Note: Descriptions are shown in the official language in which they were submitted.
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NITROSATED AND NITROSYLATED
PHOSPHODIESTERASE INHIBITOR
COMPOUNDS, COMPOSITIONS AND THEIR USES
BACKGROUND OF THE INVENTION
This invention generally relates to pharmaceuticals and more specifically to a
method
and compositions for inducing penile erections in human males suffering from
impotence, a method and compositions for treating female sexual dysfunction,
and a
method and compositions for treating human anal disease resulting from
excessive anal
sphincter tone.
Male erectile dysfunction is a widespread disorder that is thought to affect
about
ten to fifteen percent of the adult men. In a similar fashion, it is now
beginning to be
recognized that female sexual dysfunction is also a significant problem among
adult
women. With the male cases, a number of causes of these insufficiencies, in
addition to
anatomical deficiencies of the penis that preclude an erection sufficient for
vaginal
penetration, have been identified. Causes of erectile dysfunction can be
categorized as
psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and in
any male
suffering from erectile dysfunction there may be more than one cause. Female
sexual
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dysfunction may also be categorized as psychogenic, neurogenic,
endocrinologic, drug-
induced, or vasculogenic and a female with one or more of these etiologies may
also
experience a lack of satisfaction in sexual relations.
Psychogenic impotence is often the result of anxiety or depression, with no
apparent somatic or organic impairment. Neurogenic impotence may arise from,
for
example, surgery or a pelvic injury, involving the nervous system affecting
the penis or
x
vagina. Sexual dysfunction which is in endocrinologic in origin is most often
associated
with the disorders hypo- or hypergonadotropic hypogonadism and
hyperprolactinein the
male and decreases in estrogens in the female.
Vasculogenic sexual dysfunction is thought to be the most frequent cause of
sexual
dysfunction accounting for approximately fifty percent of a11 cases of organic
sexual
dysfunction. In these cases, the erectile dysfunction may be attributed to
alterations in
the flow of blood to and from the penis while in the female cases vaginal
engorgement
insufficiency and clitoral erectile insufficiency may be attributed to
alterations in blood
flow to the vagina and clitoris respectively. Atherosclerotic or traumatic
arterial
occlusive disease to the arteries which supply blood to the penis can lead to
a decrease in
the rigidity of the erect penis as well as increase the time to achieving
maximal erection.
In an analogous fashion, disease which impairs blood flow to the hypogastric-
vaginallclitoral arterial bed may lead to vaginal engorgement insufficiency
and clitoral
erectile insufficiency. In still other cases, there is an inability to retain
blood in the
penis or clitoris such that sufficient pressure for an erection can be neither
obtained nor
maintained.
There is also a high incidence of erectile insufficiency among male diabetics,
particularly those with insulin-dependent diabetes mellitus. Erectile
dysfunction in
male diabetics is often classified as "diabetogenic," although the underlying
dysfunction
is usually neurogenic and/or vasculogenic. About half of diabetic males suffer
from
erectile insuff ciency, and about half of the cases of neurogenic impotence
are in
diabetics. A significant population of female diabetics also exhibit symptoms
of sexual
dysfunction, especially those with complications directly attributed to the
disease.
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Sexual dysfunction in both males and females is sometimes a side effect of
certain
drugs, such as beta-antagonists that are administered to reduce blood pressure
in persons
suffering from hypertension, or drugs administered to treat depression or
anxiety.
Excessive alcohol consumption has also been linked to sexual dysfunction.
These forms
of sexual dysfunction may be regarded as iatrogenic sexual dysfunction.
A number of methods to treat sexual dysfunction are available. These
treatments
include pharmacological treatments, surgery and, in cases of psychogenic
dysfunction,
psychological counseling is sometimes effective. Psychogenic sexual
dysfunction often
can be cured by counseling. Insufficiency due to excessive alcohol consumption
is
sometimes cured by reducing or eliminating such consumption.
In the rare cases in males, where the insufficiency is untreatable because of
venous
leakage, surgery can usuaily be employed to repair the venous lesion and
thereby either
cure the insufficiency or, if there remains an erectile insufficiency after
repair of the
venous lesion, render the insufficiency amenable to treatment by
pharmacological
methods. Also, penile implants, which provide a mechanic means to produce an
erection
sufficient for vaginal penetration, are widely used to treat impotence. In
recent years,
implants have been employed, especially in cases where pharmacological
intervention is
ineffective. Such cases are usually associated with severe forms of
vasculogenic
impotence. Treatment of impotence with penile implants, however, entails
serious
disadvantages. Such treatment requires surgery and necessitates total
destruction of the
erectile tissues of the penis, forever precluding normal erection.
In the male population, pharmacological methods of treatment are also
available.
Such methods, however, have not proven to be highly satisfactory or without
potentialiy
severe side-effects. Papaverine is now widely used to treat impotence,
although
papaverine is ineffective in overcoming impotence due, at least in part, to
severe
atherosclerosis. Papaverine is effective in cases where the dysfunction is
psychogenic or
neurogenic and severe atherosclerosis is not involved. Injection of
papaverine, a
phosphodiesterase inhibitor and a smooth muscle relaxant, or phenoxybenzamine,
a non-
specific a-adrenergic antagonist and hypotensive, into a corpus cavernosum has
been
found to cause an erection sufficient for vaginal penetration however, these
treatments
are not without the serious and often painful side effect of priapisim. Also,
in cases
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where severe atherosclerosis is not a cause of the dysfunction,
intracavernosal injection
of phentolamine, an a-adrenergic antagonist, has been shown to produce an
erection
sufficient for vaginal penetration, however, the resulting erection is one of
significantly
shorter duration than that induced by intracavernosal injection of papaverine
or
phenoxybenzamine. Thus, often times the erection is of such short duration
that
satisfactory sexual relations are difficult or impossible. As an alternative
or, in some
cases an adjunct to phosphodiesterase inhibition or a-adrenergic blockade for
the
treatment of erectile dysfunction, prostaglandin E 1 (PGE 1 ) has been
administered via
intracavernosal injection. A major side effect frequently associated
intracorprally
delivered PGE 1 is penile pain and burning. Thus, there is a need for methods
to induce
and maintain a penile erection for a sufficient duration that satisfactory
sexual relations
are possible without also producing the undesirable side effects of those
agents currently
used. With regard to female sexual dysfunction, no pharmacological strategies
have
been yet devised for effective treatment.
A number of anorectal diseases involve excessive anal sphincter tone. For
example, anal fissures as well as acutely thrombosed external hemorrhoids are
normally
accompanied by severe anal pain. Classical treatment of these conditions has
usually
involved surgery, however, in the treatment of more severe cases, surgical
intervention is
not without adverse side effects usually involving permanent sphincter defects
and
subsequent continence disturbances. Recently, nitric oxide has been implicated
as the
chemical messenger mediating relaxation of the internal anal sphincter. The
local
application of the exogenous nitric oxide (NO) donors nitroglycerin or
isosorbide
dinitrate has been reported to improve the symptoms and, in the case of anal
fissure,
facilitate the healing process. These treatments have not been without the
production of
undesired systemic side effects the most prevalent of which is headache. Thus,
there is a
need for methods to treat human anal disease involving excessive anal
sphincter tone
without also producing the undesirable side effects of those agents currently
used.
Nitric oxide has been shown to mediate a number of actions including the
bactericidal and tumoricidal actions of macrophages and blood vessel
relaxation of
endothelial cells. NO, and NO donors have also been implicated as mediators of
nonvascular smooth muscle relaxation. This effect includes the dilation of the
corpus
cavernosum smooth muscle, an event involved in the penile and clitoral
erection
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processes and the relaxation of the anal sphincter, an event necessary for
normal
defecation as well as an improvement in the symptoms of pain associated with
many
anal diseases. However, the effects of modified of phosphodiesterase
inhibitors which
are directly or indirectly linked with a nitric oxide adduct have not been
investigated.
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SUMMARY OF THE INVENTION
In the process of arriving at the present invention it was recognized that the
risk of
toxicities and adverse effects that are associated with high doses of
phosphodiesterase
inhibitors can be avoided by the use of such phosphodiesterase inhibitors when
nitrosated or nitrosylated. Such toxicities and adverse effects include
hypotension,
syncope, as well as priapism. The smooth muscle relaxant properties of
phosphodiesterase inhibitors and of compounds that donate, release or transfer
nitrogen
monoxide work together to permit the same efficacy with lower doses of the
phosphodiesterase inhibitors.
Accordingly, in one aspect the invention provides novel nitrosated and
nitrosylated
phosphodiesterase inhibitors (NO"-PDE inhibitor) wherein n is 1 or 2. The
phosphodiesterase inhibitor can be nitrosylated or nitrosated through sites
such as
oxygen (hydroxyl condensation), sulfur (sulfliydryl condensation), carbon and
nitrogen.
The invention also provides compositions comprising such compounds in a
pharmaceutically acceptable carrier.
In another aspect the invention provides a composition comprising a
therapeutically effective amount of an phosphodiesterase inhibitor (PDE
inhibitor},
which can optionally be substituted with at least one NO or N02 moiety, and
one to ten
fold molar excess of a compound that donates, transfers or releases nitrogen
monoxide as
a charged species, i.e., nitrosonium (NO+} or nitroxyi (NO-), or as the
neutral species,
nitric oxide (NO~). The invention also provides compositions comprising such
compounds in a pharmaceutically acceptable Garner.
In another aspect, the invention provides a method for treating male impotence
in
humans which comprises administering to an individual in need thereof a
therapeutically
effective amount of a nitrosated or nitrosylated PDE inhibitor .
In another aspect, the invention provides a method for treating male impotence
in
humans which comprises administering to an individual in need thereof a
composition
comprising a therapeutically effective amount of an PDE inhibitor which can
optionally
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be substituted with at least one NO or N02 moiety, and a compound that
donates,
transfers or releases nitric oxide as a charged species, i. e. , nitrosonium
(NO+) or nitroxyl
(NO-), or as the neutral species, nitric oxide (NO~). The PDE inhibitor or PDE
inhibitor
directly or indirectly linked to at least one NO or N02 group, and nitric
oxide donor can
be administered separately or as components of the same composition.
. In another aspect, the invention provides a method for treating female
sexual
dysfunction in humans which comprises administering to an individual in need
thereof a
therapeutically effective amount of a nitrosated or nitrosylated PDE inhibitor
.
In another aspect, the invention provides a method for treating treating
female
sexual dysfunction in humans which comprises administering to an individual in
need
thereof a composition comprising a therapeutically effective amount of an PDE
inhibitor
which can optionally be substituted with at least one NO or N02 moiety, and a
compound that donates, transfers or releases nitric oxide as a charged
species, i.e.,
nitrosonium (NO+) or nitroxyl (NO-), or as the neutral species, nitric oxide
(NO~). The
PDE inhibitor or PDE inhibitor directly or indirectly linked to at least one
NO or N02
group, and nitric oxide donor can be administered separately or as components
of the
same composition.
In another aspect, the invention provides a method for treating anal disease
resulting from excessive anal sphincter tone in humans which comprises
administering
to an individual in need thereof a therapeutically effective amount of a
nitrosated or
nitrosylated PDE inhibitor .
In another aspect, the invention provides a method for treating treating anal
disease
resulting from excessive anal sphincter tone in humans which comprises
administering
to an individual in need thereof a composition comprising a therapeutically
effective
amount of an PDE inhibitor which can optionally be substituted with at least
one NO or
N02 moiety, and a compound that donates, transfers or releases nitric oxide as
a charged
species, i. e. , nitrosonium (NO+) or nitroxyl (NO-), or as the neutral
species, nitric oxide
(NO~). The PDE inhibitor or PDE inhibitor directly or indirectly linked to at
least one
NO or N02 group, and nitric oxide donor can be administered separately or as
- components of the same composition.
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The nitrosated or nitrosylated PDE inhibitor and the compound that donates,
transfers or releases nitric oxide and/or stimulates endogenous production of
NO or
EDRF in vivo can be administered separately or as components of the same
composition
in one or more pharmaceutically acceptable carriers.
The following drawings are illustrative of embodiments of the invention and do
not
limit the scope of the invention as defined by the claims.
Figure 1 Synthetic scheme for the preparation of nitrite containing
suvstituted benzene derivatives.
Figure 2 Synthetic scheme for the preparation of nitrosothiol
containing substituted benzene derivatives.
Figure 3 Synthetic scheme for the preparation of nitrate
containing substituted benzene derivatives.
Figure 4 Synthetic scheme for the preparation of nitrite
containing imidazo[2,1-b]quinazoline derivatives.
Figure 5 Synthetic scheme for the preparation of nitrosothiol
containing imidazo[2,1-b]quinazoline derivatives.
Figure 6 Synthetic scheme for the preparation of nitrate
containing imidazo[2,1-b]quinazoline derivatives.
Figure 7 Synthetic scheme for the preparation of nitrite
containing purine-6-one derivatives.
Figure 8 Synthetic scheme for the preparation of nitrosothiol
containing purine-6-one derivatives.
_g_
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Figure 9 Synthetic scheme for the preparation of nitrate containing
purine-6-one derivatives.
Figure 10 Synthetic scheme for the preparation of nitrite
- containing pyrimidin-4-one derivatives.
Figure 11 Synthetic scheme for the preparation of nitrosothiol
containing pyrimidin-4-one derivatives.
Figure 12 Synthetic scheme for the preparation of nitrate
containing pyrimidin-4-one derivatives.
Figure 13 Synthetic scheme for the preparation of nitrite
containing 2-pyridone derivatives.
Figure 14 Synthetic scheme for the preparation of nitrosothiol
containing 2-pyridone derivatives.
Figure 15 Synthetic scheme for the preparation of nitrate
containing 2-pyridone derivatives.
Figure 16 Synthetic scheme for the preparation of nitrite
containing purine-2,6-dione derivatives.
Figure 17 Synthetic scheme for the preparation of nitrosothiol
containing purine-2,6-dione derivatives.
Figure 18 Synthetic scheme for the preparation of nitrate
containing purine-2,6-dione derivatives.
Figure 19 Synthetic scheme for the preparation of nitrite
containing quinoline derivatives.
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Figure 20 Synthetic scheme for the preparation of nitrosothiol
containing quinoline derivatives.
Figure 21 Synthetic scheme for the preparation of nitrate
containing quinoline derivatives.
Figure 22 Synthetic scheme for the preparation of nitrite
containing substituted pyridine derivatives.
Figure 23 Synthetic scheme for the preparation of nitrosothiol
containing substituted pyridine derivatives.
Figure 24 Synthetic scheme for the preparation of nitrate
containing substituted pyridine derivatives.
Figure 25 Synthetic scheme for the preparation of nitrite
containing benzo[c] [1,6]naphthyridine derivatives.
Figure 26 Synthetic scheme for the preparation of nitrosothiol
containing benzo[c] [1,6]naphthyridine derivatives.
Figure 27 Synthetic scheme for the preparation of nitrate
containing benzo[c] [1,6]naphthyridine derivatives.
Figure 28 Synthetic scheme for the preparation of nitrite
containing 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido
j5,4-d]pyrimidine derivatives.
Figure 29 Synthetic scheme for the preparation of nitrosothiol
containing 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido
[5,4-d]pyrimidine derivatives.
Figure 30 Synthetic scheme for the preparation of nitrate
containing 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido
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[5,4-d]pyrimidine derivatives.
Figure 31 Synthetic scheme for the preparation of nitrite
containing 1-((3,4-dihydroxyphenyl)methyl)-6,7-isoquinoline
derivatives.
Figure 32 Synthetic scheme for the preparation of nitrosothiol
containing 1-{(3,4-dihydroxyphenyl)methyl)-6,7-isoquinoline
derivatives.
Figure 33 Synthetic scheme for the preparation of nitrate
containing 1-((3,4-dihydroxyphenyl)methyl)-6,7-isoquinoline
derivatives.
Figure 34 Synthetic scheme for the preparation of nitrite
containing substituted quinazoline derivatives.
Figure 35 Synthetic scheme for the preparation of nitrosothiol
containing substituted quinazoline derivatives.
Figure 36 Synthetic scheme for the preparation of nitrate
containing substituted quinazoline derivatives.
Figure 37 Synthetic scheme for the preparation of nitrite
containing substituted phenol derivatives.
Figure 38 Synthetic scheme for the preparation of nitrosothiol
containing substituted phenol derivatives.
Figure 39 Synthetic scheme for the preparation of nitrate
containing substituted phenol derivatives.
Figure 40 Graph of comparative in vitro relaxation effects
of dipyridamole and Example 1 in phenylephrine
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induced contacted human corpus cavernosum tissue.
The term "lower alkyl" as used herein refers to branched or straight chain
alkyl
groups comprising one to ten carbon atoms, including methyl, ethyl, propyl,
isopropyl,
n-butyl, t-butyl, neopentyl and the like.
The term "aikoxy" as used herein refers to RSOO-wherein RSO is lower alkyl as
defined in this specification. Representative examples of alkoxy groups
include
methoxy, ethoxy, t-butoxy and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously
defined appended to an alkyl group as previously defined. Examples of
alkoxyalkyl
include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl
and the
like.
The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkyi" as used herein refers to a hydroxy group as previously
defined appended to a lower alkyl group as previously defined.
The term "alkenyl" as used herein refers to a branched or straight chain C2-C,
o
hydrocarbon which also comprises one or more carbon-carbon double bonds.
The term "amino" as used herein refers to -NH2.
The term "nitrate" as used herein refers to -O-N02.
The term "alkylamino" as used herein refers to RSaNH-wherein RSO is as defined
in
this specification, for example, methylamino, ethylamino, butylamino, and the
like.
The term "dialkylamino" as used herein refers to R52R53N-wherein R52 and R53
are
independently selected from lower alkyl groups as defined in this
specification, for
example dimethylamino, diethylamino, methyl propylamino and the like.
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The term "nitro" as used herein refers to the group -NOZ and "nitrosated"
refers to
compounds that have been substituted therewith.
The term "nitroso" as used herein refers to the group -NO and "nitrosylated"
refers
- to compounds that have been substituted therewith.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring
system having one or two aromatic rings including, but not limited to, phenyl,
naphthyl,
tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups (including
bicyclic aryl
groups) can be unsubstituted or substituted with one, two or three
substituents
independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino,
dialkylamino, hydroxy, halo, and nitro. In addition, substituted aryl groups
include
tetrafluorophenyl and pentafluorophenyl.
The term "alkylaryl" as used herein refers to a lower alkyl radical to which
is
appended an aryl group. Representative arylalkyl groups include benzyl,
phenyiethyl,
hydroxybenzyl, fluorobenzyl, fluorophenylethyt and the tike.
The term "arylalkoxy" as used herein refers to an alkoxy radical to which is
appended an aryl group. Representative arylalkoxy groups include benzyloxy,
phenylethoxy, chlorophenylethoxy and the like.
The term "cycloalkyl" as used herein refers to an alicyclic group comprising
from 3
to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl,
cyclopentyi,
cyclohexyl and the like.
The term "bridged cycloalkyl" herein refers to two or more cycloalkyl radicals
fused via adjacent or non-adjacent carbon atoms, including but not limited to
adamantyl
and decahydronapthyt.
The term "cycloalkoxy" as used herein refers to R540- wherein R54 is
cycloalkyl as
defined in this specification. Representative examples of alkoxy groups
include
cyclopropoxy, cyciopentyloxy, and cyclohexyloxy and the like.
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The term "arylthio" herein refers to RSSS- wherein R55 is an aryl group.
The term "alkylsulfinyl" herein refers to RSO-S(O)2- wherein RSO is as defined
in
this specification.
The term "carboxamido" herein refers to -C(O)NHZ.
The term "carbamoyl" herein refers to -O-C(O)NHZ.
The term "carboxyl" herein refers to -C02H.
The term "carbonyl" herein refers to -C(O)-.
The term " halogen" or "halo" as used herein refers to I, Br, Cl, or F.
The term "haloalkyl" as used herein refers to a lower alkyl radical to which
is
appended one or more halogens. Representative examples of a haioalkyl group
include
trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl and the
like.
The term "haloalkoxy" as used herin refers to a haloalkyl radical to which is
appended an alkoxy group. Representative examples of haloalkoxy groups
include,
l,1,1-trichloroethoxy, 2-bromobutoxy and the like.
The term "heteroaryl" as used herein refers to a mono- or bi- cyclic ring
system
containing one or two aromatic rings and containing at least one nitrogen,
oxygen, or
sulfur atom in an aromatic ring. Heteroaryl groups (including bicyclic
heteroaryl groups)
can be unsubstituted or substituted with one, two or three substituents
independently
selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,
hydroxy,
halo and vitro. Examples of heteroaryl groups include but are not limited to
pyridine,
pyrazine, pyrimidine, pyridazine, pyrazole, triazole, thiazole, isothiazole,
benzothiazole,
benzoxazole, thiadiazole, oxazale, pyrrole, imidazole and isoxazole.
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The term "heterocyclic ring" refers to any 3-, 4-, 5-, 6-, or 7-membered
nonaromatic ring containing at Ieast one nitrogen atom, oxygen, or sulfur atom
which is
bonded to an atom which is not part of the heterocyclic ring.
The term "arylheterocyclic ring" as used herein refers to a bi- or tricyclic
ring
comprised of an aryl ring as previously defined appended via two adjacent
carbons of the
aryl group to a heterocyclic ring as previously defined.
The term "heterocyclic compounds" herein refers to mono and polycyclic
compounds containing at least one heteroaryl or heterocyclic ring.
The term "amido" as used herein refers to -NH-C(O)-R56 wherein R56 is a lower
akyi, aryl, or hereroaryl group as defined in this specification
The term "alkylamido" as used herein refers to RSON-C(O)-R56 wherein RSo is as
defined in this specification and R56 is a lower akyl, aryl, or hereroaryl
goup as defined
in this specification.
Examples of contemplated PDE inhibitors to which a nitric oxide adduct may be
directly or indirectly linked include dipyridamole, zaprinast, sildenafil,
filaminast,
denbufyllene, piclamilast, zardaverine, rolipram, papaveroline, E4021, and
triflusal.
Sources of information for the above include Goodman and Gilman, The
Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc., 1996; the
Physician's Desk Reference (49th Ed.), Medical Economics ( 1995); Drug Facts
and
Comparisons ( 1993 Ed), Facts and Comparisons ( 1993); and The Merck Index (
12th
Ed.), Merck & Co., Inc. ( 1996), all of which are incorporated herein by
reference in their
entirety.
A principal aspect of the invention relates to novel nitrosated and/or
nitrosylated
phosphodiesterase inhibitors.
One embodiment of this aspect provides compounds having the structure:
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R3 ~ / R~
~ R2
wherein,
R~ is alkoxy, cycloalkoxy, halogen, or
O
CH3
Ra\ N N\
/N
CH3
R~ is hydrogen, alkoxy, or haloalkoxy; and
R3 is selected from:
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(') O (") R
R4 N
R4- N
\ O
(iii) O (iv)
/ D O \
S\/ N~ N/\~ N-N
(1
D/ N
(v) (vi)
RAN/ /X O R~N~X SiRa
\ \ N \ N/
X
X R4
O
(vii) ~ N ~ (vm)
\ N~ D ~ ~ N I
O \~\
~~ S
O' ~ N O N~
R4 D~
N Rt2
(ix) \ / NJ (x) N
O
S N N
R4
Rte
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wherein
D is selected from (i) -NO; (ii) -NO2; (iii) -C(Rd)-O-C(O)-Y-Z-[C(Re)(R f)]P-T-
Q in
which R~ is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or
heteroaryl, Y is
oxygen, sulfur, or NR; in which R; is hydrogen, lower alkyl, Re and R f at
each
occurrence are independently selected from hydrogen, lower alkyl, cycloalkyl,
aryl.
heteroaryl, arylalkyl, amino, alkylamino, amido, alkylamido, dialkylamino,
carboxy, or
taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer
from 1 to 6,
T is a covalent bond, oxygen, sulfur or nitrogen, Z is selected from a
covalent bond,
alkyl, cycloalkyl, aryl, heteroaryi, arylalkyl or arylheterocyciic ring, and Q
is selected
from -NO or -N02; (iv) -C(O}-T~-Z-[C(Re)(Rf)]P- TZ-Q wherein T' and Tz are
independently selected from T and Re, Rf, p, Q, Z, and T are as defined in
this
specification; (v) -C(O)-Z-[G-[C(Re){R f)]P-T-Q]p wherein G is (i) a covalent
bond; (ii} -
T-C(O)-; (iii) -C(O)-T, or (iv) Y, and wherein Re, Rf, p, Q, T, Y, and Z are
as defined in
this specification; (v) -C(O)-T[C(Ry)(RZ)]P wherein Ry and RZ are
independently selected
from -T'-[C{R~)(Rf)]P G-[C(RE)(Rf)]P-TZ-Q wherein G, Re, Rf, p, Q, T, T~, and
TZ are as
defined in this specification;
R4 is selected from (i) hydrogen, (ii) -C(Ra)-O-C(O)-Y-Z-[C(Re)(Rf)]P-T-Q,
(iii)
-C{O)-T1-[C(Re)(Rf)]P- Tz-Q, (iv) -C(O)-Z-[G-[C(Re)(Rf)]P-T-Q]P; and wherein
R~, Re,
RF, p, G, T, TI, T2, Q, Y, and Z are defined as in this specification;
R5 is selected from a lone pair of electrons or -C(Rd)-O-C(O)-Y-Z-[C(RE)(Rf)]p-
T-
Q wherein Rd, Re, Rf, p, T, T', T2, Q, Y, and Z are defined as in this
specification;
R" and R12 are independently selected from hydrogen or R4 wherein R4 is as
defined in this specification with the provision that R~, and R,, are not both
hydrogen;
X is a halogen and;
DI is selected from D or hydrogen and wherein D is as defined in this
specification.
Another embodiment of this aspect provides compounds having the structure:
-18-
CA 02270118 1999-04-27
WO 98I19672 PCT/LTS97I19870
Ra
,
,N
O
N
Rio
Rs
R9
II
wherein,
R4 is as defined in this specification;
Rg is selected from hydrogen or lower alkyl;
R9 is selected from hydrogen or halogen; and
Rio is selected from:
(i) hydrogen
(ii) Rs
~N /N\
-O
O
(iii)
Ra
i
/ N
O
O
wherein R8 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure:
-19-
CA 02270118 1999-04-27
WO 98I19672 PCTIUS97/19870
11
R21 \~ N\~ \\
E
N N/
O
III
wherein,
E is selected from nitrogen or -CH-;
G is selected from nitrogen or -C(Rg)-;
R21 is selected from:
(i)
(ii)
\ / O CHs
H3C\ / O\/CH3
N
N\ S
\\
O O
R22 is selected from R12 or lower alkyl; and
Rg, R1I, and R12 are as defined in this specification.
Another embodiment of this aspect provides compounds having the structure:
-20-
CA 02270118 1999-04-27 ~~~~f ~~ 9 7 / 19 8 7 0.
1 g MOV 1998'
R4
/N O
N
R,o
R~~
,~ R8
IV
whcrein,
R,~ is sela~ed from -CHz- or sulfiu;
Rs and R= are as definod is this spocification; and
-~ R,3 is seloctod from:
f.~.:,_
,_
-21-
AMENDED SHED ,
CA 02270118 1999-04-27
WO 98I19672 PCT/US97/19870
(i) N ~ (ii)
H3
N
O
H3
N
S
(iii) ~ (iv)
r~
Rs
N
H3C0
'N
(v) (vi)
~\ N
N
O
(vii)
Rs\ / CH3
N
R~
N N
CN
wherein,
R6 and R~ are independently selected from hydrogen or R4 wherein Rq is as
defined
in this specification.
Another embodiment of this aspect provides compounds having the structure:
-22-
CA 02270118 1999-04-27
WO 98I19672 PCTIUS97/19870
Ra
H3C / N O
Rya CN
V
wherein,
R4 is as defined in this specification; and
R,4 is selected from:
(i) (ii)
y y
~N- ~%
(iii)
NJ
(iv)
i
N O
N O~
Rs
OCH3
-23-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97/19870
wherein R6 is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure:
O
R17
N N/ R1
N \ N \O
R1s
VI
wherein,
R~5 is hydrogen, lower alkyl, R4, or -(CH2}4-C(CH3)2-O-Di;
R,6 is lower alkyl; and
Rl~ is hydrogen, lower alkyl, CH3-C(O)-CH2-, CH3-O-CHz-, or D with the
provision that either R~ 5 or R~ ~ must be selected to contain D and wherein D
and D ~ are
as defined in this specification.
Another embodiment of this aspect provides compounds having the structure:
O
R1a
VII
wherein,
R4 and Rg are as defined in this specification and
Ri8 is selected from:
-24-
RR Rd
CA 02270118 1999-04-27
WO 98!19b72 PCTIUS97I19870
(i) CHs
N~
N
H3C/
(ii)
Re
//\/ N /
'o
0
and wherein Rg is as defined in this specification.
Another embodiment of this aspect provides compounds having the structure:
R~9 N
VIII
wherein,
R,9 is selected from:
-25-
CA 02270118 1999-04-27
WO 98I19672 PCT/LFS97/19870
(i)
(ii) R11
a n n
N
N ~/ ~/CF3
O
N
I
R R1z
4
(1l1) (iV)
O
H3C
N~ ~ N
O
J o
N ~ N
I I
R12
R12
and wherein R¢, R11, and R12 are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure:
OCH3
H3C~
R2
N
R4
IX
-26-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97/19870
wherein,
R,p is selected from:
() O
// \ O
O
and wherein R4 is defined as in this specification.
Another embodiment of this aspect provides compounds having the structure:
O
N (CH2)a
N N~ ~O~
N ~ ~ (CH2)a D
D~~ (CH2)a /
O N N
D~ (CH2)a N
O
X
wherein,
a is an integer from 2 to 3 and D and D, are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure:
-27-
CA 02270118 1999-04-27
WO 98I19672 PCTICTS97119870
D~
O
O~
D
/O
D~
D~\
O
XI
wherein D and D1 are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure:
HN~ ~
R23
N
J
R24 \ K- T -D
R2s
XII
wherein,
J is selected from:
-28-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97119870
R~~
(i) ~ R21 (ii) ~ T1
Re
R3o R2s ~ 2 Rt
T
Rz9
K is selected from:
(i) (ii)
V
-Y- (CHZ)p
wherein V is carbon or nitrogen;
Rzs, Rza, Rzs, R26, R27, R2g, R29, and R3Q are independently selected from
hydrogen, halogen, alkoxy, nitrile, carboxamido, or carboxyl; and
wherein p, Re, Rf, T, T', T2, Y and D are defined as in this specification.
Another embodiment of this aspect provides compounds having the structure:
R ~D
31
~- R32
XIu
wherein,
R31 is alkyl, halogen, haloalkyl, or haloalkoxy;
R32 is selected from D1 or -C(O)-R8; and
-29-
CA 02270118 1999-04-27 ~ -- L " ; ~~ % ~ 1 ~
~~IUS ~19 '~ov ~99~
wherein Dl and Ra are defined as in this specification.
Compounds of the invention which have one or more asymmetric carbon atoms
may exist as the optically pure enantiomers) pure diastereomers, mixtures of
enantiomers) mixtures of diastereomers) racemic mixtures of enantiomers,
diastereomeric racemates or mixtures of diastereomeric raceiriates. It is to
be understood
that the present invention anticipates and includes within its scope all such
isomers and
mixtures thereof.
Another aspect of the invention provides processes for making the novel
compounds of the invention and to the intermediates useful in such processes.
Some of the compounds of the invention are synthesized as shown in Figures 1
through 39 presented below) in which R,, RZ, R3, R,, Rs) R6, R~, Ra, Rg, R,~,
Ra) R1Z,
R,3, R", R~s, R,s, R,~, R,=, R~, Rte) R=,, Rte, , Rn) Rte) Rte) Rte) Rte, Rte,
Rte) Rte,
R3~, Rte, R~, R~ a, p, D, Dl, E, R,o, G) J) K and X are as definod in this
specification or as
depictod in the reaction schemes for structuc~s I-3QII; Pl is an oxygen
protecting group
and P= is a sulfur protecting group. The reactions are performed in solvents
appropriate
to the reagents and materials employed are suitable for the transformations
being
effected. It is understood by those skilled in the art of organic synthesis
that the
functionality present in the molecule must be consistent with the chemical
transformation purposed. This will, on occasion) necessitate judgment by the
mutineer
as to the order of synthetic steps) pmtocting groups roquired, and
deprotection
conditions. Substituents on the starting materials may be incompatible with
some of the
~''~'~:, a
reaction conditions required in some of the methods described, but alternative
methods
and substituents compatible with the reaction conditions will be readily
apparent to
skilled practitioners in the art. The use of sulfur and oxygen protecting
groups is well
known in the art for protecting thiol and alcohol groups against undesirable
reactions
during a synthetic procedure and many such protecting groups are known, cj.,
T.H.
Greene and P.G.M. Wuts, Protective Groerps in Organic Symtlusis, John Wiley &
Sons,
New York ( I 99 I ).
Another embodiment of this aspect provides processes for making compounds
having structures I and to the intermediates useful in such processes as
follows.
-30-
~~~~~I~E~ SHE:
CA 02270118 1999-04-27
w0 98/19672 PCT/US97/19870
Nitroso compounds of formula (I) wherein Rl, R2, Re, Rf, and p are defined as
in
this specification and a nitrite containing imide is representative of the R3
group as
defined in this specification may be prepared as outlined in Figure 1. The
amide group
of formula 1 is converted to the imide of formula 2 wherein p, Re and Rf are
defined as
in this specification by reaction with an appropriate protected alcohol
containing
activated acylating agent wherein P~ is as defined in this specification.
Preferred
methods for the formation of ilnides are reacting the amide with the preformed
acid
chloride of the protected alcohol containing acid in the presence of pyridine
at low
temperature or condensing the amide and protected alcohol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the alcohol moiety are silyl ethers such as a trimethylsilyl ether, a tert-
butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether. Deprotection of
the hydroxyl
moiety (fluoride ion is the preferred method for removing silyl ether
protecting groups)
followed by reaction a suitable nitrosylating agent such as thionyl chloride
nitrite,
thionyl dinitrite, or nitrosonium tetrafluoroborate in a suitable anhydrous
solvent such as
dichloromethane, THF, DMF, or acetonitrile with or without an amine base such
as
pyridine or triethylamine affords the compound of the formula IA.
Nitroso compounds of formula (I) wherein Ri, R2, Re, Rf, and p are defined as
in
this specification and a nitrosothiol containing imide is representative of
the R3 group as
defined in this specification may be prepared as outlined in Figure 2. The
amide group
of formula 1 is converted to the imide of formula 3 wherein p, Re and Rf are
def ned as
in this specification by reaction with an appropriate protected thiol
containing activated
acylating agent wherein P2 is as defined in this specification. Preferred
methods for the
formation of imides are reacting the amide with the preformed acid chloride of
the
protected thiol containing acid in the presence of pyridine at low temperature
or
condensing the amide and protected thiol containing symmetrical anhydride in
the
presence of a catalyst such as sulfuric acid. Preferred protecting groups for
the thiol
moiety are as a thioester such as a thioacetate or thiobenzoate, as a
disulfide, as a
thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-
trimethoxybenzyl
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
-31-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97119870
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or
strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-
trimethoxybenzyl
thioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
methylene
chloride, THF, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula IB. Alternatively, treatment
of the
deprotected thiol derived from compound 3 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
IB.
Nitro compounds of formula (I) wherein R,, R2, Re, Rf, and p are defined as in
this
specification and an nitrate containing imide is representative of the R3
group as defined
in this specification may be prepared as outlined in Figure 3. The amide group
of the
formula 1 is converted to the imide of the formula 4 wherein p, R.e and Rf are
defined as
in this specification and X is a halogen by reaction with an appropriate
halide containing
activated acylating agent. Preferred methods for the formation of imides are
reacting the
amide with the preformed acid chloride of the halide containing acid in the
presence of
pyridine at low temperature or condensing the amide and halide containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
halides are
bromide and iodide. Reaction of the imide of the formula 4 with a suitable
nitrating
agent such as silver nitrate in an inert solvent such as acetonitrile affords
the compound
of the formula IC.
Another embodiment of this aspect provides processes for making compounds
having structures II and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (II) wherein Rg, R9, Rto, Re, Rf, and p are
defined
as in this specification, and a nitrite containing amide is representative of
the R~ group as
defined in this specification may be prepared as outlined in Figure 4. The
imidazo[2,1-
b]quinazoline of formula 5 is converted to the acylimidazo[2,1-b]quinazoline
of formula
6 wherein p, Re and Rf are defined as in this specification by reaction with
an
-32-
CA 02270118 1999-04-27
WO 98/19672 PCTIUS97I19870
appropriate protected alcohol containing activated acylating agent wherein P ~
is as
defined in this specification. Preferred methods for the formation of
acylimidazo[2,1-
b]quinazolines are reacting the imidazo[2,1-b]quinazoline with the preformed
acid
chloride or symmetrical anhydride of the protected alcohol containing acid or
condensing the imidazo[2,1-b]quinazoline and protected alcohol containing acid
in the
presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or 1-
ethyl-3
(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC ~ HC1) with or
without a
catalyst such as 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole
(HOBt).
Preferred protecting groups for the alcohol moiety are silyl ethers such as a
trimethylsilyl
or tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety
(fluoride ion is the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula IIA.
Nitroso compounds of formula (II) wherein R8, R9, Rio, Re, Rf, and p are
defined
as in this specification, and a nitrosothiol containing amide is
representative of the RQ
group as defined in this specification may be prepared as outlined in Figure
~. The
imidazo[2,1-b]quinazoline of formula 5 is converted to the acylimidazo[2,1-
b]quinazoline of formula 7 wherein p, Re and Rf are defined as in this
specification by
reaction with an appropriate protected thiol containing activated acylating
agent wherein
P2 is as defined in this specification. Preferred methods for the formation of
acylated
imidazo[2,1-b]quinazolines are reacting the imidazo[2,1-b]quinazoline with the
preformed acid chloride or symmetrical anhydride of the protected thiol
containing acid
or condensing the imidazo [2,1-b]quinazoline and protected thiol containing
acid in the
presence of a dehydrating agent such as DCC or EDAC HCl with or without a
catalyst
such as DMAP or HOBt. Preferred protecting groups for the thiol moiety are as
a
thioester such as a thioacetate or thiobenzoate, as a disulfide, as a
thiocarbamate such as
N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl
thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl
thioether.
Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in
water and sodium borohydride are preferred methods for reducing disulfide
groups
while aqueous base is typically utilized to hydrolyze thioesters and N-
methoxymethyl
-33-
CA 02270118 1999-04-27
WO 98/19672 PCT/US97119870
thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids
such as
trifluoroacetic or hydrochloric acid and heat are used to remove a
paramethoxybenzyl
thioether, a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl
thioether group)
followed by reaction a suitable nitrosylating agent such as thionyl chloride
nitrite,
thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or
nitrosonium
tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride,
THF,
DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine
affords the compound of the formula IIB. Alternatively, treatment of the
deprotected
thiol derived from compound 7 with a stoichiometric quantity of sodium nitrite
in an
acidic aqueous or alcoholic solution affords the compound of the formula IIB.
Nitro compounds of formula (II) wherein Rg, R9, R~ o, Re, Rf, and p are
defined as
in this specification, and a nitrate containing amide is representative of the
R4 group as
defined in this specification may be prepared as outlined in Figure 6. The
imidazo[2,1-
b]quinazoline of formula 5 is converted to the acylimidazo[2,1-b]quinazoline
of formula
8 wherein p, Re and Rf are defined as in this specification and X is a halogen
by reaction
with an appropriate halide containing activated acylating agent. Preferred
methods for
the formation of the acylimidazo [2,1-b]quinazolines are reacting the imidazo
[2,1-
b]quinazoline with the preformed acid chloride or symmetrical anhydride of the
halide
containing acid or condensing the alcohol and halide containing acid in the
presence of a
dehydrating agent such as DCC or EDAC ~ HCl with or without a catalyst such as
DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the
acylimidazo[2,1-b]quinazoline of the formula 8 with a suitable nitrating agent
such as
silver nitrate in an inert solvent such as acetonitrile affords the compound
of the formula
IIC.
Another embodiment of this aspect provides processes for making compounds
having structures III and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (III) wherein E, G, R2,, R22, R~, Rf, and p are
defined as in this specification and a nitrite containing amide is
representative of the R"
group as defined in this specification may be prepared as outlined in Figure
7. The
purine-6-one group of formula 9 is converted to the acylated purine-6-one of
formula 10
wherein p, Re and R f are defined as in this specification by reaction with an
appropriate
-34-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97/19870
protected alcohol containing activated acylating agent wherein P 1 is as
defined in this
specification. Preferred methods for the formation of acylated purine-6-ones
are reacting
the purine-6-one with the preformed acid chloride or symmetrical anhydride of
the
protected alcohol containing acid. Preferred protecting groups for the alcohol
moiety are
silyl ethers such as a tent-butyldimethylsilyl ether or a tert-
butyldiphenylsilyl ether.
Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for
removing
silyl ether protecting groups) followed by reaction a suitable nitrosylating
agent such as
thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
in a suitable
anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile with or
without
an amine base such as pyridine or triethylamine affords the compound of the
formula
IIIA.
Nitroso compounds of formula (III) wherein E, G, R21, R22, Re, Rf, and p are
defined as in this specification and an nitrosothiol containing amide is
representative of
the R11 group as defined in this specification may be prepared as outlined in
Figure 8.
The purine-6-one group of formula 9 is converted to the acyiated purine-6-one
of
formula 11 wherein p, Re and Rf are defined as in this specification by
reaction with an
appropriate protected thiol containing activated acylating agent wherein P2 is
as defined .
in this specification. Preferred methods for the formation of acylated purine-
6-ones are
reacting the purine-6-one with the preformed acid chloride or symmetrical
anhydride of
the protected alcohol containing acid. Preferred protecting groups for the
thioi moiety
are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a
thiocarbamate
such as N-methoxymethyl thiocarbamate, or as a thioether such as a
paramethoxybenzyl
thioether, a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl
thioether.
Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in
water and sodium borohydride are preferred methods for reducing disulfide
groups
while aqueous base is typically utilized to hydrolyze thioesters and N-
methoxymethyl
thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids
such as
trifluoroacetic or hydrochloric acid and heat are used to remove a
paramethoxybenzyl
thioether, a tetrahydropyranyi thioether, or a 2,4,6-trimethoxybenzyl
thioether group)
followed by reaction a suitable nitrosylating agent such as thionyl chloride
nitrite,
thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or
nitrosonium
tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride,
THF,
DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine
-35-
~, z a~
CA 02270118 1999-04-27
1 ~ NOV )998
affords the compound of the formula IIIB. Alternatively) treatment of the
depmtected
thiol derived from compound 11 with a stoichiometric quantity of sodium
nitrite in an
acidic aqueous or alcoholic solution affords the compound of the formula IIIB.
Nitre compounds of formula (III) wherein E, G, Rig, Rte, R~, Rf, and p arc
defined
as in this specification and an nitrate containing amide is representative of
the Ri 1 group
as defined in this specification may be prepaood as outlined in Figure 9. The
purine-6-
one of formula 9 is converted'to the acylated purine-6~ne the of formula 12
wherein p,
R~ and R f are defined and X is halogen. Prefemod methods for the formation of
acylatod
purine-6-once are reacting the purine-6-one with the preformed acid chloride
or
symmetrical anhydride of the halide containing acid. Preferred halides are
bmmide and
iodide. Reaction of the of the acylated purine-6-one of the formula 12 with a
suitable
~;,..~z nitrating agent such as silver nitrate in an inert solvent such as
acetonitrile a~'ords the
compound of the formula IZIC. .
Another embodiment of this aspect provides processes for making compounds
having stc~xures IV and to the intermediates useful in such ~ooesses as
follows.
Nitroso compounds of formula (I~ wherein R,o) R~) R,r 1~, Rf and p are defined
as
in this' specification and a nitrite containing acyi hydrazide is
representative of the R4
group as defined in this specification may be prcpartd as outlined in Figure
10. The 3
(2-H~-pyridaanone or 2H-1, Z) 3, 4-thiadiaane of formula 13 is converted to
the 3 (2-
acyl~-pyridazinone or 2-aryl-l, 2, 3, 4-thiadiaane of formula 14 wherein p, R~
anti Rr are
defined as in this specification by ruction with an appropriate protected
alcohol
containing activated acyIating agent whacin Pl is as defined in this
specification.
Preferred methods for the formation of 3 (2-acyl~pyridazinone or 2-acyl-1, 2,
3, 4-
thiadiazine are reacting the 3 (2H~pyridaziaone or 2H-1, 2) 3, 4-thiadiazine
with the
preformod acid chloride or symmetrical anhydride of the protected alcohol
containing
acid or condensing the 3 (2-H~pyridazinone or 2H-1, 2, 3) 4-thiadiazine and
protected
alcohol containing acid in the presence of a dehydrating agent such as DCC or
EDAC .
HCl with a catalyst such as DMAP or HOBt. Preferred protecting groups for the
alcohol
moiety are silyl ethtrs such as a tert-butyldimethylsilyl ether or a tert-
butyldiphenylsilyl
ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred
method for
removing silyl ether protecting groups) followed by reaction a suitable
nitmsylating
-36-
HhfiENDrD SHEET_
CA 02270118 1999-04-27 n~...:~, ~
~~~ 9
~~~O~~s~
agent such as thionyl chloride nitrite, thionyl dinitrite) or nitrosonium
tetrafluoroborate
in a suitable anhydrous solvent such as dichloromethane, THF, DMF, or
acetonitrile
with or without an amine base such as pyridine or triethylamine affords the
compound of
the formula IVA.
Nitroso compounds of formula (I~ wherein R,o, R') R;3, R~) Rf and p are
defined as
in this specification and a nitrosothiol containing acyl hydrazide is
representative of the
R, group as defined in this specification may be prepared as outlined in
Figure 11. The
3 (2-H~pyridazinone or 2H-1, 2) 3, 4-thiadiazine of formula 13 is converted to
the 3 (2-
acyl)-pyridazinone or 2-acyl-1) 2, 3, 4-thiadiazine of formula 15 wherein p)
R~ and Rr are
defined as in this specification by reaction with an appropriate protected
thiol containing
activated acylating agent wherein PZ is as defined in this specification.
Prefen~ed
methods for the formation of 3 (2-acyl~pyridazinones or 2-aryl-1, 2, 3, 4-
thiadiazina
are remcting the 3 (2-H~pyridazinone or 2H-1, 2, 3, 4-thiadiazirie with the
preformed
acid chloride or symmetrical anhydride of the protected thiol containing acid
or
condensing the 3 (2-H)-pyridazinone or 2H-1) 2, 3) 4-thiadiazine and protected
thiol
containing acid in the presence of a dehydrating agent such as DCC or EDAC .
HCl
with a catalyst such as DMAP or HOBt. Preferred protecting groups for the
thiol moiety
are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, or
as a thioether
such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a
2,4,6-
trimethoxybenzyl thioether. Deprotxtion of the thiol moiety (zinc in dilute
aqueous
acid, triphenyiphosphine in water and sodium borohydride are preferred methods
for
reducing disulfide groups while mercuric trifluoroacetate, silver nitrate, or
strong acids
such as trifluoroacetic or hydrochloric acid and heat are used to remove a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-
trimethoxybenzyl
t6ioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl
nitrite) or
nitrosonium tetrafluomborate in a suitable anhydrous solvent such as methylene
chloride, THF, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula IVB. Alternatively,
tnatrnent of the
depmtected thiol derived from compound 15 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
IVB.
-37-
~,;,,.. ~.~.u ~ntt
CA 02270118 1999-04-27
\r -~..1.
~~,~5 I 9 NOV 1~98:~
Nitre compounds of formula (IV) wherein R,o, Ra, R,s) I~, R, and p are defined
as
in this specification and an nitrate containing acyl hydrazide is
representative of the R,
group as defined in this specification may be prepared as outlined in Figure
12. The 3
(2-H)-pyridazinone or 2H-1) 2, 3) 4-thiadiazine of formula 13 is converted to
the 3 (2-
acyl)-pyridazinone or 2-acyl-I) 2, 3) 4-thiadiazine of formula 16 wherein p,
R~ and Rr are
defined and X is halogen. Preferred methods for the ~ formation of 3 (2-acylr
pyridazinones or 2-acyl-1, 2, 3) 4-thiadiazines are reacting the 3 (2-
H~pyridazinone or
2H-1, 2, 3, 4-thiadiazine with the preformod acid chloride or symmetrical
anhydride of
the halide containing acid or condensing the 3 (2-H~pyridazinone or 2H-1, 2,
3) 4-
thiadiszinc and halide containing acid in the presence of a dehydrating agent
such as
DCC or F.DAC . HCl with a catalyst such as DMAP or HOBt Preferred halides are
bromide and iodide. Reaction of the 3 (2-acyl~pytidaanone or 2-acyl-1, 2, 3) 4-
thiadiazine of formula 16 with a suitable nittatiag agent such as silver
nitrate in an inert
solvent such as acetonitrile affords the compound of the formula IVC.
Another embodiment of this aspect provides processes for making compounds
having structures V and to the intcrmcdiates useful in such processes as
follows.
Nitroso compounds of formula (V) wherein R,4, Rd Ra and p are defined as in
this
specification and an nitrite containing imide is representative of the R4
group as defined
in this specification may be prepared as outlined in Figure 13. The amide
group of
formula 17 is converted to the imide of formula 18 wherein p) R= and R~ are
defined as
in this specification by reaction with an appropriate protected alcohol
containing
_ activated acyiatiag agent wherein Pl is as defined in this specification.
Preferred
~,.",-' mett~ds for the formation of imides are ring the amide with the
preformod acid
chloride of the protected alcohol containing acid in the presence of pyridine
at low
tempasture or condensing the amide and protected alcohol containing
symmetrical
anhydride is the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl
ether or a ~tcrt-
butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is
the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite) or
nitmsonium tetrafluoroborate in a suitable anhydrous solvent such as
dichlocomethane,
-38-
.. .~ . -~ '-iE~~.
CA 02270118 1999-04-27
WO 98/19672 PCTIUS97/19870
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula VA.
Nitroso compounds of formula (V) wherein R,4, Re, Rf, and p are defined as in
this
specification and a nitrosothiol containing imide is representative of the R4
group as
defined in this specification may be prepared as outlined in Figure 14. The
amide group
of formula 17 is converted to tie imide of formula 19 wherein p, R.e and R f
are defined
as in this specification by reaction with an appropriate protected thiol
containing
activated acylating agent wherein P2 is as defined in this specification.
Preferred
methods for the formation of imides are reacting the amide with the preformed
acid
chloride of the protected thiol containing acid in the presence of pyridine at
low
temperature or condensing the amide and protected thiol containing symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate,
as a disulfide,
as a thiocarbamate such as N-methoxymethyi thiocarbamate, or as a thioether
such as a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether ar a 2,4,6-
trimethaxybenzyl
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or
strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydrapyranyl thioether, or a 2,4,6-
trimethoxybenzyl
thioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tent-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
methylene
chloride, THF, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula VB. Alternatively, treatment
of the
deprotected thiol derived from compound 19 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
VB.
Nitro compounds of formula (V) wherein R~4, Re, Rf, and p are defined as in
this
specification and a nitrate containing imide is representative of the R4 group
as defined
-39-
CA 02270118 1999-04-27
WO 98I19672 PCT/US97/19870
in this specification may be prepared as outlined in Figure 15. The amide
group of the
formula 17 is converted to the imide of the formula 20 wherein p, Re and Rf
are defined
as in this specification and X is a halogen by reaction with an appropriate
halide
containing activated acylating agent. Preferred methods for the formation of
imides are
reacting the amide with the preformed acid chloride of the halide containing
acid in the
presence of pyridine at low temperature or condensing the amide and halide
containing
symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
Preferred
halides are bromide and iodide. Reaction of the imide of the formula 20 with a
suitable
nitrating agent such as silver nitrate in an inert solvent such as
acetonitrile affords the
compound of the formula VC.
Another embodiment of this aspect provides processes far making compounds
having structures VI and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (VI} wherein R15, R, 6, Re, Rf, and p are defined
as
in this specification and a nitrite containing acyl imidazolide is
representative of the R1~
group as defined in this specification may be prepared as outlined in Figure
16. The 1 H-
purine-2, 6-dione of formula 21 is converted to the acylated derivative of the
formula 22
wherein p, Re and R f are defined as in this specification by reaction with an
appropriate
protected alcohol containing activated acylating agent wherein P1 is as
defined in this
specification. Preferred methods for the formation of acylated 1 H-purine-2, 6-
diones are
reacting the 1 H-purine-2, 6-dione with the preformed acid chloride or
symmetrical
anhydride of the protected alcohol containing acid or condensing the 1H-purine-
2, b-
dione and protected alcohol containing acid in the presence of a dehydrating
agent such
as DCC or EDAC . HCl with a catalyst such as DMAP or HOBt. Preferred
protecting
groups for the alcohol moiety are silyl ethers such as a tent-
butyldimethylsilyl ether or a
tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride
ion is the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula VIA.
-40-
CA 02270118 1999-04-27
WO 98/19672 PCT/US97/19870
Nitroso compounds of formula (VI) wherein R,;, R, 6, Re, RF, and p are defined
as
in this specification and a nitrosothiol containing acyl imidazolide is
representative of
the R, ~ group as defined in this specification may be prepared as outlined in
Figure 17.
The 1 H-purine-2, 6-dione of formula 21 is converted to the acylated
derivative of the
- formula 23 wherein p, RE and R f are defined as in this specification by
reaction with an
appropriate protected thiol containing activated acylating agent wherein P2 is
as defined
in this specification. Preferred methods for the formation of acylated 1 H-
purine-2, 6-
diones are reacting the 1 H-purine-2, 6-dione with the preformed acid chloride
or
symmetrical anhydride of the protected thiol containing acid or condensing the
1 H-
purine-2, 6-dione and protected thiol containing acid in the presence of a
dehydrating
agent such as DCC or EDAC . HCI with a catalyst such as DMAP or HOBt.
Preferred
protecting groups for the thiol moiety are as a thioester such as a
thioacetate or
thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl
thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a
tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.
Deprotection of the
thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and
sodium
borohydride are preferred methods for reducing disulfide groups while aqueous
base is
typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates
and
mercuric trifluoroacetate, silver nitrate, or strong acids such as
trifluoroacetic or
hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a
tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioether group)
followed by
reaction a suitable nitrosylating agent such as thionyl chloride nitrite,
thionyl dinitrite, a
lower alkyl nitrite such as tert-butyl nitrite, or nitrosonium
tetrafluoroborate in a suitable
anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with
or
without an amine base such as pyridine or triethylamine affords the compound
of the
formula VIB. Alternatively, treatment of the deprotected thiol derived from
compound
23 with a stoichiometric quantity of sodium nitrite in an acidic aqueous or
alcoholic
solution affords the compound of the formula VIB.
Nitro compounds of formula {VI) wherein Rl;, R,6, Re, Rf, and p are defined as
in
this specification and an O-nitrosated acylated 1 H-purine-2, 6-dione is
representative of
the Rig group as defined in this specification may be prepared as outlined in
Figure 18.
The 1 H-purine-2, 6-dione of the formula 21 is converted to the acylated
derivative of the
formula 24 wherein p, Re and Rf are defined as in this specification and X is
a halogen
-41-
CA 02270118 1999-04-27
WO 98/19672 PCT/US97/19870
by reaction with an appropriate halide containing activated acylating agent.
Preferred
methods for the formation of acylated 1 H-purine-2, 6-diones are reacting the
1 H-purine-
2, 6-dione with the preformed acid chloride or symmetrical anhydride of the
halide
containing acid or condensing the 1H-purine-2, 6-dione and halide containing
acid in the
presence of a dehydrating agent such as DCC or EDAC . HCl with a catalyst such
as
DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the
acylated 1 H-
purine-2, 6-dione of the formula 24 with a suitable nitrating agent such as
silver nitrate
in an inert solvent such as acetonitrile affords the compound of the formula
VIC.
Another embodiment of this aspect provides processes for making compounds
having structures VII and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (VII) wherein Rg, Rlg, R~, R~, and p are defined
as
in this specification and a nitrite containing imide is representative of the
R4 group as
defined in this specification may be prepared as outlined in Figure 19. The
amide
nitrogen of formula 25 is converted to the imide of formula 26 wherein p, Re
and Rf are
defined as in this specification by reaction with an appropriate protected
alcohol
containing activated acylating agent wherein P1 is as defined in this
specification.
Preferred methods for the formation of imides are reacting the amide with the
preformed
acid chloride of the protected alcohol containing acid in the presence of
pyridine at low
temperature or condensing the amide and protected alcohol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the alcohol moiety are silyl ethers such as a tent-butyldimethylsilyl
ether or a tert-
butyldiphenylsilyl. ether. Deprotection of the hydroxyl moiety (fluoride ion
is the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula VIIA.
Nitroso compounds of formula (VII) wherein Rg, R~ g, Re, R f, and p are
defined as
in this specification and a nitrosothiol containing imide is representative of
the R4 group
as defined in this specification may be prepared as outlined in Figure 20. The
amide
nitrogen of formula 25 is converted to the imide of formula 27 wherein p, Re
and Rf are
-42-
CA 02270118 1999-04-27
- WO 98/19672 PCT/US97/19870
defined as in this specification by reaction with an appropriate protected
thiol containing
activated acylating agent wherein Pz is as defined in this specification.
Preferred
methods for the formation of imides are reacting the amide with the preformed
acid
chloride of the protected thiol containing acid in the presence of pyridine at
low
- temperature or condensing the amide and protected thiol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
- for the thiol moiety are as a thioester such as a thioacetate or
thiobenzoate, as a disulfide,
as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether
such as a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-
trimethoxybenzyl
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or
strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-
trimethoxybenzyl
thioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
methylene
chloride, THF, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula VIIB. Alternatively,
treatment of the
deprotected thiol derived from compound 27 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
VIIB.
Nitro compounds of formula (VII) wherein Rg, R,g, Re, Rf, and p are defined as
in
this specification and a nitrate containing imide is representative of the R4
group as
defined in this specification may be prepared as outlined in Figure 21. The
amide group
of the formula 25 is converted to the imide of the formula 28 wherein p, Re
and Rf are
defined as in this specification and X is a halogen by reaction with an
appropriate halide
containing activated acylating agent. Preferred methods for the formation of
imides are
reacting the amide with the preformed acid chloride of the halide containing
acid in the
presence of pyridine at low temperature or condensing the amide and halide
containing
symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
Preferred
halides are bromide and iodide. Reaction of the imide of the formula 28 with a
suitable
-43-
CA 02270118 1999-04-27
WO 98/19672 PCTIUS97I19870 _.
nitrating agent such as silver nitrate in an inert solvent such as
acetonitrile affords the
compound of the formula VIIC.
Another embodiment of this aspect provides processes for making compounds
having structures VIII and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (VIII) wherein R.e, Rf, and p are defined as in
this
specification and a nitrite containing imide is representative of the RI9
group as defined
in this specification may be prepared as outlined in Figure 22. The amide
nitrogen of
formula 29 is converted to the imide of formula 30 wherein p, Re and Rf are
defined as
in this specification by reaction with an appropriate protected alcohol
containing
activated acylating agent wherein P' is as defined in this specification.
Preferred
methods for the formation of imides are reacting the amide with the preformed
acid
chloride of the protected alcohol containing acid in the presence of pyridine
at low
temperature or condensing the amide and protected alcohol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl
ether or a tert-
butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is
the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine ar
triethylamine affords the compound of the formula VIIIA.
Nitroso compounds of formula (VIII) wherein Re, Rf, and p are defined as in
this
specification and a nitrosothiol containing imide is representative of the R19
group as
defined in this specification may be prepared as outlined in Figure 23. The
amide
nitrogen of formula 29 is converted to the imide of formula 31 wherein p, Re
and Rf are
defined as in this specification by reaction with an appropriate protected
thiol containing
activated acylating agent wherein P2 is as defined in this specification.
Preferred
methods for the formation of imides are reacting the amide with the preformed
acid
chloride of the protected thiol containing acid in the presence of pyridine at
low
temperature or condensing the amide and protected alcohol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
-44-
CA 02270118 1999-04-27
WO 98/l9672 PCT/US97119870
for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate,
as a disulfide,
as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether
such as a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-
trimethoxybenzyi
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
- methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate,
or strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-
trimethoxybenzyl
thioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
methylene
chloride, THF, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula VIIB. Alternatively,
treatment of the
deprotected thiol derived from compound 31 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
VIIIB.
Nitro compounds of formula (VIII) wherein Re, Rf, and p are defined as in this
specification and a nitrate containing imide is representative of the R~9
group as defined
in this specification may be prepared as outlined in Figure 24. The amide
group of the
formula 29 is converted to the imide of the formula 32 wherein p, Re and Rf
are defined
as in this specification and X is a halogen by reaction with an appropriate
halide
containing activated acylating agent. Preferred methods for the formation of
imides are
reacting the amide with the preformed acid chloride of the halide containing
acid in the
presence of pyridine at low temperature or condensing the amide and halide
containing
symmetrical anhydride in the presence of a catalyst such as sulfuric acid.
Preferred
halides are bromide and iodide. Reaction of the imide of the formula 32 with a
suitable
nitrating agent such as silver nitrate in an inert solvent such as
acetonitrile affords the
compound of the formula VIIIC.
Another embodiment of this aspect provides processes for making compounds
having structures IX and to the intermediates useful in such processes as
follows.
-45-
CA 02270118 1999-04-27
- WO 98/19672 PCT/US97/I9870
Nitroso compounds of formula (IX) wherein RZO, Re, Rf, and p are defined as in
this specification and an nitrate containing amide or sulfonamide is
representative of the
R4 group as defined in this specification may be prepared as outlined in
Figure 2~. The
amide or sulfonamide nitrogen of formula 33 is converted to the amide or
sulfonamide of
formula 34 wherein p, Re and Rf are defined as in this specification by
reaction with an
appropriate protected alcohol containing activated acylating agent wherein P ~
is as
defined in this specification. Preferred methods for the formation of amides
or
sulfonamides are reacting the amide or sulfonamide with the preformed acid
chloride of
the protected alcohol containing acid in the presence of pyridine at low
temperature or
condensing the amide or sulfonamide and protected alcohol containing
symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the alcohol moiety are silyl ethers such as a tert-butyldimethylsilyl
ether or a tert-
butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is
the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula IXA.
Nitroso compounds of formula (IX) wherein R2o, Re, Rf, and p are defined as in
this specification and an nitrosothiol containing amide or sulfonamide is
representative of
the R4 group as defined in this specification may be prepared as outlined in
Figure 26.
The amide or sulfonamide nitrogen of formula 33 is converted to the amide or
sulfonamide of formula 35 wherein p, Re and R f are defined as in this
specification by
reaction with an appropriate protected thiol containing activated acylating
agent wherein
P2 is as defined in this specification.. Preferred methods for the formation
of amides or
sulfonamides are reacting the amide or sulfonamide with the preformed acid
chloride of
the protected thiol containing acid in the presence of pyridine at low
temperature or
condensing the amide or sulfonamide and protected thiol containing symmetrical
anhydride in the presence of a catalyst such as sulfuric acid. Preferred
protecting groups
for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate,
as a disulfide,
as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether
such as a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a 2,4,6-
trimethoxybenzyl
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
-46-
CA 02270118 1999-04-27
- WO 98I19672 PCTlUS97/19870
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or
strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a 2,4,6-
trimethoxybenzyl
thioether group) followed by reaction a suitable nitrosylating agent such as
thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
methylene
chloride, TI-1F, DMF, or acetonitrile with or without an amine base such as
pyridine or
triethylamine affords the compound of the formula IXB. Alternatively,
treatment of the
deprotected thiol derived from compound 35 with a stoichiometric quantity of
sodium
nitrite in an acidic aqueous or alcoholic solution affords the compound of the
formula
IXB.
Nitro compounds of formula (IX) wherein RZp, Re, Rf, and p are defined as in
this
specification and a nitrate containing amide or sulfonamide is representative
of the Rd
group as defined in this specification may be prepared as outlined in Figure
27. The
amide or sulfonamide group of the formula 33 is converted to the amide or
sulfonamide
of the formula 36 wherein p, Re and R f are defined as in this specification
and X is a
halogen by reaction with an appropriate halide containing activated acylating
agent.
Preferred methods for the formation of amides or sulfonamides are reacting the
amide or
sulfonamide with the preformed acid chloride of the halide containing acid in
the
presence of pyridine at low temperature or condensing the amide or sulfonamide
and
halide containing symmetrical anhydride in the presence of a catalyst such as
sulfuric
acid. Preferred halides are bromide and iodide. Reaction of the amide or
sulfonamide of
the formula 36 with a suitable nitrating agent such as silver nitrate in an
inert solvent
such as acetonitrile affords the compound of the formula IXC.
Another embodiment of this aspect provides processes for making compounds
having structures X and to the intermediates useful in such processes as
follows.
Nitroso compounds of formula (X) wherein DI, Rt, Rf, , and p are defined as in
this specification and a nitrite containing ester is representative of the D
group as defined
in this specification may be prepared according to Scheme 28. The alcohol
group of
-47-
CA 02270118 1999-04-27
- WO 98l19672 PCT/CTS97/19870
formula 37 is converted to the ester of formula 38 wherein p, Re and Rf are
defined as in
this specification by reaction with an appropriate protected alcohol
containing activated
acylating agent wherein Pi is as defined in this specification. Preferred
methods for the
formation of esters are reacting the alcohol with the preformed acid chloride
or
symmetrical anhydride of the protected alcohol containing acid or condensing
the
alcohol and protected alcohol containing acid with a dehydrating agent such as
DCC or
EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred
protecting
groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a
tert-
butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is
the
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula XA.
Nitroso compounds of formula (X) wherein D,, Re, Rf, and p are defined as in
this
specification and a nitrosothiol containing ester is representative of the D
group as
defined in this specification may be prepared according to Scheme 29. The
alcohol
group of the formula 37 is converted to the ester of the formula 39 wherein p,
RE and Rf
are defined as in this specification by reaction with an appropriate protected
thiol
containing activated acylating agent wherein PZ is as defined in this
specification.
Preferred methods for the formation of esters are reacting the alcohol with
the preformed
acid chloride or symmetrical anhydride of the protected thiol containing acid
or
condensing the alcohol and protected thiol containing acid with a dehydrating
agent such
as DCC or EDAC. HCI in the presence of a catalyst such as DMAP or HOBt..
Preferred
protecting groups for the thiol moiety are as a thioester such as a
thioacetate or
thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl
thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a
tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of
the thiol
moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium
borohydride are preferred methods for reducing disulfide groups while aqueous
base is
typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates
and
mercuric trifluoroacetate, silver nitrate, or strong acids such as
trifluoroacetic or
hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a
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WO 98I19672 PCT/US97/19870
tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed
by reaction
a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, a lower
alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a
suitable
anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or
' without an amine base such as pyridine or triethylamine affords the compound
of the
formula XB. Alternatively, treatment of the deprotected thiol derived from
compound
39 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic
acid affords
the compound of the formula XB.
Nitro compounds of formula (X) wherein D1, Re, Rf, and p are defined as in
this
specification and a nitrate containing ester is representative of the D group
as defined in
this specification may be prepared according to Scheme 30. The alcohol group
of the
formula 37 is converted to the ester of the formula 40 wherein p, Re and Rf
are defined
as in this specification and X is a halogen by reaction with an appropriate
halide
containing activated acylating agent. Preferred methods for the formation of
esters are
reacting the alcohol with the preformed acid chloride or symmetrical anhydride
of the
halide containing acid or condensing the alcohol and halide containing acid
with a
dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such
as
DMAP or HOBt. PrefelTed halides are bromide and iodide. Reaction of the ester
of the
formula 40 with a suitable nitrating agent such as silver nitrate in an inert
solvent such as
acetonitrile affords the compound of the formula XC.
Nitroso compounds of formula (XI) wherein Dl, Re, Rf, and p are defined as in
this
specification and a nitrite containing ester is representative of the D group
as defined in
this specification may be prepared according to Scheme 31. The alcohol group
of
formula 41 is convened to the ester of formula 42 wherein p, Rc and Rf are
defined as in
this specification by reaction with an appropriate protected alcohol
containing activated
acylating agent wherein P ~ is as defined in this specification. Preferred
methods for the
formation of esters are reacting the alcohol with the preformed acid chloride
or
symmetrical anhydride of the protected alcohol containing acid or condensing
the
alcohol and protected alcohol containing acid with a dehydrating agent such as
DCC or
EDAC. HCl in the presence of a catalyst such as DMAP or HOBt. Preferred
protecting
groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a
tert-
butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is
the
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WO 98I19672 PCTlUS97/19870 _.
preferred method for removing silyl ether protecting groups) followed by
reaction a
suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula XIA.
Nitroso compounds of formula (XI) wherein Di, Re, Rf, and p are defined as in
this
specification and a nitrosothiol containing ester is representative of the D
group as
defined in this specification may be prepared according to Scheme 32. The
alcohol
group of the formula 41 is converted to the ester of the formula 43 wherein p,
Re and Rf
are defined as in this specification by reaction with an appropriate protected
thiol
containing activated acylating agent wherein P2 is as defined in this
specification.
Preferred methods for the formation of esters are reacting the alcohol with
the preformed
acid chloride or symmetrical anhydride of the protected thiol containing acid
or
condensing the alcohol and protected thiol containing acid with a dehydrating
agent such
as DCC or EDAC. HCI in the presence of a catalyst such as DMAP or HOBt..
Preferred
protecting groups for the thiol moiety are as a disulfide, a thioester such as
a thioacetate
or thiobenzoate, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or
as a
thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether
or a S-
triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute
aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while aqueous base is typically utilized to hydrolyze
thioesters and N-
methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or
strong
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-
triphenylmethyl
thioether group) followed by reaction with a suitable nitrosylating agent such
as thionyl
chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tent-butyl
nitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as methyene
chloride,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula XIB. Alternatively,
treatment of the
deprotected thiol derived from compound 43 with a stoichiometric quantity of
sodium
nitrite in aqueous or alcoholic acid affords the compound of the formula XIB.
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WO 98I19672 PCT/US97119870
Nitro compounds of formula (XI) wherein D1, Re, Rf, and p are defined as in
this
specification and a nitrate containing ester is representative of the D group
as defined in
this specification may be prepared according to Scheme 33. The alcohol group
of the
formula 41 is converted to the ester of the formula 44 wherein p, Re and Rf
are defined
as in this specification and X is a halogen by reaction with an appropriate
halide
containing activated acylating agent. Preferred methods for the formation of
esters are
reacting the alcohol with the preformed acid chloride or symmetrical anhydride
of the
halide containing acid or condensing the alcohol and halide containing acid
with a
dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such
as
DMAP or HOBt. Preferred halides are bromide and iodide. Reaction of the ester
of the
formula 44 with a suitable nitrating agent such as silver nitrate in an inert
solvent such
as acetonitrile affords the compound of the formula XIC.
Another embodiment of this aspect provides processes for making compounds
having structures XII and to the intermediates useful in such processes as
follows .
Nitroso compounds of formula (XII) wherein Re, R f, R23, R24, R25, J, V and p
are
defined as in this specification and a nitrite containing thioester is
representative of
theK-T-D group as defined in this specification may be prepared according to
Scheme
34. The carboxylic acid group of formula 45 is converted to the thioester of
formula 46
wherein p, Re and R f are defined as in this specification by reaction with an
appropriate
protected alcohol containing thiol agent wherein P' is as defined in this
specification.
Preferred methods for the formation of thioesters are reacting the thiol with
the
preformed acid chloride or symmetrical anhydride of the carboxylic acid or
condensing
the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC.
HC1 in
the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups
for the
alcohol moiety are silyl ethers such as a trimethylsilyl or a tent-
butyldimethylsilyl ether.
Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for
removing
silyl ether protecting groups) followed by reaction with a suitable
nitrosylating agent
such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium
tetrafluoroborate in a
suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
with or
without an amine base such as pyridine or triethylamine affords the compound
of the
formula XIIA.
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WO 98/19672 PCT/US97/19870
Nitroso compounds of formula (XII) wherein Re, Rf, R23, R24, R2s, J, V and p
are
defined as in this specification and a nitrosothiol containing thioester is
representative of
the K-T-D group as defined in this specification may be prepared according to
Scheme
35. The carboxylic acid group of formula 45 is converted to the thioester of
formula 47
wherein p, Re and R f are defined as in this specification by reaction with an
appropriate
mono protected dithiol. Preferred methods for the formation of thioesters are
reacting
the free thiol with the preformed acid chloride or symmetrical anhydride of
the
carboxylic acid or condensing the free thiol and carboxylic acid with a
dehydrating agent
such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt.
Preferred protecting groups for the thiol moiety are as a disulfide, a
thioether such as a
paramethoxybenzyl thioether, a tetrahydropyranyi thioether or a S-
triphenylmethyl
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong
acids such as
trifluoroacetic or hydrochloric acid and heat are used to remove a
paramethoxybenzyl
thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether
group).
Reaction of the free thiol with a suitable nitrosylating agent such as thionyl
chloride
nitrite, thionyl dinitrite, a lower alkyl nitrite such as tent-butyl nitrite,
or nitrosium
tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride,
THF, DMF,
or acetonitrile with or without an amine base such as pyridine or
triethylamine affords
the compound of the formula XIIB. Alternatively, treatment of the thiol in
compound
47 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic
acid affords
the compound of the formula XIIB.
Nitro compounds of formula (XII) wherein Re, Rf, R23, Rza, R2s~ J, V and p are
defined as in this specification and a nitrate containing thioester is
representative of the
K-T-D group as defined in this specification may be prepared according to
Scheme 36.
The carboxylic acid group of formula 45 is converted to the thioester of
formula 46
wherein p, R.e and Rf are defined as in this specification by reaction with an
appropriate
protected alcohol containing thiol agent wherein P ~ is as defined in this
specification.
Preferred methods for the formation of thioesters are reacting the thiol with
the
preformed acid chloride or symmetrical anhydride of the carboxylic acid or
condensing
the thiol and carboxylic acid with a dehydrating agent such as DCC or EDAC.
HCl in
the presence of a catalyst such as DMAP or HOBt. Preferred protecting groups
for the
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WO 98I19672 PCTIUS97119870 _
alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-
butyldimethylsilyl ether.
Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for
removing
silyl ether protecting groups) followed by reaction of the alcohol with a
suitable
nitrating agent such as nitric acid and acetic anhydride in ethyl
acetate/acetic acid affords
the compound of the formula XIIC.
Nitroso compounds of formula (XIII) wherein Re, R f, R3,, R32, and p are
defined as
in this specification and a nitrite containing ester is representative of the
D group as
defined in this specification may be prepared according to Scheme 37. The
carboxylic
acid group of formula 48 is converted to the ester of formula 49 wherein p, Re
and Rf are
defined as in this specification by reaction with an monoprotected protected
diol wherein
P ~ is as defined in this specification. Preferred methods for the formation
of esters are
reacting the alcohol with the preformed acid chloride or symmetrical anhydride
of the
carboxylic acid or condensing the alcohol and carboxylic acid with a
dehydrating agent
such as DCC or EDAC. HCl in the presence of a catalyst such as DMAP or HOBt.
Preferred protecting groups for the alcohol moiety are silyl ethers such as a
trimethylsiiyl
or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety
(fluoride ion is
the preferred method for removing silyl ether protecting groups) followed by
reaction
with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl
dinitrite, or
nitrosonium tetrafluoroborate in a suitable anhydrous solvent such as
dichloromethane,
THF, DMF, or acetonitrile with or without an amine base such as pyridine or
triethylamine affords the compound of the formula XIIIA.
Nitroso compounds of formula (XIII) wherein Re, Rf, R3~, R32, and p are
defined as
in this specification and a nitrosothiol containing ester is representative of
the D group as
defined in this specification may be prepared according to Scheme 3 8. The
carboxylic
acid group of formula 48 is converted to the ester of formula 50 wherein p, R~
and Rf
are defined as in this specification by reaction with an appropriate protected
thiol
containing alcohol. Preferred methods for the formation of esters are reacting
the
alcohol with the preformed acid chloride or symmetrical anhydride of the
carboxylic
acid or condensing the primary thiol and carboxylic acid with a dehydrating
agent such
as DCC or EDAC. HC1 in the presence of a catalyst such as DMAP or HOBt.
Preferred
protecting groups for the thiol moiety are as a disulfide, a thioether such as
a
paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-
triphenylmethyl
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WO 98l19672 PCT/US97/19870 _
thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid,
triphenylphosphine in water and sodium borohydride are preferred methods for
reducing
disulfide groups while mercuric trifluoroacetate, silver nitrate, or strong
acids such as
trifluoroacetic or hydrochloric acid and heat are used to remove a
paramethoxybenzyl
thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether
group).
Reaction of the free thiol with a suitable nitrosylating agent such as thionyl
chloride
nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite,
or nitrosium
tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride,
THF, DMF,
or acetonitrile with or without an amine base such as pyridine or
triethylamine affords
the compound of the formula XIIIB. Alternatively, treatment of the thiol in
compound
50 with a stoichiometric quantity of sodium nitrite in aqueous or alcoholic
acid affords
the compound of the formula XIIIB.
Nitro compounds of formula (XIII) wherein Re, Rf, R3,, R32, and p are defined
as
in this specification and a nitrate containing ester is representative of the
D group as
defined in this specification may be prepared according to Scheme 39. The
carboxylic
acid group of formula 48 is converted to the ester of formula 49 wherein p, Re
and R f are
defined as in this specification by reaction with an appropriate monoprotected
protected
diol wherein P ~ is as defined in this specification. Preferred methods for
the formation
of esters are reacting the alcohol with the preformed acid chloride or
symmetrical
anhydride of the carboxylic acid or condensing the alcohol and carboxylic acid
with a
dehydrating agent such as DCC or EDAC. HCl in the presence of a catalyst such
as
DMAP or HOBt. Preferred protecting groups for the alcohol moiety are silyl
ethers such
as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the
hydroxyl
moiety (fluoride ion is the preferred method for removing silyl ether
protecting groups)
followed by reaction of the alcohol with a suitable nitrating agent such as
nitric acid and
acetic anhydride in ethyl acetate/acetic acid affords the compound of the
formula
XIIIC. Alternatively, carboxylic acid group of the formula 48 is converted to
the ester
of the formula 51 wherein p, Re and Rf are defined as in this specification
and X is a
halogen by reaction with an appropriate halide containing alcohol. Preferred
methods
for the formation of esters are reacting the alcohol with the preformed acid
chloride or
symmetrical anhydride of the halide containing acid or condensing the alcohol
and
halide containing alcohol with a dehydrating agent such as DCC or EDAC. HCl in
the
presence of a catalyst such as DMAP or HOBt. Preferred halides are bromide and
iodide. Reaction of the ester of the formula 51 with a suitable nitrating
agent such as
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WO 98I19672 PCTIIJS97119870
silver nitrate in an inert solvent such as acetonitrile affords the compound
of the
formula XIIIC.
As noted above, another aspect the invention provides a composition comprising
(i) a therapeutically effective amount of a PDE inhibitor, which optionally
can be
substituted with at least one NO or N02 group or a group that stimulates
endogenous
production of NO or EDRF in vivo, and (ii) a compound that donates, transfers
or
releases nitrogen monoxide as a charged species, i. e. , nitrosonium (NO+} or
nitroxyl
(NO-), or as the neutral species, nitric oxide (NO~) and/or a compound that
stimulates
endogenous production of NO or EDRF in vivo.
The compounds that donate, transfer or release nitric oxide can be any of
those
known to the art, including those mentioned and/or exemplified below.
Nitrogen monoxide can exist in three forms: NO- (nitroxyl), NO~ (nitric oxide)
and
NO+ (nitrosonium). NO~ is a highly reactive short-lived species that is
potentially toxic
to cells. This is critical, because the pharmacological efficacy of NO depends
upon the
form in which it is delivered. In contrast to NO~, nitrosonium and nitroxyl do
not react
with 02 or 02- species. Consequently, administration of NO equivalents does
not result
in the generation of toxic by-products or the elimination of the active NO
moiety.
Compounds contemplated for use in the invention are nitric oxide and compounds
that release nitric oxide or otherwise directly or indirectly deliver or
transfer nitric oxide
to a site of its activity, such as on a cell membrane, in vivo. As used here,
the term
"nitric oxide" encompasses uncharged nitric oxide (NO~) and charged nitric
oxide
species, particularly including nitrosonium ion (NO+} and nitroxyl ion (NO~).
The
reactive form of nitric oxide can be provided by gaseous nitric oxide. The
nitric oxide
releasing, delivering or transferring compounds, having the structure F-NO
wherein F is
a nitric oxide releasing, delivering or transferring moiety, include any and
all such
compounds which provide nitric oxide to its intended site of action in a form
active for
their intended purpose. As used here, the term "NO adducts" encompasses any of
such
nitric oxide releasing, delivering or transferring compounds, including, for
example, S-
nitrosothiols, S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols,
sydnonimines, 2-
hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-[(E}-hydroxyimino]-5-nitro-
3-
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WO 98/19672 PCT/US97/19870
hexene amines or amides, nitrosoamines, as well a subtstates for the
endogenous
enzymes which synthesize nitric oxide. It is contemplated that any or all of
these "NO
adducts" can be mono- or poly-nitrosylated or nitrosated at a variety of
naturally
susceptible or artificially provided binding sites for nitric oxide or
derivatives which
donate or release NO.
One group of such NO adducts is the S-nitrosothiols, which are compounds that
include at least one -S-NO group. Such compounds include S-nitroso-
polypeptides (the
term "polypeptide" includes proteins and also polyamino acids that do not
possess an
ascertained biological function, and derivatives thereof); S-nitrosylated
amino acids
(including natural and synthetic amino acids and their stereoisomers and
racemic
mixtures and derivatives thereof); S-nitrosylated sugars, S-nitrosylated-
modified and
unmodified oligonucleotides (preferably of at least 5, and more particularly 5-
200,
nucleotides); and an S-nitrosylated hydrocarbons where the hydrocarbon can be
a
branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or
an
aromatic hydrocarbon; S-nitrosylated hydrocarbons having one or more
substituent
groups in addition to the S-nitroso group; and heterocyclic compounds. S-
nitrosothiols
and the methods far preparing them are described in U.S. Patent No. 5,380,758;
Oae et
al., Org. Prep. Proc. Int., 1S(3):165-198 {1983); Loscalzo et al., J.
Pharmacol. Exp.
Ther., 249(3):726729 (1989) and Kowaluk et al., J. Pharmacol. Exp. Ther.,
256:1256-
1264 ( 1990), a11 of which are incorporated in their entirety by reference.
One particularly preferred embodiment of this aspect relates to S-nitroso
amino
acids where the nitroso group is linked to a sulfur group of a sulfur-
containing amino
acid or derivative thereof. For example, such compounds include the following:
S-
nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-
nitroso--
cysteine and S-nitroso-glutathione.
Suitable S-nitrosylated proteins include thiol-containing proteins (where the
NO
group is attached to one or more sulfur group on an amino acid or amino acid
derivative
thereof) from various functional classes including enzymes, such as tissue-
type
plasminogen activator (TPA) and cathepsin B; transport proteins, such as
lipoproteins,
heme proteins such as hemoglobin and serum albumin; and biologically
protective
proteins, such as the immunoglobulins and the cytokines. Such nitrosylated
proteins are
-56-
CA 02270118 1999-04-27
~'':~ ~ J a ~ ~ o,
S ~ rJOV ~9~8
described in PCT Publ. Applic. No. WO 93/09806, published May 27, 1993.
Examples
include polynitrosylated albumin where multiple thiol or other nucleophilic
centers in
the protein are modified.
Further examples of suitable S-nitrosothiols include those having the
structures:
(i) CH3[C(R~~]xSNO
wherein x equals 2 to 20 and R~ and R~ are as defined in this specification;
(ii) HS(C((R~(R~]xSNO
wherein x equals 2 to 20; and R~ and R~ are as defined in this specification;
('iii) ONS[~X~~B~ ~d .
Cv) H2N-CH(COZH)-(CH~i~(O)NH-C(CHxSNO)-C(O)NH-CHz-COZH
wha~eia x equals 2 to 20; R~ and Rf are as defined in this specification; and
B is select~od
from the group consisting of ffuoro, C~-Cd alkoxy, cyano, carboxamido,
cycloallryl,
~Y~xY. ~YY~ ~Ylthio, alkylamino, diallcylaminlo, hydroxy, carbamoyl, N-
alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen,
vitro and
aryl.
Nitrosothiols can be prepared by various methods of synthesis. In general, the
thiol prxiusor is prepared first, then converted to the S-nitcvsothiol
derivative by
nitc~a~tion of the thiol group with NaNOZ under acidic conditions (pH is about
2.5) to
yield the S-nitroso derivative. Acids which may be used for this purpose
include
aqimous sulfuric, acetic and hydrochloric acids. Alternatively, the precursor
thiol may
be nitrosylated by treatment with an alkyl nitrite such as tart-butyl nitrite.
Another group of such NO adducts are those wherein the compounds donate,
transfer or release nitric oxide and are selected from the group consisting of
compounds
that include at least one ON-N- or ON-C- group. The compound that includes at
least
one ON-N- or ON-C- group is preferably selected finm the group consisting of
ON-N-
or ON-C-polypeptides (the term "polypeptide" includes proteins and also
polyamino
acids that do not possess an ascertained biological function) and derivatives
thereof);
ON-N- or ON-C-amino acids(including natural and synthetic amino acids and
their
stereoisomers and racemic mixtures); ON-N- or ON-C-sugars; ON-N- or ON-C-
-57-
AMENDED SHEET,, ,
CA 02270118 1999-04-27
WO 98I19672 PCT/CTS97/19870 _.
modified and unmodified oligonucleotides (preferably of at least ~, and more
particularly 5-200, nucleotides), ON-O-, ON-N- or ON-C-hydrocarbons which can
be
branched or unbranched, saturated or unsaturated aliphatic hydrocarbons or
aromatic
hydrocarbons; ON-N- or ON-C- hydrocarbons having one or more substituent
groups in
addition to the ON-N- or ON-C- group; and ON-N- or ON-C-heterocyclic
compounds.
Another group of such NO adducts is the nitrites which have an -O-NO group
wherein the organic template to which the nitrite group is appended is a
protein,
polypeptide, amino acid, carbohydrate, branched or unbranched and saturated or
unsaturated alkyl, aryl or a heterocyclic compound. A preferred example is the
nitrosylated form of isosorbide. Compounds in this group form S-nitrosothiol
intermediates in vivo in the recipient human or other animal to be treated and
can
therefore include any structurally analogous precursor R-O-NO of the S-
nitrosothiols
described above.
Another group of such adducts are nitrates which donate, transfer or release
nitric
oxide and are selected from the group consisting of compounds that include at
least one
at least one 02N-O-, 02N-N-, 02N-S- or 02N-C- group. Preferred among these are
those
selected from the group consisting of 02N-O-, 02N-N-, 02N-S- or 02N-C-
polypeptides;
02N-O-, 02N-N-, 02N-S- or 02N-C-amino acids; 02N-O-, 02N-N- 02N-S- or 02N-C-
sugars; 02N-O-, 02N-N-, 02N-S- or 02N-C-modified and unmodified
oligonucleotides;
02N-O-, 02N-N-, 02N-S- or 02N-C- hydrocarbons which can be branched or
unbranched, saturated or unsaturated aliphatic hydrocarbons or aromatic
hydrocarbons;
02N-O-, 02N-N-, 02N-S- or 02N-C- hydrocarbons having one or more substituent
groups in addition to the 02N-O-, 02N-N-, 02N-S- or 02N-C-group; and 02N-O-,
02N-
N-, 02N-S- or 02N-C-heterocyclic compounds. Preferred examples are isosorbide
dinitrate and isosorbide mononitrate.
Another group of such NO adducts is the nitroso-metal compounds which have the
structure (R)"-A-M-(NO)". R includes polypeptides (the term "polypeptide"
includes
proteins and also polyamino acids that do not possess an ascertained
biological function,
and derivatives thereof); amino acids (including natural and synthetic amino
acids and
their stereoisomers and racemic mixtures and derivatives thereof}; sugars;
modified and
unmodified oligonucleotides (preferably of at least 5, and more particularly 5-
200,
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nucleotides); and a hydrocarbon where the hydrocarbon can be a branched or
unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic
hydrocarbon; hydrocarbons having one or more substituent groups in addition to
the A-
nitroso group; and heterocyclic compounds. A is S, O, or N, a and v are each
integers
independently selected from 1, 2 and 3, and M is a metal, preferably a
transition metal.
Preferred metals include iron, copper, manganese, cobalt, selenium and
luthidium. Also
contemplated are N-nitrosylated metal centers such as nitroprusside.
Another group of such adducts are 2-hydroxy-2-nitrosohydrazines which donate,
transfer or release nitric oxide and have a R6 i R62-N(O-M+)-NO group wherein
R6, and
Rb2 include polypeptides, amino acids, sugars, modified and unmodified
oligonucleotides, hydrocarbons where the hydrocarbon can be a branched or
unbranched,
and saturated or unsaturated aliphatic hydrocarbon or an aromatic hydrocarbon,
hydrocarbons having one or more substituent groups and heterocyclic compounds.
M+ is
a metal cation, such as, for example, a Group I metal cation.
Another group of such adducts are thionitrates which donate, transfer or
release
nitric oxide and have the structure R61-S-N02 wherein R61 is as described
above.
Compounds that stimulate endogenous synthesis of NO or EDRF in vivo include
L-arginine, the substrate for nitric oxide synthase, cytokines, adenosine,
bradykinin,
calreticulin, bisacodyl, phenolphthalein, and endothelin.
When administered in vivo, the nitric oxide may be administered in combination
with pharmaceutical carriers and in dosages described herein.
The nitrosated or nitrosylated compounds of the invention are used at dose
ranges
and over a course of dose regimen and are administered in the same or
substantially
equivalent vehicles/carrier by the same or substantially equivalent oral or
nasal inhalant
devices as their non-nitrosated or non-nitrosylated counterparts. The
nitrosated or
nitrosylated compounds of the invention can also be used in lower doses and in
less
extensive regimens of treatment. The amount of active ingredient that may be
combined
with the carrier materials to produce a single dosage form will vary depending
upon the
host treated and the particular mode of administration.
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The dosage regimen for treating a disease condition with the compounds and/or
compositions of this invention is selected in accordance with a variety of
factors,
including the type, age, weight, sex, diet and medical condition of the
patient, the
severity of the disease, the route of administration, pharmacological
considerations such
as the activity, efficacy, pharmacokinetic and toxicology profiles of the
particular
compound employed, whether a drug delivery system is utilized and whether the
compound is administered as part of a drug combination., Thus, the dosage
regimen
actually employed may vary widely and therefore may deviate from the preferred
dosage
regimen set forth above.
Total daily dose administered to a host in single or divided doses may be in
amounts, for example, from about 1 to about 100 mg/kg body weight daily and
more
usually about 3 to 3 0 mg/kg. Dosage unit compositions may contain such
amounts of
submultiples thereof to make up the daily dose.
While the compounds of the invention can be administered as the sole active
pharmaceutical agent, they can also be used in combination with one or more
compounds which are known to be effective against the specific disease state
targeted
for treatment. The compositions of the invention can also be administered as
described
above or can be made to include one or more additional active compounds which
are
known to be effective against the specific disease state is targeted for
treatment.
The invention also provides a pharmaceutical pack or kit comprising one or
more
containers filled with one or more of the ingredients of the pharmaceutical
compositions
of the invention. Associated with such containers) can be a notice in the form
prescribed by a governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects approval by the
agency of
manufacture, use or sale for human administration.
These and other aspects of the present invention will be apparent to those
skilled in
the art from the teachings herein.
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Example 1
2,6-bis diethyl(3-methyl-3~nitrosothiol)butvric acid ester amino)-4 8
di~~eridino~~mido-[~.4-d~-~yrimidine
la. 3-Meth 1~-3(2 4,6-trimethox~p~vlmetl3"vlthio)butvric acid
To a solution of 3-mercapto-3-methylbutyric acid (B.J. Sweetman et al. J. Med
Chem., 14, 868 ( I 971 )) (4.6 g, 34 mmol) in methylene chloride (250 mL)
under nitrogen
and cooled over ice/salt to 5 uC (internal temperature) was added
trifluoroacetic acid (82
g, 0.72 mol). No significant temperature rise was noted during the addition.
To this
was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (M.C.
Munson et
al., J. Org. Chem., 57, 30l3 ( 1992)) {6.45 g, 32 mmol) in methylene chloride
( 150 mL)
such that the reaction temperature does not rise above 5 uC. After the
addition was
complete, the mixture was stirred for an additional 5 min at 5 uC and the
volatiles were
removed in vacuo (toluene or ethyl acetate can be used to assist in the
removal of
volatile material). The residue was partitioned between diethyl ether and
water and the
organic phase dried over anhydrous sodium sulfate, filtered and the volatile
material
removed in vacuo. The residue was treated with activated charcoal and
recrystalised
from diethyl ether/hexane. The product was isolated as an white solid in 70%
yield (7 g}
mp l03-105 ~C. 'H NMR (CDC13) 8 6.12 (s, 2H), 3.80-3.85 {m, 11 H), 2.74 (s,
2H),
1.47 (s, 6H). '3C NMR (CDC13) 8 173.9, l60.6, 158.6, l05.6, 90.5, 55.7, 5S.3,
45.9,
43.6, 28.4, 21Ø
1 b. 2 6-bis diethyl-3-methyl-3(2 4 6-trimethox hy~enXlmethylthiolbutyric acid
~~aminol-4,8-dipineridinopvrimido-[5 4-d]-pyrimidine
Under a nitrogen atmosphere, dipyridamole ( 1.50 g, 2.97 mmol) was dissolved
in
anhydrous dimethylformamide (30 mL) and 4-dimethylaminopyridine (1.46 g, 11.9
mmol) was added, followed by the product of Example 1 a (3.64 g, 11.9 mmol)
and
EDAC (2.28 g, 11.9 mmol). The resulting mixture was stirred 44 hours at 50 ~
C. The
solvent was evaporated in vacuo and, residue was partitioned between methylene
chloride and water, washed with brine and dried over anhydrous sodium sulfate.
Volatiles were evaporated and the residue was purified by flash chromatography
on
silica gel, eluting with hexane/ ethyl acetate (2:1 ) to { 1:1 ) to give the
title compound
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WO 98I19672 PCT/LTS97/19870
(l.02 g, 23 % yield). ~HENMR (CDC13, 300 MHz) 8 1.45 {s, 24 H}, l.58-l.69 (m,
12 H),
2.70 (s, 8 H}, 3.64-3.88 (m, 52 H), 4.02-4.06 (m, 8 H), 4.25-4.32 (m, 8 H),
6.10 (s, 8H).
1 c. 2.6-bis(dieth, I-3met yl-3-merca tn obutvric acid ester)amino~,4 8-
dioine~ ridino_pxrimido~5~4-d~pyrimidine
The product of Example lb (1.00 g, 0.63 mmol) was dissolved in methylene
chloride (5.5EmL) and anisole (4.0 mL, 36.9 mmol), phenol (0.400 g, 4.25
mmol), water
(4.0 mL) and trifluoroacetic acid (16 mL, 208 mmol) were added. After 1 hour
30
minutes of stirring at room temperature, toluene (5 mL) was added and
volatiles were
evaporated. The residue was purified by flash chromatography on silica gel
eluting with
hexane/ ethyl acetate (5:1 ) to (3:1 ) to give the title compound (0.360 g, 59
% yield). 1H
NMR (CDC13, 300 MHz) 8 l.47 (s 24 H), 1.b8-1.72 (m, 12 H), 2.29 (s, 4H), 2.63
(s, 8
H), 3.85-3.92 (m, 8 H), 3.97-4.03 (m, 8 H), 4.28-4.35 (m, 8H).
1 d. 2.6-bisldiethy~3-me ~(nitrosothiollbu ric acid ester)aminol-4.8-
~nine~ dinopyrimido-(5.4d1-pyrimidine
The product of Example lc (0.3S3 g, 0.36 mmol) was dissolved in acetic acid
(20EmL)
and 1N solution of hydrochloric acid (3.5 mL) was added, followed by 1 N
sodium
nitrite solution (2.2 mL). After 30 minutes stirring at room temperature, the
reaction
mixture was lyophilized, the residue was suspended in methylene chloride and
washed
with water, brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated
in vacuo and the residue was purified by flash chromatography on silica gel
eluting
methylene chloridelmethanol (12:i) to give the title compound (0.l44 g, 37 %
yield).
(CDC13, 300 MHz) 8 1.52-l.73 (m, 12 H), 1.98 (s, 24 H), 3.20-3.38 (m, 8 H),
3.39-3.92
(m, 12 H), 3 .94-4.3 5 (m, 12 H).
Exam
1-[-4-(i(I,~benzodioxol-5-ylmethylla inoj-6-chloro-2-auinazolin~]-4-~neridine-
carboxylic eth~3-methyl~3~(nitrosothiollb~~~ramide) thioester h;~drochloride
2a. 3-Met~y~thioacetyl_, butyric acid
To a solution of 3-mercapto-3-methylbutyric acid (B.J. Sweetman et al. J.
ll~Ied Chem.,
14, 868 ( 1971 )) ( 1.03 g, 7.7 mmol) in pyridine ( 1.6 mL) was added acetic
anhydride
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WO 98I19672 PCT/US97/19870
( I .57 g, 15.4 mmol) and the reaction mixture was stirred at room temperature
over night.
The reaction mixture was slowly added to a 0 ~C solution of I N HCl (20 ml)
then water
( 10 ml) was added and the reaction mixture was stirred at room temperature
for 2 hours.
The solution was extracted with diethyl ether and the organic phase was washed
with
brine and then dried over anhydrous sodium sulfate. The solvent was evaporated
in
vacuo and the residue was purified by flash chromatography on silica gel
eluting with
ethyl acetate/hexane ( 1:4) to give the title compound (0.79l g, 58 % yield).
(CDC13, 300
MHz) 8: 1.55 (s, 6 H), 2.25 (s, 3H), 2.99 (s, 2H).
2b. Mecaptoetl~,vl-3-Meth,~~l-3lthioacetvl butvramide
The product of Example 2a (0.556 g, 3.1 mmol) was dissolved in methylene
chloride
( 10 ml) containing a catalytic amount of dimethylforamide ( 10 ~1). Oxalyl
chloride
(0.556 g, 4.4 mmol) was added and the reaction mixture was stirred at room
temperature
for I hour. The volatile components were then evaporated in vacuo and the
residue
azeotroped with toluene (2 x 5 ml). The yellow oil remaining was added to a -
78 ~C
solution of 2-aminoethanethiol hydrochloride (0.341 g, 3.0 mmol), and
triethylamine
(0.303 g, 3.0 mmol) in dimethylformamide (6 ml). The reaction mixture was
stirred at
-78 ~C for 1 hour and then at room temperature for 2 hours. The reaction was
quenched
with water (20 ml) and then extracted with ethyl acetate. The organic phase
was dried
over anhydrous sodium sulfate and then concentrated in vacuo to afford the
title
compound (0.349 g, 53 % yield) which was used without further purification.
(CDC13,
300MHz)8: I.5(s,6H),2.3(s,3H), 2.6(dd,2H),2.8(s,2H),2.9(s, 1 H),3.4(dd,2
H), 6.0 (brs, I H).
2c. Meca tR oethyl-3-Methxl-3(merca~o_LuiYramide
The product of Example 2b (0.314 g, 1.4 mmol) was dissolved in methanol ( 10
ml)
and solid sodium hydroxide (85 mg, 2.1 mmol) was added. After stirring 5
minutes, the
reaction mixture was diluted with ethyl acetate (50 ml) and washed with
saturated
aqueous sodium bicarbonate, followed by brine, and then dried over anhydrous
sodium
sulfate. The volatile components were evaporated in vacuo leaving the title
compound
as a colorless oil {0.188 g, 75 % yield) which was used without further
purification.
{CDCl3, 300 MHz) 8: l.42 (s, 6 H),1.55 (s, I H), 2.17 (s, 1 H), 2.41 {s, 2 H),
2.6l (dd, J
= 12.S Hz, 6.2 Hz, 2H), 3.39 (dd, J = l2.5 Hz, 6.2 Hz, 2H).
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2d. 4-[11.3-benzodioxol-5- l~methvl)amino)-2. 6-dichloro quinazoline
A solution of 2,4,6-trichloroquinazoline (0.186 g, 0.80 mmol) in ethanol (20
mL)
was heated to 55 ~C and piperonylamine (0.l45 g, 0.96 mmol) was added. The
resulting
mixture was stirred at 55 ~C overnight. Volatiles were evaporated and the
residue was
partitioned between methylene chloride and saturated solution of ammonium
hydroxide.
The organic phase was dried over anhydrous sodium sulfate and concentrated in
vacuo
to yield 0.268 g (96 % yield) of the title compound as a white solid. 'H NMR
(300EMHz, DMSO) 8 4.59-4.63 (d, 2 H), 5.98 (s, 2 H), 6.86 (s, 2 H), 6.96 (s, 1
H), 7.62-
7.66 (d, 1 H), 7.79-7.84 (d, 1 H), 8.46 (s, 1 H), 9.24-9.28 (t, 1 H).
2e. ~~-4-(( 1.3-benzodioxol-,~,ylmethvllamino]-6-chloro-2~ iu nazol~l)-4-
~peridine-carboxylic acid ethyl ester
The product of Example 2d (0.l64 g, 0.47 mmol) and ethyl isonipecotate
(0.200EmL,
1.27 mmol) were combined in 5 g of phenol. The resulting mixture was heated at
reflex
temperature (240 i C) for 5 hours. The mixture was allowed to cool down,
dissolved in
20 ml of chloroform and washed with 1N solution of sodium hydroxide (2 5 40
mL).
The organic fraction was dried over anhydrous sodium sulfate and concentrated
in
vacuo. The residue was purified by flash chromatography on silica gel, eluting
with
hexane/ ethyl acetate (9:1 ) to {5:1 ) to give 0.164 g (53 % yield) of the
title compound as
a solid. iH NMR (300EMHz, CDC13) b 1.24-1.30 (t, 3 H), 1.70-1.79 (m, 2 H),
1.96-2.06
(m, 2 H), 2.54-2.58 (m, 1 H), 3.0l-3.l0 (t, 2 H), 4.l0-4.20 (q, 2 H), 4.66-
4.70 {d, 2 H),
4.77-4.84 (d, 2 H), 5.59 (s, 1 H), 5.97 (s, 2 H), 6.77-6.89 (m, 3 H), 7.40-
7.45 (m, 3 H).
2f. 1-lT4-j(1.3-benzodioxol-5-, lmet yhaminol-6-chloro-2-auinazolinyl~-4-
p~peridine-carboxylic acid
The product of Example 2e (0. I00 g, 0.21 mmol) was dissolved in ethanol ( I
mL) and
water (0.5 mL) was added, followed by sodium hydroxide (0.082 g, 2.05 mmol).
The
resulting mixture was heated at l00 ~C for 20 minutes. The volatiles were
evaporated,
the residue was diluted with water (2 mL) and 1N HCl was added until the pH of
the
reaction mixture registered pH 7. The reaction mixture was then filtered and
the
precipitate was washed with water (2 mL). Ethanol was added to the precipitate
and the
volatiles were evaporated to give 0.080 g (86 % yield) of the title compound
as a pale
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WO 98/19672 PCT/US97/19870
yellow solid. 'H NMR (300EMHz, DMSO) 8 1.36-l .45 (m, 2 H), l .75-1.83 (m) 2
H),
2.92-3.02 (m, 3 H), 4.54-4.60 (m, 4 H), 5.94 (s, 2 H), 6.83 (s, 2 H), 6.93 (s,
1 H), 7.21-
7.26 (d, 1 H), 7.44-7.49 (d, 1 H), 8.13 (s, 1 H), 8.5l-8.53 (t, 1 H).
2g. l~-4-[ll 3-benzodioxol-5; ly_meths,laminol-6-chloro-2-~uinazolintl,~-4-
~iperidine-
carboxxlic ethyl-(3-meth ~~I-3~,thioacet5rllbut~ramide) thioester
Under a nitrogen atmosphere, the product of Example 2f (0.147 g, 0.31 mmol)
and
triethylamine (0.043 mL, 0.31 mmol) were combined in 3 mL of DMF and heated to
50
~C to dissolve all solid. A solution of 2c (0.067 g, 0.38 mmol) in DMF (2 mL)
was
added, followed by EDAC (0.073 g, 0.38 mmol) and DMAP (0.015 g, 0.I2 mmol}.
The
resulting mixture was stirred at room temperature for 5 hours and then at 50 i
C
overnight. The reaction mixture was diluted with water (20 mL) and extracted
with
dichloromethane. The combined organic phase was washed with brine and dried
over
anhydrous sodium sulfate. The voiatiles were evaporated and the residue was
purified by
flash chromatography on silica gel eluting with hexanei ethyl acetate ( 1:2)
to give 0.038
g (21 % yield) of the title compound. ~ H NMR (300EMHz, CDC13) d: 1.48 (s, 6
H),
1.64-1.75 (m, 2 H), 1.94-2.00 (m, 2 H), 2.04 (s, 1 H), 2.45 (s, 2 H), 2.70-
2.?7 (m, 1 H),
2.91-2.96 (t, 2 H), 3.01-3.08 (t, 2 H), 3.42-3.48 (t, 2 H), 4.64-4.68 (d, 2
H), 4.87-4.94 (d,
2 H), 5.64-5.68 (m, I H), 5.96 (s, 2 H), 6.l7-6.20 (m, 1 H), 6.75-6.85 (m, 3
H), 7.38-7.45
(m, 3 H).
2h. 1-[-4-~( 1, 3-benzodioxol-S-vlmet~l)aminol-6-chloro-~-quinazolinY_l~-4-
pineri~ine
carboxylic eth l~l-(3-met ~-3(nitrosothiolLbu-tyramide) thioester hvdr loride
The product of Example 2g (0.034 g, 0.057 mmol) was dissolved in methanol/
dichloromethane ( 1 mL, 1:1 ) and 4N HCl in ether (0.100 mL) was added.
Concentration
in vacuo afforded a white solid. The white solid was then dissolved in a
mixture of
methylene chloride (3EmL) and methanol ( 1 mL), and the resulting solution was
cooled
to OiC. Tert-butyl nitrite (0.034 mL, 0.29 mmol) was added and the reaction
mixture was
stirred at 0 iC for 30 minutes. The volatiles were evaporated to give 0.037 g
(98 % yield)
of the title compound as a green solid. 'H NMR (300EMHz, CDC13) 8 1.61-1.76
(m, 4
H), 1.99 (s, 6 H), 2.66-2.85 (m, 1 H), 2.90-3.04 (m, 2 H), 3.18-3.45 (m, 4 H),
3.48 (s, 2
H), 4.59-4.86 (m, 4 H}, 5.87 (s, 2 H), 6.62-6.71 (d, 1 H}, 6.74 (s, 1 H), 6.80-
6.88 (d, 1
H), 6.90 (s, I H), 7.48-7.56 (m, 1 H), 7.65-7.76 (m, 1 H), 8.l4-8.l9 (d, 1 H),
8.43 (s, 1
H).
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1~ Vitro Comparitive Relaxation Responses
Human corpus cavernosum tissue biopsies were obtained at the time of penile
prosthesis implantation from impotent men. The tissue was maintained in a
chilled
Krebs-bicarbonate solution prior to assay. The tissue was cut into strips of
0.3 x 0.3 xl
cm and suspended in organ chambers for isometric tension measurement. Tissues
were
incrementally stretched until optimal isometrtic tension for contraction was
obtained.
Once this was achieved, the tissues were contracted with phenylephine (7 x 10-
~ M) and
once a stable contraction was achieved, the tissues were exposed to either
dipyridamole
or Example 1 ( 10-6 to 3 x 10-5 M) by cumulative additions to the chamber. At
the end of
the experiment papaverine ( 10~ M) is added to obtain maximal relaxation.
Figure 40
shows that the compound of Example 1 at doses of 10 ~M and 30 p.M is more
efficacious in relaxing the phenylephrine-induced contaction than is an
equimolar dose
of the phosphodiesterase inhibitor dipyridamole. Data are expressed as the
percent loss
in tone from the phenylephrine-induced contraction (0% = phenylephrine
contraction;
-l00% = tone after the administration of papaverine).
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