in any of claims 3 to 17.

19. 21. A pharmaceutical composition containing, as active material, the compound of formula I and/or one or more pharmaceutically-acceptable mineral or organic acid addition salts thereof in association with a suitable pharmaceutical vehicle.

20. 22. A composition as claimed in claim 21, in which the pharmaceutical vehicle is or includes one or more of talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives and glycols. ’3, A composition as claimed in claim 21 or claim 22, which also contains one )r more wetting, dispersing or emulsifying agents, and/or one or more preservatives. ’4. A composition as claimed in any of claims 21 to 23, and substantially as lescribed herein with reference to the Formulation. -14*14 Li ίί wherein R represent a hydrogen atom or the L-(-)-radical:

21. 26. A process for preparing a compound of general formula VII as defined in any 5 of claims 3 to 17.

22. 27. A compound ot general formula VII whenever prepared by a process as claimed in claim 26.