WO1984001386A1

WO1984001386A1 - New amine glucocyde derivatives, preparation and utilization method

Info

Publication number: WO1984001386A1
Application number: PCT/CH1983/000107
Authority: WO
Inventors: Hans Loibner; Wolfgang Streicher; Peter Stuetz
Original assignee: Sandoz Ag
Priority date: 1982-09-30
Filing date: 1983-09-23
Publication date: 1984-04-12
Also published as: NL8303293A; IL69850A0; PT77409A; FR2533927A1; HUT36134A; IT1174788B; SE8305231D0; DK449783D0; SE8305231L; DE3334383A1; DK449783A; PT77409B; FI833421A0; GB8325758D0; AU1983583A; FR2533927B1; GB2127818A; FI833421A

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

New amine coside derivatives, process for their preparation and their use

The invention relates to new amine coside derivatives of the formula

wherein R _{1 is} hydrogen or a group of the formulas

R ₂ for OH or NH ₂ , R ₃ for hydrogen or OH, R ₄ for hydrogen or OH, R ₅ for the amino, the methylamino, dimethylamino or, if R _{2 is} the amino group, also for the hydroxyl group and R _{6 represents} hydrogen or the methyl group, and their acid addition salts and processes for the preparation of compounds of formula I and their acid addition salts and their use. According to the invention, the compounds of the formula I are obtained by

a) a compound of the formula

or

wherein R ₁ to R _{6 have the} above meaning and X represents a cleavable group, the hydroxyl and / or amino groups, in addition to those in position 1, being protected by corresponding protective groups, reduced by methods known per se and subsequently any protective groups present known methods split off or

b) for the preparation of compounds of the formula I in which R _{5 represents} a methylamino or dimethylamino group, a compound of the formula I in which R _{5 is} the amine α group, mono- or dimethylated, or a compound of the formula 1 in which R ₅ stands for the methylamino group, methylated, it being possible for other amino groups present to be protected and for the protective group present to be split off again after the reaction. Process variant a) according to the invention can be carried out by methods known per se, for example by reduction processes as are known for the hydrogenolytic cleavage of an aziridine group. The reduction can be carried out, for example, using Raney nickel and hydrogen. The end products of the formula I can be isolated from the reaction mixture and, if appropriate, purified by methods known per se.

Process variant b) can be carried out, for example, by introducing the 6'-NH ₂ group selectively with an active carbonic acid derivative of the formula Y-COOR ₇ , in which Y is a reactive group and R ₇ is to introduce a methyl group in compounds of the formula I. Is alkyl or aralkyl, in the NH-COOR _7th Conveyed derivative and this by methods known per se, for. B. with a complex metal hydride such as LiAlH ₄ , reduced. For the introduction of two methyl groups in compounds of the formula I, all amino groups - except for the one in the 6'-position - are advantageously first protected by appropriate amino protecting groups, then the methyl groups by methods known per se, e.g. B. by reaction with formaldehyde in the presence of a conventional reducing agent or in the presence of NaH ₂ PO ₃ and finally deprotects the end product.

For example, the mesyloxy, tosyloxy,

Trifluoromethanesulfonyloxygruppe, chlorine, bromine or iodine can be used.

The protecting groups which are generally known for this purpose can be used as protective groups for the amino functions to be protected, for example -CO.O.CH ₂ .C ₆ H ₅ , -CO.OC (CH ₃ ) ₃ or -CO.O.CH ₂ .CCl ₃ .

The compounds of the formula I can be converted into their acid addition salts by known methods and vice versa.

The starting compounds of the formula purple are new and can be obtained by working in a compound of the formula

wherein R ₁ to R _{6 have the} above meaning, the OH group of the hydroxymethyl group in position 1 is converted into a cleavable group by methods known per se.

The starting materials of formula IIIb are new and can be obtained by using a compound of formula

in which R ₁ to R _{6 have the} above meaning, the amino groups, in addition to that in position 1, being able to be protected by corresponding amino protecting groups, cyclize, it being possible for protective groups present to be split off again after the reaction.

The cyclization can be carried out, for example, by processes known per se or using triphenylphosphine and azodicarboxylic acid esters (e.g. azodicarboxylic acid diisopropyiester) in a solvent which is inert under the reaction conditions, e.g. in a chlorinated hydrocarbon such as chloroform.

The compounds of the formulas IV and VI and processes for their preparation are described in published European patent application No. 0072351.

The starting products can also be used in the form of mixtures, such as those obtained in the fermentative production of these starting products. If such a mixture is used, a mixture of intermediate compounds with approximately the same component ratio is obtained, which can be directly converted further to the corresponding mixture of compounds of the formula I. If desired, these mixtures can be separated into their individual components at any point in the course of the reaction, i. H. this separation can be carried out either with the mixture of the starting compounds, the intermediate compounds or the end products of the formula I. One proceeds according to methods known per se, e.g. B. as in K.Byrne et al., J.Chromatogr. 131/191 (1977), or in U.S. Patent 3,984,395. Any separation of the mixtures with the protected end products of the formula I is preferably carried out.

The compounds of the formula I and their pharmacologically acceptable salts have interesting biological, in particular antimicrobial, properties with low toxicity and can therefore be used as medicaments. They develop an inhibitory effect against bacteria, such as Investigations in vitro with the serial dilution test and in vivo by experiments on mice using different strains of bacteria shows. This inhibitory effect was determined in vitro from a concentration of approx. 0.05 to 50 μg / ml, in vivo from a dose of approx. 0.4 to 100 mg / kg body weight. The compounds according to the invention can therefore be used as antibacterial antibiotics.

The compounds of the formula I and, if appropriate, their water-soluble, physiologically tolerable salts can be administered as medicinal products alone or in suitable pharmaceutical forms together with inorganic or organic, pharmacologically indifferent auxiliaries. For example, they are used as a component of capsules, injection or instillation preparations that contain a sufficient amount of active compounds to achieve an optimal blood level, that is about 10 to 500 mg per preparation. For the application, the dose to be administered depends on the compound used and the mode of administration and the type of treatment. In larger mammals, satisfactory results are obtained when a daily dose of approximately 0.1 to 2 g is administered. This amount can optionally be given in correspondingly smaller doses two to four times a day or in a sustained release form.

The compounds of formula I can be prepared in a manner similar to standard compounds known for this use, e.g. B. how gentamicin is used. A suitable daily dose for a particular compound of formula I depends on a number of factors, e.g. B. of their relative activity and tolerability. The compounds according to the invention are better tolerated or have a lower nephrotoxicity than the standards, are also distinguished from the standards by a broader spectrum of activity and, in particular, have an excellent action against amine-coside-resistant germs. This effect against amine-coside-resistant germs is e.g. Been example, for 1-C-methyl gentamicin C ₁ .Pentahydrochlorid determined and is 0.1 to 10 ug / ml as compared to 0.1 to> 100 ug / ml for gentamicin. The compounds according to the invention can therefore be used in a similar or lower dosage are used as the dose commonly used for gentamicin.

Preferred meanings of the substituents are:

R ₁ = Formula II or Ha

R ₂ = OH or NH ₂

R ₃ , R ₄ = H or OH

R ₅ = NH ₂ , NHCH ₃ or N (CH ₃ ) ₂

R ₆ = H or NH ₂

In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all the temperatures are given in degrees Celsius.

Example 1: 1-C-Methylqentamicin Co-Pentahydrochloride (Verf, a)

1 g ^3,2, 6 ', 3 "-Tetra-N-tert-butoxycarbonyl-1-desam ino-1-nitro-1-C-methane suifonyloxymethylgentamicin C ₂ is dissolved in 30 ml of methanol and 4 atm with Hydrogen is reduced in the presence of Raney nickel suspension. An amorphous foam is obtained after filtering off the catalyst. This is taken up in chloroform, shaken three times with dilute ammonia solution and washed until neutral. The product obtained after spinning off the solvent is dissolved in 10 ml of trifluoroacetic acid and diluted with 200 ml of diethyl ether after 7 minutes The precipitate is filtered off, dissolved in methanol and converted into the hydrochloride via 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, J ₁ = 13, J ₂ = 3.6, 1H); 2.96 (s, 3H); 5.10 (d, J = 3.6, 1H); 5.86 (d, J = 3.6, 1H).

Example 2: 1-C-Methylqentamicin C, .pentahydrochloride (Ed. A)

0.5 g of 1-C-hydroxymethyl-3,2 ', ^6, 3 "-tetra-N-tert.butoxycarbonylgentamicin C ₁ and 0.26 g of triphenylphosphine are dissolved in 10 ml of absolute chloroform, 0.2 g of diisopropyl azodicarboxylate was added The residue obtained after evaporation of the solvent can be purified by chromatography on silica gel with dichloromethane / methanol (15/1) or processed directly without purification. The residue is dissolved in methanol and at 4 bar with hydrogen and Raney nickel The residue obtained after filtering off the catalyst and evaporating is dissolved in 10 ml of trifluoroacetic acid and after 7 minutes diluted with 200 ml of diethyl ether, the precipitate is filtered off and chromatographed on silica gel with dichloromethane / methanol / 30% ammonia (15/4/1). Fractions containing the product are evaporated, dissolved in 1N methanolic hydrochloric acid and precipitated with diethyl ether to give an amorphous white powder. 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, J ₁ = 13, J ₂ = 4.2, 1H); 2.76 (s, 3H); 2.95 (s, 3H); 5.13 (d, J + 3.8, 1H); 5.87 (d, J = 3.7, 1H).

Example 3: 1-C-Methylqentamicin C _{1 a.} Pentahydrochloride

The procedure is analogous to that described in Example 1 or 2.

N-NMR (characteristic signals): 1.37 (s, 3H); 1.53 (s, 3H); 2.44 (dd, J ₁ = 13, J ₂ = 4, 1H); 2.95 (s, 3H); 5.13 (d, J = 3.6, 1H); 5.84 (d, J = 3.5, 1H).

Example 4: 1-C-methyl-6'-N-methylqentamicin C _{1 a.} Pentahydrochloride (ver. B)

220 mg of 1-C-methyl-6'-N-benzyloxycarbonylgentamicin C _{1 a} are dissolved in 50 ml of dry tetrahydrofuran, 500 mg of lithium aluminum hydride are added and the mixture is refluxed for 3 hours. Then 10 ml of methanol are carefully added, acidified with 1 ml of acetic acid and filtered through Cellt. The organic phase is evaporated and chromatographed on silica gel with chloroform / methanol / 30% ammonia (15/4/1). The product is collected with R _f value 0.21 in chlorαform / methanol / 30% ammonia (70/21/9). This is dissolved in 4 ml of 1 N methanolic hydrochloric acid and precipitated with 100 ml of diethyl ether. A white powder is obtained.

H-NMR (characteristic signals): 1.36 (s, 3H); 1.52 (s, 3H); 2.45 (dd, J ₁ = 12.5 Hz, J ₂ = 4 Hz, 1H); 2.76 (s, 3H); 2.94 (s, 3H); 5.12 (d, 3 = 3.6 Hz, 1H); 5.85 (d, J = 3.6 Hz, 1H).

The compounds required as starting products can be obtained as follows: A) 3,2 ', 6', 3 "-Tetra-N-tert.butoxycarbonyl-1-desamino-1-nitro-1-C-methanesulfonyloxymethylqentamicin C ₂

a) 3,2 ', 6', 3 "-Tetra-N-terfe.butoxycarbonyl-1-desamino-1-nttroqentamicin C ₂

A mixture of 50 g of potassium permanganate and 125 g potassium dihydrogenphosphate in 0.5 1 water is brought to 75 ° and in one portion 25 g of ^3,2, 6 ', 3 "-tetra-N-tert.butoxycarbonylgentamicin C ₂ dissolved in 0.5 l of acetal, added, the mixture is refluxed with stirring for 3 minutes, then poured onto 150 g of sodium bisulfite in ice water, filtered off from the manganese dioxide and extracted with chloroform. After drying the organic phase, the mixture is evaporated and the residue is evaporated over silica gel with ethyl acetate / Hexane (3/2) is chromatographed and the substance is isolated with R _f = 0.17 (in dichloromethane / methanol = 20/1).

b) 3,2 ', 6', 3 "tetra-N-tert.butoxycarbonyl-1-desamino-1-nitro-1-C-hydroxymethy.qentamicin C ₂

0.64 g of 3,2 ', ^6, 3 "-Tetra-N-tert-butoxycarbonyl-1-desamino-1-nitro- gentamicin C ₂ are dissolved in 5 ml of methanol and after cooling to -7 ° with 0.3 After five minutes, the solution is poured into 10 ml of 37% formaldehyde solution and brought to room temperature, after dilution with water and acidification with 0.1 N HCl, the solution is extracted with dichloromethane and the organic phase is rotated in. The substance with R _f = 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-tert.butoxycarbonyl-1-desamino-1-nitro-1-C-methanesulfonyloxymethylqentamicin C ₂

1.82 g of ^3,2, 6 ', 3 _{"-Tetra-N-tert-butoxycarbonyl-1-desamino-1-nitro-1-C-2} are hydroxymethylgentamicin C with 0.6 ml of diisopropylethylamine in 60 ml of absolute dichloromethane dissolved, 0.16 ml methanesulfonic acid chloride added and refluxed for one hour. The residue obtained after spinning off is chromatographed on silica gel using chloroform. An amorphous foam is obtained. R _f = 0.43 (in dichloromethane / methanol / 33% ammonia = 9/1 / 0.2)

B) 1-C-hydroxymethyl-3,2 ', 6', 3 "-tetra-N-tert.butoxycarbonylgentamicin C ₁

a) 3,2 ', 6', 3 "-Tetra-N-tert.butoxycarbonyl-1-desamino-1-nitroqentamicin C ₁

To a solution of 17 g of ^3,2, 6 ', 3 "-tetra-N-tert.butoxycarbonylgentamicin C ₁ and 3.4 g of 3-tert-butyl-4-hydroxy-5-methylenphenyIsulfid in 750 ml 1.2 -Dichloroethane is added in the solid state during boiling 34 g of 3-chloroperbenzoic acid. After 30 minutes the solution is spun in. The residue is shaken with 20% KHSO ₃ solution, saturated NaHCO ₃ solution and water over silica gel with ethyl acetate / Hexane (3/2) is chromatographed and the substance is isolated with R _f = 0.74 (in dichloromethane / methanol = 9/1).

b) 1-C-hydroxymethyl-3,2 ', 6', 3 "-tetra-N-tert.butoxycarbonylgentamicin C ₁

0.8 g of 3.2 ', 6', 3 "tetra-N-tert-butoxycarbonyl-1-desamino-1-nitrogentamicin C ₁ are dissolved in 20 ml of chloroform, 10 g of paraformaldehyde and 1 ml of triethylamine are added, and 30 The mixture is filtered with suction and the mother liquor is chromatographed on silica gel with ethyl acetate / hexane (2/1). R _f = 0.62 (in dichloromethane / methanol = 9/1). The product obtained is dissolved in Raney nickel suspension in 30 ml of methanol are reduced with hydrogen at 4 atm, after filtering off the catalyst, an amorphous foam is obtained, which is processed directly. C) 1-C-hydroxymethyl-3,2 ', 6', 3 "-tetra-N-tert.butoxycarbonylgentamicin C _1a

The procedure as described under B / b) and the title compound from the 3,2 ', ^6, 3 "-Tetra-N-tert-butoxycarbonyl-1-desamino-1-nitro- gentamicin C _1a (prepared analogously as described in A / a), R _f = 0.16 in dichloromethane / methanol = 9/1) R. = 0.5 (in dichloromethane / methanol = 9/1, before reduction with Raney nickel).

D) 1-C-methyl-6'-N-benzyloxycarbonylqentamicin C _{1 a}

740 mg of 1-C-methylgentamicin C _{1 a} are dissolved in 30 ml of methanol and 500 mg of N-benzyloxycarbonyioxy-5-norbornene-2,3-dicarboximide, dissolved in 5 ml of methanol and 5 ml of chloroform, are added dropwise at -15 °. After 1 hour, the mixture is warmed to room temperature. After a further 2 hours, the solution is spun in and chromatographed on silica gel using chloroform / methanol / 30% ammonia (15/4/1). The product with the R _f value is 0.66 (chloroform / methanol / 30% ammonia = 70/21/9).

E) 1-N, 1-C-Methylenqentamicin C _{1 a}

0.5 g of ^{1-C-hydroxymethyl-3,2,,} 6 ', 3 "-tetra-N-tert.butoxycarbonylgentamicin C _{1 a} and 0.26 g of triphenylphosphine are dissolved in 10 ml of absolute chloroform, 0.2 g Azodicarbonsäuredlisopropylester After refluxing the solvent, the residue is chromatographed on silica gel with dichloromethane / methanol (15/1) and the product with the R _f value 0.49 (dichloromethane / methanol = 9/1) is collected.

0.2 g of this 1-N, 1-C-methylene-3,2 ', 6', 3 "-tetra-N-tert.butoxycarbonylgentamicin C _1a are dissolved in 5 ml of trifluoroacetic acid and after 5 minutes diluted with 100 ml of diethyl ether The precipitate is chromatographed on silica gel with dichloromethane / methanol / 30% ammonia (15/4/1) receives an amorphous powder.

R _f = 0.3 (in chloroform / methanol / 33% NH ₃ = 1/1/1, lower phase).

H-NMR (characteristic signals): 1.2 (s, 3H); 1.37 (dd, J ₁ = 13.8, J ₂ = 4.5, 1H); 1.56 (s, 1H); 2.01 (s, 1H); 2.51 (s, 3H); 4.91 (d, J = 3.6, 1H); 5.23 (d, J = 3.6, 1H).

F) 1-N, 1-C-methylene gentamicin C ₁

The procedure is analogous to that described under E).

1-N, 1-C-methylene-3,2 ', ^6, 3 "-tetra-N-tert.butoxycarbonylgentamicin C _1: R _f = 0.47 (in dichloromethane / methanol = 9/1)

Title link:

R _f = 0.36 (in chloroform / methanol / 33% NH ₃ = 1/1/1, lower phase).

H NMR (characteristic signals): 1.25 (s, 3H); 1.27 (d, J = 1.3H); 1.39 (dd, J ₁ = 13.5, J ₂ = 4.6, 1H); 1.59 (s, 1H); 2.01 (s, 1H); 2.67 (s, 3H); 2.69 (s, 3H); 4.96 (d, J = 3.6, 1H); 5.33 (d, J = 3.6, 1H).

Claims

Claims:

1. New amine coside derivatives of the general formula

wherein R _{1 is} hydrogen or a group of the formulas

R ₂ for OH or NH ₂ , R ₃ for hydrogen or OH, R ₄ for hydrogen or OH, R ₅ for the amino, the methylamino, dimethylamino or, if R _{2 is} the amino group, also for the hydroxyl group and R _{6 represents} hydrogen or the methyl group, and their acid addition salts and processes for the preparation of compounds of formula I and their acid addition salts and their use.

2. A process for the preparation of new amine coside derivatives of the general formula I, characterized in that a) a compound of the formula

wherein R ₁ to R _{6 have the} above meaning and X for a cleavable

Group stands, where the hydroxyl and / or amino groups can be protected by appropriate protective groups, reduced by methods known per se and then splitting off any protective groups present by methods known per se or

b) for the preparation of compounds of the formula I in which R _{5 is} a methylamino or dimethyamino group. represents a compound of the formula I in which R _{5 is} the amino group, mono- or dimethylated, or a compound of formula I in which R _{5 is} the methylamino group, where other amino groups present can be protected and protective groups present after the reaction be split off again.

3. chemotherapeutic composition containing a compound according to claim 1 in free form or in the form of a physiologically tolerable acid addition salt, together with pharmacologically ogive indifferent auxiliaries.

4. Compounds according to claim in free form or in the form of a physiologically compatible acid addition salt for use as chemotherapeutic agents.