Note: Descriptions are shown in the official language in which they were submitted.
CA 02249562 1998-09-22
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CERTAIN FUSED PYRROLECARBOXAMIDES AS GAGA BRAIN RECEPTOR LIGANDS.
BACKGROUND OF THE INVENTION
' 1
held of the Invention
This invention relates to certain fused pvtrolecarboxanilides which
selectively bind to
GABAa receptors. This invention also relates to pharmaceutical compositions
comprising
such compounds. It further relates to the use of such compounds in treating
anxiety, sleep and
seizure disorders. and overdoses of benzodiazepine-type drugs, and enhancing
alermess.
Desctrilation of the Related Art
-Aminobutvric acid lGABAI is regarded as one of the major inhibitory amino
acid
transmitters in the mammalian brain. Over 30 years have elapsed since its
presence in the
brain was demonstrated (Roberts & Frankel, J. Biol. Chem ~,$7: 55-63, 1950;
Udeniriend. J.
Biol. Chem. ~: 65-69, 1950). Since that time, an enormous amount of effort has
been
devoted to implicating GAGA in the etiology of seizure disorders, sleep,
anxiety and
cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8_: 21-44, 1985).
Widely, although
unequally, distributed through the mammalian brain, GAGA is said to be a
transmitter at
approximately 30% of the synapses in the brain. In most regions of the brain.
GABA is
associated with local inhibitory neurons and only in two regions is GABA
associated with
longer projections. GABA mediates many of its actions through a complex of
proteins
localized both on cell bodies and nerve endings; these are called GABAa
receptors.
Postsvnaptic responses to GAGA are mediated through alterations in chloride
conductance
that generally, although not invariably, lead to hvperpolarization of the
cell. Recent
'_'~ investigations have indicated that the complex of proteins associated
with postsvnaptic GABA
responses is a major site of action for a number of structurally unrelated
compounds capable
of modifying postsvnaptic responses to GABA. Depending on the mode of
interaction, these
compounds are capable of producing a spectrum of activities (either sedative.
anxiolvtic, and
anticonvulsant. or wakefulness. seizures, and anxiety).
SUBSTITUTE SHEET (RULE 26)
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1,4-Benzodiazepines continue to be amone the most widely used drugs in the
world.
Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam.
flurazepam,
and triazolam. These compounds are widely used as anxiolytics, sedative-
hypnotics, muscle
relaxants, and anticonvulsants. A number of these compounds are extremely
potent drugs;
s such potency indicates a site of action with a high affinity and specificity
for individual
receptors. Early electrophysiological studies indicated that a major action of
benzodiazepines
was enhancement of GABAergic inhibition. The benzodiazepines were capable of
enhancing
presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated
event
(Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent
electrophysiological studies (reviewed in Tallman et al. 1980, Science 207:
274-81, Haefley et
al., 1981, Handb. Exptl. Pharmacol. 33: 95-102) have generally confirmed this
finding, and
by the mid-1970s, there was a general consensus among electrophysiologists
that the
benzodiazepines could enhance the actions of GABA.
With the discovery of the "receptor" for the benzodiazepines and the
subsequent
definition of the nature of the interaction between GABA and the
benzodiazepines, it appears
that the behaviorally important interactions of the benzodiazepines with
different
neurotransmitter systems are due in a large part to the enhanced ability of
GABA itself to
modify these systems. Each modified system, in turn, may be associated with
the expression
of a behavior.
Studies on the mechanistic nature of these interactions depended on the
demonstration
of a high-affinity benzodiazepine binding site (receptor). Such a receptor is
present in the
CNS of all vertebrates phylogenetically newer than the honey fishes {Squires &
Braestrup
1977, Nature 1~6: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &
Okada,
1977, Br. J. Psychiatry 1~: 261-68). By using tritiated diazepam, and a
variety of other
compounds, it has been demonsuated that these benzodiazepine binding sites
fulfill many of
the criteria of pharmacological receptors; binding to these sites in vitro is
rapid, reversible,
stereospecific, and saturable. More importantly, highly significant
cotrelations have been
shown between the ability of benzodiazepines to displace diazepam from its
binding site and
activity in a number of animal behavioral tests predictive of benzodiazepine
potency
_2_
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i Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler & Okada,
1977, Science
198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). The average
therapeutic
doses of these drugs in man also correlate with receptor potency (Tallman et
al. 1980, Science
' 07: 2 7 4-28 I ).
In 1978, it became clear that GABA and related analogs could interact at the
low
affinity ( 1 mM) GABA binding site to enhance the binding of benzodiazepines
to the
clonazepam-sensitive site (Tallman et al. 1978, Nature, 274: 383-85). This
enhancement was
caused by an increase in the affinity of the benzodiazepine binding site due
to occupancy of
the GABA site. The data were interpreted to mean that both GABA and
benzodiazepine sites
were allosterically linked in the membrane as part of a complex of proteins.
For a number of
GABA analogs, the ability to enhance diazepam binding by 50% of maximum and
the ability
to inhibit the binding of GAGA to brain membranes by 50% could be directly
correlated.
Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA
receptor
antagonist (+) bicuculline; the stereoisomer (-) bicuculline is much less
active (Tallman et al.,
1978, Nature, 274: 383-85).
Soon after the discovery of high affinity binding sites for the
benzodiazepines, it was
discovered that a triazolopyridazine could interact with benzodiazepine
receptors in a number
of regions of the brain in a manner consistent with receptor heterogeneity or
negative
cooperativity. In these studies, Hill coefficients significantly less than one
were observed in a
number of brain regions, including cortex, hippocampus, and striatum. In
cerebellum,
triazolopyridazine interacted with benzodiazepine sites with a HiI1
coefficient of 1 (Squires et
al., 1979, Phatma. Biochem. Behav. 1~: 825-30, Klepner et al. 1979,
Phantlacol. Biochem.
Behav. 11: 457-62). Thus, multiple benzodiazepine receptors were predicted in
the cortex,
hippocampus, striatum, but not in the cerebellum.
Based on these studies, extensive receptor autoradiographic localization
studies were
carried out at a light microscopic level. Although receptor heterogeneity has
been
demonstrated (Young & Kuhar 1980, J. Phatmacol. Exp. Ther. 212: 337-46, Young
et al.,
1981 J. Pharmacol Exp. ther 2~: 425-430, Niehoff et al. 1982, J. Pharmacol.
Exp. Ther. 221:
670-75), no simple correlation between localization of receptor subtypes and
the behaviors
-3-
SUBSTITUTE SHEET (RULE 26)
CA 02249562 2005-06-29
associated with the region has emerged from the early studies. In addition, in
the cerebellum,
where one receptor was predicted from binding studies, autoradiography
revealed
heterogeneity of receptors (Niehoff et al.. 1982. J. Pharmacol. Exp. Ther. ~,
2~: 670-75).
A physical basis for the differences in drug specificity for the two apparent
subtypes of
benzodiazepine sites has been demonstrated by Sieghart & Karobath, 1980,
Nature ?8~: 285-
87. Using gel electrophoresis in the presence of sodium dodecyl sulfate, the
presence of
several molecular weight receptors for the benzodiazepines has been reported.
The receptors
were identified by the covalent incorporation of radioactive flunitrazepam, a
benzodiazepine
which can covalently label all receptor types. The major labeled bands have
molecular
weights of 50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines
inhibit labeling
of the slightly higher molecular weight forms (53,000, 55,000, 57,000)
(Seighart et al. 1983,
Eur. J. Phatmacol. 88: 291-99).
At that time, the possibility was raised that the multiple forms of the
receptor represent
"isoreceptors" or multiple allelic forms of the receptor (Tallinan & Gallager
l 985, Ann. Rev.
Neurosci. $, 21-44). Although common for enzymes, genetically distinct forms
of receptors
have not generally been described. As we begin to study receptors using
specific radioactive
probes and electrophoretic techniques, it is almost certain that isoreceptors
will emerge as
important in investigations of the etiology of psychiatric disorders in
people.
The GABAa receptor subunits have been cloned from bovine and human cDNA
libraries
(SchofieId P R et al., Zentrum fur Molekulare Biologie, University of
Heidelberg, FRG FEBS
letters (1989 Feb 2?), 244(2), 361-364; Garrett K M et al., Biochemical and
biophysical research
communications (1988 Oct 31), 156(2):1039-1045). A number of distinct cDNAs
were identified
as subunits of the GABAa receptor complex by cloning and expression. These are
categorized
into a, Vii, 'y, 8, E, and provide a molecular basis for the GABAa receptor
heterogeneity and
distinctive regional pharmacology (Shivers, Brenda D. et al, Cent. Mol. Biol.,
Univ. Heidelberg,
Heidelberg, Fed. Rep. Ger. Neuron (1989), 3(3):327-337; Levitan, Edwin S. et
al., MRC Mol.
Neurobiol. Unit, MRC Cent., Cambridge, UK. Nature (London, United Kingdom)
(1988),
335(6185):76-?9). The y subunit appears to enable drugs like benzodiazepines
to modify the
GABA responses (Pritchett D B et al., ZMBH, Universitat Heidedberg, FRG Nature
(1989 Apr
13), 338(6216), 582-S.). The presence of low Hill coefficients in the binding
of ligands to the
GABAa receptor indicates unique profiles of subtype specific pharmacological
action.
Drugs that interact at the GABAa receptor can possess a spectrum of
pharmacological
activities depending on their abilities to modify the actions of GABA. For
example, the beta-
-4-
CA 02249562 1998-09-22
WO 97/34870 PCT/US97/04623
carbolines were first isolated based upon their ability to inhibit
competitively the binding of
diazepam to its binding site (Nielsen et al.. 1979, Life Sci. 25: 679-86). The
receptor binding
assay is not totally predictive about the biological activity of such
compounds; agonists.
partial agonists, inverse agonists, and antagonists can inhibit binding. When
the beta-
carboline structure was determined, it was possible to synthesize a number of
analogs and test
these compounds behaviorally. It was immediately realized that the beta-
carbolines could
antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980. Nature
288: 609-10).
In addition to this antagonism, beta-carbolines possess intrinsic activity of
their own opposite
to that of the benzodiazepines; they become known as inverse agonists.
l 0 In addition, a number of other specific antagonists of the benzodiazepine
receptor were
developed based on their ability to inhibit the binding of benzodiazepines.
The best studied of
these compounds is an imidazodiazepine (Hunkeler et al., 1981, Nature 2~0: 514-
516). This
compound is a high affinity competitive inhibitor of benzodiazepine and beta-
carboline
binding and is capable of blocking the pharmacological actions of both these
classes of
15 compounds. By itself, it possesses little intrinsic pharmacological
activity in animals and
humans (Hunkeler et al., 1981, Nature 290: S I4-16; Dan agh et al., 1983, Eur.
J. Clin.
Phalzrtacol. 14: 569-70). When a radiolabeled form of this compound was
studied (Mohler &
Richards, 1981, Nature 294: 763-65), it was demonstrated that this compound
would interact
with the same number of sites as the benzodiazepines and beta-carbolines, and
that the
20 interactions of these compounds were purely competitive. This compound is
the ligand of
choice for binding to GABAa receptors because it does not possess receptor
subtype
specificity and measures each state of the receptor.
The study of the interactions of a wide variety of compounds similar to the
above has
led to the categorizing of these compounds. Presently, those compounds
possessing activity
25 similar to the benzodiazepines are called agonists. Compounds possessing
activity opposite to
benzodiazepines are called inverse agonists. and the compounds blocking both
types of
activity have been termed antagonists. This categorization has been developed
to emphasize
the fact that a wide variety of compounds can produce a spectrum of
pharmacological effects,
to indicate that compounds can interact at the same receptor to produce
opposite effects, and
-$-
SUBSTITUTE SHEET (RULE 26)
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to indicate that beta-carbolines and antagonists with intrinsic anxiogenic
effects are not
svnonvmous.
A biochemical test for the pharmacological and behavioral properties of
compounds
that interact with the benzodiazepine receptor continues to emphasize the
interaction with the
s GABAergic system. In contrast to the benzodiazepines, which show an increase
in their
affinity due to GABA (Tallman et al., 1978, Nature 274: 383-85, Tallman et
al., 1980, Science
207: 274-81 ), compounds with antagonist properties show little GABA shift
(i.e., change in
receptor affinity due to GABA) (Mohler & Richards 1981, Nature 294: 763-65),
and the
inverse agonists actually show a decrease in affinity due to GABA (Braestrup &
Nielson
1981, Nature 2~4: 472-474). Thus, the GABA shift predicts generally the
expected
behavioral properties of the compounds.
Various compounds have been prepared as benzodiazepine agonists and
antagonists.
For Example, U.S. Patents Nos. 3,455,943, 4,435,403, 4,596,808, 4,623,649, and
4,719,210,
German Patent No. DE 3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach
assorted
1 S benzodiazepine agonists and antagonists and related anti-depressant and
central nervous
system active compounds.
U.S. Patent No. 3,455,943 discloses compounds of the formula:
R~ ~ X
~ y
R2 N
R3
wherein Rl is a member of the group consisting of hydrogen and lower alkoxy;
R2 is a
member of the group consisting of hydrogen and lower alkoxy; R3 is a member of
the group
consisting of hydrogen and lower alkyl; and X is a divalent radical selected
from the group
consisting of
-6-
SU85T1TUTE SHEET (RULE 26)
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~NH \ 'N
~ lower alkyl
lower alkyl lower alkyl
and
\/N
lowe~r'alkyl
and the non-toxic acid addition salts thereof.
Other references, such as U.S. Patent No. 4,435,403 and German patent DE
3,246,932
disclose compounds containing the following structural skeleton:
A~
~N
I,
'N H
H
where A is carbon or nitrogen.
A variety of indole-3-carboxamides are described in the literature. For
example, J.
Org. Chem., 42: 1883-1885 (1977) discloses the following compounds.
O
/ C-N.H / O ~H
\ \ I I C _N \
J \
N /
H C~ H Br
O p /
\
/ C-NCH / C._N~H I
N / N
H I
H
J. Heterocylic Chem., 14: 519-520 ( 1977) discloses a compound of the
following
formula:
_7_
SUBSTtTUTE SHEET (RULE 26)
CA 02249562 2005-06-29
/ C-NCH
N
H
None of these indole-3-carboxamides includes an oxy substiuent at the 4-
position of
the indole ring.
U.S. Patent No. 5,484,944, discloses compounds of the general formula:
O
N
c ~ '' T H
~N
I
X
or the pharmaceutically acceptable non-toxic salts thereof wherein:
T is halogen, hydrogen, hydroxyl, amino or straight or branched chain Iower
alkoxy
having 1-6 carbon atoms;
X is hydrogen, hydroxyl or straight or branched chain lower alkyl having 1-6
carbon
atoms;
W is phenyl, 2- or 3-thienyl, 2-, 3-, or 4-pyridyl or 6-quinolinyl, each of
which may be
mono or disubstituted with halogen, cyano, hydroxy, straight or branched chain
lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where
each alkyl is independently straight or branched chain lower alkyl having 1-6
carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon
atoms, or NRl CORD, COR?, CONK 1 R2 or COZRZ where R 1 and R~ are the
same or different and represent hydrogen or straight or branched chain lower
alkyl having 1-6 carbon atoms; and
C
represents
-g_
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R3 ~O O
O
Y \ R3 ~ N Ra w/ Nw
R5 ( / arR \ ~ or ~ or
R5
Rs Rs Rs ~CH2)n
wherein:
Y represents nitrogen or C-R4;
Z represents N-R7 or a carbon atom substituted with Rg and R9, i.~.,
C(Rg)(R9);
n is 1, 2, 3, or 4;
R3 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower
alkyl
having 1-6 carbon atoms, or phenylalkyl or 2-, 3, or 4-pyridylalkyl where each
alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;
R4 is halogen or trifluoromethyl; or
-OR10, -COR10, -C02R10, -OCOR10, or -R10, where R10 is
hydrogen, phenyl, 2,- 3, or 4-pyridyl, straight or branched chain lower alkyl
having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where
each
alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or
-CONR11R12 or -(CH2)mNR11R12~ where m is 0, 1, or 2; R11
represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon
atoms; and R12 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched
chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-
pyridylalkyl where each alkyl is straight or branched chain lower alkyl having
1-6 carbon atoms; or NR11R12 forms a heterocyclic group which is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl;
R5 and Rb are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6
carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon
atoms;
-9-
SUBSTITUTE SHEET (RULE Z6)
CA 02249562 2004-11-05
R7 is hydrogen. phenyl. .-. 3-. or 4-pyridy 1. straight or branched chain
lower alkyl
having 1-6 carbon atoms. or phenylalkyl or ?-. 3-, or 4-pyridylalkyl where
each
alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;
Rg is hydrogen or straight or branched chain lower alkyl having 1-6 carbon
atoms; and
R9 is -COR13, -CO~R13 or -R13, where R13 is hydrogen, phenyl, 2-, 3-, or 4-
pyridyl,
straight or branched chain lower alkyl having l-6 carbon atoms, or phenylalkyl
or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain
lower
alkyl having 1-6 carbon atoms; or
-CONR14R15 or -~~2)k~14R15~ where k is 0, 1, or 2; R14
represents hydrogen, straight or branched chain lower alkyl having I-6 carbon
atoms; and R15 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched
chain lower alkyl having 1-6 carbon atoms, or phenylaikyl or 2-, 3-, or 4-
pyridylalkyl where each alkyl is straight or branched chain lower alkyl having
1-6 carbon atoms; or NR14R15 forms a heterocyclic group which is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl.
International Publication No. W095/11885 , filed October 26, 1994 and
published
May 4, 1995, ~ also discloses
pvcrole derivatives of the general formula described in U.S. Patent No.
5,484.944. i.e.,
y0 X
W
N
H
The substituents on this general formula are as defined in U.S. Patent No.
5,484,944. In
addition. ! U.S. Patent No. 5,608,0?9, filed June 7, 1995 and issued on March
4, 199?, .
. discloses compounds of the general formula set forth in
U.S. Patent No. 5.484,944.
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SUMMARY OF THE INVENTION
An obj ect of the present invention is to provide certain
fusedpyrrolecarboxamides as GABA
brainreceptor ligands. In accordance with an aspect of thepresent invention,
there is provided a
compound of the formula:
O O
,W
'N
H
3 rm ~ ~~T
R4 ~'3n _ N
1
X
or the pharmaceutically acceptable non-toxic salts thereof wherein:
W is aryl or heteroaryl, each of which is optionally substituted with up to
five groups selected
independently from
halogen, cyano, hydroxy, alkyl or cycloalkyl having 3-7 carbon atoms,
amino or mono- or dialkylamino where each alkyl is independently lower alkyl
or
cycloalkyl having 3-7 carbon atoms,
alkoxy or cycloalkyl allcoxy having 3-7 carbon atoms, or
NR1COR2, COR2, CONR1R2 or C02R2 where R1 and RZ are the same or different
and represent hydrogen or alkyl or cycioalkyl having 3-7 carbon atoms; and
T is halogen, hydrogen, hydroxyl, amino or alkoxy;
X is hydrogen, hydroxyl or alkyl;
mis0, l,or2;
n is 0, 1, or 2; and
R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or
C02R5 where
RS is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R~ where R6 and R~ are
selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon
atoms,
phenyl, 2-,3-, or 4-pyridyl , or NR6R7 forms a heterocyclic group which is
mozpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R3-R4 together represent ,cyclic moiety having 3-7 carbon atoms.
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In accordance with another aspect of the invention, there is provided a
compound of the
formula:
Re
Rg
O O
'N
H
R rt' I ~~H Rto
3
R4 n N
1
H
wherein
R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or
C02R5 where
R5 is allyl or cycloalkyl having 3-7 carbon atoms, CONR6R7 where R6 and R7 are
selected independently from hydrogen, alkyl, cycloalkyi having 3-7 carbon
atoms,
phenyl, 2-,3-, or 4-pyridyl , or NR6R7 forms a heterocyclic group which is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R3-R~ together represent a cyclic moiety having 3-7 carbon atoms;
Rg is hydrogen, halogen, hydroxyl, alkyl, allcoxy, cycloalkyl aikoxy having 3-
7 carbon atoms,
amino, mono- or diaikylamino; and
Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycioalkyl alkoxy
having 3-7 carbon
atoms, amino, mono- or dialkyiamino, NR1COR2, COR2, or C02R2 where RI and
RZ are the same or different and represent hydrogen, alkyl, or cycloalkyl
having 3-7
carbon atoms; and
RIO is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or
dialkylamino;
m is 0, I, or 2; and
n is 0, I, or 2.
-lla-
CA 02249562 1999-09-21
In accordance with another aspect of the invention, there is provided a
compound of the
formula:
O
O G
N~
H
~'' H
R4 N
H
w here
G represents thienyl, thiazolvl. pvridvl, napthyridinyi, quinolinyl, or
phenyl, each of which is
optionally mono-. dl- or trisubstituted with halogen. alkyl, alkoxy, or
hydroxy; and
R3 and R4 are the same or different and represent hydrogen or alkyl, provided
that not both
R3 and R4 are hydrogen.
This invention provides novel compounds of Formula I which interact with a
GABAa
binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising compounds of
Formula I. The invention also provides compounds useful in the diagnosis and
treatment of
anxiety, sleep and seizure disorders, overdose with ben2odiazepine drugs and
for
enhancement of memory. Accordingly, a broad embodiment of the invention is
directed to
compounds of general Formula I:
O O
NEW
H
~~-T
R3
N
Ra ~ 1
X
I
-11b-
CA 02249562 1999-09-21
or the pharmaceutically acceptable non-toxic salts thereof wherein:
W is aryl or heteroaryl; and
T is halogen, hydrogen, hydroxyl, amino or straight or branched chain lower
alkoxy having 1-
6 carbon atoms;
X is hydrogen, hydroxyl or straight or branched chain tower alkyl having 1-6
carbon atoms;
m is 0, l, or 2;
n is 0, 1, or 2; and
R3 and R4 are the same or different and are selected from hydrogen, straight
or branched
lower alkyl having 1-6 carbon atoms, CORS or C02R5 where R5 is straight or
branched lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon
atoms,
CONR6R7 where R( and R7 are selected independently from hydrogen, straight or
branched chain lodver alkyl having 1-6 carbon atoms, cycloalkyl having 3-7
carbon
atoms, phenyl, 2-,3-, or 4-pyridyl, or NRbR~ forms a heterocyclic group which
is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R3-R4 together represent a cyclic moiety having 3-7 carbon atoms; and
where each alkyl substituent in Formula 1 is optionally substituted with at
least one group
independently selected from hydroxv, mono- or dialkyl amino, phenyl or
pytidyl.
These compounds are highly selective agonists, antagonists or inverse agonists
for
GABAa brain receptors or prodrugs of agonists. antagonists or inverse agonists
for GABAa
brain receptors. In other words, while the compounds of the invention all
interact with
GABAa brain receptors, they do not display identical physiologic activity.
Thus, these
compounds are useful in the diagnosis and treatment of anxiety, sleep and
seizure disorders,
overdose with benzodiazepine drugs and for enhancement of memory. For example,
these
compounds can be used to treat overdoses of benzodiazepine-type drugs as they
would
competitively bind to the benzodiazepine receptor.
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DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "aryl" refers to aromatic carbocyclic groups having a
single
ring (e.g., phenvi), multiple rings (e.g., biphenyl), or multiple condensed
rings in which at
least one is aromatic. (e.g., l.?,3,4-tetrahydronaphthyl, naphthyl, anthryl,
or phenanthryl),
which can optionally be substituted with e.g., halogen, lower alkyl, lower
alkylthio.
trifluoromethyl, lower acyloxy, aryl, and heteroaryl.
A preferred aryl group is phenyl optionally substituted with up to five groups
selected
independently from halogen, cyano, hydroxy, straight or branched chain lower
alkyl having I-
b carbon atoms or cycloalkyl having 3-7 carbon atoms, amino, mono or
dialkylamino where
each alkyl is independently straight or branched chain lower alkyl having 1-6
carbon atoms or
cycloalkyl having 3-7 carbon atoms, straight or branched chain lower alkoxy
having 1-6
carbon atoms, cycloalkyl alkoxy having 3-7 carbon atoms, or NR1COR2, COR2,
CONRIR2
or C02R2 where R1 and R? are the same or different and represent hydrogen or
straight or
branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7
carbon atoms
I S By heteroaryl is meant aromatic ring systems having at least one and up to
four hetero
atoms selected from the group consisting of nitrogen, oxygen and sulfur.
Examples of
heteroaryl groups are pytidyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl,
pyridazinyl,
oxazolyl, napthvridinyl, isoxazolyl, phthalazinyl, furanyl, quinolinyl,
isoquinolinyl, thiazolyl,
and thienyl, which can optionally be substituted with, e.g., halogen, lower
alkyl, lower alkoxy,
lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and
hydroxy.
The aryl and heteroaryl groups herein are systems characterized by 4n+2 n
electrons,
where n is an integer..
In addition to those mentioned above, other examples of the aryl and
heteroaryl groups
encompassed within the invention are the following:
/_~, - ~ , , w
N~ ~~ C~'~ ~ y I ~J I
N N /
S
-13-
SUBSTITUTE SHEET {RULE 26)
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WO 97/34870 PCT/US97/04623
\ ~~ \ N~~ N~ N~~ \ /~
I / / I / / / / /~
X2
Ny I , l .\
o~ o~ ' ~ o o N ,-'~
0
I/ ~I/
0
As noted above, each of these groups can optionally be mono- or
polysubstituted with
groups selected independently from, for example, halogen, lower alkyl, lower
alkoxy, lower
alkyithio, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
Still other examples of various aryl and heteroaryl groups are shown in Chart
D of
published International Application WO 93/17025.
By "alkyl" and "lower alkyl" in the present invention is meant straight or
branched chain alkyl groups having 1-6 carbon atoms, such as, for example,
methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyi, 2-pentyl,
isopentyl, neopentyl, hexyl,
2-hexyl, 3-hexyl, and 3-methylpentyl. Unless indicated otherwise, the alkyl
group
substituents herein are optionally substituted with at least one group
independently selected
from hydroxy, mono- or dialkyl amino, phenyl or pyridyl.
Where R, and R, are both alkyl, each alkyl is independently selected from
Iower alkyl.
By "alkoxy" and "lower alkoxy" in the present invention is meant straight or
branched
chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy,
ethoxy,
propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl,
isopentoxy,
neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
As used herein "cycloalkyi alkoxy" refers to groups of the formula
-14-
SUBSTITUTE SHEET (RULE 26~
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(CH 2~H -(CR'R")b0-
where a is an integer of from 2 to 6; R' and R" independently represent
hydrogen or
alkyl; and b is an integer of from 1 to 6.
By the term "halogen" in the present invention is meant fluorine. bromine.
chlorine, and
iodine.
By "N-alkylpiperazyl" in the invention is meant radicals of the formula:
-N N-R
U
where R is alkyl as defined above.
By "monoalkylamino" as used herein is meant an amino substitutent substituted
with
one ( 1 ) alkyl group where the alkyl group is lower alkyl as defined above or
cycloalkyl having
from 3-7 carbon atoms.
By "dialkylamino" as used herein is meant an amino substitutent substituted
with two
(2) alkyl groups where the alkyl groups are independently lower alkyl groups
as defined
above or cycloalkyl groups having from 3-7 carbon atoms.
The novel compounds encompassed by the instant invention can be described by
general formula I set forth above or the pharmaceutically acceptable non-toxic
salts thereof.
In addition, the present invention encompasses compounds of Formula II.
R8
R9
H~
Rio
Rs H
Ra ,
H
II
-15-
SU85T1TUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
wherein
R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or
CO?RS where
R5 is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R7 where R6 and R~ are
selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon
atoms,
phenyl, 2-,3-. or 4-pyridyi , or NR6R~ forms a heterocyclic group which is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R3-R4 together represent a cyclic moiety having 3-7 carbon atoms;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7
carbon atoms,
amino, mono- or dialkylamino; and
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy
having 3-7 carbon
atoms, amino. mono- or dialkylamino. NR1COR2, COR2, or C02R~ where R1 and
R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl
having 3-7
carbon atoms; and
Rlp is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or
dialkylamino;
m is 0, 1, or 2; and
nis0, l,or2.
Preferred compounds of Formula II are those where the phenyl group is mono-,
dl-, or
trisubstituted in the 2,4, and/or positions relative to the point of
attachment of the phenyl
ringto the amide nitrogen.
In addition, the present invention encompasses compounds of Formula III.
R8
R9
O O
~H R
~o
N
H
III
wherein
R3 and R4 are the same or different and represent hydrogen or alkyl;
-16-
SUBSTTTUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
Rg is hydrogen. halogen. hydroxyl. alkyl. alkoxy, cvcioalkvi aikoxy having 3-7
carbon atoms.
amino. mono- or dialkvlamino: and
R9 is hydrogen, haloeen, cyano. hydroxy, alkyl, alkoxy, cycloalkyl alkoxy
having 3-7 carbon
atoms, ammo, mono- or dialkylamino, NRI COR2, COR2, or C02R2 where R1 and
R? are the same or different and represent hydrogen, alkyl, or cycloalkyl
having 3-7
carbon atoms; and
R10 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or
dialkylamino.
Preferred compounds of Formula III are those where the phenyl group is mono-,
dl-, or
trisubstituted in the 2,4, and/or ~ positions relative to the point of
attachment of the phenyl
ring to the amide nitrogen. Particularly preferred compounds of Formula III
are those where
the phenyl group in trisubstituted in the 2,4, and 5 postitons relative to the
point of
attachment of the phenyl ring to the amide nitrogen, and Rg, R,, and R,o are
independently
selected from hyrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not
all of Rg, R"
and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula IV.
R8
R9
O O
N
H I
Rio
R ~N
3
H
IV
wherein
R3 represents alkyl;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7
carbon atoms,
amino, mono- or dialkylamino; and
R9 is hydrogen, halogen, cyano. hydroxy, alkyl, alkoxy, cycioalkyi aikoxy
having 3-7 carbon
atoms, amino, mono- or dialkylamino, NRICOR2, COR2, or C02R2 where RI and
-17-
SUBSTITUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
R? are the same or different and represent hydrogen. alkyl, or cvcloalkyl
having 3- i
carbon atoms: and
R10 is hydrogen, halogen. hydroxyl, alkyl, alkoxy, amino, mono- or
dialkvlamino.
Prefen ed compounds of Formula IV are those where Rg, R" and R,o are
independently
selected from hydrogen. halogen, hydroxy, alkoxy, and alkyl, provided that not
all of RQ, R4,
and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula V.
R$
R9
O O
_H R
R3 ~ ~~H ~o
R4/~/ N
H
V
wherein
R3 and R4 are the same or different and represent alkyl;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7
carbon atoms,
amino, mono- or dialkylamino; and
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy
having 3-7 carbon
1S atoms, amino, mono- or dialkylamino, NR1COR2, COR2, or C02R2 where R1 and
R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl
having 3-7
carbon atoms; and
Rl0 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or
diaikylamino.
Preferred compounds of Formula V are those where Rg, Rq, and R,o are
independently
selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not
all of Rs, R"
and R,o are hydrogen. Particularly preferred compounds of Formula V are those
weree R, an
R4 are both methyl, and Rs, R.,, and R,o are independently selected from
hydrogen, halogen,
hydroxy, alkoxy, and alkyl, provided that not all of Rs, Rq, and R,~ are
hydrogen.
_18_
SUSST1TUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
In addition. the present invention encompasses compounds of Formula VI
R8
_ / Rg
.. O
H~
Rio
R3 H
Ra .. ,
H
VI
wherein
q is an integer of from 2-6;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7
carbon atoms,
amino, mono- or dialkylamino; and
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy
having 3-7 carbon
atoms, amino, mono- or diallcylamino, NRICOR2, COR2, or C02R2 where R1 and
R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl
having 3-7
carbon atoms; and
RI0 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or
dialkylamino;
m is 0, 1, or 2; and
n is 0, 1, or 2.
Preferred compounds of Formula VI are those where Re, R9, and R,o are
independently
selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not
all of Rg, R9,
and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula VII.
-19-
SUBSTITUTE SHEET (RULE 26)
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N~G
H
Rs H
Ra . i
H
VII
where
G represents aryl or heteroary such as, for example, thienyl, thiazolyl,
pyridyl, napthvridinyl,
quinolinyl, or phenyl, each of which is optionaly mono-, di- or trisubstituted
with
halogen alkyl alkoxy, or hydroxy; and
R3 and R4 are the same or different and represent hydrogen or alkyl, provided
that not both
R3 and R4 are hydrogen.
Preferred compounds of Formula VII are those where R3 and R4 are C 1 _3 alkyl,
and
more preferably methyl. Other preferred compounds of Formula VII are those
where R3 is
hydrogen and R4 is C 1 _3 alkyl, and more preferably R4 is methyl.
Preferred compounds of Formula VII include a G group selected from the
following:
/ Ra / Rb~Rc
Ra ~ Ra Ra / /
Rc
Ra
Ra Ra / ~~ Rc
~I
Rc ~, Rb
Ra~/ .~Rb Ra /~/Rc
R ,
a
-20-
SUBSTITUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
/~Rd Rb\//\iRd Rb~~Rc
\ I \ I
~~ Rb //~Rc S~~Re
I
. ~\ , l
Rb
S //~~ / N'u N
l R9
l Re ~ ~ ~\ ~ ~ \ /
N N
/NUN\ / \
I ~/ \
\~ . / w
N /
f
\/~ ~~ S, ~~~ I/ R
I Nv~Re . ~N
N
In the above G groups, the following definitions apply.
Ra is halogen;
Rb is hydroxy;
Rc represents alkoxy;
Rd represents alkyl;
Re represents hydrogen or Rd;
Rf represents hydrogen, or R~; and
Rg represents hydrogen, Ra or R~.
In those formulas where more than one of the same substituent appears. those
substituents are the same or different.
Particularly preffered Ra groups in G are fluorine. Particularly preferred Rc
groups in
G are methoxy and ethoxy. Particularly preferred Rd groups in G are methyl and
ethyl.
-21-
SUSST1TUTE SHEET (RULE 26)
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Representative compounds of the invention are shown below in Table 1.
Table 1
O O ~ ~ O O
N \ N \
H3C I H3C I ~ H F
'N ~N
H3C H H3C H
Compound 1 Compound 2
OCH3
O O \ ~ O O \
~N _N
H ~ ~ H
H3C
H C H H3C N
3 H
Compound 3 Compound 4
O O / ~ O / OCH3
\ O \
N N
H F I ~ H
F
H3C H HsC H
Compound S Compound 6
S
0
~N N N N
H ~ ~ H
HsC N HsC N
H3C H H3C H
Compound 7 Compound 8
/ ~ /
O O I O O
N wN ~ N N wN /
O H ~ O H
H3C 'H H3C 'H
Compound 9 Compound 10
-22-
SUBSTITUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/046Z3
The following numbering system is used to identify positions on the pyrrole
ring
portion of the compounds of the invention:
O
s N
s ~ ~ H
1 / z
s N
H
Representative compounds of the present invention, which are encompassed by
Formula l, include, but are not limited to the compounds in Table I and their
pharmaceutically
acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of
acids such as
hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,
toluenesulfonic,
10 methanesulfonic, nitric, benzoic, citric, tartaric, malefic, hydroiodic,
alkanoic such as acetic,
HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will
recognize a
wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the prodrugs, preferably acyIated
prodrugs, of
the compounds of Formula I. Those skilled in the art will recognize various
synthetic
1 S methodologies which may be employed to prepare non-toxic pharmaceutically
acceptable
addition salts and acylated prodrugs of the compounds encompassed by Formula
I.
The pharmaceutical utility of compounds of this invention are indicated by the
following assay for GABAa receptor binding activity.
Assays are carried out as described in Thomas and Tallman (J. Bio. Chem. 156:
9838-
20 9842 , J. Neurosci. 3_: 433-440, 1983). Rat cortical tissue is dissected
and homogenized in 25
volumes (w/v) of 0.05 M Tris HCl buffer (pH 7.4 at 4°C). The tissue
homoeenate is
centrifuged in the cold (4°C) at 20,000 x g for 20'. The supernatant is
decanted and the pellet
is rehomogenized in the same volume of buffer and again centrifuged at 20,000
x g. The
supernatant is decanted and the pellet is frozen at -20°C overnight.
The pellet is then thawed
25 and rehomogenized in 25 volume (original wt/voI) of buffer and the
procedure is carried out
-23-
SU8ST1TUTE SHEET (RULE 26)
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WO 97/34870 PCT/US97/04623
twice. The pellet is tinallv resuspended in ~0 volumes ~wwol of 0.05 M Tris
HCl buffer (pH
-.-i at 40°C).
Incubations contain 100 ml of tissue homogenate, I00 ml of radioligand 0.5 nM
(3H-
ROI ~-1788 [3H-Flumazenil] specific activity 80 Ci/mmol), drug or blocker and
buffer to a
total volume of 500 ml. Incubations are carried for 30 min at 4oC then are
rapidly filtered
through GFB filters to separate free and bound ligand. Filters are washed
twice with fresh
0.05 M Tris HCl buffer (pH 7.4 at 4oC) and counted in a liquid scintillation
counter. 1.0 mM
diazepam is added to some tubes to determine nonspecific binding. Data are
collected in
triplicate determinations, averaged and % inhibition of total specific binding
is calculated.
Total Specific Binding = Total - Nonspecific. In some cases, the amounts of
unlabeled drugs
is varied and total displacement curves of binding are carried out. Data are
converted to Ki's;
results for compounds of this invention are listed in Table 2.
TABLE 2
Compound
Number K; (nM)
1 21
2 12
3 13
4 1
5 0.5
6 1
7 10
8 80
9 4
10 12
1 S The compounds of general formula I may be administered orally, topically,
parenterally, by inhalation or spray or rectally in dosage unit formulations
containing
conventional non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The
term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular,
intrastemal injection or infusion techniques. In addition, there is provided a
pharmaceutical
-24-
SU85T1TlJTE SHEET (RULE 26)
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formulation comprising a compound of general formula I and a pharmaceutically
acceptable
carrier. One or more compounds of general formula I may be present in
association with one
or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or
adjuvants and if
desired other active ingredients. The pharmaceutical compositions containing
compounds of
general formula I may be in a form suitable for oral use, for example. as
tablets. troches,
lozenges, aqueous or oily suspensions, dispersible powders or granules,
emulsion, hard or soft
capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method
known
to the art for the manufacture of pharmaceutical compositions and such
compositions may
contain one or more agents selected from the group consisting of sweetening
agents, flavoring
agents. coloring agents and preserving agents in order to provide
pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in admixture
with non-toxic
pharmaceutically acceptable excipients which are suitable for the manufacture
of tablets.
These excipients may be for example, inert diluents, such as calcium
carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating
agents, for example, corn starch, or alginic acid; binding agents, for example
starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate, stearic acid
or talc. The
tablets may be uncoated or they may be coated by known techniques to delay
disintegration
and absorption in the gastrointestinal tract and thereby provide a sustained
action over a
longer period. For example, a time delay material such as giyceryl monosterate
or glyceryl
distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable
for the manufacture of aqueous suspensions. Such excipients are suspending
agents, for
example sodium carboxvmethylcellulose, methylcellulose,
hydropropylmethylcellulose,
sodium alginate, polvvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting
-25-
SU85T1TUTE SHEET (RULE 26)
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agents may be a naturally-occurring phosphatide. for example, lecithin. or
condensation
products of an alkylene oxide with fatty acids, for example polyoxyethylene
stearate, or
condensation products of ethylene oxide with long chain aliphatic alcohols,
for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with
partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
monooieate, or
condensation products of ethylene oxide with partial esters derived from fatty
acids and
hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions
may also contain one or more preservatives, for example ethyl, or n-propyl p
hydroxybenzoate, one or more coloring agents, one or more flavoring agents,
and one or more
sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil,
or in a mineral oil
such as liquid paraffin. The oily suspensions may contain a thickening agent,
for example
beeswax, hard paraffin or cetyi alcohol.. Sweetening agents such as those set
forth above, and
flavoring agents may be added to provide palatable oral preparations. These
compositions
may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by
the addition of water provide the active ingredient in admixture with a
dispersing or wetting
agent. suspending agent and one or more preservatives. Suitable dispersing or
wetting agents
and suspending agents are exemplified by those already mentioned above.
Additional
excipients, for example sweetening, flavoring and coloring agents, may also be
present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-
water
emulsions. The oily phase may be a vegetable oil, for example olive oil or
arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may
?5 be naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or partial esters
derived from fatty
acids and hexitol, anhydrides, for example sorbitan monoleate, and
condensation products of
the said partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monoleate.
The emulsions may also contain sweetening and flavoring agents.
-26-
SU85TiTUTE SHEET (RULE 26)
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Syrups and elixirs may be formulated with sweetening agents. for example
glycerol,
propylene glycol. sorbitor or sucrose. Such formulations may also contain a
demulcent, a
preservative and flavoring and coloring agents. The pharmaceutical
compositions may be in
the form of a sterile injectable aqueous or oleaginous suspension. This
suspension may be
formulated according to the known art using those suitable dispersing or
wetting agents and
suspending agents which have been mentioned above. The sterile injectable
preparation may
also be sterile injectable solution or suspension in a non-toxic parentally
acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and
solvents that may be employed are water, Ringer's solution and isotonic sodium
chloride
solution. In addition, sterile, fixed oils are conventionally employed as a
solvent or
suspending medium. For this purpose any bland fixed oil may be employed
including
synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid
find use in the
preparation of injectables.
The compounds of general formula I may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be
prepared by
mixing the drug with a suitable non-irritating excipient which is solid at
ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the rectum to
release the drug.
Such materials are cocoa butter and polyethylene glycols.
Compounds of general formula I may be administered parenterally in a sterile
medium. The drug, depending on the vehicle and concentration used, can either
be suspended
or dissolved in the vehicle. Advantageously, adjuvants such as local
anaesthetics,
preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram
of body
weight per day are useful in the treatment of the above-indicated conditions
(about 0.5 mg to
about 7 g per patient per day). The amount of active ingredient that may be
combined with
the carrier materials to produce a single dosage form will vary depending upon
the host
treated and the particular mode of administration. Dosage unit forms will
generally contain
between from about 1 mg to about S00 mg of an active ingredient.
-27-
SUBSTffUTE SHEET (RULE 26)
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It will be understood. however. that the specific dose level for any
particular patient
will depend upon a variety of factors including the activity of the specific
compound
employed, the age, body weight. general health, sex. diet, time of
administration. route of
administration. and rate of excretion, drug combination and the severity of
the particular
disease undergoing therapy.
An illustration of the preparation of compounds of the present invention is
given in
Scheme I.
-28-
SUBSTITUTE 5liEET (RULE 26)
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Scheme I
O O OH
K.,CO;. BrCH,COCO,_Et ~.,-CO,Et
1
R3 / CHC13 R3
R~ , ,n O R~~ i ~n O
MsCI, Et3N
CH.,CI.,, 0° C
r - -
0 0
CO.,Et CO.,Et
R3 { rt, ( ~ NH40Ac. DMF R3 {
R4 / ~ ~ n H 100° C R4 ~ ~ n O
SN NaOH, EtOH.
85o C W
O O HN
CO.,H ~ O
{ n, ~ \ EtgN, CIC02E~ ~ {
Rs l R3
R4 ~~ H DMF, 0° C R4 ~ N
1
CO,Et
1 N NaOH. -
EtOH.
85 C ~ W
HN
O
R3
R4 ..
where W, m, n, R3, and R4 are defined as above.
Those having skill in the art will recognize that the starting materials may
be varied
and additional steps employed to produce compounds encompassed by the present
invention,
as demonstrated by the following examples. In some cases protection of certain
reactive
functionaiities may be necessary to achieve some of the above transformations.
In general the
-29
SUBST1TUTF SHEET tRULE 26)
CA 02249562 2004-11-05
need for such protecting ?roups will be apparent to those skilled in the art
of organic synthesis
as well as the conditions necessary to attach and remove such groups.
The invention is illustrated further by the following examples which are not
to be
construed as limiting the invention in scope or spirit to the specific
procedures described in
them.
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Example 1
Preparation of starting materials and intermediates
The starting materials and various intermediates may be obtained from
commercial
sources, prepared from commercially available organic compounds, or prepared
using well
known synthetic methods.
Representative examples of methods for preparing intermediates of the
invention are
set forth below.
1. Ethyl 3-hydroxy 4-oxo-6-methyl-2,3,4,5,6,7
hexahvdrobenzofuran-3-carboxvlate
O OH
C02Et
To a stirred mixture of 5-methyl-1,3-cyclohexanedione (10.25 g, 81 mmol) and
potassium carbonate (22.46 g, 162 mmol) in dichloromethane (200 mL) at
0°C was added a
solution of ethyl bromopyruvate ( 10.7 mL, 85 mmol) in dichloromethane (50
mL). The
reaction was allowed to reach ambient temperature, stirred for 18 hours, then
poured into
saturated aqueous ammonium chloride. After adjusting to neutral pH with
aqueous
hydrochloric acid, the mixture was extracted 2X with dichloromethane, the
combined organic
layers were dried over sodium sulfate, filtered, and concentrated in vacuo to
give ethyl 3-
hydroxy 4-oxo-b-methyl-2,3,4,5,6,7-hexahydrobenzofi.trap-3-carboxylate ( 18.48
g).
'0 2. Ethyl4-oxo-6-methyl-4,5,6,7-
tetrahvdrobenzofuran-3-carboxylate
O
C02Et
a 'O
A solution of methanesulfonyl chloride (6.1 mL, 78.5 mmol) in dichloromethane
(50
mL) was added to a stirring solution of ethyl 3-hydroxy 4-oxo-b-methyl-
2,3.4,5,6,7-
?5 hexahydrobenzofuran-3-carboxylic acid (18.48 g, 76 mmol) and triethylamine
(21.4 mL, 154
mmol) in dichloromethane ( 150 mL) at 0°C. The mixture was allowed to
reach ambient
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SU85T1TUTE SHEET (RULE 26)
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temperature. stirred for 2 hours. then poured into aqueous 1 N sodium
hydroxide and extracted
with ethyl acetate. The organic layer was washed with brine, dried over
magnesium sulfate.
filtered. and concentrated in vacuo to give ethyl 4-oxo-6-methyl-4,5,6,7-
tetrahydrobenzofuran-3-carboxylate ( 16.86 g).
3. 4-oxo-6-methyl-4,5,6,7-tetrahydro
1H-indole-3-carboxylic acid
O
G02H
a 'N
H
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-
carboxylate
( 15.7 g, 7I mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-
dimethylformamide
75 mL) was heated at 100°C for 2 hours. The reaction mixture was
concentrated in vacuo, ice
water was added, and the precipitate collected, rinsed with water then diethyl
ether and dried
to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94
g). To this
ester was added aqueous SN sodium hydroxide (50 mL) and ethyl alcohol ( 10 mL)
and the
mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an
ice water bath,
acidified with aqueous hydrochloric acid, and the precipitate collected,
rinsed with water then
diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxylic acid
(5.2 g). m.p. 210-211°C.
4. 4-Oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (m.p. 231-
232°C) was prepared essentially according to the procedures described
in Parts 1-3 of this
examples.
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SUBSTITUTE SHEET (RULE 26)
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Example 2
O
O
~N
F
'N
H
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indole-3-
carboxylic
acid ( 155 mg, 0.75 mmol) and triethylamine (209 ~L, 1.5 mmol) in
dimethylformamide (4
mL) at 0°C was added ethyl chloroformate ( 143 ~L, 1.5 mmol). After
stirring an additional
45 minutes, 2-fluoroaniline ( 145 ~L, 1.5 mmol) was added. The reaction
mixture was stirrred
for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted
2X with ethyl
acetate. The combined organic layers were washed with water, dried over
magnesium sulfate,
filtered, and concentrated in vacuo . To the residue was added aqueous SN
sodium hydroxide
(5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30
minutes. After
cooling in an ice water bath, the reaction mixture was acidified with
hydrochloric acid, the
precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-
fluorophenyl)-4-
oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).
Example 3
The following compounds are prepared essentially according to the procedures
described in Examples 1 and 2.
(a) N-Phenyl-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indole-3-carboxamide
(Compound 1 ).
(b) N-(2-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indo1e-3-
carboxamide; mp 259-261 °C.
(c) N-(3-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indo1e-3-
carboxamide; mp 268-270°C.
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SUBSTTTUTE SHEET (RULE 26)
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WO 97/34870 PCTNS97/04623
(d) N-(2, 4- Diflurophenyl)-4-oxo-6.6-dimethvl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide.
(e) N-(2,4-Difluorophenyl)-4-oxo-6.6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide .
N-(3Methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6, 7-tetrahydro-1 H-indole-3-
carboxamide.
(g) N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 190-192°C.
(h) N-(3-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 282-284°C.
(i) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 213-215°C.
(j) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide.
(k) N-(2-Fluoro-~-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide.
(1) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyi-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 225-227°C.
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SU85T1TUTE SHEET (RULE Z6)
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(ml N-(2-Methoxphenyi)-:~-oxo-6,6-dimethvl-4.5,6.7-tetrahydro-1H-indole-3-
carboxamide (Compound 3).
(n) N-(4-Ethoxvphenyl)-4-oxo-6,6-dimethyl-4.5,6,7-tetrahydro-1H-indo1e-3-
carboxamide.
(o) N-(4-Methoxyphenyi)-4-oxo-6.6-dimethyi-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide.
(p) N-(2-Hydroxy-~t.-methylphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 201-203°C.
(q) N-Phenyl-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide
(Compound 4); mp 278-279°C.
(r) N-(2-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide (Compound 5); mp 264-265°C.
(s) N-{3-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 302-303°C.
(t) N-(4-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 262-264°C.
(u) N-(3-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 234-235°C.
(v) N-(4-Hydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide: mp 320°C.
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SU8ST1TUTE SHEET (RULE 2fi~
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(w) N-(2-Fiuoro-4-hydroxvphenvl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-IH-indole-
3-carboxamide; mp 330°C.
(x) N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 236-238°C.
(y) N-(4-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 260-261 °C.
(z) N-(2-Fluoro-4-methoxvphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-
3-carboxamide (Compound 6); mp 217-2I9°C.
(aa) N-(4-Ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
I S carboxamide; mp 269°C.
(bb) N-(2-Fluoro-4-ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 224-225°C.
(cc) N-(3,4-Dihydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 267-269°C.
(dd) N-(2-Hydroxy-4-methylphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-
3-carboxamide; mp 258-260°C.
2S
(ee) N-(3-Thienyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide (Compound 7).
(ff) N-(2-Thiazoyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro- 1H-indole-3-
carboxamide.
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SUBSTITUTE SHEET (RULE 26)
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(ggj N-(5-Methyl-2-thiazolyl)-4-oxo-6.6-dimethyl-4.x,6,7-tetrahydro-1H-indole-
3-
carboxamide.
(hh) N-(3-Pvridyl)-4-oxo-6.6-dimethyl-4,5.6,7-tetrahydro-1H-indole-3-
carboxamide; mp 237-239°C.
(ii) N-(4-Methoxy-3-pvridyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide; mp 217-218°C.
(jj) N-(2-Chloro-1,8-napthyridin-7-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-
1H-
indole-3-carboxamide; mp 278-280°C.
(kk) N-(1,8-Napthyridin-2y1)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide (compound 8); mp 389-390°C.
{1l) N-(3-Pyridyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;
mp 225-227°C.
(mm) N-(4-Pyridyl)-4-oxo-6-methyi-4,5,6,7-tetrahydro-1H-indoie-3-carboxamide;
mp 280-290°C.
(nn) N-(1,8-Napthyridin-2-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide (Compound 9).
(oo) N-(6-Methyl-1,8-napthridin-2-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide; mp 338-340°C(d).
(pp) N-(2-Quinolinyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide
(Compound 10); mp 273-275°C.
(qq) N-(4-Pyridyl)-4-oxo-b,6-dimethyl-4,5,6,7-tetrahydro-1H-indoie-3-
carboxmide.
The invention and the manner and process of making and using it, are now
described
in such full, clear, concise and exact terms as to enable any person skilled
in the art to which it
pertains, to make and use the same. It is to be understood that the foregoing
describes
preferred embodiments of the present invention and that modifications may be
made therein
without departing from the spirit or scope of the present invention as set
forth in the claims.
To particularly point out and distinctly claim the subject matter regarded as
invention, the
following claims conclude this specification.
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SUBSTITUTE SHEET (RULE I6)
