Note: Descriptions are shown in the official language in which they were submitted.
X-8244 -1-
Piperidine Derivatives
This invention relates to 3,4,4-trisubstituted-
piperidinyl-N-alkyl-carboxylates and their methods of
use as peripheral opioid antagonists.
A substantial body of evidence indicates that
peripheral opioid peptides and their receptors have a
major physiological role in the regulation of gut
motility. Consequently gastrointestinal disorders such
as idiopathic constipation and irritable bowel syndrome
may relate to a dysfunction of opioid receptor mediated
control and, agents which act as antagonists for these
receptors may benefit a patient suffering from such a
dysfunction.
Natural and synthetic opiates such as morphine
have been used extensively in the mediation of pain.
However, these agents can produce undesirable side
effects such as constipation, nausea, and vomiting which
are peripheral to the desired action as analgesics.
Thus, a peripheral opioid antagonist should not sub-
stantially affect the analgesic effects of the opiate
'!
~~~ xJ ~~
X-8244 _2_
while acting to control gastrointestinal function and to
minimize the undesirable side effects of the narcotic
drug.
A number of opioid antagonists have been
reported including naloxone and naltrexone (Blumberg
et al., Toxicol. Appl. Pharmacol., _10, 406, 1967).
These compounds are disclosed as having useful
analgesic activity and in some cases acting as potent
narcotic antagonists.
It would be advantageous to have compounds
which would act as antagonists to the peripheral effects
of opiate analgesics and endogenous opioid peptides. It
would also be advantageous if these compounds had a
minimal effect on the analgesic activity of the opiate
drugs. It would be further advantageous to have compounds
which can act to minimize the effects of idiopathic
constipation and irritable bowel syndrome.
It has now been found that the N-substituted
piperidines of the instant invention are useful as
peripherally selective opioid antagonists. The instant
compounds can also be useful in relieving the symptoms of
idiopathic constipation and irritable bowel syndrome.
Certain of the instant compounds are also useful as
intermediates in preparing new piperidine compounds.
ry ~ ~ ,.~a
X-8244 -3-
According to the present invention there is
provided the traps-3,4-isomer of a compound of the Formula
_ ~Rt
CHs
T
2
N
wherein: (CH2)"CH-C-A
R1 is hydrogen or Cl-CS alkyl;
RZ is hydrogen, C1-CS alkyl ar CZ-C6 alkenyl;
R3 is hydrogen, C1-Clo alkyl, C3-Clo alkenyl,
phenyl, cycloalkyl, CS-C$ cycloalkenyl, cycloalkyl-
substituted C1-C3 alkyl, C5-C8 cycloalkenyl-substituted
C1-C3 alkyl, or phenyl-substituted C1-C3 alkyl;
A is OR4 or NRSRs;
wherein:
R4 is hydrogen, C1-Clo alkyl, CZ-Clo alkenyl,
cycloalkyl, CS-C$ cycloalkenyl, cycloalkyl-substituted
C1-C3 alkyl, C5-C$ cycloalkenyl-substituted Cl-C3 alkyl
or phenyl-subsituted C1-C3 alkyl;
R5 is hydrogen or C1-C3 alkyl;
Rs is hydrogen, C1-Clo alkyl, C3-Clo alkenyl,
cycloalkyl, phenyl, cycloalkyl-substituted C1-C3 alkyl,
CS-C8 cycloalkenyl, CS-C8 cycloalkenyl-substituted
G1-C3 alkyl, phenyl-substituted C1-C3 alkyl, or (CHZ)q-B;
or
CA 02064373 2002-07-29
X-8244 -4-
R5 and R6 together vrrith N form a saturated non aromatic 4 to
6 membered heterocyclic ring;
wherein:
O-N 0
I)
B is ~ ,CW or NR~R8;
N R6
wherein:
R~ is hydrogen or C1-C3 alkyl;
R8 is hydrogen, C1-C1° alkyl, C3-Clo alkenyl,
cycloalkyl-substituted C1-C3 alkyl, cycloalkyl, CS-C8
cycloalkenyl, CS-C8 cycloalkenyl-substituted C1-C3
alkyl, phenyl or phenyl-substituted C1-C3 alkyl; or
R~ and R$ are each CH2 which together with N
form a 4 to 6 membered heterocyclic ring;
W is OR9, NR1°R11~ or OE;
wherein:
R9 is hydrogen, C1-Clo alkyl, C2-Clo alkenyl,
cycloalkyl, C5-C8 cycloalkenyl, cycloalkyl-substituted
C1-C3 alkyl, C5-C8 cycloalkenyl-substituted C1-C3 alkyl
or phenyl-substituted C1-C3 alkyl;
R1° is hydrogen or C1-C3 alkyl;
R11 is hydrogen, C1-Clo alkyl, C3-Clo
aikenyl, phenyl, cycloalkyl, C5-C$ cycloalkenyl,
cycloalkyl-substituted C1-C3 alkyl, C5-C8 cycloalkenyl
substituted C1-C3 alkyl, phenyl-substituted C1-C3
O
alkyl or (CHZ)mCY; or
~~~~:~'~~~
X-8244 -5-
R1° and R11 are each CHZ which together with
N form a 4 to 6 membered hetercyclic ring;
II H3~ ~\ II
E is (CH2)mC-D, ~ r0 , or -R12-OCRis
wherein: -CH2 /O
R12 is C1-C3 alkyl substituted methylene,
R13 is C1-Cio alkyl;
D is OR14 or NRiSRls;
wherein:
R14 is hydrogen, C1-Clo alkyl, CZ-Cio
alkenyl; cycloalkyl, CS-C$ cycloalkenyl, cycloalkyl-
substituted Cl-C3 alkyl, CS-C$ cycloalkenyl-substituted
C1-C3 alkyl, or phenyl-substituted C1-C3 alkyl;
Ris is hydrogen, C1-Clo alkyl, C3-Clo
alkenyl, phenyl, phenyl-substituted C1-C3 alkyl,
cycloalkyl, C5-C$ cycloalkenyl, cycloalkyl-substituted
Cl-C3 alkyl or CS-Cs cycloalkenyl-substituted C1-C3
alkyl;
R16 is hydrogen or C1-C3 alkyl; or
R15 and Rls are each CH2 which together with
N form a 4 to 6 membered heterocyclic ring;
Y is OR1' or NRl8Rls;
wherein:
R1' is hydrogen, C1-Clo alkyl, C2-C1o
alkenyl, cycloalkyl, CS-C$ cycloalkenyl, cycloalkyl-
substituted C1-C3 alkyl, CS-C8 cycloalkenyl-substituted
C1-C~ alkyl, or phenyl-substituted Cl-C3 alkyl;
Ri$ is hydrogen or C1-C3 alkyl;
2064373
X-8244 -6-
R19 is hydrogen, C1-C1o alkyl, C3-C1o
alkenyl, phenyl, cycloalkyl, CS-C8 cycloalkenyl,
cycloalkyl-substituted C1-C3 alkyl, CS-C$ cycloalkenyl-
substituted C1-C3 alkyl, or phenyl-substituted C1-C3
alkyl; or
Ri8 and Ri9 are each CH2 which together with
N form a 4 to 6 membered heterocyclic ring;
n is 0-4;
q is 1-4;
m is 1-4;
or pharmaceutically acceptable salts thereof.
Another aspect of the present invention
provides a method for using an effective amount of the
compounds of the instant invention to treat constipation,
nausea or vomiting induced by the use of opiates in a
patient.
Another aspect of the present invention
provides a method for treating the symptoms of idiopathic
constipation or irritable bowel syndrome.
Another aspect of the instant invention
provides pharmaceutical formulations comprising an
effective amount of a compound of the instant invention
in combination with a pharmaceutically acceptable
excipient.
The term "C1-CS alkyl", as used herein,
represents a branched or linear alkyl group having from
one to five carbon atoms. Typical C1-CS alkyl groups
include methyl, ethyl, n-propyl, iso-propyl, butyl,
iso-butyl, sec-butyl, tert-butyl, pentyl and the like.
206~37~
X-8244 -7-
Other such terms represent straight chain or branched
alkyl groups of the specified number of carbon atoms,
eg. "C1-C3 alkyl" represents methyl, ethyl, n-propyl,
and isopropyl.
The terms "CZ-Cs alkenyl", "CZ-Clo alkenyl"
and "C3-Clo alkenyl" refer to groups containing 2 to 6,
2 to 10, and 3 to 10 carbon atoms respectively and one
double bond. The group can be branched or straight
chain. Examples of such groups include 2-propenyl
(-CHZ-CH=CHZ), 1-butanyl (-CH=CHCHZCH3) and the like.
The term "cycloalkyl" represents C3-C8 cyclo-
alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl. "Substituted
CS-Cs cycloalkyl°' includes cycloalkyl groups
substituted with C1-C3 alkyl, C1-C3 alkoxyl or halo.
The term "cycloalkyl-substituted C1-C3 alkyl"
represents a linear C1-C3 alkyl group substituted at a
terminal carbon with a C3-C8 cycloalkyl group. Typical
cycloalkyl-substituted alkyl groups include cyclohexyl-
methyl, cyclohexylethyl, cyclopentylethyl, cyclopentyl-
propyl and the like.
The term "CS-C$ cycloalkenyl" represents and
olefinically unsaturated cyclic ring having five to
eight carbon atoms.
The term "phenylalkyl" represents a linear
C1-C3 alkyl chain substituted at a terminal carbon with
a substituted or unsubstituted benzene ring. Typical
phenylalkyl groups include phenylmethyl, phenylethyl and
3-(4-methylphenyl)propyl.
CA 02064373 1999-11-04
X-8244 -8-
The term "phenyl" includes a benzene ring as
well as a benzene ring substituted with one or two
C1-CZ alkyl groups.
The "4 to 6-membered N-containing heterocyclic
ring" referred to herein includes aromatic and nonaromatic
rings such as pyrroles and piperidines.
While all of the compounds of the present
invention are useful peripheral opioid antagonists,
certain of the present compounds are preferred for that
use. Preferred compounds of Formula I are those in
which R1 is hydrogen, R2 is methyl; R3 is cyclohexyl,
cyclohexylmethyl, phenyl or benzyl; n is 1 or 2; A is OH
or NH(CHZ)xC(O)W where x is 1 to 3; and W is OR9, NHRli
or -ORi2-O-C(O)R13; wherein R9 is hydrogen, C1-C5 alkyl,
benzyl, or substituted-cyclohexyl; R11 is hydrogen or
C1-C5 alkyl; R12 is C1-C3 alkyl substituted methylene; and
R13 is C1-C3 alkyl.
Certain of the compounds of the instant
invention can serve as intermediates in the preparation
of other compounds of the invention. Compounds which
are preferred are those in Formula I in which R1 is
hydrogen or CH3; RZ is CH3; R3 is cyclohexyl, cyclohexyl-
methyl, benzyl, or phenyl; A is OH, methoxy or ethoxy;
and n is 1 or 2.
The piperidines of the invention as illustrated
in Formula I can occur as the trans and cis stereo-
chemical isomers by virtue of the substituents at the 3-
2~~~~fi.~
X-8244 -9-
and 4-positions of the piperidine ring. The term
"traps" as used herein refers to R2 in position 3 being
on the opposite side from the methyl group in position
4, whereas in the "cis" isomer R2 and the 4-methyl are
on the same side of the ring. The present invention
contemplates the individual stereoisomers as well as
racemic mixtures. In the most preferred compounds of
the present invention, the group R2 at the 3-position is
situated on the opposite side of the ring, i.e., traps
to the methyl group in the 4-position and on the same
side of the ring, i.e., Zusammen or Z, relative to the
higher priority phenyl group at the 4-position. These
traps or Z-isomers can exist as the 3R,4R-isomer as
shown in Formula II
II
CA 02064373 1999-11-04
X-8244 -10-
or the 3S,4S-isomer of Formula III
ORS
i CHR2 I I I
-H
O
I
(CH~~CH-C-A
R3
The terms "R" and "S" are used herein as
commonly used in organic chemistry to denote specific
configuration of a chiral center. The term "R" refers
to "right" and refers that configuration of a chiral
center with a clockwise relationship of group
priorities (highest to second lowest) when viewed along
the bond toward the lowest priority group. The term
"S" or "left" refers to that configuration of a chiral
center with a counterclockwise relationship of group
priorties (highest to second lowest) when viewed along
the bond toward the lowest priority group. The
priority of groups is based upon their atomic number
(heaviest isotope first). A partial list of priorities
and a discussion of stereo chemistry is contained in
the book: The Vocabulary of Organic Chemistry, Orchin,
et al., John Wiley and Sons Inc., publishers, paaP 126.
The preferred compounds of the present
invention are those of Formula I in which the
configuration of substituents on the piperidine ring is
3R and 4R.
2064373
X-8244 -11-
When R3 is not hydrogen, the carbon atom
attached to R3 is asymmetric. As such, this class of
compounds can further exist as the individual R or S
stereoisomers at this chiral center, or the racemic
mixture of the isomers, and all are contemplated within
the scope of the present invention. Preferably, a
substantially pure stereoisomer of the compounds of this
invention is used, i.e., an isomer in which the con-
figuration at the chiral center is R or S, i.e., those
compounds in which the configuration at the three chiral
centers is preferably 3R, 4R, S or 3R, 4R, R.
Furthermore, other asymmetric carbons can be
introduced into the molecule depending on the structure
of A. As such, these classes of compounds can exist as
the individual R or S stereoisomers at these chiral
centers, or the racemic mixture of the isomers, and all
are contemplated as within the scope of the present
invention.
Preferred compounds of the instant invention
include the following:
U-OCHZCH3; U-OH; G-OH; U-NHCHZC(O)NHCH3; U-
NHCH2C(O)NH2; G-NHCHZC(O)NHCH3; U-NHCHZC(O)NHCH2CH3; G-
NH(CHZ)3C(O)OCHZCH3; G-NHCH2C(O)OH; M-NHCHZC(O)NHZ; M-
NH(GHZ)ZC(0)OCHZ(G6Hs); X-OCHZCH3; X-OH; X-NH(CH2)ZCH3;
Z-NH(CHZ)3C(O)OCH2CH3; X-NHCHZC(O)OH; Z-NH(CHZ)2N(CH3)23
Z-NH(CHZ)2C(O)NHCH2CH3; X-OCHZ(C6Hs); X-N(CH3)2; Z-
NH(GHZ)3C(O)NHCHg; Z-NH(CH2)3C(O)NH2; Z-NH(CHZ)3C(O)-
NHCHZCH3; X-OCH2C(O)OCH3; X-OCHZC(O)NHCH3; and X-
N(CH3)CHZC(O)CH2CH3;
2064373
X-8244 -12-
in which:
O
U represents Q-CHZCHZCHC°.
O
G represents Q-CH2CH2CHC-;
Hz
Hz Hz
Hz
0
M represents Q-CH2CH-C-;
2 o CHa
H2 H2
HZ H2
H2
0
Z represents Q°CHZIHC
CH2
206373
X-8244 -13-
O
X represents Z-NHCH2C-;
OH
wherein:
Q represents trans-3,4-dimethyl cHs
°~CHg
~a
~ x
N
Particularly preferred compounds of the
instant invention include the following:
Z-OH; Z-NH(CHZ)ZC(O)OH; G-NH(CH2)ZC(O)NHZT
G-NH(CHZ)2C(O)NHCH3; G-NHCH2C(O)NH2; G-NFiCH2C(O)NHCHZCH3;
G-NH(CH2)3C(O)NHCH3; G-NH(CHZ)ZC(O)OH; G-NH(CHZ)3C(O)OH;
X-NH2; X-NHCH(CH3)2; X-OCH2CH(CHg)2; X-OCHZCgHg; X-OH;
X-O(CH2)4CH3; X-O-(4-methoxycyclohexyl); X-OCH(CH3)OC(O)CH3;
X-OCHZC(O)NFiCH2(CsHs); M-NHCHZC(O)OH; M-NH(CHZ)2C(O)OH;
M-NH(CHZ)2C(O)NH2; U-NHCHZC(O)OCHlCH3; and U-NHCHZC(O)OH;
wherein Z, G, X and U are as defined above.
2064373
X-8244 -14-
The compounds of the instant invention can be
named in several ways. For example the compound with
the structure IIa OH
,,,CHa
~~CH3
,z IIa
N O
CH2-CH2-CH-~C-OCH2CH3
can be named trans-4-(3-hydroxyphenyl)-3,4-A-phenyl-
1-piperidine butanoic acid, ethyl ester or ethyl-
trans-4-[4-(3-hydroxyphenyl)-3,4-dimethyl-1-
piperidinyl]-2-phenylbutanoate.
The piperidines of this invention form
pharmaceutically acceptable acid addition salts with a
wide variety of inorganic and organic acids. Typical
acids used include sulfuric, hydrochloric, hydrobromic,
phosphoric, hypophosphoric, hydroiodic, sul.famic,
citric, acetic, malefic, malic, succinic, tartaric,
cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic,
benzenesulfonic, methanesulfonic, trifluoroacetic,
hippuric and the like.
The compounds of the present invention can be
prepared by a variety of procedures well known to those
of ordinary skill in the art. The 3-substituted-4-
methyl-4-(3-hydroxy- or alkanoyloxyphenyl)piperidine
derivatives employed as starting materials in the
synthesis of the instant compounds can be prepared by
CA 02064373 1999-11-04
X-8244 -15-
the general procedure taught by Zimmerman in U.S. Patent
No. 4,115,400 (1978), and Zimmerman et al. in U.S.
Patent No. 4,891,379 (1990). The starting material for
the synthsis of the compounds of the present invention,
(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine, can
be prepared by the procedure of Barnett in U.S. Patent
4,581,455, but adjusted as described in such patent so
that the (3-stereochemistry is preferred. This process
is depicted in Scheme l, wherein R2° is C1-C3 alkyl, R21
is Cl-C6 alkyl, R22 is Cl-C4 alkyl, R23 and R24
independently are Cl-C3 alkyl or, when taken together
with the nitrogen atom to which they are attached, form
piperidine, piperazine, N-methylpiperazine, morpholine
or pyrrolidine, and J is halogen, preferably chlorine or
bromine.
206373
X-8244 -16-
Scheme 1
O
ORS ORS
N
Rz, ~ R~ ORa°
I
Br Li OH
NJ
io
Ha
ORz° OR2o ~ ~R2o
CH HzCO
G~H NR~R2'~~----- CH 1. nauLi
NHR~RZ° 3 ~ 2. CH3J
HzSO,
N
2 0 HZ; Pd
ORS ORS OH
CH3 -_.-.-...~,. CH3 ~_.",. CH3
~CH3 H3 CH3
N N
R~ H H
2064373
X-8244 -17-
The first step of the above-described process
involves the formation of the 3-alkoxyphenyllithium
reagent by reacting 3-alkoxybromobenzene with an alkyl-
lithium reagent. This reaction is typically performed
under inert conditions and in the presence of a suitable
non-reactive solvent such as dry diethyl ether or
preferably dry tetrahydrofuran. Preferred alkyllithium
reagents used in this process are n-butyllithium, and
especially sec.-butyllithium. Generally, approximately
an equimolar to slight excess of alkyllithium reagent
is added to the reaction mixture. The reaction is con-
ducted at a temperature between about -20°C and about
-100°C, more preferably from about -50°C to about -55°C.
Once the 3-alkoxyphenyllithium reagent has
formed, approximately an equimolar quantity of a 1-
alkyl-4-piperidone is added to the mixture while main-
taining the temperature between -20°C and -100°C. The
reaction is typically complete after about 1 to 24
hours. At this point, the reaction mixture is allowed
to gradually warm to room temperature. The product is
isolated by the addition to the reaction mixture of a
saturated sodium chloride solution in order to quench
any residual lithium reagent. The organic layer is
separated and further purified if desired to provide the
appropriate 1-alkyl-4-(3-alkoxyphenyl)piperidinol
derivative.
The dehydration of the 4-phenylpiperidinol
prepared above is accomplished with a strong acid
206~3'~3
X-8244 -18-
according to well known procedures. While dehydration
occurs in various amounts with any one of several strong
acids such as hydrochloric acid, hydrobromic acid, and
the like, dehydration is preferably conducted with
S phosphoric acid, or especially p-toluenesulfonic acid
in toluene or benzene. This reaction is typically
conducted under reflux conditions, more generally from
about 50°C to about 150°C. The product thus formed is
generally isolated by basifying an acidic aqueous
solution of the salt form of the product and extracting
the aqueous solution with a suitable water immiscible
solvents. The resulting residue following evaporation
can then be further purified if desired.
The 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetra-
hydropyridine derivatives are prepared by a metallo-
enamine alkylation. This reaction is preferably
conducted with n-butyllithium in tetrahydrofuran (THF)
under an inert atmosphere, such as nitrogen or argon.
Generally, a slight excess of n-butyllithium is added to
a stirring solution of the 1-alkyl-4-(3-alkoxyphenyl)-
tetrahydropyridine in THF cooled to a temperature in the
range of from about -SO°C to about 0°C, more preferably
from about -20°C to about -10°C. This mixture is
stirred for approximately 10 to 30 minutes followed by
the addition of approximately from 1.0 to 1.5 equiva-
lents of methyl halide to the solution while maintaining
the temperature of the reaction mixture below 0°C. After
about 5 to 60 minutes, water is added to the reaction
zos4373
X-8244 -19-
mixture and the organic phase is collected. The product
can be purified according to standard procedures, but
the crude product is preferably purified by either
distilling it under vacuum or slurrying it in a mixture
of hexane:ethyl acetate (65:35, v:v) and silica gel for
about two hours. According to the latter procedure, the
product is then isolated by filtration followed by
evaporating the filtrate under reduced pressure.
The next step in the process involves the ap-
plication of the Mannich reaction of aminomethylation
to non-conjugated, endocyclic enamines. This reaction
is preferably carried out by combining from about 1.2 to
2.0 equivalents of aqueous formaldehyde and about 1.3 to
2.0 equivalents of a secondary amine NHR23Rz4 in a
suitable solvent. While water is the preferred solvent,
other non-nucleophilic solvents such as acetone and
acetonitrile can also be employed in this reaction. The
pH of this solution is adjusted to approximately 3.0-4.0
with an acid which provides a non-nucleophilic anion.
Examples of such acids include sulfuric acid, the
sulfonic acids such as methanesulfonic acid and p-
toluenesulfonic acid, phosphoric acid, and tetrafluoro-
boric acid. The preferred acid is sulfuric acid. To
this solution is added one equivalent of a 1-alkyl-4-
methyl-4-(3-alkoxyphenyl)tetrahydropyridine, typically
dissolved in aqueous sulfuric acid, and the pH of the
solution is readjusted with the non-nucleophilic acid or
CA 02064373 1999-11-04
X-8244 -20-
a secondary amine as defined above. The pH should be
maintained in the range of from about 1.0 to 5.0 with a
pH of about 3.0 to 3.5 being preferred during the
reaction. The reaction is substantially complete after
about 1 to 4 hours, more typically about 2 hours, when
conducted at a temperature in the range of from about
50°C to about 80°C, more preferably at about 70°C. The
reaction is next cooled to approximately 30°C and added
to a sodium hydroxide solution. This solution is
extracted with a water immiscible organic solvent, such
as hexane or ethyl acetate, and the organic phase,
following thorough washing with water to remove any
residual formaldehyde, is evaporated to dryness under
reduced pressure.
The next step of the process involves the
catalytic hydrogenation of the 1-alkyl-4-methyl-4-(3-
alkoxyphenyl)-3-tetrahydropyridinemethanamine prepared
above to the corresponding trans-1-alkyl-3,4-dimethyl-
4-(3-alkoxyphenyl)piperidine. This reaction actually
occurs in two steps. The first step is the hydrogen-
olysis reaction wherein the exo C-N bond is reductively
cleaved to generate the 3-methyltetrahydropyridine. In
the second step, the 2,3-double bond in the tetra-
hydropyridine ring is reduced to afford the desired
piperidine ring.
Reduction of the enamine double bond intro-
duces the crucial relative stereochemistry at the 3 and
4 carbon atoms of the piperidine ring. The reduction
-- 2064373
X-8244 -21-
does not occur with complete stereoselectivity. The
catalysts employed in the process axe chosen from among
the various palladium and preferably platinum catalysts.
The catalytic hydrogenation step of the
process is preferably conducted in an acidic reaction
medium. Suitable solvents for use in the process
include the alcohols, such as methanol or ethanol, as
well as ethyl acetate, tetrahydrofuran, toluene, hexane,
and the like.
Proper stereochemical outcome has been found
to be dependent on the quantity of catalyst employed.
The quantity of catalyst required to produce the desired
stereochemical result is dependent upon the purity of
the starting materials in regard to the presence or
absence of various catalyst poisons.
The hydrogen pressure in the reaction vessel
is not critical but can be in the range of from about 5
to 200 psi. Concentration of the starting material by
volume is preferably around 20 ml. of liquid per gram of
starting material, although an increased or decreased
concentration of the starting material can also be
employed. Under the conditions specified herein, the
length of time for the catalytic hydrogenation is not
critical because of the inability for over-reduction
of the molecule. While the reaction can continue for up
to 24 hours or longer, it is not necessary to continue
2064373
X-8244 -22-
the reduction conditions after the uptake of the theoret-
ical two moles of hydrogen. The product is isolated by
filtering the reaction mixture for example through
infusorial earth, and evaporating the filtrate to
dryness under reduced pressure. Further purification of
the product thus isolated is not necessary and prefer-
ably the diastereomeric mixture is carried directly on
to the following reaction.
The alkyl substituent is next removed from the
1-position of the piperidine ring by standard dealkyl-
ation procedures. Preferably, a chloroformate derivative,
especially the vinyl or phenyl derivatives, are employed
and removed with acid. Next, the alkoxy compound
prepared above is dealkylated to the corresponding
phenol. This reaction is generally carried out by
reacting the compound in a 48% aqueous hydrobromic acid
solution. This reaction is substantially complete after
about 30 minutes to 24 hours when conducted at a temper-
ature between 50°C to about 150°C, more preferably at
the reflux temperature of the reaction mixture. The
mixture is then worked up by cooling the solution,
followed by neutralization with base to an approximate
pH of 8. This aqueous solution is extracted with a
water immiscible organic solvent. The residue following
evaporation of the organic phase is then preferably used
directly in the following step.
2064373
X-8244 -23-
The compounds employed as starting materials
to the compounds of the invention can also be prepared
by brominating the 1-alkyl-4-methyl-4-(3-alkoxyphenyl)-
3-tetrahydropyridinemethanamine prepared above at the
3-position, lithiating the bromo compound thus prepared,
and reacting the lithiated intermediate with a methylhalide
such as methyl bromide to provide the corresponding
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)tetrahydropyridine-
methanamine. This compound is then reduced and converted
l0 to the starting material as indicated above.
As noted above, the compounds of the present
invention can exist as the individual stereoisomers.
Preferably reaction conditions are adjusted as
disclosed by Barnett (supra) or as set forth in Example
1 hereof to be substantially stereoselective and
provide a racemic mixture of essentially two
enantiomers. These enantiomers can then be resolved.
The preferred procedure employed to prepare the resolved
starting materials used in the synthesis of these
compounds includes treating a racemic mixture of alkyl-
3,4-dimethyl-4-(3-alkoxyphenyl)piperidine with either
(+)- or (-)-di-benzoyl tartaric acid to provide the
resolved intermediate. This compound is dealkylated
at the 1-position with vinyl chloroformate and finally
converted to the desired 4-(3-hydroxyphenyl)piperidine
isomer. This reaction scheme is represented in the
following Scheme 2:
2064373
X-8244 -24-
Scheme 2
ORa°
CH3
NJ
a
(+~. a~ c.~. a~~~o,,~
to
oR~ oR~
CH ~H3
3
CH3 wrCH3
N N
R22 Raa
O O
a
CICOCH=CHI CICOCHsCHz
r
oar oa~~
~,CH3 ' 'H3
CH3 ~..CH~
N N
O~O ~
O"-O
CH CH
CHZ ' CH2
OH OH ORS
CH3 CH3
C~ .--~ ~ H3 s. .-CH3
N N N N
H H H H
2064373
X-8244 -25-
wherein R2° and R22 are as defined above.
As will be understood by those skilled in the
art, the individual enantiomers of the invention can
also be isolated with either (+) or (-) dibenzoyl
tartaric acid, as desired, from the corresponding
racemic mixture of the compounds of the invention.
Preferably the (+)-trans enantiomer is obtained.
Although the (+)trans-3,4 stereoisomer is
preferred, all of the possible stereoiosmers of the
instant compounds are within the contemplated scope of
the present invention. Racemic mixtures of the
stereoisomers as well as the substantially pure
stereoisomers are within the scope of the invention.
The term "substantially pure" is used herein to refer
to at least about 90 mole percent, more preferably at
least about 95 mole percent and most preferably at
least about 98 mole percent of the desired stereoisomer
is present compound to other possible stereoisomers.
Intermediates and compounds with the instant
invention can be prepared by reacting a 3,4-alkyl-
substituted-4-(3-hydroxyphenyl)piperidine with a com-
pound of the formula LCHZ(CHZ)n-1CHR3C(O)E where L is a
leaving group such as chlorine, bromine or iodine, E is
a carboxylic acid, ester or amide, and R3 arid n are as
defined hereinabove. Preferably L is chlorine and the
reaction is carried out in the presence of a base to
alkylate the piperidine nitrogen. For example 4-chloro-
2-cyclohexylbutanoic acid, ethyl ester can be contacted
with (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine
CA 02064373 1999-11-04
X-8244 -26-
to provide 4-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-
1-piperidine]butanoic acid, ethyl ester. Although the
ester of the carboxylic acid is preferred, the free acid
itself or an amide of the carboxylic acid can be used.
In alternative synthesis, the substituted
piperidine can be contacted with an a-methylene alkyl
ester to alkylate the piperidine nitrogen. For example,
2-methylene-3-phenylpropanoic acid, ethyl ester can be
contacted with a desired piperidine to provide 2-benzyl-
3-piperidinepropanoic acid ethyl ester.
Another synthetic route can involve the
reaction of a substituted piperidine with a haloalkyl-
nitrile. The nitrile group of the resulting piperidine
alkylnitrile can be hydrolyzed to the corresponding
carboxylic acid.
With each of the synthetic routes, the resulting
ester or carboxylic acid can be reacted with an amine or
alcohol to provide modified chemical structures. In the
preparation of amides, the piperidine-carboxylic acid or
-carboxylic acid ester is reacted with an amine in the
presence of a coupling agent such as dicyclohexylcarbodiimide,
boric acid, borane-trimethylamine, and the like. Esters
can be prepared by contacting the piperidine-carboxylic
acid with the appropriate alcohol in the presence of a
coupling agent such as p-toluenesulfonic acid, boron
trifluoride etherate or N,N'-carbonyldiimidazole.
Alternatively, the piperidine-carboxylic acid chloride
can be prepared using a reagent such as thionyl chloride,
phosphorus trichloride, phosphorus pentachloride and the
CA 02064373 2002-07-29
X-8244 -27-
like. This acyl chloride can be reacted with the
appropiate amine or alcohol to provide the corresponding
amide or ester. Examples of such reactions are provided
in the appended examples.
The following examples are provided for
purposes of illustration and are not to be construed as
limiting the scope of the claimed invention.
As used in the instant examples, the following
terms have the meanings indicated. "Hobt" refers to 1-
hydroxybenzotriazole hydrate. "THF" refers to tetrahydro-
furan. "DMF" refers to dimethylformamide. "TEA" refers
to triethylamine. "DCC" refers to dicyclohexylcarbodiimide.
The column chromatography procedure used
involved gravitational flow with Allied Fischer silica
gel (70-150 mesh). Gradient solvent procedures were
employed using the solvent systems specified in the
particular example. The gradient procedure involved
starting the indicated solvent system and incrementally
changing the solvent mixture until the indicated final
solvent system was obtained. Fractions containing
product were evaporated generally under reduced vacuum
to provide product.
Preparative liquid chromatography was performed
with the Waters Prep LC/500~apparatus using dual silica
prep pack cartridges. Gradient solvent systems were
employed as listed in the particular example.
Optical rotations were determined using
methanol as the solvent.
For those examples indicated, purification of
the specified compound was accomplished by preparative,
CA 02064373 2002-07-29
X-8244 -28-
centrifugal, thin layer chromatography on a Harrison
Model 7924A~Chromatron using Analtech silica gel GF
rotors. The plate thickness and solvent system
employed are indicated in the particular example
The hydrochloride salt of the particular
compound was prepared by placing the free base into
ethyl ether. While stirring this ether solution. a
solution of HC1 in ethyl ether was added dropwise until
the base-containing solution became acidic. A preciptate
formed which was filtered and dried to provide the
corresponding hydrochloride salt of the free base.
In the instant Examples Q-, X-, Z-, M-, G-,
and U- are used to represent the moieties indicated
hereinabove.
Example 1
Preparation of (+)-(3R,4R)-4-(3-hydroxyphenyl)-3,4-
dimethylpiperidine (Q-H].
3-Bromophenol was combined with an equal
molar amount of 2-bromopropane in ethanol and in the
presence of potassium carbonate to provide 3-bromo-
isopropoxybenzene.
The 3-bromo-i-propoxybenzene (200 g, 0.08703 mol)
was combined with THF (540 ml) under nitrogen and cooled
to about -75°C. n-Butyl lithium (565 ml, 0.8306 mol)
was added dropwise while maintaining the mixture at less
than -70°C. After 2 hours 1,3-Dimethyl-4-piperidone
(106.7 g, 0.8389 mol) was added while maintaining the
temperature of the mixture between -80°C and -70°C.
264373
X-8244 -29-
After stirring 2 hours at -70°C., the reaction mixture
was then added to 6N HC1 (280 ml) while maintaining the
temperature at 20-25°C. The pH was adjusted to 1 with
12 N HC1. The aqueous layer containing product was
separated and heptane (320 ml) was added along with 50%
NaOH (48 ml, pH = 13-14) and the resulting mixture
allowed to stand overnight. The mixture was heated to
45-50°C and the upper layer was separated. The re-
maining aqueous layer was extracted with heptane (320 ml)
at 45-50°C. The combined organic fractions were washed
with de-ionized water (120 ml) at 45-50°C. The resulting
organic layer was vacuum distilled at a pot temperature
of about 55°C at 100 mmHg. Crystallization from
heptane and drying provided 151.8 g of 3-(3-i-propoxy-
phenyl)-1,3-dimethyl-4-hydroxypiperidine. Melting point
75.0-76.0°C.
This 4-hydroxypiperidine (463 g, 1.758 mol)
was combined with ethyl acetate (2275 ml) under nitrogen.
The solution was cooled to 0-5°C and ethyl chloroformate
(205 ml, 2.144 mol) was added while maintaining the
temperature below 15°C. The reaction mixture was
stirred for an additional 3 hours at room temperature.
The mixture was then added to 5N NaOH (750 ml) with
stirring (pH = 12-13) the organic layer was separated
and washed with de-ionized water. Solvent was removed
by evaporation at 50°C to provide 591 g of a viscous oil.
This viscous oil (284.8 g) was dissolved in
ethanol (2.6 L) and warmed to 55°C under nitrogen.
(+)-Di-p-toluoyl-D-tartaric acid, monohydrate was added
-w 206373
X-8244 -30-
and the solution heated to reflux. After stirring
overnight at room temperature, the mixture was cooled to
0-5°C before filtering. The filter cake was washed
with cold ethanol, air dried for 30 minutes then vacuum
dried at 45-50°C. Recrystallization from ethanol
provided 201.7 g of product with a melting point of
153.5-155°C (dec). This material had a ratio of
isomers by proton NMR of 97:3.
Product prepared in this manner (411.7 g) was
added to heptane (1200 m1) and 2N NaOH (550 ml) over a
minute period. pH of the mixture was adjusted to
about 13 with 50% NaOH and stirred until all solid had
dissolved. The layers were separated and the organic
layer washed with 1N NaOH (275 ml), de-ionized water
15 (275 ml) and the saturaed aqueous sodium chloride
(210 ml). The organic fraction was dried over 175 g of
sodium sulfate, filtered and washed with heptane
(125 ml). The solvent was removed by evaporation to
provide 189.4 g of a colorless viscous oil.
[a]589 of -6.92° (c = 1.01, methanol).
This viscous oil product (50.0 g) and decalin
(250 ml) were heated at 190-195°C for 19 hr under
nitrogen while removing the ethanol formed by distil-
lation. The solution was cooled to 15-20°C under
nitrogen and 1N HC1 (155 ml) was added with stirring.
The aqueous fraction was separated and extracted with
heptane (2 x 30 ml). The pH of the aqueous layer was
zos~3~~
X-8244 -31-
adjusted to about 13 by adding 50% NaOH and extracted
with heptane. 36.5 g of a yellow-orange liquid were
removed from the organic layer.
~a~sss= -67.24°.
This yellow-orange liquid product (19.6 g) was
combined with THF (175 ml) and cooled to -15°C to -20°C
under nitrogen, n-Butyl lithium (70.0 ml) was added
with stirring over about 0.5 hr while maintaining the
internal temperature at about -10°C to about -20°C.
The mixture was stirred for another 0.5 hr at -10°C
to -15°C and then cooled to -45 to -50°C. Dimethyl
sulfate (7.7 ml) was added slowly over 20-30 minutes
while maintaing the temperature between -45°C and
-50°C. The mixture was then stirred for an additional
30 minutes at about -50°C. This reaction mixture was
then added slowly to a dilute solution of aqueous
ammonium hydroxide (15.5 ml aqueous ammonium hydroxide
solution plus 55 ml de-ionized water) at 0-5°C. The
mixture was warmed to 20-25°C over 30-45 minutes and
stirred an additional 2 hrs at 20-25°C. The organic
layer was recovered and washed with de-ionized water
followed by removal of solvent by evaporation to provide
21.44 g of 4-(3-i-propoxyphenyl)-1,4,5-trimethyl-2,3-
dehydropiperidine as an orange liquid.
This dehydropiperidine (21.2 g) and methanol
(195 ml) were combined under nitrogen and cooled to
0-5°C. Sodium borohydride (4.2 g) was added slowly
while maintaining the temperature below 15°C. The
reaction mixture was stirred at room temperature for 3
CA 02064373 1999-11-04
X-8244 -32-
hrs. Acetone (21 ml) was added to the reaction mixture
and stirred for 5 minutes. A saturated solution of
sodium bicarbonate (25 ml) was added and the mixture
stirred for 5 minutes. The alcohols were removed by
evaporation at 50°C. De-ionized water (95 ml) and ethyl
acetate (95 ml) were added and the resulting mixture
stirred to form a solution. Phases were separated and
the aqueous phase extracted with ethyl acetate (20 ml).
Combined organic fractions were washed with de-ionized
water (95 ml) and the solvent removed by evaporation at
50°C to provide (+)-4-(3-i-propoxyphenyl)-1,3,4-
trimethylpiperidine as a yellow liquid (20.5 g).
Anhydrous ethanol (75 ml) and (+)-di-p-
toluoyl-D-tartaric acid, monohydrate (12.48 g) were
combined and heated to 55-60°C under nitrogen. An
ethanol solution of the trimethyl piperidine (8.07 g in
ml) was added while heating to reflux (about 75°C).
De-ionized water (6 ml) was added to obtain a clear
homogeneous solution which was stirred at reflux for
20 0.5 hr. Cooling, filtering, washing with cold ethanol,
and drying provided 15.07 g of (+)-4-(3-i-propoxy-
phenyl)-1,3,4-trimethylpiperidine~(+)-di-p-toluoyl-D-
tartaric acid salt with a melting point 145-147.5°C
(dec).
Toluene (1400 ml) and 2N NaOH (700 ml) were
combined and cooled to 15-20°C. The piperidine-tartaric
salt (395.0 grams) was added with stirring at 15-25°C
and stirring continued until all solids. had dissolved.
The layers were separated and the organic fraction
CA 02064373 1999-11-04
X-8244 -33-
washed with 1N NaOH (385 ml) and di-ionized water (385
ml). The organic fraction was filtered and the solvent
removed by evaporation (50°C) to provide 164.8 g of the
free base as an oil.
[a~589 - +74.18°.
To a mixture of the free base (+)-4-(3-i-
propoxyphenyl)-1,3,4-trimethyl-piperidine (25 g) in
toluene (160 ml) at 80-90°C was added phenylchloro-
formate (17.2 g). The mixture was heated at reflux
(110°C) for 2 hrs and then cooled to 45-50°C. NaOH
(5 ml, 50%, in 40 ml water) was added and the mixture
stirred with cooling to room temperature. After 30
minutes the layers were separated and the organic layer
washed with a 1:1 mixture of methanol and 1N HC1, a 1:1
mixture of methanol and 1N NaOH, and then washed with
water. Evaporation of the solvent provided 33.9 g of the
phenyl carbamate as an oil.
The phenyl carbamate (13.95 g), 48%
HBr (17.4 ml) and glacial acetic acid (4.7 ml) were
combined and refluxed for 18 hours. The solution was
cooled to room temperature; water (50 ml) was added; and
the solution was extracted 3 times with t-butyl methyl
ether (30 ml aliquots). The pH of the aqueous phase was
adjusted to 8.5-8.8 with 50% NaOH solution. Methanol
(15 ml) was added and the pH adjusted to 10.5 with the
50% NaOH solution. The mixture was stirred for 1.5
hours, cooled to 5°C and filtered to provide the white
solid (+)-trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine (6.86 g).
[a]sss - +380.37 (methanol).
20643'3
X-8244 -34-
Example 2
Preparation of 3-phenyl-2-(ethoxycarbonyl)-1-
propene.
N-butyl lithium (201 ml of 1.6 M) was added
dropwise to diisopropyl amine (45 ml) in dry tetrahydro-
furan (870 ml) at -78°C. After stirring at this tem-
perature for 0.5 hours ethyl-2-benzylacetoacetate (39.6
g, 0.18 M) in THF (250 ml) was added dropwise at 0°C.
After stirring for 20 minutes, paraformaldehyde (35.42 g)
was added at room temperature followed by stirring for
one hour and refluxing for 4 hours. The reaction
mixture was filtered and the liquid evaporated to
dryness. The residue was dissolved in a mixture of
KHCO3/HZO and methylene chloride (1:1) and stirred for
0.5 hours. The layers were separated and the methylene
chloride layer was dried over KZC03 and then evaporated
to dryness to yield 46.4 g of named product. This
product was purified with a Prep-500 chromatograph
eluting with hexane to 5% ethyl acetate/hexane gradient
to yield 30 g of a clear liquid.
ms (fd) = 190 M+
CA 02064373 1999-11-04
X-8244 -35-
Example 3
Preparation of 3-cyclohexyl-2-(ethoxycarbonyl)-1-
propene.
A. Ethyl-2-benzylacetoacetate (50 g, 0.227 M)
was dissolved in ethanol (435 ml) and combined with 5%
Rh/A1203 (15 g) and stirred at room temperature over-
night under hydrogen pressure (60 psi). The mixture
was filtered and solvent removed under vacuum. The
residue was diluted with ethyl acetate and washed with
water. The organic layer was dried over K2C03 and the
solvent removed under vacuum to provide 49 g of ethyl-2-
aceto-3-cyclohexylpropanoate.
B. Ethyl-2-acetohexylpropanoate (20 g) was
contacted with N-butyllithium (101 mL 1.6 M), diiso-
propylamine (23 mL in dry THF, 440 mL) and paraformaldehyde
(18 g) as in Example 2 to provide 19 g of crude product
which was purified by bulb-to-bulb distillation at
130°C, 0.1 mmHg to provide 10 g of the named product as
a clear liquid.
ms (fd) - 196 M+
Example 4
A. Preparation of traps-4-(3-hydroxyphenyl)-
3,4-dimethyl-a-(phenylmethyl)-1-piperidinepropanoic
acid, ethyl ester hydrochloride. [Z-OCHZCH3~HC1].
Trans-(+)-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine (6.0 g, 29 mmole) and 3-phenyl-2-(ethoxy-
carbonyl)-1-propene (6.1 g) were dissolved in methanol
CA 02064373 1999-11-04
X-8244 -36-
(300 ml) and stirred at room temperature under nitrogen.
During the 10 day reaction time, the mixture was evapo-
rated two times and rediluted with methanol on days 5
and 9. On day 10 the mixture was evaporated to dryness
to provide 13 g of solid which was passed through a
silica column eluting with hexane to ethyl acetate
gradient providing 11.4 g of purified product.
Analysis fOr C25H33N~3'HC1:
Theory: C, 69.50; H, 7.93; N, 3.24
Found: C, 69.36; H, 7.69; N, 3.21
B. Preparation of 4-(3-hydroxyphenyl)-3,4-
dimethyl-a-(phenylmethyl)-1-piperidinepropanoic acid
monohydrate. [Z-OH~HZO].
To 1.0 g of the product from 4A was added
dioxane (60 ml) and 6 N HC1 (30 ml). The mixture
was heated to reflux for two hours, cooled and the
solvent removed under vacuum. The residue was rediluted
with water and the pH adjusted to 9.8 with ammonium
hydroxide. The desired acid was extracted with 3:1
butanol/toluene solution. The solvent was removed and
the residue was passed through a silica column eluting
with a mixture of methanol and ethyl acetate (20:80,
v:v). The resulting material was slurried in ethyl
ether, and filtered to give 650 mg of product having
m.p. 120-131°C.
Analysis for C23H31N04:
Theory: C, 71.66, H, 8.11; N, 3.63
Found . C, 71.89; H, 8.09; N, 3.71
CA 02064373 1999-11-04
X-8244 -3~-
Example 5
A. Preparation of 3-L3,4-dimethyl-4-
(3-hydroxyphenyl)-1-piperidinyl]-2-(cyclo-
hexylmethyl)propanoic acid ethyl ester hydrochloride.
[M-OCHZCH3~HC1].
The procedure of Example 4A was used with
trans-(~)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
(4.0 g) and 2-(ethoxycarbonyl)-3-phenyl-1-propene
(4.61 g). The solvent was removed under vacuum and the
residue diluted with ethyl acetate and water. The pH
was adjusted to 9.8 with IN NaOH and the mixture was
extracted with ethyl acetate. This organic layer was
dried over K2C03. The solvent removed to yield 4.3 g.
The HC1-salt was prepared having a melting point
101-111°C.
Analysis for C25H39N03~HC1:
Theory: C, 68.55; H, 9.20; N, 3.19
Found . C, 68.32; H, 9.16; N, 3.18
B. Preparation of 3-[3,4-dimethyl-4-(3
hydroxyphenyl)-1-piperidinyl]-2-(cyclohexylmethyl)
propanoic acid monohydrate. [M-OH~H20].
2.88 g of compound from preparation 5A was
added to dioxane (75 ml) and 6N HC1 (75 ml) and allowed
to reflux with stirring for five hours. The solvent was
removed under reduced pressure and the residue was taken
into H20. The pH.of the water was adjusted to 9.8
with ammonium hydroxide. The solution was extracted
with a mixture of butanol and toluene (3:1, v:v) and
CA 02064373 1999-11-04
X-8244 -38-
dried over magnesium sulfate. The solvent was removed
by vacuum to yield 2.6 g of solid. This material was
purified by column chromatography eluting with a 1:1
ethyl acetate-methanol mixture. After removal of
solvent, the material was triturated with ethyl ether
and filtered to give 640 mg of product.
m.p. - 145-150°C
AnalySlS for C23H35N~3'H20:
Theory: C, 70.55; H, 9.52; N, 3.57
Found . C, 70.78; H, 9.34; N, 3.54
Example 6
Preparation of ethyl-2-phenyl-4-chlorobutanoate.
Diisopropylamine (2.71 ml, 1.1 eq) was added
to dry THF (10 ml) and cooled to -78°C. N-butyllithium
(11.01 ml of 1.6 Molar, 1.1 eq) was added dropwise. The
mixture was stirred at -78°C for 30 minutes and ethyl-2-
phenylacetate (2.9 g, 1.0 eq) was dissolved in dry THF
(20 ml) and the solution added dropwise to the reaction
mixture. The mixture was stirred at -78°C for 0.25
hour and then allowed to warm to -30°C and stirred for
an additional 0.25 hour. 1,3-Dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone (DMPU) (2.13 ml, 1.0 eq) was
dissolved in dry THF (20 ml) and added dropwise to the
mixture. The resulting mixture was maintained at -30°C
for ten minutes. This mixture was then cannulated under
N2 pressure to a flask which had been charged with ethyl
ether (100 ml) and 1-bromo-2-chloroethane (7.3 ml, 5.0
2064~'~3
X-8244 -39-
eq) at -10°C. The mixture was stirred for three hours
at -ZO°C to -5°C. The mixture was cooled to -30°C and
quenched with a saturated ammonium chloride solution.
The mixture was extracted with ethyl ether which was
then dried over K2C03. The solvent was stripped to
provide 3.2 g of product which distilled at 70-71°C
under 0.01 mmHg.
ms (fd) = 226 M+
Example 7
Preparation of ethyl-2-cyclohexyl-4-chlorobutanoate.
Diisopropylamine (2.71 ml, 1.1 eq.) was added
to dry THF (10 ml) and cooled to -78°C. N-Butyllithium
(11.01 ml of 1.6 Molar solution, 1.0 eq.) was added and
the mixture stirred at -78°C for 0.5 hour. To this
mixture was then added dropwise a solution of ethyl-2-
cyclohexylacetate (3.0 g, 1.0 eq.) in THF (20 ml) at
-78°C and stirred for 0.5 hour. DMPU (2.13 ml, 1.0 eq.)
in TI3F (20 ml) was added dropwise and allowed to stir at
-78°C for 10 minutes. To this mixture was added 1-
bromo-2-chloroethane (1.46 ml, 1.0 eq.) in THF (10 ml)
and the mixture stirred at -5°C for 15 minutes. The
mixture was then warmed to room temperature and stirred
for 1.0 hour. The mixture was cooled to 0°C, quenched
with saturated ammonium chloride solution, extracted
with ethyl ether and the ether layer was washed three
times with water. The organic layer was separated,
CA 02064373 1999-11-04
X-8244 -40-
dried over K2C03 and the solvent removed to provide
3.6 g of product. This was fractionally distilled to
provide 3.0 g of product. Boiling Point 66'-70'C at 0.05
mmHg.
Analysis for Ci2H2102C1:
Theory: C, 61.93; H, 9.09
Found . C, 61.66; H, 9.23
Example 8
A. Preparation of traps-4-[(3-Hydroxyphenyl)-
3,4-dimethyl-1-piperidine]-2-phenyl butanoic acid, ethyl
ester hydrochloride. [U-OCH2CH3~HC1].
Ethyl-4-chloro-2-phenylbutanoate (2.43 g),
trans-(+)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
[Q-OH] (2.0 g), NaHC03 (905 mg), NaI.(1.53 g), and
dimethylformamide (DMF) (120 ml) were combined and
heated to reflux for two hours. The mixture was cooled
and evaporated to dryness. The solid was taken into H20
and the pH adjusted to 9.8 with IN NaOH. This mixture
was extracted with ethyl acetate and the organic layer
dried over K2C03. The solvent was removed under vaccum
to provide 5 g of crude product. This product was
subjected to column chromatography eluting with ethyl
acetate to provide 4.0 g of material. This material was
converted to the HC1 salt.
Analysis: C25H33N30'HCl
Theory: C, 69.51; H, 7.93; N, 3.24
Found . C, 69.72; H, 7.77; N, 3.34
206~3'~3
X-8244 -41-
Example 8B
B. Preparation of trans-4-[(3-Hydroxyphenyl)-
3,4-dimethyl-1-piperidine]-2-phenyl butanoic acid hydro-
chloride. [U-OH~HCl].
The ethyl ester product of Example 8A (3.0 g)
was combined with 6N HC1 (250 ml) and dioxane (30 ml).
The mixture was stirred at reflux fox 18 hours. The
solvent was removed under vacuum. The residue was taken
into H20, the pH was adjusted to 9.8 with TEA and the
desired product extracted with a 3:1 butanol-toluene
solution. The organic layer was dried over MgS04 and
the solvent removed under vacuum to yield 2.6 g white
solid. The compound was converted to the HC1 salt.
m.p. = 140-150°C
Analysis: Ca3HZ9N30~HCl
Theory: C, 68.39; H, 7.49; N, 3.47
Found : C, 68.19; H, 7.27; N, 3.47
Example 9
A. Preparation of trans-4-[(3-hydroxyphenyl)-
3,4-dimethyl-1-piperidine]-2-cyclohexylbutanoic acid,
ethyl ester hydrochloride. [G-OCHZCH3~HCl].
DMF (80 ml) was added to trans-(+)-3,4-di-
methyl-4-(3-hydroxyphenyl)piperidine (1.0 g) followed by
NaI (735 mgs, 1.0 eq), KZC03 (677 mgs, 1.0 eq) and then
ethyl 4-chloro-2-cyclohexylbutanoate (1.0 eq). The
mixture was refluxed for 2 hours, cooled and poured
into water. The pH was adjusted to 9.8 with 1 NaOH.
20~~373
X-8244 -42-
The mixture was extracted with ethyl ether and the
organic layer dried over KZC03. The solvent was removed
under vacuum to provide 1.6 g of solid. The hydro-
chloride salt was prepared to yield 1.1 g of a white
solid.
m.p. 80-95°C.
Analysis: CZSH39N~3~HC1
Theory: C, 68.55; H, 9.20; N, 3.20
Found : C, 68.27; H, 9.18; N, 3.37
Example 9B
Preparation of traps-4-[(3-hydroxyphenyl)-3,4-
dimethyl-1-piperidinyl]-2-cyclohexylbutanoic acid
hydrochloride. [G-OH~HC1].
Product (HC1 salt) from Example 9A (1.0 g) was
combined with 6N HC1 (100 ml) and the mixture refluxed
for 18 hours. The hot mixture was filtered and the
filtrate evaporated under vacuum to provide a white
solid. The solid was triturated with ethyl acetate and
filtered. The white solid was dried in a vacuum oven to
provide 600 mg as the HCl salt. This salt was taken
into water and the pH adjusted to 9.8 with TEA. The
product was extracted with a 3:1 butanol:toluene mixture
and dried over Mgs04. The solvent was removed to
provide 460 mg of product as a white solid. The HC1
salt was made.
m.p. - 140-160°C (foam)
2064373
X-8244 -43-
AnalyslS: C23H35N03~HC1:
Theory: C, 67.38; H, 8.85; N, 3.42
Found : C, 67.44; H, 8.94; N, 3.58
Example 10
Preparation of trans-4-[(3-hydroxyphenyl)-3,4-
dimethyl-1-piperidinyl]-2-phenyl-N,N-dimethylbutanamide
hydrochloride. [U-N(CH3)2~HCl].
Acid prepared as in Example 8B (1.5 g, 3.72
mmoles), dimethylamine hydrochloride (334 mg), DCC (845
mg), 1-hydroxybenzotriazole hydrate (553 mg), diisopropyl
ethyl amine (5.85 ml), and DMF (100 ml) were combined
and stirred at room temperature for 24 hours. The
mixture was poured into water and the pH adjusted to 9.8
with 1N NaOH. The mixture was extracted with ethyl
acetate and the organic layer dried over KZC03. The
solvent was removed under vacuum to yield 1.56 g of
desired product. The product was passed through a
silica column with methanol to provide 800 mg of material.
The HC1 salt was prepared and filtered to yield 810 mgs.
ms (fd) = 394 M~
Analysis: C25H3~N202~HC1:
Theory: C, 69.67; H, 8.19; N, 6.50
Found : C, 69.37; H, 8.06; N, 6.40
2fl64373
X-8244 -44-
Example 11
Preparation of 2-[[4-[4-(3-hydroxyphenyl)-
3,4-dimethyl-1-piperidinyl]-1-oxo-2-phenylbutyl]amino]-
acetic acid ethyl ester monohydrochloride. [U-NHCHZC(O)-
OCH2CH3~HC1].
The following materials were combined in dry
DMF (75 ml): substituted-butanoic acid prepared as in
Example 8B (1.5 g, 4 mmole), glycine ethyl ester (558
mg), triethylamine (404 mg), Hobt (540 mg), DCC (824
mg). The above materials were mixed together at room
temperature under nitrogen and stirred for three days
with the DCC added after solubilization of the solids.
The reaction was then filtered and evaporated to dryness.
The residue was solubilized in ethyl acetate, washed one
time with water and dried over KZC03. The solvent was
evaporated to provide 800 mg of solid product. The
product was subjected to column chromatography eluting
with a gradient of ethyl acetate to a 9:1 (v: v) ethyl
acetate-methanol mixture to provide 400 mg of a semi-
solid material. This was converted to HCl salt to
provide 270 mg of white solid.
m.p. - 102-107°C
ms ( fd) = 452 M+, 453 M+-~l
Analysis: CZ~H36N204~HC1
Theory: C, 66.31; H, 7.63; N, 5.73
Found : C, 65.99; H, 7.75; N, 5.92
206433
X-8244 -45-
Example 12
Preparation of 2-[[4-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-2 -phenyl-1-oxobutyl]amino]-
ethanoic acid monohydrate. [U-NHCH2C(O)OH~H20].
Ethyl ester prepared as in Example 11 (1.6 g,
3.5 mmole) and lithium hydroxide (440 mg) were combined
in 60 ml of a mixture of tetrahydrofuran, methanol, and
water (v:v:v, 3:1:1) and stirred at room temperature.
After three hours the mixture was poured into 100 ml of
a 10 weight percent aqueous solution of HCl. The
mixture was then extracted with a butanol/toluene (v: v,
3:1) solution. The organic layer was backwashed one
time with water, dried over K2C03 and the solvent
evaporated under vacuum to yield 1.51 g of solid product.
The product was subjected to column chromatography
eluting with a gradient of ethyl acetate/methanol (9:1,
v:v) to ethyl acetate/methanol (1:1, v:v) under nitrogen
pressure providing 360 mg of product as a white solid.
m.p. - 145-150°C with decomposition
ms (fd) = 424 M+
AnalyslS C25H32N204~H20~
Theory: C, 67.85; H, 7.74; N, 6.33
Found : C, 67.55; H, 7.87; N, 6.05
206433
X-8244 -46-
Example 13
Preparation of N-(methyl)-2-[[4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-phepyl-1-oxo-
butyl]amino]acetamide monohydrochloride. [U-NHCH2C(O)-
NHCH3~HC1].
U-NHCHZC(O)fJCH2CH3eHC1 (400 mg) prepared as
in Example 11, methylamine (10 m1, 40% in water),
methanol (5 ml) were mixed together and stirred at room
temperature overnight. The solvent was removed to
provide 392 mg of an oil which was subjected to column
chromatography eluting with a gradient of ethyl acetate
to ethyl acetate/methanol (v: v, 9:1). 225 mg of a semi-
solid was recovered. The HC1 salt was prepared and
dried to provide 220 mg of white solid.
m.p. - 115-119°C
Analysis for C2gH35N3~3'HC1
Theory: C, 65.88; H, 7.66; N, 8.86
Found : C, 65.63; H, 7.47; N, 8.70
Example 14
Preparation of traps-N-(2-amino-2-oxoethyl)-4-[3,4-
dimethyl-4-(3-hydroxyphenyl)-1-piperidinyl]-2-phenyl-
butanamide monohydrochloride monohydrate. [U-NHCHaC(o)-
NH2sHC1~H20].
The procedure of 13 was followed with product
from Example 11 (400 mg), ammonium hydroxide (10 ml,
28%), and methanol (5 ml) to yield 390 mg of a semisolid.
This product was subjected to column chromatography
CA 02064373 1999-11-04
X-8244 -47-
eluting with a gradient of ethyl acetate/methanol (v: v,
9:1) to ethyl acetate/methanol (v: v, l:l). The solvent
was removed to yield 240 mg of solid.
ms (fd) - 423 M+ and 424 M++1
The HC1 salt was prepared and dried to provide 200
mg of a white solid.
m.p. - 128-132°C
AIlalySlS for C25H33N3~3'HC1'H2~:
Theory: C, 62.81; H, 7.59; N, 8.79
Found . C, 63.04; H, 7.74; N, 8.54
Example 15
Preparation of N-ethyl-2-[[4-[4-(3-hydroxyphenyl)-
3,4-dimethyl-1-piperidinyl]]-2-phenyl-1-oxobutylamino]-
acetamide monohydrochloride monohydrate. [U-NHCHZC(O)-
NHCHZCH3~HC1~H20].
The same procedure as in Example 13 was
followed using the product from the procedure of Example
11 (400 mg) and ethylamine (20 ml, 70% in H20) except that
the reaction was run for 3.5 days. 400 mg of an oil was
recovered. This was subjected to column chromatography
eluting with a gradient of ethyl acetate to methanol
providing 250 mg of a solid.
ms (fd) - 451 M+ and 452 M++1
CA 02064373 1999-11-04
X-8244 -48-
The HC1 salt was prepared and dried to provide
200 mg of solid.
m.p. - 95-105°C (foam)
AIlalySlS fOr CZ~Hg~NgOg'HC1'H20:
Theory: C, 64.08; H, 7.97; N, 8.30
Found . C, 64.37; H, 7.78; N, 8.19
Example 16
Preparation of 3-[[2-cyclohexyl-4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-1-oxobutyl]amino]-
propionic acid ethyl ester monohydrochloride. [G-NH-
(CHZ)2C(O)OCHZCH3~HC1].
The butanoic acid (G-OH] prepared as in
Example 9B (1.45 g, 3.9 mmole), ethyl-3-aminopropionate
(600 mg), triethylamine (394 mg) and Hobt (527 mg) were
combined in dry DMF (75 ml) followed by the addition of
DCC (308 mg). The mixture was stirred at room temperature
for 64 hours under nitrogen, evaporated to dryness, and
the residue dissolved in ethyl acetate. The ethyl
acetate layer was washed two times with water, dried
over K2C03 and then evaporated to dryness to yield 2.16
g of material. This material was subjected to column
chromatography eluting with a gradient of ethyl
acetate/hexane (v:v, 1:1) to ethyl acetate. Removal of
solvent provided 1.35 g of product with a mass spec of
472 M+ and 473 M++1. The HCl salt was prepared and
dried to provide 1.5 g of white solid.
m.p. - 117-122°C
2064373
X-8244 -4g-
Analysis: C28H44N204~HC1
Theory: C, 66.21 A, 9.03 N, 5.31
Found : C, 66.05; A, 8.91; N, 5.40
Example 17
Preparation of N-(3-amino-3-oxopropyl)-4[3,4-
dimethyl-4-(3-hydroxyphenyl)-1-piperidinyl]-2-butanamide
monohydrochloride. [G-NH(CHZ)2C(O)NH2sHC1].
The ethyl propionate (HCl salt) [G-NH(CHZ)2-
C(O)OCHZCH3] prepared as in Example 16 (400 mg) and
ammonium hydroxide (25 ml, 28% in H20) were mixed and
stirred at room temperature overnight. The mixture was
evaporated to dryness and the residue was taken into
butanol/toluene (v:v, 3:1) and water. The pH was
adjusted to 9.8 with 1N NaOH and the.layers were separated.
The organic layer was washed one time with water, dried
over KZC03 and then evaporated under vacuum to yield 350
mg of material. This material was subjected to column
chromatography eluting with ethyl acetate to methanol
gradient. Removal of the solvent provided 200 mg of
product with a mass spec of 443 M+ and 444 M++l. The
HC1 salt was prepared and dried to yield 160 mg of white
solid.
m.p. - 119-124°C (with decomposition)
Analysis for CZgH41N3o3'AC1:
Theory: C, 65.05; H, 8.82; N, 8.75
Found : C, 64.76; H, 8.75; N, 8.38
~06~3'~3
X-8244 -50-
Example 18
Preparation of N-[3 -(methylamino)-3-oxopropyl]-4-
[4-(3-hydroxyghenyl)-3,4-dimethyl-1-piperidinyl]-2-
cyclohexyl-butanamide monohydrochloride. [G-NH(CHZ)z--
C(O)NHCH3oHC1].
The procedure of Example 17 was followed with
the ethyl propionate product (HC1 salt) prepared as in
Example 16 (450 mg), methylamine (25 ml, 40% in H20) and
dioxane (10 ml) to provide 470 mg of material. This
material was subjected to column chromatography eluting
with ethyl acetate/methanol (v: v, 9:1) to methanol
gradient. Solvent was removed to provide 290 mg of
product.
ms (fd) = 458 M+, 459 M++1
The HCl salt was prepared and dried to provide 275 mg of
a white solid.
m.p. - 124-130°C
Analysis for CZ~H43N3O3~HCl:
Theory: C, 65.63; H, 8.98; N, 8.50
Found : C, 65.42; H, 9.01; N, 8.29
Example 19
Preparation of traps-N-[2-ethoxy-2-oxoethyl]-4-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-
cyclohexylbutanamide hydrochloride. [G-NHCHZC(0)OCH2-
CH3~HC1].
The butanoic acid prepared as in Example 9B
(900 mg), glycine ethyl ester~HC1 (348 mg), Hobt (338
mg), TEA (253 mg), and DCC (515 mg) were combined and
CA 02064373 1999-11-04
X-8244 -51-
the reaction texture was stirred for 72 hours at rooan teu~perature.
The mixture was evaporated to dryness under vacuum. The
residue was dissolved into water/ethyl acetate and the
pH of the water layer was adjusted to 9.8 with 1N sodium
hydroxide. The layers were separated and the organic
layer washed with water, dried over KZC03 and the
solvent was evaporated under vacuum to yield 1.25 g of
oily material. This material was subjected to column
chromatography eluting with ethyl acetate. Solvent
removal provided 720 mg of product. This material was
converted to the HC1 salt.
ms (fd) - 458 M+
m.p. - 98-101°C
AllalySlS: C2~H42N204~HC1
Theory: C, 65.50; H, 8.75; N, 5.66
Found . C, 65.84; H, 8.81; N, 5.87
Example 20
Preparation of N-(2-amino-2-oxoethyl)-4-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-cyclohexyl-
butanamide hydrochloride monohydrate. [G-NHCHZC(O)-
NHZ~HC1~H20].
The procedure of Example 17 was followed with
the butanamide product (HC1 salt) prepared as in Example
19 (400 mg), ammonium hydroxide (25 ml, 28% in water)
and methanol (10 ml) with the mixture being stirred
overnight. 350 mg of material was recovered and sub-
jected to column chromatography eluting. with a gradient
2~G~3'~3
X-8244 -52-
of ethyl acetate to ethyl acetate/methanol (v: v, 1:1).
Removal of solvent yielded 220 mg of product with a mass
spec of 429 M+ and 430 M++1. The HC1 salt was prepared
and dried to yield 170 mg of white solid.
m.p. - 129-134°C.
Analysis for C25H39N3~3'HC1~H20:
Theory: C, 62.03; H, 8.75; N, 8.68
Found : C, 62.46; H, 8.53; N, 8.20
Example 21
Preparation of N-[2-(methylamino)-2-oxoethyl]-4-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-cyclohexyl
butanamide hydrochloride. [G-NHCHZC(O)NHCH3~HC1].
The procedure of Example 17 was followed with
the butanamide product [G-NHCHZC(O)OCHZCH3] (HC1 salt)
prepared as in Example 19 (600 mg) and methylamine (35
ml, 40% in H20) to yield 580 mg of material. This
material was subjected to column chromatography eluting
with a gradient of ethyl acetate to ethyl acetate/-
methanol (v:v, 1:1) providing 300 mg of product. The
HC1 salt was prepared and dried to yield 275 mg of a
white solid.
ms (fd) = 444 M+
m.p. = 119-124°C.
Analysis for C2gH41N303'HCl'H20:
Theory: C, 62.68; H, 8.90; N, 8.44
Found : C, 62.39; H, 8.64; N, 8.23
2~6~3'~3
X-8244 -53-
Example 22
Preparation of N-[2-(ethylamino)-2-oxoethyl]-4-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-cyclohexyl
butanamide hydrochloride. [G-NHCHZC(O)NHCHZCH3~HC1].
The procedure of Example 17 was followed with
the butanamide (HC1 salt) product prepared as in Example
19 (600 mg) and ethylamine (30 ml, 70%) to yield 660 mg
of material. This material was subjected to column
chromatography eluting with a gradient of ethyl acetate
to ethyl acetate/methanol (v: v, 1:1). Solvent removal
provided 320 mg of product. The HC1 salt was prepared
and dried to yield 350 mg of white solid.
ms (fd) = 458 M+
m.p. - 123-126°C.
Analysis for CZ~Hg3N303~HC1~H20:
Theory: C, 63.31; H, 8.98; N, 8.21
Found : C, 63.53; H, 8.92; N, 8.47
Example 23
Preparation of 4-[[2-cyclohexyl-4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-1-oxobutyl]amino]-
butanoic acid ethyl ester monohydrochloride
monohydrate. [G-NH(CHZ)3C(O)OCHZCH3~HC1~H20]. '
The butanoic acid product prepared as in
Example 9B (1.5 g), ethyl-4-aminobutanoate hydrochloride
(671 mg), TEA (405 mg) Hobt (540 mg) were combined in
dry DMF (150 ml). DCC (824 mg) was added last. The
mixture was stirred 64 hours at room temperature under
2~6~3'~3
X-8244 -54-
nitrogen. After evaporation to dryness, the residue was
taken into ethyl acetate which was washed two times with
water and dried over KZC03. Evaporation to dryness
yielded 2.23 g of residue. This material was subjected
to column chromatography eluting with a gradient of ethyl
acetate to methanol/ethyl acetate (v: v, 9:1). Removal
of solvent provided 1 g of product.
ms (fd) = 486 M+ and 487 M++1
350 mg of this product was converted to HCl salt to
yield 300 mg of white solid after drying.
m.p. - 76-79°C.
Analysis for CZgH46N2~4'HC1'H2~
Theory: C, 64.30; H, 9.05; N, 5.18
Found : C, 63.90; H, 9.01; N, 5.12
Example 24
Preparation of N-methyl-4-[[4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-cyclohexyl-1-
oxobutyl)amino]butanamide monohydrochloride mono-
hydrate. [G-NH(CHZ)3C(O)NHCH3~HC1~H20).
Butanoate product prepared as in Example 23
(450 mg) and methylamine (15 ml, 40% in water) were
mixed and stirred at room temperature for three hours.
Evaporation of the reaction mixture to dryness provided
a residue which was dissolved into butanol-toluene (v: v,
3:1) and water. The water layer was taken to a pH of
9.8 with 1N NaOH and the layers separated. The organic
layer was washed one time with water, dried over K2C03
2064373
X-8244 -55-
and the solvent removed to yield 470 mg of a viscous
oil. This material was column chromatographed eluting
with a gradient of ethyl acetate to ethyl acetate/methanol
(v:v, 1:1) providing 250 mg of product. The HC1 salt was
prepared and dried to yield 250 mg of white solid.
m.p. = 78-84° C. (foam)
Analysis for C28H45N303~HC1~H20:
Theory: C, 63.91; H, 9.20; N, 7.99
Found : C, 64.21; H, 8.95; N, 7.83
to
Example 25
Preparation of 3-[[2-cyclohexyl-4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-1-oxobutyl]amino]-
propanoic acid phenylmethyl ester hydrochloride
monohydrate. [G-NH(CHZ)2C(O)OCHZ(CsHs)~HC1~H20].
The butanoic acid of Example 9B (900 mg)
[G-OH], ~-alanine benzyl ester~para-tosylate (878 mg),
Hobt (338 mg), DCC (515 mg) and TEA (253 mg) were
combined in DMF (100 ml) and stirred for 64 hours at
room temperature. The solution was evaporated to
dryness under vacuum. The residue was partitioned
between ethyl acetate and water and the water layer was
adjusted to a pH of 9.8 with 1N NaOH. The layers were
separated and the organic layer washed one time with
water, dried over K2C03 and evaporated to yield 1.57 g
of material. This material was column chromatographed
eluting with a gradient of ethyl acetate to ethyl
acetate-methanol (1:1, v:v) providing 620 mg of product.
CA 02064373 1999-11-04
X-8244 -56-
This was converted to HCl salt.
ms (fd) - 534 M+ and 535 M++1
m.p. - 87-90°C
Analysis for CggH46N204'HCl~HZO:
Theory: C, 67.23; H, 8.39; N, 4.75
Found . C, 67.31; H, 8.43; N, 5.03
Example 2fi
Preparation of 3-[4-[3,4-dimethyl-4-(3-hydroxy-
phenyl)-1-piperidinyl]-2-cyclohexyl-1-oxobutylamino]-
propanoic acid monohydrate. [G-NH(CH2)ZC(O)OH~HZO).
Propanoate prepared in Example 25 (1.5 g) was
dissolved in ethanol and 5% Pd on carbon was added and
the solution was stirred overnight under 60 Psi hydrogen
pressure. The mixture was filtered and evaporated
to dryness to yield 1.43 g of material. This material
was triturated in ethyl acetate and filtered to yield
1.11 g of product.
ms (fd) - 444 M+ to 445 M++1
m.p. - 90-93°C.
Analysis for CZSH4oNz04'HzO:
Theory: C, 67.53; H, 9.09; N, 6.06
Found . C, 67.77; H, 8.96; N, 5.90
Example 27
Preparation of 2-[[2-cyclohexyl-4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-1-oxobutyl]amino]-
acetic acid monohydrate. [G-NHCHZC(O)OH~H20].
206~3'~3
X-8244 -57-
Butanamide (HC1 salt) [G-NHCHZC(O)OCHZCH3~HC1]
prepared as in Example 19 (400 mg), 6N HC1 (30 ml), and
dioxane (30 ml) were combined and refluxed for four
hours. The mixture was evaporated to dryness and the
residue was partitioned between butanol-toluene (v: v,
3:1) and water. The pH of the water was adjusted to 9.8
with ammonium hydroxide and the layers were separated.
The organic layer was dried over MgS04 and evaporated to
provide 540 mg of material. This material was subjected
to column chromatography eluting with ethyl acetate/-
methanol (v:v, 1:1). Removal of solvent provided 172 mg
of product.
ms (fd) = 430 M+ and 431 M++1
m.p. - 148-153°C.
Analysis for CZSHasN204'HzO:
Theory: C, 66.94; A, 8.90; N, 6.24
found : C, 66.64; H, 8.84; N, 5.88
Example 28
Preparation of 4-[[2-cyclohexyl-4-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-1-oxobutyl]amino]-
butanoic acid monohydrate. [G-NH(CAZ)3C(O)OH~HZO].
The butanoate prepared using the procedure
of Example 23 (550 mg); 6N HCl (20 ml) and dioxane (20
ml) were combined and refluxed for two hours. The
reaction mixture was evaporated to dryness. The residue
was taken into water and butanol-toluene (v: v, 3:1).
The pH of the water layer was adjusted to 9.8 using
CA 02064373 1999-11-04
X-8244 -58-
ammonium hydroxide and the layers were separated. The
organic layer was washed one time with water, dried over
MgS04 and evaporated to provide 490 mg of dry material.
This material was subjected to column chromatography
eluting with a gradient of hexane/ethyl acetate (v: v,
1:1) to ethyl acetate. Solvent removal provided 300 mg
of product.
ms (fd) - 458 M+ .
m.p. - 113-118°C. (with decomposition)
Analysis for C27H42Nz04~H20:
Theory: C, 67.99; H, 9.23; N, 5.88
Found . C, 67.85; H, 8.88; N, 5.65
Example 29
Preparation of 2-[[3-[4-(3-hydroxyphenyl-3,4-
dimethyl-1-piperidinyl)-2-cyclohexylmethyl-1-
oxopropyl)amino]acetic acid ethyl ester monohydro-
chloride. [M-NHCHZC(O)OCHZCH3~HC1).
The propanoic acid prepared as in Example 5B
(1.0 g), Hobt (384 mg), triethylamine (0.4 ml), glycine
ethyl ester~HC1 (374 mg), dimethylformamide (50 ml) and
DCC (586 mg) were combined and stirred for four days at
room temperature. Solvent was removed and the residue
was passed through a silica column eluting with ethyl
acetate. Removal of solvent yielded 990 mg of product.
The HC1 salt was prepared and triturated~ in ethyl ether
and filtered to yield a white solid.
m.p. 97-107°C
CA 02064373 1999-11-04
X-8244 -59-
Analysis for C27H4zN204~HC1:
Theory: C, 65.50; H, 8.75; N, 5.66
Found . C, 65.73; H, 8.50; N, 5.76
S Example 30
Preparation of 2-[[3-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-2-(cyclohexylmethyl)-1-oxopropyl]-
amino]acetic acid monohydrate. [M-NHCHZC(O)OH~H20].
The product of Example 29 (1.08 g), lithium
hydroxide (302 mg), and water/methanol/THF (20 ml,
1:1:3) were combined and stirred at room temperature for
four hours. The reaction mixture was poured into 10%
HC1/water and the mixture was extracted with butanol-
toluene (v:v, 3:1). The organic layer was washed one
time with water, dried over MgS04, and evaporated to
provide 1.05 g of material. This material was subjected
to column chromatography eluting with a gradient of
ethyl acetate to ethyl acetate/methanol (1:1) providing
510 mg of solid material.
m.p. - 112-116°C.
ms (fd) - 430 M+ to 431 M++1
Analysis for CZSH38N204~H20:
Theory: C, 66.90; H, 8.92; N, 6.25
Found . C, 67.10; H, 8.77; N, 6.24
20643'3
X-8244 -60-
Example 31
Preparation of N-ethyl-2-[[3-[4-(3-hydroxyphenyl)-
3,4-dimethyl-1-piperidinyl]-2-(cyclohexylmethyl)-1-oxo-
propyl]amino]acetamide monohydrochloride monohydrate.
[M-NHCH2C(O)NHCHaCH3~HCl~H20].
The procedure of Example 17 was followed with
the ester of Example 29 (400 mg) and ethylamine (20 ml,
70% in H20) to yield 390 mg of material. This material
was subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(v: v, 9:1). Solvent removal yielded 200 mg of product.
ms (fd) = 457 M~ and 458 M++1
The HC1 salt was prepared and dried at 60°C to provide
173 mg of white solid.
m.p. - 137-140.5°C.
Analysis for C27H4aNs0a~HC1~H20:
Theory: C, 63.32; H, 9.05; N, 8.21
Found : C, 63.12; H, 8.82; N, 7.95
Example 32
Preparation of N-[2-methylamino-2-oxoethyl]-3-
[4-(3-hydroxphenyl)-3,4-dimethyl(-1-piperidinyl]-2-
cyclohexylmethylpropanamide monohydrochloride. [M-NHCH2-
C(O)NHCH3~HCl].
The procedure of Example 31 was followed with
the propanamide prepared as in Example 29 (400 mg) and
methylamine (20 ml, 40% in water) to provide 380 mg of
material which was subjected to column chromatography
CA 02064373 1999-11-04
X-8244 -61-
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1). Solvent removal provided
210 mg of product.
ms (fd) - 443 M+, 444 M++1
The HC1 salt wa prepared and dried to provide 171 mg of
solid.
m.p. - 131-135°C.
AIlalySlS for CZgH41N303'HCl:
Theory: C, 65.05; H, 8.82; N, 8.75
Found . C, 65.37; H, 8.81; N, 8.88
Example 33
Preparation of 2-[[3-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-2-(cyclohexylmethyl)-1-oxo-
phenyl]amino]acetamide monohydrochloride. [M-NHCH2C(O)-
NHZ~HC1].
The procedure of Example 31 was followed with
the propanamide prepared as in Example 29 (400 mg) and
ammonium hydroxide (20 ml, 28% in H20) except that the
mixture was stirred for three days and then evaporated
to dryness under vacuum. 350 mg of material were
recovered which was subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1). Solvent removal provided
240 mg of product.
ms (fd) - 429 M+ and 430 M++1
The HC1 salt was prepared and dried at 60°C to provide
186 mg of solid.
m.p. - 140-144°C.
CA 02064373 1999-11-04
X-8244 -62-
Analysis for C25H39N303~HC1:
Theory: C, 64.43; H, 8.65; N, 9.02
Found . C, 64.69; H, 8.86; N, 8.93
Example 34
Preparation of 3-[[2-(cyclohexylmethyl)-1-oxo-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propyl]-
amino]propanoic acid phenylmethyl ester monohydro-
chloride. [M-NH(CH2)ZC(O)OCHZ(CsHS)~HC1].
Propanoic acid product of the Example 5B
procedure (809 mg), ~-alanine benzyl ester-p-tosylate
(760 mg), Hobt (293 mg), TEA (0.364 ml), DCC (447 mg),
and DMF (80 ml) were combined and stirred at room
temperature for three days. The mixture was stripped to
dryness and diluted with butanol-toluene (v:v, 3:1) and
water. The pH was adjusted to 9.8 with IN NaOH and the
organic layer was separated. The organic layer was
dried over KZC03 and the solvent removed. The residue
was diluted with ethyl acetate and passed through a
column of silica gel. The recovered product was converted
to the HC1 salt and triturated with ethyl ether and
filtered to provide 600 mg of white solid.
m.p. - 80-90°C.
Analysis for C33H46N204~HC1:
Theory: C, 69.39; H, 8.29; N, 4.90
Found . C, 69.50; H, 8.42; N, 4.93
~0~43°~3
X-8244 -63-
Example 35
Preparation of 3-[[3-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-2-(cyclohexylmethyl)-1-oxopropyl]-
amino]propanoic acid hydrochloride. [M-NH(CH2)ZC(O)_
OHeHCl].
The propanoic acid ester product of Example
34 (950 mg) was contacted with 5% Pd on carbon in
ethanol under 60 pounds per square inch hydrogen pressure.
The solvent was stripped and the residue passed through
a silica column eluting with methanol to give 760 mg of
product. This was converted to the HCl salt to provide
404 mg of white solid. m.p. - 115-120°C.
Analysis for C26H4oN204°HC1:
Theory: C, 64.91; H, 8.59; N, 5.82
Found : C, 65.04; H, 8.58; N, 5..90
Example 36
Preparation of 3-[[2-(cyclohexylmethyl)-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-1-oxo-
propyl]amino]propanoic acid ethyl ester monohydro-
chloride. [M-NH(CHZ)ZC(O)OCHZCH3~HC1].
Propanoic acid product of the procedure of
Example 5B (1 g), ~-alanine ethyl ester hydrochloride
(400 mg) triethylamine (263 mg) Hobt (351 mg), were
combined in dry dimethylformamide (75 ml) and then DCC
(536 mg) was added, These reactants were mixed together
at room temperature under nitrogen fox 3 days. The
reaction mixture was filtered and evaporated to dryness.
2~6~3'~3
X-8244 -64-
The residue was dissolved in ethyl acetate, which was
washed one time with water, dried over KZC03 and evaporated
to provide 1.74 g of material. This material was
subjected to column chromatography eluting with a
gradient of ethyl acetate/hexane (v: v, 1:1) to ethyl
acetate. Removal of the solvent provided 520 mg of
solid which was coverted to the HC1 salt to provide 270
mg of solid.
m.p. = 86-89°C.
ms (fd) = 472 M+ and 473 M++1
Analysis for GZ$H44N204~HCl:
Theory: C, 66. OS; H, 8.91; N, 5.51
Found : C, 65.86; H, 8.72; N, 5.81
Example 37
Preparation of N-[3-(methylamino)-3-oxopropyl]-3
-[3,4-dimethyl-4-(3-hydroxyphenyl)-1-piperidinyl]-2-
cyclohexylmethylpropanamide monohydrochloride. (M-NH-
(CH2)ZC(O)NHCH2CH3~HC1].
The procedure of Example 17 was followed with
the propanoic acid ester product of the procedure of
Example 36 (450 mg) and ethylamine (20 ml, 70% in H20)
to provide 440 mg of material. This material was
subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(v: v, 9:1) providing 250 mg of product.
ms (fd) = 471 M+ and 472 M++1
This product was coverted to the HC1 salt and dried to
provide 225 mg of solid.
2~6~37~
X-8244 -65-
m.p. - 109-113°C.
Analysis for CZgH~5N3Og~HC1
Theory: C, 66.18; H, 9.13; N, 8.27
Found : C, 66.36; H, 9.29; N, 8.53
Example 38
Preparation of 3-[[1-oxo-2-cyclohexylmethyl)-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propyl]-
amino]propanamide hydrochloride. [M-NH(CHZ)ZC(O)-
NH2 ~HC1 ] .
Propanoic acid ethyl ester prepared as in
Example 36 (300 mg) and ammonium hydroxide (15 ml, 28%
in H20) were combined and stirred at room temperature
for three days. Upon evaporating to dryness under
vacuum, 270 mg of material were recovered. This material
was subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(v:v, 9:1). Removal of solvent provided 170 mg of
product.
ms (fd) = 443 M+ and 444 M++1
This product was converted to the HCl salt and dried to
provide 108 mg of solid.
m.p. = 101-105°C.
Analysis for CZgH41N303'HCl
Theory: C, 65.04; H, 8.82; N, 8.75
Found : C, 65.29; H, 9.07; N, 8.87
2643?3
X-8244 -66-
Example 39
Preparation of 4-[[3-[3,4-dimethyl-4-(3-hydroxy-
phenyl)-1-piperidinyl]-2-(cyclohexhymethyl)-1-oxopropyl]-
amino]butanoic acid ethyl ester monohydrochloride. [M-
NH(CHZ)~C(0)OCH2CH3~HCl].
The propanoic acid product of the Example 5B
procedure (809 mg), ethyl-4-aminobutyrate~HC1 (399 mg),
HOBT (293 mg), TEA (0.364 ml), DCC (447 mg) were combined
in DMF (80 ml) and stirred for 72 hours at room
temperature. The reaction mixture was evaporated to
dryness under vacuum. The recovered material was
subjected to column chromatography eluting with ethyl
acetate/hexane (1:1) to yield 610 mgs after solvent
removal. This material was converted to the HC1 salt
yielding 540 mg of white solid.
m.p. - 70-85°C.
ArialySlS: C2oH4gN2O4~HCl
Theory: C, 66.58; H, 9.06; N, 5.35
Found : C, 66.49; H, 9.05; N, 5.30
Example 40
Preparation of 4-[[1-oxo-2-(cyclohexylmethyl)-3-
[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propyl]-
amino]butanamide hydrochloride. [M-NH(CHZ)3C(O)NHZ~HCL].
The procedure of Example 17 was followed with
the butanoic acid ester of Example 39 (300 mg) and
ammonium hydroxide (15 ml, 28%), with the mixture being
stirred for three days. 260 mg of material were recovered
CA 02064373 1999-11-04
X-8244 -67-
and subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(9:1, v:v). Solvent evaporation under vacuum provided
100 mg of product.
ms (fd) - 457 M+
The product was converted to the HC1 salt and dried to
provide 63 mg of solid.
m.p. - 90-94°C
Analysis for CZ~H43N303~HC1:
Theory: C, 65.63; H, 8.98; N, 8.50
Found . C, 65.98; H, 8.98; N, 8.35
Example 41
Preparation of N-[4-(methylamino)-4-oxobutyl]-3-
[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-
cyclohexylmethylpropanamide monohydrochloride. [M-NH-
(CHZ)3C(O)NHCH3~HC1].
The procedure of Example 17 was followed with
butanoic acid ethyl ester prepared as in Example 39
(400 mg) and methylamine (20 ml, 40% in H20), except that the
mixture was stirred overnight. 350 mg of material were
recovered and subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1) to provide 270 mg of product.
ms (fd) - 471 M+ and 472 M++1
This product was converted to the HC1 salt and dried to
provide 250 mg of white solid.
m.p. - 89-94°C.
CA 02064373 1999-11-04
X-8244 -68-
Analysis for CZ$H45N303~HC1:
Theory: C, 66.18; H, 9.13; N, 8.29
Found . C, 65.97; H, 9.12; N, 8.08
Example 42
Preparation of N-[4-(ethylamino)-4-oxobutyl]-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl[-2-cyclohexyl-
methyl propanamide monohydrate hydrochloride. [M-NH-
(CH2)3C(O)NHCH2CH3~HC1~H20].
The procedure of Example 17 was followed with
the butanoic acid ethyl ester product of the procedure
of Example 39 (400 mg) in ethylamine (20 ml, 70% in H20)
to provide 340 mg of material which was subjected to
column chromatography eluting with a gradient of ethyl
acetate to ethyl acetate/methanol (v: v, 9:1). Solvent
removal provided 200 mg of product.
ms (fd) - 485 M+, 486 M++1
This was converted to the HC1 salt and dried to provide
210 mg of white solid.
m.p. - 95-100°C.
Analysis fOr C29H47N3O3~HCl~HZO:
Theory: C, 64.48; H, 9.33; N, 7.78
Found . C, 64.19; H, 9.14; N, 7.68
Example 43
Preparation of 2-[[3-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-1-oxo-2-(phenylmethyl)propyl]-
amino]acetic acid ethyl ester hydrochloride. [X-
OCHZCH3~HC1].
CA 02064373 1999-11-04
X-8244 -69-
Propanoic acid [Z-OH] from the procedure of
Example 4B (1.23 g), Glycine ethyl ester~HC1 (486 mg),
Hobt (473 mg), TEA (0.487 ml) were combined in DMF (100
ml) and cooled to 0°C. To this was added DCC (719 mg)
and the mixture allowed to warm to room tempex'ature.
The mixtured was stirred for three,da.ys at room tem-
perature, filtered and the solvent removed under vacuum.
The residue was diluted with butanol-toluene (v: v, 3:1)
and water. The pH was adjusted to 9.8 with ammonium
hydroxide. The organic layer was separated and dried over
K2C03 and the solvent was removed. The residue was
passed through a silica column eluting with ethyl
acetate/hexane (v:v, 3:1). The solvent was removed to
yield 1.17 g of product. This was converted to the HC1
salt to provide 1.0 g of white solid.
m.p. - 75-87°C.
Analysis for CZ~H36N204~HC1:
Theory: C, 66.31; H, 7.63; N, 5.72
Found . C, 66.06; H, 7.55; N, 5.80
Example 44
Preparation of 2-[[3-(4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-1-oxo-2-(phenylmethyl)propyl]-
amino]acetic acid monohydrate. [X-OH~H20].
Acetic acid ester prepared as in Example 43
(HC1 salt) (600 mg) was dissolved in ethanol (20 ml) and
1N NaOH (2.6 ml) was added. The mixture was allowed to stir
at room temperature for two hours and the solvent removed
206373
X-8244 -70-
under reduced pressure. The residue was taken into H20
and the pH adjusted to 7 with 1N HC1. The H20 was
removed under vacuum and the residue dried. The residue
was slurried in ethanol, filtered, and the solvent
removed to yield 500 mg of material. This material was
passed through a silica column eluting with ethyl
acetate/methanol (3:2). The solvent was removed to
yield 450 mg of material. This was recrystallized from
an ethyl acetate/methanol (1:1) mixture to provide 378
mg of final product as a white solid.
m.p. - 161-165°C.
Analysis for C25H32N2~4'H20~
Theory: C, 68.16; H, 7.32; N, 6.36
Found : C, 68.08; H, 7.30; N, 6.22
Example 45
Preparation of N-ethyl-2-[[2-(phenylmethyl)-1-oxo-
3-[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylJpropyl]-
aminoJethanamide. (X-NHCH2CH3).
Acetic acid ester product prepared as in
Example 43 (HC1 salt) (300 mg) was combined with
ethylamine (50 ml, 70%) and stirred for one hour. The
solvent evaporated and the residue dissolved in ethyl
acetate. The organic layer was washed with water,
dried over K2C03 and the solvent removed to provide 240
mg of a solid.
ms (fd) = 451 M~
2~)6~~3'~3
X-8244 -71-
Analysis for CZ~H3~N303
Theory: C 71.81 H 8.29 N 9.30
Found: C 71.96 H 8.18 N 9.49
Example 46
Preparation of N-(2-amino-2-oxoethyl)-3-[3,4-
dimethyl-4-(3 -hydroxyphenyl)-1-piperidinyl]-2-phenylmethyl
propanamide monohydrochloride monohydrate. [X-
NHZSHC1oH20].
Acetic acid ester product prepared as in
Example 43 (HC1 salt) (500 mg), ammonium hydroxide
(10 ml, 28%) and methanol (5 ml) were combined and
stirred at room temperature overnight. The mixture was
evaporated to dryness under vacuum and the residue was
partitioned between butanol-toluene (v:v, 3:1) and
water. The pH of the water layer was adjusted to 9.8
with 1N NaOH and the layers separated. The organic
layer was washed one time with water and dried over
KZC03. The solvent was evaporated to yield 470 mg of a
viscous oil. This oil was passed over a silica column
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1). Removal of solvent
provided 270 mg of an oil.
ms (fd) = 423 M+, 424 M++1
This product was converted to the HC1 salt to provide
250 mg of white solid which was triturated in ethyl
acetate and filtered to yield 230 mgs white solid.
m.p. - 134-137°C.
2~6~3'~3
X-8244 -72-
Analysis for C25H34Na03~HC1~H20:
Theory: C, 62.81; H, 7.59; N, 8.79
Found : C, 62.58; H, 7.31; N, 8.59
Example 4?
Preparation of N,N-dimethyl-2-[[3-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenylmethyl)-1-
oxypropyl]amino]acetamide monohydrochloride mono-
hydrate. [X-N(CH3)Z~HC1~H20].
The procedure of Example 46 was followed with
acetic acid ester (HC1 salt) product of the Example 43
procedure (500 mg), dimethylamine (10 ml, 40 wt. % in
water) and methanol (5 ml) with the reaction mixture
stirred for two hours. 350 mg of material were recovered
which was passed through a silica column eluting with
ethyl acetate. 230 mg of product were recovered.
ms (fd) = 451 M++1
This material was converted to the HC1 salt to provide
200 mg of white solid.
m.p. - 119-123°C.
Analysis for C2~H3~N3~3~HC1'H20:
Theory: C, 64.28; H, 7.85; N, 8.61
Found : C, 64.57; H, 7.68; N, 8.53
Example 48
Preparation of N-(1-methylethyl)-2-[[3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-(p~enyl-
methyl)-1-oxopropyl]amino]acetamide hydrochloride mono-
hydrate. [X-NHCH(CH3)2~HC1~H20].
206~3'~3
X-8244 -73-
Acetic acid ester (HC1 salt) product of the
procedure of Example 43 (750 mg) [X-OCH2CH3] , 2-
aminopropane (106 mg), Hobt (243 mg) were mixed in DMF
(50 ml) followed by the addition of DCC (371 mg). This
mixture was stirred at room temperature for 64 hours
under nitrogen. The mixture was evaporated to dryness
and the residue dissolved in ethyl acetate, which was
then washed two times with water and dried over KZC03.
The solvent was removed to provide 880 mg of material
which was passed through a silica column eluting with
ethyl acetate. Solvent Evaporation provided 450 mg of
product.
ms (fd) = 465 M+, and 466 M++1
The HC1 salt was formed and the white solid dried at
60°C.
m.p. - 124-128°C.
Analysis for C28H39N3O3~HC1~H20:
Theory: C, 64.66; H, 8.14; N, 8.08
Found : C, 64.83; H, 8.30; N, 8.34
Example 49
Preparation of N-[2-propylamino-2-oxoethyl]-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-phenyl-
methyl propanamide monohydrate hydrochloride. [X-
NH(CHZ)ZCH3~HC1~H20]. [X-NH(CHZ)ZCH3~HC1~H20].
Acetic acid ester (HC1 salt) prepared as in
Example 43 (750 mg), 1-aminopropane (106 mg) and
Hobt (243 mg) were combined in DMF (50 ml) followed by
2~6~37~
X-8244 -74-
the addition of DCC (371 mg) using the procedure of
Example 48. 1.2 g of material were obtained and
passed through a silica column eluting with ethyl
acetate to provide 500 mg of product.
ms (fd) = 465 M+, 466 M++1
This product was converted to the HC1 salt and dried to
provide 510 mg of white solid.
m.p. - 115-120°C.
AnalyslS for CZgH39N3~3~HC1-H2~:
Theory: C, 64.66; H, 8.14; N, 8.08
Found : C, 64.91; H, 7.86; N, 7.97
Example 50
Preparation of N-[2-[(2-methylpropyl)amino)-2-oxo-
ethyl]-3-[3,4-dimethyl-4-(3-hydroxyphenyl)-1-piperidinyl)-
2-phenylmethyl propanamide monohydrate hydrochloride.
[X-NHCHZCH(CH3)2~HC1~H20).
The procedure of Example 48 was followed with
acetic acid ester (HC1 salt) prepared as in Example 43
(600 mg), 2-methyl-1-aminopropane (102 mg), Hobt (189
mg), dry DMF (50 ml) and DCC (288 mg). 940 mg of
material were isolated and passed through a silica
column eluting with ethyl acetate to provide 300 mg of
product.
ms (fd) of 479 M+.
This product was converted to the HC1 salt and dried to
provide 210 mg of white solid.
m.p. - 107-110°C.
2i~6 ~~'~3
X-8244 -75-
Analysis for C29H41N303~HC1~H20:
Theory: C, 65.21; H, 8.30; N, 7.87
Found : C, 65.51; H, 8.07; N, 7.80
Example 51
Preparation of 2-[[2-(phenylmethyl)-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-1-oxopropyl]-
amino]ethanoic acid 2-propyl ester monohydrochloride.
[X-OCH(CH3)2~HC1].
Acetic acid ester (HC1 salt) prepared as in
Example 43 (1.0 g), isopropyl alcohol (20 ml), and 3
angstrom molecular sieve (50 mg) were combined followed
by the addition of isopropyl alcohol saturated with
gaseous HC1 (20 ml). The reaction mixture was refluxed
for 48 hours and the solvent removed. The residue was
diluted with water and the pH adjusted to 9.8 with
TEA. The mixture was extracted with ethyl acetate which
was then dried over K2C03. The solvent was removed and
the residue passed through a silica column eluting with
ethyl acetate. The recovered product was converted to
the HC1 salt to provide 700 mg of white solid after
drying. The solid was triturated in ethyl acetate and
filtered to yield 650 mgs of white solid.
m.p. - 75-120°C (foam):
Analysis for CZ$H38N204~HC1
Theory: C, 66.85; H, 7.81; N, 5.57
Found : C, 66.98; H, 7.64; N, 5.52
206~3~3
X-8244 -76-
Example 52
Preparation of 2-[(2-(phenylmethyl)-1-oxo-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-.1-piperidinyl]propyl]amino]-
ethanoic acid cyclohexyl ester monohydrochloride. [X-
0-(C6H11)~HC1].
To acetic acid ester (HC1 salt) prepared as
in Example 43 (1.0 g) and 3 angstrom molecular sieve
(0.5 g) was added cyclohexanol (20 ml) followed by
cyclohexanol saturated with gaseous HC1 (20 ml).
The mixture was allowed to stir 72 hours at room temper-
ature. The mixture was then heated to 50°C fox 24
hours, cooled, filtered, and stripped to dryness. The
resulting material was triturated in hexane. The
solvent Was removed; the residue dissolved in water, and
the pH adjusted to 9.8 with triethylamine. The Product
was extracted with ethyl acetate which was then dried
over K2C03. The solvent was removed and the residue was
passed through a silica column eluting with ethyl
acetate/hexane (v: v, 4:1). After removing the solvent,
the product was converted to the HC1 salt to give 65 mg
of white solid.
m.p. - 100-140°C (foam):
Analysis fOr C32H44N204~HC1:
Theory: C, 68.55; H, 7.98; N, 5.16
Found : C, 68.80; H, 7.82; N, 5.05
20G~~~'~3
X-8244
Example 53
Preparation of 2-[(2-(phenylmethyl)-1-oxo-3-[4-(3
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propylamino]
ethanoic acid cyclohexylmethyl ester monohydrochloride.
(X-OCHZ(C6H11)~HC1].
Acetic acid ester prepared as in Example 43
(HC1 salt) (750 mg) and cyclohexylmethanol saturated
with Gaseous HC1 (20 ml) were combined and heated to
60°C for 24 hours. The mixture was evaporated to
dryness under vacuum. The residue was diluted with
water and ethyl acetate and the pH adjusted to 9.8
with triethylamine. The organic layer was separated,
and dried over KZC03. The solvent was removed and the
residue passed through a silica column eluting with
i5 hexane/ethyl acetate (v: v, 1:1). Removal of solvent
provided the product which was converted to the HC1 salt
and triturated in ethyl ether to provide 263 mg of tan
solid.
m.p. - 140-155°C (foam):
Analysis for C3~H4gN204~HC1:
Theory: C, 68.98; H, 8.14; N, 5.03
Found : C, 69.18; H, 8.05; N, 4.83
Example 54
Preparation of 2-[[2-(phenylmethyl)-1-oxo-3-(4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propyl]amino]-
ethanoic acid 2-methylpropyl ester monohydrochloride.
[X-OCHZCH(CH3)Z~HC1].
CA 02064373 1999-11-04
X-8244 -78-
Acetic acid ester prepared as in Example 43
(HC1 salt) (1.0 g), 3 angstrom molecular sieve (0.5 g)
and isobutyl alcohol saturated with Gaseous HC1 (40 ml)
were combined and stirred at room temperature for 72
hours. The mixture was then heated to 50°C for 24
hours. The reaction mixture was filtered and the filtrate was
stripped to dryness. The resulting residue was diluted
with water and the pH adjusted to 9.8 with triethylamine.
The product was extracted into ethyl acetate and the
organic layer dried over K2C03. The solvent was removed
and the residue passed through a silica column eluting
with ethyl acetate/hexane (v: v, 4:1). The recovered
product was converted to the HC1 salt to provide 500 mg
of a white solid.
Analysis for CZ9H4oN204~HC1:
Theory: C, 67.36; H, 7.99; N, 5.41
Found . C, 67.65; H, 7.94; N, 5.36
Exam le 55
Preparation of 2-[[2-(phenylmethyl)-1-oxo-3-[4-(3-
hydroxyphenyl)3,4-dimethyl-1-piperidinyl]propyl]amino]-
ethanoic acid phenylmethyl ester hydrochloride. [X-
OCHZ(CsHS)~HC1].
Acetic acid ester prepared as in Example 43
(HC1 salt) (1.0 g), 3 angstrom molecular sieve (0.5 g),
and benzyl alcohol (40 ml) saturated with Gaseous HC1
were combined and stirred at room temperature for 72
hours. The mixture was then heated at 50°C for 24
zoo=~3 ; 3
X-8244 -7g-
hours. The mixture was filtered and the solvent removed
under vacuum. The residue was diluted with water and
the pH was adjusted to 9.8 with triethylamine. The
product was extracted into ethyl acetate which was dried
over KZC03. The ethyl'acetate was evaporated under
vacuum and the resulting residue passed through a silica
column eluting with ethyl acetate/hexane (v: v, 4:1).
The resulting product was converted to the HC1 salt and
dried to provide 300 mg of white solid.
m.p. - 80-110°C (foam):
Analysis for C32H38N204~HC1~H20:
Theory: C, 67.53; H, 7.26; N, 4.92
Found : C, 67.51; H, 7.09; N, 4.99
Example 56
Preparation of 2-[[2-(phenylmethyl)-1-oxo-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propyl]amino]-
propanoic acid phenylmethyl ester hydrochloride. [Z-
NH(CHZ)2C(O)OCHZ(CsHs)~HC1].
Propanoic acid prepared as in Example 4B (1.23
g), benzyl-3-amino-propionate~p-tosylate (1.22 g), Hobt
(473 mg) and TEA (0.418 ml) were combined in DMF (100
ml) and stirred ten minutes at 0°C. DCC (719 mg) was
then added and the mixture allowed to warm to room
temperature and the stirring was continued for three
days at room temperature. The solvent was removed and
the residue diluted with butanol-toluene (v:v, 3:1) and
water. The pH of the aqueous layer was adjusted to 9.8
20643'3
X-8244 _gp-
with ammonium hydroxide and the mixture extracted with
butanol-toluene (3:1). The organic layer was separated
and dried over K2C03. The solvent was removed and
resulting residue passed through a silica column
eluting with ethyl acetate/hexane (v: v, 3:1). Removal
of solvent provided 1.2 g of product. The product was
converted to the HC1 salt and dried to provide a white
solid.
m.p. - 70-85°C.
Analysis for Cg3H40N2~4~HC1:
Theory: C, 70.13; H, 7.31; N, 4.96
Found : C, 70.40; H, 7.27; N, 5.21
Example 57
Preparation of 2-[[3-[4-(3-hydroxyphenyl)3,4-di-
methyl-1-piperidinyl]-1-oxo-2-(phenylmethyl)propyl]-
amino]propanoic acid monohydrate. [Z-NH(CH2)ZC(O)-
OH~H20].
The product of Example 56 (700 mg) was con-
tacted with 5% Pd/C and H2 at 60 psi overnight. The
mixture was filtered and the solvent was removed. The
residue was diluted with a water/ethanol mixture. The
pH was adjusted to 7.0 with 1N NaOH. This solvent was
removed and the residue slurried in ethanol and filtered
to remove NaCl. The solvent was removed from the
filtrate and the residue passed through silica gel
column eluting with ethyl acetate/ethanol (v: v, 1:1).
The solvent was removed and the solid was dried to
provide 366 mg of product.
m.p. - 98-100°C.
CA 02064373 1999-11-04
X-8244 -81-
AnalySlS for CZgH34N2~4~H2~
Theory: C, 68.39; H, 7.94; N, 6.12
Found : C, 68.59; H, 8.03; N, 5.72
Example 58
Preparation of [[3-[4-(3-hydroxyphenyl)-3,4-
dimethyl-1-piperidinyl]-1-oxo-2-(phenylmethyl)propyl]-
amino]propanoic acid ethyl ester monohydrochloride. [Z-
NH(CHZ)ZC(O)OCHZCH3~HC1].
Propanoic acid prepared as in Example 4B (1.65
g), ~-alanine ethyl ester~HC1 (691 mg), TEA (454 mg),
Hobt (608 mg) and dried DMF (75 ml) were combined
followed by DCC (928 mg) and stirred 64 hours at room
temperature under nitrogen. The mixture was evaporated
to dryness and the residue partitioned between ethyl
acetate and water. The layers were separated with the
organic layer being washed with water, dried over K2C03
and evaporated to dryness to provide 2.0 g of material.
This material was passed through a silica column eluting
with a gradient of hexane/ethyl acetate (v:v, 1:1) to
ethyl acetate providing 1.26 g of product. This product
was converted to the HC1 salt and dried to provide 1.3 g
of white solid.
m.p. - 119-124°C
ms (fd) - 466 M+
24~6~3'~3
X-8244 -g2-
Example 59
Preparation of N-(methyl)-3-[[3-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenylmethyl)-1 -
oxopropyl]amino]propanamide monohydrochloride. [Z-
NH(CHZ)2C(O)NHCH3eHC1].
Propionic acid ethyl ester prepared as in
Example 58 (450 mg), methylamine (15 m1, 40% in water),
and methanol (10 ml) were combined and stirred at room
temperature for three hours. The reaction was evaporated
to dryness. The residue was partitioned between
butanol/toluene (v:v, 3:1) and water. The H20 layer was
adjusted to a pH of 9.8 with 1N NaOH and the layers
separated. The organic layer was washed one time with
water, dried over KZC03, and evaporated to provide 440
mg of material. This material was subjected to column
chromatography eluting with a gradient of ethyl acetate
to ethyl acetate/methanol (v:v, 9:1) providing 344 mg of
product.
ms (fd) = 451 M+, 452 M++1
The product was converted to the HC1 salt and dried to
provide 260 mg of white solid.
m.p. - 95-99°C (foam):
Analysis for CZ~H3~N3O3~HC1:
Theory: C, 66.45; H, 7.85; N, 8.61
Found : C, 66.75; H, 7.99; N, 8.46
2643?3
X-8244 -83-
Example 60
Preparation of N-(ethyl)-3-[[3-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenylmethyl)-
1-oxopropyl]amino]propanamide monohydrochloride. [Z-
NH(CHZ)2C(0)NHCHZCH3~HC1].
The procedure of Example 59 was followed
using propionic acid ethyl ester prepared as in Example
58 (400 mg) and ethylamine (20 ml, 70 wt. % in water)
with stirring for 3.5 days. The 380 mg of material
recovered was subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v:v, 1:1) providing 360 mg of
product.
ms (fd) = 465 M+, 466 M++1
This material was converted to the HC1 salt and dried to
provide 300 mg of white solid.
m.p. - 86-90°C.
~~IlalySl.S fOr CZgHggNgOg ~HC1:
Theory: C, 66.98; H, 8.03; N, 8.37
Found : C, 66.69; H, 7.89; N, 8.28
Example 61
Preparation of 4-[[3-[4-(3-hydroxyphenyl)-3,4-
dimethyl-1-piperidinyl]-1-oxo-2-(phenylmethyl)propyl]-
amino]butanoic acid ethyl ester monohydrochloride
monohydrate. [Z-NH(CHZ)3C(O)OCHZCH3~HC1~H20].
~~fl6~3~3
X-8244 -84-
Propanoic acid prepared as in Example 4B (HC1
salt) (530 mg), TEA (0.452 ml), ethyl-4-aminobutyrate~HC1
(297 mg), Hobt (218 mg), DMF (60 ml), were combined
followed by the addition of DCC (333 mg). The mixture
was stirred at room temperature for three days, filtered
and the solvent removed. The residue was diluted with a
water/ethyl acetate mixture and the water layer adjusted
to a pH of 9.8 with TEA. The mixture was extracted with
ethyl acetate and the organic layer separated and dried
over K2C03. The solvent was removed to yield 1.0 gram
of material. This was passed through a silica gel
column eluting with ethyl acetate. The solvent was
removed to yield 300 mg of product. This product was
converted to the HC1 salt to give 370 mg of white solid.
m.p. - 65-70°C.
Analysis for C2gH41N204~HzO~HCl:
Theory: C, 65.09; H, 8.09; N, 5.23
Found : C, 65.26; H, 7.74; N, 5.53
Example 62
Preparation of N-(methyl)-4-[[3-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenylmethyl)-1-
oxopropyl]amino]butanamide monohydrochloride mono-
hydrate. [Z-NH(CHZ)3C(O)NHCH3~HC1~H20].
The procedure of Example 59 was followed with
the product from the procedure of Example 61 (HC1 salt)
(400 mg), methylamine (10 ml, 40 wt. % in water) and
methanol, (10 ml) with a three hour reaction time. 400
2064373
X-8244 -g5-
mg of material were recovered and subjected to column
chromatography eluting with a gradient of ethyl acetate
to ethyl acetate/methanol (v: v, 9:1). After evaporation
of solvent, 280 mg of product were recovered.
ms (fd) = 465 M+, 466 M++1
This material was converted to the HC1 salt and dried to
provide 260 mg of white solid.
m.p. - 90-93°C (foam):
Analysis for C28H39N303~HCl~HZO:
Theory: C, 64.78; H, 7.96; N, 8.09
Found : C, 64.38; H, 7.73; N, 7.89
Example 63
Preparation of 4-[(3-[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]-2-(phenylmethyl)-1-oxopropyl]-
amino]butanamide monohydrochloride. .[Z-NH(CH2)3C(O)-
NHZ~HC1].
The procedure of Example 59 was followed with
the product from the procedure of Example 61 (HC1 salt)
(400 mg), ammonium hydroxide (10 ml, 28% in water) and
methanol (5 ml) with the reaction mixture heated at 40°C
for two days. The 400 mg of material recovered was
subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(v: v, 9:1) which provided 250 mg of product.
ms (fd) = 451 M+
This product was converted to the HC1 salt and dried to
provide 200 mg of tan solid.
m.p. - 101-107°C.
CA 02064373 1999-11-04
X-8244 -86-
Analysis for C27H3~N303~HC1:
Theory: C, 66.44; H, 7.85; N, 8.61
Found . C, 66.04; H, 7.86; N, 8.46
Example 64
Preparation of N-(ethyl)-4-[[3-[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenylmethyl)-1-
oxopropyl]amino]butanamide monohydrochloride. [Z-
NH(CHZ)3C(0)NHCHZCH3~HC1].
The procedure of Example 59 was followed with
the product from the procedure of Example 61 (HC1 salt)
(450 mg) and ethylamine (15 ml, 70% in water) with
stirring for 3.5 days to provide 440 mg of material.
This material was subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, l:l) providing 230 mg of product.
ms (fd) - 479 M+, 480 M++1
This product was converted to the HC1 salt and dried to
provide 210 mg of white solid.
m.p. - 105-110°C
Analysis for CZgH41Ng0g~HCl:
Theory: C, 67.49; H, 8.20; N, 8.14
Found . C, 67.62; H, 8.28; N, 8.07
2064373
X-8244 _g7-
Example 65
Preparation of ([2-[[4-(3 -hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]-
methylamino]acetic acid ethyl ester monohydrochloride.
[Z-N(CH3)CH2C(O)OCHZCH3~HC1].
Product from the procedure of Example 4B (1.5
g), sarcosine ethyl ester~HC1 (614 mg), TEA (405 mg),
Hobt (540 mg) were combined in dry DMF (75 ml) and then
DCC (824 mg) was introduced. The mixture was stirred at
room temperature under nitrogen for three days. The
mixture was filtered and evaporated to dryness. Re-
sulting residue was dissolved in ethyl acetate, washed
one time with water and dried over K2C03. Evaporation
of the solvent yielded 1.72 g of material. This material
was subjected to column chromatography eluting with a
gradient of hexane/ethyl acetate (1:1) to ethyl acetate.
The solvent was removed to yield 910 mg of product. A
portion of this product was converted to the HC1 salt to
produce a white solid.
ms (fd) = 466 M+
m.p. - 91-95°C
Analysis for CZ$H38N204~HC1:
Theory: C, 66.85; H, 7.81; N, 5.57
Found : C, 66.63; H, 7.81; N, 5.62
Example 66
Preparation of [[2-[[4-(3-hydroxyphenyl)-3,4-di-
methyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]-
methylamino]acetic acid monohydrate. [Z-N(CH3)CH2C(O)-
OHeH20].
206433
X-8244 _88-
Product from the procedure of Example 65 (660
mg) and lithium hydroxide (176 mg) were combined in a
mixture of THF/H20/methanol (20 ml, 3:1:1) and stirred
at room temperature for three hours. The reaction
mixture was poured into 10% HC1 in water and extracted
with a butanol-toluene (3:1) solution. The organic
layer was washed with water and dried over KZC03.
Evaporation of the solvent under vacuum yielded 700 mg
of a semi-solid material. This material was subjected
to column chromatography eluting with a gradient of ethyl
acetate to ethyl acetate/methanol (v:v, 1:1). The
solvent was removed to yield 350 mg of solid material.
ms (fd) = 438 M+, 439 M++1
This material was recrystallized from ethyl
acetate to yield 220 mg of crystalline product.
m.p. of 134-136°C
Analysis for CZ6H34Nz04~H20:
Theory: C, 68.39; H, 7.95; N, 6.39
Found : C, 68.25; H, 7.76; N, 6.11
Example 67
Preparation of [[2-[[2-[[4-(3-hydroxyphenyl)-3,4-
dimethyl-1-piperidinyl]methyl]-3-phenyl-1-oxopropyl]-
amino]acetyl]amino]acetic acid ethyl ester monohydro-
chloride. [Z-NHCHZC(O)NHCH2C(O)OCHZCH3~HC1].
The procedure of Example 65 was used with
the product from the procedure of Example 48 [Z-OH] (1.5
g), Glycyl Glycine ethyl ester~HCl (786 mg), TEA
20643'3
X-8244 -g9-
(405 mg), Hobt (540 mg), dry DMF (75 ml) and DCC (824
mg). 1.36 g of material were recovered. This material
was passed over a silica column eluting with ethyl
acetate to provide 790 mg of product.
ms (fd) = 509 M+
A portion of the material was converted to the HC1 salt
and dried to yield a white solid.
m.p. - 105-110°C.
AnalySlS for C29H39N3~5'HCl:
Theory: C, 63.78; H, 7.38; N, 7.69
Found : C, 63.77; H, 7.47; N, 7.75
Example 68
Preparation of N-(carboxylmethyl)-2-[[3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-(phenyl-
methyl)-1-oxopropyl]amino]acetamide monohydrate. [Z-
NHCHZC(O)NHCH2C(O)OH~H20].
Procedure of Example 66 was followed with
the ester product from Example 67 (500 mg) and lithium
hydroxide (126 mg) in THF/H20/methanol (20 ml, 12:4:4).
The mixture was stirred four hours at room temperature
and 400 mg of material recovered. This material was
passed over a silica column eluting with a gradient of
ethyl acetate/methanol (v: v, 9:1) to methanol to provide
210 mg of solid product.
m.p. - 124.5-127°C.
ms (fd) = 482 M+
Analysis for CZ~H3sN3Os~H20:
Theory: C, 64.91; H, 7.47; N, 8.41
Found : C, 64.64; H, 7.28; N, 8.62
CA 02064373 1999-11-04
X-8244 -90-
Example 69
Preparation of N-[2-(dimethylamino)ethyl]-3-[4-
(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine]-2-
phenylmethylpropanamide dihydrochloride. [Z-NH(CHZ)2-
N(CH3)2~2HC1].
Procedure of Example 65 was followed with
product from the procedure of Example 4B (1 g), Dim-
ethylethylene Diamine (238 mg), Hobt (364 mg), dry DMF
(50 ml) and DCC (556 mg). After evaporating the
solvent, the residue was dissolved in a butanol/toluene
mixture (3:1) which was washed one time with water and
dried over KZC03. The solvent was evaporated to provide
1.94 g of crude material. This material was subjected
to column chromatography eluting with a gradient of
ethyl acetate/methanol (v: v, 9:1) to ethyl acetate/methanol
(v:v, 1:1). Removal of solvent provided 700 mg of
product.
ms (fd) - 437 M+, 438 M++1
This product was coverted to the di-hydrochloride salt
yielding a white solid.
m.p. - 89-93°C.
Analysis for C2~H3gN302~2HC1:
Theory: C, 63.52; H, 8.10; N, 8.23
Found . C, 63.32; H, 8.20; N, 8.42
Example 70
Preparation of 2-methylamine, 4-ethyl-oxadiazole
monohydrochloride.
CA 02064373 1999-11-04
X-8244 -91-
A. Sodium (9.2 g) was added to methanol (200
ml) to provide sodium methoxide. Hydroxylamine hydro-
chloride (26.2 g) was then added. Propionitrile (24.16
g) in methanol (50 ml) was added dropwise. The mixture
was then stirred for 48 hours at room temperature. The
solvent was removed and the solid was taken into ethyl
ether and filtered. The ether filtrate was removed and the
residue was passed through a silica column eluting with
ethyl acetate to provide 13 g of N-Hydroxy-propane-
inidamide [H3CCHZC(NHOH)NH2].
ms (fd) - 89 M+
B. Glycine ethyl ester hydrochloride (27.92
g) was combined with a mixture of water (382 ml) and
dioxane (700 ml) and 1N NaOH (380 ml). To this mixture
was added di-tert-butyldicarbonate (94 g) dropwise while
maintaining the reaction mixture at 0°-5°C. The mixture
was then stirred overnight at room temperature. Dioxane
was removed under vacuum and the remaining mixture
extracted with ethyl acetate. The organic layer was
recovered and dried over KZC03. The solvent was removed
to yield 40 g of material. Bulb to bulb distillation at
145°C under 0.05 mm Hg provided 20 g of di-tert-butyl-
dicarbonate-glycine ethyl ester as a colorless oil.
[ (CH3) 3COC (O) NHCHZC (O) OCHZCH3]
Analysis: (C9H1~N04)
Theory: C, 53.19; H, 8.43; N, 6.89
Found . C, 53.05; H, 8.12; N, 6.80
ms (fd) - 203 M+
CA 02064373 1999-11-04
X-8244 -g2-
C. To ethanol (20 ml) under a nitrogen
blanket was added sodium (436 mg) followed by powdered
molecular sieve (4 angstrom) (20 mg) and the oxime
from Example 70A. above (1.3 g). To this mixture was
added the product from Example 70B. above (3.26 g)
dropwise as a solution in ethanol (20 ml). The mixture
was then refluxed for 16 hours, filtered over"Celite"* and
the solvent removed. The resulting oil was partitioned
between methylene chloride and water. The organic layer
was dried over sodium sulfate. The solvent was removed
under vacuum to provide a yellow oil (3.0 g). This
material was passed through a silica column eluting with
ethyl acetate to provide 1.0 g of oxadiazole.
Analysis: C10H17N303
Theory: C, 53.32; H, 6.71; N, 18.66
Found . C, 52.12; H, 7.59; N, 18.99
ms (fd) - 228 M++1
To 900 mg of the oxadiazole were added dioxane
(60 ml) and 1N HC1 (70 ml). The mixture was allowed to
stir for two hours at room temperature. Water was
removed under vacuum. Acetonitrile (100 ml) was added
and solvent removed under vacuum. The product was
recrystallized from acetonitrile to afford 430 mg of
solid product.
* Trademark
2064373
X-8244 -93-
O
N/ CH2NH2 ~ HCI
CH.~CHz
m.p. - 158-161°C
ms (fd) = 127 M+
Analysis for CSH9N30~HCl
Theory: C, 36.71; H, 6.16; N, 25.68
Found : C, 35.83; H, 5.84; N, 24.86
Example 71
Preparation of 3-[4-(3-hydroxyphenyl)-3,4-dimethyl-
1-piperidinyl]-2-(phenylmethyl)-N-[(3-ethyl-1,2,4-oxa-
diazol-5-yl)methyl]propanamide.
O-N
Z - NHCHZ
N CH2CH3
Carboxylic acid product from the procedure of
Example 4B (918 mg), amine~HC1 product from Example 70
C. (400 mg), Hobt (338 mg), TEA (253 mg), dry DMF (75
ml) and DCC (515 mg) were combined and stirred at room
temperature under nitrogen for three days. The mixture
was then evaporated under vacuum to dryness. The
residue dissolved in ethyl acetate, washed two times
with water and the solution dried over KZC03. The
liquid was evaporated under vacuum to provide 1.71 g of
material. This material was subjected to column
20643'3
X-8244 -g4-
chromatography eluting with a gradient of hexane/ethyl
acetate (1:1) to ethyl acetate to afford 710 mg of a
viscous oil. This product was converted to HC1 salt.
ms (fd) = 476 M+, 477 M++1
m.p. - 103-107°C.
Analysis for C28H3sN403~HC1:
Theory: C, 65.55; H, 7.27; N, 10.92
Found : C, 65.26; H, 7.15; N, 10.70
Example 72
Preparation of 2-(2-Aminoacetyl)(amino)-N-
(Phenylmethyl)-acetamide. [H2NCHZC(O)NHCH2C(O)NHCHZ-
(CsHs]~
A. The procedure of Example 65 was followed
with t-butoxycarbonyl glycine (3 g), benzylamine (1.82 g),
Hobt (2.30 g) and DCC (3.50 g) to provide 5.16 g of
solid product. t-butoxycarbonyl-2-Amino-N-(Phenyl-
methyl)-acetamide[(CH3)3COC(O)-NH-CHZ-C(O)-NH-CH2-CsHs].
B. The product from 72A above (5.16 g) was
combined with 6N HC1 (200 ml) and stirred overnight at
room temperature. The mixture was then diluted with
water (200 ml) and the pH adjusted to 11.5 with NaOH
(50%) and ice, This mixture was extracted with a
mixture of butanol and toluene (3:1). The organic
layer was backwashed one time with water dried over
K2C03 and evaporated under vacuum to provide 2.1 g of
solid material. This material was subjected to column
chromatography eluting with a gradient of ethyl
CA 02064373 1999-11-04
X-8244 -95-
acetate/methanol (v: v, 9:1) to ethyl acetate/methanol
(v: v, 1:1). 1.60 g of product was recovered. 2-Amino-
N-(Phenylmethyl)-Acetamide[H2NCHZC(O)NHCHZC6H5].
ms (fd) - 164 M+
C. Product from 72B above (1.5 g), t-butoxy-
carbonyl glycine (1.59 g), Hobt (1.85 g) and dry DMF (75
ml) were combined followed by DCC (1.22 g). The mixture
was stirred under nitrogen at room temperature for three
days. The resulting mixture was filtered and evaporated
to dryness. The residue was dissolved in ethyl acetate,
filtered and dried over K2C03. The solvent was evapo-
rated to provide 8.14 g of butoxycarbonyl-2-(2-aminoacetyl)-
(amino)-N-(Phenylmethyl)-acetamide[(CH3)COC(O)NHCHZC(O)-
NHCHZC(O)NHCHZC6H5].
D. Product from 72C above (8.14 g) was
combined with 6N HC1 (150 ml) using the procedure of
Example 72B to provide 2 g of product. This material
was subjected to column chromatography eluting with a
gradient of ethyl acetate to ethyl acetate/methanol
(1:1) providing 700 mg of crystalline product.
[HZNCH2C(O)NHCHZC(O)NHCHZC6H5].
m.p. - 113-116°C.
ms (fd) - 201 M+
Example 73
Preparation of X-NH-CHZC(0)-NH-CHZC6H5.
Carboxylic acid product of the procedure of
Example 4B (886 mg), amine product from Example 72 D
(700 mg), Hobt (405 mg) and dry DMF (50 ml) were combined
2~643~3
X-8244 -96-
and then DCC (618 mg) was added. This mixture was
stirred 72 hours at room temperature, filtered and
evaporated under vacuum to provide 2.0 g of material.
This material was subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1) providing 860 mg of product.
ms (fd) = 570 M+, 571 M++1
This product was converted to the HC1 salt.
m.p. - 119-122°C.
Analysis Cg4H42N4~4~HC1:
Theory: C, 67.26; H, 7.14; N, 9.23
Found : C, 67.48; H, 7.07; N, 9.12
Example 74
Preparation of NH2CH2C(O)N(CH3)CH2C(O)OCH2CH3~HC1.
A. t-butoxycarbonyl glycine (3 g), Sarcosine
Ethyl Ester~HC1 (2.61 g), TEA (1.72 g), Hobt (2.30 g)
and DMF (125 ml) were combined and DCC (3.5 g) was
added. This mixture was stirred for 72 hours at room
temperature, filtered and evaporated to dryness under
vacuum. 8.1 g of material was recovered. This was
passed through a silica column eluting with a gradient
of ethyl acetate to ethyl acetate/methanol (1:1) pro-
viding 2.9 g. of product [(CH3)30C(O)NHCH2C(O)N(CH3)-
CH2C(O)OCH2CH3].
ms (fd) = 274 M+, 275 M++1
B. The product from Example 74A (2.90 g),
1N HC1 (50 ml), and ethyl acetate (ZO ml) were combined
and stirred at room temperature for three hours. The
20~43'~~
X-8244 -97-
mixture was evaporated to dryness. The residue
triturated in acetonitrile and ethyl ether. The solid
which formed was filtered to provide 900 mg of the HC1
salt. [HZNCHZC(O)N(CH3)CHZC(O)OCHZCH3~HC1].
ms (fd) = 174 M+
Example 75
Preparation of X-N(CH3)CH2C(O)OCH2CH3.
Carboxylic acid product from the procedure of
Example 4B (Z-OH) (1.15 g), product from Example 74B
(900 mg), TEA (434 mg), Hobt (580 mg) and dry DMF (50
ml) were combined followed by the addition of DCC (886
mg). The mixture was stirred for three days at room
temperature under nitrogen. The mixture was filtered
and evaporated to dryness. The residue was dissolved in
ethyl acetate, washed one time with water, dried over
K2C03 and the solvent evaporated to provide 2.47 g of
material. This was subjected to column chromatography
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 9:1) providing 1.7 g of material.
This was again passed through a silica column eluting
with ethyl acetate to provide 150 mgs of semi-solid
material.
ms (fd) = 523 M+, 524 M++1
The material was converted to HC1 salt to yield 100 mgs
a white powder.
m.p. = 104-107°C
CA 02064373 1999-11-04
X-8244 -98-
Analysis for CgOH41N3~5'HC1:
Theory: C, 64.33; H, 7.56; N, 7.50
Found . C, 64.61; H, 7.55; N, 7.27
Example 76
Preparation of HZNCH2C(O)NHCHZC(O)NHCHZCH3.
A. t-butoxycarbonyl glycine (3 g), ethyl-
amine~HC1 (1.39 g), TEA (1.72 g), Hobt (2.3 g) and
dry DMF (100 ml) were combined and DCC (3.5 g) was
added. The mixture was stirred for three days at room
temperature under nitrogen, then filtered and evaporated
to dryness. 6 g of material was recovered. This
material was subjected to column chromatography eluting
with a gradient of ethyl acetate to ethyl acetate/methanol
(1:1) providing 4.01 g of (CH3)3COC(O)NHCHZC(O)NHCHZCH3.
ms (fd) - 202 M+
B. Product from 76A above (4 g) and 6N HC1
(150 ml) were mixed and stirred overnight at room
temperature. Acetonitrile was added and the solution
was evaporated to dryness. The resulting solid was
slurried in ethyl ether, filtered and dried to provide
1.84 g. of H2NCHZC(O)NHCH2CH3~HC1.
ms (fd) - 102 M+
C. The product from 76B above (1.80 g),
t-butoxycarbonyl glycine (2.28 g), TEA (1.31 g), Hobt (1.76 g)
and dry DMF (150 ml) were combined and DCC (2.68 g) was
added. The mixture was stirred for three days at room
temperature under nitrogen, filtered and evaporated to
CA 02064373 1999-11-04
X-8244 -99-
dryness. The residue was dissolved in ethyl acetate
which was washed one time with water, dried over KZC03
and evaporated to provide 2.15 g of material. This
material was subjected to column chromatography eluting
with a gradient of ethyl acetate/methanol (v:v, 9:1) to
ethyl acetate/methanol (v:v, 1:1) providing 920 mg of
(CH3) 3COC (O) -NFiCH2C (O) NHCHZC (O) NHCH2CH3.
ms (fd) - 259 M+
D. The product from 76C above (900 mg) and
6N HCl (40 ml) were combined as in Example 74 B to
provide 700 mg of product as the HC1 salt.
ms (fd) - 160 M+
Example 77
Preparation of X-NHCHZC(O)NHCHZC(O)NHCHZCH3.
The procedure of Example 76A was followed
with the carboxylic acid prepared from the procedure of
Example 4B (Z-OH) (774 mg), amine~HC1 product from
Example 76 D (458 mg), TEA (293 mg), Hobt (391 mg),
dry DMF (50 ml) and DCC (597 mg). 1.74 g of material
was recovered. This material was subjected to column
chromatography eluting with a gradient of ethyl acetate
to ethyl acetate/methanol (1:1) providing 510 mg of
product.
ms (fd) - 508 M+, 509 M++1
This product was converted to HC1 salt to provide 400 mg
of solid.
m.p. - 110-115°C
2064373
X-8244 -100-
Analysis for C2gH4pN404'HC1:
Theory: C, 63.90; H, 7.58; N, 10.28
Found : C, 64.16; H, 7.29; N, 10.06
In Examples 78 thru 82, W is
OCH3
~,,.CH3
'%.,H H3 O
C _
~CH2 - CH/
~CH2--
Example 78
Preparation of W-OCHZCH3.
A. Trans-(+), 1,3,4-trimethyl-4-(3-methoxy-
phenyl)piperidine (3.48 g) vinyl Ghloroformate (2.73 ml)
and proton sponge (7.13 g) were mixed in 1, 2-
dichloroethane (150 ml), refluxed for 2 hours, cooled
to room temperature and evaporated to dryness. The
resulting residue was dissolved in ethyl ether, washed
two times with cold 1 N HC1, one time with water, dried
over KZC03, and evaporated to dryness to provide 4.51 g
of the carbamate product. The carbamate was mixed with
ethanol (100 ml) an,d ethanol/gaseous HC1 (100 ml) and
refluxed for 1.5 hours. The mixture was cooled to room
temperature and evaporated to dryness. The residue was
dissolved in 1 N NaOH and ethyl ether added. The ether
layer was separated, washed with water, dried over
CA 02064373 1999-11-04
X-8244 -101-
K2C03 and evaporated to provide 3.0 grams of material.
This was vacuum distilled in a bulb-to-bulb distillation
apparatus at 220°C and 0.1 mmHg to provide 2.86 g of
traps-3,4-dimethyl-4-(3-methoxyphenyl)-piperidine.
B. The product from 78A above (2.86 g) and 3-phenyl-
2-(ethoxycarbonyl)-1-propene prepared as in Example
2 (2.72 g) and methanol (50 ml) were mixed and stirred
at room temperature under nitrogen for 10 days. The
mixture was evaporated 2 times and rediluted with
methanol on day 5 and day 9. On day 10 the mixture was
evaporated to dryness to provide 5.46 g of material
which was subjected to column chromatography eluting
with a gradient of hexane to ethyl acetate. Removal of
solvent provided 4.05 g of product.
ms (fd) - 409 M+, 410 M++1
A portion of the product was converted to the HC1 salt.
m.p. - 61°-64°C
Analysis for C26H35N03~HC1:
Theory: C, 70.01; H, 8.13; N, 3.14
Found . C, 70.00; H, 8.02; N 3.17
Example 79
Preparation of W-OH.
The method of Example 12 was followed with
W-OCHZCH3 prepared as in Example 78B (2.03 g) and
lithium hydroxide (6.29 mg) in THF/H20/methanol (63:21:21).
Evaporation of the solvent yielded 1.82 grams of cry-
2064373
X-8244 -102-
stalline material as the HCl salt. This material was
recrystallized from acetonitrile to provide 610 mg of
crystalline product.
ms (fd) = 481 M+
m.p. = 196.5°-198°C
Analysis C24H31N03~HC1:
Theory: C, 68.77; H, 7.72; N, 3.35; C1, 8.48
Found : C, 68.84; H, 7.79; N, 3.33; C1 8.49
Example 80
Preparation of W-NHCH3.
W-OCH2CH3 prepared by the procedure of Example
78B (700 mg) and methylamine (25 ml 40% weight percent
in water), were mixed and stirred at 50°C for 4 days.
The reaction mixture was evaporated to dryness and the
residue was partitioned between a butanol-toluene (3:1)
mixture and water. The pH of the water was adjusted to
9.8 with IN NaOH and layers were separated. The organic
layer was washed one time with water and dried over
KZC03 and evaporated to provide 600 mg of material.
This material was subjected to column chromatography
eluting with a gradient of hexane/ethyl acetate (9:1) to
ethyl acetate providing 140 mg of product.
ms (fd) = 396 M+
This product was converted to the HC1 salt and dried to
provide 110 mg of solid.
m.p. - 86°-90°C
20643'73
X-8244 -103-
AnalySlS fOr C25H34N2~2~HC1:
Theory: G, 69.67; H, 8.18; N, 6.50
Found : C, 69.91; H, 8.35; N, 6.33
Example 81
Preparation of W-NHCH2C(O)OCHZCH3.
W-OH prepared as in Example 79 (4.15 g),
glycine ethyl ester~HC1 (1.40 g), TEA (1.01 g), Hobt
(1.35 g) and dry DMF (300 ml) were combined and DCC
(2.06 g) was then added. The mixture was stirred at
room temperature under nitrogen for 3 days, filtered and
evaporated to dryness. The residue was dissolved in
ethyl acetate, washed with water, dried over KZC03 and
evaporated under vacuum to provide 5.65 g of material.
This material was subjected to column chromatography
eluting with a gradient of hexane/ ethyl acetate (9:1)
to ethyl acetate providing 3.40 g of product.
ms (fd) = 466 M+
2 g of this material were converted to the HCl salt and
dried to provide 2.13 g of white solid.
m.p. - 122°-126°C
Analysis for CZ$H3gNZO4~HCl
Theory: C, 66.85; H, 7.81; N, 5.57
Found : C, 67.11; H, 7.99; N, 5.61
20~43'~~
X-8244 -104-
Example 82
Preparation of W-NHCHZC(O)NHCH3.
The procedure of Example 80 was followed with
W-NH~CHZC(O)OCH2CH3 prepared as in Example 81 (600 mg)
and methylamine (25 ml, 40 wt % in water) for 2 hours at
room temperature. 580 mg of product was recovered.
This was passed over a silica column eluting with ethyl
acetate to provide 350 mg of material.
ms (fd) = 451 M+
This was converted to the HC1 salt and dried to provide
380 mg of a white solid.
m.p. - 101°-106°C
Analysis for C2~Hg7NgOg~HC1:
Theory: C, 66.44; H, 7.85; N, 8.61
Found : C, 66.25; H, 7.90; N, 8.58
Example 83
Preparation of W-NHCHZC(O)NHCH2CH3.
The procedure of Examgle 80 was followed with
W-NHCH2C(O)OCHZCH3 prepared as in Example 81 (600 mg)
and ethylamine (25 ml, 70 wt % in water stirring for two
hours at room temperature. 610 mg of material were
recovered. This material was passed over a silica
column eluting with ethyl acetate to provide 400 mg of
product.
ms (fd) = 465 M+
This product was converted to the HC1 salt and dried to
provide 425 mg of white solid.
CA 02064373 1999-11-04
X-8244 -105-
m.p. - 103°-108°C
Analysis for CZ$H39N303~HC1:
Theory: C, 66.98; H, 8.03; N, 8.37
Found . C, 66.71; H, 8.11; N, 8.38
Example 84
A. Preparation of N,N-dimethyl-2-hydroxyacetamide
Methyl-2-hydroxyethanoate (10 g) and dimethyl-
amine (100 ml, 40 weight percent in water) were mixed
and stirred at room temperature for three hours. The
mixture was evaporated to dryness to provide approximately
10 g of material. This material was subjected to column
chromatography eluting with a gradient of hexane/ethyl
acetate (V:V, 4:1) to ethyl acetate. Removal of the
solvent provided 8.12 g of crystalline product.
ms (fd) - 103 M+
m.p. - 40°-42°C
I.R. - 1655.4 cm 1 (carbonyl)
Analysis for C4H9N02:
Theory: C, 46.59; H, 8.80; N, 13.59
Found . C, 46.44; H, 8.69; N, 13.60
B. Preparation of N-methyl-2-hydroxyacetamide
The procedure of 84A was followed using
methylamine (100 ml, 40 weight percent in water) as the
amine. 10.2 g of material was obtained which was
slurried in toluene and evaporated to remove water.
2064373
X-8244 -106-
This material was passed over a silica column eluting
with ethyl acetate to provide 7.13 g of solid product.
m.p. - 66.5°-68°C
ms (fd) = 89 M+
Analysis for C3H~N02:
Theory: C, 40.44; H, 7.92; N, 15.72
Found : C, 40.36; H, 7.75; N, 15.54
C. Preparation of N-ethyl-2-hydroxyacetamide
The procedure of 84A was followed with ethyl-
amine (100 ml, 70 weight percent in water) as the amine
to provide 11.26 g of an oil. This material was passed
over a silica column eluting with ethyl acetate. 7.2 g
of product was recovered as white crystals.
m.p. - 79°-82°C
ms (fd) = 103 M+
Analysis for C4H9N02:
Theory: C, 46.59; H, 8.80; N, 13.58
Found : C, 46.86; H, 8.41; N, 14.00
D. Preparation of 2-hydroxyacetamide
The procedure of 84A was followed using
ammanium hydroxide (100 ml, 28% in H20) to provide 10.3
g of crystalline material. This material was recrystal-
lized from ethyl acetate/ethanol (v: v, 4:1) to provide
6.0 g of white crystal product.
m.p. - 111°-112.5°C
ms (fd) = 75 M+
2064~'~~
X-8244 -107-
Analysis for C2HSNO2:
Theory: C, 32.00; H, 6.71; N, 18.66
Found : C, 32.02; H, 6.49; N, 18.43
E. Preparation of N-benzyl-2-hydroxy-
acetamide
The procedure of 84A was followed with methyl-
2-hydroxyethanoate (8 g) and benzylamine (10 ml in 30
ml H2o). After one hour material precipitated out of
solution. The mixture was stirred overnight, and the
solid recovered by filtration to provide 4.12 g of
white solid. The solvent was removed from the filtrate
by vacuum to provide 4.71 g of material. The solid and
filtrate were combined and passed over a silica column
eluting with a gradient of ethyl acetate to ethyl
acetate/methanol (v: v, 1:1). Removal of solvent provided
8 g of white crystal product.
m.p. = 101°-102°C
ms (fd) = 165 M+ ,
I.R. = 1634,88 cm 1 (carbonyl)
Analysis for C9H11N02:
Theory: C, 65.44; H, 6.71; N, 8.48
Found : C, 65.39; H, 6.83; N, 8.62
In Examples 85 through 95, X represents Z-
NHCH2C(O)- where Z is as set forth for Example 73.
~U(~4~~1~
X-8244 -108-
Example 85
Preparation of X-OCHZC(O)OCH3.
The carboxylic acid X-OH prepared as in
Example 44 (1.5 g), methyl glycolate (315 mg), Hobt (473
mg) and dry DMF (125 ml) were combined and DCC (721 mg)
was then added. The mixture was stirred at room temperature
under nitrogen for 24 hours. The mixture was filtered
and evaporated under vacuum to dryness. The residue was
dissolved in ethyl acetate which was washed once with
water, dried over K2C03 and evaporated under vacuum to
provide 1.86 g of an orange semi-solid material. This
material was subjected to column chromatography eluting
with a gradient of hexane/ethyl acetate (v:v, 9:1) to
ethyl acetate. Removal of the solid provided 1.41 g of
an orange material which was then passed over a chromatron
using 4000 micron plate and eluting with hexane/ethyl
acetate (1:1) to provide 980 mg of material.
ms (fd) = 497 M+
This material was converted to the HC1 salt and dried to
provide 770 mg of tan solid.
m.p. = 98°-104°C
Analysis for CZ$H36N206~HCl:
Theory: C, 63.09; H, 7.00; N, 5.26
Found : C, 62.81; H, 7.08; N, 4.97
20643?3
x-x244 -l09-
Example 86
Preparation of X-O(CH2)4CH3.
The carboxylic acid X-OH prepared as in
Example 44 (500 mg), amyl alcohol (20 ml) and amyl
alcohol saturated with gaseous HCl gas (20 ml) were
combined and refluxed under nitrogen for 1.5 hours. The
mixture was then evaporated to dryness and the residue
partitioned between ethyl acetate and water. The pH of
the water layer was adjusted to 9.8 with 1N NaOH. The
layers were separated and the ethyl acetate layer washed
one time with water, dried over K~C03 and evaporated to
provide 660 mg of a viscous oil. This material was
subjected to column chromatography eluting with a ,
gradient of hexane/ethyl acetate (v:v, 9:1) to hexane/ethyl
acetate (v:v, I:1). Removal of solvent provided 400 mg
of a white foam.
ms (fd) = 494 M+, 495 M++1
This material was converted to the HC1 salt and dried
to provide 300 mg of white solid.
m.p. - 75-81°C
Analysis for C3oH~2N204~HC1:
Theory: C, 66.71; H, 8.21; N, 5.19
Found : C, 66.44; H, 8.07; N, 5.35
2b643"~3
X-8244 -110-
Example 87
Preparation of X-O-CH2C(O)NH2.
The procedure of Example 85 was followed with
X-OH prepared as in Example 44 (500 mg), 2-hydroxy-
acetamide (90 mg), Hobt (162 mg), dry DMF (50 ml) and
DCC (247 mg) to provide 660 mg of an orange oil. This
material was passed over a silica column eluting with
ethyl acetate providing 310 mg of a white foam. This
material was passed over a chromatron using 2000
micron plate and eluting with ethyl acetate to provide
260 mg of product.
ms (fd) = 482.4 M++1
This was converted to the HC1 salt and dried to provide
a white solid.
m.p. - 111°-116°C
Analysis for: C2~H35N305~HCl:
Theory: C, 62.60; H, 7.00; N, 8.11
Found : C, 62.61; H, 6.97; N, 7.71
Example 88
Preparation of X-OCH2C(O)NHCH3.
The procedure of Example 85 was followed with
X-OH prepared as in Example 44 (500 mg), N-methyl-2-
hydroxyacetamide (107 mg), Hobt (162 mg), DMF (500 ml),
and DCC (247 mg) to provide 890 mg of an oil. This
material was passed over a silica column eluting with
ethyl acetate with 400 mg of material recovered. This
CA 02064373 1999-11-04
X-8244 -111-
was passed over a chromatron using 2000 micron plate and
eluting with ethyl acetate to provide 260 mg of a white
solid.
ms (fd) - 497 M++1
This material was converted to the HCl salt and dried to
provide 218 mg of a tan solid.
m.p. - 114°-118°C
Analysis for C28H3~N305~HC1:
Theory: C, 63.21; H, 7.20; N, 7.90
Found . C, 62.90; H, 7.15; N, 7.50
Example 89
Preparation of X-OCH2C(O)NHCHZCH3.
The procedure of Example 85 was followed with
X-OH prepared as in Example 44 (530 mg), N-ethyl-2-
hydroxyacetamide (134 mg), Hobt (176 mg), dry DMF (50
ml), and DCC (268 mg) to provide 810 mg of a viscous oil.
This was passed over a silica column eluting with ethyl
acetate with 400 mg of a white foam recovered. This was
passed over a chromatron with a 2000 micron plate
eluting with ethyl acetate to provide 300 mg of product.
ms (fd) - 510 M++1
This material was converted to the HC1 salt and dried at
60°C to provide a white solid.
m.p. - 109°-113°C
Analysis for C29H39N305~HC1:
Theory: C, 63.78; H, 7.38; N, 7.69
Found . C, 63.38; H, 7.32; N, 7.47
20643'~~
X-8244 -112-
Examvple 90
Preparation of X-OCHZC(O)N(CH3)2.
The procedure of Example 85 was followed with
X-OH prepared as in Example 44 (500 mg), N,N-dimethyl-
2-hydroxyacetamide (124 mg), Hobt (162 mg), dry DMF (50
ml), and DCC (247 mg) to provide 615 mg of an orange
semi-solid materia. This was passed over a silica
column eluting with ethyl acetate to provide 260 mg of
an orange foam. This was passed over a chromatron with
a 2000 micro plate eluting with ethyl acetate to provide
230 mg of a white foam.
ms (fd) = 509 M+, 510 M++1
This material was converted to the HC1 salt and dried at
60°C to yield 220 mgs of white solid.
m.p. - 124°-130°C
Analysis for C2gH3gN305~HCl~~Zi320:
Theory: C, 62.74; H, 7.38; N, 7.57
Found : C, 62.78; H, 7.53; N, 7.69
Example 91
Preparation of X-NHCHZ(C6Hli)~
The procedure of Example 85 was followed with
X-OH prepared as in Example 44 (500 mg), N-cyclohexyl-
methylene-2-hydroxyacetamide (205 mg), Hobt (162 mg),
20643'3
X-8244 -113-
dry DMF (40 ml), and DCC (247 mg) to provide 715 mg of
pale orange foam. This material was passed over a
silica column eluting with ethyl acetate to provide
600 mg of material which was then passed over a
chromatron using a 2000 micron plate eluting with ethyl
acetate to provide 170 mg of product.
ms (fd) = 519 M+, 520 M++1
This material was converted to HC1 salt and dried at
60°C for two hours to provide a white solid.
m.p. - 136°-140°C
Analysis for C32H45N303~HCl:
Theory: C, 69.11; H, 8.34; N, 7.56
Found : C, 68.83; H, 8.38; N, 7.81
Example 92
Preparation of X-O-(4-methoxycyclohexyl)~-
hydrochloride.
X-OH prepared as in Example 44 (424 mg),
KZC03 (1.83 g), CIS-4-methoxycylohexyl-p-toluen-
sulfonate (1.52 g) were combined in dry DMF (70 ml) and
the mixture heated under nitrogen for 20h at reflux.
The mixture was cooled, filtered, and evaporated under
vacuum to yield 640 mgs. This material was subjected to
column chromatography eluting with a gradient of
hexane/ethyl acetate (v: v, 1:1) to ethyl acetate.
Removal of the solvent provided 370 mg of a viscous oil.
ms (fd) = 537 M++1
2064373
X-8244 -114-
This material was converted to the HC1 salt and dried at
60°C to provide 300 mg of a white solid.
m.p. - 116°-119°C
Analysis for Cg2H44N2Og~HCl:
Theory: C, 67.06; H, 7.91; N, 4.89
Found : C, 66.80; H, 7.82; N, 4.87
Example 93
Preparation of X-OCH2C(O)NHCHZ(CsHs)~hydrochloride~
monohydrate.
X-OH prepared as in Example 44 (500 mg),
N-benzyl-2-hydroxyacetamide (198 mg), Hobt (162 mg), dry
DMF (40 ml) and DCC (247 mg) were combined as in Example
85 to provide 910 mg of a tan oil. This material was
passed over a silica column eluting with ethyl acetate
with 415 mg of an orange foam recovered. This material
was passed over a chromatron using a 2000 micron plate
and eluting with ethyl acetate to provide 160 mg of
material.
ms (fd) = 571 M+, 572 M++1
This material was converted to HC1 salt and dried at
60° to yield a white solid.
m.p. - 115°-120°C
Analysis for C3~H41N3Os~HC1~H20:
Theory: C, 65.21; H, 7.08; N, 6.71
Found : C, 65.23; H, 7.29; N, 6.71
X-8244 -115-
Example 94
Preparation of X-OCH(CH3)OC(O)CH3~hydrochloride.
XOH prepared as in Example 44 (463 mg) and
KZC03 (1.83 g) were heated at 70°C for ten minutes. The
mixture was then cooled to room temperature and 1-
bromoethylacetate (894 mg) in DMf (20 ml) was added
dropwise at room temperature. After stirring one hour
at room temperature, the solution was filtered and
evaporated. The residue was partitioned between ethyl
acetate and water with the water layer pH adjusted to
9.8 with 1N NaOH. The layers were separated and the
ethyl acetate layer washed one time with water, dried
over KZC03 and evaporated to provide 620 mg of a dark
oil. This material was passed over a silica column
eluting with a gradient of hexane/ethyl acetate (v: v,
1:1) to ethyl acetate. Removal of solvent provided 330
mg of a dark oil which was placed over the chromatron
using a 2 mm plate and eluting with a gradient of
hexane/ethyl acetate (v:v, 1:1) to ethyl acetate. The
resulting solution was stirred over decolorizing
charcoal and the solvent removed to provide 200 mg of a
tan oil having a mass spec of 511 (M+ + 1). This
product was converted to HC1 salt and dried at 60°C to
provide 190 mg of a tan solid.
m.p. - 94°-98°C (with decomposition)
CA 02064373 1999-11-04
X-8244 -116-
Analysis for C29H38N206~HC1:
Theory: C, 63.67; H, 7.19; N, 5.12
Found . C, 63.65; H, 7.32; N, 5.15
Example 95
Preparation of X-OCHZ ~ ~ ~HC1~H20.
HC
3
XOH prepared as in Example 44 (636 mg) and
KZC03 (1.89 g) were combined and cooled to 0°C under a
nitrogen atmosphere. 4-bromomethyl-5-methyl-1,3-dioxol-
2-one (1.07 g) in dry methylene chloride (20 ml) was
added dropwise. The mixture was allowed to warm to room
temperature and stirred for one hour. The mixture was
filtered and evaporated to dryness to provide 1.0 g of a
dark oil. This was subjected to column chromatography
eluting with a gradient of hexane/ethyl acetate (1:1) to
ethyl acetate/methanol (v:v, 9:1). The removal of
solvent provided 300 mg of a tan oil.
ms (fd) - 537 M++1
A portion of this product was converted to HC1 salt and
dried at 60°C to provide a white solid.
m.p. - 72°-75°C
20643'3
X-8244 -117-
Analysis for C3oH3sN20?~HC1~H20:
Theory: C, 60.95; H, 6.65; N, 4.74
Found : C, 60.84; H, 6.47; N, 4.82
Example 96
Preparation of sec-butyl-2-aminoaceate~para-tosylate
Glycine (7.51 g), paratoluenesulfonic acid
(20.92 g), isobutyanol (20 ml) and toluene (200 ml) were
combined and refluxed for five hours with a Dean Stark
trap. The reaction mixture was cooled and evaporated
to dryness to provide 28.13 g of crystalline product.
The crystalline product was recrystallized from hexane/ethyl
acetate (v: v, 4:1) to provide 27.12 g of white crystals.
m.p. - 73°-74°C
ms (fd) = 132 (free base) = M+
I.R. = 1738.9 cm 1 (carbonyl)
Analysis for CsH13N20~p-tosylate
Theory: C, 51.47; H, 6.98; N, 4.62
Found : C, 51.56; H, 6.96; N, 4.59
Example 97
Preparation of (+)(3R,4R)-traps-[[2-[[4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-
phenylpropyl)amino]acetic acid monohydrate [(+)X-OH~H20
of Example 85].
A. Preparation of (+)-traps-(3R,4R)-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-phenyl-
methylpropanoic acid, ethyl ester.
2~6~3~3
X-8244 -118-
The procedure of Example 4A was followed with
(+)-trans-(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-
piperidine (4.4 g, 20 mmole) and 2-ethoxycarbonyl-3-
phenylpropene (4.5 g) in methanol (225 ml). The
reactants were stirred at room temperature under nitrogen
for ten days with the reaction mixture then evaporated
to dryness to provide 8.8 g of a viscous oil. This
material was passed through a Prep-500 liquid chromato-
graphy eluting with a gradient of hexane to 10% ethyl
acetate/hexane. 8.0 g of a white foam was recovered.
ms (fd) = 395 M+
B. Preparation of (+)-trans-(3R,4R)-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-phenylmethyl
propanoic acid. [(+)-Z-OH].
The product from 97A above (6 g, 15 mmole)
and lithium hydroxide (1.89 g) were combined in a
mixture of THF/methanol/water (192 ml/64 ml/64 ml) and
stirred at room temperature for three hours. The
mixture was then poured into 1N HC1 and stirred for
five minutes. The aqueous solution was then adjusted
to a pH of 9.8 with triethylamine and extracted with n-
butanol/tolune (3:1). The organic layer was dried over
MgS04 and evaporated to provide 7.14 g of a white foam.
This material was subjected to column chromatography
eluting with a gradient of ethyl acetate/methanol (9:1)
to ethyl acetate/methanol (1:1). Removal of solvent
provided 3.98 g of a white powder.
ms (fd) = 367 M+, 368 M++1
2~643'~3
X-8244 -119-
C. Preparation of (+)X-OCHZCH(CH3)z~
The carboxylic acid product (+)Z-OH from 97B
above (2.45 g, 6.7 mmole), the amine from Example 96
(1.82 g), triethylamine (604 mg), Hobt (806 mg), DCC
(1.23 g) were combined in dry DMF (180 ml) and stirred
at room temperature under nitrogen for 72 hours. The
mixture was then filtered and evaporated to dryness.
The residue was partitioned between ethyl acetate and
water. The pH of the water layer was adjusted to 9.8
with 1N NaOH and the layers were separated. The
organic layer was dried over K2C03 and then evaporated
to provide 3.21 g of an orange foam. This material was
passed over a silica column eluting with a gradient of
hexane/ethyl acetate (9:1) to ethyl acetate. The
removal of solvent provided 2.31 g of a white foam.
ms (fd) = 481 M+
D. Separation of diastereomers.
4.36 g of an isomeric mix prepared as in
Example 97C above was passed over a Prep-500 liquid
chromatograph using a gradient of hexane/triethylamine
(99:1) to hexane/ethyl acetate/triethylamine (75:24:1).
An 8 liter forerun was discarded and 300 ml fractions
were then collected.
Fractions 38-45 contained 99% of a first peak
by HPLC. Removal of solvent provided 580 mg of a white
foam (Diastereomer A). [(+)-(3R,4R)-X-OCHZCH(CH3)2]~
ms (fd) = 481 M+
[a]ass = +172.65°
2~~~373
X-8244 -120-
Analysis for C2gH4oN204:
Theory: C, 72.47; H, 8.39; N, 5.83
Found : C, 72.49; H, 8.59; N, 5.63
This was converted to the HC1 salt.
m.p. - 91°-95°C
Analysis for:
Theory: C, 67.36; H, 7.99; N, 5.42
Found: C, 67.06; H, 7.98; N, 5.30
Fractions 57-65 were analyzed to contain 85%
of a second peak by HPLC. Removal of solvent provided
490 mg of a solid material. Recrystallization from iso-
propyl ether provided 410 mg of crystalline product
(diastereomer B).
m.p. - 136°-136.5°C
ms (fd) = 481 M+
[a]ass = +153.03°
AnalySlS fOr: CZgH4pN204~
Theory: C, 72.47; H, 8.39; N, 5.83
Found : C, 72.42; H, 8.26; N, 6.04
E. Formation of title compound [(+)X-OH].
Diastereomer A prepared as in Example 97D
above (300 mg), dioxane (15 ml) and 6N HCl (15 ml) were
combined and refluxed for six hours. The mixture was
cooled to room temperature and evaporated to dryness.
The resulting solid was partitioned between water and
butanol/taluene (3:1). The water layer was adjusted to
a pH of 9.8 using triethylamine. The layers were
separated and the organic layer dried over MgS04 and
evaporated to dryness. The solid material was passed
CA 02064373 1999-11-04
X-8244 -121-
over a silica column eluting with a gradient of ethyl
acetate/methanol (9:1) to methanol. Evaporation of
solvent yielded 126 mgs of a white solid.
m.p. - 135°-138°C
ms (fd) - 424 M+, 425 M++1
AIISlySIS for C25H32DTZO4'H2O:
Theory: C, 67.87; H, 7.74; N, 6.32
Found . C, 67.49; H, 7.45; N, 5.97
Example 98
Preparation of (-)-(3S,4S)-trans-[[2-[(4-(3-
hydroxyphenyl)-3,4-dimethyl)-1-piperidinyl]methyl]-1-
oxo-3-phenylpropyl]amino]acetic acid [(-)X-OH of
Example 85].
A. Preparation of (-)-trans-(3S,4S)-3-
[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-
phenylmethyl-propanoic acid ethyl ester.
The procedure of Example 97A was followed
using (-)-trans (3S,4S)-4-(3-hydroxyphenyl)-3,4-
dimethylpiperidine (10 g, 48 mmole) and 2-ethoxy-
carbonyl-3-phenylpropene (10.2 g) in methanol (500 ml).
18.31 g of a tan viscous oil was recovered. This was
passed over a PREP-500 liquid chromatograph eluting
with a gradient of hexane to 10% ethyl acetate/hexane to
providing 17.40 g of a white foam.
ms (fd) = 395 M+
B. Preparation of (-)-(3S,4S)-3-[4-(3-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-
phenylmethyl-propanoic acid.
2064373
X-8244 -122-
The procedure of Example 97B was followed
with the product from Example 97A (12.5 g, 32 mmole),
lithium hydroxide (3.98 g) in THF/methanol/water (400
ml/130 ml/130 ml). 10.75 g of a tan foam was recovered.
This was subjected to column chromatography eluting
with a gradient of ethyl acetate/methanol (9:1) to ethyl
acetate/methanol (1:1). Removal of the solvent provided
8.97 g of a white powder.
ms (fd) = 368 M++1
C. Preparation of (-)-X-OCHZ-CH(CH3)2~
The procedure of Example 97C was followed
with the product from Example 98B (5.12 g, 14 mmole),
amine from Example 96 (4.54 g), triethylamine (1.5 g),
Hobt (2.0 g) DCC (3.04 g) in dry DMF (400 ml). 7.81 g
of an orange foam was recovered. This was passed over a
silica column eluting with a gradient of hexane/ethyl
acetate (9:1) to hexane/ethyl acetate (1:1). Removal of
the solvent provided 5.5 g of a white foam.
ms ( fd ) = 481 I~+
D. Separation of diastereomers.
The procedure of Example 97D was followed
using 4.20 g of the (-)-isomeric mix of Example 98C.
Fractions 33-40 showed 98% of a first peak by
HPLC. Removal of. solvent provided 435 mg of a white
foam (diastereomer A).
ms (fd) = 481 M+
~«lass = -172.11°
Analysis for C2gH40N2~4~
Theory: C, 72.47; H, 8.39; N, 5.83
Found : C, 72.31; H, 8.51; N, 5.66
206~37~
X-8244 -123-
Fractions 54-63 showed 88% of a second peak
by HPLC. Removal of solid provided 510 mg of
material. This was recrystallized from isopropyl ether
to provide 460 mg of a crystalline product. HPLC
showed 99% of this second peak (diastereomer B).
ms (fd) = 481 M+
[«)3ss = -153.95°
Analysis for C29H4oN2O4:
Theory: C, 72.47; H, 8.39; N, 5.83
Found : C, 72.67; H, 8.35; N, 5.88
E. Preparation of (-)X-OH.
The procedure of Example 97E was followed
with Diastereomer B from Example 98D (200 mg), dioxane
(10 ml) and 6N HC1 (10 ml) to provide 210 mg of material.
This was passed over a silica column eluting with a
gradient of ethyl acetate/methanol (9:1) to methanol.
Removal of the solvent provided 101 mg of product.
m.p. - 130°-133°C
ms (fd) = 421 M++1
[a) 365 (-115.16°)
Analysis for C25H32N2~4~H2~
Theory C 67.87 H 7.74 N 6.32
Found C 68.07 H 7.34 N 6.15
The instant compounds are useful in blocking
peripherial opioid receptors and preventing peripherally
opiate induced side effects. These side effects induced
by the administration of an opiate such as morphine to a
206433
X-8244 -124-
mammal can include constipation, nausea, and vomiting.
These compounds can also be useful in the treatment of
irritable bowel syndrome and idiopathic constipation.
While not wishing to be bound by the theory, it is
believed that the instant compounds act as opioid
antagonists and bind to peripherial opioid receptors
outside of the brain. The compounds do not substantially
pass through the blood-brain barrier and therefore do
not mitigate the opioid's effect on central (brain and
spinal cord) opioid receptors. Consequently, these
compounds should also be substantially free of other
centrally mediated effects.
In order to determine in vivo opioid receptor
antagonism, the mouse writhing analgesis test was used.
Test compounds were measured for their ability to block
morphine-induced analgesia.
Five CF-1 male mice (Charles River, Portage,
MI), weighing approximately 20 g after being fasted
overnight, were observed simultaneously for the
writhing response. The writhing response was defined
as a contraction of the abdominal musculature, followed
by the extension of the hind limbs, and was induced by
the intraperitoneal adminstration of 0.6% acetic acid
in a volumne of 1 ml/100 g body weight. The
observation period was 10 min. in duration, beginning
5 min. after injection of acetic acid. The percent
inhibition of writhing was calculated from the average
number of writhes in the control (non-drug) group.
Each data point is the mean (~ standard error) for five
mice. The EDso was defined as the dose of agonist that
206433
X-8244 -125-
inhibited mean writhing by 50%. The ADso was defined
as the dose of antagonist that reduced the inhibition
of writhing produced by a 1.25 mg/kg dose of morphine
sulfate to 50%. Each mouse was only used once. All
drugs were administered subcutaneously (1 ml/100 g bwt)
20 min. before the injection of acetic acid.
Determinations of peripheral opioid activity
were conducted. Mice maintained (6 mice/cage) on 0.01 M
saccharin water with 1 g/1 morphine sulfate for a
minimum of 10 days with mice averaging 3.0+ g
water/mouse/day for at least three days are used as
subjects. The morphine water was removed 45 min. prior
to injection with the proposed opioid antagonist.
Initial testing consisted of 5 mice/dose of compound.
The antagonist was given by the subcutaneous or oral,
route of administration, and the mice were placed in
11-14" x 4 7/12 I.D. clear plastic cylinders with white
paper towels used for a floor.
The mice were then monitored visually for 30
minutes post-injection for the presence of jumping and
of diarrhea. Jumping was scored as positive if at least
one jump occurred in 30 min. Diarrhea was scored as
positive when feces were moist enough to stain the white
paper at the base of the cylinder. After 30 minutes of
testing, the mice were placed back in original cages,
put back on morphine water, and not tested again for 48
hrs. Lower doses of the antagonist compounds were
20643'3
X-8244 -126-
tested until threshold doses for diarrhea were determined.
Diarrhea is a peripherally mediated sign of precipitated
opiate abstinence.
The extent of the effect on peripheral activity
compared to central activity of the present compounds
can be determined by comparing the ADsofor the mouse
writhing test with the EDso for the mouse diarrhea test.
The higher the ratio, the greater the relative antagonism
of the peripheral opioid receptors by a particular
compound. This ratio for each compound is provided in
Table I.
X-8244 -127-
TABLE I
Example No.(1~ ADsa~2~ EDso~3~ Ratio~4~
4A 1.08 0.012 9
4B 8.90 0.011 809
5A 1.2 0.06 20
5B 1.6 0.24 7
8A 0.70 0.02 35
8B 0.64 0.012 53
9B 1.50 0.02 75
10 0.54 0.06 9
11 2.4 0.017 141
12 40 0.015 2667
13 >40 0.32 >125
14 >40 0.92 >43
15 >40 0.30 >133
17 >40 0.06 >667
18 >40 0.045 >888
20 32.1 0.004 802
21 >20 0.16 >125
22 >40 0.08 >500
20643'3
X-8244 -128-
TABLE I Continued
Example No.~l) ADso~2~ EDsot3~ Ratio~4j
23 >20 0.14 >140
24 >40 0.10 >400
25 11.5 0.29 40
26 7.5 0.03 250
27 15.3 0.30 51
28 >40 0.01 >4000
29 3.9 0.17 23
30 >40 0.017 >2353
31 5.3 0.14 38
32 7.3 0.16 45
33 10.2 0.17 60
34 15.1 0.18 84
35 40 0.06 667
36 3.8 0.32 12
37 3.9 0.09 43
38 >40 0.06 >667
39 11.9 0.66 18
2064~'~3
X-8244 -129-
TABLE I Continued
Example No.~l~ ADso~2) EDso~3~ Ratio~4~
40 4.5 1.30 3.5
41 4.5 0.17 26
42 2.1 0.26 8
43 1.9 0.013 146
44 >40 0.15 >266
45 2.6 0.24 11
46 40 0.07 571
47 40 0.15 267
48 >40 0.10 >400
49 6.08 0.10 61
50 14.3 0.54 26
51 3.8 0.15 25
52 8 0.20 40
53 >40 1.70 >23
54 23 0.02 1150
55 7.5 0.12 63
56 40 0.06 667
57 >40 0.10 >400
2064~'~3
X-8244 -130-
TABDE I Continued
Example No.~l~ ADSO~2~ ED5ot3~ Ratio~4~
59 5.9 0.54 11
60 11.2 0.10 112
61 3.3 0.05 66
62 18.3 0.15 122
63 26 0.29 90
64 >40 0.90 >45
65 2.8 0.92 3
66 14.0 <3.0 <4.7
67 5.5 O.I5 36
68 >40 0.23 >174
69 30 1.70 51
71 2.1 0.19 11
73 20 1.73 11
75 5.2 0.073 71
77 >40 1.31 >31
78B 1.6 0.055 29
79 1.7 0.13 13
80 3.9 0.16 24
206~~'~~
X-8244 -131-
TABLE I Continued
Example No.~l) ADso~2) EDso~3) Ratiot4)
81 13.2 3.28 4
82 .95 0.055 17
83 0.71 0.04 2
85 9.5 0.05 190
86 >40 0.017 >2353
87 19 0.71 27
88 13.5 0.07 193
89 6.0 >10 <1
90 2.2 0.1 22
91 4.0 0.5 8
92 7.7 .005 1540
93 29.0 .008 3625
94 20 .009 2222
95 2.7 0.19 14
97D* 12.7 0.04 317
97D** 32 0.6 53
97E 8.9*** 0.07*** 127
98D* 2.9 0.76 4
98D** 15.3 0.06 255
98E 6.2*** 0.10*** 62
2os437~
X-8244 -132-
(1) compound tested corresponds to Example Number
(2) mg/kg in mouse writhing test
(3) mg/kg in mouse diarrhea test
(4) ratio of ADSO to EDS~
* Diastereomer A
** Diastereomer B
*** I. V. administration because of lack of sample
The compounds of the present invention have
been found to display excellent activity in an opioid
receptor binding assay which measures the affinity of
the compounds to to bind to mu receptors. This assay
was conducted by the following procedure.
Male Sprague Dawley rats for mu site
experiments were sacrificed via decapitation and the
brains were removed. The brain tissue, rat whole brain
minus cerebellum for mu was homogenized in a Teflon and
glass tissue homogenizes. A supernatant I, pellet IV,
fraction was frozen in a nitrogen freezer at 1.33 g/ml
concentration and stored for not longer than five weeks
prior to use. Pellets were rehydrated with
physiological buffer prior to use.
For mu sites increasing concentrations of
experimental compound, [0.1 to 1000 nanomolar (nM)],
Kreb-Hepes buffer pH 7.4, and tritiated naloxone (0.5 nM)
(3H ligand) were combined in polystyrene tubes at room
temperature. The reaction was initiated by the addition
of the resuspended tissue which had been preincubated at
37°C. for 20 minutes. The reaction mixture was incubated
in a 37°C. water bath for 20 minutes. The reaction was
CA 02064373 2002-07-29
X-8244 -133-
terminated by rapid filtration, (Brandel Cell Harvestor),
through Whatman GF/B glass filters that had been presoaked
in Krebs-Hepes buffer pH 7.4. The filters were then
washed 2x with 5 ml of ice cold Krebs-Hepes buffer
pH 7.4. Washed filters were placed in scintillation
vials and 10 ml "RedySolv"* (Brandel), was added and
samples counted in a Searle D-300~beta counter. Means
and standard error statistics were calculated for
triplicate experimental determinations in certain cases.
The incubation time for the reaction mixture was 20
minutes at 37°C.
Ki values were calculated using a minitab
statistical program according to the following formula:
1 + concentration of 3 H ti4and
Kp
wherein ICso is the concentration at which 50% of the
3H ligand is displaced by the test compounds and KD is
the dissociation constant for the 3H ligand at the
receptor site. ItD can be determined as described by
Bennett, "Methods in Binding Studies", Neurotrans-
mitter Receptor Binding, Yamamura, et al., ed.,
p. 57-90, Raven Press, N.Y. (1978).
The results of the evaluation of certain
compounds of the present invention in the opioid
receptor binding assay are set forth below in Table
II. In the Table, column 1 sets forth the Example
Number of the compound evaluated, column 2 the Ki
* Trademark
X-8244 -134-
value in nanomolar (nM) at the mu receptor and columns
3 and 4 the percent displacement b~y the test compound
at the indicated concentration, ie., 10 nm or 100 nm.
TABLE II
[3H] NAL Binding Assay
(mu receptor)
Example Ki(1) 10 nM(2) 100 nM(2)
4A 1.38 92 98
4B 2.62 83 97
5A 13.80 61 93
5B l.ll 93 99
8A 2.01 88 g5
8B 0.27 100 100
9B 0.66 90 93
10 1.17 89 100
11 0.30 81 89
12 1.89 84 94
13 0.43 94 95
14 6.42 87 g3
15 1.07 99 100
17 0.43 97 100
18 0.43 97 97
20 0.78 98 100
2064373
X-8244 -135-
TABLE II Continued
Example Ki~l~ 10 nM~2~ 100 nM~2~
21 0.45 96 100
22 0.33 100 96
23 1.65 100 96
24 0.45 100 100
25 0.22 100 100
26 1.17 76 91
27 0.91 92 99
28 3.09 86 95
29 2.94 98 100
30 0.42 89 93
31 0.40 100 97
32 0.72 97 100
33 1.19 95 100
34 36.60 78 97
35 0.54 98 100
36 0.47 79 86
37 1.09 93 97
38 0.48 98 99
2064~'~3
X-8244 -136-
TABLE II Continued
Example Ki~l~ 10 nM~2~ 100 nM~2~
39 3.75 91 98
40 0.75 95 100
41 0.39 100 100
42 0.57 100 97
43 0.64 g8 gg
44 0.89 87 94
45 1.28 93 98
46 0.31 gg g5
47 2.11 89 95
48 1.82 96 100
49 0.54 98 100
50 1.20 94 100
51 5.43 85 97
52 -- 53 92
53 -- 2 11
54 2.27 78 98
55 -- 83 97
56 0.49 g7 gg
57 0.50 92 g8
2os4~73
X-8244 -137-
TABLE II Continued
Example Ki~l~ 10 nM~2~ 100 nM~2~
59 4.64 88 100
60 1.89 100 100
61 1.91 98 99
62 1.18 89 98
63 2.00 89 100
64 1.23 94 100
65 -- 57 95
66 1.96 70 85
67 0.37 79 91
68 1.51 79 86
69 -- 57 89
71 0.71 81 94
73 1.80 84 90
75 1.15 90 99
77 1.35 88 95
78B -- 0 2
-- 0 15
80 -- 0 37
81 -- 21 55
20643'3
X-8244 -138-
TABLE II Continued
Example Ki(1) 10 nM(2) 100 nM(2)
82 -- 31 73
83 -- 52 83
85 -- 93 98
86 -- 74 91
87 -- 94 99
88 -- 93 99
89 -- 94 99
90 -- ~ 93 99
91 -- 69 94
92 -- 85 97
93 -- 81 95
94 -- 76 95
95 -- 79 94
97D -- 86 99
97E -- 80 90
98D -- 57 92
98E -- 69 87
97D -- 11 70
98D -- 80 96
(1) In nanomoles
(2) % displacement
206433
X-8244 -139-
While it is possible to administer a compound
of the invention directly without any formulation, the
compounds are preferably employed in the form of a
pharmaceutical formulation comprising a pharmaceutically
acceptable excipient and at least one compound of the
invention. Such compositions contain from about 0.1
percent by weight to about 90.0 percent by weight of a
present compound. As such, the present invention also
provides pharmaceutical formulations comprising a
compound of the invention and a pharmaceutically
acceptable excipient therefor.
In making the compositions of the present
invention, the active ingredient is usually mixed an
excipient which can be a carrier, or a diluent or be
diluted by a carrier, or enclosed within a carrier which
can be in the form of a capsule, sachet, paper or other
container. When the carrier serves as a diluent, it can
be a solid, semi-solid or liquid material which acts as
a vehicle, excipient or medium for the active ingredient.
Thus, the composition can be in the form of tablets,
pills, powders, lozenges, sachets, cachets, elixirs,
emulsions, solutions, syrups, suspensions, aerosols (as
a solid or in a liquid medium), and soft and hard
gelatin capsules.
Examples of suitable excipients, include
lactose, dextrose, sucrose, sorbitol, mannitol, starches,
2064373
X-8244 -140-
gum acacia, calcium phosphate, alginates, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, tragacanth, gelatin, syrup, methyl cellulose,
methyl- and propylhydroxybenzoates, talc, magnesium
stearate, water, and mineral oil. The formulations can
also include wetting agents, emulsifying and suspending
agents, preserving agents, sweetening agents or flavoring
agents. The Formulations of the invention can be
formulated so as to provide quick, sustained, or delayed
release of the active ingredient after administration to
the patient by employing procedures well known in the
art.
For oral administration, a compound of this
invention is preferably admixed with one or more ex-
cipient, and molded into tablets or enclosed in gelatin
capsules.
The compositions are preferably formulated in
a unit dosage form, each dosage containing from about 1
to about 500 mg more usually about 5 to 300 mg of the
active ingredient. The term "unit dosage form" refers
to physically discrete units suitable as unitary
dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect,
in association with a suitable pharmaceutical excipient.
In order to more fully illustrate the
operation of this invention, the following formulation
examples are provided. The samples are illustrative
20643?3
x-8244 -141-
only, and are not intended to limit the scope of the
invention. The formulations may employ as active
compounds any of the compounds of the present
invention. Specific compounds are provided as
illustrative with Z, ~, X.
Formulation 1
Hard gelatin capsules are prepared using the
following ingredients:
Concentration
Amount Per by Weight
Capsule (percent)
Z-NH(CH2)2C(O)NHZ 20 mg 10.0
starch dried 200 mg _ 43.0
magnesium stearate 1~ 2.0
460 mg 100.0
The above ingredients are mixed and filled into hard
gelatin capsules in 460 mg quantities.
20643'3
X-8244 -142-
Formulation 2
Capsules each containing 20 mg of medicament
are made as follows:
Concentration
Amount Per by Weight
Capsule (percent)
G-NH(CHZ)2C(O)NH2 20 mg 10.0
starch 89 mg 44.5
microcrystalline
cellulose 89 mg 44.5
magnesium stearate 2 mg 1.0
200 mg 100.0 mg
The active ingredient, cellulose, starch and magnesium
stearate are blended, passed through a No. 45 mesh U.S.
sieve and filled into a hard gelatin capsule.
Formulation 3
Capsules each containing 100 mg of active
ingredient are made as follows:
Concentration
Amount Per by Weight
Capsule (percent)
G-NH(CHZ)3C(O)NHCH3 100 mg 30.0
polyoxyethylene sorbitan
monooleate 50 microg 0.02
starch powder 250 mg 69.98
350.05 mg 100.00
20643'3
X-8244 -143-
The above ingredients are thoroughly mixed and placed
in an empty gelatin capsule.
Formulation 4
Tablets each containing 10 mg of active
ingredient are prepared as follows:
Concentration
Amount Per by Weight
Tablet (percent)
X-OCHZCH(CH3)2 10 mg 10.0
starch 45 mg 45.0
microcrystalline
cellulose 35 mg 35.0
polyvinylpyrrolidone
(as 10% solution
in
water) 4 mg 4.0
sodium carboxymethyl
starch 4.5 mg 4.5
magnesium stearate 0.5 mg 0.5
talc 1 mg 1.0
100 mg 100.0
The active ingredient,
starch and
cellulose
are passed through No. 45 mesh sieve and mixed
a U.S.
thoroughly. The
solution of polyvinylpyrrolidone
is
mixed with the resultant axe then passed
powders which
through a No. 14 granule so
mesh U.S. sieve.
The
produced is dried 50-60C and passed through
at a No.
20643'73
X-8244 -144-
18 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate and talc, previously passed through
a No. 60 mesh U.S. sieve, are then added to the granule
which, after mixing, is compressed on a tablet machine
to yield a tablet weighing 100 mg.
Formulation 5
A tablet formula may be prepared using the
ingredients below:
Concentration
Amount Per by Weight
Capsule (percent)
X-O(CHZ)4CH3 250 mg 38.0
cellulose
microcrystalline 400 mg 60.0
silicon dioxide fumed 10 mg 1.5
stearic acid 5 mg 0.5
665 mg 100.0
The components are blended and compressed to form
tablets each weighing 665 mg.
20643'73
X-8244 -145-
Formulation 6
Suspensions each containing 5 mg of
medicament per 5 ml dose are made as follows:
per 5 ml of
suspension
M-NHCHZC(0)OH 5 mg
sodium carboxymethyl cellulose 50 mg
syrup 1.25 m1
benzoic acid solution 0.10 ml
flavor q.v.
color q,v,
water q.s. to 5 ml
The medicament is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethylcellulose
and syrup to form a smooth paste. The benzoic acid
solution, flavor and color is diluted with some ofthe
water and added to the paste with stirring. Sufficient
water is then added to produce the required volume.
~0643'~3
X-8244 -146-
Formulation 7
An aerosol solution is prepared containing
the following components:
Concentration by
Weight ( ercent)
U-NHCHZC(O)OH 0.25
ethanol 29.75
Propellant 22
(chlorodifluoromethane) 70.00
100.00
The active compound is mixed with ethanol and the
mixture added to a portion of the Propellant 22, cooled
to -30°C and transferred to a filling device. The
required amount is then fed to a stainless steel
container and diluted further with the remaining amount
of propellant. The valve units are then fitted to the
container.
