NL8002177A - NOGAMYCIN, NOGAMYCIN ANALOGA, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL PREPARATIONS BASED ON THE SAME - Google Patents

Description

4

Nogamycin, nogamycin analogs, method of preparation thereof and pharmaceutical preparations based on it.

The antibiotic ratheramycin and a method of preparing it are described in U.S. Patent 3,183,157.

Antibiotics of Rararol and Rararene available by acid hydrolysis of Ratheramycin, and O-methylnogalarol available by acidic methanolysis of Ratheramycin and Rararol are described in U.S. Pat. No. 3,501,569.

Nogalamic acid (formula 2) is obtained by modification of ratheramycin (formula 1).

US Pat. No. 4,064,340 describes the conversion of ratheramycinic acid to nogamycin (formula la-1a) by reaction with dimethylformamide. The nogamycin thus obtained has a different structure than nogamycin which has been prepared by the method according to the invention.

In U.S. Patent 4,086,245 and

U.S. Patent Application 924,975 discloses 7-o-alkylnogarols (Formula 3, wherein R represents an alkyl group of 1-4 carbon atoms) and their preparation by acid alcoholysis of nogamycins.

Furthermore, Tong et al. In Abstracts of Papers, 175th ACS Meeting, Medicinal Division, paper 48 describe a method for obtaining two diastereoisomers of a 7- (2-aminoethylthio) derivative by reaction of daunomycinone and 2-amino- ethanethiol in trifluoroacetic acid as a solvent.

In the above-mentioned United States Patent Specification 4,086,245 and United States Patent Application 924,975, mention is made of the favorable biological properties of the 7-O-alkylnogarols described therein and in the above-mentioned United States Patent Specification No. 4,017,340 of nogamycin itself.

The invention relates to compounds of the formula wherein B represents a nucleophilic group except an O-lower alkyl group and T represents a hydroxyl group wherein the groups B and T are bonded to the ring system in a configuration, as well as biologically acceptable acid addition salts thereof.

The nucleophilic group represented by B includes ratherosyl, a sulfide anion, organic acid anion, amino, substituted amino, azido and carbanion.

* The formula 4 includes nogamycin as well as 7-nogarols and 7-deoxynogarols with different substituents in the 7-position.

The invention further relates to a method of preparing the new compounds of formula 15 as pure stereoisomers of a preferred configuration. Preferred configuration stereoisomers exhibit excellent antibacterial activity.

In the stereoisomers of the preferred configuration, the substituent on the 7-olate and the hydroxyl group are in the 9-20 position in front of (a) or behind (β) the plane of the ring system (for the numbering of the places refer to the formula la ). Since it is not clear whether the green isomers in the 7-position and 9-position in the o- or g-configuration in the stereoisomers of the preferred configuration, the preferred configuration is hereinafter referred to as "con".

According to the method of the invention, the novel nocamycin of the invention, nogamycin, is prepared as described in the aforementioned U.S. Patent 4,064,340 or a 7-O-alkylnogarol prepared in accordance with the above U.S. Patent 4,086,245 or U.S. Patent Application 924,975 and a haloacetic acid mixed at a temperature between -15 and 30 ° C. Nucleophilic reagents are added to the reaction mixture or a solution of the residue obtained after removing excess acid from the reaction mixture, nucleophilic groups are introduced at the 7-35 site to form a pure stereoisomer 800 2 1 77

J

3 with the preferred configuration.

With this method, new 7-nogarols and new 7-deoxynogarols with different substituents in the 7-position can also be prepared.

The heterocyclic ring on the 1 "carbon atom of the nogamycin of the invention is in the β position so that the 2" carbon atom is behind the 1 "carbon atom.

Such a configuration has not previously been described.

The nogamycin according to the invention is thus con 1 ”β-nogamycin of the formula 5 (formula 4 wherein B is ratherosyl) and has not been described previously. In formula 5, the 9-OH and 7-ratheros group can be in front of or behind the plane of the ring system.

In addition to being able to represent ratherosyl, B may further represent alkylthioxy, acyloxy, amino, alkylamino, alkoxyalkylamino, aminoalkvlakoxy and bis (carbalkoxy) methyl.

Alkylthioxy includes methylthioxy, ethylthioxy, n-propylthioxy, isopropylthioxy, η-butylthioxy, isobutylthioxy and tert-butylthioxy.

Acyloxy includes acetoxy, n-propionyloxy, isopropio-nflxy, n-butyryloxy, isobutyryloxy and tert.butyryloxy.

Bis (carbalkoxy) methyl includes bis (carbomethoxy) -methyl, bis (carbethoxy) methyl, bis (carbo-n-oronoxv) methyl, bis (carbo-isopronoxy) methyl, bis (carbo-n-butoxy) methyl, bis (carbo-isobutoxy) methyl and bis (carbo-tert-butoxy) methyl.

Aminoalkyloxy includes aminomethyl methoxy, aminoethyl methoxy, aminopropyl methoxy, aminobutyl methoxy and isomers thereof.

Alkylamino includes methylamino, dimethylaraino, ethylamino, diethvlamino, pronylamino, butvlamino, and isomers thereof.

Alkoxyalkylamino includes methoxypropvlamino, methoxyethylamino, ethoxyethylamino, oropoxyethylamino and isomers thereof.

The above listing of Examples 35 of nucleophilic groups should not be construed as limiting.

800 2 1 77 4

A wide range of new compounds, including con 1 "β-nogamycin, can be prepared by the process of the invention. In addition, known processes of the prior art 7-0 -alkylnararols can be prepared by the process of the present invention, the configuration of which can be post-processed say they are described in the aforementioned U.S. Pat. No. 4,086,245 but without mention of the formation of another isomer thereof.

The process according to the invention can be carried out in one or two steps and is shown in scheme A in which R 1 and R 2 in formula 6 each represent a hydrogen atom, lower alkoxy or nogalosyl group, wherein R 1 or R 1 each represents a hydrogen atom and in the formula 1 'B' represents a nucleophilic group and T represents a hydroxyl group in which groups B 'and T are in the configuration.

15 "Nucleophile" is to be understood in its broadest sense as reagents and groups with a solitary electron pair.

Besides being able to represent the above-mentioned groups for B (ratherosyl, alkylthioxv, acyloxy, bis (carbalkoxy) methyl, aminoalkylalkoxy and alkoxyalkylamino), B 'may further represent alkoxy, arfloxy, aralkoxy and the corresponding sulfoxy groups as well as a nitrogen containing group of the formula 7.

The group of formula 7 may be a nitrogen-containing heterocyclic group with up to 7 carbon atoms which, in addition to the nitrogen atom to which the groups R 1 and R 2 are attached, contains a nitrogen atom or else an oxygen atom or sulfur atom. The group of Formula 7 may also be an amino group wherein R 1 and R "each are hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkenyl, cycloalkenylalkyl, aryl, aralkyl, aralkenyl, aryloxyalkyl, heterocyclic ring or heterocycloalkyl carbon atoms and as heteroatom nitrogen, oxygen or sulfur and optionally substituted by 1 or 2 hydroxy, carboxy, amino, lower alkoxy, benzyloxy, halogen or lower alkyl groups.

Alkenyl includes ethylene, propylene, butylene and isomers thereof.

Haloacetic acid includes mono-, di- and trifluoro-800 2 1 77 * fc-5 acetic acid and mono-, di- and trichloroacetic acid.

When carrying out the method according to the invention, a nucleophilic reagent is added to a mixture of the haloacetic acid and con 1 "8-nogamycin according to the invention, nogamycin as known from the above-mentioned publications, or 7-0-alkylnogamycin. haloacetic acid is not a solvent, a solvent can be added, for example, trifluoroacetic acid acts as a solvent The reaction with the nucleophilic reagent can be carried out in a single step but when an excess of haloacetic acid and solvent are present, they can first be removed under reduced pressure. the residue is composed of an intermediate (step 1 in reaction scheme A).

The residue is then unloaded for reaction with the nucleophilic reagent (step 2 in reaction scheme A).

It is believed that in the one-step and two-step embodiments the same intermediate is formed consisting of a complex of nogamycin reactant and haloacetic acid.

Suitable solvents for the mixture of nogamycin reactant and haloacetic acid are, in the first place, excess trifluoroacetic acid and further ether, dioxane and tetrahydrofuran which is preferred after excess trifluoroacetic acid. The reaction is carried out at a temperature between -15 and 30 ° C for 0.25-6 hours.

For example, the formed substituted 7-nogarol, 7-substituted-7-deoxynogarol or 1 "8-nogamycin of the preferred configuration of the invention can be separated by precipitation in water of pH 7-7.2 followed by extraction with chloroform , ethyl acetate or preferably methylene chloride The extract can be purified by chromatography on silica gel eluting, for example, a mixture of chloroform and methanol (95: 5) or a mixture of chloroform, methanol and water (78: 20: 2).

The identity of the product can be determined by thin layer chromatography.

The con 1 "8-nogamycin and the nogamycin analogs 8002 1 77 6 according to the invention can be acylated in the usual manner with, for example, an acid halide or anhydride. One or more of the hydroxyl groups present can be acylated.

The acylation is carried out in the presence of an acid binding agent. Suitable acid binding agents include amines, such as pyridine, quinoline and isoquinoline, and buffer salts such as sodium acetate. Pyridine is preferred. Suitable carboxylic acids for the acylation include (a) saturated and unsaturated straight or branched aliphatic carboxylic acids, for example, acetic acid, propionic acid, butyric acid, isobutyric acid, tert-butyl acetic acid, valeric acid, isovaleric acid, caproic acid, caprylic acid, decanoic acid, dodecanoic acid, lauryl acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, acrylic acid, croton acid. *, 15 undecylenic acid, oleic acid, hexenoic acid, heptic acid and octynic acid; (b) saturated or unsaturated alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentene carboxylic acid, methylcloplopentene carboxylic acid, cyclohexane carboxylic acid, dimethylcyclohexane carboxylic acid and dlpropylcyclohexane carboxylic acid; (c) saturated or non-saturated alicyclic aliphatic carboxylic acids, for example cyclopentanoic acetic acid, cyclopentane propionic acid, cyclohexane acetic acid, cyclohexane butyric acid and methylcyclohexane acetic acid; (d) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethyl benzoic acid, isobutyl benzoic acid and methyl butyl benzoic acid, * (e) aromatic, aliphatic carboxylic acids, for example phenylacetic acid, phenylpropionic acid, phenylvaleric acid, cinnamic acid, phenylpropiol acid and naphthylacetic acid. Also suitable are halogen, nitro, amino, cyano and lower alkoxy substituted derivatives of the aforementioned carboxylic acids. Lower alkoxy includes methoxy, ethoxy, propoxy, butoxy, amyloxy and hexyl-30 oxy as well as isomers thereof. Examples of such substituted carboxylic acids are mono-, di- and trichloroacetic acid, a- and 8-chloropropionic acid, a- and γ-bromobutyric acid, a- and δ-iodovaleric acid, mevalonic acid, 2- and 4-chlorocyclohexaeuicarboxylic acid, shikimic acid, 2-nitro- 1-methylcyclobutane carboxylic acid, 1,2,3,4,5,6-hexachlorocyclo-35 hexane carboxylic acid, 3-bromo-2-methylcyclohexane carboxylic acid, 4- and 5-800 2 1 77 7 bromo-2-methylcyclohexane carboxylic acid, 5- and 6- Bromo-2-methylcyclohexane carboxylic acid, 2,3-Dibromo-2-methylcyclohexane carboxylic acid, 2,5-Dibromo-2-methylcyclohexane carboxylic acid, 4,5-Dibromo-2-methylcyclohexane carboxylic acid, 5,6-Dibromo-2-methylcyclohexane carboxylic acid, 3- 5-bromo-3-methylcyclohexane carboxylic acid, 6-bromo-3-methylcyclohexane carboxylic acid, 1,6-dibromo-3-methylcyclohexane carboxylic acid, 2-bromo-4-methylcyclohexane carboxylic acid, 1,2-dibromo-4-methylcyclohexane carboxylic acid, 3-bromine -2,2,3-trimethylcyclopentanecarboxylic acid, 1-bromo-3,5-dimethyl-cyclohexanecarboxylic acid, homogentistic acid, o-, m- and p-chloro-10 benzoic acid, anisln acid, veratouric acid, trimethoxybenzoic acid, trimethoxy cinnamic acid, 4,4'-dichlorobenzoic acid, o-, m- and p-nitrobenzoic acid, cyanoacetic acid, 3,4- and 3,5-dinitrobenzoic acid, 2,4,6-trinitro- benzoic acid, covanopropionic acid, and ethoxymic acid.

Acid addition salts of the compounds of the invention can be prepared by adding an appropriately selected acid to the compound to a pH less than about 7.0 and preferably about 2-6. Suitable acids include tartrate acid, glucuronic acid and lactic acid which give water-soluble salts, and hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid and bromo-hydrogen acid whose salts are less water soluble.

The compounds of the formula IV, their acylated derivatives and their acid addition salts inhibit the growth of microorganisms and can be used, for example, to clear silkworm breeding sites and to prevent or cure infections caused by Bacillus subtills. compounds suitable for preventing or masking odors in fish and fish crates caused by contamination with Bacillus subtills. In addition, the compounds can be used to treat birds infected with Mycobacterium avium.

Furthermore, it has been shown that con-7-acetylnogarol, con-7-methylthio-7-deoxynogarol, con-7-methylamino-7-deoxynogarol, con-7-dimethylamino-7-deoxynogarol, con-7-ethylamino-7-deoxy -nogarol, con-7-diethylamino-7-deoxynogarol and con-7-azido-7-deoxynogarol exhibit anti-tumor activity against P388 leukera cells (demonstrated in mice in vivo). The aforementioned con-7-amino compounds are furthermore remarkably less toxic than other con-nogamycins.

As another example of a microorganism whose growth is inhibited by the compounds of the invention, Streptococcus pyogenes can also be mentioned which also causes infections.

When the acylated compounds of the formula IV are administered, the acyl group is enzymatically removed.

The invention further relates to oral and parenteral pharmaceutical preparations containing as active ingredient a compound of the formula IV, an acylated derivative or a pharmaceutically acceptable acid addition salt thereof.

Oral preparations can be solid or liquid. In addition to the active ingredient, tablets contain a diluent or carrier, for example, talc, magnesium stearate, dicalcium-15 phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia gum or methyl cellulose. For hard capsules, the active ingredient is mixed with a diluent or carrier.

The capsules are then filled with the mixture. Soft gelatin capsules are prepared by machine-encapsulating a suspension of the active ingredient in a vegetable oil, light liquid petrolatum or other inert oil. Syrups are prepared by dissolving the active ingredient in an aqueous carrier together with sugar, an aromatic flavoring and a preservative. For the preparation of elixirs, an alcohol is used as the carrier together with a sweetener such as sugar or saccharin and an aromatic flavoring agent. An aqueous carrier and a suspending agent such as gum acacia, gum tragacanth or methyl cellulose are used for the preparation of suspensions.

Water is preferably used as the sterile vehicle for parenteral preparations. For the preparation of injectable solutions, the active ingredient is dissolved in water for injections. The solution is then sterilized on a filter, after which the vial or ampoule is filled with the sterilized solution and then closed. An additive 35 such as a local anesthetic, preservative or buffer comb 800 2 1 77 * 9 are included. To increase stability, the aqueous preparation is freeze-dried while removing water in vacuo. A bottle or ampoule is filled with the dry lyophilized powder and closed. In use, the preparation is reconstituted with water for injection from another vial or ampoule. Parenteral suspensions can be prepared in much the same way, the sterilization being performed by exhibiting the active ingredient to ethylene oxide before suspending in the sterile vehicle. To promote an even distribution of the active ingredient in the carrier, a surfactant or wetting agent is used.

The preparations are administered in discrete doses such as tablets, capsules, pills, powders, wafers, granules, cachets, teaspoons, table spoons and drops. The amount of active ingredient in each dose is dependent upon, inter alia, the mode of administration, and the activity of the active ingredient. In order to effectively combat bacterial infections in humans, a unit dose of about 500-5000 mg of active compound is generally maintained. During the treatment, the dose can be increased, taking care that no undesired side effects occur.

Example I

Con β'β-nogamycin.

A solution of 1 g (1.37 mmol) of nogamycin in 20 ml of trifluoroacetic acid is cooled in an ice bath. A 53 wt.% Suspension of 821 mg of sodium hydride in mineral oil (18.1 mmol) is washed twice with 10 ml of anhydrous tetrahydrofuran and then added to 2 g (9.1 mmol) of veose in 30 ml of anhydrous tetrahydrofuran. After stirring at room temperature for 1 hour, the mixture is then added to the cold nogamycin solution in tetrafluoroacetic acid. The mixture is then adjusted to pH 7.1 with 1 N hydrochloric acid and diluted with 100 ml of water. The aqueous solution is extracted four times with 100 ml of methylene chloride each time, after which the extracts are combined and evaporated under reduced pressure. The red viscous residue is dissolved in a little methylene chloride and a large volume of Skellysolve B (a mixture of hexane isomers) is added to the solution. After removing the precipitate (1.52 g) by filtration, the filtrate is evaporated under reduced pressure. The residue is chromatographed on 20 g of silica gel in a short column eluting with a mixture of methylene chloride and methanol (9: 1). The colored fractions are collected and evaporated. The residue obtained is dissolved in a little methylene chloride and the solute is precipitated with Skellysolve B. The precipitates are combined and chromatographed (HPLC) on 60 g of silica gel eluting with a mixture of methylene chloride and methanol (96: 4). of 10 ml fractions. After this, the ratio of methylene chloride and methanol is changed to 93: 7. A total of 15 105 fractions are collected. The fractions are examined for the presence of con 1 "β-nogamycin by thin layer chromatography using a mixture of chloroform, methanol and water as the solvent (78:20: 2). The Rf value for con 1" β-nogamycin is 0, 53. Based on the results, fractions 51-105 were selected and pooled and then evaporated to dryness under reduced pressure. The residue (325 mg) was chromatographed on 2 mm thick preparative plates using a mixture of chloroform, methanol and water (78: 20: 2) as the solvent. The band or front containing con 1 ”β-nogamycin was removed and extracted with a mixture of methylene chloride and methanol. Thus 185 mg con 1 "β-nogamycin were obtained. Melting point: 217-219 ° C (decomposition); / o / + 596 ° (c 0.147, CHClg); UV (C ^ OH) 236 nm (ε 51,600), 258 (ε 24,200), 292 shoulder (ε 9,750), 478 (ε 15,300); IR (nujol) 3440, 1660, 1610, 1580, 1410, 1280, 1210, 1090, 1050, 990, 930, 910, 880, 850, 820, 30 770, 720 and 690 cm ”1; 1 H NMR (CDCl 3) ppm 1.23, 1.46, 1.74 (s, m, s, 12 H, CH 3 C), 2.61 /“ s, 6 H, (CH 2 nJ, 3.26, 3.42, 3.55 (3.9 s, 9 H, CH 3 O), 2.0-2.2, 3.1-, 4.2 (m, CHO and CHN), 5.03, (m, 1 Η, H-7), 5.23 (d, 1H, Hl "), 5.90 (d, 1 Η, H-1 '), 6.60 (s , 1 Η, H-3), 7.25 (s, 1H, H-11); 13 C NMR (CDCl 3) ppm 190.9 (C-5), 179.4 (C-12), 161.2 35 (C-6), 155.6 (C-4), 148.3 (Cl), 147.0 (C-10a), 137.9 (C-2), 132.7 800 2 1 77 11 ( C-11a), 129.6 (C-6a), 125.6 (C-3), 120.8 (C-11), 116.1 (C-12a), 114.4 (C-4a), 112.5 (C-5a), 102.2 (Cl "), 97.6 (C-11), 84.3 (C-4"), 81.5 (C-2 "), 79.0 ( C-3 "), 75.1 (C-5 *), 72.7 (C-2 '), 71.0 (C-4), 70.8 (C-7), 70.4 (C -5 "), 67.6 (C-9), 66.1 (C-31), 61., 4, 61.2, 48.2, 5 (3 CH 3 O), 43.9 (C -10), 41.6 / ((CH 2 nJ /, 40.2 (C-8), 30.5 (C-9 CH 3), 24.0 (C-5 ', CH 3>, 18.5 ( C-5 ”CH 3), 15.3 (C-5 'CH 3); mass spectrum m / e 729.3011 (calculated for C37H47N014 729.2997).

Elemental analyzes%, calculated for C37H47N014! C 60.90; H 6.49; N 1.92; 10 found: C 59.09; H 6.39; N 1.83.

Example II

Con-7-O-methylnogarol.

A solution of 1 g of nogamycin in 20 ml of tri-15 fluoroacetic acid is stirred under cooling in an ice bath for 5 hours. A solution of sodium methoxide in methanol is added dropwise to the stirred solution until the mixture turns violet. 100 ml of water are then added and the pH is adjusted to 7.0 with sodium methoxide, after which the reaction mixture is extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride solutions are concentrated to dryness under reduced pressure. 0.5 g of the residue (1.004 g) is stirred with 15 ml of 0.1 M glucuronic acid, 10 ml of water and 10 ml of methanol for 15 min. Afterwards, the mixture is filtered and the filtrate is neutralized with 1 N sodium 25 hydroxide aqueous solution (pH 7.0). After stirring at pH 7 for about 30 min, the precipitate is collected by filtration. Thus, 211 mg of con-7-O-methylnogarol were obtained. Thin layer chromatography using a mixture of chloroform, methanol and water (78: 20: 2) as the running agent showed that the product was homogeneous and identical to a product prepared by methanolysis. / α / D 897 ° (c: 0.1525, CHCl 3); 13 C NMR spectrum identical with a comparison sample. Mass spectrum m / e 541.

Elemental Analysis: Found: C, 61.65; H 5.82; N 2.56.

35 800 2 1 77 12

Example III

Conversion of con-7-O-methylnogarol into 7-0-ethylnogarol.

A solution of 200 mg of con-7-O-methylnogarol in 5 ml of trifluoroacetic acid is added slowly after stirring at room temperature for 0.5 hour and a solution of sodium ethoxide in ethanol until the mixture turns violet. The reaction mixture is then poured into 50 ml of water and the pH is adjusted to 7.2 with 1 N HCl. The aqueous reaction mixture is then extracted three times with 50 ml of methylene chloride each time. The combined methylene chloride solutions are dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The residue is washed with Skellysolve B. Then, the residue (2.02 mg) is purified by preparative thin layer chromatography using 2 mm thick silica gel plates and a mixture of chloroform, methanol and water (78: 20: 2). ) as a walking aid. The faster conveyor belt is removed and extracted with a mixture of chloroform and methanol (9: 1) as a first fraction and the slower conveyor belt as a second fraction. The first fraction contained 94 mg of product having the same Rf value as con 7-O-ethylnogarol in the aforementioned solvent mixture. The identity of the product as con 7-O-ethylnogarol was further confirmed by a mass spectrum (m / e 555) and an NMR.

Example iv.

Con 7-methylthio-7-deoxynogarol.

A solution of 0.5 g of nogamycin in 10 ml of trifluoroacetic acid is concentrated to dryness after standing at room temperature for 1.25 hours under reduced pressure, after which 15 ml of dry tetra-hydrofuran are added. After cooling, a small excess of hydrated sodium ammonium mercaptide is added and the mixture is stirred at 0 ° C for 1 hour. Afterwards, the solvent is removed by evaporation under reduced pressure, after which the residue is dissolved in 100 ml of water. The pH is adjusted to 7.8 with 1 N hydrochloric acid and extracted twice with 50 ml of chloroform each time.

80 0 2 1 77 13

The combined chlorophorra solutions are concentrated to dryness under reduced pressure. The residue is chromatographed on 30 g of silica gel eluting with a mixture of chloroform and methanol (95: 5) to collect 10 ml of fractions. The fractions are analyzed by thin layer chromatography using a mixture of chloroform, methanol and water (78: 20: 2) as the solvent, with as reference a product with an Rf value 0.56. Based on the results, fractions 34-69 were selected and pooled and then concentrated to dryness under reduced pressure. There was thus obtained 10 2 04 mg of con 7-methylthio-7-deoxynogarol (yield 53%).

“O7d + 719 ° (c: 0.115, CHCl 3) 237 nm (ε 48,100), 262 (ε 23,250), 280 shoulder (ε 10,800), 479 (ε 16,050); IR (nujol) 3440, 1660, 1620, 1575, 1285, 1245, 1220, 1105, 1055 and 1005 cm -1; 1 H NMR (CDCl3) ppm 1.48 (s, 3H, CH3C), 1.74 (S , 3 H, CH 3 C), 2.38 (s, 3 H, CH 3 S), 2.57 15 / js, 6 H, CH 3) 2N_7, 2.81 (m), 3.53 (m, 1 H, CHO ), 3.69 (m, 1 H, CHO), 4.38 (m, 1 Η, H-7), 5.95 (d, 1 Η, Hl), 6.59 (s, 1 Η, H-3), 7.30 (s, 1H, H-11); 13 C NMR (CDCl 3) Ppm 191.1 (C-5), 179.7 (C-12), 160.3 (C-6 ), 155.7 (C-4), 148.2 (Cl), 146.1 (C-10a), 137.7 (C-2), 132.1 (C-11a), 130.3 (C -6a), 125.5 (C-3), 120.6 (C-11), 114.4 (C-12a), 112.5 (C-4a), 110.2 (C-5a), 97.6 (C-11), 75.1 (C-5 '), 72.7 (C-2), 70.5 (C-4), 68.7 (C-9), 66.1 ( C-3 »), 43.9 (C-10), 41.6 /” (CH3) 2N_7, 38.5 (C-7), 36.9 (C-8), 31.2 (C-9 CH3) , 23.9 (C-5 * CH 3), 16.5 (CH 3 S), mass spectrum m / e 557.

Elemental analysis,% calculated for C28H31N09Si 25 C 60.36; H 5.60; N 2.52; S 5.75;

Found: C 58.75; H 5.60; N 2.98; S 5.44.

Example V

Con 7-0-acetylnogarol.

A solution of 1 g of nogamycin in 25 ml of trifluoroacetic acid is stirred at room temperature for 1.25 hours. Afterwards, excess trifluoroacetic acid is removed under reduced pressure, after which the residue is dissolved in 100 ml anhydrous tetrahydrofuran. 3 g of anhydrous sodium acetate are added to the solution and the mixture is stirred for 68 hours. Afterwards, 800 2 1 77 14 the solvent is removed under reduced pressure, after which the residue is dissolved in 100 ml water. The aqueous solution is adjusted to pH 7 and then extracted three times with 35 ml of chloroform each time. The combined chloroform solutions are concentrated to dryness under reduced pressure. The residue is chromatographed on 30 g of silica gel with a mixture of chloroform and methanol (9: 1) as eluent, collecting 10 ml of fractions. The fractions are analyzed by thin layer chromatography using a mixture of chloroform, methanol and water (78: 20: 2) as the solvent, and a product with an Rf value of 0.48 as reference. Based on the results, fractions 23-34 were selected and combined and then evaporated under reduced pressure. Thus, 71 ml of con 7-

O-acetylnogarol obtained. / a / + 674 ° (c: 0.1995, CHCl_); UV

"* U 5 5 15 (C2H5OH) 236 nm (ε 40,150), 259 (ε 21,250), 289 shoulder (e 8,550), 478 (ε 13,150); 1 H NMR (CDCl ^ ppm 1.45 (s, 3 H, CH-jC), 1.73 (s, 3H, CH3C), 2.05 (s, 3H, CH3CO), 2.2-3 (m, CH2 and CHN), 2.62 / * *, OH (CH3) 2n7, 3.1-3.8 (m, CHO), 4.23 (m, 1 Η, H-7), 5.93 (d, 1 Η, H-1 '), 6.62 (s, 1 Η, H-3), 7.23 (s, 1 H, H-11); 13 C NMR (CDCl 3) ppm 190.8 (C-5), 179.5 (C-12), 169.3 (CH3CO), 161.2 (C-6), 155.7 (0-4) ', "148.2 (Cl), 146.7 (C-10a), 137.7 (C-2 ), 133.2 (C-11a), 127.3 (C-6a), 125.7 (C-3), 120.2 (C-11), 115.8 (C-12a), 113.9 (C-4a), 112.8 (C-5a), 97.5 (Cl ·), 75.1 C-5 '), 72.6 (C-2'), 70.3 (C-4 ' ), 67.6 (C-9), 66.2 (C-3 '), 63.9 (C-7), 43.6 (C-10), 41.6 / ((CH ^ NJ, 35 1.7 (C-8), 29.3 (C-9 25 CH 3), 24.0 (C-5 'CH 3), 21.0 (CH 3 CO), mass spectrum m / e 511 (M + -CH 3 COOH).

Example VI

Con-7-bis (carbethoxy) methyl-7-deoxynogarol, A solution of 250 mg of nogamycin in 5 ml of trifluoroacetic acid is prepared. After standing for 1.5 hours, the acid is removed by evaporation under reduced pressure. The residue is dissolved in 10 ml anhydrous tetrahydrofuran and added dropwise to a suspension prepared by adding 0.5 g sodium hydride as a 53% by weight suspension in mineral oil and 1.5 ml diethyl malonate to 40 ml anhydrous tetrahydrofuran with cooling at 0 ° c. After 15 800 2 1 77 min, the pH is adjusted to 7 with 1N hydrochloric acid, after which the reaction mixture is concentrated under reduced pressure. Water (25 ml) is added to the residue and extracted three times with 15 ml of chloroform each time. The combined chloroform solutions 5 are concentrated to dryness under reduced pressure. The residue is chromatographed on 10 g of silica gel eluting with a mixture of chloroform and methanol (95: 5) to collect 5 ml of fractions. The fractions are analyzed by thin layer chromatography using a mixture of chloroform, methanol and water (78: 20: 2) as the solvent, and a sample with an Rf value 0.42 as reference. Based on the results, fractions 14-26 were selected and pooled and then concentrated under reduced pressure. The residue (50 mg) was again subjected to thin layer chromatography using 2 mm thick plates and a mixture of acetone and methanol (9: 1) as the eluent. Thus, con 7-bis- (carbethoxy) methyl-7-deoxynogarol was obtained. Thin layer chromatography using the aforementioned extender showed that the product was homogeneous. 1 H NMR (CDCl 3) ppm 1.10 (t, 3 H, CH 3 CH 3), 1.33 (t, 3 H, "CH 3 CH 2), 1.45 (s, 3 H, CH 3 C), 1.70 (s, 3 H, CH 3 C), 2.46 20 / ~ s, 6 H, (CH 3) 2N_7, 2.20-4.40 (m, CH 2 # CH 2 <>, CHO, CHN), 4.80 ( d, 1

H, CO CO), 5.08 (d, 1 H, H-1 '), 7.10 (s, 1 Η, H-3), 7.15 (s, 1 CH

> Vs'co H, H-11).

25 Example skin

Con 7- (2-methoxyethylamino) -7-deoxynogarol.

A solution of 500 mg of nogamycin in 5 ml of trifluoroacetic acid is prepared. After standing at room temperature for 2 hours, excess acid is removed by evaporation under reduced pressure. The residue is dissolved in 25 ml of anhydrous tetrahydrofuran. 2-Methoxyethylamine is added dropwise to the solution until the solution turns violet. After adjusting the pH to 7.2 with 1 N hydrochloric acid, 50 ml of water are added and the mixture is extracted three times with 50 ml of methylene chloride each time. The 800 2 1 77 16 combined methylene chloride solutions are concentrated to dryness under reduced pressure. The oily residue is washed with Skellysolve B. Then the residue (288 mg) is dissolved in 25 ml of tetrahydrofuran and dry chlorine-5 hydrogen gas is passed through the solution until a precipitate forms. The precipitate is removed by filtration and recrystallized from a mixture of methanol and acetone to yield two portions of product. The products are combined and dissolved in water. The aqueous solution is first adjusted to pH 9 with 0.1 N aqueous sodium hydroxide solution and then to pH 8 with 0.1 N HCl, then the solution is extracted with methylene chloride while maintaining the pH at 8 with a base. The combined methylene chloride solutions are dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Thus, 107 mg of 15 con 7- (2-methoxyethylamino) -7-deoxynogarol were obtained. Thin-layer chromatography with a mixture of chloroform, methanol and water (78: 20: 2) as the running medium and a product with an Rf value of 0.50 as reference showed that the product was homogeneous, IR (Nujol) 3310, 1665 , 1615, 1580, 1565, 1450, 1405, 1370, 1280, 1210, 1095, 1040, 995, 20 905, 875, 850, 830, 770 and 715 cm -1; 1 H NMR (CDCl 3) ppm 1.43 (s , 3 H, CH3C), 1.75 (s, 3 H, CH3), 2.57 / s, 6 H, (CB ^), 3.33 (s, 3 H, CH30), 2.15- 3.55 (CHj, CH2O, CH2N, CHO, CHN), 4.33 <m, 1 Η, H-7), 6.00) d, 1 H, H-1 '), 6.58 (s, 1 Η , H-3), 7.30 (s, 1H, H-11)] 13 C NMR (CDCl 3) ppm 191.0 (C-5), 179.4 (C-12), 160.1 (06) , 155.7 (04), 25 148.4 (Ol), 147.3 (OlOa), 137.8 (02), 132.2 (Olla), 131.4 (06a), 125.6 (03) , 120.9 (Oil), 116.0 (Ol2a), 114.4 (04a), 112.4 (05a), 97.7 (Ol ·), 75.1 (05 ·), 72.7 (C -2 '), 71.6 (0 ^ 0), 70.6 (04), 68.1 (09), 66.0 (03), 58.8 (2 C ^ O), 50.6 (07), 47.1 (CH ^), 44.6 (010), 41.6 / ”(CH3) 2n 7, 34.3 (08), 30.5 (09 CH3), 23.8 (05 30 CH3).

Example VIII

Con 7-Ethylamino-7-deoxynogarol.

A solution of 1 g of disnogamycin in 5 ml of tri-35 fluoroacetic acid is stirred at room temperature for 2.5 hours. At the end of 800 2 1 77 * 17, the solution is concentrated to dryness under reduced pressure.

The residue is dissolved in 20 ml of anhydrous tetrahydrofuran. Ethylamine is passed through the solution under cooling in an ice bath until the mixture turns violet. The mixture is then evaporated to dryness under reduced pressure. The residue is dissolved in anhydrous tetrahydrofuran and dry chlorine hydrogen gas is passed through the 2nd solution until no more precipitate is formed. The orange precipitate is collected by filtration and crystallized in a mixture of methanol and acetone. After removing the solvent-mixture, the product is dissolved in 60 ml of water. The pH of the aqueous solution is adjusted to pH 8.0 with 1 N aqueous sodium hydroxide solution and extracted four times with 20 ml each of a mixture of chloroform and methanol (9: 1). The combined solutions are dried over anhydrous sodium sulfate and, after filtration, concentrated under vacuum to dryness. Thus, 383 mg of con 7-ethylamino-7-deoxynogarol were obtained. Rf: 0.10 (SiO 2; CHCl 3 -CH 3 OH-H 2 O; 78: 20: 2); UV (EtOH) Amax 234 (ε 29,406), 249 shoulder (ε 23,366), 259 shoulder (ε 18,119), 268 shoulder (ε 15,248), 290 shoulder (ε 9,406), 478 (ε 11,980); IR (nujol) 3375, 1665, 1510, 20 1590, 1575, 1290, 1225, 1170, 1120, 1060, 1010, 945, 920, 890, 845, 785 and 710 cm-1; 13C NMR (CDCl3 + CD3OD) ppm 190.8 (C-5), 179.6 (C-12), 159.9 (C-6), 155.6 (C-4), 148.2 (Cl) , 147.0 (C-10a), 137.7 (C-2), 132.3 (C-11a), 131.3 (C-6a), 125.5 (C-3), 120.8 ( C-11), 116.0 (C-12a), 114.4 (C-4a), 112.4 (C-5a), 97.6 (Cl ·), 75.2 (C-5 '), 72.8 25 (C-2), 70.6 (C-4), 68.4 (C-9), 66.0 (C-3 '), 50.6 (C-7), 44 .4 (C-10), 42.0 (CH2NH), 41.6 / "(CH- ^ nJ, 34.2 (C-8), 30.3 (C-9 CH3), 23.8 (C -5 'CH 3), 14.9 (CH 3 CH 2).

Example IX

Con 7-methvlamino-7-deoxynogarol.

30

A solution of 500 mg of disnogamycin in 5 ml of trifluoroacetic acid is stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure. The residue is dissolved in 10 ml anhydrous tetrahydrofuran. Methylamine is passed through the solution under cooling in an ice bath until the 800 2 1 77 18 mixture turns violet. The mixture is then concentrated to dryness under reduced pressure. The residue is dissolved in 10 ml of tetrahydrofuran and 50 ml of water are added to the solution.

The aqueous solution, which has a pH 8.0, is extracted five times with 50 ml of methylene chloride each time. The methylene chloride solutions are combined and filtered after drying over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue is dissolved in 10 ml of methylene chloride and 150 ml of Skellysolve B are added to the solution to form a precipitate. The collected precipitate (241 mg) is dissolved in 25 ml of tetrahydrofuran and dry chlorine hydrogen gas is passed through the solution until no more precipitate is formed. The precipitate is collected and recrystallized in a mixture of methanol and tetrahydrofuran to yield two portions of product. The combined product (204 mg) is dissolved in 30 ml of water. After the pH of the aqueous solution has been adjusted to 8.0 with an aqueous sodium hydroxide solution, it is extracted four times with 50 ml of methylene chloride each time. The combined methylene chloride solutions are dried over anhydrous sodium sulfate and concentrated in vacuo after filtration. Thus, 85 mg of con 7-methylamino-7-deoxy-nogarol were obtained. Rf: 0.12 (SiO2; ChCl3-CH2 OH-^ O; 78: 20: 2); UV (EtOH); Xmax 235 nm (ε 34,225), 248 shoulder (ε 20,820), 258 shoulder (ε 18,139), 290 shoulder (ε 9,621), 480 (ε 12,050); IR (nujol) 3390, 1670, 1625, 1595, 1585, 1305, 1225, 1105, 1050, 1005, 945, 25 920, 890, 830, 780 and 725 cm -1; 13 C NMR (CDCl 3 + CD30D) ppm91.0 (C-5), 179.5 (C-12), 160.0 (C-6), 155.7 (C-4), 148.3 (Cl), 147.2 (C-10a), 137.9 (C-2), 132.4 (C-11a), 131.3 (C-6a), 125.6 (03), 120.9 (Oil), 116.0 (Ol2a), 114.3 (04a), 112.4 (05a), 97.6 (C-1 '), 75.1 (05 *), 72.8 (02'), 70.6 (04 '), 68.4 (09), 66.0 (03'), 30 52.5 (07), 44.5 (OIO), 41.6 / ((CH ^ NJ, 34.3 (CH3 -NH), 33.6 (08), 30.4 (09 CH 3), 23.9 (05 ', CH 3).

Example X.

Con 7-dimethylamino-7-deoxynogarol.

Proceed as in example IX with in place of methylamino diethylamine in 8002177 *. Thus, 146 mg of con-7-dimethylamino-7-deoxynogarol were obtained. Rf: 0.21 (SiC2; CHCl) ^ -CH ^ OH- ^ O (78: 20: 2); UV (EtOH) Xmax 237 nm (ε 27,530), 248 shoulder (ε 20,260), 260 shoulder (ε 14,740), 270 shoulder (ε 13,149), 289 (ε 8.474), 5 478 (ε 10.065); IR (nujol) 3375, 1655, 1615, 1585, 1290, 1220, 1100, 1050, 1005, 920, 840, 780 and 735 cm -1; 13 C NMR (CDClg + CD30D) ppm 190.6 (C-5), 180.0 (C-12j, 161.6 (C-6), 155.6 (C-4), 148.0 (Cl), 147.6 (C-10a), 137.4 (02), 132.8 (Olla), 129.6 (06a), 125.5 (03), 120.4 (Oil), 116.2 (Ol2a), 114.7 (04a), 112.5 (05a), 97.5 (ΟΓ), 10 75.2 (05 '), 72.8 (02'), 70.5 (04 '), 68.6 (09), 66.0 (03') , 56.4 (07), 45.1 (OIO), 41.9 / "(CH ^ 2N_7, 41.5 /" (CH3) 2N_7, 35.2 (C-8), 30.4 (C-9 CH3 ), 23.9 (C-5 'CH 3).

Example XI

Con 7-diethylamino-7-deoxynogarol.

15

Proceed according to example IX with instead of methylamine diethylamine which is added in an amount of 2 ml. There were thus obtained 295 mg of con 7-diethylamino-7-deoxy-nogarol. Rf: 0.14 (SiO2] CHC2 -CR8 OH- ^; 78: 20: 2); ÖV 20 (EtOH) Xmax 236 nm (ε 31,156), 248 shoulder (ε 23,129), 259 shoulder (ε 17,925), 270 shoulder (ε 15,136), 290 shoulder (ε 9,184), 478 (ε 11,361); IR (nujol) 3375, 1655, 1620, 1590, 1295, 1225, 1115, 1055, 1015, 925, 915, 835 and 790 cm -1; 1 H NMR (CDCl3 + CD30D) ppm 1.00 (t, 3H, CH3CH2), 1.18 (t, 3H, CH3CH2), 1.40, 1.73 (2s, 6H, 25CH3C), 2.54 / ~ 2.6H, (CH 2 Ny, 2.75-4.50 (CHO, CHN), 5.52 (s, 1H, H-7), 5.92 (d, 1H, H-1 '), 6.49 (1H, s, H-3), 7.13 (s, 1H, H-11).

Example XII

Con 7-azido-7-deoxynogarol 30 A solution of 1 g of disnogamycin in 10 ml of trifluoroacetic acid is stirred at room temperature for 2.5 hours. Afterwards, excess acid is removed by evaporation under reduced pressure. The residue is dissolved in 30 ml of anhydrous acetone.

2 g of sodium azide are added to the solution and the mixture is stirred for 18 hours. Afterwards, 100 ml of water is added 800 2 1 77 20, after which the pH is adjusted to 7.3 with a 5 wt.% Aqueous sodium hydrogen carbonate solution. The reaction mixture is then extracted three times with 50 ml of methylene chloride each time. The combined methylene chloride solutions are concentrated under reduced pressure. The residue is chromatographed on 100 g of silica gel eluting with a mixture of acetone, methylene chloride and methanol (75:15:10) to collect 5 ml of fractions. The fractions are analyzed by thin layer chromatography using a mixture of acetone, methanol and water (80: 18: 2) and a mixture of chloroform, methanol and water (78: 20: 2) as the runnants. The azide-containing fractions are combined and concentrated to dryness under reduced pressure. There was thus obtained 242 mg of con 7-azido-7-deoxynogarol (yield 32%. Rf: 0.45 (SiC> 2; CHC13-CH30H-H20; 78: 20: 2); ÜV (EtOH) λmax 236 nm (ε 33.762), 258 (ε 17.685), 287 (ε 7.717), 476 (ε 11.093); 15 IR (Nujol) 3425, 2100, 1655, 1615, 1570, 1415, 1335, 1285, 1250, 1220, 1145, 1115, 1100, 1050, 1000, 965, 935, 915, 880, 835, 775 and 720 cm-1; 13 C NMR (CDCl ^ CD ^ D) ppm 189.6 (C-5), 176.0 (C-12) , 160.8 (C-6), 155.7 (C-4), 147.1 (Cl), 146.0 (C-10a), 137 (C-2), 133.1 (C-11a) , 128.8 (C-6a), 125.8 (C-3), 120.4 (C-11), 115.1 (C-12a), _____________________ 20 114.5 (C-4a), 112, 0 (C-5a), 97.4 (Cl), 75.3 (C-5), 72.6 (C-2 '), 70.2 (C-4), 68.6 (C -9), 66.3 (C-3 '), 55.6 (C-7), 43.9 (C-10), 42.1 (C-8), 41.6 / “(CH3) 2Nj , 29.8 (C-9 CH 3), 24.0 (C-5 'CH-1), mass spectrum (FD) m / e 552 (calculated for C 27 H 28 N 4 ° 9 552).

Proceeding according to example II using the corresponding sodium alkoxides, the following con 7-O-alkylnogarols are prepared: con 7-O-ethylnogarol, con 7-On-propylnogarol, con 7-O-isopropylnogarol, con 7- On-butylnogarol, con 7-O-isobutyl-stillarol, con 7-o-tert, butylnogarol.

Proceeding according to example III using the corresponding sodium alkoxides, the high yield con 7-O-alkylnogarols are obtained, for example con 7-On-propylnogarol, con 7-O-isopropylnogarol, con-7-On-butylnogarol, con 7- O-isobutylnogrol and con 7-O-tert-butylnogarol.

Proceeding according to example II or III under 800 2 1 77 21 using the corresponding sodium amino alkoxides, con 7-0-aminoethylnogarol, con 7-0-amino-n-propylnogarol, con 7-0-amino-isopropylnogarol, con 7 O-amino-n-butylnogarol, con 7-O-aminoiso-butylnogarol and con 7-O-amino tert-butylnogarol prepared according to the invention.

Proceeding according to Example IV-VIII using the corresponding sodium alkyl mercaptide, sodium acylate, dialkyl malonate, alkoxyalkylamine, ammonia and alkylamine as nucleophilic reagent, the following compounds are prepared: 10 con 7-ethylthio-7-deocynogarol, con 7-n- propylthio-7-deoxynogarol, con 7-i sopropylthio-7-deoxynogarol, con 7-n-butylthio-7-deoxynogarol, con 7-isobutylthio-7-deoxynogarol, 15 con 7-tert.butylthio-7-deoxynogarol, con 7 -On-propionylnogarol, con 7-O-isopropionylnogarol, con 7-0-n-butyrylnogarol, con 7-O-isobutyrylnogarol, 20 con 7-O-tert-butyrnogarol, con 7-bis (carbo-n-propoxy) methyl -7-deoxynogarol, con 7-bis (carboisopropoxy) methyl-7-deoxynogarol, con 7-bis (carbo-n-butyryl) methyl-7-deoxynogarol, con 7-bis (carboisobutyryl) methyl-7-deoxynogarol, 25 con 7-bis (carbotert.butyryl) methyl-7-deoxynogarol, con 7-methoxypropylamino-7-deoxynogaro1, con 7-methoxyisopropylamino-7-deoxynogarol, con 7-ethoxyethylamino-7-deoxynogarol, con 7-propoxyethylamino- 7-deoxynogarol, 30 con 7-isopropoxyethylamino-7-deoxynogarolf con 7-amino-7-deoxynogarol, con 7-n-propylamino-7-deoxynogarol, con 7-isopropylamino-7-deoxvnogarol, con 7-n-butylamino-7 -deoxynogarol, 35 con 7-isobutylamino-7-deoxynogarol, 800 2 1 77 22 con 7-tert.butylamino-7-deoxynogarol.

Other novel substituted con-configuration nogamycin analogs may be prepared by reacting con-0-nogarayein of the invention, known nougamycin or 7-0-5 alkylnogamycin, and an appropriately selected nucleophilic reagent in the presence of a haloacetic acid in particular trifluoroacetic acid.

10 800 2 1 77

Claims (31)

1. A compound characterized by the formula 4 in which B represents a nucleophilic group with the exception of -O-lower alkyl and T a hydroxyl group in which the groups B and T are bound in a ring system (a or β-configuration) to the ring system as well as the pharmaceutically acceptable acid addition salts thereof. 2. A compound according to claim 1, characterized in that B represents ratherosyl, sulfide anion, organic acid anion, amino, substituted amino, azido or carbanion. A compound according to claim 2, characterized in that B represents ratherosyl, lower alkylthioxyl, low acyloxy, lower alkyl-amino, azido, bis (carbalkoxy) alkyl, alkoxyalkylamino or amino-alkylalkoxy. Compound according to claim 3, characterized in that B represents ratherosyl and the compound is con-beta-nogamycin. Pharmaceutically acceptable acid addition salt of the compound according to claim 4 ._____________________ A compound according to claim 3, characterized in that B represents methylthio and the compound is con 7-methylthio-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 6. A compound according to claim 3, characterized in that B represents acetoxy and the compound is con 7-o-acetylnogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 8. Compound according to claim 3, characterized in that B (biscarbethoxy) represents methyl and the compound is con 7-bis (carbethoxy) methyl-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 10. A compound according to claim 3, characterized in that B represents 2-methoxyethylamino and that the compound is con 7- (2-methoxymethylamino) -7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 12. A compound according to claim 3, characterized in that B represents methylamino and the compound is con 7-raethylamino-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 14. A compound according to claim 3, characterized in that B represents dimethylamino and that the compound is con 7-dimethylamino-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 16, A compound according to claim 3, characterized in that B represents ethylamino and that the compound is con 7-ethyl-amino-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 18, A compound according to claim 3, characterized in that B represents diethylamino and that the compound is con 7-diethyl-amino-7-deoxynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 20. 25 A compound according to claim 3, characterized in that B represents azido and that the compound is con-7-azido-7-deox-ynogarol. A pharmaceutically acceptable acid addition salt of the compound of claim 22. 30 A compound according to claim 4, 6, 8, 10, 12, 14, 16, 18, 20 or 22, characterized in that the compound is acylated in which the acyl group consists of a carboxylic acid residue with 2-18 carbon atoms, optionally substituted by halogen, nitro, amino, cyano or lower alkoxy, as well as the pharmaceutically acceptable acid addition salts thereof. 800 2 1 77 25, A method of preparing a compound, characterized in that a compound is prepared of the formula 1 'wherein B' represents a nucleophilic group and T represents a hydroxyl group with the groups B 'and T' in a con configuration (a or 5-configuration) are bonded to the ring system by mixing a compound of the formula 6 wherein and R 2 each represents hydrogen, lower alkoxy or ratherosyl where R 1 or R 1 is always hydrogen, with a haloacetic acid and treating the mixture with a nucleophile reagent. The process according to claim 25, characterized in that the obtained compound of formula 1 'is converted into a pharmaceutically acceptable salt. 27. A method according to claim 25, characterized in that trifluoroacetic acid is used as haloacetic acid. The process according to claim 25, characterized in that the nucleophilic reagent used is an -O-alkyl compound, -O-aryl compound, -S-aryl compound, -S-alkyl compound, -O-acyl compound, bis (carbalkoxy) alkyl compound, ammonia, alkylamine, azide, ratherosyl compound, alkoxyalkylamine or aminoalkylalkoxy compound. 29. Process according to claims 25-28, characterized in that the compound prepared is con 7-O-methylnogarol, con 7-methylthio-7-deoxynogarol, con 7-O-acetylnogarol, con 7-bis (carbetho-xy) methyl -7-deoxynogarol, con 1 "S-nogamycin, con 7-O-ethylnogarol, 25 con 7- (2-methoxyethylamino) -7-deoxynogarol, con 7-methylamino-7-deoxynogarol, con 7-dimethylamino ~ 7-deoxynogarol is con 7-ethylamino-7-deoxynogarol, con 7-diethylamino-7-deoxynogaro1 or con 7-azido-7-deoxynogarol. 30. A pharmaceutical composition with antibacterial activity, characterized in that the composition as active ingredient contains a compound of the formula 4 as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof. 31. Compounds, methods of preparing the same, compounds available by methods as well as pharmaceutical preparations as described in the description and examples. 800 2 1 77 ch3 oh N ^ j '] *, o CHl L' O ^ O 0 COCHj X Ji i CHi cvfTTTr ° H • VVYV 'OH 0 OH 0 j CHjO fil0 j / CHs \ f <h "\ CH3. / I] Γ + Μ 3 * I2 I OCH, ΟΟΗ ^ CH3 OH CH3 J 9 0 CHj 0H TY ^ fV OH 0 OH HB * CH3 OH 7Νγν Ch3 Αν), I 0 CH3 HO ^ X. ji Λ / ch; I | j ^ -oh 'VYW1 la OH 0 OH 0, cl H3C0X0 * Y \ i "3" r 800 2 1 77 oh? 3 The Upjohn Company, Kalamazoo, Michigan, USA America Y * OH hc> s. “9 A] IO COH ° H MrWvCH> ζη \ ΧΥΎΎ ° η ho o I \ 0H, ° CH1 ™ Η ' % Ί οίγΧ CH. 2 t 3 OH 1 ULM3 / N> V ^ x 0CH * ch3 ^ iT γη 3 oh 0 ^ h or CHÏ | Τ Jj T T.I V \ OH,. 4 HO O jC. CH B CH 'X. O ----- 0H HO' ^ Mi Ji A CHS '- \ v C ^ 3 I | ^ 5 ^ * 0Η '' JCj I S_. J ~ H> N \ HO P> OH \ 5 urn OCH chY T 11) \ HicoiiS οΓ o oh r1'r, .. \ * \ ch '»/ haLoacetic acid \ HCOrrO V 6 stapl.Τ' \ XhaLoacetic acid \ cnB ' \ intermediate \ BV ^ \ ^^ stapll __Γ ____ / R '-N 800 2 1 77 NR "7 The Upjohn Company, Kalamazoo, Michigan, USA. America