Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TITLE OF THE INVENTION
TOCOLYTIC OXYTOCIN RECEPTOR ANTAGONISTS
~l~LD OF THE ~VENTION
This application is a continuation-in-part of U.S. Serial No.
08/378,113, filed January 24, 1995, the contents of which are hereby
incorporated by reference.
The present invention provides novel compounds, novel
compositions, methods of their use and methods of their manufacture;
such compounds are generally ph~ cologically useful as agents in
obstetric and gynecologic therapy in m~mm~l~. More specifically, the
compounds of the present invention can be used in the treatment of
preterm labor, dysmenorrhea and for stopping labor preparatory to
Caesarean delivery.
BACKGROUND OF THE rNVENTION
In the field of obstetrics, one of the most important
problems is the m~n~gement of preterm labor. A significant number of
the pregnancies progressing past 20 weeks of gestation experience
premature labor and delivery, which is a leading cause of neonatal
morbidity and mortality. Despite major advances in neonatal care,
retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use
include ,~2-adrenergic agonists, magnesium sulfate and ethanol.
Ritodrine, the leading ,~2-adrenergic agonist, causes a number of
cardiovascular and metabolic side effects in the mother, including
tachycardia, increased renin secretion, hyperglycemia (and reactive
hypoglycemia in the infant). Other ,~2-adrenergic agonists, including
terbn~lin~ and albuterol have side effects similar to those of ritodrine.
r 30 Magnesium sulfate at plasma concentrations above the therapeutic range
of 4 to 8 mg/dL can cause inhibition of cardiac conduction and
neuromuscular tr~n~mi~sion, respiratory depression and cardiac arrest,
thus making this agent unsuitable when renal function is impaired.
Ethanol is as effective as ritodrine in preventing premature labor, but it
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does not produce a corresponding reduction in the incidence of fetal ,,
respiratory distress that ~lmini~stration of ritodrine does.
It has been proposed that a selective oxytocin antagonist
would be the ideal tocolytic agent. In the last few years, evidence has
5 accumulated to strongly suggest that the hormone oxytocin may be a
physiological initi~tor of labor in several m~mm~ n species including
hllm~n~. Oxytocin is believed to exert this effect in part by directly
contracting the uterine myometrium and in part by enhancing the
synthesis and release of contractile prostaglandins from the uterine
10 endometrium/decidua. These prostaglandins may, in addition, be
important in the cervical ripening process. By these mech~nicm~, the
process of labor (term and preterm) is initiated by a heightened
sensitivity of the uterus to oxytocin, resulting in part as a result of a
well-documented increase in the number of oxytocin receptors in this
15 tissue. This "up-regulation" of oxytocin receptors and enhanced uterine
sensitivity appears to be due to trophic effects of rising plasma levels of
estrogen towards term. By blocking oxytocin, one would block both the
direct (contractile) and indirect (enhanced prostaglandin ~ynthesis)
effects of oxytocin on the uterus. A selective oxytocin blocker, or
20 antagonist, would likely be more efficacious for treating preterm labor
than current regimens. In addition, since oxytocin at term has major
effects only on the uterus, such an oxytocin antagonizing compound
would be expected to have few, if any, side effects.
The compounds of the present invention can also be useful
25 in the treatment of dysmenorrhea. This condition is characterized by
cyclic pain associated with menses during ovulatory cycles. The pain is
thought to result from uterine contractions and ischemia, probably
mediated by the effect of prost~gl~ndin~ produced in the secretory
endometrium. By blocking both the direct and indirect effects of
oxytocin on the uterus, a selective oxytocin antagonist can be more ,~
efficacious for treating dysmenorrhea than current regimens. An
additional use for the present invention is for the stoppage of labor
preparatory (i.e., prior) to Caesarean delivery.
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It is, therefore, a purpose of this invention to provide
substances which more effectively antagonize the function of oxytocin in
disease states in ~nim~l~, preferably m~mm~ls, especially in hllm~ns. It
is another purpose of this invention to prepare novel compounds which
5 more selectively inhibit oxytocin. It is still another purpose of this
invention to provide a method of antagonizing the functions of oxytocin
in disease states in m~mm~l~. It is also a purpose of this invention to
develop a method of preventing or treating oxytocin-related disorders
of preterm labor and dysmenorrhea by antagonizing oxytocin.
It has now been found that compounds of the present
invention are antagonists of oxytocin and bind to the oxytocin receptor.
When the oxytocin receptor is bound by the compounds of the present
invention, oxytocin is antagonized by being blocked from its receptor
and thus being unable to exert its biologic or pharmacologic effects.
These compounds are useful in the treatment and prevention of
oxytocin-related disorders of ~nim~ls, preferably m~mm~ls and
especially hllm~n.~. These disorders are primarily preterm labor and
dysmenorrhea. The compounds would also find usefulness for stoppage
of labor preparatory to Caesarean delivery. Additionally, such
compounds are useful in inducing contraception in m~mm~l~ inasmuch
as oxytocin antagonists have now been shown to inhibit the release of
oxytocin-stimulated luteinizing hormone (LH) by anterior pituitary
cells.
Compounds of the present invention are also inhibitors of
vasopressin and can bind to the vasopressin receptor. These compounds
are useful in inducing vasodilation, treating hypertension, inducing
diuresis and inhibiting platelet agglutination.
SUMMARY OF THE INVENTION
The compounds and their pharmaceutically acceptable salts
of the present invention are of the general formula
"
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- 4 -
~X~O R8 R3
~C~N~(CH2)r~ ~CN~ 4
O R
wherein
X is selected from CH2 or O;
Rl is selected from hydrogen, mono- or di-C1 5 alkyl, Cl 5 alkoxy-
substituted Cl 5 alkyl, CO2H or CONH2,
R2 is selected from hydrogen or Cl 5 alkoxy;
R3 is selected from hydrogen, Cl 5 alkyl, di-, tri- or tetra-methyl,
Cl 5 alkoxy-substituted Cl 5 alkyl, hydroxy-substituted Cl 5 alkyl,
Cl 5 alkoxycarbonyl, CO2H or CONH2;
15 R4 is selected from hydrogen, Cl 5 alkoxycarbonyl, C1 1o alkyl,
C3 g cycloalkyl-substituted C1 5 alkyl, CoR5, S02R6,
R9
I
-CH
N'CN or ~NJ
(~) n
R5 is selected from Cl lo alkyl, Cl 5 alkoxy or NHCOR6;
20 R6 is Cl lo alkyl;
R7 is selected from hydrogen, halogen, amino, mono- or
di-C1-5 alkylamino, C1-10 alkyl or C3 ~ cycloalkyl;
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R8 is selected from hydrogen, Cl 5 alkyl or halogen;
R9 is selected from hydrogen and Cl S alkyl;
n is an integer of from 0 to 1; and
m is an integer of from 1 to 3;
provided that when R 1 and R3 are both simultaneously hydrogen: then
(a) R8 is Cl 5 alkyl or halogen, and R2 is C1 5 alko~y, or
(b) R4 is
-5 alkyl
--(R7)m
(~) n
Thus, the only time that R1 and R3 can both simultaneously be
hydrogen, is when one of two things occurs: (a) either Rg i.s Cl 5 aLkyl
or halogen, and R2 is Cl 5 alkoxy; or (b) R4 is
Cl 1-5 alkyl
-CH
(R7)m
(~) n
In other words, if neither (a) nor (b) applies, then Rl and R3 can not
both ~imlllt~neously be hydrogen.
In one embodiment of the instant invention are the
compounds wherein
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R1 is selected from hydrogen, Cl 5 alkyl or C~NH2;
R3 is selected from hydrogen, Cl 5 alkyl, Cl 5 alkoxy-substituted .
Cl 5 alkyl, Cl 5 alkoxycarbonyl, C02H or CoNH2;
R4 is selected from hydrogen, Cl 5 alkyl, C3-8 cycloalkyl-substituted
C1 5 alkyl, CORS, S02R6 or
-CH
(R )m
(~)n
RS is C1 5 alkyl;
R6isC1 5alkyl;
R7 is selected from hydrogen, chlorine, amino, mono- or
di-Cl 5 alkylamino, C1 5 alkyl or C3-8 cycloalkyl; and
m is an integer of from 1 to 3, preferably, 1 to 2; where R2, R8, R9
and n are as defined above.
In a class are the compounds of the formula
~X~O
r(CH2)n~~ ~CN~R4
~ OCH3
wherein
R3 is selected from hydrogen, Cl 5 alkyl, CH20CH3,
_
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Cl 5 alkoxycarbonyl, C02H or CoNH2;
R4 is selected from hydrogen, methyl, ethyl, isopropyl,
CH2-cyclopropyl, COCH3, SO2CH3,
R9 C H3 R9
-CH~ -CH~
H3C (O)n or R (O)n; and
R7 is selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;
where R1, R9 and n are as defined above.
In a subclass are the compounds wherein X is O; where Rl,
10 R3, R4, R7,R9 and n are as defined above.
In a second subclass are the compounds wherein X is CH2;
where R1, R3, R4, R7, R9 and n are as defined above.
Illustrative of the invention are the compounds of the
structure
fX~O
~f ~O~cN~ R4
~ OCH3
wherein
R4 is selected from hydrogen, isopropyl, COCH3, SO2CH3,
H3C
-CH2~ -CH2$~
H3C (O)n or R (O)n;
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where X, R7 and n are as defined above.
Further illustrating the invention are compounds of the
formula
~~ CH
N~ 4
~ OCH3
S wherein
R4 is selected from hydrogen, isopropyl, COCH3, S02CH3,
H3C
-C H2~ -CH2~
H3C (O)n or R (O)n;
where X, R7 and n are as defined above.
Exemplifying the invention are compounds of the
formula
~X~;O
~N ~ ~/~ 4
~ OCH3
wherein R3 is selected from Cl 5 alkyl, CH20CH3, C02CH2CH3,
C02H or CONH2; where X and R4 are as defined above. Preferably,
15 R3 is Cl 5 alkyl.
An example of the invention are compounds of the formula
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~X~f~O R3
~Nb,l~ ~IN~ 4
~ OCH3
wherein R3 is Cl 5 alkyl; where X and R4 are as defined above.
An illustration of the invention are compounds of the
formula
X O
~ ~ 1
~ ~'~r CH /~ ~N~ 4
O OC H3
wherein
R 1 is selected from methyl or CONH2; and
R4 is selected from hydrogen, methyl, ethyl, isopropyl,
CH2-cyclopropyl, COCH3 or SO2CH3; where X is as defined above.
~ More specifically exemplifying the invention are
compounds of the formula
~X~p;O R1
CH2/~ ~N~
. O OC H3
15 wherein
R1 is Cl 5 alkyl; and
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- 10-
R4 is selected from hydrogen, methyl, ethyl, isopropyl, "
CH2-cyclopropyl, COCH3 or S02CH3; where X is as defined above
Another example of the invention are compounds of the
formula
X O
R3
~ ~N~rCH/~ ~/' 4
O OC H3
wherem
R3 is selected from Cl 5 aLkyl, CH20CH3, Cl 5 aLkoxycarbonyl, C02H
or CONH2; where X and R4 are as defined above.
Further exemplifying the invention are compounds of the
formula
X n
CH2/~ R~
oOCH3
wherein
15 R3 is Cl 5 aLkyl; and
R4 is selected from hydrogen, isopropyl, COCH3, SO2CH3,
H3C
-CH2~' -CH2$;;~ -
H3C (O)n or R (O)n;
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where X, R7 and n are as defined above.
More particularly illustrating ~e invention are compounds
of the formula
~X~O R8
(CH2)n~ ~N~ R4
O R2
S wherein
R4 is
-CH
(R7)m
(~) n
10 R7 is selected from hydrogen, chlorine, arnino, mono- or di-Cl 5
alkylamino, Cl 5 alkyl or C3-8 cycloalkyl; and
R9 is Cl 5 aLkyl; where X, R2, R8, m and n are as defined above.
Another illustration of the invention are compounds of the
1 5 formula
~X~O
~N~ ~N--CH\~
~ OCH3 [l ~ (R )m
N,
(o) n
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wherein
R7 is selected from hydrogen, C1 5 alkyl and C3-8 cycloalkyl; and
R9 is methyl; where X, m and n are as defined above.
Still another example of the invention are compounds of the
formula
~X~O R8
~N~ (CH2)n~ \CN' R4
O R2
wherein
R2 is Cl 5 alkoxy;
R4 is selected from Cl 3 alkoxycarbonyl, C1 -10 alkyl,
C3 ~ cycloalkyl-substituted Cl-5 alkyl, COR5, S02R6,
~9
-CH
N'CN or
(~) n
R5 is selected from C2 10 alkyl or NHCOR6; and
R~ is selected from Cl 5 alkyl or halogen; where X, R6, R7, R9, m and
n are as defined above.
More specifically exemplifying the invention are
compounds of the formula
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~X~O R8
~N ~ ~N ~ R 4
o OCH3
wherein
R4is
-CH
~ (R )m
(~) n
R7 is selected from hydrogen, Cl 5 alkyl or C3-8 cycloalkyl;
R8 is selected from methyl, fluorine, chlorine or bromine; and
10 R9 is hydrogen or methyl, where X, m and n are as defined above.
In a preferred embodiment of the instant invention is a
compound of the formula
~N~ ~ ~13
o OCH3
wherein R 10 and R 1 1 are each independently selected from hydrogen,
15 halogen or Cl-6 alkyl;
R 12 and R 13 are each independently selected from hydrogen,
C 1 6 aLkyl or C02-C l 6 alkyl;
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R14 is selected from hydrogen, CO-Cl 6 aL~yl, C02-Cl 6 aLkyl or
R16
H~R17
2 ~=N~
R1s (~)n
R15, R16 and R17 are each independently selected from hydrogen or
C1 6 alkyl; and
5 n is integer from zero to one;
provided that when Rl0, Rl 1, R12 and R13 are all simultaneously
hydrogen, then R14 is
R16
-~ C~R17
H2 ~=N
R1s (~)n
wherein R15, R16 and R17 are each independently C1 6 alkyl;
10 and the pharmaceutically acceptable salts thereof.
In a class of this preferred embodiment is the compound
wherein
R 1 0 is selected from hydrogen or methyl;
R 1 1 is selected from hydrogen, bromine or fluorine;
15 R12 is selected from hydrogen or methyl;
R13 is selected from hydrogen or CO2CH3;
R14 is selected from hydrogen, COCH3, CO2C(CH3)3 or
R16
-~ C~R17
H2 ~=N
R1s (~)n
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R15, R16 and R17 are each independently selected from hydrogen,
methyl, ethyl or 2-propyl; and
n is integer from zero to one;
provided that when R10, Rl 1, R12 and R13 are all simultaneously
5 hydrogen, then R14 is
R16
-~ C~R17
H2 \I=N~
R1s (~)n
wherein R15, R16 and R17 are each independently selected from
methyl, ethyl or 2-propyl,
and the pharmaceutically acceptable salts thereof.
In a subclass of this preferred embodiment is the compound
of the formula
O OCH3
wherein all other variables are as defined above;
and the pharmaceutically acceptable salts thereof.
Exemplifying this preferred embodiment is the compound
selected from
~'f~~ F
~N~ ~N~CH3
O OC H3 O
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- 16-
F C~
N N~N~
O OCH3 CH
3 or
F
~N~ ~~~Cl H3C~CH3
~,N ~ N ,~N~
O OCH3 CH3
and the pharmaceutically acceptable salts thereof.
More specifically illustrating the instant invention is a
5 ph~rm~ceutical composition comprising a pharmaceutically acceptable
carrier and a pharmacologically effective amount of any of the
compounds of the instant invention described above to prevent preterm
labor in a m~mm~l in need thereof.
Further illustrating the invention is a method of eliciting an
10 oxytocin antagonizing effect in a m~mm~l, comprising the step of
~lmini~tering to said m~mm~l a ph~rm~cologically effective amount of
any of the compounds of the instant invention described above.
A further illustration of the instant invention are methods
of treating preterm labor, stopping labor preparatory to cesarian
15 delivery, and treating dysmenorrhea in a m~mm~l in need thereof,
comprising the step of ~lmini~tering to said m~mm~l a
pharmacologically effective amount of any of the compounds of the
instant invention described above.
Further exemplifying the invention are methods of
20 increasing fertility and embryonic survival in a farm ~nim~l, and
controlling the timing of estrus in a farm ~nim~l, comprising
~lmini~tering to the farm ~nim~l a pharmacologically effective amount
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of any of the oxytocin antagonist compounds of the present invention
described above.
Another example of the invention is a method for
improving survival of a farm ~nim~l neonate comprising controlling
5 timing of parturition to effect delivery of the neonate during daylight
hours by ~(lmini.stering to a farm ~nim~l which is expected to deliver
the neonate within 24 hours a pharmacologically effective amount of
any of the compounds of the present invention described above.
Additional examples of the invention are the use of any of
10 the compounds described above in the preparation of a medicament for
the treatment of preterm labor, dysmenorrhea or stoppage of labor
prior to cesarian delivery in a m~mm~l in need thereof.
More particularly illustrating the invention is a drug which
is useful for treating preterm labor, dysmenorrhea or stopping labor
15 prior to cesarian delivery in a m~mm~l in need thereof, the effective
ingredient of the said drug being any of the compounds descibed above.
Additional illustrations of the instant invention are methods
of antagonizing vasopressin from binding to its receptor site, inducing
vasodilation, treating hypertension, inducing diuresis and inhibiting
20 platelet agglutination in a m~mm~l in need thereof comprising the step
of ~lmini~stering to said m~mm~l a pharmacologically effective amount
of any of the compounds of the instant invention described above.
Salts encompassed within the term "pharmaceutically
acceptable salts" refer to non-toxic salts of the compounds of thi.s
25 invention which are generally prepared by reacting the free base with a
suitable organic or inorganic acid. Representative salts include the
following:
Acetate, Benzenesulfonate, Benzoate, Bicarbonate,
Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate,
30 Chloride, Clav~ n~te, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glllt~m~te,
Glycollylars~nil~te, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
_
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Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate,
Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate
(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate,
Tannate, Tartrate, Teoclate ,Tosylate, Triethiodide and Valerate.
The compounds of the present invention, may have chiral
centers and occur as racemates, racemic mixtures and as individual
diastereomers, or enantiomers with all isomeric forms being included in
the present invention. Therefore, where a compound is chiral, the
separate enantiomers, subst~nti~lly free of the other, are included within
the scope of the invention; further included are all mixtures of the two
enantiomers. Also included within the scope of the invention are
polymorphs and hydrates of the compounds of the instant invention.
The term "pharmacologically effective amount" shall mean
that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, ~nim~l or hllm~n that
is being sought by a researcher or clinician.
The term "alkyl" shall mean straight or branched chain
alkanes of one to ten total carbon atoms, or any number within this
range (i.e., methyl, ethyl, l-propyl, 2-propyl, n-butyl, t-butyl, etc.).
The term "aryl" shall mean phenyl, napthyl or fluorenyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of
three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., araLkoxyaryloxy) it
shall be interpreted as including those limitations given above for
"alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cl-10)
shall refer independently to the number of carbon atoms in an alkyl or
cyclic alkyl moiety or to the alkyl portion of a larger substituent in
which alkyl appears as its prefix root.
The term "halogen" shall include iodine, bromine, chlorine
and fluorine.
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As used herein, in the definition of Rl, the term "mono- or
di-Cl 5 alkyl" shall mean that the piperidine ring cont~ining the R
substituent can be mono- or di-substituted with a Cl 5 alkyl group.
R1
'~/1
Thus, when Rl is di-Cl 5 alkyl, then sS~S shall mean
C1 5 alkYI
C1 5 alkyl
N~s~ . Moreover, when Rl is di-Cl 5 alkyl, the C1 5
alkyl groups can be the same or different. Similarly, in the definition
of R3, the term "di-, tri- or tetra-methyl" shall mean that the piperidine
ring con~ining the R3 substituent can be di-, tri- or tetra-substituted
with a methyl group. Thus, when R3 is dimethyl, trimethyl and
'C/l ~s~'~,~CH3
10 tetramethyl, then R shall mean N~ R4
~/~N~ 4 CH3~ ~ R4
H3C R and CH3 ' respectively.
The term "preterm labor" shall mean expulsion from the
uterus of a viable infant before the normal end of gestation, or more
particularly, onset of labor with effacement and dilation of the cervix
15 before the 37th week of gestation. It may or may not be associated with
vaginal bleeding or rupture of the membranes.
The term "dysmenorrhea" shall mean painful menstruation.
The term "Caesarean delivery" shall mean incision through
the abdominal and uterine walls for delivery of a fetus.
The term "substituted" shall be deemed to include multiple
degrees of substitution by a named substitutent.
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Where multiple substituent moieties are disclosed or
claimed, the substituted compound can be independently substituted by
one or more of the disclosed or claimed substituent moieties, singly or
plurally.
The ability of the compounds of the present invention to
antagonize oxytocin makes these compounds useful as ph~rm~cologic
agents for m~mm~ls, especially for hllm~ns, for the treatment and
prevention of disorders wherein oxytocin may be involved. Examples
of such disorders include preterm labor and especially dysmenorrhea.
These compounds may also find usefulness for stoppage of labor
preparatory to Cesarean delivery.
The present invention is also directed to combinations of
the compounds of formula I with one or more agents useful in the
treatment of oxytocin related disorders such as preterm labor,
dysmenorrhea and stopping labor prior to cesarean delivery. For
example, the compounds of the instant invention may be effectively
~lmini.stered in combination with effective amounts of other agents used
in the treatment of preterm labor, such as antenatal steroids (e.g.,
dexamethasone). Preferred combinations are simultaneous or
alternating treatments of an oxytocin receptor antagonist of the present
invention and an antenatal steroid. These combinations have beneficial
effects on the neonate by both decreasing uterine activity to prolong
gestation and increasing fetal maturation. In accordance with the
method of the present invention, the individual components of the
combination can be ~lministered separately at different times during the
course of therapy or concurrently in divided or single combination
forrns. The instant invention is therefore to be understood as embracing
all such regimes of simlllt~neous or alternating treatment and the term
"~lmini~stering" is to be interpreted accordingly. It will be understood
that the scope of combinations of the compounds of this invention with
other agents useful for treating oxytocin related conditions includes in
principle any combination with any pharmaceutical composition useful
for treating preterm labor, dysmenorrhea or stopping labor prior to
cesarean delivery.
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The oxytocin antagonist compounds of the present
invention are also useful for improving reproductive efficiency in farm
~nim~l~. In certain farm ~nim~l~ (e.g., sheep, cattle, swine, horses and
goats), the beginning of the estrous cycle is typically marked by
behavioral estrus when the female ~nim~l accepts the male for m~ting.
Ovulation of the ovarian follicle occurs shortly after onset of estrus and
cells in the follicle give rise to the corpus luteum. The cells that form
the corpus luteum produce progesterone and they also produce
oxytocin. The secretion of oxytocin from the corpus luteum and/or
pituitary acts on the uterine endometrium to s~im~ te the secretion of
prostaglandins (in particular PGF) which, in turn, causes the regression
of the corpus luteum of the ovary. PGF is, therefore, the luteolytic
hormone. In the cycling ~nim~l (i.e., where mating and fertilization
have not occurred), destruction of the corpus luteum removes the
lS source of progesterone which is key to the preparation of the uterus for
pregnancy. The presence of a viable conceptus (i.e., the embryo and its
associated membranes) is necessary to prevent the luteolytic process. In
fact, the first key signal that the conceptus must produce is the one to
prevent regression of the corpus luteum (i.e., the maternal recognition
of pregnancy signal). Thus, in the ~nim~l where mating and
fertilization have occurred, the conceptus secretes a factor that
antagonizes the action of oxytocin to induce luteolysis. This results in
m~intenance of a functioning corpus luteum and the continued secretion
of progesterone which is obligatory to the initiation of pregnancy.
A~lmini~tration of an oxytocin antagonist of the present
invention at this critical period after fertilization (i.e., just prior to or
during the period of maternal recognition of pregnancy) supplements
the natural signal from the conceptus (i.e., maternal recognition of
pregnancy) to prolong corpus luteal function. The result is to increase
pregnancy rates by enhancing the chances of impregnation through a
reduction in embryonic loss. Thus, to improve fertility and embryonic
survival in a farm ~nim~l, a mated ~nim~l, for example, a mated ewe, is
treated with an oxytocin antagonist compound beginning on between day
10 to day lS after onset of estrus. The oxytocin antagonist compound is
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~lmini~tered to the mated ~nim~l for a period of one day to three
weeks, preferably one week to three weeks, most preferably one week
to two weeks.
The compounds of the present invention are also useful for
S controlling the timing of parturition in farm ~nim~l~ so that delivery of
the neonates occurs during the daytime. Approximately 80% of
livestock are delivered at night and up to S to 10% of newborns die
because the deliveries are not monitored properly. An oxytocin
antagonist compound of the present invention ~lmini~tered to the
10 mother on the evening before expected delivery delays parturition so
that the delivery occurs during the daylight hours. By delaying the
timing of parturition, proper monitoring of the delivery and the
neonates is ensured, resulting in increased survival rates of the
newborns.
In addition, the oxytocin antagonists of the instant invention
can also be used to control the timing of estrus in a cycling farm ~nim~l
by preventing luteal regression. An oxytocin antagonist compound of
the instant invention is ~lministered to a cycling farm ~nim~l prior to
expected estrus to prevent regression of the corpus luteum. Daily
~lmini~tration of the compound retards estrus until ~lministration of
the compound ceases. Preferably, the oxytocin antagonist compound i,s
:~lmini~tered at least 1 day prior to expected estrus. By delaying e.strus
in a group of farm ~nim~l~, a farmer can synchronize estrus among the
group to provide time and cost savings in farm m~n~gement.
The compounds of the present invention also bind to the
vasopressin receptor and are therefore useful as vasopressin antagonists.
Vasopressin antagonists are useful in the treatment or prevention of
disease states involving vasopressin disorders, including their use as
diuretics and their use in congestive heart failure.
The compounds of the present invention can be
~lmini~tered in such oral dosage forms as tablets, capsules (each
including timed release and sustained release formulations), pills,
powders, granules? elixers, tinctures, suspensions, syrups and emulsions.
Likewise, they may also be ~lmini~tered in intravenous (both bolus and
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00~50
- 23 -
infusion), intraperitoneal, subcutaneous or intramuscular form, all using
forms well known to those of ordinary skill in the pharmaceutical arts.
An effective but non-toxic amount of the compound desired can be
employed as a tocolytic agent.
S The dosage regimen lltili7ing the compounds of the present
invention is selected in accordance with a variety of factors including
type, species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of ~lministration; the
renal and hepatic function of the patient; and the particular compound
or salt thereof employed. An ordinarily skilled physician or
veterinarian can readily determine and prescribe the effective amount of
the drug required to prevent, counter or arrest the progress of the
condition.
Oral dosages of the present invention, when used for the
indicated effects, will range between about 0.03-6.0 gm/day orally.
More particularly, when a-lmini~tered orally for the treatment of
preterm labor, an effective daily dose will be in the range of 0.05
mglkg to about 100 mg/kg of body weight, preferably, from 0.5 mglkg
to 50 mglkg, ~lmini~tered in single or divided dose. For oral
~lministration, the compositions are preferably provided in the form of
tablet.s cont~ining 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,
50.0, 100 and 500 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated. A
medicament typically contains from about 0.01 mg to about 500 mg of
the active ingredient, preferably, from about 1 mg to about 100 mg of
active ingredient. Intravenously, the most preferred doses will range
from 0.01 to about 1.0 mg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may be
~lmini~tered in a single daily dose, or the total daily dosage may be
a~lmini.~tered in divided doses of two, three or four times daily.
Furthermore, preferred compounds for the present invention can be
~lmini~tered in intranasal form via topical use of suitable intranasal
vehicles, or via transdermal routes, using those forms of transdermal
skin patches well known to those of ordinary skill in that art. To be
CA 02210138 1997-07-10
WO 96/22775 PCT/US~)6/009'50
- 24 -
~lmini~tered in the form of a transdermal delivery system, the dosage
~lmini~ctration will, of course, be continuous rather than intermittant
throughout the dosage regimen.
In the methods of the present invention, the compounds
herein described in detail can form the active ingredient, and are
typically ~flmini~tered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein as
"carrier" materials) suitably selected with respect to the intended form
of ~lmini~tration, that is, oral tablets, capsules, elixirs, syrups and the
like, and consistent with conventional pharmaceutical practices.
For instance, for oral ~lmini~tration in the form of a tablef
or capsule, the active drug component can be combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents and coloring agents
can also be incorporated into the mixture. Suitable binders include
starch, gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth or
sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes
and the like. Lubricants used in these dosage forms include sodium
oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, 7~nth~n gum and
the like.
The compounds of the present invention can also be
~lmini~tered in the form of liposome delivery systems, such as small
nnil~mellar vesicles, large lmil~mellar vesicles and multilamellar
vesicles. Liposomes can be formed from a variety of phospholipids,
such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered
by the use of monoclonal antibodies as individual carriers to which the
compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable drug
carriers. Such polymers can include polyvinylpyrrolidone, pyran
CA 02210138 1997-07-10
WO 96/22775 PCT/US96100850
- 25 -
copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds of the
present invention may be coupled to a class of biodegradable polymers
useful in achieving controlled release of a drug, for example, polylactic
acid, polepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and
cross-linked or amphipathic block copolymers of hydrogels.
Abbreviations used in the instant specification, particularly
the Schemes and Examples, are as follows:
Boc = t-butyloxycarbonyl
BOP = benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
DCC = 1 ,3-dicyclohexylcarbodiimide
DCM = dichloromethane
DEAD = diethyl azodicarboxylate
DIEA = diisopropylethylamine
DMAP = 4-dimethylaminopyridine
DMF = dimethylformamide
Et = ethyl
EtOAc = ethyl acetate
EtOH = ethanol
EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
FAB MS = fast atom bombardment mass spectroscopy
HOBT or HBT = 1-hydroxybenzotriazole
HPLC = high performance liquid chromatography
LDA = lithium diisopropylamide
m-CPBA or MCPBA = meta-chloroperoxybenzoic acid
Me = methyl
MeOH = methanol
MOM = methoxymethyl
NCS = N-chlorosuccinimide
NMR = nuclear magnetic resonance
CA 02210138 1997-07-10
WO 96/2277~ PCT/US96/00850
- 26 -
Ph = phenyl
PPTS = pyridinium p-toluenesulfonate
TFA = trifluoroacetic acid
THF= tetrahydrofuran
TLC = thin layer chromatography
TMEDA = N, N, N', N'-tetramethylethylene~ min~
TMS = trimethylsilyl
TMS-allyl = allyltrimethylsilane
The compounds of the present invention can be prepared
readily according to the following reaction schemes and examples, or
modifications thereof, using readily available starting materials,
reagents and conventional synthesis procedures. In these reactions, it is
also possible to make use of variants which are themselves known to
1~ those of ordinary skill in this art, but are not mentioned in greater
detail.
The compounds and ph~rm~ceutically acceptable salts of the
present invention can be synthesized according to the general methods
outlined in Schemes 1-17 and the description of the schemes which
20 follow. In Schemes 1-17 which follow, the variables "X," "Rl," "R2,"
"R3" and "R7" are as defined above.
CA 02210138 1997-07-10
WO 96/22775 PCT/US96100850
SCHEME 1
~ J~,CH3 OH
LDA, CH31 ~ J NaBH4 ~ J
BocBoc methyl2-(R2)-
4-hydroxybenzoate,
CH3 ~ DEAD, Ph3PCH3
HO~O~ NaOH ~ N~ Boc
1 -(piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1 -(piperidin-4-yl)-3 ,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
~X~f~O CH3
'~2 ~N~ Boc
\ HCI
~X~;O \ CH3
~N~ NH
CA 02210138 1997-07-10
W O 96/22775 PCTrUS96/00850
- 28 -
SCHEME 1 (CONT'ED)
0~ 2 CH2N2 CH3
HO~ Boc N2~ N~Boc
AgOCOPh, MeOH
CH3
CH30~ N~B
/ 1. NaOH
/ 2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzox~in-2-one, or
1 -(piperidin-4-yl)-3,4-dihydro-
~X~O ¦ quinolin-2(1 H)-one EDC HOBT
g~ ~N~CH2~ ~N~B
O R2
~X~;O HCI CH3
~N~CH2~ ~NH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 29 -
SCHEME 2
OCH3 OCH3 OCH3
1. PhOCOCI ~ t-BuOK ~ oxalicacid
~J 2. i-PrMgX ~ N~I
~ OPh Boc
lithium triethyl- I OH
borohydr~ NaBH4 ~
Boc Boc Boc
methyl 2-(R2)-
4-hydroxybenzoate,
DEAD, Ph3P
~ ~ CH30 ~
HO~ Boc NaOH ~ R2 Boc
O R2
1 -(piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzox~in-2-one, or
1 -(piperidin-4-yl)-3,4-dihydro-
~X~ O ~ quinolin-2(1 H)-one, EDC, HOBT
~N ~
O R2
\ HCI
~X~O
[~ ~N~
O R2
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 30 -
SCHEME 2 (CONT'ED)
HO~
O R2
1. (COC1)2
N~ Boc
AgOCOPh, MeOH
b~3'~ ,~
R2
1. NaOH
2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1-(piperidin-4-yl)-3,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
'
O R2
~X~f~O HCI
~,N~ O~
N~CH2~ l NH
O R2
CA 02210138 1997-07-10
WO 96122775 PCT/US96/OOP50
SCHEME 3
O o
J~1. (t-BuOC0)20 ~
r 1 ~ ~ ~ NaBH4
HO~ J 2. t-BUOH, DCC~ t BUO~N~
O ~ Boc
OH methyl2-(R2)-
~ 4-hydroxybenzoate, ~O~'O-t-Bu
t-BUO~ J EAD, Ph3P ~ CH30~ ~ Boc
~NaOH
~0~ '0-t-Bu
H0~ ~,N~ Boc
O R2
1 -(piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzox~in-2-one, or
1 -(piperidin-4-yl)-3,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
~X~O ' O
~N~,~O ~ O-t-Bu
O R2
X~;o \ HCI
- ~S~N~C ~~'~ OH
~ N~ ~,NH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
SCHEME 3 (CONT'ED)
'~ ~X O-t-Bu
1. (COC1)2
2. CH2N2
O
~~ ~ O-t-Bu
N2~ N~ Boc
AgOCOPh, MeOH
"~
1. NaOH
2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1 -(piperidin-4-yl)-3 ,4-dihydro-
x~o ~ quinolin-2(1 H)-one, EDC, HOBT
~,N~ ~~ ~O-t-Bu
~, N~CH2~,) ~ Boc
O R2
HCI O
~N~ ~ ~O~f ~ OH
N~CH2~ ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 33 -
SCHEME 4
O O
1. (t-BUOc0)20 ~ NaBH4
J 2. EDC, HOBT, H2N~NJ
O ~ Boc
OH O
~ methyl 2-(R2)- ~ ~D'NH2
H2N~ DEAD, Ph3P ~ ~ Boc
~aOH
Ho~ ' Boc
O R2
1 -(piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1 -(piperidin-4-yl)-3,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
,N ~ ~C~
~X~f~O HCI O
~,N~j~ ~O~Jl'NH2
N~ ~NH
O R2
CA 02210138 1997-07-10
PCrlUS~/OO~SO
WO 96/22775
- 34 -
SCHEME 4 (CONT'ED)
o
~ ~NH2
HO~ N~ Boc
O R2 \ 1. (COC1)2 0
\ 2- CH2N2 0 ll
~ 2
N2~ ~N' Boc
O R2
AgOCOPh, MeOH
O
CH30R~ ~Boc
1. NaOH
2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzox~in-2-one, or
1 -(piperidin-4-yl)-3 ,4-dihydro-
X O . quinolin-2(1H)-one, EDC, HOBT
~ O
~N~ ~,0~ NH2
--~ ~,N~ Boc
O R2
O
N~CH2~ NH
O R2
997 o7-10 pC~r~S961~o~
~VO 9612277~
35 -
SCHE~AE 5
OH
/~ ~~ 1 pPTs, aCet~
~~<~ S-Bu~i~TMFD~ 2 ~laBI~
1~ J CH30C~2C~ ' C~30 Boc
CH30 BoC methy~ Z-(R2)-
BoC / 4 hydroxYbenZ~a
~' DE~D, Ph3P
,~ ~O ~ oC~13
CH30~ ~ Boc
o R2
l~laO~
,~ ~0 ~ ~ oCH3
HO~ ' Boc
O R2 t (piperidin-4 Yn)2-one~ or
uin~ 4 d~hYdr~-
~' Boc
~ HCI
N~
CA 02210138 1997-07-10
WO 96/22775 PCI/US96100850
- 36 -
SCHEME 5 (CONT'ED)
~ ~OCH3
HO~ ~N~ Boc
O R2 \ 1. (COc1)2
\~ 2. CH2N2
~ ~--OCH3
N2~ ~,N~ Boc
AgOCOPh, MeOH
CH30~3' ~Boc
1. NaOH
2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
X 0 1-(piperidin-4-yl)-3,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
~N ~ ~~~~ OCH3
N~CH2--~ ~N' Boc
X O HCI
~N ~ ~~~f OCH3
N~CH2~' ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
SCHEME 6
O O
CH3 2-aminobenzyl alcohol,
,~ LDA, CH31 ~ ,r NaBH3CN
Boc Boc
~NHOH ~N ~ ~N~O
COC12
Boc Boc
2-(R2)-4-(N-Boc-4-
~~~~ CH piperidinyloxy)benzoic acid,
~N~o EDC, HOBT
HCI
CH3
~N~ O~
~N~' ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCT/U~,,''00~50
- 38 -
SCHEME 6 (CONT'ED)
~O
~,CH3
2-(R2)-4-(N-Boc-4-
piperidinyloxy)phenylacetic acid,
EDC, HOBT
~~~~ CH
[~ ~N~CH2~ ~N~ Boc
O R2
HCI
~~~~ CH
\CNH
O R2
CA 02210138 1997-07-10
WO 96/2277S PCTIUS96/008~0
- 39 -
SCHEME 7
OCH3 1. Phococl ~CH3 OCH3
2. i-PrMgX 1 t-BuOK 1 .
¢N~ ~N~ 3 oxallc acid
lithi rn tri~alcohol NaBH3CN ~ H~H
Boc
~CN ~ HCI ~CN10
Boc
2-(R2)-4-(N-Boc-4-
piperidinyloxy)benzoic acid,
0~0 EDC, HOBT
~N~ ~N~B
~~~o \HCI
N~ ~NH
CA 02210138 1997-07-10
WO 96122775 PCI'/US96/00850
- 40 -
SCHEME 7 (CONT'ED)
~0
O
2-(R2)-4-(N-Boc-4-
piperidinyloxy)phenylacetic acid,
r EDC, HOBT
~O~fzO
[~ ~N~CH2~ ~N~ B
O R2
r HCI
~0~;0
[~ ~N~CH2~ ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCTIUS96/00~50
- 41 -
SCHEME 8
O o
~1~1. (t-BuOC0)20 ~1~
H~~'NJ 2- ND3C, HOBT, H2N~NJ
H 1 2-aminobenzyl
" ~ Boc ~hol, NaBH3CN
~CN1O HCI ~N\ ~ COCI2 NH
H2N~J H2N~ H2Nb~
~ ~ Boc ~ Boc
2-(R2)-4-(N-BoG4-
piperidinyloxy)benzoic acid,
EDC, HOBT
~0~0
~N~ ~CN~ B
H2N O
HCI
fO~O
1~ ~N~ ~CNH
H2N O
CA 02210138 1997-07-10
WO 96122775 PCT/US9GI~,1135
- 42 -
SCHEME 8 (CONT'ED)
~o
~N~ ~
H2N o~
2-(R2)-4-(N-Boc-4-
piperidinyloxy)phenylacetic acid,
~O~f~O EDC, HOBT
~N~CH2~ ~N~ B
r HCI
~0~;0
~N~CH2~ ~N H
H2N ~ R2
CA 02210138 1997-07-10
WO 96122775 PCT/US96/00850
- 43 -
SCHEME 9
o
[~~~ s-BuLi,TMEDA ~~ PPTS,acetone
CH30CH2CI J~ N
IN ~ Nl CH30 Boc
Boc CH30 Boc2-aminobenzyl alcohol,
NaBH3CN
r~O ~0 ~OH
~N10 ~ N ~ cOC12 NH
CH30~ CH30J~ CH30
Boc Boc
2-(R2)-4-(N-Boc-4-
piperidinyloxy)benzoic acid,
EDC, HOBT
~0~0
~N~ ~~C
CH30
HCI
~O~f~;O
0~ ~N~,~ ~NH
CA 02210138 1997-07-10
WO 96/22775 . PCT/US96/00850
- 44 -
SCHEME 9 (CONT'ED)
~N10
CH30 ~
2-(R2)-4-(N-Boc-4-
piperidinyloxy)phenylacetic acid,
~~~f~;~ EDC, HOBT
~N~CH2~ ~N~B
C H30
HCI
~O~f~O
[~ ~N~CH2~ \CNH
C H30
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 45 -
SCHEME 10
'' ~3'~ NH
J~ aniline
[~ --R1 NaBH3CN ~ ~ R1
N N 3-ethoxy-
acryloyl chloride
CH2Ph CH2Ph
3-(2-aminophenyl)-~N~o
propionamide ~J R 1 INJ R
CH2Ph
CH2Ph
H2 Pd/C
5~/0 HCI ~ ~~
--R1 ~ H2 Pd/C
CH2Ph CH2Ph
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 46 -
SCHEME 10 (CONT'ED)
~o
2-(R2)-4-(N-Boc-4- J~
piperidinyloxy)benzoic ac~
EDC, HOBT / N
R1 H
'C/ ~~~
O R2 2-(R2)-4-(N-Boc-4-
HCI piperidinyloxy)pheny
acetic acid,
R1 EDC, HOBT
'C/,' ~~ ~
N~' ~NH
1~N R1
[~ ~C N~CH2~ ~N~
HCI
g~ N~CH2~ ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCI/US96/00850
- 47 -
SCHEME 1 1
f ~ R1 R3
~N~(CH2)n~ ~C~NH
3-chloromethyl-
2-methylpyridine
or
3-chloromethyl-2-
methylpyridine-N-oxide,
X O DMF, DIEA
R1 ~ R3
~ ~2 ~
(o) n
1. (PhO)2C=NCN~X O
2. NH3 ¦ ~ R1 R3
> ~ N~f /~ ~~~/~
~N~ (CH2)n~ ~,N~ NH2
O R2 N-CN
~X~f~;O R3
CH3SO2CI ~--N~/ ~0~ /
N~ (CH2)n~ ~,N - SO2C H3
O R2
CA 02210138 1997-07-lo
WO 96/22775 PCT/US96100850
- 48 -
SCHEME 11 (CONT'ED)
~X~O / R3
~C-N~(CH2)n~ ~CNH
\CH3COCI
~X~O R3
O R~
cyclopropanecarboxaldehyde
NaBH3CN
~X~f ~O / R3
~CN ~ (CH2)n~ ~, N- CH
CA 02210138 1997-07-10
WO 96/22775 PCT/US~('00~50
- 49 -
SCHEME 12
EtOJ~ 7 LiAlH4 HO~
SOCI2~ \MnO2
mCPBA ~J (R7)m HJ~ (R7)
"B" "C"
~X~O / R3
[~ ~C, N~ (CH2)n~ ~, NH
O R2
"B", DMF, DIEA
or
"C", NaBH3CN
J l ~N ~(CH2)n~ 'C'
CA 02210138 1997-07-10
WO 96/22775 PCI~/US~6/008~;0
- 50 -
SCHEME 12 (CONT'ED)
~X~;O R3
~N~f /~ ~0~
~N~(CH2)n~ l~,NH
"A", DMF, DIEA
~X~O / R3
~,N~(CHz)n~ ~,N CH~
CA 02210138 1997-07-10
WO 96122775 PCTIU~,''OQ850
SCHEME 13
Cl
CH30~ ~ CH30~0H
O R2 ~ R2
N-Boc-3-methyl-
piperidin-4-ol
~ DEAD, Ph3P
3 ~
HO~ ~,N CH30~ N~ Boc
1 -(piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1 -(piperidin-4-yl)-3 ,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
~x~f~o Cl CH3
~N~ "0
O R2
\ HCI
\~
~x~o Cl CH3
~N~ NH
O R2
CA 02210138 1997-07-10
WO 96122775 PCTIUS~6/OQ~50
- 52 -
SCHEME 13 (CONT'ED)
~0~3 1 (COCl)z ~
HO~ . ~,N~ Boc N26~/ N~ Boc
AgOCOPh, MeOH
Cl CH3
CH30~ O~N~ Boc
/ 1. NaOH
/ 2. 1-(piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzoxazin-2-one, or
1 -(piperidin-4-yl)-3,4-dihydro-
~X~O ¦ quinolin-2(1H)-one EDC, HOBT
~N~CH2~ ~N~ B
O R2
HCI
~X~f~O ~ Cl CH3
[~ ~N~CH2~ ~NH
O R2
CA 02210138 1997-07-10
WO 96/2277S PCT/US96/008S0
- 53 -
SCHEME 14
O O
CH3 2-aminobenzyl alcohol,
N LDA, CH31 ~ ~ NaBH3CN
Boc Boc
~OH ,~o ~O
NH N10 ~Nlo
COCI
Boc Boc
2-(R2)-4-(N-Boc-5-chloro-4-
~~~~ CH Cl piperidinyloxy)benzoic acid,
~N~O~CEDC, HOBT
HCI
CH3 Cl
~N~ ~NH
CA 02210138 1997-07-10
WO 96122775 PCTlUbr'':l'B50
- 54 -
SCHEME 14 (CONT'ED)
~0
O
,~,CH3
2-(R2)-4-(N-Boc-5-chloro-4-
piperidinyloxy)phenylacetic acid,
EDC, HOBT
~ ~ CH3 Cl
g3' ~N~CH2~ ~N~ Boc
O R2
HCI
~ ~ CH3 Cl
[~ ~N~CH2~ ~NH
O R2
CA 02210138 1997-07-10
WO 96/22775 PCI/US96.'00P50
- 55 -
SCHEME 15
CH3
Ç~OMOM C4HgLi~ ~OMOM C4HgLi/ ~OMOM
OMOM OMOM OMOM
/C4HsLi~
~ CO2
CH3 CH3
~ HCI ~OMOM
CH30~ ~ HO~ TMS
O OH O OMOM
D EAD, P Ph3,
N-Boc-R3-4-piperidinol
CH30~ ~N~ B
O OH CH3 ~ R3
1. NaH, CH31 ~ ~/~
2. NaOH HO~ ~N~BoC
O OCH3
1. (COCI)2
CH3 2. CH2N2
O R3 3. AgOCOPh
HO~--~ ~CN~B 4. NaOH
OCH3
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SCHEME 15 (CONTINUED)
HO~J~ 'C Boc ~ 'C Boc
OCH3 O OCH3
1 _(R1 -piperidin-4-yl)-1 ,2-dihydro-4(H)-
3,1-benzoxazin-2-one, EDC, HOBT
or
1 (R1-piperidin-4-yl)-3,4-dihydro-
quinolin-2(1 H)-one, EDC, HOBT
\CN~(cH2)n~j ~CN'BOC
O OCH3
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SCHEME 16
H3C~oH DEAD, PPh3, H3C~:~O~/
CH30~ piperidinol CH30~ ~N~B
O OH O OH
1. NaH, CH31
2. NaOH
Boc HO~ ~N~B
/ O OCH3
1. (coc1)2
2. CH2N2
3. AgOCOPh
4. NaOH
1 (R1-piperidin-4-yl)-1,2-dihydro-4(H)-
3,1-benzoxazin-2-one, EDC, HOBT
or
1 (R1-piperidin-4-yl)-3,4-dihydro-
quinolin-2(1H)-one, EDC, HOBT
~X~;O
H3C~o~ /R3
N~(CH2)n~ ~ Boc
O OCH3
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SCHEME 17
0 1. CH3NHOCH3 0
H~J~ R7 2. CH3MgBr , H3C J~--R7
O /~//A
H3CJ~' R7 H202 NH40Ac
NaBH3CN
O
o~/R o=CN(CH3)2 H C~
N NK2CO3 / N
CH3
1. Boc20
4 R7/TMS-allyl 2 MCPBA
HO ~ ~,aqueous
formaldehyde
N~,N
CH3
~~C ~f~R o=CN(CH3)
N N~o K2CO3 / N~
CH3 / ~
R7~S-allyl
HO~ aqueous
N~,N~o
CH3
-
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_ 59 _
SCHEME 17 (CONTINUED)
X O
~; R7
~N~ ~OH HO~
~N~(CH2)n~ ~N~N~(O)n
O OCH3 CH3
/
DEAD, PH3P
~X~O
~N~ ~~C ~
O OCH3 CH3
NaBH3CN,
R7
~/~
(O)n
CH3
~X~O
(~ ~N~(CH2)n~ ~NH
O OCH3
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Compounds of the present invention where Rl or R3 are
non-hydrogen substituents requires the preparation of piperidin-4-ones
or piperidin-4-ols that are substituted at the 2- or 3-position. Examples
for the preparation of such 2- or 3-substituted piperidin-4-ones and 2-
5 or 3-substituted piperidin-4-ols and their subsequent conversion to
compounds of the present invention are given in Schemes 1-9. A broad
range of substituents can be introduced at the Rl and R3 positions using
methods as exemplified in Schemes 1-9 and by other methods f~mili~r
to those with ordinary skill in the art. Schemes 1 and 6 utilize a ketone
10 alkylation process and Schemes 5 and 9 utilize processes similar to those
described by P. Beak and co-workers (Tetrahedron Letters, 1989, vol.
30, pp. 1197-1200, Journal of Organic Chemistry, 1990, vol. 55, pp.
2578-2580) to obtain 3-substituted piperidin-4-ones and 2-substituted
piperidin-4-ols that can be used as intermediates to prepare compounds
15 of the present invention cont~ining non-hydrogen Rl and R3
substituents. Schemes 2 and 7 utilize processes similar to those
described by D. L. Comins and co-workers (Tetrahedron Letters, l9P~9,
vol. 30, pp. 5053-5056, Tetrahedron Letters, 1986, vol. 27, pp. 4549-
4552) and Schemes 3, 4, and 8 utilize 4-ketopipecolic acid (C.
20 Muhlemann, et al., Organic Syntheses, D. L. Coffen, editor, 1993, vol.
72, pp. 200-206) for the preparation of 2-substituted piperidin-4-ones
and 2-substituted piperidin-4-ols that can be used as intermediates to
obtain compounds of the present invention Cont~ining non-hydrogen R
and R3 substituents. Processes that involve cyclization of ene-iminium
25 species (for example: S. Hayes, et al., Journal of Organic Chemistry,
1991, vol. 56, pp. 4084-4086, and C. Agami, et al., Tetrahedron, 1992,
vol. 48, pp. 431 -442) are also useful for the preparation of 2- or 3-
substituted piperidin-4-ones and 2- or 3-substituted piperidin-4-ol~s that
can be used as intermediates to obtain compounds of the present
30 invention cont~ining non-hydrogen Rl and R3 substituents. Piperidin-4-
ones and piperidin-4-ols substituted at the 2- or 3-position can be used
to prepare compounds of the present invention with Rl being a non-
hydrogen substituent and which contain either the 1,2-dihydro-4(H)-3,1
benzoxazinone ring system (X = O, Schemes 6-9) or the 3,4-dihydro-
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2(1H)-quinolinone ri~gi~systeffi (X ~ C~2; Schème 10). The 3,4-
dihydro-2(1H)-quinolinone ring system can be prepared using methods
analogous to those described by H. Ogawa and co-workers (Journal of
Medicinal Chemistry, 1993, vol. 36, pp. 2011-2017) as indicated in
5 Scheme 10. A variety of R4 substituents can be incorporated into the
compouIlds of the present invention as exemplified in Scheme 11. For
example, the piperidine nitrogen can be derivatized by alkylation with
an alkyl halide, by reductive alkylation with an aldehyde and a reducing
agent such as sodium cyanoborohydride, by acylation with an activated
10 carbonyl compound (e.g., carboxylic acid chloride,
hydroxybenzotriazole ester, carboxylic acid anhydride, chloroformate,
etc.), by guanylation with a cyanoimine derivative, or by sulfonylation
with a sulfonyl chloride or sulfonic acid anhydride. Compounds of the
present invention in which the R4 substituent is a substituted or
15 unsubstituted picolyl or picolyl N-oxide group can be prepared as
exemplified in Scheme 12. A substituted or unsubstitutued pyridinyl
ester is converted to an alcohol using a reducing agent such as lithium
aluminum hydride. The alcohol is converted to an aldehyde using an
oxidizing agent such as manganese dioxide, or converted to a
20 chloromethyl derivative by treatment with a chlorin~ting agent such as
thionyl chloride. The aldehyde can be used to reductively alkylate the
free piperidine, or the chloromethyl derivative can be used to alkylate
the piperidine, giving compounds of the present invention in which R4 is
a substituted or an unsubstituted picolyl group. Treatment of the
25 chloromethyl derivative with an oxidizing agent such as m-
chloroperoxybenzoic acid gives the chloromethylpyridine-N-oxide
derivative, which is then used to alkylate the piperidine to provide
compounds of the present invention in which R4 is a substituted or an
unsubstituted picolyl N-oxide group. Syntheses of intermediates for
30 preparation of compounds of the present invention in which Rx is
halogen or alkyl are given in Schemes 13-16. Reagents such as N-
chlorosuccinimide or N-bromosuccinimide, N-iodosuccinimide, iodine,
bromine, fluorine, etc., can be used to halogenate a para-hydroxy
benzoic acid derivative as shown in Scheme 13, which can then be
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further derivatized to obtain compounds of the present invention in
which R8 is halogen as shown in Schemes 13 and 14. Directed ortho
metalation reactions can be used to prepare alkylated aromatics as
shown in Scheme 15, which can then be further elaborated to benzoic
acid and phenylacetic acid derivatives which are usful for preparing
compounds of the present invention in which RX is an alkyl group as
shown in Schemes 15 and 16. Syntheses of intermediates which are
useful for preparing compounds of the present invention in which an
alkyl group is substituted at the R9 position are given in Scheme 17.
Pyridine carboxylic acid derivatives can be converted to pyridyl alkyl
ketones, which can then be used to reductively alkylate the terminal
piperidine ring to give compounds of the present invention in which an
alkyl group is substituted at the R9 position. Alternatively, the pyridyl
alkyl ketone derivatives can be reductively ~min~ted with ammonia and
the resulting aminoalkyl pyridines can be converted to pyridinylalkyl
piperidinols by reaction with 1,1-dimethyl-4-piperidinone using a
procedure similar to that reported by M. E. Kuehne and co-worker
(Journal of Organic Chemistry, 1991, vol. 56, pp. 2701-2712) followed
by ketone reduction, or by reaction with allyltrimethylsilane and
aqueous formaldyhyde using a procedure similar to that reported by P.
A. Grieco and co-workers (Journal of the American Chemical Society,
1986, vol. 108, pp. 3512-3513). The pyridinylalkyl piperidinols are
then used in ether forming reactions to give compounds of the present
invention in which R9 is alkyl as shown in Scheme 17.
It is understood that the R1, R3, RX, and R9 substituents in
compounds of the present invention include but are not limited to the
specific substitutents given in Schemes 1-17. Also, Schemes 1-17 serve
to exemplify methods for preparation of compounds of the present
invention, but other methods and variations of those given, which are
f~mili~r to those of ordinary skill in the art, are also useful for
preparing compounds of the present invention.
The most preferred compounds of the invention are any or
all of those specifically set forth in these Examples and the following
Tables 1-12. These compounds are not, however, to be construed as
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forming the only genus ~at is considered as the invention, and any
combination of the compounds or their moieties may itself form a
genus. The following examples further illustrate details for the
preparation of the compounds of ~e present invention. Those skilled in
5 the art will readily understand that known variations of the conditions
and processes of the following preparative procedures can be used to
prepare these compounds.
All solvents were reagent grade and stored over 4A
molecular sieves. THF was distilled from calcium hydride under inert
10 atmosphere. Dioxane was dried and freed of peroxides by passage
through a column of activity I neutral alllmin~. Determination of
reaction pH was estimated by spotting an aliquot from the reaction
mixture on wetted E. Merck "colorpHast" pH 1-14 indicator strips.
Silica coated TLC plates were used to monitor all reactions (E. Merck,
15 5 x 10 cm Silica Gel 60 F254). MeOH(NH3) used for TLC refers to a
methanol solution saturated with NH3 gas at 0~C. Pressurized silica gel
column chromatography using 230-400 mesh silica gel was performed
according to the method of Still, Kahn, and Mitra (J. Orf~. Chem.
(1978) vol. 43, p.2923). All temperatures are degrees Celsius unless
20 noted otherwise.
Analytical HPLC were run on a Spectra Physics
SP4270/8800 instrument using the following conditions:
Column: Vydac Clg, 0.21 x 15 cm
25 UV detection at 214 nm
Mobile Phases A = 0.1 % by volume TFA in H2O; B = MeOH;
C = 0.1 % by volume TFA in acetonitrile
Method A:
Gradient T = 0 min, 95% A, 5% C
T = 15 min, 5% A, 95% C
Flow = 2.0 mL/min
Method B:
Gradient T = 0 min, 95% A, 5% C
T = 30 min, 5% A, 95% C
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Flow = 1.5 mL/min
lH NMR spectra were measured at 300 MHz on a Varian
XL-300, at 400 MHz on a Varian XL-400, and at 360 MHz on a Nicolet
5 NT-360 using (CH3)4Si as an internal standard All NMRs for the
compounds of the Examples which follow were consistent with
structures. Past atom bombardment mass spectra (FAB MS) were
obtained on a VG-ZAB-HF spectrometer.
EXAMPLE 1
1-((1 -(2,4,6-Trimethoxybenzoyl)piperidin-4-yl)-4H-3, 1 -benzoxazin-
2( 1 H)-one
~~~~ CH
O OCH3
Step 1. 1-t-Butyloxycarbonyl-4-piperidinone (20 g, 0.10
mol), 2-aminobenzyl alcohol (13 g, 0.11 mol), and acetic acid (14 mL,
0.22 mol) were dissolved in dry toluene (500 mL). The solution was
refluxed under inert atmosphere for 3 h with azeotropic removal of
water. The solution was cooled to ambient temperature and concentrated
20 under reduced pressure to one half of the original volume. To the
solution was added NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL).
Acetic acid (10 mL, 0.15 mmol) was added dropwise over a period of
about 1 h. The reaction was stirred at ambient temperature for 24 h.
The mixture was concentrated under reduced pressure and the residue
25 was dissolved in EtOAc (750 mL). The EtOAc layer was washed with
saturated aqueous NaHCO3 (3x 500 mL) and brine (250 mL). The
EtOAc layer was dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. The residue was purified by pressurized silica
gel column chromatography, using a gradient elution of 15-30% EtOAc-
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hexanes. 1-t-Butyloxycarbonyl-4-((2-
hydroxymethyl)phenylamino)piperidine was obtained as a gum (TLC: Rf
= 0.30 (30:70 EtOAc:hexanes); HPLC(method A) retention time - 8.89
min).
Step 2. 1-t-Butyloxycarbonyl-4-((2-
hydroxymethyl)phenylamino)-piperidine (24 g, 78 mmol) from step 1
above was dissolved in dry THF (250 mT ) and cooled to 0~C under an
atmosphere of nitrogen. To the solution was added DIEA (41 mL, 0.24
mol) and triphosgene (8.54 g, 28.8 mmol). The reaction was stirred at
0~C for lh, and then at ambient temperature for 24 h. Ether (250 mL)
was added, the mixture was cooled to 0~C and then filtered to remove the
hydrochloride salt of DIEA. The filtrate solvents were removed under
reduced pressure and the residue was dissolved in EtOAc (750 mL). The
EtOAc solution was washed with 5% aqueous citric acid (2x 500 mL),
water (250 mI,), and saturated aqueous NaHCO3 (2x 500 mL). The
EtOAc layer was dried (MgSO4), filtered, and the solvent was removed
under reduced pressure. The residue was boiled in ether (ca. 200 mL)
until the solid had dissolved. Cooling overnight gave l-(N-t-
butyloxycarbonyl-4-piperidinyl)-4H-3,1 -benzoxazin-2(1 H)-one as off-
white crystals, mp 143-145~C (TLC: Rf = 0.28 (30:70 EtOAc:hexanes);
HPLC(method A) retention time = 8.77 min; FAB MS: m/z 333 (M+ +
H))-
Step 3. A stirred solution of l-(N-t-butyloxycarbonyl-4-
piperidinyl)-4H-3,1-benzoxazin-2(1H)-one (19 g, 57 mmol) from step 2
above in EtOAc (500 mL) was cooled to 0~C. HCl gas was bubbled
through the solution for 30 min. Stirring was continued at 0~C for 1 h,
during which time a precipitate had formed, and the reaction was
warmed to ambient temperature for 1 h. The stirred suspension was
cooled to 0~C and cold ether (250 mL) was added. The precipitate was
collected by filtration and washed with ether. The solid was dried
under reduced pressure for 18 h, giving 1-(4-piperidinyl)-4H-3,1-
benzoxazin-2(1H)-one hydrochloride as a white amorphous solid (TLC:
Rf = 0.29 (90: 10: 1 CH2C12:MeOH:NH4OH); HPLC(method A)
retention time - 3.88 min; FAB MS: m/z 233 (M+ + H)).
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Step 4: To a solution of the hydrochloride salt of 1-(4-
piperidinyl)-4(H)-3,1-benzoxazin-2(1H)-one (150 mg, 0.56 mmol) from
Step 3 above in DMF (5 mL) was added 2,4,6-trimethoxy-benzoic acid
(120 mg, 0.56 mmol), HOBT (92 mg, 0.60 mmol), and EDC (140 mg,
5 0.73 mmol). To the stirred solution was added DIEA (0.19 mL, 1.1
mmol) until the reaction was pH 7 as judged by spotting an aliquot on
wetted E. Merck "colorpHast" pH 1-14 indicator strips. The reaction
was stirred at ambient temperature for 18 h and the solvent was
removed under reduced pressure. The residue was dissolved in EtOAc
10 (50 mL) and washed with 5% aqueous citric acid (25 mL), water (25
mL), and saturated aqueous NaHCO3 (25 mL). The EtOAc layer was
dried (MgSO4), filtered, and the solvent was removed under reduced
pressure. The residue was purified by pressurized silica gel column
chromatography using a gradient elution of 1-3% MeOH-CHC13. The
15 title compound was obtained as an amorphous solid.
Analysis calculated for (C23H26N2O6~ 0.6 H2O)
C, 63.17; H, 6.27; N, 6.41
Found C, 63.13; H, 5.9~; N, 6.14
TLC: Rf = 0.37 (9~:2 CHC13:MeOH)
20 HPLC (method A): retention time 7.77 min
FAB MS: m/z 427 (M+ + H)
EXAMPLE 2
25 1 -(1 -(4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoyl)-
piperidin-4-yl)-4(H)-3 ~ 1 -benzoxazin-2(1 H)-one
~0~0
~N~ \CNC~2C(CH3)3
O OCH3
Step 1: To a strirred solution of triphenylphosphine (57.2
g, 0.21~ mol) and methyl 2,4-dihydroxybenzoate (29.2 g, 0.174 mol) in
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dry THF (250 mL) at 0~C was added a solution of N-t-butyloxy-4-
piperidinol (43.8 g, 0.218 mol) and diethyl azodicarboxylate (37.9 mL,
0.218 mol) in dry THF (150 mL) dropwise over a period of 2 h. The
resulting solution was warmed to ambient temperature over 2 h and
5 stirred for an additional 16 h. The solvent was concentrated to half of
the original volume under reduced pressure, ether (200 mL) was added,
and the mixture was cooled to 0~C for 3 h. The precipitated
triphenylphosphine oxide was removed by filtration and washed with
cold ether, and the filtrate solvents were removed under reduced
10 pressure. The residue was purified by pressurized silica gel column
chromatography using a gradient elution of 10-25% EtOAc-hexane.
Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoate
was obtained as a waxy solid.
Step 2: To a solution of methyl 4-(N-t-butoxycarbonyl-4-
15 piperidinyloxy)-2-hydroxybenzoate (50 g, 0.14 mol) from Step 1 above
and iodomethane (17.4 mL, 0.28 mol) in DMF (300 mL) at 0~C was
added NaH (6.55 g of a 60% suspension in mineral oil, 0.164 mol) in
several portions over a period of 2 h. The resulting suspension was
warmed to ambient temperature and stirred for 18 h. The mixture was
20 quenched with methanol (5 mL) and concentrated under reduced
pressure. The residue was suspended in EtOAc (500 mL) and washed
with water (2x 250 mL) and brine (250 mL). The EtOAc layer was
dried (MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by pressurized silica gel column
25 chromatography using a gradient elution of 20-40% EtOAc-hexane.
Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoate
was obtained as a gum that solidified on standing (TLC: Rf= 0.25 (3:1
hexane:EtOAc); HPLC (method A) retention time = 9.72 min).
Step 3: Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-
30 2-methoxybenzoate (35 g, 96 mmol) from Step 2 above was dissolved in
MeOH (250 mL) and to the solution was added 2 N NaOH (100 mL, 200
mmol). The stirred mixture was warmed to 70~C for 3 h. The solution
was cooled to ambient temperature, concentrated under reduced
pressure, cooled to 0~C and 0.5 M aqueous citric acid solution (300
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mL) was added. To the suspension was added EtOAc (500 mL) and
water (300 mL). The EtOAc layer was separated and the aqueous phase
was washed with EtOAc (200 mL). The combined EtOAc layers were
washed with brine (250 mL), dried (MgSO4), filtered, and the solvent
5 was removed under reduced pressure to give 4-(N-t-butoxycarbonyl-4-
piperidinyloxy)-2-methoxybenzoic acid as a foam that solidified on
standing in vacuo (HPLC (method A) retention time = 8.46 min).
Step 4: 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-
methoxybenzoic acid from step 3 above wa.s coupled to the
10 hydrochloride salt of 1 -(4-piperidinyl)-4(H)-3,1-benzoxazin-2(1H)-one
from step 3 of Example 1 using the procedure given in step 4 of
Example 1. The crude product was purified by pressurized silica gel
column chromatography using a gradient elution of 1-4% MeOH-DCM.
The title compound was obtained as a white foam by evaporation of a
15 DCM solution under reduced pressure.
Analysis calculated for (C31H3gN3O7, 0.35 DCM, 0.1
H20)
C, 63.04; H, 6.73; N, 7.04
Found C, 63.05; H, 6.77; N, 7.20
20 TLC: Rf = 0.15 (98:2 DCM:MeOH)
HPLC (method A): retention time 10.06 min
FAB MS: m/z 566 (M+ + H)
EXAMPLE 3
1 -(1 -(4-(4-Piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -
benzoxazin-2(1 H)-one
~0~0
g3' ~N ~ ~N H
O OCH3
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1-(1-(4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one from
Fx~mrle 2 (5.0 g, 8.8 rnmol) was treated with 4N HCl in dioxane (40
mL) at ambient temperature for 1 h. The dioxane was evaporated
5 under reduced pressure and the residue was triturated in EtOAc-ether
and filtered. The solid was dried in vacuo for 24 h to give the
hydrochloride salt of the title compound. A small portion of this
material was purified to greater than 99% homogeneity by preparative
reverse phase HPLC using an acetonitrile-water gradient con~ining
10 0.1 % TFA. The TFA salt of the title compound was obtained as an
amorphous solid by Iyophili7~tion.
Analysis calculated for (C26H31N3O5, 1.35 TFA, 0.~5
H20)
C, 55.24; H, 5.31; N, 6.73
15 Found C, 55.27; H, 5.29; N, 6.70
TLC: Rf = 0.33 (90: 10:0.5 DCM:MeOH:NH40H)
HPLC (method A): retention time 6.14 min
FAB MS: m/z 466 (M+ + H)
EXAMPLE 4
1 -(1 -(4-(4-(N-Acetyl)piperidinyloxy)-2-methoxybenzoyl)piperidin-4-
yl )-4(H)-3 ~ 1 -benzoxazin-2(1 H)-one
~O~fO
~N~ N~CH3
O OCH3 0
To a solution of the hydrochloride salt of 1-(1-(4-(4-
piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -
benzoxazin-2(1H)-one (0.25 g; 0.50 mmol) from Example 3 in DCM (5
mL) at ambient temperature was added acetic anhydride (0.75 mmol)
and DIEA (1.0 mmol). The solution was stirred at ambient temperature
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for 24 h, diluted with DCM (20 mL), washed with saturated aqueous r
NaHCO3 (50 mL), dried (MgSO4), and filtered. The solvent was
removed under reduced pressure and the residue was purified by
pressurized silica gel column chromatography using a gradient elution
5of 2-5% MeOH-DCM. The title compound was obtained as an
amorphous solid by lyophili7~tion from acetonitrile-H2O.
Analysis calculated for (C2gH33N3O6, 0.05 CH3CN, 1.4
H20)
C, 63.06; H, 6.77; N, 7.99
10Found C, 63.11; H, 6.44; N, 7.95
TLC: Rf = 0.28 (95:5 DCM:MeOH)
HPLC (method A): retention time 7.35 min
FAB MS: mlz 507 (M+ + H)
EXAMPLE 5
1 -(1 -(4-(N-Methylsulfonyl-4-piperidinyloxy)-2-methoxybenzoyl)-
piperidin-4-yl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~0~0
~N~ ~NSO2CH3
O OCH3
The hydrochloride salt of 1 -(1 -(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one from
Example 3 (0.25 g; 0.50 mmol) was mesylated with methanesulfonyl
chloride (0.60 mmol) and DIEA (1.1 mmol) in DCM (10 mL) at
ambient temperature for 18 h. The mixture was diluted with DCM (20
mL) and washed with saturated aqueous NaHCO3 (50 mL), dried
(MgSO4), and filtered. The solvent was removed under reduced
pressure and the residue was purified by preparative reverse phase
HPLC using an acetonitrile-water gradient cont~ining 0.1 % TFA. The
title compound was obtained as a white solid by lyophili7~tion.
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Analysis calculated for (C27H33N306S, 1.3 TFA, 0.25
H20)
C, 51.05; H, 5.04; N, 6.03
Found C, 51.04; H, 5.03; N, 6.40
TLC: Rf = 0.28 (95:5:0.5 DCM:MeOH:NH40H)
HPL,C (method A): retention time 8.30 min
FAB MS: m/z 544 (M+ + H)
EXAMPLE 6
1 -(1 -(4-(1 -t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoyl)piperidin-
4-yl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~0~0
~N~3' co2c(CH3)3
Step 1: N-t-Butyloxycarbonyl-3-piperidinylmethanol was
etherified with ethyl 4-hydroxybenzoate using the procedure given in
Step 1 of Example 2. The crude product was purified by pressurized
silica gel column chromatography using a gradient elution of 10-25%
EtOAc-hexanes. 4-(N-t-Butyloxycarbonyl-3-
piperidinylmethoxy)benzoic acid ethyl ester was obtained as an oil.
Step 2: 4-(N-t-Butyloxycarbonyl-3-
piperidinylmethoxy)benzoic acid ethyl ester was saponified with
aqueous NaOH in MeOH using the procedure given in Step 3 of
Example 2. 4-(N-t-Butyloxycarbonyl-3-piperidinylmethoxy)benzoic
acid was obtained as a foam by evaporation of a DCM solution.
Step 3: 4-(N-t-Butyloxycarbonyl-3-
piperidinylmethoxy)benzoic acid was coupled to the hydrochloride salt
of 1-(4-piperidinyl)-4(H)-3,1-benzoxazin-2(IH)-one from step 3 of
Example 1 using the procedure described in step 4 of Example 1. The
crude product was purified by pressurized silica gel column
CA 02210138 1997-07-10
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chromatography using a gradient elution of 1-4% MeOH-DCM. The
title compound was obtained as a white foam by evaporation of a DCM
solution under reduced pressure.
Analysis calculatedfor(C31H39N306, 1.1 CH2C12)
C, 59.95; H, 6.46; N, 6.53
Found C, 59.54; H, 6.65; N, 7.05
TLC: Rf = 0.24 (97:3 DCM:MeOH)
HPLC (method A): retention time 10.55 min
FAB MS: m/z 550 (M+ + H)
EXAMPLE 7
1 -(1 -(2,4-dimethoxybenzoyl)-2-cyano-4-piperidinyl)-4(H)-3,1 -
benzoxazin-2(1 H)-one
~0
~N~o
~CN
0~
OCH3
Step 1: 1-(4-Piperidinyl)-1,2-dihydro-4(H)-3,1-
benzoxazin-2-one hydrochloride (150 mg, 0.559 mmol) from ~tep 3 of
Example 1 (9g~ mg, 3.6~ mmol) was treated with aqueous sodium
carbonate and the resulting free base was extracted into ether. The
20 dried (sodium sulfate) ether layer was evaporated in vacuo and the
residue evaporated three times from methylene chloride/methanol. The
residue was treated with methylene chloride and filtered to remove
insoluble material. The methylene chloride solution was evaporated to
dryness in vacuo and the residue treated with acetic acid (0.197 mL) and
25 water (2 mL). To the resulting solution was added an aqueous
- -
CA 02210138 1997-07-10
WO 96/22775 PCI'/US9G/C 8!;0
suspension of pulverized calcium hypochlorite (637 mg). The mixture
was stirred at ambient temperature for 30 min, then combined wi~
water and extracted with e~er. The ether layer was washed with water
and with brine, dried over sodium sulfate, filtered, and evaporated to
5 dryness in vacuo to give 1-(N-chloro-4-piperidinyl)-4(H)-3,1-
benzoxazin-2(1H)-one.
Step 2: 1 -(N-Chloro-4-piperidinyl)-4(H)-3,1 -benzoxazin-
2(1H)-one from Step 1 above (230 mg, 0.86 mmol) was dissolved in
warm ether (30 mL) and the solution was added dropwise to a
10 suspension of potassium superoxide (135 mg, 1.9 mmol) and 18-crown-
6 (10 mg, 0.04 mmol) in ether (10 mL). The mixture was stirred at
ambient temperature for five days, with two additional lots of 135 mg
each of potassium superoxide being added on the second and third days.
The reaction was filtered and the filtrate was added dropwise to an ether
15 solution of trimethylsilylcyanide (0.172 mL, 12~ mg, 1.3 mmol). The
mixture was stirred at ambient temperature for 18 hours, then
evaporated to dryness in vacuo. The residue was chromatographed on
silica gel eluted with 4:96 MeOH:CH2C12. The combined product
fractions were evaporated to dIyness in vacuo, and the residue was
20 evaporated twice from ether to give 1-(2-cyano-4-piperidinyl)-4(H)-
3,1-benzoxazin-2(1H)-one (FAB MS: M+H @ m/z=25~).
Step 3: 1-(2-Cyano-4-piperidinyl)-4(H)-3,1-benzoxazin-
2(1H)-one from Step 2 above (l9~s mg, 0.77 mmol) was dissolved in
methylene chloride (2 mL) and treated with 2,4-dimethoxybenzoyl
25 chloride (170 mg, 0.84 mmol) followed by triethylamine (0.12 mL, 85
mg, 0.85 mmol). The mixture was stirred at ambient temperature for
one hour, then chromatographed on silica gel eluted with 1 :9
ether:CH2C12. The product fractions were combined and evaporated to
dryness in vacuo. The residue was crystallized from ether to give the
30 title compound: mp 176-177~C.
TLC: Rf= 0.33 tl :9 ether:CH2C12)
FAB MS: M+H @ m/e= 422
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- 74 -
Anal. cal'd for C23H23N3O5:
C, 65.54; H, 5.50; N, 9.97.
Found: C, 65.51; H, 5.52; N, 9.89.
S EXAMPLE ~
1-(1 -(2,4-dimethoxybenzoyl)-2-carboxamido-4-piperidinyl)-4(H)-3 ,1-
benzoxazin-2( 1 H)-one
~0
~N~o
~L CONH2
N OCH3
~OCH3
1-(1-(2,4-dimethoxybenzoyl)-2-cyano-4-piperidinyl)-4(H)-
3,1-benzoxazin-2(1H)-one from Example 7 (1~.4 mg, 0.044 mmol) was
dissolved in warm 95% ethanol (2 mL). The solution was cooled, and
aqueous sodium hydroxide (0.005 mL of a 10% solution; 0.0125
mmol)) was added followed by 30% hydrogen peroxide (0.005 ml, 0.05
15 mmol). The mixture was stirred at 45-50~C for 6 h, then at ambient
temperature for 66 hr. The mixture was concentrated in a stream of
nitrogen, and the residue was treated with water, made basic with
saturated sodium bicarbonate solution, and extracted with ethyl acetate.
The organic layers were combined and washed with brine, dried over
20 sodium sulfate, and filtered, and the filtrate was evaporated to dryness
in vacuo. The residue was chromatographed on silica gel eluted with
3:97 MeOH:CH2C12. The product fractions were combined and
evaporated to dryness in vacuo, and the residue was crystallized from
ether to yield the title compound: mp 210-212~C.
25 Anal. cal'd for C23H25N3o6-o.os C4Hloo-o.4sH2o:
CA 02210138 1997-07-10
WO 96t22775 PCT/US~6/00850
C, 61.74; H, 5.90; N, 9.31.
Found: C, 61.66; H, 5.61; N, 9.01.
TLC: Rf=0.33 (3:97 MeOH:CH2C12)
FAB MS: M+H @ mlz= 440
s
EXAMPLE 9
1 -(1 -(2,4-Dimethoxybenzoyl)-3-methoxycarbonyl-4-piperidinyl)-4(H)-
3,1 -benzoxazin-2(1 H)-one
~N~lo
~COOCH3
N~ OCH3
0~
OCH3
Step 1: Methyl 4-oxo-3-piperidinecarboxylate
hydrochloride (3.5 g, 18.1 mmol) was stirred in methylene chloride (30
mL) and treated with di-t-butyl dicarbonate (3.6 g, 16.5 mmol)
followed by triethylamine added dropwise to m~in~in the pH of the
mixture (moistened E. Merck colorpHast sticks) in the range 7-8. The
mixture was stirred at ambient temperature for 18 h, then washed with
1 N HCl followed by saturated aqueous sodium bicarbonate. The
organic layer was dried over sodium sulfate, filtered, and evaporated to
dryness in vacuo to give methyl l-Boc-4-oxo-3-piperidinecarboxylate.
Step 2: Methyl l-Boc-4-oxo-3-piperidinecarboxylate from
Step 1 above (3.86 g, 15 mmol) was combined with 2-aminobenzyl
alcohol (l.S g, 12.2 mmol) and acetic acid (1.29 mL, 1.35 g, 22.5
mmol) in methanol (10 mL). Sodium cyanoborohydride (0.94 g, 15
mmol) was added and the mixture was stirred at ambient temperature
for 3.5 h. The solvent was removed in vacuo and the residue treated
with ethyl acetate (100 mL). The solution was washed with saturated
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aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and
evaporated to dryness in vacuo. The residue was chromatographed on
silica gel eluted with 1:4, 1:2, and 3:5 EtOAc:hexane. The combined
product fractions were evaporated to dryness in vacuo to give methyl 1-
Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate.
Step 3: Methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-
piperidine carboxylate from Step 2 above (4.1 g, 11.3 mmol) was
stirred in THF (40 mL) in an ice bath and treated with triphosgene
(1.11 g, 3.74 mmol) followed by triethylamine (4.7 mL, 3.41 g, 33.7
mmol). The mixture was stirred at ambient temperature for 1~ h, then
treated with an additional 0.47 g of triphosgene and 1.9 mL of
triethylamine, and stirred an additional 4.5 h. Water was added and the
mixture was extracted with ethyl acetate. The combined ethyl acetate
layers were washed with 2 N HCl then with saturated aqueous sodium
bicarbonate, dried over sodium sulfate, filtered, and evaporated to
dryness in vacuo. The residue was chromatographed on silica gel eluted
with CHC13 followed by 1 :99 MeOH:CHC13. The combined product
fractions were evaporated to dryness in vacuo to give methyl 1-Boc-4-
(3,1-benzoxazin-2-one-1-yl)-3-piperidine carboxylate.
Step 4: Methyl 1-Boc-4-(3,1-benzoxazin-2-one-1-yl)-3-
piperidine carboxylate from Step 3 above (0.6 g, 1.5 mmol) wa~i stirred
in ethyl acetate in an ice bath, then saturated with HCI gas and ~tirred
another 15 min in the cold. The mixture was evaporated in vacuo.
Three portions of ethyl acetate were successively added and evaporated
in vacuo to give methyl 4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine
carboxylate hydrochloride.
Step 5: Methyl 4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine
carboxylate hydrochloride from Step 4 above (0.26 g, 0.97 mmol) was
stirred in methylene chloride (10 mL), and 2,4-dimethoxybenzoyl
chloride (0.19 g, 0.95 mmol) was added followed by triethylamine
(0.26 mL, 0.19 g, 1.9 mmol). The mixture was stirred at ambient
temperature for 2.5 h, then chromatographed on silica gel eluted with
500: 10: 1 CHC13 :MeOH:NH40H. The combined product fraction~s were
evaporated to dryness in vacuo. The residue was rechromatographed on
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WO 96/22775 PCT/US96/00850
silica gel eluted with 4:1 EtOAc:hexane and the combined product
i' fractions were evaporated to dryness in vacuo to give the title
compound as a mixture of diastereomers (amorphous solid): mp 75-
100~C (indistinct).
S Anal. cal'd for C24H26N207-0.05 EtOAc-0.6 H20:
C, 61.88; H, 5.92; N, 5.96.
Found: C, 61.75; H, 5.87; N, 6.29.
TLC: Rf= 0.26, 0.39 (EtOAc)
FAB MS: M+H @ m/z= 455
HPLC: 38% + 58%
E~AMPLE 10
1-( 1 -(4-(4-piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-
4(H)-3 1-benzoxazin-2(1H)-one
O O
~N~N ~ ~O~N H
H3CO
~tep 1: To a solution of 2-methoxy-4-(N-t-
butyloxycarbonyl-4-piperidinyloxy)benzoic acid (3.2 g; 9.1 mmol)
from Step 3 of Example 2 in THF was added thionyl chloride (1 mL;
13.7 mmol) and pyridine (2 drops) while under a nitrogen atmosphere.
The solution was stirred for 4 hours and then concentrated under
reduced pressure to dryness. The residue was suspended in ether and
filtered, and the filtrate was concentrated to dryness to yield 2-methoxy-
4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoyl chloride.
Step 2: A two phase mixture of ether (66 mL) and 40%
aqueous potassium hydroxide (20 mL) was cooled to 0~C and N-nitroso-
methylurea (6.6 g) was added portionwise over 30 minlltes. The
resulting yellow diazomethane/ether solution was decanted and dried
over potassium hydroxide. The diazomethane/ether solution was
- ~ =
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- 78 -
decanted and cooled to 0~(:~. At this point, a solution of 2-methoxy-4-
(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoyl chloride from Step 1
above in THF was added dropwise to the diazomethane/ether solution.
The resulting bronze solution was warmed to ambient temperature and
S stirred for 3 hours. Nitrogen was bubbled through the reaction mixture
for 1 hour to remove excess diazomethane and the solution was
concentrated under reduced pressure to dryness. The residue was
purified by pressurized silica gel column chromatography (elute with
6:94 ether:methylene chloride) to yield 2-methoxy-4-(N-t-butyloxy-
10 carbonyl-4-piperidinyloxy)phenyldiazomethyl ketone.
Step 3: A solution of 2-methoxy-4-(N-t-butyloxycarbonyl-
4-piperidinyloxy)phenyldiazomethyl ketone (930 mg; 2.48 mmol) from
Step 2 above in dry methanol (7 mL) was refluxed and a solution of
freshly prepared silver benzoate (100 mg) in triethylamine (1 mL) was
lS added portionwise over 45 minlltes. The solution was refluxed for an
additional 30 minutes, then cooled and filtered. The filtrate was
concentrated to dryness and the crude oil was purified by pressurized
silica gel column chromatography (elute with S:9S methanol:methylene
chloride) to yield methyl 2-methoxy-4-(N-t-butyloxycarbonyl-4-
20 piperidinyloxy)phenylacetate.
Step 4: To a solution of methyl2-methoxy-4-(N-t-
butyloxycarbonyl-4-piperidinyloxy)phenylacetate (1.37 g; 3.6 mmol)
from Step 3 above in 27 mL of THF was added aqueous lithium
hydroxide solution (4.5 mL, l.OlM) dropwise. The reaction mixture
25 was stirred for 16 hours and concentrated to dryness under reduced
pressure. The residue was partitioned between ethyl acetate and O.S M
aqueous hydrochloric acid. The organic phase was separated and the
aqueous phase was extract with ethyl acetate (2x). The combined
organic extracts were dried over sodium sulfate, filtered, and the
30 solvent was removed under reduced pressure to yield 2-methoxy-4-(N-
t-butyloxycarbonyl-4-piperidinyloxy)phenylacetic acid.
Step 5: To a solution of the hydrochloride salt of 1-(4-
piperidinyl)-4(H)-3,1-benzoxazin-2(1H)-one from Step 3 of Example 1
(250 mg; 0.93 mmol) in 8 mL of DMF was added 2-methoxy-4-(N-t-
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- 79 -
butyloxycarbonyl-4-piperidinyloxy)phenylacetic acid (340 mg; 0.93
mmol) from step 4 above, EDC (213 mg; 1.11 mmol), and HOBT (147
mg; 1.09). Triethylamine (0.55 mL) was added to make the solution
basic (pH 8-9). After stirring for 18 hours, the solvent was removed
5 under reduced pressure. The residue was partitioned between ethyl
acetate and sodium bicarbonate (sat., aqueous). The ethyl acetate layer
was washed with saturated aqueous sodium bicarbonate and brine, dried,
filtered, and concentrated under reduced pressure to an oil. The crude
solid was purified by pressurized silica gel column chromatography
10 (elute with 3:97 methanol:methylene chloride). 1-(1-(4-(1-tert-
Butyloxycarbonyl-4-piperidinyloxy)-2-methoxyphenylacetyl)-piperidin-
4-yl)--4(H)-3,1-benzoxazin-2(1H)-one was obtained as a white solid
from ether.
Step 6: 1-(1-(4-(1 -tert-Butyloxycarbonyl-4-
15 piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-4(H)-3,1-
benzoxazin-2(1H)-one from Step 5 above (0.20 g, 0.35 mmol) was
dissolved in ethyl acetate and cooled in an ice bath. Once cool, the
solution was saturated with gaseous HCI for 30 minutes. The mixture
wa~ evaporated to dryness. Ether was added and removed in vacuo
20 three times, and the residue was triturated with ether and filtered to
yield the hydrochloride salt of the title compound as a white solid.
Analysis: Calc'd for C27H33N305, 1.45 HCI 0.95 H2O
Calc'd: C, 58.96; H, 6.66; N, 7.64.
Found: C, 58.94; H, 6.66; N, 7.70.
25 FAB MS: M/Z = 480 (M+ + H)
EXAMPLE 1 1
1-(1-(4-( 1 -(2-methyl-3-pyridylmethyl)-4-piperidinyloxy)-2-methoxy-
30 benzoyl)piperidin-4-vl)-4(H)-3 ,1 -benzoxazin-2( 1 H)-one
.
CA 02210138 1997-07-10
WO 96/22775 PCT/US~)G/~ iO
- 80 -
~0~ 0
h'N~ ~'Cl ~
N~ N ~ N
O OCH3 CH3
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one
hydrochloride from Example 3 (125 mg, 0.249 mmol) in DMF (5 mL)
5 was added 3-chloromethyl-2-methylpyridine (36.9 mg, 0.260 mmol)
and DIEA (96.5 mg, 0.13 mL, 0.747 mmol). The solution was stirred
at 40~C for 18 hours. The solvent was removed under reduced
pressure. The residue was partitioned between aqueous saturated
NaHCO3 (10 mL) and methylene chloride. The organic phase was
10 dried (MgSO4), filtered, and the solvent was removed under reduced
pressure. The residue was purified by pressurized silica gel column
chromatography using 95:5:0.5 methylene chloride:methanol:NH40H a~
eluant. The title compound was dissolved in methanol and 1.0
equivalent of l N aqueous HCl was added. The solution was evaporated
15 to dryness under reduced pressure. The residue was crystallized from a
mixture of ethyl acetate and methanol to give the monohydrochloride
salt of the title compound as a white crystalline solid.
Analysis calculated for C33H3p~N405, 1.0 HCl, 1.6 H20
C, 62.32; H, 6.69; N, 8.81
20 Found C, 62.44; H, 6.29; N, 8.80
TLC: Rf = 0.28 (95:5:0.5 DCM:MeOH:NH40H)
HPLC (Method A) retention time 5.79 min
FAB MS: m/z = 571 (M+ + H)
EXAMPLE 12
(4-(N-tert-Butyloxycarbonyl-4-piperidinyloxy)-2-methoxyphenyl-
acetyl)piperidin-4-yl)-3.4-dihydro-2(1 H)-quinolinone
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- 81 -
~0
O OCH O 'I<
To 30 mL of DMF was added l-(piperidin-4-yl)-3,4-
dihydro-2(1H)-quinolinone (1.0 gm, 4.34 mmol; prepared by the
method of Ogawa et al. J. Med. Chem. 1993, vol. 36, pages 2011-2017).
5 To the stirred solution was added 4-(N-tert-butyloxycarbonyl-4-
piperidinyloxy)-2-methoxyphenylacetic acid (1.59 gm, 4.34 mmol)
from Step 4 of Example 10, followed by HOBT (730 mg, 4.8 mmol),
EDC (911 mg, 4.8 mmol) and DIEA (1.0 mL, 5.7). After stirring at
ambient temperature for 18 h the solvent was removed under reduced
10 pressure and the residue was partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with water (2x) and brine, and was dried over anhydrous MgSO4. The
solution was filtered and the solvent was removed under reduced
pressure to give an oil which was purified by pressurized silica gel
15 column chromatography using 98:2 CH2C12:MeOH as eluant. The
product-containing fractions were evaporated under reduced pressure to
give the title compound as an amorphous solid.
Analysis: C33H43N306 0.2 H2O
C, 68.17; H, 7.53; N, 7.23
20 Found C, 68.60; H, 7.50; N, 7.27
TLC: Rf = 0.45 (95:5 CHC13:MeOH)
HPLC (method A): retention time = 10.34 min, purity = 99%
FAB MS: m/z= 578 (M + H+)
EXAMPLE 13
1 -(1 -(4-(4-Piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-3,4-
dihydro-2(1 H)-quinolinone
,
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- 82 -
~0 - ,
[~ ~CN~CH2~ ~NH
O OCH3
To 75 mL of dry ethyl acetate under N2 was added 1-(1-(4-
(N-tert-butyloxycarbonyl-4-piperidinyloxy) -2-methoxyphenylacetyl)-
piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (1.2 g, 2 mmol) from
5 Example 12, and the solution was cooled to 0~C in an ice-water bath.
HCl gas was bubbled into the solution at 0~C for 30 min. The solution
was stirred for an additional 30 min at 0~C then the ice bath was
removed and N2 was bubbled through the solution to remove the exces~
HCl. Addition of hexane caused precipitation of the HCl salt. The solid
10 was dried in vacuo to remove solvent and then was partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate. The organic
layer was washed with water and brine and was dried over anhydrous
MgSO4. The solvent was removed underreduced pressure. The
residue was dissolved in methylene chloride and the solvent was
15 removed under reduced pressure to give the title compound as an
amorphous solid.
Analysis: C2gH35N3O4~ 1.3 CH2Cl2~ 0.15 H2O
C, 59.57; H, 6.47; N, 7.11
Found C, 59.59; H, 6.28; N, 7.23
20 TLC: Rf = 0.15 (90: 10 CHCl3:MeOH)
HPLC (method A): retention time = 7.1 min
FAB MS: m/z= 478 (M + H~)
EXAMPLE 14
1 -(1 -(4-Hydroxy-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -
benzoxazin-2(1 H)-one
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- 83 -
~0~0
~N~,$
O OCH3
Step 1. To a well-stirred, 0~C solution of methyl 2,4-
dihydroxybenzoate (50 g, 300 mmol) in acetone (1000 mL) was added
K2CO3 (150 g, 1000 mmol) and benzyl bromide (39 mL, 330 mmol).
The solution was allowed to warm to ambient temperature over 48 h.
The mixture was filtered through celite and the filtrate solvent was
removed under reduced pressure. The residue was dissolved in EtOAc
(1000 mL) and washed with water (250 mL) and saturated aqueous
NaHCO3 (500 mL). The EtOAc layer was dried (MgSO4), filtered, and
the EtOAc was removed under reduced pressure. The residue was
purified by pressurized silica gel column chromatography using 5:1
hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-hydroxybenzoate was
obtained as a white powder.
Step 2. To a stirred, 0~C solution of methyl 4-benzyloxy-
2-hydroxybenzoate (12 g, 46 mmol) from step 1 above in DMF (150
mL) was added NaH (2.76 g of a 60% suspension in mineral oil, 69
mmol) and methyl iodide (7.2 mL, 116 mmol). The solution was
warmed to ambient temperature and stirred for 18 h. The reaction
mixture was poured onto ice and the resulting solution was extracted
with ether (3 x 200 mL). The organic phase was dried (MgSO4),
filtered and the solvent was removed under reduced pressure. The
residue was purified by pressurized silica gel column chromatography
using 4:1 hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-
methoxybenzoate was obtained as a white powder.
Step 3. A round-bottomed flask cont~ining methyl 4-
benzyloxy-2-methoxybenzoate (16.48 g, 60 mmol) from step 2 above
was purged with argon and 10% palladium on carbon catalyst was added
(2 g). Methanol (200 mL) was slowly added followed by HOAc (2
mL). The solution was kept under 1 atm of H2 and stirred for 24 h.
The catalyst was removed by filtration through celite and the filtrate
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- 84 -
solvents were removed under reduced pressure. The residue was
purified by pressurized silica gel column chromatography using 1:1
hexanes:EtOAc as eluant. Methyl 4-hydroxy-2-methoxybenzoate was
obtained as an amorphous solid.
Step 4. To a stirred solution of methyl 4-hydroxy-2-
methoxybenzoate (11 g, 60 mmol) from step 3 above in THF:H2O (100
mL:10 mL) was added LiOH-H2O (3 g, 71 mmol). The solution was
stirred for 24 h and then made acidic (pH 5) by the addition of 10%
aqueous HCl. The solution was extracted with CH2C12 (3 x 50 mL).
The combined organic layers were dried (MgSO4) and filtered. The
filtrate solvent was evaporated under reduced pressure to afford 4-
hydroxy-2-methoxybenzoic acid as an amorphous solid.
Step 5: 1 -(4-Piperidinyl)-4(H)-3,1 -benzoxazin-2(1 H)-one
hydrochloride from Step 3 of Example 1 and 2-methoxy-4-
hydroxybenzoic acid from Step 4 above were coupled using the
procedure given in step 4 of Example 1. The crude product was
purified by pressurized silica gel column chromatography using 98:2
DCM:MeOH as eluant. The title compound was obtained as an
amorphous solid.
Analysis: C21 H22N2O5 0.2 MeOH
calc. C 65.48 H 5.91 N 7.21
found 65.44 5.77 7.39
TLC: Rf = 0.4 (95:5 CHC13:MeOH)
HPLC (method A): retention time = 7.21 min
25 FAB MS: m/z= 383 (M + H+)
EXAMPLE 15
1 -(1 -(4-(4-(N-Aminocarbonyl)piperidinyloxy)-2-
30 methoxybenzoyl)piperidin-4-yl)-4(H)-3~ 1 -benzoxazin-2(1 H)-one
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- 85 -
~0~ 0
~N"~$ ~N~ NH2
O OCH3 o
The hydrochloride salt of 1-(1-(4-(4-piperidinyloxy)-2-
methoxy benzoyl)piperidin-4-yl)--4(H)-3,1 -benzoxazin-2(1 H)-one (1 g,
2.15 mmol) from Example 3 was dissolved in 20 ml of water to give a
S solution with pH 1.7. The pH of the solution was adjusted to 3 with the
addition of 50% potassium hydroxide and 208 mg (2.58 mmol) of
potassium isocyanate was added. The reaction was stirred at ambient
temperature overnight, then heated to 75~ C for 12 hr while maintaining
the pH at approximately 3. (HCI was employed to lower the pH when
10 required.) After 36 hr, the reaction mixture was concentrated to
dryness and the residue was partitioned between chloroform and
water/methanol. The organic phase was washed with water and brine,
then dried and concentrated yielding a semi-solid. This material was
chromatographed on silica gel (chloroform-methanol, 96:4, v/v) to
15 yield the title compound.
Elem. Anal. calc'd for C27H32N4O6-0.3 MeOH-0.3CHCl3:
Calc'd: C, 59.33; H, 6.24; N, 9.88.
Found: C, 59.35; H, 6.22; N, 9.58.
FAB MS: m/z 509 (M~ + H).
EXAMPLE 16
1 -(1 -(4-(4-(N-(N'-Cyanoamidine))piperidinyloxy)-2-methoxybenzoyl)-
piperidin-4-yl)--4(H)-3.1 -benzoxazin-2(1 H)-one
.~
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~0~;0
~N~,~ \CN~ N-CN
O OCH3 N H2
Step 1: To 10 ml of water cont~ining 258 mg of potassium
carbonate was added 10 ml of ethyl acetate cont~ining the hydrochloride
salt of 1-(1-(4-(4-piperidinyloxy)-2-methoxy benzoyl)piperidin-4-yl)-
5 4(H)-3,1-benzoxazin-2(1H)-one (~1.0 g, 1.7 mmol) from Example 3. To
this mixture was added 405 mg (1.7 mmol) of N-cyanodiphenyl-
imidocarbonate. The reaction mixture was stirred for 2 hr at ambient
temperature, diluted with ethyl acetate and the layers were separated.
The organic phase was washed with water, then was dried, and
10 concentrated to give of N-[l -(1 -(4-(4-piperidinyloxy)-2-
methoxybenzoyl) piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one]-~-
cyano-O-phenylisourea as a white amorphous solid.
Step 2: A solution of 30 ml of methanol cont~ining 500 mg
of N-[1 -( l -(4-(4-piperidinyloxy)-2-methoxybenzoyl) piperidin-4-yl)-
l S 4(H)-3, l -benzoxazin-2(1 H)-one]-~-cyano-O-phenylisourea from step l
above was saturated with ammonia at 0~ C. The reaction flask was
capped with a septum and the reaction was allowed to stand at ambient
temperature overnight. The reaction mixture was cooled and more
ammonia was added. After a total reaction time of 24 hr, all volatiles
20 were removed in vacuo and the residue was chromatographed on .~ilica
gel (chloroform-isopropanol, 98:2, v/v) to give the title compound.
Elem. Anal. calc'd for C2gH32N6Os-0.25 IPA-0.25CHCl3:
Calc'd: C, 60.32; H, 5.98; N, 14.55.
Found: C, 60.57; H, 5.91; N, 14.51.
25 FAB MS: m/z 533 (M+ + H).
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EXAMPLE 17
.,
1-(1 -(4-(1 -(N-oxo-2-methyl-3-pyridylmethyl)-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3 .1 -benzoxazin-2( 1 H)-one
0~0
~ ~N~ ~NJ~N~o
O OCH3 CH3
Step 1. To a stirred solution of ethyl 2-methylnicotinate
(1.50 g, 9.09 mmol)) from step 1 above in THF (65 mL) at 0~C was
added LAH (9.1 mL of a 1.0 M solution in THF; 9.1 mmol). The
mixture was stirred at ambient temperature for 1~ h and then quenched
10 by the sequential addition of ethyl acetate (0.1 mL), water (0.1 mL),
15% aqueous NaOH (0.1 mL) and water (0.2~ mL). The solids were
removed by filtration through celite and the filtrate solvents were
removed under reduced pressure. 3-Hydroxymethyl-2-methylpyridine
was obtained as an oil (TLC: Rf = 0.40 (5:95 MeOH:CH2C12)).
Step 2. To a stirred solution of 3-hydroxymethyl-2-
methylpyridine (1.00 g, 8.13 mmol) from step 1 above in CH2C12 (40
mL) at ambient temperature was added SOC12 (9.5 g, ~0 mmol). The
mixture was stirred for 4 h, and the solvent and excess SOC12 were
evaporated under reduced pressure. The residue was partitioned
20 between CH2C12 (50 mL) and saturated aqueous NaHCO3 (100 mL).
The organic layer was separated, and the aqueous layer was washed with
additional CH2C12 (2 x 40 mL). The combined organic layers were
evaporated under reduced pressure to give 3-chloromethyl-2-
methylpyridine as a solid which was used in the next step without
25 purification (TLC: Rf = 0.~5 (95:5 CH2C12:MeOH); FAB MS m/z 142
(M+ + H))-
- Step 3. To a stirred solution of 3-chloromethyl-2-
methylpyridine (0.50 g; 3.5 mmol) from step 2 above in CHC13 (40
mL) was added MCPBA (1.1 g of 50% MCPBA by weight; 3.5 mmol).
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After 1.5 h, the solution was extracted with saturated aqueous NaHCO3
(40 mL), water (40 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure. The residue was purified by pressurized silica
gel column chromatography using 97:3 CH2C12:MeOH as eluant. 3-
5 Chloromethyl-2-methylpyridine-N-oxide was obtained as a solid (TLC:
Rf = 0.30 (97:3 CH2C12:MeOH); FAB MS m/z 158 (M+ + H)).
Step 4: To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-
2-methoxybenzoyl)piperidin-4-yl)-4(H)-3, 1 -benzoxazin-2(1 H)-one from
Example 3 (6.24 g, 13.4 mmol) in DMF (150 mL) under argon
10 atmosphere was added 3-chloromethyl-2-methylpyridine-N-oxide from
Step 3 above (2.33 g, 14.8 mmol) and DIEA (3.5 mL, 20 mmol). The
reaction mixture was stirred at ambient temperature for 4~s hours. The
solvent was removed under reduced pressure. The residue was
partitioned between saturated aqueous NaHCO3 (100 mL) and CH2cl2
15 (100 mL). The organic phase was dried (MgSO4), filtered, and the
solvent was removed under reduced pressure. The residue was purified
by pressurized silica gel column chromatography using 97:3:0.3
CH2C12:MeOH:NH4OH as eluant to give the title compound. To a
solution of the title compound (500 mg) in MeOH (10 mL) was added
20 1.1 equivalents of aqueous HCl and the solvent was removed under
reduced pressure. The residue was dissolved in 5:1 H2O:CH3CN and
lyophilized to give a white solid. The amorphous HCl salt (500 mg) wa.s
dissolved in hot isopropanol (8 mL). Cooling to ambient temperature
gave a crystalline mono-hydrochloride, mono-hydrate salt of the title
25 compound.
Analysis calculated for C33H38N4O6~ 1.0 HCI, 1.0 H2O
C, 61.81; H, 6.45; N, 8.74
Found C, 61.54; H, 6.32; N, 8.60
TLC: Rf = 0.30 (95:5:0.5 CH2C12:MeOH:NH4OH)
30 HPLC (method A) retention time = 5.84 min
FAB MS m/z 587 (M+ + H)
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EXAMPLE 18
1 -(1 -(4-(1 -(N-oxo-2,4-dimethyl-3-pyridylmethyl)-4-piperidinyloxy)-2-
- methoxvbenzoyl)piperidin-4-yl)-4(H)-3 ~ 1 -benzoxazin-2(1 H)-one
~0~0
1~ ~N ~ ~N ~N~
5O OCH3 CH3
Ethyl 2,4-dimethylnicotinate, prepared by the method of
Ohno, et al., Journal of the American Chemical Society (1979), vol.
101, pp. 7036-7040,was converted in three steps to 3-chloromethyl-2,4-
dimethylpyridine N-oxide using procedures analogous to those given in
10 steps 1 -3 of Example 17. 3-Chloromethyl-2,4-dimethylpyridine N-
oxide (0.94 g; 5.4 mmol) and 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one from
Example 3 (2.0 g; 4.3 mmol) were coupled using the procedure given in
step 4 of Example 17. The title compound was purified by pressurized
15 silica gel column chromatography using a gradient elution of 99:1:0.05
to 97:3:0.015 CH2C12:MeOH:NH4OH. A methanolic solution of the
free base of the title compound containing 2 e4uivalents of 2 N aqueous
HCl was evaporated under reduced pressure. The residue was
Iyophilized from H2O:CH3CN to give the hydrochloride salt of the title
20 compound as an amorphous solid.
Analysis calculated for C34H40N406, 1.55 HCl, 0.55 H2O
C, 61.21; H, 6.44; N, 8.40
Found C, 61.20; H, 6.44; N, 8.23
TLC: Rf= 0.22 (97:3:0.3 CH2C12:MeOH:NH40H)
25 HPLC (method A) retention time = 6.10 min
FAB MS m/z 601 (M+ + H)
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EXAMPLE 19
1 -(1 -(4-(1 -(N-oxo-2-ethyl-3 -pyridylmethyl)-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~0~0
~ ~N~,J~ ~NJ~N~o
O OCH3 CH2CH3
2-Ethylnicotinic acid, obtained by the method of J.
Epsztajn, et al., Synthetic Comrnunications (1992), vol. 22, pp. 1239-
1247, was converted to methyl 2-ethylnicotinate by treatment with HCI
in MeOH. 3-Chloromethyl-2-ethylpyridine N-oxide was obtained from
10 methyl 2-ethylnicotinate in three steps using procedures analogous to
those given in steps 1-3 of Example 17. 3-Chloromethyl-2-
ethylpyridine N-oxide (0.23 g; 1.3 mmol) and 1-(1-(4-(4-
piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -
benzoxazin-2(1H)-one from Example 3 (0.50 g; 1.1 mmol) were
15 coupled using the procedure given in step 4 of Example 17. The title
compound was purified by pressurized silica gel column
chromatography using a gradient elution of 99:1:0.05 to 97:3:0.015
CH2C12:MeOH:NH4OH. The hydrochloride salt of the title compound
was obtained by evaporation of a MeOH solution of the free base
20 cont~ining 2 equivalents of 2 N aqueous HCl. The residue was
lyophilized from H2O:CH3CN to give the hydrochloride salt of the title
compound as an amorphous solid.
Analysis calculated for C34H40N4O6, 1.25 HCl, 0.15 H20
C, 62.92; H, 6.45; N, 8.63
25 Pound C, 62.91; H, 6.45; N, 8.66
TLC: Rf = 0.22 (98:2:0.1 CH2C12:MeOH:NH4OH)
HPLC (method A) retention time = 6.10 min
FAB MS m/z 601 (M+ + H)
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EXAMPLE 20
~r
1 -(1 -(4-(1 -(2-amino-3-pyridylmethyl)-4-piperidinyloxy)-2-
methoxvbenzoyl)piperidin-4-vl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~0~0
[~ ~N ~ ~N~[~N
S O OCH3 NH2
Step 1: To a stirred solution of 3-methyl-2-
phthalimidopyridine (A. E. Moormann et al., Synthetic Communications
(1987), vol. 17, pp. 1695-1699; 0.50 g; 2.1 mmol) in CH2C12 (20 mL)
was added N-bromosuccinimide(0.37 g; 2.1 mmol). The solution was
stirred at ambient temperature for 24 h. The solvent was removed
under reduced pressure and the crude 3-bromomethyl-2-
phthalimidopyridine was dissolved in DMF (10 mL). To the DMF
solution was added 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one from
Example 3 (0.95 g; 2.0 mmol) followed by DIEA (0.54 mL; 3.1 mmol).
The reaction mixture was stirred at ambient temperature for 24 h. The
DMF was removed under reduced pressure and the residue was
partitioned between CH2C12 and saturated aqueous NaHCO3 solution.
The organic phase was washed with brine, dried (MgSO4), filtered, and
the solvent was removed under reduced pressure. The residue was
purified by pressurized silica gel column chromatography using a
gradient elution of 95:5:0.25 CH2C12:MeOH:NH4OH as eluant to give
1 -(1 -(4-(1 -(2-phth~limido-3-pyridylmethyl)-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one as an
- 25 amorphous solid (TLCRf = 0.49 (92:8:0.4 CH2C12:MeOH:NH4OH);
HPLC RT = 12.9 min (Method B), FAB MS m/z = 702 (M+ + 1)).
Step 2: To a solution of 1-(1-(4-(1-(2-phth~limido-3-
pyridylmethyl)-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-
4(H)-3,1-benzoxazin-2(1H)-one from Step 1 above (0.90 g; 1.3 mmol)
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in EtOH (10 mL) was added hydrazine (0.083 mL; 2.6 mmol). The
reaction mixture was stirred at ambient temperature for 72 h. The
solvent was removed under reduced pressure and the residue was
purified by preparative reverse phase HPLC using a water-acetonitrile
5 gradient cont~ining 0.1% TFA. The fractions cont~ining product were
lyophilized to give the TFA salt of the title compound as an amorphous
solid.
Analysis calculated for C32H37N5O5~ 2.7 TFA, 0.55 H2O
C, 50.57, H, 4.62; N, 7.87
10 Found C, 50.51; H, 4.64; N, 7.84
TLC: Rf = 0.35 (92:8:0.4 CH2C12:MeOH:NH4OH)
HPLC (Method B) retention time = 9.8 min
FAB MS m/z 572 (M+ + H)
EXAMPLE 21
1-(1-(4-( 1 -cyclopropylmethyl-4-piperidinyloxy)-2-
methoxyphenylacetyl)piperidin-4-vl)-3 .4-dihydroquinolin-2-one
~0
~N ,~
O OCH3
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-
methoxyphenylacetyl)piperidin-4-yl)-3,4-dihydroquinolin-2-one from
Example 13 (1.0 g; 2.1 mmol) and cyclopropane carboxaldehyde (0.22
g; 3.1 mmol) in 99:1 MeOH:HOAc (25 mL) was added NaBH3CN (0.26
g; 4.2 mmol). The mixture was stirred at ambient temperature for 1 g
h. The solvents were removed underreduced pressure. The residue
was partitioned between EtOAc and saturated aqueous NaHCO3
solution. The organic phase was washed with brine, dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. The
residue was purified by preparative reverse phase HPLC using a water-
~ =
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acetonitrile gradient cont~ining 0.1% TFA. The fractions cont~ining
product were lyophilized to give the TFA salt of the title compound as
an amorphous solid.
r Analysis calculated for C32H41N3O4~ 1.9 TFA, 0.1 H2O
C, 57.31; H, 5.79; N, 5.60
Found C, 57.31; H, 5.80; N, 5.85
TLC: Rf = 0.5 (90:10 CH2C12:MeOH)
HPLC (method A) retention time = 7.8 min
FAB MS m/z 532 (M+ + H)
EXAMPLE 22
1 -(1 -(4-(1 -(1 -(3-pyridyl)ethyl)-piperidin-4-yloxy)-2-methoxybenzoyl)-
piperidin-4-vl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~O~f~O
~ OCH3 CH3
To stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one from
Example 3 (0.20 g; 0.43 mmol) in dichloroethane (2.15 mL) was added
3-acetylpyridine (0.095 mL, 0.86 mmol) and sodium
20 triacetoxyborohydride (182 mg, 0.86 mmol). Approximately 0.1 mL of
acetic acid was added. The solution was stirred at ambient temperature
for a total of 5 days. Every 24 h an additional 2 equivalents each of the
3-acetylpyridine and sodium triacetoxyborohydride was added to the
reaction mixture. The reaction solvent was removed under reduced
25 pressure and the residue was purified by pressurized silica gel column
chromatography using 95:5 CH2C12:MeOH(NH3) and then further
purified by preparative reverse-phase HPLC using an acetonitrile-water
gradient cont~ining 0.1 % TFA. Removal of solvent by Iyophili7~tion
gave the TFA salt of title compound as an amorphous powder.
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TLC: Rf = 0.70 [4: 1 CH2C12:MeOH(NH3)]
HPLC (method A): retention time 5.83 min.
FAB MS: m/z 571 (M+ + H)
EXAMPLE 23
1 -(1 -(4-(1 -(2,6-dimethyl-4-pyridylmethyl)-piperidin-4-yloxy)-2-
methoxybenzovl)piperidin-4-yl)-4(H)-3.1 -benzoxazin-2(1 H)-one
CH3
~N ~ 'CN~ ~'CH
O OCH3
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)- 1,2-dihydro-4(H)-3,1 -benzoxazin-2-
one hydrochloride from Example 3 (125 mg, 0.249 mmol) in DMF (5
mL) was added 4-chloromethyl-2,6-dimethylpyridine (47.1 mg, 0.299
mmol) and DIEA (96.5 mg, 0.13 mL, 0.747 mmol). The solution was
15 stirred at 50~C for 18 hours. The solvent was removed under reduced
pressure. The residue was partitioned between aqueous saturated
NaHCO3 (10 mL) and methylene chloride. The organic phase wa,s
dried (MgSO4), filtered, and the solvent was removed under reduced
pressure. The residue was purified by pressurized silica gel column
20 chromatography using 5% methanol in methylene chloride as eluant.
The product was further purified by preparative reverse phase HPLC
using an acetonitrile:water gradient cont~ining TFA. The TFA salt of
the title compound was obtained as a white amorphous solid by
lyophili7~tion.
25 Analysis calculated for C34H4lN4o5~ 2.5 TFA, 0.4 CH2cl2
C, 52.30; H, 4.94; N, 6.19
Found C, 52.28; H, 4.84; N, 6.33
TLC: Rf = 0.28 in 5% methanol in methylene chloride
HPLC (Method A) retention time 5.79 min
-
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FAB MS m/z 585 (M++ H)
EXAMPLE 24
5 1 -(1 -(4-(1 -(2-chloro-3-pyridylmethyl)-piperidin-4-yloxy)-2-methoxy-
benzoyl)piperidin-4-yl)-4(H)-3.1 -benzoxazin-2(1 H)-one
~0~0
~N ~ ~N J~N
O OCH3 Cl
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4(H)-3,1 -benzoxazin-2(1 H)-one
10 hydrochloride from Example 3 (125 mg, 0.249 mmol) in DMF (5 mL)
was added 3-chloromethyl-2-chloropyridine (48.4 mg, 0.299 mmol) and
DIEA (96.5 mg, 0.13 mL, 0.747 mmol). The solution was stirred at
50~C for 18 hours. The solvent was removed under reduced pressure.
The residue was partitioned between aqueous saturated NaHCO3 (10
15 mL) and methylene chloride. The organic phase was dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. The
residue was purified by pressurized silica gel column chromatography
using 3% methanol in methylene chloride as eluant. The product was
further purified by preparative reverse phase HPLC using an
20 acetonitrile:water gradient cont~ining TFA. The TFA salt of the title
compound was obtained as a white amorphous solid by lyophili7~tion.
Analysis calculated for C32H35ClN4O5, 1.65 TFA
C, 54.40; H, 4.74; N, 7.19
Found C, 54.34; H, 4.~s1; N, 7.26
25 TLC: Rf = 0.24 in 3% methanol in methylene chloride
HPLC (Method A) retention time 6.69 min
- FAB MS m/z 591 (M++ H)
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EXAMPLE 25
1-( 1 -(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-methoxy-3-
methylbenzoyl)piperidin-4-vl)-4H-3~ 1 -benzoxazin-2( 1 H)-one
~0~0
~N~ ~3~CH~N~O~f ~CH3
O OCH3 ~ CH3
4-(N-t-Butoxycarbonyl -4-piperidinyloxy)-2-methoxy-3 -methylbenzoic
acid (1.0 g, 2.7 mmol) was prepared from methyl 2,4-dihydroxy-3-
methylbenzoate using a three step procedure analogous to steps 1-3 of
Example 2. 1 -(4-Piperidinyl)-4H-3, 1 -benzoxazin-2(1H)-one
10 hydrochloride and 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxy-
3-methylbenzoic acid were coupled using the procedure given in step 4 of
Example 1. The crude product was purified by pressurized silica gel
column chromatography using a gradient elution of 1-3% MeOH:CH2C12.
1-( 1 -(4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxy-3-
15 methylbenzoyl)piperidin-4-yl)-4H-3, 1 -benzoxazin-2( 1 H)-one was
obtained as an amorphous solid.
Analysis: calculated for (C32H41N3O7~ 0.~5 H2O)
C, 64.60; H, 7.23; N, 7.06
Found C, 64.57; H, 6.96; N, 7.10
20 TLC: Rf = 0.45 (95:5 CH2C12:MeOH)
HPLC (method B) retention time = 19 min
FAB MS: m/z 580 (M+ + H)
EXAMPLE 26
1-( 1 -(4-(4-piperidinyloxy)-2-methoxy-3-methylbenzoyl)piperidin-4-yl)-
4H-3~ 1 -benzoxazin-2( 1 H)-one
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~0~0
~N bJ~C~NH
o OCH3
A stirred solution of 1-(1-(4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-
methoxy-3 -methylbenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one
(1.5 g, 2.6 mmol) from Example 25 above in EtOAc (50 mL) was
5 cooled to 0~C. HCl gas was bubbled through the solution for 30 min,
during which time a precipitate had formed. The mixture was warmed
to ambient temperature and stirred for 1 h. The suspension was cooled
to 0~C and the solid was collected by filtration and washed with cold
EtOAc. The solid was dried under reduced pressure for 18 h, giving
10 the hydrochloride salt of the title compound as a white amorphous solid.
Analysis: calculated for (C27H33N3O5, 2.3 HCl, 0.15 EtOAc)
C, 57.49; H, 6.38; N, 7.29
Found C, 57.43; H, 6.32; N, 7.28
TLC: Rf = 0.1 (90:10:1 CH2Cl2:MeOH:NH4OH)
15 HPLC (method B) retention time = 10.5 min
FAB MS: m/z 4~0 (M+ + H)
EXAMPLE 27
20 1-( l -(4-(N-acetyl-4-piperidinyloxy)-2-methoxy-3 -
methylbenzoyl)piperidin-4-yl)-4H-3. 1 -benzoxazin-2(1 H)-one
O O
~N~ ~3~CH~N~CH3
O OCH3 O
-
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To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-2-methoxy-3-
methylbenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one
hydrochloride (0.50 g, 1.0 mmol) from Example 26 above in CH2cl2
(20 mL) was added acetic anhydride (0.32 mL, 3.1 mmol) and DIEA
(0.52 mL, 3.0 mmol). The reaction mixture was stirred at ambient
temperature for 18 h. The solution was diluted with CH2Cl2 (50 mL)
and was washed with saturated aqueous NaHCO3 (3x 75 mL). The
organic phase was dried (MgSO4), filtered, and the solvent was
removed under reduced pressure. The residue was purified by
pressurized silica gel column chromatography using 98:2
CH2Cl2:MeOH as eluant to give the title compound as an amorphous
solid.
Analysis: calculated for (c2gH35N3o6~ 0-75 H2O)
C, 65.09; H, 6.88; N, 7.85
Found C, 65.09; H, 6.70; N, 7.84
TLC: Rf= 0.45 (95:5:0.5 CH2Cl2:MeOH:NH4OH)
HPLC (method B) retention time = 13.3 min
FAB MS:m/z522(M++H)
EXAMPLE 2~
l -(1-(4-(1 -(N-oxo-2-methyl-3-pyridylmethyl)-4-piperidinyloxy)-2-
methoxy-3-methylbenzoyl)piperidin-4-vl)-4H-3 ~ l -benzoxazin-2( l H)-one
~O~f~O
~N~ CH~NJ~N~
O OCH3 CH ~
25 1-(1-(4-(4-Piperidinyloxy)-2-methoxy-3-methylbenzoyl)piperidin-4-yl)-
4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.50 g, 1.0 mmol) from
Example 26 in DMF and 3-chloromethyl-2-methylpyridine-N-oxide
from step 3 of Example 17 were coupled using a procedure analogous
to that given in step 4 of Example 17. The title compound was purified
-
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_ 99 _
by pressurized silica gel column chromatography using 97:3:0.3
CH2C12:MeOH:NH40H as eluant. The title compolmd was obtained as
an amorphous solid.
Analysis calculated for C34H40N406, 0.65 CH2Cl2~ 0.05 H2O
C, 63.36; H, 6.35; N, 8.53
Found C, 63.37; H, 6.23; N, 8.69
TLC: Rf = 0.32 (95:5:0.5 CH2C12:MeOH:NH4OH)
HPLC(method B) retention time = 10.2 min
FAB MS m/z 601 (M+ + H)
EXAMPLE 29
l -( l -(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-methoxy-5-
bromobenzoyl)piperidin-4-YI)-4H-3.1 -benzoxazin-2(1H)-one
~~f~~ B
~N ~?~ ~N~O~CH3
O OCH3 ~ CH3
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxy-5-bromobenzoic
acid (1.0 g, 2.7 mmol) was prepared from methyl 2,4-dihydroxy-5-
bromobenzoate using a three step procedure analogous to steps 1-3 of
Example 2. l -(4-Piperidinyl)-4H-3, l -benzoxazin-2(1 H)-one
20 hydrochloride and 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxy-
5-bromobenzoic acid were coupled using the procedure given in step 4 of
Example 1. The title compound was purified by pressurized silica gel
column chromatography using 40% EtOAc:hexanes as eluant and was
obtained as an amorphous solid.
25 Analysis: calculated for (C3 l H3gBrN3O7, 0.20 EtOAc, 1.5 H2O)
C, 55.4~; H, 6.22; N, 6.11
Found C, 55.49; H, 5.94; N, 6.08
TLC: Ri = 0.30 (4: l hexanes:EtOAc)
HPLC (method A) retention time = I0.5 min
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EXAMPLE 30
1 -(1 -(4-(4-piperidinyloxy)-2-methoxy-S-bromobenzoyl)piperidin-4-yl)-
5 4H-3.1 -benzoxazin-2(1 H)-one
~0~0 Br
~N ~ ~N H
O OCH3
The title compound was prepared from 1-(1-(4-(N-tert-
butyloxycarbonyl-4-piperidinyloxy)-2-methoxy-5-
bromobenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one of
10 Example 29 using a procedure analogous to that given in step 3 of
Example 1. The hydrochloride salt of the title compound was obtained
as an amorphous solid.
Analysis: calculated for (C26H30BrN3os~ 1.85 HCl, 0.15 EtOAc)
C, 51.10; H, 5.33; N, 6.72
lS Found C, 51.14; H, 5.30; N, 6.73
TLC: Rf = 0.11 (95:5:0.5 CH2C12:MeOH:NH4OH)
HPLC (method A) retention time = 6.6 min
EXAMPLE 31
1 -(1 -(4-(N-acetyl-4-piperidinyloxy)-2-methoxy-5-
bromobenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one
~0~;0 Br
[~ ~N~ ~N~CH3
O OCH3 O
-
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The title compound was prepared from 1-(1-(4-(4-piperidinyloxy)-2-
methoxy-5-bromobenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one
of Example 30 using a procedure analogous to that given in Example 4.
- The title compound was purified by pressurized silica gel column
5 chromatography using 98:2 CH2C12:MeOH as eluant and was obtained
as an amorphous solid by evaporation from EtOAc-CH2C12 under
reduced pressure.
Analysis: calculated for (C28H32BrN306, 0.05 EtOAc, 0.45 CH2C12)
C, 56.12; H, 5.47, N, 6.85
10 Found C, ~6.11; H, ~.45; N, 6.87
TLC: Rf = 0.34 (98:2 CH2C12:MeOH)
HPLC (method A) retention time = 8.0 min
EXAMPLE 32
1-(1-(4-( 1 -(N-oxo-2-methyl-3-pyridylmethyl)-4-piperidinyloxy)-2-
methoxy-S-bromobenzoyl)piperidin-4-vl)-4H-3 1-benzoxazin-2(1H)-one
~0~0 Br
h--N~ b'o~--
N~ ~, N ~,N~
O OCH3 CH3
1 -(1 -(4-(4-Piperidinyloxy)-2-methoxy-S-bromobenzoyl)piperidin-4-yl) -
20 4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.50 g, 1.0 mmol) from
Example 30 in DMF and 3-chloromethyl-2-methylpyridine-N-oxide
from step 3 of Example 17 were coupled using a procedure analogous
to that given in step 4 of Example 17. The title compound was purified
by pressurized silica gel column chromatography using 97:3:0.3
25 CH2(:~12:MeOH:NH40H as eluant. The hydrochloride salt of the title
compound was obtained as an amorphous solid by lyophili7~tion from
CH3CN-H2O cont~ining aqueous HCl.
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Analysis: calculated for (C33H37BrN406, 2.5 HCl, 1.2 H2O)
C, 51.99; H, 5.54; N, 7.35
Found C, 51.98; H, 5.44; N, 7.33
TLC: Rf = 0.34 (96:4:0.4 CH2C12:MeOH:NH4OH)
5 HPLC (method A) retention time = 6.4 min
EXAMPLE 33
1-( 1 -(4-(trans-2-methoxycarbonyl-4-piperidinyloxy)-2-
10 methoxybenzoyl)piperidin-4-yl)-4H-3 .1 -benzoxazin-2( 1 H)-one
¢~N~ ~ NH
O OCH3
Step 1. To a stirred, 0~C solution of 1-{ 1 -[4-hydroxy-2-
methoxybenzoyl]-piperidin-4-yl}-4H-3,1-benzoxazin-2(1H)-one (0.40 g,
1.0 mmol) from Example 14 and triphenylphosphine (0.58 g, 2.2
15 mmol) in dry THF (15 mL) was added a solution of DEAD (0.35 mL,
2.2 mmol) and N-Boc-cis-2-methoxycarbonyl-4-hydroxypiperidine
(0.54 g, 2.1 mmol; prepared by the method given in, J. Org. Chem.
(199i) vol. 56, p. 4085) in dry THF (5 mL) over a period of 2 h. The
mixture was warmed to ambient temperature and stirred for 18 h. The
20 solvent was removed under reduced pressure and the residue was
dissolved in CH2C12 (50 mL) and extracted with saturated aqueous
NaHCO3(25 mL), water (25 mL), and brine (25 mL). The organic
phase was dried (MgSO4), filtered, and the solvent was removed under
reduced pressure. The residue was purified by pressurized silica gel
25 column chromatography using 1:1 EtOAc:CH2C12 as eluant to give 1-
( 1 -(4-(N-Boc-2-methoxycarbonyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one as an
amorphous solid.
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Step 2. To a solution of 1-(1-(4-(N-Boc-2-
methoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl) -
4H-3,1-benzoxazin-2(1H)-one (0.37 g, 0.59 mmol) from step 1 above in
CH2C~12 (10 mL) was added TFA (3 mL). The solution was stirred at
5 a~nbient temperature for 2 h. The solvents were removed under
reduced pressure and the residue was dissolved in CH2C12 (50 mL) and
extracted wi~ saturated aqueous NaHCO3(2x 25 mL). The organic
phase was dried (Mg~04), filtered, and the solvent was removed under
reduced pressure. The residue was purified by pressurized silica gel
10 columnchromatographyusing 1:1 EtOAc:CH2C12aseluant. 1-(1-(4-
(trans -2-methoxycarbonyl -4-piperidinyloxy) -2 -
methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one as an
amorphous solid by Iyophili7~tion from CH3CN:H20.
Analysis calculated for ~28H33N307~ 0.6 H2O
C, 62.93, H, 6.45; N, 7.86
Found C, 62.90; H, 6.23, N, 7.80
TLC: Rf = 0.4 (95:5:0.5 CH2C12:MeOH:NH4OH)
HPLC (method A) retention time = 7.1 min
FAB MS m/z 524 (M+ + H)
EXAMPLE 34
1-( 1 -(4-(N-acetyl-trans-2-methoxycarbonyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one
~0~0
~ ~N ~
~ OC H3 C H3
The title compound was prepared from 1-(1-(4-(trans-2-
methoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-
4H-3,1-benzoxazin-2(1H)-one of Example 33 using a procedure
analogous to that given in Example 4. The title compound was purified
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by pressurized silica gel column chromatography using 98:2
CH2C12:MeOH as eluant and was obtained as an amorphous solid by
lyophili7~tion from CH3CN:H20.
Analysis calculated for C30H35N308, 1.2 H2O
C, 61.35; H, 6.42; N, 7.16
Found C, 61.34; H, 6.17; N, 7.08
TLC: Rf = 0.45 (95:5 CH2C12:MeOH)
HPLC (method A) retention time = 7.5 min
FAB MS m/z 566 (M+ + H)
EXAMPLE 35
1-( 1 -(4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4H-3 ~1 -benzoxazin-2( 1 H)-one
O O
CH3
~ ~ ~I< CH3
O OCH3 ~ CH3
Step 1. To a solution of LDA (44 mmol) in THF (150 mL)
at -78~C was added N-Boc-4-piperidinone (8.0 g, 40 mmol) in THF (50
mL) over a period of 30 min. The solution was stirrred at -78~C for 3
h, and iodomethane (5.8 g, 40 mmol) was added. The resulting solution
20 was stirred at -78~C for 2 h and then warmed to ambient temperature
for 18 h. The mixture was diluted with saturated aqueous NH4Cl (150
mL), the layers were separated, and the aqueous phase wa~i extracted
with EtOAc (100 mL). The combined organic phases were dried
(MgSO4), filtered, and the solvents were removed under reduced
25 pressure. The residue was purified using pressurized silica gel column
chromatography using a gradient elution of 100:0 to 95:5
hexanes:EtOAc. N-13oc-3-methyl-4-piperidinone was obtained as an oil.
Step 2. To a stirred solution of N-Boc-3-methyl-4-
piperidinone (3.4 g, 12.7 mmol) from step 1 above in MeOH (30 mL) at
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0~C was added sodium borohydride (0.48 g, 12.7 mmol) over a period
of 30 min. The mixure was was warmed to ambient temperature and
stirred for 18 h. The mixture was diluted with water (100 mL) and
extracted with CH2C12 (3x 30 mL). l~he combined organic layers were
5 dried (MgSO4), filtered, and the solvent was removed under reduced
pressure. The residue was purified by pressurized silica gel column
chromatography using a gradient elution of 100:0 to 90:10
hexanes:EtOAc. N-Boc-3-methyl-4-hydroxypiperidine was obtained as
an oll.
Step 3. N-Boc-3-methyl-4-hydroxypiperidine from step 2
above was coupled to methyl 2-methoxy-4-hydroxybenzoate from step 3
of Example 14 using Mitsunobu conditions as given in step 1 of
Example 2. Methyl 4-(N-tert-butyloxycarbonyl-3-methyl-4-
piperidinyloxy)-2-methoxybenzoate was purified by pressurized silica
gel column chromatography using a gradient elution of 100:0 to 90:10
hexanes:EtOAc and was obtained as an amorphous solid.
Step 4. Methyl 4-(N-tert-butyloxycarbonyl-3-methyl-4-
piperidinyloxy)-2-methoxybenzoate from step 3 above was saponified
using the procedure given in step 3 of Example 2. 4-(N-tert-
butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-methoxybenzoic acid
was obtained as an amorphous solid.
Step 5. 4-(N-tert-butyloxycarbonyl-3-methyl-4-
piperidinyloxy)-2-methoxybenzoic acid from step 4 above was coupled
to 1 -(4-piperidinyl)-4H-3, 1 -benzoxazin-2( 1 H)-one hydrochloride from
step 3 of Example 1 using the procedure given in step 4 of Example 1.
1 -(1 -(4-(N-tert-butyloxycarbonyl-3 -methyl-4-piperidinyloxy) -2-
methoxybenzoyl)piperidin-4-yl)-4H-3, 1 -benzoxazin-2( 1 H)-one was
obtained as an amorphous solid.
Analysis calculated for C32H41N3O7, 0.6 DMF, 0.25 CH2C12
C, 63.42; H, 7.14; N, 7.82
Found C, 63.41; H, 7.10; N, 7.91
TLC: Rf= 0.35 (95:5 CH2C12:MeOH)
HPLC (method A) retention time = 10.3 min
FAB MS m/z 5~0 (M+ + H)
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EXAMPLE 36
1-(1-(4-(3-methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-
5 4H-3 ~ 1 -benzoxazin-2(1 H)-one
o~f ;O CH3
~N ~ ~NH
O OCH3
1 -(1 -(4-(N-tert-butyloxycarbonyl-3-methyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one from
Example 35 was converted to 1-(1-(4-(3-methyl-4-piperidinyloxy)-2-
10 methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one using the
procedure given in step 3 of Example 1. The hydrochloride salt of the
title compound was obtained as an amorphous solid.
Analysis calculated for C27H33N3Os, 2.3 HCl, 0.25 CH3CN
C, 57.56; H, 6.33; N, 7.93
15 Found C, 57.56; H, 6.52; N, 7.96
TLC: Rf = 0.2 (80:20 CH2C12:MeOH(NH3))
HPLC (method A) retention time = 6.5 min
FAB MS m/z 479 (M+ + H)
EXAMPLE 37
1 -(1 -(4-(N-acetyl-3-methyl-4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-vl)-4H-3 ~ 1 -benzoxazin-2(1 H)-one
~;O CH3
~N~ N~CH3
O OCH3 O
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1 -(1-(4-(3-Methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-
4H-3,1-benzoxazin-2(1H)-one from Example 36 was converted to l-(1-
(4-(N-acetyl-3 -methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-
~ 4-yl)-4H-3,1-benzoxazin-2(1H)-one using the procedure given in
Example 4. The title compound was obtained as an amoIphous solid.
Analysis calculated for C29H35N306, 0.5 H2O
C, 65.64; H, 6.70; N, 7.83
Found C, 66.78; H, 6.76; N, 8.06
TLC: Rf = 0.75 (90:10 CH2Cl2:MeOH(NH3))
HPLC(method A) retention time = 7.5 min
FAB MS m/z 522 (M+ + H)
EXAMPLE 38
1-(1-(4-(1-(N-oxo-2-methyl-3-pyridylmethyl)-3-methyl-4-piperidinyl-
oxy)-2-methoxybenzovl)piperidin-4-yl)-4H-3. 1 -benzoxazin-2(1 H)-one
~o~O CH3
~N~ NJ~N~
O OCH3 CH3
1 -(l -(4-(3-Methyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-
4H-3,1-benzoxazin-2(1H)-one from Example 36 and 3-chloromethyl-2-
methylpyridine-N-oxide from step 3 of Example 17 were coupled using
a procedure analogous to that given in step 4 of Example 17. The title
compound was purified by pressurized silica gel column
chromatography using 97:3:0.3 CH2Cl2:MeOH:NH4OH as eluant and
was obtained as an amorphous solid.
- 25 Analysis calculatedforC34H40N406, 1.1 CH2cl2
C, 60.73; H, 6.13; N, 8.07
~ Found C, 60.75; H, 6.07; N, 7.94
TLC: Rf = 0.6 (90:10 CH2C12:MeOH(NH3))
HPLC (method A) retention time = 6.5 min
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FAB MS m/z 601 (M+ + H)
EXAMPLE 39
1-(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-
methoxybenzoyl)piperidin-4-yl)-4H-3 .1 -benzoxazin-2( 1 H)-one
F
'I<CH3
O OCH3 ~ CH3
Step 1. Methyl 4-hydroxy-2-methoxybenzoate (10 g, 55
mmol) from step 3 of Example 14 and 1-fluoro-3,5-dichloropyridinium
trifluoromethanesulfonate (21 g, 66 mmol) were refluxed in
dichloromethane (250 mL) for 4~ h. The solution was washed with 5%
aqueous citric acid (250 mL) and the organic phase was dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. The
residue was purified by pressurized silica gel column chromatography
using 99:1 CH2C12:MeOH as eluant. Cryst~11i7~tion from ether gave
methyl 5-fluoro-4-hydroxy-2-methoxybenzoate.
Step 2. Methyl 5-fluoro-4-hydroxy-2-methoxybenzoate
from step 1 above was coupled to N-Boc-4-piperidinol using Mitsunobu
conditions as given in step 1 of Example 2. Methyl 4-(N-tert-
butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoate was
obtained as a gum (TLC Rf = 0.19 (3:7 EtOAc:hexanes); HPLC (method
A) retention time = 9.9 min).
Step 3. Methyl 4-(N-tert-butyloxycarbonyl-4-
piperidinyloxy)-5-fluoro-2-methoxybenzoate from step 2 above was
saponified using the procedure given in step 3 of Example 2. 4-(N-tert-
butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoic acid
was obtained as an amorphous solid (HPLC (method A) retention time =
~.6 min).
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Step 4. 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-
fluoro-2-methoxybenzoic acid from step 3 above and 1-(4-piperidinyl)-
4H-3,1-benzoxazin-2(1H)-one hydrochloride from step 3 of Example 1
were coupled using the procedure given in step 4 of Example 1. 1-(1-
5 (4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-
me~oxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one was
obtained as a~ amorphous solid.
Analysis calculated for C31H3gFN3O7, 0.2 EtOAc, 0.25 H20
C, 63.04; H, 6.67; N, 6.94
10 Found C, 63.06; H, 6.56; N, 6.93
TLC: Rf = 0.17 (4: 1 EtOAc:hexanes)
HPLC (method A) retention time = 9.8 min
FAB MS m/z 584 (M~ + H)
EXAMPLE 40
1 -(1 -(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-
4H-3 ~ 1 -benzoxazin-2(1 H)-one
F
~N'DJ~ ~NH
O OCH3
20 The title compound was prepared from 1-(1-(4-(N-tert-
butyloxycarbonyl-4-piperidinyloxy)-5 -fluoro-2-
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one of
Example 39 using the procedure given in step 3 of Example 1. The
hydrochloride salt of 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-
25 methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one was
obtained as an amorphous solid.
Analysis calculated for C26H30Fl'13O5, 2.0 HCI, 0.15 EtOAc
C, 56.08; H, 5.87; N, 7.38
Found C, 56.02; H, 5.94; N, 7.37
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TLC: Rf = 0.12 (96:4:0.4 CH2C12:MeOH:NH4OH)
HPLC(method A) retention time = 6.2 min
FAB MS m/z 484 (M+ + H)
EXAMPLE 41
1 -(1 -(4-(N-acetyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)-
piperidin-4-vl)-4H-3.1 -benzoxazin-2(1 H)-one
~ ~; F
¢~ ~N~ ~N~CH3
O OCH3 O
10 The title compound was prepared from 1-(1-(4-(4-piperidinyloxy)-5-
fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one
of Example 40 using the procedure given in Example 4. 1-(1-(4-(N-
acetyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-
4H-3,1-benzoxazin-2(1H)-one wa~ obatined as an amorphou~ solid.
15 Analysi~ calculated for C2~H32FN3O6~ 0.45 EtOAc, 0.65 H2O
C, 62.03; H, 6.45; N, 7.2~
Found C, 62.02; H, 6.22; N, 7.26
TLC: Rf = 0.33 (97:3 CH2C12:MeOH)
HPLC (method A) retention time = 7.4 min
20 FAB MS m/z 526 (M+ + H)
EXAMPLE 42
1 -(1 -(4-(1 -(N-oxo-2,4-diethyl-6-methyl-3-pyridylmethyl)-4-
25 piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -
benzoxazin-2(1 H)-one
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F CH3
~q~N~ ~b~o~ CH3
N~h~ N~N~
O OCH3 CH
Step 1. Ethyl propionylacetate (25 g, 0.17 mol), hexan-
2,4-dione (12.5 g, 0.11 mol), and ammonium acetate (51 g, 0.66 mol)
were combined and heated with stirring at 110~C for 96 h. The
reaction mixture was diluted with EtOAc (300 mL) and washed with
water (2x 150 mL) and brine (100 mL). The organic phase was dried
(MgSO4), filtered, and the solvent was removed under reduced
pressure. The residue was purified by pressurized silica gel column
chromatography using 92:8 hexanes:EtOAc as eluant. Ethyl 2,6-
diethyl-4-methylnicotinate (Rf = 0.38 (9:1 hexanes:EtOAc)) was isolated
as the major product and ethyl 2,4-diethyl-6-methylnicotinate (Rf =
0.25 (9:1 hexanes:EtOAc)) was isolated as the minor product.
Step 2. To a .solution of ethyl 2,4-diethyl-6-
methylnicotinate (0.55 g, 2.5 mmol) from step 1 above in THF (65 mL)
at 0~C was added LAH (2.5 mL of a 1.0 M solution in THF; 2.5 mmol).
The mixture was stirred at ambient temperature for 18 h and then
quenched by the sequential addition of ethyl acetate (0.1 mL), water
(0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.2~s mL). The
solids were removed by filtration through celite and the filtrate solvent~;
were removed under reduced pressure. The residue was purified by
pressurized silica gel column chromatography using 99:1
CH2C12:MeOH as eluant. 2,4-Diethyl-3-hydroxymethyl-6-
methylpyridine was obtained as an oil (TLC Rf = 0.32 (98:2
CH2C12:MeOH; FAB MS m/z = 180 (M+ + H)).
Step 3. To a solution of 2,4-diethyl-3-hydroxymethyl-6-
methylpyridine (0.35 g, 2.0 mmol) from step 2 above in CH2C12 (15
~ mL) was added thionyl chloride (0.9 g, 8 mmol) dropwise. The
mixture was stirred at ambient temperature for 18 h and the solvent was
removed under reduced pressure. The residue was partitioned between
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CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic
phase was dried (MgSO4), filtered, and the solvent was removed under
reduced pressure. The residue was purified by pressurized silica gel
column chromatography using 85:15 hexanes:EtOAc as eluant. 3-
5 Chloromethyl-2,4-diethyl-6-methylpyridine was obtained as an
amorphous solid (TLC Rf = 0.10 (9:1 hexanes:EtOAc); FAB MS m/z =
198 (M+ + H))-
Step 4. To a solution of 3-chloromethyl-2,4-diethyl-6-
methylpyridine (0.32 g, 1.6 mmol) from step 3 above in CHCl3 (25
10 mL) was added MCPBA (0.70 g of a 50% by weight mixture; 2.0
mmol) and the mixture was stirred at ambient temperature for 1~ h.
The solution was extracted with saturated a4ueous NaHCO3 (2x 20 mL),
dried (MgSO4), filtered, and the solvent was removed under reduced
pressure. 3-Chloromethyl-2,4-diethyl-6-methylpyridine-N-oxide was
15 obtained as an amorphous solid (TLC Rf = 0.39 (96:4 CHCl3:MeOH);
FAB MS m/z = 214 (M+ + H)).
Step 5. 3-Chloromethyl-2,4-diethyl-6-methylpyridine-N-
oxide from step 4 above and 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-
methoxybenzoyl)piperidin-4-yl)-4H-3, 1 -benzoxazin-2( 1 H)-one from
20 Example 40 were reacted using the procedure given in step 4 of
Example 17. The crude product was purified by pressurized silica gel
column chromatography using 97:3:0.3 CH2Cl2:MeOH:NH4OH as
eluant. The hydrochloride salt of 1-(1-(4-(1-(N-oxo-2,4-diethyl-6-
methyl-3 -pyridylmethyl)-4-piperidinyloxy)-5 -fluoro -2-
25 methoxybenzoyl)piperidin-4-yl)-4H-3 ,1 -benzoxazin-2( 1 H)-one was
obtained by lyophili7~tion from CH3CN-H2O cont~ining a4ueous HCl.
Analysis calculated for C37H45FN406, 0.7 HCl, 2.3 H20
C, 61.06; H, 6.97; N, 7.70
Found C, 61.04; H, 6.97; N, 7.72
30 TLC: Rf = 0.30 (97:3:0.3 CH2Cl2:MeOH:NH4OH)
HPLC (method A) retention time = 6.7 min
FAB MS m/z 661 (M+ + H)
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EXAMPLE 43
1 -(1 -(4-(1 -(N-oxo-2-ethyl-4-methyl-3-pyridylmethyl)-4-
piperidinyloxy)-~-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -
5 benzoxazin-2(1 H)-one
F
~N~ ,O~ H3C~
~N~ N~N~
O OCH3 CH3
Step 1. Ethyl 2-ethyl-4-methylnicotinate was prepared in a
manner analogous to that reported for ethyl 2,4-dimethylnicotinate by
Ohno et al., J. Am. Chem. Soc. (1979) vol. 101, p. 7036. Ethyl
10 propionylacetate (25 g, 0.17 mol), acetaldehyde (10.6 g, 0.24 mol), and
acetaldehyde-ammonia complex (11.7 g, 0.09 mol) were combined and
heated at 90~C for 96 h. The mixture was evaporated under reduced
pressure to remove water and excess reagents. The residue was distilled
under reduced pressure (ca. 1 Torr) and the fraction boiling from 140-
15 155~C was collected and further purified by pre,ssurized silica gelcolumn chromatography using a gradient elution of 95:5 to 85:15
CH2C12:EtOAc. Ethyl 2-ethyl-6-methylnicotinate (Rf = 0.2~ (92:8
CH2C12:EtOAc)) was isolated as the major product and ethyl 2-ethyl-4-
methylnicotinate (Rf = 0.17 (92:8 CH2C~12:EtOAc)) was isolated as the
20 minor product.
Steps 2-5. Ethyl 2-ethyl-4-methylnicotinate from step 1
above was converted to 3-chloromethyl-2-ethyl-4-methylpyridine-N-
oxide in three steps using procedures analogous to those given in steps
1-3 in Example 17, and 3-chloromethyl-2-ethyl-4-methylpyridine-N-
25 oxide was used to alkylate 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-
methoxybenzoyl)-piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one from
Example 40 using a procedure analogous to that given in step 4 of
Example 17. The crude product was purified by pressurized silica gel
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column chromatography using 97:3:0.3 CH2Cl2:MeOH:NH4OH as
eluant. The hydrochloride salt of 1-(1-(4-(1-(N-oxo-2-ethyl-4-methyl-
3 -pyridylmethyl)-4-piperidinyloxy)-5 -fluoro-2-
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one was
5 obtained by lyophili7~ion from CH3CN-H20 con~ining aqueous HCl.
Analysis calculated for C35H41FN406, 2.5 HCl, 0.95 H2O
C, 56.73; H, 6.18; N, 7.56
Found C, 56.72; H, 6.07; N, 7.60
TLC: Rf = 0.24 (97:3:0.3 CH2Cl2:MeOH:NH4OH)
10 HPLC (method A) retention time = 6.4 min
FAB MS m/z 633 (M+ + H)
EXAMPLE 44
1 -(1 -(4-(1 -(N-oxo-2-ethyl-4,6-dimethyl-3-pyridylmethyl)-4-
piperidinyloxy)-S-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -
benzoxazin-2(1 H)-one
F
~N~ ~o~ H3C~CH3
N~ J N~N~
O OCH3 CH3
Step 1. Ethyl propionylacetate, pentan-2,4-dione, and
20 ammonium acetate were reacted to give ethyl 2-ethyl-4,6-
dimethylnicotinate using a procedure analogous to that given in step 1 of
Example 42.
Steps 2-5. Ethyl 2-ethyl-4,6-dimethylnicotinate from step 1
above was converted to 3-chloromethyl-4,6-dimethyl-2-ethylpyridine- .
25 N-oxide in three steps using procedures analogous to those given in
steps 2-4 of Example 42, and 3-chloromethyl-4,6-dimethyl-2-
ethylpyridine-N-oxide was used to alkylate 1-(1-(4-(4-piperidinyloxy)-
5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-
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one from E~ample 40 using a procedure analogous to that given in step
4 in Example 17. The crude product was purified by pressurized silica
gel column chromatography using 97:3:0.3 CH2C12:MeOH:NH40H as
eluant. The hydrochloride salt of 1-(1-(4-(1-(N-oxo-2-ethyl-4,6-
5 dimethyl-3-pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one was
obtained by lyophili7~tion from CH3CN-H20 cont~ining aqueous HCl.
Analysis calculated for C: 36H43FN406~ 2.5 HCl, 1 -4 H20
C, 56.66; H, 6.38; N, 7.34
10 Found C, 56.68; H, 6.27; N, 7.42
TLC: Rf = 0.22 (97:3:0.3 CH2C12:MeOH:NH40H)
HPLC (method A) retention time = 6.4 min
FAB MS m/z 647 (M+ + H)
EXAMPLE 45
1 -(1 -(4-(1 -(2-ethyl-4,6-dimethyl-3-pyridylmethyl)-4-piperidinyloxy)-5-
fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-
2~ 1 H)-one
F
~'~'~ H3C~C H3
N ~ N ~ N
O OCH3
CH3
Step 1. Ethyl propionylacetate, pentan-2,4-dione, and
ammonium acetate were reacted to give ethyl 2-ethyl-4,6-
dimethylnicotinate using a procedure analogous to that given in step 1 of
Example 42.
Steps 2-4. Ethyl 2-ethyl-4,6-dimethylnicotinate from step l
above was converted to 3-chloromethyl-4,6-dimethyl-2-ethylpyridine in
two steps using procedures analogous to those given in steps 2 and 3 o~
Example 42, and 3-chloromethyl-4,6-dimethyl-2-ethylpyridine was u.sed
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to aL~ylate 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2- ,
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one from
Example 40 using a procedure analogous to that given in step 4 in
Example 17. The crude product was purified by pressurized silica gel
5 column chromatography using 97:3:0.3 CH2C12:MeOH:NH4OH as
eluant. The hydrochloride salt of 1-(1-(4-(1-(2-ethyl-4,6-dimethyl-3-
pyridylmethyl)-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)-
piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained by
lyophili7~tion from CH3CN-H2O containing aqueous HCl.~0 Analysis calculated for C36H43FN4O5~ 1.65 HCl, 0.05 H2O
C, 62.49; H, 6.52; N, ~.10
Found C, 62.47; H, 6.43; N, 8.01
TLC: Rf= 0.28 (97:3:0.3 CH2C12:MeOH:NH4OH)
HPLC (method A) retention time = 6.0 min
15 FAB MS m/z 631 (M+ + H)
EXAMPLE 46
1 -(1 -(4-(1 -(N-oxo-2-methyl-3-pyridylmethyl)-4-piperidinyloxy)-5-
20 fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-
2(1 H)-one
~'p~ F
'C ~~'
N ~ N q~N
O OCH3 CH3
The title compound was prepared from 1-(1-(4-(4-piperidinyloxy)-5-
fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one
25 of Example 40 and 3-chloromethyl-2-methylpyridine-N-oxide from step
3 of Example 17 using the procedure given in step 4 of Example 17.
The title compound was purified by pressurized silica gel column
chromatography using 97:3:0.3 CH2C12:MeOH:NH40H as eluant. The
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hydrochloride salt of the title compound was obtained as an amorphous
solid by lyophili7~tion from CH3CN-H20 cont~inin~ aqueous HCl.
Analysis calculated for C33H37FN406, 2.4 HCl, 0-25 H20
C, 56.89; H, 5.77; N, 8.04
5 Found C, 56.89; H, 5.77; N, 7.90
TLC: Rf = 0.26 (96:4:0.4 CH2Cl2:MeOH:NH4OH)
HPLC (method A) retention time = 6.1 min
FAB MS m/z 604 (M+ ~ H)
EXAMPLE 47
(4-( l -(N-oxo-2-isopropyl-3-pyridylmethyl)-4-piperidinyloxy)-5-
fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-
2(1 H)-one
F
~ ~N~ ~NJ~N~
O OCH3 H3C CH3
Ethyl 2-isopropylnicotinate was converted in three steps to 3-
chloromethyl-2-isopropylpyridine-N-oxide using procedures analogous
to those given in steps 1-3 in Example 17. The title compound was
prepared from 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-
20 methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one of
Example 40 and 3-chloromethyl-2-isopropylpyridine-N-oxide using the
procedure given in step 4 of Example 17. The title compound was
purified by pressurized silica gel column chromatography using
97:3:0.3 CH2Cl2:MeOH:NH4OH as eluant. The hydrochloride salt of
25 the title compound was obtained as an amorphous solid by lyophilization
from CH3CN-H2O cont~ining aqueous HCl.
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Analysis calculated for C35H41FN406, 2.5 HCl, 0.7 H2O
C, 57.07, H, 6.14; N, 7.61
Found C, 57.09; H, 6.07; N, 7.52
TLC: Rf = 0.32 (96:4:0.4 CH2C12:MeOH:NH4OH)
5 HPLC (method A) retention time = 6.7 min
FAB MS m/z 633 (M+ + H)
EXAMPLE 4g
10 1 -(1 -(4-(1 -(N-oxo-2-isopropyl-6-methyl-3-pyridylmethyl)-4-
piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -
benzoxazin-2(1 H)-one
~'~~ F
--N~C ~b--o~ CH3
N~ ~N ~N~
O OCH3 H3C CH3
Ethyl 2-isopropyl-6-methylnicotinate was prepared using a procedure
15 analogous to that given in step 1 of Example 43 using ethyl 3-oxo-4-
methylpentanoate in place of ethyl propionylacetate. Ethyl 2-isopropyl-
6-methylnicotinate was converted in three steps to 3-chloromethyl-2-
isopropyl-6-methylpyridine-N-oxide using procedures analogous to
those given in steps 1-3 in Example 17. The title compound was
20 prepared from 1 -(1 -(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)-
piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one of Example 40 and 3-
chloromethyl-2-isopropyl-6-methylpyridine-N-oxide using the
procedure given in step 4 of Example 17. The title compound was
purified by pressurized silica gel column chromatography using
25 97:3:0.3 CH2C12:MeOH:NH4OH as eluant. The hydrochloride salt of
the title compound was obtained as an amorphous solid by lyophili7~ion
from CH3CN-H2O cont~ining aqueous HCl.
Analysis calculated for C36H43FN4O6~ 2.5 HCl, 0.35 H2O
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C, 58.09; H, 6.26; N, 7.53
FoundC, 58.09; H, 6.21; N, 7.48
TLC: Rf = 0.35 (96:4:0.4 CH2Cl2:MeOH:NH40H)
HPLC (method A) retention time = 6.8 min
5 FAB MS m/z 647 (M+ + H)
EXAMPLE 49
l -(1 -(4-(1 -(N-oxo-2,4,6-trimethyl-3 -pyridylmethyl)-4-piperidinyloxy)-
10 5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3, l -benzoxazin-
2(1 H)-one
F
~N~ ~~ H3C~CH3
N~ N ~.~N~
O OCH3 CH3
Ethyl 2,4,6-trimethylnicotinate was prepared using a procedure
analogous to that given in step 1 of Example 42 using ethyl acetoacetate
15 in place of ethyl propionylacetate. Ethyl 2,4,6-trimethylnicotinate was
converted in three steps to 3-chloromethyl-2,4,6-trimethylpyridine-N-
oxide using procedures analogous to those given in steps 1-3 in Example
17. The title compound was prepared from 1-(1-(4-(4-piperidinyloxy)-
5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-
20 one of Example 40 and 3-chloromethyl-2,4,6-trimethylpyridine-N-
oxide using the procedure given in step 4 of Example 17. The title
compound was purified by pressurized silica gel column
chromatography using 97:3:0.3 CH2C12:MeOH:NH4OH as eluant. The
hydrochloride salt of the title compound was obtained as an amorphous
25 solid by lyophili7~tion from CH3CN-H20 cont~inin~ aqueous HCl.
Analysis calculated for C35H41FN406, 1.6 HCl, 0.95 H2O
C, 58.35; H, 6.33; N, 7.91
Found C, 59.32; H, 6.33; N, 7.90
TLC: Rf= 0.25 (97:3:0.3 CH2C12:MeOH:NH4OH)
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HPLC (method A) retention time = 6.2 min
FAB MS m/z 633 (M+ + H)
EXAMPLE 50
s
1 -(1 -(4-(1 -(N-oxo-2,6-diethyl-4-methyl-3-pyridylmethyl)-4-
piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-
2(1 H)-one
~0~0
N~ 0~ H3C~f CH3
~N~ N~N~
O OC H3 C H3
10 Ethyl 2,6-diethyl-4-methylnicotinate from step 1 of Example 42 was
converted in three steps to 3-chloromethyl-2,6-diethyl-4-
methylpyridine-N-oxide using procedures analogous to those given in
steps 1-3 in Example 17. The title compound was prepared from 1-(1-
(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -
15 benzoxazin-2(1H)-one from Example 3 and 3-chloromethyl-2,6-diethyl-
4-methylpyridine-N-oxide using the procedure given in step 4 of
Example 17. The title compound was purified by pressurized silica gel
column chromatography using 97:3:0.3 CH2Cl2:MeOH:NH4OH as
eluant. The hydrochloride salt of the title compound was obtained as an
20 amorphous solid by lyophili7~tion from CH3CN-H2O cont~ining
aqueous HCl.
Analysis calculated for C37H46N4O6~ 2.0 HCl, 0.05 H2O
C, 62.01; H, 6.77; N, 7.82
Found C, 61.99; H, 6.74; N, 7.70
25 TLC: Rf= 0.24 (97:3:0.3 CH2Cl2:MeOH:NH4OH)
HPLC (method A) retention time = 6.7 min
FAB MS m/z 643 (M+ + H)
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v EXAMPLE 51
1 -(1 -(4-(1 -(N-oxo-2-ethyl-4,6-dimethyl-3 -pyridylmethyl)-4-
piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-
5 2(1H)-one
O O
~N~ o~ H3C~CH3
N~ ~N ~N~
O OCH3 CH3
The title compound was prepared from 1-(1-(4-(4-piperidinyloxy)-2-
methoxybenzoyl)piperidin-4-yl)-4H-3,1 -benzoxazin-2(1 H)-one from
Example 3 and 3-chloromethyl-4,6-dimethyl-2-ethylpyridine-N-oxide
10 from Example 44 using the procedure given in step 4 of Example 17.
The title compound was purified by pressurized silica gel column
chromatography using 97:3:0.3 CH2C12:MeOH:NH4OH as eluant. The
hydrochloride salt of the title compound was obtained as an amorphous
solid by lyophili7~tion from CH3CN-H2O cont~ining a4ueous HCl.
15 Analysis calculated for C36H44N4O6~ 2.5 HCI, 0.05 H2O
C, 59.98; H, 6.52; N, 7.77
Found C, 60.00; H, 6.34; N, 7.86
TLC: Rf= 0.21 (97:3:0.3 CH2C12:MeOH:NH4OH)
HPLC (method A) retention time = 6.2 min
20 FAB M~ m/z 629 (M+ + H)
EXAMPLE 52
As a specific embodiment of an oral composition, 100 mg
25 of the compound of Example 22 is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill a size
O hard gel capsule.
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EXAMPLE 53
RAT & HUMAN OT/AVP BINDING ASSAYS
The high arrilliLy binding of [3H]oxytocin (OT) to uterine
5 tissue and [3H]arginine vasopressin (AVP) to liver (AVP-V1 site) and
kidney (AVP-V2 site) tissue was determined using crude membrane
preparations as described previously [Pettibone, D.J., et al., J.
Pharmacol. and Exper. The7-., 256(1): 304-308 (1991)]. Uterine tissue
was taken from nonpregnant adult Sprague-Dawley rats (Taconic
10 Farms, Germantown, NY) pretreated (18-24 h) with diethylstilbestrol
propionate (DES; 300 ,ug/kg, i.p.). Uterine tissue (full thickness) was
also taken with informed consent from nonlabor pregnant women
undergoing cesarean section at 38 to 39 weeks gestation (Oregon Health
Sciences Center, Portland, OR). Liver and kidney medulla samples
15 were taken from male rats and from human surgical and early
postmortem donors (National Disease Research Interchange,
Philadelphia PA; Analytical Biological Services, Wilrnington, DE).
Competition studies were conducted at equilibrium using 1
nM [3H]oT or 0.5 nM [3H]AVP in the following buffer: 50 mM Tris, 5
20 mM MgC12, 0.1 % bovine serum albumin. Nonspecific binding was
determined using 1 ,uM unlabeled OT or AVP in their respective assays.
The binding reactions were initiated by the addition of tissue
preparation and termin~ted by filtration using a Skatron cell harvester
(model 7019, Skatron, Inc., Sterling, VA). Ki values were calculated
25 for each compound using three to six separate ICso determinations
(Ki=ICso/[l- c/Kd]); [Cheng, Y-C; Prusoff, W.H.; Biochem Pharmacol
22:3099 (1973)] with mean Kd values obtained from replicate (n = 3)
equilibrium saturation binding assays (10 point, 100 fold concentration
range): [3H]oT rat uterus, 0.69 nM; hllm~n myometrium, 1.1 nM;
30 [3H]AVP: rat liver, 0.21 nM; rat kidney, 0.27 nM; human liver, 0.27
nM; human kidney, 1.4 nM. Computer analysis of the saturation assay,s
by EBDA/LIGAND [McPherson, G.A.: Kinetic, Ebda, Ligand, Lowry:
A Collection of Radioligand Binding Analysis Programs, Elsevier
Science Publishers, Amsterdam (1985)] indicated that both radioligand~s
35 apparently bound to single sites in all tissues examined. The final
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protein concentration for the various tissues in each assay ranged from
150 to 300 ,ug/ml [Lowry, P.H.; Rosebrough, N.J.; Farr, A.L., Pc~n~l~ll,
R.J.; J. Biol. Chem., 193:265-275 (1951)].
ICso values were determined for the [3H]oT and [3H]AVP
5 binding assays by linear regression of the relation log concentration of
compound vs. percent inhibition of specific binding. Data is either
reported as a given percentage of inhibition at a specified concentration,
or if an IC50 was calculated, as a nanomolar concentration.
Representative compounds of the present invention were found to have
10 IC50 values for the hllm~n oxytocin receptor in the range of 2 nM to
1,000 nM.
The oxytocin antagonistic effect of the compounds of the
present invention can be further evaluated according to the in vitro
and/or in vivo functional assays described in detail in D.J. Pettibone et
15 al., Drug Devel.Res. 1993, 30, 129-142.
Additional preferred oxytocin antagonist compounds of the
instant invention, useful for treating oxytocin-related conditions such as
preterm labor, dysmenorrhea and stopping labor prior to cesarean
delivery, are shown below in Tables 1 through 12.
TABLE 1
o
~X~
~,N~ R1 ~o~
N~CH2--~J ~,N~ R4
~ OCH3
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X Rl R_
O CH3 H
O CH3 CH3
O CH3 CH2CH3
O CH3 isopropyl
O CH3 CH2-cyclopropyl
O CH3 COCH3
O CH3 SO2CH3
O CONH2 H
O CONH2 CH3
O CONH2 CH2CH3
O CONH2 isopropyl
O CONH2 CH2-cyclopropyl
O CONH2 COCH3
O CONH2 SO2CH3
CH2 CH3 H
CH2 CH3 CH3
CH2 CH3 CH2CH3
CH2 CH3 isopropyl
CH2 CH3 CH2-cyclopropyl
CH2 CH3 COCH3
CH2 CH3 SO2CH3
CH2 CONH2 H
CH2 CONH2 CH3
CH2 CONH2 CH2CH3
CH2 CONH2 isopropyl
CH2 CONH2 CH2-cyclopropyl
CH2 CONH2 COCH3
CH2 CONH2 SO2CH3
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TABLE 2
)' O
~,N~Cl ~~~Cl,R3
N~ ~l N~ R4
~ OC H3
X R3 R-
o CO2H H
O CO2H CH3
O C02H CH2CH3
o CO2H isopropyl
o CO2Et H
O CO2Et CH3
O C02Et CH2CH3
o CO2Et isopropyl
o CONH2 H
o CONH2 CH3
O CONH2 CH2CH3
o CONH2 isopropyl
CH2 CO2H H
CH2 CO2H CH3
CH2 C02H CH2CH3
CH2 CO2H isopropyl
CH2 CO2Et H
CH2 CO2Et CH3
CH2 CO2Et CH2CH3
CH2 CO2Et isopropyl
CH2 CONH2 H
CH2 CONH2 CH3
r CH2 CONH2 CH2CH3
CH2 CONH2 isopropyl
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TABLE 3
O
~X~
~N~ ~O~ CH3
~(CH2)n~ ~,N~ R4
~ OCH3
X R4 n
O H 0
O CH3 0
O CH2CH3 0
O isopropyl O
O CH2-cyclopropyl 0
O COCH3 o
O S02CH3 o
O H3C ~ O
-CH2~
CH3
O H3C~ 0
-CH2'~jss 0
CH3
O ~ O
-CH2~
CH3
O ~ O
-CH2~N
CH2CH3
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X R4 n
O ~q O
-CH2~
H C,CH_cH
o 1~9 o
-CH2~
O ~ O
-CH2'~:sZ O
CH3
O ~ O
-CH2~f5 N_o
CH2CH3
O ~ O
-CH2~N_o
H C ,CH--CH
O ~ O
-CH2~ 0
O H
O CH3
O CH2CH3
O isopropyl
o CH2-cyclopropyl
O COCH3
O S02CH3
CH2 H 0
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X R_ n
CH2 CH3 o
CH2 CH2CH3 0
CH2 isopropyl 0
CH2 CH2-cyclopropyl 0
CH2 COCH3 0
CH2 S02CH3 0
CH2 H3C ~ o
-C H2~
CH3
CH2 H3C~f~ ~
-CH2~ o
CH3
CH2 ~ O
-CH2~
CH3
CH2 I~:q O
-CH2~N
CH2CH3
CH2 ~ O
-CH2~
H C_CH_cH
CH2 ~ O
-CH2~
J
CH2 ~ q O
-CH2~ 0
CH3
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X R- n
CH2 I~q ~
-CH2~N_o
CH2CH3
CH2 ~ O
-CH2~N~o
H C,CH_cH
CH2 ~ O
-CH2'~gs 'O
CH2 H
CH2 CH3
CH2 CH2CH3
CH2 isopropyl
CH2 CH2-cyclopropyl
CH2 COCH3
CH2 S02CH3
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TA13LE 4
o
~X~ ICH3
[~ ~N ~ (CH2)n~ ~N~ R4
O OCH3
X R4 B
O H 0
o CH3 0
O CH2CH3 0
O isopropyl O
O CH2-cyclopropyl 0
O COCH3 0
O S02CH3 o
O H3C ~ o
-CH2~
CH3
O H3C~ o
-CH2~ 0
CH3
O ~ O
-CH2~
CH3
O ~ O
-CH2~fs N
CH2CH3
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X R_ n
O ~ O
-CH2~s
H C,CH_cH
O ~ O
-CH2~
~\
O ~ O
-CH2~ 0
CH3
O ~ O
-CH2'~fsN--O
CH2CH3
O ~ O
-CH2~N_o
H C,CH_cH
O ~ O
-CH2~ 0
O H
o CH3
O CH2CH3
O isopropyl
O CH2-cyclopropyl
O COCH3
O S02CH3
CH2 H 0
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X R4 n
CH2 CH3 0
CH2 CH2CH3 0
CH2 isopropyl 0
CH2 CH2-cyclopropyl 0
CH2 COCH3 0
CH2 S02CH3 o
CH2 H3C ~ o
-CH2'~fs
CH3
CH2 H3C~ o
-CH2~:s 0
CH3
CH2 ~q O
-CH2~s:s
CH3
CH2 ~ 0
-CH2~
CH2CH3
CH2 ~ O
-CH2~6sN
H C,CH_cH
CH2 ~ O
-CH2~
~ ..
CH2 ~ O
-CH2~fs o
CH3
CA 02210138 1997-07-10
WO 96/2277S
PCTIUS96/00850
- 133 -
X R_ n
CH2 ~ O
-CH2~ N_o
CH2CH3
CH2 ~ O
-CH2'~fs N_o
H C ,CH--CH
CH2 ~ O
-CH2~ 'O
CH2 H
CH2 CH3
CH2 CH2CH3
CH2 isopropyl
CH2 CH2-cyclopropyl
CH2 COCH3
CH2 S02CH3
CA 02210138 1997-07-10
PCT/US96/00~50
WO 96/22775
- 134-
TABLE S
o
~X~ 1
~N' R4
O OCH3
X R4
O H
O isopropyl
O COC~H3
O S02~H3
O H3C
-CH2'~f:
CH3
O H3C ~
-CH2~ 0
CH3
-C H2J~N
CH3
-CH2J~N
CH2CH3
O
~ -CH2~N
C,CH_CH
CA 02210138 1997-07-10
WO 96/22775
PCT/US3 5.'00~50
- 135-
X R4
J O -~
-CH
~\
O ~
-CH2~ 0
CH3
-CH2J~N--O
CH2CH3
~ fq
-CH2~ssN~o
H C,CH_cH
O ~
-CH2'~s:s 0
~\
CH2 H
CH2 isopropyl
CH2 COCH3
CH2 S02CH3
CH2 H3C~
-CH2~
CH3
CH2 H3C~
Il I
-CH2~f N'~
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 136-
X R_
C~I2
-CH2~
CH3
C~H2 ~q
-CH2~N
CH2CH3
CH2 ~
-CH2 ~N
H C,CH_cH
C~H2 ~q
-CH2~s
~\
2 ~
-CH2~fs o
CH3
CH2 ~
-CH2J~fsN--O
CH2CH3
C~H2 , ~1
-CH2~fZN-O
H C,CH_cH
C~2 ~
CA 02210138 1997-07-10
WO 96122775 PCT/US9f /oo~co
- 137-
TABLE 6
~X~O
\~N~ ~N~R4
~ OC H3
X R4
O . H
O isopropyl
o COCH3
O S02CH3
O H3C
-CH2~
CH3
O H3C ~
-CH2~s5 o
CH3
O ~
-CH2~fs
CH3
O ~
-CH2~5
CH2CH3
~ fi~
-CH2'~f N
H3C ' --CH3
CA 02210138 1997-07-10
WO 96/22775 PCI/US~5'~'0
- 138-
X R4
O ~
-CH2~
O ~
-CH2~ 0
CH3
-CH2J~N--O
CH2CH3
O ~
-CH2--~ N_o
H C ,CH--CH
O ~
-CH2~ 'O
~\
CH2 H
CH2 isopropyl
CH2 COCH3
CH2 S02CH3
CH2 H3C
-C H2~ss
CH3
CH2 H3C~
2~ss o
CH3
CA 02210138 1997-07-10
WO 96/22775 PCI~/US~C/00~CO
- 139-
~.
X R4
C~H2 ~q
-CH2~N
CH3
C~H
-CH2~sS
CH2CH3
(~H2 ~q
-CH2~
H C,CH_cH
(~H2
-CH2'~
~\
C~2 ~
-CH2~fs o
CH3
CH2 ~
-CH2~ N_o
CH2CH3
C~H2 ~
-CH2~N_o
H C,CH_cH
C~I2
-CH2~ 'O
CA 02210138 1997-07-10
WO 96122775 PCTIUS96/00850
- 140-
TABLE 7
~X~O
~N~,CH3 ~,~~
CH2/~ N~ R4
O OCH3
X B4
O H
O isopropyl
O COCH3
O S02CH3
O CH3
O CH2CH3
O CH2-cyclopropyl
CH2 H
CH2 isopropyl
CH2 COCH3
CH2 S02CH3
CH2 CH3
CH2 CH2CH3
CH2 CH2-cyclopropyl
CA 02210138 1997-07-10
WO 96122775 PCT/US96/00850
- 141 -
TABLE
)~ O
CH3
rCH2~ ~ R4
O OCH3
x B4
O H
O isopropyl
O COCH3
O S02CH3
O CH3
O CH2CH3
O CH2-cyclopr
CH2 H
CH2 isopropyl
CH2 COCH3
CH2 ~02CH3
CH2 CH3
CH2 CH2CH3
CH2 CH2-cyclopropyl
CA 02210138 1997-07-10
WO 96/22775 PCI/US96/00850
- 142-
TABLE 9
~X~O
[~ ~N~r l~ ~N~R
~ OCH3 ~=~N--(~)n
x B7 a
O H O
O CH3 o
O CH2CH3 0
O isopropyl O
O cyclopropyl O
O H
O CH3
O CH2CH3
O isopropyl
O cyclopropyl
CH2 H O
CH2 CH3 o
CH2 CH2CH3 0
CH2 isopropyl O
CH2 cyclopropyl O
CH2 H
CH2 CH3
CH2 CH2CH3
CH2 isopropyl
CH2 cyclopropyl
CA 02210138 1997-07-10
WO 96122775 PCT/US96/00850
- 143-
TABLE 10
~X~ ~ R8
~N~ ~N~ 4
O OCH3
X R~ R_
O CH3 H3C
-CH2~
CH3
O CH3 H3C ~
-CH2~p 0
CH3
O CH3
2~
O CH3 ~
-CH2J~fss
CH2CH3
O CH3 ~
-CH2~:ss
H3C-- H--C H3
O CH3 ~q
-C H2~ss N
/\
CA 02210138 1997-07-10
WO 96/22775 PCT/US~6/C~S50
- 144-
X B8 R_
O CH3
-CH2~ 0
CH3
O CH3 ~
-CH2~N_o
CH2CH3
O CH3 ~
-CH2'~fs N_o
H C,CH_cH
O CH3 ~
-CH2~ 'O
O CH3 CH3
O CH3 CH3
CH~N
O CH3 CH3
CH3CH~N
O CH3 CH3
CH~N~
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 145-
X R_ R_
O CH3 CH3
'~
~N
O CH3 CH3
O CH3 CH3
,~
CH3 ,N
O CH3 CH3
CH3Ct~N
O CH3 CH3
,~
CH3~ ,N
CH3 0
O CH3 CH3
~ F H3C~
-CH2~s5
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96.'0C850
- 146-
X R8 R4
~ F H3C ~
-CH2~ 0
CH3
O F
-CH2~s
CH3
O F
-CH2~
CH2CH3
~ F ~9
-CH2~s5
H C,CH_cH
O F ~
-CH2~,
O F ~
-CH2~ 0
CH3
O F ~
-CH2~s N_o
CH2CH3
O F ~
-CH2'~f N_o
H C,CH_cH
CA 02210138 1997-07-10
WO 96122775 PCT/US~)6/OQU50
- 147-
X R8 R_
O F ~
-CH2~:s o
/~
O F CH3
O F CH3
CH~N
~ F CH3
CH3
~ F CH3
CH~
CH3
O F CH3
O F CH3
O F CH3
/~
CH~N~
o
CA 02210138 1997-07-10
WO 96/2277S PCT/US96/00850
- 148-
X R8 R_
~ F CH3
CH3CH~ ,N
~ F CH3
,~
CH3~' ,N
CH3 0
O F CH3
~ Cl H3C
-CH2~
CH3
~ Cl H3C ~
-CH2~ 0
CH3
O Cl
-CH2~SZ
CH3
CA 02210138 1997-07-10
PCT/U~G/00~50
WO 96/22775
- 149-
- x R8 B-
~ Cl
-CH2'~f N
CH2CH3
~ Cl ~
-CH2~
H C,CH_cH
O Cl ~
-CH2~:5
O Cl ~
-CH2'~fs 0
CH3
O Cl ~
-CH2~fsN-O
CH2CH3
O Cl 1~9
-CH2~fs N-o
H C,CH_cH
~ Cl ~
-CH2~ 0
,. ~\
CA 02210138 1997-07-lo
WO 96/22775 PCT/US96/00850
- 150-
X R8 R4
~ Cl CH3
O Cl CH3
CH~NoJ
~ Cl CH3
,~
CH3CH~N~
~ Cl CH3
3~N
CH3
O Cl CH3
~N
O Cl CH3
~,
CA 02210138 1997-07-10
WO 96122775 PCT/US96/00850
- 151 -
X R8 R_
~ Cl CH3
,1~
CH~ N~
~ Cl CH3
,~
CH3CH~ ,N
~ Cl CH3
CH3~ ,N
CH3 0
~ Cl CH3
~ ~o
~ Br H3C~
-CH2~fs
CH3
~ Br H3C~
-CH2~ 'O
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 152-
X R8 R_
O B r ~:q
-CH2~Ss
CH3
O Br ~
-CH2~7 N
CH2CH3
~ Br ~
-CH2~
H C,CH_cH
~ Br ~
-CH2~6s
/~
O Br ~q
-CH2~ 0
CH3
O Br ~
-CH2~N_o
CH2CH3
O Br ~
-CH2'~f N_o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US9f '00850
- 153-
X R8 R_
~ Br ~
-CH2~ o
~ Br CH3
~ Br CH3
CH~N
~ Br CH3
,~
CH3CH~N
~ Br CH3
,~
~N
CH3
~ Br CH3
~ Br CH3
" O
CA 02210138 1997-07-10
WO 96/22775 PCT/US~6/~ iO
- 154-
X R8 R_
~ Br CH3
CH~N~
~ Br CH3
,~
CH3CH~ ,N
~ Br CH3
CH~ IN~
CH3 0
~ Br CH3
~ 'O
CH2 CH3 H3C~
-CH2~
CH3
CH2 CH3 H3C~
-CH2~ 0
CH3
CH2 CH3 f q
-CH2~N ..
CH3
CA 02210138 1997-07-10
WO 96t22775 PCTtUS96tO0850
- 155-
X R8 R4
CH2 CH3
-CH2~
' CH2CH3
CH2 CH3 ~
-CH2~
H C,CH_cH
CH2 CH3 ~
-CH2~
CH2 CH3 ~
-CH2~ 'O
CH3
CH2 CH3 ~
-CH2~N_o
CH2CH3
CH2 CH3 ~
-CH2~fs N_o
H C ,CH--CH
CH2 CH3 ~
-CH2~ 'O
/~
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 156-
X R8 R_
CH2 CH3 CH3
CH2 CH3 CH3
CH3 N
CH2 CH3 CH3
,~
CH3CH~N
CH2 CH3 CH3
,~
3~ N
CH2 CH3 CH3
,~
~--N
CH2 CH3 CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 157-
X R~ R_
CH2 CH3 CH3
, ~
CH3 ,N
CH2 CH3 CH3
CH3CH~ ,N
CH2 CH3 CH3
CH~ ,N
CH3 0
CH2 CH3 CH3
,~
~N~ ~'
CH2 F H3C
-C H2~s5
CH3
~H2 F H3C ~
-CH2~ 'O
CH3
CA 02210138 1997-07-10
PCI/US96/00850
WO 96/22775
- 158-
R8 R
(~H2 F
-CH2~fs
CH3
CH2 F ~
-CH2'~f5
CH2CH3
(~H2 F ¦~q
-CH2~
H C,CH_cH
CH2 F ~
-CH
CH2 F ~
-CH2~js5 ~
CH3
C~2 F ~q
-CH2~ssN~O
CH2CH3
CH2 F ~
-CH2~SSN-o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US9510C850
- 159-
X R8 R_
CH2 F
-CH2~ 0
(~H2 F CH3
CH2 F CH3
CH~N
CH2 F CH3
CH3C N
(~H2 F CH3
CH3~N
CH3
C~H2 F CH3
~N
CH2 F CH3
r N
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 160-
X R8 R4
CH2 F CH3
CH3 ,N
CH2 F CH3
CH3C~ ,N
CH2 F CH3
CH~ ,N
CH3 O
CH2 F CH3
,~
~ No~
CH2 Cl H3C
-CH2~
CH3
CH2 Cl H3C ~
-CH2~Z O
CH3
CA 02210138 1997-07-10
WO 96/22775 PCTtUS96/00850
- 161 -
X R8 R_
CH2 Cl ~9
-CH2~ N
CH3
CH2 Cl ~:q
-CH2~
CH2CH3
CH2 Cl f 9
-CH2~
H C,CH_cH
CH2 Cl ~
-CH2~
CH2 Cl f q
-CH2~ 'O
CH3
CH2 Cl f q
-CH2~sZN~O
CH2CH3
CH2 Cl ~9
-CH2~ N-o
H C,CH_cH
CA 02210138 1997-07-lo
WO 96/2277S PCT/US96100850
- 162-
X R8 R_
CH2 Cl ~:q
-CH2~ 0
CH2 Cl CH3
CH2 Cl CH3
,~
CH~' N
CH2 Cl CH3
CH3CH~N
CH2 Cl CH3
,~,
N
CH3
CH2 Cl CH3
CH2 Cl CH3
CA 02210138 1997-07-lo
WO 96/22775 PCT/US96/00850
- 163-
X R8 R_
CH2 Cl CH3
CH2 Cl CH3
CH3CH~ ,N
CH2 Cl CH3
,~
CH~ IN
CH3 0
CH2 Cl CH3
,~
~~ N
CH2 B r H3C
-C H2~
CH3
CH2 B r H3C ~
-CH2~ 0
CH3
CH2 B r ~q
-C H2~:s N
CH3
CA 02210138 1997-07-10
PCr~USg6/008~0
wo 96/22775
- 164-
X R8 R_
C~H2 B r
-C H2~
CH2CH3
CH2 B r ~
-CH2~sN
H C,CH_cH
CH2 B r ~
-CH2~
CH2 Br ~
-CH2~:s5 ~
CH3
CH2 B r ~
-CH2'~fs N_o
CH2CH3
CH2 B r ~q
-CH2~s5N~o
H C ,CH--CH
CH2 B r ~
-CH2~ 0
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/0-~50
- 165-
X R_ R_
C~H2 Br CH3
,~
C~H2 Br CH3
,~
CH~N
CH2 Br CH3
,~
CH3CH~N
CH2 Br CH3
CH3~,
CH3
CH2 Br CH3
~N
CH2 Br CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US~)6/00~50
- 166-
X R8 R_
CH2 B r CH3
CH~ N~
~H2 Br CH3
CH3C~ ,N
~H2 B r CH3
CH3~N~
CH3 0
CH2 Br CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/008S0
- 167-
TABLE 1 1
~X~O R8
~N~ ~N~ 4
O OCH3
X R8 R_
O CH3 H3C~
O CH3 H3C~
-CH2~ 'O
CH3
O CH3
-CH2'~fs
CH3
O CH3 ~
-CH2~s
CH2CH3
O CH3 ~
-CH2~sS
H C,CH_cH
CA 02210138 1997-07-10
WO 96/2277~ PCT/US96/00850
- 168-
X R8 R_
o CH3
-CH2~
~\
O CH3 ~
CH3
o CH3 ~
-CH2~N_o
CH2CH3
o CH3 ~:q
-CH2~ N-o
H C,CH_cH
o CH3 ~q
-CH2J~ ' O
O CH3 CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 169-
X R8 R_
O CH3 CH3
'X~
CH3 N
O CH3 CH3
CH3CH~N
O CH3 CH3
,~
~N
CH3
O CH3 CH3
~N
O CH3 CH3
O CH3 CH3
CH~N, ~'
CA 02210138 1997-07-10
WO 96/22775 PCT/US9~ $50
- 170-
X R_ R4
O CH3 CH3
,~
CH3CH~ ,N
O CH3 CH3
CH~ ,N
CH3 0
O CH3 CH3
O F H3C~
-CH2~
CH3
~ F H3C ~
-CH2~ 0
CH3
O F ~:~
-CH2~N
CH3
CA 02210138 1997-07-10
WO 96/22775 PCI/US96/00850
- 171 -
X R_ R4
O F ~q
-CH2~
CH2CH3
O F ~
-CH2~~
H C,CH_cH
O F ~
-CH2~s
O F ~
-cH2~ s5 'O
CH3
O F ~
-CH2~ssN - o
CH2CH3
O F ~
-CH2~N~o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCTIUS9G/CC850
- 172-
X R_ R_
o F ~q t
-CH2~ 0
O F CH3
~ F CH3
,~
CH~'N
~ F CH3
CH3C~N
~ F CH3
,~
3~N
CH3
O F CH3
~ F CH3
~, ..
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 173 -
X R_ R_
O F CH3
CH3
~ F CH3
CH3CH~ ,N
~ F CH3
CH3~ ,N~
CH3 0
O F CH3
~N
o
~ Cl H3C
-CH2~
CH3
~ Cl H3C ~
-CH2~ 'O
CH3
CA 02210138 1997-07-10
PCT/US~'00~50
WO 96/22775
- 174-
X R_ R_
~ Cl
-CH2~
CH3
~ Cl
-CH2~
CH2CH3
~ Cl ~
-CH2~
H C ,CH--CH
O Cl ~q
-CH2~
~ Cl ~
-CH2~ 0
CH3
~ Cl ~
-CH2~N_o
CH2CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 175-
X R_ R_
~ Cl
-CH2~N_o
H C ,CH--CH
~ Cl ~
-CH2~ 0
~ Cl CH3
~ Cl CH3
CH3 N
~ Cl CH3
CH3
~ Cl CH3
CH3~N
CH3
~= ~
CA 02210138 1997-07-10
WO 96/22775 PCT/US9''.,S850
- 176 -
X R_ R_
~ Cl CH3
~N
~ Cl CH3
O Cl CH3
CH~ N~
~ Cl CH3
CH3C~ ,N
~ Cl CH3
CH~N
CH3 0
~ Cl CH3
~N
o
CA 02210138 1997-07-10
WO 96/22775
PCT/US9G~IC ~8SO
- 177-
X R8 R4
~ Br H3C~
-CH2~
CH3
~ Br H3C~
-CH2~ 0
CH3
O Br ~q
2~
O Br ~q
-CH2~
CH2CH3
O Br ~
-CH2~fs
H C,CH_cH
O Br ~q
-CH2~
O Br ~
-CH2~ 0
r CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US9C100$CO
- 178-
X R_ R_
O Br
-CH2~N_o
CH2CH3
O Br ~q
-CH2~N_o
H C ,CH--CH
O Br fq
-CH2~s ~0
~\
~ Br CH3
~ Br CH3
,~
CH~N
~ Br CH3
,~
CH3C~NO'
~ Br CH3
N
CH3
~ Br CH3
,~
~N
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 179-
X R_ R4
~ Br CH3
~ Br CH3
,~
CH3 ,N
~ Br CH3
~,~
CH3C
~ Br CH3
CH3~N~
CH3 0
CA 02210138 1997-07-10
W O 96/22775 PCT~US96/00850
- 1 80 -
X R_ R_
O Br ,~
~0
CH2 CH3 H3C~
-CH2~
CH3
CH2 CH3 H3C ~
-CH2~ 0
CH3
CH2 CH3
-C H2~
CH3
CH2 CH3 ~
-C H2~
CH2CH3
CH2 CH3 ~
-CH2~
H C ,CH--CH
CH2 CH3 ~
-CH2~
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 181 -
X R_ R_
CH2 CH3 ~
CH3
CH2 CH3 ~
-CH2~ N_o
CH2CH3
CH2 CH3 ~
-CH2~N_o
H C,CH_cH
CH2 CH3 ~
-CH2~ 'O
~\
CH2 CH3 CH3
,~
CH2 CH3 CH3
CH3 N
CH2 CH3 CH3
CH3CH~N
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 182-
X R_ R_
CH2 CH3 CH3
3~N
CH3
CH2 CH3 CH3
~N
CH2 CH3 CH3
~,
CH2 CH3 CH3
CH3 N
CH2 CH3 CH3
,~
CH3CH~ ,N
CH2 CH3 CH3
3~ N,
CH3 0
CA 02210138 1997-07-10
WO 96122775 PCT/US96'0(~850
- 183 -
X R_ R4
2 CH3 CH3
.~ ~
~N,
CH2 F H3C
2~
(~H2 F H3C ~
CH3
CH2 F
-CH2'~f5
CH3
CH2 F 1~9
-CH2'~p
CH2CH3
CH2 F ~
-CH2~
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 184-
X R_ R_
C~2 F
-CH2~
~\
CH2 F ~q
-CH2~ 0
CH3
~H2 F ~
-CH2~s N_o
CH2CH3
CH2 F fq
-CH2~f N_o
H C,CH_cH
~H2 F ~
-CH2~::s 0
~\
C~H2 F CH3
CH2 F CH3
,~
CH~ N~
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/OQ850
- 185-
X R_ R_
C~H2 F CH3
CH3CH~N~
CH2 F CH3
3~N
CH2 F CH3
~N
C~H2 F CH3
~,
C~H2 F CH3
CH3 N
C~H2 F CH3
CH3C~ ,N
-
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 186-
X R_ R_
CH2 F CH3
,~
CH3~ ,N
CH3 0
CH2 F CH3
~o
CH2 Cl H3C
-CH2J~S
CH3
CH2 Cl H3C ~
-CH2~ 0
CH3
CH2 Cl ~q
-CH2~ 5
CH3
CH2 Cl
-CH2~
CH2CH3
CH2 Cl ~
-CH2~
H3C ' --CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96100850
- 187 -
X R_ R_
CH2 Cl
-CH
CH2 Cl ~
CH3
CH2 Cl ~
-CH2~N_o
CH2CH3
CH2 Cl 1~9
-CH2~N_o
H C,CH_cH
CH2 Cl ~
-CH2~ 'O
CH2 Cl CH3
CH2 Cl CH3
CH~N
CA 02210138 1997-07-lo
WO 96/22775 PCT/US96/00850
- 188-
X R_ R_
CH2 Cl CH3
,L~
CH3C~N
CH2 Cl CH3
--~N
CH2 Cl CH3
~N
CH2 Cl CH3
CH2 Cl CH3
,~
CH~N
CH2 Cl CH3
CH3CH~ ,N
CA 02210138 1997-07-10
WO 96/22775 PCTIUS96/00850
- 189-
X R_ R4
CH2 Cl C - H3
,L~
,
CH3 0
CH2 Cl CH3
CH2 Br H3C~
-CH2~
CH3
CH2 Br H3C~
-CH2~ 'O
CH3
C~H2 Br
-CH2~5
CH3
C~H2 Br ~
~ -CH2~fss N
CH2CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 190-
X R_ R_
C~2 Br
-CH2--f
H C,CH_cH
C~H2 Br ~
-CH2~sN
C~H2 Br ~
-CH2~ 0
CH3
(~H2 Br ~
-CH2~fsN--O
CH2CH3
~H2 Br ~
-CH2~ N-o
H C,CH_cH
CH2 B r ~
-CH2~ 0
C~H2 Br CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US95'008~0
- 191 -
X R8 R4
C~H2 Br CH3
CH~N~
C:~H2 Br CH3
CH3CH~N
CH2 Br CH3
3~N
CH3
C~H2 Br CH3
~ '
~N
C~H2 Br CH3
(~H2 Br CH3
CH~N
CA 02210138 1997-07-10
WO 96t22775 PCTIUS96/00~50
- 192-
X R_ R_
CH2 Br Cl H3
CH3C o
CH2 Br "~
N
CH3 0
CH2 B r "~
~N
CA 02210138 1997-07-10
WO 96/22775 PCTIUS96/00850
- 193-
TABLE 12
~X~O
~N~ R8~N~ 4
O OCH3
X R_ R4
O CH3 H3C~
-CH2~fsN
CH3
O CH3 H3C ~
-CH2~ 'O
CH3
O CH3
O CH3
-CH2~
CH2CH3
O CH3
-CH2~
H C,CH_cH
CA 02210138 1997-07-lo
WO 96122775 PCTIUS96/00850
- 194-
X R_ R4
O CH3
-CH2~
O CH3 ~
-CH2~ 0
CH3
o CH3 f q
-CH2~fsN--O
CH2CH3
O CH3 ~
-CH2'~f N-O
H C,CH_cH
O CH3 ~
-CH2~ 0
O CH3 CH3
CA 02210138 1997-07-10
WO 96/22775 PCI/US96/00850
- 195-
.
X R_ R4
O CH3 CH3
CH~N~
O CH3 CH3
CH3
O CH3 CH3
~N
CH3
O CH3 CH3
~N~
O CH3 CH3
O CH3 CH3
CH~N
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 196-
X R8 R_
O CH3 CH3
CH3CH~ IN
O CH3 CH3
~NI
CH3 0
O CH3 CH3
,~
~No~
~ F H3C
-CH2~
CH3
~ F H3C ~
-CH2~ 0
CH3
O F ~q
-CH2~
CH3
CA 02210138 1997-07-10
WO 96l22775
PCT/US96/00850
- 197-
X R8 R4
O F
-CH2~s
O F CH2CH3
-CH2~
H C ,CH--CH
-CH2J~N
O F ~
-CH2~ 'O
O F CH3
-CH2~N_o
O F CH2CH3
-CH2~N_o
H C,CH_cH
O F ~
-CH2~N~o
CA 02210138 1997-07-10
WO 96/22775 PCI/US96/00850
- 198-
X R_ R_
~ F "
O F
~ F CH3
CH3
~ F CH3
3~N
CH3
O F CH3
~ F CH3
CA 02210138 1997-07-10
WO 96/22775
PCT/US96/00850
- 199-
X R_ R_
~ F CH3
~,
~ F CH3
CH3
~ F CH3
CH~
CH3 0
O F CH3
,~
~N
o
~ Cl H3C
~ Cl H3C ~
-CH2'~fs 0
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00~50
- 200 -
X R_ R_
~ Cl
-CH2~
CH3
O Cl fq
-CH2~
CH2CH3
~ Cl ~
-CH2~
H C ,CH--CH
O Cl ~q
-CH
O Cl If q
C H3
~ Cl ~
-CH2~N_o
CH2CH3
O Cl ~
-CH2~s N-o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 201 -
X R_ R4
~ Cl
-CH2~ 0
O Cl CH3
~ Cl CH3
CH~N
~ Cl CH3
CH3CH~N
~ Cl CH3
3~N
CH3
O Cl CH3
O Cl CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US9GI'~ 50
- 202 -
X R_ R4
~ Cl CH3
CH3 N,
~ Cl CH3
,~
CH3C~ ,N
~ Cl CH3
,~
CH3~ ,N
CH3 0
O Cl CH3
,~
~N
o
~ Br H3C~
-CH2~5
CH3
~ Br H3C~
-CH2~ 0
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/U$9"0Q850
- 203 -
X R_ R_
O Br 1~9
-CH2~
CH3
O Br ~
-CH2~
CH2CH3
~ Br ~
-CH2~
H C,CH_cH
~ Br ~
-CH2J~
O Br ~q
-CH2~fs 0
CH3
O Br ~
-CH2'~fsN--O
CH2CH3
O Br ~
-CH2~ N~o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 204 -
X R_ R_
o Br ~ r
-CH2'~f 0
~ Br CH3
~ Br CH3
,~
CH~'N
~ Br CH3
,~
CH3Ct~N
~ Br CH3
,~
~N
CH3
~ Br CH3
,~,
~N
~ Br CH3
O
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 205 -
X R_ R_
~ Br CH3
CH~N~
~ Br CH3
CH3CH~ ,N
~ Br CH3
,
CH3 0
~ Br CH3
~N
o
CH2 CH3 H3C~
-CH2~N
CH3
~H2 CH3 H3C ~
-CH2~ 0
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 206 -
X R_ R_
CH2 CH3
-CH2~
CH3
CH2 CH3 If q
-CH2~ N
CH2CH3
CH2 CH3 ~
-CH2~
H C,CH_cH
CH2 CH3 ~
-CH2~
CH2 CH3 ~
-CH2~ss 0
CH3
CH2 CH3 If q
-CH2~N_o
CH2CH3
CH2 CH3 ~
-CH2~N_o
H C,CH_cH
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 207 -
X R_ R_
CH2 CH3
-CH2~ 'O
CH2 CH3 CH3
CH2 CH3 CH3
CH~N
CH2 CH3 CH3
CH3CH~N
CH2 CH3 CH3
N
CH3
CH2 CH3 CH3
~N
CH2 CH3 CH3
~r O
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 208 -
X R8 R_
CH2 CH3 CH3
CH3 ,N
CH2 CH3 CH3
CH3C~ IN
CH2 CH3 CH3
CH3~ N~
CH3 0
CH2 CH3 CH3
~ No
CH2 F H3C~
-CH2~
CH3
CH2 F H3C ~
-CH2~ 0
CH3
CH2 F ~
-CH2~N
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 209 -
X R_ R_
CH2 F
-CH2~
CH2CH3
~H2 F ~
-CH2~
H C,CH_cH
~H2 F ~
-CH2~
CH2 F ~
-CH2~ 0
CH3
CH2 F ~
-CH2~s5N~o
CH2CH3
CH2 F ~
-CH2'~f N-O
H C,CH_cH
C~2 F
~H2 F CH3
~N~
CA 02210138 1997-07-10
WO 96/22775 PCT/US~)6/00~50
- 210 -
X R_ R4
(~H2 F CH3
CH~N~
(~H2 F CH3
CH3CH~N
(~H2 F CH3
,~
~N
CH3
CH2 F CH3
CH2 F CH3
N
CH2 F CH3
Jl J
CH3 N
CH2 F CH3
CH3C~N
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 211 -
X R8 R_
CH2 F CH3
CH~
3~ N,
CH3 0
CH2 F CH3
~No
CH2 Cl H3C~
-CH2~
CH3
CH2 Cl H3C~
-CH2~ 0
CH3
CH2 Cl ~q
-CH2~
CH3
CH2 Cl ~
-CH2~
CH2CH3
CH2 Cl ~
-CH2~
r H3C ' --CH3
CH2 Cl ~9
-CH2~
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 212 -
X R_ R_
CH2 Cl
-CH2~ 0
CH3
CH2 Cl ~
-CH2~N_o
CH2CH3
CH2 Cl ~
-CH2~ N-o
H C,CH_cH
CH2 Cl 1~9
-CH2J~ 'O
(~H2 Cl CH3
CH2 Cl CH3
CH3 N
CH2 Cl CH3
,~
CH3CH~N
CH2 Cl CH3
CH~N
CH3
CA 02210138 1997-07-10
WO 96/22775
PCTtUS96tO0850
- 213 -
-
X R8 R4
CH2 Cl CH3
~N~
CH2 Cl CH3
CH2 Cl CH3 ~
r
CH~ ,N
CH2 Cl CH30
CH3CH~N~
CH2 Cl CH3 ~
CH3~N~
CH2 Cl CH3
,~,
~ ,N~
CH2 Br H3C~
-CH2~gSN
CH3
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 214 -
X R_ R_
(~H2 Br H3C~
-CH2~s 0
CH3
C~H2 B r ~q
-CH2~
CH3
~H2 Br ~
-CH2~
CH2CH3
CH2 Br ~
-CH2~
H C,CH_cH
CH2 Br ~
-CH2~,
CH2 Br ~
-CH2~ 0
CH3
C~H2 B r ~
-CH2'~fs N_o
CH2CH3
CA 02210138 1997-07-10
WO 96/22775
PCTIUS96/00850
- 215 -
X R_ R4
(~I2 Br 1~9
-CH2~ N_o
(:~H2 Br H C,CH_CH
-CH2JÇq ~O
CH2 Br CH3
GH2 Br CH3 N
~H2 Br CH~N
,~
(~H2 Br CH3CH~N~
~N
C~H2 Br CHC3H3
~N
CA 02210138 1997-07-10
WO 96/22775 PCI~/US96/00850
- 216 -
X R8 R4
C~H2 Br CH3
~L~
CH2 Br CH3
CH3 N,
CH2 B r CH3
,~
CH3C~ ,N
CH2 Br CH3
CH3~N~
CH3 0
~H2 Br CH3
~N,
CA 02210138 1997-07-10
WO 96/22775 PCT/US96/00850
- 217 -
While the invention has been described and illustrated with
r~felellce to certain preferred embodiments thereof, those skilled in the
art will appreciate that various changes, modifications and substitutions
can be made therein without departing from the spirit and scope of the
5 invention. For example, effective dosages other than the preferred
dosages as set forth hereinabove may be applicable as a consequence of
variations in the responsiveness of the m~mm~l being treated for
prevention of preterm labor, or for other indications for the compounds
of the invention indicated above. Likewise, the specific
10 ph~ cological responses observed may vary according to and
depending upon the particular active compound selected or whether
there are present ph~ ceutical carriers, as well as the type of
formulation and mode of ~lmini~tration employed, and such expected
variations or differences in the results are contemplated in accordance
15 with the objects and practices of the present invention. It is intended,
therefore, that the invention be limited only by the scope of the claims
which follow and that such claims be interpreted as broadly as is
reasonable.
