Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1
INDOLE DERIVATIVES AND THEIR USE FOR THE TREATMENT
OF MALIGNANT AND OTHER DISEASES BASED ON PATHOLOGICAL
CELL PROLIFERATION
This is a divisional application of Canadian Patent
Application Serial No. 2,330,756 filed on April 22, 1999.
The invention relates to tyrosine kinase inhibitors of the
bis-indolyl compound type, pharmaceuticals containing them
l0 and their use for the treatment of malignant and other
diseases based on pathological cell proliferation. It should
be understood that the expression "the invention" and the
like encompasses the subject matter of both the parent and
the divisional applications.
The activation of tyrosine-specific protein kinases is a key
event in stimulation of the division of animal cells.
Norma7.ly, this stimulation is effected by exogenous factors,
e.g. growth factors, when the proliferation of a certain
cell type is necessary for the overall function of a tissue
or organ. In tumours, cell proliferation is also linked with
the activity of tyrosine kinases. In tumour cells, however,
an aberrant activity of kinases is often present, which is
caused by overexpression, constitutively active kinase
mutants or ectopic activity of growth factors. The PDGF
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la
receptor is one of the growth factors with relevance for
human tumours. PDGF is one of the main mitogens in the serum
and is present in high concentrations in blood platelets.
Its most important function in the adult body is wound
healing. An undesired activity of the PDGF receptor is
involved in the proliferation of various tumours, e.g.
gliomas, glioblastomas, sarcomas, mastocarcinomas, ovarian
carcinomas and colonic: carcinomas. An aberrant activation of
the PDGF/PDGF receptor- system also assumes a key position in
l0 patho7_ogical hyperproliferation of mesenchymal cells in the
context of arteriosclerosis, restenosis after balloon
angioplasty, arthritis and fibrotic diseases.
A few growth factor receptor tyrosine kinases, whose
tyrosine kinase domains have high sequence homology to the
tyrosine kinase domain of the PDGF receptors, are also of
importance for the tumour process and
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pathological hyperproliferation. These include the
receptors for the vascular endothelial cell growth
:factor (VEGF)KDR/Flk-1 and Flt-1 with great importance
for tumour vascularization, Kit/SCF receptor, for which
constitutively active versions were observed in
carcinomas and Flk-2/Flt-3, a receptor involved in the
proliferation of leukemia cells of various forms of
disease. It can be expected that further members of
i:his kinase family with relevance for pathological
proliferation will be identified. In addition to
mitogenic stimulation, the actions of the ligands of
these receptors often also include the stimulation of
cell migration, anti-apoptotic actions and effects on
membrane transport. systems for ions, water and chemical
compounds. To a varying extent, uncontrolled effects of
this type are also involved in the pathological process
in tumours and other diseases.
Uf the various possibilities for switching off the
signal of receptor tyrosine kinases, the specific
direct inhibition of the activity of the kinase is the
most promising.
'I'he invention is therefore aimed at creating compounds
which are suitable as inhibitors of tyrosine kinases,
in particular of the PDGF receptor tyrosine kinases and
further, related tyrosine kinases such as KDR/Flk-1,
Kit/SCF receptor and FLK/Flt-3. This object is achieved
by the compounds of the general formula I according to
the invention:
Rs
.A~ X ~Z
R'
in which Z is a group having the general formula (II)
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R~s B. Rio
F G(
wB~~~Rs
R' _'R8
(~~)
where A can be a nitrogen, oxygen or sulphur atom [sic]
and B, B' can be a carbon, nitrogen, oxygen or sulphur
atom and the ring systems F and G independently of one
another can be either saturated or unsaturated 5- and
6-membered rings,
X is a group having the general formula III or IV
~CH2)~C'R~4R~~m~CH~n
A
R~s
in which A has the same meaning as above, 1 and n can
assume the numbers from 0 to 6, m the numbers 1 and 2,
and R1° and R15 either together form an oxygen atom or
R14 is a hydroxyl group and Rls is a hydrogen atom or Rl4
and R15 are hydrogen atoms and where R16 is a hydrogen
atom, an alkyl or aryl radical, halogen-, amino-, or
azido-substituted alkyl or aryl radical, an
alkyloxymethyl radical or substituted alkyloxymethyl
radical,
Rz and R13 together form a linkage having the general
formula V or VI
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(V)
Nt)
where the dashed bond is a double or single bond, A and
R16 have the same meaning as above and o can assume the
numbers 1 and 2,
RZ and R13 are identical or different radicals of the
general formula VII or hydrogen atoms,
Ntl)
where the dashed bond is a double or single bond, A and
R16 have the same meaning as above and R1' is a halogen
atom or a radical. of the general formula VIII
Nt ~ JP
~R'°
(VIII)
such that p can be = 0, 1 or 2 (if p = 0 then it is an
ar_yclic primary amine and Y carries an additional
hydrogen atom), Y can be a carbon, oxygen or nitrogen
atom and if Y is a carbon or nitrogen atom, R1g is a
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hydrogen atom or an alkyl or aryl radical, substituted
alkyl or aryl radical, saturated or unsaturated
heterocycle, alkoxycarbonyl radical, aminocarbonyl
methyl radical or substituted aminocarbonylmethyl
radical,
Rz and R13 together form a linkage having the general
formula IX or X
Rss Rio
I
O~N~O O~Nw
(X)
(IX)
where W is either a carbon or a nitrogen atom, q can
assume a number [ sic ] between 0 and 6 and R'9 and Rz°
can be hydrogen atoms, alkyl radicals or substituted
alkyl radicals,
in which R1 and R' are identical or different and are
hydrogen atoms, alkyl or aminoalkyl radicals,
phenylsulphonyl radicals, alkylsilylmethoxymethyl
radicals, a sugar or substituted sugar,
where R3, R4, R5, R~', Re, R9, R1° and R11 are identical or
different and in each case is a hydrogen atom, an
alkoxy-, amino-, halogen-, cycloalkyl-, cyclohetero-
alkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy
or alkoxymethyl group, nitro group, a halogen atom or
an O-alkoxy group of the general form -O-(C=O)-Rzi,
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where RZ1 is an alkoxy-, amino-, halogen-, cycloalkyl-,
cycloheteroalkyl--, aryl- or heteroaryl-substituted
alkyl, alkoxy or alkoxymethyl group.
Preferred compounds according to the invention are
those having the above general formula I, in which Z is
a group having the general formula II and X is a group
having the general formula III, R2 and R13 are hydrogen
atoms, A is a nitrogen~atom and B is a nitrogen, oxygen
or sulphur atom and R3, R°, R5, R6, R?, R8, R9, R1°, Rll,
R14 and R15 have the same meaning as above, where these
compounds correspond to the following formula XI:
Ra Rn
Rio
w i
Rs ~ ~ N ~ ~ B ~ ~ R9
R° R' R' R°
R~4 R~s
(Xl)
Particularly preferred compounds are those of the
formula XI in wh_Lch Rl~ and R15 together form an oxygen
atom.
Additionally preferred compounds according to the
invention are those having the above general formula I
in which z is a group having the general formula II and
X is a group having the general formula III, R1 and RZ
are hydrogen atoms, A and B are nitrogen atoms, and Ri,
R3, Rq; R5, R6, R', R8, R9, R1°, R11 and R16 have the same
meaning as above, where these compounds correspond to
the following formula XII:
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D
r~
R'~
(Xil)
Additionally preferred compounds according to the
invention are those having the general formulae XIII
and XIV below
(XIII) (XIV)
in which a is the numbers 3. 4, 5, 8 or 12, q is the
numbers 0 , 1, 2 , :3 , 5 or 6 . R19 , Rz° are hydrogen a toms
or alkyl groups and Rl, R3, R°, R5, R6, R', Re, R9, Rlo,
Rll and R16 are identical or different and have the same
meaning as above.
Additionally preferred compounds according to the
invention are those having the following general
formula XV
R'°
I
R3 O ~ R~s
Rio
\ N N ~ R9
1
R~
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_ g _
in which b is the numbers 1, 2 or 3, R16 is a hydrogen
atom or an alkyl group and Ri, R3, R4, R5, R6, R', R8, R9,
Rlo~ Rii and R16 are identical or different and have the
same meaning as above.
Exemplified carbon ranges for substituents are as follows:
Ci-iz alkyl; C6_1q aryl; C1_6 alkoxymethyl; C1_6 alkoxycarbonyl;
amino Ci_6 alkyl; C,3_~ cycloalkyl; Cz_6 heterocycloalkyl; C3_g
heteroaryl; C1_6 alkoxy; and C1_6 alkylsilylmethoxymethyl.
The invention also provides a pharmaceutical composition
comprising a compound as defined herein, together with a
pharmaceutically acceptable carrier, for the inhibition of
a PDGF receptor tyrosine kinase. The invention also
provides such a pharmaceutical composition for the
treatment of tumours, arteriosclerosis, restenosis after
balloon angioplasty, arthritis or fibrotic diseases.
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8a
The compounds of the formula XI can be prepared by one
of the two following schemes:
R"
R,o
a
t I N~R~
IO= Ra
Ph
d _
R" ~ R"
R~ ,o t ~ R,o
~ ~I I ~ ~ i I
Rs ~ N~~ ~ R° Rs ~ N~N~R°
H 'Of H H H R°
a) LDA/THF, b) HSiPh3/THF, c) PDC/DMF, d) 10~
NaOH/EtbOH, e) KzCOs/MeOH,
f) N2H9/2-(2-hydroxyethyloxy)-ethanol
R"
R
\ CH3 O p H3C \ Rio
Me Si
RS / N~SiMe3 EtO~~~OEt 3 ~N ~ R9
R° H H R°
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D
n = 2 or 3
For the preparation of the compounds according to the
invention in which R2 and R13 are a radical having the
above general formula VII or together form a linkage
having the general formula V, IX or X, a 2,2'-bis-1H-
i_ndolylalkane or a derivative thereof having the
general formula XI
R
R
D
(XI)
in which X, Ri, R3, R9, R5, R6, R', Ra, R9, Rl° and Rli
have the same meaning as above, is initially reacted
with dibromomaleimide.
Compounds according to the invention in which R2 and R13
together form a linkage having the general formula VII
are then reacted with a primary or secondary amine
having the following general formula XVI or XVII or
piperazine
H
I
'N[:~,p
~Y\ H-N W-~-C-~W N-H
(~I) - (XVII}
in which p, q, Rl' and W have the same meaning as above.
_ .,
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The following examples illustrate the invention,
without restricting it.
Example 1
Bis(N-phenylsulphonylindol-2-yl)-1-methanol
Lithium diisopropylamide is prepared at -78°C from
30.40 ml (216.3 mmol) of diisopropylamine and 125.3 ml
(200.5 mmol) of n-.BuLi (1.6 M in hexane) in 200 ml of
absol. THF. The solution is stirred at -78°C for 10 min
and then at 0°C for 30 min, before 49.13 g (190.9 mmol)
of 1-phenylsulphonylindole in 300 ml of absol. THF are
added dropwise at 0°C in the course of 10 min. The
reaction solution is stirred at 0°C for a further
30 min. After cooling again to -78°C, 60.00 g
(210.3 mmol) of phenylsulphonyl-2-carbaldehyde in
200 ml of absol. THF are added dropwise and the mixture
is allowed to warm to room temp. overnight. The mixture
is poured onto 1 per cent HC1 and the org. phase is
separated off after addition of ether. The aq. phase is
extracted with ether, and the combined org. phases are
washed successively with NaHC03 and satd. NaCl solution
and dried over Na2S0q. The solvent is stripped off in
vacuo and the crude product is purified by column
chromatography (SiOZ; CH2C12): colourless crystals,
yield 86.5 g (84~).
M.p.: 185°C (MeOH).
The following were prepared analogously:
Example 2
Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanol
M.p.: 113 - 114°C (MeOH)
Example 3
(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-
sulphonylindol-2-yl)-1-methanol
M..p.: 104 - 105°C (CHzCl2/hexane)
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Example 4
(5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-
N-phenylsulphonylindol-2-yl)-1-methanol
M.p.: 119 - 121°C (CHZC12/hexane)
Example 5
(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-
sulphonylindol-2-;yl)-1-methanol
M.p.. 99 - 101°C (CHzClz/hexane)
Example 6
(5-Methoxy-2-phenylmethyloxy(1-phenylsulphonylindol-
2-yl)methyl-1-phenylsulphonylindol
M.p.: 62 - 64°C
Example 7
Di-(5-Methyloxy-l-phenylsulphonylindol-2-yl)phenyl-
methyloxymethane
M.p.: 100 - 101°C
Example 8
(3-Dimethylaminomethyl-1-phenylsulphonylindol-
2-yl)(1-phenylsulphonylindol-2-yl)methan-1-of
M.p.. 116 - 117°C
Example 9
(7-Methoxy-N-phenylsulphonylindol-2-yl)(N-phenyl-
sulphonylindol-2-yl)-1-methanol
M.p.: 149 - 151°C
Example 10
Dibenzothiophen-2--yl-1-methanol
M.p.: 130 - 131°C
Example 11
Ei-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-
sulphonyl-1H-2-indolyl.)methanol
M.p.: 180°C
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Example 12
7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-
sulphonyl-1H-2-indolyl)methanol
M.p.: 148 - 150°C
Example 13
Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-
2-indolyl)-1-methanol
M.p.: 71 - 73°C
Example 14
Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-
2-indolyl)-1-methanol
M.p.: 118 - 119°C
Example 15
Benzo(b]furan-2-y:l(5-methoxy-1-phenylsulphonyl-1H-
2-indolyl)-1-methanol
M.p.: 71 - 73°C
Example 16
:Bis(N-phenylsulphonylindol-2-yl)methan-1-one
'rhe solution of 20.00 g (36.9 mmol) of bis-
(N-phenylsulphonylindol-2-yl)-1-methanol in 200 ml of
absol. DMF is cooled to 0°C. After addition of 90.4 g
of pyridinium dichromate (PDC), it is stirred at room
temp. for 20 h. For work-up, 700 ml of H20 and 700 ml
of CHZC12 are added. The aq. phase is extracted with 2 x
200 ml of CHZC12. The combined org. extracts are washed
with 500 ml of HzO. After stripping of the solvent in
vacuo and addition of CHZC12, the product precipitates:
colourless crystals; yield 15.0 g (75$).
M.p.: 244°C (MeOH/ether)
The following were prepared analogously:
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Example 17
5-Methoxy-N-phenylsulphonylindol-2-yl)-
(N-phenylsulphonylindol-2-yl)methan-1-one
M.p.. 205°C (MeOH)
Example 18
Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanone
Example 19
Bisindol-2-ylmethan-1-one
10.0 g (18.5 mmo:1) of bis(N-phenylsulphonylindol-2-
yl)methan-1-one are dissolved in 380 ml of 99 per cent
EtOH. After addition of 210 ml of 10 per cent NaOH, the
solution is heated under reflex for 20 H. For work-up,
the EtOH is stripped off, 500 ml of satd. NaCl solution
and 500 ml of CHZC12 are added and the phases are
separated. The aq. phase is extracted with 2 x 200 ml
of CHZC12, and the combined org. extracts are dried over
Na2S09 and concentrated in vacuo. The bisindole is
deposited as a crude product and can be recrystallized
from CH2C12, yellow crystals, yield 4.5 g (93$)
M.p.: 272 - 273°C (CHZC12)
The following were prepared analogously:
Example 20
(5-Methoxyindol-2-:yl)-(indol-2-yl)methan-1-one
M.p.: 233 - 235°C (MeOH)
Example 21
Bis(5-methoxyindol-2-yl)-1-methanone
M.p.: 202 - 204°C
Example 22
D:ibenzothiophen-2-yl-1-methanone
M.p.: 161°C
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Example 23
5-Methyl-1-phenylsulphonyl-3-indolyl(1-phenylsulphonyl-
2-indolyl)-1-methanone
M.p.: 114 - 116°C
Example 24
(1H-Indol-2-yl)-(1H-indol-3-yl)-1-methanone
M.p.: 260 - 261°C (MeOH)
Example 25
:Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-
2-indolyl)-1-methanone
M.p.: 190°C
Example 26
Benzo[b]thiophen-2-yl(7-methoxy-1H-2-indolyl)-
1-methanone
M.p.: 155°C
Example 27
Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-
:Z-indolyl)-1-methanone
M.p.: 82 - 83°C
2 5 l:xamp 1 a 2 8
Benzo[b]thiophen-2-yl(5-methoxy-1H-2-indolyl)-
1-methanone
M.p.. 200°C
Example 29
7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-
sulphonyl-1H-2-indolyl)methanone
M.p.: 129 - 130°C
Example 30
7-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone
M.p.: 151°C
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Example 31
6-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-
sulphonyl-1H-2-indolyl)methanone
M.p.: 184 - 186°C
Example 32
6-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone
td.p.: 184 - 186°C
Example 33
1-Methyl-1H-2-indalyl(1-ethyl-5-methyloxy-1H-
2-indolyl)-1-methanone
M.p.: 148 - 149°C
Example 34
1H-2-Indolyl(1-met.hyl-5-methyloxy-1H-2-indolyl)-
1-methanone
M.p.: 190°C
Example 35
1-Methyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-
1-methanone
M.p.: 176 - 177°C
Example 36
l.-Ethyl-1H-2-indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-
l.-methanone
M.p.: 99-100°C
Example 37
1H-2-Indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-
1-methanone
M.p.: 142 - 143°C
Example 38
1-Ethyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-
1-methanone
M.p.: 101 - 102°C
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Example 39
1-Benzyl-1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-
1-methanone
M.p.: 132°C
:Example 40
1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-
1-methanone
M.p.. 180 - 182°C '
Example 41
:l-Benzyl-1H-2-indolyl(5-methoxy-1H-2-indolyl)-1-
methanone
M.p.: 167 - 168°C
Example 42
5-Benzyloxy-1H-2-indolyl(1H-2-indolyl)methanone
M.p.: 199 - 201°C
Example 43
'.~-Hydroxy-1H-2-indolyl(1H-2-indolyl)methanone
M.p.: > 220°C
Example 44
5-Ethoxy-1H-2-indolyl(1H-2-indolyl)methanone
M.p.. 168 - 169°C
Example 45
1H-2-Indolyl[5-(2-morpholin-1-ylethyloxy)-1H-
2-indolyl]methanone
M.p.: 98 - 101°C
Example 46
LH-2-Indolyl[5-(3-dimethylaminopropyloxy)-1H-2-
i.ndolyl]methanone
M.p.: 163 - 166°C
Example 47
5-(4-Iodobutyloxy)-1H-2-indolyl(1H-2-indolyl)methanone
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M.p.: 110 - 113°C
Example 48
1H-2-Indolyl[5-(2-dimethylaminoethyloxy)-1H-2-
indolyl]methanone
M.p.: 143 - 145°C
Example 49
5-Cyclohexylmethy:foxy-1H-2-indolyl(1H-2-indolyl)-
methanone
M.p.: 185°C (dec.)
Example 50
5-(5-Iodopentyloxy)-1H-2-indolyl(1H-2-indolyl)methanone
M.p.: 127 - 130°C
Example 51
1H-2-Indolyl[5-(1-phenylethyloxy)-1H-2-indolyl]-
methanone
M.p.: 151 - 153°C
Example 52
1H-2-Indolyl[5-(2--piperidin-1-ylethyloxy)-1H-
2-indolyl]methanome
M.p.: 104 - 106°C
Example 53
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic] ethanoate
M.p.: 223 - 224°C
Example 54
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 4-meth-
axybenzoate
M.p.: > 230°C
Example 55
[2-(1H-2-Indolylcarbonyl)-1N-5-indolyl)][sic] butanoate
M.p.: 201 - 204°C
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Example 56
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-(N,N)-
dimethylaminoethanoate
M.p.. 215 - 217°C
Example 57
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
propanoate
M.p.. > 230°C
Example 58
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
2-thiophenylethanoate
M.p.: 224 - 226°C
Example 59
[2-(1H-2-Indol_ylcarbonyl)-1H-5-indolyl)][sic] O-acetyl-
salycylate [sic]
M.p.: 133 - 135°C
Example 60
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 4-phenyl-
benzoate
M.p.: > 220°C
Example 61
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-phenyl-
propanoate
M.p.. 211 - 313°C [sic]
Example 62
[2-(1H-2-Indolylcarbonyl)-1N-5-indolyl)][sic] a-acetyl-
phenylethanoate
M.p.: 194 - 196°C
Example 63
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] benzoate
M.p.: > 230°C
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Example 64
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
3-methoxyphenylethanoate
M.p_: 212 - 215°C
Example 65
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-chloro-
benzoate
M.p.. > 230°C
Example 66
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic]
4-nitrobenzoate
M.p.. > 230°C
Example 67
[2-(1N-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
3,4,5-trimethoxybenzoate
M.p.: 216 - 219°C
Example 68
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic) cinnamate
M.p.: 226 - 228°C
Example 69
[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic]
2-furanylcarboxylate [sic]
M.p.: > 230°C
Example 70
Di(1-phenylsulphonyl-1H-2-indolyl)methane
22.4 ml of trifluoroacetic acid (TFA) are added
dropwise after 30 min to a solution of 26.67 g
(49.2 mmol) of bis(N-phenylsulphonylindol-2-yl)-1-
methanol and 15.00 g (57.8 mmol) of triphenylsilane in
400 ml of absol. CH2C12. After stirring at room temp.
for 1 h, H20 is added and the mixture is cautiously
neutralized with solid Na2C03 with ice-cooling. After
separating the phases, drying the org. phase over Na2S04
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and distilling off the solvent, the crude product is
purified by column chromatography (Si02; CH2C12/hexane
6:4), colourless crystals, yield 22.5 g (87$).
M.p.: 144 - 145°C (ether)
The following were prepared analogously:
Example 71
Bis(5-methoxy-N-phenylsulphonylindol-2-yl)methane
M.p.: 159-160°C (CHZC12/hexane)
Example 72
(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-
sulphonylindol-2-yl)methane
M.p.. 98 - 100°C (CH2C12/hexane)
Example 73
(5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-N-
phenylsulphonylindol-2-yl)methane
M.p.: 168 - 170°C (CH2C12/hexane)
Example 74
Di(1H-2-indolyl)methane
15.0 g (28.5 mmol) of 57 are boiled with 20 g of KZC03
in 800 ml of MeOH and 200 ml of Hz0 for 14 days. For
work-up, 500 ml of satd. NaCl solution are added and
the phases are separated. After drying the org. phase,
the solvent is stripped off in vacuo. The crude product
is purified by column chromatography, colourless
crystals, yield 5.4 g (76$).
M.p.: 189 - 191°C
The following were prepared analogously:
Example 75
(5-Methoxyindol-2-yl)-(indol-2-yl)methanone
M.p.. 112°C (MeOH)
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Example 76
(1H-Indol-2-yl)-(1-H-indol-3-yl)-1-methane
M.p.: 161 - 163°C (aq. EtOH)
Example 77
1,3-Di(1H-2-indolyl)propane
38.0 g (0.21 mol) of trimethylsilyl-o-toluidide are
dissolved in 950 ml of abs. hexane and 291.0 ml
(0.47 mol) of n--BuLi (1.6 M in hexane) are added
dropwise at room temp. and the mixture is heated to
r_eflux for 4 h. It is then cooled to -78°C and 20.5 ml
(0.11 mol) of diethyl glutarate in 380 ml of abs. THF
are added dropwise= at this temp. The mixture is stirred
at -78°C for 1 h, and is then slowly allowed to come to
x-oom temp. overnight and subsequently heated to bailing
for a further 2 h.. After cooling, it is poured onto 1 1
c>f ice water and extracted with 5 x 500 ml of ethyl
acetate, the combined org. phases are dried over Na2S09
and the solvent is stripped off in vacuo. White
crystals, yield 6.55 g (23.9 mmol, 22~).
M.p.: 143 - 145°C (ethanol)
The following was prepared analogously:
Example 78
1,3-Di(1H-2-indolyl)ethane
M.p.: 264 - 267°C
Example 79
1,2-Di-(1-phenylsulphonyl-1H-2-indolyl)-1-ethene
[lacuna] (17.9 mmol) of TiCl9 with a syringe and 2.0 g
(30.5 mmol) of Zn powder are subsequently added. The
mixture is heated under reflux for 30 min. After this,
3 g (10.5 mmol) of 22, dissolved in 50 ml of THF, are
added dropwise again at 0°C. The solution is heated
under reflux overnight. 300 ml of 20 per cent K2C03
soln. are poured into the cooled solution and it is
stirred further overnight at room temp. The sludgy
residue is then filtered off and washed with THF, the
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org. phase is separated off from the filtrate and the
aqueous phase is extracted with CHZC12.
The combined org. phases are washed with water, dried
over NazS04 and freed from the solvent in vacuo.
Purification is carried out by column chromatography
(Si02; CHzClz/hexane 2:1) . Yield: 1.1 g (2.0 mmol, 390)
of yellow crystals.
M.p.: 272°C
Example 80
Bis(5-methoxy-N-phenylsulphonylindol-2-yl)phenoxy-
methane
188 mg of NaH (60o in paraffin) are added at 0°C to a
solution of 2 g (3.7 mmol) of bis(-N-phenylsulphonyl
indol-2-yl)-1-methanol in 20 ml of THF. 13.5 mg of
tetrabutylammoniwn iodide and 0.45 ml of benzyl bromide
are subsequently added and the mixture is stirred at
20°C. Water and ether are then cautiously added, the
ether phase is separated off and the aqueous phase is
washed twice with ether. The org. phase is dried over
Na2S04 and the solvent is then stripped off. Yield:
0.86 mg (81g)
M.p.: 192°C (dec.)
Example 81
1,2,3,8,9,10-Hexahydroindolo[3',2':5,6]pyrrolo-
[3',4':3,4)-cyclohepta[b)indole-1,3-dione
Half of 0.73 ml (9.75 mmol) of anhydrous ethyl bromide
i.s added to 236 mg (9.75 mmol) of Mg turnings in 6 ml
of absol. THF. After the reaction has started, the
remainder of the ethyl bromide is added dropwise such
that the solution continues to boil. It is then boiled
until the Mg turnings have dissolved (about 30 min).
After cooling to room temp., 1.00 g (4.06 mmol) of
methylene-2,2'-bisindole in 25 ml of absol. toluene and
1 ml of absol. THF is added dropwise and the mixture is
stirred at 45°C for 45 min. After cooling to room temp.
again, 1.04 g (4.06 mmol) of dibromomaleimide in 50 ml
of absol. toluene and 2 ml of absol. THF are added
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dropwise over the course of 1 h, then the mixture is
heated under reflux overnight. For work-up, 100 g of
:ice and 50 ml of 20 per cent citric acid are added,
then the mixture is extracted by shaking with 2 x 50 ml
of ethyl acetate. The org. extracts are washed with
H20, dried over Na2S04 and concentrated. The crude
product is purified by column chromatography (Si02, 1.
CHZC12/ethyl acetate 8:2; 2. CHZC12/ethyl acetate 7:1):
red crystals, yield 290 mg (22~) m.p.. > 350°C (ethyl
acetate).
The following were prepared analogously:
Example 82
1,2,3,8,9,10-Hexahydro-5-methoxyindolo[3',2':5,6]-
pyrrola[3',4':3,4)-cyclohepta[b]indole-1,3-dione
NI.p.. >350°C (EtOH)
Example 83
1,2,3,8,9,10,11,12-Octahydroindolo[3',2':5,6]pyrrolo-
[3',4'3,4]cyclonona[b]indole-1,3-dione
M_p. . 137°C (CHZC12) (dec_ )
Example 84
1,2,3,8,9,10,11-Heptahydro-2-methylindolo[3',2':5,6]-
pyrrolo[3',4':3,4]-cycloocta[blindole-1,3-dione
M.p.: > 350°C
Example 85
2-Benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-
[3',2':5,6]-pyrrolo[3',4':3,4]-cyclohepta[b]indole-1,3-
d:ione
M.p.: > 350°C (EtOH)
Example 86
1,2,3,8,9,10,-Hexahydro-2-methylindolo[3',2':5,6]-
pyrrolo[3',4':3,4)-cyclohepta[b]indole-1,3,dione
M.p.. > 350°C (CHZC:12)
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Example 87
3,8,9,10-Tetrahydro-8-[2-(N,N-dimethylamino)ethyl]-1H-
indolo[3',2':5,6]furo[3',4':3,4]cyclohepta[b]indole-
1,3-dione
M.p.. > 350°C (MeOH)
Example 88
2-Benzyloxymethyl-1,2,3,8,9,10-hexahydro-8-[2-(N,N-di-
methylamino)ethyl]indolo[3',2':5,6]pyrrolo[3',4':3,4]-
cyclohepta[b]indole-1,3-dione
2d. p.: 164 - 165°C (MeOH)
Example 89
1,2,3,8,9,10-Hexahydro-3-methyl-8-[2-(N,N-dimethyl-
amino)ethyl]indolo[3',2':5,6]pyrrolo[3',4':3,4]-
cyclohepta[b]indole-1,3-dione
M.p.: 185°C (MeOH)
Example 90
1.,2,3,8,9,10-Hexahydro-8-[2-(N,N-dimethylamino)ethyl]-
indolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-
1,3-dione
M.p.: 213 - 214°C (EtOH)
Example 91
3-Bromo-4-(2-(2-(1Ii-2-indolyl)ethyl)-1H-3-indolyl)-
1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 169°C
Example 92
3-Bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-
1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione .
M.p.: 165°C (dec.)
Example 93
3-Bromo-4-(2-(5-(1H-2-indolyl)pentyl)-1H-3-indolyl)-1-
methyl-2,5-dihydro--1H-.pyrrole-2,5-dione
M_p.: 125°C (dec.)
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Example 94
Bis(indol-3-yl)methanone
Analogously to Example 31 using triphosgene instead of
dibromomaleimide.
M.p.. 297 - 299°C
Example 95
Diastereomer mixture of 8-(3,4,6-tri-O-benzyl-(3-D-
glucopyransoyl)-2-benzyloxymethyl-1,2,3,8,9,10-hexa-
hydroindolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]-
indole-1,3-dione and
8-(3,4,6-tri-O-benzyl-a-D-mannopyranosyl)-2-
benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-
[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-
dione
Diastereomer mixture of the disubstituted O-glycosides
468.7 mg (1.02 mmol) of 2-benzyloxymethyl-1,2,3,8,9,10-
hexahydroindolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta-
[b]indole-1,3-dione are added to a suspension of
91_8 mg (3.06 mmol) of NaH (80~ ~in paraffin oil) in
7.6 ml of absol. THF. After 30 min, the solution of 1,2-
anhydro-3,4,6-tri-O-benzyl-D-glucopyranose in 16 ml of
absol. THF is added dropwise. The mixture is stirred at
50°C for 5 h and at 60°C for 1 h. For work-up, the
reaction solution is poured onto 10 ml of satd. NaHC03
solution and extracted with 3 x 10 ml of ethyl acetate.
The compbined org. extracts are washed with 15 ml of
satd. NaCl solution, dried over NazS04 and concentrated
in vacuo. The product is separated by column
chromatography (1. column: SiOz; toluene/isopropylamine
8:2; 2. column: SiOz: CHZClz/MeOH 12:1) from by-products
and unreacted starting material. The diastereomer
mixture is separated by HPLC.
Example 96
Diastereomer mixture of 8-((3-D-glucopyranosyl)-
1,2,3,8,9,10-hexahydroindolo[3',2':5,6]pyrrolo-
[3',4':3,4]cyclohepta[b]indole-1,3-dione and 8-(a-D-
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mannopyranosyl)-1.,2,3,8,9,10-hexahydroindolo-
[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-
dione
150 mg (0.17 mmol) 8-(3,4,6-tri-O-benzyl-2-benzylo-
xymethyl-D-glucopyranosyl)-1,2,3,8,9,10-hexahydro-
indolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-
1,3-dione, as a diastereomer mixture, are dissolved in
50 ml of absol. FtOH and, after the addition of 200 mg
of Pd/C (5$), the solution is stirred under an Hz
pressure of 7 bar for 5 h. It is then filtered off with
suction through Celite, rinsed with 50 ml of CH2C12 and
the solution is concentrated in vacuo. Without
purification, the product is dissolved in 15 ml of
absol. THF and the solution is cooled to 0°C. NH3 is
then passed in for 10 min and the mixture is stirred at
room temp. for 1 h. After stripping off the THF in
vacuo, the residual oil is purified by column
chromatography (S:i02: CHzCl2/MeOH 8:2) : red oil, yield
1.0 mg (12~) .
Example 97
1,2,3,3a,8,9,10,14c-Octahydroindolo[3',2':5,6]pyrrolo-
[3',4':3,4]cyclohepta[b]indole-1,3-dione
1.20 g (18.4 mmol) of Zn granules are washed with 2 x
3 ml of 2 N HC1., then immediately added to 90 mg
0 . 33 mmol ) of HgClZ in 1. 5 ml of H20 and 1. 5 ml of
cons. HCl and the mixture is shaken at room temp. for
10 min. The aq. phase is decanted and the zinc amalgam
is additionally washed with 2 x 3 ml of dil. HC1 before
it is added to a solution of 60.0 mg (0.18 mmol) of
1,2,3,8,9,10-hexahydroindalo[3',2':5,6]pyrrolo-
[3',4':3,4)cyclohepta(b]indole-1,3-dione in 1.5 ml of
5 N HC1, 1.5 ml of EtOH and 1.5 ml of toluene and
heated under reflux. After 1 h, as soon as the reaction
solution has cooled to room temp. Hz0 is added and the
mixture is extracted with 2 x 10 ml of CHZCIz. The org.
extracts are dried over Na2S04, concentrated in vacuo
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and purified by column chromatography (Si02;
CHzClz/ethyl acetate/MeOH 8:2:0.5): colourless wax,
yield 14 mg (23~).
Example 98
2,5-Dihydro-3,4-bis(N-trimethylsilylethoxymethylindol-
2-yl)-1H-pyrrolo[sic]-2,5-dione
1.05 g (1.96 mmo.l) of 2-tributylstannyl-N-trimethyl-
silylethoxymethylindole in 5 ml of absol. DMF are added
dropwise to a solution of 22.65 mg (0.02 mmol) of
tetrakistriphenylphosphine palladium and 450.0 mg
(1.77 mmol) of 3,4-dibromo-2,5-dihydro-1H-pyrrolo[sic]-
2,5-dione in 10 ml of absol. DMF and the mixture is
subsequently heated at 110°C for 1 h. After cooling, it
is poured onto 50 ml of Hz0 and extracted with 2 x 50 ml
of ether. The ether phases are washed with 100 ml of
H20, dried over Na2S09 and concentrated. The products
can be separated by column chromatography (1. column:
Si02; CHzCl2/MeOH/hexane 20:1:2, 2. column: SiO2;
CHzCl2/ethyl acetate 20:1) .
Yellow wax, yield 200 mg (19~).
The following were prepared analogously:
Example 99
2,5-Dihydro-3,4-bisindol-2-yl-1H-pyrrolo[sic]-2,5-dione
M.p.: 197°C (dec.) (CHZC12/hexane)
Example 100
2,5-Dihydro-3,4-(N-phenylsulphonylindol-2-yl)-IH-
pyrrolo[sic]-2,5-dione
M.p.: 196 - 197°C (dec.) (acetone)
Example 101
2,5-Dihydro-1-methyl-3,4-bis(N-phenylsulphonylindol-2-
yl)-1H-pyrrolo[sic)-2,.5-dione
M.p.: 147°C (ether)
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Example 102
2,5-Dihydro-3,4-b:isindol-2-yl-1-methyl-1H-pyrrolo[sic]-
2,5-dione
M.p.. 247°C (CH2C12/hexane) (dec.)
Example 103
2,5-Dihydro-3-indol-2-yl-1-[2-(N,N-dimethylamino)-
ethyl]-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-
2,5-dione
2,5-Dihydro-1-[2-(N,N-dimethylamino)ethyl]-3,4-bis(N-
phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione
4.12 mmol of 2,5-dihydro-3,4-bis(N-phenylsulphonyl-
indol-2-yl)-1H-pyrrolo[sic]-2,5-dione are dissolved in
30 ml of absol. DMF, and 200 mg (5.00 mmol) of KH are
cautiously added with stirring. After stirring for 1 h
at room temp., the halide is added and the mixture is
~;tirred at toom temp. for 24 h. For work-up, the
mixture is poured onto ice water. DMF and HZO are
distilled off in vacuo, the residue is dissolved in
CH2C12 and the solution is washed with H20. After drying
over Na2S09, the solvent is stripped off in vacuo and
the residue is purified by column chromatography (Si02;
ethyl acetate). Yield 448 mg. 121 and 122 could be
separated by column chromatography.
The following were obtained analogously:
Example 104
2,5-Dihydro-3,4-bis(indol-2-yl)-1[2-(N,N-dimethyl-
amino)ethyl]-1H-pyrrolo[sic]-2,5-dione
orange wax
Example 105
1--(2-Bromoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonyl-
indol-2-yl)-1H-pyrrolo[sic]-2,5-dione
yellow-brown wax
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Example 106
1-(2-Bromoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenyl-
sulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione
M.p.: 160°C (dec.)
Example 107
1-(2-Bromoethyl)-2,5-dihydro-3,4~-bis(indol-2-yl)-1H-
pyrrolo[sicl-2,5-dione
M.p.: 104 - 109°C
Example 108
1-(2-Azidoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonyl-
indol-2-yl)-1H-pyrrolo[sicl-2,5-dione
M.p.: 165°C (dec.)
Example 109
1-(2-Azidoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenyl-
sulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione
M.p.: 190°C (dec.)
Example 110
1-(2-Aminoethyl)-2,5-dihydro-3-indol-2-yl-4-
(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione
M.p.: 180°C (dec.)
Example 111
3-Bromo-4-(2-(3-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)propyl)-1H-3-
indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
200 mg (0.7 mmol) of 1,3-di(1H-2-indolyl)propane are
dissolved in 4 ml of absol. THF and cooled to 0°C.
1.09 ml (1.7 mmol) of n-BuLi (1.6 M in hexane) are then
added dropwise in the course of 30 min and the mixture
is stirred at room temp. for 2 h. 0.46 g (1.71 mmol) of
N--methyldibromomaleimide in 4 ml of absol. THF is then
slowly added dropwise. The mixture is stirred overnight
at: room temp. -and then poured onto 10 ml of 2 N HC1_
The mixture is then extracted with ether (2 x 10 ml)
and ethyl acetate (3 x 10 ml), the org. phase is dried
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over Na2S04 and the solvent is stripped off in vacuo.
The residue is purified by column chromatography (Si02,
CAZClz). Red powder, yield: 0.20 g (44$).
M.p.: 160°C (dec.)
The following were prepared analogously:
Example 112
3-Bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 137°C (dec.)
Example 113
3-Bromo-4-(2-(3-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-
3-pyrrolyl)-1H-2-i.ndolyl)propyl)-1H-3-indolyl)-2,5-
dihydro-1H-pyrrolea-2,5-dione
2d.p.: > 350°C
Example 114
3-Bromo-4-(2-(5-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-
3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-
dihydro-1H-pyrrole-2,5-dione
ri.p. : > 350°C (dec. )
Example 115
3-Bromo-4-(2-(8-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-
3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-indolyl)-2,5-
d.ihydro-1H-pyrrole-2,5-dione
M.p.: 180°C (dec.)
Example 116
3-Bromo-4-(2-(2-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)ethyl)-1H-3-
indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 179°C
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Example 117
3-Bromo-4-(2-(4-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1H-3-
indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 190°C (dec.)
Example 118
3-Bromo-4-(2-(8-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-
indolyl)-1-methyl--2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 185°C (dec.)
Example 119
3-Bromo-4-(2-(10-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)decyl)-
1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 164°C (dec.)
Example 120
3-Bromo-4-(2-(10-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-
3-pyrrolyl)-1H-2-indolyl)decyl)-1H-3-indolyl)-2,5-
dihydro-1H-pyrrole-2,5-dione
M.p.: 164°C (dec.)
Example 121
3-Bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)doceyl)-1H-
3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 126 - 129°C
The following was obtained by reaction of the compound
of Example 114 with dimethylamine:
Example 122
3-N,N-dimethylamino-4-(2-(5-(3-(4-N,N-dimethylamino-
2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)-
pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
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Example 123
1-Methyl-3-(1-pyrrolidinyl)-4-(2-(5-(3-(1-methyl-4-
(1-pyrrolidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-
1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-
pyrrole-2,5-dione
1.0 g (1.5 mmo1) of 3-bromo-4-(2-(5-(3-(4-bromo-
1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-
indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-
pyrrole-2,5-dione is dissolved in 5 ml (60.6 mmol) of
pyrrolidine and stirred overnight at room temp. Excess
pyrrolidine is then distilled off. The residue is
completely freed from solvent residues in an oil-pump
vacuum and then purified by column chromatography
(Si02, CHZCIz/ethyl acetate 95:5). Yield: 480 mg (49~).
M.p.: 289°C
The following were prepared analogously:
Example 124
1-Methyl-3-(1-piperidinyl)-4-(2-(5-(3-(1-methyl-4-(1-
piperidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-
2-indolyl)pentyl)--1H-3-indolyl)-2,5-dihydro-1H-pyrrole-
2,5-dione
M.p.. 262°C
Example 125
7.-Methyl-3-(1-morpholinyl)-4-(2-(5-(3-(1-methyl-4-
(1-morpholinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-
1.H-2-indolyl)pentyl)-1X-3-indolyl)-2,5-dihydro-1H-
pyrrole-2,5-dione
M.p.: 168 - 170°C
Example 126
1-Methyl-3-(1-tetrahydroisoquinolinyl)-4-(2-(5-(3-(1-
methyl-4-(1-tetrahydroisoquinolinyl)-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 141 - 142°C
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Example 127
1-Methyl-3-(1-(4-(3-trifluoromethylphenyl)piperazinyl)-
4-(2-(5-(3-(1-methyl-4-(1-(4-(3-trifluoromethyl-
phenyl)piperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-
pyrrolyl-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-
dihydro-1H-pyrrole-2,5-dione
M.p.: 140 - 141°C
Example 128
1-Methyl-3-(1-(4-isopropylaminocarbonylmethyl-
piperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-
isopropylaminocarbonylmethylpiperazinyl))-2,5-dioxo-
2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.. 126 - 128°C
Example 129
1-Methyl-3-(1-(4-isopropylaminocarbonylmethyl-
piperazinyl)-4-(2--(5-(3-(4-bromo-1-methyl-2,5-dioxo-
2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 156°C
Example 130
l.-Methyl-3-(1-(4-pyrrolidinylcarbonylmethyl-
piperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-
pyrrolidinylcarbonylmethylpiperazinyl))-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 158°C (dec.)
Example 131
1~-Methyl-3-(1-(4-pyrrolidinylcarbonylmethyl-
piperazinyl))-4-(2--(5-(3-(4-bromo-1-methyl-2,5-dioxo-
2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2;5-dione
M.p.: 158 - 159°C
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Example 132
1-Methyl-3-(1-(4--piperidinopiperidinyl))-4-(2-(5-(3-(1-
methyl-4-(1-(4-piperidinopiperidinyl))-2,5-dioxo-2,5-
dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-
indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p. . 230 - 232°C: (dec. )
Example 133
1-Methyl-3-(1-(4-piperidinopiperidinyl))-4-(2-(5-(3-(4-
bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-
2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-
2,5-dione
M.p.: 162 - 164°C
Example 134
1-Methyl-3-(1-(4-ethoxycarbonylpiperazin-1-yl))-4-(2-
(5-(3-(1-methyl-(4-ethoxycarbonylpiperazin-1-yl)-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-
1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione
M.p.: 149 - 150°C
Example 135
1-Methyl-3-(1-(4-(N-(4-hydroxyphenyl)ethylamine))-4-(2-
(5-(3-(1-methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-
pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-
dihydro-1H-pyrrole-2,5-dione
M.p.: 120 - 122°C (dec.)
Example 136
1-Methyl-3-(1-(4-(N-1,2-diaminoethyl)-4-(2-(4-(3-(1-
methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-
1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-
pyrrole-2,5-dione
M.p.: 180°C (dec.)
Example 137
1-Methyl-3-(1-(4-(N-1,.2-diaminoethyl)-4-(2-(4-(3-(1-
methyl-(4-(N-1,2-diaminoethyl)-2,5-dioxo-2,5-dihydro-
CA 02496859 1999-04-22
' WO 99/57117 - 35 - PCT/DE99/01214
1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1X-3-indolyl)-2,5-
dihydro-1H-pyrrole-2,5-dione
M.p.: > 240°C (dec.)
Example 138
4,39-Dimethyl-1,4,14,29,39,42-hexaazaoctacyclo-
[40.2.2.0(2,6).0(7,15).0(8,13)_0(28,36).0(30,
35).0(37,41)]hexatetraconta-2(6),7(15),8(13),9,
11,28(36),30(35),31,33,37(41)-decaene-3,5,38,40-
tetraone
0.75 mmol of 3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-
1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione
is dissolved in 200 ml of absol. DMF, treated with
0.5 ml of abs. NEt3 and heated to 80°C. The solution of
0.75 mmol of piperazine in 100 ml of absol. DMF and
0.5 ml of NEt3 is then slowly added dropwise to the
warm solution and the mixture is then stirred at 80°C
for 48 h. The solvent is then removed in vacuo to the
greatest possible extent and the residue is treated
with 100 ml of 1N HCl. This solution is then extracted
with ethyl acetate (in total about 600 ml), the
combined extracts are dried over Na2S0q and the solvent
is stripped off i:n vacuo. Purification is carried out
by column chromatography (SiOz, CHZC12/EA9.5:0.5).
Grange crystals, yield: 0.267 g (52~).
M.p.: 194 - 195°C
The following were prepared analogously:
Example 139
8,43-Dimethyl-5,8,:18,33,43,46-hexaazanonacyclo-
[44.2.2.2(2,5)_0(6,10).0(11,19).0(12,17).0(32,
40).0(34,39).0(41,45)]dopentaconta-6(10),11(19),-
12(17),13,15,32(40),34(391,35,37,41(45)-decaene-
7,9,42,44-tetraone
M.p.: > 250°C _
CA 02496859 1999-04-22
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Example 140
9,44-Dimethyl-6,9,19,34,44,47-hexaazanonacyclo-
[45.2.2.2(3,6).0(7,11).0(12,20).0(15,18).0(33,
412).0(35,40)_0(42,46)]tripentaconta-?(11),12(20),-
13(18),14,16,33(41),35(40),36,38,44(46)-decaene-
8,10,43,45-tetraone
M.p.: 286°C (dec.)
Example 141
10,45-Dimethyl-7,10,20,35,45,48-hexaazanonacyclo-
[46.2.2.2(4,7).0(8,12).0(13,21).0(14,19).0(34,
42).0(36,41).0(43,47)]tetrapentaconta-8(12),13(21),-
14(19),15,17,34(42),36(41),37,39,43(47)-decaene-
9,11,44,46-tetraone
M.p.. > 250°C
Example 142
11,46-Dimethyl-8,11,21,36,46,49-hexaazanonacyclo-
[47.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(35,
43)_0(37,42).0(44,48)]pentapentaconta-9(13),14(22),
15(20),16,18,35(43),37(42),38,40,44(48)-decaene-
10,12,45,47-tetraone
M.p.: 276°C (dec.)
Example 143
13,48-Dimethyl-10,13,23,38,48,51-hexaazanonacyclo-
[49.2.2.2(7,10).0(11,15).0(16,24).0(17,22).0(37,45).-
0(39,44).0(46,50)]heptapentaconta-11(15),16(24),-
1'7(22),18,20,37(45),39(44),40,42,46(50)-decaene-
12,14,47,49-tetraone
M.p.: 245°C (dec.)
Example 144
19,49-Dimethyl-11,14,24,39,49,52-hexaazanonacyclo-
[50.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(38,46).-
0(40,45).0(47,51)]octapentaconta-12(16),17(25),18(23),-
19,21,38(46),40_(45),41.,43,47(51)-decaene-13,15,48,50-
tetraone
M.p.: 325°C (dec.)
CA 02496859 1999-04-22
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Example 145
4,30-Dimethyl-1,4,14,20,30,33-hexaazaoctacyclo-
[31.2.2.0(2,6).0(7,15).0(8,13).0(19,27).0(21,26).-
0(28,32)]heptatriaconta-2(6),7(15),8(13),9,11,-
19(27),21(26),22,24,28(32)-decaene-3,5,29,31-tetraone
M.p.. 314 - 318°C
Example 146
8,34-Dimethyl-5,8,18,24,34,37-hexaazanonacyclo-
[35.2.2.2(2,5).0(6,10).0(11,19).0(12,17).0(23,31).-
0(25,30).0(32,36)]tritetraconta-6(10),11(19),12(17),-
13,15,23(31),25(30),26,28,32(36)-decaene-7,9,33,35-
tetraone
M.p.. 197 - 200°C
Example 147
9,35-Dimethyl-6,9,19,25,35,38-hexaazanonacyclo-
[36.2.2_2(3,6).0(7,11).0(12,20).0(13,18).0(24,32).-
0(26,31).0(33,37)ltetratetraconta-7(11),12(20),13(18),-
14,16,24(32),26(31),27,29,33(37)-decaene-8,10,34,36-
tetraone
M.p.: 337°C (dec.)
Example 148
10,36-Dimethyl-7,10,20,26,36,39-hexaazanonacyclo-
[37.2.2.2(4,7).0(8,12).0(13,21).0(14,19).0(25,33).-
0(27,32).0(34,38)]pentatetraconta-8(12),13(21),14(19),-
7.5,17,25(33),27(32),28,30,34(38)-decaene-9,11,35,37-
tetraone
M.p.: 245°C (dec.)
Example 149
11,37-Dimethyl-8,11,21,27,37,40-hexaazanonacyclo-
[38.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(26,34).-
0(28,33).0(35,39)]hexatetraconta-9(13),14(22),15(20),-
16,18,26(34),28(33),29,31,35(39)-decaene-10,12,36,38-
tetraone _
M.p.: 325°C (dec.)
CA 02496859 1999-04-22
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Example 150
13.39-Dimethyl-10,13,23,29,39,42-hexaazanonacyclo-
[40.2.2.2(7,10).0(11,15).0(16,24).0(17,22).0(28,36).-
0(30,35).0(37,41))octatetraconta-11(15),16(24),17(22),-
18,20,28(36),30(35),31,33,37(41)-decaene-12,14,38,40-
tetraone
M.p.: 245°C (dec.)
Example 151
14,40-Dimethyl-11,14,24,30,40,43-hexaazanonacyclo-
[41.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(29,37)_-
0(31,36).0(38,42)]nonatetraconta-12(16),17(25),18(23),-
19,21,29(37),31(36),32,34,38(42)-decaene-13,15,39,41-
tetraone
M.p.: 325°C (dec.)
Example 152
1,4,14,22,32,35-Hexaazaoctacyclo-
[33.2.2.0(2,6).0(7,15).0(8,13).0(21,29).0(23,28).-
0(30,34))nonatriaconta-2(6),7(15),8(13),9,11,21(29),-
23(28),24,26,30(34)-decaene-3,5,31,33-tetraone
M.p.. 314 - 318°C
Example 153
5,8,18,26,36,39-Hexaazanonacyclo-
[37.2.2.2(2,5).0(6,10).0(11,19).0(12,17).0(25,33).-
0(27,32).0(34,38))pentatetraconta-6(10),11(19),12(17),-
13,15,25(33),27(32),28,30,34(38)-decaene-7,9,35,37-
tetraone
M.p.: 197 - 200°C
Example 154
9,37-Dimethyl-6,9,19,27,37,40-hexaazanonacyclo-
[38.2.2_2(3,6).0(7,11).0(12,20).0(13,18).0(26,34).-
0(28,33).0(35,39)lhexatetraconta-7(11),12(20),13(18),-
14,16,26(34),28(33),29,31,35(39)-decaene-8,10,36,38-
tetraone
M.p.. > 350°C
CA 02496859 1999-04-22
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Example 155
7,10,20,28,38,41-Hexaazanonacyclo[39.2.2.2(4,7).
0(8,12).0(13,21).G(14,19).0(27,35).0(29,34).0(36,40)]-
heptatetraconta-8(12),13(21),14(19),15,17,27(35),-
'1.9(34),30,32, 36(40)-decaene-9,11,37,39-tetraone
M.p.. 290 - 292°C
Example 156
:L1,39-Dimethyl-9,11,21,29,39,42-hexaazanonacyclo-
[40.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(28,36).-
0(30,35).0(37,41)]octatetraconta-9(13),14(22),15(20),-
:16,18,28(36),30(35),31,33,37(41)-decaene-10,12,38,40-
tetraone
M.p.. 310°C (dec.)
Example 157
:13,41-Dimethyl-10,13,23,31,41,44-hexaazanonacyclo-
[42.2.2.2(7,10).0(11,15).0(16,24).0(17,22).0(30,38).-
0(32,37).0(39,43)]pentaconta-11(15),16(24),17(22),18,-
20,30(38),32(37),33,35,39(43)-decaene-12,14,40,42-
tetraone
M.p.: 310°C (dec.)
Example 158
:14,42-Dimethyl-11,14,24,32,42,45-hexaazanonacyclo-
[43.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(31,39).-
0(33,38).0(40,44)]unpentaconta-12(16),17(25),18(23),-
:19,21,31(39),33(38),34,36,40(44)-decaene-13,15,41,43-
tetraone
M.p.: 321 - 324°C
Example 159
6,13-Dimethyl-5,6,7,8,9,10,11,12,13,14,19,20,21,22,23,-
:?4-hexadecahydrodipyrrolo[3',9':15,16:3',4':5,6]indolo-
[2',3':13,14](1,4]diazacyclohexadecyno[8,7:b]indol-5,-
'7,12,14-tetraone
M.p.: > 240°C
CA 02496859 1999-04-22
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Example 160
1,4,14,29,39,42-Hexaazaoctacyclo[40.2.2.0(2,6).-
G(7,15).0(8,13).0(28,36).0(30,35).0(37,41)]hexatetra-
conta-2(6),7(15),8(13),9,11,28(36),30(35),31,33,37(41)-
decaene-3,5,38,40-tetraone
M.p.: 194 - 195°C
Example 161
'_~,8,18,33,43,46-Hexaazanonacyclo[44.2.2.2(2,5).-
0(6,10).0(11,19).0(12,17).0(32,40).0(34,39).-
0(41,45)]dopentaconta-6(10),11(19),12(17),13,15,-
32(40),34(39),35,37,41 (45)-decaene-7,9,42,44-tetraone
M.p.. 236 - 238°C
Example 162
6,9,19,34,44,47-Hexaazanonacyclo[45.2.2.2(3,6).0(7,11)-
.0(12,20).0(15,18).0(33,412)[sic].0(35,40).0(42,46)]-
t:ripentaconta-(11),12(20),13(18),14,16,33(41),-
35(40),36,38,42 (46)-decaene-8,10,43,45-tetraone
M.p.: 231 - 233°C
Example 163
7,10,20,35,45,48-Hexaazanonacyclo[46.2.2.2(4,7).-
0(8,12).0(13,21).0(14,19).0(34,42).0(36,41).0(43,47)]-
tetrapentaconta-8(12),13(21),14(19),15,17,34(42),-
36(41), 37,39,43(47)-decaene-9,11,44,46-tetraone
M.p.: 209 - 211°C
Example 164
8.11,21,36,46,49-Hexaazanonacyclo[47.2.2.2(5,8).-
0(9,13).0(14,22).0(15,20).0(35,43).0(37,42).0(44,48)]-
pentapentaconta-9(13),14(22),15(20),16,18,35(43),-
37(42),38, 40,44(48)-decaene-10,12,45,47-tetraone
M.p.: 282 - 284°C
Example 165
10,13,23,38,48,51--Hexaazanonacyclo(49.2.2.2(7,I0).-
O(11,15).0(16,24).0(17,22).0(37,45).0(39,44).0(46,50)]-
CA 02496859 1999-04-22
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heptapentaconta-11(15),16(24),17(22),18,20,37(45),39
(44),40,42,46(50)--decaene-12,14,47,49-tetraone
M.p.: 176 - 179°C
Example 166
:L1,14,24,39,49,52--Hexaazanonacyclo[50.2.2.2(8,11).-
0(12,16).0(17,25)..0(18,23).0(38,46).0(40,45).0(47,51)]-
octapentaconta-12(16),17(25),18(23),19,21,38(46),-
40(45), 41,43,47(51)-decaene-13,15,48,50-tetraone
M.p.: 147 - 150°C
Example 167
:L,4,14,20,30,33-Hexaazaoctacyclo[31.2.2.2(2,6).-
I)(7,15).0(8,13).0(19,27).0(21,26).0(28,32))-
heptatriaconta-2(Ei),7(15),8(13),9,11,19(27),-
:Z1(26),22,24,28(32)-decaene-3,5,29,31-tetraone
M.p.: 350°C (dec.)
Example 168
5,8,18,24,34,37-Hexaazanonacyclo[35.2.2.2(2,5).-
I)(6,10).0(11,19).0(12,17).0(23,31).0(25,30).0(32,36)]-
tritetraconta-6(10),11(19),12(17),13,15,23(31),-
25(30),26,28,32(3Ei)-decaene-7,9,33,35-tetraone
2d. p.: 285°C (dec.)
Example 169
Ei,9,19,25,35,38-Hexaazanonacyclo[36.2.2.2(3,6).-
0(7,11).0(12,20).CI(13,18).0(24,32).0(26,31).0(33,37)]-
tetratetraconta-7f11),12(20),13(18),14,16,24(32),-
26(31),27,29,33 (37)-decaene-8,10,34,36-tetraone
M.p.. 215°C
Example 170
7,10,20,26,36,39-Hexaazanonacyclo(37.2.2.2(4,7).-
0(8,12).0(13,21).0(14,19).0(25,33).0(27,32).0(34,38))-
pentatetraconta-8(12),13(21),14(19),15,17,25(33),
27(32),28, 30,34(38)-decaene-9,11,35,37-tetraone
iri.p. : 330°C (dec. )
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Example 171
8,11,21,27,37,40-Hexaazanonacyclo[38.2.2.2(5,8).-
0(9,13).0(14,22).0(15,20).0(26,34).0(28,33).0(35,39)]-
hexatetraconta-9(13),14(22),15(20),16,18,26(34),-
28(33),29, 31,35(39)-decaene-10,12,36,38-tetraone
M.p_: 335.5°C (dec.)
Example 172
20,13,23,29,39,42--Hexaazanonacyclo[40.2.2.2(7,10).-
0(11,15).0(16,24).0(17,22).0(28,36).0(30,35).0(37,41)]-
octatetraconta-11(15),16(24),17(22),18,20,28(36),
30(35),31,33,37(41)-decaene-12,14,38,40-tetraone
M.p.. 243 - 245°C
Example 173
11,14,24,30,40,43-Hexaazanonacyclo[41.2.2.2(8,11).-
0(12,16).0(17,25)"0(18,23).0(29,37).0(31,36).0(38,42)]-
nonatetraconta-12(16),17(25),18(23),19,21,29(37),-
31(36),32,34,38(42)-decaene-13,15,39,41-tetraone
M.p.: 258 - 260°C
Example 174
4,32-Dimethyl-1,4,14,22,32,35-hexaazaoctacyclo-
[33.2.2.2(2,6).0(7,15).0(8,13).0(21,29).0(23,28).-
0(30,34)]nonatriaconta-2(6),7(15),8(13),9,11,21(29),-
23(28),24,26,30(34)-decaene-3,5,31,33-tetraone
M.p.: > 350°C
Example 175
8,36-Dimethyl-5,8,18,26,36,39-hexaazanonacyclo-
[37.2.2.2(2,5).0(8,10).0(11,19).0(12,17).-
0(25,33).0(27,32).0(34_38)]pentatetraconta-
6(10),11(19),12(17),13,15,25(33),27(32),28,30,34(38)-
decaene-7,9,35,37-tetraone
M.p_: 310°C (dec.)
Example 176 _
10,38-Dimethyl-7,10,20,28,38,41-hexaazanonacyclo-
[39.2.2.2(4,7).0(8,12).0(13,21).0(14,19).-
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0(27,35).0(29,34).0(36.40))heptatetraconta-
8(12),13(21),14(19),15,17,27(35),29(34),30,32,36(40)-
decaene-9,11,37,39-tetraone
M.p.. 280°C (dec.)
Example 177
13,46-Dimethyl-1,7,10,13,23,36,46,49-octaazanonacyclo-
[47.2.2.2(7,10).0(11,15).0(16,24).0(17,22).-
0(35,43).0(37,42).0(44,48)]pentapentaconta-
11(15),16(24),17(22),18,20,35(43),37(42),38,40,44(48)-
<iecaene-12,14,45,47-tetraone
M.p.:> 220°C
Example 178
4,31-Dimethyl-1,4,14,21,31,34-hexaazaoctacyclo-
[32.2.2.2(2,6).0(7,15).0(8,13).0(20,28).-
0(22,27).0(29,33)]octatriaconta-2(6),7(15),8(13),9,11,-
:?0(28),22(27),23,25,29(33)-decaene-3,5,309(sic],32-
tetraone
M.p.:> 240°C (dec.)
Example 179
8,35-Dimethyl-5,8,18,25,35,38-hexaazanonacyclo-
[36.2.2.2(2,5).0((i,10).0(11,19).0(12,17).-
O(24,32).0(26,31).0(33,37)]tetratetraconta-
6(10),11(19),12(17),13,15,24(32),26(31),27,29,33(37)-
decaene-7,9,34,36--tetraone, m.p.:> 240 (dec.)
F;xample 180
(1-(2-Dimethylaminoethyl)-1H-3-indolyl)(1H-3-indolyl)-
1-methanone
0.5 g of bis(indol-3-yl)methanone is dissolved in 30 ml
of acetone. After addition of 0.92 g of KZC03 and 0.27 g
of 2-dimethylamino-1-chloroethane hydrochloride, the
mixture is heated to reflux for 70 h. The acetone is
stripped off and the residue is treated with 30 ml of
water and 30 ml of ethyl acetate. After stirring for
15 min, the org. phase is separated off and the aqueous
phase is extracted by shaking a further two times with
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15 ml of ethyl acetate each time. The combined org.
phases are dried over Na2S04 and the solvent is stripped
off_ Purification is carried out by column
chromatography (Si02, EA/MeOH 10:1). Yield: 0.14 g
(200)
M.p.: 180 - 182°C
The following were prepared analogously:
Example 181
I;1-(2-Morpholinoet.hyl)-1H-3-indolyl)(1H-3-indolyl)-
1-methanone
rz.p.. 192 - 194°C
Example 182
E3is(1-(2-morpholinoethyl)-1H-3-indolyl)-1-methanone
rz.p.: 91 - 93°C
Example 183
(1-(2-Piperidinoethyl)-1H-3-indolyl)(1H-3-indolyl)-
1-methanone
M.p.: 223 - 225°C
Example 184
Bis(1-(2-piperidinoethyl)-1H-3-indolyl)-1-methanone
M.p.: 152 - 155°C
Example 185
(1-(3-Dimethylaminopropyl)-1H-3-indolyl)(1H-3-indolyl)-
1-methanone
M.p.: 144 - 146°C
Example 186
(1-(3-Pyrrolidinopropyl)-1H-3-indolyl)(1H-3-indolyl)-
1-methanone
M.p.: 148 - 152°C
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Example 187
(1-(2-Dimethylaminoethyl)-1H-2-indolyl)(1H-2-indolyl)-
7_-methanone
M.p.: 147 - 150°C
Example 188
(1-(2-Morpholinoet.hyl)-1N-2-indolyl)(1H-2-indolyl)-
1-methanone
V~ax
Example 189
(1-(2-Piperidinoethyl)-1H-2-indolyl)(1H-2-indolyl)-
1-methanone
V~la x
Example 190
(1-(2-Pyrrolidinoe~thyl)-1H-2-indolyl)(1H-2-indolyl)-
1-methanone
VVax
Example 191
11,46-Dimethyl-21,36-bis(2-(1-piperidinyl)ethyl-
8,11,21,36,46,49-hexaazanonacyclo-[47.2.2.2(5,8).-
0(9,13).0(14,22).0(15,20).0(35,43).0(37,42).-
0(44,48)]pentapent.aconta-9(13),14(22),15(20),-
7_6,18,35,(43),37(42),38,40,44(48)-decaene-10,12,45,47-
tetraone
M.p.: 125 - 130°C
Example 192
3,3'-Dimethoxydiglyoxyl-1,8-(2,2'-bisindolyl)octane
Oxalyl dichloride is added dropwise under an NZ
atmosphere to a solution of 1.15 g (4.00 mmol) of 1, 8-
(2,2'-bisindolyl)octane in 20 ml of absol. THE at 0°C
and the mixture is stirred at room temperature for 2 h.
20 ml of MeOH are then allowed to run in dropwise. The
mixture is stirred overnight at room temperature. For
work-up, the mixture is treated with 100 ml of 1 N HC1,
neutralized with 2 N NaOH and the mixture is extracted
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with EA (3 x 25 ml). After drying over NaS04 [sic], the
solvent is stripped off.
M.p.. > 250°C (dec.)
Example 193
3-(2-(4-(1H-2-Indolyl)butyl)-1H-3-indolyl)-1-methyl-
2,5-pyrrolidinedione
A solution of 240 mg (0.50 mmol) of 3-bromo-4-(2-(4-
(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-
dihydro-1H-pyrrole-2,5-dione and 140 mg (0.25 mmol) of
Pd(OH)2/C (20~) in 30 ml of MeOH is stirred under an HZ
atmosphere at room temperature for 24 h. For work-up,
the mixture is faltered, the filtrate is concentrated
~snd the residue is purified by column chromatography
(SiO2:CHzCl2/EA 95:5). On concentrating the pure
fraction, the product is crystallized by addition of
PE. Yield: 48.0 mg (24$), beige powder
M.p.: 180 - 182°C
Example 194
'test for measurement of the inhibition of PDGF-
dependent tyrosine phosphorylation for compounds
according to the invention
Swiss 3T3 cells are cultured for 1 week under standard
conditions (DMEM with glutamine, 4 g of glucose/l, 10~
FCS Antibiotika, 5-7.5~ COZ) and are confluent and no
:longer proliferating at the end of the culture period.
The medium is replaced by serum-free DMEM and the cells
are incubated at: 37°C for 2 h with the compounds
according to the invention or, in control experiments,
with DMSO (final concentration 0.1-1~). The cells are
then stimulated at room temperature for 5 min by
addition of PDGF-BB to a final concentration of
100 ng/ml, in controls addition of the corresponding
~:olvent takes place. The cells are then washed twice
with ice-cold. PBS and lysed in a Triton X-100-
containing lysis buffer (composition and process as
described in Selective platelet-derived growth factor
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receptor kinase Mockers reverse sis-transformation
M. Kovalenko, A. Gazit, A. Bohmer, C. Rorsman,
L. Ronnstrand, C.H. Heldin, J. Waltenberger,
F.D. Bohmer, A. hevitzki (1994) Cancer Res. 54, 6106-
6114). The lysates are centrifuged and the protein
concentration is determined. 10 ~g of lysate protein
are applied directly to nitrocellulose membranes (Dot-
blot apparatus or corresponding multi-well plates with
nitrocellulose bares).
'tyrosine phosphorylation is detected by standard
processes using antiphosphotyrosine antibodies.
'typically, a monoclonal antiphosphotyrosine antibody,
conjugated to horseradish peroxidase (POD), and
detection of the POD activity by means of
chemiluminescence detection is used. Quantification is
carried out either by grey value analyses of films used
Eor the luminescence detection or directly using a
:luminometer. Customarily, the PDGF stimulation of the
cells results in a 3- to 10-fold increase in the
aignal.
The compounds were primarily employed in duplicate in
the final concentration 10 ~tg/ml. In the case of active
compounds, a titration was carried out in the stages
:30 E,~M, 10 ECM, 3 EtM, 1 ~M, 0.3 ~M and 0.1 N.M as a
duplicate determination. The results are shown in
Table 1.
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Table 1
Exampl Compound IC 5 0 (
a ).tM )
19 Bisindol-2-ylmethan-1-one 1
20 (5-Methoxyindol-2-yl)-(indol-2- 0.1-0.3
yl)methan-1-one
21 Bis(5-methoxyindol-2-yl)-1- 10-30
methanone~
28 Benzo[b]t.hiophen-2-yl(5-methoxy-1
1H-2-indolyl)-1-methanone
43 5-Hydroxy-1H-2-indolyl(1H-2- 0.1-0.3
indolyl)methanone
45 1H-2-Indolyl[5-(2-morpholin-1- 1-3
ylethyloxy)-1H-2-indolyl]methanone
48 1H-2-Indolyl[5-(2-dimethylamino- 0.3-1
ethyloxy)-1H-2-indolyl]methanone
53 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.1-0.3
indolyl)] ethanoate
55 [2-(1H-2-Indolylcarbonyl)-1H-5- 1-3
indolyl)) butanoate
56 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.1
indolyl))2-(N,N)-
dimethylaminoethanoate
57 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1
indolyl)] propanoate
58 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1
indolyl)) 2-thiophenylethanoate
The qualitative detection of the effects on the
tyrosine phosphorylation of the PDGF receptor and
cellular substrates is carried out by analysis of the
cell - lysates by means of polyacrylamide gel
electrophoresis and immunoblotting using anti
phosphotyrosine antibodies according to standard
processes.
The compounds according to the invention were
furthermore investigated in vitro using isolated plasma
membranes of Swiss 3T3 cells and using PDGF receptor
purified from overexpressing cells, tested in intact
A431 cells (and in some cases also in Swiss 3T3 plasma
membranes) for po:>sible inhibition of the EGF receptor
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tyrosine kinase and tested for inhibition of
recombinant Src kinase. The results are chosen in
Table 2.
DNA synthesis tests in Swiss 3T3 cells which are
stimulated with different growth factors are suitable
for characterizing selective antiproliferative actions
of receptor tyro~;ine kinase inhibitors. The compounds
were investigated with respect to their action on the
DNA sythesis stimulated in these cells by PDGF-BB,
bFGF, FCS and the combination of EGF and insulin. These
:stimulants are approximately equipotent and increase
the DNA synthesis in previously growth-arrested Swiss
3T3 cells to 5- to 20-fold. The dose dependencies of
the corresponding experiments and the IC50 values
obtained are likewise shown in Table 2.
Furthermore, the compounds were investigated for a
possible antitransforming action using sis-transformed
IJIH3T3 cells. In these cells, a transformed phenotype
characterized, inter alia, by irregular multilayered
growth and colony formation in soft agar is maintained
by expression of PDGF-BB and permanent activation of
i=he endogenous PDGF receptors. The IC50 values obtained
are likewise shown in Table 2.
Accordingly, actions on the PDGF receptor kinase by the
compounds were found in the following tests:
-- PDGF receptor autophosphorylation in intact Swiss 3T3
cells
-- PDGF receptor autophosphorylation in isolated
membranes of Swiss 3T3 fibroblasts and
-- PDGF receptor autophosphorylation in purified
receptor preparations.
No actions were observed in analogous tests with the
receptor tyrosine kinase for the epidermal growth
factor and with the cytosolic tyrosine kinase Src up to
a concentration of 30 ~M. The compounds thus have
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specificity for the inhibition of the PDGF receptor
tyrosine kinase in relation to other tyrosine kinases.
Table 2
Test IC 50 ((.tM)
Example Example Example
19 20 21
PDGFR phosphorylation 1 0.1-0.3 10-30
in
vivo
(Swiss 3T3
cells)
PDGFR phosphorylation 0.3-1 < 0.03 n.d.
in
~ritro
(Swiss 3T3
membranes)
PDGFR phosphorylation 0.1-0.3 n.d, n.d.
in
~ritro
(purified
PDGF receptor)
EGFR phosphorylation
in
vivo > 10 > 10 n.d.
(A 431 cells)
src kinase
phosphorylation
in vivo > 30 > 30 n.d.
(src NIH
cells)
Reversion
of the
transformed +++ . n.d. n.d.
morphology
of
sis-3T3 cells
DNA synthesisPDGF-
(Swiss 3T3 stimulated 3-10 n.d n..d
cells) - FGF-
stimulated 3-10 n.d. n.d.
EGF/insulin-
stimulated > 30 n.d. n.d.
10$ F'CS > 30 n.d. n.d.
Colony formation
(sis-3T3 3-10 I n.d I n.d
cells) I
