Indian Patents
Title of Invention

SUBSTITUTED PYRROLOPYRIDINONE DERIVATIVES USEFUL AS PHOSPHODIESTERASE INHIBITORS
Abstract The invention relates to novel pyrrolopyridinone derivatives of the formula (I) or (II): pharmaceutical compositions containing the compounds and their use for the treatment of sexual dysfunction.
Full Text SUBSTITUTED PYRROLOPYRIDINONE DERIVATIVES USEFUL AS
PHOSPHODIESTERASE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority from United States provisional application
Serial No 60/204,646 filed May 17,2000, the contents of which are hereby
incorporated by reference.
FIELD OF THE INVENTION
The invention relates to novel pyrrolopyridinone derivatives, intermediates
used in, synthesis of and pharmaceutical compositions containing the
compounds and their use for the treatment of sexual dysfunction. The
compounds of the present invention are phosphodiesterase inhibitors usefull for
the treatment of sexual dysfunction, more particularly male erectile dysfunction.
BACKGROUND OF THE INVFNTION
Erectile dysfunction (ED) is defined as the inability to achieve or maintain
an erection sufficiently rigid for satisfactory sexual intercourse. Currently it is
estimated that approximately 7-8% of the male population suffer from some
degree of EO. the equivalent of at least 20 million men in the United States alone
Since the likelihood of ED increases with age, it is projected that the incidence of
this condition will rise in the future as the average age of the population increases.
Male erectile dysfunction may be the consequence of psychogenic
and/or organic factors Although ED is multi-factorial, certain sub-groups within
the male population are more likely to present with The symptoms of the
disorder. In particular, patients with diabetes, hypertension, heart disease, and
multiple sclerosis have a particulariy high prevalence of ED. In addition,
patients who take certain classes of drugs such as antihypertensives,
antidepressgnts, sedatives, and anxiolytics are more prone to suffer from ED.
Treatments for ED Include a variety of pharmacologic agents, vacuum
devices, and penile prostheses. Among the pharmacologic agents, papaverine,
phentolamine, and alprostadil are currently used in practice. These agents are
only effective after direct intracavernosal or intraurethral injection, and are
associated with side effects such as priapism, fibrosis, penile pain and hematoma
at the injection site. Vacuum devices are a noninasive alternative treatment for
ED. These devices produce an erection by creating a negative pressure around
the shaft of the penis resulting in an increased blood flow into the corpus
cavernosum via passive arterial dilation. Although this form of therapy is
frequently successful in ED of organic origin, complaints include the lack of
spontaneity and the time involved in using a mechanical device, and difficulty and
discomfort with ejaculation. A variety of semi-rigid or inflatable penile prostheses
have been used with some success, particularly in diabetic men. These devices
are generally considered when other treatment options have failed, and are
associated with an increased risk of infection and ischemia.
Recently, the phosphodiesterase V (PDEV) inhibitor, sildenafil (Viagra®)
was approved by the FDA as an orally effective medication for the treatment of
ED. Sildenafil, 5-[2-ethoxy-5-(4-fnethvlpiperazin-1 -ylsulphonyl)phenyl]-1 -rnethyl-3-
n-propyl-6,7-dihydro-1H-pyrazolo]4oJ4,3-dlpynimidin-7-one and a number of related
analogs and their use as antianginai agents are described in U.S. Patent Nos.
5,250,534 and 5,346,901. The use of sildenafil and related analogs for treating
male erectile dysfunction is described in PCT International Application Publication
No. WO 94/28902. published December 22,1994. In clinical studies, the drug
improved sexual function in about 70% of the men who suffer from ED of
psychogenic or organic etiology. However, the drug showed less dramatic efficacy
in patients who had undergone a radical prostatectomy, with improved erections in
43% of patients who took sildenafil versus 15% on placebo. In addition, the use
of sildenafi! is associated with several undesirable side effects including
headache, flushing and disrupted color vision which result from non-selective
effects on a varietv of tissues. In spite of these shortcomings, the drug is viewed
by patients as preferable to other treatments which involve the introduction of
medication directly into the penis via injection, the use of an external device or a
surgical procedure.
Daugan et.al, in US Patent No. 5.859,009 and EP 0740668 B1 describe the
synthesis of a series of tetracydic derivatives as inhibitors of cyclic guanosine 3',5'
monophosphate specifically phosphodiesterase, and their use in treating
cardiovascular disorders. Daugan et.al., in WO97/03675 teach the use of the
tetracyclic derivatives for the treatment of impotence.
Garinaux, J.-F. et al., in Tetrahedron Letters 38(17), (1997), pp 2997-3000
disclose the synthesis of tricydic quinolone derivatives via oxidation of 1,2,3,4-
tetrahydro-ß-carbolines.
pfenninger, E. in DE 2803541 and US Patent No. 4,235,907 discloses
substituted 9H-pyrrolo-[3,4-b]quinolin-9-ones and their use in the treatment of
allergic asthma.
Sexually stimulated penile erection results from a complex interplay of
physiological processes involving the central nervous system, the peripheral
nervous system, and the smooth muscle. Specifically, release of nitric oxide from
the non-adrenergic, non-cholinergic nerves and endothelium activates guanylyl
cyclase and increases intracellular cGMP levels within the corpus cavemosum.
The increase in intracellular cGMP reduces intracellular calcium levels, resulting in
trabecular smooth muscle relaxation, which, in turn, results in corporal volume
expansion and compression of the sub-tunical venules leading to penile erection.
PDEV has been found in human platelets and vascular smooth muscle,
suggesting a role for this enzyme in the regulation of intracellular concentrations
of cGMP in cardiovascular tissue. In fact, inhibitors of PDEV have been shown to
produce endothelial-dependent vasorelaxation by potentiating the increases in
intracellular cGMP induced by nitric oxide. Moreover, PDEV inhibitors selectively
lower the pulmonary arterial pressure in animal models of congestive heart failure
and pulmonary hypertension. Hence in addition to their utility in ED, PDEV
inhibitors would likely be of therapeutic benefit in conditions like heart failure,
pulmonary hypertension, and angina.
Agents that increase the concentration of cGMP in penile tissue, either
through enhanced release or reduced breakdown of cGMP, are expected to be
effective treatments for ED. The intracellular levels of cGMP are regulated by the
enzymes involved in its formation and degradation, namely the guanyiate cyclases
and the cyclic nucleotide phosphodiesterases (PDEs). To date, at least nine
families of mammalian PDEs have been described, five of which are capable of
hydrolyzing the active, cGMP, to the inactive, GMP, under physiological conditions
(PDEs I, II, V, VI, and IX). PDE V is the predominant isoform in human corpus
cavernosum. Inhibitors of PDEV, therefore, would be expected to increase the
concentration of cGMP in the corpus cavernosum and enhance the duration and
frequency of penile erection.
Additionally, selective PDE inhibitors are known to be useful in the
treatment of various disorders and conditions including male erectile
dysfunction (ED), female sexual arousal dysfunction, female sexual
dysfunction related to blood flow and nitric oxide production in the tissues of
the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular
disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary
rest stenosis, angina pectoris, myocardia! infarction, heart failure, ischemic
heart disorders, hypertension, pulmonary hypertension, asthma, intermittent
claudication and diabetic complications.
Accordingly, it is an object of the invention to identify compounds which
increase the concentration of cGMP in penile tissue through the inhibition of
phosphodiesterases, specifically PDEV. It is another object of the invention to
identify compounds which are useful for the treatment of sexual dysfunction,
particularly erectile dysfunction and/or impotence in male animals and sexual
dysfunction in female animals. Still another object of the invention is to identify
methods for treating sexual dysfunction, especially erectile dysfunction, using the
compounds of the present invention.
It is another object of the invention to identify compounds which are
useful for the treatment of conditions of disorders mediated by PDEV, such as
male erectile dysfunction, female sexual dysfunction, cardiovascular disorders,
atherosclerosis, arterial occlusive disorders, thrombosis, coronary reststenosis,
angina pectoris, myocardial infarction, heart failure, ischemic heart disorders,
hypertension, pulmonary hypertension, asthma, intermittent claudication or
diabetic complications.
We now describe a series of pyrrolopyrkjinone derivatives with the ability to
inhibit phosphodiesterase type V in enzyme assays.
SUMMARY OF THE INVENTION
The present invention provides novel pyrroiopyridinone derivative
compounds useful as phosphodiesterase inhibitors. More particularly, the
present invention is directed to compounds of the general formula (I) or (II):
wherein
R1 is selected from the group consisting of hydrogen, carboxy, -C(O)-C1-
C6alkyl, -C(O)-C1-C6alkoxy. -C(O)-NH-C1-C6alkyl-NH2, -C(O)-NH-C1-C6alkyl-
NHRA, -C(O)-NH-C1-C6alkyl-N(RA)2, -C(O)-NH2, -C(O)-NHRA, -C(O)-N(RA)2, -
C1-C6alkyl-NH2, -C1-C6alkyl-NHRA, -C1-C6alkyl-N(RA)2. -NH-C1-C6alkyl-N(RA)2;
where each RA is independently selected from the group consisting of
C1-C6alkyl, aryl, C1-C6aralkyI and heteroaryl, where the aryl, aralkyl or
heteroaryl may be optionally substituted with one to three RB;
where each R8 is independently selected from the group consisting of
halogen, nitro, cyano, C1-C6aHcyl, C1-C6alkoxy, C1-C6alkylcarbonyl, carboxyC1-
C6alkyl, C1-C6alkylsulfonyl, trifluoromethyl, amino. di(C1-C6alkyl)amino,
acetylamino, cart)oxyC1-C6alkyicarbonylamino, hydroxyC1-C6alkylamino, NHRA
and N(RA)2;
R2 is selected from the group consisting of C5-C10alkyl (optionally
substituted with one to three substituents independently selected from halogen,
hydroxy, nitro, amino, NHRA or N(RA)2), aryl (optionally substituted with one to
three substituents independently selected from Rc), cycloalkyl (optionally
substituted with one to three substituents independently selected from RA),
heteroaryl (optionally substituted with one to three substituents independently
selected from Rc), and heterocycioalkyl (optionally substituted with one to three
substituents independently selected from Rc);
where Rc is selected from the group consisting of halogen, nitro, cyano,
C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-C6alkyl)
and N(C1-C6alkyl)2;
R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-
C6alkylcarbonyl, C2-C6alkenylcarbonyl and C2-C6alkynylcarbonyl;
b is an integer from 0 to 4;
R4 is independently selected from the group consisting of halogen,
hydroxy, carboxy, oxo, nitro, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl,
trifluoromethyl, phenyl (wherein the phenyl group may be optionally substituted
with one to three substituents independently selected from R°), phenylsulfonyl,
naphthyl, C1-C6aralkyl, -O-aralkyl, (wherein the aralkyl group may be optionally
substituted with one to three substituents independently selected from RD),
heteroaryl (wherein the heteroaiyl may be optionally substituted with one to
three substituents independently selected from R°), heterocycioalkyi, NH2,
where each RD is independently selected from halogen, hydroxy, carboxy,
oxo, C1-C4alkyl, C1-4alkylthio, hydroxyC1-4alkyl, C1-C4alkoxy, C1-C4alkyoxycarbonyl,
C1-C4alkylcarbonyi, trifluoromefhyl, trifluoromethoxy, NH2, NHRA, N(RA)2,
C(0)N(RA)2. acetylamino, nitro, cyano, formyl, C1-C6alkylsulfonyl, carboxyC1-
C6alkyl and aralkyl;
c is an integer from 0 to 4;
R5 is independently selected from the group consisting of halogen, nitro,
hydroxy, C1-C6alkyl. C1-C6alkoxy, -NH2, -NHRA, -N(RA)2, -ORA, -C(O)NH2,
-C(0)NHRA, -C(0)N(RA)2, -NHC(O)RA, -SO2NHRA, -SO2N(RA)2, where RA is as
defined above, phenyl (optionally substituted with one to three substituents
independently selected from R8), heteroaryl (optionally substituted with one to
three substituents independently selected from RB) and heterocycloalkyl
(optionally substituted with one to three substituents independently selected from
RB);
a is an integer from 0 to 1;
Y selected from the group consisting of -C1-C6alkyl-, -C(O)-, -(C1-
C6alkyl)carbonyl -(C2-C6alkenyl)carbonyS-, -(C2-C6alkynyl)carbonyl-, -
carbonyl(C1-C6alkyl)-, -carbonyl(C2-C6alkenyl)-, C(O)O-C1-C6alkyl)-, -C(S)-, -
SO2, -(C1-C6alkyl)sulfonyl-, -sulfonyl(C1-C6alkyl)-, -C(O)NH-, -C(O)NH-(C1-
C6alkyl)-, -C(OXC3-C7cycloalky!)-and -(C3-C7cycloalkyl)-C(O)-;
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and any of the compounds described above.
An illustration of the invention is a pharmaceutical composition made by mixing
any of the compounds described above and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a pharmaceutical
composition comprising mixing any of the compounds described above and a
pharmaceutically acceptable carrier.
Exemplifying the invention is a method of treating a condition selected from
the group consisting of male erectile dysfunction (ED), impotence, female sexual
dysfunction, female sexual arousal dysfunction, female sexual dysfunction related
to blood flow and nitric oxide production in the tissues of the vagina and clitoris,
premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial
occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris,
myocardial infarction, heart failure, ischemic heart disorders, hypertension,
pulmonary hypertension, asthma, intermittent claudication and diabetic
complications in a subject in need thereof comprising administering to the subject
a therapeutically effective amount of any of the compounds or pharmaceutical
compositions described above.
An example of the invention is a method for increasing the concentration of
cGMP in penile tissue through the inhibition of phosphodiesterases, specifically
PDEV, in a male subject in need thereof comprising administering to the subject
an effective amount of any of the compounds or pharmaceutical compositions
described above.
Further exemplifying the invention is a method of producing endothelial-
dependent vasoreiaxation by potentiating the increases in intracellular cGMP
induced by nitric oxide in a subject in need thereof comprising administering to the
subject an effective amount of any of the compounds or pharmaceutical
compositions described above.
An example of the invention is the use of any of the compounds described
above in the preparation of a medicament for (a) treating sexual dysfunction,
especially male erectile dysfunction, (b) treating impotence, (c) increasing the
concentration of cGMP in penile tissue through inhibition of phosphodiesterase,
especially PDEV and/or (d) treating a condition selected from the group consisting
of premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis,
arterial occlusive disorders, thrombosis, coronary reststenosis, angina pectoris,
myocardial infarction, heart failure, ischemic heart disorders, hypertension,
pulmonary hypertension, asthma, intermittent claudication and diabetic
complications in a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel pyrrotopyridinone derivatives useful
for the treatment of sexual dysfunction, particularly male erectile dysfunction (ED).
Although the compounds of the present invention are useful primarily for the
treatment of male sexual dysfunction or erectile dysfunction, they may also be
useful for the treatment of female sexual dysfunction, for example female sexual
arousal dysfunction, female sexual dysfunction related to blood flow and nitric
oxide production in the tissue of the vagina and clitoris, and of premature labor
and dysmenorrhea.
More particularly, the compounds of the present invention are of the
formula (I) or (II):
wherein all variables are as defined above, and pharmaceutically
acceptable salts thereof.
Preferably, R1 is hydrogen.
In an embodiment of the present invention R2 is selected from the group
consisting of phenyi (optionally substituted with one to two substituent selected
from halogen, nitro, cyano, C1-C3atkyi, C1-rC3alkoxy, trifiuoromethy!,
trifluoromethoxy, NH2, NH(C1-C3alkyl) or N(C1-C3alkyl)2), heteroaryl and
heterocycloalkyl. Preferably, R2 is selected from the group consisting of 3,4-
methyienedioxyphenyl, 3,4-dimethoxyphenyl, 5-(2,3-dihydroben2ofuryl), 3,4-
dihydrobenzo-[1,4]-dioxin-6-yl, 5-benxofuryl, 5-indanyl and 3-thienyl. More
preferably, R2 is selected from the group consisting of 3,4-
methylenedioxyphenyl, 5-(2,3-dihydrobenzofuryl), 3,4-dihydrobenzo-[1,4]-
dioxin-6-yl, 3-thienyl, 5-indanyl and 5-benzofuryl, More preferably still, R2 is
selected from the group consisting of 3,4-methyienedioxyphenyl, 5-(2F3-
dihydrobenzofuryl), 3,4-dihydrobenzo-[1,4]-dioxin-6-yl, 3-thienyl, 5-indanyl and
5-benzofuryl. Most preferably, R2 is selected from the group consisting of 3,4-
methylenedioxyphenyl, and 5-(2,3-dihydrobenzofuryl).
Preferably, R3 is selected from the group consisting of hydrogen and C1-
C4a!kyt. More preferably, R3 is selected from the group consisting of hydrogen
and methyl. Most preferably, R3 is hydrogen.
Preferably, b is an integer from 0 to 4. More preferably b is in integer
from 0 to 1.
In an embodiment of the present invention, R4 is selected from the
group consisting of halogen, hydroxy, carboxy, oxo, C1-C3alkyl, C1-C3alkoxy,
C1-C3alkoxycarbonyl, phenyl (wherein the phenyi may be optionally substituted
with one to two substituents selected from hydroxy, carboxy, C1-C4alkyl, Cl
4alky!thio, hydroxyC1-4alkyl. C1--C4alkoxy. C1-C4alkyoxycartonyi, C(O)N(RA)2,
trifluoromethyl, trifluoromethoxy, amino, (C1-4alkyl)amino, di(C1-4alkyl)amino,
nitro, cyano or formyl), O-arafkyl, heteroaryl (wherein the heteroaryi may be
optionally substituted with one to two substituents selected from hydroxy,
carboxy, oxo, C1-C3alkyI, C1-C3alkoxy, C1-C3alkyoxycarbony1, C(O)N(RA)2,
trifluoromethyl, trifluoromethoxy, amino, nitro, C1-C3alkylcarbonyl or C1-
the group consisting of bromo, hydroxy, carboxy, oxo, methyl, phenyl, 4-
hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethytphenyl, 4-
carboxyphenyl, 4-methylphenyl, 4-methaxyphenyl, 3,4dimethaxypnenyl, 4-
methoxycarbonyl, 4-methoxycarbonylphenyl, 3-trifluoramethylphenyl, 4-
cyanophenyl, 4-aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyi, 4-
nitrophenyt, 4-formytphenyl, 4-methylhiophenyl, benzyloxy, 2-pyridinyi. 3-
pyridinyl, 4-pyridinyl, N-oxy-2-pyridJnyl, 3-thienyl, 2-furyl, 1-imidazolyl, 5-(1-
benzyl-2-methylimidazolyl), 5-(1,2-dimethylimidazolyl), 5-(1 -methylimidazoly),
. More preferably, R4 is selected from the
group consisting of 5-bromo, 2-hydroxy, 6-hydroxy. 4-carboxy, phenyl, 4-
hydroxyphenyl, 3-hydroxymethyfphenyl, 4-hydroxymethylphenyl, 4-
carboxyphenyl, 4-methylphenyl, 4-methylthiophenyl, 4-methoxyphenyl. 3,4-
dimethoxyphenyl, 4-methoxycarbonyi, 4-methoxycarbonylphenyJ, 3-
trifluoromethylphenyi, 4-aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-
nrtrophenyl. 4-cyanophenyl, 4-formylphenyl, benzyioxy, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-furyl, 3-thienyl, N-oxo-2-pyridinyl, 1-imidazolyl, 5-(1-benzyl-2-
More preferably still, R4 is selected from the
group consisting of 5-brorno, 2-hydroxy, 6-hydroxy, 4-carboxy, phenyl, 4-
hydroxyphenyl, 3-hydroxymethylphenyl. 4-hydroxymethyphenyl,, 4-
carboxyphenyl, 4-methyfphenyl, 4-methyithiophenyl, 4-methoxyphenyi. 3,4-
dimethoxyphenyl, 4-methoxycarbonyl, 4-methoxycarbonylphenyl, 3-
trifluoromethylphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 3-nitrophenyl, 4-
nltrophenyl, 4-cyanophenyl, 4-formylphenyl, benzyloxy, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, N-oxo-2-pyridinyi, 3-thienyl. 2-furyl, 14midazolyl. 5-(1-benzyl-2-
methylimidazoly!), 5-{1,2-dimethylimidazotyl), 3,4-methylenedioxyphenyl,
preferably still, R4 is selected from the group consisting of 6-hydroxy, 4-
carboxy, phenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyi, 4-methylphenyl, 4-
methylthiophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxycarbonyl,
3-trifluoromethylphenyl, 3-nitrophenyl, 4-nitrophenyl, 2-pyridinyl, 3-pyridinyl, 4-
pyridinyl, N-oxo-2-pyridinyl, 3-thienyl, 5-(1-benzyl-2-methylimidazolyl), 5-(1,2-
In a preferred embodiment c is 0. In another preferred embodiment a is
an integer from 0 to 1.
In an embodiment of the present invention, Y is selected from the group
consisting of -C1-C4alkyl, -C(S)-, -C(O)- -C(O)O(C1-C4afoyl)-, -C(O)-(C1-
C4alkyl)-, -C(O)C2-C4alkenyl)-, C(O)-(C3-C7cycloalkyl)- and -C(O)NH-(C1-
C3alkyl)-. Preferably, Y is selected from the group consisting of -CH2. -C(S)-,
-C(O)-, -C(O)O-CH2-, -C(O)-CH2CH2, -C(O)-CH=CH-, -C(O)NH-CH2 -C(O)-
cyclopropyl and -C(O)CH2-. More preferably, Y is selected from the group
consisting of -C(O)-, -C(O)O-CH2-, -C(O)-CH2CH2 -C(O)-CH=CH-, and -C(O)-
cyclopropyl. More preferably still, Y is selected from the group consisting of -
C(O)-, -C(O)O-CH2- and -C(O)-CH=CH-. Most preferably, Y is selected from
the group consisting of -C(O)- and -C(O)O-CH2;
The term "alkyl", whether used alone or as part of a substituent group,
shall mean straight or branched chain alkanes of one to ten carbon atoms, or
any number within this range. For example, alkyl radicals include, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-
methyi)butyl, 2-pentyl, 2-methylbutyi, neopentyl, n-hexyl and 2-methyipentyi.
Similarly, aikenyl and alkynyl groups include straight and branched chain
alkenes and alkynes having two to ten carbon atoms, or any number within this
range.
The term "alkoxy" shall denote an oxygen ether radical of the above
described straight or branphed chain alkyl group. For example, alkoxy radicals
include methoxy, ethoxy, h-propoxy, n-butoxy, sec-butoxy, tert-butoxy, and the
like.
The term "aryl indicates an aromatic group such as phenyl, naphthyl, and
the like.
The term "aralkyl" denotes an alkyl group substituted with an aryl group
For example, benzyl, phenylethyl, and the like. Similarly, the term "aralkenyl"
denotes an aikenyl group substituted with an aryl group, for example
phenytethyienyl, and the like.
The term "heteroaryl" as used herein represents a stable five or six
membered monocydic aromatic ring system containing one to three
heteroatoms independently selected from N, O or S; and any nine or ten
membered bicyclic aromatic ring system containing carbon atoms and one to
four heteroatoms independently selected from N, O or S. The heteroaryl group
may be attached at any heteroatom or carbon atom which results in the
creation of a stable structure. Examples of heteroaryl groups include, but are
not limited to pyridinyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl,
pyrazolyl.pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,
benzofuranyl, benzothienyi, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl,
benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyt, isoquinolinyl,
purinyl. Preferred heteroaryl groups include pyrimidinyl, pyridinyl, furyl,
imidazolyl, benzofuryj and thiazoiyl.
The term "cydoalkyl" as used herein represents a stable three to eight
membered monocyclic ring structure consisting of saturated carbon atoms.
Suitable examples include cyclopropyl, cyclobutyi, cydopentyl, cyclohexyl,
cyctoheptyt and cyctooctyl.
The term "heterocycloalkyl" represents a stable saturated or partially
unsaturated, three to eight membered monocyclic ring structure containing
carbon atoms and one to four, preferably one to two, heteroatoms independently
selected from N, O or S; and any stable saturated, partially unsaturated or
partially aromatic, nine to ten membered bicyclic ring system containing carbon
atoms and one to four heteroatoms independently selected from N, O or S. The
heterocycloalky! may be attached at any carbon atom or heteroatom which
results in the creation of a stable structure. Suitable examples of
heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,
morphol'myl, dithianyl, trithianyl. dioxolanyi, dioxanyl, thiomorphoiinyl, 3,4-
methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-{1,4]-dioxin-6-yl,
2,3-dihydro-furo(2f3-b]pyridinyl. 1,2-(methylenedioxy)cyclohexane, indanyl, 2-
oxa-bicyclop.2.1Jheptanyl, and the like. Preferred heterocycloalkyl groups
include piperidinyl, pyrrolidinyl, morpholinyl, indanyl, 2-oxa-bicyclo[2.2,1]heptanyl,
3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo-[1, A]-
dioxin-6-yl.
As used herein, the notation shall denote the presence of a stereogenic
center.
It is intended that the definition of any substituent or variable at a
particular location in a molecule be independent of its definitions elsewhere in
that molecule. It is understood that substituents and substitution patterns on
the compounds of this invention can be selected by one of ordinary skill in the
art to provide compounds that are chemically stable and that can be readily
synthesized by techniques known in the art as well as those methods set forth
herein. It is further intended that when b or c is >1, the corresponding RA or R5
substituents may be the same or different.
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomersy Where the
compounds possess two or more cniral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds may exist as
polymorehs and as such are intended to be included in the presenTlrTvention.
In addition, some of the compounds may form solvates with water (i.e..
hydrates) or common organic solvents, and such solvates are also intended to
be encompassed within the scope of this invention.
Under standard nomenclature used throughout this disclosure, the
terminal portion of the designated side chain is described first, followed by the
adjacent functionality toward the point of attachment. Thus, for example, a
"phenylC1-C6 alkylamiriocarbonylC1-C6alkyl" substituent refers to a
group of the formula
The term "sexual dysfunction" as used herein, includes mate sexual
dysfunction, male erectile dysfunction, impotence, female sexual dysfunction,
female sexual arousal dysfunction and female sexual dysfunction related to
blood flow and nitric oxide production in the tissues of the vagina and clitoris.
The term "subject" as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of treatment,
observation or experiment.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue system, animal or human that is being sought by
a researcher, veterinarian, medicai doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
For use in medicine, the sate of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." Other salts may, however, be
useful in the preparation of compounds according to this invention or of their
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts
of the compounds include acid addition salts which may, for example, be
formed by mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid,
fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid,
tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the
compounds of the invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts, e.g., sodium or
potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts;
and salts formed with suitable organic ligands, e.g., quaternary ammonium
salts. Thus, representative pharmaceutically acceptable salts include the
following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate.
borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavularvate,
pitrate, dihydrochloride, edetate, edisytete, estolate, esylate, fumarate.
gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isethionate, lactate, lactobionate, laurate, malate, mateate, mande'.ate,
mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate,
nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosyiate,
triethiodide and valerate.
The present invention includes within its scope prodrugs of the
compounds of this invent on. In general, such prodrugs wilt be functional
derivatives of the compounds which are readily convertible in vivo into the
required compound. Thus, in the methods of treatment of the present
invention, the term "administering" shall encompass the treatment of the
various disorders described with the compound specifically disclosed or with a
compound which may not be specifically disclosed, but which converts to the
specified compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
Abbreviations used in the specification, particularly the Schemes and
Examples, are as follows:
Compounds of formula (I) wherein R3 is hydrogen, may be prepared
according to two alternative processes from a suitably substituted compound of
formula (III):
wherein R1 R2, R5 and c are as previously defined, which is selected
and used as a starting reagent
The conmpound of formulaa (III) is a known compound or compound
prepared by known methods for example according to the process outlined in
Scheme 1 below:
Accordingly, a compound of formula (IV), a known compound or compound
produced by known methods, is reacted with a suitably substituted aldehyde of
formula (V), In an organic solvent such as DCM, THF, toluene, and the like, in the
presence of an acid catalyst such as TFA, tosic acid, and the like, to produce the
corresponding compound of formula (ill).
Generally, in the first of two alternative processes, the compounds of
formula (I) may be prepared by reacting a suitably substituted compound of
formula (III) to produce the corresponding substituted pyrrolopyridinone
derivative. In the second process of two alternative processes, the compounds
of formula (I) may be prepared by initially reacting a suitably substituted
compound of formula (III) to form a tricyclic pyrrolopyridinone moiety, followed
by introduction of additional substttuents. This second process is particularly
preferred for preparation of compounds of formula (I) wherein Y is -C(S), -
C(O)O-RAor-C(O)RA.
More specifically, compounds of formula (I) wherein R3 is hydrogen, may
be prepared from a suitably substituted compound of formula (111) according to
the processes outlined in Scheme 2.
In the first process, a suitably substituted compound of formula (III) is
reacted with a suitably substituted compound of formula (VI), wherein X is
halogen, hydroxy, tosylate, mesylate, p-nitrophenoxide or the like, preferably X
is halogen, hydroxy or p-nitrophenoxide, in an organic solvent, such as DMF,
THF, DCM, toluene, and the Sike. to produce the corresponding compound of
formula (VII). For compounds of formula (I) wherein (Y)a is (Y)o (i.e. where a is
0 such that Y is absent), the reaction mixture is preferably heated to a
temperature of greater than or equal to about 100oC. For compounds of
formula (I) wherein (Y)a is (Y)o (i.e. where a is 0 such that Y is absent) and
is yridinyl the reaction mixture is preferably catalyzed at a temperature
in the range of about 30-120°C with a catalyst such as Pd(OAc)2, Pd2dba3,
Pd(dppf)Cl2, and the tike, in an organic solvent such as 1,4-dioxane, THF,
DMF, DCM, toluene, and the like, to yield the corresponding compound of
formula (VII).
The compound of formula (VII) is next reacted with an oxidizing agent
such as NalO4, KO2, singlet oxygen, oxygen gas. ozone, and the like,
preferably oxygen gas applied at about atmospheric pressure, to produce the
corresponding pyrrolopyridinone derivative of formula (la). When the oxidizing
agent is oxygen gas, the reaction is carried out in the presence of a base such
as sodium hydride, potassium-t-butoxide, and the like.
In the alternative process outlined in Scheme 2, a suitably substituted
compound of formula (III) is first reacted with an oxidizing agent such as NalC4,
KO2, singlet oxygen, oxygen gas, ozone, and the like, preferably oxygen gas
applied at about atmospheric pressure, to produce the corresponding
compound of formula (VIII). When the oxidizing agent is oxygen gas, the
reaction is carried out in the presence of a base such as sodium hydride,
potassium-t-butoxide, and the like.
The compound of formula (VIII) is next reacted with a suitably
substituted compound of formula (VI), where X is hafogen, hydroxy, tosylate,
mesylate, p-nitrophenoxide or the like, preferably X is halogen, hydroxy or p-
nitrophenoxide, in an organic solvent such as DMF, THF, DCM, toluene, and
the like, optionally in the presence of a catalyst such as DMAP, to produce the
corresponding substituted pyrrolopyridinone of formula (la). For compounds of
formula (I) wherein (Y)a is (Y)o (i.e. where a is 0 such that Y is absent), the
reaction mixture is preferably heated to a temperature of great than or equal to
about 50oC. For compounds of formula (VIII) wherein (Y)a is (Y)o (i.e. where a
is 0 such that Y is absent) and is pyridinyl, the reaction mixture is
preferably catalyzed at a temperature in the range of about 30-120°C with
catalyst such as Pd(OAc)2, Pd2dba3, Pd(dppf)Cl2. and the like, in an organic
solvent such as 1,4-dioxane, THF, DMF, DCM, toluene, and the like, to yield
the corresponding compound of formula (la).
Klternatively, for compounds of formula (I) wherein (Y)a is CH2 and
is unsubstituted or substituted aryl or unsubstituted or substituted
heteroaryl, the compound of formula (VIII) may be prepared by reacting a
compound of formula (la) with hydrogen gas, where the hydrogen gas is
applied at a pressure in the range of about atmospheric pressure to about 80
p.s.i., in the presence of a catalyst such as Pd, R, palladium on carbon, and
the like, in an organic solvent such as methanol, ethanol, ethyl acetate, and the
like. The compound of formula (VIII) may then be further functionalized as
described above.
Compounds of formula (I) wherein b is 1 (i.e. wherein the group
represented by is substituted with one R4 substituent) may be prepared
from a suitably substituted compound of formula (III) according to three
alternative processes.
In the first process, a suitably substituted compound of formula (III) is
initially converted to the corresponding pyrrolopyridinone according to the
process outlined in Scheme 2, followed by two step substitution at the pyrrole
nitrogen, as outlined in Scheme 3.
Specifically, the compound of formula (VIII) is reacted with a suitably
substituted compound of formula (IX), wherein X is a halogen, in the presence
of a base such as TEA, DIPEA, and the like, in an organic solvent such as
DMF, DCM, THF, and the like, preferably at a temperature in the range of
about 20 to about 150°C, to yield the corresponding compound of formula (X).
The compound of formula (X) is reacted with a suitably substituted
boronic acid of formula (XI) or a suitably substituted tributyl-stannane of
formula (XII), to yield the corresponding compound of formula (Ib). When
selected reagent is a boronic acid of formula (XI), the compound of formula (X)
is reacted in an organic solvent such as DMF, THF, dioxane, and the like, in
the presence of a catalyst such as Pd(Ph3P)4, Pd(dppf)(OAc)2, and the like,
preferably at a temperature in the range of about 80-150°C. When the
selected reagent is a tributyl-stannane of formula (XII), the compound of
formula (X) is reacted in a solvent such as DMF, in the presence of a catalyst
such as Pd(dppf)(OAc)2.
In the second process, the compound of formula (III) is initially
substituted with a bromo-substituted then converted to the
More particularly, a suitably substituted compound of formula (HI) is
reacted with a suitably substituted compound of formula (XIII), wherein X is a
halogen, in the presence of a base such as TEA. DIPEA, and the like, in an
organic solvent such as DMF, toluene, and the like, preferably at a temperature
ini the range of about 100 to about 150°C, to yield the corresponding
compound of formula (XIV).
The compound of formula (XIV) is reacted with an oxidizing agent such
as NalO4, KO2, singlet oxygen, oxygen gas, ozone, and the like, preferably
oxygen gas applied at atmospheric pressure, to produce the corresponding
compound of formula (XV).
the compound of formula (XV) is reacted with a suitably substituted
boronic acid of formula (XI) or a suitably substituted tributyl-stannane of
formula (XII), to yield the corresponding compound of formula (Ic). When
selected reagent is a baronic acid of formula (XI), the compound of formula
(XV) is reacted in an organic solvent such as DMF, dioxane, water, and the
like, in the presence of a catalyst such as Pd(Ph3P)4, Pd(dppf)(OAc)2, and the
like, preferably at a temperature in the range of about 80 to about 160°C.
When the selected reagent is a tributyl-stannane of formula (XII), the
compound of formula (XV) is reacted in a solvent such as DMF, TEA, and the
like, in the presence of a catalyst such as Pd(dppf)(OAc)2.
More particularly, the compound of formula (XIV) is reacted with a
suitably substituted boronic acid of formula (XI) or a suitably substituted
tributyl-stannane of formula (XII), to yield the corresponding compound of
formula (XVI). When selected reagent Is a boronic acid of formula (XI), the
compound of formula (XIV) is reacted in an organic solvent such as DMF,
dioxane, water, and the like, in the presence of a catalyst such as Pd(Ph3P)4,
Pd(dppf)(OAc)2, and the like, preferably at a temperature in the range of about
80 and about 120°C. When the selected reagent is a tributyl-stannane of
formula (XII), the compound of formula (XIV) is reacted in a solvent such as
DMF, dioxane, and the like, in the presence of a catalyst such as
Pd(dppf)(OAc)2.
The compound of formula (XVI) is reacted with an oxidizing agent such
as NalO4, KO2, singlet oxygen, oxygen gas, ozone, and the like, preferably
oxygen gas applied at atmospheric pressure, to produce the corresponding
compound of formula (Ic).
Compounds of formula (I) wherein b is an integer selected from 2, 3 and
4, (i.e. wherein the is substituted with 2, 3 or 4 R4 groups) may similarly
be prepared according to the processes outlined in Schemes 3,4 and 5, with
appropriate substitution of the containing reagent with the
corresponding reagent wherein the is substituted with 2, 3 or 4 bromine
groups, which bromine groups are sequentially reacted to incorporate the
desired R4 groups.
Compounds of formula (I) wherein (Y)a is C(O) may be prepared
according to two alternative processes. In the first process, a pyrrolopyridinone
compound of formula (VIII) is initially substituted with a suitably selected
carboxylic acid or acid chloride, followed by further substitution of the
with the R4 substituent, as outlined in Scheme 6.
More particularly, a suitably substituted pyrrolopyridinone compound of
formula (VIII) is reacted with a suitably substituted carboxylic acid or acid
chloride of formula (XVIII), wherein W is OH or Cl, in an organic solvent such
as DMF, THF, dioxane, and the like, and when W is OH in the presence of a
catalyst such as PyBrop, DCC, and the like, and when W is Cl in the presence
of a base such as TEA, DIPEA, and the like, preferably at a temperature in the
range of about 0 to about 30°C, to yield the corresponding compound of
formula (XVIII).
The compound of formula (XVIII) is reacted with a suitably substituted
boronic acid of formula (XI), in an organic solvent such as DMF, dioxane,
water, and the like, in the presence of a catalyst such as Pd(Ph3P)4, and the
like, preferably at a temperature in the range of about 80 to about 120°C, to
yield the corresponding compound of formula (Id).
In the second process, a suitably substituted compound of formula (III)
is initially converted to the corresponding pyrrolopyridinone, followed by two
step substitution using a suitable selected carboxylic acid, followed by boronic
acid or stannane, as outlined in Scheme 7.
More particularly, a suitably substituted compound of formula (III) is
reacted with a suitably substituted carboxylic acid of formula (XVII), wherein W
is halogen or hydroxy, in an organic solvent such as TEA, DIPEA, and the like,
preferably at a temperature in the range of about 80 to about 130°C, to yield
the corresponding compound of formula (XIX).
The compound of formula (XIX) is reacted with a suitably substituted
boronic acid of formula (XI) or a suitably substituted tributyl-stannane of
formula (XII), to yield the corresponding compound of formula (XX). When
selected reagent is a boronic acid of formula (XI), the compound of formula
(XIX) is reacted in an organic solvent such as DMF, dioxane, water, and the
like, in the presence of a catalyst such as Pd(Ph3P)4, Pd(dppf)(OAc)2, and the
like, preferably at a temperature in the range of about 80 to about 120°C.
When the selected reagent is a tributyl-stannane of formula (XII), the
compound of formula (XIX) is reacted in a solvent such as DMF, dioxane, and
the like, in the presence of a catalyst such as Pd(dppf)(OAc)2.
The compound of formula (XX) is reacted with an oxidizing agent such
as NalO4, KO2, singlet oxygen, oxygen gas, ozone, and the like, preferably
KO2, to produce the corresponding compound of formula (Id).
Compounds of formula (I), wherein R3 is other than hydrogen, and
compounds of formula (II), may be prepared according to the process outlined
in Scheme 8.
More specifically, a compound of formula (la) is reacted with a suitably
substituted compound of formula (XXI), where X is halogen, hydroxy, tosylate,
mesylate, and the like, preferably X is halogen, in an organic solvent such as
THF, DMF, dichloromethane, toluene, and the like, preferably THF or DMF, to
yield a mixture of the corresponding substituted compound of formula (le) and
the corresponding substituted compound of formula (II). When in the
compound of fonmula (XXI), X Is halogen, the reaction is preferably carried out
in the presence of an organic or inorganic base such as triethylamine,
diisopropylethylamine, potassium carbonate, sodium hydride, sodium
hydroxide and the like.
The compounds of formula (le) and (II) are preferably separated by
known methods such as recrystailization, column chromatography, HPLC, and
the like.
Compounds of formula (VII) wherein Ya is Yo (i.e. wherein Y is absent) and
is 2-(4-substituted)thiazolyl, may be prepared according to a process as
outlined in Scheme 9.
Accordingly, a suitably substituted compound of formula (III) is reacted with
Fmoc-NCS, in an organic solvent such as DCM, DMF, THF. and the like,
preferably at room temperature, to produce the corresponding compound of
formula (XXII).
The compound of (XXII) is reacted with 20% piperidine, in an alcohol such
as methanol, ethanol, and the like, to produce the corresponding amine of formula
(XXIII).
The amine of formula (XXIII) is reacted with a suitably substituted a-halo
methyl ketone of formula (XXIV), in the presence of an organic solvent or mixture
such as DMF, ethanokdioxane, and the like, in the presence of a base such as
TEA, DIPEA, and the like, preferably at a temperature of about 70°C, to produce
the corresponding compound of formula (Vlla).
Specific diastereomers of the compounds of formula (I),, more
particularly compounds of formula (I) wherein R1 is hydrogen and an R-
configuration at the chiral center of the R2 bond to the pyrrolopyridinone is
desired, may be prepared according to the process outlined in Scheme 10.
Accordingly, a suitably substituted compound of formula (XXV), a known
compound or compound prepared by known methods, wherein R1 is hydrogen
and Ar is an aryi group, preferably naphthyl, more preferably 1-naphthyl, is
reacted with a suitably substituted aldehyde, a compound of formula (XXVI), in
an organic solvent such as p-xyiene, o-xylene, toluene, DCM, and the like, at a
temperature in the range of about 25-270°C, under aprotic or protic conditions,
to yield a mixture of the corresponding diastereomers, compounds of formula
(XXVII) and (XXVIII).
The R-diastereomer, the compound of formula (XXVII) is separated from
the compound of formula (XXVIII) by recrystallization or silica gel
chromatography.
The compound of formula (XXVII) (the S-diastereomer) is converted to
the desired R-diastereomer, the compound of formula (XXVIII), by stirring the
compound of formula (XXVII) in an acid such as TFA, HCI, TsOH, and the like,
in the presence of an organic solvent such as CH2CI2, DCM, 1m4-dioxane, and
the like, to yield the desired R-diastereomer, the compound of formula (XXVIII).
The compound of formula (XXVIII) is reacted with an oxidizing agent
such as oxygen gas, singlet oxygen, KO2, NalO4, ozone, and the like,
preferably oxygen gas at about atmospheric pressure, to yield the
corresponding compound of formula (XXIX). When the oxidizing agent is
oxygen gas, the reaction is carried out in the presence of a base such as
sodium hydride, potassium-t-butoxide, and the like, in an organic solvent such
as DMF, DMSO, NMP, and the like.
The compound of formula (XXIX) is reacted with a reducing agent such
as hydrogen gas, in the presence of a catalyst such as palladium on carbon, in
a polar solvent such as methanol, ethanol, and the like, to yield the
corresponding compound of formula (Villa).
The compound of formula (Villa) may then be further reacted to yield the
corresponding compound of formula (I) according to the process outlined in
Scheme 3 above.
For compounds of formula (I), wherein R1 is other than hydrogen, a second
chiral center will exist at the bond of the R1 group to the pyrrolopyridinone. If a
specific orientation of the R1 group is present in the starting reagent, the
compound of formula (XXV) in Scheme 10 above, its orientation will impact the
conversion of diastereomers.
Where the processes for the preparation of the compounds according to
the invention give rise to a mixture of stereoisomers, these isomers mav be
separated by conventional techniques such as preparative chromatography.
The compounds may be prepared in racemic form, or individual enantiomers
may be prepared by enantioselective synthesis, by resolution or from
enantiomerically enriched reagents. The compounds may, for example, be
resolved into their component enantiomers by standard techniques, such as
the formation of diastereomeric pairs by salt formation with an optically active
acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid
followed by fractional crystallization and regeneration of the free base. The
compounds may also be resolved by formation of diastereomeric esters,
amides or amines, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved using a chiral
HPLC column.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. This may be achieved by
means of conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press,
1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Oraanic
Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the art.
The utility of the compounds to treat sexual dysfunction can be
determined according to the procedures described in Example 95, 96 and 97
herein.
The present invention therefore provides a method of treating sexual
dysfunction, more particularly male erectile dysfunction in a subject in need
thereof which comprises administering any of the compounds as defined
herein in a quantity effective to treat ED. The compound may be administered
to a patient by any conventional route of administration, including, but not
limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and
parenteral. The quantity of the compound which is effective for treating ED is
between 0.01 mg per kg and 20 mg per kg of subject body weight.
The present invention also provides pharmaceutical compositions
comprising one or more compounds of this invention in association with a
pharmaceuticaliy acceptable carrier. Preferably these compositions are in unit
dosage forms such as tablets, pills, capsules, powders, granules, sterile
parenteral solutions or suspensions, metered aerosol or liquid sprays, drops,
ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal,
sublingual or rectal administration, or for administration by inhalation or
insufflation./ Alternatively, the composition may be presented in a form suitable
for once-weekly or once-monthly administration; for example, an insoluble salt
gf the active compound,such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection, for preparing solid
compositions such as tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g. conventional tableting ingredients such as com
starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalciurn phosphate or gums, and other pharmaceutical diluents, e.g. water, to
form a solid preformulation composition containing a homogeneous mixture of
a compound of the present invention, or a pharmaceuticaliy acceptable salt
thereof. When referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is dispersed evenly
throughout the composition so that the composition may be readily subdivided
into equally effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit dosage forms of
the type described above containing from 1 to about 1000 mg of the active
ingredient of the present invention. The tablets or pills of the novel
composition can be coated or otherwise compounded to provide a dosage form
affording the advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter being in
the form of an envelope over the former. The two components can be
separated by an enteric layer which serves to resist disintegration in the.
stomach and permits the inner component to pass intact into the duodenum or
to be delayed in release. A variety of material can be used for such enteric
layers or coatings, such materials including a number of polymeric acids with
such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by injection include,
aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and
flavoured emulsions with edible oils such as cottonseed oil, sesame oil,
coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Suitable dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate, dextran,
sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or
gelatin.
The method of treating sexual dysfunction, more particularly male erectile
dysfunction described in the present invention may also be carried out using a
pharmaceutical composition comprising any of the compounds as defined herein
and a pharmaceuticaliy acceptable carrier. The pharmaceutical composition
may contain between about 1 mg and 1000 mg, preferably about 1 to 200 mg, of
the compound, and may be constituted into any form suitable for the mode of
administration selected. Carriers include necessary and inert pharmaceutical
excipients, including, but not limited to, binders, suspending agents, lubricants,
flavorants, sweeteners, preservatives, dyes, and coatings. Compositions
suitable for oral administration include solid forms, such as pills, tablets, caplets,
capsules (each including immediate release, timed release and sustained
release formulations), granules, and powders, and liquid forms, such as
solutions, syrups, elixers, emulsions, and suspensions. Forms useful for
parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may be
administered in divided doses of two, three or four times daily. Furthermore,
compounds for the present invention can be administered in rntranasal form via
topical use of suitable intranasal vehicles, or via transdermal skin patches well
known to those of ordinary skill in that art. To be administered in the form of a
transdermal delivery system, the dosage administration will, of course, be
continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover,
when desired or necessary, suitable binders, lubricants, disintegrating agents
and coloring agents can also be incorporated into the mixture. Suitable binders
include, without limitation, starch, gelatin, natural sugars such as glucose or
beta-lactose, com sweeteners, natural and synthetic gums such as acacia,
tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the
like.
The liquid forms may include suitably flavored suspending or dispersing
agents such as the synthetic and natural gums, for example, tragacanth, acacia,
methyl-cellulose and the like. For parenteral administration, sterile suspensions
and solutions are desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the
form of liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from
a variety of phospholipids, such as cholesterol, stearylamine or
phophatidylcholines.
Compounds of the present invention may also be delivered by the use of
monoclonal antibodies as individual earners to which the compound molecules
are coupled. The compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer, poiyhydroxypropyimethaciylarnidephenol,
polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted
with palmitoyl residue. Furthermore, the compounds of the present invention
may be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacryiates and cross-linked or amphipathic block
copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing
compositions and according to dosage regimens established in the art whenever
treatment of sexual dysfunction, more particularly male erectile dysfunction is
required.
The daily dosage of the products may be varied over a wide range from 1
to 1,000 mg per adult human per day. For oral administration, the compositions
are preferably provided in the form of tablets containing 1.0, 5.0, 10.0,15.0, 25.0,
50.0,100,250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the patient to be treated- An effective amount of the
drug is ordinarily supplied at a dosage level of from about 0,01 mg/kg to about 20
mg/kg of body weight per day. Preferably, the range is from about 0.1 mg/kg to
about 10 mg/kg of body weight per day, and especially from about 0.1 mg/kg to
about 3 mg/kg of body weight per day.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
administration, the strength of the preparation, the mode of administration, and
the advancement of the disease condition. In addition, factors associated with
the particular patient being treated, including patient age, weight, diet and time of
administration, will result in the need to adjust dosages.
The following Examples are set forth to aid in the understanding of the
invention, and are not intended and should not be construed to limit in any way
the invention set forth in the claims which follow thereafter. Unless otherwise
indicated, 1H NMRs were run on a Bruker instrument.
EXAMPLE 1
1-(3,4-Methylenedioxvphenyl)-2-benzyl-2,3.4,9-tetrahydro-1H-6-carboline
To a solution of the 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-
1H-ß-carboline (prepared according to the process as disclosed in
WO97/43287. Intermediate 7, page 24) (7.37 g, 25 mmol) in dry DMF (25 mL)
was added triethylamine (3.52 mL, 25 mmol) and benzyl bromide (3.00 mL, 25
mmol). The mixture was stirred at ambient temperature overnight and added
dropwise to a solution of sodium hydroxide (25 mmol) in water (200 mL). A
precipitate was formed, collected by vacuum filtration, washed with water (2 x
50 mL), and dried in vacua overnight to yield the product as a freely flowing
pale yellow powder.
MS (m/z) 383 (MH+)
1H NMR (CDCI3) 5 2.57-2.89 (series of m, 3H), 3.18-3.23 (m, 1H), 3.33
(d, J = 13.7 Hz, 1H), 3.63 (d, J = 13.7 Hz, 1H). 4.55 (s, 1H), 5.94 (nd, J - 2.2
Hz, 2H), 6.77-7.52 (series of m, 13H).
EXAMPLE 1A
f RV1 -(3.4-MethvlenedioxvphenvlV2-benzvl-2.3.4.9-tetrahvdro-1 H-B-carboHne
Following the procedure as described in Example 1, (R)-1-(3,4,-
methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-B-carboline was reacted to
produce the title compound.
MS (m/z) 383 (MH+)
EXAMPLE 2
1-(2.3-Dihvdrobenzofuran-5-vlV2-benzvl-2.3.4.9-tetrahvdro-1H-ß-carbortne
The title product was prepared according to the process described in
Example 1 using 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-B-
carboline as the starting reagent.
MS (m/z) 381 (MH+)
1H NMR (CDCb) 8 2.59-2.90 (series of m, 3H), 3.13-3.24 (m, 3H). 3.33
(d, J = 13.5 Hz, 1H), 3.93 (d, J = 13.5 Hz. 1H), 4.56 (t, J = 8.6 Hz, 2H), 6.75 (d,
J = 8.1 Hz, 1H), 7.05-7.35 (series of m, 10H), 7.49-7.52 (m, 1H)
EXAMPLE 2A
(R V1 -f 2.3-Dihvdrobenzofuran-5-vl V2-benzvt-2.3.4.9-tetrahvdro-1 H-ß-carboline
Following the procedure as described in Example 2, (R)-1-(2,3-
dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-ß-carboline was reacted to
produce the title compound.
MS (m/z) 381 (MH+)
[a} = -56.9° (c=0.62, CH3OH)
EXAMPLE 3
1.2.3.4-Tetrahvdro-2-benzvl-3-(3,4-methvlenedioxvDhenyl)-9H-Dvrrolo-[3.4-
blquinolin-9-one (#54)
1 -(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-4etrahvdro-1 H-ß-
carboline (0.79 g, 2.0 mmol) (prepared as in Example 1) was dissolved in dry
DMF (15 mL). Potassium t-butoxide (0.56 g, 5.0 mmol) was added, followed
by oxygen, bubbled in via syringe needle. The mixture was maintained at room
temperature for one hour and then poured onto a mixture of 1N HCI (5 mL),
water (35 mL) and ethyl acetate (35 mL). A fluffy yellow precipitate was
collected, the organic layer removed, and the aqueous solution extracted with
ethyl acetate (15 mL). The extracted layer was agitated and set aside
overnight. The following day an additional quantity of product (as a precipitate)
was collected. Drying of the combined solids yielded the product as a yellow
powder.
MS (m/z): 397 (MH+)
1H-NMR (DMSO-dS) 6 3.52 (dd, J = 11.9, 3 Hz, 1 H), 3.63 (d, J - 13.2
Hz, 1 H). 3.84 (d, J - 13.2 Hz, 1 H), 3.93 (dd, J = 11.9, 3 Hz, 1 H), 5.10 (s, 1
H), 6.05 (nd, J = 3.4 Hz, 2 H), 6.98 (s, 3 H), 7.26-7.36 (m. 6 H), 7.54-7.59 (m, 2
H). 8.10 (d, J = 8 Hz, 1 H), 11.42 (s, 1 H).
EXAMPLE 3A
(R)-1.2.3.4-Tetrahvdro-2-benzvl-3-f3.4-methvlenedioxvDrtenvlV-9H-Dvrrolo-r3.4-
biQuinolin-9-one (#67)
Following the procedure as described in Example 3, (R)-1-(3,4-
Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1 H-p-carboline was reacted
to produce the title compound.
MS (m/z) 397 (MH+)
EXAMPLE 4
1.2l3.4-Tetrahvdro-2-benzyl-3-(2.3-dihydrobenzofuran-5-yl).9H-pyrrolo-[3,4-
btauinolin-9-one (#60)
1 -(2,3-Dihydrobenzofuran-5-yl)-2-benzy1-2,3,4,9-tetrahydro-1 H-(J-
carboline (prepared as in Example 2) (3.10 g, 8.15 mmol) was dissolved in dry
DMF (20 mL). Potassium t-butoxide (2.29 g, 20.38 mmol) was added, followed
by oxygen, bubbled in via syringe needle. The solution was stirred for 1.5 h.
To the reaction mixture was added a solution of HCI in ether (10 mL, 2M) and
the solution dripped into rapidly stirring water. The resulting suspension was
stirred overnight. A brown solid was filtered off and washed with water. The
filtrate was neutralized with 1N NaOH, resulting in a yellow precipitate. The
solid was filtered, washed with water, dried briefly, and partially dissolved in
THF/methanol. The precipitate solid was filtered and washed with ether to
yield the product as a pale yellow solid.
MS (m/z) 395 (MH+)
1H NMR (DMSO-d6) 5 3.19 (t, J = 8.7 Hz, 2H), 3.53 (d, J = 11.8 Hz, 1H),
3.61 (d, J = 12.2 Hz, 1H), 3.82 (d, J = 12.2 Hz, 1H), 3.92 (d, J - 11.8 Hz, 1H),
4.55 (t, J= 8.7 Hz, 2H), 5.08 (s. 1H), 6.81 (d, J = 8.1 Hz, 1H), 7.16-7.59 (series
of m, 9H), 8.10 (d, J = 8.1 Hz, 1H), 11.42 (s, 1H).
EXAMPLE 4A
(RV1.2.3.4-Tetrahvdro-2-benzvl-3-(2.3-dihvdrobenzofuran-5-vlV9H-Pvrrolo-
f3.4-blQuinolin-9-one (#77)
Following the procedure as described in Example 4, (R)-1-(2,3-
Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4f9-tetrahydro-1 H-B-carboline was
reacted to produce the title compound.
MS (m/z) 395 (MH+)
[a] = -110.0° (c = 0.43. CH3OH); HPLC Chiralpak OD 0.46 x 25 cm,
0.1%DEA/ MeOH, Tr= 5.36 0 min.
EXAMPLE 5
1.2.3.4-Tetrahydro-3-(3.,4-methylenedioxyphenyl)-9H-pvrrolo-[3.4-blquinolin-9-
one. hvdrochloride salt (#4)
Method a: HCI Salt
To a suspension of 1,2,3,4-tetrahydro-2-benzyl-3-(3,4-
methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (prepared as in
Example 3) (1.12 g, 2.82 mmol) in methanoi (50mL) and 10% Pd/C (500 mg)
was added HCI in ether solution (1.41 ml_, 2N). The reaction mixture was
agitated under a hydrogen atmosphere (45 psi) in a Parr apparatus for 6 h.
The resulting solution was filtered through Celite and concentration in vacuo to
yield the product as a green solid.
MS(m/z)307(MH+)
1H NMR (DMSO-d6) 5 4.39-4.48 (m, 2H), 6.09 (broad s, 3H), 6.97-7.05
(m, 3H), 7.40 (t, J = 7.1 Hz, 1H), 7.60-7.71 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H),
9.68 (s, 1H), 11.13 (s, 1H).
Method B: Free Base
1-(3,4-methylenedioxyphenyl)-2.,3,4,9-tetrahydro-1H-ß-carboline, a
known compound, (prepared according to the process as disclosed in
WO97/43287, Intermediate 7, page 24) (15.35 g, 52.5 mmol) was dissolved in
dry DMF (90 mL). Potassium tert-butoxide (10.02 g, 89.3 mmol) was
introduced in one portion and the suspension was stirred until a clear solution
was obtained. Oxygen gas was then passed through the solution via a syringe
needle for 50 min. The reaction was quenched by the addition of glacial acetic
acid (5.11 mL, 89.3 mmol) and poured into diethyl ether (1L), which resulted in
a precipitate that was collected by filtration. The product was purified by flash
chromatography (0-50% EtOH/THF) to yield the product as a yellow powder.
MS (m/z): 307 (MH+)
1H-NMR (CD3OD) 5 4.18 (d, J = 13.7 Hz, 1 H), 4.36 (d, J = 13.7 Hz, 1
H), 4.92 (broad s, 2 H), 5.43 (s, 1 H), 5.92 (s, 1H), 6.74 (s, 1 H), 6.81 (s, 1 H),
7.36-7.70 (series of m, 4 H), 8.31 (d. J = 8.6 Hz, 1 H).
EXAMPLE 5A
(R)-1,2,3,4-Tetrahvdro-3-(3.4-methylenedioxyphenvl)-9H-pyrrolo-[3.4-
blquinolin-9-one. hydrochloride salt (#48)
Following the procedure as described in Example 5, Method A, (R)-
1,2l3,4-tetrahydro-2-benzyl-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-
b]quinolin-9-one was reacted to produce the title compound.
MS (m/z) 307 (MH+)
EXAMPLE 6
1.2.3.4-Tetrahvdro-3-(2.3-dihvdrobenzofuran-5-vlV9H-pvrrolo-f3.4-b]quinolin-9-
one. hvdrochloride salt
Method A: HCI Salt
The title product was prepared according to the process described in
Example 4 with substitution of appropriate reagents.
MS (m/z) 305 (MH+)
1H NMR (DMSO-d6) 6 3.17-3.20 (m, 2H), 4.38-4.60 (m, 4H), 6.10 (s, 1H)
6.85 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.40 (t, J = 7.1
Hz, 1H), 7.61 (t, J - 8.2 Hz, 1H), 7.68(d. J = 7.2 Hz, 1H). 8.17 (d, J = 8.9 Hz,
1H),9J1(s, 1H), 11.17 (S, 1H).
Method B: Free Base
1-(2,3-dihydro-5-benzofuranyl)-.@@@S^.g-tetrahydro-IH-p-carboline (1.06
g, 3.64 mmol), a known compound, (prepared according to the process as
disclosed in WO97/43287, Intermediate 10, page 25) was dissolved in dry
DMF (8 mL). Potassium tert-butoxide (829 mg, 7.38 mmol) was introduced in
one portion and the suspension was stirred until a clear solution was obtained.
Oxygen gas was then passed through the solution via a syringe needle for 50
min. The reaction was quenched by the addition of glacial acetic acid (0.42
mL, 7.34 mmol) and poured into diethyl ether (50 mL), which resulted in a
precipitate that was collected by filtration. The product was purified by flash
chromatography (0-50% MeOH/THF) to yield the product as a yellow powder.
MS (m/z): 305 (MH+)
1H-NMR (CD3OD) 8 3.17 (t, J = 8.7 Hz, 2H), 3.29-3.31 (m, 2 H), 4.18 (d,
J = 12.9 Hz, 1 H), 4.38 (d, J = 12.9 Hz, 1 H), 4.53 (t, J = 8.7 Hz, 2 H), 5.44 (s, 1
H), 6.74 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 7.13 (s, 1 H), 7.40 (t, J =
7.9 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 8.29 (d, J = 8.1
Hz, 1 H).
EXAMPLE 6A
(R)1.2.3.4-Tetrahydro-3-(2.3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3.4-
biouinolin-9-one. hydrochloride salt
Following the procedure as described in Example 6, Method A, (R)-
1,2,3.4-tetrahydro-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-
b]quinolin-9-one was reacted to produce the title compound.
MS (m/z) 305 (MH+)
[a} = +39.0° (C = 0.605,1% TFA in CH3OH)
EXAMPLE 7
(4.Pvridinyfimethyl-4-nitrophenylcarbonic acid ester
To a solution of 4-pyridinylcarbinol (50 mmol) and triethylamine (50
mmol) in dry dichloromethane (100 mL) was added a solution of 4-
nitrophenylchloroformate (50 mmol). The reaction mixture was stirred
overnight at ambient temperature, resulting in a yellow precipitate which was
removed by filtration, and concentrated. The semisolid residue was treated
with THF (50 mL) to form a white precipitate. The precipitate was collected by
filtration, concentrated and purified by flash chromatography (20% THF/CHCI3)
to yield the product as an orange solid.
MS (m/z) 275 (MH+)
1H NMR (CDCI3) 5 5.33 (s, 2H), 7.36 (d, J - 5.8 Hz, 2H), 7.41 (d, J = 9.4
Hz, 2H), 8.30 (d, J = 9.4 Hz, 2H), 8.68 (d, J = 5.8 Hz, 2H).
EXAMPLE 8
6-F2-(1-Moroholinotethoxv1-2-benzofurancarlx)xylic acid
A solution of 6-methoxy-2-benzofurancarboxylate methyl ester (868 mg,
4.52 mmol) in dry benzene was treated with triphenylphosphine (1.18 g, 4.52
mmol) and 1-(2-hydroxyethylHnorpholine (0.72 mL, 4.57 mmol) under an
argon atmosphere. DEAD (0.55 mL, 4.5 mmol) was added dropwise to the
reaction mixture, at room temperature. The solution was stirred overnight,
concentrated in vacua and the residue purified by flash chromatography (0-
10% MeOH/CHCl3).
The purified product was subjected to saponification for 3 h in a 1:1
mixture of methanol and aqueous 1N NaOH (80 mL) at reflux temperature.
The reaction mixture was neutralized with concentrated HCI and concentrated
to yield a residue which was triturated with methanol (20 mL). The resulting
salt was removed by filtration and concentrated to yield a second residue that
was similarly triturated with THF. The third residue was dried under vacuum to
yield the product as a yellow powder.
MS (m/z) 292 (MH+)
1H NMR (DMSO-d6) 5 2.57 (broad s, 4H), 2.87 (t, J = 5.3 Hz, 2H), 3.64
(t, J = 4.6 Hz, 4H). 4.23 (t, J = 5.5 Hz, 2H), 6.97 (dd, J = 8.7,2 Hz, 1H), 7.31 (s,
1H), 7.53 (s, 1H), 7.63 (d, J - 8.7 Hz, 1H).
EXAMPLE 9
1-(3.4-Methvlenedioxvphenvl)-2-ftert-butoxvcarbonvlV2.3.4,9-tefa-ahvdro-1H-6-
carboline
To a suspension of i-^^-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-
p-carboline (27.7 g, 94.8 mmol) (prepared according to the process as
disclosed in WO97/43287, Intermediate 7, page 24) in dry methanol (300 mL)
was added t-butylpyrocarbonate (25.0 g, 114 mmol). Shortly after the addition
of the pyrocarbonate, a clear solution was formed. The solution was stirred at
ambient temperature for 1 h, resulting in formation of a white precipitate. The
solid was collected by filtration, washed with a 1:1 mixture of diethyl
etherpentane, and dried in vacuo to yield the product as a white solid.
MS(m/z):415(MNa+)
1H-NMR (CDCb) 5 1.53 (s, 9H), 2.75-3.17 (series of m, 3 H), 4.22
(broad, 1 H), 5.93 (s, 2 H). 6.31 (broad, 1 H), 6.64-6.72 (m, 2 H), 6.80 (s, 1 H),
7.12-7.33 (series of m, 3 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.93 (broad, 1 H);
EXAMPLE 10
1-(3.4-Methvlenedioxvp|henvl)-2-(benzvloxvcarbonvl)-2.3.4.9-tetrahvdro-1H-(3-
carboline
To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-
carboline (9.11 g, 31.1 mmol) (prepared according to the process as disclosed
in WO97/43287, Intermediate 7, page 24) in dry dichloromethane (100 mL)
were added triethyiamine (8.80 mL, 63.1 mmol) and dimethyfaminopyridine (5
mg), followed by the dropwise addittan of benzylchloroformate (4.60 mL, 30.6
mmol) over a period of 30 min. The reaction mixture was stirred for 16 h,
transferred to a separatory funnel, washed with 2N HCI, brine, dried over
anhydrous magnesium sulfate and concentration in vacuo. Flash
chromatography yielded the product as a white solid.
MS(m/z):425(M-1)
1H-NMR (CDCI3) 5 2.78-2.95 (broad m, 2 H), 3.15-3.25 (m, 1 H), 4.40
(broad, 1 H), 5.14 (d, J = 12.3 Hz, 1 H), 5.22 (d, J = 12.3 Hz, 1H), 5.90 (s, 2 H),
6.35 (broad 1 H). 6.80 (broad, 3 H), 7.09-7.35 (series of m, 8 H), 7.53 (d, J =
7.6 Hz, 1 H), 7.70 (broad, 1 H);
EXAMPLE 11
1 -(3.4-DimethoxvDhenvlV-2.3.4.9-tetrahvdro-1 H-B-carbotine
To a solution of tryptamine (5.0 g, 0.0312 mol) and 3,4-dimethoxy
benzaldehyde (5.7 g, 0.0312 mol) in CH2CI2 (220 mL) was added TFA (4.5 mL,
0.0584 mol). The deep blue solution was stirred at room temperature for 20 h.
The reaction mixture was neutralized with NaHCO3 (4.9 g, 0.0584 mol) in H2O
(50 mL) and the organic layer washed with brine (2 x 100 mL). The reaction
mixture was dried with MgSO4 and the solvent evaporated. Product was
isolated by column chromatography (silica gel; CH3OH:EtOAc = 1:9) as a
yellowish oil, which solidified slowly upon standing at room temperature.
mp: 146-148°C; MS (m/z) 307 (M-1), 309 (MH+)
1H NMR (CDCI3) 6 2.70 -2.92 (m, 2H), 3.05 (m, 1H), 3.31 (m, 1H), 3.65
(s. 3H). 3.81 (s, 3H), 5.01 (s, 1H). 6.72 (m, 2H), 7.12 (m, 3H), 7.52 (m, 1H),
8.18 (s,1H)
EXAMPLE 12
1-(3.4-Methylenedioxyphenyl)-2-[5-(4-methoxvDhenyl)-pvrimidin-2-yl]-2.3.4.9-
tetrahvdro-1 H-B-carboline
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-carboline (2.72 g,
9.6 mmol) (prepared according to the process as disclosed in WO97/43287,
Intermediate 7, page 24) and 2-chloro-5-(4-methoxyphenyl)pyrimidine (1.04 g,
4.78 mmol) were stirred in DMF (20 mL, anhydrous) at 120 °C for 16 h. The
resulting mixture was quenched with saturated NH4CI, extracted with ethyl
acetate and dried with MgSO4. The reaction mixture solvent was evaporated
and the residue purified by column chromatography (silica gel, ethyl
acetate.hexanes = 1:2) to yield the product as a white solid,
mp: 200-202 °C; MS (m/z): 477 (MH+)
1H-NMR (DMSO-de) § 2.71 (m, 2 H), 3.25 (m, 1H). 3.78 (s, 3 H), 4.93 (d,
J= 12 Hz, 1 H), 5.99 (d, J - 5 Hz, 2 H), 6.76 ( d, J = 8 Hz, 1 H), 6.87 (d, J = 8
Hz, 2 H). 7.02 (d, J - 9 Hz, 2 H), 7.06 (d. J = 7 Hz, 1 H), 7.11 (s, 1H), 7.31 (d,
J = 8 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H), 7.59 ( d, J = 9 Hz, 2 H), 8.74 (s, 2H),
11.00(s, 1H);
EXAMPLE 13
1-(3.4-Methvlenedioxvphenv0-2-f5-(3.4-dimethoxvphenvn-Dyrimidin-2-vn-
2.3.4.9-tetrahvdro-1 H-B-carboline
Following the same procedure as outlined in Example 12,1-(3,4-
methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-carboline (3.73 g, 12.8 mmol)
(prepared according to the process as disclosed in WO97/43287, Intermediate
7, page 24) and 2-chloro-5-(3,4-dimethoxylphenyl)pyrimidine (1.60 g, 6.4
mmol) in DMF (50 mL, anhydrous) were reacted to yield the product as a white
solid.
mp: 173-175 °C; MS (m/z): 507 (Ml-T)
1H-NMR (CDCI3) 8 2.89 (d, J = 15 Hz, 1 H), 3.02 (m, 1 H), 3.39 (m. 1 H),
3.92. 3.94 (2s, 6 H), 5.03 (d, J= 12 Hz, 1 H), 5.92 (d, J = 4 Hz, 2 H), 6.71 (d, J
- 7 Hz, 1 H), 6.87-7.32 (m, 6 H), 7.56 (d, J = 7 Hz, 2 H), 7.80 (s, 1H), 8.56 (s,
2H);
EXAMPLE 14
1-(3.4-MethvlenedioxvDhenvtV2-r5-(4-methv tetrahvdro-1 H-fi-carboKne
Following the same procedure as outlined in Example 12,1-(3,4-
methylenedioxyphenyl)-2f3,4,9-tetrahydro-1 H-p-carboline (2.19 g, 7.5 mmol)
(prepared according to the process as disclosed in WO97/43287, Intermediate
7, page 24) and 2-chloro-5-(4-methylphenyl)pyrimidine (1.03 g, 5 mmol) in
toluene (50 mL, anhydrous) and DBU (0.9 mL) were reacted to yield the
product as a white solid.
MS (m/z): 459 (MH+)
1H-NMR (CDCI3) 8 2.43 (s, 3 H), 2.85 (d. J = 14 Hz, 1 H), 3.01 (t, J = 12
Hz, 1 H), 3.38 (t, J = 12 Hz. 1 H). 5.04 (dd. J = 14 Hz, 1 H). 5.88 (d, J = 4 Hz, 2
H), 6.73 (d, J = 7 Hz, 1 H). 6.89 (d. J = 7 Hz. 1 H). 7.02 (s, 1 H), 7.25-7.50 (m,
7 H), 7.56 (d, J = 7 Hz. 1 H), 7.79 (s. 1H), 8.54 (s, 2H);
EXAMPLE 15
1-(314-MethvlenedioxyphenvlV2-(pvridin-4-vl)methvl-2.3.4.9-tetrahvdro-1H-6-
carboline
A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-
carboline (2.92 g, 10 mmol) (prepared according to the process as disclosed in
WO97/43287, Intermediate 7, page 24), 4-picolylchioride hydrochloride (1.64 g,
10 mmol) and DBU (3.1 g, 20 mmol) in DMF (50 mL) was stirred at room
temperature for 16 h. Water (100 mL) and ethyl acetate (100 mL) were added
to the reaction mixture. The solute, present in the organic phase, was purified
by column chromatography (siica gel, ethyl acetate) to yield the product as an
off-white solid.
MS(m/z)382(M-1)
1H NMR (CDCI3) 8 2.65 (m, 1 H), 2.75 (d, 1 H), 2.88 (m, 1 H), 3.15 (m, 1
H), 3.35 (d, J = 15 Hz, 1 H), 3.92 (d, J = 15 Hz, 1 H), 4.57 (s, 1 H), 5.94 (s, 1
H), 6.79 (d, J = 8 Hz, 1 H), 6.89 (m, 2 H), 7.20-7.40 (m, 7 H), 7.51 (d, J = 6 Hz,
1 H),8.53(d, J = 7Hz,1H);
EXAMPLE 16
1 -(3.4-Methvlenedioxvphenyl)-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1 H-ß-
carboline
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-carborine (2.3 g,
8.0 mmol) (prepared according to the process as disclosed in WO97/43287,
Intermediate 7, page 24) and 2-chloropyrimidine (0.914 g, 8.0 mmol) were
stirred in anhydrous DMF (15 mL) at 140°C for 24 h. The reaction mixture was
diluted with ethyl acetate (100 mL) and washed with saturated aqueous NH4CI
solution (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 50
mL). The combined organic layers were washed with brine (2 x 80 mL) and
dried with MgSO4. The solvents were evaporated and the product was isolated
by column chromatography ( salca gel, EtOAc:Hexane = 1:9 ) as a yellowish
solid.
mp: 176-177°C;
MS (m/z): 371 (MH+), 369 (M-1); Anal, calculated for C22H18N4O2, C
71.34, H 4.90, N 15.13; found C 70.57, H. 4.92, N 15.38
1H NMR (CDCI3) 5 2.71 (m, 1H), 2.92 (m, 1H), 3.29 (m, 1H), 4.92 (dd,
1H, J = 14, 7 Hz), 5.91 (d, 2H, J= 6 Hz), 6.43 (t, 1H, J = 6 Hz). 6.63 (d, 1H, J =
10 Hz), 6.81 (d, 1H, J = 10 Hz), 6.95 (s, 1H), 7.08 (m, 3H), 7.21 (d, 1H, J = 8
Hz), 7.54 (d, 1H, J= 10 Hz), 8.12 (s, 1H), 8.30 (d, 2H, J = 6 Hz);.
EXAMPLE 17
1-f3.4-MethvlenedioxvDhenvl)-2-f5-(4-chlorophenyl)-pyrimidin-2-yl]-2,3,4,9-
tetrahvdro-1 H-ß-carboline
Following the same procedure as outlined in Example 12 above, 1-(3,4-
methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-3-carboline (295 mg, 1 mmol)
(prepared according to the process as disclosed in WO97/43287, Intermediate
7, page 24) and 2-chloro-5-(4-chlorophenyl)pyrimidine (113 mg, 0.5 mmol) in
DMF (5 mL, anhydrous) were reacted to yield the product as a white solid.
MS (m/z): 479 (MH+)
1H-NMR (CDCI3) 5 2.87 (dd, J = 4, 14 Hz, 1 H), 3.01 (dt, J = 5, 12 Hz, 1
H), 3.38 (dt, J = 4, 14 Hz, 1 H), 5.04 (dd, J = 5, 14 Hz, 1 H), 5.91 (d. J = 4 Hz, 2
H), 6.73 (d, J = 7 Hz, 1 H), 6.89 (d, J = 7 Hz, 1 H), 7.00 (s, 1 H), 7.20 (s, 1 H),
7.25 (m, 2 H), 7.30 (d, J = 7 Hz, 1 H), 7.40 (m, 4 H), 7.56 (d, J = 7 Hz, 1 H),
7.83 (s, 1H),8.54(s, 2H);
EXAMPLE 18
f5-^3.4-DimethoxvphenvlVDvrimidin-2-vn-1-(3.4-dimethoxvphenvn-2.3.4.9-
tetrahvdro-1 H-B-carboline
Following the same procedure as outlined in Example 16,1-(3,4-
methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-p-carboline (prepared according
to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-
chloro-5-(3,5-dimethoxyphenyl)pyrirnidine were reacted to yield the product as
a white solid.
mp. 184-186 °C;
MS (m/z) 523 (MH+), 521 (M-1)
1H NMR (CDCI3) 8 2.81 - 3.20 (m, 2H), 3.40 (m, 1H), 3.71 (s, 3H), 3.79
(s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 5.01 (dd, 1H, J ~ 14 Hz, 5Hz), 6.68 (d, 1H, J
= 8 Hz), 6.70 -7.19 (m, 7H), 7.28 (t, 1H, J = 8 Hz), 7.52 (t, 1H. J = 8 Hz). 8.20
(s, 1H),8.52(s,2H);
EXAMPLE 19
1.2t3.4-Tetrahydro-3-(-3,4-dimethoxvphenyl)-9H-Dyrrolo-[3,4-b]Quinotin-9-one
(#12)
1-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-ß-carboiine (1.854 g,
6.04 mmol) (prepared as in Example 11) and KOf-Bu (1.14 g, 10.15 mmol)
were stirred in DMF (60 mL) at room temperature for 10 min. Oxygen was
bubbled through the solution for 1h. The reaction mixture was neutralized with
1N HCI solution (10.15 mL, 10.15 mmol) and the water removed in vacuo as
an azeotrope with toluene. Sica gel (~ 5g) was added to the residual DMF
solution, followed by dietfiyl ether (600 mL), which resulted in precipitation of
the product onto the silica gel. The diethyl ether was decanted and the silica
gel was washed with diethyl ether (2 x 100 mL). After the solvent was
decanted and any remaining trace amounts evaporated, the residue was
purified by column chromatograph (silica gel; EtOH:EtOAc = 1:9) to yield the
product as a bright yellow solid. The product was recrystallized from methanol.
mp. 223-225 °C;
MS (m/z): 323 (MH+), 321 (M-1)
1H NMR (CD3OD) 8 3.71 (s, 3H), 3.88 (s. 3H), 4.18 (d, 1H, J - 14 Hz),
4.38 (d, 1H, J = 14 Hz), 5.41 (s, 1H), 6.83 (m, 3H), 7.39 (t, 1H, J = 7 Hz), 7.58
(m, 2H), 8.22 (d, 1H, J = 6 Hz), 11.85 (s, 1H);
EXAMPLE 20
1.2.3.4-Tetrahvdro-2-f5-(4-methoxyphenvlV-pyrimidin-2-yl]-3-(3,4-methylene-
dioxyphenyl)-9H-pyrrolo-[3,4-b1guinolin-9-one (#2)
Sodium hydride (60% in mineral oil, 36 mg, 0.9 mmol) and 1-(3,4-
methylenedioxyphenyl)-2-[5-(4-methoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-
tetrahydro-1H-8-carboline (186 mg, 0.39 mmol) (prepared as in Example 12) in
DMF (10 mL, anhydrous) were stirred at room temperature for 30 min. Dry air
was then bubbled through the solution for 16h. Ethyl acetate (100 mL) and
saturated NaHCO3 were added, the organic phase was washed with water,
brine, and dried with MgSO4. Solvent was evaporated and the residue
triturated with ethyl acetate to yield the product as a white solid.
mp: 325-327 °C;
MS (m/z) 491 (MH+); 489 (M-1)
1H NMR (DMSO-d6) 5 3.77 (s. 3 H), 4.86 (d, J - 12 Hz, 1 H), 4.96
(dd, J= 15 Hz, 1 H ), 5.98 (s, 2 H), 6.29 (d, J=2.5 Hz, 1 H), 6.87 (d, J = 8 Hz, 1
H), 6.95 (d, J = 9 Hz, 2 H), 6.98 (s, 1 H), 7.02 (d, J = 4 Hz, 3 H), 7.34 (t, J= 7
Hz, 1 H). 7.57 (d, J = 9 Hz, 2 H), 7.63 (dd, J - 8 Hz, 3 H), 8.16 (d, J = 8 Hz, 1
H), 8.69 (broad, s, 2 H); 11.85 (s, 1 H);
EXAMPLE 21
1,2,3,4-Tetrahvdro-2-r5-(3,4-dimethoxvphenyl)-pyrimidin-2-yl]-3-(3.4-
methvlenedioxvphenyl)-9H-pyrrolo-[3.4-b]quinolin-9-one (#1)
Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-
methylenedioxyphenyl)-2-{5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-
tetrahydro-1H-ß-carboline (218 mg, 0.43 mmol) (prepared as in Example 13) in
DMF (10 mL, anhydrous) were stirred at room temperature for 30 min. Dry air
was then bubbled through the solution for 16h. Ethyl acetate (100 mL) and
saturated NaHCO3 were added, the organic phase was washed with water,
brine, and dried with MgSO4. Solvent was evaporated and the residue purified
by chromatography (silica gel, ethyl acetate) to yield the product as a white
solid.
MS (m/z) 521 (MH+); 519 (M-1)
1H NMR (DMSO-de) 6 3.77 (s, 3 H), 3.83 (s, 3 H), 4.86 (d, J - 12 Hz, 1
H), 4.96 (dd, J= 15 Hz, 1 H ), 5.99 (s, 2 H), 6.31 (d, J = 2.5 Hz, 1 H), 6.87
(d, J = 8 Hz, 1 H), 6.95 (d, J = 9 Hz, 2 H), 6.98 (s, 1 H), 7.02 (m, 1 H), 7.17 (d,
J = 7 Hz, 1 H), 7.22 (s, 1 H), 7.35 (t, J = 7 Hz. 1 H), 7.62 (m, 2 H), 8.17 (d, J = 8
Hz, 1 H), 8.74 (broad, s, 2 H); 11.85 (s, 1 H);
EXAMPLE 21A
(S)-1,2,3,4-TetrahvdrD-2-r5-(3,4-dimethoxvphenvl)-Dyrimidin-2-yi]n-3-(3,4-
methylenedioxyphenyl)-9H-Dvrrolo-[3,4-blquinolin-9-one(#35)
Following the procedure as described in Example 21, (S)-1-(3t4-
methy!enedioxyphenyl)-2-[5-^3,4-clirnethoxyphenyl)-pyrimidJn-2-yl]-2,3t4,9-
tetrahydro-1H-p-carboline was reacted to yield the title compound.
EXAMPLE 21B
(R)-1,2,3,4-Tetrahvdro-2-r5-(3.4-dimethoxyphenyl)-pyrimidin-2-yl-3-(3,4-
methylenedioxyphenyl)-9H-Pvrrolo-[3,4-b]quinolin-9-one(#36)
Following the procedure as described in Example 21, (R)-1-(3,4-
methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-
tetrahydro-1H-ß-carboline was reacted to yield the title compound.
EXAMPLE 22
1,2,3,4-Tetrahvdro-2-[5-(4-methylphenyl)-pvrimidin-2-yl]-3-(3.4-rnethylene-
dioxvphenyl)-9H-ovrrolo-ß.4-b1auinolin-9-one(#7)
Following the same procedure as outlined in Example 21, sodium
hydride (60% in mineral oil, 43 mg, 1.09 mmol) and 1-(3,4-
methylenedioxyphenyl)-2-[5-(4-rnethylphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-
1 H-p-carboline (278 mg, 0.60 mmol) (prepared as in Example 12) in DMF (15
mL, anhydrous) were reacted to yield the product as a white solid.
MS (m/2) 475 (MH+)
1H NMR (DMSO-de) 5 2.32 (s, 3 H), 4.86 (d, J = 12 Hz, 1 H), 4.96
(dd, J = 15 Hz, 1 H ), 5.98 (s, 2 H), 6.30 (d, J=2.5 Hz, 1 H), 6.87 (d, J = 8 Hz, 1
H), 6.95 (d, J = 9 Hz, 2 H). 7.02 (d, J = 4 Hz, 3 H). 7.24 (d, J= 7 Hz, 2 H), 7.34
(t, J= 7 Hz, 1 H), 7.40-7.65 (m, 3 H), 8.16 (d, J = 8 Hz, 1 H), 8.69 (broad, s, 2
H);11.85(s, 1 H);
1,2,3,4-Tetrahvdro-[5-(3.4-dimethoxvphenyl)-pvrimidin-2-yl]-3.4-
dlmethoxyphenyl)-9H-pvrrotor3,4-b]quinolin-9-one (#15)
Following the same procedure as outlined in Example 19, [5-(3,4-
Dimethoxyphenyl)-pyrimidin-2-yl]-1-(3,4-methoxyphenyl)-2,3,4,9-tetrahydro-
1 H-B-carboline (prepared as in Example 18) was reacted to yield the product
as a white solid.
MS (m/z) 535 (MH+), 537 (MH")
1H NMR (CD3OD) 8 3.74 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 3.85 (s. 3H),
5.0 (m, 2H), 6.31 (s, 1H), 6.75 -7.15 (m, 5H), 7.36 (t, 1H, J =8 Hz), 7.32 (d,
1H, J = 8 Hz), 7.61 (m, 2H). 8.29 (d, 1H, J = 8 Hz), 8.58 (s, 2H);
EXAMPLE 24
1,2,3,4-Tetn3hvdro-3-(3;.4-methvlenedioxvphenvlV2-(pvridin-4-yl)methyl-9H-
pvrrolo-[3.4-b]Quinolin-9-one (#5)
Following the same procedure as outlined in Example 21, sodium
hydride (60% in mineral oil, 40 nrtg, 1.0'mmol) and 1-(3,4-
methyienedtoxyphenyl)-2-(pyridln-4-yl)methyl-2,3,4,9-tetrahydro-1H-ß-canroline
(192 mg, 0.50 mmol) (prepared as in Example 15) in DMF (10 mL, anhydrous)
were reacted to yield the product as a white solid.
MS (m/z) 398 (MH*)
1H NMR (DMSO-d6) d 3.58 (d, J = 14 Hz, 1 H), 3.76 (d, J - 15 Hz, 1 H),
3.88 (d, J - 15 Hz, 1 H), 4.01 (d, J = 14 Hz, 1 H), 5.17 (s, 1 H), 6.03 (s, 1 H),
6.97 (s, 3 H), 7.7.35 (m, 3 H), 7.60 (m, 2 H). 7.34 (t, J= 7 Hz, 1 H), 8.11 (d, J =
8 Hz, 1 H), 8.53 (d, J = 6 Hz 2 H); 11.45 (s, 1 H);
EXAMPLE 25
1,2,3,4-Tetrahvdro-2-(terf-butoxvcarbonvl)-3-(3.4-methvlenedioxvphenvl)-9H-
Pvrrolo-f3.4-biQuinolin-9-one (#3)
2-t-Butoxycarbonyl-1 -(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-
p-carboline (4.09 g, 10.4 mmol) (prepared as in Example 9) was dissolved in
dry DMF (100 mL). Potassium f-butoxide (2.55 g, 22.7 mmol) was introduced
in one portion and the suspension was stirred until a dear solution was
obtained. Oxygen gas was then passed through the solution via a syringe
needle for 16 h. The reaction was quenched by the addition of glacial acetic
acid (25 mrnol) and poured into a mixture of diethyl ether and water, which
resulted in a precipitate that was collected by filtration. The product was
purified by flash chromatography (0-10% MeOH/CHCI3) to yield the product as
a white solid.
MS(m/z):405(M-1)
1H-NMR (CDCI3) 6 1.38-1.65 (series of s, 9 H), 4.79-4.88 (m, 2 H), 5.86-
6.27 (series of m, 3 H), 6.71-7.50 (series of m, 7 H), 11.57 and 11.64 (s, 1 H);
EXAMPLE 26
1,2,3,4-Tetrahvdro-2-(ben2vloxvcarbonvl)-3-(3.4-methvlenedioxvDhenvlV9H-
pvtrolo-f3.4-biQuinolin-9-one (#27)
2-benzyfoxycarbonyl-1-(3,4-methylenedioxyphenyl)-2,3I4,9-tetrahydro-
1H-B-carboline (3.63 g, 8.51 mmol)) (prepared as in Example 10) was
dissolved in dry DMF (25 mL). Potassium f-butoxide (2.40 g, 21.4 mmol) was
introduced in one portion and the suspension was stirred until a clear solution
was obtained. Oxygen gas was then passed through the solution via a syringe
needle for 16 h. The reaction was quenched by the addition of glacial acetic
acid (1.23 mL, 21.0 mmol) and poured into water (250 mL), which resulted in a
precipitate that was collected by filtration. The product was purified by flash
chromatography (2-10% MeOH/CHCU) to yield the product as a red powder.
MS(m/z):439(M-1)
1H-NMR (CDCI3) 5 4.63-5.18 (series of m, 4 H), 5.71-5.85 (series of m, 3
H), 6.54-6.72 (series of m, 3 H), 6.98-7.01 (m, 1 H), 7.25-7.57 (series of m, 7
H), 8.27-8.32 (m, 1 H), 10.04 and 10.33 (s, 1 H);
EXAMPLE 27
(E)-4-[3-Oxo-3-[1,2,3,4-tetrahvdro-3-(2.3-dihvdroben2ofurah-5-yl)-9H-pvrrolo-
f3r4-b1ouinolin-9-one-2-vn-1-propenvnbenzoic acid, methyl ester (#20)
A. A solution of (EH-carbomethoxycinnamic acid (5.09 g, 24.7 mmol) was
dissolved in dry THF (25 mL) and treated under an argon atmosphere with
oxalyl chloride (3.00 mL, 34.4 mmol) and a drop of dry DMF. After heating at
50°C for 2 hours, the reaction mixture was concentrated in vacuo to yield the
acid chloride of (E)-carboxymethyl cinnamic acid as a tan solid.
B. The product from Part A (78 mg, 0.35 mmol) was added to a solution of
1,2,3I4-tetrahydro-3-(2,3-dihydrobenzofuran-5-y1)-9H-pyrrolo-[3I4-b]quinolin-9-
one (93.5 mg, 0.31 mmol) (prepared as in Example 6), THF (3 mL),
triethylamine (0.20 mL, 1.43 mmol), and DMAP (5 mg). The mixture was
stirred for 16 h at room temperature, diluted with 1N HCI (10 mL) and the
resulting white precipitate collected by filtration. The solid was washed with
water (3X), with diethyl ether (3X) and dried in vacuo to yield the product as a
slightly pink solid.
MS (m/z): 493 (MH+)
1H-NMR (DMSO) 5 3.10-3.m, 2H), 3.87 (s, 3 H), 4.43-4.52 (m, 2 H),
4.70-5.14 (series of m, 2 H). 6.23 and 6.61 (s, 1 H), 6.72-6.79 (m, 1 H), 7.07-
8.19 (series of m, 12 H), 10.69 and 10.77 (s, 1 H).
EXAMPLE 28
1,2,3,4-Tetrahvdro-3-(3.4-methvlenedioxvphenvl)-2-[5-(3-trifluoro-
methvlDhenvl)fuipvn-9H-Pvrrolo-[3.4-b]Quinolin-9-one (#13)
To a solution of 5-(3-trifluoromethylphenyl)-2-furoic acid (80.44 mg,
0.314 mmol) in 1:1 DCMrTHF (5 mL, anhydrous) was added oxalyl chloride
(43.85 mg, 0.345 mmol), followed by two drops of DMF. The mixture was
stirred at room temperature for 1 h. A suspension of 1,2,3,4-tetrahydro-3-(3,4-
methylenedioxyphenyl)-9H-pyrrolo-[3,4-blquinolin-9-one (96.2 mg, 0.314 mmol)
(prepared as in Example 5), triethylamine (0.13 mL), and DMAP (trace) in 1:1
DCM:THF (5 mL) was added. The resulting mixture was stirred at room
temperature for 16h. Ethyl acetate (50 mL) was added, and the solution was
washed with aq. NaHCO3, ferine, 1N HCI, brine and then dried with MgSO4.
The solvent was evaporated and the residue triturated with ethyl acetate to
yield the product as a white solid.
mp: 219-221 °C
MS (m/z): 545 (MM*), 567 (M+23), 543 (UK)
1H-NMR (DMSO-d6) 5 5.09 (d, J = 14 Hz, 1 H), 5.46 (d. J = 14 Hz, 1 H),
5.99 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J = 8 Hz, 1 H), 6.97 (d, J = 9 Hz, 1 H), 7.02
(s, 1 H), 7.33 (d. J = 8 Hz, 1 H). 7.38 (d, J = 4 Hz, 1 H), 7.43 (d, J - 4 Hz, 1 H),
7.60 (m, J = 8 Hz. 2 H), 7.77 (d, J= 5 Hz, 2 H), 8.16 (d, J = 4 Hz, 3 H), 11.55 (s,
1H).
EXAMPLE 29
1,2,3,4-Tetrahvdro-3-(3.4-methvienedioxvDhenyl)-2-(6-hvdroxv-2-benzo-furovl)-
9H-Dvrrotof3.4-b1auinolin-9-one (#9)
To a solution of 6-hydroxy-2-benzofuranoic acid (0.054 g, 0.3 mmol) in
tetrahydrofuran (5 ml_) at 0°C was added dropwise oxalyi chloride (0.046 g,
0.36 mmol) followed by DMF (2 drops). The solution was warmed to 25°C and
stirred for 30 min, then concentrated in vacuo. The residue was dissolved in
tetrahydrofuran (5 mL), and added to a solution of 1,2,3,4-tetrahydro-3-(3,4-
methylenedioxyphenyl)-9H-pvrrolo-[3,4-b]quinolin-9-one (0.092g, 0.3mmol)
(prepared as in Example 5) in THF (5 ml), triethyiamine (0.045g, 0.45mmol)
and 4-dimethylammopyridine (0.01 g, cat.). The solution was stirred for 20 h at
25°C, and then concentrated in vacuo. The resulting crude residue was
purified by silica gel column chromatography, eluting with 3% methanol in
dichloromethane, to yield the product as a clear oil.
1H NMR (CD3OD): 6 5.25 (d, J = 15 Hz, 1H), 5.48 (d, J - 15 Hz, 1H).
5.91 (s, 2H), 6.45 (broad s, 1H), 6.84 (m, 3H), 6.93 (m, 2H), 7.00 (s, 1H). 7.25-
7.89 (overlapping m's, 5H), 8.32 (d, 1H).
EXAMPLE 30
(E)-4-[3-Oxo-341,2,3,4-tetrahvdro-3-(3.4-methvlenedioxvphenyl)-9H-Dvrrolo-
f3.4-b1auinotin-9-one-2-vn-1-DroDenvnbenzoic acid methvl ester (#6)
Following the procedure outlined in Example 20,1,2,3,4-tetrahydro-3-
(3,4-methylenedraxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (398 mg, 1.30
mmol) (prepared as in Example 5) was reacted with the acid chloride of (E>
carboxymethyl cinnamtc acid (301 mg, 1.34 mmol), in the presence of
triethylamine (0.54 mL, 3.87 mmol) in a 1:1 mixture of dichloromethane:THF
(40 mL) to yield the product as a tan solid.
MS(m/z):493(M-1)
1H-NMR (CD3OD) 5 3.86 (s, 3 H), 4.69-5.29 (series of m, 2 H), 5.93-6.02
(m, 2 H), 6.27 and 6.62 (s, 1 H), 6.89-8.21 (series of m, 13 H), 9.50 and 11.96
(broad s, 1 H).
EXAMPLE 31
1,2,3,4-Tetrahvdro-2-(imidazol-1-yl)thiocarbonyl-3-(3.4-methylenedioxy-
phenyl)9H-pvrrolo-[3.4-b]quinolin-9-one (#18)
To a suspension of 1,1'-thiocarbonyldiimidazole (0.192 g, 1.08 mmol) in
DMF (5 mL, anhydrous) at 0°C was added 1,2,3,4-tetrahydro-3-(3,4-
methylenedioxyphenyl)-9H-pyrrolo-[3,4-b3quinolin-9-one (0.30 g, 0.98 mmol)
(prepared as in Example 5). The mixture warmed to room temperature and
stirred for 20 h. The solution was diluted with water and extracted into ethyl
acetate. The organic layers were combined and washed with aq. NaHCO3 and
brine, dried with MgSO* and concentrated in vacuo, to yield the product as a
light tan solid.
mp:211-215°C(dec.)
MS(m/z):415(M-1)
1H-NMR (CD3OD) 5 4.71 - 5.16 (m, 1 H), 5.46 (d, J = 15Hz, 1 H), 6.36-
7.17 (overlapping m's, 5 H), 7.42 (m, 2 H), 7.52 (m, 1 H), 7.58 (m. 2 H), 8.28
(m. 1 H).
EXAMPLE 32
(E)-4-r3-Oxo-3-[1,2,3,4-tetrahvdro-3-(3.4-methylenedioxyohenyl)-9H-pyrrolo-
[3,4-blquinolin-9-one-2-yl]-1-proDenvnbenzoic acid (#8)
(E)A-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-
pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoic acid methyl ester (149
mg, 0.30 mmol), (prepared as in Example 30) was suspended in a 1:1 mixture
of 1 N aqueous sodium hydroxide:methanol (10 mL) and heated to reflux for 8
h. The reaction mixture was treated with aqueous HCI to pH 1, resulting in a
white precipitate. The precipitate was collected by filtration and washed with
water (30 mL) and diethyi ether (160 mL) to yield the product as a white solid.
MS (m/z): 481 (MH+)
1H-NMR (DMSO) 8 4.71-5.13 (series of d, 2 H,), 5.95-5.98 (m, 2 H), 6.23
and 6.61 (s, 1 H), 6.84-7.78 (series of m, 10 H), 7.89-7.92 (m, 3 H), 8.13-8.17
(m,1H), 11.94 (broad s,1H).
EXAMPLE 33
1,2,3,4-Tetrahydro-3-(3.4-methvlenedtoxvphenvl)-2-[5-(4-nitroDhenyl)-furoyl]-
9H-pyrrotof3.4-btauinolin-9-one (#16)
1,2,3,4-Tetrahydro-3-(3,4-methyleriedioxyphenyl)-9H-pyrrolo-[3,4-
b]quinolin-9-one (70.3 mg, 0.229 mmol) (prepared as in Example 5), 5-(4-
nitrophenyl)-2-furoic acid (58.9 mg, 0.25 mmol) and PyBrOP (0.118 g, 0.25
mmol) were stirred in DMF (3 mL) and DIPEA (0.088 mL, 0.50 mmol) for 16 h.
The reaction mixture was poured into ethyl acetate (80 mL) and the resulting
organic layer washed with 1N aqueous HCI (3 x 50 mL), saturated aqueous
Na2CO3 solution (1 x 50 mL) and brine (1 x 50 mL). The organic layer was
dried with MgSO4 and the solvent evaporated in vacuo. Column
chromatography of the residue (silica gel, 5% CH3OH / CH3CI) yielded the
product as a yellow powder.
MS (m/z): 522 (MH+), 520 (M-1)
1H NMR (DMSO-cfe) 5 5.05 (d, 1H. J = 14 Hz), 5.45 (d, 1H, J = 14 Hz),
6.0 (s, 2H), 6.42 (s, 1H). 6.95 (m, 3H), 7.32-7.41 (m, 2H), 7.55 -7.65 (m, 3H).
8.12 (m, 3H), 8.39 (m, 2H), 11.91 (s, 1H).
EXAMPLE 34
1,2,3,4-tetrahvdro-3f3.4>methvtenedioxvphenvl)2-f5-(4-aminoDhenvlV-furovl1-
9H-Pvrrotof3.4-b1auinolin-9-one (#261
1,2,3,4-Tetrahydro*3-(3,4-methylenedioxyphenyl)-2-[(5-(4-nltrophenyl))-
furoyl]-9H-py!Tok>[3,4-b]quinolin-9-one (25 mg, 0.0479 mmol) (prepared as in
Example 33) was stirred with 10% Pd on Carbon (5.1 mg, 0.00479 mmol)
under 1 atm H2 at room temperature for 14 h. The solvent was evaporated and
product isolated by preparative TLC as a yellow powder.
MS (m/z): 492 (MH*); 490 (M-1)
1H NMR (CD3OD) S 5.25 (d, 1H, J = 14 Hz), 5.45 (d, 1H,./ = 14 Hz),
5.91 (s, 2H), 6.45 (s, 1H), 6.70 - 8.60 (m, 13 H).
EXAMPLE 35
1,2,3,4-Tetrahvdro-3-f3.4-methvlenedioxvDhenvlV2-r2-hvdroxvnicotinov0-9H-
Dvrrolor3.4-b1-Quinolin-9-one (#25)
Following the procedure outlined in Example 33, with appropriate
substitution of reagents, the product was obtained as a pale yellow solid.
MS (m£r): 428 (MH*); 426 (M-1)
1H NMR (CD3OD) 54.65 (d, J- 14 Hz). 5.10 (d, 1H, J = 14 Hz), 5.85 (s,
2H), 5.92 (s. 1H), 6.50 -7.10 (m, 3H), 7.30 -7.70 (m, 5H), 8.25 (m, 2H).
EXAMPLE 36
1,2,3,4-Tetrahvdro-3-f3.4-methvlenedioxvDhenvlV2-r5-(4-methoxvDhenvl)-
furoyl]-9H-pyrrolo[3.4-b]-quinolin-9-one (#21)
Following the procedure outlined in Example 33, with appropriate
substitution of reagents, the product was obtained as a pale yellow solid.
MS (m/z): 507 (MH+); 505 (M-1)
1H NMR (CDCb) 8 3.85 (s, 3H), 5.10 (d, 1H, J = 14 Hz), 5.38 (d, 1H, J =
14 Hz), 6.02 (s, 2H), 6.41 (s, 1H), 6.80 - 8.35 (m, 13H), 11.80 (s,, 1H).
EXAMPLE 37
1,2,3,4-Tetrahvdro-3-f3.4-methvlenedioxvDhenvl)-2-[5-(4-hvclroxvphenyl)
furoyl]-9H-pvrrolor3.4-b]-quinolin-9-one(#22)
Following the procedure outlined in Example 33, with appropriate
substitution of reagents, the product was obtained as a pale yellow solid.
MS (m/z): 493 (MH+); 491 (M-1)
1H NMR (DMSO-cfe) 5 5.05 (d, 1H, J = 14 Hz), 5.15 (d, 1H, J = 14 Hz),
5.75 (s, 2H), 6.31 (s, 1H), 6.80 ~ 8.35 (m, 13H), 11.60 (s, 1H).
EXAMPLE 38
1,2,3,4-Tetrahydro-3-(3.4-methvlenedioxvphenvl)-2-[5-(4-
methoxycarbonyphenyl)-furoyl]-9H-pvrrolof3.4-b]-quinolin-9-one(#24)
Following the procedure outlined in Example 33, with appropriate
substitution of reagents, the product was obtained as a pale yellow solid.
1H NMR (DMSO-d6) 5 4.10 (s, 3H), 5.10 (d, 1H, J = 14 Hz), 5.50 (d, 1H,
J = 14 Hz), 6.02 (s, 2H), 6.45 (s, 1H), 6.80 - 8.35 (m, 13H);
EXAMPLE 39
1,2,3,4-Tetrahvdro-3-(3,4-methvtenedioxvphenvl)-2-[5-(4-formylphenyl)-furovn-
9H-Pvrrolo[3,4-b1-quinolin-9-one(#23)
Following the procedure outlined in Example 33, with appropriate
substitution of reagents, the product was obtained as a pale yellow solid.
MS (m/z): 503 (M-1)
1H NMR (DMSO-d6) 6 5.10 (d, 1H, J = 14 Hz), 5.55 (d, 1H, J = 14 Hz),
6.02 (s. 2H), 6.45 (s, 1H), 6.80 - 8.35 (m, 13H).
EXAMPLE 40
(E)-4-[3-Oxo-3-[1,2,3,4--tetrahydro-3-(3,4-methylenedioxvphenyl)-4-methyl-9H-
pwroto-[3,4-b]quinolin-9-one-2-yl]-1-proDenvnbenzoic acid, methyl ester (#63)
&
(E)-4-[3-Oxo-3-n.2,3,4-tetrahydro-3-(3,4-methylenedioxvphenvl)-9-methoxY-
9H-Dvrrolo-[3,4-b]quinolin-2-vn-1-proDenvnbenzoic acid, methvl ester (#64)
A solution of (E)-4-[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-
methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-
propenyl]benzoic acid methyl ester (349 mg, 0.62 mmol) (prepared as in
Example 30) and iodomethane (0.060 mL, 0.96 mmol) in dry acetone (10 mL)
was treated with anhydrous potassium carbonate (241 mg, 1.74 mmol) and
heated to reflux for 3 h under an argon atmosphere. The reaction mixture was
concentrated in vacua and the residue purified by flash chromatography (0-
10% methanol in dichloromethane) to yield a mixture of the N- and O-
methylated products.
The mixture of N- and O-methylated products was separated by column
chromatography (0-10% MeOH/DCM) to yield the N-methylated product (E)-4-
[3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-4-methyl-9H-
pyrrolo-[3,4-b]quinolin-9-one-2-yl]-1-propenyl]benzoic acid, methyl ester as a
tan solid.
MS(m/z):509(M-1)
1H-NMR (CDCI3) 8 3.55 (s, 3 H), 3.93 (s, 3 H), 5.10 (m, 2 H), 5.94 (nd, J
= 3.7 Hz, 2 H), 6.53 (s, 1 H), 6.78 (d, J = 7.9 Hz, 1 H), 6.86-6.96 (m, 3 H), 7.44-
7.76 (series of m, 6 H), 8.05 (d, J = 8.2 Hz, 2 H), 8.55 (d, J = 7.4 Hz).
and the O-methylated product (E)-4-[-3-Oxo-3-[1,2,3,4-tetrahydro-3-(3,4-
methylenedioxyphenyl)-9-methoxy-9H-pyrrolo-[3,4-b]quinolin-2-yf]-1-
propenyi]benzoic acid, methyl ester as a pink solid.
MS(m/z):509(M-1)
1H-NMR (CDCI3) 5 3.93 (s, 3 H), 4.38 (s, 3 H), 5.45 (d, J = 17.1 Hz, 1 H),
5.64 (d. J - 17.1 Hz, 1 H), 5.91 (s, 2 H), 6.26 (s, 1 H), 6.75-7.09 (series of d, 4
H), 7.39-8.23 (series of m, 9 H).
EXAMPLE 41
1,2,3,4-TetrahYdro-2-(pvrimidin-2-vn-3-(3.4-methvlenedioxvphenvlV9H-Pvrrolo-
r3.4-blauinolin-9-one (#11)
To a solution of 1-(3,4-methylenedioxyphenyl)-2(pyrimidin-2--yl)-2,3,4,9-
tetrahydro-1 H-ß-carboline (0.153g, 0.415 mmol) (prepared as in Example 16)
in anhydrous DMF (4.1 mL) was added KOtBu (0.079 g, 0.70 mmol, 1.7 eq.).
After 5 min, oxygen gas was bubbled through the solution for 1 h. Diethyl ether
(45 mL) was added to the reaction mixture and the supernatant decanted.
Brine (2 mL) was added to the residue and the pH was adjusted to pH~7 by
addition of a few drops of 1N HCI. The water was removed in vacuo as an
azeotrope with toluene. The resulting deep red residue was dissolved in a
minimum amount of THF, and purified by column chromatography (silca gel;
EtOH : CH2CI2 = 1: 9) to yield the product as a white solid.
MS (m/z): 383 (M*1); 385 (MH+)
1H NMR (DMSO-d6) 54.84 (dd, 2H, J - 14 Hz, 10 Hz), 5.98 (s, 2H), 6.25
(s, 1H), 6.69 (t 1H, J = 5 Hz), 6.85 (d, 1H, J = 8 Hz), 6.92 (d, 1H, J = 8 Hz),
7.00 (s, 1H), 7.33 (t, 1H, J = 7 Hz), 7.60 (m, 2H), 8.15 (d, 1H, J = 8 Hz), 8.41
(broad s,2H), 11.9(s. 1H).
EXAMPLE 42
1,2,3,4-Tetrahydro-2-(pyrimidin-2-yl)-3-(3.4-methylenedioxvDhenyl)-9H-pyrrolo-
T3.4-b1quinoitn-9-one (#11)
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-
b]quinolin-9-one (100 mg, 0.3265 mmol) (prepared as in Example 5) and 2-
chloropyrimidine (38 mg, 0.3265 mmol) were stirred in DMF (2.5 mL) at 100 °C
for 16 h. The solvent was removed under vacuum and the residue purified by
column chromatography (silica gel, 5% CH3OH / CH3CI) to yield a yellow oil.
Trituration of the oil with MeOH afforded the product as a pale yellow solid.
MS (m/z): 383 (M-1); 385 (MH*)
1H NMR (DMSO-d6) 6 4.84 (dd, 2H, J = 14 Hz, 10 Hz). 5.98 (s, 2H), 6.25
(s, 1H), 6.69 (t, 1H, J = 5 Hz), 6.85 (d, 1H, J = 8 Hz), 6.92 (d, 1H, J = 8 Hz),
7.00 (s, 1H). 7.33 (t, 1H, J = 7 Hz), 7.60 (m, 2H). 8.15 (d, 1H, J - 8 Hz), 8.41
(broad s,2H), 11.9(s, 1H).
EXAMPLE 43
1,2,3,4-Tetrahvdro-2-rf4-Dvridinvl)methvloxvcarbonvl1-3-/3.4-
methvlenedioxvphenyl)-9H-pyrrolo-[3,4-blquinolin-9-one. hydrochloride salt
(#37)
A mixture of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-
pyrrolo-[3,4-b]quinolin-9-one, hydrochloride salt (101 mg, 0.33 mmol) (prepared
as in Example 5), (4-pyridinyl)methyl-4-nrtrophenylcarbonic acid ester (106 mg,
0.38 mmol) (prepared as in Example 7) and triethylamine (2 eq.) was heated to
reflux for 1 h. The reaction mixture was concentrated in vacuo and purified by
flash chromatography (0-10% MeOH/CHGI3). The corresponding salt was
formed by precipitation of the methanolic solution of the free base with a
solution of HCI-ether.
MS (m/z) 442 (MH+)
1H NMR (CD3OD) 8 5.02-5.62 (series of m, 4H), 5.93-6.00 (m, 2H), 6.23
and 6.44 (s, 1H), 6.82-7.04 (m, 3H), 7.71-7.90 (m, 4H), 8.12 (d, J = 6.2 Hz.
1H), 8.44 (s, 1H), 8.78 (s, 1H), 8.84 (s, 1H).
EXAMPLE 44
1,2,3,4-Tetrahvdro-2-f(4-pyridinvl)methvloxvcarbonvn-3-(2,3-
dihvdrobenzofuran-5-yl)-9H-Pyreolo-[3.4-b]auinolin-9-one(#53)
Following the procedure outlined in Example 36,1,2,3,4-tetrahydro-3-
(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one, hydrochloride
salt (prepared as in Example 6) and (4-pyridinyl)methyl-4-nitrophenylcarbonic
acid ester (prepared as in Example 7) were reacted to yield the product as a
slightly pink solid.
MS (m/z) 440 (MH*)
1H NMR (DMSO-d6) 6 2.82-2.94 (m. 2H), 4.35-5.26 (series of m, 6H),
5.91 (s, 1H) 6.45-7.58 (series of m, 9H), 8.30-8.46 (m, 2H), 12.26 (broad, 1H).
EXAMPLE 45
1,2.3.4-Tetrahvdro-2-[[5-[2-(4-moroholinyl)ethoxyl-2-benzofurvl]carbonyl]-3-
(3,4-methylenedioxyphenvl)-9H-pvrrolo-f3.4-blQuinolin-9-one. hvdrochloride
salt (#49)
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyiT0lo-[3,4-
b]quinolin-9-one, hydrochloride salt (222 mg, 0.65 mmol) (prepared as in
Example 5) and 6-[2-(1-^orpholino)ethoxy]-2-benzofurancarboxylic acid (209
mg, 0.72 mmol) (prepared as in Example 8) were suspended in dry THF (10
mL). To this mixture was added PyBrOP (358 mg, 0.77 mmol) and
triethylamine (0.40 ml_, 2.87 mmol). The mixture was stirred overnight under
an argon atmosphere and concentrated in vacuo. Purification of the residue by
flash chromatography (0-10% MeOH/CHCI3) yielded the free base. The
corresponding salt was formed by precipitation of the methanolic solution of the
free base with a solution of HCI-ether.
MS (m/z) 580 (MH+)
1H NMR (DMSO-d6) 5 3.17-3.24 (m, 2H), 3.52-3.61 (m, 4H), 3.80 (t, J =
11.7 Hz, 2H). 3.98 (d, J = 12.1 Hz, 2H), 4.53 (broad s, 1H), 5.10 (d, J = 13.3
Hz, 1H), 5.40 (d, J = 13.3 Hz, 1H), 6.00 (s, 2H), 6.42 (s, 1H), 6.90-7.08 (series
of m, 4H), 7.32-7.66 (series of m, 4H), 7.73 (d, J - 8.5 Hz, 1H), 8.16 (d, J = 8.0
Hz, 1H), 10.81 (s, 1H), 12.06 (s, 1H).
Example 46
1-(2.3-dihvdrobenzofuranyl)-2-[5-(4-methoxvphenyl)-Dvrimidin-2-vn-2.3.4.9-
tetrahvdro-1 H-ß-carboline
1 -(2,3-dihydrobenzo-5-furanyl)-2,3,4,9-tetrahydro-1 H-ß-carboline
(prepared according to the process as disclosed in WO97/43287, intermediate
10, page 25) (3.35 g, 11.54 mmol), 5-(4-methoxyphenyl)-2-chloropyrimidine
(2.55 g, 11.54 mmol), and N,N-diisopropylethylamine (3.5 mL) were stirred in
DMF (10 mL, anhydrous) at 120°C for 16 h. The resulting mixture was
quenched with 10%NaCI and extracted with ethyl acetate. The organic layer
was washed with 10% NaCI, brine, and then dried with MgSO4. The reaction
mixture solvent was evaporated, the resulting residue triturated with CH2CI2
and filtered. The filtrate was purified by column chromatography (silica gel,
ethyl acetate:hexanes = 4:6) to yield the product as a white solid.
mp: 242-243 °C
MS (m/z): 475 (MH+), 483 (M-1)
1H-NMR (DMSO-de) 6 *2.50 (s, 1 H), 2.83 (m, 2H), 3.12 (t, J = 8.7 Hz, 2
H), 3.24 (m, 1 H), 3.78 (s, 3 H), 4.49 (t, J- 8.7 Hz, 2 H), 4.90 (d, J= 12 Hz, 1 H),
6.72 (d, J = 8.2 Hz, 1 H), 7.03 (m, 4 H), 7.06 (d, J = 7 Hz, 1 H), 7.17 (d, J - 9.3
Hz, 2 H), 7.30 (d, J = 8 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 2
H), 8.73 (s, 2H), 11.00 (s,1H)
Example 47
1,2,3,4-Tetrahydro-2-[5-(4-methoxvphenyl)-pvrimidin-2--yl]-3-(3.4-
dihvdrobenzofuranvl)-9H-pyrrolo-[3.4-b)quinolin-9-one (#39)
Sodium hydride (60% in mineral oil, 87 mg, 2.18 mmol) and 1-(2,3-
dihydro-5-benzfuranyl)-2,3,4,94etrahydro-2-[5-(4-metboxyphenyl)-2-
pyrimidinyl]-1H-ß-carboline (450 mg, 0.95 mmol) (prepared as in Example 46)
in DMF (30 mL, anhydrous) were stirred at room temperature for 30 min. Dry
air was then bubbled through the solution for 16h. Ethyl acetate (200 mL) was
then added to the solution. The resulting mixture was washed with 10% NaCI
solution, brine and then dried with MgSO*. The soivent was evaporated and
the residue triturated with ethyl acetate to yield the product as a white solid.
mp: 301-302°C;
MS (m/z) 489 (MH+); 487 (M-1)
1H NMR (DMSO-de) 6 3.11 (t, J = 8.7 Hz, 2 H), 3.77 (s, 3H), 4.47 (t, J =
8.7 Hz, 2H), 4.89 (m, 2H), 6.29 (s, 1H), 6.72 (d, J = 8.1 Hz. 1H). 6.95 (d, J =
8.7 Hz, 2H), 7.29 (m, 3H), 7.57 (d, J = 8.6 Hz, 2 H), 7.64 (d, J - 8.2 Hz, 2 H),
8.16 (d, J * 8.0 Hz, 1 H), 8.67 (s, 2 H), 11.87 (s, 1 H)
Example 47A
(R)-1,2.3.4-Tetrahvdro-2-[5-(4-methoxvphenvlV-pvrimidin-2-vl l-3-(3.4-
dihvdrobenzofuranyl)-9H-pvrrolo-[3.4-blautnolin-9-one (#66)
(R)-1,2,3,4-tetrahydro-3-(2,3-dihyclrobenzofuran-5-yl)-9H-pyrrolo-[3,4-
b]quinolin-9-one (0.23g, 0.678 mmol) (prepared as in Example 6A), and 5-(4-
methoxyphenyl)-2-chlorqpyrimidine (0.167g, 0.758 mmol) were stirred with
diisopropyf ethyl amine (0.33 mL) and KF (44.8 mg, 0.758 mmol) in DMF (5
mL) at 60°C for 36 h. The reaction mixture was diluted with CH2CI2 (75 mL)
and EtOAc (75 mL). This was washed with 1N aqueous HCI (3 X 100 mL).
This was then washed with brine (2 X 100 mL). After drying over MgSCU, this
was concentrated to yellow oil. The crude product was purified by silica gel
column to yield the product as white solid.
MS (m/z): 499 (MH+), 497 (M-1)
1H NMR d CDCI3 3.02 (t, 2H, J = 11.7 Hz), 3.82 (s. 3H), 4.44 (t, 2H, J =
11.7HZ), 4.95 (d, 1H, J= 15.6 Hz), 5.08 (d, 1H, J= 15.6 Hz), 6.24 (s, 1H), 6.62
(d, 1H, J = 7.8 Hz), 6.92 (d. 2H, J = 7.8 Hz), 7.14 -7.61 (m, 7H), 8.45 (m, 3H).
9.65 (s,1H)
Rf = 0.47 (10% CH3OH/CHCI3). Elemental analysis: for C30H24N4O3,
calculated %C 73.76, %H 4.95, %N 11.47, %O 9.82; found %C 73.73, %H
4.87, %N 11.40, O% 9.65.
Example 48
(R)-1,2,3,4-Tetrahvdro-3-(3.4-methvlenedioxvphenyl)-2-[5-(3-
trifluoromethvtphenvl)furo-2-vn- 9H-pyrrolo-[3.4-b1quinolin-9-one (#50)
To a solution of 5-(3-trifluoromethylphenyl)-2-furoic acid (504.4 mg, 1.97
mmol) in 1:1 DCM.THF (10 mL, anhydrous) was added oxalyl chloride (275
mg, 2.17 mmol), followed by two drops of DMF. The reaction mixture was
stirred at room temperature for 2 h. To the reaction mixture were added
triethylamine (1.1 mL), DMAP (trace), and a suspension of enantiomerically
pure 1,2,3,4-tetrahydro-3-(3t4-methylenedioxyphenyl)-9H-pyrrolo-(3,4-
b]quinolin-9-one (603 mg, 1.97 mmol) (prepared as in Example 5A), in 1:1
DCM:THF (10 mL). The resulting mixture was stirred at room temperature for
16h. Ethyl acetate (100 mL) was added, and the solution was washed with aq.
NaHCO3, brine, 1N HCI, brine and then dried with MgSO4. The reaction
mixture solvent was evaporated and the residue triturated with ethyl acetate to
yield the product as a white solid.
mp: 219-221 °C
MS (m/z): 545 (MH+), 543 (M-1).
1H-NMR (DMSO-d6) 6 5.09 (d, J = 13 Hz, 1 H). 5.47 (d, J = 13 Hz, 1 H),
6.00 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J = 8 Hz, 1 H), 6.97 (d, J = 8 Hz, 1 H). 7.02
(s, 1 H), 7.33 (d, J = 7 Hz, 1 H), 7.38 (d, J = 4 Hz, 1 H), 7.43 (d, J = 4 Hz, 1 H),
7.60 (m, J = 8 Hz, 2 H), 7.77 (d, J= 5 Hz, 2 H), 8.16 (d, J = 5 Hz. 3 H), 11.90 (s.
1H)
Example 49
1-(2,3-Dihvdrobenzofuranyl)-2-(5-(2-Pyridinvl)-pvrimidin-2-yl]-2,3,4.9-tetrahvdro-
1H-ß-carboline
1 -(2,3-dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-ß-carboline (prepared
according to the process as disclosed in WO97/43287, Intermediate 10, page
25) (1.35g, 4.66 mmol), 2-chioro-5-(2-pyridinyl)-pyrirnidine (893 mg, 4.66 mmol)
and N.N-diisopropylethylarinine (1.4 mL) were stirred in DMF (10 ml_,
anhydrous) at 120°C for 16 h. The resulting mixture was quenched with 10%
NaCI and extracted with ethyl acetate. The extracted organic layer was
washed with 10% NaCI, brine and then dried with MgSO4. The reaction
mixture solvent was evaporated and the residue purified by column
chromatography (silica gel, ethyl acetate:hexanes = 4:6) to yield the product as
a white solid.
mp: 170-171 °C
MS (m/z): 446 (MH+), 444 (M-1)
1H-NMR (DMSO-de) 6 2.85 (d, J= 5 Hz, 2 H), 3.12 (t, J- 8.7 Hz, 2H).
3.27 (d, J =12.4 Hz, 1 H), 4.96 (d, J= 12.6 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H),
6.99 (t, J = 7.4 Hz, 1 H), 7.07 (t, J = 7.1 Hz, 2 H), 7.21 (s, 2H), 7.31 (d, J - 8.2
Hz, 2 H), 7.47 (d J = 7.6 Hz, 1H), 7.85 (d, J =7.8 Hz, 1 H), 7.93 (d,, J - 8 Hz, 1
H), 8.62 ( d, J = 4.5 Hz, 1 H), 9.13 (s, 2H). 11.01 (s, 1H)
Example 50
1.2.3,4-Tetrahydro-2-[5-(2-pvridinvl)-pvrimidin-2-vl 1-3-(3,4-
dihvdrobenzofuranyl)-9H-pvrrolo-[3.4-blquinolin-9-one (#61)
Sodium hydride (60% in mineral oil, 182 mg, 4.55 mmol) and 1-(2,3-
dihydro-5-ben2ofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyJ)-2-pyrimidinyl]-1H-
ß-carboline (16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) in
DMF (30 ml_, anhydrous) were stirred at room temperature for 30 min. Dry air
then was bubbled through the reaction mixture for 16 h. Ethyl acetate (200
mL) was added, and the resulting mixture was washed with 10% NaCI solution,
brine, and then dried with MgSO4. The reaction mixture solvent was
evaporated and the residue triturated with ethyl acetate to yield the product as
a white solid.
mp: 201-203 °C
MS (m/z) 460 (MH+); 458 (M-1)
1H NMR (DMSO-de) 5 3.11 (t, J = 8.5 Hz, 2H), 4.46 (t, J = 8.5 Hz, 2H),
4.91 (m, 2H), 6.34 (s, 1H), 6.73 (d, J = 8.1 Hz, 1H), 7.31 (m, 4H), 7.59 (t, J =
8.6 Hz, 2 H), 7.84 (d, J = 7.1 Hz, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 7.9
Hz, 1 H), 8.60 (d, J = 4.5 Hz, 1 H), 8.98 (s 1H), 9.12 (s, 2 H), 11.90 (s, 1 H).
Example 50A
(RV1,2,3,4-Tetrahvdro-2-f5-(2-pvridinvl)-Pvrimidin-2-v11-3-(3.4-
dihvdrobenzofuranvlV9H-pvrrok>-r3.4-blQuinoHn-9-one (#65^
A. 1 -methyl-5-(2-pyridinyl)-2(1 H)pyrimidone
A mixtuce of 2-(2-pyridiny*)malondialdehyde (5 g, 0.0335 mole), methyl
urea (4.72 g, 0.0637 mole), and toluenesulfonic acid (450 mg) was refluxed in
toluene (100 mL) in an apparatus fitted with a Dean-Stark water separator for 4
h. The mixture was cooled and the precipitate was filtered. The solid was
triturated with water and recrystallized from ethanol to yield the product.
MSm/z(M+H)188
1H NMR (DMSO-de) 5 7.48 (m, 1H), 7.98 (m, 1H), 8.18(d, J - 8.0 Hz,
1H), 8.75 (s, 1H), 9.41 (s,2H).
B. 2-chloro-5-(2-pyridJnyi)pyrimidine
A mixture of 1-methyl-5-(2-pyridinyl)-2(1H)pyrimiclone (8.994 g, 0.048
mole), phosphorus pentachloride (2.156 g, 0.0104 mole), and phosphorus
oxychloride (24 mL) was refluxed at 120 °C for 8 h. POCI3 was distilled out
under reduced pressure. The residue was cooled to room temperature and
ice-water was added. The mixture was extracted with EtOAc, the organic layer
was washed with 15% NaCI solution, brine and dried over MgSO4. Solvent
was distilled out under reduced pressure to yield a solid. The water layer was
adjusted to pH 6-7 by using saturated Na2CO3, then extracted with EtOAc.
The organic layer was washed with 15% NaCI, brine, dried over MgSO4.
Solvent was distilled out under reduced pressure to give a solid. After
trituration with MeOH, additional product was obtained.
MSm/z(M+H)192
1H NMR (DMSO-cfe) 5 3.56 (s, 3H), 7.33 (m, 1H), 7.89 (d, J = 8.8 Hz,
2H), 8.61 (d, J = 4.7 Hz, 1H), 8.95 (s, 1H), 9.31 (s. 1H).
C. (R)-1,2,3,4-tetrahydro-2-{5-(2-pyridinyl)-pyrimidin-2-yt ]-3-(3,4-
dihydrobenzofuranyl)-9H-pyrroto-[3,4-b]quinolin-9-one
A mixture of (R)-1,2,3,4-Tetrahydro-3-(2,3-dihydrobenzofuran-5-y1)-9H-
pyrrolo-[3,4-bJquinolin-9-one, hydrochloride salt (1.273 g, 0.00373 mole)
(prepared in example 6A), 2-chloro-5-(2-pyridinyl)pyrimidine (0.714 g, 0.00373
mole), KF (0.216 g, 0.00373 mole), and diisopropylethylamine (2.27 mL) in
DMF (45 mL) was heated at 55 CC for 4 h. EtOAc was added, and the mixture
was washed with 0.5N citric acid, then with 15% NaCI, brine and dried over
MgSO4. Solvent was distilled out under reduced pressure to give a solid. The
solid was dissolved in 10% methanol in dichloromethane and purified via
column chromatography (EtOAc to 10% CH3OH in EtOAc) to yield the title
compound.
mp 231-233 °C
MS m/z (M+H) 460
1H NMR (DMSO-cfe) 5 3.11 (d, J = 8.7 Hz, 2H), 4.46 (d, J = 8.7 Hz, 2H),
4.92 (m, 2H), 6.34 (d, J= 1.6 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 7.28 (m, 4H),
7.59 (m, 2H), 7.82 (m, 1H), 7.91 (d, J= 8.0, 1H), 8.16 (d, J = 8.0,1H), 8.60, J =
4.5 Hz, 1H), 8.98 (s, 1H), 9.12 (s, 1H), 11.92 (s, 1H)
The title compound was dissolved in methanol, one equivalent of 0.02M
methane sulfonic acid (in methanol) was added. Solvent was distilled out
under reduced pressure to yield the methane sulfonic salt.
[a] = -236.2 • (c=1.0333 g/dL, CH3OH).
Example 51
2-chloro-5-bromopyrimidine
2-chloro-5-bromopyrimidine was prepared from 2-hydroxypyrimidine
(purchased from Frontier Scientific Inc.) according to the procedure disclosed
in US Patent No. 5,693,611, Preparation 6, Column 17.
Example 52
1-(3.4-Methvlenedioxvphenvl)-2-f5-bromopvrimidin-2-vn-2.3.4.9-tetrahvdro-1H-
B-carboline
To the solution of 1-(3,4-methylenedioxyphenyl)-2t3,4.9-tetrahydro-1H-
8-carboline (4.38 g, 15.0 mmol) (prepared according to the process as
disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-
bromopyrimidine (2.90 g, 15.0 mmol) (prepared as in Example 51) in dry
degassed DMF (30 ml) was added N, N-diisopropylethylamine (4.2 mi, 30
mmol). The mixture was heated at 120-130°C overnight. The mixture was
then cooled and diluted with ethyl acetate. The solution was washed with 0.5
N citric acid, water and brine, then dried over Na2SO4 and concentrated in
vacuo. Purification by flash column (silical gel, hexane.ethyl acetate = 6:1, v /
v, followed by hexanerethyl acetate = 4:1, v / v ) yielded the product as a white
solid.
MS (m/z) 451 and 449 (MH*), 447 and 449 (M-1).
1H NMR (CDCI3) 5 2.82-3.02 (m, 2 H), 3.30-3.40 (m, 1 H), 4.92 (dd, J =
18.1 Hz, 1 H), 5.92 (d, J = 3.2 Hz, 2 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.85 (d, J =
8.0 Hz, 1 H). 6.95 (s, 1 H), 7.02 (s, 1 H), 7.13-7.21 (m, 2 H), 7.30 (d, J = 7.7
Hz, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.73 (s, 1 H), 8.34 (s, 2 H).
Example 53
1,2,3,4-Tetrahvdro-2-(5-bromopvrimidin-2-yl)-3-(3.4-methylenedioxvDhenyl)-
9H-pyrrolo-[3.4-blquinotin-9-one (#55)
Method A:
A solution of 1-(3i4-methylenedioxyphenyl)-2-(5-bromopyrimidin-2-yl)-
2,3,4,9-tetrahydro-1 H-p-carboUne (1.0 g, 2.2 mmol) (prepared as in Example
52) in dry DMF (40 ml) was cooled in an ice bath. NaH (60% in mineral oil,
0.18 g, 4.4 mmol) was added and the mixture was stirred at 0°C for 45 min.
Dried air was bubbled through the solution and the mixture was allowed to
warm to room temperature overnight. The reaction mixture was quenched with
water and extracted with ethyl acetate. The organic phase was washed with
brine and water, then dried over Na2SO4. concentrated and purified by flash
column (silica gel, hexanerethyl acetate = 1:1, v / v, followed by neat ethyl
acetate) to yield the product as a white solid.
MS (m/z) 465 and 463 (MH+), 463 and 461 (M-1).
1H NMR (DMSO-d6) 5 4.80 (d, J = 8.2 Hz, 1H), 4.89 (dd, J = 6.8 Hz, 1
H), 5.98 (s, 2H), 6.20 (s, 1H), 6.85-6.93 (m, 2 H), 6.98 (s, 1 H), 7.34 (t, J = 7.3
Hz, 2 H), 7.57-7.64 (m, 3H), 8.15 (d, J = 8.0 Hz, 2 H).
Method B:
To the solution of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyf)-9H-
pyrrolo-[3,4-b] quinolin-9-one (31 mg, 0.1 mmol) (prepared as in Example 5,
free base) and 2-chloro-5-bromopyrimidine (19 mg, 0.1 mmol) (prepared as in
Example 51) in dry degassed DMF (2 ml) was added N, N-
diisopropylethylamine (28 nl, 0.2 mmol). The mixture was heated at 120-
130°C overnight. The solution was cooled, diluted with ethyl acetate and
washed by 0.5N citric acid, water and brine, then dried over Na2SO4 and
concentrated in vacuo. Purification by flash column (silica gel, hexane.ethyl
acetate = 1:1, v/v, followed by neat ethyl acetate) yielded the product as a
white solid.
MS (m/z) 465 and 463 (MH+), 463 and 461 (M-1).
1H NMR (DMSO-de) 54.80 (d, J = 8.2 Hz, 1H), 4.89 (dd, J = 6.8 Hz, 1
H), 5.98 (s. 2H), 6.20 (s, 1H), 6.85-6.93 (m, 2 H), 6.98 (s, 1 H), 7.34 (t, J = 7.3
Hz, 2 H), 7.57-7.64 (m, 3H), 8.15 (d, J = 8.0 Hz, 2 H).
Example 54
1,2,3,4-Tetrahvdro-2-[5-(3-Pvridinvl)-pvrimidin-2-yl-3-(3.4-
methvlenedioxvphenvl)-9H-pyrrolo-f3.4-b1quinolin-9-one(#56)
Method A:
A stirred mixture of palladium(ll) acetate (0.8 mg, 3.6 u,mol) and 1,1'-
bis(diphenylphosphino)ferrocene (dppf) (2.4 mg, 4.3 nmol) in dry DMF (1.0 ml)
was warmed to 50°C for 15 mm and then cooled. 1,2,3,4-tetrahydro-2-(5-
bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-
9-one (20 mg, 43 µmol) (prepared as in Example 53), pyridine-3-boronic acid
(6.0 mg, 43 µmol) and triethylamine (8 µI, 60 nmol) were added to the solution
and the mixture was heated to 90°C for 16 h. The solution was diluted with
ethyl acetate and filtered through filter paper. The organic phase was washed
with brine and water, and then dried over Na2SO4. A small amount of silica gel
was added into the solution and the solution was dried in vacuo. Purification
by flash column (silica gel, 10% ammonium hydroxide in water acetonitrile =
1:10, v/v) yielded the product as a white solid.
MS(m/z)460(M-1).
1H NMR (DMSO-d6) d 4.88 (d, J = 4.1 Hz, 1H), 4.99 (d, J = 4.1 Hz, 1 H),
5.99 (s, 2H), 6.31 (s, 1H), 6.88 (d, J = 7.9 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H),
7.04 (s, 1H), 7.34 (t, J = 6.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.56-7.70 (m, 2H),
8.08 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1 H), 8.53 (d, J = 4.1 Hz, 1H).
8.72-8.82 (broad, 1H), 8.89 (s, 2H), 11.87 (s, 1H).
Method B:
A solution of 1-(3,4-methylenedioxyphenyl)- 2-[5-(3-pyridinyl)-pyrimidin-
2-yl]-2,3,4,9-tetrahydro-1H-p-carboline (100 mg, 0.22 mmol) (prepared as in
Example 55), in dry DMF (4.0 ml) was cooled in an ice bath. NaH (60% in
mineral oil, 31 mg, 0.78 mmol) was added and the mixture was stirred at 0°C
for 45 min. Dried air was bubbled through the solution and the mixture was
allowed to warm to room temperature overnight. The reaction was quenched
by water and extracted by ethyl acetate. The organic phase was washed with
brine and water, then dried over Na2SO4, concentrated and purified by flash
column (silica gel, 10% ammonium hydroxide in watenactonitrile =1:10, v/v) to
yield the product as a white solid.
MS(m/z)460(M-1).
1H NMR (DMSO-d6) 64.88 (d, J = 4.1 Hz, 1H), 4.99 (d, J = 4.1 Hz, 1 H),
5.99 (s, 2H), 6.31 (s, 1H), 6.88 (d, J = 7.9 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H),
7.04 (s, 1H), 7.34 (t, J = 6.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.56-7.70 (m, 2H),
8.08 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1 H), 8.53 (d, J = 4.1 Hz, 1H),
8.72-8.82 (br, 1H), 8.89 (s, 2H), 11.87 (s, 1H).
Example 55
1-(3.4-Methvlenedioxyphenyl)-2-[5-(3-pvridinvl)-pvrimidin-2-yl)-2.3.4.9-
tetrahvdro-1 H-ß-carboline
A stirred mixture of palladium(ll) acetate (27 mg, 0.12 mmol) and 1,1'-
bis(diphenylphosphino)feniocene (dppf) (83 mg, 0.15 mmol) in dry DMF (20 ml)
was warmed to 50°C for 15 min and then cooled. 1-(3,4-
methylenedioxyphenyl)-2-(5-bromopyrimidin-2-vl)-2,3,4,9-tetrahydro-1H-ß-
carboline (674 mg, 1.5 mmol) (prepared as in Example 52), pyridine-3-boronic
acid (203 mg, 1.7 mmol) and triethylamine (0.3 ml, 2.1 mmol) were added to
the solution and the mixture heated to 90°C for 16 h. The solution was diluted
with ethyl acetate and filtered through filter paper. The organic phase was
washed with brine and water, then dried over Na2SO4. A small amount of silica
gel was added into the solution and the solution was dried in vacuo.
Purification by flash column (silica gel, hexane:ethyl acetate = 1:1, v/v, followed
by hexane.ethyl acetate = 1:2, v/v) yielded the product as a white solid.
MS (m/z) 448 (MH+) and 446 (M-1).
1H NMR (CDCI3) 5 2.85-3.10 (m, 2H), 3.33-3.48 (m, 1 H), 5.06 (dd, J =
8.5 Hz, 1H), 5.94 (d, J = 4.7, 2H), 6.73 (d, J = 8.0, 1H), 6.90 (d, J = 8.0,1H),
7.02 (s, 1 H), 7.13-7.23 (m, 2 H), 7.32-7.42 (m, 2 H), 7.56 (d, J = 7.4 Hz, 1H),
7.79-7.84 (m, 2H), 8.58 (s, 1H), 8.60(s, 2H) 8.77 (s, 1H).
Example 56
1,2,3,4-Tetrahvdro-2-[5-(4-pvridinyl)-pvrimidin-2-vn-3-(3,4-
methylenedioxvqhenyl)-9H-pyrrolo-r3,4-b1auinolin-9-one(#57)
A stirred mixture pf 1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-
methylenedioxyphenyl)-9H-pynDlo-[3,4-b]quinolin-9-one (46 mg, 0.1 mmol)
(prepared as in Example 53), (PPh3)4Pd (3.5 mg, 3.0 µmol) and 4-tri-n-
butylstannylpyridine (37 mg, 0.1 mmpl) in dry DMF (2.0ml) was heated at
140°C fpr 12 h. More catalyst (3.5 mg) was added and the mixture was
refluxed fpr 4 h and then cooled. The solution was diluted with ethyl acetate
and filtered through filter paper. The prganic phase was washed with brine and
water, then dried over Na2SO4 A small amount of silica gel was added into the
solution and dried in vacuo. Purification by flash column (silica gel, neat
acetonitrile followed by 10% ammonium hydroxide in wateractonitrile = 1:10,
v/v) yielded the product as a white solid.
MS (m/z) 460 (M-1).
1H NMR (DMSO-d6) 5 4.93 (d, J = 4.2 Hz, 1H), 5.00 (d, J = 4.2 Hz, 1 H),
6.01 (s, 2H), 6.33 (s, 1H), 6.90 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 1 H),
7.05 (s, 1H), 7.34 (broad, 1 H), 7.62 (broad, 2H), 7.77 (d, 2H), 8.19 (d, J = 7.9
Hz, 1 H), 8.61 (broad, 2H), 8.78 (broad, 1H), 9.00 (broad, 1H).
Example 57
1,2,3,4-Tetrahvdro-3-(3.4-methvlenedioxyphenvl)-2-f5-(2-bromoy-furovl)-9H-
pyrrolor3.4-B1auinolin-9-one (#30)
5-Bromo-2-furoic acid (1.44 g, 7.54 mmol) in THF (20 mL) was stirred
with oxalyl chloride (1.06 mL, 7.54 mmol) at room temperature. To the mixture
was added 2 drops of DMF resulting in a vigorous reaction with evolution of
gas. After the evolution of gas ceased, an additional quantity of oxalyi chloride
(0.1 mL, 0.71 mmof) was introduced via syringe and the mixture was stirred at
room temperature for 10 min and then stirred at 90°C for 10 min. Solvent and
excess oxalyl chloride were removed in vacuo, resulting in a pale yellow
crystalline solid. To the solid was added THF (20 mL) and a solution of 3-(2,3-
dihydro-5-benzofuran}-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one (2.1
g) (prepared as in Example 6), in THF (20 mL). Et3N (4.55 mL, 32.6 mmol)
and a catalytic amount of DMAP (40 mg) were then added to the reaction
mixture. A few drops of DMF were added, resulting in a clear reaction mixture.
The reaction mixture was stirred at room temperature for 4 h. The reaction
mixture solvent was evaporated resulting in a solid residue. The residue was
re-dissolved in CHCI3 (200 mL), washed with water (3 x 200 mL) and the
organic layer dried over MgSO* The organic solvent was evaporated to yield
the product as a off-white solid.
MS (m/z): 480, (MH+), 478 (M-1)
1H NMR CDCI3 6 5.03 (d, 1H, J = 15.5 Hz), 5.23 (d, 1H, J - 15.5 Hz).
5.85 (d, 2H, J - 8.0 Hz), 6.40 (m, 2H), 6.56 (m, 1H), 6.81 (m, 2H), 7.00 (d, 1H,
J = 4.3 Hz). 7.32 (t, 1H, J * 8.6 Hz), 7.53 (t, 1H, J = 8.6 Hz), 7.65 (d, 1H, J '
8.6 Hz), 8.38 (d, 1H, J= 8,6 Hz), 12. 8 (s, 1H).
Example 58
4-(4-MethvlV-Diperaztnvlcarbonvl benzeneboronic acid
4-Carboxybenzeneboronic acid (0.332g, 2 mmol), 1-methylpiperazine
(0.22 mL, 2 mmol) and PyBrOP (0.9334g, 2 mmol) were stirred with DIPEA
(0.696mL, 4 mmol) in DMF (7 mL) at room temperature for 16 h. Preparatory
TLC (10% MeOH/CHCI3) yielded the product as white solid.
MS (m/z): 251 (MH*), 249 (M-1)
1H NMR CD3OD 6 2.36 (s, 3H), 2.43 (s, 2H), 2.57 (s, 2H), 3.51 (s, 2H).
3.82 (s, 2H), 7.34 (s, 2H), 7.76 (s. 2H).
Example 59
1,2,3,4-Tetrahvdro-3-(3,4-methylenedioxyphen yl)-2-(5-(4-(1 -(4-methyl )-
DiperazinvlcarbonvtVphenyl)-furoyl)-9H-pyrrolof3.4-b]quinolifi-9-one(#44)
1,2,3,4-Tetrahydro-3-(3,4-methylenedixoyphenyl)-2-(5-(2-bromo-furoyl)-
9H-pynrolo[3,4-b]quinoiin-9-one (59.6 mg, 0.12 mmol) (prepared as in Example
57), was stirred with Pd(PPh3)4 (7.37 mg, 0.0062 mmol) in dioxane (5.5 mL)
with N2 bubbling for 10 min. A solution of 4-(4-methyl)-piperazinylcarbonyl
benzeneboronic acid (37.0 mg, 0.15 mmol) and K2CO3 (51.5 mg, 0.37 mmol) in
H2O (1.1 mL) was then added. The reaction mixture was stirred at 100°C for 1
h. The solvent was evaporated, the residue purified by preparatory TLC (10%
MeOH/ CHCI3) and then triturated with ether/MeOH (15 mL/ 1mL), to yield the
product as a pale yellow powder.
MS (m/z): 603 (MH+), 601 (M-1)
1H NMR CD3OD 5 2.32 (s, 3H), 2.53 - 2.62 (m, 4H), 3.53 (broad s, 2H),
3.83 (broad s, 2H), 5.17 (d, 1H, J= 15.5 Hz), 5.41 (d, 1H, J - 15.5 Hz), 5.83 (s,
2H), 6.22 (s, 1H), 6.70 (m, 1H), 6.82 (m, 2H), 7.03 (m, 1H), 7.25 - 7.34 (m,
2H), 7.46 ~ 7.56 (m, 4H), 7.93 (d, 2H, J = 8.6 Hz), 8.31 (d, 2H, J = 8.6 Hz).
Example 59A
(R)-1,2,3,4-Tetrahvdro-3-(3,4-methvlenedioxvphenvl)-2-(5-(4-f 1 -(4-methyl )-
piperazinvlcarbonvlVphenvl)-furovl)-9H-pvrrolo[3.4-b]ouinolin-9-one(#69)
A 5-(4-(4-methyl)-piperazinylcarbonyl phenyQfuroic acid, methyl ester
A mixture of 4-(4-methyl)-piperazinylcarbonyl benzeneboronic acid
(prepared as in Example 58) (1.31 g, 5.28 mmol), methyl bromofuroic ester
(1.08g, 5.28 mmol (prepared from 5-bromofuroic acid in HCI/MeOH for 5 h at
room temperature) was degassed by N2 bubbling in dioxane (45 mL) and H2O
(9 mL) for 10 min. To this was added with Pd(PPh3)4 (0.627g, 0.528 mmol)
and K2CO3 (2.185g, 15.84 mmol). The solution was stirred at 100°C for 3 h.
Solvent was evaporated and the residue was dissolved in CH2CI2 (100 mL).
This was washed with brine (3 X 100 mL), dried over MgSO4, concentration
under vacuum and the crude product purified by silica gel column (5%
CH3OH/CHCI3) to yield the product as yellow solid.
MS (m/z): 315 (MH+), 313 (M-1)
1H NMR 5 CDCI3 2.32 ~ 2.48 (m, 7H), 3.48 (s, 2H), 3.80 (s, 2H), 3.92 (s,
3H,), 6.81 (d, 1H, J= 2.0 Hz), 7.24 (d, 1H, J = 2.0 Hz), 7.49 (d, 2H, J = 7.9 Hz),
7.83 (d, 2H, J = 7.9 Hz)
Rf = 0.51 (10% CH3OH/CHCI3).
B. 5-(4-(4-methyl)-piperazinylcarbonyl phenyl)furoic acid
To the product from Step A above (5-(4-(4-methyl)-piperazinylcarbonyl
phenyl)furoic acid, methyl ester) (1.08g, 3.29 mmol), dissolved in THF (98.7
mL) was added UOH (16.45 mL, 0.2 N in H2O). The solution was stirred at
room temperature for 3.5 h and was neutralized by HCI (3.29 mL, 1.0 M in
ether). After concentration, the crude material was used without further
purification.
MS (m/z): 329 (MH+), 327 (M-1)
1H NMR 8 CD3OD 2.35 (s, 3H), 2.36 - 2.58 (br s, 4H,), 3.48 (s, 2H), 3.85
(s, 2H), 6.90 (d. J= 2.0 Hz). 7.02 (d, 1H, J= 2.0 Hz), 7.46 (d, 2H, J = 7.9 Hz),
7.95 (d, 2H, J = 7.9 Hz)
C. (R)-1,2,3,4-Tetrahydro-3-(3.4-methylenedioxyphenyl)-2-{5-[4-(1 -(4-
methyl)-piperazinylcarbonyl)-phenyl]furoyl}-9H-pyrrolo[3,4-b]quinolin-9-one
(#69)
A mixture of R-1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenvl)-9H-
pyrrolo-[3,4-b]quinolin-9-one, hydrochloride salt (1.12 g, 3.29 mmol) (prepared
as in Example 5A), and the product from Step B (1.034 g, 3.29 mmol) was
stirred with PyBroP (1.535 g, 3.29 mmol) and diisopropyl ethyl amine (1.716
mL, 9.87 mmol) in DMF (30 mL) at room temperature for 12 h. The reaction
mixture was diluted with CH2CI2 (75 mL) and EtOAc (75 mL). This was purified
on a silica gel column (neat CH2CI2, to 2.5 % CH3OH/CH2CI2) to yield the
product as an off-white solid.
MS (m/z): 603 (MH+), 601 (M-1)
1H NMR 5CD3OD d 2.32 (s, 3H), 2.43 - 2.55 (m. 4H), 3.53 (br s, 2H),
3.83 (br s, 2H), 5.25 (d, 1H, J = 15.5 Hz), 5.51 (d, 1H, J = 15.5 Hz), 5.87 (s,
2H), 6.29 (s, 1H), 6.70 (m, 1H), 6.82 (m, 2H), 7.08 (m, 1H), 7.20 - 7.39 (m,
2H), 7.46 - 7.58 (m, 4H), 8.01 (d, 2H, J = 8.6 Hz), 8.31 (d, 2H, J = 8.6 Hz)
HPLC Chiralpak OD 4.6 x 250 mm, 1% DEA/MeOH, Tr= 4.846 min)
Example 60
1,2,3,4-Tetrahvdro-3-(3,4-methvlenedioxvDhenv furovh-9H-Dvrrolo|[3,4-b]quinolin-9-one. sodium salt (Na salt of #22)
Following the procedure outlined in Example 59, with appropriate
substitution of reagents, the product was obtained as a off-white solid.
MS (m/z): 493 (MH*). 491 (M-1)
'H NMR CDCI3 8 5.21 (d, 1H, J = 15.6 Hz), 5.57 (d, 1H, J = 15.6 Hz),
6.12 (s, 2H), 6.51 (s. 2H) 6 68 (d. 1H, J = 4.1 Hz). 6.98 - 7.14 (m, 4H). 7.38 (s,
1H), 7.48 (t, 1H, J = 8.6 Hz). 7.62 -7.79 (m, 4H). 8.08 (s, 1H), 8.28 (d, 1H, J =
8.6 Hz).
Example 61
(4-(2-1-pvrrolinyl)ethoxvtohenyl) boronic acid
(Prepared according to the procedure described by Hoye, T. R. and Chen, M.
in J, Org. Chem. 1996, 61, 7940.)
To a solution of 1-[2-(4-bromophenoxy)ethyl]-pyrrolidine (2.70g, 10
mmol) in THF (40 mL) was added n-butyl lithium (6.9 mL 1.6 M in hexanes, 11
mmol) at -78°C. The reaction mixture was stirred at -78°C for 15 min and then
at 0°C for 15 min. Trimethy) borate (2.5 mL, 22 mmol) was then added to the
reaction mixture at 0°C. The mixture was gradually warmed to room
temperature overnight. Methyl borate in the reaction mixture was hydroiyzed
by reacting with saturated NH4CI aqueous solution (100mL) at room
temperature for 30 min. The upper organic layer was collected. The aqueous
layer was extracted with CHCt3 (2X100 mL). The organic layers were
combined, washed with brine (2X100 mL) and dried with MgSO4. The solvent
was evaporated, resulting in a dense oil which was purified by column
chromatograph (10% MeOH/CHCI3 and 1% Et3N) to yield the product as a
white solid.
MS (m/z): 236, (MH+), 234 (M-1)
1H NMR CO3OD d 1.81 (m, 4H), 2.67 (m, 4H), 2.89 (t, 2H, J - 6.0 Hz),
4.08 (t, 2H, J = 6.0 Hz), 6.74 (d, 2H, J = 8.6 Hz), 7.62 (d, 2H, J = 8.6 Hz).
Example 62
1,2,3,4-Tetrahvdro-3-(3.4-methvlenedioxvDhenvl)-2-(5-(4-(2-n-
pvrrolidinvl)ethoxv)phenvlV-furovlV9H-PViTolor3.4^b1auinolin-9-one(#45)
Following the procedure outlined in Example 59, with appropriate
substitution of reagents, the product was obtained as a off-white solid.
MS (m/z): 590, (MH+), 588 (M-1)
1H NMR CDCI3 6 2.18 (s, 4H), 2.55 (s, 4H), 2.75 (m, 2H), 2.90 (m, 2H),
4.67 (d, 1H, J = 15.6 Hz), 4.82 (d, 1H, J = 15.6 Hz), 5.18 (s, 2H), 5.81 (m, 1H),
6.08 (m, 1H), 6.21 (s, 2H), 6.35 (s, 1H), 6.60 (s, 1H), 6.82 (m, 3H), 6.92 (m,
1H), 7.04 (m, 1H), 7.21 (s, 2H), 7.62 (d. 1H, J = 8.6 Hz).
Example 63
3-(2.3-Dihvdro-5-benzofuranvlV1,2,3,4-tetrahvdro-2-(benzviV-9/^-
pyrrolor3.4HbTquinolin-9-one (#60)
1-(2,3-Dihydro-5-benzofuranyl)-2-benzyl-2,3,4,9-tetrahydro-1H-ß-
carboline (prepared as in Example 2) (5.25 g, 13.81 mmol), potassium dioxide
(3.92 g, 55.24 mmol) and 18-crown-6 (3.65 g, 13.81 mmol) were mixed with
DMF (100mL) in a 200 mL flask. The reaction mixture was maintained at room
temperature overnight. The reaction mixture was slowly added into a separate
500 mL flask containing a mixture of EtOAc (172 mL), H2O (172 mL) and 1N
aqueous HCI (50 mL). The mixture was observed to produce tiny gas bubbles.
The reaction mixture was stirred at 0°C for 30 min, resulting in the formation of
a precipitate at the surface of the two liquid layers. The precipitate was
collected by filtration, washed with H2O (20 mL) and then dried in a vacuum
oven to yield the product as a off-white solid.
MS (m/z): 395, (MH*), 393 (M-1 )..
1H NMR CDCI3 d 3.12 (t, 2H, J = 8.7 Hz), 3.50 -3.65 (m, 2H), 3.99 (d,
1H, J= 13.0 Hz), 4.22 (d, 1H, J = 13.0 Hz), 4.55 (t, 2H, J = 8.7 Hz), 4.91 (s,
1H), 6.74 (d, 1H, J = 8.7 Hz), 7.11 -7.32 (m, 9H), 7.48 (t, 1H, J = 8.7 Hz), 8.30
(t, 1H,J = 8.7Hz)
Example 64
3-(3.4-Methvlenedioxvphenvn-1,2,3,4-tetrahvdro-2-[5-(3-
trifluoromethvnphenvl-2-furovn-9H-pyrrolor3.4-b1auinolin-9-one (#13)
Following the procedure outlined in Example 63, with appropriate
substitution of reagents, 1-(3,4-methylenedioxyphenyl)-2-benzyi-2,3,4,9-
tetrahydro-1 H-p-carboline (0.381 g, 0.719 mmol) was reacted to yield the
product as a off-white solid. Note that for full formation of the precipitate, the
two liquid reaction mixtures were maintained at room temperature for 48 h,
rattier than overnight.
MS (m/z): 545 (MH*), 567 (M+23), 543 (M-1)
1H-NMR (DMSO-d6) 5 5.09 (d, J = 14 Hz, 1 H), 5.46 (d, J - 14 Hz, 1 H),
5.99 (s, 2 H), 6.39 (s, 1 H), 6.91 (d, J = 8 Hz, 1 H). 6.97 (d, J = 9 Hz, 1 H), 7.02
(s, 1 H), 7.33 (d, J = 8 Hz, 1 H), 7.38 (d. J = 4 Hz, 1 H), 7.43 (d, J = 4 Hz, 1 H),
7.60 (m, J = 8 Hz, 2 H), 7.77 (d, J= 5 Hz. 2 H), 8.16 (d, J = 4 Hz, 3 H), 11.55 (s,
1H).
EXAMPLE 65
1-(3,4-Methvlenedioxvphenvl)-2-[4-(4-methoxvphenynthiazol-2-vr|-2.3.4.9-
tetrahvdro-1 H-6-carboline
A. 1 -(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethyloxycarbonyi)
thiocarbamoyl]-2,3,4,9-tetrahydro-1H-ß-carboiine
A mixture of 1-(3,4-methyJenedioxyphenyl)-2,3,4,9-tetrahydro-1H-ß-
carboline (2.66 g, 9.08 mmol) (prepared according to the process as disclosed
in WO97/43287, Intermediate 7, page 24) and Fmoc-tsothiocyanate (2.82 g.
10.14 mmol) was dissolved in dry dichloromethane (50 mL). The mixture was
stirred for 16 hours at ambient temperature, and then concentrated in vacuo.
Purification by flash chromatography (0-10% methanol in dichloromethane)
yielded the protected thiourea as a pale yellow solid.
MS (m/z): 574 (MH+)
1H-NMR (CDCI3) 5 2.86 (dd, J = 12.9, 5.1 Hz, 1 H), 3.09 (dt, J = 17.1,
6.9 Hz, 1 H), 3.56 (dt, J = 12.9, 5.1 Hz, 1 H), 4.19 (t, J = 6.9 Hz, 1 H), 4.43-4.53
(m, 2 H). 5.91 (s, 2 H), 6.70 (d, J = 8 Hz, 1 H), 6.90 (br d, J - 7.6 Hz, 1 H), 6.97
(br s, 1 H), 7.11 -7.78 (series of m, 17 H)
B. 1-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl)-2,3,4,9-tetrahydro-1H-
ß-carboline
A solution of the protected thiourea from Part A (4.78 g, 8.33 mmol) in
20% (v/v) piperidine in methanol was heated to reflux for 5 h. The mixture was
concentrated in vacuo to yield a crude residue which was purified by flash
chromatography (S1O2, 0-10% methanol in dichloromethane) to yield a yellow
solid.
MS (m/z): 352 (MH+)
1H-NMR (CDCI3) 5 2.69-2.87 (series of m, 2 H), 3.10-3.19 (m, 1 H), 4.24
(br s, 1 H), 6.00 (d, J = 3.3 Hz, 2 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.87 (d, J = 8.0
Hz, 1 H). 7.00-7.11 (series of m, 3 H), 7.30 (d, J - 8.0 Hz, 1H), 7.46 (d, J = 7.7 '
Hz, 1H), 7.74 (br s, 3 H), 11.06 (s, 1 H)
C. 1 -(3,4-Methylenedioxyphenyl)-2-[4-(4-methoxyphenyl)thiazol-2yll-
2,3,4,9-tetrahydro-1H-ß-carboline
To a solution of the thiourea from Part B (223 mg, 0.63 mmol) in a 1:1
mixture of dioxane:ethanol (5 mL) was added 4-methoxyphenyl-21-
bromoacetophenone (175 mg, 0.76 mmol) and triethylamine (0.40 mL). The
mixture was heated to 70°C for 3 h, cooled to room temperature and
concentrated in a rotary evaporator. The residue was purified by flash
chromatography (SiO2, 0-10% methanol in dichloromethane) to yield a
colorless solid.
MS (m/z): 482 (MH+)
1H-NMR (CDCI3) 6 2.86-2-3.07 (series of m, 2 H), 3.61-3.71 (m, 1 H),
3.78 (s, 3 H). 3.91-4.02 (m, 1 H), 5,99 (d, J = 3.3 Hz, 2 H). 6.58 (s, 1 H), 6.80-
7.11 (series of m, 8 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.82
(d, J = 8.7 Hz, 2 H). 10.93 (s, 1 H)
EXAMPLE 66
1-(3.4-Methvienedioxyphenvl)-2-[4-phenylthiazol-2-yn-2.3.4.9-tetrahvdro-1H-ß-
carboline
A. 1 -(3,4-Methylenedioxyphenyl)-2-[3-(fluorenylmethytoxycarbonyl)
thiocarbamoyl]-2,3,4,9-tetrahydro-1H-ß-carboline
A mixture of 1-(3,4-methytenedioxyphenyl)-2,3.4,9-tetrahydro-1H-ß-
carboline (2.66 g, 9.08 mmol) (prepared according to the process as disclosed
in WO97/43287, Intermediate 7, page 24) and Fmoc-isothiocyanate (2.82 g,
10.14 mmol) was dissolved in dry dichloromethane (50 mL). The mixture was
stirred for 16 hours at ambient temperature, and then concentrated in vacuo.
Purification by flash chromatography (0-10% methanol in dichloromethane)
yielded the protected thiourea as a pale yellow solid.
MS (m/z): 574 (MH+)
1H-NMR (CDCb) 5 2.86 (dd, J = 12.9, 5.1 Hz, 1 H), 3.09 (dt, J = 17.1, 6.9
Hz, 1 H), 3.56 (dt, J = 12.9, 5.1 Hz, 1 H), 4.19 (t, J = 6.9 Hz, 1 H), 4.43-4.53 (m,
2 H), 5.91 (s, 2 H), 6.70 (d, ^ = 8 Hz, 1 H), 6.90 (br d, J = 7.6 Hz, 1 H). 6.97 (br
s, 1 H), 7.11-7.78 (series of m. 17 H)
B. i-(3,4-Methylenedioxyphenyl)-2-(thiocarbamoyl>-2,3,4,9-tetrahydro-1H-
P-carboline
A solution of the protected thiourea from Part A (4.78 g, 8.33 mmol) in 20%
(v/v) piperidine in methanol was heated to reflux for 5 h. The mixture was
concentrated in vacuo to yield a crude residue which was purified by flash
chromatography (SiO2, 0-10% methanol in dichloromethane) to yield a yellow
solid.
MS (m/z): 352 (MH+)
1H-NMR (CDCI3) 8 2,69-2.87 (series of m. 2 H), 3.10-3.19 (m, 1 H), 4.24 (br
s, 1 H), 6.00 (d, J = 3.3 Hz, 2 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.87 (d, J - 8.0 Hz,
1 H), 7.00-7.11 (series of m, 3 H), 7.30 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz,
1H), 7.74 (br s, 3 H), 11.06 (s, 1 H)
C. 1-(3,4-Methylenedioxyphenyl)-2-[4-phenylthiazol-2yl]-2,3,4,9-tetrahydro-
1 H-p-carboline
To a solution of the thiourea of Part B (227 mg, 0.65 mmol) was added p-
bromoacetophenone (159 mg, 0.80 mmol) and triethylamine (0.40 mL). This
mixture was heated to 70°C for 3 h, cooled to room temperature and
concentrated in a rotary evaporator. The residue was purified by flash
chromatography (SiO2, 0-10% methanol in dichloromethane) to yield a pale
yellow solid.
MS (m/z): 452 (MH+)
1H-NMR (CDCI3) 8 2.87-2-3.06 (series of m, 2 H), 3.63-3.73 (m, 1 H), 3.93-
3.99 (m. 1 H), 5.99 (d, J * 3.3 Hz, 2 H), 6.59 (s, 1 H), 6.81-7.11 (series of m, 5
H), 7.25-7.69 (series of m, 6 H), 7.89 (d, J = 7.4 Hz, 2 H), 10.95 (s, 1 H)
Example 67
3-(2.3-Dihvdto-benzofuran-5-vlV1,2,3,4-tetrahvdro-3R-9H-Dvrrotof3.4-
bfauinolinone
A: [2-(1H-lndol-3-yl)-ethl)-(1-naphthalen-1-yl-ethyl)-arnine was prepared
according to the process described in Kawate, T.; Yarnanaka, M.; Nakagawa,
M. in Heterocydes. 1999, 50,1033
B: R- and S- Diastereomers of 1 -(-2,3-dihydro-benzofuran-5-yl)-2-(1 R-1 -
naphthafen-1 -yl-ethyl)-2,3,4,9-tetrahydro-1H-ß-carbotine
[2-(1H-lndol-3-yl)-ethyl]-(1-naphthalen-1-yl-ethyl)-amine (1.0 g, 3.18
mmol) and 2,3-dihydro-benzofuran-5-carbaldehyde (2.356 g, 15.92 mmol) were
stirred in p-xylene (20 mL) at 165oC for 7 h. To the reaction mixture was added
silica gel (10 g) and hexane (200 mL). The reaction mixture was filtered and
the colorless filtrate was discarded. The silica gel was washed with ethyl
acetate (100 mL). The ethyl acetate solvent was evaporated, the concentrated
crude material was dissolved in a small amount of CH2CI2 and packed on a
silica gel column. The column was eluted with 5% ethyl acetate/hexane to
yield two diastereomers.
1-(-2,3-dihydro-benzofuran-5-yl)-2-(1 R-1 -naphthalen-1-yl-ethyl)-2,3,4,9
tetrahydro-1S-1H-ß-carbofine (the non-desired diastereomer A) (Rf = 0.59 in
30% EtOAc/Hexane) was obtained as yellow solid.
1H NMR 300 MHz (CDCI3) d 1.581.62 (d, 3H, J = 6.5 Hz), 2.61 (m, 1H),
2.91 (m, 1H), 3.05 -3.20 (m, 4H), 4.51 (t, 2H, J = 8.8 Hz), 4.72 (m, 1H), 4.81
(s, 1H), 6.68 (m, 1H), 6.92 (m. 4H), 7.05 - 7.65 (m, 5H), 7.70 ~ 7.95 (m, 4H)
MS (m/z) MH+{445), MH(443).
1 -(-2,3-dihydro-benzofuran-5-yl)-2-(1 R-1 -naphthalen-1 -yl-ethyl)-2,3,4,9-
tetrahydro-1R-1H-ß-carboline (the desired diastereomer B) (Rf := 0.51 in 30%
EtOAc/Hexane) was obtained as a yellow solid.
1H NMR 300 MHz (CDCI3) 6 1.58 (d. 3H, J = 6.5 Hz), 2.65 (m, 1H), 2.91
(m, 2H), 3.05 (t, 2H. J = 8.8 Hz), 3.15 (m. 1H), 4.51 (t, 2H, J = 8.8 Hz), 4.65 (m,
1H). 5.10 (s, 1H), 6.68 (m, 1H). 6.85 (s, 2H), 7.11 (m, 2H), 7.20 -7.50 (m, 5H),
7.68 (m, 2H), 7.81 (m, 1H), 8.21 (m, 1H)
MS (m/z) MH*(445), MK(443).
C: Conversion of S-diastereomer to R-diastereomer
1-(-2,3-dihydro-benzofuran-5-yl)-2-( 1 R-1-naphthalen-1-yl-ethyl)-2,3,4,9-
tetrahydro-1S-1H-ß-carboline (the non-desired diastereomer A) (190 g, 0.428
mmol) was stirred in 1000 mL CH2CI2 with TFA (52 mL, 701 mol) at room
temperature overnight. The reaction was quenched with NaOH (35 g, 0.875 mol)
in water (100 mL). The reaction mixture was mixed well and then let stand for 0-5
hours, during which time a precipitate formed. The precipitate was filtered, the
solid washed with water and dried under high vacuum to yield the product as a
solid.
1H NMR was identical to that of 1-(-2,3-dihydro-benzofuran-5-yl)-2-(1R-1-
naphthalen-1-yl-ethyl)-2,3,4,9-tetrahydro-1R-1H-ß-carboline (the desired
diastereomer).
D: 3-(2,3-Dihydro-benzofuran-5-yl)-2-(1R-1-naphthaten-1 -y)-ethyl)-1,2,3,4-
tetrahydro-3R-9H-pyrrola[3,4-b]quinolinone
1 -(2,3-Dihydro-benzofuran-5-yt)-2-(1 R-1 -naphthalen-1 -yl-ethyl)-2,3,4,9-
tetrahydro-1R-1H-ß-carboline (0.6469 g, 1.46 mmol) and potassium-t-butoxide
(0.279 g, 2.48 mmol) were stirred in DMF (14 mL) at room temperature. O2
gas was bubbled into the reaction mixture overnight. The reaction was
quenched with HCI (2.48 mL, 1 N aqueous). Ethyl acetate (50 mL) and H2O
(50 mL) were then added. The organic layer was separated. The aqueous
layer was extracted with ethyl acetate (50 mL) and CH2CI2 (50 mL). The
organic layers were washed with brine (3 X 50 mL) and dried over MgSO4.
The resulting product was concentrated and purified via silica gel (2%
methanol / CH2CI2) to yield the product as a yellow solid.
1H NMR 300 MHz (CDCI3) 5 1.65 (d. 3H, J ' 6.5 Hz), 3.05 (t, 2H. J - 8.8
Hz), 4.01 (m, 2H), 4.51 (t, 2H, J = 8.8 Hz), 4.68 (m. 1H), 5.31 (s, 1H), 6.62 Is,
1H), 6.88 -7.89 (m, 12H), 8.25 (d, 1H)
MS (m/z) MH+ (459), MH(457).
E: 3-(2,3-Dihydro-benzofuran-5-yl)-1.2,3,4-tetrahydro-3R-9H-pyrrolo[3,4-
b]quinolinone
3-(2,3-Dihydro-benzofuran-5-yl)-2-(1 R-1-naphthalen-1 -yl-ethyl)-1,2,3,4-
tetrahydro-3R-9H-pyrrolo[3,4-bJquinolinone (24 mg, 0.0524 mmol) was
dissolved in 5 mL ethanol. To the reaction mixture was added 10% Pd /C (50
mg) and HCI (1.0 M in diethyl ether (0.05 mL, 0.05 mL)). The reaction mixture
was stirred under 35 psi of H2 gas for 3 hours at room temperature. The
catalyst was filtered away on a P*ug of Celite. The reaction mixture was
concentrated to yield crude product. Purification by preparative TLC (5%
MeOH /CH2CI2) yielded the title product as yellowish solid.
1H NMR 300 MHz (CDC13) d 13.23 (d, 2H, J = 8.8 Hz). 4.59 (t, 2H, J = 8.8
Hz), 4.78 (m, 2H), .32 (s, 1H). 6.88(m. 1.H), 7.31 (m, 2H), 7.72 (m, 3H), 8.32
(m, 1H).
MS (m/z) MH+ (305), MH- (303)
EXAMPLE 68
3-Benzo[1,3]dioxol-5-yl-2-(5-bromo-furan-2-carbonyl)-1,2,3,4-tetrahydro-
pvrrolo[3,4-blquinolin-9-one
To a solution of 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) in THF (20
mL) was added oxalyl chloride (0.66mL, 7.541 mmol). 2 drops of DMF were
then added to the reaction mixture, with bubbles of CO observed to come out
vigorously. Oxalyl chloride ((COCI)2, (0.1 mL) was then added. The reaction
mixture was stirred at room temperature for 10 min and at 90°C for 10 min.
Solvent and excess (COCI)2 were taken off under vacuum to yield 5-bromo-
furan-2-carbonyt chloride as a pale yellow crystalline solid.
The solid 5-bromo-furan-2-carbonyl chloride was dissolved in THF (20
mL). A solution of 3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-9H-
pyrrolo[3.4-b]quinolinone (2.1 gf 6.856 mmol) in THF (20 mL) was then added.
Triethyiamine (4.55 mL, 32.64 mmol) and DMAP (40 mg, 0.327 mmol) were
then added in sequentially. A few drops of DMF were added to the reaction
mixture to keep the solution clear. The reaction mixture was stirred at room
temperature for 4 hours and then concentrated under vacuum. The residue
was dissolved in CHCl3 (200 mL) and washed with H2O (3x200 mL), The
organic layer was dried over MgSO4 to yield the title product as an off-white
solid. No further purification was necessary.
1H NMR 300 MHz (CD3OD) d 4.87 (d, 1H, J = 11.5 Hz), 5.19 (d. 1H, J -
11.5 Hz), 5.78 (m, 2H), 6.24 ~ 7.60 (m. 8H), 8.39 (d, 1H, J = 8.3 Hz)
MS (m/z): 479, 481 (MH\479, 477 (MH')
EXAMPLE 69 through 79
General Procedure
3-Benzo[1,3]dioxol-5-yl-2-(5-bromo-furan-2-carbonyl)-1,2,3,4-tetrahydro-
pyrrolo[3,4-b]quinolin-9-one (0.100 g, 0.2086 mmol) was stirred with a mixture
of a suitably substituted boronic acid (0.2296 mmol, 1.1 eq), Pd(PPh3)4 (12. 4
mg, 0.01043 mmol), K2CO3 (86.4 mg, 0.6258 mmol) in 1,4-dioxane (8 mL) and
H2O (2 mL) was degased under H2 and then stirred at 100'C for 1.5 hours.
The crude reaction mixture was loaded onto a silica gel preparative TLC plate
and eluted with 5% CH3OH/CH2CL2 to yield the isolated product as a solid.
Compound #110 (reacted with phenvl boronic acid)
1H NMR 300 MHz (CD3OD) 5 5.19 (d, 1H, J = 11.5 Hz), 5.42 (d, 1H, J =
11.5 Hz), 5.93 (s, 2H), 6.38 (s. 1H), 6.74 ~ 8.31 (m, 14H)
MS (m/z): 477 (MH+), 475 (MH")
Compound #111 (reacted with 4-methvlthioDhenyl boronic acid)
1H NMR 300 MHz (CO3OD) 5 5-21 (d, 1H, J = 11.5 Hz), 5.44 (d, 1H, J =
11.5 Hz). 5.91 (s, 2H), 6.40 (s, 1H), 6.77 (d, 1H, J = 9.0 Hz), 6.98 ( s, 2H), 7.21
- 7.81 (m, 11H), 8.31 (d, 1H, J = 9.0 Hz)
MS (m/z): 523 (MH*), 521 (MH")
Compound #112 (reacted with 3-thienyi boronic acid)
1H NMR 300 MHz(CD3OD)5 5.22 (d, 1H, J= 11.5 Hz). 5.43 (d, 1H, J =
11.5 Hz), 5.88 (s, 2H), 6.38 (s. 1H), 612 - 8.38 (m. 12H)
MS (m/z): 483 (MH+), 481 (MhT)
Compound #116 (reacted with 4-methYlohenvl boronic acid)
1H NMR 300 MHz (CD3OD) 5 2.Z5 (s, 3H), 5.21 (d, 1K J = 11.5 Hz),
5.42 (d, 1H, J= 11.5 Hz), 5.80 (s. 2H), 6.38 (s, 1H). 6.74 - 8.31 (m, 13H)
MS (m/z): 491 (MH*), 489{MH1
Compound #113 (reacted with 2-nitroprtenvl boronic acid)
1H NMR 300 MHz (CD3OD) 5 5.25 (d, 1H, J = 11.5 Hz). 5.42 (d, 1H, J =
11.5 Hz), 5.88 (s, 2H), 6.39 (s. 1H), 6.68 - 8.66 (m. 13H)
MS (m/z): 522 (MH+), 520(MH)
Compound #117 (reacted with 2-thienyl boronic acid)
1H NMR 300 MHz (CD3OD) 5 5.19 - 5.42 (m, 2H), 5.93 (s, 2H), 6.40 (s,
1H), 6.74-8.35 (m, 11H)
MS (m/z): 467 (MH+), 465 (MH")
Compound #118 (reacted with 3.4-methvlenedioxvphenvl boronic acid)
1H NMR 300 MHz (CDaOD) 5 5.19 ~ 5.42 (m, 2H), 5.93 (m, 4H), 6.38 (s,
1H), 6.74-8.31 (m, 12H)
MS (m/z): 521 (MH+), 519 (MH")
Compound #119 (reacted with 4-cvanoohenvl boronic acid)
1H NMR 300 MHz (CD3OD) 6 5.21 - 5.42 (m, 2H), 5.70 (m, 2H). 6.18 (s,
1H), 6.60 -8.51 (m, 13H)
MS (m/z): 502 (MH*), 500 (MK)
Compound #120 (reacted with 4-hvdroxvmetlwlohenvl boronic acid)
1H NMR 300 MHz (CD3OD) 5 4.79 (s, 2H), 5.25 (d? 1H, J = 11.5 Hz),
5.52 (d, 1H, J = 11.5 Hz), 5.89 (s, 2H), 6.48 (s, 1H), 6.70 - 8.31 (m, 13H)
MS (m/z): 507 (MH*), 505 (MH")
Compound #121 (reacted with 3-rwdroxvmethvlphenvl boronic acid)
1H NMR 300 MHz (CD3OD) 8 4.79 (s, 2H), 5.21 (d, 1H, J - 11.5 Hz),
5.48 (d. 1H. J = 11.5 Hz), 5.89 (s, 2H), 6.31 (s, 1H). 6.62 - 8.31 (m, 13H)
MS (m/z): 507(MH+), 505 (MH)
Compound #122 (reacted with 4-dimethviaminophenvi boronic acid)
1H NMR 300 MHz (CD3OD) 5 5.21 - 5.50 (d, 1H, J = 11.5 Hz), 5.90 (s,
2H), 6.40 (d, 1H), 6-64 - 8.31 (m, 13H)
MS (m/z): 520 (MH*), 518 (MH*)
EXAMPLE 80
3-r2.3-Dihvdro-ben2ofuran-5-^V2-Pvrim>din-2-v1-1,2,3,4-tetrahvdro-pvrrotor3.4-
biquinolin-9-one (#123)
3-(2,3-D«hydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-
b]quinolin-9-one-HCl salt (0.15 g, 0.440 mmol) was stirred with
chloropyrimidine (60.5 mg, 0.528 mmol). KF (31 mg, 0.528 mmol) and DIEA
(0.19 mL, 1 -1 mmoO at 60°C for 16 h. The reaction mixture was diluted with
H2O (20 mL). The solid was filtered and dried on a suction funnel under
vacuum. After silica gei preparative TLC, the title product was isolated as a
yellow solid.
1H NMR 300 MHz (CDCI3) 5 3.10 (t, 2H, J = 8.8 Hz), 4.52 (t, 2H, J = 8.8
Hz), 4.92 (m, 2H), 6.15 -8.45 (m, 10 H). 9.81 (br, s, 1H)
MS (m/z) 383(MH+), 381 (MH").
EXAMPLE 81
3-Benzofuran-5-vl-2^5-ovridin-2-vl-ovrirnidin-2-vlV-1,2,3,4-tetrahvdro-
DvnTolof3.4-b1auinol»n-9-one (#126)
A: Benzofuran-5-carbaldehyde was prepared according to the process
described by Hiroya, K.; Hashimura, K.; Ogasawara, K. in Heterocycles, 1994,
Vol. 38, No. 11,2463-72
B: 1-Benzofuran-5-yl-2,3,4,9-tetrahydro-1 H-p-carboline was prepared
according to the process outlined in Example 12,
'H NMR 300 MHz (CDCI3) 8 2.68 -2.95 (m, 2H). 3.10 (m, 1H), 3.28 (m.
1H), 5.25 (s, 1H), 6.65 (s, 1H). 7.15 (m, 3H), 7.38 (m, 2H), 7.51 (m, 1H), 7.58
(s.1H),8.22(s, 1H)
MS (m/z) MH+ (289), MH" (287).
C: 1 -Benzofuran-5-yl-2-(5-pyridin-2-yl-pyrimidin-2-yl)-2, 3,4,9-tetrahydro-1 H-p-
carboline was prepared according to the process outlined in Example 12.
1H NMR 300 MHz (CDCl2) 6 3.00 (m, 2H), 3.40 (m, 1H). 5.11 (m. 1H),
6.65 (s, 1H), 7.15 -8.00 (m, 12H), 8.61 (m, 1H), 8.91 (m, 1H), 8.22 (s, 2H)
MS (m/z) MH+ (444), MH" (442).
D: 1 -(5-benzofuryl)2,34,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1 H-p-
carboline (30 mg, 0-06764 mmol) and KOfBu (12-9 mg, 0.115 mmol) were
stirred in DMF (1 mL) under O2 gas for 10 hours at room temperature.
Preparative TLC (5% methanoi in CH2CI2) yielded the title product as yellow
solid.
1H NMR 300 MHz (CD3OD) 6 5.15 (m, 2H), 6.55 (s, 1H), 6.82 -8.98 (m,
15H)
MS (mlz) 458, (MH+), 456 (MH).
EXAMPLE 82
3-(2.3-Dihvdro-benzofuran-5-vl)-2-r5-n-oxv-Dvridin-2-vl)-Dvrimidin-2-vfl-1,2,3,4-
tetrahvdro-Dvrrolof3.4-biQuinolin-9-one (#125V
3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-2-[5-(2-pyridinyl)-2-
pyrimidinyl]-(3/?)-9H-pyrrolo(3,4-/j]quinolin-9-one (4.5 mg, 0.010 mmol) and
mCPBA (1.73 mg, 0.010 mmol) were stirred in THF (2 mL). A few drops of
DMF were added to make the solution clear. The reaction mixture was stirred
at room temperature for 80 hours and then at 60°C for 8 hours. Preparative
TLC (10% MeOH in CH2CI2) yielded the title product as off-white solid, with
some recovered starting material
1H NMR 300 MHz (CD3OD) 6 3.12 Hz), 6.35 (s, 1H), 6.55 (d, 1H), 7.21 ~ 8.99 (m, 11H)
MS (m/z)458, (MH*), 456(MH)
EXAMPLE 83 Through 86
1-(2.3-Dihvdro-benzofuran-5-yl)-2-[5-f2.3-dimethvl-3H-imidazol-4-vlVDvrimidin-
2-vn-2.3.4.9-tetrahvdro-1H-B-carboline
2-(5-bromo-2-pyrimidinyi)-1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-
tetrahydro-1H-ß-carboline (0.45 g, 1,OOmmol), 1,2-dimethyl-1H-imidazole (0.18
g, 1.87 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), PPh3 (26 mg, 0.1 mmol) and
K2CO3 (0.28 g, 2 mmol) were stirred in 3.5 mL DMF at 140oC for 14 hours.
The mixture was poured into aqueous 10% NaOH solution (50 mL). The
resulting solution was extracted with CH2CI2 (3x50 mL) and dried over Na2SO4.
Purification by preparative TLC yielded the title product as yellow powder.
1H NMR 300 MHz (CDCI3) 8 2.21 (s, 3H), 2.35 (s, 3H), 2.90 (m, 2H),
3.10 (t, 2H, J = 8.8.Hz), 3.35 (m, 1H), 4.52 (t, 2H, J = 8.8.H2), 4.91 (m, 1H),
6.68-7.61 (m,10H)
MS (m/z) 463 (MH+), 461 (MH').
The following compounds were similarly prepared according to the
procedure described above with appropriate selection and substitution of
suitably substituted reagents.
2-[5-(3-Benzyl-2-methyl-3H-imidazol-4-yl)-pyrimtdin-2-vn-1-(2.3-diriydro-
benzofuran-5-vtV2.3.4.9-tetrahvdro-1H-ß-carboline
MS (m/z) 539, (MH+), 537 (MH).
3-(213-Dihvdro-benzofuran-5-yl)-2-I5-(2.3-dimethvt-3H-imidazol-4-v1VDvrirnidin-
2-vq-1,2,3,4-tetrahvdro-Dvrrolo[3.4-ß]quinolin-9-one (#128)
1H NMR 300 MHz (CD3OD) 5 3.08 (t, 2H, J = 9.5 Hz), 3.28 (s, 3H), 3.50
(s, 3H)( 4.42 (t, 2H, J= 9.5 Hz), 5.0 2 (br, s, 2H), 6.24 (s, 1H). 6.63 (m, 1H),
6.84 (s, 1H), 7.19 (m, 2H), 7.31 (m, 1H), 7.53 (s, 2H), 8.35 (m, 3H)
MS (m/z) 477, (MH*), 475 (MH').
2-[5-3-Benzvl-2-methvl-3H-irrwdazol-4-vl>-Pvrimidin-2-v}1-3-(2.3-clihvdro-
benzofuran-5-yl)1,2,3,4-tetrartvdro-Dvrrotof3.4-b1auinoHn-9-one ^#127)
1H NMR 300 MHz (CD3OD) 5 1.90 (s, 3H), 2.21 (s, 2H), 3.12 (t, 2H, J =
8.8 Hz), 4.48 (t, 2H, J = 8.8 Hz), 5.12 (m, 2H), 6.15 (s, 1H), 6.61 ~ 8.85 (m,
15H)
MS (m/z) MH* (553), MH' (551).
EXAMPLE 87
3-(2.3-Dihvdro-benzofuran-5-vl)-2-ovridin-2-vl-1,2,3,4-tetrahvdro-pvrrolor3.4-
b]quinolin-9-one (#129)
3-(2,3-dihydro-5-benzofuranyl)-1,2l3,4-tetrahydro-9H-pyrrolo[3,4-
b]quinolin-9-one HCl (0.30g, 0.88 mmol) and 2-bromo-pyridine (2 mL). Pd2dba3
(0.23g, 0.25 mmol). BINAP (0.47g, 0.75 mmol) and NaOtBu (0.66g, 6-87
mmol) were stirred in 1,4-dioxane (4 mL) at 90°C for 1 hour- The resulting
mixture was concentrated and then filtered on a plug of Celite with CH2CI2.
Purification by preparative TLC (5% CH3OH / CH2CI2) yielded the title product
as a yellow solid.
1H NMR 300 MHz (CD3OD) 5 2.92 (t, 2H, J = 9.5 Hz), 4.40 (t, 2H, J- 9.5
Hz), 4.54 (d, 1H, J = 22 Hz), 4.85 (d, 1H. J = 22 Hz), 6,55 (m, 2H), 7.10 (m,
3H), 7.35 (m, 4H)( 8.02 (m, 1H), 8.30 (d. 1H, J = 9.3 Hz)
MS (m/z) 382, (MH+), 380 (MH")
EXAMPLE 88
3-Benzo[1,3]dioxol-5-yl-2-(4-imidazol-1 -yl-phenvl )-1 ,2,3.4-tetrahvdro-
Dvrrolof3.4-b1ouinolin-9-one (#1331
3-(1,3-benzodioxol*5-yl}-1,2,3,4-tetrahydro-9H-pyrrolo[4-b]quJnolin-9-
one (30.6 mg, 0.1 mmol), 1-(4-bromo-phenyl)-1H-imidazole (22.3 mg, 0.1
mmol), Pd2dba3 (4.6 mg, 0.005 mmol), biphenyl-2-yi-di-tert-butyi-phosphane
3.0 mg, 0.01 mmoi) and NaOfBu (14 mg. 0.14 mmot) were stirred in 1,4-
dioxane (0.6 mL) at 89°C for 17 hours. Purification by preparative TLC (5%
CH3OH /CH2CI2) yielded the title product as yellow powder.
'H NMR 300 MHz (CD3OD) 8 4.70 (d, 1H), 5.02 (d, 1H). 5.48 (s, 2H),
5.88 (s, 2H), 6.75 - 8.32 (m, 14H)
MS (m/z) MH*(449), MH'(447)
EXAMPLE 89
2-r2.3'1BiDvridinvl-6'-vl-3-(2.3-dihvdro-benzofuran-5-vlV1,2,3,4-tetrahvclro-
pvrrolof3.4-biQuinolin-9-one (# 134)
A: 2-(5-Bromo-pyridin-2-yl)-1 (2,3-dihydro-benzofuran-5-yl)-2,3,4,9-
tetrahydro-1 H-ß-carboline
1 -(2,3-dihydro-5-benzofurany1>-2,3,4,9-tetrahydro-1 H-ß-cart>oline (11.6
g, 40 mmol), 2, 5-dibromopyridine (10.42 g, 44 mmol), Pd2dba3 (1.465 g, 1.6
mmol), dppp (1.32 g, 3.2 mmol) and NaOfBu (5.38 g, 56 mmol) were stirred in
60 mL DMF at 80°C for 3 days. The reaction mixture was filtered through a
plug of Celite with CH2CI2. The reaction mixture was then concentrated, the
crude mixture was then loaded on Foxy column (110 g silica gel) and eluted
with ethyl acetate / hexane (3:7). The product crystallized out in test tubes.
The product was concentrated and then recrystallized from THF to yield the
product as yellow crystals.
1H NMR 400 MHz (THF-d8) d 0.91 (m, 1H). 1.15 (m, 1H), 1.25(t. 2H, J =
9.5 Hz), 1.60 (m, 1H), 2.31 (m, 1H), 2.60 (t, 2H, J = 9.5 Hz), 4.75 (d, 1H, J =
7.6 H), 5.02 (d, 1H. J = 7.6 Hz). 5.10 -5.28 (m, 4H), 5.380 (m, 2H), 5.58 (m,
1H), 5.72 (m, 1H), 6.28 (s, 1H), 8.12 (s, 1H)
MS (m/z) 446,448 (MH+), 444, 446 (MH>
B: 2-[2,3']Bipyridinyl-6'-yl-1 -(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-
tetrahydro-1 H-ß-carboline
The product from step A above (0.4 g, 0.896 mmoi), 24ributy1stannanyl-
pyridine (0.8 g, 2.17 mmol) and Pd(PPh3)4 (0.12 g, 0.104 mmol) were stirred in
1,4-dioxane (5 ml) at 88*C for 24 h. The reaction mixture was filtered through
a plug of Celite with CH2CIz and then concentrated to a small volume.
Preparative TLC (3:7 ethyl acetate / heaxne; then 5% CH3OH / CH2CI2) yielded
the product as a yellow solid.
'H NMR (CDCI3) 5 2.82 (m, 1H), 3.10 (m, 3H), 3.58 (m, 1H), 4.31 (m,
1H), 4.53 (t, 2H, J - 9.5 z), 6.71 (, d, 1H. J = 7.6 Hz), 6.85 (d. 1H, J = 7.6 Hz)
MS (m/z) 445, (MH*)r 443 (MH")
C: 2-[2,3]Bipyridinyl-6'-yl-3-(2,3-dihydro-benzofuran-5-yJ)-1,2,3,4-
tetrahydro-pyrrolol3,4-b]quinolin-9-one (#134)
Following the procedure describe in Example 19 with appropriate
selection and substftutbn of reagents, yielded the title product as a solid.
yH NMR 300 MHz (CDCI3) 5 3.16 (t, 2H, J = 9.5 Hz), 4.43 (t, 2H. J = 9.5
Hz), 4.98 - 5.20 (m. 2H), 6.12 (s, 1H), 6.60 - 8.70 (15 H)
MS (m/z)459 (MH+),457 (MH)
EXAMPLE 90
3-(2.3-Dihvdro-ben2ofuran-5-vlV2-r5-(3-methvl-3H-imiclazol-4-vlVpvridin-2-vn-
1,2,3,4-tetriahvdrD-DviTolor3.4-blquinolin-9-one (#137)
A: 2-Chloro-5-(3-methyI-3H-imldazol-4-yl)-pyridine
2-Chloro-4-iodo-pyridine (0.239 g, 1 mmol), 1-methyi-1H-imidazole (0.41
g, 5 mmol), Pd(0Ac)2 (22.5 mg, 0.1 mmol), PPh3 (53 mg, 0.2 mmol) and
CS2CO3 (0.326g, 1 mmol) were stirred in DMF (3 mL) at 120*C, for 6 hours.
Purification by preparative TLC yielded the product as an oil containing 1-
methyl-1H-imidazole. The product was used for the next step without further
purification.
1H NMR (CDCI3) 5 3.68 (s, 3H), 7.19 (s, 1H), 7.27 (s, 1H), 7.56 (s, 1H),
7.68 (dd, 1H),8.45(d,1H)
MS (m/z) MH+ (194).
B: 3-(2,3-Dihydro-benzofuran-5-yl)-2-[5-(3-methyl-3H-imidazol-4-yl)-pyridin-
2-yi]-i ,2,3,4-tetrahydro-pyrrolo[3,4-b]qu'moIin-9-one (#137)
3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-
9-one (0.127 g, 0.372 mmol), 2-chloro-5-(3-methyl-3H-imida2Ol-4-yl)-pyridine
(0.06 g, 0.31 mmol), PdfOAcfe (3.5 mg, 0.0155 mmol), biphenyl-2-yl-
dicydohexyl-phosphane (5.43 mg, 0.0155 mmol) and NaOtBu (0.104 g, 1.085
mmol) were stirred in 1,4-dioxane (0.6 mL) at 90*C. Purification by preparative
TLC (5% MeOH in CH2CI2) yielded the product as yellow solid.
1H NMR 300 MHz (CDCI3) 5 3.12 (t, 2H), 3.60 (s, 3H), 3.50 (t, 2H), 5.12
(m, 2H), 6.08 (s, 1H), 6.70 (m. 2H), 7.20 -8.55 (m, 10 H)
MS (m/z) MH* (462), MH" (460)
EXAMPLE 91
2-[5-(3-Benzyl-3H-imidazol-4-yl)-pyridin-2-yl3-3-(2,3-dihydro-benzofuran-5-yl)-
1 T2,3,4-tetrahydro-pyrrolo[3,4-b]quino!in-9-one (#138)
A: 5-(3-Benzyl-3H-imidazoW-yl)-2-chloro-pyridine
Following the procedure described in Example 90, Step A, with
appropriate selection and substitution of reagents, yielded the product as a
solid.
1H NMR (CDCI3) d 5.15 (s, 2H), 6.86 -8.30 (m, 10 H)
MS (m/z) MH+ (270)
B: Following the procedure described in Example 90 Step B, with
appropriate selection and substitution of reagents, yteW the product as a solid.
1H NMR 300 MHz (CD3OD) 5 3.12 (t, 2H), 3.60 (m, 2H), 4.55 (t, 2H),
5.10 (m, 2H), 6.05 (s, 1H), 6.45 -8.54 (m, 12H)
MS (m/z) MH* (538), MH (536).
EXAMPLE 92
3-(2.3-Dihvdro-benzofufan'5-vl)-2-pvridin-2-vl-1,2,3,4-tetrahvdro-pvirrolo[3.4-
biquinolin-9-one (#136)
3-(2,3-dihydro-5-benzofuranyl)-1t2,3,4-tetrahydro-(3R)-9H-pyrroio[3,4-
6]quinolin-9-one HCI (0.0341 g. 0.1 mmol), 2-iodo-pyridine (0.0341 g, 0.2
mmol), Pd2dba3 (22.9 mg, 0.025 mmol), BINAP (46.7 mg, 0.075 mmol) and
NaOtBu (58 mg, 0.6 mmol) were stirred in 1,4-dioxane (0.8 mL) at 50°C for 3
hours. Purification by preparative TLC (5 % methanol / CH2CI2) yielded the
product as a yellow solid.
1H NMR 300 MHz (CD3OD) 5 2.92 (t, 2H, J = 9.5 Hz). 4.40 (t, 2H, J = 9.5
Hz), 4,54 (d, 1H, J = 22 Hz), 4.85 (d, 1H. J = 22 Hz), 6.55 (m, 2H), 7.10 (m,
3H), 7.35 (m, 4H), 8.02 (m, 1H). 8.30 (d, 1H, J = 9.3 Hz)
MS (m/z) MH* (382), MH" (380)
HPLC trace: Chiral OD. methanol. 25°C, tr = 5.201 min.
Example 93
3-r2.3-dihvdro-benzofurn-5-vl)-2-r5-f3H-imidazol-4-vlVDvridin-2-v tetrahvdro-pvrTotof3.4-b\quinoiin-9-one
A stirred solution of 2-[5-(3-Benzyl-3H-imidazol-4-yl)-pyridin-2-yl]-3-(2,3-
dihydro-benzofuran-S-ylJ-i^.a^tetrahydro-pyrrolofS^-bJquinolin-g-one (0.005
mmol, 1 equivalent), prepared as in Example 91, and p-toluenesulfonyl
hydrazide (0.25 mmol, 50 equivalents) in CH3OH (3 mL) at about 80*C is
added to a solution of sodium acetate (0.5 mnnol, 100 equiv.) in H2O (2 mL)
over about a 2 h period. The mixture is stirred for about another 3 h at about
80°C, then cooled to about 25°C, and the solvent evaporated. The residue is
dissolved into CH2CI2 (20 mL), washed with saturated aqueous NaCI (10 mL),
dried (Na2SO4), and concentrated to yield the title product.
Example 94
3-(2,3-Dihvdro-benzofpran-5-vl)-2-[5-(2-methvl-3H-imidazol-4-vlVpyrimidin-2-
v(1-1,2,3,4-tetrah vdro-pvrrolo[3.4-blquinolin-9-one
Following the procedure described in Example 93, 2-{5-{3-ben2yl-2-
methyl-3H-imidazol-4-yl)-pyrimidin-2-yl]-3-(2,3-dihydro-ben2ofuran-5-yl)-
1,2,3,4-tetrahydro-pyrrolo[3.4-b]quinolin-9-one, prepared as in Example 86, is
reacted to yield the title compound.
Example 95
IN VITRO TESTING
Cydic Nucleotide Phosphodiesterase (PDEt Assay
PDEV Isolation
PDEV was isolated from rabbit and human tissues according to the
protocol described by Boolell et al. [Boolell, M., Alien, M. J., Ballard, S. A., Ge[o-
Attee, S., Muirhead, G. J., Naytor, A. M., Osterloh, I. H., and Gingell, C) in
International Journal of Impotence Research 1996 8,47-52 with minor
modifications.
Briefly, rabbit or human tissues were homogenized in an ice-cold buffer
solution containing 20mM HEPES (pH 7.2), 0.25M sucrose, 1mM EDTA, and
1 mM phenylmethylsulphonyl fluoride (PMSF). The homogenates were centrifuged
at 100,000g for 60 minutes at 4*C. The supernatant was filtered through 0.2jiM
filter and loaded bo a Pharmacia Mono Q anion exchange column (1ml bed
volume) that was equilibrated v«th 20mM HEPES, 1mM EDTA and O.SmM PMSF.
After washing out unbound proteins, the enzymes were eluted with a linear
gradient of 100-600 mM NaCI in the same buffer (35 to 50 ml total, depending on
the tissue. Enzymes from the skeletal muscle, corpus cavemosum, retina, heart
and platelet were eluted with 35,40, 45, 50, and 50 ml respectively.) The column
was run at a flow rate of 1ml/min and 1ml fractions were collected. The fractions
comprising various PDE activities were pooled separately and used in teter
studies.
Measurement of Inhibition of PDEV
The PDE assay was carried out as described by Thompson and Appleman
in Biochemistry 1971 10, 311-316 with minor modifications, as noted below.
The assays were adapted to a 96-well format. The enzyme was assayed in
5mM MgCI2,15mM Tris HCl (pH 7.4), 0.5 mglm! bovine serum albumin, 1 µM
cGMP or cAMP, 0.1 µCi [3H]-cGMP or [3H]-cAMP, and 2-10 µl of column elution.
The total volume of the assay was 100 µl. The reaction mixture was incubated at
30*C for 30 minutes. The reaction was stopped by boiling for 1 minute and then
cooled down on ice. The resulting [3H]5'-mononucleotides were further converted
to uncharged [3H3-nucleosides by adding 25 yl 1 mg/ml snake venom
(Ophiophagus hannah) and incubating at 30°C for 10 minute. The reaction was
stopped by the addition of 1 ml Bio-Rad AG1-X2 resin slurry (1:3). All the charged
nucleotides were bound by the resin and only uncharged [3H]-nucleosides
remained in the supernatant after centrifuging. An aliquot of 200 ^l was taken and
counted by liquid scintillation. PDE activity was expressed as pmol cyclic
nucleotide hydrolyzed/min/ml of enzyme preparation.
Inhibitor studies were earned out in assay buffer with a final concentration
of 10% DMSO. Under these conditions, the hydrolysis of product increased with
time and enzyme concentration in a linear fashion
Example 96
In Vitro Determination of Kt fr>r Phosphodiesterase Inhibitors:
The assays were adapted to a 96-well format. Phosphodiesterase was
assayed in 5mM MgCI2,15mM Tris HCI (pH 7.4), 0.5 mg/ml bovine serum
albumin. 30 nM 3H-cGMP and test compound at various concentrations. The
amount of enzyme used for each reaction was such that less than 15% of the
initial substrate was converted during the assay period. For all measurements,
the test compound was dissolved and diluted in 100% DMSO (2%DMSO in
assay). The total volume of the assay was 100 µl. The reaction mixture was
incubated at 30'C for 90 minutes. The reaction was stopped by boiling for 1
minute and then immediately cooled by transfer to an ice bath. To each well was
then added 25 yl 1 mg/ml snake venom (Ophiophagus hannah) and the reaction
mixture incubating at 30"C for 10 minute. The reaction was stopped by the
addition of 1 ml Bio-Rad AG1-X2 resin slurry (1:3). An aliquot of 200 uJ was taken
and counted by liquid scintillation.
The % inhibition of the maximum substrate conversion (by the enzyme
in the absence of inhibitor) was calculated for each test compound
concentration. Using GraphPad Prism's nonlinear regression analysis
(sigmoidal dose response), the % inhibition vs log of the test compound
concentration was plotted to determine the IC50. Under conditions where
substrate concentration « Km of the enzyme (Km = substrate concentration at
which half of the maximal velocity of the enzyme is achieved), K is equivalent
to the IC50 value.
Following procedures as described herein, the compounds as listed in
Tables 1-6 were prepared. PDEV inhibitory activities for these compounds are
presented either as the IC50 (µM), as a percent inhibition at a given concentration
of test compound or as a Ki value in the Tables below. Unless otherwise noted.
PDEV inhibitory activities were measured using human tissue. The abbreviation
"stereo" refers to the stereogenic configuration, the abbreviation "Rac" shall
denote a racemic mixture.
Example 97
IN VIVO TESTING
Following the procedure disclosed by Carter et al., (Carter, A. J., Ballard, S.
A., and Naylor, A. M.) in The Journal of Urology 1998,160, 242-246, the
compounds as listed in Taoie 7 were tested for in vivo efficacy,V with results as
tabulated below.
Example 98
As a specific embodiment of an oral composition, 100 mg of the compound
of Example 21 is formulated with sufficient finely divided lactose to provide a total
amount of 580 to 590 mg to fill a size O hard gel capsule.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual
variations, adaptations and/or modifications as come within the scope of the
following claims and their equivalents.
We claim:
1. A compound of formula (I) or (II);
wherein
R1 is selected from the group consisting of hydrogen, carboxy,
-C(O)-C1-C6 alkyl, -C(O)- C1-C6 alkoxy, -C(O) -NH-C1-C6
alkyl-NH2, -C(O)-NH-d-Q alkyi-NHRA, -C(O)-NH-d-Q
alkyl-N (RA)2, -C(O)NH2, -C(O)-NHRA, -C(O)N (RA)2, -C1-
C6 alkyl-NH2, -C1-C6 alkyl-NHRA, -C1-C6 alkyi- N (RA)2, -NH-
C1-C6 alkyl-N (RA)2;
where each RA is independently selected from the group
consisting of C1-C6 alkyi, aryl, C1-C6 aralkyl and hctcroaryl,
where the aryl, aralkyl or heteroaryi may be optionally
substituted with one to three RB;
where each RB is independently selected from the group
consisting of halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 aflcyloarbonyi, carboxy C1-C6 alkyi, C1-C6 alkylsulfonyl,
trifluoromcthyi, amino, di (C1-C6 alkyl) amino, acetyiamino,
carboy C1-C6 alkylcarbonylamino, hydroxy C1-C6
alkylamino, NHRA and N (RA)2;
R2 is selected from the group consisting of C5-C10 alkyi
(optionally substituted with one to three substituents
independently selected from halogen, hydroxy, nitro, amino,
NHRA or N (R\), aryi (optional^ substituted with one to
three substituents independently selected from R°), cycloalkyl
(optionally substituted with one to three substituents
independently selected from RA), heteroaryi (optionally
substituted with one to three substituents independently
selected from R°), and heterocycloalkyl (optionally substituted
with one to three substituents independently selected from R°);
where R° is selected from the group consisting of halogen,
nitro, cyano, C1-C6 alkyi, C1-C6 alkoxy, toifluromethyi,
trifluoromcthoxy, NH2, NH (C1-C6 alkyl) and N (C1-C6 alkyl)2;
R is selected from the group consisting of hydrogen, Ci-Q
allcyl, C1-C6 alkybarbonyi, C1-C6 alkenyicarbonyl and C2-C6
alkynylcarbonyl; /
b is an integer from 0 to 4;
R4 is independently selected from the group consisting of
halogen, hydroxy, carboxy, oxo, nitro, C1-C6 alkyl, C1-C6
alkoxy, C1-C6 alkoxycarbonyi, trifluoromethyi, phenyl
(wherein the phenyl group may be optionally substituted with
one to three substituents independently selected from RD),
phenylsulfonyl, naphthyl, C1-C6 aralkyl, -O-aralkjd, (wherein
the aralkyl group may be optionally substituted with one to
three substituents independently selected from R°), heteroaryl
(wherein the heteroaryl may be optionally substituted with one
to three substituents independently selected from RD)
heterocydoalkyl, NH2, NHRA, N (RA)2,
where each RD is independently selected from halogen,
hydroxy, carboxy, oxo, C1-C4 alky], CM alkyfthio, hydroxy
C^ alkyl, C1-C4 alkoxy, C1-C4 alkoxycazbonyl,
trifhioromethyl, trifluorameihoxy NH2, NHRA, N (RA)2, C
(O) N(RA)2, SO2N (RA)2, aceiylamino, nitro, cyano, fomiyJ,
C1-C6 alkylsuifonyl, caiboxy C1-C6 alkyl and aralkyl;
c is an integer from 0 to 4;
R5 k independently selected from the group consisting of
halogen, nttro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -NH2, -
NHRA, -N (R^, -ORA, -C(O)NH2, -C(O)NHRA, -C(O)N(RA)2,
-NHC(O)RA, -SO2NHRA, -SO2N(RA)2, where RA is as defined
above, phenyl (optionally substituted with one to three
substituents independently selected from RB), heteroaryi
(optionally substituted with one to three substituents
independently selected from RB) and hctcrocycloalkyl
(optionally substituted with one to three substituents
independently selected from RB);
a is an integer from Oto 1;
Y selected from the group consisting of - C1-C6 alkyl-, -C (O),
-(C1-C6 alkyl) carbonyl-, - (C1-C6 alkenyl) carbonyl-, - (C1-C6
alkynyi) carbonyl-, - carbonyl (C1-C6 alkyl)-, -carbonyl (C2-C6
alkaiyl), -C(OP-( C1-C6 alkyl), -C(S)-, SO2-, -( C1-C6 alkyl)
sulfbnyl-, -sulfonyl (C1-C6 alkyl)-, -C(O)NH-, -C(O)NH-( C1-
C6 alky!)-, C(O) (C3-C7 cycloalkyl)- and -(C1-C6 cydoalkyl)-
is selected from the group consisting of aryl, heteroaryi,
cyeloalkyl and hctcrocydoalkyl;
provided that when R1 is hydrogen, R3 is hydrogen, b is 0, c is
0,a is 1, Yis-CH2-, and
is phenyl, then R2 is not trimcthoxyphcnyl;
and pharmaccutically acceptable salts, thereof.
2. The compound of Claim 1 wherein
R1 is hydrogen;
R2 is selected from the group consisting of phenyl (optionally
substituted with one to two substituent selected from halogen,
nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, trifluoromcthyl,
trifluoromcthoxy, NH2, NH (C1-C3 alkyl) or N (C1-C3 alkyl)2),
hcteroaryl and hetaxxsydoalkyl;
R3 is selected from the group consisting of H and C1-C4 alkyl;
b is an integer from 0 to 4;
R4 is selected from the group consisting of halogen, hydroxy,
carboxy, oxo, C1-C6 alkyl, C1-C3 alkoxy, C1-C3
alkDxycarbonyl, phenyl (wherein the phenyl may be optionally
substituted with one to two substituents selected from hydroxy,
carboxy, C1-C4 alkyl, C1-4 alkylthio, hydroxy C1-4 alkyl, C1-C4
alkoxy, C1-C4 alkoxycarbonyl, C(O)N(RA)2, trinuoromethyl,
trifluromethoxy, amino, (C1-4 alkyi)amino, di (C1-4 alkyl)
amino, nitro, cyano or fbrmyl), O-aralkyl, hcteroaryi (wherein
the heteroaiyi may be optionally substituted with one to two
substituents selected from hydroxy, carboxy, oxo, C1-C6
alkoxy, C1-C3 alkyoxycarbonyl, C(O)N(RA)2, trifluoromethyl,
trifluromethoxy, amino, nifcro, C1-C3 alkylcaibonyl or C1-4
aralkyl), heterocydoalkyl
c is 0;
a is an integer from 0 to 1;
Y is selected from the group oonastng of - C1-C4 alkyl-, -C
(S) -, - C(OH - C(O)O-( C1-C4 alkyl -C(O) (C1-C4 alkyl), -
C (OKC2-C4 alkenyl)-, C(O)-(C3-C7 cyclokyl) and -
C(O)NH-( C1-C3 alkyl);
is selected from the group consisting of phenyl, hetcroaiyl and
hcterocydoalkyl,
and pharmaceutically acceptable salts thereof.
3. The compound of Claim 2 wherein
R2 is selected from the group consisting of 3, 4 -
methydenediaxyphenyl, 3, 4 - dimethaxyphenyl, 5-(2, 3-
dihydrobcnzofiiryi), 3, 4-dihydrob«nzo-[l, 4]dioxin-6-yl, 5-
benzofuryi, 5-indanyl and 3-thienyi;
R3 is selected from the group consisting of H and methyl;
R4 is selected from the group consisting of bromo, hydroxy,
catboxy, oxo, methyl, phenyl, 4-hydroagrphenyi, 3-
hydrxKymcA^phenji 4 - ttdroxymeti^phenyl, 4-
carboxyphcnyl, 4- mcthylphenyl, 4- methoxyphenyi, 3, 4-
dimcthoxyphcnyl, 4- mcthcxycarbonyi, 4-
mcthaxycarbonylphcnyl, 3- trifluoromcthylphen>i 4-
cyanophenyl, 4- aminophenyl, 4- dimdhyiaminophcnyl, 3-
nitrophcnyl, 4-nitrophenyl 4-formyiphcnyl, 4-
methyithiophcnyl, benzyloxy, 2-pyridinyl, 3- pyridynyl, 4-
pyridinyl, N-oxy-2-pyridinyl, 3-thieny!, 2- foryl, 1- imidazolyl,
5- (1-benzyl- 2-mcthyiiimdazolyl), 5- (1, 2-
dimethyMnudazolyl), 5- (1- bonzyfimidazolyl), 3, 4-
mcthyicncdioxyphcnyl,
Y is selected from the group consisting of -CH2-, -C(S), -
C(O), -C(O)OCH2CH2-, -C(O) -CH-CH-, - C(O) NH- CH2-
(107), -C(O) cydopropyi and -C (O) CH2;
is selected from the group consisting of phenyl, 2-finyl, 2-
benzo (b) fuiyl, 2-pyrimidin)d, 2-pyridtnyl, 3-pyridinyl, 4- py-
ridinyl, 1- imidazolyl, 2-imidazolyl, 2- tinazotyl, and 2- oxa-
bicycb [2.2.1] hcptanyl;
and phannaccutically acceptable salts thereof.
4. The compound of Claim 3 wherein
R2 is selected from the group consisting of 3, 4-
methjienediQxyphenyl, S- (2, 3- dihydrobenjaofuryl), 3, 4-
dihydrobcnzo- [1,4] - dioxinr6- y\ 3-thienyi, 5-mfanyl and 5-
bcnzofuryl;
R3 is H;
bis an integer from 0 to 1;
R4 is selected from the group consisting of 5- bromo, 2-
hydrcxy, 6- hydroxy, 4- carboxy, phenyl, 4- hydroxyphenyl, 3-
hydraxymethyiphenyi, 4- hydroxymdhylphcnyl, 4-
carboxyphenji 4- mcthy^ihcnyl, 4- mctitylthiophcnyl, 4-
metiioxyphcnyl, 3, 4- dimcthoxyphenyi, 4- mcthoxycarbonjd,
4- mcthoxycarbonyiphenyl, 3- trifluoromothy^henyl, 4-
armnophcnyl, 4- dimcth)dammophcnyi, 3- nitrophenyl, 4*
nitrophenjd, 4- cyanophenjd, 4- formylphenyl, benzyloxy, 2-
pyridinyl, 3- pyridmyl, 4- pyridinjd, 2- fiirjd, 3- thienyl, N-
oxo- 2- pyridinyl, 1- imidazolyl, 5- (1- benzyl- 2-
methyKmidazolyl), 5-1, 2- dimethyiimidazolyi), 3, 4-
mcthylcnedioxyphenyl,
Y is selected from the group conskting of- C(O), - C(O)O-
CH2-, - C(O) CH2CH2-, -C(O)CH=CH-, and - C(O)-
cyclopropyl;
is selected from the group consisting of phenyl, 2- furyl, 2-
benzo (b) furyl, 2- pyrimidinyl, 2- pyridinyi 3- pyridinyl, 4-
py-ridinyl and 2- thiazolyl;
and pharmaccutiaally acceptable salts thereof.
5. The compound of Claim 4 wherein
R2 is selected from the group constating of 3, 4-
methyienediaxyphwiyl, 3- (2, 3- dihydrobofizofutyl), 3, 4-
dihydrobenzo- [1, 4]- dioxin- 6- yl, 3- thienyl, 5- indanyl and
5-benzofuryi;
R4 is selected from the group consisting of 5- hromo, 2-
hydraxy, 6- hydroxy, 4- carboxy, phenyl, 4- hydraxyphenyl, 3-
hydraxymcthylphenyl, 4- tr/droxymethylphenyl, 4-
carboxyphenyl, 4- methylphenyl, 4- methylthiophesnyl, 4-
methoxyphenyl, 3, 4- dimethoxyphenyl 4- mcthoxycarbonyl,
4- methoxycarbonylphenyl, 3- trifluromethylphenyl, 4-
aminophenyl, 4- dimethylanmiophenyl, 3- ratrophenyl, 4-
nitrophenyl, 4- cyanophenjd, 4- formylphenyi, benayloxy, 2-
pyridinyl, 3- pyridinyl, 4- pyridinyl, N- oxo- 2- pyridinji 3-
thiony!, 2- fuiyl, 1- imidazo^, 5- (1- bentyi- 2-
methylimidazolyl), 5- (1, 2- methylimidazolyl), 3, 4-
methyienediaxyphenyl,
Y is selected from the group consisting of- C(O), - C(O)O
CH2- and - C(O) CH=CH-;
and pharmaceutically acceptable salts thereof.
6. The compound of Claim 5 wherein
R4 is selected from the group consisting of 6- hydroxy, 4-
carboxy, phenyl, 4- hydroxyphenyl, 3- hydroxymefhyl- phenyl,
4- mcthylphenyl, 4- mcthyhbophenyl, 4- mcthoxyphciryl, 3, 4-
dimeAoxyphenyl, 4- mcthaxycarbonyi, 3-
trifluoromethyiphenyl 3- nitrophcaiyl, 4- nitraphonyl, 2-
pyridinyl, 3- pyridinyl, 4- pyridinyl, N- oxo- 2- pyridinyl, 3-
thienyl, 5- (1- benzyl 2- methylimidazolyl), 5- (1, 2-
dimethylimdazolyl),
and pharmaccutically acceptable sails thereof.
7. The compound of Claim 6 wherein
R2 is selected from the group consiflting of 3, 4-
methylenedioxyphenyl, and 5- (2, 3- dihydrobenzofuryi);
R4 is selected fixxn the group consisting of hydroxy, 4-
methyphenyl, 4- methoxyphmyl, 3, 4- dimethoxyphenyl, 4-
mcthaxycarbonyl, 3- trifliramcthylphcnyl, 4- nitrophcnyl, 2-
pyridmyl, 3- pyridinyl,
Y is selected fixrni the group consisting of -C(O)- and -
C(O)O- CH2-;
is selected from the group cosasting of 2- furyl, 2- benzo(b)
furyl 4- pyridinjd, 2- pyrimidinyl and 2- thiazdyl;
and pharmaccutically acceptable safa thereof.
8. The compound of Claim 7 selected from the group consisting
of
R-l. 2, 3, 4- Tetrahydro- 2- [5- (3, 4- o*ne!hoxyphenyi>
pyrimidin- 2- yl]-3- (3, 4- methylenedkxyphenyl) 9H- pyrro-
10- [3, 4- b] qumolin- 9- one;
R- 1, 2, 3, 4- Tetrahydro- 2- [(4- pyridinyl)
mcthyloxycaibonyl]- 3- (3, 4- methylenedioxyphcnyl) 9H-
pyrrolo- [3, 4- b] quinolin- 9- one;
R- 1, 2, 3, 4- Tetraaydro- 2- [5- (2- pyndmyfy- pyrimidiii- 2-
yl) 3- (3, 4- dihydrobcn2Dfbranyl)- 9H - pyrrolo- [3, 4- b]
quino- lin- 9- one;
R- 1, 2, 3, 4- Tctrahydro- 2- [5- (4- mcthoxyphenyl]-
pyrimidm- 2- yl]- 3- (3, 4- diydrobenzofiiranyl) 9H- pyrrolo-
[3, 4- b] quinolin - 9- one;
R- 1, 2, 3, 4- Tctrahydro- 3- (3, 4- me%lcncdioxyphenyl) 2-
(5- (4- (1- (4- mcthyl) pipeazinyicarbonyl) phcnyl)- furo-
yl)- 9H- pyrrolo [3,4- b] quinolin- 9- one;
R- 1, 2, 3, 4- Tetrahydro- 2- (2- pyridmyi)- 3- (2, 3- dihydro-
5- bcnzofiiranyl)- 9H- pyrrolo [3, 4- b] quinolin- 9- one;
and pharmaccutically acceptable salts thereof.
9. A pharmaceutical composition comprising a phan&aoeuticafy
acceptable carrier and a compound of claim 1.
10. A medicament for the treatment of sexual dysfunction
comprising a compound as claimed in claim 1.
11. A medicament for the treatment of a condition selected from
the group consisting of male crcctivc dysfunction (ED),
impotence, female sexual arousal dysfunction, female sexual
dysfunction related to blood flow and nitric oxide production
in the tissues of the vagina and clitoris, premature labor,
dysmenorrhea, cardiovascular disorders, atherosclerosis,
arterial occtusive disorders, thrombosis, coronary rest stenosis,
angina pectoris, myocardial infarction, heart failure, ischemic
heart disorden, hypertension, pulmonary hypertension, asthma,
intermittent ckudicatkni and diabetic complications.
The invention relates to novel pyrrolopyridinone derivatives of the
formula (I) or (II): pharmaceutical compositions containing the
compounds and their use for the treatment of sexual dysfunction.

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Patent Number 225470
Indian Patent Application Number IN/PCT/2002/01416/KOL
PG Journal Number 46/2008
Publication Date 14-Nov-2008
Grant Date 12-Nov-2008
Date of Filing 18-Nov-2002
Name of Patentee ORTHO-MCNEIL PHARMACEUTICAL, INC.
Applicant Address U.S. ROUTE 202, RARITAN, NJ 08869
Inventors:
# Inventor's Name Inventor's Address
1 LANTER, JAMES, C 3 ALBION COURT, FLEMINGTON, NJ 08822
2 SUI, ZHIHUA 11 RUNNING BROOK CIRCLE, FLEMINGTON, NJ 03892
3 MACIELAG MARK J 8 SENECA TRAIL, BRANCHBURG, NJ08876
4 GUAN, JIHUA 702 BOUND BROOK AVENUE, RARITAN, NJ 08869
5 JIANG, WEIQIN 8 GLEN EYRE DRIVE, BRIDGEWATER NJ 08307
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/US01/14391
PCT International Filing date 2001-05-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/204.646 2000-05-17 U.S.A.