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Description  |
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BACKGROUND OF THE INVENTION
Oleandomycin, its production in fermentation broths and its use as an
antibacterial agent were first described in U.S. Pat. No. 2,757,123, the
disclosure of which is incorporated herein by reference. The naturally
occurring compound is known to have the structure
##STR1##
The conventionally accepted numbering scheme and stereochemical
representation for oleandomycin 1. and similar compounds is shown at a
variety of positions.
Several synthetic modifications of this compound are known, particularly
those in which from one to three of the free hydroxyl groups found at the
2', 4" and 11-positions are esterified as acetyl esters. In addition,
there are described in U.S. Pat. No. 3,022,219 similar modifications in
which the acetyl in the above-mentioned esters is replaced with another,
preferably unbranched lower alkanoyl of two to six carbon atoms or
trifluoroacetyl moiety.
Also known are semi-synthetic oleandomycins in which one or several of the
hydrogens of the hydroxyl groups mentioned above are replaced with a
tri(lower alkyl)silyl and preferably a trimethylsilyl group.
SUMMARY OF THE INVENTION
The novel compounds of the present invention consist of the products of
sequential, synthetic transformations performed upon natural oleandomycin
and its derivatives. In addition, the chemical methods used in these
transformations have been discovered to operate on only the functional
group being changed.
The compounds of the present invention are oleandomycin derivatives and
have the structure
##STR2##
and the pharmaceutically acceptable acid addition salts thereof wherein:
R is selected from the group consisting of hydrogen and n-alkanoyl having
from two to three carbon atoms;
R.sub.1 is selected from the group consisting of hydrogen and n-alkanoyl
having from two to three carbon atoms;
R.sub.2 is selected from the group consisting of hydrogen and n-alkanoyl
having from two to three carbon atoms;
Z is selected from the group consisting of --N.dbd.CHN(R.sub.3).sub.2,
--N(R.sub.3).sub.2, --NHR.sub.5, --NH.sub.2, --OR.sub.4, --N.sub.3, Cl and
imidazol-l-yl;
R.sub.3 is alkyl having from one to three carbon atoms;
R.sub.4 is selected from the group consisting of hydrogen, alkanoyl having
from two to six carbon atoms and SO.sub.2 R.sub.7 ;
R.sub.5 is selected from the group consisting of
##STR3##
and --SO.sub.2 R.sub.7 ;
R.sub.6 is selected from the group consisting of hydrogen, alkyl having
from one to six carbon atoms, amino (--NH.sub.2), alkylamino having from
one to six carbon atoms, pyridyl, anilino, .alpha.-thienyl, and
##STR4##
said substituent X being selected from the group consisting of hydrogen,
halogen, alkyl having from one to four carbon atoms, alkoxylcarbonyl
having from one to four carbon atoms in the alkoxy group, CF.sub.3, alkoxy
having from one to four carbon atoms, CONH.sub.2 and --NO.sub.2 ; and
R.sub.7 is selected from the group consisting of alkyl having from one to
six carbon atoms and
##STR5##
said substituent Y being selected from the group consisting of hydrogen,
alkyl having from one to four carbon atoms, chloro and --CF.sub.3.
The novel compounds of the present invention are able to combat infections
caused by susceptible organisms and are valuable as antibiotic and
antibacterial agents. Of interest in this connection are several preferred
embodiments of the present invention. These embodiments include
8,8a-deoxy-8-hydroxymethyl oleandomycin and its esterified derivatives;
that is, those derivatives in which from one to three of the hydroxyl
groups at positions 2', 4" and 11 are esterified with alkanoyl groups
having from two to three carbon atoms, 8,8a-deoxy-8-tosyloxymethyl
oleandomycin and its esterified derivatives wherein the esterifying groups
and their positions are defined as above, 8,8a-deoxy-8-aminomethyl
oleandomycin and its esterified derivatives wherein the esterifying groups
and their positions are defined as above, 8,8a-deoxy-8-N-acyl and
N-sulfonyl aminomethyl oleandomycin and their esterified derivatives
wherein the esterifying groups and their positions are defined as above,
8,8a-deoxy-8-N-(acetyl)aminomethyl oleandomycin and its esterified
derivatives wherein the esterifying groups and their positions are defined
as above, 8,8a-deoxy-8-N-(formyl)aminomethyl oleandomycin and its
esterified derivatives wherein the esterifying groups and their positions
are defined as above, 8,8a-deoxy-8-(dimethylaminomethylidenyl)aminomethyl
oleandomycin and its esterified derivatives wherein the esterifying groups
and their positions are defined as above, 8,8a-deoxy-8-chloromethyl
oleandomycin and its esterified derivatives wherein the esterifying groups
and their positions are defined as above,
8,8a-deoxy-8-(imidazol-1-yl)methyl oleandomycin and its esterified
derivatives wherein the esterifying groups and their positions are defined
as above and 8,8a-deoxy-8-azidomethyl oleandomycin and its esterified
derivatives wherein the esterifying groups and their positions are defined
as above.
DETAILED DESCRIPTION OF THE INVENTION
The novel oleandomycin compounds of the present invention are prepared from
natural oleandomycin and its acylated derivatives in which from one to
three of the hydroxyl groups at positions 2', 4" and 11 are acylated with
alkanoyl groups having from two to three carbon atoms. The methods by
which the acylated derivatives of natural oleandomycin are prepared are
described in U.S. Pat. No. 3,022,219.
Structure A above illustrates the configuration of these oleandomycin
compounds. It can be seen from a comparison of structure A and
oleandomycin that the differences between the compounds of the present
invention and oleandomycin are contained in partial structure B and the
groups R, R.sub.1 and R.sub.2.
##STR6##
Therefore, the compounds of the present invention will be represented
herein by the partial structure B.
For the purposes of the following discussion, esterified derivatives shall
be taken to mean oleandomycin compounds in which from one to three of the
hydroxyl groups at positions 2', 4" and 11 are esterified with n-alkanoyl
groups having from two to three carbon atoms. In addition, any of the
unesterified (at positions 2', 4" and 11) compounds of the present
invention are convertible, unless otherwise stated, into any of their
claimed, esterified derivatives as defined above according to the method
of U.S. Pat. No. 3,022,219 and this process is hereby disclosed.
It is also hereby disclosed that the claimed esterified derivatives of the
oleandomycin compound-starting materials for the processes of the present
invention are also functionable in those processes unless otherwise
stated.
The process shown in reaction 1 for preparation of the new
6,6a-deoxy-8-hydroxymethyl oleandomycin, formula C, or its 2'-acyl or
2',4"-diacyl derivatives is the reductive cleavage of the 8,8a-expoxide of
natural oleandomycin, 2'-acyl-oleandomycin or 2',4"-diacyloleandomycin
with any reagent which performs a selective reduction on the epoxide to
yield the primary alcohol. Typical reagents include the metal amalgams
such as zinc amalgam, magnesium amalgam and especially aluminum amalgam.
##STR7##
p The typical procedure for the process of reaction 1 comprises allowing
contact between oleandomycin or its acylated derivatives above and the
metal amalgam in an oleandomycin-soluble solvent such as alkanol, ether,
moist ether, benzene, aqueous alkanol, tetrahydrofuran, aqueous
tetrahydrofuran, dioxane, aqueous dioxane or mixtures thereof until the
reaction is essentially complete. The temperature range for the reaction
includes ambient temperature to that of refluxing solvent and the typical
procedure will call for ambient temperature.
After separation of the complex inorganic salts, the product can be
isolated and purified according to appropriate methods which will depend
upon the product's physical characteristics. The techniques that can be
employed include recrystallization, lyophilization, chromatography, high
pressure liquid chromatography and extraction.
If desired, the 8-hydroxymethyl group of the oleandomycin, formula C,
2',4"-diacyl derivative can be protected with a silyl group such as
trimethyl silyl or preferably dimethyl-t-butyl silyl according to the
methods reported for attachment of such groups. Then, any of the protected
compounds can, if desired, be converted into the triesterified
derivatives, as defined above, by the method of U.S. Pat. No. 3,022,219,
followed by removal of the 8-hydroxymethyl protecting group according to
common and known procedures.
The preparation of the new 8,8a-deoxy-8-chloromethyl oleandomycin, formula
D, or its esterified derivatives is accomplished by the process, shown in
reaction 2, of contacting 8,8a-deoxy-8-hydroxymethyl oleandomycin or its
esterified derivatives with N-chlorosuccinimide and triphenyl phosphine in
a polar, aprotic solvent such as dimethylformamide at temperatures from
-30.degree. C. to ambient.
##STR8##
After the reaction is essentially complete, the product can be isolated by
partition of the reaction residue between a buffered, basic aqueous phase
and an organic phase in which the product is soluble. Final purification
can be achieved by chromatographic, crystallization, lyophilization or
high pressure liquid chromatographic techniques, the choices of which will
depend upon the product's physical characteristics.
The preparation, reaction 3, of the new 8,8a-deoxy-8-(sulfonyloxy)methyl
oleandomycin, formula E, or its esterified derivatives is accomplished by
contacting 8,8a-deoxy-8-hydroxymethyl oleandomycin, formula C, or its
esterified derivatives with a sulfonating agent which can be any sulfonyl
chloride. The preferred sulfonyl chlorides are those compounds of the
formula R.sub.7 SO.sub.2 Cl wherein R.sub.7 is defined as above.
##STR9##
The typical procedure which functions to allow reaction 3 to proceed is as
follows. If a sulfonyl chloride is employed as the sulfonating agent,
formation of oleandomycin, formula E, will typically be accomplished by
contacting oleandomycin, formula C, or its esterified derivatives with
above one equivalent of sulfonyl chloride in an organic amine solvent such
as triethylamine, pyridine or lutidine, diluted, if desired, with an inert
organic solvent such as chloroform, benzene, methylene chloride or
toluene.
The product can then be isolated by partitioning the reaction mixture
between a buffered, basic aqueous phase and an organic phase in which the
product is soluble, followed by purification of the product by
chromatographic, crystallization or lyophilization techniques, the choice
of which will depend upon the product's physical characteristics.
The preparation of the new 8,8a-deoxy-8-(acyloxy)methyl oleandomycin,
formula F, or its esterified derivatives is accomplished in a manner
similar to the sulfonyl chloride procedure above by contacting
8,8a-deoxy-8-hydroxymethyl oleandomycin, formula C, or its esterified
derivatives with an acylating agent of the formula
##STR10##
said v being an integer from one to five.
##STR11##
Additionally, if an anhydride or mixed anhydride is employed as the
acylating agent, contact of oleandomycin, formula C, or its esterified
derivatives with about one equivalent of that type of acylating agent in
any inert organic solvent in which the oleandomycin, formula C, and
acylating agent are soluble will cause the formation of oleandomycin,
formula F.
The new 8,8a-deoxy-8-(imidazol-1-yl)methyl oleandomycin, formula G, or its
esterified derivatives is prepared by displacement of the 8-sulfonyloxy
group, preferably 8-tosyloxy, of 8,8a-deoxy-8-(sulfonyloxy)methyl
oleandomycin, formula F, or its esterified derivatives with imidazole.
A typical procedure calls for warming a solution of oleandomycin, formula
F, and imidazole in a polar, aprotic solvent such as dimethylformamide or
dimethyl sulfoxide at temperatures from 25.degree. to 100.degree. C. until
the displacement is essentially complete. Isolation of the product can be
achieved by partition of the reaction residue between a buffered, basic
aqueous phase and an organic phase in which the product is soluble,
typically ethyl acetate. The resulting crude product can then be purified
by the techniques of chromatography, recrystallization or lyophilization,
the choice of which will depend upon the product's physical
characteristics.
##STR12##
In a similar fashion, the sulfonyloxy group, preferably tosyloxy, of
oleandomycin F or its esterified derivatives can be displaced with azide
ion thus allowing the preparation of new 8,8a-deoxy-8-azidomethyl
oleandomycin H or its esterified derivatives.
##STR13##
The compounds of the present invention wherein Z is an amine or amine
derivative are prepared from 8,8a-deoxy-8-azidomethyl oleandomycin or its
esterified derivatives by reduction of the azide under various conditions
and, if desired in certain cases, condensation of the resulting
8,8a-deoxy-8-aminomethyl oleandomycin or its esterified derivativea with
amidation, sulfonamidation or imination agents. These oleandomycin
compounds resulting from such transformations consist of
8,8a-deoxy-8-aminomethyl oleandomycin I,
8,8a-deoxy-8-N-(dialkyl)aminomethyl oleandomycin, formula J,
8,8a-deoxy-8-N-(dialkylaminomethylidenyl)aminomethyl oleandomycin, formula
K, 8,8a-deoxy-8-N-(R.sub.6 CO)-aminomethyl oleandomycin, formula L,
8,8a-deoxy-8-N-(R.sub.7 SO.sub.2)aminomethyl oleandomycin, formula M, and
their esterified derivatives. The preparation of each of these
oleandomycin compounds is described below.
Under normal, low pressure (up to 100 p.s.i.) catalytic hydrogenation
conditions, 8-azidomethyl oleandomycin, formula H, or its esterified
derivatives is reduced to 8,8a-deoxy-8-aminomethyl oleandomycin, formula
I, or its esterified derivatives according to reaction 7.
##STR14##
A typical method employs oleandomycin, formula H, soluble solvents such as
water, methanol, ethanol, isopropanol, or mixtures thereof and noble metal
catalysts such as palladium on carbon, platinum oxide and the like for the
hydrogenation of oleandomycin, formula H, to oleandomycin, formula I.
After the hydrogenation is essentially complete, the product may be
isolated by chromatography, lyophilization, or recrystallization of the
reaction residue, the selection of which will depend upon the product's
physical characteristics.
The N-dialkyl 8,8a-deoxy-8-aminomethyl oleandomycin, formula J, compounds
or their esterified derivatives are formed from 8,8a-deoxy-8-azidomethyl
oleandomycin, formula H, or its esterified derivatives by catalytic
reductive alkylation as shown in reaction 8.
Using the same catalytic hydrogenation method as that described above for
the formation of oleandomycin, formula I, and including in the solvent an
appropriate amount of n-alkanal having from one to three carbon atoms,
hydrogenation of 8-azidomethyl oleandomycin, formula H, or its esterified
derivatives forms in situ 8,8a-deoxy-8-aminomethyl oleandomycin, formula
I, or its esterified derivatives, which then is reductively alkylated with
the n-alkanal.
##STR15##
After the alkylated derivative has been formed by this process, the
product can be isolated by partition of the reaction residue between a
buffered, basic aqueous phase and an organic phase in which the product is
soluble. It is then purified by recrystallization or chromatographic
techniques, the choice of which will depend upon the product's physical
characteristics.
The imine derivatives, formula K, of 8,8a-deoxy-8-aminomethyl oleandomycin,
formula I, or its esterified derivatives are formed from the 8-aminomethyl
compound, formula I, or its esterified derivatives by contacting it with
dialkylformamide dimethylacetal having from one to three carbon atoms in
the alkyl group in a polar, aprotic solvent such as dimethylformamide,
dimethyl sulfoxide or dialkylformamide as shown in reaction 9.
##STR16##
After the reaction is essentially complete, it is quenched by pouring it
onto ice water. After extraction, or use of other appropriate isolation
techniques, the product can be purified by chromatography or
recrystallization, the choice of which will depend upon the product's
physical characteristics.
The amide
##STR17##
and sulfonamide (R.sub.7 SO.sub.2 --) derivatives, formulae L and M,
respectively, of 8,8a-deoxy-8-aminomethyl oleandomycin, formula I, or its
esterified derivatives are formed by contact of oleandomycin, formula I,
or its esterified derivatives with an amidating or sulfonamidating agent
of the formula:
##STR18##
alkyl-NCO having from one to four carbon atoms in the alkyl group, PhNCO,
nicotinyl chloride, isonicotinyl chloride, picolinyl chloride,
.alpha.-thienyl chloride, alkyl-SO.sub.2 Cl having from one to five carbon
atoms in the alkyl group,
##STR19##
wherein: v is an integer from one to five; X is selected from the group
consisting of hydrogen, halogen, alkyl hving from one to four carbon
atoms, alkoxycarbonyl having from one to four carbon atoms in the alkoxy
group, CF.sub.3, alkyloxy having from one to four carbon atoms,
--CONH.sub.2 and --NO.sub.2 ; and Y is selected from the group consisting
of hydrogen, chloro, alkyl having from one to four carbon atoms and
--CF.sub.3.
##STR20##
The usual procedure employs dilute alkali or an organic amine such as
pyridine, triethylamine or lutidine as a base in the case of the acid and
sulfonyl chloride agents in order to neutralize the formed hydrogen
chloride. Selection of the base will depend upon the type of product and
the agent used. In addition, the organic amine can also function as
solvent or it can be diluted with an inert organic solvent such as
chloroform, benzene or methylene chloride. Water miscible or water
immiscible solvents such as tetrahydrofuran or chloroform are both
employed with the dilute alkali base. In the case of urea formation
(R.sub.6 .dbd. NH.sub.2, NH-alkyl or PhNH), the solvent chosen must be one
which will not react with the isocyanate starting material. In the case of
the anhydride and mixed anhydride agents, a solvent in which both the
oleandomycin, formula I, and the agent are soluble can be employed with
success, and a base is not necessary. Such solvents include methanol,
ethanol, ethyl acetate, acetone, isopropanol, n-propanol, chloroform,
methylene chloride, tetrahydrofuran, dioxane, dimethoxyethane and methyl
ethyl ketone. The temperature range for the reaction in all cases includes
that of an ice bath to that of the refluxing solvent and typically will be
ambient temperature. After the reaction is essentially complete, the
reaction residue can be partitioned between a buffered, basic aqueous
phase and an organic phase in which the product is soluble, typically
chloroform or ethyl acetate. The resulting crude, isolated product can
then be purified by chromatography, lyophilization, recrystallization,
high pressure liquid chromatography or extraction/evaporation techniques,
the choice of which will depend upon the product's physical
characteristics.
The processes described above together produce all the novel products of
the present invention. From the description of these processes, it is
evident that they are inter-related and dependent, in some cases, upon a
previously formed product of the present invention. That inter-relation is
presented in Scheme A wherein the integers indicate the particular
reaction of the processes above.
##STR21##
The pharmaceutically-acceptable acid addition salts of the oleandomycin
compounds of the present invention are prepared by contacting a solution
of a compound of the present invention in a suitable solvent such as
acetone with a stoichiometric equivalent of a mineral acid such as
hydrochloric, hydrobromic, phosphoric or sulfuric acid; an organic acid
selected from the group consisting of aspartic, citric, tarataric,
gluconic, succinic and stearic acid; or an alkyl sulfuric acid such as
lauryl sulfuric acid. The salt precipitates after the neutralization
reaction or, if necessary, after partial evaporation of the reaction
solution. The product may be recovered by filtration, centrifugation or
lyophilization.
The oleandomycin compounds of the present invention are effective in
inhibiting the growth of microorganisms, especially Gram-positive
microorganisms That is, the high activity against Gram-positive organisms
in general shown by these compounds can be contrasted in some respect with
the lower activity shown against certain especially virulent and well
known Gram-negative organisms. The following table illustrates the in
vitro antibiotic spectrum of the compound of the instant invention. The
tests were run according to the "minimum inhibitory concentration" (MIC)
method of Ericsson and Sherris [H. M. Ericsson and J. C. Sherris, Acta.
Pathol. Microbiol. Scand. Suppl., 217B, 64 (1971)].
TABLE I.
__________________________________________________________________________
MIC Values (mcg./ml.) of some semi-synthetic oleandomycin derivatives -
C.sub.8 modifications
##STR22##
Staph.aureus
Staph.aureus
Strep.py.
E.coli
Klebsiella pn.
Salm.typhm.
Neisseriae Sicca
Z R.sub.1
R.sub.2
01A005*
01A400R*
02C203*
51A226**
53A009**
58D009**
66C001**
__________________________________________________________________________
OH Ac
H 6.25 12.5 1.56 >200 >200 >200 0.39
Cl H Ac
3.12 50 1.56 200 >200 >200 .ltoreq.0.1
TsO Ac
H 100 >200 3.12 >200 >200 >200 3.12
imidazol-1-yl
H Ac
0.39 6.25 -- >200 >200 >200 .ltoreq.0.1
N(CH.sub.3).sub.2
H Ac
25 50 50 >200 >200 >200 1.56
##STR23##
H Ac
6.25 50 1.56 >200 >200 >200 0.20
##STR24##
H Ac
>200 >200 >200 >200 >200 >200 6.25
##STR25##
H Ac
25 100 12.5 >200 >200 >200 1.56
##STR26##
H Ac
50 >200 50 >200 >200 >200 >200
NH.sub.2
H Ac
6.25 25 50 >200 >200 >200 .ltoreq.0.10
N.sub.3
H Ac
3.1 12.5 3.1 >200 >200 >200 0.20
__________________________________________________________________________
* = Gram-positive
** = Gram-negative
The ability of some compounds of the present invention to protect against
in vivo infections was determined by subcutaneous or oral administration
to mice infected with Staph. aureus 01A005. Using the test procedure of
Retsema [J. A. Retsema, et al., Antimier. Agents and Chemother., 9, 975
(1976)] it was determined that, in particular,
8,8a-deoxy-8-azidomethyl-4"-acetyloleandomycin,
8,8a-deoxy-8-hydroxymethyl-2'-acetyloleandomycin,
8,8a-deoxy-8-chloromethyl-4"-acetyloleandomycin,
8,8a-deoxy-8-(imidazol-1-yl)methyl-4"-acetyloleandomycin and
8,8a-deoxy-8-(N-acetyl)aminomethyl-4"-acetyloleandomycin all gave
protection against infection which was comparable to natural oleandomycin.
For effective prophylactic and anti-infectious in vivo use, the
oleandomycin compounds of the present invention may be administered either
alone or in combination with a pharmaceutically-acceptable carrier, by the
oral or parenteral routes. The ultimate choice of route and dose is made
by the attending physician and is based upon the patient's unique
condition. However, the usual dosage for administration to humans lies in
the range of approximately 500-2000 mg. P.O. per day, and preferably in
about one to four doses. However, this dosage may vary somewhat with the
weight of the subject being treated; in general, about 10-40 mg./kg. of
body weight per day can be employed.
The compounds of this invention can be combined with inert pharmaceutical
excipients such as lactose, mannitol and starch, and formulated into
dosage forms such as tablets, capsules and the like. For parenteral
administration, these compounds can be formulatd with an inert,
parenterally acceptable vehicle such as water, saline, sesame oil,
propylene glycol and the like. These various pharmaceutical dosage forms
are compounded by methods well known to the pharmacist's art.
EXAMPLE 1
8,8a-Deoxy-8-hydroxymethyl-2',4"-diacetyloleandomycin 1
To a suspension of 10 g. of amalgamated aluminum (prepared from one-quarter
inch squares of aluminum foil by the method of Ferris, Sanchez and
Manusco, Org. Syn. Coll. Vol. V, page 32) in 200 ml. of 10% aqueous
tetrahydrofuran at room temperature and contained in a 1 liter,
three-necked, round bottom flask equipped with a mechanical stirrer was
added dropwise a solution of 5.0 g. (6.4 mmoles) of
2',4"-diacetyloleandomycin in 50 ml. of 10% aqueous tetrahydrofuran. The
resulting suspension was stirred at room temperature for 48 hrs. and the
aluminum salts separated by filtration through diatomaceous earth. The
filtrate was added to a mixture of ethyl acetate and water and the organic
phase was separated and washed twice with wter, once with saturated sodium
chloride solution, dried over anhydrous sodium sulfate, filtered and the
solvent evaporatd from the filtrate under reduced pressure. The resulting
material was placed on a column of silica gel and eluted with ethyl
acetate to yield 850 mg. of the title compound as a white foam. The NMR of
the product exhibited the following characteristic resonances:
NMR -- (CDC1.sub.3) .differential.ppm: 5.43 (1H) m; 3.40 (3H) s; 2.25 (6H)
s; 2.10 (3H) s; 2.06 (3H) s.
By employing the procedure of Example 1, the following
8,8a-deoxy-8-hydroxymethyl-2'-acyloleandomycins or
8,8a-deoxy-8-hydroxymethyl-2',4"-diacyloleandomycins can be made by
substituting for 2',4"-diacetyloleandomycin the appropriate oleandomycin
in which from one to two of the free hydroxyl groups at positions 2' and
4" are esterified with alkanoyl groups having from two to three carbon
atoms: 8,8a-deoxy-8-hydroxymethyl-2'-propionyloleandomycin and
8,8a-deoxy-8-hydroxymethyl-2',4"-di-n-propionyloleandomycin.
In addition, formation of 8,8a-deoxy-8-hydroxymethyl-2',4",11-triacyl
oleandomycin derivatives can be accomplished by first preparing the
8-(dimethyl-t-butyl silyloxy)methyl derivative of compound l or its
2',4"-dipropionyl analog according to the procedure of Corey, J. Am. Chem.
Soc., 94, 6190 (1974) and then acylating it according to the procedures of
U.S. Pat. No. 3,022,219 followed by cleavage of the silyl group with
tetra-n-butyl ammonium fluoride.
EXAMPLE 2
8,8a-Deoxy-8-hydroxymethyl-2'-acetyloleandomycin 2
By employing the procedure of Example 1, 2'-acetyloleandomycin was
converted into the title compound. It exhibited the following
characteristic NMR spectrum:
NMR CDCl.sub.3 .delta.ppm: 5.46 (1H) m; 3.46 (3H) s; 2.30 (6H) s; 2.08 (3H)
s.
EXAMPLE 3
8,8a-Deoxy-8-hydroxymethyloleandomycin 3
By employing the procedure of Example 1, oleandomycin was converted into
the title compound. It had the following characteristic resonances in the
NMR spectrum:
NMR CDCl.sub.3 .delta.ppm: 5.40 (1H) m; 4.95 (1H) m; 4.20 (1H) d; 3.36 (3H)
s; 2.23 (6H) s.
EXAMPLE 4
8,8a-Deoxy-8-tosyloxymethyl-2',4"-diacetyloleandomycin 4
To a solution of p-toluenesulfonyl chloride (988 mg.; 5.16 mmoles) in 3 ml.
of pyridine cooled to 0.degree. C. was added 2.0 g. (2.58 mmoles) of
8,8a-deoxy-8-hydroxymethyl-2',4"-diacetyloleandomycin l as a solid in one
portion. After stirring at 0.degree. C for three hours, the solution was
poured into a mixture of ethyl acetate and water and the pH adjusted to
8.5 with saturated sodium bicarbonate solution. The organic phase was
separated and washed successively with water, dilute hydrochloric acidd of
pH 3.5, water, sodium bicarbonate solution of pH 8.5, and saturated sodium
chloride solution. Evaporation under reduced pressure of the organic layer
gave 2.30 g. of white foam which was chromatographed on a 15 by 8.5 cm.
column of silica gel. Elution with ethyl acetate and acetone in a 9:1
ratio gave 1.62 g. of the title compound as a white foam. The NMR
exhibited the following characteristic resonances:
NMR -- (CDCl.sub.3) .delta.ppm: 7.56 (4H) q; 5.35 (1H) m; 3.35 (3H) s; 2.43
(3H) s; 2.25 (6H) s; 2.10 (3H) s; 2.05 (3H) s.
EXAMPLE 5
8,8a-Deoxy-8-tosyloxymethyl-2'-acetyloleandomycin 5
Following the procedure of Example 4, the title compound was prepared from
8,8a-dexoy-8-hydroxymethyl-2'-acetyloleandomycin 2. The NMR exhibited the
following characteristic resonances:
NMR CDCl.sub.3 .delta.ppm: 7.56 (4H); 5.38 (1H) m; 3.43 (3H) s; 2.46 (3H)
s; 2.30 (6H) s; 2.05 (3H) s.
By employing the procedure of Example 4, the following
8-tosyloxymethyloleandomycins can be prepared by subsituting for
oleandomycin l the appropriately esterified
8,8a-deoxy-8-hydroxymethyl-oleandomycin; that is, an
8-hydroxymethyloleandomycin compound in which from one to three of the
free hydroxyl groups at positions 2', 4" and 11 are esterified with
alkanoyl groups having from two to three carbon atoms, and by substituting
the appropriate sulfonyl chloride for p-toluenesulfonyl chloride:
8,8a-deoxy-8-methylsulfonoxymethyl-2'-propionyloleandomycin,
8,8a-deoxy-8-propylsulfonoxymethyl-2',4"-diacetyloleandomycin,
8,8a-8-deoxy-m-trifluoromethylphenylsulfonoxymethyl-2',4"-diacetyloleandom
ycin, 8,8a-deoxy-8-tosyloxymethyl-2',4",11-triacetyloleandomycin,
8,8a-deoxy-8-tosyloxymethyl-2',4"-11-tripropionyloleandomycin and
8,8a-deoxy-8-(p-chlorophenylsulfonoxy)methyl-2',4"-diacetyloleandomycin.
The procedure of Example 4 can also be used to acylate
8,8a-deoxy-8-hydroxymethyl-2',4"-diacyloleandomycin and its other
appropriately esterified derivatives at the 8-hydroxymethyl position by
substituting the appropriate acid chloride for tosyl chloride. In this
case, the products obtained will be the alkanoyl esters at the 8a-position
instead of tosyloxy derivatives at the 8a-position as they are in Example
4, e.g., compounds such as
______________________________________
##STR27##
R R.sub.1 R.sub.2 alkyl
______________________________________
hydrogen acetyl acetyl methyl
acetyl acetyl acetyl propyl
propionyl propionyl propionyl
butyl
______________________________________
These products can also be prepared by substituting the appropriate
anhydride in place of the acid chloride. In this case, it will be
convenient but not necessary to employ pyridine as a solvent. Other common
inert organic solvents such as chloroform and methylene chloride can also
be employed here.
EXAMPLE 6
8,8a-Deoxy-8-hydroxymethyl-4"-acetyloleandomycin 6
A solution of 3.43 g. (4.4 mmoles) of
8,8a-deoxy-8-hydroxymethyl-2',4"-diacetyloleandomycin l in 50 ml. of
methanol was stirred at ambient temperature for 20 hours. Evaporation of
the solvent under reduced pressure gave the title compound as a white
foam. The NMR exhibited the following characteristic resonances:
NMR -- (CDCl.sub.3) .delta.ppm: 5.43 (1H) m; 3.35 (3H) s; 2.28 (6H) s; 2.08
(3H) s.
The following oleandomycins can also be prepared according to the procedure
of Example 6 by substitution of the appropriate oleandomycin for
oleandomycin l: 8,8a-deoxy-8-hydroxymethyl-4"-propionyloleandomycin and
8,8a-deoxy-8-hydroxymethyl-4",11-diacetyloleandomycin.
EXAMPLE 7
8,8a-Deoxy-8-tosyloxymethyloleandomycin 7
By employing the procedure of Example 6,
8,8a-deoxy-8-toxyloxymethyl-2'-acetyloleandomycin was converted into the
title compound. It exhibited the following characteristic NMR resonances:
NMR (CDCl.sub.3) .delta.ppm: 7.56 (4H) q; 5.43 (1H) m; 3.40 (3H) s; 2.43
(3H) s; 2.31 (6H) s.
EXAMPLE 8
8,8a-Deoxy-8-tosyloxymethyl-4"-acetyloleandomycin 8
By employing the procedure of Example 6,
8,8a-deoxy-8-tosyloxymethyl-2',4"-diacetyloleandomycin was converted into
the title compound. It exhibited the following characteristic NMR spectrum
resonances:
NMR (CDCl.sub.3) .delta.ppm: 7.56 (4H) q; 5.38 (1H) m; 3.36 (3H) s; 2.43
(3H) s; 2.31 (6H) s; 2.10 (3H) s.
Also by employing the procedure of Example 6, the following oleandomycins
can be prepared by substituting the appropriately esterified
8,8a-deoxy-8a-tosyloxymethyloleandomycin for oleandomycin 8:
8,8a-deoxy-8-tosyloxymethyl-4",11-diacetyloleandomycin,
8,8a-deoxy-8-tosyloxymethyl-4"-propionyloleandomycin and
8,8a-deoxy-8-tosyloxymethyl-4",11-dipropionyloleandomycin.
EXAMPLE 9
8,8a-Deoxy-8-azidomethyl-4"-acetyloleandomycin 9
A solution of 2.65 g. (3 mmoles) of
8,8a-deoxy-8-tosyloxymethyl-4"-acetyloleandomycin 8 in 30 ml. of
dimethylsulfoxide contained in a 200 ml. three-necked round bottom flask
equipped with a magnetic stirrer, thermometer and a nitrogen inlet was
treated with 585 mg. (9 mmoles) of solid sodium azide in one portion. The
flask was immersed in an oil bath and heated at 50.degree. C. for 5.5
hours, then the contents were poured into a mixture of ice, water and
ethyl acetate and the pH adjusted to 8.5 with sodium bicarbonate. The
organic phase was separated and washed twice with equal volumes of water,
once with an equal volume of saturated sodium chloride solution, dried
over anhydrous sodium sulfate, filtered and the solvent evaporated from
the filtrate under reduced pressure to give 2.25 g. of the title compound
as a white foam. It produced a strong band in the infrared at 2095
cm.sup.-1 and exhibited the following characteristic resonances in the
NMR:
NMR (CDCl.sub.3) .delta.ppm: 5.46 (1H) m; 3.33 (3H) s; 2.28 (6H) s; 2.10
(3H) s.
By employing the procedure of Example 9, the following oleandomycins can be
prepared by substitution of the appropriately esterified
8,8a-deoxy-8-tosyloxymethyloleandomycin for oleandomycin 8:
8,8a-deoxy-8-azidomethyl-2',4"-dipropionyloleandomycin,
8,8a-deoxy-8-azidomethyl-4"-propionyloleandomycin,
8,8a-deoxy-8-azidomethyl-4",11-diacetyloleandomycin,
8,8a-deoxy-8-azidomethyl-11-acetyloleandomycin,
8,8a-deoxy-8-azidomethyl-4",11-dipropionyloleandomycin and
8,8a-deoxy-8-azidomethyl-2',4",11-triacetyloleandomycin.
EXAMPLE 10
8,8a-Deoxy-8-azidomethyloleandomycin 10
By employing the procedure of Example 9,
8,8a-deoxy-8-tosyloxymethyloleandomycin 7 was converted into the title
compound. Its infrared spectrum showed a strong band at 2100 cm.sup.-1 and
its NMR spectrum had the following characteristic resonances:
NMR (CDCl.sub. 3) .delta.ppm: 5.11 (1H) m; 3.45 (3H) s; 2.30 (6H) s.
EXAMPLE 11
8,8a-Deoxy-8-aminomethyl-4"-acetyloleandomycin 11
To a solution of 9.34 g. (12.3 mmoles) of
8,8a-deoxy-8-azidomethyl-4"-acetyloleandomycin 9 in 200 ml. of methanol
was added 9.0 g. of 10% palladium on charcoal and the mixture was
hydrogenated on a shaker hydrogenation apparatus for 1 hour. After removal
of the catalyst from the reaction solution by filtration through
diatomaceous earth and evaporation of the solvent from the filtrate under
reduced pressure, the residue was chromatographed on a 80 .times. 4.5 cm.
column of Sephadex LH-20 (Pharmacia Fine Chemicals, Piscataway, N.J.) by
elution with tetrahydrofuran which produced 7.6 g. of the title compound
as a white foam. It exhibited the following characteristic resonances in
the NMR:
NMR (CDCl.sub. 3) .delta.ppm: 5.30 (1H) m; 3.36 (3H) s; 2.30 (6H) s; 2.10
(3H) s.
EXAMPLE 12
8,8a-Deoxy-8-aminomethyloleandomycin 12
By employing the procedure of Example 11, 8,8a-deoxy-8-azidomethyl
oleandomycin 10 was converted into the title compound. It exhibited the
following characteristic NMR partial spectrum:
NMR (CDCl.sub. 3) .delta.ppm: 5.13 (1H) m; 3.38 (3H) s; 2.26 (6H) s.
Similarly, the following compounds can be prepared:
8,8a-deoxy-8-aminomethyl-4"-propionyloleandomycin,
8,8a-deoxy-8-aminomethyl-4", 11-diacetyloleandomycin,
8,8a-deoxy-8-aminomethyl-11-acetyloleandomycin,
8,8a-deoxy-8-aminomethyl-4"-propionyloleandomycin,
8,8a-deoxy-8-aminomethyl-4",11-dipropionyloleandomycin and
8,8a-deoxy-8-aminomethyl-11-acetyloleandomycin.
EXAMPLE 13
8,8a-Deoxy-8-chloromethyl-4'-acetyloleandomycin 13
A solution of 2.5 g. (3.23 mmoles) of
8,8a-deoxy-8-hydroxymethyl-2',4"-diacetyloleandomycin l in 8 ml. of
dimethylformamide contained in a 50 ml. 3-necked round bottom flask
equipped with a magnetic stirrer, thermometer and nitrogen inlet, was
cooled to 0.degree. C. and treated with 861 mg. (6.46 mmoles) of
N-chlorosuccimide. After stirring at 0.degree. C. for ten minutes, the
solution was cooled to -10.degree. C. and 1.69 g. (6.46 mmoles)
triphenylphosphine was added as a solid in small portions over a 30 minute
period while maintaining the temperature of the solution between -10 and
0.degree. C. When the addition was complete, the reaction mixture was
allowed to warm to room temperature and stirring was continued for 30
minutes. The mixture was then poured into a two phase mixture of ethyl
acetate and water, the pH adjusted to 8.5 and the organic phase was washed
with water and saturated sodium chloride solution. The organic phase was
dried over anhydrous sodium sulfate, filtered to remove the drying agent
and the solvent evaporated from the filtrate under reduced pressure to
yield 2.6 g. of a white solid. This material was taken up in 50 ml. of
methanol and stirred at room temperature for 20 hours. The solvent was
evaporated from this reaction solution under reduced pressure and the
residue was chromatographed on Sephadex LH-20 (Pharmacia Fine Chemicals,
Piscataway, N.J.) with methanol eluent to give 1.24 of the title compound
as a white foam. It showed the following characteristic resonances in the
NMR:
NMR (CDCl.sub. 3) .delta.ppm: 5.43 (1H) m; 3.33 (3H) s; 2.28 (6H) s; 2.06
(3H) s.
EXAMPLE 14
8,8a -Deoxy-8-dimethylaminomethyl-4"-acetylolcandomycin 14
To a solution of 1.51 g. (2.0 mmoles) of
8,8a-deoxy-8-azidomethyl-4"-acetyloleandomycin 9 in 30 ml. of methanol was
added 1.5 ml. of a 37% aqueous solution of formaldehyde (.about.20 mmoles
of formaldehyde) and 1.5 g. of 10% palladium on carbon and the mixture was
hydrogenated on a shaker hydrogenation apparatus at 50 psi overnight.
After removal of the catalyst from the reaction slurry by filtration
through diatomaceous earth and evaporation of the solvent from the
filtrate under reduced pressure, the residue was crystallized from ethyl
acetate and then recrystallized from isopropyl alcohol to give 800 mg. of
the title compound, m.p. 180.5.degree.-182.degree. C. It showed the
following characteristic resonances in the NMR:
NMR (CDCl.sub. 3) .delta.ppm: 5.53 (1H) m; 3.38 (3H) s; 2.31 (6H) s; 2.20
(6H) s; 1.26 (3H) s.
The reductive alkylation procedure of Example 14 can also be employed to
prepare the following compounds by substitution of the appropriately
esterified 8,8a-deoxy-8-azidomethyloleandomycin for the oleandomycin
compound 9 of Example 14 and by substituting the appropriate amount of
n-alkanal for formaldehyde:
______________________________________
##STR28##
R R.sub.1 R.sub.2 R.sub.3
______________________________________
acetyl hydrogen acetyl ethyl
propionyl hydrogen propionyl ethyl
acetyl acetyl acetyl propyl
hydrogen hydrogen acetyl propyl
______________________________________
In these cases, use of a solution of the appropriate amount of aldehyde in
methanol, instead of water as was done in Example 14, will be the method
of choice.
EXAMPLE 15
8,8a-Deoxy-8-(N-benzoyl)-aminomethyl-4"-acetyloleandomycin 15
To a solution of 500 mg. (0.685 mmoles) of
8,8a-deoxy-8-aminomethyl-4"-acetyloleandomycin 11 in 100 ml. of 25% by
volume aqueous tetrahydrofuran was added one normal aqueous sodium
hydroxide to adjust the pH to 9. To this basic solution was then dropwise
added a solution of 240 mg. (1.71 mmoles) benzoyl chloride in 30 ml. dry
THF and the solution stirred until reaction was essentially complete
according to the difference in Rf of the product and starting material
spots on thin layer chromatography. The THF was then removed in vacuo and
the resultant aqueous layer was covered with 100 ml. ethyl acetate while
maintaining the aqueous layer at pH 9. After extracting the aqueous layer
with 2 .times. 50 ml. portions of the ethyl acetate, the organic layers
were combined, dried over magnesium sulfate and filtered to removed the
drying agent. Removal of the solvent from the filtrate by vacuum
evaporation yielded a residue which was chromatographed on a 25 g. column
of silica gel packed in chloroform. Elution with chloroform and then with
2% methanol in chloroform followed by removal of the solvent from the
product fractions allowed the isolation of 270 mg. of the title compound.
It exhibited the following characteristic resonances in the NMR:
NMR (CDCl.sub. 3) .delta.ppm: 7.50 (5H) m; 6.90 (1H) m; 5.28 (1H) m; 3.36
(3H) s; 2.30 (6H) s; 2.16 (3H) s.
EXAMPLE 16-18
8,8a-Deoxy-8-(N-acyl or sulfonyl)aminomethyl-4"-acetyloleandomycin
The following compounds were prepared according to the procedure of Example
15 by substitution of the appropriate carboxylic acid or sulfonyl chloride
in place of benzoyl chloride.
______________________________________
Example NMR (partial spectrum)
No. Acyl A or sulfonyl B
.delta.ppm CDCl.sub.3
______________________________________
thienoyl = .alpha. .delta.7.46(3H)m; .delta.6.73(1H)m;
compound 16 .delta.5.26(1H)m; .delta.3.36(3H)s;
.delta.2.30(6H)s; .delta.2.20(3H)s.
17 A = nicotinyl .delta.8.10(1H)m; .delta.7.26(3H)m;
compound 17 .delta.5.08(1H)m; .delta.3.36(3H)s;
.delta.2.30(6H)s; .delta.2.10(3H)s.
18 B = methyl sulfonyl
.delta.7.03(1H)bs; .delta.5.45(1H)m;
compound 18 .delta.3.40(3H)s; .delta.3.00(3H)s;
.delta.2.30(6H)s; .delta.2.13(3H)s.
##STR29##
oleandomycin compounds 16, 17 and 18
______________________________________
The following oleandomycins can also be prepared according to the procedure
of Example 15 by substitution of the appropriately esterified
8,8a-deoxy-8-aminomethyloleandomycin for the starting oleandomycin
compound 11 of Example 15 and by substitution of the appropriate
carboxylic acid chloride for benzoyl chloride.
______________________________________
##STR30##
R R.sub.1 R.sub.2 R.sub.6
______________________________________
acetyl acetyl acetyl phenyl
propionyl
hydrogen propionyl p-chlorophenyl
acetyl hydrogen propionyl propyl
acetyl hydrogen acetyl p-trifluoromethylphenyl
hydrogen hydrogen acetyl p-methoxyphenyl
hydrogen hydrogen propionyl m-trifluoromethylphenyl
hydrogen acetyl acetyl o-nitrophenyl
hydrogen propionyl propionyl m-ethylphenyl
propionyl
hydrogen propionyl propyl
acetyl hydrogen acetyl pentyl
acetyl acetyl acetyl p-carboxyethylphenyl
acetyl hydrogen acetyl m-hydroxyphenyl
propionyl
hydrogen propionyl o-carbamoylphenyl
hydrogen acetyl acetyl picolinyl
propionyl
propionyl propionyl isonicotinyl
______________________________________
The following oleandomycins can also be prepared according to the procedure
of Example 15 by substitution of the appropriately esterified
8,8a-deoxy-8-aminomethyloleandomycin for the starting oleandomycin
compound 11 of Example 15 and by sub | | |
