Note: Descriptions are shown in the official language in which they were submitted.
i236830
X-6286 -1-
C-20- and C-23-MODIFIED CRAWLED DERIVATIVES
This invention relates to MacWorld anti-
bionics, and more specifically to a novel group of C-20
and C-23 modified derivatives of tylosin and tylosin-like
macrolides.
Improved antibiotics are continually in
demand. In addition to antibiotics which are useful for
treating human diseases, improved antibiotics are also
needed in the veterinary field. Increased potency,
expanded spectrum of bacterial inhibition, increased in
viva efficacy, and improved pharmaceutical properties
(such as greater oral absorption, higher blood or tissue
concentrations, longer body half life, and more Advent-
genus rate or route of excretion and rate or pattern of
metabolism) are some of the goals for improved
antibiotics.
Tylosin is a well-known therapeutic agent in
the veterinary field. (See, for example, Tetrahedron
Letters 1970, 2339 and U.S. Patent No. 3,178,341).
Tylosin and tylosin-like macrolides have been modified
in an attempt to obtain derivatives having improved
properties. A large number of derivatives have been
made, but improvement in activity has not previously
been obtained to the desired degree.
More specifically this invention relates to
C-20- and C-23-modified MacWorld derivatives having
formula (I);
I. ,.
;. Jo
~3G830
X-6286 -2-
I/ Shea
Shut/ sty
I
SHEA \ /
OH'
1 0
(I)
15 wherein
R is hydrogen, idea, broom, sheller, flyer, cyan
-or, -Oar, -SO , Acadia, -NO R7, N-phthalimido
or R9;
Al is i) hydrogen or -OH;
ii) sheller, flyer, broom, idea -OAR, -O-tetra-
hydrofuranyl, -O-tetrahydropyranyl, -SO ,
Acadia, -NR6R7, or N-phthalimido; or R ;
R9 is i) a monocyclic amino group of the formula
-N(CH2)n which is optionally substituted
at one or more of the carbon atoms by a
C1-C3-alkyl, hydroxyl, methoxyl, ethoxyl,
o
-N(R8)2, -C-N(R8)2, carbomethoxy,
!!
,,
12;~;1!330
X-6286 3
carboethoxy, or phenol group; and n is an
integer from 4 through 15;
ii) a monocylic saturated or unsaturated
nitrogen-containing heterocyclic ring
bonded through the nitrogen atom, sand
ring having 1) from 5 to 7 ring atoms
which include up to 3 additional hotter-
atoms selected from nitrogen, oxygen and
sulfur, and 2) up to 3 substituent groups
selected from methyl, ethyl end phenol;
or
iii) a bicyclic or tricyclic secondary amino
group selected from 1,2,3,4-tetrahydro-
quinolin-1-yl; decahydroquinolin-1-yl;
1,2,3,4-tetrahydroisoquinolin-2-yl;
decahydroisoguinolin-2-yl; indolin-1-yl;
isoindolin-2-yl; decahydrocyclohepta-
[b]pyrrol-1-yl; decahydrocyclohepta-
[c]pyrrol-2-yl; decahydrocyclo-
pent[c]azepin-2-yl; decahydrocyclo-
pent[d]azepin-3-yl; 2,3,4,5-tetrahydro-
1~-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-
1~-3-benzazepin-3-yl; azabicycloheptanyl;
azabicyclooctanyl; azabicyclononanyl;
azabicyclodecanyl or azatricyclodecanyl;
R2 is hydrogen, optionally substituted Cluck-
alkanoyl or optionally substituted bouncily,
phenylacetyl or phenylpropionyl;
lZ3~
X-6286 -4-
R3 is hydrogen, hydroxyl, optionally substituted
Cl-C5-alkanoyloxy or optionally substituted
benzoyloxy, phenylacetoxy or phenylpropionyloxy
or
OH
SHEA
1 0 I
Ho
(mycarosyloxy)
R4 is hydrogen, optionally substituted Cl-C4-alkyl,
cyclohexyl, optionally substituted bouncily,
phenethyl or phenoxyethyl;
An is
i) phenol, derivatized phenol, or naphthyl;
ii) an optionally substituted heteroaryl
group selected from pyridinyl, pyrimidinyl,
pyridazinyl, personnel, triazinyl,
indolyl, isoquinolinyl, quinolinyl,
quinazolinyl, cinnolinyl, quinoxalinyl,
phthalazinyl, benzotriazolyl, benzoxazolyl,
benzimidazolyl, carbazolyl, or acridinyl;
or
Sue
X-6286 -5-
iii) optionally substituted Cl-C5-alkanoyl;
optionally substituted bouncily,
phenylacetyl, phenylpropionyl, phonics-
acutely or phenylthioacetyl; methane-
S sulfonyl; trifluoromethanesulfonyl; or
optionally substituted phenylsulfonyl;
R5 is optionally substituted Cl-C4-alkyl; cycle-
Huxley; optionally substituted phenol, bouncily
or phenethyl; or an optionally substituted
heteroaryl group selected from imidazolyl,
pyrazolyl, pyridinyl, pyrimidinyl, personnel,
pyridazinyl, triazinyl, triazolyl, tetrazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, thinly and
lo furanyl;
R6 is hydrogen, optionally substituted Cl-C6-alkyl,
phenol, bouncily, phenethyl or C3-C8-cycloalkyl;
R7 is an R6 group or optionally substituted Cluck-
alkanoyl, optionally substituted bouncily,
phenylacetyl, phenylpropionyl, phenoxyacetyl
or phenylthioacetyl, or alkoxycarbonyl; and
R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl
or the R8 groups taken together form a polyp
ethylene moiety such that -N(R8)2 constitutes
a cyclic amino group selected from pyrrolidinyl,
piperidinyl, hexahydroazepinyl or
octahydroazocinyl;
provided 1) that, when R or R4 is hydrogen, Al cannot be
hydrogen or -OH; 2) that, when R or Al is -NHR6 or R4 or
R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen,
~2:~6830
X-628~ -6-
hydroxvl, or mycarosyloxy and or cannot be a type (iii)
substituent; 3) that, when R2 is hydrogen, R3 must be
hydrogen, hydroxyl or mycarosyloxy; 4) when R is
hydrogen or hydroxy, R is not NR6R7 and to the salts,
particularly the acid addition salts, of these
compounds.
The compounds of this invention are useful as
antibiotics and/or as intermediates to antibiotics.
Monocyclic saturated or unsaturated nitrogen-
containing heterocyGlic rings which are bonded therewith nitrogen atom and which have from five to seven ring
atoms, including up to tree additional heteroatoms
selected from nitrogen, oxygen and sulfur, include
groups such as puerilely, pyrazolyl, imidazolyl, 1,2,4-
oxadiazinyl, 1,3,4-thiadiazinyl, 1,2,4-triazolyl,
l~-tetrazolyl, 1,4-dia~epinyl, morpholino, trio-
morpholino, piperazinyl, thiazolidinyl, oxazolidinyl,
and tetrahydro-1,4-thiazin-4-yl. Such rings can have up
to three substituents selected from methyl, ethyl and
I phenol on appropriate carbon and/or nitrogen ring
atoms(s).
The term "Cl-C5-alkanoyl" as used herein means
an azalea moiety derived from a carboxylic acid containing
from one to five carbon atoms. In such a moiety, the
alkyd group can be straight, branched, or cyclic. When
optionally substituted, the alkyd group can bear one to
three halo substituents. halo substituents are selected
from the group consisting of Of, By and F. Acutely,
chloroacetyl, trichloroacetyl, trifluoroacetyl, prop-
nil, n-butyryl, isobutyryl, n-valeryl, and isovaleryl
38
X-6286 7
are examples of such groups. The term "Cl-C5-alkanoyloxy"
refers to the corresponding acyloxy moiety.
The terms "optionally substituted bouncily,
phenylacetyl, phenylpropionyl, phenoxyacetyl or phenol-
thioacetyl", "optionally substituted bouncily, phenylacetylor phenylpropionyl", "optionally substituted benzoyloxy,
phenylacetoxy or phenylpropionyloxy'i, "optionally
substituted phenol, bouncily or phenethyl", "optionally
substituted bouncily, phenethyl or phenoxyethyl" and
"optionally substituted phenylsulfonyl" mean that the
phenol portion of the moiety is optionally substituted
by from one to five halo or methyl groups or by from one
to two methoxyl, vitro or hydroxyl groups.
The term "derivatized phenol" refers to a
phenol group which has from one to five halo, methoxyl
or Cl-C4-alkyl substituents, or from one to two vitro,
amino, methyl amino, ethyl amino, dimethylamino, deathly-
amino, C4-ClO-methyleneamino, Acadia, hydroxy, hydroxy-
methyl, amino methyl, (methylamino)methyl,
(ethylamino)methyl, (dimethylamino)methyl, (deathly-
amino methyl (C4-ClO-methyleneamino)methyl, formal,
acutely, bouncily, methoxycarbonyl, ethoxycarbonyl,
carboxamido, N-methylcarboxamido, N,N-dimethylcarbox-
amino, cyan, phenol, phonics or bouncily substituents.
The term "optionally substituted heteroaryl
group" as used herein means that the heteroaryl group
may have at least one suitable substitu~ent(s) such as a
Cl-C4-alkyl, halo, methoxy, ethics, hydroxy (or the veto
tautomer) or phenol group.
~236830
X-6286 -8-
The terms "Cl-C3-alkyl", "Cl-C4-alkyl" or
"Cl-C6-alkyl" as used herein mean a straight- or
branched-chain alkyd group cartooning the specified
number of carbon atoms. Such groups include methyl,
ethyl, isopropyl, n-butyl, tert-butyl, r.-hexyl, and the
like. "Optionally substituted" Cl-C4-alkyl or Cluck-
alkyd means that the alkyd group contains one or more
flyer or sheller substituents.
"C3-C8-cycloalkyl" refers to a cycloalkyl
group containing from three to eight carbon atoms.
Examples of such groups are cyclopropyl, cyclohexyl and
cyclooctyl.
The term "alkoxycarbonyl" represents a member
of a group selected from t-butoxycarbonyl, methoxy arbonyl,
ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phonics-
carbonyl and benzyloxycarbonyl.
The term "C4-C10-methyleneamino" represents a
cyclic amino substituent of the formula -N(CH2)n wherein
n is an integer from four to ten. Pyrrolidinyl, piper-
vinyl, and octahydroazocinyl are examples of such groups.
The invention also provides a process for
preparing a MacWorld of formula (I) by
(a) reducing a starting MacWorld of formula
(I) wherein Q is formal and Al is R1, provided Al is
not hydroxyl, to give a MacWorld of formula (I) wherein
R is hydroxyl;
123~B30
g
X-6286
ITCH
SHEA H2--Q
Q --SHEA/ I \ ( I I )
lo by
( SHEA ) 2
I
I
(b) reacting a starting MacWorld of formula
(II) wherein Q is formal and Q1 is Al with an amine of
the formula HNR6R6 or HR9 in the presence of a reducing
agent to give a MacWorld of formula (I) wherein R is
NR6R6 or R9, or
(c) reacting a starting MacWorld of formula
(II) wherein Q is -SHEA and I is Al with diethylazodi-
25 carboxylate or dimethylazodicarboxylate, triphenyl- -
phosphine, and a reagent selected from
(i) an aside transfer agent, to give a
MacWorld of formula (I) wherein R is
Acadia,
~Z36 930
x-6286 -10-
(ii) phthalimide to give a MacWorld of
formula (I) wherein R is phthalimido,
(iii) a phenol of formula ARCH to give a
MacWorld of formula (I) wherein R is
-OAR, where AR is a category i) or ii) AR
group,
(iv) an alkyd halide or polyhalide to give a
MacWorld of formula (I) wherein R is C1,
Bra or I, or
(v) a mercaptan of formula HER to give a
MacWorld of formula (I) wherein R is
SO, or
(vi) a carboxylic or sulfonic acid of the
formula ARCH, where AR is a category
(iii) AR group, to give a MacWorld of
formula (I) wherein R is OAR,
(d) reacting a starting MacWorld of formula
(II) wherein Q is -SHEA and Q is R with triphenyl-
phosphine and a halogen source to give a MacWorld of
formula (I) wherein R is Of, Bra or I,
(e) reacting a starting material of formula
(II) wherein Q is -SHEA and Q is R with an assaulting
agent derived from a carboxylic or sulfonic acid of
formula ARCH, where AR is a category (iii) AR group to
give a MacWorld of formula (I) wherein R is OAR, or
(f) reacting a starting MacWorld of formula
(II) wherein Q is -SHELLEY where L is a leaving group and
Q is R or a leaving group with
(i) an alkali metal aside or halide or a
tetraalkylammonium aside or fluoride
I.
~236830
X-6286
where alkyd is methyl, ethyl, propel or
bottle, to give a MacWorld of formula (I)
wherein R is Acadia, F, Of, Bra or I, or
(ii) a marketed ion of formula R5S- to give
a MacWorld of formula (I) wherein R is
RUSS-, or
(iii) an amine of the formula NR6R6 or HR9 to
give a MacWorld of formula (I) wherein R
is NR6R6 or R9, or
(iv) a source of cyanide ion to give a macro
tide of formula (I) wherein R is -ON;
TV an alcohol of the formula Horn and a
source of silver ion to provide a macro-
tide of formula (I) wherein R is or
where R4 is other than hydrogen;
(g) hydrolyzing a MacWorld of formula (II)
wherein Q is CHAR and Al is
Ho Ho fH3
Ho--/ \~, Ho I or H0_\--Q\~
OUCH Jo bCH3 OWE
.~...~
~23683~
X-52~5 -12-
to give a MacWorld of formula (I) wherein R1 is
hydroxyl, or
(h) removing the hydroxy protecting group
from a MacWorld of formula IT wherein Q is -CHAR and
Q is protected hydroxy or
(i) reacting a starting MacWorld of formula
(II) wherein Q is -CHAR and Al is hydroxyl with deathly-
azodicarboxylate or dimethylazodicarboxylate, triphenyl-
phosphine, and a reagent selected from
(i) an aside transfer agent to give a MacWorld
of formula (I) wherein Al is Acadia,
(ii) phthalimide to give a MacWorld of
formula (I) wherein Al is phthalimido,
(iii) a phenol of formula Arch where An is a
category (i) or (ii) An group to give a
MacWorld of formula (I) wherein R1 is
-Oar,
(iv) an alkyd halide or polyhalide to give a
MacWorld of formula (I) where Al is Of,
Bra or I, or
(v) a mercaptan of formula HSR5 to give a
MacWorld of formula (I) wherein R is
SO , or
(vi) a carboxylic or sulfonic acid of the
formula Awry, where An is a category (i)
An group, to give a MacWorld of formula
(I) wherein Al is Oar or
(j) reacting a MacWorld of formula (II)
wherein Q is -CRY and Al is hydroxyl with an assaulting
agent derived from a carboxylic or sulfonic acid of
lZ36830
X-6286 -13-
formula ARCH where AR is a category (iii) AR group to
give a MacWorld of formula (I) wherein R is OAR or
(k) reacting a MacWorld of formula (II)
wherein Q is R and Q1 is hydroxyl with triphenyl-
phosphine and a halogenating agent to give a MacWorld
of formula (I) wherein R is Of, By or I, or
(1) reacting a MacWorld of formula (II)
wherein Q is -CHAR and Al is a leaving group with
(i) an alkali metal aside or halide or a
tetraalkylammonium aside or fluoride
where alkyd is methyl, ethyl, propel, or
methyl to give a MacWorld of formula (I)
wherein R is Acadia, F, Of, Bra or I,
(ii) a marketed ion of formula R S- to give
a MacWorld of formula I wherein R is
R S-, or
(iii) an amine of the formula HNR6R6 or HO to
give a MacWorld of formula (I) wherein
R1 is HR6R6 or R, or
(m) reducing a MacWorld of formula (II)
wherein Q is -SHEEHAN and Q is Al or Q is R and Q1 is
Acadia to give a MacWorld of formula (I) wherein R is
-SHEEHAN or R is amino, or
(n) assaulting a MacWorld of formula (II)
wherein Q is -SHUNNER or R is NHR6 to give a MacWorld
of formula (I) wherein R is -SHUNNER or R is -NR6R7, or
(o) esterifying a MacWorld of formula (I),
or
(p) salifying a MacWorld of formula (I), or
(q) hydrolyzing a MacWorld of formula (I)
wherein R3 is mycarosyloxy in acid solution at a pi
I.,
lZ36~30
X-6286 -14-
below 4 to give a MacWorld of formula (I) wherein R3 is
hydroxy, or
r) deoxygenating a MacWorld of formula (I)
wherein R3 is hydroxy to give a MacWorld of formula (I)
S wherein R3 is hydrogen,
(s) reacting a MacWorld of formula (II)
wherein Q is SHEA and Al is I with a reducing agent to
give a compound of formula I) wherein R is hydrogen, or
(t) reacting a MacWorld of formula (II)
wherein Q is -C~2- sulfonate and Q1 is R1 with a source
of iodide ion to give a MacWorld of formula (I) wherein
R is idea.
In general, macrolides of formula (I) are
prepared by effecting a modification at the C-20 post-
lion of a MacWorld that has the desired group at thwack position, or by effecting a modification at the
C-23 position of a MacWorld that has the desired group
at the C-20 position, or by effecting modifications at
the 20- and 23- positions simultaneously. In addition,
macrolides of formula (I) may be modified at 2'-, 4'-,
20-, and 23- positions using known methods to produce
other macrolides of formula (I).
The following aye known macrolides which are
useful in preparing the macrolides of this invention:
demycinosyltylosin (DOT), 20-dihydro-23-demycinosyltylosin
(dihydro-DMT), 23-de(mycinosyloxy)tylosin (DOT),
20-dihydro-23-de(mycinosyloxy)tylosin (dihydro-DMOT),
5-O-mycaminosyltylonolide (OUT), dodder-
mycaminosyltylonolide (dihydro-OMT), Dixie-
mycaminosyltylonolide (DOT), 20-dihydro-23-deoxy-5-O-
I
.
X-6286 -15-
mycaminosyltylonolide (dihydro-DOMT), dodder-
deo~y-23-demycinosyltylosin (DH-DO-DMT and dodder-
20-deoxy-5-O-mycaminosyltylonolide (DH-DO-OMT).
DOT, dihydro-DMT, DOT, dihydro-DMOT, DOT,
and dihydro-DOMT are antibiotics described by Richard I.
Waltz, Gene M. Wild, and Eugene T. Steno in U.S. Patents
4,321,361 and 4,321,362, both of which issued on March 23,
1982. DH-D0-DMT and DH-DO-OMT are described by Richard I.
Waltz, Herbert A. First, Gene H. Wild and Eugene T. Steno
in U.S. Patent 4,304,856, which issued December 8, 1981.
OUT and dihydro-OMT are described by Marvin Norman and
Robert D. Moron in U.S. Patent 3,459,853, issued on
August 5, 1969.
The structures of the starting antibiotics are
shown in formulas 2-11:
2 0 f SHEA
Shelley/ SCHICK
Q1-CH2 / I
CH3--CH2~ --OH y f
(I ~N-CH3
\~_~Q2
Ho
~Z36~30
X-6286 -16-
Q Al Q2
2 DOT: ECHO -OH mycarosyl
3 dihydro-DMT: -SHEA OH "
4 OUT: ECHO -OH H
5 5 dihydro-OMT: -SHEA -OH
6 DOT: ECHO mycarosyl
7 dihydro-DMOT: . -SHEA H
8 DOT: ECHO H H
9 dihydro-DOMT: -SHEA H
10 10 DH-DO-DMT -SHEA -OH mycarosyl
11 DH-DO-OMT -SHEA -OH H
Other known macrolides are also useful starting Metro-
also as will be clear from the following discussion.
Methods for modifying the Causation
The desired group at the C-20 position can be
obtained by using a known starting material that already
has the desired group, or by modifying the C-20 position
of an available starting material. The C-20 position
may be modified before or after the other required
modifications, if any, are made in the starting
material.
Known macrolides of formula (II) wherein Q is
US -SHEA include dihydro-DMT (3), dihydro-OMT (5), dodder-
DOT (1), and dihydro-DOMT (9).
Macrolides of formula (I) or (II) wherein R is
hydroxyl or Q is SHEA can be prepared by reducing a
MacWorld of formula (II) wherein Q is formal to provide
the corresponding dodder compound. Chemical
~23~
X-6286 -17-
reduction can be effected, for example, by treating the
MacWorld with an approxlmatelv stoichiometric amount of
sodium bordered in an alcoholic solvent.
Macrolides of formula (I) ox (II) wherein R is
OH or Q is SHEA may be converted to other macrolides of
formula (I) by modifying the C-20 hydroxyl group, using
any of a variety of known synthetic methods. Several
methods are described hereinafter.
Known macrolides of formula IT wherein Q is
methyl include D~-DO-DMT (10) and DH-DO-OMT (11).
Macrolides of formula (I) or (II) wherein R is
hydrogen or Q is methyl can be prepared by reacting a
MacWorld of formula (II) wherein Q is -SHEA with a
reducing agent such as a hydrides for example sodium
bordered in a bipolar aprotic solvent such as dimeth-
ye sulfoxide, dimethylformamide, or sulf~lane, or an
organotin hydrides such as tri-n-butyltin hydrides or a
metal, for example powdered zinc; in a nonreactive
organic solvent such as Tulane or nitromethane.
Macrolides of formula (I) or (II) wherein R is
Of, Bra or I, or Q is -Shekel, -Shabbier, or -KIWI are
prepared by reacting a MacWorld of formula (II) where Q
is -SHEA with triphenylphosphine and a halogenating
agent in a nonreactive organic solvent such as dichloro-
25' methane. Suitable halogenating agents include alkyd
halides and polyhalides, such as carbon tetrachloride.
Macrolides of formula (I) or (II) wherein R is
Of, Bra or I, or Q is -C~2Cl, -Shabbier, or -SHEA are also
prepared by reacting a MacWorld of formula (II) wherein
Q is -SHEA with triphenylphosphine,
1236830
X-6286 -18-
diethylazodicarboxylate or dimethylazodicarboxylate, and
an alkyd halide or polyhalide.
The di(alkyl)azodicarboxylate/triphenyl-
phosphine reaction and its various applications are
- 5 described in O. Mitsunobu, Synthesis 1 (l), 1-28
(1981). The reaction generally produces dehydration
between an alcohol ROW and an acidic component HO to
provide a product RX.
Macrolides of formula (I) or (II) wherein R is
10F, at, Bra or I, or Q it -CHEF, -Shekel, -C~2Br, or -SHEA
are also prepared by reacting a MacWorld of formula
(II) wherein Q is ECHO with on alkali metal or twitter-
(alkyl)ammonium halide in a nonreactive organic solvent
such as tetrahydrofuran.
15Macrolides of formula (I) or (II) wherein R is
Acadia or Q is -SHEEHAN are prepared by reacting a MacWorld
of formula (II) wherein Q is ECHO with an alkali metal
or tetra(alkyl)ammonium aside in a nonreactive organic
solvent. Macrolides of formula (I) or (II) wherein R is
Acadia or Q is -SHEEHAN are also prepared by reacting a
MacWorld of formula (II) wherein Q is -SHEA with
triphenylphosphine, diethylazodicarboxylate or dim ethyl-
azodicarboxylate, and an aside transfer agent, such as
diphenylphosphoryl aside, in a nonreactive organic
solvent such as tetrahydrofuran.
Macrolides of formula (I) or (II) wherein R is
cyan or Q is -CHICANO are prepared by reacting a MacWorld
of formula (II) wherein Q is -SHELLEY, where L is halide or
a sulfonic ester group, with a cyanide salt in a non-
reactive organic solvent, such as dimethylsulfoxide.
joy
X-6286 -19-
Macrolides of formula (I) or (II) wherein R is
or or Q is SHARI are prepared by reacting a MacWorld
of formula (II) wherein Q is SHELLEY with an alcohol of the
formula Herr where R4 is other than hydrogen in the
presence of a source of sliver ion.
Macrolides of formula (I) or (II) wherein R is
Oar or Q is Shari are prepared by reacting a MacWorld
of formula (II) wherein Q is -SHEA, with triphenyl-
phosphine, di(alkyl)azodicarboxylate, where alkyd is
methyl or ethyl, and a phenol of formula Arch, where An
is a category i) or ii) An group.
Macrolides of formula (I) or (II) wherein R is
Oar or Q is Shari and An is optionally substituted
bouncily, phenylacetyl, phenylpropionyl, phenoxyacetyl,
or phenylthioacetyl are prepared by reacting a MacWorld
of formula (II) wherein Q is -KIWI with an assaulting
agent derived from a carboxylic acid of formula Arch,
where An is as defined above. Typical assaulting agents
include androids, acid halides (usually in combination
with a base or other acid scavenger), and active esters.
Suitable organic solvents include pyre dine and triethyl-
amine. Acylation can also be achieved using a mixture
of an organic acid and a dehydrating agent such as
N,N'-dicyclohexylcarbodiimide.
Macrolides of formula (I) or (II) wherein R is
Oar or Q is Shari and An is an azalea group as defined in
the previous paragraph are also prepared using the
di(alkyl)a~odicarboxylate/triphenylphosphine procedure,
i.e., by reacting a MacWorld of formula (II) wherein Q
is -SHEA with triphenylphosphine,
~Z3G830
X-~286 -20-
di(alkyl)azodicarboxylate, and a carboxylic acid of the
formula Awry.
Macrolides of formula (I) or IT wherein R is
Oar or Q is Corey and An is methanesulfonyl, trifler-
methanesulfonyl or optionally substituted phenylsulfonylare prepared by reacting a MacWorld of formula (I)
wherein Q is -SHEA with an activated derivative, such
as the android or acid halide, of a sulfonic acid of
the formula Awry. If the acid halide is used, the
reaction is carried out in the presence of a base,
usually pardon.
Macrolides of formula (I) or (II) wherein R is
Oar or Q is Shari and An is defined in the previous
paragraph are also prepared using the delocalized-
carboxylate/triphenylphosphine procedure, i.e., by reacting a MacWorld of formula (II) wherein Q is -KIWI
with triphenylphosphine, di(alkyl)azodicarboxylate and a
sulfonic acid of the formula Arch.
Macrolides of formula (I) or (II) wherein R is
SR5 or Q is -CHAUCER are prepared by reacting a MacWorld
of formula IT wherein Q is -SHELLEY with marketed ion
of the formula R9S . L may be halide or a sulfonic or
sulfonic ester group.
Macrolides of formula (I) or (II) wherein R is
SR5 or Q is -CHIHUAHUAS are also prepared using the di(alkyl)-
azodicarboxylate/triphenylphosphine procedure, i.e., by
reacting a MacWorld of formula tip) wherein Q is -SHEA
with triphenylphosphine, di(alkyl)azodicarboxylate and a
mercaptan of formula HSR5.
~Z36~30
X-6286 -21-
Macrolides of formula (I) or (II) wherein R is
NR6R7 or Q is -CH2NR6R7 are prepared by reacting a
MacWorld of formula (II) wherein Q is -SHUNNER with an
assaulting agent derived from a carboxylic acid of the
formula Horn.
Macrolides of formula (I) or (II) wherein R is
phthalimido, or Q is -CH2-phthalimido are prepared by
reacting a MacWorld of formula (II) wherein Q is -SHEA
with triphenylphosphine, di(alkyl~azodicarboxylate, and
phthalimide.
Compounds of formula (I) or (II) wherein R4
or L is methanesulfonyl, trifluoromethanesulfonyl or
optionally substituted phenylsulfonyl, as well as
compounds wherein R or L is idea or broom, are useful as
intermediates for the preparation of additional come
pounds of this invention via Sol or SNOW substitution
reactions.- Suitable reaction conditions for displacing
a leaving group by a nucleophile via either an Sol or
SNOW mechanism are well exemplified in the art of nucleon
Philip substitution reactions.
The formula (I) or (II) compounds wherein R is-NHR7 and R7 is an azalea group are prepared via the
Acadia derivative (R=N3). The Acadia derivative is
first reduced to the 20-amino derivative (R = No
triphenylphosphine in aqueous tetrahydrofuran (TEN) is
an example of a suitable reducing agent for this pun-
pose. The 20-amino derivative can then be selectively
assaulted on the amino group, using standard acylation
procedures, to give those derivatives wherein R7 is an
azalea group.
~236~30
X-6286 -22-
Macrolides of formula (I) or (II) wherein R is
-NOR I or R9 or Q is SHUNNER or CHAR can be prepared
by reductive lamination of the C-20 alluded grollp of
DOT, OUT, DOT, and DOT using one of two methods.
Method 1:
A derivative with a leaving group at C-20
(idea, inflate, etc.), prepared as described swooper, is
reacted with the appropriate amine in a suitable solvent,
such as acetonitrile, until the desired 20-modified
derivative is formed via displacement of the C-20
leaving group by the nucleophilic amine.
Method 2:
In this method, the alluded group of compound
2, 4, 6, or 8 is reacted directly with the corresponding
amine in the presence of a suitable reducing agent in an
appropriate solvent until the desired product is formed.
Sodium cyanoborohydride is an example of a suitable
reducing agent, and an hydrous methanol is a useful
solvent for this reaction. The reaction may be carried
out under a nitrogen atmosphere, but this is usually not
required. With less reactive amine, more forcing
conditions for forming the intermediate iminium complex
between the MacWorld and amine may be required, e.g.
heating, use of a drying agent or water scavenger or
heating under conditions of azeotropic removal of water
in solvents such as Bunsen or Tulane.
f'- !
1;~3~30
X-6286 - - -23-
Methods for modifying the C-23-position
The desired group at the C-23 position is
likewise obtained by using an available starting Metro-
at that already has the desired group at the c-23
position, or by modifying the C-23 position of an
available starting material.
Known macrolides of formula (II) wherein Al is
hydroxyl include DOT (2), dihydro-DMT (3), OUT (4),
dihydro-OMT (5), DH-DO-DMT (10), and DH-DO-OMT (11).
Macrolides of formula (I) or (II) wherein Al
or Q1 is hydroxyl can be prepared by acid hydrolysis of
a MacWorld of formula (II) wherein Q1 is
Ho ITCH Of Ho
HO , HO_\ Jo , o r HO_\ I
OUCH/ SHEA Ohs OH/ OH
The hydrolysis is carried out at a pi between 1.5 and
2.5, as described in U.S. Patent No. 3,459,853.
Macrolides of formula (I) or (II) wherein
or Al is hydroxyl can be modified to give other
macrolides of formula (I) using the methods described
:~236~30
X-6286 -24-
herein before for converting a C-20 hydroxyl group to the
desired group. Thus, the DEAD reaction may be used to
effect many of the C-23 modifications. Other procedures
for modification of the C-23 position are described by
A. Tanaka et at in J. Antibiotics 35 (1) 113-116 (1982).
Another process applicable to C-23 modifica-
lions is a two step process in which the 23-hydroxyl
group is first converted to a leaving group, and the
leaving group is then displeased by a suitable
nucleophile.
First, the 23-hydroxyl group is converted to a
suitable leaving group, such groups being well known in
the art. The inflate anion is a preferred leaving
group. With very reactive nucleophiles, however, other
leaving groups, such as the mesylate anion, the tessellate
anion, iodide or bromide may also be suitable.
The 23-O-triflate is preferably prepared by
reaction of the 23-OH intermediate with an activated
derivative of trifluoromethanesulfonic acid, such as the
android, preferably in the presence of a hindered
pardon derivative such as letdown or s-collidine
at a temperature of from -80C to room temperature. The
hydroacyl groups at positions other than 23- may be
protected by acutely groups which can be removed by
methanolysis, for instance by refluxing in methanol.
Using this procedure, the 23-O-triflate can be prepared
without concomitant reactions at the other hydroxyl
groups which are present. A similar reaction can be
used to prepare the corresponding mesylate or tessellate
directly.
~Z36830
X-6286 -25-
When inflate is used as the leaving group, it
is not necessary to isolate the intermediate inflate
derivative; displacement with the appropriate nucleophile
can be carried out in situ. When less reactive leaving
groups are used, the intermediate is sufficiently stable
and may be isolated prior to the displacement reaction
if so desired.
The second step in the preparation of the C-23
modified derivatives involves displacement of the
leaving group by the appropriate nucleophile under
suitable conditions which are well exemplified in the
art of displacement reactions.
When is is desired to prepare compounds of
formula IT in which Al is SR5 the most convenient
nucleophile is a compound of formula HSR5. For prep
ration of an aside, the nucleophile is preferably an
alkali metal aside such as lithium aside. The pyre-
Dunham compound is preferably prepared by reaction with
pardon base. When Al is NR6R7 or R9, the nucleophile
is an amine of the formula EAGERER or HR9.
The nucleophilic displacement reaction is
preferably conducted at temperatures in the range from
-80C to 100C, typically room temperature using an
inert organic solvent such as a chlorinated hydrocarbon
like dichloromethane.
The C-23 derivatives wherein Al is -NHR7 can
be prepared via the Acadia derivative (R=N3). The
Acadia derivative is first reduced to the 23-amino
derivative using a reducing agent specific to Acadia
groups, such as crimes chloride or triphenylphosphine.
lZ361~30
X-6286 -26-
Aqueous organic solvents such as ethereal solvents, for
example tetrahydrofuran (THY) are useful for this
purpose. The reduction can be effected at temperatures
in the range from 0 to 100C. The 23-amino derivative
5 can then be selectively assaulted using standard azalea- -
lion procedures, to give those derivatives wherein R7 is
an azalea group. As will be appreciated by those skilled
in the art the acylation can be effected at temperatures
in the range of from -20 to 70C.
It should be noted that, when the compounds of
formulas 3 or 5 are used as starting materials, two
primary hydroxyl groups are present which react in a
similar manner. The primary hydroxyl group at C-20,
however, is usually replaced more rapidly than the
hydroxyl group at C-23. Although many of the procedures
described swooper give mixtures of 20-monosubstituted
derivatives and 20,23-disubstituted derivatives, such
mixtures can be readily separated by techniques known in
the art, such as, for example, chromatography using
silica gel as the adsorbent. Formation of C-20-monosub-
stituted derivatives may be optimized by not carrying
the reaction to completion, for example, by using less
than two molar equivalents of reactant(s). Conversely,
when C-20, C-23-disubstituted derivatives are sought,
the reaction should be carried to completion and two
molar equivalents or an excess of reactant(s) should be
used.
Compounds wherein the substituent Al differs
from the substituent R can be prepared by modifying the
hydroxyl group at C-23 before reducing the alluded at
C-20.
1Z362~30
X-628~ -27-
When preparing formula ( I ) compounds wherein R
is hydrogen, compounds lo and 11 may be used as starting
materials and modified at the C-23 hydroxyl group as
previously described.
An alternate method for preparing compounds
with different substituents at C-20 and C-23 is to
modify the C-20 position of a MacWorld not having a
free C-23 hydroxyl group. One example of this approach
is to prepare a C-20-modified derivative of desmycosin,
tylasin, macrocin, lactenocin, demethylmacrocin and
demethyllactenocin, followed by hydrolysis at the
neutral sugar(s), using procedures known in the art
(see, for example, U.S. Patent 3,459,853). By this
procedure, a 20-modified derivative of OUT can be
selectively prepared, which in turn can be modified at
the C-23 position, as discussed Syria.
Use of a protecting group for the hydroxyl
group at C-23 of OUT and DOT prior to reduction of the
alluded also permits selective modification of C-20.
Removal of the protecting group after appropriate
modification of C-20 yields C-20-modified derivatives
having a hydroxyl group at C-23, which may then be
modified as outlined previously. Examples of useful
protecting groups are ester moieties, such as acutely and
trichloroacetyl, and groups such as tetrahydropyranyl
and tetrahydrofuranyl. The tetrahydropyranyl and
tetrahydrofuranyl protecting groups are described, for
example, by Tanaka et at., swooper.
~Z36830
X-~286 I -
The modified derivatives of OUT, DOT and
DH-DO-OMT can also be prepared by acidic hydrolysis of
mockers from the corresponding modified derivatives of
DOT, DOT and DH-DO-DMT, respectively, prepared by the
methods previously described. Procedures for the acidic
hydrolysis of mockers from DOT and DOT to form OUT and
DOT, respectively, are found in U.S. Patents 4,321,361
- and 4,321,362. Acidic hydrolysis of DH-DO-DMT to give
DIMWIT is described in U.S. Patent 4,304,856.
Myra specifically, the mockers sugar can be
hydrolytic ally cleaved at a pi of less than 4, prefer-
by in the range from 0.5 to 2.0, at a temperature in
the range of from 0 to 60C, conveniently at about room
temperature. The hydrolysis can ye effected using a
lo strong aqueous mineral acid such as hydrochloric or
sulfuric acid or a strong organic acid such as
p-toluenesulfonic acid.
A method of preparing 4'-deoxydesmycosin is
described in J. of Antibiotics 34, 1381-84 (1981). The
process involves (1) treatment of desmycosin with acidic
ethanol in accordance with a procedure described in
Antibiot. & Chemoth. 11, 320-27 (1961), to obtain the
corresponding diethylacetal; (2) acylation of the
diethylacetal with acetic android in acetonitrile in
the absence of external base, in accordance with a
procedure described in J. Orcr. Chum. I 2050-52 (1979,
to obtain the dustily derivative; I reacting
the Dow Octal derivative with 2,3-dihydrofuran
in dichloromethane in the presence of pyridinium
p-toluenesulfonate in the manner described in J. Or.
~:36830
X-~286 -29-
Chum. 42, 3772-74 (1974) to obtain the Boyce-
tetrahydrofuranyl)derivative; (4) removal of the 2' and
octal groups by dissolving the product of step (3)
in methanol (50C, overnight); I reacting the product
of step (4) with 1.5 mole equivalent of benzenesulfonyl
chloride in pardon at -40C for 4 hours, to provide
the 4'-O-benzenesulfonyl derivative; I immediately
reacting the 4'-O-benzenesulfonyl derivative with 1.5
equivalent of sodium iodide in methyl ethyl kitten at
180C for 15 minutes to obtain 4' idea derivative; (7)
reductively deiodinating the idea derivative using
tri(n-butyl)stannane in Bunsen in the presence of
2,2'-azobis-isobutyronitrile at 80C for 2 hours; and
(8) Deb locking the diethylacetal and tetrahydrofuranyl
groups by hydrolysis of the product of step (7) in elm
aqueous hydrochloric acid-acetonitrile (2.5:1 v/v) for
- 30 minutes at 25C to obtain 4'-deoxydesmycosin.
The Dixie derivatives of this invention,
i.e. the compounds of formula (I) wherein R3 is hydrogen,
are readily prepared by procedures analogous to those
described swooper, using 4'-deoxy-OMT, 4'-deoxy-DOMT or
4'-deoxy-D~-DO-OMT as the starting material. These
starting materials can be prepared via procedures
outlined in J. Antibiotics 34, 1381-1384 (1981).
alternatively, deoxygenation at 4' may be accomplished
in OUT, DOT or DH-DO-OMT subsequent to modification of
the C-20 and/or C-23 positions.
The formula (I) compounds which are ester
derivatives are prepared by esterifying the respective
C-20 and/or C-23-modified derivative on the 2', 4',
1236830
X-6286 -30-
and/or 23-hydroxyl groups (when present) by treatment
with assaulting agents, using standard methods example-
fled in the art. The preparation of ester derive-
lives of the C-20- and/or C-23-modified derivatives is
accomplished by procedures similar to those described by
Waltz et at. in U.S. Patents 4,321,361 and 4,321,362.
Esterification of the 2', 4' and/or 23-hydroxyl groups
of these modified derivatives may be accomplished by
acylation of the hydroxyl groups using prove-
dunes similar to those outlined in U.S. Patents Nazi, 4,487,923 and 4,396,613.
Alternatively, the formula (I) compounds which
are esters may be prepared by starting with the appear-
private esters of compounds 2-11, prepared as described
Syria. Furthermore, it should be noted that the formula
(I) ester compounds can be hydrolyzed to yield the
corresponding formula (I) compounds; thus utilizing the
esters as protecting groups during reactions to modify
the C-20 and/or C-23 positions.
The C-20-modified derivatives of this invent
lion form salts, particularly acid addition salts.
These acid addition salts are also useful as antibiotics
and are a part of this invention. In another aspect,
such salts are useful as intermediates, for example, for- - -
separating and purifying the derivatives. In addition,
the salts have an improved volubility in water.
Representative suitable salts include those
salts formed by standard reactions with both organic and
inorganic acids such as, for example, sulfuric, hydra-
caloric, phosphoric, acetic, succinic, citric, lactic,
~Z361~30
X-6286 -31-
malefic, fumaric, palmitic, colic, pamoic, music,
D-glutamic, d-camphoric, glutaric, glycolic, phthalic,
tartaric, formic, Laurie, Starkey, salicylic, methane-
sulfonic, benzenesulfonic, sorbic, picnic, benzoic,
cinnamic, and like acids.
Pharmaceutically acceptable acid addition
salts are an especially preferred group of salts of this
invention.
Illustrative formula (I) compounds of this
invention are listed in Table I.
~23~3~
X-~286 -32-
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X-~285 _33_
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3~36830
X-6286 _34_
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~23~30
X-6286 --36-
I_ = _ _ _
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v
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X-6286 _37_
O = o
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,,, ,, Jo
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o o I o
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O
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= = = = 3 s us
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a U ,Ç~1 I O rl O O n or O rl O
I: u a I a u a u u u a
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a a u o u us O ON end U N I
a o a o o o o a
o o I Jo u I so u u I u u
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u u a o o o
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z
pa
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~236~30
X-6286 -38-
The derivatives of this invention inhibit the
growth of pathogenic bacteria, especially gram-positive
bacteria, and MYcoplasma species. Certain of the
derivatives are active against some gram-negative
bacteria, such as Postural species. The minimal
inhibitory concentrations (Micas) at which illustrative
compounds inhibit certain bacteria are given in Tables II
and III. The Micas in Table II were determined by
standard agar-dilution assays. The Micas in Table III
10 , were obtained using a conventional broth-dilution
micro titer test.
. .
lZ3G830
X-6286 _39_
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X-6286 I o_
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X-6286 -41-
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X-6286 -42-
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X-6286 44
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X-628~ _45_
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X-6286 -48-
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lZ3~i~30
X-6286 -52-
Some of the derivatives of this invention have
shown i viva antimicrobial activity against export-
mentally induced infections in laboratory animals. When
two doses of test compound were administered to mice
experimentally infected with S. pvoqenes C203, the
activity observed was measured as an EDDY value
[effective dose in mg/kg to protect 50% of the test
animals: see Warren Wick, et at., J. Bacterial. 81,
233-235 (1961)]. EDDY values observed for illustrative
compounds are given in Table IV.
Table IV
EDDY Values of Illustrative Formula (I) Compounds
Test Compound Streptococcus pudginess C203
Subcutaneous Oral
1 >30 >100
22 >30 >100
24 >10 >50
>10 >50
33 >25 >100
34 >25 78
US >12.5 >100
36 >10 so
37 >-10 >100
38 >10 >100
46 >10 >50
amg/kg x 2; doses given 1 and 4 hours post-infection
compound numbers from Table I.
.
~Z36~30
X-6286 ~53~
Certain of the formula (I) compounds of this
invention have also shown in viva activity against
infections induced by gram-negative bacteria. Table V
summarizes the results of tests in which illustrative
compounds were evaluated against a Postural infection
in one-day-old chicks. The compounds were administered
parenterally after challenge of the chicks with Pasteup
relic multocida (0.1 ml of a lo 4 dilution of a twenty-
hour tryouts broth culture of an Asian P. multocida
given subcutaneously). In these tests, unless indicated
otherwise, all non-medicated infected chicks died within
24 hours of Postural challenge. In the tests Siam-
rimed in Table v, the compounds were administered by
subcutaneous injection at a dosage of 30 mg/kg, 1 and 4
hours post-challenge of the chicks with P. multocida.
Table V
Activity of Formula (I) Compounds
Administered Subcutaneously to
Postural multocida-Infected Chicks
Test Com~oundbNumber of Deaths Number Treated
l 9/10
22 Lowe
26 10/10
8/10
37 10/10
38 Lowe
administered subcutaneously; 30 mg/kg x 2
compound numbers from Table I
lZ3~i830
X-6286 -54_
The compounds which are preferred for on viva
activity against gram-positive microorganisms are those
formula (I) compounds wherein R is -N(R6)2. Another
preferred group are the formula (I) compounds wherein I
is -OH or soar and An is a group (iii) substituent.
Still another group of compounds preferred for in vitro
activity against gram-positive bacteria and for activity
against Mycolasma species are the formula (I) compounds
wherein Al is R9.
This invention also relates to methods of
controlling infections caused by gram-positive bacteria
and MycoPlasma species. In carrying out the methods of
this invention, an effective amount of a specified
formula (I) compound is administered parenterally to an
infected or susceptible warm-blooded animal.
The dose which is effective to control the
infection will vary with the severity of the infection
and the age, weight, and condition of the animal. The
total dose regrade for protection parenterally will
generally, however, be in the range of from about 1 to
about 100 mg/kg and preferably will be in the range of
from about 1 to about 50 mg/kg. Suitable dosage rouge-
miens can be constructed.
In another aspect, this invention relates to
US compositions useful for the control of infections caused
by gram-positive bacteria and MYco~lasma species. These
compositions comprise a specified compo~md of formula
(1) together with a suitable vehicle. Compositions may
be formulated for parenteral administration by methods
recognized in the pharmaceutical art.
~Z3~830
X-6286 ~55~
Effective injectable compositions containing
these compounds may be in either suspension or solution
form. In the preparation of suitable formulations it
will be recognized that, in general, the water syllable-
try of the acid addition salts is greater than that of the free bases. Similarly, the bases are more soluble
in dilute acids or in acidic solutions than in neutral
or basic solutions.
In the solution form the compound is dissolved
in a physiologically acceptable vehicle. Such vehicles
comprise a suitable solvent, preservatives such as
bouncily alcohol, if needed, and buffers. Useful solvents
include, for example, water and aqueous alcohols,
glycols, and carbonate esters such as deathly carbonate.
Such aqueous solutions contain, in general, no more than
50% of the organic solvent by volume.
Injectable suspension compositions require a
liquid suspending medium, with or without adjutants, as
a vehicle. The suspending medium can be, for example,
aqueous polyvinylpyrrolidone, inert oils such as vegeta-
bye oils or highly refined mineral oils, or aqueous
carboxymethylcellulose.
Suitable physiologically acceptable adjutants
are necessary to keep the compound suspended in suspend
soon compositions. The adjutants may be chosen from among thickeners such as carboxymethylcellulose, polyvi-
nylpyrrolidone, gelatin, and the alginates. Many
surfactants are also useful as suspending agents.
Lecithin, alkylphenol polyethylene oxide adduces,
naphthalenesulfonates, alkylbenzenesulfonates, and the
lZ36~330
X-5286 -56-
polycxyethylene sorbitan esters are useful suspending
agents.
Many substances which affect the hydra-
fullest, density, and surface tension of the liquid
suspending medium can assist in making injectable
suspensions in individual cases. For example, silicone
anti foams, sorbitol, and sugars can be useful suspending
agents.
In order to illustrate more fully the opera-
lion of this invention, the following examples are provided:
Preparation 1
2',4'-Di-O-acetYl-20-dihYdro-OMT
20-Dihydro-OMT (3.1 g, 5.2 Molly) was dissolved
in acetone (100 ml) and was treated over a five-minute
period with acetic android (2.0 ml, 21.2 Molly). After
stirring for nine hours at room temperature, the react
lion mixture was quenched into saturated sodium vicar-
borate solution (500 ml) and the product was extracted
into dichloromethane (2 x 250 ml). The combined
dichloromethane extracts were dried (sodium sulfate) and
filtered and the filtrate was evaporated under reduced
pressure. The residue was dried in vacua overnight to
yield 3.4 g (96%) of 2',4'-di-O-acetyl-20-dihydro-OMT.
Preparation 2
23-Iodo-20,23-dideoxv-20-dihvdro-OMT
20-Deoxy-20-dihydro-OMT (2.0 g, 3.4 Molly),
tetrabutylammonium iodide (3.8 g, 10.3 Molly) and
s-collidine (1.36 ml, 10.3 Molly) were dissolved in
.
Sue
X-~285 -57-
dichloromethane (40 ml). The solution was cooled to
-78 under an argon atmosphere and then was treated
drops with triflic android (Owe ml). After 5
minutes at -78, the cooling bath was removed and the
solution was stirred for 30 minutes at room temperature.
Since tlca analysis showed urea ted starting material
was still present, the solution was cooled to -78 again
and then treated with additional triflic android
(0.03 ml). The cooling bath was again removed and the
reaction was stirred at room temperature for 30 minutes.
The solution was extracted with saturated sodium vicar-
borate solution, dried (Nazi) and filtered. The
filtrate was evaporated to dryness and the crude product
was purified by flash chromatography on silica gel,
eluding with alienor gradient of dichloromethane (1 L)
and 5% methanol in dichloromethane (1 L). Fractions
containing the desired product were located by tic
analysis, combined and evaporated under reduced pressure
to yield 2.0 g of 23-iodo-20,23-dideoxy-20-dihydro-OMT.
thin layer chromatography
Example
2',4'-Di-O-acetYl-20-O-phenYlacetYl-20-
dihydro-OMT and 2',4'-di-O-acetvl-20,23-di-O-phenYl-
acet~l-20-dihvdro-OMT
2',4'-Di-O-acetyl-20-dihydro-OMT (3.0 g,
4.4 Molly) was dissolved in dichloromethar.e (50 ml) and
pardon (2 ml). The solution was cooped to -78 and
. . .
~Z~683~
X-6286 -58-
treated drops with phenylacetyl chloride (0.725 ml,
5.5 Molly) over a 2-minute period with vigorous stirring.
After 15 minutes at -78, the cooling bath was removed
and the solution was stirred at room temperature for six
hours. The solution was then poured into saturated
sodium bicarbonate solution (100 ml) and the product was
extracted into dichloromethane (2 x 50 ml). The come
brined dichloromethane extracts were dried (sodium
sulfate) and filtered and the filtrate was evaporated.
The residue (4 g) was separated on a Waters Prep 500
chromatography eluding with a linear gradient of Tulane
(4 L) and ethyl acetate (4 L). Fractions containing the
desired products were located by tic analysis, combined
and evaporated under reduced pressure to yield 2.3 g of
2',4'-di-O-acetyl-20-O-phenylacetyl-20-dihydro-OMTT and
0.6 g of 2',4'-di-O-acetyl-20,23-di-O-phenylacetyl-20-
dihydro-OMT.
Example 2
20-O-PhenYlacetyl-2o-dihydro-oMT
2',4'-Di-O-acetyl-20-O-phenylacetyl-20-
dihydro-OMT (1.2 g, 1.5 Molly) was dissolved in methanol
(80 ml) and water (20 ml) and the solution was reflexed
for 1.5 hr. After cooling to room temperature, solvent
was evaporated under reduced pressure and the residue
was dissolved in dichloromethane (50 ml), dried (sodium
sulfate) and filtered. Evaporation of the filtrate
yielded 0.92 g of 20-O-phenylacetyl-20-dihydro-OMT.
* Trademark
lZ3G830
X-6286 -59-
Example 3
20,23-Di-O-Phenylacetyl-20-dihvdro-OMT
In a manner similar to that of Example 2,
2',4'-di-O-acetyl-20,23-di-O-phenylacetyl-20-dihyddreamt
(0.48 g) was hydrolyzed to yield 0.44 g of Dow-
phenylacetyl-20-dihydro-OMT.
Example 4
20-N-Methvlamino-20-deoxy-20-dihvdro-OMT
OUT (1.2 g) and methyl amine hydrochloride
(1.36 g) were dissolved in dry methanol (40 ml). After
stirring for one hour at room temperature, sodium
cyanoborohydride (500 my) was added. The solution was
stirred for 3 hours and then was poured into saturated
sodium bicarbonate solution (200 ml). The product was
extracted into dichloromethane (2 x 200 ml) and the -
combined extracts were dried (Nazi) and filtered. The
filtrate was evaporated and the residue (Owe g) was
dissolved in dichloromethane and separated by flash
chromatography on silica gel Grace 60),' eluding with a
linear gradient of l liter of dichloromethane-methanol-
gone. ammonium hydroxide (90:10:0.5) and l liter of
dichloromethane-methanol-conc. ammonium hydroxide
(75:25:0.5). Fractions containing the desired product
were located by tic analysis, combined and evaporated
under reduced pressure to yield 0.14 g of the title
compound.
* Trademark
~23~830
X-6286 -60-
Example 5
- 20-N-Benzylamino-20-deoxv-20-dihydro-OMT
Using a procedure like that of Example 4, OUT
(2.2 g) and benzylamine (4.1 ml) in methanol (60 ml)
were treated with sodium cyanoborohydride (1.0 g).
After extractive workup, the crude product was purified
by silica gel chromatography on a waters Prep 500
instrument, eluding with a linear gradient of dichloro-
-- methane (4 Lo and dichloromethane-methanol-conc. ammonia
us hydroxide (90:10:0.5, 4 L), to yield 0.21 g of the
title compound.
Example 6
20-'N-Dimethvlamino-20-deoxY-20-dihYdro-OMT
Using a procedure like that of Example 4, OUT
(1.2 g) and dimethylamine hydrochloride (1.6 g) in
methanol (40 ml) were treated with sodium cinnabar-
hydrides (0.5 g). After extractive workup and purifica-
lion by silica gel chromatography as described in example
5, 0.61 g of the title compound was obtained.
Example 7
20-N-Benzvlamino-20-deoxv-20-dihvdro-DMOT
Using a procedure like that of Example 4, DOT
(1.56 g) and benzylamine (4.0 ml) in methanol (60 ml)
were treated with sodium cyanoborohydride (1 g). After
extractive workup, the crude product was purified by
flash chromatography on silica gel, eluding with a
-linear gradient of dichloromethane (1 L) and dichloro-
~LZ3~;830
X-6286 -61-
methane-methanol (3:1, 1 L) to yield 0. pa g of the title
compound.
Example 8
20-N-Phenethylamino-20-deoxY-20-dihydro-DMT
DOT (10.4 g) and phenethylamine (2.8 ml) were
dissolved in dry methanol (420 ml) and the solution was
stirred for 30 minutes at room temperature. Sodium
cyanoborohydride (3.5 g) was added and the solution was
stirred for 2.5 hours. The solution was poured into
saturated sodium bicarbonate solution (1 1) and the
product was extracted into dichloromethane (4 x 500 my
The combined extracts were dried (Nazi) and filtered
and the filtrate was evaporated. The residue was
dissolved in a small volume of dichloromethane and
separated by flash chromatography on silica gel, eluding
with a linear gradient of dichloromethane-methanol-conc.
ammonium hydroxide (1 L of 125:1:0.1 to 1 L of Lyle)
followed by an additional 1 L of the latter solvent
mixture. Fractions containing the desired product were
located by tic analysis, combined and evaporated to
yield 2.8 g of the title compound.
Example 9 --
20-N-PhenethYlamino-20-deoxv-20-dihydro-OMT
20-N-Phenethylamino-20-deoxy-20-dihydro-DMT
(1.5 g) was dissolved in lo sulfuric acid (60 ml) and
stirred for 1 hour at room temperature. The solution
was slowly poured into saturated sodium bicarbonate
l?Z36~30
X-6286 -62-
solution (500 ml) and the product was extracted into
dichloromethane (3 x 300 ml). The combined extracts
were dried (Nazi) and filtered and the filtrate was
evaporated under reduced pressure to yield 0.88 g of the
- 5 title compound.
Example 10
20~23-Di-N-Phthalimido-2ol23-dideoxy-2
d-hYdro-DMT
0-Dihydro-DMT (1.49 g, 2.0 Molly), triphenyl-
phosphine (2.1 g, 8 Molly) and phthalimide (1.18 g,
8.0 Molly) were dissolved in tetrahydrofuran (50 ml)
under an argon atmosphere. Deathly azodicarboxylate
(1.4 g, 8 Molly) was added drops and the solution was
stirred for 30 minutes at room temperature. Methanol
(about 1 ml) was added to decompose excess reagent an dafter stirring for 10 minutes, the solution was evapo-
rated under reduced pressure. The residue was part-
toned between ethyl acetate and 0.1 M acetic acid
(100 ml each) and a few ml of petroleum ether were added
to break the emulsion that formed. The aqueous layer
was separated, made alkaline with solid sodium bicarbon-
ate and extracted with dichloromethane. The organic
extracts were dried (Nazi) and filtered and the
filtrate was evaporated. The residue was dissolved in a
small volume of dichloromethane and separated by flash
chromatography on silica gel, eluding first with dichloro-
methane (300 ml) followed by a linear gradient of
dichloromethane (1 L) and 9% methanol in dichloromethane
(1 L). Fractions containing the desired product were
1236t~30
X-6286 -63-
located by tic analysis, combined and evaporated to
dryness to Yield 0.17 g of the title compound.
Example 11
20,23~ N-Phthalimido-20,23-dideoxY-20-
dihYdro-OMT
20,23-Di-N-phthalimido-20,23-dideoxy-20-
dihydro-DMT (100 my) was dissolved in lo sulfuric acid
(10 ml) and Dixon (3 ml) and stirred for 1 ho at room
temperature. The reaction was then neutralized with
solid sodium bicarbonate and extracted with dichloro-
methane twice. The combined extracts were dried (Nazi)
and filtered and the filtrate was evaporated to dryness
under reduced pressure and then dried in vacua to yield
the title compound.
Example 12
20-N-Phthalimido-20-deoxv-20-dihYdro-DMOT
20-Dihydro-DMOT (3.64 g, 5 Molly), triphenyl-
phosphine (2.62 g, 10 Molly) and phthalimide (1.47 g,
10 Molly) were dissolved in tetrahydrofuran (40 ml) under
a nitrogen atmosphere. The solution was treated drops
with deathly azodicarboxylate (1.58 ml, 10 Molly) and
then stirred for 1 ho at room temperature. The excess
reagent was quenched with methanol (25 ml) and the
solution was evaporated under reduced pressure. The
residue was dissolved in a small volume of dichloro-
methane and separated by flash chromatography on silica
gel, eluding with dichloromethane (1 L) followed by a
linear gradient of dichloromethane (1 L) and 5% methanol
1236~30
X-~286 -64-
in dichloromethane (1 L). Fractions containing the
desired product were located by tic analysis, combined
and evaporated to dryness to yield 2.44 g of the title
compound.
Example 13
.
?O-N-Phthalimido-20-deoxv-20-dihydro-DMT
In a manner analogous to that of example 12,
20-dihydro-DMT (2.96 g), triphenylphosphine (2.0 g) and
phthalimide ~1.18 g) were dissolved in tetrahydrofuran
(35 ml) and treated with deathly azodicarboxylate
(1.4 ml). Since tlc.analysis of the reaction mixture
after 30 minutes showed a significant amount of unrequited
20-dihydro-DMT in addition to a mono-substituted and a
di~substituted derivative, additional p~thalimide
(296 my), triphenylphosphine (523 my) and deathly
azodicarboxylate ~0.33 ml), were added. After stirring
for an additional 0.5 ho at room temperature, the
reaction was quenched with methanol and worked up as
described in example 12 to yield, from chromatography on
silica gel as described above, 0.79 g of 20-N-phthal-
imido-20-deoxy-20-dihydro-DMT along with 2.16 g of
20,23-di-N-phthalimido-20,23-dideoxy-20-dihydro-DMMT.
Example 14
20-N-Phthalimido-20-deoxy-20-dihYdro-DOMT
20-N-Phthalimido-20-deoxy-20-dihydro-DMOT
(1.0 g) was dissolved in lo sulfuric acid (80 ml) and
stirred for 1 ho at room temperature. The solution was
slowly added to saturated sodium bicarbonate solution
~36830
X-6286 I
(500 ml) and then was extracted with dichloromethane (3
x 300 ml). The combined extracts were dried (Nazi)
and filtered and the filtrate was evaporated unsex
reduced pressure to yield 0.50 g of the title compound.
Example 15
20-N-Phthalimido-~O-deoxv-20-dihvdro-OMT
20-N-Phthalimido-20-deoxy-2Q-dihydro-D~
(355 my) was hydrolyzed in lo sulfuric acid (50 ml) for
1 hr. After workup as described in example 14, 1~0 my
of the title compound was obtained.
Example 16
20,23-Dî-O-~henYl-20-dihvdro-OMT
20-Dihydro-OMT (1 g, 1.7 Molly), _riphenyl-
phosphine (1.3 g, 5.1 Molly) and phenol (0.47 g, 5.1
Molly) were dissolved in tetrahydrofuran (30 ml) under a
nitrogen atmosphere. The solution was cooled in an ice
bath and treated with deathly azcdicarboxylate (0.89 g,
5.1 Molly) over a 2-minute period. The cooling bath was
removed and the solution was stirred for 1 ho at room
temperature. Methanol ~10 ml) was added and, after
stirring for 15 minutes, the solution was evaporated
under reduced pressure. The residual oil was treated
with Tulane and the white insoluble material was
filtered. The filtrate was evaporated and the residue
was partitioned between dichloromethane and saturated
sodium bicarbonate solution. The organic layer was
separated, dried (Nazi) and filtered and the filtrate
was evaporated. The residue was separated by flash
~Z36~30
X-6286 -66-
chromatography on silica gel, eluding with mixtures of
methanol-dichloromethane as follows: 400 ml of 0%,
250 ml of 2%, 250 ml of 3%, 500 ml of 4% and 250 ml each
of 6%, 8%, 10% and 16% methanol in dichloromethane.
Fractions containing the desired product were located by
tic analysis, combined and evaporated to yield 144 my of
20,23-di-O-phenyl-20-dihydro-OMT.
Preparation Example 17
dodder -O-Pherlylpropionyl-oMT
23-O-Phenylpropionyl-OMT (1.9 g, 2.6 Molly) was
dissolved in 1:1 isopropanol:water ~30 ml). Sodium
bordered (0.025 g, 0.65 Molly) was added to this
solution and the reaction was stirred for 0.5 hr. The
pi of the reaction was adjusted from pi 10.5 to pi 7.0
with lo sulfuric acid. The solution was concentrated to
aqueous under reduced pressure and saturated Nikko
solution was added. The product was extracted into
dichloromethane and the extracts were dried (Nazi and
filtered. The filtrate was evaporated under reduced
pressure to yield 1.75 g (92%) of the title compound as
a white foam.
Example 18
20-DihYdro-23-OctahYdroazocin-l-Yl-23-deoxY-
OUT
23-Octahydroazocin-l-yl-OMT (900 my, 1.3 Molly)
was reduced with sodium bordered (12 my, 0.33 Molly)
in 1:1 isopropanol-water (15 ml) as described in example
~.23G~30
X-6286 --57-
17, yielding 815 my ~90%) of the dodder derivative.
Example 19
20-O-Phenvl-20-dihYdro-23-O-~henYlPropion
OUT
20-Dihydro-23-O-phenylpropionyl-OMT (1.7 g,
2.3 Molly), triphenylphosphine (1.2 g, 4.6 Molly) and
phenol (0.43 g, 4.6 Molly) were dissolved in tetrahydro-
Furman ~45 ml) under a nitrogen atmosphere. The solution
was cooled in an ice bath and then was treated drops
with deathly azodicarboxylate (0.8 g, 4.6 Molly). After
5 minutes, the cooling bath was removed and the solution
was stirred for 2 ho at room temperature. Since tic
analysis of the reaction indicated tune presence of
unrequited starting material, one-half of the initial
amounts (2.3 Molly of triphenylphosphine, phenol and
dietXyl azodicarboxylate were each added. After stir-
ring for another 30 minutes, methanol (10 ml) was added
to decompose excess reagent and the solution was evapo-
rated under reduced pressure. The residual oil was
treated with Tulane and the insoluble material was
filtered. The filtrate was evaporated under reduced
pressure and the residue was separated by flash chrome-
tography on silica gel, eluding step-wise with mixtures
of methanol-diChloromethane as follows: 400 ml of 0%,
250 ml of 2%, 250 ml. of 4%, 750 ml of 6% and 250 ml of
8% methanol in dichloromethane. Fractions containing
the desired product were located by tic analysis,
combined and evaporated under reduced pressure to yield
0.26 g of 20-0-phenyl-20-dihydro-23-O-phenylpropionyl-
OUT.
1236i330
X-6286 -68-
Example 20
20-0-Phenvl-20-dihYdro-23-OctahYdroazocin-l-
yl-OMT
20-Dihydro-23-octahydroazocin-1-yl-OMT (800 my,
1.2 Molly), triphenylphosphine ( 940 my, 3.6 Molly) and
phenol (340 my, 3.6 Molly) were dissolved in tetrahydro-
Furman (20 ml). The solution was treated with deathly
azodicarboxylate (630 my, 3.6 Molly), stirred for 1 hour,
and worked up as described in example 19. The crude
product was purified by flash chromatography on silica
gel, eluding stops with mixtures of methanol-dichloro-
methane as follows: 400 ml of 0%, 250 ml of 2%, 500 ml
of 3%, 250 ml each of 4%, 6%, 8%, 12% and 16% methanol
in dichloromethane. Fractions containing the desired
product were located by tic analysis, combined and
evaporated to yield 90 my of the title compound.
Example 21
2',4',23-Tri-O-acetvl-20-deoxy-20-dih~dro-OMT
I 20-Deoxy-20-dihydro-OMT I g) was dissolved in
pardon (70 ml). The solution was treated with acetic
android (4 ml) and then was stirred overnight at room
temperature. The solution was evaporated under reduced
pressure and the residue was dissolved in dichloromethane
and cyclohexane and then re-evaporated to remove most of
the pardon. The residue was dissolved in dichloro-
methane, extracted with saturated sodium bicarbonate
solution, dried (Nazi) and filtered. The filtrate was -
1~6~30
X-6286 -69-
evaporated to dryness and the residue was redissolved
and re-evaporated to remove pardon as before and
finally was suspended in hexane and filtered. The solid
residue (5.3 g) was separated on a Waters Prep 500
chromatography over silica gel, eluding with a linear
gradient of Tulane (1 L) and toluene-ethyl acetate
(1:3, 1 Lo. Fractions containing the desired product
were located by tic analysis, combined and evaporated to
dryness to yield 3.72 g of 2',4',23-tri-O-acetyl-20-
deoxy-20-dihydro-OMT.
Example 22
23-0-PhenYlacetyl-20-deoxv-20-dihydro-OMT
20-Deoxy-20-dihydro-OMT (2 g, 3.4 Molly) was
dissolved in dichloromethane (40 ml) and pardon
(0.55 ml). The solution was cooled to -78 and treated
with phenylacetyl chloride (0.55 ml, 4.1 Molly). The
cooling bath was removed and the reaction was allowed to
warm to room temperature and then stirred for an add-
tonal 0.5 ho at room temperature. Since tic analysis
of the reaction showed the presence of starting Metro-
at, the solution was again cooled to -78 and treated
with additional phenylacetyl chloride (0.35 ml).
Sequence was repeated again, using 0.08 ml of phenol-
acutely chloride the final time. The final reaction
mixture was extracted with saturated sodium bicarbonate
solution, dried (Nazi and filtered and the filtrate
was evaporated to dryness. The residue was separated by
flash chromatography on silica gel, eluding with a
linear gradient of dichloromethane (1 L) and 20%
~Z36830
X-6286 -70-
methanol in dichloromethane (1 L). Fractions containing
the desired product were identified by tic analysis,
combined and evaporated to yield the title compound.
Example 23
23-PhenYlthio-20,23-dideoxv-20-dihydro-OMT
20-Deoxy-20-dihydro-O~ (3.0 g, 5.15 Molly) was
dissolved in dichloromethane (40 ml) and s-collidine
(1.36 ml). The solution was cooled to -78 and treated
with triflic android (1.0 ml initially, then 0.3 ml
additionally); thiophenol (1.25 ml) was added at -78
and the mixture was stirred at -78 for 1.5 hr. The
reaction was stirred for another 2.5 ho while warming to
room temperature and then was extracted with saturated
sodium bicarbonate solution, dried (Nazi) and filtered.
The filtrate was evaporated and the residue was washed
with hexane and then separated by flash chromatography
on silica gel; eluding with a linear gradient of dichloro-
methane (1 L) and 20% methanol in dichloromethane (1 L).
Fractions containing the desired product were located by
tic analysis, combined and evaporated to yield 700 my of
the title compound.
Example 24
23-Octahvdroazocin-l-vl-20,23-dideoxv-20-
dihydro-OMT
23-Iodo-20,23-dideoxy-20-dihydro-OMT (69 my)
and heptamethyleneimine (0.05 ml) were dissolved in
acetonitrile (2 ml) and the solution was reflexed for 2
ho under an argon atmosphere. The solution was cooled
lZ3~330
X-6286 -71-
to room temperature and poured into saturated sodium
bicarbonate solution lo ml). The product was extracted
into dichloromethane and the extracts were dried Nazi)
and filtered. The filtrate was evaporated and the
residue was separated by preparative tic or. a 20 x
20 cm, 2 mm thick plate of silica jowl. Merck),'*
developing with dichloromethane-me~hanol-conc. ammonium
hydroxide (90:10:2). The band on the silica gel plate
was located by W light and was scraped from the plate,
lo dried in vacua to remove solvent and then eluded with
dichloromethane-methanol (1:1, 50 ml) for 45 minutes.
The mixture was filtered and the filtrate was evaporated
to dryness to yield 65 my of the title compound.
Example 25
23-(4-~Ydroxypi~eridino)~20l23-dideoxy-20-
dihvdro-OMT
23-Iodo-20,23-dideoxy-20-dihydro-OMT lo g,
1.6 Molly) and 4-hydroxypiperidine (0.32 g, 3.2 Molly)
were dissolved in acetonitrile (20 ml) and reflexed
under an argon atmosphere for 2 hr. Additional 4-
hydroxypiperidi.ne (300 my) was added to consume unrequited
starting material and the solution was reflexed for an
additional 3 hr. The solution was cooled to room
temperature and then evaporated under reduced pressure.
The residue was dissolved in dichloromethane, extracted
with saturated sodium bicarbonate solution, dried
(Nazi) and filtered. The filtrate was evaporated and
the residue was purified by flash chromatography on
* Trademark
~Z36830
X-6286 -72-
silica gel, eluding with a linear gradient of dichloro-
methane (1 L) and 12% methanol in dichloromethane (1 L).
Fractions containing the desired product were located by
tic analysis, combined and evaporated to yield 865 my of
S the title compound.
Example 26
23-0-~2,3-DimethoxyphenYl)-20-deox~-2G-dihYdro-
OUT
20-Deoxy-20-dihydro~OMT (3.0 g, 5.15 Molly),
triphenylphosphine (2.7 g, 10.3 Molly) and 2,3-dimethoxy-
phenol (1.59 g, 10.3 Molly) were dissolved in tetrahydro-
Furman (150 ml3 under an argon atmosphere. The solution
was treated with ~1iethyl azodicarboxylate (1.7 ml,
10.3 Molly) and then was stirred for 40 minutes at room
temperature. Methanol (2 ml) was added to decompose
excess reagent and the solution was evaporated to
dryness under reduced pressure. The residue was taken
up in Tulane and the insoluble material was filtered.
The filtrate was extracted with saturated sodium vicar-
borate solution, dried (Nazi) and filtered and the filtrate was evaporated to dryness. The residue was
purified by chromatography on silica gel (Waters Prep
500), eluding with dichloromethane (2 L) followed by a
linear gradient of dichloromethane (2 L) and 10% Matthew-
not in dichloromethane (2 L); the column was finallyeluted with 2 L of the latter solvent. Fractions
containing the desired product were located by tic
analysis, combined and evaporated to yield 2.06 g (54%)
of the title compound.
~Z3~830
X-628~ ~73
Example 27
23-0-(3-Pvridyl)-20,23-dideoxy-20-dihYdro-OMT
20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 Molly),
triphenylphosphir,e (2.7 g, 10.3 Molly) and 3-hydroxy-
S pardon (979 my, 10.3 Molly) were dissolved in twitter-
hydrofuran (50 ml) under an argon atmosphere and treated
with deathly azodicarboxylate (1.7 ml, 10.3 Molly).
After workup and chromatography as described in example
26, 0.63 g of the title compound was obtained.
Example 28
23-O-(m-DimethylaminoPhenyl)-20-deoxy-20-
, dihYdro-OMT
20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 Molly),
triphenylphosphine (2.7 g, 10.3 Molly) and m-dimethyl-
amino phenol (1.4 g, 10.3 Molly) were dissolved in twitter-
hydrofuran (50 ml) under an argon atmosphere. Deathly
azodicarboxylate (1.7 ml, 10.3 Molly) was added and the
solution was stirred for 1 ho at room temperature.
Since starting material had not been consumed at this
point, additional triphenylphosphine (1.35 g), m-dimethyl-
amino phenol (0.70 g) and deathly azodicarboxylate
(0.85 ml) were added and the solution was stirred for
another 0.5 hr. Mesh (about 3 ml) was then added to
quench the reaction and the solution was evaporated
under reduced pressure. The residue was worked up as
described in example 26 and purified by chromatography
on silica gel (Waters Prep 500), eluding with
1236830
X-6286 -74-
dichloromethane (2 L) followed by a linear gradient of
dichloromethane (4 L) and 15% methanol in dichlorome~hane
(4 L). Fractions containing the desired product were
located by tic analysis, combined and evaporated to
dryness to yield 1.12 g of the title compound as a
purple glassy solid.
Example 29
20-Di~henvlamino-20-deoxv-20-dihYdro-OMI
-
OUT (3.0 g, 5 Molly) was dissolved in dim ethyl-
formamide (10 ml) and the solution was diluted with
Tulane (100 ml). Diphenylamine (1.69 g, 10 Molly) and
~-toluenesulfonic acid hydrate (150 my) were added and
the solution was reflexed using a Dean-Stark trap to
separate water. After 4 ho, 20 ml of condensate was
withdrawn and the solution was reflexed overnight. The
solution was cooled to room temperature and evaporated
under reduced pressure. The residue was dissolved in a
solution of sodium cyanoborohydride (1.25 g) in dry
methanol (75 ml) and the solution was stirred for 2 ho
at room temperature. Solvent was evaporated under
reduced pressure and the residue was partitioned between
ethyl acetate (75 ml) and water (75 ml). The organic
layer was separated and then extracted with 0.5 M, pi
6.5 phosphate buffer (75 ml) and with 0.5 M, pi 4.5
phosphate buffer (2 x US ml). The combined latter
extracts were back-extracted with ethyl acetate (75 ml)
and the combined ethyl acetate solutions were dried
(Nazi) and filtered. The filtrate was evaporated to
dryness and the residue was dissolved in a small volume
Sue
X-6285 ~75~
of dichloromethane, filtered and purified by chromatog-
rough on silica gel (Waters Prep 500), eluding with a
linear gradient of dichloromethane (4 L) and 5% methanol
plus 0.5% gone. ammonium hydroxide in dichloromethane
(4 L) followed by 3 L of the latter solvent mixture.
The fraction containing the desired compound was located
by the analysis and was evaporated to dryness to yield
113 my of the title compound.
Example 30
20-DH-DO-20-[3-Azabicvclo(3.2.2)-nonan-3-v~l-OMT
OUT (3.0 g., OWE moles) was dissolved in
lo an hydrous methanol (15 ml.). 3-Azabicyclo[3.2.2]-nonane
(1.2S g., 10 moles) was dissolved in an hydrous methanol
(15 ml.) and filtered to remove a white impurity. The
filtrate was added to the OUT solution and the resulting
solution was stirred for 5-10 minutes at room tempera-
lure in the presence of molecular sieves (PA). NaBH3CN(0.63 g., 10 moles) was added, and the reaction was
stirred at room temperature for 17 hours. The reaction
mixture was filtered, and the filtrate was evaporated
under vacuum to give a foam which was redissolved in
ethyl acetate (150 ml.). The ethyl acetate solution was
washed with water (150 ml.) and separated. A major
portion of the product was then extracted from the ethyl
acetate solution with 0.5M Nope buffer (150 ml., pi
6.5~. The phosphate buffer solution was evaporated
under vacuum to remove residual ethyl acetate. The pi
of the buffer solution was adjusted to about 11 with ON
Noah, forming a white precipitate which was collected by
~Z36~30
X-6286 -76-
filtration and dried to give 2.06 g. (58% yield) of
20-DH-DO-20-[3-azabicyclo(3.2.2)nonan-3-yl]OMT. [Tiara-
lion Pea values: 7.7 and 9.3; FDMS parent ion (M +
1) = 707].
Example 31
20-DH-DO-20-MorPholino-oMT
Following the procedure outlined in Example 1,
OUT (3.0 g., 5.0 moles), morpholine (Owe ml., 10
moles), NaBH3CN (Owe g., 5 moles) and an hydrous Mesh
(30 ml.) were reacted in the presence of molecular
sieves (PA). Since a precipitate did not form when the
pi of the buffer was adjusted to 11, the product was
extracted from the buffer with SCHICK to give 1.66 g.
(50% yield) of 20-DH-DO-20-morpholino-OMT as a white
foam. [Titration Pea values: 6~5, 8.4; FDMS parent ion
(M + 1) = 669].
Example 32
20-DH-DO-20-(4-PhenYlpiperidin-l-yl)-oMT
OUT (5.97 g., 10 moles), 4-phenylpiperidine
(3.22 g., 20 moles), NaBH3CN (1.25 g., 20 moles) and
methanol (60 ml.) were reacted using the procedure of
Example 1, but substituting a pi 4.5 buffer for extract
lion, to give 3.7 g. of the title compound [FDMS parent
ion (M I 1) = 743].
~Z36830
X-6286 -77-
Example 33
20-DH-DO-23-DeoxY-20,23-di(octahYdroazocin-l-Yl)-OOUT
20,23-di-iodo-OMT (1.2 g., 1.5 moles) was
dissolved in acetonitrile (20 ml.). Heptamethyleneimine
(1.7 g., 1.9 ml., 15 moles) was added to this solution,
and the reaction mixture was stirred at reflex furl
hours. Volatile were removed, and the resulting red
oil was dissolved in SCHICK ~150 ml.). This solution
was washed with saturated Nikko solution (100 ml.) and
the SCHICK phase was separated and dried over Nazi,
filtered, and evaporated under vacuum. The residue
obtained was subjected to flash column chromatography on
silica gel 60 packed in MeOH/CH2C12 (1:9). The column
was eluded stops with MeOH/CH2C12 as follows:
300 ml. of 1:9, 500 ml. of 1:4, 250 ml. of 3:7, 250 ml.
of 2:3, 500 ml. of 1:1, and 500 ml. of 7:3. The desired
fractions were combined to give 221 my. (19% yield) of
20-DH-DO-23-deoxy-20,23-di(octahydroazocin-1-yl)-OOUT as
a white foam. [Titration Pea values: 6.9, 8.05, 8.9;
FDMS parent ion (M + 1) = ~90].
eye
The following compounds can be prepared by the
methods of the preceding examples.
20-DH-DO-20-(octahydroazocin-1-yl)DMT
20-D~-DO-20-~piperidin-1-yl)DMOT
20-DH-DO-20-(piperidin-1-yl)DOMT
20-DH-DO-20-(4-hydroxypiperidin-1-yl)DOMT
.,
lZ3GS30
X-6286 -78-
20-DH-DO-20-(decahydroazecin-1-yl)OMT
20-DH-DO-20-(octahydroazocin-1-yl)DOMT
20-DH-DO-20-(azacyclotridecan-1-yl)OMT
20-DH-DO-20-(hexahydroazepin-1-yl)DMT
20-D~-DO-20-(1,2,3,4-tetrahydroisoquinolin-
2-yl)OMT
- 20-DH-DO-20-(1,2,3,4-tetrahydroquinolin-1-
ye omit
20-DH-DO-20-(azacycloundecan-1-yl OMIT
20-DH-DO-29-(4-methylpiperidin-1-yl)OMT
20-DH-DO-20-(pyrrolidin-1-yl)DMT
20-DH-DO-20-(octahydro-lH-azonin-l-yl)OMT
20-DH-DO-20-(octahydroazocin-1-yl)DMOT
20-DH-DO-20-(octahydroazocin-1-yl)DOMT
20-DH-DO-20-(4-phenylpiperidin-1-yl)DMT
20-DH-DO-20-(4-phenylpiperidin-1-yl)-4'-deoxy-
OUT
20-DH-DO-20-(decahydroazecin-1-yl)-4'-
deoxy-OMT
20-DH-DO-20-(hexahydroazepin-1-yl)-4'-
deoxy-OMT
20-DH-DO-20-(1,2,3,4-tetrahydroisoquinolin-
2-yl)DOMT
20-DH-DO-20-(decahydrocyclopent[c]azepin-
25 l-yl)OMT
20-DH-DO-20-(7-azabicyclo[2.2.1]heptan-1-yl)OMT
Example 57
Injectable Formulations
A) A formula (I) base is added to propylene
glycol. Water and bouncily alcohol are added so that the
owe
X-6286 79
solution contains 50% (by volume) propylene glycol, 4%
(by volume) bouncily alcohol, and 200 mg/ml of a formula
(I) base.
B) A solution is prepared as described in Section
S A except that the solution contains 50 mg/ml of a
formula (I) base.
C) A solution is prepared as described in Section
A except that the solution contains 350 mg/ml of a
formula (I) base.
D) A solution is prepared as described in Section
A except that the solution contains 500 mg/ml of a
formula (~) tart rate.
E) A suspension is prepared by adding a finely
ground formula (I) compound to carboxymethyl cellulose
with thorough mixing so that the suspension contains 200
my of the formula (I) base per ml of suspension.
Often the most practical way to administer the
compounds is by formulation into the feed supply or
drinking water. A variety of feeds, including the
common dry feeds, liquid feeds, and pelleted feeds, may
be used.
The methods of formulating drugs into animal
feeds are well-known. A preferred method is to make a
concentrated-drug premix which in turn is used to
prepare medicated feeds. Typical premixes may contain
from about 1 to about 200 grams of drug per pound of
premix. Premixes may be either liquid or solid
preparations.
The final formulation of feeds for animals or
poultry will depend upon the amount of drug to be
administered. The common methods of formulating,
S ' ' A
123G~30
X-62~ -80-
mixing, and pelleting feeds may be used to prepare feeds
containing a compound of formula (I).
Many substances which affect the hydrophilicity,
density, and surface tension of the liquid suspending
S medium can assist in making injectable suspensions in
individual cases. For example, silicone anti foams,
sorbitol, and sugars can be useful suspending agents.
1231i~30
X-~;2~6 -81-
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