Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~981Z3
',
Back~round of the Invention
Field of the Invention
!
l I This invention relates to novel antibacterial agents and, in particu-
¦1 lar, to a series of 4"-deoxy-4"-sulfonylamino-oleandomycins and their pharma-
5 ¦ ceutically acceptable acid addition salts.
1~
Description of the Prior Art
Oleandomycin, its production in fermentation broths and its use as an
antibacterial agent were first described in U.S. Patent 2,757,123. The natu-
rally occurring compound is known to have the following structure: ¦
¦ (CH3)2
~ "`'""`
2
The conventionally accepted numbering scheme and stereochemical representation
for oleandomycin and similar compounds is shown at a variety of positions.
~~ U.S. Patents 3,884,902 and 3,983,103 claim 4"-erythromycin sulfonate
'l~ esters and N-sulfonylerythromycylamines, respectively, which have biological
15 l~ Drofiles different from the compounds claimed in the present invention.
¦ Several synthetic modifications of oleandomycin are known, particu-
larly those in which from one to three of the free hydroxyl groups found at the
2', 4" and ll-positions are esterified as acetyl esters. In addition, there
' are described in U.S. Patent 3,022,219 similar modifications in which the
20 ' acetyl in the above-mentioned esters is replaced with another, preferably un-
;branched lower alkanoyl of three to six carbon atoms.
.,
--2--
,. ' ~
--~ $~ Z3
Summary of the Invention
The semi-synthetic oleandomycin antibacterial agents of this invent-
ion are of thc ~ormulae:
N (CH3) 2
HO
0~ 0 ~
R 0
""..1~ ~
~lHso2R
OCH3
~ ~C~13) 2
", O
and HO """,. ~
",...,1~ ~
0~ , O
O ~J
T NHso2R2
OCH 3
,............ ...
Z3
and a pharmaceutically acceptable acid addition salt thereof, wherein R is
alkyl ha.ving from one to three carbon atoms; pyridyl; l,l,l-trifluoroethyl;
phenyl; monosubstituted phenyl wherein said substituent is selected from the
group consisting of fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyano,
carboxamido, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoro-
methyl, a].kyl having from one to four carbon atoms and acetamido; disubstitit-.
ed phenyl wherein said substituents are each selected from the group consist-
ing of chloro, nitro, amino, methoxy and methyl; trichlorophenyl; hydroxy-
dichlorophenyl; benzyl; naphthyl; thienyl; chlorothienyl; 2-acetamido-5-
thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2-
pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl and furyl wherein
said substituent is selected from the group consisting of carbomethoxy and
alkyl having one to two carbon atoms; or l-methyl-5-carbomethoxy-3-pyrryl;
Rl i.s alkanoyl having two to three carbon atoms; R2 is phenyl; thienyl;
monosubstituted phenyl wherein said substituent is selected from the group
consisting of chloro, fluoro, methyl, methoxy and trifluoromethyl; or alkyl
substituted thienyl said alkyl having from one to two carbon atoms.
The amine starting materials leading to the compounds of the present
invention are comprised, because of the synthetic method used in their prep-
aration, of two 4"-epimeric amines. Hence, the sulfonamido compounds of the
present invention which are formed from said amines are also comprised of an
epimeric mixture. Experimentally, it is observed that both epimeric sulfon-
amides are present in the final product in varying ratios depending on the
choice of
B
~ ~9~Z3
synthetic method used to prepare the amine intermediate. If the isolated
product consists predominantly of one of the epimersJ said epimer can be
puri.fiecl by repeated recrystallization from a suitable solvent to a
constant melting point. The other epimer, the one present in smaller
amounts in the originally isolated solid materialJ is the predominant
product in the mother liquor. It can be recovered therefrom by methods
known to those skilled in the art, as for example, the evaporation of
the mother liquor and repeated recrystallization of the residue to a
product of constant melting point or by chromatography.
Although said mixture of epimers can be separated by methods
known to those skilled in the art, for practical reasons it is advantageous
to use said mixture as it is isolated from the reaction. However, it is
frequently advantageous to purify the mixture of epimers by at least one
recrystallization from an appropriate solvent, subjecting it to column
chromatographyJ solvent partitioning or by trituration in an appropriate
solvent. Said purificationJ while not necessarily separating the epimersJ
removes such extraneous materials as starting materials and undesirable
by-products.
B
~ 39~Z3
The absolute stereochemical assignment for the epimers has not been
complcted. I30th epimers of a given compound, however, exhibit the same type
of activity, e.g., as antibacterial agents.
Preferred compounds related to 1 are those wherein R is thienyl and
substituted thienyl wherein said substitutuent is alkyl having from one to two
carbon atoms or carbomethoxy.
Preferred compounds related to 2 comprise those wherein R2 is
substituted phenyl, thienyl and alkyl substituted thienyl said alkyl having
~rom one to two carbon atoms.
Preferred among these compounds because of their antibacterial
utility are ll-acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin,
ll-acetyl-4"-
_~ _
~L~913~Z3
deoxy-4"-(3-thienylsulfonylamino)oleandomycin, 11-acetyl-4"-deoxy-4"-(3-methyl-
2-thienylsulfonylamino)oleandomycin, 4"-deoxy-4"-(p-chlorophenylsulfonylamino)-;
oleandomycin, 4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin, 4"-deoxy-4"-
(3-thienylsulfonylamino)oleandomycin, 4"-deoxy-4"-(3-methyl-2-thienylsulfonyl-
5 1i amino)oleandomycin, 11-acetyl-4"-deoxy-4"-(2-bromoethylsulfonylamino)oleandomy-
cin, 11-acetyl-4"-deoxy-4"-(2-methylthioethylsulfonylamino)oleandomycin and
ll-acetyl-4"-deoxy-4"-(vinylsulfonylamino)oleandomycin.
1~ '
109~i1Z3
Detailed Description of the Invention
¦ In accordance with the process for synthesi~ing the 4"-deoxy-4"-
sulfonylamino-oleandomycin derived antibacterial agents of form~lae 1 and 2,
the following scheme, starting with 4"-deoxy-4"-am$no-oleandomycin or an 11-
a1k~DOY1 derivatlve thereof, i6 illu~tratlve.
R
dq" ~ ~ ~OzCl ~ C~3
"`~ ,."~ > ~ "~"
2 ~ ~ NHS02R2
2 OCH3
B ~
1 ~9l~23
wherein R, Rl and R2 are as previously defined.
The above-identified reactions are carried out between a 4"-deoxy-4"-
amino-oleandomycin and an appropriate sulfonyl halide in the presence of a acid
scavenger in a reaction-inert solvent.
In practice, one mole of the 4"-amino-oleandomycin is contacted with
one mole of the sulfonyl halide plus as much as a 2-3% excess of said halide.
The acid scavenger, which can be inorganic or organic in nature, is employed
to the extent of one mole plus aa much as 4-6% excess.
The scavenger can consist of alkali metal or alkaline-earth metal
hydroxides, hydrides orcarbonates as well as a tertiary organic amine. In addi-
tion, secondary amines, such as diisopropyl amine, whlch are sufficiently hin-
¦teret auch that they do not react with the sulfonyl halide reactant can also be
employed. The preferred class of acid scavengers is tertiary amines. Especiall~
preferred within this class is triethylamine.
The reaction-inert solvent used in the aforementioned process should
be one which appreciably solubilizes the reactants and does not react to any
appreciable extent with either the reactants or the products formed. Preferred
are polar solvents which are miscible or immiscible with water. Especially
preferred are methylene chloride and acetone-water.
Sincç heating of amino-oleandomycins leads to some decomposition, it
is preferred that the process leading to 1 or 2 be conducted at 0-25C. Es- I
pecially preferred is a reaction conducted at ambient or room temperature.
Reaction time is not critical and is dependent on reaction tempera-
ture, concentration and inherent reactivity of the starting reagents. When the
reactions are cQnducted at room temperature at the hereinafter mentioned concen-
trations, the reaction is essentially complete in 2 to 48 hours.
~ I
; ~~ j
The reaction, on completion, can be worked-up in one of two manners,
both of which are known to those skilled in the art. The first work-up
mcthod c:omprises adding the reaction mixture to water ~ollowed by separation
o the water immiscible solvent, which contains the desired product, and
its subsequent remova] to give the crude product. When a water miscible
solvent is employed as the reaction-inert solvent, the product is extracted
from the water quenched reaction mixture using a water immiscible solvent,
such as methylene chloride.
The second method of work-up comprises concentration of the reaction
mixture to dryness followed by the extraction of the product from the salt
resulting from the scavenger base and hydrogen halide by-product using
acetone. The acetone extract can be concentrated to give crude product.
l'he crude product or an acetone soluti.on thereof is purified by
chromatographing on silica gel, a procedurc well known in the art, or
recrystallization.
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~L~913~23
The starting 4"-amino compounds used in the synthesis of antibacterial
agents of the present invention are synthesized by oxidation of the natural
oleandomycin followed by a reductive amination of the resultant ketone as here-
l inafter described.
5 1l In the utilization of the chemotherapeutic activity of those compounds
Il of the present invention which form salts, it is preferred, of course, to use
j, pharmaceutically acceptable salts. Although water-insolubility, high toxicity,
I¦ or lack of crystalline nature may make some particular salt species unsuitable ¦
- If or less desirable for use as such in a given pharmaceutical application, the
~ water insoluble or toxic salts can be converted to the corresponding pharmaceu-
~tically acceptable bases by decomposltion of the salt with a suitable base or
alternately they can be converted to any desired pharmaceutically acceptable
acid addition salt.
Examples of acids which provide pharmaceutically acceptable anions
l are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous,
phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic,
aspartic, glutamic, pyroglutamic and lauryl sulfuric acids.
The novel 4"-deoxy-4"-amino-oleandomycin derivatives described herein
, exhibit in vitro activity against a variety of Gram-positive microorganisms
l, such as Staphylococcus aureus and Streptococcus pyogenes and against certain
Gram-negative microorganisms such as those of spherical or ellipsoidal shape
(cocci). Their activity is readily demonstrated by in vitro tests against
various microorganisms in a brain-heart infusion medium by the usual two-fold
serial dilution technique. Their in vitro activity renders them useful for
topical application in the form of ointments, creams and the like; for sterili-
zation purposes, e.g., sick-room utensils; and as industrial antimicrobials,
for example, in water treatment, slime control, paint and wood preservation.
~ 8~23
:'
For in vitro use, e.g., for topical application, it will often be
convenient to compound the selected product with a pharmaceutically-acceptable
carrier such as vegetable or mineral oil or an emollient cream. Similarly,
they may be dissolved or dispersed in liquid carriers or solvent, such as
5 1I water, alcohol, glycols or mixtures thereof or other pharmaceutically-acceptable
inert media; that is, media which have no harmful effect on the active ingre-
!l dient. Fàr such purposes, it will generally be acceptable to employ concen-
¦ trations of active lngredients of from about 0.01 percent to about 10 percent
llby weight based on total composition.
lO i Additionally, many compounds of this invention are active versus Gram-
positive microorganisms via the oral and/or parenteral route of administration
in animals, including man. ~heir in vivo activity is more limited as regards
susceptible organisms and i9 determined by the usual procedure which comprises
inoculating mice of substantially uniform weight with the test organism and sub-
sequently treating them orally or subcutaneously with the test compound. Inpr~ctice, the mice, e.g. lO, are given an intraperitoneal inoculation of suit-
ably diluted cultures containing approximately 1 to lO times the LD100 (the
lowest concentration of organisms required to produce 100% deaths). Control
tests are simultaneously run in which mice receive inoculum of lower dilutions
as a check on possible variation in virulence of the test organism. The test
compound is administered 0. 5 hour post-inoculation, and is repeated 4, 24 and
48 hours later. Surviving mice are held for four days after the last treatment
and the number of survivors is noted.
'i
9~ 3
, W~len used in vivo, these novel compounds can be administered orally
jor parenterally, e.g., by subcutaneous or intramuscular injection, at a dosage
f from about 1 mg./kg. to about 200 mg./kg. of body weight per day. The
l favored dosage range is from about 2 mg./kg. to about 100 mg./kg. of body weighq
~per day and the preferred range from about 2 mg./kg. to about 50 mg./kg. of
¦body weight per day. Vehicles suitable for parenteral injection may be either
aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution,
l or non-aqueous such as fatty oils or vegetable origin (cotton seed, peanut oil,¦
¦Icorn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not
lO l¦interfere with therapeutic efficiency of the preparation and are non-toxic in
~¦the volume or proportion uaed (glycerol, propylene glycol, sorbitol). Addi-
!~ tionally, compositions suitable for extemporaneous preparation of solutions
l~prior to administration may advantageously be made. Such compositions may in- ¦
¦¦clude liquid diluents, for example, propylene glycol, diethyl carbonate, gly-
15 ¦I cerol, sorbitol, etc.; buffering agents, hyaluronidase, local anesthetics and
Il inorganic salts to afford desirable pharmacological properites. These compound9
I~ may also be combined with various pharmaceutically-acceptable inert carriers in
¦¦ cluding solid diluents, aqueous vehicles, non-toxic organic solvents in the for~
l of capsules, tablets, lozenges, troches, dry mixes, suspensions, solutions,
20 1 elixirs and parenteral solutions or suspensions. In general, the compounds are¦
used in various dosage forms at concentration levels ranging from about 0.5
,I percent to about 90 percent by weight of the total composition. I
I The following examples are provided solely for the purpose of illus- !
¦ tration and are not to be construed as limitations of this invention, many
25 ~ variations of which are possible without departing from the spirit or scope
¦ thereof.
~1 .
l~ -13- 1
il I
98~Z3
i, 1
il I
EXAMPLE 1
I ll-Acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin
To 30 ml. of dry methylene chloride is added 2.9 g. (4.0 mmoles) of
ll-acetyl-4"-deoxy-4"-amino-oleandomycin, 740 mg. (4.1 mmoles) of 2-thienyl-
sulfonyl chloride and 0.58 ml. (4.2 mmoles) of triethylamine, and the resultingreaction mixture allowed to stir at room temperature for 18 hrs. The reaction
mixture is poured into 50 ml. of water and is subsequently washed with a satu-
rated brine solution and dried over sodium sulfate. The solvent is removed
under reduced pressure and the residual foam purified by chromatographing over
a silica gel column using acetone as the solvent and eluate. The fractions
contalning the product are combinet and concentrated in vacuo to dryness, 1.3 g
NMR (~, CDC13): 2.03 (3H)~; 2.30 (6H)s; 2.63 (2H)d; 3.16 (3H)s and
j 6.8-7.8 (3H)m.
l ~XAMPLE 2
I
15 l¦ Starting with ll-acetyl-4"-deoxy-4"-amino-oleandomycin and the ap-
¦l propriate sulfonyl chloride and employing the procedure of Example 1, the
j following compounds are prepared:
9t~1Z3
OCN5
R NMR (~, CDC13~
2.08 (3H)s; 2.30 (6H)s; 2.67 (2H)m;
Cl ~ 3.23 (3H)s and 6.87 and 7.45 (2H)s.
¦ N CH3 2.09 (3H)s; 2.42 (6H)s; 2.70 (2H)m
5 ¦ CH3GNH Y S\~ and 3.26 (3H)s.
O ~ 2.0 (3H)s; 2.33 (6H)s; 2.40 (3H)s;
CH3C~H ~ S ~ 2i66 (2H)d; 3.33 (3H)s and 7.86
. ~ 2.03 (3H)s; 2.33 (6H)s; 2.66 (2H)d;
. N 3.03 (3H)s and 7.40-9.16 (4H)m.
N ~ 2.06 (3H)s; 2.36 (6H)s; 2.71 (2H)s;
7 92 (4H)m.
~ ~ 2.08 (3H)s; 2.31 (6H)s; 2.59 (6H)s;
~ N 2~65 (2N)s 5~01 ~5N)s ~nd 7~11 (l)s.
.'
-15-
~(~98~23
,
1,~
2.07 (3H)s; 2.32 (6H)s; 2.67 (2H)s;
3.20 (3H)s; 7.32 (lH)m; 7.43 (lH)m
S and 8.02 (lH)m.
2.06 (3H)s; 2.29 (6H)s; 2.64 (2H)m;
3.26 (3H)s; 6.52 (lH)m; 6.77 ~lH)m
N and 7.29 (lH)m.
H
~ 2.07 (3H)s; 2.62 (6H)s; 3.25 (3H)s;
j C 3 2 CH 3.83 (3H)s; 3.95 (3H)s and 7.30 (2H)m.
,__~ 2.08 (3H)s; 2.31 (6H)s; 2.68 (2H)m;
3.25 (3H)s; 6.74 (lH)m; 7.48 (lH)m
0 and 8.00 ( lH) m .
,
;
. .
' - 16 -
~g8~z3
,
"
li EXAMPLE 3
The procedure of Example 1 is repeated, starting with the requisite
sulfonyl chloride and ll-alkanoyl-4"-deoxy-4"-amino-oleandomycin, to give the
l following congeners: ll-propionyl-4"-deoxy-4"-(2-thienylsulfonylamino)-
5 ! oleandomycin; 11-propionyl-4"-deoxy-4"-(2-acetamido-5-thiazolylsulfonylamino)-
oleandomycin; ll-propionyl-4"-deoxy-4"-(2-benzimidazolylsulfonylamino)oleando- 1mycin; ll-acetyl-4"-deoxy-4"-(4,5-dimethyl-2-pyrimidinylsulfonylamino)oleando- jmycin; ll-propionyl-4"-deoxy-4"-(4,6-dimethyl-2-pyrimidinylsulfonylamino)-
oleandomycin; ll-propionyl-4"-deoxy-4"-(3-chloro-2-thienylsulfonylamino)olean-
domycin; 11-acetyl-4"-deoxy-4"-(4-chloro-2-thienylsul~onylamino)oleandomycin;
I ll-acetyl-4"-deoxy-4"-(2-chloro-4-thienylsulfonylamino)oleandomycin; ll-acetyl-,
¦ 4"-deoxy-4"-(2-pyridylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-(3-~I pyridylsulfonylamino)oleandomycin; ll-acetyl-4"-deoxy-4"-(4-pyridylsulfonyl-
!1 amino)oleandomycin; 11-acetyl-4"-deoxy-4"-(2-furylsulfonylamino)oleandomycin;15 ~l 11-propionyl-4"-deoxy-4"-(2-pyrrylsulfonylamino)oleandomycin; 11-propionyl-4"-
deoxy-4"-(1-methyl-5-carbomethoxy-3-pyrrylsulfonylamino)oleandomycin; and 11-
propionyl-4"-deoxy-4"-(3-thienylsulionyl = ino)ole~n~omytin.
I, .
.,
, I
9~3~23
,
II EXAMPLE 4
~ Acetyl-4"-deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin
~l l
To a solution of 2.91 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4"-amino,
I oleandomycin and 528 ~1 (4.2 mmoles) of triethylamine in 20 ml. of methylene
chloride is added in portions 865 mg. (4.1 mmoles) of p-chlorophenylsulfonyl
chloride, and the resulting reaction mixture allowed to stir at room tempera-
ture overnight. The reaction is concentrated to dryness in vacuo and the resi
due treated with 10 ml. of acetone. The suspension is filtered and the fil---
l trate chromatographed on 160 g. of silica gel using acetone as eluate. Frac- ¦
10 l¦ tlons 51 through 63 comprlsing 10 ml. each are collected and concentrated unde~
reduced pressure to give 857 mg. of the pure product. Fractions 42-52 and 64-i
92 yielded 1.21 g. of less pure product.
NMR (~, CDCl3): 2.13 (3H)s; 2.36 (6H)s; 2.73 (2H)d; 3.13 (3H)s and
~l 7.3-8.2 (4H)q.
15 1I Similarly, 20 g. of 11-acetyl-4"-deoxy-4"-amino-oleandomycin, 7.24 g.
Il of p-chlorophenylsulfonyl chloride and 5.36 g. of triethylamine in a solvent
system comprising 350 ml. of acetone and 350 ml. of water gave 17.1 g. of the j
,I desired product which crystallized from the reaction mixture, m.p. 202-203.5 C
I The analytical sa=ple ls rectystallized from ethanol w~ter.
I .
, -18-
~9~3lZ3
EXA~PLE 5
Employing the procedure of Example 4 and starting with the requisite
sulfonyl chloride and ll-acetyl-4"-deoxy-4"-amino-oleandomycin, the following
compounds are prepared: H ~i ~CH3~2
I O ~ ~
CH3CO, y ~ "` ~
¢~HS02R
l OCH3
5 1 R NMR (~, CDC13)
2.08 (3H)s; 2.33 (6H)s; 2.70 (2H)d;
I ~ 3.11 (3H)s; and 7.5-8.2 (4H)q.
2.08 (3H)s; 2.31 (6H)s; 2.66 (2H)d;
F ~ 3.06 (3H)s and 7.0-8.4 (4H)m.
~ 2.03 (3H)s; 2.33 (6H)s; 2.66 (2H)d;
3.10 (3H)s; and 7.3-8.0 (4H)m.
Cl
2.03 (3H)s; 2.33 (6H)s; 2.63 (2H)d;
3.23 (3H)s and 7.2-8.4 (4H)m.
F
~ 2.13 (3H)s; 2.35 (6H)s; 2.70 (2H)d;
~ 2.90 (3H)g and 7.0-8.2 (4H)m.
~ 2.10 (3H)s; 2.33 (6H)s; 2.66 (2H)d;
Br ~ 3.10 (3B)~ and 7.5-7.93 (4B)m.
1~ -19-
1~9B123
EXAMPLE 6
The procedure of Example 4 is again repeated starting with the appro-
priate sulfonyl chloride and ll-alkanoyl-4"-deoxy-4"-amino-oleandomycin to
give the following products: ll-propionyl-4"-deoxy-4"-(p-chlorophenylsulfonyl-
S amino)oleandomycin; ll-acetyl-4"-deoxy-4"-(m-bromophenylsulfonylamino)oleando-
mycin; ll-acetyl-4"-deoxy-4"-(m-fluorophenylsulfonylamino)oleandomycin; 11-
propionyl-4"-deoxy-4"-(m-iodophenylsulfonylamino)oleandomycin; ll-propionyl-
4"-deoxy-4"-(p-fluorophenylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-
4"-(p-bromophenylsulfonylamino)oleandomycin; 11-acetyl-4"-deoxy-4"-(m-iodo-
phenylsulfonylamino)oleandomycin and 11-acetyl-4"-deoxy-4"-(o-bromophenylsul-
fonylamino)oleandomycln.
EXAMPLE 7
ll-Acetyl-4"-deoxy-4"-(o-tolylsulfonylamino)oleandomycin
A solution of 2.9 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin, 780 mg. (4.1 mmoles) of o-tolylsulfonyl chloride and .58 ml.
(4.2 mmoles) of triethylamine in 30 ml. of methylene chloride is allowed to
¦ stir at room temperature for 48 hrs. The reaction is quenched in 50 ml. of
¦I water and the separated organic layer washed with a saturated brine solution
and dried over sodium sulfate. The solvent is removed in vacuo and the resi-
dual yellow foam chromatographed on 200 g. of silica gel in a 3 cm. diameter
column. The product is eluted from the column with acetone collected in 10 ml.
fractions. Those fractions containing the pure product, as assayed by thin-
layer chromatography, are combined and concentrated to dryness under reduced
pressure to give 1.3 g.
NMR (~, CDC13): 2.06 (3H)s; 2.33 (6H)s; 2.46 (2H)d; 2.73 (3H)s and
7.1-8.2 (4H)m.
.'
1(~98~23
,
EXAMPLE 8
The procedure of Example 7 is repeated, starting with the sppropriate ¦
sulfonyl chloride and ll-acetyl-4"-deoxy-4"-amino-oleandomycin, to give the
following compound~:
Cd3CO "~ ~ C~3)2
OC~33
R NMR (~, CDC13)
/~==\ 2.03 (3H)s; 2.30 (6H)s; 2.66
CH 0-~ (2H)d; 3.06 (3H)s; 3.83 (3H)s;
3 W and 6.8-8.2 (4H)m.
ll 2.03 (3H)s; 2.33 (6H)s; 2.66
10 ¦ CH C ~ (2H)d; 3.06 (3H)s; and 7.3-
¦ ( 3~3 ~ 8.0 (4H)m.
OCH3
2.08 (3H)s; 2.30 (6H)s; 2.66
(2H)d; 2.83 (3H)s; 4.03 (3H)s;
~ and 6.8-8.2 (4H)m.
~ 2.06 (3H)s; 2.30 (6H)s; 2.43
CH3~ (3H)s; 3.10 (3H)s; 2.66 (2H)d;
~__Y 7.23-7.40 (2H)d; and 7.76-
7.93 (23)d.
-21-
i
9~23
EXAMPLE 9
I
Starting with the appropriate ll-alkanoyl-4"-deoxy-4"-amino-oleando-
mycin and sulfonyl chloride and employing the procedure of Example 7, the
following analogs are synthesized: ll-acetyl~4"-deoxy-4"-(_-tolylsulfonyl-
amino)oleandomycin; ll-propionyl-4"-deoxy-4"-(p-methoxyphenylsulfonylamino)-
oleandomycin; ll-acetyl-4"-deoxy-4"-(m-methoxyphenylsulfonylamino)oleandomycin;
ll-propionyl-4"-deoxy-4"-(p-tolylsulfonylamino)oleandomycin; 11-acetyl-4"-deoxy _
4"-(p-isopropylphenylsulfonylamino)oleandomycin; 11-acetyl-4"-deoxy-4"-(o-
ethylphenylsulfonylamino)oleandomycin; ll-propionyl-4"-deoxy-4"-(o-[n-propyl]-
phenylsulfonylamino) ol eandomycin; 11-acetyl-4"-deoxy-4"-(p-[s-butyl]phenylsul-
fonylamino)oleandomycin; and 11-propionyl-4"-deoxy-4"-(p-[n-butyl]phenyl8ul-
fonylamino)oleandomycin.
EXAMPLE 10
¦1 11-AcetYl-4"-deoxy-4"-phenylsulfonylamino-oleandomycin
15 ¦I To a solution of 2.91 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
¦~ oleandomycin and 424 mg. (4.2 mmoles) of triethylamine in 30 ml. of methylene
¦ chloride and cool in an ice bath is added 722 mg. (4.1 mmoles) of benzenesul-
¦ fonyl chloride: After 10 min., the bath is removed and the reaction mixture
~ allowed to stir at room temperature overnight. The reaction iS quenched with
20 , 50 ml. of water and the organic layer w~shed with a saturated brine solution
and dried over sodium sulfate. Removal of the solvent provides the crude pro-
duct which is further purified by chromatographing over 160 g. of silica gel
using acetone as the eluate. Cuts (10 ml. each) 61-93, which contain the pure
Il product as determined by thin-layer chromatography, are combined and concentra-
25 ¦ ted to dry under reduced pressure to give 1.5 g. of the desired product.
NMR (~, CDCl~): 2.06 (3H)S; 2.30 (6H)S; 2.63 (2H)d; 3.06 (3H)s;
¦ and 7.3-~.2 (5H)m.
-22-
398~Z3
I Also prepared by the procedure of Example 10 when the appropriate
¦ starting materials are employed are:
ll-acetyl-4"-deoxy-4"-(2-naphthylsulfonylamino)oleandomycin
NKR (~, CDC13~: 2.03 (3H)s; 2.26 (6H)s; 2.65 (2H)d; 2.96 (3H) ; and
7.4-8.6 (7H)m; and
ll-acetyl-4"-deoxy-4"-benzylsulfonylamino-oleandomycin
NMR (~, CDC13): 2.00 (3H)s; 2.30 (6H)s; 2.63 (2H)d; 3.46 (3H)s;
4.33 (2H)s; and 7.36 (5H)s.
EXAMPLE 11
11-Acetyl-4"-deoxy-4"-(p-benzyloxycarbonylphenylsulfonylamino)oleandomycin
A solution of 2.55 g. (3.5 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin, 1.12 g. (3.6 mmoles) of p-benzyloxycarbonylphenylsulfonyl chlor-
i ide and 379 mg. (3.75 mmoles) of triethylamine in 25 ml. of methylene chloride
¦¦ is allowed to stir at room temperature overnight. The solvent is removed in
¦ vacuo and the residue triturated in 10 ml. of acetone. The solids are filtered
and the filtrate chromatographed on 280 g. of silica gel using acetone as the
eluate and fraction sizes of 10 ml. Fractions 90-203, which by thin-layer
chromatography contain most of the pure product, are combined and concentrated
~ under reduced pressure to give 1.25 g. of the desired product.
20 ¦ NMR (~, CDC13): 2.04 (3H)s; 2.30 (6H)s; 2.66 (2H)d; 3.01 (3H)s;
5.48 (2H)s; 7.50 (5H)s; and 8.03-8.53 (4H)m.
1;Z3
EXAMPLE 12
Starting with the appropriate sul~onyl chloride and ll-acetyl-4"-deoxy~
4"-amino-oleandomycin and employing the procedure of Example 11 gives the fol-
lowing compounds:
Ci3CO", ~ ~
3SOzi
OCH3
R NMR (~, CDC13)
_ i
2.06 (3H)s; 2.30 (6H)s; 2.66
(2H?d; 3.03 (3H)s; 3.96 (3H)
l ~ s; and 7.3-9.0 (4H)m.
! 3 CH3
2.05 (3H)s; 2.30 (6H)s; 2.65
(2H)d; 3.01 (3H)s; 5.43 (2H)d;
7.46 (5H)s; and 7.33-8.70 (4H)m.
\~CH 0
C ~ \ 2.06 (3H)s; 2.30 (6H)s; 2.66
3 ~ (2H)d; 3.06 (3H)s; 4.0 (3H)s;
and 7.8-8.4 (4H)m.
~ 2.10 (3H)s; 2.30 (6H)s; 2.70
C83O (2H)d, 3.0 (3H)s; and 4.10
~ ,
.'
I -24-
i I
~ g8~23
EXAMPLE 13
The procedure of Example 11 is again repeated, starting with the re-
quisite ll-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride to
give the following compounds~ acetyl-4"-deoxy-4"-(o-benzyloxycarbonylphenyl _
sulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-(p-methoxycarbonylphenyl-
sulfonylamino~oleandomycin; ll-propionyl-4"-deoxy-4"-(m-benzyloxycarbonylphenyl
sulfonylamino)oleandomycin; ll-propionyl-4''-deoxy-4''-(p-benzyloxycarbonylphenyl _
sulfonylamino)oleandomycin; ll-propionyl-4"-deoxy-4"-(o-methoxycarbonylphenyl-
sulfonylamino)oleandomycin; and ll-propionyl-4"-deoxy-4"-(o-benzyloxycarbonyl-
phenylsulfonylamino)oleandomycin.
EXAMPLE 14
ll-Acetyl-4"-deoxy-4"-(p-carboxyphenylsulfonylamino)oleandomycin
A suspension of 400 mg. of 10% palladium-on-charcoal in 40 ml. of
ethyl acetate containing 800 mg. of 11-acetyl-4"-deoxy-4"-(p-benzyloxycarbonyl-
phenylsulfonylamino)oleandomycin is shaken in a hydrogen atmosphere at aninitial pressure of 50 p.s.i. at room temperature for 2 hrs. An additional
250 mg. of catalyst is added and the reaction continued for 2 hrs. The spent
catalyst is filtered and the solvent removed in vacuo to give 450 mg. of the
¦ desired product.
NMR (~, CDC13): 2.06 (3H)s; 2.86 (6H)s; 2.68 (2H)d; 3.30 (3H)s; and
7.5-8.4 (4~)=.
Il _ ~5_
1,~. 1
11)981Z3
I EXAMPLE 15
Starting with the appropri~e ll-alkanoyl-4"-deoxy-4"-(benzyloxycar-
¦ bonylphenylsulfonylamino)oleandomycin described in Example 12 and 13 and employl
ing the procedure of Example 14, the following compounds are prepared: ll-acety. _
4"-deoxy-4"-(m-carboxyphenylsulfonylamino)oleandomycin; 11-acety1-4"-deoxy-4"- L
¦ (o-carboxyphenylsulfonylamino)oleandomycin; ll-propionyl-4"-deoxy-4"-(m-rarboxy
phenylsulfonylamino~oleandomycin; ll-propionyl-4"-deoxy-4"-(p-carboxyphenyl-
sulfonylamino)oleandomycin; and ll-propionyl-4"-deoxy-4"-(o-carboxyphenylsul-
fonylamino)oleandomycin. ~~
10 1 EXAMPLE 16
¦~ ll-Acetyl-4"-deoxy-4"-(o-nitrophenylsulfonylamlno)oleandomycin
¦~ Five gram9 (6.8 mmole8) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin,
1.5 g. (7.0 mmoles) of o-nitrobenzene5ulfonyl chloride and .98 ml. of triethyl-
amine are combined in 50 ml. of methylene chloride and allowed to stir at room
temperature for 48 hrs. The reaction mixture is quenched with an equal volume
of water, and the organic phase washed with a saturated brine solution and
;! dried over sodium sulfate. Removal of the solvent under reduced pressure pro- ¦ -
~¦ vides the crude product as a foam. The product is purified by chromatographingll
l! on 140 g. of silica gel in a 3 cm. diameter column using acetone as the eluate.¦
20 ¦ Fractions 20-30, comprising 50 ml. each, are collected, combined and concentra-
ted to dryness to give 3.4 g. of the desired compound.
NMR (~, CDC13): 2.10 (3H)s; 2.33 (6H)S; 4.36 (2H)d; 2.~0 (3H)S; and
7.4-8.4 (4U)m.
-26-
11 1
! I
,1 i
- ~98~3
Similarly, when the proper starting materials are employed
and the above procedure is repeated the following compounds are pre-
pared:
ll-acetyl-4"-deoxy-4"-(m-nitrophenylsulfonylamino)oleandomycin
NMR (~, CDC13): 2.06 (3H)s; 2.30 (6H)s; 2.66 (2H)d;
3006 (3H)s; and 7.4-9O0 (4H)m and
ll-acetyl-4"-deoxy-4"-(p-nitrophenylsulfonylamino)oleandomycin
NMR (~, CDC13): 2.10 (3H)s; 2D35 (6H)s; 2068 (2H)d;
3.06 (3H)s; and 8.0-8.6 (4H)m.
EXAMPLE 17
ll-Acetyl-4"-deoxy-4"-(p-hydroxyphenylsulfonylamino)oleandomycin
A solution of 2.55 g. (3.5 mmoles) of 11-acetyl-4"-deoxy-
4"-amino-oleandomycin, 701 mg. (3.65 mmoles) of p-hydroxyphenyl
sulfonyl chloride and 51.8 ~1. of triethylamine in 25 ml. of methylene ;
chloride is allowed to stir at room temperature for 48 hrs. The
solvent is removed in vacuo and the residue treated with 10 ml. of
acetone. The insolubles are filtered and the filtrate chromatographed
over 200 g. of silica gel using acetone as the eluate. Fractions
116-175, which by thin-layer chromatography contains the pure productJ
are combined and concentrated to dryness under reduced pressure to
give 550 mg. of the desired product.
NMR (~, CDC13): 2.0 (3H)s; 2.33 (6H)s; 2.68 (2H)d;
3.06 (3H)s; and 6.6-8.0 (411)m.
~ 27 ~
98~23
1~ 1
¦ EXAMPLE 18
I
Starting with the re~uisite ll-alkanoyl-4"-deoxy-4''-amino-oleandomycin
and sulfonyl chloride and employing the procedure of Example 17, the following
compounds are prepared: ll-acetyl-4"-deoxy-4"-(m-hydroxyphenylsulfonylamino)-
S oleandomycin; ll-propionyl-4"-deoxy-4"-(p-hydroxyphenylsulfonylamino~oleandomycin;
ll-propionyl-4"-deoxy-4"-(_-hydroxyphenylsulfonylamino)oleandomycin; ll-acetyl-
4"-deoxy-4" (o-hydroxyphenylsulfonylamino~oleandomycin; and 11-propionyl-4"-
Ideoxy-4''-(o-hydroxyphenylsulfonylamino)oleandomycin.
¦ EXAMPLE 19
i
11-Acetyl-4"-deoxy-4"-(m-carboxamldophenylsulfonylamino)oleandomycin
To 20 ml. of methylene chlorite containing 2.91 g. (4.0 mmoles) of llj
acetyl-4"-deoxy-4"-amino-oleandomycin and 434 mg. (4.2 mmoles) of triethylamine
is added 898 mg. (4.1 mmoles) of _-carboxamidophenylsulfonyl chloride, and the
resulting reaction mixture allowed to stir for 48 hrs. The solvent is removed ¦
15 ¦in vacuo and the residue treated with 25 ml. of acetone. The triethylamine
hydrochloride is filtered and the filtrate chromatographed on 160 g. of silica
gel. Fractions containing 50 ml. each are collected and examined by thin-layer
chromatography to determine the purity of the product. Fractions 66-93 are com
Ibined and concentrated under reduced pressure to give 800 mg. of the desired
20 product. I
NMR (~, CDC13): 2.06 (3H)S; 2.33 (6H)S; 2.70 (2H)s; 3.10 (3H)s; and !
7,4-9 0 (4H)m. I
I ,
Il , . .
Il -28-
11 :
11~981Z3
1~ 1
1~ l
¦ EXAMPLE 20
The procedure of Example 19 is repeated, starting with the appropriate
ll-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride to give the 1.
following congeners: ll-propionyl-4"-deoxy-4"-(m-carboxamidophenylsulfonylamino3-
oleandomycin; 11-acety1-4"-deoxy-4"-(o-carboxamidophenylsulfonylamino)oleando-
~mycin; ll-acetyl-4"-deoxy-4"-(p-carboxamidophenylsulfonylamino)oleandomycin;
ll-propiony1-4"-deoxy-4"-(o-carboxamidophenylsulfonylamino) ol eandomycin; and
propionyl-4"-deoxy-4"-(p-carboxamidophenylsulfonylamino)oleandomycin.
EXAMPLE 21
l ll
10 I ll-Acetyl-4"-deoxy-4"-(p-acetamidophenylsulfonylamino)oleandomyc in
l A solution of 2.91 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4'1-amino-
¦oleandomycin, 955 mg. (4.1 mmoles) of p-acetamidophenylsulfonyl chloride and
424 mg. (4.2 mmoles) of triethylamine in 20 ml. of methylene chloride is allowe~
~to stir for 48 hrs. at room temperature. The reaction mixture is concentrated
lunder reduced pressure to a foam which is then treated with 10 ml. of acetone.
The insoluble triethylamine hydrochloride is filtered and the filtrate chroma-
tographed on 160 g. of silica gel using acetone as the eluate. Cuts 42-86,
which by thin-layer chromatography contained most of the pure product, are
combined and concentrated in vacuo to give 1.2 g. of the desired product.
NMR (~, CDC13): 2.06 (3H)s; 2.23 (3H)s; 2.35 (6H)s; 2.70 (2H)s;
3.13 (3U)s; and 7.6-3.2 (bd)~.
11 '1
I -29-
l l
' ',
981Z3
EXAMPLE 22
The procedure of Example 21 is repeated, employing as
starting reagents the appropriate ll-alkanoyl-4"-deoxy-4"-amino-
oleandomycin and requisite sulfonyl chloride, to give the following
compounds: ll-propionyl-4"-deoxy-4"-(_-acetamidophenylsulfonylamino)
oleandomycin; ll-propionyl-4"-deoxy-4"-(o-acetamidophenylsulfonyl-
amino)oleandomycin; ll-acetyl-4"-deoxy-4"-(_-ace~amidophenylsulfonyl-
amino)oleandomycin; and ll-propionyl-4"-deoxy-4"-(o-acetamidophenyl-
sulfonylamino)oleandomycin.
EXAMPLE 23
ll-Acetyl-4"-deoxy-4"-(p-cyanophenylsulfonylamino)oleandomycin
A solution of 2.55 g. (3.5 mmoles) of ll-acetyl-4"-deoxy-
4"-amino-oleandomycin, 734 mgO (3.65 mmoles) of ~-cyanophenylsulfonyl
chloride and 518 ~l. (3.75 mmoles) of triethylamine in 25 ml. of
methylene chloride is allowed to stir at room temperature overnight.
The solvent is removed _ vacuo and the residue treated with lO ml.
of acetone. The insolubles are filtered and the filtrate chromato-
graphed on 120 g. of silica gel using acetone as the eluate and
collecting fractions of lO ml. each. Fractions 47-83 are combined
2G and concentrated under reduced pressure to give 281 mg of the desired
product.
NMR (~, CDC13): 2010 (3H)s; 2.36 (6H)s; 2.71 (2H)d;
3.06 (3H)s; and 7.7-8.4 (4H)m.
- 30 ~
98123
EXA*IPLE 24
Starting with the requisite ll-alkanoyl-4"-deoxy-4"~amino-oleandomycin
and cyanobenzenesulfonyl chloride and employing the procedure of Example 23, the
following compounds are synthesized: ll-acetyl-4"-deoxy-4"-(m-cyanophenylsul-
fonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-(o-cyanophenylsulfonylamino)-
oleandomycin; ll-propionyl-4"-deoxy-4"-(p-cyanophenylsulfonylamino)oleandomycin;
¦ll-acetyl-4"-deoxy-4"-(o-cyanophenylsulfonylamino)oleandomycin; and ll-propionyl
¦4"-deoxy-4"-(m-cyanophenylsulfonylamino)oleandomycin.
I EXAMPLE 25
10 ¦ 11-Acet~1-4"-deoxy-4"-(p-trlfluoromethylphen~lsulfonylamino)oleantom~cin
To a solution of 2.55 g. (3.5 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin and 518 ~1. (3.75 mmoles) of triethylamine in 25 ml. of methylene
chloride is added 891 mg. (3.65 mmoles) of p-trifluoromethylphenylsulfonyl
chloride, and the resulting reaction mixture allowed to stir for 18 hrs. The
solvent is removed under reduced pressure and the residue triturated with 15
ml. of acetone. The solids are filtered and the filtrate chromatographed over
silica gel to give 287 mg. of the desired product.
NMR (~, CDC13): 2.03 (3H)s; 2.31 -(6H)s; 2.63 (2H)d; 3.40 (3H)s; and
7.15-8.3 (48)=.
'
~1 -31- ~
10981Z3
EXAMPLE 26
The procedure of Example 25 is repeated, starting with the appropriate
reagents, to give the following congeners~ propionyl-4"-deoxy-4"-(_-tri-
¦ fluoromethylphenylsulfonylamino)oleandomycin; ll-acetyl-4"-deoxy-4"-(o-tri-
5 ¦ fluoromethylphenylsulfonylamino)oleandomycin; 11-acetyl-4"-deoxy-4"-(m-tri-
fluoromethylphenylsulfonylamino)oleandomycin; ll-propionyl-4''-deoxy-4''-(p-tri-
fluoromethylphenylsulfonylamino~oleandomycin; and ll-propionyl-4"-deoxy-4"-(o-
trifluoromethylphenylsulfonylamino)oleandomycin.
EXAMPLE 27
10 11-Acetyl-4"-deoxY-4"-(2,2,2-trifluoroethylsulfonylamino)oleandomYcin
A solution of 2.55 g. (3.5 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin, 666 mg. (3.65 mmoles) of 2,2,2-trifluoroethylsulfonyl chloride
and 379 mg. (3.75 mmoles) of triethylamine in 25 ml. of methylene chloride is
~1 allowed to stir for 30 hrs. at room temperature. An additional 333 mg. of the
15 ¦¦ sulfonyl chloride and 270 ~1. of triethylamine are added and the stirring con-
tinued for 4 hrs. The solvent is then removed in vacuo and the residue treatec
with 20 ml. of acetone. The solids are filtered and the filtrate chromatograph~ d
l on llO mg. of silica gel using acetone as the eluate and taking 10 ml. fraction~ .
¦¦ Fractions 50-80 are combined and concentrated to give 385 mg. of the desired
20 ¦ product.
¦ NMR (~, CDC13): 2.06 (3H)s; 2.26 (6H)s; 2.60 (2H)d; and 3.36 (3H)s.
Similarly, starting with ll-propionyl-4"-deoxy-4"-amino-oleandomycin
in place of the ll-acetyl ester and employing the above procedure there is pre-
pared ll-propionyl-4"-deoxy-4"-(2,2,2-trifluoroethylsulfonylamino)oleandomycin.
1~ ~0913lZ3
EXAMPLE 28
ll-Acetyl-4"-deoxy-4"-(methylsulfonylamino)oleandomycin
A solution of 2.91 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin, 467 mg. (4.1 mmoles) of methylsulfonyl chloride and 424 mg. (4.2
mmoles) of triethylamine in 25 ml. of methylene chloride is allowed to stir at
room temperature overnight. The solvent is removed under reduced pressure and
the residue treated with 20 ml. of acetone. The triethylamine hydrochloride is
¦filtered and the filtrate containing the product chromatographed on 180 g. of
¦silica gel using acetone as the qolvent and taking 6 ml. fractions. Cuts 67-133
are combined and concentrated in vacuo to give 1.2 g. of the desired product.
NMR (~, CDC13): 2.06 (3H)s; 2.28 (6H)s; 3.06 (3H)s; 2.61 (2H)d; and
8.40 (3H)s.
EXAMPLE 29
Starting with the requisite alkyl sulfonyl halide and ll-alkanoyl-4"-
deoxy-4"-amino-oleandomycin, and employing the procedure of Example 28, the fol-
-33-
1C~913~23
~S02R
OCH3
Rl R
CH3CO- C2H5-
CH3CO- n~C3H7~
CH3CO- i C3H7
CH3CH2CO- CH3
CH3CH2CO- C2H5
CH3CH2CO- n C3H7
C~3C32co- l_C3~/_
~ '
Il -34-
I
98~Z3
ll
¦ EXAMPLE 30
ll-Acetyl-4"-deoxy-4i'-(3,4-dichlorophenylsulfonylamino)oleandomycin
ll-Acetyl-4"-deoxy-4"-amino-oleandomycin (2.9 g., 4.0 mmoles), 1.0 g.
(4.1 m~oles) of 3,4-dichlorophenylsulfonyl chloride and .57 ml. (4.2 mmoles) of
l triethylamine are combined in 30 ml. of methylene chloride and the resulting
solution allowed to stir at room temperature for 18 hrs. The reaction is
quenched with 50 ml. of water, and the organic phase washed with a saturated
brine solution and dried over sodium sulfate. The solvent is removed in vacuo ¦
and the residue chromatographed on 150 g. of silica gel using acetone as the
eluate. Those fractlons contalning the product, as indicated by thin-layer
chromatography, are combined and concentrated to dryness to give 1.3 g. of the
desired product.
N~R (~, CDC13~: 2.0 (3H)s; 2.30 (6H)s; 2.60 (2H)d; 3.06 ~3H)s; and
7.2-8.1 (3H)m.
EXAMPLE 31
15 ¦ Following the procedure of Example 30, and starting with the appro-
¦1 priate reagents, the indicated compounds are prepared:
1 .
CR3CO~ 2R
OCH3
-35-
. ~L~981;~3
R N~ , CDC13)
! Cl
2.0 (3H)s; 2.36 (6H)s; 2.70
r (2H)d; 3.33 (3H)s; and 7.3-
~ 8.6 (3H~m.
Cl
/Cl
~ 2.10 (3H)s; 2.31 (6H)s; 2.66
Cl ~ (2H)d; 3.30 (3H)s; and 7.2-
8.4 (3H)m.
CH3
~ 2.03 (3H)s; 2.30 (6H)s; 2.66
Cl ~~ ~ (3H)s; 3.10 (3H)s; and 7.1-
10 ¦ ~--J 8.1 (3H)m*.
/~:~ 2.06 (3H)s; 2.33 (6~)s; 2.70
Cl ~ /~ (2H)d; 3.13 (3H)s; and 7.4-
8.6 (3H)m.
~ N02
i N2
l 1 ~ 2.06 (3H)s; 2.40 (6H)s; 2.66
I C ~ (2H)d; 3.25 (3H)s; and 7.2-
8.6 (3H)m*.
2.06 (3H)s; 2.33 (6H)s; 2.63
CH30 - (2H)d; 2.81 (3H)s; 3.63 t3H)s;
and 7.0-8.2 (3H)m*.
! No2
~ 2.06 (3H)s; 2.36 (6H)s; and
2 ~ 8.4-9.0 (3H)m*.
* NMR: DMS0/CDCl3
-36-
!l I
il
"
~ass~z3
EXA~PLE 32
The procedure of Example 30 i8 again repeated, starting with the re-
qui8ite 11-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride, to
give the following analogs: ll-acetyl-4"-deoxy-4"-(2,6-dichlorophenylsulfonyl-
amino)oleandomycin; 11-propionyl-4"-deoxy-4"-(4-methyl-2-chlorophenylsulfonyl-
amino)oleandomycin; ll-propionyl-4"-deoxy-4"-(2-methyl-5-chlorophenylsulfonyl-
amino)oleandomycin; ll-propionyl-4"-deoxy-4"-(2-nitro-4-chlorophenylsulfonyl-
amino)oleandomycin; ll-acetyl-4"-deoxy-4"-(3-nitro-4-chlorophenylsulfonylamino)-oleandomycin; ll-acetyl-4"-deoxy-4"-(3-nitro-5-chlorophenylsulfonylamino)-
oleandomycin; 11-propionyl-4"-deoxy-4"-(3-me~hoxy-5-nitrophenylsulfonylamino)-
oleandomycin; ll-acetyl-4"-deoxy-4"-(3-nitro-4-methylphenylsulfonylamino)-
oleandomycin; ll-acetyl-4"-deoxy-4"-(3,5-dinitrophenylsulfonylamino)oleandomycin ;
ll-acetyl-4"-deoxy-4"-(2,6-dimethoxyphenylsulfonylamino)oleandomycin; ll-pro-
pionyl-4"-deoxy-4"-(2,4-dimethoxyphenylsulfonylamino)oleandomycin; ll-acetyl-
4"-deoxy-4"-(2-methyl-5-methoxyphenylsulfonylamino)oleandomycin; 11-aceLyl-4"-
deoxy-4"-(2,3-dimethylphenylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-
4"-(2,4-dimethylphenylsulfonylamino)oleandomycin; and 11-acetyl-4"-deoxy-4"-(3-
nitro-4-= yls~lfonyla~ino)oleandomycin.
-37-
981;~3
i E ~PLE 33
ll-Acetyl-4"-deoxy-4"-(2,3,4-trichlorophenylsulfonylamino)oleandomycin
A solution of 2.9 g. (4.0 mmoles) of 11-acetyl-4"-deoxy-4"-amino-
oleandomycin, 1.15 g. (4.1 mmoles) of 2,3,4-trichlorophenylsulfonyl chloride and.57 ml. (4.2 mmoles) of triethylamine in 30 ml. of methylene chloride is allowedto stir at room temperature for 18 hrs. The organic layer is washed with water
(1 x 50 ml.) and a saturated brine solution (1 x 50 ml.) and subsequently dried
over sodium sulfate. The solvent is removed in vacuo and the residuP is re-
moved in vacuo and the residue chromatographed on 150 g. of silica gel using
acetone as the solvent, taking fraction of 7 ml. each. Fractions 60-100 are
comblned and concentrated to give 800 mg. of the deslred product.
NMR (~, CDC13): 2.06 (3H)s; 2.33 (6H)s; 2.63 (2H)d; 3.2 (3H)s; and
7.2-8.2 (2H)m.
Similarly, by starting with the appropriate reagents and following th~
above procedure, the following compounds are synthesized: 11-acetyl-4"-deoxy-4"(3,4,5-trichlorophenylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-
(2,4,6-trichlorophenylsulfonylamino)oleandomycin; and 11-acetyl-4"-deoxy-4"-
t~ V A
-38-
1~9~23
EXAMPLE 34
l Acetyl-4"-deoxy-4"-(2-hydroxy-3,5-dichlorophenylsulfonylamino)
oleandomycin
The procedure of Example 33 is repeated, starting with
2.55 g. (3.5 mmoles) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin,
954 mg. (3O65 mmoles) of 2-hydroxy-3,5-dichlorophenylsulfonyl
chloride and 518 ~lo (3.75 mmoles) of triethylamine in 25 ml. of
methylene chloride to give, after chromatographing on 220 g. of
silica gel, 483 mg. of the desired product.
NMR (~, CDC13/DMSO): 2.03 (3H)s; 2.50 (6H)s; 3.05 (3H)s;
and 7.2-7.8 (2H)m.
EXAMPLE 35
Starting with the requisite ll-alkanoyl-4"-deoxy-4"-
amino-oleandomycin and sulfonyl chloride and employing the pro-
cedure of Example 33, the following congeners are prepared:
O
O
OCH3
39 ~
lU9~ilZ3
C33CO- ~ OU
C33CO- Cl
C33CO- ~ OH
S 1I CU3C0- ~ Cl
CH3CH~CO- HO coCll
CH3CH2C- ~cOH
C33C32CO- ~ Cl
CH3C3~CO- ~
lO9~1Z3
EXAMPLE 36
ll-Acetyl-4"-deoxy-4"-(3-amino-4-chlorophenylsulfonylamino)oleandomycin
A suspension of 500 mg. of 10% palladium-on-charcoal in 50 ml. of
ethyl acetate containing 1.0 g. of 11-acetyl-4"-deoxy-4"-(3-nitro-4-chlorophenylsulfonylamino~oleandomycin is shaken in a hydrogen atmosphere at an initial
¦pressure o 50 p.s.i. at room temperature overnight. The spent catalyst is fil-¦
¦tered and the solvent removed in vacuo. The residual white foam is chromato-
~graphed on 160 g. of silica gel using acetone as the eluate, taking 50 ml. cuts.
¦I The fractions containing the product are combined and concentrated under reduced
10 l¦pre~sure to give 450 mg. of the desired material.
N~R (~, CDC13): 2.03 (3H)8; 2.33 (6H)5; 2.66 (2H)d; 3.16 (3H)S;
and 7.2-8.0 (3H)m.
Prepared in a 9imilar manner, employing the appropriate nitro com-
l pound of Example 16 are:
15 ¦¦ 11-acetyl-4"-deoxy-4"-(m-aminophenylsulfonylamino)oleandomycin
NMR (~, CDC13): 2.03 (3H)s; 2.30 (6H)S; 2.63 (2H)d; 3.10 (3H)S;
and 7.0-7.8 (4H)m and
ll-acetyl-4"-deoxy-4"-(p-aminophenylsulfonylamino)oleandomycin
l N~R~(~, CDC13): 2.06 (3H)S; 2.31 (6H)s; 3.02 (3H)s; and 6.4-7.8
(4U)dd.
Il .
Il l
Il -41-
11 l
~981Z3
! EXAMPLE 37
',i
Starting with the requisite nitro compounds in Example 31 and 32
,and employing the reduction procedure of Example 36, the following amino com-
¦¦pounds are prepared~ acetyl-4"-deoxy-4"-(2-amino-4-chlorophenylsulfonyl-
5 ~lamino)oleandomycin; 11-acetyl-4"-deoxy-4"-(2-amino-4-methoxyphenylsulfonylamino~-
oleandomycin; ll-acetyl-4"-deoxy-4"-(2,4-diaminophenylsulfonylamino)oleandomy- ¦
cin; ll-propionyl-4"-deoxy-4"-(2-amino-4-chlorophenylsulfonylamino)oleandomycin~
ll-acetyl-4"-deoxy-4"-(3-amino-4-chlorophenylsulfonylamino)oleandomycin; 11-
l lacetyl-4"-deoxy-4"-(3-amino-5-chlorophenylsulfonylamino)oleandomycin; ll-pro-
10 1,pionyl-4"-deoxy-4"-(3-methoxy-5-aminophenylsulfonylamino)oleandomycin; ll-acetyl-
¦¦4"-deoxy-4"-(3-amino-4-methylphenyl~ulfonylarnino)oleandomycln; and ll-acetyl-
¦14"_deoxy-4"-(3,5-diaminophenylsulfonylamino)oleandomycin.
EXAMPLE 38
1 11-Acetyl-4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin
15 ,I To 100 g. (0.13 mole) of 11-acetyl-4"-deoxy-4"-amino-oleandomycin in
900 ml. of methylene chloride is added 593 ml. of triethylamine, and the solu-
tion allowed to stir for 10 minutes. 3-Methyl-2-thienylsulfonyl chloride
,1(41.9 g.; 0.213 mole) in 300 ml. of methylene chloride is subsequently added
dropwise over a period of one hour and the reaction mixture allowed to stir at
20 '.room temperature for 48 hours. The reaction mixture is added to 2 1. of water
and the organic layer separated, washed successively with water (2 x 250 ml.)
jand a brine solution (1 x 250 ml.) and dried over sodium sulfate. The solvent
iis removed in vacuo and the residue chromatographed on a 105 cm. x 6.5 cm.
,column containing 1.5 kg. of silica gel. The product, which is eluted with
`acetone, is collected in the 2.3 1. to 6 1. eluate fractions. The fractions
are combined, and the solvent removed under reduced pressure to give a foam.
Treatment of the residual foam with diethyl ether gave 66.4 g. of the desired
product, m.p. 184-185.5 C.
-42-
~ 3123
¦ NMR (~, CDC13): 2.04 (3H)s; 2.41 (6H)s; 2.45 (3H)s; 2.62 (2U)m;
3.02 (3H)s; 6.84 and 7.32 (2H).
¦ To 2 g. of the above free base in 15 ml. of ethyl acetate is added
l 0.12 ml. of phosphoric acid and the resulting solution allowed to stir at room
temperature. After 20 minutes crystals commence to form and after 2 hours arel
filtered, washed with ethyl acetate and dried to give 1.3 g. of 11-acetyl-4"- ¦
deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin phosphate.
NMR ~, CD30D); 2.01 (3H)s; 2.45 (3H)s; 2.56 (2H)m; 2.83 (6H)s;
l 3.0 (3H)s; 6.88 and 7.42 (2H).
10 1 EXAMPLE 39
The procedure oE Example 38 is repeated, starting with the appro-
priate sulfonyl chloride and ll-acetyl-4"-deoxy-4"-amino-oleandomycin to give
the following congeners:
~(CH3)2
'I CU3C0 .", ~ ""` ~
~""'0"
~NHS02Rl
.,
`:
-43-
1 1~981Z3
,
ll
1 Rl NMR (~, CDC13)
jl ~ 2.08 (3H)s; 2.33 (6H)s; 2.38 (3H)s;
O ~ 2.68 (2H)m; 3.27 (3H)s; 6.08 and
CH3 6.92 (2H).
S I ~ 2.08 ~3H)s; 2.36 ~6H)s; 2.68 (2H)m;
3.30 (3H)s; 3.71 (3H)s; 6.44-6.70
CH3 (lH)m and 7.18-7.39 (2H)m.
CH3 2.03 ~3H)s; 2.25 (3H)s; 2.51 (6H)s;
~ 2.61 (2H)m; 3.15 (3H)s; 7.07 ~lH)m
10 ~ S and 7.38 (lH)m.
1~ ~
! C H ~ 2.06 (3H)s; 2.33 (6H)s; 2.65 (2H)m;
2 5 S 3.22 (3H)s; 6.73 and 7.45 (2H).
! 2.08 (3H)s; 2.34 (6H)s; 2.54 (3H)s;
15 !~ CH3 ~ S ~ 7 46 (22H)s; 3.25 (3H)s; 6.73 and
',1. '.
EXAMPLE 40
" The procedure of Example 38 is again repeated, starting with the re-
quisite sulfonyl chloride and appropriate ll-alkanoyl-4"-deoxy-4"-amino-
l'oleandomycin, to give the following analogs: ll-acetyl-4"-deoxy-4"-(3-ethyl-
20 1! 2-thienylsulfonylamino)oleandomycin; 11-propionyl-4"-deoxy-4"-(3-methyl-2-
thienylsulfonylamino)oleandomycin; ll-acetyl-4"-deoxy-4"-(5-ethyl-2-pyrrylsul-
fonylamino)oleandomycin; ll-propionyl-4"-deoxy-4"-(4-ethyl-2-thienylsulfonyl-
amino)oleandomycin; ll-acetyl-4"-deoxy-4"-(1-ethyl-3-pyrrylsulfonylamino)-
Ioleandomycin; ll-propionyl-4"-deoxy-4"-(5-ethyl-2-furylsulfonylamino)oleando-
25 'mycin; 11-acetyl-4"-deoxy-4"-(4-ethyl-3-furylsulfonylamino)oleandomycin; and
ll-acetyl-4"-deoxy-4"-(3-ethyl-2-furylsulEonylamino)oleandomycin.
-44-
8~Z3
,1 ,
EXAMPLE 41
~ Acetyl-4"-deoxy-4"-(5-carbomethoxy-2-pyrrylsulfonylamino~oleandomycin
¦~ A solution of 2.96 g. (.0041 mole) of 11-acetyl-4"-deoxy-4"-amino-
l oleandomycin and 0.62 ml. of triethylamine in 50 ml. of dry methylene chloride ¦
5 1 cooled to ice bath temperatures is treated portionwise with 1.0 g. (.0044 mole)¦
of 2-carbomethoxy-5-pyrrylsulfonyl chloride. The reaction mixture is allowed
to warm to room temperature and stir for 3.5 hours, and is then poured into
200 ml. of water. The pH of the aqueous layer is adjusted to 9.5 with lN
l aqueous sodium hydroxide and the methylene chloride layer separated, washed
10 1 successively with water and saturated brine and dried over sodium sulfate.
Removal of the solvent under reduced pressure gives 3.8 g. of the crude produc~
as a white foam.
' The above foam is subsequently chromatographed on a silica gel column
" 3.25 cm. x 38 cm. using acetone as the eluate. Fractions 40-220, comprised of
15 ll approximately 10-12 ml. each, are collected and combined. Removal of the
eluate solvent in vacuo gives 3.4 g. of the desired product as a white foam.
NMR (~, CDCl3): 2.05 (3H)s; 2.58 (6H)s; 2.67 (2H)m; 3.25 (3H)s;
3.90 (3H)s; 7.20 (lH)m and 7.52 (lH)m.
I EX~LE 42
20 ,' The procedure of Example 41 is repeated, starting with the appropriate
j sulfonyl chloride and ll-acetyl-4"-deoxy-4"-amino-oleandomycin, to give the
following analogs:
I
;'
-45-
~ ~9l~ 3
'
_0 N(C 3)2
``~0 ~0
Rl ~R (~,CDC13)
2.09 (3H)s; 2.32 (6H)s; 2.69 (2H)m;
llCH 02C ~ 3.22 (3H~s; 3.95 (3H)s; 7.61 and
5 1l 3 7.75 (2H) .
.
CH 0 C
i! 3 2 ~ 2.11 (3H)s; 2.34 (6H)s; 2.70 (2H)m;
1' ~/ \~ 3.24 (3H)s; 3.94 (3H)s; 8.06 and
'¦ S 8.28 (2H) .
, I .
I~ 2.08 (3H)s; 2.29 (6H)s; 2.67 (2H)s;
10 ICH 0 C~ 3.18 (3H)s; 3.94 (3H)s; 7.02 and
,1 3 2 o 7.20 (2H) .
I, :
- 46 -
~ 3lZ3
'I EXA~LE 43
~l i
~ 4"-Deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin
¦ A solution of 3.0 g. of 4"-deoxy-4"-amino-oleandomycin, 865 mg. of
p-chlorophenylsulfonyl chloride and 424 mg. of triethylamine in 25 ml. of
5 ~ methylene chloride is allowed to stir at room temperature overnight. The sol-
vent is removed in vacuo and the residue treated with 20 ml. of acetone. The
insoluble triethylamine hydrochloride is filtered and the filtrate chromato-
graphed on 180 g. of silica gel using acetone as the eluting solvent and taking¦
50 ml. cuts. Fractions 18-27 are combined and concentrated under reduced pres l
10 ¦ sure to give 1.10 g. of the desired product.
NMR (~, CDC13): 2.33 (6H); 2.83 (2H)d; 3.06 (3H)s; and 7.2-8.4
(L~)m .
~` .
-47-
1 1~98~23
EXA~PLE 44
The procedure of Example 43 is repeated, starting with the appropriat
sulfonyl chloride and 4"-deoxy-4"-amino-oleandomycin, to give the following
comp~und$:
~ 52~2
oc~3
Cl
F
CF3
CF3
-48-
915 123
EX~PLE 45
4"-Deoxy-4"-(p-toluenesulfonylamino)oleandomycin
By a procedure similar to Example 43, 30 g. (4.0 mmoles) oE 4"-deoxy
l 4"-amino-oleandomycin, 782 mg. (4.1 mmoles) of p-toluenesulfonyl chloride and
424 mg. (4.2 mmoles) of triethylamine in 25 ml. of methylene chloride are
allowed to stir at ambient temperatures overnight. On work-up the crude prod- I
uct is chromatographed on 180 g. of silica gel, taking 10 ml. cuts. Fractions ¦
90-148 are combined and concentrated to dryness to give 1.4 g. of the desired
product.
NMR (~, CDC13): 2.33 (6H)s; 2.46 (3H)s; 2.83 (2~)d; 3.10 (3H)s; and
7.10-8.0 (4H)m. I
Also, by a similar procedure, is prepared 4"-deoxy-4"-(2-thienylsul- 1
fonylamino)oleandomycin.
j¦ NMR (~, CDC13): 2.29 (6H)s; 2.88 (2H)m; 3.2 ~3H)s; 5.6 (lH)m and
15 ~1 7.33 (3H)m.
EXAMPLE 46
Starting with 4"-deoxy-4"-amino-oleandomycin and the requisite sul-
fonyl chloride and employing the procedure of Example 43, the following con-
geners are synthesized:
I N(CH3)2
UO ",~ ~
o .", O
~NHS02R2
Il OCH3
;',
~ -49-
98~Z3
R2
CH3
CN30
CH3 ~_
C2H5/~
CH
-50-
EXAMPLE 47
Il-A~ l-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin hydrochloride
To 8.7 g. o 11-acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleando-
mycin in 50 ml. of dry ethylacetate is added 10 ml. of a 1~ ethylacetate
solution of hydrogen chloride is added. The solution is concentrated to
dryness in vacuo and the residual mono-hydrochloride salt is triturated
with ether and filtered.
EXAMPLE 48
ll-Acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin phosphate
To a solution of 15.0 g. of 11-acetyl-4"-deoxy-4"-(2-thienylsulfonyl-
amino)oleandomycin in 100 ml. of ethyl acetate is added l.0 ml. of phosphoric
acid. The resulting suspension is allowed to stir for four hours at room
temperature. The solids are filtered, washed with ethyl acetate and dried
to give 12.5 g. of the desired salt, m.p. 168C. (dec.).
In a similar manner is prepared ll-acetyl-4"-deoxy-4"-(3-methyl-2-
thienylsulfonylamino)oleandomycin phosphate, m.p. 184-188C. and ll-acetyl-4"-
deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin phosphate, m.p. 204-205C.
! ~9~3123
l l
l l
I . ~
I PREPARATION A
¦ 4"-Deoxy-4"-oxo-oleandomycins
I. ll-Acetyl-4"-deoxY-4"-oxo-oleandomycin
a. 11,2'-DiacetYl-4"-deoxy-4"-oxo-oleandomycin
!
~ To a 4.5 g. of N-chlorosuccinimide, 50 ml. of benzene and 150 ml. of
toluene in a dry flask fitted with a magnetic stirrer and nitrogen inlet and
cooled to -5C. is added 3.36 ml. of dimethylsulfide. After stirring at 0C.
for 20 min., the contents are cooled to -25C. and treated with 5.0 g. of 11,2'-1
diacetyl-oleandomycin in 100 ml. of toluene. Cooling and stirring are continuedi
for 2 hrs. followed by the addition of 4.73 ml. of triethylamine. The reaction
mixture is allowed to stir at 0C. for 15 min., and is subsequently poured into
500 ml . of water. The pH i8 adjusted to 9.5 with lN aqueous sodium hydroxide
and che organic layer separated, washed with water and a brine solution and
i dried over sodium sulfate. Removal of the solvent in vacuo gives 4.9 g. of the
¦ desired product as~a foam.
NMR (~, CDC13): 3.48 (3H)s, 2.61 (2H)m, 2.23 (6H)s and 2.03 (6H)s.
¦b. ll-Acetyl-4"-deoxy-4"-oxo-oleandomycin
. A solution of 4.0 g. of 11,2'-diacetyl-4"-deoxy-4"-oxo-oleandomycin
¦in 75 ml. of methanol is allowed to stir at room temperature overnight. The
¦ reaction mixture is concentrated under reduced pressure to give the product as
a foam. A diethyl ether solution of the residue, on treatment with hexane,
gives 2.6 g. of ehe product as a white solid, m.p. 112-117C.
NMR (~, CDC13): 3.43 (3H)s, 2.60 (2H)m, 2.23 (6H)s and 2.01 (3H)s.
¦ Similarly, by employing 11,2'-dipropionyl-4"-deoxy-4"-oxo-oleandomyci~
or 11-propionyl-2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in the above procedure,
ll-propionyl-4"-deoxy-4"-oxo-oleandomycin is prepared.
. I
! I I
:~98123
. i,
II. 4"-Deoxy-4"-oxo-oleandomycin
~a. 2'-Acecyl-4"-deoxy-4"-oxo-oleandomycin
Dimethyisulfide (0.337 ml.) is added to a turbid solution of 467 mg.
lof N-chlorosuccinimide in 20 ml. of toluene and 6 ml. of benzene cooied to -5OC.¦
land maintained under a nitrogen atmosphere. After stirring at 0C. for 20 min. ¦
the mixture is cooled to -25C. and 1.46 g. of 2'-acetyloleandomycin and 15 ml.
lof toluene are added. -Stirring is continued for 2 hrs. at -20C. followed by
¦the addition of 0.46 ml. of triethylamine. The reaction mixture is maintained
lat -20C. for an additional 5 min. and then allowed to warm to 0C. The mixture¦
is poured, with stirring, into 50 ml. of water and 50 ml. of ethyl acetate. The
pH of the aqueous mixture is adjusted to 9.5 by the addition of aqueous sodium
hydroxide solution. The organic layer is subsequently separated, dried over
sodium sulfaee and concentrated in vacuo to a white foam (1.5 g.). Trituration
with die~hyl ether gives 864 mg. of crude product, which on recrystallization
twice from methylene chloride-diethyl ether gives 212 mg. of the pure product,
- m.p. 183-185.5C.
Anal. Calc d 37 61 13
Found: C, 60.9; H, 8.4; N, 1.9.
1. NMR ~, CDC13): 5.60 (lH)m, 3.50 (3H)s, 2.73 (2H)m, 2.23 (6H)s and
~ . 2.03 (3H)s.
¦b. 4"-Deoxy-4"-oxo-oleandomycin
A solution of 1.0 g. of 2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in
20 ml. of methanol is allowed to stir at room temperature overnight. The solu-
tion is concentrated in vacuo to give the desired product as a white foam,
1937 mg.
! NMR (~, CDC13): 5.60 (lH)m, 3.50 (3H)s, 2.85 (2H)m and 2.26 (6H)s.
!
~ ~3
Il C
1~98i23
I .
PREPARATION B I .
4"-Deoxy-4"-amino-oleandomycins '.
. '.
I. ll-Acetyl-4"-deoxy-4"-amino-oleandomycin
To a suspension of 10 g. of 10% palladium-on-charcoal in lOO ml. of
S methanol is added 21.2 g. of ammonium acetate and the resulting slurry is
treated with a solution of 20 g. of 11-acetyl-4"-deoxy-4"-oxo-oleandomycin in
100 ml. of the same solvent. The suspension is shaken at room temperature in
a hydrogen atmosphere at an initial pressure of 50 p.s.i. After 1.5 hrs., the
catalyst is filtered and the filtrate is added with 8tirring to a mixture of
1200 ml. Of water and 500 ml. of chloroform. The pH is adjusted from 6.4 to 4.5
and the organlc layer iS 8eparated. The aqueous layer, after a further extrac-
tion wlth 500 ml. of chloroform, is ereated with 500 ml. of ethyl acetate and
the pH adjusted to 9 5 with lN sodium hydroxide. The ethyl acetace layer is
!separated and the aqueous layer extracted again with ethyl acetate. The ethyl
llacetate extracts are combined, dried over sodium sulfate and concentrated to a
yellow foam (18.6 g.), which on crystallization from diisopropyl ether, provides
6.85 g. of the purified product, m.p. 157.5-160C.
NMR (~, CDC13): 3.41 (3H)s, 2.70 (2H)m, 2.36 (6H)s and 2.10 (3H)s.
1. The other epimer, which exists in the crude foam to the extent of 20- ¦
¦25%, is obtained by gradual concentration and filtration of the mother liquors.
In a similar manner, starting with ll-propionyl-4"-deoxy-4"-oxo-
,oleandomycin in the above procedure, gives ll-propionyl-4"-deoxy-4"-amino-
~oleandomycin.
98~Z3
!
I II. 4"-Deoxy-4"-amino-oleandomycin
¦ A solution of 20 g. of 2'-acetyl-4"-deoxy-4"-oxo-oleandomycin in
125 ml. of methanol, after stirring at room temperature overnight, is treated
Iwith 21.2 g. of ammonium acetate. The resulting solution is cooled in an ice
Ibath and treated with 1.26 g. of sodium cyanoborohydride. The cooling bath is
¦then removed and the reaction mixture allowed to stir at room temperature for
j2 hrs. The reaction is poured into 600 ml. of water and 600 ml. of diethyl
ether and the pH adjusted from 8.3 to 7.5. The ether layer is separated and
the aqueous extracted with ethyl acetate. The extracts are set aside and the p~
¦ of the aqueous adjusted to 8.25. The diethyl ether and ethyl acetate extracts
¦¦made at this pH are al80 set aside, and the pH raised to 9.9 The diethyl ether
and ethyl acetate extracts at this pH are comblned, washed successively with
water (lx) and a saturated brine solution and dried over sodium sulfate. The
latter extracts, taken at pH 9.9, are concentrated to a foam and chromatographed
¦on 160 g. of silica gel, using chloroform as the loading solvent and initial
¦eluate. After eleven fraction, which amounts to 12 ml. per fraction, are taken,¦
the eluate is changed to 5% methanol - 95~ chloroform. At fraction 370 the
i eluate is changed to 10% methanol - 90% chloroform and at fraction 440, 15%
methanol - 85% chloroform is used. Fractions 85-260 are combined and concen-
i¦trated in vacuo to dryness to provide 2.44 g. of the desired product.
¦ NMR (~, CDC13): 5.56 (lH)m, 3.36 (3H)s, 2.9 (2H)m and 2.26 (6H)s.
i `,
. I
i
~ .' I
I' ~ I
I
~1 1
