JPS6350360B2 - - Google Patents

Description

[Detailed description of the invention] The present invention provides a series of novel fusidic acid derivatives,
its salts and its easily hydrolyzable esters
of these compounds.
Production methods and drugs containing these compounds
It also relates to compositions. The new compound is
It has the following general formula: That is, [In the formula, Q₁and Q₂is a group [formula] or an acid Represents an elementary atom, and A may be an oxygen atom or a sulfur atom.
represents a sulfinyl group, R₁is methyl,
chill, propyl, isopropyl, butyl, isobutyl
Known isomers of tyl, tert-butyl, pentyl,
Carbons such as xyl, heptyl and octyl groups
Straight chain or branched alkyl group of number 1 to 8 (such
Alkyl groups optionally include halogen atoms, hydroxy
cy, alkyloxy, aralkyloxy, ary
ruoxy, alkanoyloxy, aralkanoyl
Oxy, aroyloxy, sulfhydryl, al
Killthio, aralkylthio, arylthio, al
Kanoylthio, aroylthio, azide, nitro,
Cyano, Thiocyano, Hydroxycarbonyl, A
Rukyloxycarbonyl, aryloxycarbo
Nyl, amino, alkylamino, dialkylami
, arylamino, alkanoylamino and
It may be substituted with an aroylamino group. )
means R₁furthermore, allyl, crotyl
or an alkali having 2 to 6 carbon atoms such as propargyl group.
Kenyl or alkynyl group; cyclopropyl, cyclo
butyl, cyclopentyl, cyclohexyl, cyclopentyl
Chlohepetyl group or their monohalo-, dihalo
-, lower alkyl-, lower alkoxy- or
3-7 carbon atoms such as hydroxy-substituted analog groups
Cycloalkyl group; benzyl, phenylethyl,
Aralkyl such as phenyl or furfuryl group
group, heterocycloalkyl group (heteroalicyclic group) or
Aryl groups (these groups optionally contain halogen atoms)
child, nitro group, lower alkyl group, hydroxyl group
Alternatively, it may be substituted with an alkoxy group. )
It may also be R₁is 2-pyrrolyl,
3-pyrrolyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl
Lysyl, 4-pyridyl, 2-pyrimidyl, 4-pyridyl
rimidyl, 5-pyrimidyl, 2-pyrazolyl, 3
-pyrazolyl, imidazolyl (e.g. 1-methyl
(2-imidazolyl), triazolyl (e.g.
5-methyl-1,2,4-triazol-3-y
), tetrazolyl (e.g. 1-methyl-1H-tetra
torazol-5-yl), thiazolyl, thiazia
Zolyl (e.g. 5-methyl-1,3,4-thia
5-6 rings, such as diazol-2-yl)
an oxygen atom, a sulfur atom or a nitrogen atom
It may be a heterocyclic group containing. ] In the formula, the dotted line between C-24 and C-25 is
The corresponding carbon atoms (C-24 and C-25) are double
be connected by a bond or a single bond
It shows. Unless otherwise stated, lower
The term alkyl refers to an alkyl group having 1 to 4 carbon atoms.
means. A particularly important compound is Q₁and Q₂are based together
[Formula] Is it Q?₁Or Q₂one of is an oxygen atom, A is an oxygen atom, and a sulfur atom is also
or represents a sulfinyl group, R₁has 1 carbon
~4 linear or branched alkyl groups (this group is
Optionally, a halogen atom, hydroxyl or azide
It may be substituted with a group. ), C
The bond between -24 and C-25 is a double bond or a single bond.
It is a compound that has a double bond. It exhibits particularly excellent properties among the above-mentioned compound groups.
The thing is R₁is optionally replaced by a fluorine atom
is an ethyl or isopropyl group
It is a compound. The compounds of the invention may be used as is.
However, in addition, its salt or easily hydrolyzed
It can also be used in the form of a degradable ester.
Particularly preferred salts are alkali metal salts and alkali metal salts.
Pharmaceutically acceptable non-toxic like lithium salts
For example, sodium salt, potassium salt
salts, magnesium salts or calcium salts.
Ru. Ammonium salts, lower alkyl amines (e.g.
triethylamine) salt, hydroxy lower alkyl
Kylamine (e.g. 2-hydroxyethylamine)
amine, bis-(2-hydroxyethyl)-amine or
tri-(2-hydroxyethyl)-amine) salt,
Chloalkylamines (e.g. dicyclohexyl
amine) salt, benzylamine (e.g., N,
N′-dibenzyl-ethylenediamine) salt and
A suitable non-toxic amine such as dibenzylamine
Salts are likewise particularly preferred. For some purposes, especially local treatments, these
Silver salts of the compounds of this invention can also be used. An example of an ester that can be easily hydrolyzed is
acetoxymethyl, pivaloyloxymethyl
and benzoyloxymethyl ester and
As for their corresponding 1'-oxyethyl derivatives
alkanoyloxyalkyl, aralkanoyl
Oxyalkyl or aroyloxyalkyl
Esters; methoxycarbonyloxymethyl and
and ethoxycarbonyloxymethyl ester
and their corresponding 1′-oxyethyl derivatives.
alkoxycarbonyloxyalkyl esters such as
Lactonyl esters such as phthalidyl esters
Stel; such as diethylaminoethyl ester
Listing dialkylaminoalkyl esters
I can do it. Of course, fusidic acid has antibacterial properties,
Changes to its structure completely eliminate its activity
It is also a well-known fact that the
Light compounds are of interest in vitro and in vivo
Clearly exhibits antibacterial and pharmacological properties
It became. Therefore, the compounds of the present invention are useful for humans and animals.
It can be used to treat bacterial infections of objects. Living
According to in vitro studies, the following table shows that
For example, the compound of the present invention
Genus, Streptococcus, Corynebacterium
Genus, Neisserium, Clostridium and
Bacteroides species and Bacillus subtilis
It has high antibacterial activity against many bacteria such as
do. 【table】 Furthermore, the compound of the present invention has a lower chemical content than fusidic acid.
Scientifically stable. For example, the 16-aryl of fusidic acid
Under certain conditions, the setoxy group is hydrolyzed to form a hydrolyzate.
In this case, the activity is greatly reduced.
On the other hand, in the compound of the present invention, the group at position 16 is
For example, 2% (by weight)
amount/volume) of the compound of the present invention in a buffer solution of PH9.6.
The diluted solution was kept at 40℃ for 30 days using thin layer chromatography.
Graphie also detected trace amounts of decomposition products.
Nakatsuta. Similar to fusidic acid, the novelty of the present invention
The compound is efficiently absorbed from the stomach and intestinal tract, and
is also virtually non-toxic. As a first step, the compound of formula
The compound is reacted with the compound of the general formula to obtain the compound of the general formula.
by a method characterized by producing a compound.
can be manufactured by [In these formulas, Q₁′ and Q₁was defined earlier
Or, [formula] (here ni, R₂is alkanoyl, aralkanoyl or
represents an aroyl group. ) means ;Q₂and C
The dotted line between −24 and C-25 is as defined above.
has a meaning; the wavy line between C-16 and the hydroxyl group
If the latter (hydroxyl group) is in the alpha direction,
This indicates that the bond is in the beta direction.
ri;X is a hydrogen atom or Na⁺,K⁺,Ag⁺,
Ammonium ion or trialkylammonium
It means a cation such as mu ion; Y is a chlorine source.
child, meaning a bromine atom or an iodine atom;
TeR₃For example, methyl, ethyl, tert-butyl
A straight chain or branched atom having 1 to 6 carbon atoms such as
alkyl group, e.g. benzyl, paranitrobendi
or paramethoxybenzyl or
is an unsubstituted aralkyl group, e.g. acetonyl or
Alkanoylmethyl such as fenacil or
Aroylmethyl group, e.g. acetoxymethyl,
Pivaloyloxymethyl or benzoyloxymethyl
Alkanoyloxyalkyl or
is an aroyloxyalkyl group or an alkyl group.
Represents a oxymethyl group or a cyanomethyl group. ] The reaction takes place at room temperature or slightly higher.
at low temperatures, such as dimethylformamide.
It is carried out in an active organic solvent. The method for preparing the starting compound of formula is described in the text.
As can be seen in the publication, our pending UK complete specification
Written in Book No. 39891 (1974) and similar
The compound can also be produced by a method. In a second step, a compound of formula
Converted to compound a or b. (In these formulas, Q₁′,Q₂,R₃, Y and C-24
The dotted line between and C-25 has the same meaning as defined above.
has. ) This transformation involves triphenylphosphine, tria
Rukylphosphine, triarylphosphine or
Hexamethylphosphoric triamide (hexamethylphosphoric triamide)
Carbon tetrachloride also
or polyhalogenated methane such as carbon tetrabromide.
Alternatively, such as N-chloro-succinimide
React with N-halogenamide or General formula: (CH₃)₂N+=CH-O-R_FourY^- (In the formula, R_Fouris a substituted or unsubstituted phenyl group,
enyloxycarbonyl group, alkyl group, benzo
represents an yl group or an acetyl group, and Y is a chlorine source.
child, bromine atom or iodine atom. )
By reacting with immonium salts
can be done. The reaction is carried out at room temperature or below.
For example, ether, tetrahydrofuran
Ran, dimethylformamide, acetonitrile
It is carried out in an inert organic solvent such as formula ao
Compounds of and b can also be represented by compounds of formula
For example, halogens such as phosphorus pentachloride or phosphorus trichloride
or thionyl chloride.
(thionyl chloride) or
Halogenated halogenomethylene-dimethyliminium
It can also be produced by reacting with
Ru. Represented by formulas a and b of compounds of general formula
When converting to a compound, a substitution reaction is usually carried out.
Standing at the carbon atom at the position (C-16) where
A reversal of body position occurs. Alpha direction to C-16
Compounds of the formula having a hydroxyl group are of the formula a
converted into a compound, with a hydrogen in the beta direction at C-16
A compound of formula having a roxyl group is a compound of formula b
converted into things. However, the compound of formula a is inorganic
or organic halides, such as lithium bromide.
um, tetrabutylammonium bromide, sodium bromide
potassium iodide or sodium iodide
and a suitable organic solvent such as dimethylformamium.
room temperature in acetonitrile or acetone.
react at or slightly higher temperature
is converted into a more stable compound of formula b.
can be set. The hydroxyl group at C-16 is
A compound of formula in the Lehua direction is a compound of formula
substances, such as phenyl bromide-N,N-dimethylform
dimethylform using an excess of muimidate.
When reacted in an amide, the formula a that is first formed is
is converted to a compound of formula b during the reaction.
Ru. Intermediates of formulas a and b are according to the invention
is a novel and interesting compound that forms part of
Ru. In the next step, the compound of formula b is converted to the general formula
When reacted with a compound of
A compound with the general formula is formed with a reversal of the locus.
do. (In these formulas, Q₁′,Q₂,R₁,R₃and C-24
The dotted line between and C-25 has the meaning previously defined;
A means an oxygen atom or a sulfur atom. ) If A of the formula and represents an oxygen atom,
In this case, the compound of the formula to be reacted is used as a solvent.
The reaction is preferably carried out using a silver salt or a mercury salt.
(e.g. silver carbonate, silver trifluoroacetate or acetic acid)
mercury) or bases (e.g. potassium carbonate, charcoal).
sodium acid or sodium alcoholate)
at room temperature or slightly above
It is done in degrees. If A of the formula and
In the case of U atoms, the reaction is carried out in an inert organic solvent.
Among them, preferably ethanol or dimethyl fluoride.
In Lumamide, a base (e.g. potassium hydroxide)
or sodium hydride) at room temperature or in the presence of
is lower or slightly above room temperature.
It is carried out at a high temperature. In the final step, a compound of formula
Sodium hydroxide in aqueous methanol or aqueous ethanol
potassium hydroxide, sodium carbonate or charcoal
Hydrolysis in the presence of a base, such as potassium acid
can be converted into a compound of formula by
Wear. A compound of formula Q₁′ and Q₂is based on
[Formula] or means O, R₃is easily hydrated When representing a decomposable ester group, further
without any reaction or conversion;
It becomes a compound of the present invention. A compound of formula Q₁′ and Q₂is the basis
[Formula] or means oxygen atom, R₃is replaced or unsubstituted benzyl group or cyanomethyl,
represents an alkanoylmethyl or aroylmethyl group
If the compound is
You can also do it. R₃is a benzyl group or cyanome
When a chill group is meant, catalytic reduction is preferred.
Ku, R₃has an acetonyl group or phenacyl group
If indicated, reduction with zinc in acetic acid is performed.
can become. A compound of the formula, in which Q₁is an oxygen atom
represents Q₂is an oxygen atom or a group [formula] also means the corresponding compound of the formula
T-Q₁and Q₂Does it mean the group [formula]? by an oxidation reaction well known to those skilled in the art.
can be manufactured. A compound of the general formula or, in which:
When A is a sulfinyl group, the corresponding formula
or a compound in which A is sulfur
For example, hydrogen peroxide, metaperoxide
Oxidation such as sodium iodate or chromic acid
It is produced by reacting with a chemical agent. The reaction is
For example, water, acetic acid, ethanol or acetone
in an inert solvent at or below room temperature or
It is carried out at a temperature slightly above room temperature. Easily hydrolyzable esters of compounds of formula
can be manufactured by known methods described in the literature.
I can do it. Inventive version in which C-24 and C-25 are a single bond
Compounds can also be reduced from corresponding unsaturated analogs.
supporting e.g. palladium as a catalyst, e.g.
It can be produced by catalytic reduction using carbon
I can do it. The intermediate compound of the formula can also be one of the following:
or can be manufactured by a more advanced method.
be. That is, (a) A compound of the general formula, in which A is an ion
It is a U atom, and R₁is aryl or aromatic
For heterocyclyl groups, the general formula
A compound in which the hydroxyl group at C-16
has alpha (α) configuration and ho
Suphin (e.g. tributylphosphine or
triphenylphosphine) and general formula
R₁SSR₁produced by reacting with the compound
can be built. The reaction is preferably carried out in an inert solvent.
Preferably dimethylformamide or pyridine
It is carried out at medium, room temperature or below. (b) As another example, a compound of formula and
In the formula, the hydroxyl group at C-16 is alpha
It has the configuration (α) and Q₁′ is different from the group [formula] is an alkyl sulfonic acid or an alkyl sulfonic acid.
Reactive derivatives of lylsulfonic acid (e.g.
by reacting with acid chlorides or acid anhydrides).
This produces a compound of the general formula shown below. [In the formula, Q₂,R₃and between C-24 and C-25
The dotted line indicates that previously defined for the compound of formula
Q₁' is an oxygen atom or group
[Formula] (R here₂is alkanoyl, aral Kanoyl or aroyl group. ) means,
R_Fiveis alkylsulfonyl, arylsulfonyl
onyl group, preferably methanesulfonyl
represents a para-toluenesulfonyl group. ] In the next step, the compound of formula
When reacted with a compound of the general formula, the compound of the general formula
generate. In the formula and, A is an oxygen source
When referring to a child, the compound of the formula is referred to as a solvent.
The reaction can be carried out at room temperature or
At slightly higher temperatures, often
Presence of an organic base (e.g. triethylamine)
It takes place below. A of the formula and is a sulfur source
When representing a child, the reaction is a compound of formula b.
(In the formula, A means a sulfur atom.)
The same using the method described above to convert it to
It is done like this. (c) To give yet another example, the general formula
(In the formula, A is an oxygen atom, a sulfur atom, or a sulfur atom.
means a rufinyl group, R₁is a hydroxyl group
represents an alkyl group substituted with ) compound
to a compound of formula a or b of a compound of formula
corresponds to the method described above for the conversion of
Compound (wherein, R₁is replaced by halogen
means an alkyl group. ) to convert to
I can do it. In the next step, the halogen-substituted alkyl of the formula
Kill derivatives can be combined with aliphatic or aromatic alcohols.
Preferably in the presence of a silver salt or a base; aliphatic or
is an aromatic mercaptan and preferably the presence of a base
Under; ammonia or aliphatic or aromatic atom
With salts of lower fatty acids or benzoic acids;
Silver oxide, sodium fluoride, alkali metal azide
de, nitrite, cyanide or thiocyanide
and; or lower thio fatty acids or thioamino acids.
By reacting with a salt of zoic acid, the formula (formula
Medium, R₁For example, fluorine atom, alkyloxy
cy, aralkyloxy, aryloxy, al
Killthio, aralkylthio, arylthio, a
mino, alkylamino, dialkylamino, a
dido, nitro, cyano, thiocyano, alkano
yloxy, aralkanoyloxy, aroyl
Oxy, alkanoylthio or aroylthio
means an alkyl group substituted by an o group
Ru. ) can be a compound. (d) Chemicals with an unsaturated bond between C-24 and C-25
Compounds are often reduced to intermediates of the corresponding formula.
can be successfully hydrogenated. The compound of formula is the compound of the present invention already mentioned above.
can be converted to . It is a further object of the present invention to
Provides pharmaceutical compositions useful in treating home infections
Is Rukoto. For this purpose, the composition of the invention contains active ingredients.
As a minute, the compound of formula, it's non-toxic and pharmaceutical
Salts with bases that are acceptable to and easily hydrolyzed
At least one selected from the group consisting of water esters
Pharmaceutical carriers in which one compound is solid or liquid
or with a diluent. In the composition, the carrier composition for the therapeutically active ingredient is
The proportions vary between 1% and 95% by weight.
It can be moved. Compositions include granules, tablets, pills, sugar
Coated tablets, suppositories, extended-release tablets, suspensions, and injections.
in various dosage forms, or in the case of mixtures, in
into a tube or similar container.
You can also Oral, enteral, parenteral or topical
Pharmaceutical organic or inorganic solid or
may contain a liquid carrier or diluent containing a compound of the invention.
It can be used to prepare compositions containing
Water, gelatin, lactose, starch, stearic acid
Gnesium, talc, animal and vegetable oils, benzyl
coal, gum, polyalkylene glycol, petroleum
Used in resin, coconut oil, lanolin or medicine
All other carriers present in this compound
suitable as a carrier. Also, stabilizers, wetting agents,
Using emulsifiers, changing osmotic pressure, and adjusting the appropriate pH of compounding agents
Salts can also be used as appropriate to maintain
Ru. Furthermore, the composition can be used in the treatment of infectious diseases.
Can be suitably administered with the compounds of the present invention
Other pharmaceutically active ingredients, e.g. other suitable
antibiotics, especially those with increased activity and/or resistance.
It may contain an antibiotic that suppresses expression.
Such antibiotics include penicillins, cephalos
Porins, tetracyclines, rifamycin
erythromycin, lincomycin and
Contains lindamycin. Together with the compound of the present invention
Other compounds that are advantageously used, especially in topical therapeutic agents.
Compounds include, for example, hydrocortisone, triamium
Adrenocortical hormones such as cinolone or fluocinolone
Includes Lumon. Granules, tablets, capsules or sugar-coated tablets
In some cases, the pharmaceutical compositions of the present invention have the efficacy of the present invention.
It is preferable that it contains 25-98% of the substance, and
For suspensions used for oral administration, the corresponding amount (percentage)
It is preferable that the amount of carbon dioxide is between 2 and 25%. parenteral
When used for
Preferably, the aqueous solution is administered by intravenous injection.
Alternatively, the compound of the present invention may be added to 1 to 20% of the active ingredient.
It can also be administered by injection as a pharmaceutical composition containing
good. The compounds of the present invention can be used in a pharmaceutically acceptable non-toxic manner.
Preferred when administered in the form of a salt with a neutral base.
Examples of salts include sodium salts that are easily soluble in water.
or diethanolamine salts, but other
Pharmaceutically acceptable non-toxic salts, e.g.
Slightly soluble to give certain favorable absorption rates
Salts can be used. As shown above, compounds of formula and salts thereof
Classes include suspensions, ointments and creams (emulsions).
It can be prepared into a pharmaceutical dosage form. oral administration
Agents for administration may also include the compound of formula itself.
in the form of a clouding agent or in a pharmaceutically acceptable formulation.
It may also be in the form of a soluble salt, the preparation being a carrier.
Contains 20 to 100 mg of active ingredient per 1 ml. Drugs for topical treatment contain compounds of formula 100
Ointment or cream containing 0.5 to 10g per gram
It can be in the form of an emulsion. Another object of the invention is to provide the desired
Compounds of the present invention that can be administered so as to obtain the activity of
The problem lies in selecting the dosage. In the treatment of the human whole body system, the formula is used for adults.
Calculated as a compound of 50 mg or more and 1000 mg or less,
Administer dosage unit doses preferably containing 200 to 750 mg.
It is convenient to give. Herein, the term "dose unit amount" refers to
A unit that can be administered to a patient in feces and packaging.
This refers to the dosage per dose, which refers to the amount of the active ingredient itself.
or active ingredients in solid or liquid form for pharmaceutical use
physically consisting of a mixture with a diluent or carrier
It is a stable unit dosage. In unit dosage form, the compounds of the invention may be administered once per day.
Administer at least twice a day or at appropriate intervals.
However, the number of doses always depends on the patient's physical condition and symptoms.
administration should be carried out according to the instructions of the practitioner.
be exposed. For systemic treatment, the daily dosage is
or 0.5 to 3 g as the compound of the formula. The term "unit dose" in relation to topical treatment is
Units that can be administered locally to the patient, i.e. 1
dosage per square centimeter of infected area
0.1 to 10 mg of the compound of the present invention per tol, preferably 0.2
Apply ~1 mg. When the composition is injected, the effective dosage unit dose
Aqueous or oil-based (active) ingredients that can be administered by injection
solutions that are suitable for parenteral administration or
Closed ampoules, vials or vials containing the dispersion
Containers similar to these are used. Parenteral drugs are used to treat diseases that require emergency treatment.
It is particularly useful for A series of patients suffering from infections
For therapy, tablets or capsules are preferred
This is a dosage form in which the drug is administered orally (particularly when the drug is
When administered (in the form of extended-release tablets), the effects are sustained.
This is because it can be obtained. In the treatment of infectious diseases,
The tablets contain the other active ingredients mentioned above.
It is convenient to Yet another object of the present invention is to
To provide a method of treating patients with severe symptoms,
The method provides adult patients with a compound of formula 1
0.25-4g per day, preferably 0.5-3g
or equivalent molar amounts of the compound of formula
It is characterized by administering salt. Preferably a book
The compounds of the invention may be prepared in a dosage form containing the aforementioned dosage units.
administered. Next, in order to explain the present invention in detail, intermediates
Here are some examples of the manufacturing method.
These examples are not intended to limit the invention.
stomach. Synthesis example 1 3-O-acetyl-16-deacetoxy-16al
Phenacyl ester of fur-bromofusidic acid A 3-O-acetyl-16-epideacetylfusi
Phenacyl ester of dinic acid 3-O-acetyl-16-epideacetylfushi
Sodium salt of dinic acid (5.38 g; 10 mmol)
and fenacil bromide (2.2 g; 11 mmol)
was dissolved in dimethylformamide (40ml).
After standing at room temperature for 16 hours, 150 ml of the solution
dilute with ether and add it with water (4 x 50 ml).
After washing and drying, evaporate the solvent under reduced pressure.
and 6.2 g of 3-O-acetyl-16-epideace
The phenacyl ester of tilfusidic acid is a colorless
Obtained as a foam. B 3-O-acetyl-16-deacetoxy-16a
Phenacyl ester of lehua-bromfusidic acid
le Dimethylformamide (1.1ml; 40mmol)
and phenyl chloroformate (5.04 ml; 40 mmol)
suspended in 80 ml petroleum ether (boiling point <50°C)
The suspension was stirred vigorously at room temperature. 1 o'clock
In between, carbophenoxy chloride N,N-dimethyl
Chilformimidate forms as colorless crystals
do. This initial product was stirred for an additional 16 hours.
While continuing, we lose carbon dioxide (carbon dioxide gas),
Crystalline phenyl chloride N,N-dimethylform
Give Muimidate. This compound is then
Phenol (3.76 g; 40 mmol) and triethyl
Ether of Ruamine (5.56 ml; 40 mmol)
(10ml) solution into the stirred reaction mixture.
N,N-dimethylformamide by
Converted to diphenyl acetal. 1 more
Chloride formed as a by-product after stirring for a period of time
Separate the triethylammonium and 50ml petroleum
Washed with ether. Acetyl bromide (2.0ml;
27 mmol) and the washing solution while stirring.
When added to a mixture of liquids, phenyl bromide N,N-
Dimethylformimidate as colorless crystals
generate. Collect this and use petroleum ether (20ml)
Washing with water removes traces of phenyl acetate.
Ta. Immonium bromide thus obtained (6 g;
26 mmol) has a large hygroscopic property, but this
immediately, 3-O-acetyl-16-epideacetylfushi
Phenacyl ester of dinic acid (6.2g; 9.8ml
mol) in dimethylformamide (40 ml).
added. After standing for 48 hours at room temperature, the solution was
Dilute with 100ml of 0.1N (normal) hydroxide
Sodium solution (100ml) and water (3 x 50ml)
After washing and drying, the solvent was evaporated under reduced pressure.
When methanol (50ml) is added, the residue crystallizes.
do. Separate the crystals, wash with methanol, and dry.
When dried, 5.2 g of 3-O-acetyl-16-de
Acetoxy-1-alpha-bromofusidic acid
The phenacyl ester (melting point: 141-142℃) is
Obtained. Synthesis example 2-8 3-O-acetyl-16-deacetoxy-16al
Esters of far-bromofusidic acid A. Substituting phenacyl bromide with the compounds shown in Table 1.
Follow the procedure in Synthesis Example 1A using a steallating agent.
and 3-O-acetyl-16- shown in Table 1
Esters of epideacetyl fusidic acid are obtained.
It was. B 3-O-acetyl-16- in Synthesis Example 1B
Phenacyl ester of epideacetyl fusidic acid
3-O-acetyl shown in Table 1 instead of
-16-epideacetyl fusidic acid esters
3-O- shown in Table 1 by using
Acetyl-16-deacetoxy-16 alphaab
Esters of romfusidic acid were obtained. 【table】 【table】 Synthesis example 9 3-O-acetyl-16-deacetoxy-16al
Paranitrobenzyl fur-bromofusidic acid
ester 3-O-acetyl-16-epideacetylfusidy
Sodium salt of phosphoric acid (21.5 g; 40 mmol) and odor
paranitrobenzyl (9.5 g; 44 mmol)
Dissolved in dimethylformamide (200ml). child
When the solution of is left at room temperature for 16 hours, during that time,
3-O-acetyl-16-epideacetylfucidin
The paranitrobenzyl ester of the acid is formed. Next
, phenyl bromide N,N-dimethylformimide
(36g; See Synthesis Example for the preparation method of this reagent.
1B) and the resulting reddish-brown solution at room temperature.
I left it under for 48 hours. While stirring, add methanol (700ml) and water.
(280 ml), the crystalline substance will precipitate. Conclusion
Remove the crystals and wash with methanol-water (3:1) mixture.
When washed and dried, 26.1g of 3-O-acetyl-16
-Deacetoxy-16 alpha-bromofusidic acid
paranitrobenzyl ester of (melting point: 151−157
°C) was obtained. Methanol - recrystallize from water
A pure product for elemental analysis (melting point: 157-159℃) was obtained.
Ta. Synthesis example 10−12 3-O-acetyl-16-deacetoxy-16al
Esters of far-bromofusidic acid Listed in Table 2 instead of paranitrobenzyl bromide
The procedure of Synthesis Example 9 using the esterification agent obtained
According to Table 2, 3-O-acetyl-
16-deacetoxy-16 alpha-bromofucidine
Esters of the acid were obtained. 【table】 Synthesis example 13 3-O-acetyl-16-deacetoxy-16al
Benzyl ester of fur-bromofusidic acid A 3-O-acetyl-16-deacetylfucidin
benzyl ester of acid Sodium salt of 16-deacetylfusidic acid
(84.7g; 0.17mol) of dimethylformamide
(200 ml) solution with benzyl bromide (25 ml; 0.21 mole).
) was added. After stirring at room temperature for 5 hours,
The diluted solution was cooled to 0°C and diluted with pyridine (200
ml; 2.5 mol) and acetic anhydride (170 ml; 1.8 mol)
) was added. After leaving it at room temperature for 16 hours,
Cool the mixture again to 0°C until the temperature is below 15°C.
50ml while stirring at a speed such that
of water (this will take about an hour)
Ru. ). Next, methanol (800ml) and water (400ml)
ml) to complete the precipitation of the target compound.
However, after stirring this at 10℃ for 1 hour, it was removed.
and washed with ice-cold methanol (3 x 20 ml).
When dried, 68 g of 3-O-acetyl-16-de
Benzyl ester of acetyl fusidic acid is colorless
It was obtained as crystals (melting point: 154-158°C). B 3-O-acetyl-16-deacetoxy-16a
Benzyl ester of lehua-bromofusidic acid The above benzyl ester (68 g; 112 mmol)
), sodium bromide (46.2 g; 448 mmol),
Pyridine (22 ml; 276 mmol) and dimethyl
Mixture of formamide (400ml) for 30 minutes at room temperature
After stirring, the mixture was cooled to 0°C. Phenic chloroformate
(56.5 ml; 448 mmol) was added over 45 minutes,
The resulting mixture was stirred at room temperature for 18 hours. after that,
Add methanol (400ml) and water (300ml)
The reaction product was precipitated as colorless crystals. this
and methanol-water (2:1 mixture, 2x
60 ml) and petroleum ether (3 x 30 ml).
After drying, 62.9g of 3-O-acetyl-16-
Deacetoxy-16 alpha-bromofusidic acid
Benzyl ester (melting point 124-126℃) was obtained.
Ta. Synthesis example 14−15 3-O-acetyl-16-deacetoxy-16al
Esters of far-bromofusidic acid A. Phenacyl bromide or odor instead of benzyl bromide
Procedure for Synthesis Example 13A using nitrobenzyl
According to the method, 3-O-acetyl as shown in Table 3
Esters of le-16-deacetyl fusidic acid
Obtained. B In the procedure of Synthesis Example 13B, 3-O-acetyl
Benzyl ester of L-16-deacetyl fusidic acid
3-O-acetyl as shown in Table 3 instead of ter
-16-deacetylfusidic acid esters
By using 3-O- shown in Table 3
Acetyl-16-deacetoxy-16 alphaab
Romfusidic acid was obtained. 【table】 Synthesis example 16 3-O-acetyl-16-deacetoxy-16al
pivaloyloxime of fur-bromofusidic acid
chill ester A 3-O-acetyl-16-deacetoxy-16be
pivaloyloxime of ter-bromofusidic acid
chill ester 3-O-acetyl-16-epideacetylfushi
Pivaloyloxymethyl ester of dinic acid
(17.4 g; 28 mmol) in dry ether (200
ml) and add triphenylphosphine to this.
(16 g; 60 mmol) and tetrabrometa
(20 g; 60 mmol) was added. 16:00 at room temperature
After stirring for a while, the reaction product is filtered to separate it from the by-products.
triphenylphosphine oxide produced by
(Excluding triphenylphosphine oxide). liquid
was evaporated under reduced pressure and the residue was purified using silica gel.
Dry column chromatography (cyclohexyl)
When purified by San: ethyl acetate = 8:2)
10.6g 3-O-acetyl-16-deacetoxy
-16-beta-bromphusidic acid pivaloyl
Oxymethyl ester is ether-petroleum ether
colorless crystals (melting point: 120−122
°C). ether-petroleum ether
Elemental analysis with melting point of 120-122℃ when recrystallized from
A pure product was obtained. B 3-O-acetyl-16-deacetoxy-16a
Pivaloyloxy of Lehua-Bromfusidic Acid
methyl ester 3-O-acetyl-16-deacetoxy as described above
-16beta-bromofusidic acid pivaloylox
dimethyl ester (5 g) to tetrabutyl bromide
ammonium (5g) in acetonitrile (60ml)
By reacting at room temperature for 3 days, 16 alkaline
The fur compound was epimerized (isomerized). anti
The reaction mixture was evaporated under reduced pressure and the residue was dissolved in ether.
In addition, tetrabutylammonium bromide was crystallized.
let Separate the crystals and wash the liquid with water (2 x 50 ml).
After drying and removing the solvent under reduced pressure, 4.87g of
3-O-acetyl-16-deacetoxy-16alf
Pivaloyloxymethyl of arbromfusidic acid
The ester was obtained as a colorless gum. Synthesis example 17 3-O-acetyl-16-deacetoxy-16al
Acetoxymethyl ester of fur-bromofusidic acid
Stell A 3-O-acetyl-16-deacetoxy-16be
Acetoxymethyl ester of ter-bromofusidic acid
Stell Following the procedure in Synthesis Example 16A, 3-O-acetyl
pivaloy of Le-16-epideacetylfusidic acid
3-O-acetic acid instead of hydroxymethyl ester
Aceto of thyl-16-epideacetyl fusidic acid
When using oxymethyl ester, melting point is 119-120℃
3-O-acetyl-16-deacetoxy-16be
Acetoxymethyl ester of ter-bromofusidic acid
Stell was obtained. B 3-O-acetyl-16-deacetoxy-16a
Acetoxymethyl of Rufa-Bromfusidic Acid
ester Following the procedure in Synthesis Example 16B, 3-O-acetyl
Le-16-deacetoxy-16beta-bromufushi
Substitute for pivaloyloxymethyl ester of dinic acid
3-O-acetyl-16-deacetoxy-16
Acetoxymethyl beta-bromofusidic acid
By using ester, melting point 102-105℃
3-O-acetyl-16-deacetoxy-16a
Acetoxymethyl of Rufa-Bromfusidic Acid
An ester was obtained. Synthesis example 18 3-O-acetyl-16-deacetoxy-16al
Far-bromo-24,25-dihydrofusidic acid
phenacyl ester A 16-deacetyl-24,25-dihydrofucidine
phenacyl ester of acid 16-deacetyl-24,25-dihydrofucidine
The sodium salt of the acid (4.99 g; 10 mmol)
Fena bromide in methylformamide (25ml) solution
Add Sil (1.99 g; 10 mmol) and mix
The mixture was stirred at room temperature for 4 hours. Ether (100ml)
After diluting with water, wash the mixture with water (4 x 25 ml)
did. After separating the organic layer and drying, reduce to approximately 20 ml.
A crystalline substance was precipitated when the solution was concentrated. cold
After leaving it in the warehouse for 2 hours, remove the crystals and
After washing with water and drying, 4.52g of the target compound was obtained.
A product (melting point: 92-94°C (decomposition)) was obtained. B 3-O-acetyl-16-deacetyl-24,25
-Phenacyl ester of dihydrofusidic acid 16-deacetyl-24,25-dihydrofucidine
Phenacyl ester of acid (2.38 g; 4 mmol
Stir the pyridine (8 ml) solution of
Add acetic anhydride (4 ml) to this and mix.
The material was left at room temperature for 16 hours. Scrape the reaction mixture
Add diisopropyl ether (60ml) while stirring.
Upon dilution, a colorless substance precipitates out. this crystal
Collect, wash with diisopropyl ether and dry
1.92g of the target compound (melting point: 133-135
°C) was obtained. C 3-O-acetyl-16-deacetoxy-16a
Rufa-bromo-24,25-dihydrofusidic acid
phenacyl ester of 3-O-acetyl-16-deacetyl-24,25
-Phenacyl ester of dihydrofusidic acid
(1.59 g; 2.5 mmol), sodium bromide (1.03
g; 10 mmol) and pyridine (0.52 ml;
6.5 mmol) dimethylformamide (15 ml)
Stir the solution and add phenyl chloroformate to it.
(1.26 ml; 10 mmol) was added dropwise at 0°C.
After the dropwise addition (requires approximately 15 minutes), the reaction mixture was heated to 0°C.
The mixture was stirred for 2 hours at room temperature and then for 16 hours at room temperature. The mixture
Stir the mixture and add methanol-water to it.
When (1:1, 15ml) is added dropwise, crystals will precipitate.
However, take this, wash it with methanol, and dry it.
1.22g of the target compound with a melting point of 127-129℃ was obtained.
It was done. Recrystallized from methylene chloride-methanol
Then, a sample for elemental analysis with a melting point of 130-132℃ was obtained.
It was. Synthesis example 19−20 3-O-acetyl-16-deacetoxy-16al
Ester of fur-24,25-dihydrofusidic acid
kind A In Synthesis Example 18A, instead of phenacyl bromide
Add benzyl bromide or paranitrobenzyl bromide to
By using 16 as shown in Table 4 below
-deacetyl-24,25-dihydrofusidic acid
Esters were obtained. B 16-deacetyl-24,25-dihydrofucidine
In place of phenacyl esters of acids shown in Table 4
16-deacetyl-24,25-dihydrofushidi
Procedure for Synthesis Example 18B using phosphoric acid esters
According to the 3-acetyl ester shown in Table 4,
A stell derivative was obtained. C3-O-acetyl-16-deacetyl-24,25
- of phenacyl ester of dihydrofusidic acid
3-O-acetyl-16 as shown in Table 4 instead
-deacetyl-24,25-dihydrofusidic acid
Using esters, follow the procedure in Synthesis Example 18C.
and 3-O-acetyl-16- shown in Table 4
Deacetoxy-16 alpha-brome-24,25-
Esters of dihydrofusidic acid were obtained. 【table】 【table】 Synthesis example 21 3-O-formyl-16-deacetoxy-16al
Benzoyloxime of fur-bromofusidic acid
chill ester A Benzoyl of 16-epideacetyl fusidic acid
oxymethyl ester 16-epideacetylfusidic acid (35.5g; 75
mmol) in methanol (150ml),
Using phenolphthalein as an indicator,
Titrate with 5N sodium hydroxide solution.
This gives the sodium salt. Evaporate under reduced pressure
After drying, remove the remaining amorphous sodium salt.
Dissolve in methylformamide (150ml) and rest.
Chloromethyl aromatic acid (14.08g; 82.5mmol)
was added and the mixture was stirred at room temperature for 16 hours. water
(200ml) and transfer the mixture to ether (400ml)
Extracted with. Separate the organic layer and add water (4 x 100ml)
44.6g after washing with water, drying and evaporating under reduced pressure.
Benzoyl 16-epideacetylfusidic acid
Oxymethyl ester is obtained as an amorphous substance.
It was. B 3-O-formyl-16-deacetoxy-16a
benzoyloxy of lehua-bromofusidic acid
methyl ester Previously synthesized 16-epideacetyl fusidic acid
dimethyl benzoyloxymethyl ester of
Formamide (300ml), phenyl bromide N,N
- Dimethylformimidate (67g; approx. 290mg)
Limol) was added under stirring, resulting in a reddish-brown solution.
was left at 5°C for 6 to 7 days. Then that mixture
Add methanol (150ml) to the mixture and stir vigorously.
While stirring, add water (150ml) from the dropping funnel.
When heated, crystals precipitated. Take the crystals and methane
21.7g after washing with water (1:1) and drying
3-O-formyl-16-de with a melting point of 131-135°C
Acetoxy-16 alpha-bromofusidic acid
Benzoyloxymethyl ester was obtained.
When recrystallized twice from ether-methanol,
The melting point rose to 140-142°C. Synthesis example 22−24 3-O-formyl-16-deacetoxy-16al
Esters of far-bromofusidic acid A In the procedure of Synthesis Example 21A, chlorobenzoate
Benzyl bromide, chloropivalate instead of methyl
to use chloromethyl or chloromethyl acetate.
Therefore, the 16-epideacetate shown in Table 5 below
Esters of tilfusidic acid were obtained. B 16-Epidacetyl fusidic acid benzoyl
In place of oxymethyl ester shown in Table 5
Esters of 16-epideacetyl fusidic acid
and following the procedure of Synthesis Example 21B, Table 5
3-O-formyl-16-deacetoxy shown in
Esters of C-16 alpha-bromofusidic acid
type was obtained. 【table】 【table】 Synthesis example 25 3-O-formyl-16-deacetoxy-16al
Benzyl ester of fur-bromofusidic acid A Benzyl ester of 16-deacetylfusidic acid
le Sodium salt of 16-deacetylfusidic acid
(4.97 g; 10 mmol) of dimethylformamide
benzyl bromide (1.5 ml; 12.5
mmol) and the mixture was stirred at room temperature for 4 hours.
did. After adding water (100ml), the mixture was
Extract with tel (2 x 50ml) and mix as needed.
Wash the organic extract with water (4 x 20 ml) and dry.
and evaporated under reduced pressure. The residue thus obtained
Dissolve the sample in ether (50 ml) and add petroleum while stirring.
When ether (50ml) was added, crystals precipitated.
Ta. Take the crystals and make ether-petroleum ether
Washed with (1:2) and dried, 4.92g melting point 117
The target compound was obtained at -119°C. B 3-O-formyl-16-deacetylfucidin
benzyl ester of acid Benzyl ester of 16-deacetylfusidic acid
(4.52 g; 8 mmol) of pyridine (8 ml)
Stir the solution and add acetic acid formic anhydride to it.
(acetic anhydride formic acid) (4 ml) was added dropwise at 0℃ and mixed.
The item was left in the cold for 15 minutes. Scrape the reaction mixture
Add diisopropyl ether (40ml) while stirring.
Upon dilution, crystals precipitated. 2 hours in the refrigerator
After standing, collect the crystals and diisopropyl ether.
4.04 g melting point 143-145 when washed with gel and dried
The target compound was obtained at a temperature of . ether-diiso
Melting point 145− when recrystallized from propyl ether
A sample for elemental analysis was obtained at 147°C. C 3-O-formyl-16-deacetoxy-16a
Benzyl ester of lehua-bromofusidic acid 3-O-acetyl-16-deacetylfucidin
Instead of the benzyl ester of the acid, the above 3-O
-formyl-16-deacetylfusidic acid ben
using the diester and following the procedure in Synthesis Example 13B.
3-O-formyl-16-deacetoxy-
16 Alpha-bromofusidic acid benzyl ester
Teru as colorless crystals (melting point: 125-127℃)
Obtained. Synthesis example 26 3-O-formyl-16-deacetoxy-16al
pivaloyloxime of fur-bromofusidic acid
chill ester A 16-deacetylfusidic acid pivaloyloxy
dimethyl ester Amorphous 16-deacetyl fusidic acid (5.8
g; 10 mmol) of amorphous silver salt in dimethyl fluoride.
Chlorme pivalate in lumamide (50 ml) solution.
Add chill (1.48 ml; 10 mmol) and stir the mixture.
Stirred at room temperature for 48 hours. Separate insoluble substances,
It was washed with ether (2x25ml). liquid
and washing liquid, and add it with ether (100ml).
After dilution, the resulting mixture was diluted with water (4 x 50 ml).
, dry the organic layer and evaporate under reduced pressure.
and the crude ester were obtained as a yellow foam.
Dry column chromatography using silica gel
E (developing solvent: cyclohexane: ethyl acetate
= 3:7) to purify the residue to achieve the purpose.
The ester is obtained as an amorphous substance, but
It was not possible to crystallize it. Nuclear magnetic resonance absorption spectrum (CDCl)₃) is δ=
0.90 (d, 3H), 0.93 (s, 3H), 0.98 (s, 3H),
1.22(s, 9H; C(CH ₃)₃), 1.38(s, 3H),
1.62 and 1.68 (2bs, 6H), 2.99 (m, 1H; CH
-13), 3.77 (m, 1H; CH-3), 4.33 (m,
1H;CH-11), 5.00 (m, 1H; CH−16),
5.12 (m, 1H; CH−24), and 5.15 and 5.42
(2d, J=7, 2H; OCH ₂O) shows absorption in ppm
vinegar. Tetramethylsilane was used as an internal standard substance.
there was. B 3-O-formyl-16-deacetylfucidin
pivaloyloxymethyl ester of acid Benzyl ester of 16-deacetylfusidic acid
pivalo of 16-deacetyl fusidic acid instead of
Synthesis example 25B using yloxymethyl ester
According to the procedure, 3-O-formyl-16-de
Pivaloyloxymethyl acetyl fusidic acid
An ester was obtained. C 3-O-formyl-16-deacetoxy-16a
Pivaloyloxy of Lehua-Bromfusidic Acid
methyl ester In Synthesis Example 13B, 3-O-acetyl-16
- of benzyl ester of deacetyl fusidic acid
3-O-formyl-16-deacetylfushi instead
Using pivaloyloxymethyl ester of dinic acid
3-O-formyl-16-der
Setoxy-16-alpha-bromofusidic acid pyridine
Baloyloxymethyl ester is a colorless foam.
obtained as quality. nuclear magnetic resonance absorption spectrum
(CDCl₃) are δ=0.78(s, 3H), 0.87(d, J
=7, 3H), 1.00 (s, 3H); 1.23 (s, 9H, C
(CH ₃)₃), 1.47 (s, 3H), 1.61 and 1.68 (2bs,
6H), 3.45(m, 1H;CH−13), 4.35(m,
1H;CH-11), 5.08 (m, 1H; CH-3),
5.12 (1, 1H, CH-24), 5.62 (bt, 1H, CH
−16), 5.82 and 5.92 (2d, J=6, 2H; OCH
₂O), and 8.15 (bs, 1H,HCO) Absorption to ppm
Indicated. Tetramethylsila as an internal standard
I used a button. Synthesis example 27 3-O-formyl-16-deacetoxy-16al
Far-bromo-24,25-dihydrofusidic acid
acetoxymethyl ester A 16-epideacetyl-24,25-dihydrofushi
Acetoxymethyl ester of dinic acid 16-epideacetyl-24,25-dihydrofushi
of zinate sodium salt (20.6 g; 40 mmol)
Acetic acid solution in dimethylformamide (160ml)
Add lormethyl (4.0 ml; 44 mmol) and mix.
The mixture was stirred at room temperature for 18 hours. Ether (500
After diluting with water (2 x 150 ml,
4 x 75 ml) and dry the organic layer under reduced pressure.
When evaporated, the target compound forms a colorless foam.
obtained. B 3-O-formyl-16-deacetoxy-16a
Rufa-bromo-24,25-dihydrofusidic acid
acetoxymethyl ester of Above ester (40 mmol) and sodium bromide
(20.6 g; 0.2 mol) in dimethylforma
Stir the solution dissolved in Mido (200ml).
and add phenyl chloroformate (25.2
ml; 0.2 mol) was added dropwise. After addition (approximately 45 minutes),
The mixture was incubated at 0 °C for 3-4 h and then at room temperature for an additional 10 h.
Stirred for ~12 hours. The precipitated sodium chloride
Separate and add dimethylformamide (2 x 25 ml)
I washed it. Combine the liquid and washing liquid and add methanol to this.
Crystals precipitate by adding water (1:1, 300ml).
I put it out. Take the crystals and add methanol-water (1:
Wash and dry with 1), and finally add ether-diisopropyl
When recrystallized from lopyl ether, 15.35 g of molten
The target compound with a temperature of 126-127°C was obtained. Synthesis example 28−32 16-deacetoxy-16 alpha-bromofushidi
Esters of acid In the operation of Synthesis Example 16, 3-O-acetyl-
16-epideacetylfusidic acid pivaloylox
16-epideacetyl phthalate instead of dimethyl ester
Penzyl, fenacil, pivaloyl of sydic acid
oxymethyl, acetoxymethyl or benzoyl
By using oxymethyl ester, Table 6
16-deacetoxy-16 alphaab listed in
Esters of romfusidic acid were obtained. 【table】 【table】 Synthesis example 33 3-O-acetyl-11-keto-16-deacetoxy
C-16 alpha-bromofusidic acid
luester 3-O-acetyl-16-deacetoxy-16al
Phenacyl ester of fur-bromofusidic acid
(6.98 g; 10 mmol) in acetone (70 ml)
Add Johns reagent (3.0ml) to the mixture and bring the mixture to room temperature.
Stir at room temperature for 30 minutes. Dilute with ether (100ml)
and after adding water (70ml) the mixture was left for another 10 minutes.
Stir for a while. Separate the organic layer and re-evaporate the aqueous layer.
Extracted with tel (100ml). Organic all in one
Wash the extract with water until it becomes neutral, and after drying,
When concentrated to about 50ml, colorless crystals precipitate out.
Ta. After leaving it in the refrigerator for 1 hour, remove the crystals.
washed with ice-cold ether and dried, 5.37
g of 3-O-acetyl-11-keto-16-deaceto
Oxy-16 alpha-bromofusidic acid
ester (melting point: 120-121°C) was obtained. mother
When the liquid is concentrated, an additional 0.95 g of the target compound (melting point
114-116°C) was obtained. Methylene chloride-diiso
Melting point 120−121 when recrystallized from propyl ether
A sample for elemental analysis at ℃ was obtained. Synthesis example 34 3-O-acetyl-11-keto-16-deacetoxy
C-16-alpha-bromofusidic acid benzene
luester 3-O-acetyl-16-deacetoxy-16al
phenacyl ester of fur-bromofusidic acid
3-O-acetyl-16-deacetoxy-16 instead
Benzyl ester of alpha-bromofusidic acid
and following the procedure of Synthesis Example 33, 3-O-a
Cetyl-11-keto-16-deacetoxy-16alf
The benzyl ester of arbromfusidic acid is colorless.
It was prepared as a foam. nuclear magnetic resonance absorption spectrum
Spectrum (CDCl₃) is δ=1.00(s, 3H), 1.05
(s, 3H), 1.02 (d, 3H), 1.27 (s, 3H), 1.62
and 1.68 (2bs, 6H), 2.06 (s, 3H; CH ₃CO),
3.30 (m, 1H; CH-13), 4.95 (m, 1H, CH−
3), 5.05 (m, 1H, CH−24), 5.22(s, 2H;
CH ₂C₆H_Five), 5.60 (bt, 1H, CH−16), and
7.35(s, 5H; aromatic CH) shows absorption in ppm
Ta. Tetramethylsilane was used as an internal standard substance.
there was. Synthesis example 35 3-O-formyl-11-keto-16-deacetoxy
C-16 alpha-bromo-24,25-dihydrof
Acetoxymethyl ester of sidic acid In the procedure of Synthesis Example 33, 3-O-acetyl-
16-deacetoxy-16 alpha-bromofucidine
Instead of phenacyl ester of acid, 3-O-form
Mil-16-deacetoxy-16 alpha-brome
Acetoxymethyl of 24,25-dihydrofusidic acid
By using an ester, 3-O-formyl
-11-keto-16-deacetoxy-16 alphaab
Acetoxy of rom-24,25-dihydrofusidic acid
The methyl ester is obtained as a colorless foam.
Ta. Nuclear magnetic resonance absorption spectrum (CDCl)₃) is δ=
0.87 (d, J=5.5, 6H), 1.02 (s, 3H), 1.04
(s, 3H), 1.25 (s, 3H), 2.12 (s, 3H; CH
₃CO), 3.35 (m, 1H; CH−13), 5.10(m,
1H;CH-3), 5.68 (bt, 1H; CH−16), 5.81
and 5.90 (2d, J=5.5, 2H; OCH ₂O), and 8.15
(bs, 1H;HCO) showed absorption at ppm. internal mark
Tetramethylsilane was used as a quasi-substance. Synthesis example 36 3-keto-16-deacetoxy-16 alphaab
Acetoxymethyl ester of romfusidic acid A 3-keto-16-epideacetyl fusidic acid
acetoxymethyl ester 3-keto-16-epideacetyl fusidic acid
Potassium salt (3.06 g; 6 mmol) in dimethyl
Chloromethyl acetate in formamide (30ml) solution
(0.6 ml; 6.6 mmol) and stirred the mixture at 18:00.
The mixture was stirred at room temperature for a while. Ether the reaction mixture
(100 ml) and washed with water (4 x 30 ml).
Separate the organic layer, dry and evaporate under reduced pressure.
and 3.2 g of the target compound as a colorless foam.
Obtained. B 3-keto-16-deacetoxy-16 alpha-
Acetoxymethyl ester of bromfusidic acid 16-epideacetyl-24,25-dihydrofushi
Instead of acetoxymethyl ester of dinic acid,
3-keto-16-epideacetyl fusidine as described above
Synthesis using acetoxymethyl ester of phosphoric acid
Melting point 144−145 by following the procedure of Example 27B
3-keto-16-deacetoxy-16 alpha at °C
- Acetoxymethyl ester of bromfusidic acid
was obtained. Synthesis example 37 3-O-acetyl-16-deacetoxy-16be
Methoxymethyl ester of terchlorofusidic acid
le 3-O-acetyl-16-epideacetylfusidy
Methoxymethyl ester of acid (1.4g; 2.5ml
mole), triphenylphosphine (2.6g; 10ml
mol) and N-chloro-succinimide (1.3
g; 10 mmol) in dry ether (50 ml)
did. After standing at 43℃ for 1 hour, the precipitated truffles
Enylphosphine oxide (triphenylphosphine oxide)
Separate the liquid (suphine) and evaporate the liquid under reduced pressure.
Ta. The residue was subjected to dry column chroma using silica gel.
tographie (cyclohexane:ethyl acetate=
7:3) yields 1.14 g of petroleum ether.
3-O-acetyl-16-deacetate crystallized from
Methoxy-16beta-chlorofusidic acid
Methyl ester (melting point: 148-151℃) was obtained.
Ta. When recrystallized from cyclohexane, the melting point
A compound for elemental analysis was obtained at 149-151°C. Synthesis example 38 3-O-acetyl-16-deacetoxy-16be
Benzyl ester of terchlorfusidic acid Phenyl chloroformate (0.3 ml; 2.4 mmol)
Add to N,N-dimethylformamide (15ml)
Carbophenoxy chloride N,N-dimethyl
Chilformimidate was obtained. the resulting solution
3-O-acetyl-16-epideacetyl fusi
Benzyl ester of dinic acid (500 mg; 0.82 mmol)
) was added. After standing at room temperature for 16 hours, the reaction mixture was
The mixture was diluted with ether (100 ml) and added with 2N sodium hydroxide.
Wash with thorium solution (25 ml) and water (3 x 25 ml).
After drying, evaporation under reduced pressure yields 480 mg of ether.
- crystallized from petroleum ether, melting point 163-165°C
3-O-acetyl-16-deacetoxy-16base
Benzyl ester of terchlorfusidic acid was obtained.
It was. Ethyl acetate - recrystallized from petroleum ether
A pure product for elemental analysis with a melting point of 165-166℃ was obtained.
Ta. Synthesis example 39 3-O-acetyl-16-deacetoxy-16al
Benzyl ester of fur-chlorfusidic acid 3-O-acetyl-16-deacetylfusidic acid
Benzyl ester (1.36g) of dimethylform
In a mixture of amide (10ml) and pyridine (0.44ml)
Stir the dissolved solution under ice-cooling for 30 minutes.
Then phenyl chloroformate (1.13 ml) was added. room temperature
After stirring for 16 h at
(100ml) diluted with 2N (normal) sodium hydroxide
Wash with gum solution (25 ml) and water (3 x 50 ml),
After drying, it was evaporated under reduced pressure. Ether the residue (10
ml) and add petroleum ether to form a reaction.
The substance precipitates out as colorless crystals, but this is different.
When washed with petroleum ether and dried, the melting point is 115−.
3-O-acetyl-16-deacetoxy- at 117℃
Benzyl ester of 16 alpha achlorfusidic acid
was gotten. Ethyl acetate - reconsolidated from petroleum ether
Upon crystallization, the melting point rose to 120-122°C. The invention will be explained in more detail in the following examples.
However, although the present invention is limited by this,
It's not. Example 1 16-deacetoxy-16beta-isopropylthi
Ofcisic acid A 3-O-acetyl-16-deacetoxy-16be
Paranito of ter-isopropylthiofusidic acid
lobenzyl ester Potassium hydroxide (pure) in ethanol (1000ml)
10 g of 85%; 150 mmol) and iso
Propyl mercaptan (30ml; 320mmol)
Add 3-O-acetyl-16-dea to a solution of
Setoxy-16 alpha-bromofusidic acid
Ranitrobenzyl ester (28.6 g; 40 mm
) and the resulting suspension was stirred for 4 days.
Ta. Then, add 500ml of water to collect the target substance.
It was completely precipitated. Take the crystals and add water to the
21.5g after washing with nol (1:2) and drying
crude 3-O-acetyl-16-deacetoxy-16
Palani of beta-isopropylthiofusidic acid
Trobenzyl ester (melting point: 157-161℃)
Obtained. B 16-deacetoxy-16beta-isopropyl
Thiofusidic acid Hydroxylation of ethanol (800ml) and 2N (normative)
Add the above powder to the mixture of sodium aqueous solution (200ml).
Suspension of ranitrobenzyl ester
was heated to 60°C for 3 hours. The resulting dark solution
Acidify with 4N (normal) hydrochloric acid (125ml) and dissolve
While the liquid is still warm, treat it with 5g of activated carbon for 15 minutes.
Ta. After filtering, add 500ml of water and cool to room temperature.
After removing the crystals, washing them with water and drying them, 14.1
g of 16-deacetoxy-16beta-isopropyl
ruthiofussidic acid (melting point: 223-229℃) was obtained.
It was. Melting point 229 when recrystallized from 2-butanone
A pure product for elemental analysis at -231°C was obtained. Example 2-8 16beta-thio of 16-deacetoxyfusidic acid
ethers A 3-O-acetyl-16-deacetoxyfushidi
16beta of paranitrobenzyl acid ester
thioethers Table 7 instead of isopropyl mercaptan
Example 1A using the listed mercaptans
According to the operating method described in Table 7, the 3
-O-acetyl-16-deacetoxyfusidic acid
16 beta-thio of paranitrobenzyl ester
Ethers were prepared. 【table】 B 16-beta of 16-deacetoxyfusidic acid
Oethers 3-O-acetyl-16-deacetoxy-16be
Paranito of ter-isopropylthiofusidic acid
Listed in Table 7 instead of lobenzyl ester
3-O-acetyl-16-deacetoxyfusidy
16beta of paranitrobenzyl acid ester
Using thioethers, the procedure of Example 1B was followed.
Accordingly, 16-deacetoxyfusi shown in Table 8
The 16 beta-thioether of dinic acid was prepared.
Ta. 【table】 Nuclear magnetic resonance absorption spectra of the compound of Example 10B
Tol (CDCl)₃) is δ=0.97(s, 6H), 1.32(s,
3H), 1.60 and 1.68 (2bs, 6H), 3.00 (m, 1H;
CH-13), 3.73 (m, 1H; CH-3), 3.78
(bs, 2H; SCH ₂), 4.22 (d, 1H; CH−16),
4.30 (m, 1H; CH-11), 5.10 (m, 1H; CH
-24), 6.1-6.4 (m, 2H; aromatic CH)as well as
7.32 (bs, 1H; aromatic CH) shows absorption in ppm
Ta. Tetramethylsilane as an internal standard substance
Using. Example 11 16-deacetoxy-16beta-isopropylthi
O-24,25-dihydrofusidic acid A 3-O-acetyl-16-deacetoxy-16-
Beta-isopropylthio-24,25-dihydro
Paranitrobenzyl ester of fusidic acid 3-O-acetyl-16-deacetoxy-16a
paranitrobendi of lehua-bromfusidic acid
3-O-acetyl-16- instead of ester
Deacetoxy-16 alpha-brome-24,25-
Paranitrobenzyl ester of dihydrofusidic acid
Using a cell phone and following the procedure of Example 1A, 3
-O-acetyl-16-deacetoxy-16beta
-isopropylthio-24,25-dihydrofushidi
Paranitrobenzyl ester of phosphoric acid has a melting point of 113
Obtained as colorless crystals at -116°C. B 16-deacetoxy-16beta-isopropyl
Thio-24,25-dihydrofusidic acid 3-O-acetyl-16-deacetoxy-16be
Paranito of ter-isopropylthiofusidic acid
Instead of lobenzyl ester, 3-O-acetyl ester
Le-16-deacetoxy-16beta-isopropyl
using ruthio-24,25-dihydrofusidic acid,
Following the procedure of Example 1B, the melting point is 232-234°C.
16-deacetoxy-16beta-isopropyl
Thio-24,25-dihydrofushidic acid was obtained.
Ta. Example 12 16-deacetoxy-16beta-cyclohexyl
Thiofusidic acid Potassium hydroxide (purity) in ethanol (100ml)
85% (400 mg; 6.1 mmol) and cyclohexane
Dissolve xyl mercaptan (2 ml; 16 mmol)
Add 3-O-acetyl-16-deacetoxy to the solution
-16 alpha-bromofusidic acid paranitrobe
and dilyzyl ester (1.43 g; 2 mmol),
The resulting solution was left at room temperature for 5 days. after that,
The reaction mixture was diluted with 150 ml of ether and diluted with water (3
x 75ml), dried and evaporated under reduced pressure.
Ta. The remaining crude 3-O-acetyl-16-dea
Setoxy-16beta-cyclohexylthiofushidi
Oil containing paranitrobenzyl ester of phosphoric acid
Dissolve the substance in ethanol (80ml) and add 20ml of
A 2N (normal) aqueous sodium hydroxide solution was added. 60
After stirring at ℃ for 3 hours, 100ml of water was added and the obtained
Dilute the dark solution with 4N (normal) hydrochloric acid (15 ml).
Acidified and extracted it twice with ether. one
Wash the combined organic extract with water (3 x 50 ml),
After drying, it was evaporated. Remove oily residue with silica gel
Dry column chromatography using
Refined with petroleum ether: acetic acid = 70:30:0.5)
Then, ether with a melting point of 215-220℃ - petroleum ether
16-deacetoxy-16beta-sic crystallized from
Lohexylthiofusidic acid was obtained. Ethyl acetate
Melting point: 216-220 when recrystallized from petroleum ether
A pure product for elemental analysis at ℃ was obtained. Example 13-15 Table 9 instead of cyclohexyl mercaptan
Example 12 using the mercaptans listed in
Following the procedure, the 16-deacetate shown in Table 9
16 beta-thioethers of xifushidic acid were obtained.
It was done. 【table】 Nuclear magnetic resonance absorption spectrum of the compound of Example 15
(CD₃OD) is δ=0.89 (d, J=6, 3H), 1.00
(s, 3H), 1.03 (s, 3H), 1.38 (s, 3H), 1.62
(bs, 6H), 2.13 (s, 3H; SCH ₃)3.03(m,
1H;CH-13), 3.67 (m, 1H; CH-3), 4.03
(d, J=9, 1H; CH−16), 4.26 (m, 1H;
CH-11) and 5.10 (m, 1H; CH−24) ppm
showed absorption. Tetramethyl as an internal standard
Silane was used. Example 16 16-deacetoxy-16beta-ethylthiofushi
Zinc acid of ethyl mercaptan (2.5 ml; 34 mmol)
Sodium hydride in dimethylformamide (10ml) solution
Lium (55% - 650 mg suspension in oil; 15 mmol)
added. If the generation of hydrogen gas has stopped, 3-
O-acetyl-16-deacetoxy-16 alpha-
pivaloyloxymethyl ester of bromfusidic acid
Ter (750 mg; 1.1 mmol) was added. 1 hour,
After standing at room temperature, the reaction mixture was diluted with ethyl acetate (50
ml), diluted with 1N (normal) hydrochloric acid (25 ml) and
Extracted with water (2x25ml). Dry the organic layer;
After filtration, it was evaporated under reduced pressure. The crude thus obtained
Dry column chromatography of adult organisms using silica gel
Graphie (ether: petroleum ether: acetic acid =
40:60:0.5) to produce pure 3-O-
Acetyl-16-deacetoxy-16beta-ethyl
Thiofusidic acid is obtained as a colorless gummy substance
However, this was mixed with ethanol (20 ml) and 2N (normal) hydroxy acid.
75 Dissolve in a mixture of sodium chloride aqueous solution (5 ml).
It was left at ℃ for 2 hours. Then the reaction mixture is
After acidifying with 1N (normal) hydrochloric acid (15 ml),
Extracted with ethyl acetate (50ml). Dilute the organic layer with water (20
ml) twice, dried and evaporated under reduced pressure.
An oily substance is obtained, which is converted into ether-petroleum ether.
When crystallized from 16-deacetoxy-16
ter-ethylthiofcisic acid has a melting point of 195-198℃.
Obtained as colorless crystals. Example 17-20 16beta-thio of 16-deacetoxyfusidic acid
ethers Listed in Table 10 instead of ethyl mercaptan
mercaptans according to the procedure of Example 16.
16-Deacetoxyfucidin shown in Table 10
16 beta-thioethers of the acid were obtained. 【table】 Nuclear magnetic resonance absorption spectrum of the compound of Example 17
(CD₃OD) is δ=0.90 (d, 3H), 0.99 (s,
6H), 1.37 (s, 3H), 1.62 and 1.66 (2bs, 6H),
2.58 (m, 2H; CH ₂S), 3.00 (m, 1H;CH−
13), 3.67 (m, 1H; CH-3), 4.11 (d, 1H;
CH-16), 4.24 (m, 1H; CH−11) and 5.12
(m, 1H;CH-24) It showed absorption at ppm. internal
Tetramethylsilane was used as a standard substance. Nuclear magnetic resonance absorption spectrum of the compound of Example 19
(CDCl₃) is δ=0.95(s, 6H), 1.10(s,
3H), 1.35 (s, 3H), 1.60 and 1.65 (2bs, 6H),
3.10 (m, 1H; CH-13), 3.74 (m, 1H; CH−
3), 4.30 (m, 1H; CH−11), 4.77(d, 1H;
CH-16), 5.11 (m, 1H; CH−24) and 7.0−
7.4 (5H; aromatic CH) showed absorption at ppm. Inside
Tetramethylsilane was used as a standard substance. Nuclear magnetic resonance absorption spectrum of the compound of Example 20
(CDCl₃) is δ=0.97(s, 6H), 1.36(s,
3H), 1.62 and 1.66 (2bs, 6H), 3.06 (m, 1H; C
H-13), 3.66 (m, 1H; CH - 3), 3.74 (bs,
2H; SC H2 ) _, 4.08 (d, 1H; CH - 16), 4.24
(m, 1H; C H -11), 5.14 (m, 1H; C H -24)
and 7.3 (bs, 5H: aromatic C H ) ppm. Tetramethylsilane was used as an internal standard substance. Example 21 16-deacetoxy-16beta(1'-methyltetrazol-5'-ylthio)fusidic acid Benzoyloxymethyl ester of 16-epideacetylfusidic acid (2.2 g; 3.4 mmol) and di(1-methyltetrazol-5'-ylthio) 5-yl) disulfide (1.5 g; 6.5 mmol) was dissolved in dry pyridine (20 ml). The solution was cooled in an ice bath and tributylphosphine (1.44 ml; 6 mmol) was added to it. After standing at room temperature for 18 hours, water (200ml) and ether (400ml) were added to the reaction mixture. Separate the organic layer and add 1N (normal) hydrochloric acid twice.
Washed twice with water, dried and evaporated under reduced pressure. The residue was dissolved in methanol (50 ml) and potassium carbonate (2.4 g; 17.5 mmol) was added. After stirring at room temperature for 18 hours, the solution was diluted with 4N (normal) hydrochloric acid (8
ml) and added water (200ml) and ether (100ml). The organic layer was separated, washed twice with water, dried and evaporated to give 1.84 g of crude product, which was subjected to dry column chromatography on silica gel (ether:acetic acid = 100:
Purification according to 0.5) gave 800 mg of 16-deacetoxy-16beta-(1'-methyltetrazol-5'-ylthio)fusidic acid as a colorless foam. Nuclear magnetic resonance absorption spectrum ( _CDCl3 ) is
δ=1.00 (s, 3H), 1.06 (s, 3H), 1.40 (s,
3H), 1.62 and 1.68 (2bs, 6H), 3.17 (m, 1H; C
H-13), 3.75 (m, 1H; CH - 3), 3.87 (s,
3H; 1'-C H ₃ ), 4.37 (m, 1H, C H -11) and
Absorption was observed at 5.42 (m, 1H; C H -16) ppm.
Tetramethylsilane was used as an internal standard substance. Example 22 16-deacetoxy-16beta-(2',5'-dichloro-phenylthio)fusidic acid 3-O-acetyl-16 in dry pyridine (4 ml)
- methoxymethyl ester of epideacetyl fusidic acid (490 mg; 0.87 mmol) and di(2,
5-dichlorophenyl) disulfide (1.07g:
3.75 mmol) was cooled to 0°C,
To this was added tributylphosphine (0.72 ml; 3.0 mmol). The resulting solution was left at 5°C for 3 days, diluted with ether (100 ml), washed with 4N (normal) hydrochloric acid, 2N (normal) sodium hydroxide solution and water, dried and evaporated under reduced pressure. I let it happen. Dissolve the residue in a mixture of ethanol (20 ml) and 2N (normal) sodium hydroxide solution (8 ml) and add to
It was left at ℃ for 1 hour. The reaction mixture was acidified with 4N (normal) hydrochloric acid (5 ml) and then diluted with ether (100 ml).
and water (200ml) were added. Separate the organic layer;
After washing twice with water, it was dried and evaporated under reduced pressure.
Crystallization of the residue from ether-petroleum ether gave 16-deacetoxy-16beta-(2',5'-dichlorophenylthio)fusidic acid, melting point 161-164°C. Example 23 16-deacetoxy-16beta-(2'-azidoethylthio)fusidic acid A Parabenzyl ester of 3-O-acetyl-16-deacetoxy-16beta-(2'-bromoethylthio)fusidic acid 50 ml dimethylformamide 3 g of phenyl bromide, N,N −
Dimethylformimidate was added. 18 at room temperature
After standing for an hour, the reaction mixture was dissolved in ether (50
ml), washed with 2N (normal) sodium hydroxide solution (20 ml) and water (3 x 50 ml), dried and evaporated under reduced pressure. The residue is ether
Crystallizes when petroleum ether is added. The product is separated, washed with petroleum ether, and dried to yield 800
mg of 3-O-acetyl-16- with a melting point of 148-150℃
Deacetoxy-16beta-(2'-bromoethylthio)fusidic acid paranitrobenzyl ester was obtained. B 16-deacetoxy-16beta-(2'-azidoethylthio)fusidic acid The 2'-bromoethylthioether prepared above was dissolved in 25 ml of diethylformamide, lithium azide (400 mg; 8.2 mmol) was added to the reaction mixture. was left at 20°C for 24 hours. 100 ml of ether was added thereto and the resulting solution was washed with water (4 x 50 ml), dried and evaporated under reduced pressure. Pour the residue into ethanol (50ml) and 2N (normal)
dissolved in a mixture of sodium hydroxide solution, 60
After standing for 3 hours at °C, the solution was acidified using 8 ml of 4N (normal) hydrochloric acid and water (100 ml) and ether (100 ml) were added. The organic layer was separated, washed with water (4 x 50ml), then dried and evaporated under reduced pressure. When ether and petroleum ether were added to the residue, 16-deacetoxy-16beta-(2'-azidoethylthio)fusidic acid was precipitated as colorless crystals, which were collected, washed with petroleum ether, and dried to yield 140 mg. The target compound (melting point: 173-179°C) was obtained. Example 24 Sodium salt of 16-deacetoxy-16beta-(2'-methoxyethylthio)fusidic acid 3-O-acetyl-16- in methanol (50 ml)
Silver carbonate (1 g; 1.3 mmol) is dissolved in a solution of paranitrobenzyl ester of deacetoxy-16beta-(2'-bromoethylthio)fusidic acid (see Example 23A for the synthesis of this compound) (1 g; 1.3 mmol). 3.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. Insoluble matter was separated and washed with methanol (10 ml). The liquid and washing liquid were combined and it was evaporated under reduced pressure. The residue was dissolved in ethanol (100ml) and 2N (normal) sodium hydroxide solution (20ml).
ml). After stirring for 3 hours at 60°C, the dark solution was acidified with 4N hydrochloric acid (15ml) and water (200ml) and ether (200ml) were added. The organic layer was separated, washed twice with water, dried and evaporated under reduced pressure. The residue was subjected to dry column chromatography using silica gel (ether:
When purified using acetic acid = 100:0.5), the target compound is obtained as a colorless foam, which is dissolved in methanol (25 ml), titrated with a 2N (normal) aqueous sodium hydroxide solution, and evaporated. Addition of acetone converted it to the crystalline sodium salt.
When the crystals are collected, washed with acetone, and dried, 16−
The sodium salt of deacetoxy-16beta-(2'-methoxyethylthio)fusidic acid was obtained. The nuclear magnetic resonance absorption spectrum (CD ₃ OD) is δ=
1.00 (s, 6H), 1.36 (s, 3H), 1.62 (bs, 6H),
2.78 (2H; CH ₂ S), 3.51 (2H; CH ₂ O), 3.68
(m, 1H; C H −3), 4.10 (d, 1H; C H −
16), 4.21 (m, 1H; C H -11) and 5.11 (m,
Absorption was observed at 1H; C H -24) ppm. Tetramethylsilane was used as an internal standard substance. Example 25 16-Deacetoxy-16beta-(2'-isopropylthioethylthio)fusidic acid Potassium hydroxide (500ml) in ethanol (50ml)
mg; 9 mmol) and isopropyl mercaptan (1.5 ml; 16 mmol).
-O-acetyl-16-deacetoxy-16beta-
Paranitrobenzyl ester of (2'-bromoethylthio)fusidic acid (see Example 23A for the synthesis of this compound) (1 g; 1.3 mmol) was added and the mixture was stirred at room temperature for 16 hours. Water (100 ml) and ether (75 ml) were added and the organic layer was separated, then washed with 2N (normal) sodium hydroxide solution (2 x 25 ml) and water (2 x 25 ml), dried and evaporated under reduced pressure. I let it happen. The residue was dissolved in a mixture of ethanol (100ml) and 2N (normal) sodium hydroxide solution (20ml) and the solution was stirred at 60°C for 3 hours. 4N (assumed) hydrochloric acid (15ml), water (250ml)
ml) and ether (100ml) were added and the organic layer was separated, washed with water (2 x 50ml), then dried and evaporated under reduced pressure. The target compound was separated from the residue by dry column chromatography (ether: petroleum ether: acetic acid = 70:30:0.5).
mg of 16-deacetoxy-16beta-(2'-isopropylthioethylthio)fusidic acid was obtained as a colorless foam. The nuclear magnetic resonance absorption spectrum (CDCl ₃ ) is δ=0.96 (bs, 6H), 1.22 (d, J=
7, 6H), 1.33 (s, 3H), 1.58 and 1.67 (2bs,
6H), 2.73 (bs, 4H; SC H ₂ C H ₂ S), 2.91 (m,
1H; S- CH ( _CH3 ) ₂ ), 3.01(m, 1H, CH-
13), 3.71 (m, 1H; C H -3), 4.21 (m, 1H;
C H -16), 4.28 (m, 1H; C H -11) and 5.08
Absorption was observed at (m, 1H, C H -24) ppm. Tetramethylsilane was used as an internal standard substance. Examples 26-28 Following the procedure of Example 25, substituting the mercaptans listed in Table 11 for isopropyl mercaptan, the compounds shown in Table 11 were prepared. [Table] The nuclear magnetic resonance absorption spectrum (CDCl ₃ ) of the compound of Example 28 is δ=0.99 (s, 6H), 1.37 (s,
3H), 1.61 and 1.68 (2bs, 6H), 2.78 (bs, 4H;
SC H ₂ CH ₂ S), 3.07 (m, 1H; CH -13), 3.76
(m, 1H; C H −3), 4.26 (d, 1H; C H −
16), 4.35 (m, 1H; C H -11) and 5.12 (m,
Absorption was observed at 1H; C H -24) ppm. Tetramethylsilane was used as an internal standard substance. Example 29 16-deacetoxy-16beta-(2'-phenylthioethylthio)fusidic acid 3-O-acetyl-16 in dry pyridine (7 ml)
-Deacetoxy-16beta-(2'-hydroxyethylthio)fusidic acid paranitrobenzyl ester (1 g; 1.4 mmol) and diphenyl disulfide (1 g; 4.6 mmol) were dissolved in an ice-cooled solution. Tributylphosphine (2
ml; 8.4 mmol) was added and the mixture was left at 5° C. for 16 hours. Ether (100 ml) was added and the resulting solution was washed with 4N (normal) hydrochloric acid (2 x 25 ml).
Furthermore, 2N (normal) sodium hydroxide solution (2×
25 ml) and water (2 x 25 ml), dried and evaporated under reduced pressure. The residue was dissolved in a mixture of ethanol (90 ml) and 2N (normal) aqueous sodium hydroxide solution (20 ml). After stirring at 60℃ for 3 hours, add 4N (normal) hydrochloric acid (15ml) and water (200ml).
and ether (100ml) were added. The organic layer was separated, washed with water (2x20ml) and then evaporated under reduced pressure. The residue was subjected to dry column chromatography using silica gel (ethyl acetate: cyclohexane = 1:1) to obtain 630 mg of 16-deacetoxy-16.
Beta-(2'-phenylthioethylthio)fusidic acid was obtained as a colorless foam. The nuclear magnetic resonance absorption spectrum (CDCl ₃ ) is δ=0.98 (bs,
6H), 1.35 (s, 3H), 1.61 and 1.67 (2bs, 6H),
3.78 (m, 1H; C H −3), 4.25 (m, 1H; C H −
16), 4.34 (m, 1H; C H -11), 5.11 (m, 1H;
C H -24) and 7.1-7.5 (m, 5H; aromatic C H )
It showed absorption in ppm. Tetramethylsilane was used as an internal standard substance. Example 30 16-deacetoxy-16beta-(2'-methylthioethylthio)fusidic acid 3-O-acetyl-16-deacetoxy-16beta-(2'-hydroxy Paranitrobenzyl ester of ethylthio)fusidic acid (1 g; 1.4 mmol)
The solution containing the above was kept ice-cooled, and tributylphosphine (2 ml; 8.4 mmol) was added to it.
The mixture was left at 20°C for 3 days. Next, ether (100 ml) was added and the resulting solution was mixed with 2N (normal) sodium hydroxide solution (25 ml) and water (2 x 25
ml), dried and evaporated under reduced pressure.
The residue was dissolved in a mixture of ethanol (40ml) and 2N sodium hydroxide solution (10ml). After stirring at 60°C for 3 hours, 4N (normal) hydrochloric acid (10ml), water (200ml) and ether (100ml) were added. The organic layer was separated, washed with water (3x20ml) and evaporated under reduced pressure. The residue was subjected to dry column chromatography using silica gel (ether: petroleum ether:
When purified using acetic acid = 70:30:0.5), 410mg
16-deacetoxy-16beta-(2'-methylthioethylthio)fusidic acid was obtained as a colorless oil. The crystalline sodium salt can be obtained by dissolving this oil in methanol (10 ml), titrating it with a 2N (normal) aqueous sodium hydroxide solution using phenolphthalein as an indicator, evaporating it under reduced pressure, and adding acetone. Prepared. Separating the crystals and washing with acetone and ether yields pure 16-deacetoxy-16beta-(2'-
The sodium salt of methylthioethylthio)fusidic acid was obtained. Nuclear magnetic resonance absorption spectra (CD ₃ OD) are δ = 0.98 (s, 6H), 1.36 (s, 3H),
1.62 (bs, 6H), 2.10 (s, 3H; SC H ₃ ), 2.77 (bs,
4H; SC H ₂ C H ₂ S), 3.00 (m, 1H; C H -13),
3.66 (m, 1H; C H -3), 4.11 (d, 1H; C H -
16), 4.23 (m, 1H; C H -11) and 5.13 (m,
Absorption was observed at 1H; C H -24) ppm. Tetramethylsilane was used as an internal standard substance. Example 31 16-deacetoxy-16beta-(2'-fluoroethylthio)fusidic acid A Benzoyloxymethyl ester of 3-O-formyl-16-deacetoxy-16beta-(2'-bromoethylthio)fusidic acid 16 -Deacetoxy-16beta-(2'-hydroxyethylthio)fusidic acid (53.4 mg; 1 mmol) was dissolved in methanol (10 ml) and dissolved in 2N using phenolphthalein as an indicator.
Titrate with (specified) sodium hydroxide solution to obtain its sodium salt. After evaporating under reduced pressure,
The amorphous sodium salt formed was dissolved in dimethylformamide (7.5 ml), to which chloromethyl benzoate (0.16 ml; 1 mmol) was added and the mixture was stirred at room temperature for 48 hours. Water (50
ml) was added and the mixture was extracted with ether (100ml). The organic layer was separated, washed with water (4 x 100 ml), dried and evaporated under reduced pressure to yield the amorphous benzoyloxymethyl ester of 16-deacetoxy-16beta-(2'-hydroxyethylthio)fusidic acid. It was generated as . Dissolve this in dimethylformamide (10ml),
Phenyl bromide N,N-dimethylformimidate (1.5 g; about 6.5 mmol) was added with stirring and the solution was left at 20° C. for 24 hours. Water (50
ml) and ether (50 ml) and remove the organic layer.
2N (regular) sodium hydroxide solution (2 x 25
ml) and water (2 x 25 ml), dried and evaporated under reduced pressure to yield the benzoyloxymethyl ester of 3-O-formyl-16-deacetoxy-16beta-(2'-bromoethylthio)fusidic acid. Obtained as an amorphous substance. B 16-deacetoxy-16beta-(2'-fluoroethylthio)fusidic acid Dissolve the 2'-bromoethylthioether synthesized above in acetonitrile (25 ml), add silver fluoride (500 mg), and dissolve the resulting suspension. The suspension was stirred at room temperature for 2 hours. Add ethyl acetate (50ml),
Insoluble matter was separated. Evaporate the liquid under reduced pressure,
The residue was dissolved in methanol (10 ml) and potassium carbonate (350 mg; 2.5 mmol) was added. at room temperature
After stirring for 30 minutes, water (100 ml), 4N (normal) hydrochloric acid (5 ml) and ether (100 ml) were added, the organic layer was separated, washed twice with water, evaporated and crystallized from the ether-petroleum ether. pure,
16-deacetoxy-16beta-(2'-fluoroethylthio)fusidic acid (melting point: 157-159℃)
was gotten. Example 32 11-keto-16-deacetoxy-16beta-isopropylthiofushidic acid A Paranitrobenzyl ester of 3-O-acetyl-11-keto-16-deacetoxy-16beta-isopropylthiofushidic acid Pyridium chlorochromate ( 1.07 g; 5 mmol) was suspended in methylene chloride (30 ml) with stirring, and 3-O-acetyl-16
-Deacetoxy-16beta-isopropylthiofussidic acid paranitrobenzyl ester (1.5 g; 2.1 mmol) was quickly added. After stirring for a further hour, the suspension was diluted with ether (100ml), the solvent was decanted and the black solid was washed twice with ether. The combined organic extracts were filtered and evaporated to give an oily residue which was crystallized from ether-petroleum ether. The colorless crystals thus obtained were collected, washed with petroleum ether, and dried to yield 880 mg of the desired compound with a melting point of 120-122°C. B 11-Keto-16-deacetoxy-16beta-isopropylthiofussidic acid The paranitrobenzyl ester synthesized above was dissolved in a mixture of ethanol (20 ml) and 2N (normal) sodium hydroxide solution (5 ml) and incubated for 3 hours. Heated to 60°C. Next, add 4N (normal) hydrochloric acid (3 ml), water (100 ml) and ether (100 ml).
was added under stirring. Separate the organic layer and add water (25
ml) twice, dried and evaporated under reduced pressure. When the resulting oily residue is purified by dry column chromatography using silica gel (cyclohexane: ethyl acetate = 7:3),
380 mg of 11-keto-16-deacetoxy-16beta-isopropylthiofushidic acid (melting point: 167
-169°C) was obtained (crystallized from ether-petroleum ether). Example 33 11-keto-16-deacetoxy-16beta-isopropylthio-24,25-dihydrofushidic acid Instead of paranitrobenzyl ester of 3-O-acetyl-16-deacetoxy-16beta-isopropylthiofushidic acid, 3-O-acetyl-
Using varanitrobenzyl ester of 16-deacetoxy-16beta-isopropylthio-24,25-dihydrofussidic acid and following the procedure of Example 32, 11-keto-16-deacetoxy- has a melting point of 189-191°C. 16beta-isopropylthio-24,25
-dihydrofusidic acid was obtained as colorless crystals. Example 34 3-Keto-16-deacetoxy-16beta-isopropylthiofushidic acid Acetoxymethyl ester of 16-deacetoxy-16beta-isopropylthiofushidic acid (2.0 g; 3.3 mmol) in 15 ml of dimethyl sulfoxide.
Dicyclohexylcarbodiimide (3.10 g; 15 mmol) and orthophosphoric acid (160 mg; 2 mmol) were added to the solution, and the mixture was left stirring at room temperature for 24 hours. To decompose excess carbodiimide, a solution of oxalic acid (3 g) in methanol (20 ml) was added and stirring was continued for 30 minutes. next,
Ethyl acetate (150 ml) was added and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (2 x 50 ml) and water (50 ml), dried and evaporated.
1.9 g of oily residue was obtained. This was dissolved in methanol (40 ml) and potassium carbonate (1.2 g) was added. After stirring for 1 hour, methanol was distilled off under reduced pressure, and ether (100 ml) and 4N (normal) hydrochloric acid (50 ml) were added to the residue. The organic layer was washed with water (2 x 50ml), dried and evaporated under reduced pressure. The oily residue was purified by dry column chromatography using silica gel (cyclohexane:ethyl acetate = 7:3), resulting in 3-keto-16-deacetoxy-16beta-isopropylthiofcisic acid (melting point :200-203℃) was obtained. Example 35 16-Deacetoxy-16beta-isopropylsulfinyl fusidic acid Sodium metaperiodate (6 g; 28 mmol) in 500 ml of water was added to 16-deacetoxy-16beta-isopropylsulfinyl fusidic acid (10.0 g; 18.3 mmol) in methanol (200 ml)
and 2N (regular) aqueous sodium hydroxide solution (10ml)
was added to the solution dissolved in the mixture. After standing for 1.5 hours, the resulting solution was diluted with 4N (normal) hydrochloric acid (7.5
ml) to precipitate crystals. Take the crystals, wash them with water (50ml), and dry them to find the melting point.
10 g of the desired compound was obtained at 158-159°C. The crystals thus obtained were converted into another crystalline form by treatment with boiling ethyl acetate (400 ml). After cooling to 0°C, the product was taken, washed with ether (50ml) and dried to yield 9.04g of pure 16-deacetoxy-16beta-isopropylsulfinylfusidic acid (melting point: 179-181°C). It was done. Examples 36-41 Using the 16beta-thioethers of 16-deacetoxyfusidic acid listed in Table 12 in place of 16-deacetoxy-16beta-isopropylthiofusidic acid and following the procedure of Example 35, The sulfoxides shown in Table 12 were prepared. [Table] [Table] Example 42 16-deacetoxy-16beta-isopropylsulfinyl-24,25-dihydrofushidic acid 16-deacetoxy-16beta-isopropyl instead of 16-deacetoxy-16beta-isopropylthiofushidic acid Using thio-24,25-dihydrofushidic acid and following the procedure of Example 35, 16-deacetoxy-16beta-isopropylsulfinyl-24,25-dihydrofushidic acid with a melting point of 184-186°C was prepared as a colorless Prepared as crystals. Example 43 16-deacetoxy-3-keto-16beta-isopropylsulfinylfusidic acid 16-deacetoxy-3-keto-16beta-isopropylthiofushidic acid was substituted for 16-deacetoxy-16beta-isopropylthiofushidic acid. By following the procedure of Example 35, the melting point
16-deacetoxy-3-keto-16beta-isopropylsulfinylfusidic acid was obtained as colorless crystals at 158-161°C. Example 44 11-Keto-16-deacetoxy-16beta-isopropylsulfinylfusidic acid 16-Deacetoxy-16beta-isopropylsulfinylfusidic acid (1.1
g; 2 mmol) was dissolved, and acetic anhydride (0.8 ml; 8.5 mmol) was added thereto. After standing at room temperature for 48 hours, 1 ml of water was added and after 1 hour diluted with 50 ml of ethyl acetate. Thereafter, the crystalline 3-O-acetyl-16-deacetoxy- 16beta-isopropylsulfinylfusidic acid (melting point: 176-178°C) was obtained. John's reagent (0.78 ml) was added to a suspension of this compound (770 mg) in acetone (100 ml). After standing for 10 minutes at room temperature, water (100 ml) was added to the reaction mixture and the resulting solution was diluted to 125 ml under reduced pressure.
3-O-acetyl-11-keto-16
-Deacetoxy-16beta-isopropylsulfinylfusidic acid was precipitated as colorless crystals. The crystals were collected, washed with water, and dried to obtain 570 mg of the compound (melting point: 151-160°C). This compound (400mg) was mixed with ethanol (20mg).
It was dissolved in a mixture of 2N (normal) aqueous sodium hydroxide solution (2 ml) and left at room temperature for 6 days. Next, 4N (normal) hydrochloric acid (2 ml) was added under stirring to precipitate the target compound as colorless crystals, which were collected, washed with water (15 ml), and dried to yield 230 mg of the compound (melting point 174 −178°C) was obtained. Recrystallization from ethyl acetate gives a pure product with a melting point of 181-183°C.
11-keto-16-deacetoxy-16beta-isopropylsulfinylfusidic acid was obtained. Example 45 3,11-diketo-16-deacetoxy-16beta-isopropylsulfinyl fusidic acid A solution of 16-deacetoxy-16beta-isopropylthiofushidic acid (500 mg; 0.94 mmol) in acetone (100 ml) was mixed with Johns reagent (1.6 ml) was added. After standing at room temperature for 10 minutes, 100 ml of water was added to the reaction mixture under stirring. The produced white crystals were collected, washed with water, and dried to obtain 450 mg of a mixture of 3,11-diketo-16-deacetoxy-16beta-isopropylthiofushidic acid and the target compound. The crystals were dissolved in hot ether (20ml) and cooled to 0°C to precipitate pure 3,11-diketo-16-deacetoxy-16beta-isopropylsulfinylfusidic acid. The crystals were collected, washed with cold ether, and then dried to obtain 60 mg of the compound having a melting point of 154-162°C. Example 46 16-deacetoxy-16beta-ethoxyfusidic acid 3-O-acetyl-16 in ethanol (300 ml)
-deacetoxy-16 alpha-bromofusidic acid phenacyl ester (20.94 g; 30 mmol)
Silver carbonate (16.55 g; 60 mmol) was added to the suspension, and the mixture was allowed to stand at room temperature after being protected from light.
Stirred for 18 hours. The insoluble matter was separated and washed with ethanol (2 x 30ml). A 5N (normal) aqueous sodium hydroxide solution (120 ml) was added to the combined solution and washing solution, and the mixture was refluxed for 2 hours. After cooling to room temperature, most of the ethanol was distilled off under reduced pressure and the remaining material was added with ethyl acetate (150 ml).
and water (100ml) were added. The mixture was stirred and acidified with 4N (normal) hydrochloric acid, the organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (50ml). The combined organic extracts were washed with water, dried and evaporated under reduced pressure to give an oily residue which was crystallized from diisopropyl ether. The colorless crystals thus obtained are collected, washed with diisopropyl ether, and dried.
5.42 g of 16-deacetoxy-16beta-ethoxyfusidic acid (melting point: 169-171°C) was obtained. Treatment of the mother liquor yields an additional 2.20 g of the target compound (168
-170℃) was obtained. Recrystallized twice from methanol-diisopropyl ether, melting point 177-178
A pure product for elemental analysis at ℃ was obtained. Examples 47-49 16-deacetoxy-16beta-alkyloxyfusidic acids By using the alcohols shown in Table 13 instead of ethanol in the operation of Example 46, 16-deacetoxy-16beta-alkyloxyfusidic acids shown in Table 13 −16
Beta-alkyloxyfusidic acids were obtained. [Table] Example 50 16-deacetoxy-16beta-(2'-fluoroethoxy)fusidic acid Benzoyloxymethyl ester of 3-O-formyl-16-deacetoxy-16alpha-bromofusidic acid in 2-fluoroethanol (25 ml) Silver carbonate (6.89 g; 25 mmol) was added to a solution of silver carbonate (8.75 g; 12.5 mmol), and the mixture was
Stirred at room temperature for 16 hours protected from light. The insoluble matter was separated and washed twice with ether. The combined liquid and washing liquid were evaporated to dryness under reduced pressure. The remaining oil, containing crude benzoyloxymethyl ester of 3-O-formyl-16-deacetoxy-16beta-(2'-fluoroethoxy)fusidic acid, was dissolved in methanol (85 ml). After adding potassium carbonate (3.46 g; 25 mmol), the mixture was stirred at room temperature for 30 minutes. Most of the solvent was distilled off under reduced pressure and water (100ml) and ether (100ml) were added to the residue. After acidifying the mixture with 4N (normal) hydrochloric acid while stirring, the organic layer was separated, the aqueous layer was re-extracted with ether (50 ml), and the combined organic layers were neutralized with water. I washed it until it was clean. Target acid derivative and by-product
In order to separate the 16-deacetyl fusidic acid from the lactone, the ether solution obtained above was extracted with 0.5N (normal) sodium hydroxide solution (3 x 50 ml) and then washed with water (3 x 25 ml). . Ether (100 ml) was then added to the combined aqueous layer and washings, and the mixture was acidified with 4N (normal) hydrochloric acid while stirring. After separating the organic layer and extracting the aqueous layer with ether (50 ml), the combined organic extracts were washed with water until neutral, then dried and evaporated under reduced pressure. Ta. The resulting amorphous residue was dissolved in diisopropyl ether (30 ml), and when the wall of the vessel was tapped, crystals precipitated. After standing in the refrigerator overnight, the crystals were collected, washed with diisopropyl ether, and dried to yield 2.32 g of 16-deacetoxy-16beta-(2'-fluoroethoxy).
Fusidic acid (melting point: 158-160°C) was obtained. An additional 0.48 g of the target compound (melting point: 155-
159℃) was obtained. Recrystallization twice from methanol-diisopropyl ether gave a pure product for elemental analysis (melting point: 162-163°C). Example 51-52 16-deacetoxy-16beta-alkoxyfusidic acids Using the alcohols shown in Table 14 instead of 2-fluoroethanol and following the procedure of Example 50, the 16-deacetoxy-16beta-alkoxyfusidic acids shown in Table 14 are Deacetoxy-16beta-alkyloxyfusidic acids were obtained. [Table] [Table] Example 53-62 16 beta-ethers of 16-deacetoxyfusidic acid 16-deacetoxy- in place of benzoyloxymethyl ester of 3-O-formyl-16-deacetoxy-16 alpha-bromofusidic acid When the acetoxymethyl ester of 16-alpha-bromofusidic acid is replaced with the alcohol listed in Table 15 in place of 2-fluoroethanol and the procedure of Example 50 is followed, the 16-deacetoxyfucidin shown in Table 15 is produced. 16 beta-ethers of the acid were obtained. [Table] [Table] Example 63 16-deacetoxy-16beta-ethoxy-24,
25-dihydrofusidic acid A 3-O-acetyl-16-epideacetyl-
24,25-Dihydrofusidic acid pivaloyloxymethyl ester 3-O-acetyl-16-epideacetyl-24,
25-dihydrofusidic acid (31.12 g; 60 mmol)
Add triethylamine (11.92 ml; 84 mmol) to a dimethylformamide (250 ml) solution of
After stirring for a minute, more chloromethyl pivalate (17.76 ml; 120 mmol) was added. 20 at room temperature
After stirring for an hour, the mixture was diluted with ethyl acetate (750ml) and washed thoroughly with water (4x250ml, 2x50ml) to remove starting material and most of the dimethylformamide. The organic layer was dried and evaporated under reduced pressure to yield 42 g of an oily residue. Dissolve this residue in ether (50ml) and add petroleum ether (200ml) to
was added and the mixture was stirred for 2 hours. The crystalline precipitate thus obtained was separated and washed with ether-petroleum ether (1:4). The combined solution and washing solution were evaporated to dryness under reduced pressure to yield 36 g of crude 3-O.
The pivaloyloxymethyl ester of -acetyl-16-epideacetyl-24,25-dihydrofushidic acid is obtained as a foam, which could not be crystallized. B 3-O-acetyl-16-deacetoxy-16 alpha-methanesulfonyloxy-24,25-dihydrofushidic acid pivaloyloxymethyl ester methylene chloride (75 ml) and pyridine (75 ml)
ml) of crude 3-O-acetyl-16-epideacetyl-24,25-dihydrofusidic acid pivaloyloxymethyl ester (30 g; containing about 45 mmol of pure compound) was stirred. Then, at −20° C., a solution of methanesulfonyl chloride (13.8 ml; approximately 180 mmol) in methylene chloride (25 ml) was added. After the addition (required approximately 15 minutes), the mixture was stirred at -15°C for 1.5 hours, then it was left in the refrigerator overnight. After adding ice (about 15g) and stirring for 0.5 hours,
The mixture was poured into a mixture of ether (250ml) and water (100ml) and shaken vigorously. The organic layer was separated and the aqueous layer was re-extracted with ether (100ml). The combined organic layers were washed with water, 4N (normal) hydrochloric acid (to remove pyridine), a saturated aqueous sodium chloride solution, a 0.5M aqueous sodium bicarbonate solution, and once again with a saturated aqueous sodium chloride solution. After drying, Evaporation under reduced pressure gives 28.5 g of crude 3-O-acetyl-16-deacetoxy-16 alpha-methanesulfonyloxy-24,25-dihydrofusidic acid pivaloyloxymethyl ester as a yellow foam. , it was not possible to crystallize it. This relatively unstable product was used in the next step without further purification. Infrared absorption spectrum (IR): 1170 and 1365 cm ^-1 C 3-O-acetyl-16-deacetoxy-16beta-ethoxy-24,25-dihydrofusidic acid pivaloyloxymethyl ester 3-O-acetyl-16-deacetoxy-16beta-ethoxy-24,25-dihydrofusidic acid O-acetyl-16
A solution of pivaloyloxymethyl ester (2.6 g) of -deacetoxy-16 alpha-methanesulfonyloxy-24,25-dihydrofushidic acid was stirred at 60-65°C for 2 hours. Water (100ml) was added and the mixture was diluted with ethyl acetate (2x25
ml). The combined organic extracts were washed with water, dried, and evaporated under reduced pressure to yield 1.98 g.
A yellow gummy substance is obtained. The residue was purified by dry column chromatography using silica gel (cyclohexane:ethyl acetate = 85:15) to yield 0.72 g of 3-O-acetyl-16-
Deacetoxy-16beta-ethoxy-24,25-
Pivaloyloxymethyl ester of dihydrofusidic acid was obtained as a colorless foam. D 16-deacetoxy-16beta-ethoxy-
24,25-dihydrofusidic acid A 5N (normal) aqueous sodium hydroxide solution (2 ml) was added to a solution of the above 16 beta-ethoxy ester in ethanol (10 ml), and the mixture was left at room temperature overnight. After adding water (50ml), the mixture was acidified using 4N (normal) hydrochloric acid and extracted with ethyl acid (2x25ml). After washing the combined organic extracts with water, drying and evaporating under reduced pressure, 0.52 g of amorphous material crystallized from the ether.
was gotten. The crystals were collected, washed with ether and dried to yield 0.26 g of 16-deacetoxy-16beta-ethoxy-24,25-dihydrofusidic acid having a melting point of 189-191°C. After recrystallizing twice from ether, a sample for elemental analysis (melting point: 192-
193℃) was obtained. Example 64 16-deacetoxy-16beta-methoxy-24,
25-Dihydrofusidic acid A 3-O-acetyl-16-deacetoxy-16beta-methoxy-24,25-dihydrofusidic acid pivaloyloxymethyl ester Procedure of Example 63A-C using methanol instead of ethanol According to the method, 3-O-acetyl-16-deacetoxy-16beta-methoxy-
Pivaloyloxymethyl ester of 24,25-dihydrofusidic acid was obtained. B 16-deacetoxy-16beta-methoxy-
24,25-Dihydrofusidic acid 3-O-acetyl-16-deacetoxy-16beta-methoxy- in the procedure of Example 63D
By substituting pivaloyloxymethyl ester of 24,25-dihydrofusidic acid for the corresponding 16beta-ethoxy derivative, a melting point of 152
16-deacetoxy-16beta-methoxy-24,25-dihydrofusidic acid at -154°C was obtained. Example 65 16-deacetoxy-16beta-propyloxyfusidic acid A Pivaloyloxymethyl ester of 3-O-acetyl-16-deacetoxy-16 alpha-methanesulfonyloxyfusidic acid Equipped with thermometer, addition funnel and drying tube Crude 3-O-acetyl-16-epideacetyl fusidic acid pivaloyloxymethyl ester (10
g; containing about 15 mmol of pure product) was stirred, and to this was added methanesulfonyl chloride (4.6 ml; about 60 mmol) at -20°C.
A solution of methylene chloride (10 ml) was added dropwise. After addition, the mixture was stirred at −15° C. for 1.5 hours and left in the refrigerator overnight. Add ice (about 5g)
After stirring for 0.5 hours, the mixture was poured into water (50ml) and this was extracted with ether (2 x 50ml).
The combined organic layers were washed with water, 4N (normal) hydrochloric acid (to remove pyridine), saturated brine, 0.5M aqueous sodium bicarbonate solution, and once again with saturated brine, dried, and then dried under reduced pressure. Evaporation at 10.6 g yielded 10.6 g of crude 3-O-acetyl-16-deacetoxy-16 alpha-methanesulfonyl fusidic acid pivaloyloxymethyl ester as a yellow amorphous material. This unstable compound was used in the next step without further purification. Infrared absorption spectrum (IR): 1170 and 1355
By using para-toluenesulfonyl chloride in place of cm ^-1 methanesulfonyl chloride and following the method described above, the corresponding 16 alpha-paratoluenesulfonyloxy derivative was obtained. B 16-Deacetoxy-16 beta-propyloxyfusidic acid Crude 3-O-acetyl-16-deacetoxy-16
Alpha-methanesulfonyloxyfusidic acid pivaloyloxymethyl ester (1.42 g;
About 2 mmol) of propanol-(1) (10 ml) was mixed with triethylamine (0.28 ml; 2 mmol).
and the mixture was stirred at room temperature for 42 hours. After dilution with ethyl acetate (40ml), the mixture was washed with water, dilute hydrochloric acid and water, dried and evaporated under reduced pressure to yield 1.28g of amorphous material. When this residue was purified by dry column chromatography using silica gel (petroleum ether: ethyl acetate = 85:15), 0.36 g of 3-O-acetyl-16
-Deacetoxy-16beta-propyloxyfusidic acid pivaloyloxymethyl ester was obtained as a colorless foam. The above ester can be prepared by diluting its ethanol (5 ml) solution with 5N (normal) sodium hydroxide solution (1 ml).
Hydrolyzed by refluxing for an hour. After a similar operation as described in Example 63D, crystalline 16-deacetoxy-16beta-propyloxyfusidic acid (melting point: 176-177°C) was obtained. Examples 66-70 16-deacetoxy-16beta-alkyloxyfusidic acids By substituting the alcohols listed in Table 16 for propanol-(1) in the procedure of Example 65, the compounds shown in Table 16 are prepared. 16-deacetoxy-
16 beta-alkyloxyfusidic acids were obtained. [Table] [Table] Example 71 16-deacetoxy-16beta-(2'-azidoethoxy)fusidic acid A 3-O-acetyl-16-deacetoxy-16beta-(2'-hydroxyethyloxy)fusidic acid Phenacyl ester Phenacyl ester of 3-O-acetyl-16-deacetoxy-16 alpha-bromofusidic acid (13.96 g;
Silver carbonate (11.03 g; 40 mmol) was added to the solution. After exclusion of light, the mixture was stirred at room temperature for 3 days. The insoluble material was separated and washed with ether (2 x 20ml). The solvent was distilled off from the combined solution and washing solution under reduced pressure, and the liquid residue was dissolved in methanol (320
ml), potassium carbonate (5.53 g; 40 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was evaporated under reduced pressure and the oily residue thus obtained was dissolved in ether (200 ml) and water (200 ml).
ml). The mixture was acidified with dilute hydrochloric acid under stirring, the organic layer was separated and the aqueous layer was extracted again with ether (100ml). The combined organic extracts were washed with water until neutral, dried and evaporated under reduced pressure.
The yellow amorphous residue thus obtained is purified by dry column chromatography using silica gel (petroleum ether: ethyl acetate = 6:4) to obtain 5.54 g of the target compound as a colorless amorphous powder. could not be crystallized. B Phenacyl ester of 3-O-acetyl-16-deacetoxy-16beta-(2'-bromoethoxy)fusidic acid 3-O-acetyl-16-deacetoxy-16beta-(2'-hydroxyethyloxy)fusidic acid Phenyl bromide N,N-dimethylformimidate (4.6 g; approx. 20 mmol) was added to a solution of the phenacyl ester of (4.21 g; 6.2 mmol) in dimethylformamide (25 ml) and the mixture was stirred at room temperature for 16 hours. Ether (100ml)
After diluting with water, the mixture was washed with water (4 x 25 ml) and
The remaining organic layer was dried and evaporated under reduced pressure.
When the oily residue thus obtained was purified by dry column chromatography using silica gel (petroleum ether: ethyl acetate = 85:15),
3.16 g of phenacyl ester of 3-O-acetyl-16-deacetoxy-16beta-(2'-bromoethoxy)fusidic acid was obtained as a colorless amorphous material. C 3-O-acetyl-16-deacetoxy-16beta-(2'-azidoethoxy)fusidic acid phenacyl ester 3-O-acetyl-16-deacetoxy-16beta-(2'-
Phenacyl ester of (bromoethoxy)fusidic acid (1.04 g; 1.4 mmol) and lithium azide (0.34 g; 7 mmol) were dissolved and stirred at room temperature for 16 hours. Add the mixture to ether (80
ml) and washing with water (4 x 20 ml), the organic layer was dried and distilled under reduced pressure to yield 0.97 g of the desired compound as a foam. Infrared absorption spectrum (IR): 2100 cm ^-1 (-N ₃ ). D 16-Deacetoxy-16beta-(2'-azidoethoxy)fusidic acid Phenacyl ester of 3-O-acetyl-16-deacetoxy-16beta-(2'-azidoethoxy)fusidic acid (0.95 g; 1.34 mmol) A 5N (normal) aqueous solution of sodium hydroxide (2.7 ml) was added to a solution of 2.0 in ethanol (20 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the oily residue was dissolved in water (40ml) and extracted with ether (20ml). The aqueous layer was separated, acidified with dilute hydrochloric acid, and the resulting oily precipitate was extracted twice with ether. The combined ether extracts are washed with water, dried and evaporated to give 0.8 g of amorphous material, which is crystallized from diisopropyl ether to give 0.41 g of 16-deacetoxy-16 beta-(2 '-azidoethoxy)fusidic acid (melting point: 179-182°C) was obtained. When recrystallized twice using the same solvent, the melting point is 184-185.
A pure product for elemental analysis at ℃ was obtained. Example 72 16-deacetoxy-16beta-ethoxy-24,
25-dihydrofusidic acid A Benzyl ester of 16-deacetoxy-16beta-ethoxyfusidic acid A solution of the benzyl ester of 16-deacetoxy-16 alpha-bromofusidic acid (3.14 g; 5 mmol) in ethanol (25 ml) was added with silver carbonate (2.76 g; 10 mmol) and the mixture was stirred at room temperature for 16 hours after exclusion of light. The insoluble material was separated and washed with ethanol (2 x 5 ml) and the combined liquid and washings were evaporated under reduced pressure. The amorphous residue thus obtained was purified by dry column chromatography using silica gel (petroleum ether: ethyl acetate = 60:40) to obtain 1.66 g of the target compound as a colorless foam. . B 16-deacetoxy-16beta-ethoxy-
24,25-dihydrofusidic acid 10%-palladium supported carbon catalyst (0.4g)
was added to a solution of 16-deacetoxy-16beta-ethoxyfusidic acid benzyl ester (1.2 g; about 2 mmol) in ethanol (20 ml), and the resulting mixture was shaken under an atmosphere of hydrogen for 40 minutes. The catalyst was separated, washed with ethanol, and the combined liquor and washings were evaporated under reduced pressure.
When the resulting residue is crystallized from ether,
0.92 g of 16-deacetoxy-16beta-ethoxy-24,25-dihydrofusidic acid (melting point: 191
-192℃) was obtained. Example 73 16-deacetoxy-16beta-(2',2',2'-trifluoroethoxy)-24,25-dihydrofushidic acid 16-deacetoxy-16beta-(2',2',2'-trifluoroethoxy)-24,25-dihydrofushidic acid Fluoroethoxy) fusidic acid (278 mg; 0.5 mmol) was dissolved in 96% ethanol (5 ml).
10% - Palladium supported calcium carbonate catalyst (50
mg) was added and the mixture was shaken for 20 min under hydrogen atmosphere. The catalyst was separated and washed with 96% ethanol, and the combined liquor and washings were evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to yield 220 mg of the desired compound (melting point: 204-205°C).
was gotten. Recrystallization from the same solvent gives a melting point of 204
A sample for elemental analysis at -205℃ was obtained. Example 74 16-deacetoxy-16beta-(2'-fluoroethoxy)-24,25-dihydrofushidic acid In the procedure of Example 73, 16-deacetoxy-
16beta-(2′,2′,2′-trifluoroethoxy)
When 16-deacetoxy-16beta-(2'-fluoroethoxy)fusidic acid is used instead of fusidic acid, 16-deacetoxy-16beta-(2'-fluoroethoxy)-24,25-dihydrofusidic acid (melting point 180 -182℃) was obtained. Example 75 11-keto-16-deacetoxy-16beta-ethoxyfusidic acid 3-O-acetyl-11- in ethanol (60 ml)
To a suspension of phenacyl ester of keto-16-deacetoxy-16 alpha-bromofusidic acid (5.57 g; 8 mmol) was added silver carbonate (4.41 g; 16 mmol), and after exclusion of light the mixture was stirred at room temperature for 18
Stir for hours. The insoluble material was separated and washed with ethanol (2 x 20ml). 3-O-acetyl-
The solution containing phenacyl ester of 11-keto-16-deacetoxy-16beta-fusidic acid and the washing solution were combined into one, diluted with ethanol (80 ml), and added with 5N (normal) hydroxide. After adding aqueous sodium solution (32ml), the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, water (100 ml) and ether (100 ml) were added to the oily residue, and the mixture was acidified with 4N (normal) hydrochloric acid while stirring. After separating the organic layer and extracting the aqueous layer again with ether (100 ml), the combined extracts were washed with water until neutral.
After drying, it was evaporated under reduced pressure. The resulting oily residue was subjected to dry column chromatography using silica gel (ether: petroleum ether: acetic acid = 50:50).
=0.5). The yellow amorphous material thus obtained is crystallized from diisopropyl ether to yield 2.12 g of 11-keto-16-deacetoxy-16beta-ethoxyfusidic acid (melting point: 166-
167℃) was obtained. Recrystallization from ether-diisopropyl ether gave a sample for elemental analysis with a melting point of 167-168°C. Example 76 11-keto-16-deacetoxy-16beta-
(2'-Fluoroethoxy)fusidic acid By substituting 2-fluoroethanol for ethanol and following the procedure of Example 75, 11-keto-16
-Deacetoxy-16beta-(2'-fluoroethoxy)fusidic acid was obtained as a colorless amorphous powder. This compound could be made into a crystalline sodium salt (see Example 88). Example 77 3,11-diketo-16-deacetoxy-16beta-ethoxyfusidic acid A stirred solution of 16-deacetoxy-16beta-ethoxyfusidic acid (10.24 g hemihydrate salt; 20 mmol) in acetone (200 ml) Then John's reagent (12.0 ml) was added dropwise at 15°C. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes. Ether (300ml) and water (200ml) were added to the mixture and it was kept stirring for a further 15 minutes. Separate the organic layer and dissolve the aqueous layer in ether (100ml)
After extraction again, the combined organic extracts were washed with water until neutral and dried. When the ether solution is concentrated to about 100 ml, the colorless product begins to crystallize. After standing overnight in the refrigerator, the crystals were collected, washed with ether, and dried to yield 7.02 g of 3,11-diketo-16-deacetoxy-16beta-ethoxyfusidic acid (melting point: 185-
187℃) was obtained. Concentrating the mother liquor further
0.84 g of the target compound was obtained. A sample for elemental analysis (melting point: 187-188°C) was obtained by recrystallization from methylene chloride-diisopropyl ether. Example 78 3-Keto-16-deacetoxy-16beta-ethoxyfusidic acid 3,11-diketo-16-deacetoxy-16beta-ethoxyfusidic acid (6.05 g; 12.14 mmol), 2-ethyl-2-methyldioxane ( -1,
A mixture of 3) (60ml) and para-toluenesulfonic acid (0.24g) was refluxed on an electric heating bath for 40 minutes. After cooling to room temperature, ether (200ml)
and pyridine (0.5ml) were added and the mixture was washed with water (4 x 50ml). The organic layer was dried and evaporated under reduced pressure to yield 7.06 g of crude 3,11-diketo acid.
- ethylene ketal remains as a rubbery substance,
It was not possible to crystallize it. Dissolve the above residue in ethanol (140ml) and add 5
At <RTIgt;C,</RTI> solid sodium borohydride (2g) was added in portions. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 45 minutes. After neutralizing the mixture with acetic acid and adding water (420ml), the oily precipitate formed was extracted with ether (2x150ml).
The combined organic extracts were washed with water (4 x 25ml), dried and evaporated under reduced pressure. The resulting oily residue was crystallized from ether-diisopropyl ether to yield 3.12 g of 3-ethylene ketal of 3-keto-16-deacetoxy-16beta-ethoxyfusidic acid (melting point: 166-169°C). Ta.
Concentration of the mother liquor gave an additional 2.04 g of the desired compound (melting point: 166-169°C). Melting point: 171 when recrystallized from methylene chloride-diisopropyl ether
A sample for elemental analysis was obtained at -172℃. 3-ethylene ketal of 3-keto-16-deacetoxy-16beta-ethoxyfusidic acid (3.98
g; 7.3 mmol) in methanol (40 ml).
Acidified with 2N (normal) hydrochloric acid (2 ml) and refluxed on a steam bath for 20 minutes. After cooling, water (160 ml) was added, and the resulting oily precipitate was dissolved in ether (2 x 100 ml).
ml). The combined organic extracts were washed with water until neutral, dried and evaporated under reduced pressure. The resulting amorphous residue was crystallized from ether to yield 2.94 g of 3-keto-16-deacetoxy-16beta-ethoxyfusidic acid (melting point: 175
-177℃) was obtained. Recrystallization from the same solvent increased the melting point to 177-179°C. Example 79 Beta-diethylaminoethyl ester of 16-deacetoxy-16beta-isopropylsulfinylfusidic acid Sodium salt of 16-deacetoxy-16beta-isopropylsulfinylfusidic acid (320 mg; 0.5 mmol) in 2 ml of dimethylformamide. To this was added beta-(diethylamino)ethyl chloride (0.08 ml; 0.55 mmol). When this mixture is left at room temperature for 5 hours, crystalline material begins to precipitate. Next, add water (5 ml), take the product, wash it with water (5 ml), and dry it.
310 mg of beta-diethylaminoethyl ester of 16-deacetoxy-16beta-isopropylsulfinyl fusidic acid (melting point: 156-158 DEG C.) was obtained. Example 80 Acetoxymethyl ester of 16-deacetoxy-16beta-isopropylsulfinylfusidic acid Dissolve the sodium salt of 16-deacetoxy-16beta-isopropylsulfinylfusidic acid (320 mg; 0.5 mmol) in 2 ml of dimethylformamide; To this, chloromethyl acetate (0.05 ml; 0.55
mmol) was added. After leaving it at room temperature for 24 hours,
When ethanol (5 ml) and water (5 ml) were added, the target substance precipitated as colorless crystals, which were collected, washed with water (5 ml), and dried to yield 290 mg of the substance (melting point: 151-153°C). was gotten. When recrystallized from ethyl acetate-petroleum ether, the melting point is 152-154.
The temperature rose to ℃. Example 81 Acetoxymethyl ester of 16-deacetoxy-16beta-isopropylthiofushidic acid Using 16-deacetoxy-16beta-isopropylthiofushidic acid in place of 16-deacetoxy-16beta-isopropylsulfinyl fusidic acid, Example 81 80, acetoxymethyl ester of 16-deacetoxy-16beta-isopropylthiofusidic acid (melting point: 77-83°C) was prepared. Examples 82-89 16beta-ethers, 16beta-thioethers and 16beta-alkylsulfinyl compounds of 16-deacetoxyfusidic acid and its 3- and 11-keto derivatives Examples 1, 35, 46, 48 , 50, 75, 76 and 78 are prepared in an aqueous manner. Specifically, a solution of the corresponding acid (10 mmol) in methanol (25 ml) was titrated with a 2N (normal) methanol solution of sodium hydroxide using phenolphthalein as an indicator. After evaporation to dryness under reduced pressure, the oily or amorphous residue obtained was dissolved in acetone (approximately 100 ml). After concentrating the solution to about half its volume, when the vessel wall is scratched, the desired sodium salt begins to precipitate. In this case, after leaving the material at room temperature for 2 hours, the crystals were collected, washed with acetone, and dried to obtain the desired pure sodium salt. The sodium salts obtained by this method are shown in Table 17. The quantitative analysis results, infrared absorption spectrum, and nuclear magnetic resonance absorption spectrum data of these compounds support their structure. [Table] [Table] Example 90 Potassium salt of 16-deacetoxy-16beta-(2'-hydroxyethoxy)fusidic acid Add 16-deacetoxy-16beta-(2'-hydroxyethoxy)fusidic acid ( 2.64 g (5 mmol, calculated as hemihydrate) was dissolved and titrated with a 2N (normal) methanol solution of potassium hydroxide using phenolphthalein as an indicator. After evaporation to dryness under reduced pressure, the resulting amorphous residue was dissolved in methanol (2.5 ml) and
Acetone (60ml) was added and the mixture was heated under reduced pressure to approx.
It was concentrated to 15ml. When the vessel wall was scratched, colorless crystals precipitated, which were collected, washed with acetone, and dried to yield 2.32 g of the target compound. Example 91 16-deacetoxy-3-keto-16beta-isopropylthio-24,25-dihydrofushidic acid 16-deacetoxy-16beta-isopropyl instead of acetoxymethyl ester of 16-deacetoxy-16beta-isopropylthiofushidic acid Using acetoxymethyl ester of thio-24,25-dihydrofusidic acid and following the procedure of Example 34, 16-deacetoxy-3-keto-16beta-isopropylthio-24,25-dihydrofusidic acid was obtained. . Example 92 11-keto-16-deacetoxy-16beta-(2',
2',2'-trifluoroethoxy)fusidic acid If 2,2,2-trifluoroethanol is used in place of ethanol and the procedure of Example 75 is followed,
11-keto-16-deacetoxy-16beta-(2',
2′,2′-trifluoroethoxy)fusidic acid was obtained. Example 93 Cream (emulsion) 16-deacetoxy-16beta-isopropylthio-24,25-dihydrofusidic acid...20g Petrolatum...150g Liquid paraffin...150g Spamaceti...50g Sorbitan monopalmitate ester...50g Poly Monopalmitate ester of oxyethylene sorbitan...50g Water...530g 1000g Petrolatum, paraffin, spamaceti,
Heat sorbitan monopalmitate and polyoxyethylene sorbitan monopalmitate to 70°C, and slowly add water at 72°C while stirring. Continue stirring until the cream has cooled. 16 for cream base
-Deacetoxy-16beta-isopropylthio-
Add 24,25-dihydrofusidic acid and roll
Disperse uniformly using a mill. The resulting cream is filled into a collapsible (foldable) aluminum tube coated with lacquer. Example 94 Ointment Sodium salt of 16-deacetoxy-16beta-isopropylthiofussidic acid...20g Liquid paraffin...138g Setanol...4g Anhydrous lanolin...46g Petrolatum...792g 1000g Paraffin, cetanol, lanolin and petrolatum at 70g Melt at °C. After cooling to below 40°C, the sodium salt of 16-deacetoxy-16beta-isopropylthiofusidic acid is added and triturated. The obtained ointment was filled into a collapsible (foldable) aluminum tube coated with lacquer. Example 95 Ointment Sodium salt of 16-deacetoxy-16beta-isopropylsulfinyl fusidic acid...10g Liquid paraffin...138g Setanol...4g Anhydrous lanolin...46g Petrolatum...802g 1000g Paraffin, cetanol, lanolin and petrolatum Melt at 70℃. After cooling to below 40℃, add sodium salt of 16-deacetoxy-16beta-isopropylsulfinylfusidic acid and grind the resulting ointment into a collapsible (folding) tube coated with lacquer. Fill. Example 96 Capsules Sodium salt of 11-keto-16-deacetoxy-16beta-ethoxyfusidic acid...250g Microcrystalline cellulose...145g Magnesium stearate...5g 400g Pass the ingredients through a 60 mesh sieve and mix for 10 minutes. do. 400 mg of the mixture in hard gelatin capsules No. 00 (Parke, Davis & Kompany)
Fill the capsule using a capsule fill weight of Example 97 Preparation of tablets 16-deacetoxy-16beta-(2',2',2'-trifluoroethoxy)fusidic acid...250g Avicel PH101...120g STA-Rx1500...120g Magnesium stearate... ...10g 16-deacetoxy-16beta-(2',2',2'-trifluoroethoxy)fusidic acid, Avicel and STA-Rx are mixed and mixed with magnesium stearate after passing through a 0.7 mm sieve. The mixture is compression molded into tablets of 500 mg each. Example 98 Preparation of suspension 3-Keto-16-deacetoxy-16beta-isopropylthiofushidic acid...5.00g Citric acid...0.45g Sodium monohydrogen phosphate...0.70g Sucrose...25.00g Tween 80 …0.05g Potassium sorbate …0.20g Carboxymethyl cellulose-Na …0.50g Pure water …Amount to make a total of 100ml of suspension Finely grind the crystals and add sodium monohydrogen phosphate to the citric acid solution. , sucrose, potassium sorbate and Tween 80 dissolved in 50 ml of water, if necessary warmed slightly, are suspended. Dissolve carboxymethyl cellulose-Na in 20 ml of boiling water and after cooling add it to the other ingredients. Disperse the suspension uniformly in a mixer, and finally add pure water to make up the entire volume.
The volume should be 100ml. Example 99 Ointment A component: Sodium salt of 16-deacetoxy-16beta-isopropylthiofushidic acid...20g B component: One of the steroids: hydrocortisone, triamcinolone or fluocinolone
...10g Liquid paraffin ...138g Setanol ...4g Anhydrous lanolin ...46g Petrolatum ...802g 1000g Melt paraffin, cetanol, lanolin and petrolatum at 70°C. After cooling to below 40℃, A
Ingredients and B component are added and triturated, and the resulting ointment is filled into a lacquer-coated collapsible tube. Example 100 Component A: 16-deacetoxy-16beta-(2'-fluoroethoxy)fusidic acid...125g Component B: One of the antibiotics: amoxicillin, cephalexin, rifamycin, rifampicillin, clindamycin, lincomycin , Erythromycin or Pivmecillinam...125g Microcrystalline cellulose...145g Magnesium stearate...5g 400g Pass the ingredients through a 60 mesh sieve and mix for 10 minutes.
The mixture was poured into hard gelatin capsules No. 00 (Park).
Davis & Kompany), using a capsule fill weight of 400 mg. Example 101 Ointment A component: Tetracycline...15g B component: 16-deacetoxy-16beta-ethoxyfusidic acid...15g Liquid paraffin...138g Setanol...4g Anhydrous lanolin...46g Petrolatum...782g Paraffin, cetanol, Melt the lanolin and petrolatum at 70°C. After cooling to below 40°C, ingredients A and B are added and ground, and the resulting ointment is filled into lacquer-coated collapsible aluminum tubes.

Claims (1)

[Claims] Linear formula [In the formula, the bond at C _24-25 may be a single bond or a double bond, Q ₁ and Q ₂ represent a group, [Formula] or an oxygen atom; A represents an oxygen atom, a sulfur atom or a sulfinyl group; R ₁ is carbon number 1-8
3 to 3 in the straight chain or branched alkyl group or alicyclic group of
Represents a cycloalkyl group having 7 carbon atoms. (Herein, all R ₁ groups may optionally have a substituent.)] and pharmaceutically acceptable salts thereof and easily hydrolyzable esters thereof. 2 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ both represent [formula], and A represents an oxygen atom. and R ₁ is optionally
Compounds representing a straight chain or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, a hydroxyl group or an azide group, and pharmaceutically acceptable salts thereof, and easily hydrolyzable salts thereof. Uru ester. 3 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ both represent [formula], and A represents a sulfur atom. a compound in which R ₁ represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms, optionally substituted with a halogen atom, a hydroxyl group or an azide group, and a pharmaceutically acceptable compound thereof; and easily hydrolyzable esters thereof. 4 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ both represent [Formula], and A represents a sulfinyl group. and R ₁ is optionally
Compounds representing a straight chain or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, a hydroxyl group or an azide group, and pharmaceutically acceptable salts thereof, and easily hydrolyzable salts thereof. Ester that can be used. 5 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, one of Q ₁ and Q ₂ is an oxygen atom, and the other is [Formula] , A represents an oxygen atom, and R ₁ is a carbon number 1 optionally substituted with a halogen atom, a hydroxyl group, or an azide group.
-4 linear or branched alkyl groups, and their pharmaceutically acceptable salts and easily hydrolysable esters thereof. 6 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, one of Q ₁ and Q ₂ is an oxygen atom, and the other is [Formula] where A represents a sulfur atom and R ₁ represents a straight or branched alkyl group having 1 to 4 carbon atoms, optionally substituted with a halogen atom, a hydroxyl group or an azide group; Compounds and their pharmaceutically acceptable salts and readily hydrolyzable esters thereof. 7 In the compound represented by the formula described in claim 1, the C _24-25 bond is a single bond or a double bond, one of Q ₁ and Q ₂ is an oxygen atom, and the other is [Formula] where A represents a sulfinyl group and R ₁ represents a straight or branched alkyl group having 1 to 4 carbon atoms, optionally substituted with a halogen atom, a hydroxyl group or an azide group; Compounds and their pharmaceutically acceptable salts and readily hydrolyzable esters thereof. 8. 16-deacetoxy-16beta-isopropylthiofushidic acid and its _C24-25 -dihydro analogues, and their pharmaceutically acceptable salts and their easily Hydrolyzable ester. 9 16-deacetoxy-16beta-isopropylsulfinylfusidic acid and its C _24-25 -dihydro analogs, their pharmaceutically acceptable salts and their Easily hydrolysable ester. 10 11-keto-16-deacetoxy-16beta-isopropylthiofushidic acid and its C _24-25 -dihydro analogues, especially pharmaceutically acceptable salts thereof, in the compound according to claim 1 and easily hydrolyzable esters thereof. 11. 3-keto-16-deacetoxy-16beta-isopropylthiofushidic acid and its _C24-25 -dihydro analogs, and pharmaceutically acceptable salts and Easily hydrolysable esters thereof. 12. 16-deacetoxy-16beta-ethoxyfusidic acid and its 11-keto analogs, their pharmaceutically acceptable salts, and their easily hydrolyzable salts in the compound according to claim 1 ester. 13. 16-deacetoxy-16beta-(2'-fluoroethoxy)-fusidic acid and its 11-keto analogues, their pharmaceutically acceptable salts, and their pharmaceutically acceptable salts in the compound described in claim 1 Easily hydrolyzable esters of. 14 16-deacetoxy-16beta-(2',2',2'-
Trifluoroethoxy)-fusidic acid and its 11
- Keto analogs, as well as their pharmaceutically acceptable salts and easily hydrolyzable esters thereof. 15 16-deacetoxy-16beta-(1',3'-difluoroisopropyloxy)-fusidic acid and its pharmaceutically acceptable salts and easily hydrolyzable salts thereof in the compound described in claim 1. Uru ester. 16th equation b [wherein, Q ₁ ' is Q ₁ or [Formula] (wherein R ₂ is an alkanoyl group, aralkanoyl group or an aroyl group); Q ₂ is as defined above; Y is chlorine atom, bromine atom or iodine atom; R ₃ is a linear or branched alkyl group or aralkyl group having 1 to 6 carbon atoms, an alkanoylmethyl group, an aroylmethyl group, an alkanoyl-oxyalkyl group, an aroyl-oxyalkyl group , represents an alkyloxymethyl group or a cyanomethyl group. ] is reacted with a compound represented by the following formula R ₁ -A-H (wherein R ₁ is as defined above and A represents an oxygen atom or a sulfur atom). Seshime, the following formula (wherein Q ₁ ′, Q ₂ , R ₁ and R ₃ are as defined above, and A represents an oxygen atom or a sulfur atom.) Hydrolyzed if desired, and in the case of compounds of formula where A is a sulfur atom, optionally oxidized to give compounds of formula where A is a sulfinyl group, the free acid being converted into a pharmaceutically acceptable salt or The following formula, characterized in that it can be an easily hydrolyzable ester (In the formula, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ mean [Formula] or an oxygen atom, and A represents an oxygen atom, a sulfur atom, or a sulfinyl group; R ₁ represents a linear or branched alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms in the alicyclic ring,
All R ₁ groups may optionally carry substituents. ), a pharmaceutically acceptable salt thereof, and a process for producing an easily hydrolyzable ester thereof. 17 Oxidizing the compound of the formula (in the formula, Q ₁ and/or Q ₂ is [formula]) to produce the compound of the formula (in the formula, Q ₁ and/or Q ₂ are oxygen atoms) The manufacturing method according to claim 16. 18 A compound of the formula having a double bond between C-24 and C-25 is hydrogenated to form a compound of the formula having a single bond between C-24 and C-25, according to claim 16 manufacturing method. 19th equation (In the formula, the hydroxyl group at C-16 is located in the alpha direction, and Q ₁ ' is a group, which is different from [formula].) The compound represented by the formula is reacted with a reactive derivative of alkyl sulfonic acid to form the following general formula [wherein Q ₂ , Q ₃ and the dotted line between C-24 and C-25 have the meanings defined above, Q ₁ ' is an oxygen atom or group, [Formula] (where R ₂ means an alkanoyl, aralkanoyl or aroyl group.)
and R ₅ represents an alkylsulfonyl group. ] A compound represented by the formula R ₁ -A-H (wherein,
R ₁ represents a linear or branched alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms in the alicyclic ring, and all R ₁ groups are optionally substituted with a substituent. A represents an oxygen atom. ) is reacted with the compound of the following formula (wherein Q ₁ ', Q ₂ , R ₁ , R ₃ and A are as defined above) and then converting the compound into the desired compound represented by the formula The following formula is characterized in that it is converted into a compound (In the formula, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ mean [formula] or an oxygen atom, R ₁ and A are as defined above, and all The R ₁ group may optionally have a substituent.) A method for producing a compound represented by the above, a pharmaceutically acceptable salt thereof, and an easily hydrolyzable ester thereof. 20th equation (In the formula, Q ₁ ' and Q ₂ represent a group, [Formula] or an oxygen atom, R ₃ is an unsubstituted or substituted benzyl group,
Represents a cyanomethyl group, an alkanoylmethyl group or an aroylmethyl group. ) The following formula is characterized by reducing the compound represented by [In the formula, the C _24-25 bond may be a single bond or a double bond, Q ₁ and Q ₂ represent a group, [Formula] or an oxygen atom; A represents an oxygen atom, a sulfur atom or a sulfinyl group; R ₁ is a linear or branched alkyl group having 1 to 8 carbon atoms or 3 to 7 alicyclic groups;
represents a cycloalkyl group having 5 carbon atoms. (Herein, all R ₁ groups may optionally have a substituent.) and their pharmaceutically acceptable salts and easily hydrolyzable esters thereof manufacturing method. 21st equation (wherein Q ₁ ', Q ₂ , R ₃ and the dotted line between C-24 and C-25 have the meanings as defined above, A is an oxygen atom, a sulfur atom or a sulfinyl group; , R ₁ represents an alkyl group substituted with a hydroxyl group) is converted into the corresponding compound (R ₁ represents a halogen-substituted alkyl group) by treating with a halogenating agent, A halogen-substituted alkyl derivative of the formula is reacted with an aliphatic alcohol; an aliphatic mercaptan; and a silver fluoride or alkali metal azide to form a compound of the formula (wherein Q ₁ ', Q ₂ , R ₃ , A and C- The dotted line between 24 and C-25 has the meaning defined above, R ₁ is a fluorine atom, an alkyloxy group,
It means an alkyl group substituted by an alkylthio group or an azide group. ) and then converting the compound into the desired compound represented by the formula: (In the formula, the C _24-25 bond is a single bond or a double bond, Q ₁ and Q ₂ mean [Formula] or an oxygen atom, R ₁ and A are as defined above, and all The R ₁ group may optionally have a substituent.) A method for producing a compound represented by the above, a pharmaceutically acceptable salt thereof, and an easily hydrolyzable ester thereof. 22nd equation [In the formula, the bond at C _24-25 may be a single bond or a double bond, Q ₁ and Q ₂ represent a group, [Formula] or an oxygen atom; A represents an oxygen atom, a sulfur atom or a sulfinyl group; R ₁ is carbon number 1-8
3 to 3 in the straight chain or branched alkyl group or alicyclic group of
Represents a cycloalkyl group having 7 carbon atoms. (wherein, all R ₁ groups may optionally have a substituent)] or a pharmaceutically acceptable salt thereof or an easily hydrolyzable ester thereof. A pharmaceutical composition for treating bacterial infections, which contains the composition as an ingredient. 23. Containing at least one compound according to claim 22 as a therapeutically active ingredient, the active compound being mixed with a non-toxic pharmaceutically acceptable carrier, and the dosage unit containing the active compound in the free form. Pharmaceutical composition according to claim 22, in the form of a dosage unit for the systemic treatment of patients with bacterial infections, characterized in that it contains 100 to 1000 mg, preferably 100 to 500 mg, calculated as acid. 24. Contains at least one compound as claimed in claim 22 as a therapeutically active ingredient, the active compound is mixed with a non-toxic pharmaceutically acceptable carrier, and the dosage unit is 1 cm of the infected area. ² per
23. A pharmaceutical composition according to claim 22 in dosage unit form for the topical treatment of bacterial infections in a patient, characterized in that it is 0.1 to 10 mg. 25. The pharmaceutical composition according to claim 23, wherein the form containing the dosage unit is a tablet. 26. The pharmaceutical composition according to claim 23, wherein the form containing the dosage unit is a capsule. 27. The pharmaceutical composition according to claim 24, wherein the form containing the dosage unit is a cream (emulsion). 28. The pharmaceutical composition according to claim 24, wherein the form containing the dosage unit is an ointment. 29. The pharmaceutical composition according to claim 23, wherein the form containing the dosage unit is an injection, and the dosage unit is 50 to 500 mg of the therapeutically active ingredient, calculated as free acid. 24. The pharmaceutical composition of claim 23, wherein the form containing 30 dosage units is an oral suspension and contains 2 to 25% of the therapeutically active compound. 31 The active ingredient is 16-deacetoxy-16beta-
Isopropylthiofusidic acid and its _C24-25 -dihydro analogues, 16-deacetoxy-16beta-inpropylsulfinyl fusidic acid and its
_C24-25 -dihydro analogs, 11-keto-16-deacetoxy-16beta-isopropylthiofushidic acid and its _C24-25 -dihydro analogs, 3-keto-16
-Deacetoxy-16beta-isopropylthiofushidic acid and its _C24-25 -dihydro analogs, 16-
Deacetoxy-16beta-ethoxyfusidic acid and its 11-keto analogs, 16-deacetoxy-16beta-(2'-fluoroethoxy)-fusidic acid and its 11-keto analogs, 16-deacetoxy-16beta-(2 ',2',2'-trifluoroethoxy)-fusidic acid and its 11-keto analogs, 16-deacetoxy-16beta-(1',3'-difluoroisopropyloxy)-fusidic acid, and their pharmaceutical 23. A pharmaceutical composition according to claim 22, which is one of the acceptable salts and easily hydrolyzable esters thereof. 32. The pharmaceutical composition according to claim 24, which contains a mixture of the compound according to claim 22 and a corticosteroid (adrenocortical hormone or its analogue) as a therapeutically active ingredient. 33. The pharmaceutical composition according to claim 24, which contains a mixture of the compound according to claim 22 and tetracycline as a therapeutically active ingredient. 34 Contains a mixture of the compound described in claim 23 as a therapeutically active ingredient and an antibiotic selected from the group consisting of penicillins, cephalosporins, rifamycin, erythromycin, lincomycin, and clindamycin. A pharmaceutical composition according to claim 23.