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Tricycles, their manufacture and use as pharmaceutical agents
The present invention relates to novel tricycles, to a process for their
manufacture,
pharmaceutical compositions containing them and their manufacture as well as
the
use of these compounds as pharmaceutically active agents.
Protein kinases regulate rnany different signaling processes by adding
phosphate
groups to proteins (Hunter, T., Cell 50 (1987) 823-829); particularly
serine/threonine kinases phosphorylate proteins on the alcohol moiety of
serine or
threonine residues. The serine/threonine kinase family includes members that
control cell growth, migration, differentiation, gene expression, muscle
contraction,
glucose metabolism, cellular protein synthesis, and regulation of the cell
cycle.
The Aurora kinases are a family of serine/threonine kinases that are believed
to play
a key role in the protein phosphorylation events that are essential for the
completion of essential rnitotic events. The Aurora kinase family is made up
of
three key members: Aurora A, B and C (also known as Aurora-2, Aurora-1 and
Aurora-3 respectively). Aurora-1 and Aurora-2 are described in US 6,207,401 of
Sugen and in related patents and patent applications, e.g. EP 0 868 519 and
EP 1 051 500.
For Aurora A there is increasing evidence that it is a novel proto-oncogene.
Aurora
A gene is amplified and transcript/protein is highly expressed in a majority
of
human tumor cell lines and primary colorectal, breast and other tumors. It has
been shown that Aurora A overexpression leads to genetic instability shown by
amplified centrosomes and significant increase in aneuploidy and transforms
Ratl
fibroblasts and mouse NZH3T3 cells in vitro. Aurora A-transformed NIH3T3 cells
grow as tumors in nude rnice (Bischoff, J.R., and Plowman, G.D., Trends Cell
Biol.
9 (1999) 454-459; Giet, R., and Prigent, C., J. Cell Sci. 112 (1999) 3591-
3601; Nigg,
E.A., Nat. Rev. Mol. Cell Biol. 2 (2001) 21-32; Adams, R.R., et al., Trends
Cell Biol.
11 (2001) 49-54). Moreover, amplification of Aurora A is associated with
aneuploidy and aggressive clinical behavior (Sen, S., et al., J. Natl.Cancer
Inst. 94
(2002) 1320-1329) and arnplification of its locus correlates with poor
prognosis for
patients with node-negative breast cancer (Isola, J.J., et al., Am. J.
Pathology 147
(1995) 905-911). For these reasons it is proposed that Aurora A overexpression
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contributes to cancer phenotype by being involved in chromosome segregation
and
mitotic checkpoint control.
Human tumor cell lines depleted of Aurora A transcripts arrest in mitosis.
Accordingly, the specific inhibition of Aurora kinase by selective inhibitors
is
recognized to stop uncontrolled proliferation, re-establish mitotic checkpoint
control and lead to apoptosis of tumor cells. In a xenograft model, an Aurora
inhibitor therefore slows tumor growth and induces regression (Harrington,
E.A.,
et al., Nat. Med. 10 (2004) 262-267).
Low molecular weight inhibitors for protein kinases are widely known in the
state
of the art. For Aurora inhibition such inhibitors are based on i.e.
quinazoline
derivatives as claimed in the following patents and patent applications:
WO 00/44728; WO 00/47212; WO 01/21594; WO 01/21595; WO 01/21596;
WO 01/21597; WO 01/77085; WO 01/55116; WO 95/19169; WO 95/23141;
WO 97/42187; WO 99/06396; pyrazole and triazole derivatives as claimed in the
following patents and patent applications: WO 02/22601; WO 02/22602;
WO 02/22603; WO 02/22604; WO 02/22605; WO 02/22606; WO 02/22607;
WO 02/22608; WO 02/50065; WO 02/50066; WO 02/057259; WO 02/059112;
WO 02/059111; WO 02/062789; WO 02/066461; WO 02/068415; pyrimidine
derivatives: WO 03/077921; WO 03/078423; WO 03/078426; WO 03/078427;
WO 04/000833 or imidazole, oxazole and thiazole derivatives: WO 02/96905;
WO 04/005283;
However there remains a need for structural new compounds with improved
therapeutic properties, such as enhanced activity, decreased toxicity, better
solubility and improved pharmacokinetic profile, to name only a few.
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The present invention relates to the use of the compounds of the general
formula I,
RI
\ H
N ~ N N, NH
X\Y I / N / ~ R 3
R2
formula I,
wherein
Rl is hydrogen, alkyl or-C(O)-alkyl;
R2 is hydrogen, alkyl, cyano or halogen;
R3 is hydrogen, alkyl, (C3-C6)-cycloalkyl, alkoxy or alkylsulfanyl;
X is -C(O)- or -CH2-;
Y is -NH-, -CH2-CR4R5-, -CR4R5-CH2- or -CR4R5-; wherein
R4 is hydrogen or alkyl; and
R5 is hydrogen or alkyl,
or alternatively
R4 and R5 form together with the carbon atom to which they are
attached a cycloalkyl ring;
and all their pharmaceutically acceptable salts,
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of the
formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl,
for the manufacture of medicaments for the treatment of cancer.
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Another embodiment of the invention is the use of the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl,
as Aurora family kinase inhibitors.
Some tricycles or related compounds are known as inhibitors of erythrocyte
aggregation from US 4,835,280A, EP 0 189 103, US 4,954,498 and also frorn
Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et
al., J.
Med. Chem. 32 (1989) 1481-1491; EP 0 318 902; DE 34 17 643; DE 36 42 315 and
DE 37 01 277. US 5,212,186A describes related tricycles for the treatment of
cardiac
insuffiency, hypertension and other diseases.
WO 03/035065 relates to benzimidazole derivatives as kinase inhibitors,
especially
as inhibitors against kinase insert domain containing receptor (KDR) tyrosine
kinase, spleen tyrosine kinase (SYK) and inducible T cell kinase (ITK).
The compounds according to this invention show activity as protein kinase
inhibitors. Many diseases are associated with abnormal cellular responses
triggered
by protein kinase mediated events. These diseases include autoimmune diseases,
inflammatory diseases, neurological and neurodegenerative diseases, cancer,
cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-
related diseases. Accordingly, there has been a substantial effort in
medicinal
chemistry to find protein kinase inhibitors that are effective as therapeutic
agents.
The compounds according to this invention in particular show activity as
Aurora
family kinase inhibitors, especially as Aurora A kinase inhibitors, and may
therefore
be useful for the treatment of diseases mediated by said kinase. Aurora A
inhibitiori
leads to cell cycle arrest in the G2 phase of the cell cycle and exerts ari
antiproliferative effect in tumor cell lines. This indicates that Aurora A
inhibitors
may be useful in the treatment of i.e. hyperproliferative diseases such as
cancer and
in particular colorectal, breast, lung, prostate, pancreatic, gastric,
bladder, ovarian,
melanoma, neuroblastoma, cervical, kidney or renal cancers, leulcemias or
lymphomas. Treatment of acute-myelogenous leukemia (AML, acute lymphocytic
leukemia (ALL) and gastrointestinal stromal tumor (GIST) is included.
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Objects of the present invention are of the compounds of formula I and their
tautomers, pharmaceutically acceptable salts, enantiomeric forms,
diastereoisomers
and racemates, their use as Aurora kinase inhibitors, the preparation of the
above-
mentioned compounds, medicaments containing them and their manufacture as
well as the use of the above-mentioned compounds in the control or prevention
of
illnesses, especially of illnesses and disorders as mentioned above or in the
manufacture of corresponding medicaments.
As used herein, the term "alkyl" means a saturated, straight-chain or branched-
chain hydrocarbon containing from 1 to 6, preferably 1 or 4, carbon atoms such
as
methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl. Said alkyl is
optionally
substituted with one or several halogen atoms, preferably fluorine or
chlorine,
especially fluorine. Preferably the alkyl is substituted one to five times and
more
preferably one to three times by such halogen. Examples are trifluoromethyl,
2,2,2-
trifluoroethyl, perfluoroethyl and the like, preferably trifluoromethyl. In
one
embodiment of the invention only the "a1ky1" group as used in R3 is optionally
substituted by halogen while the other "alkyl" groups as used in R1, R2, R4
and R5
are not substituted by halogen. In another embodiment of the invention all
"alkyl"
groups are not substituted by halogen.
The term "alkoxy" as used herein means an alkyl group as defined above which
is
attached via an oxygen atom (alkyl-O-).
The term "alkylsulfanyl" as used herein means an alkyl group as defined above
which is attached via an sulfur atom (alkyl-S-).
The term "cycloalkyP" as used herein means a carbocyclic unsaturated ring
system
containing from 3 to 6, preferably from 3 to 5, carbon atoms. Such carbocyclic
unsaturated ring system can be optionally substituted one to three, preferably
one
or two times, especially one time by alkyl. Examples are cyclopropyl, 1-methyl-
cycloprop-1-yl, cyclobutyl, cyclopentyl and cyclohexyl, preferably
cyclopropyl. In
an embodiment of the invention, the term "cycloalkyl" as used in R3 denotes a
cyclopropyl. The cycloallcyl ring which is formed by R4 and R5 together with
the
carbon atom to which they are attached is preferably a cyclopentyl or
cyclohexyl
ring, especially a cyclopentyl ring.
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The term "halogen" as used herein means fluorine, chlorine, bromine and
iodine,
preferably fluorine, chlorine or bromine, and more preferred fluorine and
chlorine.
The compounds of formula I can exist in different tautomeric forms and in
variable
mixtures thereof. All tautomeric forms of the compounds of formula I and
mixtures thereof are an objective of the invention. For example, the imidazole
part
of the tricyclic ring system of formula I can exist in two tautomeric forms as
shown
here below:
R H
R\ 1
NN N- NH = / NN N~NH
X~ I/ ~ 3 X I/ N/ ~ 3
Y H R Y R
N a~
R R 2
formula I
Also, e.g. the pyrazole ring of formula I can form two tautomeric forms as
shown
here below:
1 ~
H
R N N N-NH R N ~ N N
~N
~ \ / =-= X ~\ I
X
s N \ s
Y H 2 R Y / R
R H ~ R2
formula I
As used herein, in relation to mass spectrometry (MS) the term "API+" refers
to
positive atmospheric pressure ionization mode the term "API-" refers to
negative
atmospheric pressure ionization mode and the term "ESI+" refers to positive
electrospray ionization mode.
An embodiment of the invention is the use of the compounds of formula I,
wherein
X is -CH2-;
for the manufacture of medicaments for the treatment of cancer.
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An embodiment of the invention is the use of the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl; and
X is -CH2-;
for the manufacture of medicaments for the treatment of cancer.
An embodiment of the invention is the use of the compounds of formula I,
wherein
X is -CH2-;
as Aurora family kinase inhibitors.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
X is -CH2-;and
Y is -CR4R5-;
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -CH2-; and
Y ls -CR4R5-;
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
X is -CH2-; and
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Y is -CR4R5-;
as Aurora family kinase inhibitors.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
X is -CH2-; and
Y is -NH-, -CH2-CR4R5- or-CR4R5-CH2-;
for the manufacture of medicaments for the treatment of cancer.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -CH2-; and
Y is -NH-, -CH2-CR4R5- or-CR4R5-CH2-;
for the manufacture of medicaments for the treatment of cancer.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
X is -CH2-; and
Y is -NH-, -CH2-CR4R5- or-CR4R5-CHZ-;
as Aurora family kinase inhibitors.
Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
X is -C(O)-;
for the manufacture of medicaments for the treatment of cancer.
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Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl; and
X is -C(O)-;
for the manufacture of medicaments for the treatment of cancer.
Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
X is -C(O)-;
as Aurora family kinase inhibitors.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
X is -C(O)-; and
Y is -CHZ-CR4R5- or -CR4R5-CH2-;
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CH2-CR4R5- or -CR4R5-CH2-;
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
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X is -C(O)-; and
Y is -CHZ-CR4R5- or -CR4R5-CH2-;
as Aurora family kinase inhibitors.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
X is -C(O)-; and
Y is -NH- or-CR4R5-;
for the manufacture of medicaments for the treatment of cancer.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -NH- or-CR4R5-;
for the manufacture of medicaments for the treatment of cancer.
Still another embodiment of the invention is the use of the compounds of
formula I, wherein
X is -C(O)-; and
Y is -NH- or-CR4R5-;
as Aurora family kinase inhibitors.
Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
X is -C(O)-; and
Y is -CR4Rs-;
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for the manufacture of medicaments for the treatment of cancer.
Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CR4R5-;
for the manufacture of medicaments for the treatment of cancer.
Yet another embodiment of the invention is the use of the compounds of formula
I,
wherein
X is -C(O)-; and
Y is -CR4R5-;
as Aurora family kinase inhibitors.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
X is -C(O)-; and
Y is -NH-;
for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloallcyl;
X is -C(O)-; and
Y is -NH-;
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for the manufacture of medicaments for the treatment of cancer.
Another embodiment of the invention is the use of the compounds of formula I,
wherein
X is -C(O)-; and
Y is -NH-;
as Aurora family kinase inhibitors.
Medicaments containing a compound of the present invention or a
pharmaceutically acceptable salt thereof and a therapeutically inert carrier
are an
object of the present invention, as is a process for their production, which
comprises bringing one or more compounds of the present invention and/or
pharmaceutically acceptable salts and, if desired, one or more other
therapeutically
valuable substances into a galenical administration form together with one or
more
therapeutically inert carriers.
In accordance with the invention the compounds of the present invention as
well as
their pharmaceutically acceptable salts are useful in the control or
prevention of
illnesses. Based on their Aurora tyrosine kinase inhibition and their
antiproliferative activity, said compounds are useful for the treatment of
diseases
such as cancer in humans or animals and for the production of corresponding
medicaments. The dosage depends on various factors such as manner of
administration, species, age and/or individual state of health.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of diseases mediated by an
inappropriate
activation of Aurora family tyrosine kinases, especially Aurora A tyrosine
kinase.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of cancer.
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Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of colorectal, breast, lung, prostate,
pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical,
kidney or
renal cancers, leukemias or lymphomas.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of acute-myelogenous leukemia (AML,
acute
lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
Another embodiment of the invention is the use of one or more compounds of
formula I for the manufacture of medicaments for the treatment of diseases
mediated by an inappropriate activation of Aurora family tyrosine kinases.
Another embodiment of the invention is the use of the compounds of formula I
as
Aurora A tyrosine kinase inhibitors.
Another embodiment of the invention is the use of the compounds of formula I
as
anti-proliferating agents.
Another embodiment of the invention is the use of one or more compounds of
formula I for the treatment of cancer.
Another embodiment of the invention is the use of one or more compounds of
formula I for the manufacture of medicaments for the treatment of diseases
mediated by an inappropriate activation of Aurora family tyrosine kinases.
Another embodiment of the invention is the use of one or more compounds of
formula I for the manufacture of medicaments for the treatment for the
treatment
of cancer.
Another embodiment of the invention is the use of one or more compounds of
formula I for the manufacture of medicaments for the treatment of colorectal,
breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma,
neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas
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Another embodiment of the invention is the use of one or more compounds of
formula I for the manufacture of medicaments for the treatment of acute-
myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and
gastrointestinal stromal tumor (GIST). Another embodiment of the invention is
a
medicament containing one or more compounds of formula I as active ingredients
together with pharmaceutically acceptable adjuvants for the treatment of
diseases
mediated by an inappropriate activation of Aurora family tyrosine kinases,
especially Aurora A tyrosine kinase.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of cancer.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of colorectal, breast, lung, prostate,
pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical,
kidney or
renal cancers, leukemias or lymphomas.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I as active ingredients together with pharmaceutically
acceptable adjuvants for the treatment of acute-myelogenous leukemia (AML,
acute
lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
with the proviso that, if R' and R2 are hydrogen, X is-C(O)- and Y is -CR4R5-;
wherein R4 and R5 are methyl;
then R3 is hydrogen, (C2-C6)allcyl or (C3-C6)-cycloalkyl.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl.
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Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl; and
X is -CH2-.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -CH2-; and
Y is -CR4R5-.
Such compounds are for example:
7,7-Dimethyl-2-( 5-methyl-2H-pyrazol-3-yl)-3,5,6,7-tetrahydro-imidazo [4,5-
f] indole; and
1- [ 7,7-Dimethyl-2-( 5-methyl-2H-pyrazol-3-yl)-6,7-dihydro-3H-imidazo [4,5-
f] indol-5-yl] -ethanone.
Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -CH2-; and
Y is -NH-, -CH2-CR4R5- or -CR4R5-CH2-.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl; and
X is -C(O)-;
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with the proviso that, if R' and R2 are hydrogen, X is-C(O)- and Y is -CR4R5-;
wherein R4 and RS are methyl;
then R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl; and
X is -C(O)-.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CHz-CR4R5- or -CR4R5-CH2-.
Such compounds are for example:
8,8-Dimethyl-2- ( 5-methyl-1 H-pyrazol-3-yl)-1,5,7,8-tetrahydro-imidazo [4,5-
g] quinolin-6-one; and
2-(5-Isobutyl-2H-pyrazol-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-
g] quinolin-6-one.
Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -NH-, -CR4R5-;
with the proviso that, if R' and R 2 are hydrogen, X is-C(O)- and Y is -CR4R5-
;
wherein R4 and R5 are methyl;
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then R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl.
Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, (C2-C6)allcyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -NH-, -CR4R5-.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CR4R5-;
with the proviso that, if Rl and R2 are hydrogen, X is-C(O)- and Y is -CR4R5-;
wherein R4 and RS are methyl;
then R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl.
Still another embodiment of the invention are the compounds of formula I,
wherein
R3 is hydrogen, (C2-C6)alkyl or (C3-C6)-cycloalkyl.
X is -C(O)-; and
Y is -CR4R5-.
Such compounds are for example:
2-(5-Isobutyl-2H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-lH-imidazo[4,5-f]indol-
6-one;
2- ( 5-methyl-2H-pyrazol-3-yl)-spiro [ 7,7-cyclopentan-5,7-dihydro-3H-imidazo
[4,5-
f]indol]-6-one; or according to actual IUPAC nomenclature 2-(5-Methyl-2H-
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pyrazol-3-yl)-spiro-5,7-dihydro[ cyclopentane-1',7-imidazo [4,5-f] indol] -6(
3H) -
one;
2- (5-Isobutyl-2H-pyrazol-3 -yl) -spiro [ 7,7-cyclopentan-5,7-dihydro-1H-
imidazo[4,5-f]indol]-6-one; or according to actual IUPAC nomenclature 2-(5-
Isobutylyl-2H-pyrazol-3-yl)-spiro-5,7-dihydro [cyclopentane-1',7-imidazo [4,5-
f]indol]-6(3H)-one;
5-Ethyl-7,7-dimethyl-2-(5-methyl- lH-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one;
5-Ethyl-7,7-dimethyl-2- ( 5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo
[4,5-
f] indol-6-one;
5,7,7-Trimethyl-2- ( 5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one;
5-Ethyl-2-(5-isobutyl-2H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-
imidazo [4,5-f] indol-6-one; and
2- (5-Isobutyl-2H-pyrazol-3-yl) - 5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one.
Another embodiment of the invention are the compounds of formula I, wherein
R3 is hydrogen, alkyl or (C3-CO-cycloallcyl;
X is -C(O)-; and
Y is -NH-.
Such compounds are for example:
6- ( 5-Methyl-1 H-pyrazol-3-yl) -3,5-dihydro-lH-benzo [ 1,2-d;4,5-d' ]
diimidazol-2-
one;
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3-Methyl-6-(5-methyl- lH-pyrazol-3-yl)-3,5-dihydro-lH-benzo [ 1,2-d;4,5-
d'] diimidazol-2-one; and
3-Isopropyl-6-(5-methyl-lH-pyrazol-3-yl)-3,5-dihydro-lH-benzo [ 1,2-d;4,5-
d' ] diimidazol-2-one.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl or -C(O)-alkyl.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl.
Another embodiment of the invention are the compounds of formula I, wherein
Rl is alkyl; and
R2 is hydrogen or alkyl.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl;
R 2 is hydrogen or alkyl; and
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl;
X is -C(O)-; and
Y is -CH2-CR4R5-, -CR4R5-CHz- or -CR4R5-.
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Another embodiment of the invention are the compounds of formula I, wherein
Rl is alkyl;
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CH2-CR4R5-, -CR4R5-CH2- or -CR4R5-.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl;
R 2 is hydrogen or alkyl;
X is -C(O)-; and
Y is -CR4R5-.
Another embodiment of the invention are the compounds of formula I, wherein
Rl is alkyl;
R2 is hydrogen;
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CR4R5-.
Such compounds are for example:
5-Ethyl-7,7-dimethyl-2- ( 5-methyl-1H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo
[4,5-
f] indol-6-one;
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5-Ethyl-7,7-dimethyl- 2-(5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo
[4,5-
f) indol-6-one;
5,7,7-Trimethyl-2- ( 5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one;
5-Ethyl-2-(5-isobutyl-2H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-
imidazo [4,5-fl indol-6-one;
2- (5-Isobutyl-2H-pyr azol-3 -yl) -5,7,7-trimethyl-5,7-dihydro-3H-imidazo [
4,5-
f] indol-6-one;
5,7,7-Trimethyl-2-(l.H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo[4,5 f]indol-6-one;
5,7,7-Trimethyl-2- (5 -methyl-lH-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f ] indol-6-one;
5-Ethyl-7,7-dimethyl-2-(1H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo[4,5 f]indol-6-
one;
5-Ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f]indol-6-one; compound with acetic acid;
5-Isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo [4,5 f ] indol-6-one;
5-Isopropyl-7,7-dirnethyl-2-(5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo[4,5 ff indol- 6-one;
7,7-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-5-propyl-5,7-dihydro-lH-
imidazo[4,5 f]indol-6-one;
7,7-Dimethyl-5-propyl-2-(5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo[4,5 f]indol-6-one;
Another embodiment of the invention are the compounds of formula I, wherein
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Rl is alkyl;
R' is hydrogen or alkyl;
R3 is alkyl which is substituted one r several times by halogen;
X is -C(O)-; and
Y is -CR4R5-.
Such compounds are for example:
5-Ethyl-7,7-dimethyl-2-(5-trifluoromethyl-lH-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo [4,5-f ] indol-6-one;
5-Isopropyl-7, 7-dimethyl-2- ( 5-trifluoromethyl-2H-pyrazol-3-yl) -5,7-dihydro-
lH-
imidazo [4,5 f ] indol-6-one;
7,7-Dimethyl-5-propyl-2-( 5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo [4,5 f] indol-6-one; and
5,7,7-Trimethyl-2-( 5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo [4,5-f] indol-6-one.
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl;
R' is hydrogen or alkyl;
R3 is alkoxy or alkylsulfanyl;
X is -C(O)-; and
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Y is -CR4Rs-
Such compounds are for example:
5-Ethyl-2-( 5-methoxy-lH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-3 H-
imidazo[4,5-flindol-6-one; and
5-Ethyl-7,7-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo [4,5-fl indol-6-one
Another embodiment of the invention are the compounds of formula I, wherein
R' is alkyl;
R 2 is hydrogen or alkyl;
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -CH2-CR4R5- or-CR4R5-CH2-.
Another embodiment of the invention are the compounds of formula I, wherein
Rl is alkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -C(O)-; and
Y is -NH-.
Such compounds are for example:
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3-Methyl-6-(5-methyl-lH-pyrazol-3-yl)-3,5-dihydro-1 H-benzo [ 1,2-d;4,5-
d']diimidazol-2-one; and
3-Isopropyl-6- (5-methyl- 1H-pyrazol-3-yl) -3,5-dihydro- 1H-benzo [ 1,2-d;4,5-
d'] diimidazol-2-one.
Another embodiment of the invention are the compounds of formula 1, wherein
Rl is -C(O)-alkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl or (C3-C6)-cycloalkyl;
X is -CH2-; and
Y is -CH2-CR4R5-, -CR4R5-CH2- or -CR4R5-.
Such a compound is for example:
1- [7,7-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-6,7-dihydro-3H-imidazo [4,5-
f] indol-5-yl] -ethanone.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I, with the proviso that, if R' and R2 are hydrogen, X is-
C(O)- and Y is -CR4R5-; whereinR4 and R5 are methyl; then R3 is hydrogen, (C2-
C6)alkyl or (C3-C6)-cycloalkyl, as active ingredients together with
pharmaceutically
acceptable adjuvants
Another embodiment of the invention is a medicament containing one or more
compounds of formula I, wherein R3 is hydrogen, (C2-C6)alkyl, (C3-C6)-
cycloalkyl
or fluorine, as active ingredients together with pharmaceutically acceptable
adjuvants
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Another embodiment of the invention is a medicament containing one or more
compounds of formula I, wherein R' is alkyl or -C(O)-alkyl, as active
ingredients
together with pharmaceutically acceptable adjuvants.
Another embodiment of the invention is a medicament containing one or more
compounds of formula I, wherein Rl is alkyl, as active ingredients together
with
pharmaceutically acceptable adjuvants.
Another embodiment of the invention is the use of one of the following
compounds for the manufacture of a medicament for the treatment of cancer:
7,7-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-3,5,6,7-tetrahydro-imidazo [4,5-
f] indole;
1- [ 7,7-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl)-6,7-dihydro-3H-imidazo [4,5-
f] indol-5-yl] -ethanone;
8,8-Dimethyl-2-( 5-methyl-lH-pyrazol-3-yl)-1,5,7,8-tetrahydro-imidazo [ 4,5-
g] quinolin-6-one;
2- (5-Isobutyl-2H-pyrazol-3 -yl) -8,8-dimethyl- 1,5,7,8-tetrahydro-imidazo
[4,5-
g] quinolin-6-one;
7,7-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-imidazo[4,5 f]indol-
6-one;
2- ( 5-Isobutyl-2H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-lH-imidazo [4,5-fJ
indol-
6-one;
2- (5-methyl-2H-pyrazol-3-yl)-spiro [7,7-cyclopentan-5,7-dihydro-3H-imidazo
[4,5-
f]indol]-6-one; or according to actual IUPAC nomenclature 2-(5-methyl-2H-
pyrazol-3-yl)-spiro-5,7-dihydro [cyclopentane-1',7-imidazo [4,5-f] indol] -
6(3H)-
one;
2-(5-Isobutyl-2H-pyrazol-3-yl)-spiro[7,7-cyclopentan-5,7-dihydro-lH-
imidazo[4,5-f]indol]-6-one; or according to actual IUPAC nomenclature 2-(5-
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Isobutyl-2H-pyrazol-3-yl) -spiro-5,7-dihydro [ cyclopentane-1',7-imidazo [ 4,5-
f]indol]-6(3H)-one;
6- ( 5-Methyl-1 H-pyrazol-3-yl) -3,5-dihydro-lH-benzo [ 1,2-d;4,5-d' ]
diimidazol-2-
one;
2-(4,5-Dimethyl-IH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-lH-imidazo[4,5-
f]indol-6-one;
7,7-Dimethyl-2- [5- ( 3-methyl-butyl)-1H-pyrazol-3-yl] -5,7-dihydro- 1H-
imidazo [4,5 f ] indol-6-one;
2- (5-Ethyl-4-methyl-lH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-lH-imidazo [4,5-
f]indol-6-one;
7,7-Dimethyl-2-(1H-pyrazol-3-yl)-5,7-dihydro-1H-imidazo [4,5 f ] indol-6-one;
2-(5-Cyclopropyl-lH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-IH-imidazo [4,5-
f]indol-6-one;
2- ( 5-Isopropyl-2H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo [4,5-
f] indol-6-one;
8,8-Dimethyl-2- (5-propyl-2H-pyrazol-3-yl)- 1,5,7,8-tetrahydro-imidazo [4,5-
g] quinolin-6-one;
8,8-Dimethyl-2- (1H-pyrazol-3-yl)-1,5,7,8-tetrahydro-imidazo [4,5-g] quinolin-
6-
one;
2-(5-Cyclopropyl-lH-pyrazol-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydro-imidazo[4,5-
g] quinolin-6-one
2- ( 5-Isopropyl-2H-pyrazol-3-yl)-8,8-dimethyl-1,5,7,8-tetrahydro-imidazo [4,5-
g] quinolin-6-one;
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2-(2H-pyrazol-3-yl)-spiro-5,7-dihydro [cyclopentane-1',7-imidazo [4,5-f]
indol] -
6(3H)-one;
2-(5-Isopropyl-2H-pyrazol-3-yl)-spiro-5,7-dihydro [cyclopentane-1',7-
imidazo [4,5-f] indol] -6(3H)-one;
2-(5-Propyl-2H-pyrazol-3-yl)-spiro-5,7-dihydro[cyclopentane-1',7-imidazo[4,5-
f]indol]-6(3H)-one;
7,7-Dimethyl-2- ( 5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo[4,5-f]indol-6-one; and
2-(5-Cyclopropyl-2H-pyrazol-3-yl)-spiro-5,7-dihydro [cyclopentane-1',7-
imidazo[4,5-f]indol]-6(3H)-one.
Another embodiment of the invention is the use of one of the following
compounds for the manufacture of a medicament for the treatment of cancer:
3-Methyl-6-(5-methyl-lH-pyrazol-3-yl)-3,5-dihydro-lH-benzo [ 1,2-d;4,5-
d'] diimidazol-2-one;
3-Isopropyl-6-(5-methyl-lH-pyrazol-3-yl)-3,5-dihydro-lH-benzo[1,2-d;4,5-
d'] diimidazol-2-one;
5 -Ethyl- 7,7- dimethyl-2- ( 5-methyl-1 H-pyrazol-3-yl) -5,7-dihydro-3 H-
imidazo [4,5-
fl indol-6-one;
5-Ethyl-7,7-dimethyl-2- (5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f]indol-6-one;
5,7,7-Trimethyl-2-( 5-propyl-2H-pyrazol-3-yl) -5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one;
5-Ethyl-2- ( 5-isobutyl-2H-pyrazol-3-yl) -7,7-dimethyl-5,7-dihydro-3H-
imidazo [4,5-f] indol-6-one;
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2-( 5-Isobutyl-2H-pyrazol-3-yl)-5,7,7-trimethyl-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one;
5,7,7-Trimethyl-2-(1H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo[4,5- f ]indol-6-
one;
5,7,7-Trimethyl-2-( 5-methyl-lH-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f]indol-6-one;
5-Ethyl-7,7-dimethyl-2-(1H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-fl indol-
6-
one;
5-Ethy1-7,7-dimethyl-2-( 5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-imidazo [4,5-
f] indol-6-one; compound with acetic acid;
5-Isopropyl-7,7-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo[4,5-ff indol-6-one;
5-Isopropyl-7,7-dimethyl-2-( 5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo[4,5 f]indol-6-one;
7,7-Dimethyl-2- ( 5-methyl-2H-pyrazol-3-yl) -5-propyl-5,7-dihydro- IH-
imidazo[4,5-f]indol-6-one;
7,7-Dimethyl-5-propyl-2-(5-propyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo [4,5 f ] indol-6-one;
5-Ethyl-7,7-dimethyl-2- ( 5-trifluoromethyl-lH-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo [4,5- f ] indol-6-one;
5-Isopropyl-7,7-dimethyl-2-(5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-1H-
imidazo [4,5 f ] indol-6-one;
7,7-Dimethyl-5-propyl-2-( 5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo [4,5 f ] indol-6-one;
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5,7,7-Trimethyl-2-(5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-3H-
imidazo [4,5- f] indol-6-one;
5-Ethyl-2-( 5-methoxy-lH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-
imidazo [ 4, 5-f] indol-6-one; and
5-Ethyl-7,7-dimethyl-2-(5-methylsulfanyl-lH-pyrazol-3-yl)-5,7-dihydro-1H-
imidazo [4,5-fl indol-6-one;
Another embodiment of the invention is a process for the preparation of the
compounds of formula I, wherein
R' is alkyl or -C(O)-alkyl;
by
a) reacting a compound of formula II
R'
X N I~ NHZ
Y ~ NH2
formula II,
wherein R' is alkyl or -C(O)-alkyl and X and Y have the significance given
above for formula I;
with a compound of formula III,
O N- NH
A r~'R3
R
formula III,
wherein A is -OH, -Cl, -H or -OMe and R 2 and R3 have the significance given
above for formula I;
to give the compounds of formula I,
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R~ H
N(~ N N_ NH
Y ~ N Ra
R2
formula I,
wherein R' is alkyl or -C(O)-alkyl and R', R3, X and Y have the significance
given above for formula I;
b) isolating said compound of formula I from the reaction mixture, and
c) if desired, converting it into a pharmaceutically acceptable salt.
The compounds of formula I, or a pharmaceutically acceptable salt thereof,
which
are subject of the present invention may be prepared by any process known to
be
applicable to the preparation of chemically-related compounds. Such processes,
when used to prepare a compound of the formula I, or a pharmaceutically-
acceptable
salt thereof, are illustrated by the following representative schemes 1 and 2
and
examples in which, unless otherwise stated, X, Y, Rl, R 2 and R3 have the
significance
given herein before. Necessary starting materials may be obtained by standard
procedures of organic chemistry. The preparation of such starting materials is
described within the accompanying examples. Alternatively necessary starting
materials are obtainable by analogous procedures to those illustrated which
are
within the ordinary skill of an organic chemist.
The benzimidazole ring system of formula I can be formed by different
synthetic
pathways in analogy to methods described in the literature (Mertens, A., et
al., J.
Med. Chem. 30 (1987) 1279-1287; DE 35 31 678).
One route for the preparation of compounds of formula I (Scheme 1) starts from
diamines of formula II which can be reacted with carboxylic acids (compounds
of
formula III wherein A is OH), acid chlorides (A is Cl), aldehydes (A is H),
methyl
carboxylates (A is OMe) or activated esters (A is e.g. hydroxybenzotriazole).
For
detailed procedures see the literature cited above.
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R R.
H
NH
Z O N- NH N N N'NH
N :cc
Y NHZ A 3 Y N ~ 3
X' + /~ / -_ x \
R2 R2
II III 1
Scheme 1
Pyrazoles of formula III are commercially available or they can be prepared by
standard procedures of organic chemistry (see e.g. Stanovnik, B., and Svete,
J.,
Science of Synthesis 12 (2002) 15-225), e.g. condensation of a 1,3-dicarbonyl
compound with hydrazine (see e.g. WO 04/032928 or van Herk, T., et al., J.
Med.
Chem. 46 (2003) 3945-3951) or 1,3-dipolar cycloaddition between a diazo
compound and an acetylene (see e.g. Sewald, N., et al., Liebigs Ann. Chem.
(1992)
947-952). Pyrazoles of formula III wherein R3 is alkoxy can be prepared either
via
the 5-hydroxy-pyrazole-3-carboxylic acid esters (see e.g. Ochi, H. et al.,
Chem.
Pharm. Bull. 31 (1983) 1228-1234) with subsequent O-allcylation of the 5-
hydroxy
group with alkylhalogenides in the presence of a base such as caesium
carbonate
and the like in solvents such as dimethylformamide (DMF), N-methyl-
pyrrolidinone (NMP) and the like (see e.g. WO 03/035065) or according to the
procedure of Martins, M.A.P., et al., Synthesis 15 (2003) 2353-2357. And
pyrazoles
of formula III wherein R3 is alkylsulfanyl can be prepared via the
corresponding
oxo-ketene dithioacetals according to Mahata, P.K., et al., Tetrahedron 59
(2003)
2631-2639. Alternatively to Scheme 1, the 5-alkoxy- or 5-alkylsulfanyl-
pyrazole
moieties of compounds of formula I, wherein R3 is alkoxy or alkylsulfanyl, can
be
introduced by another sequence of reaction steps as described in WO 03/035065.
Pyrazoles of formula III wherein R2 is hydrogen, R3 is trifluoromethyl and A
is
hydroxy can be prepared in a three step procedure according to Scheme la:
condensation of 4,4,4-trifluoro-l-(2-furyl)-1,3-butanedione with benzyl
hydrazine
under acidic conditions, oxidative degradation of the furan ring with
potassium
permanganate to the carboxylic acid functionality (see e.g. Djuric, S.W., et
al., J.
Med. Chem. 43 (2000) 2975-2981; Jia, Z.J., et al., Bioorg. Med. Chem. Lett. 12
(2002) 1651-1655 or Pruitt, J.R., et al., J. Med. Chem. 46 (2003) 5298-5315)
and
cleavage of the benzyl protecting group provides the desired 5-trifluoromethyl-
2H-
pyrazole-3-carboxylic acid.
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F F
N H2 F KMnO4,
F ~ NH HCI, O acetone,
F ~ + EtOH N, N water
F O
O O I / I \
F F
F
N \OH F F
\N Na, NH3 F
O N\OH
N
H O
Scheme la
This procedure involving the N-benzyl or alternatively the p-methoxybenzyl
group
(Subramanyam, C., Synth. Commun. 25 (1995) 761-774 as intermediate protecting
group can be also applied for preparing other pyrazoles needed as starting
material.
Compounds of formula II wherein X is -C(O)-, R' is hydrogen or alkyl and Y is
-CR4R5 or -NH- can be prepared in an analogous manner as described in Mertens,
A., et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et al., J.
Med.
Chem. 32 (1989) 1481-1491; DE 34 17 643; EP 0 318 902, US 4,666,923A,
US 4,695,567A, US 4,863,945A and US 4,985,448A.. Compounds of formula II
wherein X is -C(O)- or -CH2-, Rl is hydrogen or -C(O)alkyl and Y is -CR4R5-
can
be prepared according to DE 36 42 315. And furthermore the compounds of
formula II wherein X is -C(O)- or -CH2-, R' is hydrogen or alkyl and Y is
-CR4R5-CH2- or -CH2-CR4R5- are described in DE 37 01 277.
For instance, the diamines of formula II, wherein X is -C(O)-, Ri is hydrogen
or
alkyl and Y is -CR4R5, are named IIa and can be synthesized according to
US 4,666,923A, DE 34 10 168 and Mertens, A., et al., J. Med. Chem. 30 (1987)
1279-1287 as shown in Scheme lb:
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R4 R5 R 4 R5 R4 R5
CN Step 1 ~ CN Step 2 O Step 3 1\ O
IR2L, R3L, I~ CN H2SO4 NH HZSO4, HNO3 02N / NH
NaOH
0 0
R Re R R R R5
\
Step 4 I\ Step 5 \ O Step 6 O
/ RIL, NaH N ~ H IPd, C ~ N
NaOH, Br2 OZN H OZN 1 z HzN
R R
a R e
RQ R5 N R R5 OZN \ R
Step 7 0 (I\ O Step 8 002 I O Step 9 I/ 0
Ac20 A ~J~.~%"-N AcOH, HNO3 /'N N NaOH H2N H R H R, R
Rs
Step 10 HZN 1 \
O
HZIPd, C H~N N
la R~
Scheme lb
In scheme lb, R', R4 and R5 have the significance as given above for formula I
and L
represents a leaving group as e.g. iodine, bromine, chlorine, triflate and the
like.
In an alternative procedure diamines of formula IIa, wherein R' is alkyl, can
be
obtained by an alkylation of diamines of formula IIb (compounds II wherein X
is -
C(O)-, R' is hydrogen and Y is -CR4R5,) as shown in scheme lc.
R2 RZ R3
HZN R3 N H 2 N
I 0 RIL, NaH, DMF H NI O
HZN / ~
2 /
1
Ilb H Ila N
Scheme lc
Diamines of formula Ilb can be synthesized according to scheme lb under
omission
of step 5.
Another synthesis of compounds of formula I (Scheme 2) starts frorn nitro-
compounds IV or V which are hydrogenated and subsequently cyclized with acetic
acid or hydrochloric acid to the desired benzimidazole derivative. For
detailed
procedures see Mertens, A., et al., J. Med. Chem. 30 (1987) 1279-1287;
DE 35 31 678.
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H
N-N
R O R3
/N NH R2
X I
Y NO2 R1
IV H
R~ N ~ N N-NH
X~ /
R3
/N NOa Y N R 2
X
Y NH I
V N
O ~NH
R2
R3
Scheme 2
Compounds of formulas IV and V wherein X is C(O), R' is hydrogen or alkyl and
Y
is -CR4R5, -NH- can be prepared in an analogous manner as described in
Mertens,
A., et al., J. Med. Chem. 30 (1987) 1279-1287; von der Saal, W., et al., J.
Med.
Chem. 32 (1989) 1481-1491; DE 34 17 643; EP 0 318 902. Compounds of formulas
IV and V with wherein X is C(O) or -CH2-, RI is hydrogen or -C(O)alkyl and Y
is -
CR4R5- can be prepared according to DE 36 42 315. And furthermore the
compounds of formula II wherein X is C(O) or -CH2-, Rl is hydrogen or alkyl
and
Y is -CR4R5-CH2- or -CH2-CR4R5- are described in DE 37 01 277.
The compounds according to the present invention may exist in the form of
their
pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt"
refers to conventional acid-addition salts that retain the biological
effectiveness and
properties of the compounds of formula I and are formed from suitable non-
toxic
organic or inorganic acids. Sample acid-addition salts include those derived
from
inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those
derived from
organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid,
naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid and the
like.
The chemical modification of a pharmaceutical compound (i.e. a drug) into a
salt is
a technique well known to pharmaceutical chemists to obtain improved physical
and chemical stability, hygroscopicity, flowability and solubility of
compounds. See
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e.g. Stahl, P.H., and Wermuth, G., (editors), Handbook of Pharmaceutical
Salts,
Verlag Helvetica Chimica Acta (VHCA) Zurich, (2002) or Bastin, R.J., et al.,
Organic Proc. Res. Dev. 4 (2000) 427-435.
The compounds of formula I can contain one or several chiral centers and can
then
be present in a racemic or in an optically active form. The racemates can be
separated according to known methods into the enantiomers. For instance,
diastereomeric salts which can be separated by crystallization are formed from
the
racemic mixtures by reaction with an optically active acid such as e.g. D- or
L-
camphorsulfonic acid. Alternatively separation of the enantiomers can also be
achieved by using chromatography on chiral HPLC-phases which are commercially
available.
Pharmacological activity
The compounds of formula I and their pharmaceutically acceptable salts possess
valuable pharmacological properties. It has been found that said compounds
show
activity as inhibitors of the Aurora kinase family and also show anti-
proliferative
activity. Consequently the compounds of the present invention are useful in
the
therapy and/or prevention of illnesses with known over-expression of kinases
of the
Aurora family preferably Aurora A, especially in the therapy and / or
prevention of
illnesses mentioned above. The activity of the present compounds as inhibitors
of
the Aurora kinase family is demonstrated by the following biological assay:
IC50 determination for inhibitors of Aurora A
(96 MTP-ELISA)
Assay principle
Aurora A is a serine threonine kinase involved in spindle assembly and
chromosome segregation.
The assay is a typically ELISA-type assay where biotinylated substrate (PKB-
GSK2)
is phosphorylated. Phosphorylation is detected by peroxidase (POD) labelled
polyclonal antibody (PAK<M-Ig>S-IgG-POD) and phosphopeptide monoclonal
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antibody (Mab) (MAK<P-GSK>M-27E5-IgG). The assay is validated for IC50 -
determination.
Materials
Assay plates 96-well polystyrene plates, streptavidin-coated,
Samples 10 mM in dimethylsulfoxide (DMSO)
Aurora A-His-4 C-terminally Histidine4 (His4)-tagged Aurora A
full-length protein, stock solution 0,7 mg/ml, final
conc.: 250ng/ml
PKB-GSK2 biotinylated peptide derived from human GSK3-
alpha sequence (Biotin-SGRARTSSFAEPGG-
CONHA stock solution 600 M, final conc.: 200
nM
PAK<M-Ig>S-IgG- POD Anti-mouse IgG, horse radish peroxidase(HRP)-
linked Antibody, diluted in 3% BSA/PBS-T
(1:10000), (Cell Signaling, Cat. No.: 7076)
MAK<P-GSK>M-27E5-IgG Phospho-GSK-3-alpha (Ser 21) (27E5)
Monoclonal Antibody, stock solution 1,85mg/ml,
diluted in 3% BSA/PBS-T
(1:6000), final conc.: 0,31 g/ml, (Cell Signaling,
Cat. No.: 9337B)
ATP Adenosine-5'-triphosphate 1 mM, diluted in
kinase buffer, (Roche Diagnostics GmbH, Cat. No.:
127531-001,), final conc.: 4 M
TRIS 2-Amino-2-hydroxymethyl- 1,3-propoanediol
("tris-(hydroxymethyl)-aminomethane") (MERCK
, Cat. No.: 108382.2500)
BSA Bovine Serum Albumin Fraction V, fatty acid free
(Roche Diagnostics GmbH, Cat. No. 9100221)
EDTA Titriplex III (di-Sodium-EDTA di-Hydrate), 120
mM, (MERCK, Cat. No.: 1.08418.1000)
ABTS buffer ABTS (2,2'-azino-bis(3-ethylbenzthiazoline-6-
sulfonic acid)) 16,7 mg/ml (Roche Diagnostics
GmbH, Cat. No.: 1204530)
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ABTS tablets dissolve one ABTS tablet in 50 ml of working
solution
(ABTS buffer) (Roche Diagnostics GmbH, Cat.
No.: 1112422 )
Tween 20 Polysorbat 20 (Roche Diagnostics GmbH, Cat.
No.: 10006394-001)
DTT 1,4-Dithiothreitol (Roche Diagnostics GmbH, Cat.
No.: 197777)
MgC12 x 6H20 MERCK, Cat. No.: 105833.1000
Kinase buffer 50 mM TRIS, 10 mM MgC1z,1 mM DTT, 0,1%
Tween 20, pH 7,8
PBS-T (= Wash buffer) (PBS-T) 10 g/l PBS(Phosphate buffered saline)
with 0,033% Tween 20
3% BSA/PBS-T 3 % BSA dissolved in PBS-T
Method
This assay is performed in 96-well format for IC50 determination with 5
samples
(each with 8 concentrations by twofold testing ), 100 l incubation volume and
the
following plate layout:
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1 2 3 4 5 6 7 8 9 10 11 12
A NC RS a RS a Sla Sla S2a S2a NC S3a S3a S4a S4a
B NC RS b RS b Slb Slb S2b S2b NC S3b S3b S4b S4b
C NC RS c RS c Slc Slc S2c S2c NC S3c S3c S4c S4c
D NC RS d RS d Sld Sld S2d S2d NC S3d S3d S4d S4d
E PC RS e RS e Sle Sle S2e S2e PC S3e S3e S4e S4e
F PC RS f RS f Slf Slf S2f S2f PC S3f S4f S4f S4f
G PC RS g RS g Slg Slg S2g S2g PC S3g S4g S4g S4g
H PC RS h RS h Slh Slh S2h S2h PC S3h S4h S4h S4h
NC negative control, without ATP, 1% DMSO
PC positive control, with ATP, 1% DMSO
S samples, with ATP, 1% DMSO, final conc.: a =100 M, b =20 M, c =4
M, d =0.8 M, e =0.16 M, f =0.032 M, g =0.0064 M, h=0.00128 M
Step / Action
1. Sample preparation: add 24 1 per well samples (descending sequence )
diluted
in kinase buffer to assay plate ( final conc. for DMSO 1%).
2. Add directly 16 l Aurora-A-his-4 diluted in kinase buffer to assay plate.
3. Add directly 40 l per well PKB-GSK2/ATP mixture to assay plate,
(final conc.: Aurora A = 250 ng/ml, GSK2 = 200 nM, ATP = 4 M).
Negative control: without ATP.
4. Incubate assay plate for exactly 90 min at room temperature.
5. Stop reaction by adding 20 l EDTA in all wells.
6. Wash assay plate 3 x with 200 1 washing buffer per well.
7. Add 100 l MAK<P-GSK>M27E5-IgG (1:10000) and PAK<M-Ig>S-IgG-POD
(1:6000) dissolved in 3% BSA/PBS-T to assay plate per well.
8. Incubate assay plate for 60 min at room temperature.
9. Wash assay plate 3 x with 200 l washing buffer per well
10. Add 100 l ABTS solution to assay plate per well, incubate for approx. 4
min at
RT on MTP shaker.
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11. Measure absorption at 405/492 nm.
12. Calculate % inhibition as:
( 1- (E sample - E rrc)/(E rc - E rrc)) x 100
13. Calculate IC50 using a non-linear curve fit (XLfit software (ID Business
Solution
Ltd., Guilford, Surrey, UK))
Results: Table 1
Examples IC50 Aurora A kinase inhibition [nM]
11 158
3 212
2, 5, 7, 10, 17, 18, 19, 21, 23, 25, 27, 31,
10-500
34, 35, 36, 37
4, 6, 9, 24, 28, 29, 41 500-1500
Antiproliferative activity
The activity of the present compounds as antiproliferative agents is
demonstrated
by the following biological assay:
Ce1lTiter-G1oTM assay in HCT 116 cells
The Ce1lTiter-GloTM Luminescent Cell Viability Assay (Promega) is a
homogeneous
method of determining the number of viable cells in culture based on
quantitation
of the ATP present, which signals the presence of metabolically active cells.
HCT 116 cells (human colon carcinoma, ATCC-No. CC1-247) were cultivated in
RPMI 1640 medium with G1utaMAXTM I (Invitrogen, Cat-No. 61870-010), 2,5 %
Fetal Calf Serum (FCS, Sigma Cat-No. F4135 (FBS)); 100Units/ml
penicillin/100 g/mi streptomycin (= Pen/Strep from Invitrogen Cat.No. 15140).
For the assay the cells were seeded in 384 well plates, 1000 cells per well,
in the same
medium. The next day the test compounds were added in various concentrations
ranging from 30 M to 0.0015 M (10 concentrations, 1:3 diluted). After 5 days
the
Ce1lTiter-G1oTM assay was done according to the instructions of the
manufacturer
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(CellTiter-G1oTM Luminescent Cell Viability Assay, from Promega). In brief:
the
cell-plate was equilibrated to room temperature for approximately 30 minutes
and
than the CellTiter-G1oTM reagent was added. The contents were carefully mixed
for
15 minutes to induce cell lysis. After 45 minutes the luminescent signal was
measured in Victor 2, (scanning multiwell spectrophotometer, Wallac).
Details:
1 st. day:
- Medium: RPMI 1640 with G1utaMAXTM I (Invitrogen, Cat-Nr. 61870), 5 % FCS
(Sigma Cat.-No. F4135), Pen/Strep (Invitrogen, Cat No. 15140).
- HCT116 (ATCC-No. CC1-247): 1000 cells in 60 l per well of 384 well plate
(Greiner 781098, Clear-plate white)
- After seeding incubate plates 24 h at 37 C, 5% CO2
2nd. day : Induction (Treatment with compounds, 10 concentrations):
In order to achieve a final concentration of 30 M as highest concentration
3,5 l of
10 mM compound stock solution were added directly to 163 l media. Then step
e)
of the dilution procedure described below, was followed.
In order to achieve the second highest to the lowest concentrations, a serial
dilution
with dilution steps of 1:3 was followed according to the procedure (a -e) as
described here below:
a) for the second highest concentration add 10 l of 10 mM stock solution of
compound to 20 l dimethylsulfoxide (DMSO)
b) dilute 8x 1:3 (always 10 l to 20 l DMSO) in this DMSO dilution row
(results in 9 wells with concentrations from 3333,3 pM to 0.51 M)
c) dilute each concentration 1: 47,6 (3,5 l compound dilution to 163 l
media)
e) add 10 1 of every concentration to 60 l media in the cell plate
resulting in final concentration of DMSO : 0.3 % in every well
and resulting in 10 final concentration of compounds ranging from 30 M to
0.0015 pM.
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- Each compound is tested in triplicate.
- Incubate 120 h (5 days) at 37 C, 5% CO2
Analysis:
-Add 30 l CellTiter-G1oTM Reagent (prepared from CellTiter-G1oTM Buffer and
CellTiter-G1oTM Substrate (lyophilized) purchased from Promega) per well,
-shake 15 minutes at room temperature
-incubate further 45 minutes at room temperature without shaking
Measurement:
-Victor 2 scanning multiwell spectrophotometer (Wallac), Luminescence mode
(0.5
sec/read, 477 nm )
-Determine IC50 using a non-linear curve fit (XLfit software (ID Business
Solution
Ltd., Guilford, Surrey, UK))
With all compounds a significant inhibition of HCT 116 cell viability was
detected,
which is exemplified by the compounds shown in Table 1.
Results: Table 2
Examples IC50 HCT 116 [[tM]
42 0.98
14 1.20
2 4.67
4 7.65
5, 6, 7, 8, 12, 13, 15, 16, 17, 18, 20,
22, 23, 24, 27, 2-8, 30, 31, 32, 33, 34, 0.1-10.0
35, 36, 37, 39, 41, 43, 44, 45
3, 9, 11, 38 10.0-100
The compounds according to this invention and their pharmaceutically
acceptable
salts can be used as medicaments, e.g. in the form of pharmaceutical
compositions.
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The pharmaceutical compositions can be administered orally, e.g. in the form
of
tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions
or suspensions. The administration can, however, also be effected rectally,
e.g. in
the form of suppositories, or parenterally, e.g. in the form of injection
solutions.
The above-mentioned pharmaceutical compositions can be obtained by processing
the compounds according to this invention with pharmaceutically inert,
inorganic
or organic carriers. Lactose, corn starch or derivatives thereof, talc,
stearic acids or
it's salts and the like can be used, for example, as such carriers for
tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carriers for soft
gelatine
capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid
polyols
and the like. Depending on the nature of the active substance no carriers are,
however, usually required in the case of soft gelatine capsules. Suitable
carriers for
the production of solutions and syrups are, for example, water, polyols,
glycerol,
vegetable oil and the like. Suitable carriers for suppositories are, for
example,
natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the
like.
The pharmaceutical compositions can, moreover, contain preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
flavorants, salts for varying the osmotic pressure, buffers, masking agents or
antioxidants. They can also contain still other therapeutically valuable
substances.
A pharmaceutical compositions comprise e.g. the following:
a) Tablet Formulation (Wet Granulation):
Item Ingredients mg/tablet
l. Compound of formula (I) 5 25 100 500
2. Lactose Anhydrous DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4. Microcrystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1 1 1 1
Total 167 167 167 831
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Manufacturing Procedure:
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50 C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.
b) Capsule Formulation:
Item Ingredients mg/capsule
1. Compound of formula (I) 5 25 100 500
2. Hydrous Lactose 159 123 148 ---
3. Corn Starch 25 35 40 70
4. Talc 10 15 10 25
5. Magnesium Stearate 1 2 2 5
Total 200 200 300 600
Manufacturing Procedure:
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
c) Micro suspension
1. Weigh 4.0 g glass beads in custom made tube GL 25, 4 cm (the beads fill
half of
the tube).
2. Add 50 mg compound, disperse with spatulum and vortex.
3. Add 2 ml gelatin solution (weight beads: gelatin solution = 2:1) and
vortex.
4. Cap and wrap in aluminum foil for light protection.
5. Prepare a counter balance for the mill.
6. Mill for 4 hours, 20/s in a Retsch mill (for some substances up to 24 hours
at
30/s).
7. Extract suspension from beads with two layers of filter (100 m) on a
filter
holder, coupled to a recipient vial by centrifugation at 400 g for 2 min.
8. Move extract to measuring cylinder.
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9. Repeat washing with small volumes(here 1 ml steps) until final volume is
reached or extract is clear.
10. Fill up to final volume with gelatin and homogenize.
The following examples and references are provided to aid the understanding of
the
present invention, the true scope of which is set forth in the appended
claims. It is
understood that modifications can be made in the procedures set forth without
departing from the spirit of the invention.
Examples
A: starting materials
Preparation of 5,6-diamino-l-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
i) 1 -Ethyl-3,3- dimethyl- 6-nitro- 1,3-dihydro-indol-2- one
A solution of 3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (6g, 29.10 mmol) in
anhydrous N,N-dimethylformamide (DMF) (35 ml) was treated with sodium
hydride. The resulting suspension was stirred for 1 h at 60 C. A solution of
bromo-
ethane (2.17 mL, 3.17 g, 29.10 mmol) in DMF (10 ml) was added. The mixture was
allowed to cool to room temperature and stirred for 1 h. After removal of the
solvent the mixture was quenched with water (100 ml) and extracted with ethyl
acetate (3 x 100 ml). The extract was dried over Na2SO4, evaporated and the
crude
product was purified by column chromatography on silica gel. Elution with
ethyl
acetate/n-heptane (1:3) yielded 5.94 g (87%) of a yellow solid.
MS: M = 235.3 (ESI+)
'H-NMR (400 MHz, DMSO): b(ppm) = 1.16 (t, 3H), 1.32 (s, 6 H), 3.81 (q, 2H),
7.66 (d, 1H), 7.86 (s, 1H), 7.97 (d, 1H)
ii) 6-Amino-l-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
To a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g,
25.19
mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10
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%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h.
After filtration and evaporation of the solvents 5.05 g (98%) 6-amino-l-ethyl-
3,3-
dimethyl-1,3-dihydro-indol-2-one was isolated as white solid.
MS: M = 205.0 (API+)
'H-NMR (400 MHz, DMSO): b(ppm) = 1.11 (t, 3H), 1.17 (s, 6H), 3.58 (q, 2H),
5.12 (br, 2H), 6.21 (d, 1H), 6.25 (s, 1H), 6.92 (d, 1H)
iii) N-(1-Ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-6-yl)-acetamide
A solution of 6-amino-1 -ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.05 g,
24.72
mmol) in acetic anhydride (80 ml) was stirred at room temperature for 4 h. The
mixture was poured onto ice water (150 ml), allowed to warm to room
temperature
and was stirred again for 2 h. After extraction with ethyl acetate (3 x 100
ml), the
combined organic layers were washed with sat. NaHCO3-solution (3 x 100 ml),
brine (100 ml) and dried over sodium sulfate. After removal of the solvent the
crude product was purified by column chromatography on silica gel (ethyl
acetate/n-heptane 1:1) yielding 5.6 g (91 %) N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-
dihydro-lH-indol-6-yl)-acetamide as light yellow solid.
MS: M = 247.1 (API+)
'H-NMR (400 MHz, DMSO): d(ppm) = 1.13 (t, 3H), 1.23 (s, 6H), 2.04 (s, 3H),
3.63 (q, 2H), 7.12 (d, 1 H), 7.23 (d, 1H), 7.37 (s, 1H), 9.97 (br, 1H)
iv) N-(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-lH-indol-6-yl)-acetamide
To a solution of N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-6-yl)-
acetamide ( 5.6 g, 22.73 mmol) in acetic anhydride (70 ml) nitric acid (100 %,
1.96
g, 1.29 ml, 31.2 mmol) was added at 0 C. The mixture was stirred for 30 min,
then
poured onto ice water (150 ml). After stirring for 4 h the mixture was
extracted
with ethyl acetate (3 x 100 ml). The combined organic layers were washed with
sodium hydroxide solution (1M, 100 ml) and water (100 ml), dried over sodium
sulfate and concentrated. The crude product was purified by column
chromatography on silica gel (ethyl acetate/n-heptane 1:1) to yield 5.2 g (78
%) N-
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(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-lH-indol-6-yl)-acetamide as a
yellow solid.
MS: M = 292.0 (API+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 1.16 (t, 3H), 1.31 (s, 6H), 2.13 (s, 3H),
3.71 (m, 2H), 7.54 (s, 1 H), 8.12 (s, 1H), 10.39 (br, 1H)
v) 6-Amino-l-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one
N-(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-lH-indol-6-yl)-acetamide
(5.2
g, 17.85 mmol) was dissolved in ethanol (40 ml). After addition of
hydrochloric
acid (25 %, 8 ml, 81.44 mmol) the mixture was stirred under reflux for 3 h.
The
reaction mixture was allowed to cool down to room temperature and then
quenched with water (80 ml). The yellow precipitate was isolated by suction
and
washed with ethanol/water (1:1). The solid was dissolved in ethyl acetate,
dried over
sodium sulfate and concentrated to yield 4.15 g (93 %) 6-amino-l-ethyl-3,3-
dimethyl- 5 -nitro - 1, 3 - dihydro-indol -2-one as a orange solid.
MS: M = 250.0 (API+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 1.15 (t, 3H), 1.27 (s, 6H), 3.64 (m, 2H),
6.54 (s, 1 H), 7.67 (br, 2H), 7.95 (s, 1H)
vi) 5,6-Diamino-l-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one
To a solution of 6-amino-l-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one
(4.15 g, 16.65 mmol) in ethanol (80 ml) PtO2 (0.4 g) was added and the mixture
hydrogenated at room temperature for 3.5 h. After filtration and evaporation
of the
solvents 3.25 g (89 %) 5,6-diamino-l-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-
one
was isolated as orange solid.
MS: M = 220.0 (API+)
1H-NMR (400 MHz, DMSO)- 8(ppm) = 1.10 (t, 3H), 1.13 (s, 6H), 3.53 (m, 2H),
4.08 (br, 2H), 4.48 (br, 2H), 6.27 (s, 1H), 6.50 (s, 1H)
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Preparation of 5,6-diamino-1,3,3-trimethyl-1,3-dihydro-indol-2-one
5,6-diamino-1,3,3-trimethyl-1,3-dihydro-indol-2-one was prepared in an
analogous 6-step-synthesis as described for 5,6-diamino-l-ethyl-3,3-dimethyl-
1,3-
dihydro-indol-2-one.
MS: M = 206.1 (API+)
'H-NMR (400 MHz, DMSO): S(ppm) = 1.57 (s, 6H), 3.43 (s, 3H), 4.94 (br, 4H),
6.66 (s, 1H), 6.95 (s, 1H)
Preparation of 5,6-diamino-3,3-dimethyl-1-propyl-1,3-dihydro-indol-2-one
5,6-diamino-3,3-dimethyl-l-propyl-1,3-dihydro-indol-2-one was prepared in an
analogous 6-step-synthesis as described for 5,6-diamino-l-ethyl-3,3-dimethyl-
1,3-
dihydro-indol-2-one.
MS: M = 234.1 (API+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 0.82 (t, 3H), 1.15 (s, 6H), 1.58 (m, 2H),
3.46 (q, 2H), 4.16 (br, 2H), 4.45 (br, 2H), 6.27 (s, 1H), 6.50 (s, 1H)
Preyaration of 5,6-diamino-l-isoyropyl-3,3-dimethyl-1,3-dihydro-indol-2-one
5,6-diamino-3,3-dimethyl-l-isopropyl-1,3-dihydro-indol-2-one was prepared in
an
analogous 6-step-synthesis as described for 5,6-diamino-l-ethyl-3,3-dimethyl-
1,3-
dihydro-indol-2-one.
MS: M = 234.1 (API+)
1H-NMR (400 MHz, DMSO): 8(ppm) = 1.12 (s, 6H), 1.33 (d, 6H), 4.09 (br, 2H),
4.40 (m, 1H), 4.46 (br, 2H), 6.46 (s, 1H), 6.48 (s, 1H)
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Preparation of 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid
i) 1-Benzyl-5-furan-2-yl-3-trifluoromethyl-1 H-pyrazole
To a solution of 50g (0.240mo1) 4,4,4-trifluoro-l-(2-furyl)-1,3-butanedione in
24m1 (0.024mo1) 1M solution of hydrogen chloride in ethanol and further 520m1
EtOH was added 50g (0.248mo1) benzylhydrazine dihydrochloride in small portion
at room temperature. The reaction mixture was then heated under reflux for 7h.
After cooling to room temperature the reaction mixture was neutralized with
saturated NaHCO3i the EtOH was distilled off and the residual oil/water
mixture
was extracted with 300m1 dichloromethane. The organic phase was washed twice
with 100 ml water and dried over Na2SO4 and concentrated in vacuo to give
73.7g
1-benzyl-5-furan-2-yl-3-trifluoromethyl-lH-pyrazole as a brown oil which was
used crude for the next reaction. MS: M= 293.0 (API+)
ii) 2-Benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid
To a solution of 9.5g (0.0325mol) 1-benzyl-5-furan-2-yl-3-trifluoromethyl-lH-
pyrazole in 350mL acetone was added 27.2g (0.172mo1) potassium permanganate
in 450m1 water. The reaction mixture was heated at 60 C for 4h. After cooling
to
room temperature 200m12-propanol were added and the mixture was stirred over
night, it was filtered through a Celite pad and washed with 11 acetone. The
filtrate
was concentrated in vacuo down to 150mL. The residue was dissolved in 20mL 2M
NaOH and 150mL water. The resulting aqueous phase was washed twice with 70m1
ethyl ether and was then acidified with 30m1 5M HC1 solution. The suspension
was
extracted with 200 and 50m1 ethyl acetate (EtOAc). The combined organic
extracts
were washed with 30mL water and 5mL brine and concentrated. The residue was
purified by silica gel chromatography (CH2C1Z with 1% acetic acid) to give
6.1g
(0.022mo1, 67%) of 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as
a
off-white solid. MS: M= 271.1 (ESI+)
iii) 5-Trifluoromethyl-2H-pyrazole-3-carboxylic acid
About 50m1 ammonia were condensed into a three-neck-flask in an ethanol-dry
ice
bath and 100mg (3.70mmo1) 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic
acid were added. To the solution sodium was added in small portions until the
blue
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color stayed for more then 5 minutes (about 260mg, 11.3mmol). The ammonia was
evaporated overnight. Water was added and acidified with 2N HCl solution. The
aqueous phase was extracted twice with ethyl acetate, the combined organic
phases
were dried over Na2SO4, the solvent was evaporated in vacuo to give 560mg
(3.llmmol, 84%) 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as a yellow
solid that was used without further purification. MS: M= 179.0 (API-)
5-Methoxy-lH-pyrazole-3-carboxylicacid ethyl ester
5-Hydroxy-lH-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.92 mmol) was
dissolved in anhydrous N,N-dimethylformamide (DMF) (35 ml) and cesium
carbonate (626 mg, 1.92 mmol) was added. The resulting suspension was treated
with iodomethane (120 l, 273 mg, 1.92 mmol) and stirred for 12 h at room
temperature. The reaction mixture was quenched with saturated potassium
hydrogen sulfate solution and extracted with ethyl acetate (3 x 100 ml). The
combined organic layers were washed with water (50 ml) and brine (50 ml). The
extract was dried over sodium sulfate, evaporated and the crude product was
purified by column chromatography on silica gel. Elution with ethyl acetate/n-
heptane (1:3) yielded 124 mg (38%) of a white solid.
MS: M = 171.2 (ESI+)
'H-NMR (400 MHz, DMSO): b(ppm) = 1.29 (t, 3H), 3.79 (s, 3H), 4.29 (q, 2H),
6.21 (s, 1H), 13.10 (br, 1H)
5-Methoxy-lH-pyrazole-3-carboxylic acid
5-Methoxy-lH-pyrazole-3-carboxylicacid ethyl ester (120 mg, 0.71 mmol) was
dissolved in tetrahydrofuran (THF) (2 mL). After addition of sodium hydroxide
(2M in water, 1 mL) the mixture was stirred under reflux for 2 h. The reaction
mixture was cooled to room temperature and acidified (pH 3) by addition of
hydrochloric acid and extracted with ethyl acetate (3 x 20 ml). The extract
was dried
over sodium sulfate and evaporated to yield 86 mg (86 %) of a white solid.
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Preparation of 2-(3,3-Bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-5,7-
dihydro-1 H-imidazo [4,5-fJ indol-6-one
(i) 5-Ethyl-2-(1-hydroxy-ethyl)-7,7-dimethyl-5,7-dihydro-IH-imidazo[4,5-
f) indol-6-one
A mixture of 5,6-diamino-l-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (10 g,
46
mmol), 2-hydroxy-propionic acid (9.13 g, 91.2 mmol) in HCl (100 mL, 4N) was
refluxed for 16h. After cooling, neutralization with aqueous ammonia (25 %)
and
stirring for 1.5 h the precipitate was filtered and dried in vacuo at 50 C
yielding
12.29 g(95 %) of a grey solid.
MS: M = 274.3 (ESI+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 1.17 (t, 3H), 1.28 (s, 6H), 1.48 (d, 3H),
3.73 (q, 2H), 4.90 (m, 1H), 5.68 (d, 1H, OH), 7.05 (s, 1H), 7.43 (s, 1H), 12.2
(br,
IH)
(ii) 2-Acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1 H-imidazo [4,5-f] indol-6-one
5-Ethyl-2-(1-hydroxy-ethyl)-7,7-dimethyl-5,7-dihydro-IH-imidazo[4,5-flindol-6-
one (13 g, 47.6 mmol) and manganese(IV) dioxide (16.54 g, 190 mmol) were
suspended in chloroform (400 mL) and stirred at 65 C for 16 h. The mixture
was
cooled, filtered over Celite and the filtrate concentrated in vacuo yielding
11.6 g
(90%) of a beige solid.
MS: M = 272.0 (ESI+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 1.18 (t, 3H), 1.32 (s, 6H), 2.66 (s, 3H),
3.77 (q, 2H), 7.00 and 7.40 (s, 1H, two tautomeric forms), 7.50 and 7.80 (s,
1H, two
tautomeric forms), 13.3 (br, IH)
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(iii) 2-Acetyl-5-ethyl-7,7-dimethyl-l-(tetrahydro-pyran-2-yl)-5,7-dihydro-lH-
imidazo [4,5-f] indol-6-one
2-Acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (11.7
g,
43.1 rnmol) and p-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol)were
dissolved in dichloromethane (200 mL). To this solution 3,4-dihydro-2H-pyrane
(4.81 g, 56 mmol) was added and the mixture stirred at reflux for 24 h. The
mixture
was filtered, the filtrate washed with water (2 x 100mL), dried over sodium
sulfate
and concentrated in vacuo. The crude product was purified by column
chromatography on silica (dichloromethane/methanol 93:3) yielding 6.8 g (44 %)
of a light yellow solid.
MS: M = 356.3 (ESI+)
IH-NMR (400 MHz, DMSO): 8(ppm) = 1.21 (t, 3H), 1.32 (s, 6H), 1.59 - 2.23 (m,
6H), 2.70 (s, 3H), 3.65 (t, 1H), 3.80 (m, 2H), 4.15 (d, 1H), 6.47 (d, 1H),
7.30 (s,
1H), 7.82 (s, IH)
(iv) 2-(3,3-Sis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-l-(tetrahydro-
pyran-2-yl)-5,7-dihydro-1 H-imidazo [4,5-f] indol-6-one
To a suspension of sodium hydride (0.57 g, 22.5 mmol) in toluene (20 mL) at 80
C
tert-butanol (0.88 g, 11.8 mmol) was added and the mixture stirred for 2h.
After
cooling to room temperature a suspension of 2-acetyl-5-ethyl-7,7-dimethyl-1-
(tetrahydro-pyran-2-yl)-5,7-dihydro-lH-imidazo[4,5-fJindol-6-one (2g, 5.63
mmol) and carbon disulfide (0.43 g, 5.63 mmol) in N,N-dimethylformamide
(DMF) (12 mL) was added in small portions, the mixture stirred for 30 min at
room temperature and finally stirred for 30min at 80 C. After cooling to room
temperature, water (20 mL) and ethyl acetate (15 mL) were added, the layers
separated and the aqueous layer extracted with ethyl acetate (3 x 10 mL). The
combined organic phases were washed with water (3 x 10 mL) and concentrated in
vacuo to yield 2.27 g (88%) of 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-
dimethyl-l-(tetrahydro-pyran-2-yl)-5,7-dihydro-lH-imidazo [4,5-f] indol-6-one
which was partially deprotected in the course of the reaction. It was used
without
any further purification in the next step.
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MS: M = 460.1 (ESI+)
(v) 2-(3,3-Bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-5,7-dihydro-lH-
imidazo [4,5-f] indol-6-one
Crude 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-l-(tetrahydro-
pyran-2-yl)-5,7-dihydro-1H-irnidazo[4,5-f)indol-6-one (2.25 g, 4.9 mmol) and p-
toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) was dissolved in methanol
(25
mL) and water (3 mL) and stirred at reflux for 3 h. After cooling to room
temperature, water (50 mL) was added and the mixture extracted with etyhl
acetate
(3 x 50 mL). The combined organic layers were washed with water and
concentrated in vacuo. The crude product was recrystallized from methanol to
yield
2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-5,7-dihydro-lH-
imidazo[4,5-fJindol-6-one (0.71 g, 39 %) as yellow solid.
MS: M = 376.3 (ESI+)
'H-NMR (400 MHz, CDC13): 8(ppm) = 1.31 (t, 3H), 1.42 (s, 6H), 2.63 (s, 3H),
2.72 (s, 3H), 3.83 (m, 2H), 7.13 and 7.25 (s, 1H, two tautomeric forms), 7.49
(s,
1H), 7.58 and 7.65 (s, 1H, two tautomeric forms), 11.5 (br, 1H)
B: Final Products
Examples 1 to 43
Standard Procedure :
Preparation of 1-Isopropyl-6-(5-methyl-IH-pyrazol-3-yl)-3,5-dihydro-IH-
benzo [ 1,2-d;4,5-d'] diimidazol-2-one (Example 11)
5-Methyl-lH-pyrazole-3-carboxylic acid (126 mg, 1 mmol) and 5,6-diamino-l-
isopropyl-1,3-dihydro-benzoimidazol-2-one (206 mg, lmmol) were heated to 160
C in a mixture of polyphosphoric acid (5 g) and phosphorus pentoxide (500 mg,
3.5 mmol) for 6 h. This mixture was poured on water (20 ml) and stirring
continued until a precipitate formed. After filtration the crude product was
suspended in water and neutralized by the addition of aqueous ammonia (25 %).
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The precipitate was collected, washed with water and dried in vacuo.
Purification
was achieved by chromatography on silica (dichloromethane/methanol 95:5)
yielding 1-isopropyl-6-(5-methyl-lH-pyrazol-3-yl)-3,5-dihydro-lH-benzo [ 1,2-
d;4,5-d' ] diimidazol-2-one as slightly yellow solid. Yield 36 mg (12 %)
Using the experimental conditions reported above and the appropriate starting
materials, the following derivatives 1 to 43 were prepared:
Example No. Systematic Name (Method) 1 H-NMR
7,7-Dimethyl-2-(5-
methyl-2H-pyrazol- 268 3(ESI
1 3-yl)-3,5,6,7- +)
tetrahydro-
imidazo [4,5-f] indole
1-[7,7-Dimethyl-2-
(5-methyl-2H-
2 pyrazol-3-yl)-6,7- 310.3
dihydro-3H- (ESI+)
imidazo [4,5-f] indol-
5-yl] -ethanone
8,8-Dimethyl-2-(5-
methyl-lH-pyrazol-
3 3-yl)-1,5,7,8- 296.3
tetrahydro- (ESI+)
imidazo [4,5-
] uinolin-6-one
2-(5-Isobutyl-2H-
pyrazol-3-yl)-8,8-
4 dimethyl-1,5,7,8- 338.0
tetrahydro- (API+)
imidazo [4,5-
g] quinolin-6-one
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Example No. Systematic Name (Method) 'H-NMR
[D6]DMSO, 400
MHz: 1.30 (d, 6H),
2.32 (s, 3H), 6.54
and 6.56 (s, 1H, two
tautomeric forms),
6.89 and 7.00 (s, 1H,
7,7-Dimethyl-2-(5- two tautomeric
methyl-2H-pyrazol forms), 7.30 and 7.48
-3-y1)-5,7-dihydro- 282.2 (s, IH, two
3H-imidazo[4,5-f (ESI+) tautomeric forms),
] indol-6-one 10.18 and 10.23 (br,
1H, two tautomeric
forms), 12.39 and
12.53 (br, IH, two
tautomeric forms),
12.85 and 12.89 (br,
IH, two tautomeric
forms)
2-(5-Isobutyl-2H-
pyrazol-3-yl)-7,7-
6 dimethyl-5,7- 324.0
dihydro-lH- (API+)
imidazo [4,5-flindol-
6-one
2-(5-Methyl-2H-
pyrazol-3-yl)-
spiro[7,7-
cyclopentan-5,7-
dihydro-3H-
imidazo [ 4, 5-f] in dol-
7 6] -one; or
according to the 308.3
actual IUPAC- (ESI+)
nomenclature:
2-(5-Methyl-2H-
pyrazol-3 -yl) -spiro-
5,7-
dihydro [cyclopentan
e-1',7-imidazo [4,5-
f]indol]-6(3H)-one
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Example No. Systematic Name (Method) 1H-NMR
2-(5-Isobutyl-2H-
pyrazol-3-yl)-
spiro[7,7-
cyclopentan-5,7-
dihydro-lH-
imidazo [4,5-f] indol-
8 6] -one; or
according to the 350.1
actuallUPAC- (API+)
nomenclature:
2- (5-Isobutyl-2H-
pyrazol-3-yl) -spiro-
5,7-
dihydro [ cyclopentan
e-1',7-imidazo[4,5-
f]indol]-6(3H)-one
6-(5-Methyl-lH- [D6]DMSO, 400
pyrazol-3-yl)-3,5- MHz: 2.30 (s, 3H),
9 dihydro-lH- 255 6.53 (s, 1H), 7.00 (s,
benzo[1,2-d;4,5- (API+) 2H), 10.42 (br, 2H),
d'] diimidazol-2-one 12.38 (br, 1H), 12.86
(br, 1H)
[D6]DMSO, 400
3-Methyl-6-(5- MHz: 2.30 (s, 3H),
methyl-lH-pyrazol- 269.1 3.36 (s, 3H), 6.54 (s,
3-yl)-3,5-dihydro- (API+) 1H), 7.05 (s, 1H),
1H-benzo[1,2-d;4,5- 7.13 (s, 1H), 10.65
d'] diimidazol-2-one (br, 1H), 12.50 (br,
1H), 12.86 (br, 1H)
[D6] DMSO, 400
3-Isopropyl-6-(5- MHz: 1.47 (d, 6H),
methyl-lH-pyrazol- 2.31 (s, 3H), 4.61 (m,
11 3-yl)-3,5-dihydro- 297.2 1H), 6.53 (s, 1H),
1H-benzo[1,2-d;4,5- (API+) 6.98 (s, 1H), 7.12 (d,
d'] diimidazol-2-one 1H), 7.39 (s, 1H),
10.61 (br, 1H)
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Example No. Systematic Name (MMh d) 'H-NMR
[D6]DMSO, 400
MHz: 1.17 (t, 3H),
5-Eth l-7,7- 1.31 (d, 6H), 2.31 (s,
y
dimethyl-2-(5- 3H), 3.75 (q, 2H),
6.58 (s, 1H), 6.95
12 methyl-lH-pyrazol- 310.1 and 7.22 (s, 1H, two
3-yl)-5,7-dihydro- (API+) tautomeric forms),
3H-imidazo[4,5- 7.39 and 7.55 (s, 1H,
flindol-6-one two tautomeric
forms), 12.60 (br,
1H), 12.90 (br, 1H)
[D6]DMSO, 400
5-Eth 1-7,7- MHz: d= 12.64 (bs,
y
dimethyl-2-(5- 1H), 7.48 (s, 1H),
7.09 (s, 1H), 6.59 (s,
13 propyl-2H-pyrazol- 338.1 1H), 3.76 (q, 2H),
3-yl)-5,7-dihydro- (API+) 2.64 (t, 2H), 1.72 -
3H-imidazo[4,5- 1.63 (m, 2H), 1.31 (s,
f]indol 6 one 6H), 1.19 (t, 3H),
0.95 (t, 3H)
5,7,7-Trimethyl-2-
(5-propyl-2H-
14 pyrazol-3-yl)-5,7- 324.1
dihydro-3H- (API+)
imidazo [4,5-f] indol-
6-one
5-Ethyl-2-(5-
isobutyl-2H-pyrazol-
15 3-yl)-7,7-dimethyl- 352.1
5,7-dihydro-3H- (API+)
imidazo [4,5-f] indol-
6-one
2- (5-Isobutyl-2H-
pyr azol- 3-yl )- 5, 7, 7-
16 trimethyl-5,7- 338.1
dihydro-3H- (API+)
imidazo [4,5-f] indol-
6-one
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Example No. Systematic Name (Method) 1H-NMR
2-(4,5-Dimethyl-
1H-pyrazol-3-yl)-
17 7,7-dimethyl-5,7- 294.0
dihydro-1H- (API-)
imidazo[4,5 f]indol-
6-one
7,7-Dimethyl-2- [ 5-
(3-methyl-butyl)-
18 1H-pyrazol-3-yl]- 336.1
5,7-dihydro-lH- (API-)
imidazo[4,5 f]indol-
6-one
2-(5-Ethyl-4-
methyl-lH-pyrazol-
19 3-yl)-7,7-dimethyl- 308.1
5,7-dihydro-lH- (API-)
imidazo [4,5 f ] indol-
6-one
7,7-Dimethyl-2-
(1H-pyrazol-3-yl)- 268,0
20 5,7-dihydro-lH- (ESI+)
imidazo [4,5 f] indol-
6-one
2-(5-Cyclopropyl-
1H-pyrazol-3-yl)-
21 7,7-dimethyl-5,7- 308,1
dihydro-lH- (ESI+)
imidazo [4,5 fJ indol-
6-one
2-(5-Isopropyl-2H-
pyrazol-3-yl)-7,7-
22 dimethyl-5,7- 310,1
dihydro-lH- (ESI+)
imidazo[4,5 f]indol-
6-one
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Example No. Systematic Name (Method) 1H-NMR
8,8-Dimethyl-2-(5-
propyl-2H-pyrazol-
23 3-yl)-1,5,7,8- 324,2
tetrahydro- (ESI+)
imidazo [4,5-
g] quinolin-6-one
8,8-Dimethyl-2-
(1H-pyrazol-3-yl)- 282,2
24 1,5,7,8-tetrahydro- (ESI+)
imidazo [4,5-
g] quinolin-6-one
2-(5-Cyclopropyl-
1H-pyrazol-3-yl)-
25 8,8-dimethyl-1,5,7,8- 322,2
tetrahydro- (ESI+)
imidazo [4,5-
g] quinolin-6-one
2-(5-Isopropyl-2H-
pyrazol-3-yl)-8,8-
26 dimethyl-1,5,7,8- 324,2
tetrahydro- (ESI+)
imidazo [4,5-
g] quinolin-6-one
27 2-(2H-pyrazol-3-yl)-
~ p p~N 294,2
~ ~ I dihydro[cyclopentan (ESI+)
e-1',7-imidazo[4,5-
f]indol]-6(3H)-one
2-(5-Isopropyl-2H-
28 pyrazol-3-yl)-spiro-
5,7- 336,2
dihydro[cyclopentan (ESI+)
e-1',7-imidazo[4,5-
f]indol]-6(3H)-one
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Example No. Systematic Name (Method) 'H-NMR
2-(5-Propyl-2H-
29 pyrazol-3-yl)-spiro-
o 336,2
dihydro[cyclopentan (ESI+)
e-1',7-imidazo [4,5-
f]indol]-6(3H)-one
5,7,7-Trimethyl-2-
(IH-pyrazol-3-yl)- 282,2
30 5,7-dihydro-3H- (ESI+)
imidazo[4,5 f]indol-
6-one
5,7,7-Trimethyl-2- [D6]DMSO, 400
(5-methyl-lH- MHz: d = 12.89 (m,
pyrazol-3-yl)-5,7- 296.0 1H), 12.61 (m, 1H),
31 dihydro-3H- (API+) 7=56-6.94 (m, 2H),
imidazo[4,5 f]indol- 6.55 (s, 1H), 3.19 (s,
3H), 2.32 (s, 3H),
6-one 1.31 (s, 6H)
5-Ethyl-7,7-
dimethyl-2-(1H-
32 pyrazol-3-yl)-5,7- 296,2
dihydro-3H- (ESI+)
imidazo [4,5- f] indol-
6-one
5-Ethyl-7,7-
dimethyl-2-(5-
propyl-2H-pyrazol-
33 3-yl)-5,7-dihydro- 338.2
3H-imidazo[4,5- (ESI+)
f]indol-6-one;
compound with
acetic acid
[D6]DMSO, 400
MHz: 1.28 (s, 6H),
5-Isopropyl-7,7- 1.45 (d, 3H), 2.31 (s,
dimethyl-2-(5- 3H), 4.56 (br, 1H),
34 methyl-2H-pyrazol- 324,1 6.55 (s, 1H), 6.88
3-yl)-5,7-dihydro- (API+) and 7.09 and 7.32
IH-imidazo [4,5- and 7.54 ( 2H, two
f ] indol-6-one tautomeric forms),
12.61(NH),12.87(
NH)
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Example No. Systematic Name (MMh d) 1H-NMR
[D6]DMSO, 400
MHz: 0.95 (t, 3H),
1.29 (s, 6H), 1.44 (d,
6H), 1.66 (m, 2H),
5-Isopropyl-7,7- 2.64 (t, 2H), 4.56 (br,
dimethyl-2-(5- 1H), 6.57 (s, !H),
35 propyl-2H-pyrazol- 352,2 7.71 and 7.31 (1H,
3-yl)-5,7-dihydro- (API+) two tautomeric
1H-imidazo[4,5- forms), 7.35 and 7.55
fJindol-6-one (1H, two tautomeric
forms), 12.49 and
12.60 (NH, two
tautomeric forms),
12.90 ( NH)
[D6]DMSO, 400
MHz: 0.88 (t, 3H),
1.31 (s, 6H), 1.66 (m,
7,7-Dimethyl-2-(5- 2H), 2.31 (s, 3H),
methyl-2H-pyrazol- 3.69 (t, 2H), 6.55 (s,
3-yl)-5-propyl-5,7- 324,1 1H), 6.95 and 7.22
36 dihydro-1H- (API+) (1H, two tautomeric
imidazo[4,5 f]indol- forms), 7.35 and 7.56
6-one (1H, two tautomeric
forms), 12.54 and
12.62 (NH, two
tautomeric forms),
12.88 (NH)
[D6]DMSO, 400
MHz: 0.88 (t) 3H),
0.95 (t, 3H), 1.31 (s,
7)7-Dimethyl-5- 6H), 1.67 (m) 4H),
propyl-2-(5-propyl- 2.64 (t, 2H), 3.69 (t,
2H-pyrazol-3-yl)- 352.1 2H), 6.58 (s, 1H),
37 5,7-dihydro-3H- (API+) 6.95 and 7.23 (s, 1H)
imidazo [4,5- f] indol- two tautomeric
6-one forms), 7.39 and 7.57
(s, 1H, two
tautomeric forms),
12.60 (br, 1H), 12.91
(br, 1H)
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Example No. Systematic Name (Method) 1H-NMR
[D6]DMSO, 400
MHz: 1.32 (s, 6H),
6.94 and 7.04 (1H,
7,7-Dimethyl-2-(5- two tautomeric
trifluoromethyl-2H- forms), 7.22 and 7.51
38 pyrazol-3-yl)-5,7- 336.0 (1H, two tautomeric
dihydro-lH- (API+) forms), 7.28 and 7.60
imidazo [4,5 f] indol- (1H, two tautomeric
6-one forms), 10.35 (NH),
12.88 and 12,98
(NH, two tautomeric
forms), 14.64 (NH)
5-Ethyl-7,7- [D6]DMSO, 400
dimethyl-2-(5-
trifluoromethyl-lH- MHz: 1.18 (t, 3H),
39 pyrazol-3-yl)-5,7- 364.1 1.32 (d, 6H), 3.79 (q,
(API+) 2H), 7.20 (s, 1H),
dihydro-3H-
imidazo[4,5 f]indol- 7.28 (s, 1H), 7.63 (s,
6-one 1H),
5-Isopropyl-7,7- [D6]DMSO, 400
dimethyl-2-(5- MHz: 1.18 (s, 6H),
trifluoromethyl-2H- 378.0 (d, 6H), 4.58
40 pyrazol-3-yl)-5,7- '0 (m, 1H), 7.23
dihydro-lH- (API+) (br,1H), 7.28 (s, 1H),
imidazo[4,5 f]indol- 7.62 (br,1H), 12.99
6-one (NH), 14.67 (NH)
7,7-Dimethyl-5- [D6]DMSO, 400
propyl-2-(5- MHz: 0.88 (t, 3H),
trifluoromethyl-2H- 1.34 (s, 6H), 1.67 (m,
41 pyrazol-3-yl)-5,7- 378.0 2H), 3.74 (t) 2H),
dihydro-1H- (API+) 7.18 (br) 1H), 7.28
imidazo[4,5-f]indol- (s, 1H), 7.63 (br,1H),
6-one 13.02 (NH), 14.64
(NH)
5,7,7-Trimethyl-2- [D6]DMSO, 400
(5-trifluoromethyl- MHz: d = 14.66 (s)
2H-pyrazol-3-yl)- 350.0 1H), 13.04 (s, 1H),
42 5,7-dihydro-3H- (API+) 7=63 (m, 1H), 7.29
imidazo [4,5f]indol- (m, 1H), 7.15 (m,
1H), 3.22 (s, 3H),
6-one 1.34 (s, 6H)
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Exaxnple No. Systematic Name (Method) 'H-NMR
43 2-(5-Cyclopropyl-
2H-pyrazol-3-yl)-
spiro-5,7- 334.2
Q ~ NH N-NH dihydro[cyclopentan (ESI+)
H e-1',7-imidazo[4,5-
f]indol]-6(3H)-one
Example 44:
5-Ethyl-2- (5-methoxy-lH-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-
imidazo [4,5-f] indol-6-one
5-Metho.xy-1H-pyrazole-3-carboxylic acid (86 mg, 0.61 mmol), 1-
hydroxybenzotriazole hydrate (111 mg, 0.73 mmol) and triethylamine (253 l,
184
mg, 1.82 xnmol) were dissolved in N,N-dimethylformamide (DMF) (2 ml) and after
the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) (139 mg, 0.73 mmol) dissolved in DMF (2 ml) the reaction mixture was
stirred at room temperature. After 1 hour a solution of 5,6-diamino-l-ethyl-
3,3-
dimethyl-1,3-dihydro-indol-2-one in DMF (2 ml) was added and the reaction
mixture was stirred at room temperature for 16 hours. The solvent was removed
under reduced pressure, the residue was quenched with water (20 ml) and
extracted with ethyl acetate (3 x 20 mL). The combined organic layers were
washed
with brine (15 ml), dried over sodium sulfate and evaporated. The residue was
dissolved in ethanol (5 ml) and after the addition of hydrochloric acid (10 M,
2 ml)
it was stirred under reflux for 2 hours. The ethanol was evaporated and the
residue
was adjusted to pH 9-10 with ammonium hydroxide. After the addition of water
(20 ml) the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The
combined organic layers were washed with brine (10 ml), dried over sodium
sulfate
and evaporated. The crude product was purified by column chromatography on
silica gel. Elution with ethyl acetate/sz-heptane (9:1) yielded 56 mg (28%) of
an off-
white solid.
MS: M = 326.1 (API+)
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1H-NMR (400 MHz, DMSO): S(ppm) = 1.19 (t, 3H), 1.32 (s, 6H), 3.76 (q, 2H),
3.84 (s, 3H), 6.28 (s, 1H), 7.14 (s, 1H), 7.56 (s, 1H), 12.80 (br, 2H)
Example 45:
5-Ethyl-7,7-dimethyl-2-(5-methylsulfanyl-lH-pyrazol-3-yl)-5,7-dihydro-lH-
imidazo [4,5-fJ indol-6-one
Hydrazine monohydrate (0.92 g, 1.8 mmol) was added to a suspension of 2-(3,3-
bis-methylsulfanyl-acryloyl) - 5-ethyl-7,7-dimethyl-l-(tetrahydro-pyran-2-yl)-
5,7-
dihydro-lH-imidazo[4,5-f)indol-6-one (0.68 g, 1.81 mmol) in acetonitrile (15
mL)
and stirred for 24 h. After cooling to room temperature the precipitate was
collected, washed with acetonitrile and ether to yield 0.5 g (81 %) of a pale
white
powder.
MS: M = 342.1 (API+)
'H-NMR (400 MHz, DMSO): 8(ppm) = 1.19 (t, 3H), 1.31 (s, 6H), 2.53 (s, 3H),
3.76 (m, 2H), 6.83 (s, IH), 6.95 - 7.65 (br m, 2H, tautomeric forms), 12.75
(br,
1H), 13.45 (br, 1H)
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