CA1064906A - Process for the preparation of new 16-ethers of fusidic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A new series of fusidic acid derivatives, salts and easily hydrolyzable esters thereof, and processes for the preparation of these compounds are provided herein. The new compounds have the general formula in which the C24-25 bond is a single or a double bond, and in which Q1 and Q2 stand for

Description

~.~64~6 The present invention relates to processes for the preparation of a new series of fusidic acid derivatives, their salts and their easily hydrolyzable esters, and to the novel compounds so prepared.
The antibacterial properties of fusidic acid are well known, and it is also well known that variations in the structure may cause a complete loss of such activit~.
Accordingly, it is an ob~ect of an aspect of this invantion to provide novel fusidic acid derivatives whlch both in vitro and in vivo show interes~ing antimicrobial and phar~acokinetic properties.
The new compounds of a product aspect of this invention have the general formula:
yS
24 , ~/COOH

Q2~f~/~A-~ H

Ql ~l ~IOi649~
in which Ql and Q~ stand for the group HO ~ or oxygen, A represents o~ygen or sulphur or a sulfinyl radical, and Rl stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms. Rl can, for example, be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.
butyl, or the known isomers of pentyl~ hexyl, heptyl and octyl. Such specific alkyl radicals can optionally be substitu~ed with halogen atoms or hydroxy, alkyloxy, aralk~loxy, aryloxy, alkanoyloxy, aralkanoyl-oxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoyl-thio, aroylthio, azido 9 nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, amino, alkylamino, dialkylamino, .

4~3~6 arylamino, alkano~lamino, and aro~lamino groups; Rl can further ~ an alkenyl or alkynyl radical ~aving from 2 to 6 carbon atoms, e.g., allyl, crotyl or propargyl; a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the mono- or dihalo, lower alkyl, lo~er alkoxy or hydroxy substituted analogues; an aralkyl, heterocyclylalkyl or aryl radical, e.g., benzyl, phenylethyl, phenyl or furfuryl, these radicals being optionally substituted with halogen, nitro, lo~er alkyl, hydroxy or alkoxy radicals.
Rl can also be a heterocyclic radical having 5 or 6 ring atoms and containing oxygen, sulphur or nitrogen atoms, e.g., 2- or 3~pyrrolyl,

2- or 3-furyh, 2- or 3-furfuryl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazolylj imidazolyl, e.g., l-methyl-2-imidazolyl, triazolyl, eg., S-methyl-1,2,4-triazol-3-yl, tetrazolyl, e.g. l-methyl-l~-tetrazol-5-yl, thiazolyl, thiadiazolyl, e.g. 5-methyl-1,3,4-thiadiazol-2-yl.

6~9~i In formula I the dotted line between C-24 and C-25 indicates that the carbon atoms in question are connected with either a double bond or a single bond.
Where not otherwise stated the term "lower alkyl" in the radicals mentioned above stands for a Cl to C4 alkyl radical.
Of particular interest are one class of compounds in which Ql and Q2 are both a Ho~ group ~ and other class of compounds where one of Ql or Q2 is oxygen, A represents oxygen or sulphur or a sulphinyl radical~ and Rl stands for a straight or branched alkyl group with from 1 to 4 car~on atoms, optionally substituted with halogen atoms, hydroxy groups, or an azido group, and the bond between C-24 and C-25 i8 either a double bond or a single bond.
Of special quality amongst the just mentioned groups of com-pounds are those in which Rl i8 ethyl or isopropyl, optionally substituted with fluorine.

~649~6 The compounds of aspects oE the invention can be used as such or in the form of salts or easily ~ydrol~a~le esters. The salts of the compounds are the pharmaceutically acceptable, non-toxic salts 9 e.g., alkali metal salts and alkaline earth metal salts, for example, sodium, potassium, magneslum or calcium salts, as well as salts with ammonia or suitable non-toxic amines, e.g., lower alkyl amines, for example, ~riethylamine, hydroxy-lower alkylamines, for example, 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines, for example, dicyclohexyla~ine, or benzylamines, for example, N,N'-dibenzyl-ethylenediamine, and dlbenzylamine.
For certain purposes also the silver salts of the compounds may be used, especially for local treatment.
The easily hydrolyzable esters can, e.g., be alkanoyloxyalkyl, aralknoyloxyalkyl, arayloxyalkyl esters, e.g.,acetoxymethyl, pivaloyloxy-methyl, benzoyloxymethyl esters,and the corresponding l'-oxyethyl derivatives, or alkoxycarbonyloxyalkyl esters, e.g., methoxycarbonyloxy-methyl, ethoxycarbonyloxymethyl esters, and the corresponding l~-oxyethyl derivatives, or lactonyl esters, e.g., phthalidyl esters, or dialk~l-a~inoalkyl esters, e.~., diethylaminoethyl esters.
In the process according to another aspect of this invention the compounds of formula I can be prepared by a process comprising a flrst step in which a compound of the general formula II is reacted with a compound of the general formula III to form a compound of the general ~ormula IV
~ r Ql Y~Rg ~ OHR3 ! II III IV

11~64~906 --~ in whic~ ormulae Ql~ stands for ~1 as defined above or for R20~
R2 representing an alkano~l~ an aralkano~l or an aryl radical; Q2 and the dotted line between C-24 and C-25 have the meanin~ as defined above, the wavy line between C-16 and the hydroxyl group indicates that the latter can be ~-oriented or ~s-oriented; X s~ands for h~drogen or a cstion, e.g., Ns+, K+, Ag+, an ammonium or trialkyla~monium ion, Y is a chlorine, bromine or iodine atom, and R3 represents a straight or branched alkyl radical having fro~ 1 to 6 carbon atoms, e.g., methyl, ethyl, tert. butyl, an unsubstituted or substituted aralkyl radical, e.g., benzyl, p-nitrobenzyl9 or p-methoxybenzyl, an alkanoylmethyl or aroylmethyl radical, e.g.9 acetonyl or phenac~l, an alkanoyloxyalkyl or aroyloxyalkyl radical, e.g., acetoxymethyl, pivaloylo~methyl or benzoyloxymethyl, an alkyloxymethyl radical or a cyanomethyl radical.
The reaction is performed in an inert organic solvent, e.g., dimethylformamide, and at room temperature or at slightly elevated temperature.
The preparation of starting compounds of formula II i~ either known from the literative, is described in United States Patent No.
4,0049004, or can be performed by analogous procedures.
' In a second step, the compounds of formula IV are converted into compounds of the general formulae Va or Vb:

~w ~ ~4 Q 2 ~; C O (1 R 3 2~ Y

Ql ~~ Ql~~
Va Vb ln which Eorm~lse Ql~' Q2~ R3, Y, and the dotted line between C-24 and I C-25 have the meanings as defined above.
The conversion i3 performed by reacting a compound of formula ~, ~L~g; 4~06 IV ~ith a pol~halogenomethane~ e.g., tetrachloromethane or tetrabromo-methane, or a N-halogenoamide, e.g., N-chlorosuccinimide, in ~he presence of triphenylphosphine, a trislkylphosphine, a triaryl phosphite or hexamethylphosphoric triamide, or with an immonium salt of the general formula VI:
(CH ~ N+-CH-O-R4 Y~ VI
in ~hich formula R4 represents an unsubstituted or substituted phenyl radical, a phenyloxycarbonyl, alkyl) benzoyl or acetyl radical, and Y
is a chlorine, bromine or iodine ion. The reaction is performed in an inert organic solvent, e.g., ether, tetrahydroPuran, dimethylformamide, acetonitrile, and at or below room temperature. The compounds of formulae Va and Vb can also be prepared by reacting a compound of formula IV with a phosphorous halide, e.g., phosphorous pentabromide or phosphorous trichloride, with thionyl chloride, or with a (halogeno-methylene)-dimethyllminium halide.

164~06 The conversion of compounds of the general formula IV into compounds of the ~ormulae Va and Vb normally produces inversion of con-figuration at the carbon atom where the substitution takes place (C-16).
Thu9, a compound of form~la IV with an ~ -oriented hydroxyl group at C-16 is converted into a compound of formula Va, and a compound of formula IV, in which the hydroxyl group at C-16 has ~-orientation, is ~onverted into a compound of formula Vb. However, the compounds of formula Va can be transformed into ~he more stable compounds of formula Vb by reaction with an Inorganic or organic halide, e.g., lithium bromide, tetrabu~ylammonium bromide, sodium bromide, potassium iodide or sodium iodide, in an appropriate organic solvent, preferably dimethylformamide, acetonitrile or ac2tone, at room temperature or at slightly elevated temperature. When a compound of formula IV in which the hydroxyl group at C-16 i9 ~ -oriented is reacted in dimethylformamide with an exce~s of a compound of formula VI, e.g. phenyl N,N-dimethyl-formimidate bromide, the originall~ formed compound of formula Va is ~ _ g _ ~(3 Ei49~6 converted into a comRound of ~ormula Y~ duri~g the reaction.
In a next step the compounds of formula Vb are reacted with co~pounds of the general formula VII to form, with inversion of con-figuration at C-16, compounds of the general formula VIII:
~ 2s . I ~ 24 COOR
~l-A-N ~ A-R

in which formulae Ql~' Q2~ Rl, R3, and the dotted line between C-24 and -;
C-25 have the mea~ing as defined above, and A stands for oxygen or sulphur. If A in formulae VII and VIII represents oxygen, the reacting ~ ~ ~0649f~
compounds of formula VII may preferably be used as solvents, and the reaction is performed in the presence of a silver or mercury salt, e.g., silver carbonate, silver trifluoroacetate or mercuric acetate, or a base, e.g., potassium carbonate, sodium bicarbonate or sodium alcoholate, and at room temperature or at slightly elevated temperature. If A in formulae VII and VIII stands for sulphur, the reaction is performed in an inert organic solvent, preferably ethanol or dimethylformamide, in the presence of a base, e.g., potassium hydroxide or sodium hydride, and at or below room temperature or at slightly elevated temperature.
In a final step the compounds of formula VIII can be converted i~to the compounds o formula I by hydrolysis, e.g., in aqueous methanol or ethanol and in the presence of a base, e.g., sodium or potassium hydroxide or carbonate.
Compounds of formula VIII in which Ql~ and Q2 stand for the group HO ~ or O and R3 represents an easily hydrolyzable ester radical are, without further conversion, compounds of an aspect of the invention.
The compounds o formula VIII in which Ql~ and Q2 stand for ~, --11--,~

9L0~49~16 the group HO ~ or ox~gen, and R3 represents an unsubstituted or sub-stituted benzyl radical~ a cyanomethyl, alkanoylmethyl or aroylmethyl radical can also be converted into compounds of formula I ~y reduction.
If R3 stands for a benzyl or a cyanomethyl radical, catalytic hydro-genation is prefe~red, whereas, if R3 stands for an acetonyl or phenacyl radical, a reduc~ion with zinc in acetic acid can be used.
The compounds of formula I in which Ql represen~s oxygen, and Q2 stands for oxygen or the group HO ~ ~ can also be prepared from the corresponding compounds of formula I in which Ql' and Q2 stand for the group HHO ? by oxidation procedures known to a person skilled in the art.
Compounds of the general formulae I or VIII, in which A stands for a sulfinyl radical are prepared by reacting the corresponding com-pounds of formulae I or VIII, in which A standA for sulphur, with an oxidizing age~t, e.g., hydrogen peroxide, sodium metaperiodate or chromic acid. The reaction is performed in an inert solvent, e.g., water, ~iLQ649~
acetic acid, ethanol or acetone, at or below room temperature or at slightly elevated temperature.
The easily hydrolyzable esters of the compounds of formula I
can be prepared in known manner by procedures described in the literature.
Compounds of aspect~ of the invention in which there are single bonds between C-24 and C-25 can alRo be prepared from the corresponding unsaturated analogue~ by reduction, e.g.~ a catalytic hydrogenation using for ins~ance palladium on carbon as a catalyst.
Intermediate~ of formula VIII can also be prepared according to one or more of the followlng processes:
ta) The co~pounds of the general formula VIII, in which A
stands for sulphur and Rl is aroyl or aromatic heterocyclyl, can be pre-pared by reacting a compound of the general formula IV, in which the hydroxyl group at C-16 is ~C-oriented, with a phosphine, e.g., tributyl-phosphine or triphen~lphosphine, and a compound of the general formula RlSSR~

~64906 `` The reaction ia ~exformed -~p an inert organic solvent, pre-ferably dimeth~lformamide or pyridineJ and at or belo~ room temperature.
(b) In another em~odiment of the p~ocess, a compound of formula IV, in which the h~droxyl grouy at C-16 is ~c-oriented and Ql' is different from the group Ho? is reacted with a reactive deriva-tive of an alkylsulphonic or arylsulphonic acid, e.g., an acid chloride or acid anhydride, to form a compound of the genèral Eormula IX:

~ COOR3 R~ oR5 in which Q2' R3 and the dotted line between C-24 and C-25 are as defined above for compounds of formula IV, Ql~ stands for oxygen or the group ~ ~ ~ , R2 being an alkanoyl, aralkanoyl or aryl radlcal, and R5 repre~ents an alkylsulphonyl or arylsulphonyl ratical, in particular a methanesulphonyl or a p-toluenesulphonyl group.
In a next step a compound of formula IX i~ reacted with a compound of the general formula VII to form a compound of the general formula VIII. If A in formulae VII and VIII stands for oxygen, the compounds of formula VII can be used as solvents, and the reaction can be performed at room temperature or at slightly elevated temperature, in ~ome cases in the presence oE an organic base, e.g., triethylamine.
If ~ in formulae VII and VIII repre~ents sulphur, the reactlon can be performed in the same way a~ described above for the converslon of com-pounds of formula Y~ into compounds of formula VIII, in which A stands for sulphur.
~ c) In a further embodiment compoundc~ of the general formula VIII, in which A stands for oxyges, sulphur or a sulfinyl radical, and ~ represents a hydroxy-substituted alkyl radical, can be converted into corresponding compounds in w~ich Rl ~tands for a halogen-~ubstitueed ~64906 alk~l radical h~ proceQQes dPscri~ed a~oYe for the co~yersion of com-pounds of for~ula IV into compound~ fo ~ormulae Ya or Vb.
In a following step, the halogen~substltuted alk~l derivatives of formula VIII can be reacted with an aliphatic or aromatic alcohol, preferably in the presence of a silver aalt or a base, with an aliphatic or aromatic mercaptan, preferably ln the presence of a base, with ammonia or an Al iphatic or aromatic amine, or with salts of lower alkanoic acids or benzoic acid9 with silver or sodium fluoride, alkali-metal a~ides, nitriees, cyanides or thiocyanates, or with salts of lower thioalkanoic acids or thiobenzoic acld, to form compounds of formula VIII
in which Rl stands for an alkyl radical æubstituted by, e.g., a fluorine atom~ an alkyloxy, aralkyloxy, aryloxy, alkylthio, aralkylthio, arylthio, amino, alkylamino, dialkylamino, azido, nitro, cyano, thiocyan~, alkanoyloxy, aralkanoyloxy, aroyloxy, alkanoylthio or aroylthio radical.
(d~ The C-24,25 unsaturated compounds may in so~e cases advantageously be hydrogenated to the corresponding saturated inter-mediates of ~ormula VIII.
The compounds of ~ormula VIII can be converted into the com-pounds of other aspects of this invention as already described above.
The compounds of aspects of the invention can be used in the treatment of bacterial infections in humans and animals. In vitro investigations have shown, for example, that the compounds are highly potent agalnst a number oP bacteria, e.g., staphylococci, streptococci, corynebacterlae, neisseriael clostridiae and bacteroides specles, and Bacillufl ~ub~ills, as can be seen from the Eollowlng table:

D O O ~ O OO ~ O ~\ 3 (.) ~ 3 ~;t ~ ~J '\ ~iU\.-1 ~ O ~ ~I O '-_ t~ ~ C) ~ ~
~ U~ ~_... _ ._ .
bO ~ r~ ~ .
~ ~1 ~ ¢ 00 ~\1 _ ~ ~r~ ~C~l O O ~ ~ ~ O
~rl ~ O O ;t~1 0 0 0 0 0 0 0 0 0 ~`~
~: C),~ O . . . . . . . . . . . . ' o ~ ~ a) o o o o o o o o o o o o o o . _l _ rl U~
O ~ O ~O~

3 c~ o ~ 0 ~ O O r~ O O N W
h a~ O . ~ .
~r~ ~ ~ ~rt O O 0 0 0 ~U~ I ~ ~1 ~ ~ ,~ _ _ __ - _ _ O ~o ..

H h 1~ O J O ~D O~`1 0 ~ O O O~
~d ~ ~ ~ O ~ ~ O O ~) W
,-~ ~ ~ ~ . . . . , . o . . . ., . .
:~ O h ~ O O O O O O O ~ ~1 0 _I O O O
E h ~ a) c~
h . ta ~D
~ ~ _ _ _ _ r . __ a~
q~ h ~ O
O ~q ~ q GO ~ ~ t~ ~ ~O O O OO ,O ~ U~ O O U~ ~O U~
O ~ ~ ~1 ~ ~ ;t ~\t' ~ ~ /N N N ~t -1 N
~1 ~ ~ O O O O O O O O O O O O O ~
~ ~ ~ 3) ~ . . . . . . . . .. ~ . .
O ~ U~ h C) O O O O O O O O O O O O O O
~ . _ ,_ ~1 C~t ~ ~ 3 O .
bD ~bD ~ bD
O O C~t ~
C,) I O O ~rl O r~O ~rl O O O O O O O
- C.),Q ~ Ul ~1 U~ ~ IJ~~a ~ ~ a ~ ~1~ , ~rl _ , . __ . -- . . . ..
~ N N 1~ t ~ tt~:t ~
~ t ~t ~1 ~
~d ~ C~
~ t C`~ C`J ~
~ ~q ~ ~

4 _ -- . ~1 h ~ ~ ,~
u~ o o o o o o sd ~ . . _ _ _ _ ,1 .C) -4 rO~ O O ~0 0 0 lo O ~ 'a ,a ~l l l l l l l l l l ~qP o~ ~ o o t~ ~:1 0 ~:1 0 ~ ::~
U~ ~ ..
, 1 ~ $ ~t ~q $ $
, , . _ _ ~ ~ O ~ $
_l O O O O O O O O O C~
C~
~ O
.. .~ ~ ~ .. .. .. ~ ~ ~ .. ..
_ .. _ _ _ o ~o 0 ~7 .

~ 1~6~9g~i6 Furthermore, the compounds of aspects of the invention are chemîcally more stable t~an fusidic acid. For example, the 16-acetoxy group in fusidic acid under certain conditions will be hydrolyzed to a hydro~y group in w~ich case a considerable decrease of activity takes place. In the compounds of aspects of the invention, the 16-radicals are not incllned to such hydrolysis; e.g., when 2X (w/v) solutions of the compounds of ~spects of the invention in aqueous buffer of pH 9.6 were kept at 40Co for 30 days, not even traces of de~radation products could be deteceed by ~hin layer chromatography. Like fusidic acid, the naw compounds of aspects of this invention are absorbed efficiently from the gastro-intestinal tract and are practically non-toxic.
The compounds o~ aspects of this invention are provided as pharmaceueical compositions~-which are useful in the treatment of infectious diseases in the human and veterina~y practice. Such pharma-ceutical compositions therefore contain as an active component at least one .

;

~6~9~6 member ~elected ~rom the group consisting of compoun~s of the formula I, salts thereof with non-toxic, pharma-ceutically acceptable bases, and easily hydrolyzable esters together with solid or liquid pharmaceutical carriers and/or diluents.
; In the above-desc~ibed compositions, the proportion of thera-peutically active materïal to carrier substance can varybetween 1p~ and 95% by weight. The compositions can be worked up to various pharmaceutical forms o~ presen-tation, such as, for example, granu~ate, tablets, pills, dragees.,.
' . ' . .
~uppositories~ capsules~ sustained-release tablets~
3uspensions~ injection medi¢ine~ or so ~ar as mi~tu~es are concerned~ they may be filled in bottles or tubes .
or similar containers. Pharmaceutical or~anic or in-organic, solid or liquid carriers and~or diluents suitable for oral, enteral, parenteral or topical ad-ministration can be used *o make up compositlons con-taining bhe present compounds. Water, ~elatlne, lactose~
~tarch~ magns~ium stearate~ talc, vegetable and animal oils and ~ats~ benzyl alcohol~ gum~ po~yalkylon~ glycol, petroleum ~elly, cocoa buttcr, lanolin or othcr known carriers ~or m~icaments are all sui~able, w~ile sta- -bilizin~ agents, w~tting and emulsifying agenta, sàlts ~, . .

- 18 _ ;

for varying the osmotlc pressure or buffers for securing an adequate pH-value of the'composition can be'used'as auxiliary agents.
Furthermore,'the'composition may contain other`pharmaceutically active components which can appropriately be administered together with the'compounds of aspects of the'invention in the'treatment of infectious diseases, such as, for example,'other'suitable antibiotics, in particular such antibiotics, wh;ch may enhance the'activity and/or prevent develop-ment of resistance to provide a composition according to another'aspect of this invention. Such antibiotics include penicillins, cephalosporins, tetracyclines, rifamycins, erythromycin, lincomycin and clindamycin.
Other compounds which advantageously may be`combined with the compounds of aspects of the'invention, especially in topical preparations, include e.g. corticosteroids, like hydrocortisone,'triamcinolone or flucinolone.
For granulates'~ tablets, capsules or dragees the pharmaceutical composition of aspects of the'invention appropriately contains rom 25 per cent to 98 per cent of the active substance of the invention, and in oral suspensions the corresponding amount is appropriately from 2 - 25 per cent.
For parenteral use the'compounds are preferably given by intra-2~ venous infusion of an aqueous solution ~0~90~ .

containing from 0.1 to 2 per cent o~ the active in-gredient, or the compound rnight be given by injection of the compounds in pharmaceutical co~positions ~ith from 1 to 20 per cent active ingredient.

When the compounds are administered in the form .~ of salts with pharmaceutically acceptable non-toxic bases, the preferred salts are for instance the easily water soluble sodium salts or the diethanol-amine salts, but other pharmaceutically acceptable and non-toxic salts may be used, for instance salts which are slightly soluble in water,in order to obtain a particular and appropriate rate of.absorption.

As indicated abave~ the compounds o~ rormula I
and their salts may be worked up to pharlnaceutical . .
forms of presentation including suspensions, ointments and creams, A pharmaceutical preparation .. .. . . .
, for oral treatment may also be in the form of a suspension of a compo~d of ~ormula I as such or in the ~orm o~ a sparingly so~ubl~ salt with a .
pharmaceutioally acceptable baseJ the prepara~ion contain:l.ng ~rom 20 to 100 mg por ml of vehlole.
A pharmaceutical preparatiori for topical treatment may be in the form of an ointment or cream con-tainlng a compound o~ formula I.in an amount of from 0.5 to 10 g per 100 g of preparation.

b 1a~64~06 The compound~ of aspec~s of ~his invention are -admlnistered in compositiong at a selected dose, which dose can be administered so that the desired activity is achieved without simultaneous secondary effects.
In the hllman systemic therapy, the compounds and their salts are conveniently administered (to adults) in dosage units containing not less than 50 mg and up to 1000 mg, preferably from 200 LO 750 mg, calculated as the com-pound o~ formula I.
- By the term "dosage unit" is mean~ a unitary, i.~.
- a single ~ose which is capable or,being admillistered -to a patient, and which may be readily handled and packed~
remaining as a physically stable unit dose comprising .
either the active material as such or a mixt~re o~ it ~ith solid or liquid pharmacoutical diluents or car~
riers.
In.the form of a dosage uni-t~ the compound may . be administered once or more times a day at appropr.iat~
interyals~ always depending, however, on -th~ condition o~ the patient, and in accordance with thc prescription made by the medical practitioner.

.
Thus in systemic treatrnent a dail~ dose will .preferably be an amount of from 0.5 to 3 g of a com-.pound o:f formula I.

~ , . .
' ' ' .

.- 21 -~6~ 6 By the term "dosage uni-t" is in connection with the topical use meant a unitar~, i.e. a single dose capable o~ b~ing adminis-tered topically to the patients and a~plicating pe~ sq. centimeter o* the i~ected area from 0.1 mg to 10 mg and pr,e~erably from 0.2 mg to 1 mg of the compound'in question, If the composition is to be injccted, a sealed ampoule, a vial or a similar container may be provided containing a parenteraLly acceptable aqueous or oily in~ectable solution or dispersion,of the active material as the dosage unit. ~
The par~nteral preparations are in partiaular useful '.
in the breatment of conditions in which a quic~ res~onse to the treatment is desirable. In the continuous therapy o~ patients suffering ~rom infectious diseases, the tablets or capsules may be the appropriate form o~

. . .
pharmaceutical preparation owing to the prolonged effect , obtained when the drug is gi,ven orally, in particular in the form of sustained-release tablets.
In the treatment of infectious d:lseasos, such tablets may advantageously contai~ other active com-poncn t s, as mon t:Loncd hercinbo:f ore ~.

. ' ' , '~
, ~ ' - 22 -, g~
In the follo~ing are given some examples on the preparation of intermediates which are illustrative but not limiting for the invention.

.
.

9~6 Prep~r~tion 1 3-0-Acetyl-16-deelcetoxy-16a-bromofusidic acid phenacyl ester A. 3-0-Acetyl-16-epldeacetylfusidic acid phenacyl ester The sodium salt of 3-0-acetyl-16-epideacetylfusidic acid (5.38 g; 10 mmol) and phenac~l bromide (2.2 g;
lI n~ol) were dissolved in dimethylformamide (40 ml).
After standing for 16 hours at room temperature, the solution was diluted with 150 ml of ether, washed with water (4 x 50 ml), dried, and evapo~ated in vacuo to give 6.2 g of 3-0-acetyl-16-epideacetylfusidic acid phenacyl ester a~ a colourless foam.

B. ~-0-Acetyl-16-deacetoxy-16-bromofusidic acid phenacyl ester A suspension of dimethylformamide (1.1 ml; ~0 mmol) and phenyl chloroformate (5.04 ml; 40 mmol) in 80 ml of petroleum ether (Bp.~ 50C) was stLrred vigorously a-t room temporature During one hour carbophenoxy N~N-dimethylformLmldate chlorido was ~ormed as colourlosq ory~tals. Thls lnltial product lost carbo~ d:Loxide on further stirring for 16 hours to gi~e crystalline phenyl N,N-dimebhylformimidate chloride This in turn - ~ID64~gD6 was converted into N,N-dimethylformamide diphenyl-acetal by adding a solution o.f phenol (3.76 g; 40 mmol)~
and triethylamine;(5.56 ml; 40 mmol) in ether (10 ml) to the stirred reaction mixture. After stirring for an additional hour~ the triethylammonium chloride, formed as a by-product, was filtered off and washed with 50 ml of petroleum ether~ When acetyl bromide (2.~ ml; 27 mmol) was added with stirring to the combined filtrate and washing, phenyl N,N-dimethyl-formimidate bromide was formed as colourless crystals, which were collected and washad wi~h petroleum ether (20 ml) to remove traces of phenyl acetate.
. . The immonium bromide thus obtained (6 g; 26 mmol) was very hvgroscopic, and was immediately added to a solution of 3-0-ace~yl-16-epideacetylfusidic acid phenacyl ester (6.2 ~; 9.8 mmol) in dimethylformamide (40 ml). After standing for 48 hours at room temperature~
this solution was diluted w.ith ether (100 ml)~ washed with 0.1 N sodium hydroxide (100 ml) and water (3 x 50 ml)~
dried~ and evaporated in vacuo, Addition of metha.nol (50 ml) caused the residue to crystall~ze. The orystals were ~ilterod o~ was}ied w.ith methanol, and dried to afford 5.2 g of 3-0-acetyl-16-deacetoxy-16a-bromofusidic aoid phenacyl ester~ melting point 141-142C.

~ , .

, 1~)64~ 6 : Preparations 2-8 3-0-Acetyl~16-deacetoxy-16a-bromofusidic acid esters A. By following the procedure of Preparation 1 A
but substituting the esterifying agents shown in table I for the phenacyl bromide, the 3-0-acetyl-16-epideacetylfusidic acid esters indicated in table I
were obtained.

B. By substituting the 3-0-acetyl-16-epideacetyl-fusidic acid esters indicated in table I for the 3-0-acetyl-16-epideacetylfusidic acid phenacyl ester in -the procedure of Preparation 1 B, the 3-0-acetyl-16-deacetoxy-16~-bromofusidic acid esters shown in table I were obtained.

Table I: next page .
- ~', '. .

~COOR2 HO~"~ R
:' , ' ~ ' ' ".
~ CH3COO `
. .
''' ~

.,~ . . ~ , .

~0649~6 -. .
. . Resulting conlpounds Preparation Esterifying agent Rl R2 Mp (C) 2 A chloromethyl acetale OH CH20COCH3 amorphous 2 B , Br CH20COCH3 102-105 3 A chloromethyl pivalate OH CH20COC(CH3)3 amorphous 3 B . . . Br CH20COC(CH3)3 amorphous 4 A chloromethyl benzoate OH CH20COC6H5amorphous 4 B _ - Br CH20COC6H5 93-94

5 A chloroacetonitrile OH CH2CN amorphous 5 B ~ . Br CH2CN 122-123

6 A ben~yl bromide . OH CH2 6 5 108-109 6 B. . Br CH2C6H5 ' 128-129

7 A ' p-methyl ben~yl . bromide OH CM2C6HI~CH3amorphous 7 B . Br CH2C6H4CH3amorphous . 8 A chloromethyl methyl l ether . OH CH20CH3 ~ amorphous B . ~ Br CH20CH3 amorphous '' .
. Preparatio~ 9 3-0-Ac~tyl-16-deacotoxy_16a_bromo:~tlsld:Lc ac:kl p-nltrobonzyl ester The sodium salt of 3-0-acetyl-16-epideacetylfusidic aold (21.5 ~; 40 mmol) and p-nitroben~yl bromide (9.5 g;
44 mmol) were dissolved in dimethylformamide (200 ml).

1064gO6 This solution was left at room temperature for 16 hours, during which period 3-0--acetyl-16-~pideacetylfusidic acid p-nitrobenzyl ester was formed, Phenyl N~N-dimethylformimidate bromide (36 g; see Preparation 1 B
.for the preparation of this reagent) ~as then added, and the resulting red-brown solution was kept at room temperature for 48 hours. Methanol (700 ml) and water (280 ml) were added with stirring to precipitate a crystalline product. The crystals were filtered off, washed with methanol:water 3:1, and dried to a~ford 26.1 g of 3-0-acetyl-16-deacetoxy-1Sa-bromofusidic acid p-nitrobenzyl ester, melting point: 151-157 C.
Rec~ystallizat.ion from methanol?water gave the ana-lytically pure compound, melting point: 157-159C.

Preparations 10-12 3-0-Acetyl-16-deacetoxy-16a-bromofusidic acid esters By following the procedure of Preparation 9 but substituting the esterif~ing agents listed in table II
for p-nitrobenzyl bromide~ the 3-0-acebyl-16-deacetoxy-16a-bromofusidic acid esters shown in table II were obtained.

.

Table II: next page ~ .
COOR

HO", ~ ~Br .- , ~~ .

CH3COO~

.

~ ~ 10~49~6 ~ Resulting compounds Preparation Esterifying agent R Mp ( C) p-benz~lphenacyl 'cH2coc6H4cH2c6H5 127-129 bromide 11 p-methoxyphenacyl 2 6 4 3 114-116 12 bromoacetone CH2COCH3 80-81 .
Preparation 13 3-0-Acetyl-16-deacetoxy-16a-bromofusidic acid ben~yl ester A 3-0-Acetyl-16-deacetylfusidic acid benzyl ester.
To the sodium salt of 16-deacbtyl~usidic acid (84.7 g; 0.17 mol) in dimethyl~ormamide (Z00 ml) was added benzyl bromide (25 ml; 0.21,mol),. After stir-ring ~or 5 hours at room temperature, the resulting solution was cooled to 0C, and pyridine (200 ml;
2.5 mol) and acetic anhydride (170 ml; 1.8 mol) were added., After,standing for 16 hours at room temperature, the mixture was again cooled to 0C, and 50 ml o~ water was added ~ith stirring at such a rat'e, that the tem-perature remaLned below 15C (about 1 hour was re-quired f'or this addition). Then methanol (800 ml) and water (400 ml) were added t;o oomplete the pre-cipitation of the desired product, which, after stir-ring for 1 hour at 10C, was filtered of~, washed with ice-cold methanol (3 x 20 ml)~ and dried to yield 68 g ' ' - 29 _ 9~6 of 3-0-acetyl-16-d~acetylfusidic acid benzyl ester as colourlcss crystals~ melting point 154-158C.

B. 3-0-Acetyl-16-deacetoxy-16~-bromofusidic acid benzyl ester The above benzyl e.stér (68 g; 112 mmol), sodium bromide (46.2 ~; 448 mmol) pyridi~ (22 ml, 276 mmol) and dimethylformamide (400 ml) was stirred for 30 minutes at room temperature and then cooled to 0 C.
Phenyl chloroformate (56-.5 ml; 448 mmol) was added over a period of 45 minutes, and the resulting mixture was stirred at room temperature for 18 hours. After thi~ period, the reaction product was precipitated by addition of methanol (400 ml) and ~ater ~300 ml) as coi.ourless crystals~ which were filtered off, washed with methanol:water (2 x 60 ml of a 2:1 mixture) and petroleum e-ther (3 x 30 ml), and dried to yield 62.9 g of 3-0-acetyl-16-deacetoxy-16a-bromofusidic acid benzyl ester, melting point 124-126C, PrepElra tions 14~

3-O-Acetyl-~6-deacotoxy-l6~-bromofusldic acid esters A. Following the procedure o~ Preparation 13 A but substituting phenacyl bromide or p-nitrobenzyl bromide ~or tho benzyl bromide, the 3-0-acetyl-16-deacetyl-fusidic acid esters indicated in table III were obtained ' .
~ . - 3 -~64~

B. By substituting the 3-0-acetyl-16-deacetylfusidic acid esters shown in table III for the 3-O-acetyl-16-deacetylfusidic acid benzyl ester in the procedure of Preparation 13 B, the 3-O-acetyl-16-deacetoxy-16a-bromo~usidic acid esters indicated in tabl~ III
were obtained.

Table III:

¦~COOR2 ~~ Rl Resulting compounds . . ' _ _ Preparation Rl R2 ~P ( C) ~ ._ . .. ._._ -14 A ~-OH CH2COC6H5 149-151 14 B . a-Br .CH2COC6H5 141-142 15 A . ~-OH 2C6H4NO2 (p) 141-143 15 O ' a-Br CH2C6H4N2 (P) 157-159 Preparation 16 O~=~ y______eacetoxy-16a-bromofusidic acid pivaloyl-oxymeth~l_ester A. 3.-0-Acetyl-16-deacetoxy-16~-bromofusidic acid piva~loxymethyl ester .

6~90~
3-0-Acety1-16-epideacet~lfusidic acid pivaloyloxy-methyl ester (1704 g; 28 mmol) was dissolved in dry ether (200 ml), and triphenylphosphine ~16 g; 60.mmol) and tetrabromomethana (20 g; 60 mmol) was added.
~- After stirring for 16 hours at room temperature,the reaction mixture was filtered to remove triphenyl~
phosphine oxide~ wh1ch was formed as a by-product The filtrate was evaporated in vacuo, and the residue . was purifi.ed by dry column chromatography on silica gel (cyclohexane:ethyl acetate 8~2) to give 10.6 g of 3-0-acetyl-16-deacetoxy-16~-bromofusidic acid pivaloyloxyme-thyl ester as colourless crystals, ob-tained from ether-petroleum ether, meltlng point 120-122C, Recrystallization ~rom ether-petroleum ether afforded the analytically pure compound, melting point 120-122C.

B. 3-0~ y1-16-deacetoxy-16a-bromofusidic acid pivaloyloxy-methyl ester The 3-0-acetyl-16-deacetoxy-16~-bromo:~usldic acid pivaloyloxymethyl ester described above (5 g) was epimerized to tho 16~-compound by roactin~ wlth to-trabutylammonium broniide (5 g) in acetonitrile (60 ml) for three days at room temperature, The reaction mixture was evaporated in vacuo~ and ether was added to ~ the residue causing tetrabùtylammonium bromide to 1~ 0~' crystallize. The crystals were filtered off, and the filtrate was washed with water (2 x 50 ml), dried~
and evaporated ~ vacuo to yield 4.87 g of 3-0-acetyl-16-deacetoxy 16a-bromofusidic acid pivaloyloxymethyl ester as a colourl~ess gum.

.

~ ~ - Preparation 17 : - .
~-0-Acetyl-16-deacetoxY-16a-bromofusidic acid acetoxv-methyl ester A. ~-0-Acetyl-16-deacetoxy-16~-bromofusidic acid acetoxymethyl ester By following the procedure described in Pre-paration 16 A and substituting 3-0-acetrl-16-epide-acetylfusidic acid acetoxymethyl ester for the 3-0-acetyl-16-epideacetylfusidic acid pivaloyloxymethyl ester, 3-0-acetyl-16-deacetoxy~16~-bromofusidic acid acetoxymethyl.ester was prepared, melting point 119-120C.
. ~ ' ' ' ' ' ~

B. ~-0-AcetYl-16-deacetoxy-16a-bromofusidic acid aoetoxymethyl ester ~y ~ollowlng tho procedure descrlbod in Preparatlon 16 B and subs~ituting 3-0-acetyl-16-deacetoxy-16~-bromo-fusidic acîd acetoxymethyl ester for the 3-0-acetyl-16-deacetoxy-16~-bromofusid.ic acid pivaloyloxymethyl ester9 3-0-aoetyl-16-deacetoxy_16a-bromofusidic acid acetoxy-methyl ester, melting point 102-105C, was prepared.
' , .
~ . - 33 ~

~, .
. ~:
, ~6~906 Preparation 18 3-0-Acetyl-l6-dodcetoxy-16a-b_omo-24 ? 25-dihydrofusidic acid ~henacyl ester A. 16-Deacetyl-24~2~=dillydrofusidic acid_phenacyl ester To a solution of 16-deacetyl-24,25-dihydrofusidic acid sodium salt (4.99 g, 10 mmol) in dimethylform-amide (25 ml) was added phenacyl bromide (1.99 g;
10 mmol), and the mixture was stirred at room tem-perature for 4 hours. After dilution with ether (100 ml), the mixture was washed w~th water (4 x 25 ml).
The organic phase was separated, dried, and concen-trated to about 20 ml whereby a crysballine product precipitated. After being kept in the refrigerator for 2 hours~ the crystals were filtered Ofr, washed with ether, and dried to afford 4.52 g of the desired compound, meltlng point g2-g4c. (dec.).
.
B. -O-Acetyl-16-deacetyl-2L~2~-dihydrofusidic acid phenacyl ester To a stlrred solution o~ 16-deacetyL 2i~25-dihydro-~u~:Ldio acid phenaoyl ester (2.38 gt 4 mmol) in pyridine (8 ml) was added acetic anhydride (4 ml), and the mixture was left at room temperature for 16 hours. After dilution o~ the stLrred reaction mixture with diisopropyl ether .

9~6 (60 ml), crystallization of a colourless product occurred. The cr~stals were colIectcd, washed with diisopropyl ether and dried to yield 1.92 g of the desired compound, melting point 133-135C.

C. 3-0-Acety1'-16-deacetoxy-16a-bromo-24,25-dihy-drof'usidic acid phenacyl ester Phenyl chlbroformate (1.26 ml; 10 mmol) was added dropwise at 0C to a stirred solution of 3-0-acetyl-16-deacetyl-24,25-di~ydrofusidic acid phenacyl ester (1.59 g; 2.5 mmol), sodium bromide (1.03'g;
10 mrnol), and pyridine (0.52 ml; 6.5 mmol) in di-methylformarnide (15 ml). After the addition was f'inished (~ 15 min.), the reaction mixture was stirx-ed for 2 hours at 0C, f'ollowed by 16 hours at room tem-perature. Dropwise-addition of methanol:water 1:1 (15 ml) to the stirred mixture precipitated a cry-stalline product which was filtered of'f`, washed with methanol, and dried to gi.~e 1.22 g of` the desired compound, melting po.int 127-129C J Recrystallization :~rom methylene chlorido-methanol gave the analytical samplo~ melting point 130-132C.

. Preparationsl9-20 3-0-~cetrl-16-deacetoxy-16a-bromo-24,25-dihydrof'usidic acid esters ~.

A. By substituting benzyl bromide or p-nitrobenzyl - 35 ~

10~ 6 bromide for the phenacyl bromide in the procedure of Preparation 18 A, the 16-deacetyl-2~,25~dihydrofusidic acid esters indicated in table IV below were obtained.

B. Following -the procedure of Preparation 18 B, but substituting the 16-deacetyl-24,25-dihydrofusidic acid esters shown in table IV for the 16-deacetyl-24,25-dihydrofusidic acid phenacyl ester, the 3-0-acetyl ester derivatives indicated in table IV were obtained.

C. Following the procedure of Pre~aration 18 C, but substituting the 3-0-ace-tyl-16-deace-tyl-2l~25-dihy-drofusidic acid esters shown in table IV ~or the 3-0-acetyl-16-deaoetyl-24,25-dihydro~usidic acid phenacyl ester, the 3-0-acetyl-16-deacetoxy-16a-bromo-2l~,25-dihydrofusidic acid esters indicated in table IV were obtained.

Table IV : next page ' R2 , . RlO

.

;4~6 Resulting compounds Preparation Rl R2 R3 Mp ( C) 19 A ~ ~-OH CH2C6H5 amorphous 19 B 3 ~-OH CH2C6H5 162-163 19 C CH3C ~-Br 2 6 5 104-105 20 A ~ OH 2 6 4 Z amorphous : 20 B 3 ~-OH 2 6 4 2 amorphous 20 C CH3CO a-Br 2 6 4 2 147-1~9 Preparation 21 3-0-Formyl-16-deacetoxy-16a-bromofusidic acid benzoy~
oxymethyl ester A. 16-Epideacetylfusidic acid ben~oyloxymethyl este_ 16-Epideacetyl~usidic acid (35.5 g; 75 mmol) was dissolved in methanol (150 ml) and converted into its sodium salt by titration with 5 N sodium hydroxide using phenolphthalein as indioator. After evaporation to dryness in ~acuo~ the resulting amorphou9 sodium salt was dissolved in dimethyl~ormamido (150 ml), ohloromethyl b~n~oat~ ,08 ~ ~2.5 mmol) wag addefl~
and the mixture was stirred at room temperature ~or 16 hours. Water (200 ml) was added, and the mixture was extracted with ether (l~oo ml). The organic phase ~, ~
, ~ 37 -. . .

~"

lOGq~90G
.
was separated, washed with water (4 x 100 ml), dried, and evaporated in vacuo to yield 44.6 g of 16-epide-acetylfusidic acid benzoyloxymethyl ester as an amorphous product, B. ~-0-Fo~myl-16-deacetoxy-16a-bromofusidic acid benzoyloxymethyl ester The 16-epideacetylfusidic acid benzoyloxymethyl ester prepared above was dissolved in dimethylformamide (300 ml), phenyl N,N-dimethylformimidate bromide ~67 g;
ca. 290 mmol) was added with stirri~g, and the red-brown solution was kept at 5C for 6-7 days. To the mix~ure was added methanol (150 ml), and~ with v:Lgorous stirring, water (150 ml) from a separating ~unnel to preclpitate a orystalline product. T~e crystals were filtered off~ washed with methanol:water 1:1~ and dried to afford 27.1 g of 3-0-formyl-16-deacetoxy-16a-bromofusidic acid benzoyloxymethyl ester, melting point 131-135C. Two reorystallizations from ether-methanol raised the melting point to 140-142C.

Preparat:Lorls 22--24 3-0-Formyl-16-deacetoxy-16a-bromofusidic acid esters ,.
, A. By substituting benzyl bromide~ chloromethyl . ' .

( -10~ 36 pivalate ~r ch~oromethyl ~cetate for the chloromethyl ben~oate in the procedurc of Preparation 21 A the 16-epideacetylfusidic.acid esters indicated in table V
below were obtained.

.

B. Following the procedure of Preparation 21 B, but substituting the 16-epideacetylfusidic acid esters show~ in table V for the 16-epideacetylfusidic acid benzoyloxymethyl ester, the 3-O-formyl-16-deacetoxy-16~-bromofusidic acid esters indicated in table V were obtained, Table V-- , ,11 . ~ CO0~3 ~ 2 Resulting compounds __ _ .
Preparation Rl R2 R3 . Mp ( C) . _ 22 A H OH CT-I2C6H~ 95-98 22 BTICO Br C~2C6TT5 125-127 23 ~ H OH C.H20COC(CH3)3 amorphous 23 BHCO Br CH20COC(CH3)3 amorphous 2l~ A H OH CTT20CO 3 amorphous Z4 l3 ¦.HCO l 3r ¦ CHzOCOCH ¦ 123-lZ5 .
' - 39 -. , .

~' ' .

~i4~6 Preparation 25 ~-O-Formyl-l~-deacetoxy-16-bromofusidic acid benzyl ester A. 16-Deacetylfusidic acid benzyl ester To a solution of 16-deacetylfusidic acid sodium salt ~4.97 g; 10 mmol) in-dimethylformamide (Z5 ml) was added benzylbromide (1.5 ml; 12~5 mmol), and the mixture was stirred at room temperature for 4 hours.
After addition of water tlOO ml), the mixture was extracted with ether (2 x 50 ml), and the combined organic extracts were washed with water (4 x 20 ml), dried, and evaporated in vacuo. The residue thus obtained was dissolved in ethor (50 ml)~ and on ad-dlt:Lon of petroleum ether (50 ml) with stirring a orystalline product precipitated. The crystals were filtered o~f, washed with ether:petroleum ether 1:2, and dried to gi~e 4.92 g of the desired cc,mpound, melting point 117-119 C.
, B. 3~0-Formyl-16-deacetyl~usldlc acid bon~yl estor ~ co~lc ~ormlo anhydrlclo (l~ ml) was added dropwise at 0C to a stirred solution o~ 16-deacetrl~usldic acid benzyl ester (4.52 g; 8 mmol) in pyridine (8 ml), and the mlxture was l~ept at the low tomperature for 15 minutes. On dilution of the stirred reaction mixture `, ~i _ 40 - i ~6~96~6 - -with diisopropyl ether (40 ml)~ a crystalline product precipitated. After being kept in the refrigerator for~
2 hours, the crystals were collected, washed with di-isopropyl ether, and dried to yield 4.04 g of the desired compound, melttng point 143-145C. Recrystallization from ether-diisopropyl ether afforded the analytical sample, melting point 145-147Co 3-0-Formyl-16-deacetoxy-16a-bromofusidic acid benzyl ester.
By following the procedure of preparation 13 B
and substituting the above 3-0-formyl-16-deac~-tyl-fusidic acid benzyl ester for the 3-0-acetyl-16-deacetylfusidic acid benzyl ester, 3-0-formyl-16-deacetoxy-16a-bromofusidic acid benzyl ester was prepared as colourless crystals; melting point 125-127 C.

' Preparation 26 3-0-Fornyl~l6-deacetoxy-16a-bromo~usidic acid pi.valoyl-oxymethyl ester A. 16-Deacetylfusid:Lc acid pivaloYloxymethyl es~er To a solut:Lon of the amorphous silver salt of 16-deacetylfusidic acid (5.8 g; 10 mmol) in dimethyl-formamide (50 ml) was added chloromethyl pivalate (1.48 ml; lO mmol), and the mixture was stirred a-t _ 41 -~06490G

room temperature for 48 hours. Filter aid was used to remove insoluble material, which was washed with c ether (2 x 25 ml).r The combined filtrate and washings ~ere diluted with ether (100 ml) 9 the resulting mixture was washed with water (4 x 50 ml)~ and the organic phase dried and evaporated in vacuo to afford the crude ester as a yellowish foam. Purification o~ the re-sidue by dry column chroma-tography on silica gel (developing solvent: Cyclohexane:ethyl acetate 3:7) yielded the desired ester as an amorphous product which failed to crystallize.
The NMR spectrum (CDC13) shows signals at d = 0.90 (d~ 3H), 0.93 (s, 3H), 0.98 (s,-3H), 1.22 (s, 9H;
C(CH3)3), 1.38(s, 3~1), 1.62 and 1.68 (2 bs, 6H), 2 99 (m, lH; CH-13), 3.77 (m, lH; CH-3), 4.33 (m, lH; CH-ll), 5.00 (m~ lH; CH-16), 5.12 (m~ lH; CH-24), and 5.15 and 5.42 (2 d~ J=7, 2H; OCH20) ppm. Tetramethylsllane was used as internal reference.

B. 3~0-Formyl-16-deacetyl~usiclic ao:id pivalo~loxy-, ~ ollowing the procedure of Preparation 25 B~ but substituting 16-deacetylfusidic acid pivaloyloxymethyl ester ~or the 16-deacetylfusidic acid benzyl ester~ the 3-0-~ormyl-16-deacetyl~usidic acid pivaloyloxymethyl ester was obtained.

~ 42 -- :LQ~9~6 .
C, ~-0-Form~1-16-dcacetoxy-16a-bromofusidic acid p~aloyloxymethyl ester By substituting 3-0-formyl-16-deacetylfusidic acid pivaloyloxymethyl ester ror the 3-0-acetyl-16-deacetylfusidic acid benzyl ester in the procedure of Preparation 13 ~ 3-0-formyl-16-deacetoxy-16a- j bromofusidic acid pivalo~loxymethyl ester was obtained as a colourless foam.
The NMR spectrum (CDC13) shows signals at ~ = 0.78 (s, 3H), 0.87 (d, J_7,3H-), 1.00 (s, 3H); 1.23 (s, 9H, C(~H3)3), 1.47 (s, 3H), 1.61 and 1.68 (2 bs, 6H)~ 3.4~ (m~ lH; CH-13)~ 4.35 (mj H; CH-ll)~ 5.08 (m, lH; CH-3), 5.12 (m, lH, CH-24), 5.62 (bt, lH, CH-16), 5.82 and 5~92 (Z d~ J=6, 2H; OGH20)~ and

8.15 (bs, lH~ HC0) ppm. Tetramethylsilane was used as internal re~erence.

' Preparation 27 3-O-Formyl-16-deacetoxy-l6a-bromo-24~25-dihydr fusidic aoid aoeto~ymethyl ester h. 16-Epidoaoetyl-2l~,?5-dlhydrofusidic acld acet-oxymothyl ostor To a solution of 16-epideacetyl-24,25-dihydro-fusidic acid potassium salt (20.6 g; 40 mmol) in dimethylfor~lamide (160 ml) Iras added chloromethyl 4 3 - .

c acetate (4.0 ml; 44 mmol), ~nd the mixture was stirred at room temperature for 18 hours. ~fter . Y
dilution with ether (500 ml), the mixture was washed with water (2 x 150 ml, 4 x 75 ml)~ and the organic layer was dried and evaporated in vacuo to give the desired compound as a colourless foam.

B 3-0-Formyl-16-deacetoxy-16~-bromo-24,25-dihydro-fusidic acid ac toxymethyl ester To a stirred solution of the above ester (40 mmolj and sodium bromide (20 6 g; ~.2 mol~ in dimethylform-.amide (200 ml) was added dropwise at 0C phenyl chloro-formate (25.2 ml; 0.2 mol). After the addition was finished {~ (45 minutes), the mixture was stirred at 0 C for 3-4 hours and at room temperature for a further 10-12 hours. Precipitated sodium chloride was filtered off and washed with dimethylformamide ~2 x 25 ml). To the combined filtrate and washings was added methanol:water l:l (300 ml) wlth stirrLng to precipitate a orystalline product. The crystals were ~lltered of~ washod with mOtllanOl:WatOr ~
dried~ and finally recrystalli7ed from ether-diiso-propyl ether to afford 15.35 g of the desired compound, molt:Lng point 1~6-127C.

_ 44 -' ~L~64~

Preparations 28-32 6-Deacetoxy-16a-bromofusidic acid esters By substituting 16-epideacetylfusidic acid benzyl, phenacyl, pivaloyloxymethyl, acetoxymethyl or benzoyloxymethyl ester for the 3-0-acetyl-16-epideacetylfusidic acid pivaloyloxymethyl ester in the procedure of Preparation 16, the 1~-deacetoxy-16a-bromofusidic acid esters listed in table VI were obtained.

Table VI :
~ ' ' .
~ COOR

HO ~" ~ Br j , HO~` ~

-Resulting compounds _ .
Preparation R . Mp( C) _ ._ 28 CH2C6H5 amorphous 29 CH2C006H5amorphous CH20COC(CH3)3 a~lorphous 32 CH20COC6H5 amorphous .~ . .

. _ 4~ - .

.
. . .

1al6~

Pre~aration ~3 3-0-Acetyl-ll-keto-16-deacetoxy-16a-bromofusidic acid phenacyl ester To a solution of 3-o-acetyl-l6-deacetoxy-l6a bromofusidic acid phenacyl ester ~6.98 g; 10 mmol) in acetone (70 ml) was added Jones reagent (3.0 ml), and the mixture was stirred for 30 minutes at room temperature After dilution with ether (100 ml) and addition of water (70 ml), the mixture was stirred for a further 10 minutesc The organic layer was separated and the aqueous,layer reextracted .
with ether (100 ml). The combined organic extracts were washed with water until neutral, dried~ and concentrated to 50 ml, whereby precipitation of a colourless crystalline product occurred. A~ter being kept in the refrigerator for 1 hour, the crystals were ~iltered off, washed with ice-cold ether, and dried to gi~e 5.37 g of 3-0-acetyl-11-keto-16-deacetoxy-16a-bromofusidic acid phenacyl ester, melting point 120-121 C. On concentration o~ the mother liquor another 0.95 g of the desired compound~ melting point ~116C, was obtainod. Rocrysta:L:li~ation from . . methylene chloride - diisopropyl ether afforded the analytical sample, melting point 120-121C.

~. ~ .

. ~6 - .

~64so~

Preparation 34 ~-0-Acetyl-ll-keto-16-deacetox~-16a-bromofusidic acid benzyl ester By following the procedure of Preparation 33 and substituting 3-0-acetyl-16-deacetoxy-16a-bromo-fusidic acid benzyl ester for 3-0-acetyl-16-deacetox~r-16a-bromofusidic acid phenacyl ester9 3-0-acetyl-11-keto-16-deacetoxy-16a-bromofusidic acid benzyl ester was prepared as a colourless foam.
The NMR spectrum (CDC13) shows signals at ~=1.00 (s~ 3I~)~ 1.05 (s~ 3H)~ 1.02 (d, 3H), 1-27 (s, 3H)~
1.62 and 1.68 (2 bs~ 6H)~ 2.06 (s~ 3H; CH3C0), 3.30 (m, lH; CH-13), 4.95 (m, lH, C_-3)~ 5;05 (m, lH, CH-24), 5,22 (s~ 2H; CFI~C6H5)~ 5.60 (bt~ lH; CH-16)~ and 7.35 (s~ 5H; arom. CH) ppm. Tetramethylsilane was used as internal reference.

~ ' , ' .
Preparation 35 3-0-Formyl-ll-koto_16-deacetoxy-16a-bromo-21~,2~-clihydro _usidic aoid acetoxymethy:l ester By substltut:ln~ 3-0-formyl-16-doaoetoxy L6a-bromo 24,25-dihydrofusidic acid acetoxymethyl ester for the 3-0-acetyl-16-deacetoxy-16a-bromofusidic acid phenacy ` os ~or in the proceduro o~ Preparation 33, 3-0-formyl-11-~ 47 ~

~116~6 keto-16-deacetoxy-16a-bromo-24~25-dihydrofusidic acid acotoxymethyL ester was obtained as a colourless foarn.
The NMR spectrum~'(CDC13) shows signals at d = 0.87 (d, J=5.5, 6H), 1.02 (s, 31I), 1.04 s, 3H), 1.25 (s, 3H), Z-12 (s~ 3H; CH3C0), 3.35 (m, lH; CH-13), 5.10 (m, lH;
CH-3), 5.68 (bt, lH; CH-16)9 5,81 and 5.90 (2 d, J=5.5, 2H; OCH20)~ and-8,15 (bs~ lH; HC0) ppm. Tetramethylsilane was used as internal reference.

Preparation ~6 ~-Keto-16-deacetoxy-16a-bromofusidic acid acetoxy-rnethyl ester A. 3-Keto-16-~ideacetylrusid:ic'acid ace-t,oxyrneth~l , ester To a solution o~ 3-keto-16-epideacetylfusidic acid potassium .salt (3.o6 g; 6 mmol) in dimethyl-~ormamlde (30 ml) was added chloromethyl acetate (o.6 ml; 6,6 mmol), and the mlxture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ether (100 ml) and washed with water (l~ x 30 ml). The or~an:ic phase was separated~ driod~
and evaporated ln vacuo to afford 3.2 g of tho desired compound as a colourless foam. ' ~ , . .

_ 48 -6~ 6 B. 3-Keto-16-deacetoxy-16~ -4romofusidic acid acetoxymethyl ester By following the procedure described in Preparation 27 B but substituting the above 3-keto-16-epideacetylfusidic acid acetoxymethyl ester for the 16-epideacetyl-24,25-dihydrofusidic acid acetoxymethyl ester, 3-keto-16-deacetoxy-16~ -bromofusidic acid acetoxymethyl ester, melting point 144-145C., was obtained.

-Preparation 37 3-0-Acetyl-16-deacetoxy-16~ -chlorofusidic acid methoxymethyl ester 3-0-Acetyl-16-epideacetylfusidic acid methoxymethyl ester (1.4 g; 2.5 mmol), triphellylphosphine (2.6 g; 10 mmol) and N-chloro-succinimide (1.3 g, 10 mmol) were dissolved in dry ether (50 ml). After standing for one hour at 35C., the triphenylphosphine oxide which precipitated was filtered off, and the filtrate was evaporated in vacuo .
The residue was purified by dry column chromatography on silica gel (cyclohexane:ethyl acetate 7:3) to afford 1.14 g of 3-0-acetyl-16-deacetoxy-16~ -chlorofusidic acid methoxymethyl ester, which was crystallized from petroleum ether, melting point 148-151C. Recrystal-lization from cyclohexane afforded the analytically pure compound, melting point 149-151C.

~lal64~6 Pre~aration ~8 t .
~ 0 Acet 1 16 deacetox -16R-chlorofusidic acid benzvl y _ _ y ester - Carbophenoxy N,N-dimethylformimidate chloride was prepared by adding phenyl chloroformate (0.3 ml; 2.4 mmol) to N~N-dimethylformamide (15 ml). To the resulting solution was added 3-0-acetyl-16-epideacetylfusidic acid benzyl ester (500 mg; 0.82 mmol). After standing for 16.hours at room temperature the reaction mixture was diluted wi.th ether (100 ml), washed with 2 N sodium hydroxide (25 ml) and water (3 x 25 ml), dried and evaporated in vacuo to give 480 mg of 3-0-acetyl-16-deacetoxy-16~-chlorofusidic acid benzyl ester~ which was crystallized from ether-petroleum ether, melt~ng polnt 163-165C. Recrystalli~ation from ethyl acetate-petroleum ether afforded the analytically pure compound, melting point 165-166C.
.

Preparation 3~ .

To a stirred ice-cooled solution of 3-0-acetyl-16-deacetylfusidic acid benzyl ester (1.36 g) in dimethyl-~ormamlde (10 ml) and pyridine (0.4ll ml) was added phenyl chloroformate (1.13 ml) over a period of 30 minutes.

~L064~0~

After stirring at room temperature for 16 hours, the resulting solution was diluted with ether (100 ml)j t washed with 2 N sodi~m hydroxide (25 ml) and water (3 x 50 ml), dried and evaporated in vacuo. The residue was dissolved in ether (10 ml) and petroleum ether was added to precipitate the reaction product as colourless crystals, which were flltered off, washed with petroleum ether, and dried to yield 3-0-acetyl-16-deacetoxy-16a-chlorofusidic_acid benzyl ester, melting point 115-117C. Recrystallization from ethyl acetate-petroleum ether raised the melting point to 120-122 C.
The invention i~ various aspects will be further descrlbed in the following Examples which are not to be construed as llmiting the :invention.

.

. - 51 - .

( `
1~6q~9~6 Exa~pl~ l --16-Dt~ac0tox~r-16~-isopropyl-thiofusidic acid A, ~-0-Acetyl-16-deacetoxy-16~-isopropylthio-fusidic ac;~d p-nitroben~yl ester 3-0-Acetyl-16-deace-toxy-16a-bromofusidic acid p~nitrobenzyl ester (28.6 g; 40 mmol~ ~ras added to a solution of potassium h~droxide (10 g of 85~o purity; 150 mmol) and isopropyl mercaptan ~30 ~1;
320 mmol~ in ethanol (1000 ml), and the suspension was - stirred for four days. ThereaPter~ 500 ml of water as added to complete the precipitation of ~he desired product. The crystals were ~iltered off, washed with water:ethanol ~1:2j, and dried to gi~re 21.5 g o* crude 3-0-acetyl-16-deacetoxy-16~-isopropy~thlo~usidic acid p-nitrobenzyl ester~ meltîng point: 157-161 C.
' B. 16-Deacetoxy-16~-isopropylthio~usidic acid - A suspension o~ th0 above p-nitroben~l ester in a mixture o~ ethanol (800 ml) and 2 ~ aqueous sodium h~
d~oxidc (200 ml) was heated to 60 C ~or th~oe hour~.
The resulting darlc solution ~as acid:i~ied with l~ N
hydrochloric acid (125 ml) and t.rcated ~or 15 minu-te~
~ith 5 g o~ charcoal l~lile still hot. A~-ter filtration, 500 ml of water was added~ and~ a~ter cooling to room tomperature, the crystalline product w~s ~iltered Orr, .

~;ashed with w~ter~ and dri~d to give ltl.l g o~ 16-~eaceto~-16~ opropylthiofusidic a~id7 m~lting pOiIlt 223-229C. Re.crystallization rrom 2-butanone gave the analytically pure compound~ ~elting point: 229-231C.

- Examples 2-8 16~-Thioethers of 16-deacetoxyfusidic acid A. 16~-Thioethers of 3-0-acetyl-16-deacetoxyfusidic acid p-nitrobenzyl ester ,, By following the procedurQ described in Example 1 A and substituting the mercaptans llsted in table VII for isopropyl mercaptan, the 16~-thloethers of 3-0-acetyl-16-deacetoxyfusidic acld p-nitrobenzyl ester indicated in table VII were prepared.

: Table VII: next page , ~ .
~f ooCH~ ~o2 ,~ s~

CH3C Oo ,.
.
.
. - 53 ~

, ~esulting compound _ m ~ . . . . __ . A_ _._ . ____ . __ . _ ~ --Example M~rcaptan R M (C) 2 A ethyl rnercaptan CH2CH3 167-168 3 A 2-hyd~oxyethyl CH2CH20H 192-194 mercaptan 4 A 2-aminoethyl CH2CH NH2 188-191 ~ercaptan 2 5 A allyl mercaptan C 2 2 2 167-170 6 A isobutyl mercaptan CH2CH(cH3)2 104-112 7 A sec-butyl mercaptan CH(CH3)CH2CH3 150-157 8 A cyclopentyl mercaptan cyclopentyl 100-109

9 A mercaptoacetic acid CH2COOCH 125-129 methyl ester 3

10 A furfuryl mercaptan furfuryl 146-148 B. 16~-Thioethers of 16-deacetoxyfusidic acid By follow:Lng the procedure o~ Example 1 B and substituting the 16~-thioethers of 3-O~acetyl-16-deacetoxyfusidic acid p-nitrobenzyl ester listed in table VII for 3-0 acetyl-16-deacetoxy-16~-isopropyl-thiofusidic acid p-nitroben~.yl ester, the 16~-thio-~thers of`l6-deacetoxyfusidic acld indicated in table VIII were prepared.

Table ~ ncxt page .' ;~' ' ..
C00~l H0", ~ SR

~0`

. - 54 -~0~;4~6 .
_ Resulting compounds Example R Mp ( C) .. __ 3 B C~2CH20H 179-182 4 B 2 2 2 241-250 (dec) 5 B CH2CH=CH2 l96-l9g 6 B CH2CH(CH3)2 199-202 7 B ( 3) 2 3 218-222 8 B cyclopentyl 217-223 . 9 B CH2COOH 199-202 10 B furfuryl amorphous The NMR spectrum (CDC13).of the compound of Example lO B shows signals at ~ = 0.97 (s~ 6H)~ 1.32 (s, 3H~, 1,60 and 1.68 (2 bs~ 6H), 3.00 (m~ lH; CH-13).~ 3.73 (m, lH; CH-3), 3.78 (bs, 2H; SC_2), 4.22 (d, lH; CH 16), 4.30 (m, lH; CH-llj, 5.10 (m, lH; CH-24), 6.1-6.4 (m, 2H; arom. C_) and 7,32 (bs, lH; arom. CH) ppm.

Tetramethylsilane was used as internal reference.

Example 11 , 16-Deacetoxy-l6~-isopropylthio-2Ll~25-clihydro-fusidic ao:Ld A. ~-0-Acetyl-16-deacetoxy-16~-isopropylthio-24,25-dihydrofusidic acid p-nitrobenzyl e_ter .

By :rollo~:ing the procedure o~ Example 1 A and \

'~

~ 55 -~64~

substit~ll;ing'3-0-acetyl-16~deacetoxy-16a-bromo-24,25- dihydrofusidic acid p-nitrobenzyl ester for 3-O-acetyl-16-deacetoxy-16a-bromofusidic acid p-nitrobenzyl ester, 3-O-acetyl-16-deacetoxy-16~-isopropylthio-24,25-dihydrofusidic acid p-nitro-benzyl ester was prepared as colourless crystals, melting point 113-116C.

B. 16-Deacetoxy-16~-isopropylthio-24,25-dihydro-fusidic acid By following the procedure o~ Example 1 B and substituting 3-O-acetyl-16-deacotoxy-16~-isopropyl-.
-thio-24~25-dihydrorusidic acid p-nitrobenzy.l ester for 3-O-aeetyl-16-deaeetoxy-16~-isopropylthiofusidie aeid p-nitroben~yl ester, 16-deaeetoxy-16~-isopropyl-thio-24,25-dihydrofusidie aeid was prepared, melting point 232-234C~

Exa.mple 12 16-Deaeetoxy-16~-oyelohexylthlo~us:Ldie ae.Ld 3-O-Aeotyl-16-doaeetoxy-16~-bromo~usidie ae~d p-nitro-ben~yl oster (1 43 g; 2 mmol) was added to a so:Lut:Lon of potassium hydroxide (400 mg o~ 85yo purity; 6.1 mmol) and cyelohexyl mercaptan (2 ml, 16 mmol) in ethanol (lOO ml), and the resulting solution was left at room ~., ~

~49~

temperature for five days. Thereafter, the reaction mixture was diluted with 150 ml of ethe~r, washed with ~ater (3 x 75 ~1), dricd and evaporated in vacuD. The residual oil, containing the crude 3-0-acetyl-16-deacetoxy-16~-cyclohexylthiofusidic acid p-nitrobenz-yl ester, was dissolved in ethanol (80 ml), and 20 ml Or 2 N
aqueous sodium hydroxide was added. After stirring for three hours at 60C; 100 ml of ~ater was added, and the resulting dark solution was acidificd with 4 N hydrochloric acid (15 ml) and extracted twice ~ith ether. The combined ~rg~anic phases were washed with water (3 x 50 ml ?, dried and evaporated.
The oily residue was purified by dry oolu~l~ chromatography on s:Llica gel (ether:petroleum ether:acetic acid~70:30:0.5) to give 16-deacetoxy-16~cyclohexylthiofusidic acid, crystalli~ed from ether-petroleum ether, melting point:
215-220C Recrystallization from ethyl acetate-pe-troleum ether gave the analytically pure com~ound~, melting point: 216-220C

Examplesl3-15 Following the procedure of Example 12 and substituting the mercaptans listed in tabel IX for cyclohex~l mer-captan~the 16~-thioethers of 16-deacetoxyfusidic acid indicated in table IX were prepared.

Tahle IX:
Jl ~ COOH
HO",~ ~SR

' ' HO~ .

. Resulting compound Example Mercaptan R
_ 13 2-phen~lethyl 2 2 6 5 208-214 mercaptan ~
14 ~ n-butyl merc'aptan CH2CH2CH2CH3 105-118 (dec) . 15 methyl mercap-tan CH3~ amorphous The NMR spectrurn (CD30D) of th~`compQund of Example 15 shows signals at ~= 0.89 (d, J=6, 3H), 1.00 (5, 3H), 1-03 (8~ 3H), 1.3~ (s, 3H), 1.62 (bs, 6H), 2.13 (s, 3H; SCH3)~ 3.03 (m, lH; CH-13), 3-67 (m, lH; Ca-3), 4.03 (d, J=9, lH; CH-16), 4.26 (m, lH; CH-ll) and 5,10 (m, lH; CH-24) ppm. Tetramethylsilane was used as internal rcference, .~

, .
16-Deaceto~y-16~-ethylthiofusidic acid . .
To a ~olution o~ ethyl mercaptarl ~2~5 ml; 34 mmol) lnIdimethylformamide (10 ml) was added sodium ' - 58 -' hydride (6go mg o~ a 55~/' suspension in oil; 15 mmol)~
When the ~volution o~ hydrogen ceased, 3-0-acetyl-16-deacetoxy-16a-~rornofusidic acid pivaloylo~ymethyl este~
(750 mg; 1.1 mmol) was added. After standing one hour at room temperattare, the ieaction mixture was diluted with ethyl acetate (50 ml) and extracted with 1 ~
hydrochloric acid (25 ml) and water ~2x 25 ml). The organic phase was dried, ~iltered and e~apora ted in vacuo. The crud~ procluct thus obtained was purified by dry column chromatography on silica gel ( ether:
petroleum ether:acetic acid; 40:60:0.5) and a~orded pure 3-0-acetyl-16-deacetoxy-16~-ethylthlo~usidic acld as a.oolourless gum, which wag dissoived in a mixture o~ ethanol (20 ml) and 2 N aqueous sodium hydroxide (5 ml) and left at 75 C ~or two hours. The reaction mixture was then acidified ~ith 1 ~ hydrochloric acid (15 ml) and extracted with ethyl acetate t50 ml). The organic phase was washed twice Wi.-t]l water (20 ml)~
dried~ and e~aporated in ~acuo to gi~e an oil ~ ~hich was cr~stallizecl ~rom ether-petrol~um c-ther to yi~ld 16-dcacetoxy-16~-ethylth:iofusi.d~c acid as colourless cr~stals, melting point: 195-198C~

. .

9~

Examplcs 17-20 16-~-Thioetllers of 16-doacetoxyfusi.dic acid Following~the procedure of Example 16 and sub-stituting the mercap-tans listed in table X for ethyl mercaptane,the 16~-thioethers of 16-deacetoxyfusidic acid shown in table X w.ere prepared.
': . ' Table X:
~ ' ' .
~ COOH

H~,~ ~ ~ SR
~ , HO

. Resulting coMpound _~,~ ._.
Example Mercaptan Mp ( C) 17 n-propyl mercaptan CH2CH2CH3 amorphous 18 . t-butyl mercaptan C(CH3)3 200-203 19 . phenyl mercaptan C6H5 amorphous.

benzyl mercaptan CM2C6H5 amorphou~

The NM~ spectrum (CD30D) of the compouncl of Example 17 shows signals at ~ = 0.90 (d~ 3H), 0.99 (s, 6H)~ 1.37 (s~ 3H)~ 1~62 and 1.66 (2 bs, 6H), 2.58 (m, 2H; C_2S), 3.00 (m, lII; CM-13), 3.67 (m, lH; CH-3), 4.11 (d, lH;

CH-16), 4.24 (m~ lH; CH-ll) and 5.12 (m, lH; CH-24) ppm.

Tetramethylsilane was used as internal reference.

; ~6~9~6i The NMR spectrum (CDC13) of the compound of Example 19 shows signals at ~ = 0.95 ~s, 6H), 1.10 (s, 3H), 1.35 (s, 31-I), 1 60 and 1.65 (2 bs, 6H), 3.10 (m, lH;
CH-13), 3.74 (m~ lH; CH-3), 4.30 (m, lH; CH-ll), 4.77 (d, lH; CH-16), 5.11 (m, lH; CH-24) and 7.0-7.4 ~5H;
arom. CH? ppm. Tetramethylsilane was used as internal reference.

The NMR spe~trum (CDC13) of the compound of Exa}nple 20 shows signals at ~ = 0.97 (s~ 6H), 1.36 (s, 3H), 1 62 and 1.66 (2 bs, 6H), 3.o6 (m, lH; CH-13), 3.66 (m, lH; CH-3), 3 7ll (bs, 2H; SCM2), 4 08 (d, lH; CH-16), 4.24 (m~ l~T; CH~ 5.14 (m~ lH; CH-24) and 7.3 (bs~
5H; arom. CHj ppm. Tetramethylsilane was used as internal reference.

' Exam~le 21 16-Doaceto~y-16~-tl~-methyltetrazol-5~-ylthio)rusidlc acid 16-~pldeacetylfusidic acid bcn~oyloxyme-thyl ester (2.2 ~; 3.ll mmol) and di(l-methyltetrazol-5-yl)di-sulfide (1.5 g; 6.5 mmol) l~ras dissol~ed in dry pyridine (20 ml). The solution ~as cool~d in an ice-bath and ~ . , .

~L~6~90~i tributylphosphine (1.44 ml; 6 mmol) was added. After standin~ for 18 hours at room tempera-ture, water (200 ml) and ether (400 ml) was added to the reaction mixture.
The organic phase ~as separated~ washed twice with 1 N
hydrochloric acid and twice with water, dried, and evaporated in vacuo. The residue was dissolv~d in methanol (50 ml)~ and potassium carbonate (~ 4 g; 17.5 mmol) was added. After stirring for 18 hours at room temperature~ the solution was acidified with 4 N a~ueous hydrochloric acid (8 ml), and water ~200 ml) and ether (100 mlj was added. The organic phase was separated~
washed twice ~ith water, dried, and evaporated to give 1.84 g of crude product~ which was puri~ied by clry column chromatography on silica gel (ethor:acetic acid;

100:0.5) to yield 800 mg of 16-deacetoxy-16~ methyl-tetra~ol-5t-ylthio~fusidie acld as a eolourless foam.
The nmr spectrum (CDC13) shows signals at ~_ 1.00 (s~ 3H), 1.06 ~s, 3H), 1.40 (s, 3H~, 1.62 and 1.68 (2 bs, 6H), 3.17 (m, lH; C~-13), 3.75 (m~ lH; CH-3j~ 3.87 (s~ 3H;
l~-CH3)~ ~5.37 (m~ lH, CH-ll) a~d 5.42 (111, lH; CH-16) ppm, TetramothylsilAne l~as used as internal re~erence.

Examplc 22 16-~eaeetox~-16~-~2~,5~-dichioro-phenylthio)fusid~c acid A solution of 3-0-acetyl-16~epideacetylfusidic acid methoxymethyl ester (490 mg; 0.87 mmol) and di(2~5-di-106~906 chlorophenyl)disulfide (1,07 g; 3.75 mmol) in dry pyridine (1I ml) was cooled -to 0 C, arld tributyl-pho~phine (0.7Z ml; 3.0 mmol~ was added. The resulting solution was lef~ at 5C for 3 days and then diluted with e-ther (100 ml), washed with 4 N hydrochloric acid, 2,N sodium hydroxide and water, dried, and evaporated in vacuo. The residue was dissolved in a mixture o~
ethanol (20 ml) and 2 N aqueous sodium hydroxide ~8 rnl), and kept at 60C for 1 hour. The reaction mixture was then acidified with 4 N_hydrochloric acid (5 ml), and ether ~100 ml) and water (200 ml) was added. The organic phase was separated, washed lwice with water, dried and evaporated in vacuo. The residue was crystallized from ether-petroleum ether to give I6-~eacetoxy-i6~-(2'~5'--dichlorophenylthio)fusidic acid, melting point 161-164C.

.
Example 23 16-Deacetoxy-16~-(2'-azidoethylthio~fusidic acid A 3-0-Acetyl-16-deacetoxy-16~-(2'-bromoethylthio)-.
fusidic acid p-nitrobenzxl ester To a solution of 3-0-acetyl-16-deacetoxy-16~-(2'--hydroxyothylthio)~us:ldic acid p-nitrobell~yl ester (1 g; 1.~ mmol) in 50 ml of dimethylrormamide ~as added 3 g of phenyl N~N-dimethy-lformimidate bromide. Arter s-tallclin~ at room temperat-lre for 1~ hours~ the reaction mixtule was diluted with ether (50 ml), ~ashed with .. . .. . .. .

.

~L~69L906 2 N sodium hydroxide (20 ml) and ~iater (3 x 50 ml)~
dried, and evaporated in v~cuo. ~ddition of ~ther-petrolcum ether;caused the residue to crystallize.
The product was filtered of~, ~vashed with petroleum ether, and dried to yie~d 800 mg of 3-0-acetyl-16--deacetoxy-16~-(2l-bromoethylthio)fusidic acid p-nitrobenzyl ester9 melting point 148-150 C.

B. 16-Dcacetoxy-16~-(2'-azidoethylthio)fusidic acid Ths 2'-bromoethylthioether prepared above was dis-solved in 25 ml of dimeth~-lformamide~ thium azide (400 mg; 8.2 mmol) was added~ and the reaction mixture .as left at 20C for 24 hours.-100 ml o~ ether was then added~ and the re~ulting solution t;as ~ashed with ~ater (4 x 50 ml), dr~ied~ and evaporated in vacuo. The residue was dissolved in a mixture of ethanol (50 ml) and 2 N
aqueous sodium hydroxide and a~ter being left at 60 C
~`or 3 hours~ the solution ~as acidi~ied ~ith 8 ml o~
4 N hydrochloric acid, and ~iater (100 ml) and ether (10~ ml) was added. The organic p~ase was separat~d~
wa~hed t~itll ~ator (l~ x 50 ml)~ dr:Locl, and evaporated :in v~cuo. Addition o~ ether and petroleum ether to the residue caused 16-deaceto~~-16~-(2~-azidoethylthio)-~us:iclic clcid to precipitate as colourless crystals, whicl were filtered o~f, washed with petroleuln ether, and dried to yield 1l~0 mg, melting point 173-179C.

_ 54 -~L~649~1~
Example 24 ].6-Dcacetoxy-16~-(2~-methoxyethylthio)fusidic acid sodium salt To a.solution of 3-0-acetyl-16-deacetoxy-16~-(2' -bromoethylthio)fusidic acid p-nitrobenzyl ester (see Example 23 A for the preparation of this compound) (1 g; 1.3 mmol) in methanol (50 ml) was added silver carbonate (1 g~ 3.6 mmol¦, and-the mixture was stirred at room temperature for 16 hours. The insoluble ~material was filtered off and washed with methanol (10 ml). The combined ~iltrate and~washing were evapo-rated in vacuo, and the residue was dissolved in a mixture Or ethanol (100 ml) and 2 N sodium hydroxide . -(20 ml). After stirring for 3 hours at 60 C~ the dar~
solution was acidi~ied witll 4 N hydrochloric acid (15 ml), a~d water (200 ml) and ether (200 ml) was added.
The organic phase was separated~ ~iashed twice with water, dried and evaporated in vacuo. The residue was purified by dry column chromatography on silica gel (ether:acetic acid; 100:0.5) to gi~e the deslred product a5 a colourless foam~ which was conv~rted lnto A crystalline sodillm s~lt by d:L~solvln~r:in metllanol (25 ml), titrat:ing .with 2 N aqueous sodium h~droxide,evaporating, and .adding acetone The crystals were ~iltered of~ ashed With acetono~ and dried to yield l~-deacetoxy--16~-t2~-methoxyethylthio)fusidic acid sodium salt.

~ 65 -649~6 The NM~ spectrum (CD OD) shows signals at ~ = 1.00 (s,6~1), 1.36 (6~ 3H), 1.62 (bs, 6H) 2.78 (2l-1i CM2S), 3.51 (2H; CM20), 3.68 (m, lH; CH-3), li.10 (d, lM;
;, CH-16), 4.21 (m, lH; CH-ll) and 5.11 (m, lH; CH-24) ppm. Tetramethylsilane was used as internal reference.

Example 25 16-Deacetoxy-16~-(2~-isopropylthioethylthio)fusidic acid .
To a solution of potassium hydroxlde (500 mg;
9 mmol) and isopropyl mercaptan (1.5 ml; 16 mmol) in ethanol (50 ml) was added 3-0-acetyl~16-deacetoxy~16~--(2l-bromocthyltllio)fusidic acid-p-nitroben~ylester (see Example 23A ~or the preparation of this compound) (1 g; 1.3 rnrnol)j and the mixture was stirred for 16 hours at room temperature. I~ater (100 ml) and ether (75 ml) ~as added~ tlle organic phase was separated~
washed with 2 N sodium hydroxide (2 x 25 ml) and water (2 x 25 ml), dried~ and evaporated in vacuo. The r~sidu~
~as dissolved in a mixture o~ ethallol (100 ml) and 2 N
sodium hydr~xide (20 ml), an~ the solution ~tirred ~or 3 hours at 60C. 4 N hydrochlor:Lc acld (15 ml), water (250 ml) and ether (100 ml) was added, the organic phase was separated, washed with water (2 x 50 ml~, dr~ed~and e~aporated in vacuo. The desired product was - 66 _ ~0164~C~6 isolated from the residue by dry column chromatography (etller:petroleum etller:acetic acid9 70:30:0.5) to yield 400 m~ of 16-dea~etoxy-16~-(2'-isopropylthio~thylthio)-fusîdic acid as a colourless foam.
The nmr spectr.um (CDC13) shows signals at ~ _ 0.96 (bs, 6H)9 1 22 (d, J=7, 6H), 1.33 (s, 3H), 1.58 and 1.67 (2 bs, 6H), 2.73 (bs~ 4T~; SC~2CI{2S),. 2.91 (m~ lH; S-CH (CH3)2), 3.01 (m, lH, CH-13), 3.71 (m, lH; CH-3), 4.21 (m,-lH; CH-16), 4.2S (m, lH; .
CH-ll) and 5.08 (m, lH, CH-24) ppmO Tetramethyl-silane ~as used as internal reference.

Example 26-28 By following the procedure described in Example 25 and substituting the mercaptans listed in table XI
. ~or isopropyl mercaptan, the compounds indicated ; in table XI were prepared Table XI: ~ -COO~ ' ' H0~ SCH~CH2SR

.H0~
. ,.
Example Mercaptan R Mp ( C) .. _ . . _ . .
26 ethyl mercaptan C~I2CH3 149-152 Z7 t-butyl mercaptan C(CH3)3 134-135 28 cyclohexyl cyclohexyl amorphous . mercaptan .

11~64~ 6 The NMR spectrum cf the compound of Example 28 (CDC13) shows signals at ~= 0.99 (s, 6H), 1.37 (s, 3H), 1061 and ]..68 (2bs~ 6H), 2.78 (bs~ 4~I; 5CH2CII2S), 3~07 (m, lH; CH-13), ~.76 (m, lH; CH-3), 4.26 (d, lH;
CH-16), 4.35 (m, lH; CH-ll) and 5.12 (m~ lH; CH~24) ppm. Tetramethylsilane was used as internal reference.

. Example 29 16-Deacetoxy-16~-(2'-phen~lthioethylthio)f`usidic acid To an ice-cooled solution of 3-0-acetyl-16-deacetoxy--16~-(2~-hydroxyethylthio)fusidic ac:id p-nitroben~.yl ... .
ester (1 g;-l.4 mmol) and diphenyld:isulfide (1 g; 4.6 mmol) in dry pyridine (7 ml) was added tr:ibut~lphos-phine (2 ml; 8.4 mmol), and the mixture ~as left at 5C for 16 hours. Ether (100 ml) was added, and the resultlng solution ~as washed with l~ N hydrochloric : acid (2 x 25 ml), 2 N sodium hydroxide (2 x 2; ml) and water (2 x 25 ml)~ dried~ and evaporatecl irl vacuo. The residue ~as di9solved in a mixture o~ e~hanol ~90 ml) and 2 N sodium hyclroxLde (~0 ml). Af`ter stirr:i.n~ ror 3 hours at 60C~ 4 N hydrocllloric acLd (15 ml), ~ater (200 ml) and ether (100 m}) was added. Tlie organic pilaso was s~parated~ w~shed ~itil water (2 x 20 ml)~
and evaporatod in vacuo. The residue was purified by .

.. . .

~06~
dry column chromatography on sllica gel (ethyl ace-tate:cyclohexane; 1:1) to yield 630 mg of 16-deacetoxy-16~-(2~-phenylthioethylthio)fusidic acid as a colourless ~oarn.

The nmr spectrum (CDC13) shows signals at ~ = o~gs (bs, 6H), 1-35 (s, 3H), 1.61 and 1.67 (2 bs, 6H)~

3-78 (m, lH; CH-3), 4.25 (m, lH; CH-16), 4.34 ~m, lH;
C~T-11)9 5.11 (m, lH; CH-24) and 7.1-7.5 (m~ 5H; arom CH) ppm. Tetramethylsilane was used as internal reference.

Example 30 Sodlum salt of 16-deacetoxy-16~-(2~-methylthLoethyl-thio)~usidic acid_ To an ice-cooled solut:ion of 3-0-acetyl-16-deacetoxy-16~-(2~-hydroxyethylthio)fusidic acid p-nitrobenzyl ester (1 g; 1~4 mmol) in 1 ~ll o~ dimethyl-diqulfide ( ~ 10 mmol) was added tribu*ylphosphine (2 ml; 8.4 mmol), and -the mixture was left at 20C
~or 3 days. Ether tlO0 ml) was then added~ and the resulting solutLon was washed with 2 N sodium hydrox:Lde (25 ml) and wator (2 x 25 ml)~ dr:Led, and ovaporated in vacuo. The residue was dissolved in a mixture of ethanol (40 ml) and 2 N sodium hydroxide (10 ml).
After stirr:Lng for 3 hours at 60C, 4 N hydrochloric acid (lO ml), water (200 ml), and ether (100 ml) was added. The organic phase was separated, washed with .

~64g~6 wa~er (3 x 20 rril), and evaporated in vacuo. The residue was purified by dry column chromatogr~phy on silica gel (ether:petro~eum ether:acetic acid; 70:30:0.5) to yield 410 mg of 16-deacetoxy-16~-(2~-methylthio-ethylthio)fu~sidic acid as a colourless oil. The crystalline sodium salt was prepared by dissolving this oil i~ methanol (10 ml)~ titrating with 2 N
aqueous sodium hydroxide using phenolphthalein as indicator, evaporating in vacuo, and adding acetone.
The crystals were filtered off and washed with acetone and ether to yield the pure sodium`salt of 16-deacetoxy-16~-(2l-methylthioethylthio)fusidic acid.
The NMR spectrum (CD30D) shows signals at ~ - 0.~8 (s~ 6H), 1.36 (s, 3H)~ 1.62 (bs, 6H)~ 2.10 (9~ 3H;
SCH3)~ 2.77 (bs~ 4H; SCH2CH2S)~ 3.00 (m~ lH; CH-13)~
3 66 (m~ lH; C_~3)~ 4.11 (d~ lH; CH-16)~ 4.23 (m~ lH;
CH-ll) and 5.13 (m, lH; CH-24) ppm. Tetramethylsilane was used as internal reference.

.
Exampl~ 31 16-D ~
. 3-0-~orrnyl-16-doacetoxy-16~-(2~-bromoetllylthio~-fusidic acid benzoyloxymethyl ester 1~64~36 L6-D~acetoxy-16~-(2~~hydroxyethylthio)fusidic acid (53.4 m~; 1 mmol) was dissolved in me-thanol (10 rnl) and converted into its sodium salt by titration with 2 N sodiu2n hydroxide using pnenolphthalein as indicator.
After evaporation in vacuo, the resulting amorphous sodium salt was dissolved in dimethylformamide (7.5 ml~, chloromethylbenzoate (0.1~ ml; 1 mmolj was added~ and the mixture was stirred at room temperature for 48 hours ~'ater (50 ml) was added, and the mixture was extracted with ether (100 ml). The organic p~hase was separated~
washed with water (L~ x 100 ml)~ dried and evaporatcd in vacuo to yield 16-deacetoxy-16~-(2~-hydroxyetllyl-, thio)fusidic acid benzoyloxymethyl cster as an amorphousproduot. This was dissolved in dimethylrormalnide (10 ml)~ phenyl N~N-dimethylformimidate bronlide (1.5 g;
ca. 6.5 mmol) w~s added with stirring, and the soluti~n was kept at 20C ~or Z4 hours. l~ater (50 ml) and ether (50 ml) was added, and -the organic phase was washed with 2 N sodium hydrox:Lde (2 ~ 25 m:L) and water (2 ~ 25 ml)~ dricd~ and cvaporatcd :Ln vacuo to gl~o 3-0-~orm~1-16-doacotoxy-:l6~-(2~-bromoothylthlo)-fusidic acid benzoyloxymethyl ester as an amorphous product.

~ 71 _ ~"
~L064 B. 16-Deacetoxy-16~.-(2~_fluoroethyltllio)rusidic acid The 2~-bromoethylthioetller prepared above was d.is`-solved in aceton~trile(25 ml), sllver fluoride (500 rng) was added, and the resulting suspension was stirred at room temperature for 2 hours. Ethylacetate (50 ml) was added, and the insoluble material was filtered Ofr.
The filtrate was evaporated in acuoy the residue was dissolved in methanol (10 ml), and potassium carbonate (350 mg; 2.5 mmol) wa~ added. After stirring for ~0 minutes at room temperature, water (100 ml), 4 N hy~ro-chloric.acid (5 ml) and ether (100 ml) llas added, and the organic phase was separated~ ~ashed twice ~ith watel, dried, and evaporated to yield an amorphous product, which was purified by dry column chromatography (etller:
acetic acid; 100:0.5) to yield pure 16-deacetoxy-16~-(2~-fluoroethylthio)~usidic acid, crystallized ~rom 0ther-petroleum ether, melting point 157-159C.

ll-Keto-16-doacetox~_l ~ opylthio:fusLdic .~cid thiofusidic_acid p-nitrobenzyl ester Pyridinium chlorochromate (1.07 g, 5 mmol) was susp~nded in mothylone chloride (30 ml) by stirring, while 3-0-acetyl~16-deacetoxy-16~-isopropylthio~usidic - 72 ~

~L~64~6 acid p-nitrobellzyl cster (1.5 g, 2.1 mmol) was rapidly added, After stirrl~g for an additional hour, -the suspension was diluted with ether (100 ml), the solvent was decanted, and the black solid was ~ashed twice with ether. Filtration and evaporation of the com-bined organic extracts yielded an oily residue, which crystallized from ether-petroleum ether. The colourless crystals thus obtained were collected, washed with petroleum ether, and dried to afford 880 mg of the desired product, melting point 120-122C.

~, B. ll-Keto-16-deacetoxy-16~-isopropy:lthiofusidic acid The p-nitrobenzyl ester prepared above wns dissolved in a mixture o~ ethanol (20 ml) and 2 N aqueous sodium hydroxide (5 ml) and heated to 60C ~or 3 hours. Then, 4 N hydrochloric acid (3 ml)~ water (100 ml) and ether ~00 m~ was added with stirring. The organic phase was separated, washed twice ~ith water (25 ml), dried, and evaporated in vacuo. The resulting oily residuo was puri~ied by dry column chromato~raphy on sillca gel (cycloh~xane:ethyl acetate, 7:3) to yield 38~ mg of ll-lceto-16-deacetoxy-16~-isopropylthio~usidic acid, melting point 167-169 C (crystallized from ether-petroleum ether).

. ~ ~

- 73 ~

.

1~gL9~6 Ex1mpl~ 33 ll_Keto ].6-dcacetoxy-16~-isopropylthlo-24,25-di.lly-drofusidic acid ~
By following the procedure o~ Example 32 and substituting 3_0-acetyl-16-deacetoxy-16~-isopropyl-thio-24,25~dihydrofusidic acid p-nitroben~yl ester for 3-0-acetyl-16-dea.cetoxy-16~-isopropylthiofusidic acid p-nitrobenzyl ester, ll-keto-16-deacetoxy-16~-isopropylthio-24~25-dihydrofusidlc acid was prepared as colourless crystals, melting point 189-191C.

, Example 34 3~Keto-16-deacetoxy-16~-isopropylth-io-f-usidic ac:Ld To a solution of 16~deacetoxy-16~-isopropyl-thio~usidic acid acetoxymethyl ester (2.0 g, 3.3 mmol) in 15 ml o~ dimethylsul~oxidewas added dicyclohexyl-carbodiimide (3.10 g, 15 mmol) and orthophosphoric acid (160 mg, 2 mmol), and the mixture was le~t with stirring at room temperature for 24 hours, ~A solution o~ oxalic acid (3 g) in methanol (20 ml) was then added to destroy c~cess o~ carbodl:imicle~ and stirr.~ng wa8 continued ~or 30 minutes. Ethyl acetate (150 ml) was then added, and the resulting solution was washed with saturated aqueous sodi.um hydrogen carbonate .
. _ 74 ~

~' ," .

1~64g~36 (2 x 50 ml) arld water (50 ml), dried, and evaporated to yield 1.9 ~ of an olly residue. This was dis-solved in methanol (40 ml) and potassium carbonate (1.2 g) was addc~. After stirring for one hour~the methanol was ~vaporated in vacuo, and ether (ioo ml) and ~ N hydrochloric acid (50 ml) ~ere added to th~
residue. The organic phase was washed with water (2 x 50 ml), dried, and evaporated in vacuo~ The oily residue was purified by dry column chromato-graphy on silica gel (cyclohexane:ethyl acetate, 7:3) to yield 3-keto-16-deacetoxy-16~-isopropylthiofusidic acid as colourless crystals,'collected from ether~
melting point 200-20~C.

., .

Exarnpl ~5 16 Deacetoxy-16~-iso~rop'~lsul~ ylfllsidic aeid Sodium metaperiodate (6 g; 28 mmol) in 500 ml o~
water was added to a solution of l~-deace-toxy-16~-iso-propylthiofusidic acid (lO.0 g; 18.3 mmol) in a mi~ture o~ methanol ~200 ml) and ~ ~ aqueous sodiurn hydro~ide (lO ml). ~ter standin~ ~or 1 5 hours~ the resultLn~
~olu~ion wa0 aoLdi~ied witll l~ N aqueous llyd~oelllorle aeid (7.5 ml), eausing a cr~-stalline produ~t to 'preeipitate. The erystals were filtered off, ~ashed with ~ater (50 ml), and dried to yield 10.0 g of the desired produe't, mp. 158-159C. The erysials thus ob-tained .ere transforrned into another crystal modi~ica-~L~6~6 ti.on by treating with boilin~ ethyl acetate (400 rnl).
Arter cooling to 0C~the product was ~iltered off washed ~i.th 0ther (50 ml)~ and dried to afford 9.04 g of pure 16-deace~oxy-16~-i.sopropylsulfinylfusidic acid~
meltin~ point 179-181C.
Example 36-41 By following the procedure descrlbed in Example 35 alld substituting the 16~-thioethers of 16-deaceto~y-fusidic acid listed in table XII for 16-deacetoxy-16~_iso-propylthiofusidic acid~ the sulfoxides indicated in table XII were prepared '' .

Table XII
. . ~............. . . .
~COO~I
. . ~1, HO" _ Exam- thioether o~ 16-de- _ o ple ac~toxy fusidic acid ~ Mp ~ C) I _ _ . . .~.. _ _ , 36 16~-met}lyltllioetllor C~13 151-156 37 16,~-ethyltllioothor . CH2CI-13 158-162.5 .

38 16~-t-butylthioether C(CH3)3 164-167 ; 39 16~-(2~-hydroxyethylthio)etller CH2CH20H 163-168 16~-(2~-azido~thylth o)ether CH2C}l2~3 141-147 41 16~-phenylthioether C6H5 amorphous , ' .

9~

Ex~mple 42 6-Deacetoxy-16~-iso1~ropylsulfinyl-24,25-dihydro-fusidic acid By following the procedure described in Example 35 and substituting 16-deacetoxy-16~-isopropylthio-24~25-dihydrofusidic acid for 16-deacetoxy-16~-isopropylthiofusidic acid, 16-deacetoxy-16~-iso-propylsulfinyl-24,25-dihydrofusidic acid was pre-pared as colourless crystals, melting point 184-186C.

Examp1e-43 16-Deacetoxy-3-keto-16~-isopropy~ulfi.nylfusidic acid By following the procedure described in Example 35 and substituting 16-deacetoxy-3-keto~16~-isopropyl-thiofusidic acid for 16-deacetoxy-16~-isopropylthio-fusidic acid, 16-deaceto~y-3-keto-16~-isopropylsul-finylfusidic acid was prepared as colourless crystals~
melting point 158-161C.

.
Exmnple ~4 ll-~eto-16-deaceto~r-16~-isopropvlsulf`ill~rlfusidic acid To a solution oE 16-cleacetoxy-16~-isopropylsulfinyl-_ fusidic acid (1.1 g; 2 mmol) in 5 ml of pyridine was ' ' '`' ~;~6~

added acetic anhydride (0.8 ml; 8.5 mrnol). After standin~ for 48 hours at room temperature, 1 ml o~ water was added to the;~solution, which after an additional hour was diluted with 50 ml of ethyl acetate, washed twice with 4 N hydrochloric acid and twice with water, dried, and evaporated to gi~e 940 mg of crystalline 3-0-acetyl-16-deacetoxy-16~-isopropylsulfinylfusidic acid collected from ether, melting point 176-178 C.
To a suspension of-770 mg of this product in acetone (100 ml) was added Jones reagent (0.78 ml). After standing ~or 10 minutes at room temperature, water ~100 ml) was added to the reaction m.ixture, and the resulting solution was conce.ntrated i~n ~cuo to 125 ml causing 3-0-acetyl-11-keto-16-deacetox~-16~-lsopropyl-sulfinyl~usidic ac.id to precipitate as colcurless cr;rstals, which were filtered off, ~ashed w.ith water and dried to yield 570 mg; melting point 151-160C.
400 mg of this product was dissol~ed in a.mixture of ethanol (20 ml) and 2 ~- aqueous sodium h~-droxide (2 ml), and left at room temperature ~or 6 cla~s. Il N
aqueous hfdxochloric acid (2 ml) wa~ then ~dded with stirrin~ to prooip:ltate tho des.Lrecl product as colour-less crystals, which were collected, washed with water (15 ml), and dried to afford 230 mg, melting point .L71~-178C .

- ~ 78 _ ' ~6~9~

~ ccrystall:ization ~rom ethyl acetate gave the pure ll-keto-16-deacetoxy-16~-isopropylsulfinylfusidic acid, melting point 181 183 C.

Example 45 .
3~11-Diketo-16-deacetox~-16B-isoprooylsul~inylfusidic aci.d To a solution of 16-deacetoxy-16~-isopropylthio-fusidic acid (500 mg; 0.9~ mmol) i~ 100 ml of acetone was added 1.6 ml of Jones reagent. Arter standing.at room temperature ~or 10 millutes~ 100 ml Or water was added with stîrring to the reaction mixture. The white precipitate which formecl ~as filtered off, washed with water and dried to give 450 mg o~ a mixture o~
3~ diketo-16-deace-toxy-16~-isopropylthio~usidic acid and the desired product.
The crystals were dissolved in hot cther (20 ml) a-ld upon cooling to 0C pure 3,11-diketo-16-cleacetoxy-- -16~-isopropylsulrinylfusidic acld precip.it~tcd. The crystals were rll~ered o~, washed w:ith cold ether ancl dried to gi~e 60 mg, melting point 154-162C.

1~64~

16-Deaceto.~y-16~-etho~yfus:i.dic ac:id Silver carhonate (16.5~ g; 60 mmol) was added to a suspension of 3-0-acetyl-16-deacetoxy-16~-bromofusidic acid phenacyl ester (20.94 g; 30 ~mol) in ethanol (300 ml), and, after being protected from light9 the mixture was st1rred at room temperature for 18 hours. Insoluble material was filtered o~ and ~ashed ~i~h e-thanol (2 x 30 ml). To the combined filtrate and washings was added 5 N aqueous sodium hydro~ide ~120 ml), and the mi~ture was re~lu~ed for t~o hours. A~ter cooling to room temperature, the major part o~ ctharlol was removed in vacuo~ and to the residue l~as aclded ethyl acetate (150 ml) and l~ter (100 ml)~ 1`he stirred mixture was acLdified Wit~l 4 N hydrochloric acid~ -the organic phase ~as separated, and the aqueous phase reextracte~
~;ith ethyl acetate (50 ml?. The combi~led organic oxtracts were washed with wa-ter, dried, and evaporato~
in vacuo to yield an oily resldue, which crystallizcd ~rom diisopropyl ether~ The colourless crystals thus obt~i.ned wcro collccted, ~a~hcd l~:it.~ dLisopropyl eth~r~
a~d dried to af~ord 5.~2 g of 16-deacetox~-16~-etho~y-fusidic acid, melting point: 16~-171C. A~ter ~orlc-up _ 80 -( L9~6 of the mother liquor, a further Z~20 g o~ the desire,d colnpound, melt;ng point: 168-170C, wa~ obtained.
~o recrystallizations from methanol-diisoprop~l ether gave the analytically pure compound, melting point:
177-178C.

xamples 47-49 6-Deacetoxy _6~-al~yloxyfus_dic acids By substituting the alcohols listed in table XIII
~OI the ethanol in the procedure o~ Example 46, the 16-d~acetoxy-16~-alkyloxyfusidic acids indicate~ in tabl~
XIII were obtained.

Table X~

C00}l ~0", 1~0R
c~,ÇI' ~10" _, - .
.
. Resulting oompo~d Examp~e Aloohol R ~IP ( C) _ .___ - . ... __ ... , ._ ..... .. _ 47 Methanol . C~3 175-176 ~8 2~2~2-Trirluoro~thanol ~12C~3 202-~03 49 Hexanol-(l) 2( H2)4CH3 amorphous .

9~

, Example 50 .
16-Deaceto~y_16B-(2~-fluoroethoxy):fusid~c acid To a sol~tion of 3-0-formyl-16-deaceto~-16~-bromofusidic acid benzoyloxyrnethyl cster (8.75 g;

12.5 mmol) in 2-fluoroethanol (25 ml) was added silver carbonate (6.89 g; 25 mmol), and the mixture was stirred at room temperature and in the absence of light ~or 16 hours. The insoluble material was ~iltered o~f, ashed twlce wi-th ether, and the combined filtrabe and washings were evaporated to dryness in vacuo. The residual oil, containing the crude 3-0-formyl-16-deaceto~-16~-(2l-~luoroetho~y)~usidic acid ben~oyloxylnethyl es-ter, was dissolved in methanol (85 ml), potass.ium carbonate (3.46 g; 25 mmol),was added, and the mixture was stirred at room temperature for 30 minutes. The maior part o~
the solvent ~as removed by evaporation in vacuo~ and to the residue was added water (100 ml) and ether (100 ml). A~ter acidi~ication Or the stirred mixture with 4 N hy-drocllloric ncid~ the or~anic layor was ~parated~ the aqueou~ layer rooxtract~ with ~ther (5~ ml)~ and the _ombined organic phases were wash~d with water until neutral. In order to separate the des:;red acid derivative ~rom 16-deacet~lru.sidic acid lactone~ being ~orme~ as by-p~oduct, the ethere~l .

11J16~9~6 .solution obtained a~ove was extracted with 0. 5 Nr sodium hydroxide (3 x 50 ml) and was]led with water (3 x 25 ml). To the combined aqueous phases and washings ~as added ether ~100 ml)~ and the stirred mixture was acidified with 4 N hydrochloric acidD
After separation o~ the-organic layer, the aqueous layer was extracted ~ith èther (50 ml)~ and the com-bi~ed organic extracts were washed with ~iater until neutral, dried, and evaporated iR ~C~o. The re-sulti.ng arrlorphous residue was dissolved in diisopropyl et:her (30 ml), and on scra-tching A crystalline procluct precipitated. After being kept :;n tho re~rigerator overni~ht~ the crystals were filtered o~, washed with diisopropyl ether, and dried to arford 2.32 g of 16-deacetoxy-16~-(2~-fluoroethoxy)fusidic acid, melting point: 15~-160C. From the mQther liquor a fur-ther 0.1~8 g of the desired compound~ melting point: 155-159C~

as ob tained. I`wo recrys talli~:a t:ions *rom me thanol-diisopropyl ether gave the analyt:ically puro p.roductt m~ltlng po.~n~: 162 163C.

~064~6 . , ~x~lrl7~1~s 51-~2 16-neaceto~y-16~-al};.~lo~yfusidic acids Following the procedure of Ex~mpl~ 50, but su~-sti-tuting the alcohols listed in table XIV for the 2-~luoroethanol, the 16-deacetoxy-lo~-alh~loxyfusidic acids indicated in table XIV were obtained.

TableXIV: .

.
.. C ,, ~10~ ~ ~ OR

HO~

. Resulting compound . . . ~ . . . _. _ .. _ _ . _ . . .
Exarnple Alcohol - R Mp ( C) . . . ._ .. _.... ... ._ __ : ...... .
. ~ 51 , 2-Aceto~yethanol CH2CH2~I 17~-lS2 52 1,3-Difluoropropa~ol~(2) CH(CH2F)2 169-171 ~' .

lfi~-Ethcrs o~ 16-cleacoto~yfusi.clic acid ~ ollowing the procedure o* ~xample 5.0, but sub-~tituting 16-cleacetoxy-16a-bromo.~us:iclic acid aceto~y-methyl ester for the 3-0-formyl-16-dcacetoxy-16~-bromo-~usidic aci d benzoyloxymethyl es ter and the alcohols .. . . . . . .

~649~6 listed in tableXV for the 2-~].uoroot}larlol, the 16~-ethers o~ 16-deaceto~y~usidic acid in~icated in tablo XV
~-ere obtained, r' Table XV
. _ .

, COOH
: H~" ~ ~ OR

HO~ J
, . . Resulting co.mpou~d _ .. . .. _ _ _ .. _ . . .
Example Alcohol R ¦ Mp (C) .. . ,. , , . .. ... _ ~ ,~
53 Isopropanol CH(ClI3)2 . 189-190 54 tert,Butanol C(CH3)3179-180 2,2-Dichloroethanol CH2CHClz181-182 56 ~ Z~2~2-T~ichlor~etha~ol CH2CC13 . 212-213 : 57 1,3-Di~luoropropanol-(2) H(CH2F)2 169-171 58 l,~Diaceto~ypropan- .
. ol-(2~ CH(CH20H)2 amorphous 59 Allyl alcohol CH2CH=CH2 . 15~ 5~
2-Butellol-~l) CH2C~I=C~lC~I3 1~ô-135(doc 61 2-Propynol-tl) GH C-CH13l~-136 62 Cyclopentanol cyclopentyl188-189 .~, . .

, .

, ~64g~6 E~ample 63 16-Deaceto~-.l6R-ethoxv-24 25~dih~clro~usid:;c acid A. 3~0-Acetyl-16-epideacetyl-24,25-dihydrofusidic a.cid pivaloyloxymeth~l ester To a solution of 3-0-acetyl-16-epideacetyl-2~,25-dih~dro~usidic acid (31.12 g; 60 mmol) in dimethyl-formamide (250 ml) was added triethylamine (11.92 ml;
84 mmol) and, a~ter stirrin~ for 15 minutes, chloromethyl pivalate (17.76 ml; 1-20 mmol) r APter stirring ~or 20 hours at room temperature, the mixture was dilu-ted with ethyl acetate (750 mlj and washed thoroug~lly with water (4 ~{ 250 ml, 2 x ~0 ml) to remo~e unreacted starting material and the greater part ~ dimethyl~o~mamide~
The organic phase wa~ dr.ied and evaporated in vacuo to yield 42 g of an oily residue. The residue was dissolved in ether (50 ml), petroleum ether (200 ml) was adcled, and the Mixture was stir-red for two hours. The crystalline precipitate thus obtained was ~ilterecl o~ ashed l~ith eth~r:pctroleum ether 1:4. The combined ~iltrate and washlngs were ovaporated to dryness 1~ vaouo to glve 36 g o~ crude 3-0-acetyl-16-epideacetyl_24~25-dihydrofusi~ic acid pivaloylctxymethyl ester as a foam which failed to crystalli~e.

, ~6~6~06 B.. 3-0-Acetyl-16-deac xy-16~-methanesulfonyloxy-24 ~5-d hy~rofusidic acid pivaloylQxynle~y~
es-ter To a stirred solutiorl of crude 3-0-acetyl-16 epideacetyl-24,25-dihydrofusidic acid pi~aloyloxymethyl ester (30 g; containing ^- 45 mmol of pure compound) in a mixture of methylene chloride (75 ml) and pyridine (75 ml) was added dropwise a~ -20C a solution o~

methanesulfonyl chloride (13.8 ml; ~ 180 mmol) in meth~lene chloride (25 ml); A~ter the addition ~as finished (ca. 15 minutes), the mixture was s-tirred at -15C for l.5 hours and then kept ir~ the re~rigerator overni~rht. Ice (ca 15 g) ~as added and, a~t~r stirrin~
~or 0.5 hour, the mixture was poured into a mixturo of . . ether (250 ml) and ~rater (100 ml) and shak~n vigorously.
The organic layer ~ras separated ancl the aqueous phase reextracted with ether (100 ml). The ~ombined organic phases wore washed with wator~ 4 N hydrochlor:Lc acid (to renlove pyr:idine), saturated aqueou~s sod:iurn chlorid~
0~5 M aqueous .sodLum b:LcarbQ~ate~ and once more saturntecl aqueous soclium chloride, clried, and evaporated in vacuo to yield 28.5 g og crude 3-o-acetyl-l6-deacetoxy-l6a-methanosul~onyloxy_2ll~25_dihydrolusidic acid pivaloyl-.

,-- . _ ... . ..
. - ~7 ~

. . . , _ _ .

9u~

oxymethyl es~er as a yel]o~ish ~oam which i`ailed to crystallize. The relatively unstable product was used ror the next step without ~urther purification;
IR (~Br): 1170 and 1365 cm C. 3-O-Acetyl-16=deacetoxy-l6~~ethoxy-21J?25-dihydr fusidic acid pival_~loxymethyl est-er .
A solution of crude 3-0-acetyl-16-deaceto~y-16~-methanesuI~onyloxy-2~,25-dihydrofusidic acid pivaloyl-oxymethyl ester (2.6 g) in ethanol (25 ml) was stirred at 60-65 C ~or two hours. l~ater ~lO0 ml) was add~
and t~le mixture was ~xtracted ~it~ ~thyl acetato (2 x 25 ml) . The combined organlc extracts w~re ~ashe~ with water~ cdriod~ and e~aporated in vacuo to give 1.98 ~ o~
a ~ello~i:ish gum. The residue was purified by dry column chromato~raphy on silica gel (cyclohe~ane ethyl acetate 85:15) to yield 0.72 g of 3-0-acetyl-16-deaoetoxy-16~-ethoxy-24~25-dîh~dro~usidic ac;d piv~ioyloxymethyl ester as a colourless foam.

D. 16~Doaoeto~x ~ ~-ethoxy-2~,25-dLhydro~us:Lcllc acid To a solution o~ the 15~-ethoxy ester described above in ethanol (lO ml) was added 5 N aqueous sodiwn hydroxide (2 ml ), and the mixture was Icept at room . ~ .

:lL06~iO6 temperature ov~rni~ht. After addition Or water (50 ml), the mixture l~as acidiried with 4 N hydrochloric ~cid and extractecl with ethyl acetate (2 x 25 ml). The combined organ-c extracts ~ere washed ~ith water, dried, and evaporated in _acuo to leave 0.52 g of an a~orphous product which crystallized from ether. The crystals ~ere f`iltered of~, washed with ether and dried to afford 0726 g of 16-deacetoxy-16~-ethoxy-24,25-dihydrof~sidic acid, melting point: 189-191 C. ~o recrystallizations f`rom ether ga~e the analytical sample~
melting point: 192-193C~

Example 61~

16-Dcacetoxy-16~-methoxy-2l~,25-dihyc~ro~usi.dic acicl A. 3-0-A_e 1~ deacetoxy-16~-methoxy-2l~25-dihydro-fu_idic_acid pivaloyloxymethyl ester ~ollowing the procedure of` Example 63 A-C, but sub-stituting methanol for the ethanol, 3-0-acetyl-16-deacet-- oxy-16~-methoxy-24,25-dihydro~usidic acid pivaloyloxy-n~ethyl ester was obtained.

B. 16-Deacetoxy-16~-methoxY-?l~ t ?5-dthvdro:~usidio aoid .
~y substltut.tng 3-0-acetyl-16-deaoetoxy-16~-rllethoxy-24~25-dihydro~usldic acid pivalo~loxymethyl ester ~or the corresponclin~ 16~-ethox~ derivati~e in the procedure of ~xample 63 D~ 16-deacetoxy-16~-methoxy-24,25-dihydro-fusidic acid, melting point 152-154 C~ ~as ob*ained.

, . . _ . .... ~
. 89 -~6~9~6 Exam~le 65 16-I)eace~oxy-1.6~-propyloxy:~usiclic acid ~- 3~~~c~tYl~l6-~ 2L-6~-me~h~nes ~usidic acid_~iva.loylo_~methYl ester A solution of methanesu~onyl chloride (4.6 ml;
~ 60 ~nol) in methylene chloride (10 ml ? was added dropwise at -20C to a stirred solution of crude 3-o-acetyl-lG-e~ideacetyl~usidic acid pivaloyloxymethyl e$ter (10 g; containin~~~ 15 mmol o~ pure compound) in a mixt.ure of methylene chlor;de ~25 ml) and pyridine (25 ml), placed in a 3-~ec~ed 250 ml-~lasl~ equipped with a thermometer~ a dropping ~unnel, and a drying tube. ~ter the addition was finished~ the mi~tur~
was stirred at -15C :~or 1.5 hours and then kept in the re~rigerator overnight. Ice (ca. 5 g3 was addedS ~.
and a~ter stirring ~or 0,~ hour, the mixture was poured into water (SQ ml) and extracted with ether (2 x 50 ml)~
The combi~ed organic phases were washed with .water~
h~drochloric acid (to remcve pyridine), saturated aqueoua sodium ohloride~ 0.5 M aqueous soclium bicarbonate~ and again ~aturated a~ucous sodlum chloride~ clr.iocl~ and ovaporated in vacuo to a~ord 10.6 g o~ crude 3-0-acetyl-16-deacctoxy-16a-methanesul~onyloxy~usidic acid pivaloyl-_ ~30 -- ' .

g~
oxym~t}lyl ester as a yello~ish amorpho~ prnduct. The unstable compound was used for the next step without I`u:rth~r purifica t:ion.
IR (KBr): 1l7a, and 1355 crnBy using the ~ethod described above, but substituting p-toluenesulfonyl chloride for the methanesulfonyl chloride~ the corresponding 16a-p-toluenesulfonyloxy derivative was prepared.

B. 6-Deacetoxy-16e~propvlo~yfusidic acid .
To a solution of crude 3-0-acetyl-16-deacetoxy-16a-- methanesulfonyloxyfusidic acid pi~aloyloxymethyl ester 2 g;~v 2 mrnol) in propanol-(l) (lO ml) was ad~ed triethylamine (0,28 ml; 2 mmol?~ and the mixturo was stirred at room temperature ~or ~2 hours. ~ft~r di-lution with ethyl acetate (l~o ml)~ the mixture was washed with water~ diluted hydrochloric acid, a~d water, .
dried~ and evaporated in vacuo to give l.Z8 g o~ an amorphous product. ~his residue was puri~.ied by dry colurr~ chromatography on silica g~l (petroleum ether:
ethyl aoetate; 85:15) to yield o.36 g of 3-0-acet~1-16-d~acetoxy-16~-propylox~us:idic acid pivalo~lox~Meth~l estor as a colourloss *oam~ Thc abo~e cster wa~ hy-drolyzed by refluxing its solution in ethanol (5 ml) with 5 N aqueous sodiurn hy-droxide ~1 ml) ~or 2 hours.
~ter a similar wor~ up proce~ure as described in Example 63 D7 cr~stalline 16~deacetox~-16~-propylox~-fusidic aci~, meltin~ point: 176-177C, ~as obtained.

- 91 - ~

~i~6~9~6 Ex.l~n~les 66 -70 16-]~eacetoxy-.l6~-allc~loxyru~idi.c acids By substituting the alcohols listed in table XVI
- for the propanol-(l) in the procedure of Example 65, the 16-deacetoxy-16~-alkyloxy~usidic acids indicated in ta~le XVI ~ere obtained.

Table XVI:

Il , CC
HO~" ~ OR

~10'~`

¦ Resul~ing cornpound - _~ . .. , ............ ~ ... _ _ Example Al.cohol j R Mp ( C) .. _ .. ... . __ __ 66 Butanol-(l) CH2CH2CH2C~T3 167-}69 67 i s o-i~u-t ano 1 G~I2CII ( CH3 ) 2 189 - 1 90 68 2-Met~loxyethanol 2 2 H3 163-165 69 2-Chloroe ~hslnol CM2(:,~12Cl ~5~-159 Benzylalcohol . C~I2C6~15 113-119 _ 92 _ . .

~L196~91~6 ..

~ le 71 ' .
16-Deaceto~-16~ t~idt>etllo~)f`usidic acid A. 3-0- cetyl~ deace-toxy_16~-(2~-hydroxyethyloxy?-~usitlic_acid ~enac~~l ester To a solution of 3-0-acetyl-16-deacetoxy-16~-bromo=
fusidic acid phenacyl esler (13.96 g; 20 mmol) in a nixture of ethylene glycol mono--and diacetate (~0 ml) was added silver carbonate (11.03 g; 40 mmol).
~fter bei~g protected from light, the mixture was stirred for 3 days at room temperature. Insoluble material was filtered o~f and washed with ether (2 x 20 ml).
After removal of the solvent from the colnb:inod :~,il-trate and'washings a-t reduced pressure, the l:iqu:id res:idue was diluted with methanol (3,~0 Inl), potasslum car'bonate (5.53 g; l~o nlmol) was added, and the mi,Yture was s-tirred for 30 minutcs at room temperature. The mixture was evaporated in ~acuo, and the oily residue thus obtained was dissolved in a mixture of ether (200 ml) and water (200 ml). ~fter acidificatio~ o-~ the st:irrt~tl mixt~re with diluted hydrochloric ~cid, the or~an:ic phase w~s separated and the aqut-~ous phase rec~tracted w:~th ether (100 m~). The coml~inod or~anic extracts were washed ~ith water until neutral, dried, and evaporated ~n vac-lo. The yellowish amorpllous residue thus ob-ta:ined ~as puriried by dry colunln chrornatogr~phy on .

, , - 93 -;

.

6~
silicagel (petroleum ether - ethyl acetate, 6:4) to give 5.54 g of the desired compound as a colourless amorphous powder which failed to crystallize.
B. 3-0-ACetyl-16-deacetoxy-16~ 2'-bromoethyoxy)fusidic acid phenacyl ester Phenyl N,N-dlmethylformimidate bromide (4.6 g; ~ 20 mmol) was added to a solution of 3-0-acetyl-16-deacetoxy-16.~ -(2'-hydroxyethyloxy)-fusidic acid phenacyl ester ~4.21 g; 6.2 mmol) in dimethylformamide (25 ml), and the mixture was stirred for 16 hours at room temperature.
After dllution with ether (100 ml), the mixture was washed with water ~4 x 25 ml~, and the remaining organic phase was dried and evaporated in vacuo. The oily residue thus obtained was purified by dry column chromatography on silicagel (petroleum ether-ethyl acetate; 85:15) to give 3.16 g of 3-0-acetyl-16-deacetoxy-16~ -(2'-bromoethoxy)fusidic acid phenacyl ester as a colourless amorphous product.
C. 3-0-Acetyl-16-deacetoxy-16~- 2'-azidoethoxy)fusldlc acid phenacyl ester A solution of 3-0-acetyl-16-deacetoxy-16~-(2'-bromoethoxy)-fusidic acid phenacyl ester (1.04 g; 1.4 mmol) and lithium azide (0,34 g; 7 mmol) in dlmethylformamide (20 ml) was stirred for 16 hours at room temperature. The mixture was diluted with ether'~80 ml), washed'with water (4 x 20 ml), and the organic phase was dried and evaporated in vacuo to yield 0.97 g of the desired compoun'd as a foam. IR(KBr): 2100 cm (-N3).
D. 16-Deacetoxy-16~(2~-azidoethoxy)fusidic acid To a solution of 3-0-acetyl-16-deacetoxy-16 ~-(2'-a~idoethoxy)-fusidic acid phenacyl ester (0.95 g; 1.34 mmol) in ethanol ~20 ml) was added 5 N aqueous sodium hydroxide (2.7 ml), and the mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo, and the resulting oily residue was dissolved in water ~40 ml) and extracted with ether (20 ml). The a~ueous phase was separated, acidified with diluted hydrochloric acid, and the oily precipitate which formed was twice extracted with ether. The combined ethereal extracts were washed with water, dried, and evaporated to give 0.8 g of an amorphous product which crystalli~ed from diisopropyl ether to yield 0.41 g of 16-deacetoxy-16~ -(2'-azidoethoxy)fusidic acid, mp. 179-182C. Two recrystallizations from the same solvent gave the analytically pure compound~ melting point 184-185C.

~L~6~

.

. E~amp.le_72 16-Deacetoxy-16~-ethoxy-24.25-dih~drofusidic acid r . 16-Deacetoxy-16~-ethoxyfusidic acid benzyl ester To a solu-tion of 16-deacetoxy-16a-bromofusidic ~cid benz~i ester (3.1~ gj 5 mmol) in ethanol (25 ml) was added silver carbonate (2.76 g; 10 mmol);and~ a~ter protection from light, the mixture was stirred at room temperature ~or 16 hours. The insoluble material was ~iltered off, washed with ethanol (2 x 5 ml), and the combined filtrate and washings were evaporated in acuo.
The amorphous residue thus obtained was puri~Led by dry column chromatography oll silica gel ~pe-trole~un ct}ler:
ethyl acetate;60:40) to yield 1~66 g of -the desired com-.pound as a colourless ~oam.
'' " , .' ' ~.

B. 16-Deacetoxy-16~-ethoxy-24~25-dihydrofusidic acid 10% Palladium on carbon catalyst (0.4 g) was addçd to a solution o.f 16~deaceto~y-16~-ethoxy~us.id:;c acid benz~l ester (1.2 g;~2 mmol) :in ~th~nol (20 ml~, and .
the mixture wa8 sh~ken in a hydro~en atmosph~r~ ~o~
40.minutes. The catalyst was ~iltered Orr, washed ~rith ethanol~ and -the combined ~lltra-te and ~ashings werc ~v~porated :Ln vacuo. The resulting residue was crystallized from ether to af~ord 0.92 g of 16-deaceto~-16~-ethoxy-24;25-dihydrofusidic acid, melting point:
191_192C. _ _ , .

j.-96 -.

.. . _ .

~69.9a!6 Example 73 16-Deacetoxy-16~-(2'',2',2'-trifluoroethoxy)-24,25-di-hydrofusidic aci~
To a solu-tion of 16-deacetoxy-16~-(2~,2~,2~-tri-. , fluoroethoxy)fusidic acid (278 mg; 0.5 mmol) in 960/o, ethanol (5 ml) was added 10,~ palladium on calcium carbonate catalyst (50 mg~, and the mixture was shaken in a hyflrog~n atmosphere for 20 minutes.
The catalyst was filtered off, washed with 96~o ethanol, and the combined filtrate and washi~gs were evaporated to dryne~s in~vacuo. The residue crys,tal-. lized from diisopropyl ether to afford 220 mg of the desired cvmpound, melting point: 201~_205 C. Re_ crystallization from the same solvent ~ave the analytical sample, melting point: 20l~-205C.

Ex~mple 74 ,16-Deacetoxy-16~-(2~-fluoroetho~y)-24,25-dihydro~usidic acid By substituting 16-deacetoxy-16~-(2~-fluoroQtho~y) ~usiclic acid ~or tllc 16-doac~toxy-16~ (2~,2l,2l-tri-fluoroethoxy)fusidic acid in the procedure of Example 73 16-deacetoxy-16~-(2~-fluoroetho~y)-24~25-dihydro-~usidic acid~ mclting point: 180-182 C was obtained.

~" l i ~64g~6 Example 7 ll~Keto-16-d.eaceto~v-16~-ethoxvfusidic acid To a suspen~ion of 3-0-ace-tyl~ keto-16-deacetoxy--16a-bron,ofusidic acid phenacyl ester (5.57 g; 8 mmol~
in ethanol (60 ml) was added sil~er carbonate (4.41 g;
16 mmol), and, after being protected from light, the mixture was stirred for 18 hours at room temperature.
; Insoluble material was ~iltered off and washed with ethanol (2 x 20 ml). The combined ~iltrate and washings containing ~he c~de 3-0-acetyl~ keto-16-deacetoxy -16~-ethoxyfusidic acid phenacyl e'ster were diluted with ethanol (80 ml), 5 N aqueous sodium hydrox:ide (32-ml~ was added, and the mixture was stirred for 20 hours at room temperature. The solvent was removed in vacuo,. to the residual oil was added water (100 ml) and ether (100 ml), and the stirred mi~ture was acidified by addition of 4 ~ hydrochloric acid. The.
organic phase was separated, the aqueous phase was reextracted with ether (100 ml), and the combined nr~anic extracts ~ere washed with ~ater until neutral, driod, and evapor~tod in vc~cun. The r~sultirl~ oily residue was purified by dry column chrornato~raphy on silicagel (ether : petroleurn ether acetic acid, 50:50:0~5)~ and the yellowish arnorphous product thus obtained crystalli.zed from diisopropyl ether to give 2.12 g of 11-~eto-16-deaceto~-16~-ethoxyfusidic acid, ._ ~8 -1~69L~6 melting point 166-167 C. Recrystalli~ation from ether-diisopropyl ether afforded the analytical sample~
melting point 16~-168C.

xa~ple 76 ll-Keto-16-deaceto~y 16~-(2~-fluoroethoxy)fusidic acid ~ollowing the procedure described in Example 75 but substituting 2-fluoroethanol for the ethanol;
ll-keto-16-deacetoxy-16~-(2~-fluoroethoxy)fusidic acid was obtained as a colourless, amorphous powder.
The compound could be converted in-to a crys-talline sodium salt (see Example 88).

.. . .
' Exalllple 77 ~,ll-Diketo-16-deac~toxy-16~-e-tho~yru~idic acid Jones~ reagent (12.0 ml) was added dropwise at 15 C to a stirred solution of 16-deaceto~y-16~-ethoxy-fusidic acid (10.24 g of the hemih~drate; 20 mmol) in acetone (200 rnl). After the addition was finished, the cooling-bath wa~ removed, and the m~xturc wa~s stirred ror 30 millute~ at room tcmperature. To the mixture was added ether (300 ml) and water (200 rnl), and stirring was continued for 15 minutes. The organîc layer was ~ .

. .. . . ~
.
, _ 99 _ .. .. .

~4~6 scparated, the aqueous phase was reextracted with ether (100 ml), and the combined org~ic extracts were washed with water until neutral, and dried. On concentration of the ethereal solution to about 100 ml 9 crystallization of a colourless product began~ After beirlg kept in the refrigerator overnight, the crystals were collected, washed with ether, and dried to afford 7.02 g of 3,11-diketo-16-d0acetoxy-16~-ethoxyfusidic acid, melting point 185-187C, Concentration of the mother liquor gave another o.84 g of the desired compound. The analytical sample, melting point 187-188C, was obtained on recrystalli~ation ~rom meth~lene chloride-diisopropyl ether.

Example 78 ~-Keto-16-deacetoxy-16~-ethox~-fusidic acid A mixture of 3,11-diketo-16-deacetoxy-16~-ethoxy-fusidic acid (6.o5 g; 12.14 mmol), 2-ethyl-2-methyl dioxolane(_l~3) (60 ml)~ and p-toluenesulfonLc ac:id (0.2~ g) was refluxed for 40 minutes On an ~lectric heatin~-bath, ~Pker coolln~ to room ~emp~rature~ cth~r (200 ml) and pyridine (0.5 ml) were added, and the mixture was washed with water (4 x 50 ml). The orgal~ic ; phase was dr~ed and evaporated ~n vacuo to leave 7.o6 g '` ' ..
. . _, --1 00-- ~
:' ~
-- - ---......

~ID6~

.
of the crude 3-ethylene ketal of the 3,11-di~eto acid a~ a gUIII, wllich failed to crystalli~e.
To a stirr~ solution of the above residue in ethanol (140 ml) ~as added at 5C solid sodium boro-hydride (2 g) in portions. After the addition was finished, the cooling-bath was removed, and the mixture was stirred for 45 minutes at room temperature. The mixture was neutralized with acetic acid, water (420 ml) was added, and the oily--precipitate which formed was extracted with ether ~2 x 150 ml). The combined organic ~, extracts were washed with water (4 x 25 ml)~ dried, and evaporated in ~acuo. The resulting oily residue was crystalli~ed from ether-diisopropyl ether to afford 3.12 g of the 3-ethylelle ketal of 3-ke-to-16--deacetoxy-16~-ethoxyfusidic acid~ melting point 166-169 C.
Concentration of the mother liquor furnished another 2.04 g of the desired compound, mel-ting point 166-169 C.
Two recrystallizations from methylene chloride-diiso-propyl ether gave the an~lytical sample, melting point 171-172C. .

h solutlon o~ 3-kcto-16-d~acotoxy-16~-~thoxy-fusidic acid 3-ethylene ketal (3.~8 g; 7.3 rnrrlol) in methanol (40 ml) was acidified with 2 N hydrochloric .
.~ .
,. ~

--1 l _, acid (2 ml) and refluxed for 20 minute~ on the steam-bath. After cooling, water (160 ml) was added, and the oily precipitate, which formed, was extracted with ether (2 ~ 100 ml). The comblned organic extracts were washed with water until neutral, dried, and evaporated in vacuo. The resulting amorphous residue was crystallized from et~er to yield 2.94 g of 3-keto--16-deacetoxy-16~-ethoxyfusidic acid, melting point 175-177 C. Recrystalli~ation from the same solvent raised the melting point to 177-17~ C.

xample 79 16-Deacctox~-16~-isopropylsulrinyl~lsidic acid ~-diethylaminoethYl ester To a solution of the sodium salt of 16-deacetoxy--16~-isoprop~lsulfinylfusidic acid (320 mg; 0.5 mmol) in 2 ml o~ dimethylforrnamide was added ~-(diethylamino)-ethyl chloride (0.08 ml; 0.55 mmol). A crystalline product skarted to precipitate when this mixture was left at room temperature for 5 hours. Water (5 ml) was then added, and the procluct was ~ilte~red of~, washed with 5 ml of water and dried to afford 310 mg of 16-deaceto~y-16~-isopropylsulfinyl~usidic acid ~-diethyl-amlnoethyl ester~ melting point 156-158C.

~ 12 -;

_ . .

~;064906 E~arnple 80 16-Deacetox~-16~-isopropylsulfin~rlfusidic acid acetoxy-methyl ester .

To a solution of the sodium salt of 16-deacetoxy--16~-isopropylsulfinylfusidic acid (320 mg; 0.5 mmol3 in 2 ml of dimethylformamide was added cilloromethyl acetate (~S ml; 0.55 mmol). After standing for 24 hours at room temperature, ethanol (5 ml) and water ~5 ml) was added to precipitate the desired product as colourless crystals, which were fi~tered off, ~ashed with water (5 ml)~ and dried to give 290 mg; melting po:Lnt 151-153C. Recrystallization from ethyl acetate-petroleum ether raised the rnelting point to 152-15l~C.

Example 81 16-Deacetoxy-16~_isopropylthiofusidic acid acetoxy-.
meth~l ester By following the procedure described in Example 80 and subs~tituting 16-deacetoxy-16~-:isopropylthlo-fusidic acid for 16-deacetoxy-16~-isopropylsul~ yl-~usidlc aold 16-deaootoxy-16~ opropylthio~usid:Lc ` acid acetoxymethyl ester was prepared as colourless ; crystals of melting point 77-83C, .~ ;

, _ , ;- 1 03-' 91Dg;

Examples 82_~9 Sodium salts of 16~-ethers, 16~-thioethers and 16~-~, -alkYlsulphin~1 corpounds of 16-deacetoxyfusidic acid and its 3- and ll-keto derivatives.
Crystalline sodium salts of the compounds described - in Examples 1, 35, 46, 48, 50, 75, 76, and 78 were obtained by the following procedure: A solution of the corre-sponding acid (10 mmol) ln methanol (25 ml) was -titrated with 2 N methanolic sodium hydroxide using phenolphthalein as an indicator. After evaporation to dryness in vacuo, the oily or amorphous residue thus obtained was taken up in acetone (ca. 100 ml), the -resulting solut.1.on was concentrated to about hal~ the volume, and upon scratching the des:ired sodium salt began to crystallize. The mixture was kept for 2 hours at room temperature~ thereafter the crystals ~ere collected, washed ~-ith acetone, and dried to give the pure sodium sal~ of the desired oompound.

The sodium salts prepared by this method are listed in table X~II. Microanal~sis, IR_ and NM~ data obta:l.ned *or these compound~ are in agreement with their structure.

, .

. ' ' ,.~

_104_ _ . .

`\`

649al6 Tabl e XVII

COONa 2 ~ A-R3 ~ .
Rl ~ , .
. _ . __ .
Example Rl R2 A R Acid described - 3 in Example 82 H,a-OH H,a-OHS CH(CH3)2 83 H~a-OH H,a-OHS~ O CH~CH3)2 35 84 H,a-OH H,a-OHO CH2CH3 46 H~a-OH H,a-OH O 2 3 1~8 86 H,a-OH H~a-OHO CH2CH2F 5o 87 H~ a - OH. O CH2CH3 75 88 H~a-OH O O CH2CH2F 76 89 O H,a-OH O CH2CH3 78 : _ . .
' Exampl e 90 Pota~slum salt of` 16-deacetox~ L6B-(2l-hYdr~

; A solution o~ 16-deacetoxy-16~-(21-hydroxyethoxy)-~usidic acid (2,64 g; 5 mlnol, calculated as the hemi-hydrate) in nlethanol (10 ml) was titrated against ' :

:; , phenolphthalein with 2 N m~thanolic potassium hydroxide.
After evaporation to dryness in vacuo~ the amorphous residue thus obtained was dissolved in methanol ~2.5 ml), acetone (60 ml? was added, and the mixture ~as con-centrated to about 15 ml of reduced pressure. Colour-less crystals precipitated on scra*ching,-were filtered off, washed with acetone, and dried to afford 2.32 g o~ the desired compound.

Example 91 ~, _6-Deacetoxy-3-keto-16~-isopropylthio-24,25-dihydro-fusidic acid ~ y following the procedure of Exarnple 34 and substituting 16-deacetoxy-16~~isopropylthio-24,25~
dihydrofusidic acid acetoxymethyl ester for 16-deacetoxy-16~-isopropylthiofusidio acid acetoxy-methyl ester, 16-deacetoxy-3-keto-16~~isopropylthio-24,25-dihydrofusidic acid was prepared.

, ~xample 92 ll-Koto-16-deacetoxy-16~(2,2,2 -trifluoroethoxy) fusidic acid ~ ollowing the procedure described in Example 75 but substltuting 2,2,2-tri~luoroethanol ~or the ethanol, ll-keto-16-deacetoxy-16~-(2~2~2 -trifluoroethoxy)fusidic acid was obtained.
. .

-106_ - - - J

1a~64~06 Exampl e g ~
Cream 16-Deacetoxy-16~-isopropylthio-24,25-dihydrofusidic acid .................... 20 g Petrolatum ....... ,......................... 150 g Liquid paraffin ...................... ...... 150 g Spermaceti ..................q.............. 50 g 'Sorbitan monopalmitate .......... .......... 50 g Polyoxyethylene sorbitan mono-palm,itate ....................... .......... 50 g Water ,.,... ,,....... ;....... ;.............. 530 g Heat petrolatum, paraffin~ spermaceti~ sorbi,tan-monopalmitate, and polyoxyethylene sorbitan mono-palmltate to 70C and add slowly the water at 72C
with agitation. Continue agitation until the cream has cooled. Triturate 16-deacetoxy-16~-isopropylthio-24,25-dihydrofusidic acid into the cream base and homogenize using a roller mill. Fill the cream into laquered aluminium collapsible tubes, Exampl~ 9l~

Ointm~nt 16-~Deacetoxy-16,B-isopropylt}liofusidic acid sodium salt ~.,.....,,,.~............. 20 g L:iquLd paraL`fin .,...................... . 138 g Cetanol .................~.................. 4 g Lanolin anhydrous .......,................. 46 g Petrolatum ...................... .......... 792 g 16!1~9~6 Melt paraf~in, cetanol, lanolin, and petrolatum at 70 C. After cooling to below 40 C, triturate 16-~eacetoxy-16~iso~ropylthiofusidic acid sodium salt.

Fill the ointment into laquered collapsible aluminium tubes.

Example 95 Ointment 16-Deacetoxy-16~-isopropylsulphinyl fusidic acid sodium salt .................. 10 g - Liquid paraffin .......................... 138 g Cetanol ......................;................. 4 g Lanolin anhydrous ................... .......... 46 g Petrolatum .......................... ......... 802 g ', ~

Melt para~:Ln~ cetanol, lanolin~ and petrolatum at 70 C. After cooling to below 40 C, triturate 16-deacetoxy-16~-isopropylsulphinyl ~usidic acid sodium salt. Fill the ointment into laquered collapsible tubes.
~ , ' ll~lCe to-16-deacQ toxy-ï6~-Q thoxy:E`usidic acid sodium salt .................... ......... 250 g Microcrystalline cellulose .......... ......... 145 g Magn~s:l.um stcarate .............. 5 g 400 g ... .

~10~
- - . . _ !

` ~16~9(36 ~\ Pass the ingredients through a 60 mesh sieve and mix for 10 minutes.
Fill the mixture into hard gelatin capsules No. OO''~Parke Davis & Co.) using a capsule fil weight of 400 mg.
Example 97 Preparation of tablets 16-Deacetoxy-16~ -(2',2',2'-trifluoro-ethoxy)fusidic acid .......~..................... 250 g Avicel PH 101.......................... .......... 120 g STA-Rx 1500 ........................... .......... 120 g Magnesiumstearate ..................... ........... 10 g 16-Deacetoxy-16.~ ~(2',2',2'-trifluoroethoxy)fusidic acid, Avicel (the Trade Mark for a microcrystalline cellulose of FMC Corpora-tion, American Viscose Division) and STA-Rx (the Trade Mark for a directly compressible starch preparation of A.E. Staley Manufacturing Corporation) are mixed together, sieved through a 0.7 mm sieve and thereafter mixed with the magneslumstearate. The mlxture i8 pressed into tablets each of 500 mg.
Example 98 ' Preparation of suspension ! 3-Keto-16-deacetoxy-16~-isopropyl-thio-fusidic acid .............................. 5.00 g Citric acid .................................... 0.45 g Sodium monohydrogenphosphate ,............... ~. 0.70 g Sucrose .................................... ,. 25.00 g Tween 80 ....................................... 0-05 8 Potas~ium sorbate .............................. 0.20 g Carboxymethylcellulose-~a ...................... 0.50 g Purified water ..,........................ qs to 100 ml suspension : .

.

, ~6~90~
The crystals are micronized and suspended in a solutlon of the ci.tric acid, the.sodium monohydrogenphosphate, tne sucrose, the potas-sium sorbate and the Tween 80 (the Trade Mark for a polyosyethylene derivative of fatty acid, pattial esters of sorbitot anhydrides, of Atlas Chemical Industries) in 50 ml water, if necessary under slight warming. The carboxymethylcellulose-Na is dissolved in 20 ml of boiling water. After cooling, it is added to the other ingredients. The sus-pension is homogenized in a blender and finally purified water is added to a total volume of 100 ml.
Example 99 Ointment A: 16-Deacetoxy-16~ -isopropylthio-fusidic acid sodium salt .............. 20 g B: One of the steroids:
hydrocortison, triamcinolon or fluocinolon ........................... 10 g Liquid paraffin ...................... 138 g Cetanol ................................ 4 g Lanolin anhydrous ..................... 46 g Petrolatum ........................... 802 &
- 1000 g o , ," :, .

1~i4~

Melt paraffin~ cetanol~ lanolin~ and petrolatum at 70 C~ After cooling to below 40 C, triturate A and B, Fill the ointm~nt into laquered collapsible tubes.

Exam~e 100 A: 16-Deacetoxy-16~-(2 -fluoroethoxy3 fusidic acld .......................... 125 g - B: One of the antibiotics:
Amoxycillin, Cephalexin, Rifamycin, Rifampicin, Clindamycin or Eincomycin, Erythromycin, Pivmecillinam........... 125 g r Microcrystalline cellulose ...,,.. 145 g Magnesium stearate ................... 5 g L~oO g -Pass the ingredients throwgh a 60 mesh sieve and mix for 10 minutes. Fill the mixture into hard gelatin - capsules No. 00 (Parke Davis ~ Co.) using a ca~sule fil weight of 400 mg.

, Oln tment A: Tetracycline ...................... 15 g :13: 16-Deace toxy-16~-e thoxyfllsidic acid ,.. ,.... ~... ,... ,..... ,.. ,~. 15 g Liquid paraffin ...................... 138 g , . . .

-~49~ ~

Cetanol 9 ... , ., ..................... 4 g Lanolin a~ly~rous ............,....... ll6 g Petrolatum ........................ ... 782 g Melt paraffin~ cetanol~ lanolin~ and petrolatum at 70 C. After cooling to below 40 C, triturate A and B.
Fill the ointment into laquered collapsible aluminum tubes.

. . _ .

-112_

Claims (48)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of formula I

I

in which the C24-25 bond is a single or a double bond, and in which Q1 and Q2 stand for or oxygen; A stands for oxygen, sulphur or a sulfinyl radical; R
stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, or such straight or branched alkyl radical having from 1 to 8 carbon atoms when substituted by halogen atoms or hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, arylamino, alkanoylamino, or aroylamino groups; an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having from 3 to 7 carbon atoma in the alicyclic ring, an aryl, aralkyl or heterocyclylalkyl radical, or such alkenyl or alkynyl radical having from 2 to 6 carbon atoms, such cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such aryl, such aralkyl or such heterocyclylalkyl radical when substituted by halogen, nitro, lower alkyl, hydroxy or alkoxy radicals; or a heterocyclic radical having 5 or 6 ring atoms, containing oxygen, sulphur or nitrogen atoms, and selected from 2- or 3-pyrrolyl, 2 - or 3 - fury1, 2- of 3-fur-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl, 1-methyl-2-imidazolyl, triazolyl, 5-methyl-1,2,4-triazol-3-yl, tetrazolyl, 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl; and pharma-ceutically acceptable salts and easily hydrolyzable esters thereof, comprising one of the following steps:
(i) reacting a compound of formula Vb in which Q1' is Q1 or R2 being an alkanoyl, an aralkanoyl or an aryl radical; in which Q2 is as defined above; in which Y stand for chlorine, bromine or iodine and in which R3 stands for a straight or branched alkyl radical having from 1 to 6 carbon atoms, an aralkyl radical, an alkanoyl- or aroylmethyl radical, an alkanoyl- or aroyl-oxyalkyl radical, an alkyloxymethyl or a cyanomethyl radical, with a compound of the following formula VII: R1-A-H, in which R1 is as defined above and in which A represents oxygen or sulphur, thereby yielding a compound of formula VIII:

VIII

in which Q1' Q2, R1, and R3 are as defined above, and A is oxygen or sulphur, and thereafter subjecting said compound of formula VIII to hydrolysis;
or (ii) reacting a compound of formula IV, in which Q1', Q2 and R3 are as defined above, and the OH group at C-16 is .alpha.-oriented, A phosphine and a compound of the formula R1SSR1, in which R1 is aroyl, thereby obtaining a compound of formula VIII, and thereafter subjecting said compound of for-mula VIII to hydrolysis;
or (iii) reacting a compound of formula IX, in which Q2, R3 and the dotted line between C-24 and C-25 having the meaning as defined above, in which Q1' stands for oxygen or the group in which R2 is an alkanoyl, an aralkanoyl, or an arylradical, and in which R5 represents an alkylsulphonyl or arylsulphonyl radical, with a compound R1-A-H, in which R1 is defined above and in which A is oxygen or sulphur, to form a compound of for-mula VIII, and thereafter subjecting said compound of formula VIII to hydrolysis;
or (iv) carrying out reactions (i), (ii) or (iii) and thereafter oxidizing a compound of formula I, where A is sulphur, to a com-pound of formula I, where A is sulfinyl;
or (v) carrying out reactions (i), (ii), (iii) or (iv) and there-after transforming the free acid of formula I into a pharmaceut-ically acceptable salt or an easily hydrolyzable ester thereof.

2. A process as claimed in claim 1 wherein said heter-ocyclic radical is selected from the group consisting of furfuryl and tetrazolyl.

3. A process as claimed in claim 1 wherein the C24-25 bond is a single or double bond, wherein Q1 and Q2 both stand for A stands for oxygen; wherein R1 stands for a straight or branahed alkyl radical having from 1 to 4 carbon atoms or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

4. A process as claimed in claim 1 wherein the C24-25 bond is a single or a double bond, wherein Q1 and Q2 both stand for wherein A stands for sulphur, and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alky radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

5. A process as claimed in claim 1 wherein the C24-25 bond is a single or a double bond, wherein Q1 and Q2 both stand for , wherein A stands for a sulfinyl radical; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

6. A process as claimed in claim 1 wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for oxygen; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

7. A process as claimed in claim 1 wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for sulphur; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radlcal having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

8. A process as claimed in claim 1 wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for sulfinyl; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups.

9. A process as claimed in claim 1 in which a compound of formula I, wherein Q1 and/or Q2 are is oxidized to a compound of formula I wherein Q1 and/or Q2 are oxygen.

10. A process as claimed in claim 1 in which a compound of formula I, having a double bond between C-24 and C-25, is converted to a compound of formula I having a single bond between C-24 and C-25 by catalytic hydrogenation.

11. A process as claimed in claim 1 wherein R1 stands for an aryl or aromatic heterocyclic radical, and wherein A is sulphur, comprising carrying out the process of step (ii).

12. A process as claimed in claim 1 wherein said compound formula IX in step (iii) is prepared by reacting a compound of formula IV of step (ii), in which the hydroxyl group at C-16 is .alpha.-oriented and in which Q1' is different from the group with a reactive derivative of an alkylsulphonic or arylsulphonic acid.

13. A process as claimed in claim 1 including the step of converting a compound of formula VIII in which Q1' and Q2 stand for the group or oxygen, and R3 represents an unsubstituted or substituted benzyl radical, a cyanomethyl, alkanoylmethyl or aroylmethyl radical into a compound of formula I by hydrogenation.

14. A process as claimed in claim 1 comprising the steps of:
converting a compound of formula VIII, in which R1 stands for a hydroxy-sbustituted alkyl radical having from 1 to 8 carbon atoms into a corres-ponding compound in which R1 stands for a halo-substituted alkyl radical having 1 to 8 carbon atoms by treatment with an halogenating agent; thereafter reacting said halo-substituted alkyl derivative of formula VIII with an aliphatic or aromatic alcohol, with an aliphatic or aromatic mercaptan, with ammonia, with an aliphatic or aromatic amine, or with salts of lower alkanoic acids or of benzoic acid, with silver or sodium fluoride, with alkali metal azides, with nitrites, with cyanides or thiocyanates, with salts of lower thioalkanoic acids or with thiobenzoic acid, thereby forming a compound of formula VIII in which R1 stands for an alkyl radical having 1 to 8 carbon atoms substituted by an alkyloxy, aralkyloxy, aryloxy, alkylthio, aralkylthio, arylthio, amino, alkylamino, dialkylamino, azido, nitro, cyano, thiocyano, alkanoyloxy, aralkanoyloxy, aroyloxy, alkanoylthio or aroylthio radical respectively.

15. A process as claimed in claim 14 comprising the step of converting a compound of formula VIII in which R3 represents a sub-stituted or unsubstituted benzyl radical or a cyanomethyl radical to a compound of formula I by catalytic hydrogenation.

16. A process as claimed in claim 14 comprising the step of converting a compound of formula VIII, in which R3 represents an alkanoylmethyl or aroylmethyl radical, to a compound of formula I by hydrogenation with nascent hydrogen.

17. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-isopropylthiofusidic acid and its C24-25-dihydro analogue and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof which comprises the step of hydrolyzing 3-0-acetyl-16-deacetoxy-16.beta.-isopropylthiofusidic acid, p-nitrobenzyl ester, or its C24-25-dihydro analogue.

18. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-isopropylsulfinylfusidic acid and its C24-25-dihydro analogue, and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof which comprises the step of oxidizing the 16-deacetoxy-16.beta.-isopropylthiofusidic acid, or its C24-25-dihydro analogue.

19. A process according to claim 1 for preparing 11-keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid, and its C24 25-dihydro analogue, and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof which comprises the step of hydrolyzing 3-0-acetyl-11-keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid, p-nitrobenzyl ester, or its C24-25-dihydro analogue.

20. A process according to claim 1 for preparing 3-keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid, and its C24-25-dihydro analogue, and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, which comprises the step of hydrolyzing 3-keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid acetoxymethyl ester, or its C24-25-dihydro analogue.

21. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-ethyoxyfusidic acid and its 11-keto analogue, and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, which comprises the step of hydrolyzing 3-0-acetyl-16-deacetoxy-16.beta.-ethoxyfusidic acid phenacyl ester, or its 11-keto analogue.

22. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-(2'-fluoroethoxy)fusidic acid and its 11-keto analogue, and the non-toxid pharmaceutically acceptable salts and easily hydrolyzable esters thereof, which comprises the step of hydrolyzing 3-0-formyl-16-deacetoxy-16.beta.-(2'-fluoroethoxy)fusidic acid benzoyloxy-methyl ester or its 11-keto analogue.

23. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-(2',2',2'-trifluoroethoxy)fusidic acid and its 11-keto analogue, and the non-toxid pharmaceutically acceptable salts and easily hydrolyzable esters thereof, which comprises the step of hydrolyzing 3-0-acetyl-16-deacetoxy-16.beta.-(2',2',2'-trifluoroethoxy)fusidic acid phenacyl ester or its 11-keto analogue.

24. A process according to claim 1 for preparing 16-deacetoxy-16.beta.-(1',3'-difluoroisopropyloxy)fusidic acid and the non-toxic pharma-ceutically acceptable salts and easily hydrolyzable esters thereof, which comprises the step of hydrolyzing 3-0-acetyl-16-deacetoxy-16.beta.-(1',3'-difluoroisopropyloxy)fusidic acid phenacyl ester.

25. A compound of the formula I

in which the C24-25 bond is a single or a double bond, and in which Q1 and Q2 stand for or oxygen; A stands for oxygen, sulphur or a sulfinyl radical; R1 stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, or such straight or branched alkyl radical having from 1 to 8 carbon atoms when substituted by halogen atoms or hydroxy, alkyloxy, aralkloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, arylamino, alkanoylamino, or aroylamino groups; an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, an aryl, aralkyl or heterocyclylalkyl radical, or such alkenyl or alkynyl radical having from 2 to 6 carbon atoms, such cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such aryl, such aralkyl or such heterocyclylalkyl radical when substituted by halogen, nitro, lower alkyl, hydroxy or alkoxy radicals; or a heterocyclic radical having 5 or 6 ring atoms, containing oxygen, sulphur or nitrogen atoms, and selected from 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-fur-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl, 1-methyl-2-imidazolyl, triazolyl, 5-methyl-1,2,4-triazol-3-yl, tetrazolyl, 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl; and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 1 or by its obvious chemical equivalent.

26. A compound of claim 25, wherein said heterocyclic radical is selected from the group consisting of furfuryl and tetrazolyl, whenever produced by the process of claim 2 or by its obvious chemical equivalent.

27. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein Q1 and Q2 both stand for , wherein A stand for oxygen, R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and the non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 3 or by its obvious chemical equivalent.

28. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein Q1 and Q2 both stand for , wherein A stands for sulphur; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and the non-toxic pharmaceuti-cally acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 4 or by its obvious chemical equivalent.

29. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein Q1 and Q2 both stand for , wherein A stands for a sulfinyl radical; and wherein R1 stands for a straight or branched alkyl rsdlcal having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and pharmaceuti-cally acceptable salts and non-toxic easily hydrolyzable esters thereof, whenever produced by the process of claim 5 or by its obvious chemical equivalent.

30. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for oxygen; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and non-toxic pharmaceuti-cally acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 6 or by its obvious chemical equivalent.

31. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for sulphur; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and non-toxic pharmaceuti-cally acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 7 or by its obvious chemical equivalent.

32. A compound of claim 25, wherein the C24-25 bond is a single or a double bond, wherein one of Q1 and Q2 is oxygen and the other is , wherein A stands for sulfinyl; and wherein R1 stands for a straight or branched alkyl radical having from 1 to 4 carbon atoms, or a straight or branched alkyl radical having from 1 to 4 carbon atoms substituted with halogen atoms, hydroxy or azido groups, and non-toxic pharmaceuti-cally acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 8 or by its obvious chemical equivalent.

33. A compound of claim 25, wherein Q1 and/or Q2 are oxygen whenever produced by the process of claim 9 or by its obvious chemical equivalent.

34. A compound of claim 25 having a single bond between C-24 and C-25 whenever produced by the process of claim 10 or by its obvious chemical equivalent.

35. A compound of claim 25 wherein A is sulphur and where-in R1 is aryl or aromatic heterocyclic whenever produced by the pro-cess of claim 11 or by its obvious chemical equivalent.

36. A compound of claim 25 wherein Q1' stands for oxygen or the group wherein A is oxygen or sulphur, whenever produced by the process of claim 12 or by its obvious chemical equivalent.

37. A compound of claim 25 in which Q1' and Q2 stand for the group or oxygen, whenever produced by the process of claim 13 or by its obvious chemical equivalent.

38. A compound of claim 25 wherein R1 stands for an alkyl radical substituted by an alkyloxy, aralkyloxy, aryloxy, alkylthio, aralkylthio, amino, alkylamino, dialkylamino, azido, nitro, cyano, thiocyano, alkanoyloxy, aralkanoyloxy, arolyoxy, alkanolythio or aroylthio radical, whenever produced by the process of claim 14 or by its obvious chemical equivalent.

39. A compound of claim 25 whenever produced by the process of claim 15 or by its obvious chemical equivalent.

40. A compound of claim 25 whenever produced by the process of claim 16 or by its obvious chemical equivalent.

41. 16-Deacetoxy-16.beta.-isopropylthiofusidic acid and its C24-25-dihydro analogue and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 17 or by its obvious chemical equivalent.

42. 16-Deacetoxy-16.beta.-isopropylsulfinylfusidic acid and its C24-25-dihydro analogue, and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 18 or by its obvious chemical equivalent.

43. 11-Keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid, and its C24-25-dihydro analogue, and non-toxid pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 19 or by its obvious chemical equivalent.

44. 3-Keto-16-deacetoxy-16.beta.-isopropylthiofusidic acid, and its C24-25-dihydro analogue and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 20 or by its obvious chemical equivalent.

45. 16-Deacetoxy-16.beta.-ethoxyfusidic acid and its 11-keto analogue, and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 21 or by its obvious chemical equivalent.

46. 16-Deacetoxy-16.beta.-(2'-fluoroethoxy)fusidic acid and its 11-keto analogue, and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 22 or by its obvious chemical equivalent.

47. 16-Deacetoxy-16.beta.-(2',2',2'-trifluoroethyoxy)fusidic acid and its 11-keto analogue, and non-toxic pharmaceutically acceptable salts and easily hydrolyzable esters thereof, whenever produced by the process of claim 23 or by its obvious chemical equivalent.

48. 16-Deacetoxy-16.beta.-(1',3'-difluoroisopropyloxy)fusidic acid and non-toxid pharmaceutically acceptable satls and easily hydrolyzable esters thereof, whenever produced by the process of claim 24 or by its obvious chemical equivalent.