DE2607459A1 - NEW ANTIBIOTIC COMPOUNDS, METHODS FOR MANUFACTURING THEM AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new macrolide compounds derived from antibiotic 67-694, also known as rosamicin, can be derived. The invention is further to medicaments containing these compounds and methods directed to the manufacture of these compounds and pharmaceuticals. The new compounds have antibacterial properties Activity.

Rosamicin, previously known as antibiotic 67-694, and certain derivatives of rosamicin are described in GB-PS 1 302 142. Rosamicin is made by the microorganism Micromonospora rosaria, also described in the aforementioned British patent is described. It has the structural formula

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Telephone: (02 21) 23 45 41-4 Telex: 888 2307 dopa d Tuluyrainm: Dompalc-nt Cologne

II

OH

As the formula (II) shows, rosamicin is a dihydroxy compound with a hydroxyl group in the 3-position of the macrolide ring and a further hydroxyl group in the 2'-position ^! the glycosidically bound sugar component. Both hydroxyl groups can be esterified, but the group in the 2 "position is the group that reacts first. Thus, to form a 3-monoester it is necessary to esterify both hydroxyl groups and to use selective hydrolysis to remove the 2'-ester function Such ' hydrolysis is described in the South African patent specification 73/8630 (August 16, 1974) The new hydrolysis can also be applied to the 3,2'-diesters of the compounds according to the invention.

The invention relates to derivatives of rosamicin with of the planar general formula (I)

CH.

CH = Z

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26074ÜW

and their non-toxic pharmaceutically acceptable acid addition salts. In this formula, the dashed lines denote optional double bonds; Q stands for 0 or / OR *, Z for 0 or a group of the formula

^ H '^ CR ", ^ SR", NOR «or NOR";

R and R ¹ stand for hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms and R ″ for hydrogen or an alkyl radical with 1 to 5 carbon atoms; B, together with the carbon atoms of the 12 and 13 positions, forms the it is bonded, a single bond or a double bond or, if Q or Z does not stand for 0 or if the macrolide ring is saturated between positions 10 and or unsaturated between positions 2 and 3, it can also be an oxirane ring; W stands for OR ¹ or hydrogen, where R · has the meaning given above, with the proviso that, when the 2-position and 3-position are connected by a double bond, W is hydrogen and the two radicals D are either hydrogen or can, if the 10- and 11-positions are connected by a single bond, both also ^{stand for OR 1} , where R ^{1 has} the meaning given above, and with the further proviso that Z does not stand for / OR ¹ ; if in a compound B is a double bond, the carbon atom e of the 10- and 11-positions are connected by a double bond, the carbon atoms of the 2- and 3-positions are connected by a single bond, both radicals Ü are hydrogen, Q is 0, W is OR ¹ and R and R are ^{1 have} the meanings given above.

: hel-f

Particularly noteworthy are compounds in which the dashed lines, Q, Z, R, R ¹ , R "and W have the meanings given above, B together with the carbon atoms in the 12th and 13th positions to which it is bonded is, a single bond or a double bond, or when Q and Z are not 0 and the Makroli'dring between

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ORIGINAL INSPECTED

10 and 11 positions saturated and between the 2 and 3-positions is unsaturated, can also be an oxirane ring and both radicals D are either hydrogen or, if the 10- and 11-positions are connected by a single bond and W stands for OR ', can also be OH. Particularly compounds in which Z is 0 or

the group <OR ',
H

OR "or NOH stands. In these connec-" OR "

fertilize R and R ^{1 are} often hydrogen, acetyl or propionyl and R "hydrogen or methyl.

A preferred group is formed by derivatives of rosamicin according to the invention which do not contain an oxirane ring. These compounds are preferably described by the general formula (I ¹ ) (which is covered by the general formula I).

CH

3 CH = Z

CH.

I ¹

Here the substituents and the dashed lines *

the same meanings as in formula (I). j

1 The invention is particularly directed to compounds of the formula ..

(I ¹ ), in which the dashed lines represent single bonds j, Q, Z, R, R ¹ and R ″ the abovementioned meaning I

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have connections, W is OR ¹ , in which R 'has the abovementioned meaning, and both radicals are DV / hydrogen, in particular directed to compounds in which.

Z stands for O or before ", where R" is an alkyl radical, . ν OR "

R and R ^{1 are} preferably hydrogen and R ″ is a methyl radical. 12,13-Desepoxy-10,11-dihydrorosamicin is an outstanding representative of this group of compounds.

A preferred group of compounds according to the invention is formed by compounds of the formula (I) (or I ¹ ) in which B together with the carbon atoms in the 12- and 13-positions represents a double bond, in particular compounds in which both radicals ^{D are} hydrogen and the 10 and, 11 positions are linked by a double bond.

For the group of compounds in which W is hydrogen and the 2- and 3-positions by a double bond are linked, especially those compounds in which Q and Z are O, is 2.3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosamicin to be named as a representative.

Another group of compounds in which B is in the ^; Formula (I) together with the carbon atoms of the 12- and 13-positions represents a double bond, form compounds in which W is OR ¹ , where R * has the meaning given above, and the 2- and 3-positions by a Single bond are connected. From this group of compounds those are to be singled out in which Q is for

t τ I

<C ", in which R ^{1 has} the meaning given above.! OR

A preferred representative of this group is 9, bJ-dihydro-12,13-desepoxy-12,13-dehydrorosamicin to call.

From this group, compounds in which Q stands for O are also of interest. Particularly noteworthy are connections in which Z for <nS! ^{3 ode} * " ^N0H . Representatives of these compounds are, for example, 12,13-

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Desepoxy-12,13-dehydrorosamicin-20-dimethylacefcal and 12,13-Desepoxy-12,1 3-dehydrorosamicin-2ü-oxiiu should be mentioned.

A preferred group of compounds of the general formula (I ·), however, form those compounds in those the 12 and 13 positions and the 10 and 11 positions are connected by a double bond and the 2- and 3-positions are connected by a single bond, Q and Z stand for O and W stand for OR "· As a representative of this group of compounds is 12,13-desepoxy-12,13-dehydrorosamicin to call. The trans form of this compound is preferred.

The invention further comprises compounds of the general formula (I) in which B together with the C atoms in the 12- and 13-positions forms an oxirane ring. A group of these compounds is represented by compounds in which W is hydrogen, in particular by compounds in which the 2- and 3-positions and the 10- and 11-positions are connected by a double bond, in particular by compounds in which Q and Z stand for 0 (e.g. 2,3-dehydro-3-deoxyrosamicin). Another group of these compounds includes compounds in which W is OR », especially those compounds in which the 10- and 11-positions are connected by a single bond and both groups D are hydroxyl groups, especially those compounds in which Q and 2 are 0 (e.g. 10jll-dihydroxy-10jll-dihydro-; rosamicin). Further groups of these compounds in which W is OR ¹ form compounds in which D is hydrogen (especially those in which the 10- and 11-positions are connected by a single bond), and those in which Z is ^ 0R ¹ stands, or

^ H

bonds in which Z stands for NOR "or / OR" and

the 10- and 11-positions are linked by a double bond, furthermore compounds in which Q stands for

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/ OR ¹ stands. Representatives of these groups of compounds ^ H

are mentioned in Table I below. A preferred compound of this group is 9,9-dihydrorosaraicin.

Particularly preferred of the compounds according to the invention are ^, IS-desepoxy-iajlS-dehydrorosamicin, 9-dihydrorosamicin and 9-dihydro-12,13-desepoxy-12,13-dehydrorosamicin, including the non-toxic pharmaceutically acceptable esters and non-toxic pharmaceutically acceptable acid addition salts thereof Links. '

Non-toxic, pharmaceutically acceptable acid addition salts are to be understood as meaning the salts generally used in the pharmaceutical field. This term includes the salts formed with inorganic acids such as sulfuric acid, phosphoric acid and hydrohalic acids (e.g. hydrochloric acid) and the salts formed with carboxylic acids having 2 to 18 carbon atoms, e.g. aliphatic, cycloaliphatic, aromatic and heterocyclic carboxylic acids including dicarboxylic acids. As examples of such acids may be mentioned: acetic acid, propionic acid, butyric acid, pivalic acid, Valeriansäurej hexanoic acid, octanoic acid, decanoic acid, stearic acid, succinic acid, glutaric acid, malonic acid, tartaric acid, citric acid, maleic acid, Cyclopropylcarbonsäure, cyclopentyl carboxylic acid, adamantane _s g _acid (adamantoic)! Furanic acid, nicotinic acid, thenoic acid, picolinic acid, benzoic acid, phthalic acid, phenylacetic acid and monopotassium phosphoric acid. A preferred class of non-toxic, pharmaceutically acceptable acid addition salts is formed by the alkyl sulfate salts in which the alkyl radical contains 10 to 18 carbon atoms.

The non-toxic, pharmaceutically acceptable esters according to the invention include esters of those generally referred to in the pharmaceutical Area used acids. These include

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Esters of carboxylic acids with 2 to 18 carbon atoms. The expression includes aliphatic, cycloaliphatic, aromatic and heterocyclic esters including the half-esters with dicarboxylic acids such as maleic acid, malic acid and malonic acid. Acids with 2 to 10 carbon atoms, in particular with 2 to 5 carbon atoms, are expediently used. Of the cycloalkanecarboxylic acids, those with 4 to 11 carbon atoms can advantageously be used. In the aryl and arylalkanecarboxylic acids, the aryl radical is expediently a phenyl radical and the alkyl radical in the arylalkanecarboxylic acids is a lower alkyl radical. Of the heterocyclic carboxylic acids, it is expedient to use those in which the cyclic component contains 5 to 6 ring atoms, in particular a hetero atom (for example S or 0), and is unsaturated. For example, acids which have been mentioned above as being suitable for the preparation of pharmaceutically acceptable acid addition salts, excluding the acids used for the preparation of the alkyl sulfate salts, are suitable. ^{In cases in which a 2 1} - and a 3-hydroxyl group are esterified in a compound according to the invention, the invention also includes the mixed esters. For example, 12,13-deepoxy-12,13-dehydrorosamicin can be esterified at the 2'-position with an acylating agent derived from a hydrocarbon carboxylic acid and then esterified in the 3-position with an acylating agent derived from another hydrocarbon carboxylic acid.

From the esters of compounds are preferred in which R and / or R ¹ is acetyl, propionyl, pivaloyl, ^stearoyl,:

or benzoyl. ;

The stearates, lauryl sulfates and potassium dihydrogen phosphate salts are frequently preferred as salts.

Specific compounds according to the invention are listed in Table I below. This table applies to

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the formula I. In this table, "s" stands for a single bond (e.g. between the carbon atoms in the 2- and 3-positions) and "d" for a double bond.

The general-. Formula (I) does not express any stereochemical assignment. It is known, however, that some of the compounds of the formula (I) occur in the cis form as well as in the trans form, and some of the groups can be in the α or β position, for example the methyl radical in the 23 position, the OR ' Groups in the 9, 10, 11 and 20 positions and the OR ¹¹ and SR "groups in the 20 position.

No indication of the stereochemistry of these compounds is given in Table I below. It is to be noted that compound 2 is the trans isomer and compound 17 is the cis isomer of 12,13-deepoxy-12,13-dehydrorosamicin is.

As Table I shows, the definition of β (e.g. in claim 1 for formula I) is to be understood to include all of them an oxirane ring-containing compounds in which at least one of the aforementioned provisos is satisfied.

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FY 1 <Λ »Λ υ Ä O O O ο ο O O 8 = ° \ / ο == ο
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ORIGINAL INSPECTED

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O
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B. S. D. C. S. Table I. (Cont.) W. C. 3 f
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The compounds according to the invention can generally
prepared according to the procedure described below
will.

A: compounds of the general formula (III)

^ ^H CH = Z

CH

III

CH.

N (CH),

in which the dashed line is an optional double

OR '

is, Q for 0 or <, Z for 0 or a group of

OR 'OR "^ R

Formula <", <X"",C" _n , NOR ¹ or NOR ", R and R ¹

rl UK £> K

rl UK £> K

Are hydrogen, R "is hydrogen or an alkyl radical with
1 to 5 carbon atoms, W is OR ¹ , in which R ^{1 has} the meaning given above, or is hydrogen with the proviso that, if the 2- and 3-positions are replaced by a double bond,

are connected, W is hydrogen, and with the further

OR '

Provided that Z does not stand for <if the carbon atoms of the 2- and 3-positions in a compound are connected by a single bond, Q stands for 0, W stands for OR ¹ and; R and R 'have the meanings given above. These
Compounds can be obtained by reducing suitable '

Wise substituted compounds of the general formula,

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CH.

N (CH,),

or of non-toxic, pharmaceutically acceptable acid addition salts of these compounds, in which the dashed

-OR ¹ 'line is an optional double bond, Q for 0 or < _u ,'

OR 'Z for 0 or a group of the formula <C _H / ■ *

^, NOR ¹ or NOR ",. R and R ^{1 are} hydrogen or carbon

are lenwasserstoffcarbonyl with 2 to 18 carbon atoms, R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, W is OR ¹ , where R 'has the meaning given above, or is hydrogen with the proviso that, if the 2- and 3-positions are connected by a double bond, W is hydrogen

OR '

and with the further proviso that Z does not stand for <^, if the C atoms of the 2- and 3-positions in a compound are connected by a single bond, Q 'stands for 0, W stands for OR ¹ and R and R ^{1 have} the meanings given above, are prepared. In this process, the oxirane ring between positions 12 and 13 is replaced by a double bond, and the ester groups contained in the starting material are at least partially solvolyzed.

The above process can be carried out with alkali metal bromides or, preferably, with alkali metal iodide in an organic acid at a temperature above ambient temperature. The carbon ' acids preferably contain 1 to 4 carbon atoms. This reaction can also occur in aromatic hydrocarbons, e.g. benzene, toluene or xylene, the concentrated iodine

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containing hydrochloric acid. Another possibility is the treatment of the starting material of formula (IV) with phosphorous acid trialkoxides, trialkylphosphines, triphenylphosphines or Hexalkyl phosphoimidates.

A preferred medium for carrying out this reaction. is potassium iodide in acetic acid that is refluxed will. The reaction product can advantageously be prepared by diluting the reaction mixture with ice water, extraction the product with a water-immiscible organic solvent, washing the extract and isolating of the product can be isolated from the extract.

When carrying out the abovementioned process, it is generally necessary to use the reaction mixture to reflux in an acidic medium. This creates the risk of decomposition of the Starting material and / or the decomposition of the product. Therefore, yields of about 30% are obtained with this method to 50% of theory, and this product consists of substantial amounts of both the ice and des trans isomers

In the new processes described below, the compounds of the above general formula (III), in particular when used for the conversion of ι rosamicin into ^, lS-deepoxy-l ^ jlS-dehydrorosamicin, are obtained in yields of 85 to 95%, and these Compounds are about 90% pure. Furthermore, this new process leads to a product which is rich in the trans isomer and therefore does not require chromatographic separation of the isomers. \

ι The new method is characterized in that you!

Compounds of the general formula (IV) in a preferably dilute mineral acid solution, the chromium (II) -

contains ions, reduced in an oxygen-free atmosphere. '

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The reducing agent, i.e. the chromium (II) ions, are advantageously supplied in the form of a solution containing a chromium (II) salt in which the anion of a Mineral acid, e.g. chromium (II) chloride, chromium (II) sulfate or chromium (II> iodide), is preferred as a reducing agent is chromium (II) chloride, which is advantageous according to the method described in Inorganic Synthesis, Volume III, page 148-150, edited by McGraw-Hill in 1950, can be prepared. Preferably the Chromium chloride solution freshly prepared immediately before use to prevent the formation of higher quality To prevent chromium ions.

Furthermore, in order to achieve optimal yields of the desired product, the ratio of chromium (II) ions to the output, raw material range from 2.0 to 2.2 moles per mole. When the ratio of chromium (II) ions to starting material is below 2.0, a certain amount of the starting material remains unreduced. Conversely finds Reduction of the desired product takes place when the ratio of chromium (II) ion to starting material is above 2.2 lies.

Suitable mineral acids for carrying out this process are, for example, hydrohalic acids (for example hydrochloric acid), phosphoric acid, nitric acid and preferably sulfuric acid. Furthermore, the strength of the acid is preferably about 0.5n to 0.3n, preferably about 1, On. The concentration of the starting material in the react ^! tion mixture can advertising \ the provided in a wide range varied such that the pH of the reaction mixture does not exceed 2.0, and the pH of preferential I between 0.8 and 2, in particular, for example, 'from about 1.0 is held. Since rosamicin is basic, it reacts with 1 equivalent of acid per mole, making the! The pH of the reaction mixture rises. Preference is given to a rosamicin concentration in the reaction mixture of

■ ■ '' ■ i

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about 125 to 175 mg / ml.

The reaction takes place at temperatures of about 10 ° to AO ⁰ C ₁ , a temperature of about 25 ° C being preferred. The reaction time can be about 8 to 24 hours, with about 15 to 20 hours being preferred.

After complete conversion of the starting material, the product is isolated by conventional methods, preferably by extraction with a water-immiscible organic solvent, basifying the Reaction mixture and renewed extraction with a water-immiscible organic solvent. That Finally, the product is isolated by evaporating the solvent.

When using this process to convert rosamicin into 12,13-deepoxy-12,13-dehydrorosamicin the rosamicin preferably at 25 ° C in in-sulfuric acid under argon with chromium (II) ions that of chromium (II) chloride originate, reduced, the molar ratio of chromium chloride to rosamicin is 2.2: 1 and the Reduction is carried out about 18 hours.

Process A described above can be used, for example, for the preparation of compounds 2 and 17 (trans- and cis-form), 10, 22, 24, 25, 3b », 44 or 4y of Table I using rosamicin or appropriately substituted derivatives of rosamicin can be used as starting materials.

B: Compounds of the general formula (I) in which the dashed lines represent optional double bonds; represent, Q stands for 0 or ^ 0R ¹ , Z stands for NOR »or NOR",

R and R ^{1 are} hydrogen or hydrocarbon carbonyl with ^; 2 to 18 carbon atoms, R "is hydrogen or an alkyl; radical with 1 to 5 carbon atoms, B together with the carbon atoms of the 12- and 13-positions to which it is bonded, '

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represents a single bond or a double bond or an oxirane ring, W represents OR ¹ , in which R ^{1 has} the meaning given above, or is hydrogen with the proviso that, when the 2- and 3-positions are connected by a double bond, W is hydrogen and both radicals D are hydrogen or, if the 10- and 11-positions are connected by a single bond, they can also represent OR ¹ , in which R ^{1 has} the meaning given above, can be achieved by reacting compounds of the general formula ( I) or their acid addition salts, in which the dashed lines, Q, B, W, R, R ¹ and D have the meanings given in this paragraph and C stands for 0, are prepared with hydroxylamine or a suitable derivative of hydroxylamine. These reagents can be represented by the general formulas R ¹ ONH ₂ (V) and R ¹¹ ONH ₂ (VI), in which R ¹ and R ″ have the meanings given above. Examples of these reagents are hydroxylamine, methoxyamine and acetoxyamine .

This process can be carried out in organic solvents, e.g. alcohols having 1 to 5 carbon atoms, benzene, toluene, i tertiary amines, e.g. pyridine, ethers, esters or in an aqueous medium. Using an aqueous medium is to be expected that ester groups contained in the starting material during the Reaction to be hydrolyzed.

In this process, hydroxylamine or a hydrohalide of hydroxylamine, especially the hydrochloride, is preferably used. When using the hydrochloride (halide), the reaction medium must be a base ^! (e.g. sodium bicarbonate, triethylamine or pyridine) in the I.

Excess included. J

The process is generally carried out at elevated temperature j door (30 ⁰ C to the reflux temperature of the reaction medium), preferably between 60 ° and 100 ° C.

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For example, compounds 10 and 11 listed in Table I can be used by this method the compound 2 of Table I are prepared as starting material or from rosamicin,

Compounds in which Z is NOR ¹ or NOR ", where R ¹ and R" are not hydrogen, can be prepared by acylation or alkylation of the corresponding oxime. (In the usual acylation process, possible free hydroxyl groups in the 3-, 20- and 2 * -position are also acylated.)

C: Compounds of the general formula (I) in which the dashed lines are optional double bonds, Q for 0 or ^ 0R ¹ , Z for ^ 0R ¹ and R for water

π π

substance, B together with the carbon atoms of the 12- and 13-positions to which it is bonded represents a single bond or a double bond or an oxirane ring, W represents OR ¹ or hydrogen with the proviso that, if the 2 - and 3-positions are connected by a double bond, W is hydrogen, or in which both radicals D are hydrogen or, if the 10- and 11-positions are connected by a single bond, both can also be OR ¹ , in which R ^{1 is} hydrogen , with the exception of compounds in which B is a double bond, the carbon atoms in the 10- and 11-position are connected by a double bond and the carbon atoms in the 2- and 3-position are connected by a single bond, both radicals D are hydrogen, Q is 0, W is OR ¹ and R and R ^{1 have} the meanings mentioned ocen, can be obtained by reducing compounds of the general formula (I) in which the dashed lines, Q, B , W and D have the meanings given in this paragraph, R and R ¹ water material or carbon, hydrogen carbonyl with 2 to 18 carbon atoms and Z stands for 0, are produced. The reduction is carried out under conditions such that reduction only takes place in the 20-position. '

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Reagents such as tetrabutylamine cyanoborohydride are suitable as reducing agents in an acidic medium and lithium aluminum tri-tert-butoxyhydride, the latter is preferred. The reduction is preferably carried out in an organic solvent such as an ether (e.g. diethyl ether and ethylene glycol diethyl ether), dioxane and especially tetrahydrofuran in general at about Carried out at room temperature.

For example, this method is suitable for the reduction of rosamicin and its 12,13-deepoxy-12,13-dehydro- or 10,11-dihydro derivatives to the corresponding 20,20-dihydro compounds. In particular, the compounds 7 and 12 mentioned in Table I can be prepared by this process are prepared, using rosamicin or the compound 46 mentioned in Table I as starting materials be used.

D: compounds of the general formula Dft

VII

in which the dashed line is an optional double

OR '
bond, Q for 0 or <", Z for 0 or for a

Xl

Group of formula

.., NOR ¹ or MOR "

R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 18 C atoms, R "is hydrogen or a C ^ -C ^ -alkyl radical, B together with the C atoms in the 12- and 13-positions to which it is bound, a single bond, a double bond or a

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Oxirane ring and the radicals D are both hydrogen or, if the 10- and 11-positions are connected by a single bond, both OR ¹ can be, by eliminating the eliminable group T and a hydrogen atom in the 2-position from compounds of the general formula

N (CH,),

wherein the dashed line, B, D, Q, Z, R, R ¹ and R "; have the meanings given in this paragraph, are produced. The group T is a group such as, for example, alkylsulfonyloxy, aralkylsulfonyloxy, arylsulfonyl-

OXy (E.g. 0, .ELSO,., 011.0, H ₁ SO ,, CH, SO ,, CF..SO-., CF, CH-, SO.). obJ J ο 4 J JJ JJ JZJ

This process can be carried out by heating the starting material in the presence of a tertiary amine such as pyridine, collidine and picoline. Except for the amine, in particular Pyridine, an organic solvent such as benzene, toluene and xylene can also be present in the reaction medium be.

The compounds mentioned in labeile I 18, 19, 38, 39, 43, 44, 46 and 49 can, for example, by this process from the corresponding compounds of the formula (VIII)! getting produced. ,

In the starting material of this process, R is preferably!

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a hydrocarbon carbonyl, which, if desired, possibly removed from the product of this process during the isolation of the post-reaction product will.

The starting material for this process can, for example, be prepared from rosamicin or a suitable derivative of rosamicin in which the 2- and 3-positions are connected by a single bond and a hydroxyl group is attached to the 3-position. For example, a 2 ^f monoester of rosamicin (or 12,13-DeSePOXy-I ^, 13-dehydrorosamicin, 12,13-des-; epoxy-10,11-dihydrorosamicin, 20,20-dihydrorosamicin and 10,11-dihydrorosamicin ) treated with an alkyl or aralkyl sulfonyl halide, preferably methanesulfonyl chloride, in the presence of a tertiary amine, preferably pyridine. The product obtained in this way can be used in the process described above without isolation from the reaction medium.

E: compounds of the general formula

where Q is O or

Formula ^ 0R ¹ , ^ H

R "

, Z stands for 0 or a group of the SR ", NOR · or NOR",

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R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms in the 12- and 13-position to which it is bonded is, forms a single bond or an oxirane ring, W is OR ', where R' has the meaning given above, or is hydrogen and the two radicals D are hydrogen, can be obtained by catalytic hydrogenation of appropriately substituted compounds of the general formula (I), in the Q, Z, R, R ¹ , R "and D have the meanings given in this paragraph, the dashed lines are optional _: double bonds, B together with the C atoms of the 12- and 13-positions to which it is bonded , forms a single bond, a double bond or an oxirane ring, W represents OR «or hydrogen and R ^{1 has} the meaning given above, with the proviso that if the; 2- and 3-positions are linked by a double bond, W is hydrogen.

In this process, for example, noble metal catalysts, for example palladium carbon,! and catalysts such as Raney nickel and rhodium chloride 'triphenylphosphine complex may be used. Palladium carbon is usually preferred.

The hydrogenation is _r in a neutral solvent such as a C * -C. Alcohol, preferably methanol or ethanol, and water or in hydrocarbon carboxylic acids carried out. It should be noted that ester groups are at least partially hydrolyzed in an aqueous medium.

The reaction will generally take place at about room temperature temperature, but it is also possible to work at higher temperatures of up to about 50 ° C. I.

During this process, all of the | Double bonds saturated. This process is preferably used for the hydrogenation of compounds which \

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one. Double bond between the positions 12 and 13 and / or 10 and 11 contain. In the starting material, Q is preferably 0, W is OR ¹ and Z is 0, ^, 0R ¹

™ » ^{< H}

or "X) R". -.

Table I lists numerous compounds that can be prepared by this process (Connections 1, 3, 4, 8, 12, 13, 33-37, 40-42, 45-47 and 50).

F: compounds of the general formula I in which the dashed lines are optional double bonds,

Q stands for 0 or ^ OR ¹ , Z stands for ^ 0R ", R and R · ^ H" NDR "

Are hydrogen or hydrocarbyl carbonyl with 2 to 18 carbon atoms, R "is an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms of the 12- and 13-positions to which it is bonded, a single bond, a Forms a double bond or an oxirane ring, W is OR ¹ or hydrogen, where R ^{1 has} the meaning given above, with the proviso that when the 2- and 3-positions are connected by a double bond, W is hydrogen, and both radicals D are either hydrogen or, if the 10- and 11-positions are connected by a single bond, both can also ^{stand for OR 1} , can be obtained by treating the corresponding 20-aldehyde compounds (ie compounds of the formula (I) in which the dashed lines , B, D, Q, R, R · and W have the meanings given in this paragraph and Z stands for 0) with an alcohol having 1 to 5 carbon atoms in the presence of a catalyst which is a proton donor.

Suitable catalysts are generally known. Inorganic acids (for example HCl, HpSO ₄ ), organic acids (for example difluoroacetic acid and p-IbIuolsulfonic acid) and salts (for example tin (IV) chloride) are suitable, for example.

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The preferred catalyst for this process is difluoroacetic acid.

The reaction can be carried out without an additional solvent, but sometimes the addition of a anhydrous solvent, e.g. benzene, toluene or xylene, for example when using tin (IV) chloride as a catalyst, preferred.

Preferably, methanol, ethanol or propanol, especially methanol, are used in this process.

The process can be carried out at elevated temperature, but is preferably carried out at ambient temperature worked.

Ester groups contained in the starting material can be at least partially solvolyzed in this process.

As an example of this process, the preparation of compounds 21 and 22 of Table I from rosamicin or 12,13-desepoxy-12,13-dehydrorosamicin can be mentioned, but other compounds of the formula I, e.g. compounds 23, 24, 33 and 35-45 of Table I can be prepared accordingly.

G: Compounds of the general formula I in which the dashed lines are optional double bonds, Q is ^ OR ¹ , Z is ^ uR ¹ or ^ OR ";

R and R ^{1 are} hydrogen; R "is an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms in the 12- and 13-positions to which it is bonded forms a single bond, a double bond or an oxirane ring, W stands for OR ¹ or hydrogen with the proviso that _(when the 2- and 3-positions are linked by a double bond ■, W is hydrogen, and the two radicals D 'are either hydrogen or, when the 10- and HS SETUP are connected by a single bond, both

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can also be OR ¹ , where R ^{1 has} the abovementioned meaning, can be obtained by reducing compounds of the general formula (I) in which the dashed lines, B, D, R "and W have the meanings given in this paragraph and Q for O, Z for O or ^ OR ",

R and R ^{1 are} hydrogen or hydrocarbon carbonyl having 2 to 18 carbon atoms, in the 9-position and, if Z is 0, in the 20-position.

Suitable reducing agents are, for example, sodium borohydride, sodium cyanoborohydride, tetrabutylammonium borohydride and lithium tri-tert-butoxyaluminum hydride, where Sodium borohydride is often preferred.

The reaction is carried out in a solvent. Organic solvents, for example, are suitable Solvents, e.g. tetrahydrofuran, dioxane, alcohols (usually with 1 to 4 carbon atoms), glycol ethers, e.g. Ethylene glycol diethyl ether.

For example, with lower alkyl radicals in 20-

di
Position substituted acetals, preferably dimethylacetal, of rosamicin or of 12,13-deepoxy-12,13-dehydrorosamicin in the 9-position, preferably with sodium borohydride in an alcoholic medium, are reduced, the corresponding 9,9-dihydro analogs being obtained. For example, when this reaction is applied to 10,11-dihydrorosamicin, the compound 12! from Table I (9,9,10,11,20,20-hexahydrorosamicin) obtained.

Under the conditions of this reaction, ester groups contained in the starting material are hydrolyzed. i

According to this process, the compounds 12, 23, 24, 33 and 41 to 45 mentioned in Table I, the mixtures the 9a and 9ß forms of the corresponding compounds

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represent, are produced.

H: Compounds of the general formula (I) in which the dashed lines represent optional double bonds, Q for O or ^ OR ¹ , 2 for O, R for water

substance, R ^{1 represents} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, B forms a single bond or double bond together with the carbon atoms in the 12 and 13 positions to which it is bonded or, if Q does not represent 0 or if the macrolide ring is saturated between the 10 and 11 positions or is unsaturated between the 2 and 3 positions, it can also be an oxirane ring; W stands for OR ¹ , in which R ^{1 has} the meaning given above, or stands for hydrogen with ', with the proviso that when the 2- and 3-positions are connected by a double bond, W is hydrogen and both radicals D are hydrogen or, if the 10- and 11-positions are connected by a single bond, both can also be OR ¹ , in which R ^{1 has} the meaning given above. These compounds can be prepared by hydrolysis of compounds of the formula (I) in which the dashed lines, B, Q, R ¹ , W and D have the meanings given above in this paragraph, R has the same meaning as R ¹ and Z is ^ OR "is where R"

is an alkyl radical having 1 to 5 carbon atoms.

The hydrolysis is carried out in an aqueous medium in the present carried out an acidic catalyst. Suitable catalysts are, for example, dilute mineral acids, organic acids (e.g. with 1 to 5 carbon atoms, preferably trifluoroacetic acid) and strongly acidic ion exchange resins. In addition to water, the solvent can also be an organic solvent, e.g. acetonitrile, contain.

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In the starting material, R ″ generally contains no more than 3 carbon atoms, preferably 1 carbon atom.

At least one possible ester group in the 2 ^I position is hydrolyzed under the conditions of the reaction. Other possible ester groups are frequently also hydrolyzed during the isolation of the products from the reaction medium.

The compounds 1 to 5, 8, 9, 14 to 20, 25 to 31, 34 and 46 to 50 of Table I can be obtained from the corresponding 20-acetals can be produced by this process, optionally with subsequent esterification.

I: compounds of the general formula i

0 '

in which the dashed line is an optional double bond, Q for 0 or ^ 0R ', Z for 0 or one

Group of formula

SR ", NOR" or

H Sdr »^ -sr" NOR "stands; R ^{1 is} hydrogen or hydrocarbon carbonyl having 2 to 18 carbon atoms; R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, W for OR", in which R "has the meaning given above, or is hydrogen with the proviso that when the 2- and 3-positions are connected by a double bond are, W is hydrogen, j

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These compounds can be prepared by hydroxylation of compounds of the general formula

in which the dashed line, Q, W, Z, R ¹ and R "have the meanings given above in this paragraph and R has the same meaning as R ^1. This process is preferably used to prepare compounds in which the 2- and 3 - Positions are connected by a single bond.

The reaction can be carried out, for example, with osmium tetroxide or potassium osmate in aqueous pyridine at room temperature. Under the reaction conditions, at least one possible ester group is ^{hydrolyzed in the 2 1} -position of the starting material.

For example, the compounds 8, 40, 45 and 50 of Table I by this method from the corresponding; corresponding compounds of the formula (XI) are prepared ..

In the following description of procedures J to N, is based on compounds of the general formula (I) i

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N (CH,).

Reference wherein the dashed lines represent optional double bonds, Q for O or

Z stands for 0 or a group of the formula

OR · H

^ H OR ",

.SR ", NOR» or NOR "; R and R · hydrogen or "^ SR"

Are hydrocarbyl carbonyl with 2 to 18 carbon atoms; R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms in the 12- and 13-positions to which it is bonded forms a single bond or a double bond or, if Q or Z is not 0 or if the macrolide ring is saturated between the 10- and 11-positions or unsaturated between the 2- and 3-positions, it can also be an oxirane ring; W for OR ', in which R ^{1 has} the meaning given above, or for hydrogen stands with the proviso that, if the 2_ and 3-positions are connected by a double bond, W is hydrogen, and both radicals D are hydrogen or, if the 10- and 11-positions are connected by a single bond, also OR wherein R ¹ 'has the meaning given above, can be ^ with the further proviso that Z is not ^ 0R ¹ , if B is in a,

^H !

Connection is a double bond, the carbon atoms of the 1ο- and -position by a double bond, the carbon atoms of the 2-, and 3-position are connected by a single bond, ■ both radicals D are hydrogen, Q is 0, W is OR ',)

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R and R ^{1 have} the meanings given above.

J: Compounds of the general formula (I) which differ from ^; differ from the above definition in that Q ι is only defined as an oxo group, can be selected from the corresponding

OR 'corresponding compounds of the formula (I) in which Q is for <C stands, "by oxidation of the group in the 9-position with Means such as manganese dioxide are produced. For example, compound 2 from Table I can be prepared from compound 25 of Table I.

K: Compounds of the general formula (I) which differ from the above definition in that Z

is only an oxo group, W stands for OR ¹ and R and R 'do not stand for H, can be selected from corresponding compounds of the'

OFT ^

Formula (I), in which Z stands for <,, by oxidation of the '

H !

Group in the 20-position using a reagent which j consists of acetic anhydride and dimethylsulphoxide or of pyridine-sulfur trioxide and dimethylsulphoxide, be asked. Compound 2 of Table I, for example, can be prepared by this procedure.

L: Compounds of the general formula Ij defined above, in which the 10- and 11-positions are connected by a double bond, can also be obtained by treatment (for example with zinc) of corresponding compounds in which the 10- and 11-positions are connected by a single bond are linked and contain a mesyloxy group in the 10- and 11-position,

is to be produced. These output compounds can for example by implementing the corresponding Verbin-j

fertilize the formula (I), in which the radicals D are OH ^ be made with methanesulfonyl chloride. j

M: Compounds of the general formula (I) defined above, in which Z stands for NOR ¹ or NOR ", can be subjected to deoxamination (for example by acid hydrolysis), the corresponding compounds in which Z is an oxo group being obtained. For example, compound 2 of Table Ij

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from compound 10 of Table I.

N: Compounds of the general formula (I) defined above, in which Z stands for "SR", can with

Using a mercury dd salt in the appropriate 20-aldehyde compounds are converted.

O: In most of the processes described above, possible ester groups contained in the starting material (in particular the ester group in the 2'-position) are at least partially solvolyzed during the reaction itself or during the isolation process. The extent of solvolysis often depends on the actual; turned away from reaction conditions in a certain amount; Dimensions can be varied. The free base with a · product is obtained but preferably in place of an ester j of the base used as the starting material that does not undesirable large number ⁱ ter byproducts (several kinds of ^esters): In many cases, JE.

If esters of the compounds of the general formula (I) described above are to be prepared, must the corresponding free bases are esterified by known methods.

The acylation can be carried out, for example, with the acid anhydride or acid halide, preferably with the chloride. The reaction can be carried out in an organic solvent, for example a ketone (preferably acetone), [ or in a tertiary amine (for example pyridine and dimethyl-; aminopyridine). It is known that an acid acceptor must be present in the reaction medium when the halide is used. ■,

The corresponding ι is preferably used for this method Derivative of an aliphatic hydrocarbon carboxylic acid! with 2 to 18 carbon atoms, preferably with 2 to 5 carbon atoms, ' e.g. acetic acid, propionic acid, stearic acid and pivalic acid. acid, and an aromatic carboxylic acid, e.g. benzoic

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acid, used.

According to the method described above, 2'-monoesters, 3,2'-diesters, 3,2O, 2'-triesters, 3,9,2 · triesters (where Z is preferably a group of the formula ^ - ^OCH o or 0 is) and 3,9,2O, 2'-tetraester

manufactured. The ester group in the 2 'positions will first obtained under the usual reaction conditions. Mixed esters can also be made.

P: Esters that have a free hydroxyl group in the 2'-position contain, in particular 3-monoesters, can be prepared by selective hydrolysis of the 2'-ester group, as described in South African patent 73/8630. The other ester groups can optionally be removed by known methods.

The ester in question is preferably used in free form (not in the form of its acid addition salt) for the Solvolysis, especially in the case of solvolysis of the 2'-ester group, is used.

Q: The simple derivatives, i.e. the acid addition salts the free base and its esters of the general formula (I) also fall within the scope of the invention. at Many of the processes described above can also use acid addition salts of the starting materials will. Using suitable isolation methods, it is possible to add the acid addition salt of the desired ' Product. The free compounds (free base or ester of the general formula (I)) can according to known methods, e.g. by treating the compounds in an organic solvent (e.g. ethanol and Acetone), which optionally also contains water, with the desired acid or its salt, optionally in j Presence of a small amount of acid, which slightly acidifies the reaction mixture, in its acid addition salts

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being transformed.

The best mode of operation for carrying out the methods of the invention is illustrated by the following examples explained.

Example 1 12,13-deepoxy-12,13-dehydrorosamicin

A solution of 15 g of potassium iodide in 30 ml is heated Acetic acid to the reflux temperature. One gives drop by drop a solution of 6 g of rosamicin in 18 ml of acetic acid and heated for a further 55 minutes on the reflux condenser. The solution is cooled and poured into about 180 g of ice and then made up with 10% aqueous sodium hydroxide to about pH 9. It is extracted with ethyl acetate and the organic extracts are washed with alkaline sodium! thiosulfate solution and then with water. The organization is narrowed

niche solution to a residue that contains the desired compound.

A. The residue is chromatographed on silica gel and eluted with 3% methanol in chloroform. The fractions which, according to thin layer chromatography, contain a single compound are combined, concentrated and crystallized from chloroform-hexane to give the desired compound. It is dried to constant weight. Melting point 109-111 ° C. ßxj -33 (ethanol), ^ ^ueun ₂ 83 nm (£ 21,700). On the basis of the NMR spectrum and determinations of the Overhauser nuclear effect, this compound is assigned the 12,13-trans stereo configuration.

B. Continue eluting the chromatography column with the same solvent system to obtain fractions which contains the compound described above mixed with a more polar component, These fractions are combined and chromatographed again on silica gel using the same

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Solvent system. Elute and pool fractions based on thin layer chromatography to obtain an additional amount of the compound described above. Elute further to obtain fractions: which contain the smaller, more polar component. These fractions are combined and concentrated to a residue of the compound. ZToc_7 _D + 34 ° (ethanol),

288 nm (E 14,300). On the basis of the NMR spectrum and determinations of the Overhauser core effect, this compound is assigned the 12,13-cis stereochemistry.

Example 2 _{12,13-Deepoxy-12-t} 13 dehydrorosamiclnstearatsalz

100 mg of 12,13-deepoxy-12,13-dehydrorosamicin (trans isomer) are dissolved in 5 ml of ethanol. A solution of 50 mg of stearic acid in 5 ml of ethanol is added with stirring. The solution is concentrated under reduced pressure to a residue which is dried under high vacuum to give the desired compound. ^ _ <x_7 _n -18 ° (Ätha

nol), λ ^ ° ^Η 283 nm ( t 22,000).

Example 3

12, lS-desepoxy - ^, 13-dehydrorosamicin-potassium dihydrogen phosphate salt

100 mg of 12,13-deepoxy-12,13-dehydrorosamicin (trans isomer) are added to a solution of 24 mg of potassium dihydrogen phosphate in 25 ml of water. The mixture is stirred ₍ 30 minutes, filtered and freeze-dried, the desired salt having a melting point of 107 to 112 ° C. being obtained.

-17 ° (water), λ "| ° ^Η 283 nm (t 21,000).:

Example 4 12,13-deepoxy-12,13-dehydrorosamicin-2'-propionate

100 mg of 12,13-deepoxy-12,13-dehydrorosamicin are dissolved (trans isomer) in 25 ml of acetone and gives a total of 0.175 ml of propionic anhydride in several portions

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within 3 days. The solution is kept at room temperature for a further day, then the solvent is evaporated and rub the residue with cold, dilute ammonium hydroxide. The product is filtered off and purifies it by dissolving it in chloroform and filtering the solution through a short column of silica gel. One constricts the eluate on a residue and thereby receives the desired compound with a melting point of 90-94 ° C.

^ _- MeOH 283 nm (6 20,800), mass spectrum M ⁺ 621.

ΓΠ3.Χ

Example 5 !

ι 12,13-deepoxy-12,13-dehydrorosamicin-2'-acetate ι

1.13 g of 12,13-deepoxy-12,13-dehydrorosamicin (trans isomer) are dissolved in 15 ml of acetone and 240 mg of acetic anhydride are added. The mixture is stirred for 15 hours at room temperature, the solvent is then evaporated off under reduced pressure and the residue is triturated with dilute ammonium hydroxide solution. It is extracted with ethyl acetate, the extracts are washed with water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the desired crystalline product with a melting point of 120 ° -121 ° C. is obtained. / ö / _D -5 ° (ethanol).

In the same way, using equivalent amounts of other anhydrides such as butyric anhydride, Valeric anhydride, hexanoic anhydride and octanoic anhydride in place of acetic anhydride in the above The process described obtained the corresponding esters.

Example 6 12 ₁ 13-Deepoxy-12,13-dehydrorosamicin-2'-benzoate

100 mg of 12,13-deepoxy-12,13-dehydrorosamicin (trans isomer) are dissolved in 0.4 ml of acetone and 45 mg of sodium bicarbonate are added and 0.025 ml of benzoyl chloride. The mixture is stirred for 3 days at room temperature, then evaporated

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The solvent is removed and the residue is triturated with 1% aqueous ammonium hydroxide. The product is isolated by filtration and dried. Melting point 108-111 ° C. faj _n -2.5 ° (ethanol), λ ^Μ ? ° ^Η 228 nm (£ 16,300), 283 nm

U ΓΠ3.Χ

( t 20,500), mass spectrum M ⁺ 669.

Example 7 12,13-deepoxy-12,13-dehydrorosamicin-2'-stearate

102 mg of 12,13-deepoxy-12,13-dehydrorosamicin and 50 mg of sodium bicarbonate are added to a solution of 63 mg of stearoyl chloride in 0.5 ml of acetone. The mixture is stirred for 2 days at room temperature, then the solids are removed by filtration and the filtrate is evaporated to a residue. The residue is triturated with dilute ammonium hydroxide and the aqueous phase is decanted from the gum formed. The latter is taken up in acetone and concentrated under reduced pressure to a residue which consists of the desired compound. ßxj -9 ° (ethanol) 283 nm XÜf ° ^H (L · 20,400),

U · ITi α. Χ

Mass p ^ectr around M 832

Example 8 12,13-Desepoxy-12,1S-dehydrorosamicin-S, 2'-diacetate

744 mg of 12,13-deepoxy-12,13-dehydrorosamicin are dissolved in 10 ml of pyridine and add 400 mg of acetic anhydride. The mixture is stirred for 20 hours at room temperature, then evaporated The solvent is removed under reduced pressure and the residue is triturated with ammonium hydroxide. The solid is taken in ethyl acetate, washed with aqueous sodium bicarbonate and dried over sodium sulfate. You narrow them Solution to a residue that consists of the desired compound with a melting point of 105-1O7 ° C.

In the same way, by using other acylating agents such as propionic anhydride and benzoyl chloride instead of acetic anhydride in the process described above, the corresponding diesters, e.g.

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the 3,2'-dipropionate and 3,2 · -dibenzoate.

Example 9 12,13-Desepoxy-12, IS-dehydrorosamicin-S-acetate

A solution of 720 mg of the 3,2'-diacetate prepared according to Example 8 is stirred for 5 hours at room temperature in a mixture of 10 ml of methanol and 4 ml of water. The solvent is replaced by ethyl acetate, washed with water, dried and concentrated to a residue which consists of the desired compound with a melting point of 95-98 ° C., ßxj _Ό -4 ° (ethanol).

Example 10 12,13-Deepoxy-12,13-dehydrorosamicin-20-oxime

A solution of 100 mg of 12,13-deepoxy-12,13-dehydrorosamicin and 15 mg of hydroxylamine hydrochloride in 10 ml of ethanol containing 1 drop of pyridine is heated for one hour on the reflux condenser. The solvent is replaced by tetrahydrofuran-hexane and filtered. The filtrate is diluted with hexane and the precipitate formed is isolated by filtration, the desired compound having a melting point of 165-167 ° C., faJ _D -38 ° (ethanol).

Example 11 10,11-Dihydrorosamicin

1.2 g of rosamicin are hydrogenated in 45 ml of methanol containing 200 mg of 5% palladium carbon as a catalyst until the UV absorption at about 240 nm has disappeared. The mixture is filtered and the filtrate is concentrated to a residue which consists of the desired compound with a melting point of 94.degree.-95.degree. / aJ _D -1 ° (ethanol).

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Example 12 10,1-dihydrorosamicin-2'-acetate

580 mg of the compound prepared according to Example 11 are added to 145 mg of acetic anhydride in 15 ml of acetone in the manner described in Example 5. The reaction mixture is worked on in Example 5 described manner and hereby isolates the desired compound with a melting point of 86-87 ° C.

Example 13 12,13-Desepoxy-10, II-dihydrorosamicin ;

A solution of 150 mg of the compound prepared according to Example 1 A in 10 ml of ethanol, which contains 35 mg Contains 5% palladium carbon as a catalyst until the UV absorption at about 283 nm has disappeared. Man filtered and concentrated the filtrate to a residue, which consists of the desired compound of the melting point 78-79 ° C.

Example 14 20,20-Dihydrorosamicin

A solution of 290 mg of rosamicin in 1 ml of tetrahydrofuran is added to 150 mg of lithium aluminum tri-tert-butoxyhydride in 1 ml of tetrahydrofuran and the mixture is stirred. A further 50 mg of reducing agent is added and the mixture is stirred for 18 hours. It is diluted with water and extracted with chloroform, the organic layer is separated off, washed with water and concentrated to a residue which consists of the desired compound, λ j ^ ° ^H 239 nm ( £ 12,700), mass spectrum M ⁺ 583.

Example 15 20,20-dihydrorosamicin-3.20.2 ^t -triacetate

30 mg of the compound prepared according to Example 14 are dissolved in 1.0 ml of pyridine and 0.1 ml of acetic acid is added

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hydride, allowed to stand for 5 days at room temperature, concentrated under reduced pressure to a residue and triturated with 2% aqueous ammonium hydroxide. The solid obtained is isolated by filtration and dried, the desired compound having a melting point of 93-96 ° C. being obtained. X.JJ® £ ^H 238 nm (£ 12,700).

Example 16 12 »13-Desepoxy-12 _? 13-dehydrorosamicin-3,2'-dipropionate

10 g of 12,13-deepoxy-12,13-dehydrorosami- \ a 4 days at room temperature (25 ° C) to the action of \ 10 ml of propionic anhydride and 50 mg of dimethylaminopyridine in 30 ml of pyridine. The product is precipitated in 300 ml of 2.5% sodium carbonate. The sus- ^! pension 15 minutes, filtered, the precipitate was washed with water and dried at 50 ° C. under reduced pressure. Yield 10.1g.

4 g of this product are dissolved in chloroform and the solution is passed through 50 g of silica gel, fractions being taken of 60 ml each. The fractions 8 to 16 are combined and concentrated to a residue, the the desired product is obtained in purified form.

Yield 1.5 g Ä7p = -12.5 (c = 0.3%, ethanol) / M + 17 = 676 X "f ° ^H 283 nm (£ = 22,300)

ιι1α.Χ

Example 17 2, S-dehydro-S-deoxyrosamicin

A. Dissolve 2.75 g of rosamicin 2'-propionate in 40 ml of pyri i din and add 1 ml methanesulfonyl chloride. The solution is left to stand for 3 days at room temperature and the evaporated Solution then to a residue which is triturated with 1% ammonium hydroxide and then with hexane. You are suspended the solid product in chloroform and passes the suspension through 42 g of silica gel. You narrow the chloroform

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solution to a residue and thereby receives 1 g of rosamicin 2 ^l propionate 3 methanesulfonate.

B. Dissolve 400 mg of the product obtained in step A and 120 ml of pyridine and reflux for 4 hours. The solvent is removed under reduced pressure, the residue obtained is suspended in dilute (1%) ammonium hydroxide and extracted with ^; Chloroform. The chloroform solution is concentrated, the residue obtained is dissolved in 10 ml of 80% aqueous methanol and heated under the reflux condenser for one hour. The solvent is evaporated, the residue is triturated with chloroform and the suspension in chloroform is passed through 4 g of silica gel. The mixture is concentrated, the chloroform solution to give 131 mg of the desired product with the following physical characteristics: Melting point 104-110 ⁰ C.

/ α / ρ ⁶ = -39.1 (0.3% ethanol).

Example 18 2,3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosamicin

A. 475 mg of 12,13-deepoxy-12,13-dehydrorosamicin-2'-propionate are dissolved in 5 ml of pyridine, 0.25 ml of methanesulfonyl chloride are added and the solution is left at room temperature for 6 days stand. The solution is concentrated to a residue and the residue is triturated with 1% ammonium hydroxide. Man the solid obtained in this way is filtered off and dried under reduced pressure, 490 mg of 12,13-deepoxy-12,13-dehydrorosamicin-2-propionate-3-methane, sulfonate receives *

B. Dissolve 480 mg of the product obtained in step A in 100 ml of pyridine and reflux for 2 hours. The solvent is evaporated and the residue obtained is suspended in dilute (1%) Ammonium hydroxide. The suspension is extracted with chloroform and the extract is concentrated to a residue.

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The residue is dissolved in 20 ml of 80% aqueous methanol and the solution is refluxed for 1 hour. The solution is concentrated and the residue is chromatographed on 46 g of silica gel using one consisting of 3 parts by volume of methanol and 97 parts by volume of chloroform Solvent system to obtain the desired compound.

131 mg, m.p. 98-103 ° C i & Q ^{6 s} -21.9 (0.3% ethanol).

Example 19 Rosamicin 20 oxime

A solution of 300 mg of rosamicin and 40 mg of NH ₂ OH.HCl in 20 ml of ethanol containing one drop of pyridine is heated for 3 hours on a reflux condenser. The solvent is evaporated off under reduced pressure, the residue is dissolved in 5 ml of tetrahydrofuran, filtered and hexane is added, whereby the desired compound is precipitated. The product is filtered off. Melting point 158-161 ° C. faj ^ ⁶ -26.2 (c = 0.3% ethanol).

Example 20 Rosamicin-20-dimethyl acetal

1.0 g of rosamicin is dissolved in 10 ml of methanol, 1.0 ml is added Add difluoroacetic acid, add a drying tube and the reaction mixture is allowed to stand at room temperature (25 ° C.) for 72 hours. The reaction mixture is concentrated to about half of the original volume and precipitates in 50 ml of 10% sodium bicarbonate solution. One filters, the suspension and the precipitate is dried under reduced pressure at 40.degree.

Yield 0.8g. A / ^ ⁶ = 17.5 (c = 0.3% ethanol), ²⁴ ° ^nm (£ - 13,650).

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Example 21 9,9-Dihydro-rosamicin-20-dimethyl acetal

8.9 g of rosamicin-20-dimethylacetal (prepared in the manner described in Example 20) in 90 ml of methanol and give 2.5 g of sodium borohydride in portions every 5 minutes. The reaction mixture is stirred for a further 20 minutes. During this time takes place an exothermic reaction takes place. The reaction mixture is diluted with 500 ml of chloroform and shaken with 200 ml of 5% sodium bicarbonate solution. One separates the i The solvent layer is removed, and the chloroform layer is concentrated to a residue. The back, stood in front of 700 g of silica gel, the eluent being a solvent system of toluene, chloroform, methanol and concentrated ammonium hydroxide in a volume ratio of 3: 1: 0.5: 0.025 is used, and obtains the desired Compound in a yield of 5.9 g.

Example 22 10, ll-Dihydroxy-10 _t 11-dihydrorosamicin

A. 2.92 g of rosamicin and 1.3 g of osmium tetroxide are dissolved in 15 ml of pyridine and the mixture is stirred for 5 hours at room temperature (20 to 25 ° C). One gives a solution of 2.5 g sodium bisulfite in 25 ml pyridine and 40 ml water , the mixture is stirred for 30 minutes at room temperature, the reaction mixture is extracted with chloroform and replaced the chloroformdidi ethyl acetate. You wash them Ethyl acetate solution with a solution of ammonium sulfide in dilute ammonium hydroxide, then wash with water and dry over anhydrous sodium sulfate. Filter and evaporate the filtrate to a residue. Yield 610 mg.

B. A chromatography column is made of 60 g of silica gel using one made of 3% by volume of methanol in

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Existing chloroform solvent system. The residue obtained from stage A is adsorbed and; eluted with 4.0 1 of the solvent system and then with 4.0 1 5% methanol in chloroform, collecting fractions of 25 ml each. Combine fractions 49 to 72, which contain a single component, and evaporate to a residue to give the desired compound. Mass spectrum M ⁺ = 615, UV: no absorption above 220 nm.

Example 23

12,13-deepoxy-12,13-dehydrorosamicin lauryl sulfate salt

50 mg of 12,13-deepoxy-12,13-dehydrorosamicin are dissolved in 0.5 ml of acetone and 25.5 mg of sodium lauryl sulfate are dissolved in 5.0 ml of water. 0.01 ml of acetic acid is added to the solution and the mixture is stirred for about 45 minutes under nitrogen, the acetone being allowed to evaporate. The oily residue is kept in the refrigerator overnight and the water is then decanted. The oily residue is triturated with hexane and cooled for 2 hours. The hexane is decanted and triturated with ethanol, whereupon the solvent is removed by decantation. The product obtained is dried at about 40 ° C. under reduced pressure, the desired compound being obtained. Yield 60 mg. Melting point 129 to 132 ° C. £ oJn »15.4 °, C = ^0.3 % ethanol, A lieun 283 nm

D ^w '' max

( t = 21,000).

In the same way, using an equivalent amount of other sodium alkyl sulfates such as Sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate in place of sodium lauryl sulfate in the manner described in Example 23, the following Connections are made:

12,13-deepoxy-12,13-dehydrorosamicintetradecyl sulfate, salt, ^, lS-Desepoxy- ^ jlS-dehydrorosamicinhexadecylsulfatalz and 12,13-deepoxy-12,13 octadecyl sulfate salt "

6Ö9837 / 087

In the same manner, by using an equivalent amount of the following compounds or their Ester and using an equivalent amount of the aforementioned sodium alkyl sulfates according to the in Example 23 the analogous alkyl sulfate salts getting produced:

lOjll-dihydroxy-lOjll-dihydrorosamicin, 10,11-dihydrorosamicin, 12,13-desepoxy-10, ll-dihydrorosamicin, 20,20-dihydrorosamicin, 2,3-dehydro-3-deoxyrosamicin and 2,3 j 12,13-bis-dehydro-3-deoxy-12,13-desepoxyrosamicin.

Example 24 12,13-Desepoxy-12,13-dehydrorosamicin-20 ~ dimethylacetal

A. Dissolve 10 g of 12,13-deepoxy-12,13-dehydrorosamicin in 100 ml of methanol and add 6 ml of difluoroacetic acid. The reaction mixture is left to stand at room temperature (25 ° C.) for 72 hours. The reaction mixture is concentrated to 50 ml and precipitated in 500 ml of 10% sodium bicarbonate. The suspension is filtered and the precipitate is dried at 50 ^° C. under reduced pressure, the desired compound being obtained.

Yield 10.5g. λ YYY °. ^H 283 nm ( Z = 21,265)

B) 1.0 g of the product from step A is dissolved in chloroform and chromatographed on 100 g of silica gel using 5% methanol in chloroform as the eluent. The fractions 28 to 60 are combined. Yield 0.65 g, "XjJax" 283 nm, βxj ^ = 1.3 (etha

nol), (£ = 22,480).

Treating an equivalent amount of the following compounds to that in Example 24 in the same manner described Weisei

10,11-dihydrorosamicin

12,13-deepoxy-10,11-dihydrorosamicin

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2, S-dehydro-S-deoxyrosamicin

2,3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosamicin

lO ^ l-dihydroxy-lOjll-dihydrorosamicin.

The products formed in each case are isolated in the manner described in Example 24, using the following Connections receives:

10, ll-dihydrorosamicin-20-dimethyl acetal 12,13-deepoxy-10, ll-dihydrorosamicin-20-dimethylacetal 2, S-dehydro-S-deoxyrosamicin ^ O-dimethylacetal 2,3; 12,13-bisdehydro-3-deoxy-12, IS-desepoxyrosamicin- ^ O-dimethyl acetal

10, ll-dihydroxy-10, ll-dihydrorosamicin-20-dimethylacetal

Example 25

9,9-dihydro-12,13-desepoxy-12,13-dehydrorosamicin-20- dimethyl acetal

6.0 g of 12,13-desepoxy-12,13-dehydrorosamicin-20-dimethylacetal are dissolved in 60 ml of methanol. 3.5 g of sodium borohydride are added and the mixture is stirred for 30 minutes. One dilutes with that 10 times the volume of chloroform and shaking the resulting solution with 10% sodium carbonate solution, washes the Chloroform layer with water and concentrate to a residue. The residue is dissolved in chloroform and adsorbed the product on 100 g of silica gel. The silica gel column is eluted with 1.0 1 of chloroform and then with 5% Methanol in chloroform. The fractions 63 to 105 are combined and concentrated to a residue, whereby one receives the desired product.

Yield 3.7 g foj ^ ⁶ = +2.0 (c = 0.3%, ethanol)

_{M + 613}

Max

In the same way, an equivalent amount of the products mentioned according to Example 24 is treated to the in Example 25, using "the following

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Connections receives:

g-Dihydro-10jll-dihydrorosamicin-ZO-dimethylacetal

9-dihydro-12,13-desepoxy-10, ll-dihydrorosamicin-20-dimethyl acetal

9-Dihydro-2, S-dehydro-S-deoxyrosamicin ^ O-dimethylacetal

9-dihydro-2,3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosamicin-20-dimethyl acetal

9-dihydro-10,1-dihydroxy-10,11-dihydrorosamicin-20-dimethyl acetal

Example 26 9,9-dihydro-12,13-desepoxy-12,13-dehydrorosamicin ;

3.3 g of the product obtained according to Example 25 are dissolved in a mixture of 30 ml of acetonitrile and 30 ml of water, 1.0 ml of trifluoroacetic acid is added and the mixture is left to stand for 5 hours at room temperature. It is diluted with 150 ml of chloroform and extracted with 10% sodium carbonate solution. Extract the aqueous layer with fresh chloroform, combine the chloroform layers, wash with water and concentrate to a residue. The residue is dissolved in a mixture of toluene, chloroform, methanol and concentrated ammonium hydroxide in a volume ratio of 3: 1: 0.5: 0.25 and chromatographed on 240 g of silica gel using the same solvent mixture as the eluent. One unites the _; Fractions 49 to 73 to give the desired product.
Yield 2.15g. / äj ^ ⁶ = 3.2 ° (c = 0.3% ethanol)

ß \ + IJ ⁺ = 567 \ ^Me ° ^H 238 run It = 20,180)

UIaX

In the same way, an equivalent amount of the products mentioned in Example 25 is treated to the in Example 26 to obtain the following compounds:

9,9-dihydro-10,11-dihydrorosamicin

9,9-dihydro-12,13-desepoxy-10,11-dihydrorosamicin

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9,9-dihydro-2, S-dehydro-S-deoxyrosamicin

9,9-dihydro-2,3; 12,13-bisdehydro-3-deoxy-12,13-desepoxyrosamicin

g ^ -Dihydro-lOjll-dihydroxy-lOjll-dihydrorosamicin

In the same way, the product prepared according to Example 21, i.e. 9-dihydro-rosamicin-20-dimethylacetal, can be converted to 9-dihydrorosamicin in the manner described in Example 26.

Example 12,13-Desepoxy-12, IS-dehydrorosamicin-S-propionate

7.4 g of 12,13-deepoxy-12,13-dehydrorosamicin-3,2i-dipropionate (prepared according to Example 16) are dissolved in 150 ml of 80% methanol-water. The reaction mixture is left to stand at room temperature (25 ° C.) for 3 days. Concentrate the mixture R _e action ml to about 40 and is incident from sodium bicarbonate in 400 ml of 5%. The suspension is filtered, washed with a little water and the precipitate is dried at 50 ^° C. under reduced pressure. The product is dissolved in chloroform and chromatographed on 600 g of silica gel, eluting with chloroform, collecting the first 3.0 l of chloroform and then converting to 4% methanol in chloroform. Fractions 168 to 320 are combined and concentrated to a residue, the desired compound being obtained.

Yield 3.0 g / 07p - -8.4 (c = 0.3%, ethanol) (M + I) ⁺ = 622.

Example 20,20-dihydrorosamicin

A. Dissolve 0.9 g of rosamicin in 3 ml of tetrahydrofuran and give 660 mg of lithium tri-tert-butoxyaluminum hydride in 3 ml of tetrahydrofuran. The reaction mixture is stirred for 20 minutes at room temperature

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(25 ° C). A further 1.5 g of the reducing agent are added in portions and the reaction is allowed to take place overnight (16 Hours). The reaction mixture is diluted with 100 nsi chloroform and shaken with 50 ml aqueous sodium bicarbonate from «The chloroform solution is washed with water, concentrates and replaces the chloroform with ethyl alcohol. One narrows the alcoholic Solution with the addition of water and obtain the desired product by freeze-drying.

B. The 20,20-dihydrorosamicin prepared in the manner described is dissolved in chloroform and chromatographed on 50 g of silica gel using 4% methanol in chloroform as the eluent. Man combines the appropriate fractions and receives the purified 20,20-dihydrorosamicin. (Key figures see example "! 4.)

Example 29 12,13-deepoxy-12,13-dehydrorosamicin

50 g of rosamicin are dissolved in 300 ml of ln sulfuric acid under argon. A mixture of 51.5 g of chromium (III) chloride hexahydrate, 80 ml of water and 20 ml of sulfuric acid is added. This mixture was previously allowed to trickle through a column of 100 g of amalgamated zinc, whereby an equivalent amount of chromium (II) ions was formed (see j Inorganic Synthesis, Volume 3, pages 148-150). At this point this solution should have a pH of around 0.8 to 1.2. The reaction mixture is left under overnight (18 hours) at room temperature (25 ° C.) _;

Stand argon. The reaction mixture is extracted with ' 500 ml of ethyl ether, adjust it to pH 8 with 8N sodium hydroxide, extract it with 2.0 l of ethyl ether and filter the extract. The extract is washed with water and concentrated to a residue. One solves the j Residue in ethanol / water (1: 2) and freeze-dried. '

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Yield 44.7 g (89.4%); / α / * ⁶ ' ⁵ = -29.3 (C = 3% CHCl ₃ )

_Λ CH_OH

max ^{283 nm {} ^ ^{= 2Ο} · ^42Ο)

The compounds according to the invention are antibacterial Middle. They differ more or less from rosamicin in terms of effect, spectrum of activity and the mode of administration for which they are best suited (especially oral, topical or parenteral Administration).

In general, the compounds according to the invention are more effective against gram-positive microorganisms, they however, they also show activity against gram-negative species. As examples of microorganisms against which the compounds can be used according to the invention are strains of species such as Staphylococcus aureus, Streptococcus pyogenes, Bacillus subtilis, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Diplococcus pneumoniae, Proteus mirabilis and Proteus morganii should be mentioned.

Below are examples of some dosage forms in which the compounds according to the invention including the non-toxic, pharmaceutically acceptable acid addition salts, the non-toxic, pharmaceutically acceptable esters and the non-toxic, pharmaceutically acceptable acid addition salts of these esters can be used. The formulations excluding the preparations to be used locally are compiled in such a way that about 5 to 50 mg of antibiotic (as free base) per kg of body weight can be administered per day. For topical use, the formulations are so composed that the preparations contain about 0.5 to 2% antibiotic agent. The preparations for topical use are generally applied to the skin for about 2 to 4 χ a day

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infected area applied. It should be noted, however, that the size of the dose administered and the Frequency of administration largely depends on the type of infection, its severity and the individual characteristics the animal species treated. The compounds according to the invention are particularly suitable for the treatment of warm-blooded animals, but can also be used for in vitro purposes as a disinfectant for laboratory equipment and equipment and instruments used in the dental and medical office.

Formulation 1 capsule

12,13-deepoxy-12,13-dehydrorosamicin 250.00 mg lactose 248.75 mg

Magnesium stearate 1.25 mg

500.00 mg

Manufacturing:

1. Mix the antibiotic and lactose.

2. Add the magnesium stearate and mix.

3. You fill the capsule.

Formulation 2 Oral Suspension (for a dose of 125 mg / 5 ml)

12,13 — Desepoxy — 12,13-dehydrorosamicin— 2 · benzoate

Magnesium aluminum silicate

Sodium Carboxymethyl Cellulose U.S.P.

Sodium Citrate, U.S.P.

Flavors

dye

Methyl paraben, U.S.P.

Propyl paraben, U.S.P.

Polyoxyethylene sorbitan monooleate, U.S.P. (Polysorbate 80)

Sorbitol Solution, U.S.P.

Water ad

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25, 00 G 9, 5 G 2, 5 G 25, 0 G q S. q S. O, 9 G O, 2 G i, 0 G 500, 0 G 1000 , 0 ml

Manufacturing :

1) Heat 200 ml of water to the boil and dissolve half of the parabens in it. Cool to about 70 ° C and then mixes in the polysorbate 80. Sprinkle in the silicate and stir until a uniform, has formed a smooth suspension.

2) Heat another 200 ml of water to the boil and dissolve the rest of the parabens in it. Disperse the sodium carboxymethyl cellulose in the solution until a smooth gel is formed. One mixes the sorbitol solution and then dissolves the sodium citrate,

3) The product from stage 2 is slowly added to the product from stage 1 with constant stirring, and the product is cooled Mix at 25 ° C, add the antibiotic, tartrate as a flavor and color, and mixes well. Make up to 1000 ml with water.

Formulation 3 cream for topical use

12,13-deepoxy-12,13-dehydrorosamicin-2 - propionate

Stearic acid sorbitan monostearate sorbitan monooleate polyoxyethylene sorbitan monolaurate

Water ad

Manufacture;

1) The stearic acid, the sorbitan monostearate, is heated, the sorbitan monooleate and the polyoxyethylene sorbitan monolaurate to 65 ° C.

2) About 90% of the water is heated to 70 ° C.

3) Add the water to the product of stage 1 and mix to form the cream base.

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10 G 200 G 104 G 20th G 56 G 1000 ml

4) Slurry the antibiotic with about 10% of the water and pass through a colloid mill.

5) Add the milled slurry to the melted one Foundation, mixes and lets cool.

Formulation 4 ointment for topical use

12,13-deepoxy-12,13-dehydrorosamicin-2'-stearate 10 g

Petrolatum 990 g

1000 g

Manufacturing

1) Melt the petrolatum.

2) Slurry the antibiotic with about 10% of the petrolatum and pass through a colloid mill.

3) Mix the milled slurry with the rest of the melted petrolatum and let cool.

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Claims (1)

Claims in which the dashed lines are optional double bonds, Q for 0 or ^ 0R ^1st , 2nd for 0 or one Group of formula OR "
X) R " NOR ¹ or NüR " is, R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 10 carbon atoms, R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, ß together with the carbon atoms of the 12- and 13-positions to the it is bonded, forms a single bond or a double bond or, if Q or Z are not 0 or if the macrolide ring is saturated between the 10 and 11 positions or unsaturated between the 2 and 3 positions, it can also be an oxirane ring , W stands for OR ¹ , in which R ^{1 has} the meaning given above, or stands for hydrogen with the proviso that, when the 2- and 3-positions are connected by a double bond, W is hydrogen and both radicals D are hydrogen or , if the 1ü- ^! and 11-positions are connected by a single bond, both can also ^{stand for OR 1} , in which R ^{1 has} the abovementioned meaning, and with the further proviso that Z does not stand for <"if in of a compound B is a double bond, the carbon atoms of the 10- 609837/0878 and 11 positions by a double bond, the carbon atoms in the 2 and 3 positions are connected by a single bond, both radicals D are hydrogen, Q is O, W is OR ¹ and R and R ^{1 have} the meanings given above , and the non-toxic, pharmaceutically acceptable acid addition salts of these compounds. 2) Compounds according to claim 1, wherein the dashed lines are optional double bonds, Q, Z, R, R ¹ , R "and W have the meanings given in claim 1, B together with the carbon atoms in the 12- and 13-positions to which it is bound forms a single bond or a double bond or, if Q or Z is not O and the macro- lidring is saturated between the 10 and 11 positions and unsaturated between the 2 and 3 positions, can also be an oxirane ring, and both radicals D are either water; are material or, if the 10 and 11 positions are connected by a single bond and W stands for OR ¹ , both can also be OH. 3) Compounds according to claim 1 or 2, characterized in that R ^{1 is} hydrogen or, if it is in the 3-position, also acetyl or propionyl and, if it is in the 9- or 2o-position, also acetyl. 4) Compounds according to claim 1 to 3, characterized in that R and R ^{1 represent} hydrogen and Z represents O, where R "is an alkyl radical, or represents NOH. ■ 5) Compounds according to claims 1 to 4, characterized in that R "is hydrogen or methyl. I 6) Compounds according to claim 1 to 5, characterized gekennzeich- Ί net that the dotted lines are single bonds DAR i filters, Q, Z, R, R ¹ and R "as defined above, B together with the carbon atoms der12 - and 13- positions forms a single bond, W is OR ¹ , in which R ^{1 has} the meaning given above, and the two radicals D are hydrogen ^are · 809837/0878 7) connections according to ^ .r.spruch 6, characterized in that Z stands for O or <_, in which R "is an alkyl radical. 8) compounds according to claim 6 or 7, characterized in that; indicates that R and R ^{1 are} hydrogen atoms. 9) compounds according to claim 6 to 8, characterized in that ' draws -. that R "is a methyl radical. 10) 12,13-deepoxy-10,11-dihydrorosamicin. 11) Compounds according to claim 1 to 5, characterized in that B in the formula (I) together with the ' C atoms in the 12 and 13 positions have a double bond dung forms. 12) compounds according to claim 11, characterized in that! net that both radicals D are hydrogen and the ^! Positions 10 and 11 comparable with a double bond \ are bound. ι 13) Compounds according to claim 12, characterized in that W is hydrogen and the 2- and 3-positions linked by a double bond. 14) Compounds according to claim 13, wherein Q and Z are 0; are, in particular 2,3; 12,13-bisdehydro-3-deoxy- ■ 12,13-desepoxyrosamicin. ί 15) Compounds according to claim 11 or 12, characterized in that W for OR ·, wherein R ^{1 is} the above ge; has, stands and the 2- and 3-positions are connected by a single bond. j 16) compounds according to claim 15, characterized marked ι net that Q is ^ H, where R 'the above ■ has mentioned meaning. 1.7) 9,9-dihydro-12,13-desepoxy-12,13-dehydrorosamicin. 18) Compounds according to claim 15, characterized in that Q stands for O. 609837/0878 19) compounds according to claim 18, characterized in that that Z stands for ^) CH. or NOH. ^0CH 3, 20) 12, lS-desepoxy - ^, lS-dehydrorosamicin-ZO-dimethy1-acetal and ^, lS-Desepoxy- ^ jlS-dehydrorosamicin-20-oxime. 21) compounds according to claim 18, characterized marked- ' net that Z stands for 0. ι 22) ^, la 23) Trans-12,13-deepoxy-12,13-dehydrorosamicin. ■ 24) Compounds according to claim 1 to 5, characterized in that B in the formula (I) together with the C atoms in the 12 and 13 positions form an oxirane ring ■ forms. 25) Compound according to claim 24, characterized in that W is hydrogen. 26) compounds according to claim 25, characterized in that that the 2 and 3 positions as well as the 10 and 11 positions linked by a double bond. 27) compounds according to claim 26, characterized in that that Q and Z stand for 0. 28) 2,3-dehydro-3-deoxyrosamicin. 29) Compounds according to claim 24, characterized in that W stands for OR ·. : 30) compounds according to claim 29, characterized in that that the 10 and 11 positions are connected by a single bond and both radicals D are hydroxyl groups are. . · 31) Compounds according to claim 30, characterized in that Q and Z are 0. 609837/0878 32) lOjll-dihydroxy-lOjll-dihydrorosamicin. 33) Compounds according to claim 29, characterized in that both radicals D are hydrogen and the 10 and 11 positions are linked by a single bond. 34) Compounds according to claim 33, characterized in that Q is O. 35) 10,11-dihydrorosamicin. 36) Compounds according to claim 33, characterized in that Q is ^ OR ¹ . ^ H 37) 9,9,10,11,20,20-hexahydrorosamicin. 38) Compounds according to claim 29, characterized in that both radicals D are hydrogen and the 10 and 11 positions are linked by a double bond. 39) Compounds according to claim 38, characterized in that Q stands for ^ OR «. 40) 9,9-DihydrorosaInicin-20-dimethylaoetal. 41) Compounds according to claim 38, characterized in that Q stands for 0. 42) 20,20-dihydrorosamicin. 43) rosamicin-20-oxime. 44) Rosamicin-20-dimethyl acetal. 45) Compounds according to claim 4 to 44, characterized in that R ^{1 is} hydrocarbon carbonyl having 2 to 18 carbon atoms. 46) Compounds according to claim 4 to 44, characterized in that R with hydrocarbon carbonyl 809837/0878 2 to 18 carbon atoms. 47) compounds according to claim 45 or 46, characterized marked-t indicates that R and / or R ^{1 are} hydrocarbon carbonyl with 2 to 5 carbon atoms. "< 48) compounds according to claim 46 or 47, characterized in that that R is acetyl, propionyl, pivaloyl, stearoyl or benzoyl. 49) Compounds according to claim 1 to 48 in the form of their ^: ι pharmaceutically acceptable acid addition salts. ■ 50) Compounds according to claim 1 to 49 in the form of their stearates, lauryl sulfates and potassium dihydrogen phosphates. , 51) Process for the preparation of compounds according to Anj Claim 1 to 50, characterized in that one j a) for the preparation of compounds of the general j formula ft ¹ ^ CH = Z r ύ CH III in which the dashed line represents an optional double ' ^0RI Z for 0 or NOR ¹ or p is a bond, Q is 0 or ^ _H group of the formula ^ 0R ¹ , ^ 0R ",, r H OR "" SR " NOR "is, / R" is hydrogen or an alkyl radical with ' R and R ^{1 are} hydrogen, 609837/0878 1 to 5 carbon atoms, W for OR ', where R ^{1 is} the. has the abovementioned meaning, or is hydrogen with the proviso that W is hydrogen when the 2- and 3-positions are connected by a double bond, and with the other OR ' Provided that Z does not stand for ζ "if in of a compound the C atoms of the 2- and 3-positions are connected by a single bond, Q is O, W is OR ¹ and R and R ^{1 are} the above Have the meanings mentioned, correspondingly substituted compounds of formula CH. CH = ZN (CH ₅ ) wherein the dashed line is an optional Double bond, Q for 0 or <, Z for 0 / • OR · "or a group of the formula ^ ₁ ,, AD «« iR · ¹ ^ 0R "» "^ SR" » ^N0RI ° ^{der N0R} " ^stands » ^{R and Rt are} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R" is hydrogen or an alkyl radical with 1 to 5 carbon atoms, W stands for OR ' , wherein R ^{1 has} the meaning given above, or is hydrogen with the proviso that, when the 2- and 3-positions are connected by a double bond, W is hydrogen, and with the wide- OR 'ren stipulation that Z is not for < ?. if the carbon atoms of the 2- and 3-positions are connected by a single bond in a compound, Q 609837/0878 for O, W for OR ¹ and R and R ^{1 have} the meanings given above, or reduced non-toxic "pharmaceutically acceptable acid addition salts" of these compounds; b) for the preparation of compounds of the general formula (I) in which the dashed lines represent optional double bonds, Q for O i or / OR ·, Z stands for NOR ¹ or NOR ", R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms of the 12- and 13-positions to which it is bonded, forms a single bond or double bond or an oxirane ring, W is OR, in which R ^{1 has} the meaning given above, or is hydrogen with the proviso that, when the 2- and 3-positions are connected by a double bond, W is hydrogen, and both radicals D are hydrogen or, if the 10 ~ and 11-positions are connected by a single bond, they can also represent OR ', where R ^{1 has} the meaning given above, compounds of the general formula (I), in which the dashed lines, Q, B, W, R, R »and D have the meanings given in this claim and Z is 0, or reacts their acid addition salts with hydroxylamine or its suitable derivatives; c) for the preparation of compounds of the general formula (I) in which the dashed lines are optional double bonds, Q is 0 or ^ OR «, ί Z <0R ' _/ ^ H, R stands for hydrogen and B, together with the carbon atoms in the 12- and 13-positions to which it is bonded, forms a single bond or a double bond ¹ 609837/0878 or forms an oxirane ring, W is OR ¹ or hydrogen, with the proviso that W is hydrogen when the: 2- and 3-positions are connected by a double bond and both radicals ü are either hydrogen or when the 10- and 11-positions are connected by a single bond, can also be OR ¹ , in which R ^{1 is} hydrogen, with the exception of compounds in which B is a double bond, the carbon atoms of the 10- and 11-positions by a double bond connected and the carbon atoms in the 2- and 3-position are connected by a single bond, the two radicals D are hydrogen, Q is 0, W is OR ¹ and R and R 'have the meanings given above, Compounds of general formula (I) in which the ^: dashed lines, Q, B, W and D are those in this an; have the meanings mentioned claim, R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 10 carbon atoms and Z is O, reduced; d) for the preparation of compounds of the general formula in which the dashed line is an optional double. OR ¹ i bond, Q for 0 or < _R , Z for 0 or a group the formula < ⁰ ? '<SS ^{< ''} SR '' ^{NÖR <or N0R "If 'R} and R 'are hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R "represents hydrogen or an alkyl radical with 1 to 5 carbon atoms, B together with the carbon atoms of the 12- and 13-positions, to which it is bound ₍ 809837/0878 is, forms a single bond, a double bond or a üxiranring and the radicals D are both hydrogen are or, if the 1O and 11 positions through a single bond are connected, also both OR "can be the eliminable group T and a ' Hydrogen atom in position 2 from compounds of: general formula VIII in which the dashed line, B, D, Q, Z, R, R ¹ and R "have the meanings given in this claim, eliminated; e) for the preparation of compounds of the general formula 609837/0878 wherein Q is O or ^ OR ¹ , Z is O or a group i ^ H the formula .OR ¹ , ^ OR ", ^ SR", NOR 'or NOR "',<· HS) R" SsR ", R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R "is hydrogen or an alkyl radical with 1 to 5 carbon atoms, j B together with the carbon atoms in the 12- and 13-position which it is bonded, forms a single bond \ or an oxirane ring, W for OR ·, in which R ¹ j has the meaning given above, or is hydrogen and the two radicals D are hydrogen, correspondingly substituted compound of the general formula (I), in the Q, Z, R, R ¹ , R "and D have the meanings given above in this claim, the dashed lines are optional double bonds, B together with the C atoms of the 12- and 13-positions to which it is bonded , forms a single bond, a double bond or an oxirane ring, W is OR ¹ , in which R ^{1 has} the abovementioned meaning, or is hydrogen with j with the proviso that if the 2- and 3-positions. linked by a double bond, W is hydrogen, catalytically hydrogenated; f) for the preparation of compounds of the general formula (I) in which the dashed lines are optional double bonds, Q for O or ^ 0R ¹ , OR "^ ** H ' Z stands for <q £ ", R and R ^{1 are} hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms, R" stands for alkyl with 1 to 5 carbon atoms, B together with the carbon atoms in 12- and 13-position,; to which it is bound, a single bond, a [double bond or an oxirane ring forms j W for OR ', in which R ^{1 has} the meaning given above, or is hydrogen with the proviso that, if the 2- 609837/0878 and 3-positions are connected by a double bond ί, W is hydrogen, and both radicals D are either! Are hydrogen or, if the ICu and 11-positions are connected by a single bond, both can also stand ^{for OR 1,} corresponding 20-aldehyde compounds, ie compounds of the formula (I) in which the dashed lines, B, D, Q, R, R ¹ and W have the meanings given above in this claim and Z stands for O, with an alcohol with 1 up to 5 carbon atoms in the presence of a catalyst that has a proton endona! tor is treated; g) for the preparation of compounds of the general formula (I), in which the dashed lines optionally UR 'tative double bonds are, Q for < , Z stands for OR ¹ or .OR ", R and R · water- \ H" NDR " are material, R "is an alkyl radical with 1 to 5 carbon atoms, B forms a single bond, a double bond or an oxirane ring together with the carbon atoms in the 12 and 13 positions to which it is bonded, W for OR ¹ or hydrogen with the proviso that, when the 2- and 3-positions are connected by a double bond, W is hydrogen, and both radicals D are either hydrogen or, when the 10- and 11-positions are connected by a single bond are, both can also be OR ¹ , where R ^{1 has} the meaning given above, compounds of the general formula (I) in which the dashed lines, B, D, R "and W have the meanings given above in this claim and Q for 0, Z for 0 or ^ 0R ", R and R ¹ Hydrogen or hydrocarbon carbonyl with 2 to 18 carbon atoms are in the 9-position and when Z is 0 ^! B 0 9 B 3 7 / (QI S 7 8 stands, reduced in the 20 position; ι h) for the preparation of compounds of the general formula (I), in which the dashed lines represent optional double bonds, Q for O or ..OR ¹ , Z- for O, R for hydrogen, R · for water- ^ H Substance or hydrocarbon carbonyl with 2 to 18 carbon atoms, B together with the carbon atoms in the j 12 and 13 positions to which it is bonded, forms a single bond or double bond or, if j Q is not 0 or if the macrolide ring j is saturated between the 10 and 11 positions or i is unsaturated between the 2 and 3 positions: can also be an oxirane ring, W for OR, in which R ¹ 'has the meaning given above, or for ^hydrogen: stands for hydrogen with the proviso that if the 2- and 3-positions are connected by a double bond are, W is hydrogen, and both radicals D are hydrogen or, if the 10 and !! positions are connected by a single bond, both can also be OR ', where R' is the above Has meaning Compounds of the general formula (I) in which the dashed lines, B, Q, R ¹ , W and D have the meanings given above in this claim, R has the same meaning as R ¹ , Z is ^ .0R ", where R "is an alkyl radical having 1 to 5 C atoms is hydrolyzed; i) for the preparation of compounds of the general formula 609837/0878 CH = Z N (CH,) -W in which the dashed line is an optional
Double bond, Q for 0 or ^ 0R ¹ , Z for 0 or a group of the formula OR ", SR ", NOR »or NOR" is, R ^{1 is} hydrogen or carbonyl hydrocarbon having 2 to 18 carbon atoms, R "is hydrogen or an alkyl radical having 1 to 5 carbon atoms, W is OR ¹ , in which R ^{1 has} the meaning given above , or is hydrogen with the proviso that when the 2- and 3-positions are connected by a double bond, W is hydrogen,
Compounds of the general formula 609837/0878 in which the dashed line, O, W, Z, R 'and R "have the meanings given above and R has the same meaning as R ¹ , hydroxylated; j) for the preparation of compounds of the general formula (I) which differ from the definition in claim 1 differ in that Q is only an oxo; group is the group in the 9-position of the corresponding Compounds of the formula (I) in which Q stands for i .OR 'stands, oxidized;
<- H ' k) for the preparation of compounds of general formula (I), which differs from the definition in claim 1 in that Z is only an oxo group, W stands for OR ¹ and R and R 'do not stand for H, corresponding compounds of Formula (I) in which Z for ^ OR ¹ , oxidized in 20 positions; ^ II 1) for the preparation of compounds of the general formula (I) defined in claim 1, wherein the 10- and 11-positions are connected by a double bond, corresponding compounds in which the ' 10 and 11 positions through a single bond, are linked and a mesyloxy group is contained in the 10- and 11-positions, demesyloxylated; m) compounds of the general defined in claim 1; my formula (I), in which Z stands for NOR 'or NOR " , is deoxyaminated and thereby forms the corresponding compounds in which Z is an oxo group ^! n) for the preparation of compounds of the general formula (I) defined in claim 1, in which Z stands for 0 corresponding compounds, in which Z stands for ^ SR ", with a mercury (II) salt acts; 609837/0878 o) compounds of the above-defined general _; my formula (I), which contain at least one free OH group, esterified; [ ρ) compounds of the general formula (I) which contain at least one ester group, solvolyzed; q) Compounds of the general formula (I) in the free form or in the form of their esters in their! Converts acid addition salts. , 52) Method according to claim 51 (a), characterized in that net that the reduction with an alkali metal bromide or alkali metal iodide in an organic i Acid or in aromatic hydrocarbons containing concentrated hydriodic acid. 53) Method according to claim 52, characterized in that potassium iodide in acetic acid, which is refluxed is used. 54) Method according to claim 51 (a), characterized in that that the reduction with chromium (II) ions in a preferably dilute mineral acid solution performs under an inert atmosphere. 55) Method according to claim 54, characterized in that the chromium (II) ions in an amount of 2.0 to 2.2 moles are present per mole of starting compound. 56) Method according to claim 54 or 55, characterized in that the pH of the reaction mixture ι is between 0.8 and 2. 57) The method according to claim 54 to 56, characterized in that rosamicin at 25 ° C in ln-sulfuric acid under argon with chromium (II) ions from 609837/0178 Chromium chloride, reduced, the molar ratio of chromium chloride to rosamicin being 2.2: 1 ] . ; 58) Method according to claim 5Kb), characterized in that that the reaction with hydroxylamine or its, hydrohalide, especially with its hydrochloride performs. ! 59) Process according to claim 51 (c), characterized in that 'that the reaction is carried out with the aid of lithium aluminum ' tri-tert-butoxyhydride or tetrabutylammonium cyanoborohydride. 60) Method according to claim 51 (e), characterized in that the reaction with the help of palladium carbon as Catalyst performs. 61) Method according to claim 5Kf), characterized in that the reaction is carried out with the aid of difluoroacetic acid Performs as a catalyst. 62) Method according to claim 5Kg), characterized in that the reaction with the help of sodium borohydride ι performs. 63) Medicines with antibiotic activity, characterized by a content of a compound according to claim 1 to 50, optionally mixed with a suitable pharmaceutically acceptable carrier or Excipient. 609837/0878