Note: Descriptions are shown in the official language in which they were submitted.
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
~rrolopyrimidines and processes for their preparation
The invention relates to 7H-pyrrolo[2,3-djpyrimidine derivatives and to
processes and novel
intermediates for their preparation, to pharmaceutical formulations comprising
such deriva-
tives, and to the use of those derivatives as medicaments, and to their use in
the
preparation of medicaments.
The compounds according to the invention are compounds of formula I
Q
R~
Rz 5
~N 3
HN ~ J (I)
N
wherein
R, and RZ are each independently of the other
lower alkyl; monohalo-, dihalo- or trihalo-lower alkyl; lower alkoxy; phenyl
that is unsub-
stituted or substituted by halogen, monohalo-, dihalo- or trihalo-lower alkyl,
carbamoyl-
methoxy, carboxy-methoxy, benzyioxycarbonyl-methoxy, lower alkoxycarbonyl-
methoxy,
phenyl, amino, amino-lower alkyl, lower alkanoyiamino, lower
alkoxycarbonylamino, phenyl-
lower alkoxycarbonylamino, furoyl, thienylcarbonyl, N-lower aikylamino, N,N-di-
lower alkyl-
amino, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower
alkoxycarbonyl, carbamoyl,
N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyi, cyano, amidino, N-
{N',N'-di-lower
alkylaminomethylidene)-amino, N-((N',N'-di-lower alkyiamino)-(lower alkyl)-
methylidene)-
arnino, guanidino, ureido, N3-lower alkylureido, N3,N3-di-lower alkylureido,
thioureido, N3-
lower alkylthioureido, N3,N3-di-lower alkylthioureido, lower
alkanesulfonyiamino, benzene- or
naphthalene-suifonylarnino that is unsubstituted or lower alkyl-substituted at
the benzene or
naphthalene ring, azido or by nitro; hydrogen; unsubstituted or halo- or lower
alkyl-
substituted pyridyl; N-benzyl-pyridonium; naphthyl; cyano; carboxy; lower
alkoxycarbonyl;
carbamoyl; N-lower alkyl-carbamoyl; N,N-di-lower alkyl-carbamoyl; N-benzyl-
carbamoyl;
formyl; lower alkanoyl; lower alkenyl; lower alkenyloxy; or lower alkyl
substituted by halogen,
amino, lower alkylamino, piperazino, di-lower alkylamino, phenylamino or
phenyl (each
CA 02242354 1998-07-06
WO 97/27199 PCTIEP97100127
-2-
unsubstituted or substituted in the phenyl moiety by halogen, tower alkyl,
hydroxy, lower
alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower
alkyl-
carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amidino, amino, amino-lower
alkyl, lower
alkanoylamino, lower alkylamino, N,N-di-lower alkylamino or by
trifluoromethyl), hydroxy,
lower alkoxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-
carbamoyl,
N,N-di-lower alkyl-carbamoyl, mercapto or by a radical of the formula RS-S(Oq)-
wherein RS
is lower alkyl and q is 0, 1 or 2, or
R, and RZ together form an alkylene chain having from 2 to 5 carbon atoms
which is
unsubstituted or substituted by lower alkyl,
Q is heterocyclyl bonded via a ring nitrogen atom and having the formula IA
~R~m ~ ~ \ (IA)
,, B
A
/~ ~R~n
-N
wherein
m and n are each independently of the other from 0 to 3,
R3 and R, are each independently of the other selected from lower alkyl; amino-
tower alkyl;
N-lower alkyl-amino-lower alkyl; N,N-di-lower alkylamino-lower alkyl; lower
alkenyi; lower
aikynyl; tri-lower alkyisilanyl-lower alkynyl; monohalo-, dihalo- or trihalo-
lower alkyl; halogen;
vitro; hydroxy; lower alkoxy; lower alkanoyloxy; isothiocyanato; phenyl that
is unsubstituted
or substituted by halogen, vitro, trihalo-lower alkyl, hydroxy or by lower
alkyl; thienyl; phenyl-
lower alkoxy that is unsubstituted or substituted in the phenyl ring by
halogen, vitro, trihalo-
lower alkyl, hydroxy or by lower alkyl; carboxy; lower alkoxycarbonyl;
carbamoyl; N-lower
alkylcarbamoyl; N,N-di-lower alkylcarbamoyl; cyano; amino; N-lower
al4rylamino; N,N-di-
lower alkylamino; azido; benzoylamino that is unsubstituted or substituted in
the benzene
ring by halogen, vitro, tri-halo-lower alkyl, hydroxy or by lower alkyl; lower
alkanoylamino;
monohalo-, dihalo- or trihalo-lower alkylcarbonylamino; lower
alkanesulfonylamino; trihalo-
lower alkanesulfonylamino; lower alkylthio; lower alkylsu~inyl; lower
alkanesuifonyl; pyrrol-1-
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-3-
y1; piperidin-1-yl; pyrrolidin-1-yl and lower alkanoyl, or two radicals R3
together or two
radicals R, together form lower alkylenedioxy;
the ring marked A is a heterocyclyl having from 5 to 9 ring atoms and having
at least one
saturated bond, it being possible for a further ring hetero atom selected from
O and S to be
present in addition to the bonding nitrogen atom;
the ring system marked B is a free or benzo-, thieno-, faro-, pyrrolo- or
dihydropyrrolo-fused
carbocyclic ring having from 5 to 9 carbon atoms that is fused to the ring A
and may be
unsaturated, partially saturated or fully saturated; and
the bond marked by a parallel dotted line between the ring systems marked A
and B is
either a single bond or a Bauble bond;
and salts thereof where at least one salt-forming group is present.
The term "lower" used hereinabove and hereinbelow denotes a radical having up
to and
including a maximum of 7, especially up to and including a maximum of 4,
carbon atoms,
and especially (unless indicated to the contrary) having 1 or 2 carbon atoms.
Where the compounds of formula I contain asymmetric centres, they may be in
the form of
mixtures of enantiomers, and where several asymmetric centres are present also
in the
form of diastereoisomeric mixtures; when double bonds are present, cis/trans
isomers are
possible. The compounds of formula I are preferably in the form of pure
isomers.
Carbon atoms the substituents of which are not otherwise defined are bonded to
hydrogen
atoms; where the number of substituents is variable, a carbon atom will have
as many sub-
stituents and hydrogen atoms as will result in the carbon atom in question
being neutral and
having a complete electron octet.
Lower alkyl is preferably n-butyl, n-propyl, isopropyl, ethyl or especially
methyl.
Halogen is bromine, iodine or preferably fluorine or especially chlorine.
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-4-
Monohalo-, dihalo- or trihalo-lower alkyl is especially trifluoromethyl.
Lower alkoxy is especially methoxy.
Monohalo-, dihalo- or trihalo-lower alkyl is especially monofluoro-, difiuoro-
or (especially)
trifluoro-methyl.
Lower alkoxycarbonyl-methoxy is especially methoxycarbonyl-methoxy.
Amino-lower alkyl is especially aminomethyl,
Phenyl-substituted phenyl R, or R2 is, for example, biphenylyl, especially 4-
biphenylyl.
Lower alkanoyfamino is especially acetylamino, propionyiamino, n-butyrylamino
or
isobutyrylamino.
Lower alkoxycarbonylamino is especially methoxycarbonylamino or more
especially tert-
butoxycarbonylamino.
Phenyl-lower alkoxycarbonylamino is preferably benryloxycarbonylamino.
Furoy! is especially furan-2-carbonyl.
Thienylcarbonyl is especially thienyl-2-carbonyl.
Lower alkylamino is, for example, propylamino, ethylamino or especially
methylamino.
N,N-Di-lower aikyiamino is especially dimethylamino.
Lower alkanoyloxy is especially acetoxy.
Lower alkoxycarbonyl is especially tert-butoxycarbonyl or more especially
methoxycarbonyl.
CA 02242354 1998-07-06
WO 97/27199 PCTIEP97100127
-5-
N-Lower alkyl-carbamoyl is, for example, N-methylcarbamoyl, N-(n-butyl)-
carbamoyl or N-(2-
methyl-but-1-yl)-carbamoyl.
N,N-Di-lower alkyl-carbamoyl is, for example, N,N-dimethyl-carbamoyl.
N-(N',N'-Di-lower alkylamino-methylidene)-amino is especially N-(N',N'-
dimethylamino-
methylidene)-amino.
N-({N',N'-Di-lower alkylamino)-{lower alkyl)methylidene)-amino ist especially
N-((N',N'-di-
methyiamino)-(isopropylamino)methylidene)-amino.
N3-Lower alkylureido is especially N3-methylureido (CH3-NH-(C=O)-NH-)
N~,N3-Di-lower alkylureido is especially N3, N3-dimethyiureido ([(CH3)2-N-
(C=O)-NH-)
N3-Lower alkylthioureido is especially N3-methylthioureido (CH3-NH-(C=S)-NH-).
N3,N3-Di-lower alkylthioureido is especially N3, N3-dirnethyithioureido
([(CH3)2-N-(C=S)-NH-).
Lower alkanesulfonylamino is especially N-methanesulfonylamino {CH3-(S{=O}~)-
NH-).
Benzene- or naphthalene-sulfonylamino that is unsubstituted or lower alkyl-
substituted at
the benzene or naphthalene ring is especially 4-toluenesulfonylamino or
benzenesuffonyl-
amino.
Substituted phenyl R, or R2 may carry one or more substituents, but preferably
nat more
than 3 substituents, which may be identical or different from one another.
Preferably,
substituted phenyl R, or R2 carries only one substituent in the ortho-position
or, preferably,
in the meta- or para-position. Substituted phenyl R, or R2 is preferred to
unsubstituted
phenyl.
Unsubstituted or halo- or lower alkyl-substituted pyridyl is especially 2-
pyridyl.
CA 02242354 1998-07-06
WO 97127199 PCTlEP97100127
-6-
N-Benryl-pyridonium is especially N-benryl-pyridoniurn-2-yl.
Naphthyl is, for example, 2-naphthyl.
Lower alkanoyl is, for example, isobutyryl, butyryl, propionyl or especially
acetyl.
Amino-lower alkyl is especially 3-aminopropyl_
N-Lower alkyl-amino-lower alkyl is especially 3-(N-methylamino)-propyl.
N,N-Di-lower alkyiamtno-lower alkyl is especially 3-(N,N-dimethytamino}-
propyl.
Lower alkenyl has preferably from 2 to 7, especially from 2 to 4, carbon atoms
and is prefer-
ably vinyl, prop-1-enyl or prop-2-enyl (allyl).
Lower atkenyloxy is, for example, vtnytoxy, prop-1-enyloxy or prop-2-enyloxy
(allytoxy).
Substituted lower alkyl R, or R2 may carry one or more, but preferably not
more than 3,
substituents, which may be identical or different. Preferably, substituted
lower alkyl R, or R2
carries only one substituent.
Lower alkyl substituted by phenylamino or phenyl that is unsubstituted or
substituted in the
phenyl moiety by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower
alkoxy, carboxy,
lower alkoxycarbonyl, carbarnoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-
carbamoyl,
cyano, amidino, amino, amino-lower alkyl, lower alkanoylamino, lower
alkyiamino, N,N-di-
lower alkyiamino or by trifluoromethyl is especially methyl substituted in
that manner, and is
preferably anilino-methyl or 4-methoxyanilino-methyl, or 3- or 4-aminophenyl-
methyl.
Lower alkyl R, or R2 substituted by a radical of the formula R~-S(Oq)- wherein
RS is lower
alkyl and q is 0, 1 or 2 is especially methanesutfonyl-methyl.
An alkylene chain having from 2 to 5 carbon atoms that is formed by R, and RZ
together
and is unsubstituted or substituted by lower alkyl is preferably propylene or
butylene.
CA 02242354 1998-07-06
WO 97127199 PCTIEP97/00127
_7_
Preference is given to compounds of formula 1 wherein R, and R2 are the other
radicals
mentioned with the exception of an unsubstituted or substituted alkylene
chain.
Preferably the two radicals R, and R2 are each independently of the other
lower alkyl, or R
is unsubstituted or substituted phenyl, as defined above, while R, is hydrogen
or also lower
alkyl, especially methyl. In especially preferred compounds of formula l, R,
is methyl and R;
is methyl; or R, is hydrogen or also methyl and R2 is phenyl that is
unsubstituted or substi-
tuted especially by amino, vitro or by methoxy, especially 4-aminophenyf, 4-
nitrophenyl or ~-
methoxyphenyl.
In heterocyciyl of formula IA bonded via a ring nitrogen atom, m and n are
each
independently of the other from 0 to 3; preferably m is 0 or 1 and n is from 0
to 3; and
especially: n + m = 0 to 3, and more especially: m = 0 and n = 0 or 1.
Lower alkynyl is especially C2-C,alkynyl, preferably C2-C,,alkynyl, such as
ethynyl.
Tri-lower alkylsilanyl-lower alkynyl is especially trimethylsilanylethynyl.
Phenyl that is unsubstituted or substituted by halogen, vitro, trihalo-lower
alkyl, hydroxy or
by lower alkyl contains one or more, especially 3, but preferably one, of the
mentioned
substituents which can be selected independently of one another. Unsubstituted
phenyl is
preferred.
Thienyl is especially 2-thienyl.
Phenyl-lower alkoxy that is unsubstituted or substituted in the phenyl ring by
halogen, vitro,
trihalo-lower alkyl, hydroxy or by lower alkyl is especially benzyloxy.
Benzoylamino that is unsubstituted or substituted in the benzene ring by
halogen, vitro, tri-
halo-lower alkyl, hydroxy or by lower alkyl is especially unsubstituted
benzoylamino.
Monohalo-, dihalo- or trihalo-lower alkylcarbonylamino is especially
trifluoroacetylamino.
CA 02242354 1998-07-06
WO 97!27199 PCT/EP97100127
_g_
Trihalo-lower alkanesulfonylamino is especially trifluoromethanesulfonylamino.
Lower alkylthio is especially methylthio.
Lower alkylsulfinyl (lower alkyl-(S=O)-) is especially methyl- or ethyl-
sulfinyl.
Lower alkanesulfonyl is preferably methanesulfonyl.
Lower alkylenedioxy formed by two radicals R3 together or two radicals R,
together is
preferably bonded to two vicinal ring atoms and is especially methylenedioxy.
Lower
alkylenedioxy is especially formed by two radicals R4.
The ring marked A is a heterocyclyl having from 5 to 9 ring atoms and having
at least one
saturated bond, it being possible for a further ring hetero atom selected from
O and S to be
present in addition to the bonding nitrogen atom; preference is given to a
corresponding 5-
to 8-membered ring that does not contain a further hetero atom in addition to
the bonding
nitrogen atom, for example 2,3-dihydropyrrol-1-yl, 1,2,3,4-tetrahydropyridin-1-
yl, 2,3,4,5-
tetrahydroazepin-1-yi or 1,2,3,4,5,6-hexahydroazocin-1-yl.
The ring system marked B is a free or benzo-, thieno-, furo-, pyrrolo- or
dihydropyrroio-fused
carbocyclic ring having from 5 to 9, preferably 6, carbon atoms that is fused
to the ring A
(via two vicinal atoms completing the ring) and may be unsaturated, partially
saturated or
fully saturated, and is especially benzo, naphtho, pyrroio-fused benzo or 2,3-
dihydropyrrolo-
fused benzo.
Q is especially 2,3-dihydroindol-1-yl, 1,2,3,4-tetrahydroquinoiin-1-yl,
2,3,4,5-tetrahydro-1 H-
benzo[b]azepin-1-yl, 1,2,3,4,5,fi-hexahydrobenzo[b]azocin-1-y1, 2,3,6,7,8,9-
hexahydro-1 H-
benzo[g]indol-1-yl, 1,2,3,5-tetrahydropyrroto[2,3-f}indol-1-yl or 1,2,3,5,6,7-
hexahydro-
pyrrolo[2,3-f]indol-1-yl, each of which is unsubstituted or substituted by
from 1 to 3 radicals
R3 or R, or R3 and R, selected independently of one another from lower alkyl,
N,N-di-lower
alkylamino-lower alkyl, lower alkynyl, tri-lower alkylsilanyl-lower alkynyl,
halogen, vitro,
hydroxy, lower alkoxy, isothiocyanato, unsubstituted phenyl, unsubstituted
phenyl-lower
alkoxy, carboxy, lower alkoxycarbonyl, amino, azido, lower alkanoylamino,
trihalo-lower
afkyicarbonylamino, pyrrol-1-yl and pyrrolidin-1-yl or substituted by lower
alkylenedioxy
CA 02242354 1998-07-06
WO 97!27199 PCT/EP97100127
-g-
formed by two radicals R4 together and is bonded to two vicinal ring atoms; Q
is especially
2,3-dihydroindol-1-yl, 6-chloro-2,3-dihydroindol-1-yl, 6-bromo-2,3-
dihydroindol-1-yl, 6-
methyl-2,3-dihydroindol-1-yl or 1,2,3,4-tetrahydroquinotin-1-yl.
The bond marked by a parallel dotted line between the ring systems marked A
and B is
either a single bond or a double bond, preferably a double bond.
Salts of compounds of formula I are especially acid addition salts with
organic or inorganic
acids, especially the pharmaceutically acceptable, non-toxic salts. Suitable
inorganic salts
are, for example, carbonic acid (preferably in the form of carbonates or
bicarbonatesj;
hydrohalic acids, such as hydrochloric acid; sulfuric acid; or phosphoric
acid. Suitable
organic acids are, for example, carboxylic, phosphonic, suffonic or sulfamic
acids, for
example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic
acid, glycolic
acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic
acid, fumaric
acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,
mafic acid, tartaric
acid, citric acid, glucaric acid, galactaric acid, amino acids, such as
glutamic acid, aspartic
acid, N-methyiglycine, acetylaminoacetic acid, N-acetylasparagine or N-
acetylcysteine,
pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid,
glucose-6-
phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid,
malefic acid,
hydroxymaleic acid, methylmateic acid, cyclohexanecarboxylic acid,
adamantanecarboxylic
acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid,
3,4,5-
trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-
aminosalicylic
acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid,
glucuronic acid,
galacturonic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic
acid, ethane-
1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-
naphthalene-
disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid,
ethylsulfuric
aad, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-
propyl-
sulfamic acid, or other organic protonic acids, such as ascorbic acid.
Compounds of formula I that carry at least one free carboxy group can form
internal salts or
metal or ammonium salts, such as alkali metal or alkaline earth metal salts,
for example
sodium, potassium, magnesium or calcium salts or ammonium salts with ammonia
or
suitable organic amines, such as tertiary monoamines, for example
triethylamine or tri(2-
CA 02242354 1998-07-06
WO 97127199 PCT/EP97/00127
-10-
hydroxyethyi)amine, or heterocyciic bases, for example N-ethylpiperidine or
N,N'-dimethyl-
piperazine.
For the purposes of isolation or purification it is also possible to use
pharmaceutically
unacceptable salts, for example picrates or perchlorates. Only the salts that
are pharma-
ceutically acceptable and non-toxic (at the doses in question) are used
therapeutically and
they are therefore preferred.
As a result of the close relationship between the novel compounds (especially
of formula I)
in free form and in the form of their safis, including those salts which can
be used as inter-
mediates, for example in the purification of the novel compounds or for the
identification
thereof, hereinabove and hereinbelow any reference to the free compounds
should be
understood as including also the corresponding salts, and solvates thereof,
for example
hydrates, as appropriate and expedient.
The compounds of formula I exhibit valuable pharmacologically acceptable
properties. In
particular, they exhibit specific inhibitory actions that are of
pharmacological interest. They
act especially as inhibitors of tyrosine protein kinase and/or (further) as
inhibitors of serine/-
threonine protein kinases; they exhibit, for example, potent inhibition of the
tyrosine kinase
activity of the receptor for the epidermal growth factor (EGF) and the c-erbB2
kinase. Those
receptor-specific enzyme activities play a key role in signal transmission in
a large number
of mammalian cells, including human cells, especially epithelial cells, cells
of the immune
system and cells of the central and peripheral nervous system. For example,
the EGF-
induced activation of the receptor-associated tyrosine protein kinase (EGF-R-
PTi~ in
various cell types is a prerequisite for cell division and thus for the
proliferation of the cell
population. The administration of EGF-receptor-specific tyrosine kinase
inhibitors therefore
inhibits the reproduction of the cells. The same is true analogously of the
other protein
kinases mentioned hereinabove and hereinbelow.
The inhibition of the EGF-receptor-specific tyrosine protein kinase (EGF-R-
PTI~ can be
demonstrated using known methods, for example using the receombinant
intracellular
domain of the EGF receptor (EGF-R 1CD; see, for example, E. McGlynn et al.,
Europ. J.
Biochem. 207, 265-275 (7992)). The compounds of formula I inhibit the enzyme
activity in
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-11-
comparison with the control without inhibitor by 50 % (ICS), for example in a
concentration
of from 0.001 to 20 wM, especially from 0.01 to 5 ~,M.
The action of the compounds of formula 1 on the EGF-stimulated cellular
tyrosine
phosphorylation in the EGF receptor can be determined in the human A431
epithelium
carcinoma cell line by means of an ELISA that is described in U. Trinks et
al., J. Med.
Chem. 37(7), 1015-1027 (1994). In that test {EGFR-ELISA) the compounds of
formula I
exhibit inhibition at concentrations in the nanomolar to micromolar range.
The stimulation of dormant BALB/c3T3 cells by EGF rapidly induces the
expression of c-fos
mRNA. Pretreatment of the cells with a compound of formula I prior to the
stimulation with
EGF can inhibit the c-fos expression. That test procedure is likewise
described in U. Trinks
et a!, J. Med. Chem. 37(7), 1015-1027 (1994).
In the micromolar range also, the compounds of formula I also exhibit, for
example, inhibiton
of the cell growth of EGF-dependent cell fines, for example the epidermoid
BALB/c mouse
keratinocyte cell line (see Weissmann, B.A., and Aaronson, S.A., Cell 32, 599
(1983)) or the
A431 cell line, which are acknowledged as useful standard sources of EGF-
dependent
epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279-
282 (1985)}.
In a known test method (see Meyer e! al., Int. J. Cancer 43, 851 (1989)} the
inhibitory action
of the compounds of formula I is determined briefly as follows: BALB/MK cells
(10 0001-
microtitre plate well) are transferred to 96-well microtitre plates. The test
compounds
(dissolved in DMSO) are added in a series of concentrations (dilution series),
so that the
final concentration of DMSO is no greater than 1 96 (v/v). After the addition,
the plates are
incubated for three days, during which time the control cultures without test
compound are
able to undergo at least three cell division cycles. The growth of the MK
cells is measured
by means of methylene blue staining: after the incubation the cells are fixed
with gtutar-
aldehyde, washed with water and stained with 0.05% methylene blue. After a
washing step,
the stain is eluted with 3 °~ HCI and the optical density per well of
the microtitre plate is
measured using a Titertek multiskan at 665 nm. ICS values are determined by
means of a
computer-aided system using the formula
ICS _ [(OD,eSt - OD~")/(OD~~"°, - OOs,~,)] x 100.
CA 02242354 1998-07-06
WO 97/27199 PCT/EP97J00127
-12-
The tC~value in those experiments is defined as that concentration of the test
compound in
question which results in a 50 °6 decrease in the number of cells in
comparison with the
control without inhibitor. The compounds of formula I exhibit inhibitory
actions in the micro-
molar range, especially having an IC~ of approximately from 0.1 to 50 pM.
The compounds of formula t are also capable of inhibiting the growth of tumour
cells in vivo,
as shown, for example, by the test described below: the test is based on the
inhibition of the
growth of the human epidermoid carcinoma A431 (ATCC No. CRL 1555; American
Type
Culture Collection, Rockville, Maryland, USA; see Santon, J.B., ei aL, Cancer
Research 46,
4701-4705 (1986) and Ozawa, S., et al., Int. J. Cancer 40, 706-710 (1987)),
which is trans-
planted into female BALBIc naked mice (Bomholtgard, Denmark). That carcinoma
exhibits a
growth which correlates with the extent of the expression of the EGF receptor.
In the experi-
ment, tumours of about 1 cm3 volume grown in vivo are surgically removed from
experi-
mental animals under sterile conditions. Those tumours are comminuted and
suspended in
volumes (wlv) of phosphate-buffered saline. The suspension is injected s.c.
into the left
flank of the animals (0.2 mllmouse in phosphate-buffered saline).
Alternatively, 1 x 1 O6 cells
from an in vitro culture in 0.2 ml of phosphate-buffered saline can be
injected. The
treatment with the test compounds of formula I is begun 5 or 7 days after
transplantation
when the tumours have attained a diameter of 4-5 mrn. The test compound in
question is
administered (in different doses for different groups of animals) once daily
for 15 successive
days. The tumour growth is determined by measuring the diameter of the tumours
along
three axes that are perpendicular to one another. The tumour volumes are
calculated using
the known -formula p x L x D216 (see Evans, B.D., et al., Brit. J. Cancer 45,
466-468 (1982)).
The results are expressed as treatment/control percentages (TIC x 100 = T/C%).
In addition to or instead of inhibiting the EGF receptor tyrosine protein
kinase, the com-
pounds of formula I also inhibit other tyrosine protein kinases that are
involved in the signal
transmission mediated by trophic factors, for example the abl kinase, such as
especially the
v-abl kinase (ICS, for example, from 0.01 to 5 wM), kinases of the src kinase
family, such as
especially the c-src kinase (ICso, for example, from 0.01 to 10 wM), and also
Ick and fyn;
other kinases of the EGF family, for example the c-erbB2 kinase (HER-2), the c-
erbB3
kinase, the c-erbB4 kinase; members of the PDGF tyrosine protein kinase
family, for
CA 02242354 1998-07-06
WO 97!27199 PCTlEP97100127
-13-
example the PDGF receptor, CSF-1, Kit, VEGF-R and FGF-R; and the insulin-like
growth
factor receptor kinase (IGF-1-kinase), and also serine/threonine kinases, for
example
protein kinase C, all of which play a part in growth regulation and
transformation in mammal
cells, including human cells. Finally, the compounds of formula I can also be
used in the
inhibition of angiogenesis.
The above-mentioned inhibition of the v-abl tyrosine kinase is determined in
accordance
with the methods of N. t_ydon et al., Oncogene Research 5, 161-173 (1990) and
J. F.
Geissler et al., Cancer Research 52, 4492-4498 (1992), with (Vale]-angiotensin
i1 and [Y-32P]-
ATP being used as substrates.
The inhibition of the c-erbB2 tyrosine kinase (HER-2) can be determined, for
example,
analogously to the method used for EGF-R-PTK (see C. House et a!, Europ. J.
Biochem.
140, 363-367 (1984)). The c-erbB2 kinase can be isolated and its activity
determined in
accordance with protocols known per se, for example according to T. Akiyama et
al.,
Science 232, 1644 (1986)}.
The compounds of formula I that inhibit the tyrosine kinase activity of the
receptor for the
epidermal growth factor (EGF) or, further, the other tyrosine protein kinases
mentioned or
also serine/threonine kinases can therefore be used, for example, in the
treatment of
benign or malignant tumours (for example carcinoma of the kidneys, liver,
adrenal glands,
bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs,
vagina or
thyroid, sarcoma, glioblastomas and numerous tumours of the neck and head).
They are
able to bring about the regression of tumours and to prevent the formation of
tumour
metastases and the growth of (also micro-)metastases. More especially they can
be used in
epidermal hyperproliferation (psoriasis}, in prostate hyperplasia, in the
treatment of
neoplasias, especially of epithelial character, for example mammary carcinoma,
and in
leukaemias. It is also possible to use the compounds of formula I in the
treatment of
diseases of the immune system insofar as several or, especially, individual
tyrosine protein
kinases and/or (further} serine/threonine protein kinases are involved; the
compounds of
formula I can be used also in the treatment of diseases of the central or
peripheral nervous
System where signal transmission by at least one tyrosine protein kinase
and/or (further)
serinelthreonine protein kinase is involved.
CA 02242354 1998-07-06
WO 97!27199 PCTlEP97l00127
-14-
Generally the present invention relates also to the use of the compounds of
formula i in the
inhibition of the said protein kinases.
The compounds according to the invention can be used both on their own and in
combina-
tion with other pharmacologically active substances, for example together with
inhibitors of
enzymes of polyamine biosynthesis, inhibitors of protein kinase C, inhibitors
of other
tyrosine kinases, cytokines, negative growth regulators, for example TGF-D or
IFN-fi,
aromatase inhibitors, antioestrogens and/or cytostatics.
In the preferred subjects of the invention mentioned below, where appropriate
and
expedient it is possible to use the more specific definitions mentioned at the
beginning in
place of more general definitions.
Preference is given to a compound of formula I wherein
R, and R2 are each independently of the other
lower alkyl; monohalo-, dihalo- or trihalo-lower alkyl; lower alkoxy; phenyl
that is
unsubstituted or substituted by halogen, monohalo-, dihalo- or trihalo-lower
alkyl,
carbamoyl-methoxy, carboxy-methoxy, benzyioxycarbonyl-methoxy, lower
alkoxycarbonyl-
methoxy, phenyl, amino, amino-lower alkyl, lower afkanoylamino, lower
alkoxycarbonylamino, phenyl-lower alkoxycarbonylamino, furoyl,
thienylcarbonyl, N-lower
alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkoxy, lower alkanoyloxy,
carboxy,
lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-
carbamoyl,
cyano, amidino, N-(N',N'-di-lower alkylaminomethylidene)-amino, N-((N',N'-di-
lower
alkylamino)-(lower alkyl}-methyiidene}-amino, guanidino, ureido, N3-lower
alkylureido, N3,N3-
di-lower alkylureido, thioureido, N3-lower alkylthioureido, N',N3-di-lower
alkylthioureido,
lower alkanesulfonylamino, benzene- or naphthalene-sulfonylamino that is
unsubstituted or
lower alkyl-substituted at the benzene or naphthalene ring, azido or by vitro;
hydrogen;
unsubstituted or halo- or lower alkyl-substituted pyridyl; N-benzyl-
pyridonium; naphthyl;
cyano; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkyl-carbamoyl; N,N-
di-lower
alkyl-carbarnoyl; N-benzyl-carbarnoyl; formyl; lower alkanoyl; lower aikenyl;
lower
alkenyloxy; or lower alkyl substituted by halogen, amino, lower alkylamino,
piperazino, di-
lower alkyiamino, phenylamino or phenyl (each unsubstituted or substituted in
the phenyl
moiety by halogen, tower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy,
carboxy, lower
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
- t5 -
alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-
carbamoyl, cyano,
amidino, amino, amino-lower alkyl, lower alkanoyfamino, lower aikylamino, N,N-
di-lower
alkylamino or by trifluoromethyl), hydroxy, lower alkoxy, cyano, carboxy,
lower afkoxy-
carbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl,
mercapto or by
a radical of the formula R5-S(Oq)- wherein RS is lower alkyl and q is 0, 1 or
2, and
D is a radical of formula IA selected from 2,3-dihydroindol-t -yl; and
preferably 1,2,3,4-tetra-
hydroquinolin-1-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yi, 1,2,3,4,5,6-
hexahydrobenzo-
[b]azocin-1-yl, 2,3,6,7,8,9-hexahydro-1H-benzo[g]indol-t-yl, 1,2,3,5-
tetrahydropyrrolo[2,3-f]-
indol-1-yl and 1,2,3,5,6,7-hexahydro-pyrroio[2,3-f]indol-1-yl; each of the
mentioned radicals
being unsubstituted or substituted by from t to 3 (i.e. m + n = 0 to 3)
radicals R3 or R, or R3
and R4 selected independently of one another from lower alkyl, N,N-di-lower
alkyfamino-
iower alkyl, lower alkynyl, tri-lower alkylsilanyl-lower alkynyl, halogen,
vitro, hydroxy, lower
alkoxy, isothiocyanato, unsubstituted phenyl, unsubstituted phenyl-lower
alkoxy, carboxy,
lower alkoxycarbonyl, amino, azido, lower alkanoylamino, trihalo-lower
alkylcarbonylamino,
pyrrol-1-yl and pyrrolidin-1-yl or substituted by lower alkylenedioxy that is
formed by two
radicals R4 together and is bonded to two vicinal ring atoms; Q is especially
2,3-dihydroin-
dol-1-yl, 6-chloro-2,3-dihydroindol-1-yl, fi-bromo-2,3-dihydroindol-1-yl, 6-
methyl-2,3-dihydro--
indol-t-yl or more especially 1,2,3,4-tetrahydroquinolin-1-yl;
or a salt thereof where at least one salt-forming group is present.
Great preference is given to a compound of formula I wherein
R, and R2 are each independen~y of the other selected from hydrogen, lower
alkyl, such as
methyl, and phenyl that is unsubstituted or substituted by halogen, monohalo-,
dihalo- or
trihalo-lower alkyl, carbamoyl-methoxy, carboxy-methoxy, benzyioxycarbonyl-
methoxy,
lower alkoxycarbonyl-methoxy, phenyl, amino, amino-lower alkyl, lower
alkanoyfamino,
lower alkoxycarbonylamino, phenyl-lower alkoxycarbonylamino, furoyl,
thienylcarbonyl, N-
iower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy,
carboxy, lower
alkoxycarbonyi, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-
carbamoyl, cyano,
amidino, N-(N',N'-di-lower alkylaminornethylidene)-amino, N-((N',N'-di-lower
alkyfarnino)-
(iower alkyl)-methylidene)amino, guanidino, ureido, N3-lower alkyiureido,
N3,N3-di-lower
alkylureido, thioureido, N3-lower alkylthioureido, N3,N3-di-lower
alkylthioureido, lower
CA 02242354 1998-07-06
WO 97!27199 PCTlEP97100127
-16-
alkanesulfonylamino, benzene- or naphthalene-sulfonytamino that is
unsubstituted or lower
alkyl-substituted at the benzene or naphthalene ring, azido or by vitro, and
D is a radical of formula IA selected from 2,3-dihydroindol-1-yl; and
preferably 7,2,3,4-tetra-
hydroquinolin-1-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 1,2,3,4,5,6-
hexahydrobenzo-
[b]azocin-1-yl, 2,3,6,7,8,9-hexahydro-1H-benzo[g]indol-1-yl, 1,2,3,5-
tetrahydrapyrrolo-
[2,3-f]indol-1-yl and 1,2,3,5,6,7-hexahydro-pyrrolo[2,3-f]indol-1-yl; each of
the mentioned
radicals being unsubstituted or substituted by from 1 to 3 radicals R3 or R4
or R3 and R4
selected independently of one another from lower alkyl, N,N-di-lower
alkylarnino-lower alkyl,
lower alkynyl, tri-lower alkylsilanyl-lower alkynyl, halogen, vitro, hydroxy,
lower alkoxy,
isothiocyanato, unsubstituted phenyl, unsubstituted phenyl-lower alkoxy,
carboxy, lower
alkoxycarbonyl, amino, azido, lower alkanoylamino, trihalo-lower
alkylcarbonytamino, pyrrol-
1-yl and pyrrotidin-1-yl or substituted by lower alkylenedioxy that is formed
by two radicals
R, together and is bonded to two vicinal ring atoms; Q is especially 2,3-
dihydroindol-1-yl, 6-
chloro-2,3-dihydroindol-1-yl, 6-bromo-2,3-dihydroindol-1-yl, 6-methyl-2,3-
dihydroindol-1-yl or
especially 1,2,3,4-tetrahydroquinolin-1-yl;
or a salt thereof.
Special preference is given to a compound of formula I wherein
either the two radicals R, and R2 are each independently of the other lower
alkyl, preferably
each methyl;
or R, is hydrogen and R2 is phenyl that is unsubstituted or especially
substituted by amino,
vitro or by methoxy, especially 4-aminophenyl, 4-nitrophenyl or 4-
methoxyphenyl; and
Q is 2,3-dihydroindol-1-yl, 6-chloro-2,3-dihydroindol-1-yl, 6-bromo-2,3-
dihydroindol-1-yl, 6-
methyl-2,3-dihydroindol-1-yl or especially 1,2,3,4-tetrahydroquinolin-1-yl;
or a salt thereof.
Greatest preference is given to the compounds of formula I described in the
Examples and
the pharmaceutically acceptable salts thereof.
CA 02242354 1998-07-06
WO 97127199 PCTlEP97100127
-17-
The compounds of formula I and their salts are prepared in accordance with
processes
known per se. The process according to the invention is as follows:
a) a pyrrolo[2,3-d]pyrimidine derivative of formula Ii
2
~N
3 N/~ / 7
-N
(II),
~6
~ 'R2
wherein X is a suitable leaving group, Z is hydrogen or 1-aryl-lower alkyl and
the other sub-
stituents are as defined above for compounds of formula I, free functional
groups present in
the radicals R, and R2 being protected if necessary by readily removable
protecting groups,
is reacted with an aza compound of formula 111
O-H (III),
wherein Q is as defined above for compounds of formula I, free functional
groups present in
the radical D being protected if necessary by readily removable protecting
groups, and any
protecting groups and, if present, the 1-aryl-lower alkyl radical Z are
removed, or
b) a pyrrolo[2,3-d]pyrimidin-4-one derivative of formula IV
2
N
HN~ 7
/ -~" N
C ~ (I~~
O/ 4 5 R2
R,
wherein Z' is 1-aryl-lower alkyl and R, and Rz are as defined above for
compounds of
formula I, free functional groups present in the radicals R, and R2 being
protected if
CA 02242354 1998-07-06
WO 97/27199 PCTIEP97100127
_18_
necessary by readily removable protecting groups, is reacted in the presence
of a
dehydrating agent and a tertiary amine (which is preferably in the form of a
salt with a
strong acid) with an aza compound of the above formula III and any protecting
groups
present are removed;
and, if desired, after carrying out one of the process variants a) and b), a
compound of
formula I is converted into a different compound of formula I; and/or, if
necessary for the
preparation of a salt, a resulting free compound of formula ! is converted
into a salt or, if
necessary for the preparation of a free compound, a resulting salt of a
compound of
formula I is converted into the free compound; or an obtainable salt of a
compound of
formula I is converted into a different salt of a compound of formula I.
Detailed description of the preferred process stews
The above processes are described in more detail below (see also German
Offenlegungs-
schrift No. 30 36 390, published on 13th May 1982, and A. Jorgensen et al., J.
Heterocycl.
Chem. 22, 859 [1985)). In the following more detailed description, unless
otherwise
indicated the radicals R,, R2, D, R3 and R, and the variables m and n are as
defined far
compounds of formula 1.
General remarks:
The end products of formula I may contain substituents that can be used also
as protecting
groups in starting materials for the preparation of other end products of
formula I. Within the
scope of this text, unless the context indicates otherwise the term
"protecting group" is
therefore used to denote only a readily removable group that is not a
constituent of the
desired end product of formula I in question.
Process a)
In the compound of formula II, a suitable leaving group X is preferably
halogen, such as
bromine, iodine or especially chlorine. 1-Aryl-lower alkyl Z is preferably 1-
phenyl-lower alkyl,
such as especially 1-phenylethyl or more especially benryl.
Free functional groups present in the radicals R, and R2 and also D, which are
if necessary
protected by readily removable protecting groups, are especially amino or
lower alkyiamino,
or also hydroxy.
CA 02242354 1998-07-06
WO 97!27199 PCTIEP97100127
-19-
Protecting groups and the methods by which they are introduced and removed are
described, for example, in "Protective Groups in Organic Chemistry', Plenum
Press,
London, New York 1973, and in 'Methoden der organischen Chemie", Houben-Weyl,
4th
edition, Vol. 1511, Georg-Thieme-Verlag, Stuttgart 7974, and in Theodora W.
Greene,
"Protective Groups in Organic Synthesis, John Wiley 8~ Sons, New York 1981. It
is
characteristic of protecting groups that they can be removed readily, that is
to say without
undesirable secondary reactions taking place, for example by solvolysis,
reduction,
photolysis or under physiological conditions.
A protected amino group may be, for example, in the form of a readily
cieavable acylamino,
arylmethyiamino, etherified mercaptoamino or 2-acyl-lower aik-1-enylamino
group.
in such an acylamino group, acyl is, for example, the acyl radical of an
organic carboxylic
acid having, for example, up to 18 carbon atoms, especially an unsubstituted
or substituted
for example halo- or aryl-substituted, alkanecarboxylic acid or an
unsubstituted or sub-
stituted, for example halo-, lower alkoxy- or vitro-substituted, benzoic acid,
or a carbonic
acid semiester. Such acyl groups are, for example, lower alkanoyl, such as
formyl, acetyl or
propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-
bromo-, 2-iodo-,
2,2,2-trifiuoro- or 2,2,2-trichloro-acetyl, unsubstituted or substituted, for
example halo-,
lower alkoxy- or vitro-substituted, benzoyl, for example benzoyl, 4-
chlorobenzoyl, 4-
methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyi that is branched in
the 1-position
of the lower alkyl radical or suitably substituted in the 1- or 2-position,
especially tart-lower
alkoxycarbonyi, for example tart-butoxycarbonyl, arylrnethoxycarbonyl having
one or two
aryl radicals which are preferably phenyl that is unsubstituted or mono- or
poly-substituted,
for example, by lower alkyl, especially tart-lower alkyl, such as tart-butyl,
lower alkoxy, such
as methoxy, hydroxy, halogen, such as chlorine, and/or by vitro, such as
unsubstituted or
substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or
substituted
diphenylmethoxycarbonyf, for example benzhydryloxycarbonyl or di(4-
methoxyphenyi)-
methoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is preferably
benzoyl that
is unsubstituted or substituted, for example, by halogen, such as bromine, for
example
phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloro-
ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-
(trisubstituted silyl)-
ethoxycarbonyl wherein the substituents are each independently of the others
an
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-20-
unsubstituted or substituted, for example lower alkyl-, lower alkoxy-, aryl-,
halo- or nitro-
substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon
radical having up to
15 carbon atoms, such as corresponding unsubstituted or substituted lower
alkyl, phenyl-
lower alkyl, cycloalkyf or phenyl, for example 2-tri-lower alkylsilyl-
ethoxycarbonyl, such as 2-
trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or
2-triarylsilyl-
ethoxycarbonyl, far example 2-triphenylsilylethoxycarbonyi.
In an aryfmethylamino group, which is a mono-, di- or especially tri-
aryimethylamino group,
the aryl radicals are especially unsubstituted or substituted phenyUradicals.
Such groups
are, for example, benzyl-, diphenylrnethyl- or especially trityl-amino.
An etherified mercapto group in an amino group protected by such a radical is
especially
arylthio or aryl-lower alkylthio wherein aryl is especially phenyl that is
unsubstituted or
substituted, for example by lower alkyl, such as methyl or tert-butyl, lower
alkoxy, such as
methoxy, halogen, such as chlorine, andlor by vitro. One such amino-protecting
group is,
for example, 4-nitrophenylthio.
In a 2-acyl-lower alk-1-en-1-yl radical that can be used as an amino-
protecting group, acyl
is, for example, the corresponding radical of a lower alkanecarboxylic acid,
of a benzoic
acid that is unsubstituted or substituted, for example, by lower alkyl, such
as methyl or tert-
butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by
vitro, or
especially of a carbonic acid semiester, such as a carbonic acid lower alkyl
semiester.
Such protecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, for
example 1-acetyl-
prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, such as 1-
ethoxycarbonyl-prop-1-
en-2-yl.
Preferred amino-protecting groups are acyl radicals of carbonic acid
semiesters, especially
tert-butyioxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted,
for example as
indicated, for example 4-vitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl,
or 2-halo-
lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, and also trityl
or formyl.
The reaction between the derivative of formula 1l and the aza compound of
formula Ilf is
effected in suitable, inert polar solvents, especially alcohols, for example
lower alkanols,
such as methanol, propanol, isopropanol or especially ethanol or n-butanol. in
some cases,
CA 02242354 1998-07-06
WO 97127199 PCTIEP97f00127
-21 -
the addition of a solubiliser, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-
pyrimidinone
(DMPU), is advantageous. The reaction is effected at elevated temperatures,
for example in
a temperature range of from 70 to 150°C, preferably under reflux
conditions. For the prep-
aration of those compounds where a sterically hindered compound (for example a
2-lower
alkyl-indoiine) of formula III is used, it is preferable to use tert-butanol
or an aprotic solvent,
such as dimethylformamide, dimethylacetamide or N-methyipyrrolidin-2-one, as
solvent. If
necessary, a base is added, for example an alkali metal or alkaline earth
metal carbonate or
hydroxide, or a tertiary nitrogen base, such as pyridine, 2,6-lutidine,
collidine, N-methyl-
morpholine, triethylarnine, diisopropylethylamine, 4-dimethyiaminopyridine or
N,N-dimethyl-
aniline.
If Z in the compound of formula II is 1-aryl-lower alkyl, that radical is
removed in the
resulting precursor of the compound of formula I (with Z in place of the
hydrogen atom at
the nitrogen atom). That is effected, for example, by treatment with protonic
acids, such as
hydrochloric acid, phosphoric acid or polyphosphoric acid, at preferred
temperatures of from
20°C to 150°C and optionally in the presence of water (this is
especially the preferred
method for Z = i-phenylethyl); or preferably by treatment with Lewis acids,
especially AICI3,
in an aromatic solvent, especially in benzene and/or toluene, at elevated
temperature,
especially under reflux [this is especially the preferred variant for Z =
benzyl; see also the
analogous procedure in Chem. Pharm. Bull. 39(5), 1152 (1991)].
Removal of protecting groins
The removal of protecting groups that are not constituents of the desired end
product of
formula I is carried out in a manner known per se, for example by means of
solvoiysis,
especially hydrolysis, alcoholysis or acidolysis, or by means of reduction,
especially
hydrogenolysis or chemical reduction, optionally stepwise or simultaneously.
The removal is
effected preferably in accordance with or analogously to the methods described
in the
standard works mentioned above.
A protected amino group, for example, is freed in a manner known per se and,
according to
the nature of the protecting groups, in various ways, preferably by solvolysis
or reduction.
2-Halo-lower alkoxycarbonylamino (where appropriate after conversion of a 2-
bromo-lower
alkoxycarbonyiamino group into a 2-iodo-lower alkoxycarbonylamino group),
aroylmethoxy-
CA 02242354 1998-07-06
WO 97!27199 PCT'/EP97/00127
-22-
carbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by
treatment
with a suitable chemical reducing agent, such as zinc in the presence of a
suitable
carboxylic acid, such as aqueous acetic acid. Aroyimethoxycarbonylamino can be
cleaved
also by treatment with a nucieophilic, preferably salt-forming, reagent, such
as sodium thio-
phenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali
metal
dithionite, for example sodium dithionite. Unsubstituted or substituted
diphenylmethoxy-
carbonylamino, tart-lower aikoxycarbonylamino or 2-trisubstituted
silylethoxycarbonylamino
can be cleaved by treatment with a suitable acid, for example formic acid or
trifluoroacetic
acid; unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for
example, by
means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a
suitable
hydrogenation catalyst, such as a palladium catalyst; unsubstituted or
substituted triaryl-
methyiamino or formyiamino can be cleaved, for example, by treatment with an
acid, such
as a mineral acid, for example hydrochloric acid, or an organic acid, for
example formic,
acetic or trifluoroacetic acid, where appropriate in the presence of water,
and an amino
group protected by an organic silyl group can be freed, for example, by means
of hydrolysis
or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-
chloroacetyl, can
be freed by treatment with thiourea in the presence of a base, or with a
thiolate salt, such
as an alkali metal thiolate, of thiourea and subsequent solvolysis, such as
alcoholysis or
hydrolysis, of the resulting condensation product. An amino group protected by
2-
substituted silylethoxycarbonyl can be converted into the free amino group
also by
treatment with a salt of hydrofluoric acid that yields fluoride anions.
Process b1
1-Aryl-lower alkyl Z' in a compound of formula IV is especially 1-phenylethyl
and also
benzyl.
The compound of formula IV is in tautomeric equilibrium (lactam/lactim form),
it being
assumed that the lactam form (formula IV) predominates. Formula IV is used to
represent
the two possible forms of equilibrium.
The lactim form has the formula IVa
CA 02242354 1998-07-06
WO 97/27199 PCTlEP97/00127
-23-
/ N Z.
N
-'" N
(IVa)
HO ~ 'R2
R~
wherein the radicals are as defined for compounds of formula IV.
The dehydrating agent used is especially a strong chemical dehydrating agent,
more espe-
cially phosphorus pentoxide (P40,o).
A suitable tertiary amine is especially ammonia substituted by three radicals
selected
independently of one another from alkyl, especially lower alkyl, such as
methyl or ethyl, and
cycloalkyl having from 3 to 7 carbon atoms, especially cyclohexyl, for example
N,N-di-
methyi-N-cyciohexylamine, N-ethyl-N,N-diisopropyiamine or triethylamine, or
also pyridine,
N-methylmorphofine or 4-dimethylaminopyridine.
The tertiary amine is preferably in the form of a salt with a strong acid,
preferably an
inorganic acid, such as sulfuric acid, phosphoric acid or especially a
hydrogen halide, such
as hydrogen chloride.
The reaction between the pyrrolo-pyrimidinone of formula IV and the aza
compound of
formula III is effected at elevated temperature, for example at from 200 to
250°C.
Additional Process Steps
In the additional process steps, which are optional, functional groups of the
starting com-
pounds that are not intended to participate in the reaction may be unprotected
or may be in
protected form; for example they may be protected by one or more of the
protecting groups
mentioned above. The protecting groups may be removed from the end products,
simultaneously or in sequence, in accordance with one of the methods mentioned
under the
heading "Removal of protecting groups".
The conversion of a compound of formula I into a different compound of formula
I is
effected especially by conversion of substituents in formula I.
CA 02242354 1998-07-06
WO 9712'7199 PCTIEP97100127
-24-
For example, for the preparation of a compound of formula I wherein R, is
dimethylamino-
methyl and the other substituents are as defined above for compounds of
formula l, a com-
pound corresponding to formula I wherein R, is hydrogen and other substituents
are as
defined above for compounds of formula I, any further free functional groups
present being
protected if necessary by readily removable protecting groups, can be reacted
with N,N-di-
methyl-methyleneimmonium iodide and any protecting groups present removed. The
reaction is carried out with the exclusion of moisture in a suitable inert
solvent, for example
a suitable ether, such as a cyclic ether, such as esp~iaUy tetrahydrofuran, at
elevated
temperature, preferably under reflux.
For the preparation of a compound of formula I wherein at least one of the
radicals R, and
R2 is hydroxy-substituted phenyl and/or wherein at least one of the radicals
R3 and R4 is
hydroxy and the other substituents are as defined above for compounds of
formula I, it is
also possible for a compound corresponding to formula I wherein at least one
of the radicals
R, and R2 is lower alkoxy-substituted, especially methoxy-substituted, phenyl
and/or
wherein at least one of the radicals R3 and R4 is lower alkoxy and the other
substituents are
as defined above for compounds of formula I, any free functional groups
present being
protected if necessary by readily removable protecting groups, to be reacted
with boron
tribromide or aluminium(III) chloride, and any protecting groups present to be
removed. The
reaction is carried out with the exclusion of moisture in a suitable inert
solvent, for example
a suitable halogenated hydrocarbon, such as especially rnethylene chloride, at
temperatures of approximately from -20°C to +50°C, preferably
with ice-cooling or at room
temperature.
For the preparation of a compound of formula I wherein at least one of the
radicals R, and
R2 is amino-substituted amino andlor wherein at least one of the radicals R3
and R4 is
amino and the other substituents are as defined above for compounds of formula
I, a
compound of formula I wherein at least one of the radicals R, and R2 is vitro-
substituted
phenyl and/or wherein at least one of the radicals R3 and R, is vitro and the
other
substituents are as defined above for compounds of formula I, any free
functional groups
present being protected if necessary by readily removable protecting groups,
can be
catalyticalty hydrogenated and any protecting groups present removed. The
hydrogenation
is preferably carried out under elevated pressure or especially at normal
pressure in the
CA 02242354 1998-07-06
WO 97127199 PCTIEP97J00127
-25-
presence of a suitable hydrogenation catalyst, such as especially Raney
nickel, in an inert
solvent or solvent mixture, such as especially a mixture of a suitable cyclic
ether and a
suitable tower alkanol, such as preferably a mixture of tetrahydrofuran and
methanol, at
temperatures of approximately from 0°C to +50°C, preferably at
room temperature.
For the preparation of a compound of formula I wherein at least one of the
radicals R, and
RZ is phenyl substituted by N-(N',N'-di-lower alkylaminomethyfidene)-amino or
by N-((N',N'-
di-lower alkylamino)-(lower alkyl)-methylidene)amino and the other
substituents are as
defined above for compounds of formula I, a compound corresponding to formula
I wherein
at least one of the radicals R, and R2 is amino-substituted phenyl and the
other substituents
are as defined above far compounds of formula I, any further free functional
groups present
being protected if necessary by readily removable protecting groups, can be
reacted with a
N,N-di-lower alkylformamide diethylacetal, especially N,N-dimethylformamide
dimethyi-
acetal, or N,N-di-lower alkyl-lower alkylcarboxylic acid amide diethylacetal,
especially N,N-
dimethylacetamide dimethylacetal, in an inert solvent, for example in toluene,
and any
protecting groups present removed.
Lower alkyl R, or R2 substituted by a radical of the formula RS-S(Oq)-,
wherein RS is lower
alkyl and q is 0, or lower alkylthio R3 or R4 can be converted into
corresponding RS-S(Oq)-
wherein q is 1 or 2, that is into lower alkylsulfinyl or lower alkanesulfonyl,
respectively, by
oxidising the corresponding thio compounds, for example with hydrogen
peroxide, a
peracid, such as 3-chloroperbenzoic acid, performic acid or peracetic acid, an
alkali metal
peroxysulfate, such as potassium peroxymonophosphate, chromium trioxide or
gaseous
oxygen in the presence of platinum. The oxidation is carried out under
conditions that are
as mild as possible, using the stoichiometric amount of the oxidising agent in
order to avoid
overoxidation. Suitable solvents are especially methyiene chloride,
chloroform, acetone,
tetrahydrofuran or tert-butyl methyl ether, and the temperature is preferably
from -30 to
50°C, preferably in the range of from t S to 28°C, for example
at room temperature. For the
preparation of sulfinyl compounds it is possible to use, preferably, milder
oxidising agents,
such as sodium or potassium metaperiodate, in a polar solvent, such as acetic
acid or
ethanol.
CA 02242354 1998-07-06
WO 9?/27199 PCTlEP97100127
-26-
From compounds of formula I wherein R, and/or R2 is phenyl substituted by
cyano or by
cyano-C,-Csalkyl it is possible to obtain the corresponding cyano-lower
alkylphenyl com-
pound by reduction, for example by catalytic hydrogenation, for example in the
presence of
Raney nickel or especially Raney-Ushibara nickel, in an alcohol, such as
methanol, at
preferred temperatures of from 20 to 100°C, preferably at about
90°C, elevated hydrogen
pressures, for example from 1 to 15 MPa (about 10 to 150 atm), being
preferred, or with a
suitable complex hydride, such as lithium aluminium hydride in a suitable
solvent, especially
an ether, such as diethyl ether, preferably under refiux.
From compounds of formula 1 wherein R, and/or R2 is cyano-substituted phenyl
it is possible
to obtain the corresponding amidines by aminolysis with ammonia or by a Pinner
cleavage
via the formation of imino esters (alkyl imidates) by the addition of dry
hydrogen chloride to
a mixture of the nitrite starting material and an alcohol and subsequent
treatment with
ammonia (see Chem. Ber. 10, 1889 (1877); Chem. Ber. 11, 4, 1475 (1878) or
Chem. Ber.
16, 352, 1643 (1883)).
From compounds of formula ! wherein R, and/or R2 is amino-substituted lower
alkyl or
amino-substituted phenyl it is possible to obtain by acylation the
corresponding compounds
wherein the place of one or more of the amino groups has been taken by lower
alkanoyl-
amino or (in the case of amino-substituted phenyl as starting material)
ureido, N3-lower
alkylureido, N3,N3-di-lower afkylureido, lower alkanesulfonylamino, or benzene-
or
naphthalene-sulfonylamino that is unsubstituted or lower alkyl-substituted at
the benzene or
naphthalene ring, by acylation under customary conditions. A suitable
acylating agent is, for
example, any corresponding suitable reagent that is suitable for the acylation
of amino
groups, for example a corresponding acyl halide, such as a bromide or
chloride, a corres-
ponding anhydride or mixed anhydride, a cyanate (for the preparation of ureido
compounds), for example a corresponding alkali metal cyanate, or an
isocyanate. N-
Sulfonylation can be carried out with corresponding sulfonyl halides or
anhydrides. The
reactions take place in a solvent inert towards the reaction and at preferred
temperatures in
the range of from -20 to approximately 120°C, preferably at about room
temperature.
For the conversion of hydroxy into carbamoyl or into carbamoyl substituted as
indicated in
the substituent definitions given above or into lower alkanoyloxy,
corresponding acylating
agents are suitable, for example corresponding halides, anhydrides or mixed
anhydrides.
CA 02242354 2005-05-10
21489-9422
-27-
The reaction conditions are analogous to those given above for the acylation
of amino
groups. Acylation in situ, for example in the presence of condensation agents,
such as
carbodiimides, is also possible. For the introduction of carbamoyl or
substituted carbamoyf it
is also possible to use corresponding cyanates or alkyl isocyanates, typically
in the
presence of a suitable base.
For the conversion of at least one hydroxy or amino group as substituent in a
compound of
formula I into lower alkoxy, carbamoylmethoxy, carboxymethoxy,
benzyloxycarbonyl-
methoxy, lower alkoxycarbonylmethoxy or lower alkylamino, alkylation,
preferably in the
presence of a suitable base, is suitable. A suitable alkylating agent is, for
example, a
corresponding alkyl halide which is used at preferred temperatures of from 10
to 140°C,
especially at about room temperature.
Those and other conversions can be found also in International Application WO
95/23141,
published on 31.08.1995 .
Salts of compounds of formula I having a salt-forming group can be prepar~i in
a manner
known per se. For example, acid addition salts of compounds of formula I can
be obtained,
for example, by treatment with an acid or a suitable anion exchange reagent.
Salts can be converted into the free compounds in customary manner, for
example by
treatment with a suitable basic agent.
By treatment of free compounds of formula I obtained in that manner with acid
addition salts
it is possible to convert salts of compounds of formula I into other salts.
Stereoisomeric mixtures, for example mixtures of diastereoisomers, cis/trans
isomers or
enantiomers, can be separated into the corresponding isomers in a manner known
parse
by suitable separating procedures. Far example, mixtures of diastereoisomers
can be
separated into the individual diastereoisomers by fractional crystallisation,
chromatography,
solvent partition and the tike. Such a separation can be carried out either at
the stage of
one of the starting materials or with the compounds of formula I themselves.
CA 02242354 1998-07-06
WO 97/27199 PCT/EP97f00127
_28_
Starting.materials
The starting materials of formula II are novel, are known or can be prepared
according to
procedures known per se. They can be prepared in accordance with procedures
analogous
to those described in German Offenlegungsschriften No. 28 18 676 (published on
8th Nov.
1979) and No. 30 36 390 (published on 13th May 1982) and European Patent
Application
EP 0 682 027 (published on 15th November 1995).
The starting material of formula II wherein X is chlorine is obtained, for
example, from a
compound analogous to formula II wherein X is hydroxy by reaction with
phosphorus
oxychioride (phosphoryl chloride, P(=O)CI3), with the exclusion of moisture,
at reflux
temperature. If desired, the further reaction of the resulting starting
material of formula II
wherein X is chlorine with an aza compound of formula III can be carried out
in the same
vessel, that is to say as a one-pot process. For that purpose the reaction
mixture from the
reaction with phosphorus oxychloride is concentrated to dryness by evaporation
when the
reaction is complete, made into a slurry with a suitable solvent, such as n-
butanol, and
reacted further with the aza compound of formula II1.
A compound analogous to formula 1l wherein X is hydroxy (i.e. an isomer of a
compound of
formula IV) is obtained, for example, from a compound of formula V
H2N
/ Z'
~'~ N M.
N r.-C
R2
R,
wherein Z' is 1-aryl-lower alkyl and the other symbols are as defined above,
by reaction with
formic acid, which is preferably used in excess with respect to the compound
of formula V,
for example in from 10- to 30-fold molar excess, optionally in the presence of
an inert
solvent, such as dimethylformamide, at elevated temperature, for example at
temperatures
of from 80°C to the boiling temperature.
Alternatively, a compound analogous to formula II wherein X is hydroxy and the
other
symbols are as defined above is obtained, for example, from a compound of
formula VI
CA 02242354 1998-07-06
WO 97127199 PCT/EP97100127
-29-
H2N
Z
R6-O ~ N/
NI).
O _ R2
R~
wherein Rs is lower alkyl, such as especially ethyl, and the other symbols are
as defined
above, by reaction with a large excess of formamide in a mixture of anhydrous
dimethyl-
formamide and formic acid. The reaction is carried out at elevated
temperature, for example
from 100°C to 150°C, and preferably under a protective gas.
The 1-(Z')-2-amino-3-cyano-pyrroles of formula V used as intermediates can be
prepared in
good yields in accordance with published procedures known per se (see, for
example, Roth,
H.J., and Eger, K., Arch. Pharmaz. 30$, 179 (1975)]. For that purpose, for
example, a com-
pound of form~rla V!I
O
HO
R2 (VII)
R~
is reacted first with an amine of formula Z'-NH2 to form a compound of formula
VIlI
Z'
NH
O {VIII)
RZ
R~
which is then converted with malonic acid dinitrile of the formula CH2(CN)2
into the desired
intermediate of formula V. in detail, the reaction with the amine Z'-NH2 is
carried out under
customary condensation conditions, for example in the presence of catalytic
amounts of a
strong acid, for example hydrochloric acid or p-toluenesulfonic acid, at
elevated temperaturE~
CA 02242354 1998-07-06
WO 97/27199 PCTJEP97100127
-30-
(preferably boiling temperature) in a suitable solvent, for example benzene or
toluene, with
the separation of water, to form the respective a-aminoketone of formula VIII.
The latter is
not isolated but is immediately condensed with malonic acid dinitrile while
hot, with the
separation of water being continued, if necessary with the addition of a small
amount of a
base, such as piperidine, yielding a compound of formula V.
The compounds of formula VI used as intermediates wherein R2 is N-benzyl-
pyridonium-2-yl
and the other symbols are as defined above are obtained, for example, by
reaction of a
compound of formula VI wherein R2 is hydrogen and the other symbols are as
defined
above with N-benzyl-2-bromopyridonium bromide in a suitable solvent, such as a
halogenated hydrocarbon, such as especially methylene chloride. The reaction
is preferably
carried out under a protective gas, in the dark and under anhydrous conditions
at room
temperature or elevated temperature, for example from 20°C to
80°C, and in the presence
of 2,6-dimethylpyridine (2,6-lutidine). The other compounds of formula VI are
obtained, for
example, by reaction of a 2-amidino-acetic acid lower alkyl ester of formula
IX
H2N
R6 O "NH (IX),
O
wherein R6 is as defined above, with a 2-X-1-R2-ethan-1-one derivative of
formula X
0
x
~ RZ (~
R,
wherein the symbols are as defined above. The leaving group X is preferably
bromine.
Before the reaction begins, the 2-amidino-acetic acid lower alkyl ester of
formula IX is
liberated from its acid addition salt, such as especially its hydrochloride,
with the aid of
equimolar amounts of a base, such as especially sodium ethanolate, with ice-
cooling. The
CA 02242354 1998-07-06
WO 97127199 PCT/EP97l00127
-31 -
reaction is carried out in a suitable solvent, especially a lower alkanol,
such as preferably
ethanol, at preferred temperatures of from 0°C to 50°C,
especially at room temperature.
Aza compaunds of formula III are known or can be prepared according to methods
known
per se; some of them are also commercially available.
For example, an aza compound of formula III can be prepared in accordance with
one of
the procedures described in International Application WO 95/23141, published
on 31 st
August 1995, which is incorporated herein by reference, or in accordance with
the
references given therein.
For example, 2,3-dihydro-1,4-benzoxazine derivatives can be prepared according
to R.C.
Elderfield et al., Chapter 12 in "Heterocyclic Compounds", Vol. 6, R.C.
Elderfield Ed., John
Wiiey & Sons, Inc., New York 1957; substituted 2,3-dihydrobenzothiazinyl
compounds
analogously to R.C. Elderfield et al., Chapter 73 of the same book; 1,2,3,4-
tetrahydro-
quinolines and their starting materials analogously to "The Chemistry of
Heterocyclic
Compounds", Vol. 32, Parts 1, 2 and 3; G. Jones (Ed.), John Wifey and Sons,
New York
1977; 1,2,3,4-tetrahydroquinoiines substituted by lower alkyl or by
unsubstituted or
substituted phenyl by catalytic reduction of the corresponding quinolines
using platinum
oxide/hydrogen in methanol {see Honel et al., J. Chem. Soc. Perkin I 1980,
1933-1939);
substituted 2,3,4,5-tetrahydro-1 H-benzo[b]azepines analogously to G.R.
Proctor, Chapter 1l,
Vol 43, "The Chemistry of Heterocyciic Compounds", Part I; A. Rosowsky (Ed.),
Wiley
Interscience, New York 1984; and certain 2,3,4,5-tetrahydro-1 H-
benzo[b]azepines and
1,2,3,4,5,6-hexahydro-1H-benzo[b]azocines by reduction from the corresponding
2,3,4,5-
tetrahydro-1 H-benzo[b]azepin-2-ones and 1,2,3,4,5,6-hexahydro-1 H-
benzo[b]azocin-2-ones
(see Horning et al., J. Am. Chem. Soc. 74, 5153 (1952) and Huisgen et at.,
Liebigs Ann.
Chem. 586, 30 (1954)).
Aza compounds of formula III of the indoline type can be prepared by a series
of reactions
known per se.
Fog example, it is possible to obtain the indoline compounds of formula III
especially by
reduction of corresponding indole starting compounds. For that purpose,
generally the
CA 02242354 1998-07-06
WO 97127199 PCT/EP97/00127
-32-
corresponding indole precursors, in which the substituents (R3 and/or R4) are
aprotic or
appropriately protected, are reacted with ZnBH4 (prepared from ZnCl2, see
Gensler et al., J.
Am. Chem. Soc. 82, 6074-6081 (1960)) in an ethereal solvent, such as diethyl
ether, at a
temperature of from approximately 10 to approximately 40°C, preferably
at room tempera-
ture (see Korsuki et al., Heterocycles 26, 1771-1774 (1987)); or the indole
starting com-
pound is reacted with a borane/pyridine complex (or another borane/tert-amine
complex) in
the presence or absence of a solvent, such as tetrahydrofuran, at a
temperature of approxi-
mately from 10 to 30°C, preferably at room temperature, and then
subjected to treatment
with an acid, SUCK as hydrochloric acid, trifluoroacetic acid or acetic acid,
to form the
indoline compound.
Some indoline compounds of formula III can be prepared from other indoline
compounds by
further modification. For example, unsubstituted or suitably substituted 5-
hydroxyindolines
can be prepared from the corresponding indolines by hydroxylation (see Teuber
et al.,
Chem. Ber. 89, 489-508 (1956)) and subsequent reduction of the intermediate 5-
hydroxy-
indoies to form the 5-hydroxyindolines: potassium nitrosodisulfonate in
aqueous phosphate
buffer is added to the unsubstituted or appropriately substituted indoline in
acetone at
neutral pH and a temperature of approximatety from 0 to 25°C; the
resulting 5-
hydroxyindole derivative is then reacted with borane/pyridinelaqueous HCi to
form the 5-
hydroxyindoline derivative. Unsubstituted or suitably substituted
bromoindolines (for
example brominated in the 4- or 6-position) can be obtained from corresponding
indolines
via bromination (see Miyake et al., J. Net. Chem. 20, 349-352 (1983)). Thai
procedure can
also be used for the bromination of larger ring systems (for example 1,2,3,4-
tetrahydro-
quinolines, 2,3,4,5-tetrahydro-1 H-benzo[b]azepines and 1,2,3,4,5,6-hexahydro-
benzo[b]-
azocines, especially in the 5l7-, 6/8- and 7/9-positions). For that purpose,
generally the
unsubstituted or suitably substituted indoline is reacted with bromine in the
presence of a
halophile, such as silver sulfate, under strongly acidic conditions and at
from 0 to 25°C. In
addition, certain indolines with or without 3-alkyl substituents can be
prepared from the
corresponding 2-(2-halophenyl)alkylamines (see German Patent Application DE 34
24 900).
Furthermore, hydroxyalkylindolines can be prepared by reduction of
corresponding carboxy
precursors or of esters thereof (see Corey et al., J. Am. Chem. Soc. 92(8),
2476-2488
(1970)). Suitably substituted lower alkyl-, lower alkenyl- or allyl-
substituted indolines can be
prepared from corresponding trialkylsiiyl-protected 4-, 5- or 6-haloindoles by
nickel-
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-33-
phosphine-catalysed Grignard addition (see Tamao et al., Bull. Chem. Soc.
Japan 49, 1958-
1969 (1976)), in which case the indoline is generally N-protected by reaction
with tart-butyi-
dimethyl-silyl triflate in a halogenated solvent in the presence of a tertiary
amine. The N-
silylated haloindoline is then reacted with the corresponding alkyl-, alkenyl-
or allyl-Grignard
in an ethereal solvent in the presence of a suitable nickel-phosphine complex
(typically bis-
{triphenylphosphine)nickel(li) dichloride). Subsequent treatment with methanol
that contains
a trace of an acid, such as trifluoroacetic acid, or with fluoride anions in a
suitable solvent.
such as tetrahydrofuran, frees the desired indoline derivative.
In addition, a 4-, 5-, 6- or 7-lower alkenyl-indoiine or a free or tri-lower
alkylsilyl-substituted
lower alkynyl-indoline can be obtained by palladium-catalysed vinylation or
alkynylation of a
corresponding 4-, 5-, 6- or 7-haloindoline (see Kalinin, Synthesis 1992, 413-
432). For the
preparation of the lower aikynylindoline, the corresponding bromo- or iodo-
indoline is
reacted under reflux with a suitable lower alkyne or with
trimethylsilylacetylene or an
analogue thereof in the presence of a catalytic amount of Cul and Pd(PPh3).
3,3-Dimethylindoline can be prepared, for example, by Lewis-acid-mediated
cycfisation of
N-methylallylacetanilide, followed by hydrolysis {see Synthetic Communications
25(24),
4029-4033). A suitable Lewis acid is, for example, AICI3; the hydrolysis is
carried out, for
example, in the presence of hydrogen chloride.
Further preparation methods for numerous indoiines, indoles, oxindoles and
isatins that can
be used as intermediates can be found in the literature (see "Heterocyclic
Compounds with
Indole and Carbazole Systems", W.C. Sumpter and F. Miller, in "The Chemistry
of Hetero-
cyclic Compounds°, Vol. 8, Interscience Publishers Inc., New York 1954,
and the references
given therein).
The other starting compounds are known, can be prepared according to
procedures known
per se or are commercially available.
The reaction conditions used for the preparation of the starting materials are
especially
analogous to the reaction conditions to be found in the description and
especially in the
Examples.
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-34-
General process conditions
All the process steps given in this text can be carried out under reaction
conditions known
parse, but preferably under those specifically mentioned, in the absence or
usually in the
presence of solvents or diluents, preferably those solvents or diluents that
are inert towards
the reagents used and are solvents therefor, in the absence or presence of
catalysts,
condensation agents or neutralising agents, for example ion exchangers, such
as ration
exchangers, for example in the H+ form, depending upon the nature of the
reaction and/or
the reactants at reduced, normal or elevated temperature, for example in a
temperature
range of from approximately -100° to approximately 190°C,
preferably from approximately
-80° to approximately 150°C, for example from -80° to -
60°C, at room temperature, at from
-20° to 40°C or approximately at the boiling point of the
solvent used, under atmospheric
pressure or in a closed vessel, optionally under pressure, and/or in an inert
atmosphere, for
example under an argon or nitrogen atmosphere.
In the case of all starting materials and intermediates, salts may be present
when salt-
forming groups are present. Salts may also be present during the reaction of
such com-
pounds, provided that the reaction will not be affected.
In all reaction steps, any isomeric mixtures that are formed can be separated
into the
individual isomers, for example diastereoisomers or enantiomers, or into any
desired
mixtures of isomers, for example racemates or diastereoisomeric mixtures, for
example
analogously to the methods described under the heading "Additional process
steps".
In certain cases, for example in the case of hydrogenation, it is possible to
carry out stereo-
selective reactions so that, for example, individual isomers may be obtained
more easily.
The solvents from which those suitable for a particular reaction can be
selected include, for
example, water, esters, such as lower alkyl lower alkanoates, for example
ethyl acetate,
ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers,
for example
tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene or toluene,
alcohols, such
as methanol, ethanol or 1- or 2-propanol, nitrites, such as acetonitrile,
halogenated hydro-
carbons, such as methylene chloride, acid amides, such as dimethylformamide,
bases, such
CA 02242354 1998-07-06
WO 97127199 PCT/EP97100127
-35-
as heterocyclic nitrogen bases, for example pyridine, carboxylic acid
anhydrides, such as
lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear
or branched
hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those
solvents,
for example aqueous solutions, unless the description of the processes
indicates otherwise.
Such solvent mixtures can also be used in working-up, for example by
chromatography or
partition.
The invention relates also to those forms of the process in which a compound
obtainable as
intermediate at any stage is used as starting material and the remaining steps
are carried
out or the process is interrupted at any stage or a starting material is
formed under the
reaction conditions or is used in the form of a reactive derivative or salt,
or a compound
obtainable in accordance with the process of the invention is produced under
the process
conditions and further processed in situ, it being preferable to use those
starting materials
which result in the compounds described above as being preferred, especially
those
described as being especially preferred, more especially preferred and/or very
especially
preferred.
The preparation of compounds of formula I (and also of intermediates) is
preferably carried
out analogously to the processes and process steps given in the Examples.
The compounds of formula I, including their salts, may also be obtained in the
form of
solvates, for example in the form of hydrates or, for example, in the form of
crystals that
include the solvent used for crystallisation.
Pharmaceutical compositions, the pret~aration thereof and the use according to
the
invention of gompounds of formula I and compositions comprising those
compounds gs
active in req dient
The present invention relates also to pharmaceutical compositions that
comprise one of the
compounds of formula I as active ingredient and that can be used especially in
the
treatment of the diseases mentioned at the beginning. Special preference is
given to
compositions for enteral, such as nasal, buccal, rectal or especially oral,
administration and
parenteral, such as intravenous, intramuscular or subcutaneous, administration
to warm-
blooded animals, especially human beings. The compositions comprise the active
ingredient
on its own or preferably together with a pharmaceutically acceptable carrier.
The dose of
CA 02242354 1998-07-06
WO 97127199 PCT/EP97/00127
-36-
the active ingredient depends on the disease to be treated, and on species,
age, weight
and individual condition, individual pharmacokinetic data, the disease to be
treated and the
mode of administration.
The invention relates also to pharmaceutical compositions for use in a method
for the
therapeutic treatment of the human or animal body, a process for the
preparation thereof
(especially as agents in tumour treatment) and a method of treating the above-
mentioned
diseases, especially a tumour disease, more especially one of those mentioned
above, or
psoriasis.
Preference is given to a pharmaceutical composition suitable for
administration to a warm-
biooded animal, especially a human being, suffering from a disease that is
responsive to
the inhibition of a protein kinase, especially psoriasis or a tumour disease,
comprising a
compound of formula I, or a salt thereof where salt-forming groups are
present, in an
amount effective in the inhibition of the protein kinase, together with at
least one
pharmaceutically acceptable carrier.
The pharmaceutical compositions comprise from approximately 1 °~ to
approximately 95
active ingredient, forms of administration in single dose form preferably
comprising from
approximately 20 % to approximately 90 % active ingredient and forms of
administration
that are not in single dose form preferably comprising from approximately 5 ~
to approxi-
mately 20 % active ingredient. Unit dose forms are, for example, dragees,
tablets,
ampoules, vials, suppositories or capsules. Other forms of administration are,
for example,
ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays,
dispersions, etc.
Examples are capsules comprising from approximately 0.05 g to approximately
1.0 g of the
active ingredient.
The pharmaceutical compositions of the present invention are prepared in a
manner known
per se, for example by means of conventional mixing, granulating,
confectioning, dissolving
or lyophilising procedures.
Solutions of the active ingredient, and also suspensions or dispersions,
especially isotonic
aqueous solutions, dispersion or suspensions, are preferably used, it being
possible, for
example in the case of lyophilised compositions that comprise the active
ingredient alone or
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
-37-
together with a carrier, for example mannitol, for such solutions, suspensions
or dispersions
to be made up prior to use. The pharmaceutical compositions may be sterilised
and/or may
comprise excipients, for example preservatives, stabilisers, wetting agents
and/or
emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or
buffers, and are
prepared in a manner known per se, for example by means of conventional
dissolving or
lyophilising procedures. The said solutions or suspensions may comprise
viscosity-
increasing substances, such as sodium carboxymethylcelluiose,
carboxyrnethylcelluiose,
dextran, polyvinylpyrrolidone or gelatin.
Suspensions in oil comprise as the oil component the vegetable, synthetic or
semi-synthetic
oils customary for injection purposes. There may be mentioned as such
especially liquid
fatty acid esters that contain as acid component a long-chained fatty acid
having from 8 to
22, especially from 12 to 22, carbon atoms, for example lauric acid,
tridecylic acid, myristic
acid, pentadecylic acid, paimitic acid, margaric acid, stearic acid, arachidic
acid, behenic
acid, or corresponding unsaturated acids, for example oleic acid, elaidic
acid, erucic acid,
brassidic acid or iinoleic acid, if desired with the addition of antioxidants,
for example
vitamin E, ~i-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol
component of those
fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-
hydric, for
example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol,
propanol, butanol
or pentanol or the isomers thereof, but especially glycol and glycerol. The
following
examples of fatty acid esters are therefore to be mentioned: ethyl oleate,
isopropyl
myristate, isopropyl palrnitate, "Labrafil M 2375" (polyoxyethylene glycerol
trioleate,
Gattefosse, Paris), "Labrafil M 1944 CS" (unsaturated polyglycolised
glycerides prepared by
alcohoiysis of apricot kernel oil and consisting of glycerides and
polyethylene glycol ester;
Gattefosse, France), "Labrasol" (saturated polyglycolised glycerides prepared
by
alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester;
Gattefosse,
France) and/or "Miglyol 812" (triglyceride of saturated fatty acids with a
chain length of CB to
C,2, Huls AG, Germany), but especially vegetable oils, such as cottonseed oil,
almond oil,
olive oil, castor oil, sesame oil, soybean oil and more especially groundnut
oil.
The injection compositions are prepared in customary manner under sterile
conditions; the
same applies also to introducing the compositions into, for example, ampoules
or vials and
sealing the containers.
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100127
- 38 -
Pharmaceutical compositions for oral administration can be obtained, for
example, by
combining the active ingredient with one or more solid carriers, if desired
granulating a
resulting mixture, and processing the mixture or granules, if desired, and if
necessary by the
addition of additional excipients, to form tablets or dragee cores.
Suitable carriers are especially fillers, such as sugars, for example lactose,
saccharose,
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for
example tri-
calciurn phosphate or calcium hydrogen phosphate, and also binders, such as
starches, for
example corn, wheat, rice or potato starch, methylcellulose,
hydroxypropylmethylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone, andlor, if desired,
disinte-
grators, such as the above-mentioned starches, also carboxyrnethyl starch,
crosslinlced
polyvinylpyrrolidone, or alginic acid or a salt thereof, such as sodium
alginate. Additional
excipients are especially flow conditioners and lubricants, for example
silicic acid, talc,
stearic acid or salts thereof, such as magnesium or calcium stearate, and/or
polyethylene
glycol, or derivatives thereof.
Dragee cores can be provided with suitable, optionally enteric, coatings,
there being used
interalia concentrated sugar solutions which may contain gum arabic, talc,
polyvinyl-
pyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions
in suitable
organic solvents or solvent mixtures, or, for the production of enteric
coatings, solutions of
suitable cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethyl-
cellulose phthalate. Colourings or pigments may be added to the tablets or
dragee coatings,
for example for identification purposes or to indicate different doses of
active ingredient.
Orally administrable pharmaceutical compositions also include dry-filled
capsules consisting
of gelatin, and also soft, sealed capsules consisting of gelatin and a
plasticiser, such as
glycerol or sorbitol. The dry-filled capsules may contain the active
ingredient in the form of
granules, for example in admixture with fillers, such as corn starch, binders
and/or glidants,
such as talc or magnesium stearate, and optionally stabilisers. In soft
capsules, the active
ingredient is preferably dissolved or suspended in suitable liquid excipients,
such as fatty
oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of
ethylene or propylene
gylycol, to which stabilisers and detergents, for example of the
polyoxyethylene sorbitan
fatty acid ester type, may also be added.
CA 02242354 1998-07-06
WO 97!27199 PCTlEP97100127
-39-
Other oral forms of administration are, for example, syrups prepared in
customary manner
which comprise the active ingredient, for example, in suspended form and in a
concentration of about 5 °~ to 20 °~, preferably about 10
°~6, or in a similar concentration
that provides a suitable single dose, for example, when administered in
measures of 5 or
10 ml. Also suitable are, for example, powdered or liquid concentrates for the
preparation of
shakes, for example in milk. Such concentrates may also be packaged in single
dose
quantities.
Suitable rectally administrable pharmaceutical compositions are, for example,
suppositories
that consist of a combination of the active ingredient and a suppository base.
Suitable
suppository bases are, for example, natural or synthetic trigfycerides,
paraffin hydrocarbons,
polyethylene glycols or higher alkanols.
For parenteral administration there are suitable especially aqueous solutions
of an active
ingredient in water-soluble form, for example in the form of a water-soluble
salt, or aqueous
injection suspensions that contain viscosity-increasing substances, for
example sodium
carboxymethylceliulose, sorbitol and/or dextran, and, if desired, stabilisers.
The active
ingredient, optionally together with excipients, can also be in the form of a
iyophifisate and
can be made into a solution prior to parenteral administration by the addition
of suitable
solvents.
Solutions such as are used, for example, for parenteral administration can
also be used as
infusion solutions.
Preferred preservatives are, for example, antioxidants, such as ascorbic acid,
or
microbicides, such as sorbic acid or benzoic acid.
Ointments are oil-in-water emulsions that contain up to 70 °~, but
preferably from 20 to
50 9'°, water or aqueous phase. Suitable as fatty phase are especially
hydrocarbons, for
example Vaseline, paraffin oil or hard paraffins, which, for the purpose of
improving the
water-binding capacity, preferably contain suitable hydroxy compounds, such as
fatty
alcohols or esters thereof, for example cetyf alcohol or wool wax alcohols,
such as wool
wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan
fatty acid esters
CA 02242354 1998-07-06
WO 9?/27199 PCT/EP97/00127
-40-
(Spans, for example sorbitan oleate andlor sorbitan isostearate. Additives to
the aqueous
phase are, for example, hurnectants, such as polyalcohols, for example
glycerol, propylene
glycol, sorbitol and/or polyethylene glycol, or preservatives and perfumes.
Fatty ointments are anhydrous and contain as base material especially
hydrocarbons, for
example paraffin, Vaseline~ or paraffin oil, also natural or partially
synthetic fats, for
example coconut fatty acid triglyceride, or preferably hardened oils, for
example
hydrogenated groundnut or castor oil, and also fatty acid partial esters of
glycerol, for
example glycerol mono- and/or di-stearate, and also, for example, the fatty
alcohols,
emulsifiers and/or additives that increase the water-absorption mentioned in
connection with
the ointments.
Creams are oil-in-water emulsions that contain more than 50 °~ water.
As oily base material
there are used especially fatty alcohols, for exampte lauryl, cetyl or stearyi
alcohol, fatty
acids, for example palmitic or stearic acid, liquid to solid waxes, for
example isopropyl
myristate, wool wax or beeswax, and/or hydrocarbons, for example
Vaseline° (petrolatum)
or paraffin oil. Suitable as emulsifiers are surface-active substances having
predominantly
hydrophilic properties, such as corresponding non-ionic emulsifiers, for
example fatty acid
esters of polyalcohols or ethyleneoxy adducts thereof, such as poiyglyceric
acid fatty acid
esters or polyethylene sorbitan fatty acid esters (Tweens~, also
poiyoxyethylene fatty
alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such
as alkali metal
salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium
cetyl sulfate or
sodium stearyl sulfate, which are customarily used in the presence of fatty
alcohols, for
example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are
inter alia
agents that reduce the drying out of the creams, for example polyalcohols,
such as glycerol,
sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives
and perfumes.
Pastes are creams and ointments having secretion-absorbing powder
constituents, such as
metal oxides, for example titanium oxide or zinc oxide, and also talc and/or
aluminium
silicates, the purpose of which is to bind any moisture or secretions present.
Foams are administered from pressurised containers and are liquid oil-in-water
emulsions in
aerosol form, there being used as propellants halogenated hydrocarbons, such
as chloro-
CA 02242354 1998-07-06
WO 97!27199 PCTIEP97100127
_ 4i _
fluoro-lower alkanes, for example dichlorodifluoromethane and
dichlorotetrafluoroethane, or
preferably non-halogenated gaseous hydrocarbons, air, N20 or carbon dioxide.
As oily
phase there are used intera~ia those used above in connection with ointments
and creams,
and likewise the additives mentioned therein.
Tinctures and solutions generally have an aqueous-ethanolic base to which
there are added
inter alia polyalcohols, for example glycerol, glycols and/or polyethylene
glycol, as
humectants to reduce evaporation, and fat-restoring substances, such as fatty
acid esters
with low molecular weight polyethylene glycols, i.e. lipophilic substances
soluble in the
aqueous mixture as a replacement for the fatty susbtances removed from the
skin by the
ethanol, and, if necessary, other excipients and additives.
The invention relates also to a procedure or a method for the treatment of the
above-
mentioned pathological conditions, especially a tumour disease or psoriasis,
more
especially such diseases which are responsive to the inhibition of protein
kinases. The
compounds of formula I can be administered, prophylactically or
therapeutically, as such o~
in the form of pharmaceutical compositions, preferably in an amount effective
against the
said diseases, to a warm-blooded animal, for example a human being, requiring
such
treatment, the compounds being used especially in the form of pharmaceutical
compositions. In such treatment an individual of about 70 kg body weight will
be
administered a daily dose of from approximately 0.1 g to approximately 5 g,
preferably frorr7
approximately 0.5 g to approximately 2 g, of a compound of the present
invention.
The following Examples serve to illustrate the invention but do not limit the
scope thereof.
The short names and abbreviations used have the following meanings:
Abbreviations
abs, absolute (anhydrous)
DMF dimethylformamide
FAB-MSFast Atom Bombardment mass spectroscopy
m.p. melting point
MS mass spectroscopy
CA 02242354 1998-07-06
WO 97127199 PCT/EP97/00127
-42-
R, ratio of the seepage propagation in relation to the eluant in TLC
RT room temperature
sat. saturated
THF tetrahydrofuran
TLC thin-layer chromatography
Remarks:
Unless defined more specifically, "hexane" is a mixture of the hexane isomers.
Example 1: 4-(2.3-Dihvdroindol-1-yl)-5.8-dimethvl-7H-ovrrolof2.3-dlnyrimidine
Under an argon atmosphere, 0.2 g (1.1 mmol) of 4-chloro-5,6-dimethyl-7H-
pyrrolo[2,3-dJ-
pyrimidine (see Liebigs Ann. Chem. 1986(9), 1485-1505; CAS-Reg. No. 82703-38-
6) and
0.15 ml (1.32 mmol) of 2,3-dihydroindole (Fluka, Buchs, Switzerland) in 5 ml
of abs. n-
butanof are heated at reflux for 2 hours until the starting material is no
longer present in
TLC. The reaction mixture is concentrated by evaporation in vacuo at
50°C. The brown
residue is dissolved in 30 ml of ethyl acetate, and 10 ml of 1 N NaOH solution
are added.
The organic phase is separated off and washed three times with a small amount
of water,
dried and concentrated by evaporation. The crude product is dissolved in 10 ml
of THF, and
n-hexane is added until crystallisation begins. Stirring is carried out at
0°C and the product
is filtered off with suction and dried under a high vacuum. Pure 4-(2,3-
dihydroindol-1-yl)-5,6-
dimethyl-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of colourless
crystals having a
melting point of 220-221 °C. FAB-MS: (M+H)+ = 265 (corresponds to
C16H16N4); R, value
(toluene-acetone - 4:6) = 0.46.
Example 2: 4-(6-Chloro-2.3-dihvdroindo!-1-vl)-5.6-dlmethyl-7Hpyrroloj2L3-
dlswrimidine
This product is prepared in a manner analogous to that described in Example 1
from 4-
chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-dihydroindole
(1.1 equi-
valents, see J. Org. Chem. 55(2), 580-584 {1990); CAS Reg. No. 52 537-00-5).
Example 3: 4-(6-Bromo-2.3-dihydrotndol-1-yl)-5,6-dimethyl-7H-pyrroiof2.3-
dlpyrimidine
This product is prepared in a manner analogous to that described in Example 1
from 4-
chforo-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-bromo-2,3-dihydroindole
(1.1 equi-
valents, see WO 95/23141; CAS Reg. No. 63 839-24-7).
CA 02242354 1998-07-06
WO 97127199 PCTIEP97100I27
-43-
t=xample 4: 4-(6-Methyt-2,3-dihvdrotndol-1-y1~5,6-dimethv!-7H-pyrrolot2.3-
dlpyrimldine
This product is prepared in a manner analogous to that described in Example 1
from 4-
chloro-5,6-dimethyl-7H-pyrrolo[2,3-djpyrimidine and 6-methyl-2,3-dihydroindoie
(1.1 equi-
valents, see WO 95/23141; CAS Reg. No. 86 911-82-2).
Example 5: 4-(1,2.3,4-Tetrahydroaulnoltn-1-vl)-5.6-dimethvl-7H,Jwrrolof2.3-
dlpvrimidirte
This product is prepared in a manner analogous to that described in Example 1
from 4-
chloro-5,6-dimethyl-7H-pyrrolo[2,3-d)pyrimidine and 1,2,3,4-
tetrahydroquinoline (4 equi-
valents, Fiuka, Buchs, Switzerland). M.p: 263-264°C; FAB-MS: (M+H)+ =
279 (corresponds
to C17H18N4); R, value (toluene-acetone - (4:6)) = 0.29.
t=xample 6: 4-(2.3-Dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo(2.3-
dlpyrimidine
Under a nitrogen atmosphere, 0.5 g (1.82 mmol) of 4-chforo-6-(4-vitro-phenyl}-
7H-pyrrofo-
[2,3-djpyrimidine and 0.43 ml (2.1 equivalents) of 2,3-dihydroindole in 10 ml
of abs. n-
butanol are heated at reflux for 1.5 hours until the starting material is no
longer present in
TLC, the desired product precipitating out and being filtered off. The brown
crude product is
stirred thoroughly in about 20 ml of 1 N NaOH for about 15 minutes, and the
suspension is
filtered with suction and the residue is washed with water, n-butanol and
hexane and dried
under a high vacuum. 4-(2,3-Dihydroindol-1-yl)-6-(4-vitro-phenyl)-7H-
pyrrolo[2,3-
d)pyrimidine is obtained in the form of a rust-brown powder having a melting
point of >
300°C. FAB-MS: (M+H)+ = 358 (corresponds to C2pH15N502); R, value
(toluene-acetone -
4:6) = 0.40.
The starting material is prepared as follows:
Step 6.1: 2-Amino-3-ethoxycarbonyl-5-(4-vitro-phenyl)-pyrrole
in a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390
mmol} of 2-
amidino-acetic acid ethyl ester hydrochloride [preparation see: Liebigs Ann.
Chem., 1895
(1977)] are cooled to 0-5°C and 2.65 g (390 mmol) of sodium ethanolate
are added. 5 g
(195 mmol) of 2-bromo-1-(4-vitro-phenyl}-ethan-1-one are then added and the
mixture is
allowed to rise to room temperature and is stirred for a further 48 hours. The
reaction
mixture is then partitioned between water and ethyl acetate. The ethyl acetate
phase is
CA 02242354 1998-07-06
WO 97/27199 PCT/EP97/00127
-44-
washed three times with water and once with sat. NaCI solution, dried and
filtered, and the
filtrate is concentrated by evaporation. The reddish-brown residue is made
into a slurry in
hexane, the title compound precipitating in the form of a crude product
(purity 93 %) which
is used for the next step without further purification; MS: (M)+ = 275.
Step 6 2' 4-Hydrox~r-6-(4-nitro~~hen~rl)-7H-p~rrrolof2 3-djpyrirnidine
2.5 g (97 rnmol) of 2-amino-3-ethoxycarbonyl-5-(4-vitro-phenyl)-pyrrole, 19.4
ml of form-
amide, 9.7 ml of DMF and 3.1 ml of formic acid are stirred together at
150°C for 22 hours.
1 ml of isopropanol is added to the warm reaction mixture. After the reaction
mixture has
cooled, the precipitated product is filtered off and washed in succession 3
times with 10 ml
of ethanol each time, twice with 10 ml of isopropanol each time and twice with
10 mi of
hexane each time. The title compound is obtained in the form of rust-brown
crystals which
are used for the next step; MS: (M)+ = 256.
Step 6.3: 4-Chloro-6-(4-vitro-phen~rl)-7H-pyrrolof2,3-tl]pyrimidine
4-Chloro-6-(4-vitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is prepared, with the
exclusion of
moisture, by heating 4-hydroxy-6-(4-vitro-phenyl)-7H-pyrrolo[2,3-djpyrimidine
to boiling point
with an excess of POCI3. The suspension is concentrated to a residual volume
of 20 ml by
evaporation. The residue is introduced in portions into water, neutralised
with solid NaHCO:,,
and 0.2 litre of ethyl acetate is added. Filtration and washing with hot THF
yield the title
compound, m.p. > 280°C; FAB-MS: (M+H)+ = 275.
Example 7: 4-(2,3-Dihvdroindol-1-yl)-&(4-amino-phenYtZ 7H-pyrrolot2,3-
dlpyrimid~e
400 mg of 4-(2,3-dihydroindol-1-yl)-6-(4-vitro-phenyl)-7H-pyrrolo[2,3-
djpyrimidine
(Example 6) are hydrogenated with 150 mg of Raney nickel in methanol/THF
(35:20) at RT
and normal pressure for 10 hours. The catalyst is filtered off and the
solution is
concentrated by evaporation. The residue is dissolved in THF and the product
is
precipitated by the addition of hexane. 4-(2,3-Dihydroindo!-1-yl)-6-(4-amino-
phenyl)-7H-
pyrrolo[2,3-d]pyrimidine is obtained in the form of a colourless powder. M.p.
> 300°C;
FAB-MS: (M+H)+ = 328 (corresponds to C2pH17N5); R, value (toluene-acetone -
4:6) _
0.21.
CA 02242354 1998-07-06
WO 97/27199 PCTlEP97100127
-45-
Example 8' 4-(6-Chloro-2.3-dlhydrpindol-1-y1~6-(4-nitro-phenyl)-7H-pyrrolof2.3-
d1-
pyrimidine
This product is prepared in a manner analogous to that described in Example 6
from
4-chloro-6-(4-vitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-
dihydroindole
(1.1 equivalents).
Example 9' 4-~6-Chloro-2.3-dihydroindol-1-yl)-6-(4-amino-phenyl)-7H-
pyrrolof2,3-dl-
pyrimidine
This product is obtained in a manner analogous to that described in Example 7
by
hydrogenation of 4-(6-chloro-2,3-dihydroindol-1-yl)-6-(4-vitro-phenyl)-7H-
pyrrolo[2,3-dJ-
pyrimidine (Example 8) with Raney nickel.
Example 10' 4-(1.2.3,4-Tetrahydroquinoiin-1-yl)-6-(4-nitro-phenyl)-7H-
pyrrolof2.3-dl-
pyrimidine
This product is prepared in a manner analogous to that described in Example 6
from 4-
chloro-6-(4-vitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-
tetrahydroquinoline
(2.i equivalents). FAB-MS: (M+H)+ = 372 (corresponds to C21 H17N502); R, value
(toluene-acetone - 4:6) = 0.36.
Example 11' 4-X1,2.3 4-TetrahydroQUinolin-1-yl~-6-(4-amino-phenyl]-
7Hpyrrolo12,3-d1-
pvrimidine
This product is obtained in a manner analogous to that described in Example 7
by
hydrogenation of 4-(1,2,3,4-tetrahydroquinolin-1-yl}-6-(4-vitro-phenyl)-7H-
pyrrofo[2,3-d]-
pyrimidine (Example 10} with Raney nickel. M.p. 243-245°C; FAB-MS:
(M+H)+ = 342
(corresponds to C21 H1 gN5); R, value (toluene-acetone - 4:6) = 0.25.
Example 12: 4-(2.3-Dihydroindol-1-vl)-6-(4-methoxy-phenyl)-7H-pyrrolof2.3-dl-
pyrimidine
This product is prepared in a manner analogous to that described in Example 1
from 4-
chloro-6-(4-methoxy-phenyl)-7H-pyrrolo(2,3-d]pyrimidine and 2,3-dihydroindoie
(1.1 equi-
valents). M.p. > 300°C; FAB-MS: (M+H)+ = 343 (corresponds to C21 H1
gN40).
Example 13: Dry-filled capsules
CA 02242354 1998-07-06
WO 97127199 PCTIEP9?100127
-46-
5000 capsules, each comprising as active ingredient 0.25 g of one of the
compounds of
formula I mentioned in the preceding Examples, are prepared as foltows:
Composition
active ingredient 1250 g
talcum 180 g
wheat starch 120 g
magnesium stearate 80 g
lactose 20 g
Preparation method: The powdered substances listed above are pressed through a
sieve a
0.6 mm mesh size. 0.33 g portions of the mixture are introduced into gelatin
capsules using
a capsule-filling machine.
Example 14: Soft capsules
5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one
of the
compounds of formula I mentioned in the preceding Examples, are prepared as
follows:
Composition
active ingredient 250 g
Lauroglykol 2 litres
Preparation method: The powdered active ingredient is suspended in
Lauroglykola
(propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground
to a particle
size of about 1 to 3 ~.m in a wet pulveriser. 0.419 g portions of the mixture
are then
introduced into soft gelatin capsules using a capsule-filling machine.
Examale 15: Soft capsules
5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one
of the
compounds of formula I mentioned in the preceding Examples, are prepared as
follows:
Composition
active ingredient 250 g
CA 02242354 1998-07-06
WO 97127199 PCTIEP97J00127
-47-
PEG 400 1 litre
Tween 80 1 litre
Preparation method: The powdered active ingredient is suspended in PEG 400
(polyethylene glycol of M, from about 380 to about 420, Fluka, Switzerland)
and Tween~ 80
(polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind., Inc., USA, supplied
by Fluka,
Switzerland) and ground to a particle size of about 1 to 3 ~.m in a wet
pulveriser. 0.43 g
portions of the mixture are then introduced into soft gelatin capsules using a
capsule-filling
machine.
CA 02242354 1998-07-06
WO 97127199 PCTlEP97100127
-48-
Example 16' inhibition of the EGF-receptor-specific tyrosine kinase
In accordance with the method mentioned above and using the recombinant
intracellular
domain of the EGF receptor (Europ. J. Biochem. 207, 265-275 (1992)), the
following IC~o
values are obtained:
Compound of Example ICS (~M)
1 1.56
2.69
7 0.21
11 0.026
Example 17' Inhibition of the 4rowth of MK (mouse keratinocyte) cells in
vJtro:
The growth of BALB/MK cells in the presence of compounds of formula I is
tested in
accordance with the procedure described above. The following inhibition values
(ICS) are
obtained:
Compound of Example ICso (~M)
7 15.8
11 0.76
_Example 18' Inhlbiton of the v-abl kinasa:
In accordance with the procedure mentioned above (Oncogene Research 5, 161-173
(1990) and Cancer Research 52, 4492-4498 (1992), the following ICSO values are
obtained:
Compound of Example ICSO (~.M)
7 0.078
11 0.002
