DE1693026C3 - Antibiotic acting delta to the power of 13 (17) - and delta to the power of 13 (17); 20 (22) - fusidic acid derivatives and processes for their preparation - Google Patents

Description

wherein X and Y are each one of the groups

C = O

C-R

can be, where in the latter group R for the Λ-hydroxy group, the /? - hydroxy group, an α- or / 9-acyloxy group with not more than 4 carbon atoms and a «- or / J-acyloxy group with a carboxyl group or a primary, secondary or tertiary amino group can stand as a sub-substituent; and wherein R _{1 can be} a hydroxyl group, an alkoxy group with not more than 4 carbon atoms or an alkoxy group with a carboxyl group or a primary, secondary or tertiary amino group as a substituent and in which the "asterisk" in formula I indicates that the formula the Represents C ₂₁ -C ₂₃ trans form.

2. Salts of the compounds I and II with acids or bases.

3. Process for the preparation of the compounds according to claim 1, characterized in that a compound dei formula

Formula Γ is isomerized in trans form, which is then optionally converted by catalytic hydrogenation into the corresponding compound of formula II, or that a compound of formula III is converted directly into the corresponding compound of formula II by catalytic hydrogenation; _{and by esterifying the free carboxyl group at the C 20} atom in the compound of formula I or II initially obtained, or, if an ester group is already present, saponifying it; and by acylating one or both OH groups in the 3- and / or 11-position or, if they are acylated, saponifying them; and by converting one or both of the OH groups in the 3- and / or 11-position into keto groups, which can optionally be reduced in a manner known per se to OH groups in the <\ - and / or / 9-position .

COR ₁ The invention relates to novel antibiotics which have a cyclopentenoperhydrophenanthrene core and to a process for their production.

In particular, the invention relates to certain derivatives of zl ^{13 (} "'-Fusiden-21-carboxylic acid and _z ji3 (i7), zo (22) .p _us j ₍ j _a diene-21-carboxylic acid and their preparation.

The compounds according to the invention correspond to the formulas I and II below, in which Incidentally, the stereochemical relationships at carbon atom 20 have not yet been precisely determined are.

27 24 2

in which X, Y, R and R, have the above meaning and in which the "double asterisk" means a C ₂₁ -C ₂₃ -cis form, to a compound according to

An example of other steroid antibiotics derived from fusidic acid is 24,25-dihydrofusidic acid, which is described in DT-AS 12 28 254 including its production.
In the case of dihydrofusidic acid, the isolated double ₍ ] 1) bond of fusidic acid is hydrogenated, which leads to greater chemical stability and changes in the toxicological and microbiological properties; Most of all, however, it was found that there is a cross between ίο fusidic acid and dihydrofusidic acid

_ Resistance is what is relatively close

~ Analogy in the mechanism of action of the two

_ ties suggesting. In contrast, there is

In the above formulas, X and Y each stand for a similar analogy to the methods according to the invention

v 15 bindings, however, do not.

\ From Table I this interesting feature can be found in the

y ° individual clearly. In the table the

/ Effectiveness of the compound 3a, ll «-dihydroxy-

⁰ H ^ ^{13 '17) i! 10} ' ^{22) i} -fusidadien-21-carboxylic acid, hereinafter

\ I so designated with A, and the connection 3 «, 11« -Di-

CR hydroxy-z) ¹³ ( ⁿ > -fusidene-21-carboxylic acid, hereinafter

/ labeled B, against a number of microorga

compared with that of fusidic acid,

R denotes a λ- or ß-hydroxy group or one which is denoted by F. The effectiveness is from lower acyloxy group with no more than 4 C-atoms than the amount of the antibiotic in question in a straight or branched chain, to which kums in Mi'.ligiamm per liter, which a 50% and also a carboxyl group or a primary , depression of the organism in question causes secondary or tertiary amino groups to be bound (IC ₅₀ ).
be able; In the above formulas, Ri means a hydroxyl
or alkoxy group with not more than 4 carbon atoms in 30
straight or branched chain, to which Table I
a carboxyl group or a primary, secondary
or tertiary amino groups can be bonded; that
"Asterisks" in Formula I indicate
Formula represents the C ₂₁ -C _M transform; under the one- 35
The compounds according to the invention also include the salts
of the compounds I and II with non-toxic, pharmaceutically acceptable acids and bases.

The above compounds can be derived from fusidic acid, a known steroid antibiotic, differ from this, however, both in terms of their structure and in terms of their effectiveness. For example, experiments have shown that between the compounds according to the invention and fusidic acid has no cross-resistance, which is a very remarkable one Feature is.

Fusidic acid, formerly also known as the antibiotic ZN-6, has already been described (in the German Auslegeschrift 1192 785); the antibacterial spectrum of fusidic acid is also explained there. FusidinsäuTe is preferred in the treatment of Staphylococcus infections, such as furuncolosis, is used and is characterized, among other things, by the fact that there is no cross-resistance between Fusidic acid and the previously known antibiotics, the effect of which fails when the infection occurs It causes pathogenic microorganisms that are resistant to the usual known antibiotics have acquired.

Although it has been possible to find fusidic acid-resistant strains of staphylococci in the laboratory breed, such strains are very much in practice

seldom, but with widespread and still further microbiological researches have to be exceptional The use of fusidic acid must of course have other differences in the mechanism of action take into account that the ability of the connections result; so was under of microorganisms to acquire resistance, another demonstrated that compounds A and B im Factor is. which is to be invoiced. essentially have a bactericidal effect (what

F. A. B. Corynebacterium 0.01 1.2 1.2 diphtheriae gravis Corynebacterium 0.006 1.2 1.2 xerosis Sarcina lutea 0.2 1.6 1.6 Bacillus subtilis 0.3 0.4 0.6 Staph. aureus 0.05 1.6 1.6 (Fusidic acid - sensitive trunk) Staph. aureus 190 1.6 1.6 (Fusidic acid - sensitive trunk) Streptococcus faecalis 5 1.6 Streptococcus pyogenes 2 20th Diplococcus pneumoniae, type 1 2 50 Diplococcus pneumoniae, type 3 10 80 Neisseria. gonorrhoeae 1.6 > 100 Haemophilus 50 > 100 influenzae Bordetella pertussis 0.1 > 100

is known to be a particularly advantageous property in an antibiotic ), while fusidic acid and many other known antibiotics, such as the tetracyclines, are primarily bacteriostatic connec tions. It was also found that the effect of the compounds is independent of the size of the Inocolum (ie the concentration of the microorganisms in the test dish), which is in contrast to many antibiotics.

The compounds according to the invention are not only used as a substitute for fusidic acid or 24,25-dihydrofusidic acid in cases where the infectious disease is caused by microorganisms which have acquired resistance to the latter antibiotics; rather, the new compounds should also be used in the form of combined preparations containing fusidic acid or 24,25-dihydrofusidic acid or other antibiotics and one or more of the compounds according to the invention.

If R ₁ in the formulas I and II is a hydroxyl group, the compounds of weak acids that may be used in free form for pharmaceutical purposes though, but are preferably in the form of their salts with non-toxic pharmaceutical base for the application in question are.

With regard to the application form as well as a corresponding resorbability and distributability in the organism and similar factors, in the alcohols with which the carboxyl group at C-20 is esterified, or in the acids with which the hydroxyl groups at C ₃ and C ₁₁ esterified should be, amino groups or carboxyl groups are present as substituents. Such derivatives with relatively strong carboxyl or amino groups can be used with bases or with acids to produce salts which have particularly advantageous pharmaceutical and pharmacological properties.

The process according to the invention consists in the isomerization of a compound of the following formula:

COR ₁

(III)

wherein X, Y, R and R _{1 have} the above meanings and wherein the two asterisks indicate that the compound is in the C ₂₁ -C ₂₃ -cis form. The transform obtainable by isomerization can be converted into the corresponding compound according to formula II by subsequent catalytic hydrogenation; however, the corresponding compound of formula II can also be obtained directly by catalytic hydrogenation of a compound of the formula III. In the compound of formula I or II obtained in this way, the _{free carboxy groups located at C 20} can subsequently be esterified or, if the group in question is already in ester form, saponified; one or both of the hydroxyl groups in the 3- and 11-positions can be acylated or, if they are already acylated, saponified, and one or both hydroxyl groups in the 3- and !! - positions can be converted into one (or two ) Keto group), which can then optionally be reduced to hydroxyl groups or groups in the «- or / ^ - position in the usual way.

The isomerization can be carried out using various known reactions. According to a preferred embodiment of the process according to the invention, however, the starting substance used is a compound in which the _{carboxyl group attached to the C 20} atom is esterified, the isomerization taking place particularly easily when the ester is exposed to alkaline conditions.

The reaction can be carried out in dilute solutions, for example by adding the starting materials in a suitable solvent,

like methanol or ethanol, or in a solvent mixture, such as acetone / water, which a suitable base, such as sodium hydroxide or a weaker base such as ammonia or an organic base is added; the reaction mixture is left then stand at a suitable temperature at least until isomerization has taken place.

Although the isomerization can proceed more rapidly, it is advisable in certain cases to carry out the reaction to be carried out within considerably longer periods of time, whereby the fact plays a role that at the same time a saponification of the ester group proceeds to a more or less high degree, wherein it may then be desirable to complete the saponification in order to obtain a well-defined Reaction product obtained.

The addition of hydrogen to the C ²⁰ < ²²⁾ double bond proceeds as hydrogenation at best in the presence of a noble metal catalyst (Pt, Pd or Ru) or a modified noble metal catalyst; Raney nickel is also suitable as a catalyst.

According to the invention by isomerization and / or hydrogenation compound obtained are subjected to oxidative conditions, whereby a or both of the hydroxyl groups in the 3- and 11-positions are converted into keto groups, which are then subsequently can be reduced to one or two hydroxyl groups in the α or ^ position.

If keto groups are present in the 3- and 11-positions, these can directly form hydroxyl groups in «- or /? - position, where the reduction can also be carried out selectively by covering one of the keto groups.

These process steps are described in more detail in

German patent specification 12 53 706.

The esterification of a carboxyl group bonded to the carbon atom C ₂₀ and the acylation of one or both hydroxyl groups in the 3- and / or 11-position can take place in any order and in the usual manner.

The starting materials for compounds of the formula III are the 3- and 11-substituted / P ^ 'K ^ t ^ -Fusidic-21-carboxylic acids, in the C ₂₁ -C ₂ , -cis form, which are prepared from 24.25 -Dihydrofusidic acid,

and some of their derivatives: have these compounds the 1 orniel

COOlI

OOC ClI,

(IV

where X, Y and R have the above meanings.

By heating a compound of the formula IV or a salt thereof, there is elimination of acetic acid the corresponding compound of Formula III is formed.

The heating may be in a medium having a high boiling point, preferably a polar medium such as dimethylformamide or collidine Dimelhylsulfoxyd be carried out, and besides, it has been shown that the cleavage is facilitated xon acetic acid by the presence of lithium chloride.

The production of 24,25-Dihydiofusidinsäurc and their derivatives according to formula IV is described in DT-AS 12 28 254 and in Patenlanmeldurg 1.45 (S 14 I Vb / 12 o.

The starting materials according to formula III can expediently can be made using the following methods:

Preparation of the C ₂₁ -C ^ -cis form of 3. \. Il. \ - dihydroxy-d ¹³ < ¹⁷ >' ^2l) ( ^{2 :;)} -fusidadien-21-carboxylic acid

A mixture of the sodium salt of 24.25-dihydrofusidic acid (44 g), lithium chloride (88 g), and anhydrous dimethylformamide (380 ml) was 2 ^! / Heated to 135 to 14CV C for _{2 hours.} After cooling, the mixture was poured into about 1 liter of water, whereupon the amorphous precipitate which separated out was filtered off and washed out with water. It was then dissolved in 250 ml of ether and the ethereal solution shaken vigorously with 50 ml of 2N NaOH. The precipitate thus formed was filtered off and washed with water and acetone and then with ether. 22 g of the crystalline sodium salt dei 3 \, ll "-dihydroxy-J 13 ^{(17> 2} ° < ²² > -fusidadien-21-carboxylic acid (C ₂ IC ₂₃ -CiS-FOmI) were obtained.

The free acid was obtained by neutralizing a methanol solution of the sodium salt and the like Separation from water. This acid has a melting point after recrystallization from methanol / water from 181 to 182 ° C;

by treating an ethereal solution of the acid with diazomethane.

Mp. 129 to 130 ° C, [x] ^! _D ° -11 °. ;. * £ "209 ηιμ ( _ε 13,200) and 252 πιμ (ε 6600).

Preparation of the C ₂₁ -C ₂₃ -cis form of 3-keto- ^{1h-hydroxy-J 13 (17} i- ^iu <"'- fusidadien-21 -carboxylic acid

ίο A mixture of the known 3-keto-24,25--dihydrofusidic (20 g), Lilhiumchlorid (40 g) and anhydrous dimethylformamide (200 ml) was heated IVs hours at 135 to 140 ⁰ C. After cooling to about 100 °, the mixture was poured into 1 liter of water and the amorphous precipitate which formed was filtered off and washed with water. It was then dissolved in 200 ml of ether and the acidic compounds of the reaction mixture extracted with 1N NaOH (2 × 60 ml). The combined basic extracts were acidified with 4η hydrochloric acid, the oily precipitate formed was extracted with ether (2 × 100 ml) and the ether extract was washed with water, dried and evaporated to dryness in vacuo. The residue of 16 g was over

"5 a silica gel acid (320 g) chromatographies. The column was eluted with methylene chloride containing increasing amounts of methanol. The fractions containing the desired compound according to thin layer chromatography were combined and evaporated to give 4 g of an amorphous residue. The new Chromatographic treatment of the residue on silica gel in the manner described above gave pure 3-keto-1 ΐΛ-hydroxy-J13I17). 20 (22). fusidadien- 21 -carboxylic acid (C _n -C "" ₃ -

cis-form), /.£'° ^Η = 207 ΐτίμ (f 11200). The corresponding methyl ester was obtained by treating an ethereal solution of the acid with diazomethane as a viscous oil, /. £££ "= 207 nut (ε 12200) and 252 μ (f 6200).

The invention is now based on examples

explained in more detail.

example 1

ucnpici 1

3 *, 1 La-dihydroxy-J ¹³ i ¹⁷ > - ² ° ( ²² > -fusidadien-21-carboxylic acid (C ₂₁ -C ₂₃ -trans form)

4 g of the methyl ester of 3, Π »-dihydroxy 13 (171.20 (22). Fusidadien -21 -carboxylic acid (C ₂₁ -C ₂₃ -cis form) were dissolved in 40 ml of 5% methanolic potassium hydroxide The solution was refluxed for 4 hours and, after cooling, poured into ice water (200 ml). After extraction with ether, the solution was acidified with 4N hydrochloric acid and extracted with ether. The ether extract was washed with water until the washing water was neutral, .. dried and stripped in vacuo Äthei the residue (2.8 g) Wurd "recrystallized from ether and gave 1.8 g of material, mp 188 to 19O ⁰ C. After neuerlichem to crystallize from ether increased the melting point of Au: 192 up to 194 ° C;

209 rna (ε 18,800).

90 °, λ = ¹ ™ 209 Γημ (f 12,600) and 252 ηιμ (ε 7750). The corresponding methyl ester was obtained Analysis for C ₂₉ H ₄₆ O ₄ :

Calculated ... C 75.94, H 10.11;
found ... C 75.71, H 10, üj.

9 ^ϋ ίο

Π c i ^ ρ i c I 2 hydrogen came the I lyilrierune to the stillland, and

3UU-nihvdraxv- I "" * - fusidcn-21 -carbon- ^ r catalyst was ablillnerL Da ^ 1,! Was entered

.. _r , evaporated in vacuo and gave the desired

Compound as a colorless ami rphen kickstaiid:

400 mg 3 \ .ll \ - l ^{l: l} " ⁷¹ '- ^{il (} - ¹ - [" usidailien-21-carbon- 5

acid (Co ₁ -C ^ -cis form) were in ethanol (Id ml) [\] f -14 ') ". /.,',;""204 ιημ (> 725Γ).
dissolved and hydrogenated at room temperature and under normal pressure over 10 igcm PdCaCO. .g-ml.
the hydrogenation / to standstill. The catalyst was io

nbfiliriert and the filtrate in a vacuum to dryness H c i s ρ i c! 6th

evaporated. The residue crystallized from Me- 3-Keto.ll x-hvdroxv- I '*'"-=" - ' -fusidadien-21 -car-

ihanol / A / etomtr.l and yielded Knstalle mn c.ncm Ip. bonsaure'lC, -C ₁ - rans-I orm)
\ on 173 to 174 C:

r, ™, η.- .ι, «!,« _,, "lnm '5 1.38g of the Metlivlester voi. 3-Kcto.l 1 -v-hvdroxy-

\ f - 84. z. ';"204 mi. / 8100).,, _{.,., T1 ΐ 0 (} ,.,.,., - .. - ,, .. ..-. · _R

^{L J} "" ^x ■. ι ⁽⁾ · ^"(-) - fiisidadien - 21 - carboxylic acid _(C;, - C 03-

Analysis for C _.: ,, l I ₁ ^ O ,: cis-form) were dissolved in 20 ml of 5 ",, igem melhano-

Calculates ... C 75.60, H 10.50: lischcm potassium hydroxide and the solution 4 hours

found ... C 75.30. H 10.25. held under reflux. After cooling it was that

2 <i mix in l'is water, with ether eUra-

In game 3 and the aqueous layer with 4N-chlorinated water

3 \ .11 \ dihydroxy-1 ^{n <17} '-fusiden-21-carboxylic acid hydrochloric acid acidified. The precipitate that forms

was extracted with ether, the ether extract with

400 mg of the 3 \, 11 \ -di water prepared according to Example 1, washed, dried and closed in vacuo

hydroxy -. 1 isiiTi.sodat. fusidadicn - 21 - carboxylic acid 25 steamed. The residue (1.20 g) was over Silicarcl

(C, -Co.n-trans form) were chromatographed in ethanol (16 ml) gc- (48 g). The "factions, which

dissolves and at normal pressure and room temperature according to thin layer chromatography

10 ¹¹ JgCm Pd-TaCO ;, (200mg) hydrogenated. Any compounds desired were combined

When 40 ml of hydrogen were needed, the hydrogenation came about and on evaporation resulted in 0.58 g of amorphous substance

to a standstill. The catalyst was filtered off and 30 material;
the filtrate evaporated to dryness in vacuo.

The residue crystallized from methanol / azeto- '.ü,'"" = 208 irr /. (. · 16 " ¹ OO)
nitrile and gave colorless crystals \ om mp. 173 bis

174 C, which is identical in every respect with the pro- The IC .- ,,, - value of this compound ececnübercr Siaph.

product from example 2. 35 aureus was determined to be 5 μ.ε / ml Γ "

ι- ¹

Example 4 Example 7

3 \ - Acetoxy.11λ - hydroxy - .I ¹³ « ¹⁷ » · = ⁰ * ² "- '- fusidadicn- 3-keto-l 1 \ -hydroxy-. 1 ^I3117 ' -fusidene-21-carboxylic acid 21-carboxylic acid (CO, -Co _n -trans form)

40 A savor of 3-keto-ll. \ - hydroxy-. l ^{: 3 (i: i} · ²⁰¹ "'-

To a solution of 3U1 \ -dihydroxy-.J ^I3 < ¹⁷ > · fusidadien-21-carboxylic acid in the C, -C, ₃ -cis-form = ⁿ (") -fusidadien-21-carboxylic acid in _{C 21} -C" -trans - (0.56 g) in ethanol (20 ml) was at atmospheric form (2 g) in dry pyridine (5 ml), 2 ml were added under pressure and room temperature over 10 ", iccm Pd'CaCO: acetic anhydride. Hydrogenated after 16 hours (0.28 g). After consumption of V ml of water at room temperature, the mixture was dissolved in substance, the hydrogenation came to a standstill. The catalyst was poured in and water was poured out, and the precipitant was filtered off and the filtrate was extracted in vacuo to form a precipitate with ether. The alcohol extract was evaporated to dryness. The result was that the product was washed with dilute hydrochloric acid and water. Compound as a colorless amorphous residue; dried and evaporated in vacuo. The amorphous, _E , _OH residue (2 g) was recrystallized from acetonitrile 50 ^ ¹ "-"" ^iU4 " ¹ ^ ^ ⁷⁰⁰⁰ V

Un 1 inquired about 1.4 g of the compound searched for, mp 123. The IC- _{> n} value of this compound compared to Staph

up to 124 C. Na: h recrystallization from ether / azeto aureus was determined with 5 ^ ηιΓ
nitrile, the melting point rose to 125 to 126 ° C; ^μδ

M? -66 \ ;. ££ ^Η = 209ΐημ (* 19250). 55 «,, γλ ^, ^Beis P ^ie18 The IC ₅₀ value of this compound against Staph. ^{acid v} ^ a - C ^ -trans form)

aureus was determined to be 1 ^ g / ml. To a solution of 3-Keto.ll% -hydroxy- ^ ^{13 (17)}

_,. ... ^2Oi22) - fusidadien - 21 -carboxylic acid in the C ₁ -C ₀

ö e 1 s ρ 1 e i S 60 trans form (0.30 g) in methanol (10 mD was below:

3 \ -Acetoxy, l Κ-hydroxy- 1 ^l3 < ⁿ > -fusiden-2l-carbon- stirring Nalriiimborhydrid (0.30 g) within 10 Mi

acid grooves added in small amounts. During de

Zügai * v.-iiuk the temperature by cooling in tis A solution of 3v-acetoxy.ll x-hydroxy-P ³ "7). _{Aqueous 5C water after standing for} 3 minutes

«") -Fusidadien -21 -rarboxylic acid in the CC ₂₃ - 6 ₅ the mixture was neutralized with acetic acid, ii

The trans form (0.4% in ethanol (20 ml) was poured out in normal water and the resulting low temperature

painting pressure and room temperature over 10 ° _n igem Pd / extracted with ether. The extract was carefully

CaCO ₃ (100 mg) hydrogenated. After 44 ml had been consumed, washed with water, dried and in vacuo

evaporated to dryness. The desired compound was obtained as an amorphous substance (0.26 g):

λ ™] " - 208 m; x (r 16500).

The IC, _n value of this compound against Staph. aureus was determined to be 5 ig / ml.

Example 9

Diethalaminoethyl esters of the 3 \, 1! \ -Dihydroxy-
11 H ¹⁷ > -fusidcn-21 -carboxylic acid

A mixture of the potassium salt of 3 \ .11 \ -dihydroxy-J ^{l:! (17)} -fusiden-2l-carboxylic acid (250 mg) with diethylaminoethyl chloride (0.75 ml) was 16 hours with a mixture of acetone (10 ml) and refluxed water (0.1 nil). After cooling, the potassium chloride formed during the reaction was filtered off and excess 4N-ethanolic hydrochloric acid was added to the filtrate. The crystallized hydrachloride of the desired compound precipitated and was filtered off, washed with acetone and dried. . This gave 250 mg, m.p. 237 to 238.5 t ίο C. After recrystallization from absolute alcohol the melting point rose to 239.5 bi; 240 C.

The IC, -, "- Weri this connection to Staph aureus was determined to be 1.6 μg / ml.

Claims (1)

Patent claims: 1. Compounds of the general formulas 27 24 22 COR ₁ 15th (D COR ₁