Indian Patents
Title of Invention

AMINOQUINOLINE DERIVATIVES
Abstract Compounds of the general formula (I), and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) as well as the salts and solvates; are strong adenosine A3 receptor ligands preferably antagonists.
Full Text WO 2005/009969 PCT/HU2004/000080
AMINOQUINOLINE DERIVATIVES AND THEIR USE AS ADENOSINE A3 LIGANDS
The present invention relates to the adenosine A3 receptor ligands of
the general formula (I), within those preferably to the antagonists, as well as
to their salts, solvates and isomers (tautomers, desmotrops, optically active
isomers), to the pharmaceutical compositions containing them, to the use of
the compounds of the general formula (I) and their salts, solvates and
isomers, to the preparation of the compounds of the general formula (I) and
their salts, solvates and isomers, to the partly novel intermediates of the
general formula (II"), (III"), (IV"), (V"), (VI"), (VII"), (VIII") and (XIII")
and to the preparation thereof.
Adenosine is a well-known component of several endogenous
molecules (ATP, NAD+, nucleic acids). It plays an important regulatory
role in many physiological processes. The effect of adenosine on the heart
function was described already in 1929 (Drury and Szentgyörgyi, Physio!.
68:213, 1929). The identification of an increasing number of physiological
functions mediated by adenosine and the discovery of new adenosine
receptor subtypes are offering possibilities for the therapeutic application of
specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal
Chemistry 6:619, 1998).
To date, the receptors for adenosine have been classified into three
main classes: A1, A2 and A3. The A1 subtype is partly responsible for the
inhibition of the adenylate cyclase by coupling to G1 membrane protein, and
partly influences other second messenger systems. The A2 receptor subtype
can be subdivided into two further subtypes - A2a and A2b -, which
stimulate the adenylate cyclase activity. The sequence of the adenosine A3
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receptors have been first identified from rat testis cDNA library. Later it
was proved that it corresponds to a novel, functional adenosine receptor.
The activation of the A3 receptors is also connected with several second-
messenger systems: inhibiting of adenylate cyclase, stimulating
phospholipase C and D.
The adenosine receptors are found in several organs and regulate
their functions. Both A1 and A2a receptors play important role in the central
nervous system and cardiovascular system. In the CNS, the adenosine
inhibits the release of synaptic transmitters which effect is mediated by A1
receptors. In the heart, the A1 receptors also mediate the negative inotropic,
chronotropic and dromotropic effects of adenosine. The adenosine A2a
receptors, which are located in a relatively high amount in the striatum,
display functional interaction with the dopamine receptors in regulating the
synaptic transmission. The A2a adenosine receptors on endothelial and
smooth muscle cells are responsible for adenosine-induced vasodilation.
On the basis of RNA identification, the A2b adenosine receptors are
widely distributed in different tissues. They have been identified in almost
every cell type, but its expression is the highest in the intestine and the
bladder. This subtype probably also has important regulatory function in
the regulation of the vascular tone and plays a role in the function of mast
cells.
Contrary to A1 and A2a receptors, where the tissue distribution was
detected on the protein level, the presence of A2b and A3 receptors was
detected on the basis of their mRNA level. Expression levels for A3
adenosine receptors are rather low compared to other subtypes and they are
highly species dependent. A3 adenosine receptors are expressed primarily
in the central nervous system, in the testis and in the immune system, and
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appear to be involved in the modulation of the mediator release from the
mast cells in immediate hypersensitivity reaction.
For therapeutic use, it is essential to ensure that the molecule does
not bind, or binds only in the case of very high concentration to the A1, A2a
and A2b sub-types of the adenosine receptor.
Our present invention relates to the compounds of the general
formula.(I) as well as their salts, solvates and isomers, which have high
selectivity for the A3 sub-type of the adenosine receptor.
A3 antagonists published so far in the literature, belong to the groups
of flavonoides, 1,4-dihydropyridine derivatives, triazoloquinazolines,
thiazolonaphthyridines and thiazolopyrimidines. Most of the effective and
for the adenosine subtypes selective antagonists, however posses strong
lipophilic character, and they are therefore sparingly soluble in water. This
feature hinders the in vivo applicability of the compounds. In the literature
more and more studies are to find aiming the preparation of water soluble
adenosine A3 receptor antagonists (Ch. E. Miiller et ai., J. Med. Chem.
45:3440, 2002; A. Maconi et al., J. Med. Chem. 45:3579, 2002).
Patent application WO 02/096879 discloses 2-amino-3-
cyanoquinoline derivatives as structurally novel type, effective A3
antagonists. The compounds of the formula (1) described in patent
application WO 02/096879 are A3 antagonists with high selectivity.
In the general formula (1)
R1 stands for hydrogen atom or straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, thienyl, or furyl group, optionally substituted with one or
more straight or branched C1-4 alkyl group, straight or branched C1-4
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alkoxy group or halogen atom; a six- or five-membered
heteroaromatic ring containing one, two or three nitrogen atoms, or
one nitrogen atom and one oxygen atom, or one nitrogen atom and
one sulphur atom, optionally substituted with one or more straight or
branched C1-4 alkyl group, straight or branched C1-4 alkoxy group or
halogen atom;
R9, R10, R11, and R12 independently stand for hydrogen atom, straight or
branched C1-4 alkyl group, straight or branched C1-4 alkoxy group,
hydroxy group or halogen atom, or R9 and R12 stand for hydrogen
atom and R10 and R11 form together a methylenedioxy group;
R6 stands for hydrogen atom or a cyano group, aminocarbonyl group,
C1-4 alkoxycarbonyl group, or carboxy group;
R7 stands for hydrogen atom or straight or branched C1-4alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with
methylenedioxy-group or with one or more straight or branched C1-4
alkyl group, straight or branched C1-4 alkoxy group, hydroxy group,
trifluoromethyl group, cyano group or halogen atom; or a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one
or more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
X stands for -CH2- group, -NH- group, -NR8- group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R8 stands for
straight or branched C1-4alkyl group or C3-6 cycloalkyl group;
n represents zero, 1 or 2;
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These compounds too, have the characteristic disadvantage that they
are only sparingly soluble, which hampers their development into a drug.
Our aim was to prepare A3 ligands, within them preferably
antagonists, with quinoline structure, which exert strong antagonistic effect
and high selectivity for the A3 receptor, i.e. they inhibit the A3 receptor in
much lower concentration than they inhibit the A1 A2a and A2b receptors.
Further aims were to have stability, bioavailability, therapeutic index,
toxicity and solubility data, which enable these new compounds to develop
into drug substances, and that the new compounds possess favourable
enteric absorption to be applied orally.
We have found that the compounds of the general formula (I),
wherein
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or branched C1-4 alkyl group,
straight or branched C1-4 alkoxy group, or halogen atom; a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or a five-membered heteroaromatic ring containing
one nitrogen atom and one oxygen atom, or one nitrogen atom and
one sulphur atom, optionally substituted with one or more straight or
branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, or
halogen atom;
R4 and R5 independently stand for hydrogen atom, C3.6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an
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amino group, or an amino group substituted with one or two straight
or branched C1-4 alkyl group, a hydroxy group, a carboxy group, or
an alkoxy group substituted with a straight or branched C1-4 alkyl
group -; or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group
or a benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4acyl group, or
R4 and R5, together with the nitrogen atom, form a group of the general
*
formula a.), wherein R7 and R8 independently stand for hydrogen
atom, straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
R6 stands for hydrogen atom or straight or branched C1-4alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with
methylenedioxy group, or with one or more straight or branched C1-4
alkyl group, straight or branched C1-4 alkoxy group, hydroxy group,
trifluoromethyl group, cyano group or halogen atom; or a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one
or more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
X stands for -CH2- group, -NH- group, -NR9- group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9 stands for
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z stands for oxygen atom sulphur atom, -CHRl0-group or -NR11-
group, wherein R10 stands for hydrogen atom, straight or branched
C1-4 alkyl group, or C3-6 cycloalkyl group and R11 stands for
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hydrogen atom, straight or branched C1-4 alkyl group, C3-6 cycloalkyl
group, -SO2OH group or a straight or branched C1-4 acyl group ;
n represents zero, 1 or 2;
m represents 1,2, or 3;
o represents' 1, 2, or 3;
p represents zero or 1;
r represents zero or 1,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates thereof fulfil the above criteria,
their solubility data are by far better than those of the known 2-amino-3-
cyanoquinolines, and besides, they are highly active.
As shown by liquid phase NMR studies, in solution the compounds
of the general formula (I) are equilibrium mixtures of the tautomeric forms
(IA) and (IB). In solid phase the tautomers (IA) and (IB) can be isolated
separately, as the desmotrops (IA) and (IB).
According to the above findings, the present invention also relates to
the desmotropic isomers (IA) and (IB). The meanings of the substituents in
the general formulae (IA) and (IB) are as defined for the general formula
The compounds of the general formula (I) may have a chiral centre
depending for instance on the meaning of the set of substituents R1 , R2 , and
R3. Thus, the invention also relates to the racemic and optically active
forms of the compounds of the general formula (I) and their salts,
tautomers and desmotrops.
Detailed meanings of the above substituents are as follows:
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WO2005/009969 PCT/HU2004/000080
By a straight or branched C1-4 alkyl group we mean a methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, secondary-butyl or tertiary-butyl group,
preferably ethyl or methyl group.
By a straight or branched C1-4 alkoxy group we mean a methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary-butoxy,
tertiary-butoxy, preferably ethoxy or methoxy group.
By a C3-6 cycloalkyl group we mean a cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl group.
By a straight or branched C1-4 acyl group we mean a formyl, acetyl,
propionyl, 2-methyl-propionyl, orbutyryl group.
By the heteroaromatic ring containing one, two or three nitrogen
atoms we mean a pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,
pyridine, pyrimidine, pyridazine, pyrazine or 1,2,4-triazine ring. The ring
may optionally be substituted with a C1-4 alkyl group, C1-4 alkoxy group, or
halogen atom.
By the heteroaromatic ring containing one nitrogen atom and one
oxygen- or one sulphur atom we mean an oxazole, isoxazole, thiazole or
isothiazole ring. The ring may optionally be substituted with a C1-4 alkyl
group, C1-4 alkoxy group, or halogen atom.
The a.) group preferably represents a pyrrolidino, piperidino,
piperazino, 4-methylpiperazino, 4-formylpiperazino, 4-sulfonylpiperazino
or morpholino group.
By salts of the compounds of the general formula (I) we mean salts
formed with inorganic or organic acids and bases. Preferred salts are given
with pharmaceutically accepted acids, as for instance hydrochloric acid,
sulphuric acid, ethanesulphonic acid, tartaric acid, malic acid, citric acid,
fumaric acid, and with pharmaceutically accepted bases, as for instance
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sodium hydroxide, potassium hydroxide, and ethanolamine. Salts used for
purification or isolation, as for instance the methanesulphonate or
tetrafluoroborate salts are also subjects of the invention.
By solvates we mean solvates given with various solvents, as for
instance with water or ethanol. -
A favoured group of the compounds of the general formula (I) are'
those, wherein
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or branched C1-4 alkyl group,-
straight or branched C1-4 alkoxy group, or halogen atom;
R4 and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an
amino group, or an amino group substituted with one or two straight
or branched C1-4 alkyl group, a hydroxy group, a carboxy group, or
an alkoxy group substituted with a straight or branched C1-4 alkyl
group -; or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group
or a benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4acyl group, or
R4 and R5, together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen
atom, straight or branched C1-4alkyl group or C3-6 cycloalkyl group;
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R6 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with a
methylenedioxy group, or with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy
group, trifluoromethyl group, cyano group, or halogen atom; or a six-
or five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one
or more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
X stands for -CH2- group, -NH- group, -NR9- group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9 represents
a straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z stands for oxygen atom, sulphur atom, -CHR10-group or -NR11-
group, wherein R10 represents hydrogen atom, straight or branched
C1-4 alkyl group, or C3-6 cycloalkyl group and R11 stands for
hydrogen atom, straight or branched C1-4 alkyl group, C3-6 cycloalkyl
group, -SO2OH group or formyl group;
n represents zero, 1 or 2;
m represents 1, 2, or 3;
o represents 1, 2, or 3;
p represents zero or 1;
r represents zero or 1,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates thereof.
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A specially favoured group of the compounds of the general formula
(I) are those, wherein
R1 stands for hydrogen atom or methyl group;
R2 stands for hydrogen atom or methyl group;
R3 stands for phenyl, thienyl, or furyl group;
R and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an
amino group, or an amino group substituted with one or two straight
or branched C1-4 alkyl group, a hydroxy group, a carboxy group, or
an alkoxy group substituted with a straight or branched C1-4 alkyl
group -; or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl alkyl
group or a benzyl group, and.
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4acyl group, or
R4 and R5, together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen
atom, straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
R6 stands for 4-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,4-
methylendioxyphenyl group, 4-fluorophenyl, 2-thienyl or 2-furyI
group;
X stands for -NH- group, or oxygen atom;
Z stands for oxygen atom, sulphur atom, -CH2- group, -NH- group or
-NR11- group -wherein R11 represents a straight or branched C1-4
alkyl group, C3-6 cycloalkyl group, -SO2OH group or formyl group;
and
n represents 1;
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m represents 2;
o represents 2;
p represents zero;
r represents zero,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates thereof.
Especially favoured are the following compounds, which fulfil the
above criteria:
4-Methoxv-N-[6-(morpholin-4-yl)-4-benzylamino-3-cyanoquinolin-2-yll-
benzamide
4-Methoxv-N-[6-(4-methylpiperazin-l-yl)-4-benzvlamino-3-
cyanoquinolin-2-yl]benzamide
4-Methoxy-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-
yl)benzamide
3,4-Methylenedioxy-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolm-
2-yl)benzamide
4-Fluoro-N-(6-dimethylamino-4-benzylamino-3-cvanoquinolin-2-
yl)benzamide
4-Methoxy-N-(6-fpiperazin-l-yl)-4-benzylamino-3-cvanoquinolin-2-
yl)benzamide
4-Methoxv-N-(6-amino-4-benzylamino-3-cyanoquinolin-2-yl)benzamide
N-[4-(Benzylamino)-3-cyan-6-(4-formylpipera2in-l-yl)quinolin-2-yn-4-
methoxybenzamide
4-{4-(Benzylamino)-3-cyano-2-[(4-methoxybenzoy)amino]quinolin-6-
yl}piperazine-1-sulfonic acid
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N-{3-Cyvano-6-(formylamino)-4-[(2-thienylmethyl)amino]quinolin-2-yl}-4-
methoxvbenzamide
N-{3-Cvano-6-(formylamino)-4-[(2-thienylmethyl)amino]quinolin-2-yl}-
1,3-benzodioxole-5-carboxamide
N-[4-(Benzylamino)-3-cyano-6-(formylamino)quinolin-2-yl]-1,3:
benzodioxole-5-carboxamide
N-[4-(BenzvlaTnino)-3-cyano-6-(formylamino)quinolin-2-yl]-4-
methoxybenzamide
N-{4-(Benzylamino)-3-cyano-6-rformyl(methynamino1quinoIin-2-yl}-4-
methoxybenzamide
N-{3-Cyano-6-rformylCmethyl)amino1-4-[(2-
thienyImethyl)amino1quinolin-2-yl}-4-methoxybenzamide
{3-Cyano-2-[(4-methoxybenzoyl)amino]-4-[(2-
thienvlmethyl)amino]quinolin-6-yl}methylsulfamic acid
(4-(Benzylamino)-3-cyano-2-[(4-methoxybenzoy)amino]quinolin-6-
yl}methylsulfamic acid
(4-(Benzylamino)-3-cyano-2-[(4-methoxybenzoynamino]quinolin-6-
yl}sulfamic acid
[2-[(1,3-Benzodioxol-5-ylcarbonyl)amino1-4-(benzyIamino)-3-
cyanoquinolin-6-ylisulfamic acid
(2-rn,3-Benzodioxol-5-ylcarbonyl)amino]-3-cyano-4-[(2-
thienylmethyI)amino]quinolin-6-yl}sulfamic acid
{3-Cvano-2-[(4-methoxvbenzoyl)amino]-4-[(2-
thienylmethyl)amino]quinolin-6-yl}sulfamic acid
and
their salts, solvates, isomers (tautomers, desmotrops), as well as the
salts and solvates thereof.
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The compounds of the general formula (I) according to tne present
invention as well as their salts, solvates, and isomers (tautomers,
desmotrops, optically active isomers) and the salts, solvates thereof, display
suitable solubility, therefore they can favourably be used as active
substances of pharmaceutical compositions.
Solubility values in water and in aqueous buffer solutions (pH = 6.5
and 7.5) for the compounds of the formula (1) of patent application WO
02/096879 are less than 1 mg/L, whereas those for the compounds of the
general formula (I) of the present invention are between 1-200 mg/L.
The present invention also relates to pharmaceutical compositions
containing as active principles the compounds of the general formula (I) or
their isomers (tautomers, desmotrops, optically active isomers), salts or
solvates, which are preferably oral compositions, but inhalable, parenteral
and transdermal formulations are also subjects of the invention. The above
pharmaceutical compositions may be solids or liquids, such as tablets,
pellets, capsules, patches, solutions, suspensions or emulsions. Solid
compositions, first of all tablets and capsules are preferred.
The above pharmaceutical compositions are prepared by applying
usual pharmaceutical auxiliary materials and by using standard methods.
The compounds of the general formula (I) can be used for the
treatment of pathologies, where A3 receptor plays a role in the development
of the disease.
The compounds of the present invention having selective activity on
the A3 receptor can be used in the therapeutic and/or preventive treatment
of disfunctions of the heart, kidney, respiratory system, central nervous
system. They inhibit the protective effect of adenosine in growing tumor
cells, prevent mast cell degranulation, inhibit the cytokine production,
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reduce the inraocular pressure, inhibit the TNF release, inhibit the
migration of eosinophils, neutrophils and other immune cells, inhibit the
bronchoconstriction and plasma extravasation.
Based on these effects, adenosine A3 receptor antagonists of the
present invention may be therapeutically useful as antiinflammatory,
antiasthmatic, antiischemic, antidepressant, antiarrhytmic, renal protective,
antitumor, antiparkinson and cognitive enhancing drugs. They also may be
useful in the treatment or prevention of miocardial reperfusion injury,
chronic obstructive pulmonary disease (COPD) and adult respiratory
distress syndrome (ARDS) including chronic bronchitis, pulmonary
emphysema or dyspnea, allergic reactions (e.g. rhinitis, poison ivy induced
responses, urticaria, scleroderma, arthritis) other autoimmune diseases,
inflammatory bowel disease, Addison's disease, Crohn's disease, psoriasis,
rheumatism, hypertension, neurogical function disorders, glaucoma and
diabetes (K. N. Klotz, Naunyn-Schmiedberg's Arch. Pharmacol. 362:382,
2000; P. G. Baraldi es P. A. Borea, TiPS 21:456, 2000).
The compounds of the present invention may be preferably used for
the manufacture of a pharmaceutical composition for the treatment of
diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic and
inflammatory diseases, ischemia, hypoxia, arrythmia and renal diseases.
The present invention relates furthermore to the use of the
compounds of the general formula (I) in the treatment of the above
pathologies. The suggested daily dose is 0.1 - 1000 mg active ingredient,
depending on the nature and severeness of the disease and on the sex,
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A further subject of the invention is the preparation of the
compounds of the general formula (I).
The substituents in the formulae of the intermediates and reagents of
the general formulae (I"), (II"), (III"), (IV"), (V11), (VI"), (VII"), (VIII"),
(IX"), (X"), (XI"), (XII"), (XIII") and (XIV") have the meanings as follows.
R1" stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2" stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3" stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or branched C1-4 alkyl group,
straight or branched C1-4 alkoxy group, or halogen atom; a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or a five-membered heteroaromatic ring containing
one nitrogen atom and one oxygen atom, or one nitrogen atom and
one sulphur atom, optionally substituted with one or more straight or
branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, or
halogen atom;
R4 and R5 independently stand for hydrogen atom, C3_6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an
amino group, or an amino group substituted with one or two straight
or branched C1-4 alkyl group, a hydroxy group, a carboxy group, or
an alkoxy group substituted with a straight or branched CM alkyl
group -or a protective group; or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group
or a benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4 acyl group or a protective group, or
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R4' and R5", together with the nitrogen atom, form a nitro group or a group
of the general formula a.), wherein R7" and R8" independently stand
for hydrogen atom, straight or branched C1-4 alkyl group or
C3-6 cycloalkyl group;
R6 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with
methylenedioxy group, or with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy
group, trifluoromethyl group, cyano group or halogen atom; or a six-
or five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one
or more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
X" stands for -CH2- group, -NH- group, -NR9 - group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9' stands
for straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z" stands for oxygen atom sulphur atom, -CHR10" -group or -NR11" -
group, wherein R10 stands for hydrogen atom, straight or branched
C1-4 alkyl group, or C3-6 cycloalkyl group and R11" stands for
hydrogen atom, straight or branched C1-4 alkyl group, C3-6 cycloalkyl
group, -SO2OH group, a straight or branched C1-4 acyl group or a
protective group;
R12" stands for a straight or branched C1-4 alkylgroup;
Y" represents a living group;
n represents zero, 1 or 2;
m represents 1,2, or 3;
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WO 2005/009969 PCT/HU2004/000080
o" represents 1,2, or 3;
p represents zero or 1;
r represents zero or 1,
A further subject of the invention is the preparation of the
compounds of the general formula (I) and of the partly novel intermediates
of the general formulae (I"), (II"), (III"), (IV"), (V11), (VI"), (VII"), (VIII"),
and (XIII").
In the process according to the invention
v.) the bis-carboxamide of the general formula (II") is selectively
hydrolysed and if desired the protective group removed, or
v/i.) for the preparation of a compound of the general formula (I),
wherein R4 stands for hydrogen atom, a straight or branched C1-4 alkyl
group or benzyl group and R5 stands for a straight or branched C1-4 acyl
group, or R4 and R5 together with the nitrogen atom form a group of the
general formula a.), wherein Z stands for a -NR11 group, where R11 stands
for a straight or branched C1-4 acyl group and R1,R2,R3,R4,R5,R6,R7,X,
n, m, o, p and r are as defined above,
a compound of the general formula (I), wherein R4 stands for
hydrogen atom, a straight or branched C1-4 alkyl group or benzyl group and
R5 stands for hydrogen atom, or R4 and R5 together with the nitrogen atom
form a group of the general formula a.), wherein Z stands for -NH group
and R1, R2, R3, R6, R7, R8, R9, X, n, m, o, p and r are as defined above,
is acylated with a compound of the general formula R12 COY",
wherein R12 and Y" are as defined above, or
v/ii.) for the preparation of a compound of the general formula (I), wherein
R4 stands for hydrogen atom, a straight or branched CM alkyl group or
benzyl group and R5 stands for -SO2OH group, or R4 and R5 together with
18

WO 2005/009969 PCT/HU2004/000080
the nitrogen atom form a group of the general formula a.), wherein Z stands
for -NR11- group,where R11 stands for -SO2OH group and R1, R2, R3, R6,
R7 , R8 , R9 , X, n, m, o, p and r are as defined above,
a compound of the general formula (I), wherein R4 stands for
hydrogen atom, a straight or branched C1-4 alkyl group or benzyl group and
R5 stands for hydrogen atom, or R4 and R5 together with the nitrogen atom
form a group of the general formula a.), wherein Z stands for-NH- group
and R1, R2, R3, R6, R7, R8, R9, X, n, m, o, p and r are as defined above,
is reacted with a pyridine-SO3 complex, or with CISO3H, or
v/iii.) for the preparation of a compound of the general formula (I),
wherein R4 stands for hydrogen atom, a straight or branched C1-4 alkyl
group or benzyl group and R5 stands for -SO2OH group and'R1, R2, R3, R
R7 , R8 , R9 , X, Z, n,m, o, p and r are as defined above,
a compound of the general formula (XIII"), wherein R1, R2, R3, R6,
R9, X, and n are as defined above
is reacted with Na2S2O4 orNaHSO3,
or
is reduced and the compound of the general formula (XIV"), thus
obtained, wherein R4 stands for hydrogen atom and R1" , R2", R3", R6", R9",
X", and n", are as defined above, is sulphated with a pyridine-SO3 complex
or with CISO3H,
if desired after transforming the R4" hydrogen atom into a straight or
branched C1-4 alkyl group or a benzyl group, or
v/iv.) for the preparation of a compound of the general formula (I), wherein
R4 stands for hydrogen atom, C3-6 cycloalkyl group, benzyl group, straight
or branched C1-4 alkyl group - optionally containing an amino group, or an
amino group substituted with one or two straight or branched C1-4 alkyl
19

WO 2005/009969 PCT/HU2004/000080
group, a hydroxy group, a carboxy group, or an alkoxy group substituted
with a straight or branched C1-4 alkyl group- and R5 stands for hydrogen
atom, or
R and R5, together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group and Z stands
for -NR11 group, where R11 stands for hydrogen atom,
removing the protective group of a compound of the general formula
(I"), wherein
R4' stands for hydrogen atom, C3-6 cycloalkyl group, benzyl group, straight
or branched C1-4 alkyl group - optionally containing an amino group, or an
amino group substituted with one or two straight or branched C1-4 alkyl
group, a hydroxy group, a carboxy group, or an alkoxy group substituted
with a straight or branched C1-4 alkyl group - and R5" stands for a protective
group, or
R4" and R5", together with the nitrogen atom, form a group of the general
formula a .), wherein R7" and R8" independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group and Z stands
for-NR11 group, where R11 stands for a protecting group,
and -if desired- the substituents of the resulting compound of the general
formula (I) are transformed into each other by known methods, and/or the
the compound of the general formula (I) thus obtained is transformed into
its salt or solvate, or liberated from its salt or solvate and -if desired-
resolved into its optically active isomers and -if desired- a given desmotrop
is transformed into an other desmotropic form.
As for agents for the selective hydrolysis, alkali hydroxides,
preferably potassium hydroxide and/or sodium hydroxide dissolved in an
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WO 2005/009969 PCT/HU2004/000080
alcohol, preferably in methanol can be used, but other agents known in the
organic chemistry helping the amide hydrolysis, can also be applied.
The selective hydrolysis can be carried out in a broad temperature
range, preferable is the range between 20 °C and 100 °C.
The reaction v/i.) can be performed using an ester derivative of the
appropriate acid at elevated temperature or using an activated acid
derivative (e.g. acid-halogenid) at room temperature or elevated
temperature applying a suitable base (e.g. triethylamine).
The reaction v/ii.) can be performed using pyridine-SO3 complex in a
suitable solvent (preferably in pyridine) or using CISO3H in a suitable
solvent (preferably in pyridine or chloroform) applying a strong organic
base (like DBU) or an inorganic base (like K2CO3) at room temperature or
elevated temperature.
The reaction v/iii.) can be performed in an appropriate aqueous
alkaline solution of the nitro compound using an excess of Na2S2O4 or
NaHSO3 as reagent at room temperature or at elevated temperature ( 100°).
According to a variation of the reaction v/iii.) the nitro derivative is
reduced by any of the known methods and the resulting amino derivative is
alkylated or benzylated first under known reductive alkylation or
benzylation conditions and the alkylamino or benzylamino derivatives,
thus obtained will be sulphated as described under ii.).
The protective group may be any known protective group. Examples
of protecting groups, as well as methods for protecting and deprotecting
various functional groups are given in "Protective Groups in Organic
Synthesis", Green et al., 2nd Edition *John Wiley & Sons, Inc, New York.,
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WO 2005/009969 PCT/HU2004/000080
1991. Preferred protective groups are Boc, ethoxycarbonyl,
benzyloxycarbonyl, etc, most preferably benzyl group.
The substituents of the compounds of the general formula (I) can be
transformed into each other by known methods (Comprehensive Organic
Transformation, R. C. Larock, VCH Publisher, New York, 1989).
The salts can be prepared by adding one equivalent of the acid to the
alcoholic, preferably ethanol solution of the base and diluting the solution
with diethyl ether and finally filtering off and drying the resulting crystals.
The compounds of the general formula (IF) -wherein the meanings of
R1", R2"; R3, R4", R5", R6", R7", R8" X", Z", n", o", p", r" and m" are as defined ■
above- can be prepared by several known methods, among them by the
method demonstrated on reaction scheme 1., by acylation of the
compounds of formula (III") by an acylation method known from the
organic chemistry. As for acylating agent preferably an acid chloride, for
acid binding agent triethyl amine and/or pyridine can be used, but other
compounds known as acid binders can also be applied.
The compounds of the general formula (III") -wherein the meanings
of Rr, R2", R3", R4", R5", R6", R7", R8" X", Z", n", o", p", r" and m" are the same
as defined above- can be prepared from the compounds of formula (IV"),
by methods known per se (Nan Zhang, Bioorg. and Med. Chem. Lett., 10,
2825,2000).
The compounds of the general formula (IV") -wherein the meanings
of R4", R5", R6", R7", R8"X", Z r", o", p" and m" are as defined above- can be
22

WO 2005/(109969 PCT/H 112(104/000081)
prepared from the compounds of formula (V"), by methods known per se
(D.L. Leysen, J. Heterocyclic Chem., 24, 1611, 1987).
The compounds of the general formula (V") -wherein the meanings
of R4" ,R5" ,R7" ,R8" , Z", r", o", p" and m are as defined above- can be
prepared from the compounds of formula (VI"), by methods known per se
(Pfizer (Inc) USP 4,175,193).
The compounds of the general formula (VI") -wherein the meanings
of R4" , R5", R7" , R8", Z, r, o, p and m are as defined above- can be
prepared from the compounds of formula (VII"), by methods known per se
(D.L. Leysen, J. Heterocyclic Chem., 24, 1611, 1987).
The compounds of the general formula (VII") -wherein the meanings
of R4", R5", R7", R8", Z", r", o", p" and m" are as defined above- can be
prepared from the compounds of formula (VIII"), by methods known per se
(D. H. Klaubert and J. H. Sellstedt, J. Med. Chem, 24, 742, 1981), or are
products on the market, such as the compound where R4" and R5" together
with the nitrogen atom form a nitro group
The compounds of the general formula (VIII") -wherein the
meanings of R4", R5", R7", R8", Z", r", o" , p" and m" are as defined above- can
be prepared from the compounds of formula (IX"), by methods known per
se (J. H. Hutchinson and J. J. Cook, J. Med. Chem. 39, 4583, 1996).
The compounds of the general formulae (I), (I') (II"), (III"), (IV"), (V"),
(VI"), (VII"), (VIII"), (XIII") and (XIV") according to the invention, as well
as their preparation and biological activity are demonstrated by the
examples below, without limiting the claims to the examples.
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Example 1.
4-Methoxy-N-[6-(morpholin-4-yl)-4-benzylamino-3-cvanoquinolin-2-
yllbenzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for
phenyl group, group a.) for morpholino group, R6 for 4-methoxyphenyl
group.
a.) 2-Nitro-5-(rnorpholin-4-yl)benzoic acid:
The mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 ml of
morpholine is stirred at 120 °C for 6 hours. To the reaction mixture
150 ml of ethyl acetate is added. The precipitated yellow crystalline
material is filtered off, dissolved in 15 ml of water. The pH of the
mixture is adjusted to 6 with acetic acid. The precipitated material is
filtered off, washed with water and dried, to obtain 4.2 g of the title
compound. Mp.: 172 oC.
1H-NMR (DMSO-d6) 7.85 ppm (m, 1H), 7.0-6.9 (m, 2H), 3.67 (m, 4H),
2.85 (m,4H).
b.) 2-Amino-5-(morpholin-4-yl)benzoic acid:
The mixture of 6 gof 2-nitro-5-(morpholin-4-yl)benzoic acid, 15 ml of
cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in
120 ml of ethanol for 6 hours. The hot reaction mixture is filtered
through celite filter. The filtrate is evaporated to obtain 4.8 g of the title
compound. M.p.: 242 °C.
1H-NMR(DMSO-d6) 7.25 ppm(m, 1H), 6.96 (m, 1H), 6.62 (m, 1H),
3.69 (m,4H), 2.85 (m, 4H).
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WO2005/009969 PCT/HU2004/0000080
c.) 5-(Morpholin-4-yl)isatoic anhydride:
To the mixture of 8.9 g of 2-amino-5-(morphoIin-4-yl)benzoic acid in
60 ml of dioxane, under stirring and external cold water cooling 10 ml
of diphosgene is added dropwise. The mixture is heated under reflux
conditions for 4 hours. From the cold reaction mixture the solid material
is filtered off, washed with 50 ml of ether. The product is stirred for 5
minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine,
it is filtered off and washed with 30 ml of methanol. After drying 7 g of
the title product is obtained, m.p.: 235 °C.
'H-NMR(DMSO-d6) 7.8ppm(m, 1H),6.78 (m, 1H), 6.66 (m, 1H), 3.73
(m, 4H), 2.92 (m, 4H).
d.)2-Amino-3-cvano-4-hydroxy-6-(morpholin-4-yl)quinoline:
4 g of malonitrile is dissolved in 50 ml of dimethylformamide. To the
solution, in several portions, 2.4 g of 60% oily dispersion of sodium
hydride are added. To the clear solution 8 g of 5-(morpholin-4-yl)isatoic
anhydride is added and the mixture is stirred at room temperature for 10
hours. The reaction mixture is diluted with 70 ml of water and extracted
with 2 X 30 ml of ethyl acetate. The aqueous phase is evaporated in
vacuum, the solid residue is dissolved in 20 ml of water, the pH is
adjusted to 6 with acetic acid. The precipitated material is filtered off,
washed with water. After drying 6.5 g of the title compound is obtained,
m.p.: 291 °C.
1H-NMR(DMSO-d6)7.27ppm(m, lH),7.14(m, 1H), 7.03 (m, 1H),
3.74 (m,4H), 3.12 (m, 4H).
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WO2005/009969 PCT/HU2004/000080
e.) 2-Amino-3-cyano-4-chloro-6-(morpholin-4-yl)quinoline:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(rnorpholin-4-
yl)quinoline and 3.4 ml of phosphoryl chloride is stirred at 120 °C for 4
hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of
the mixture is adjusted to 8 with 10% sodium hydroxide solution, and
the precipitated material is filtered off. After drying 1.5 g of the title
compound is obtained, m.p.: 206 °C.
1H-NMR (DMSO-d6) 7.69 ppm (m, 1H), 7.49 (m, 1H), 7.08 (m, 1H),
6.83 (s, 2H), 3.74 (m, 4H), 3.08 (M, 4H).
f.) 2-Amino-3-cyano-4-benzvlamino-6-(morpholin-4-yl)quinoline:
3 g of 2-amino-3-cyano-4-chloro-6-(morpholin-4-yl)quinoline and 6 ml
of benzylamine are stirred at 125 °C for 3 hours. The reaction mixture is
poured onto 30 ml of water. The precipitated material is filtered off,
washed with 20 ml of water. After drying 2.3 g of the title compound is
obtained, m.p.: 202 °C.
1H-NMR (DMSO-d6) 8.14 ppm (m, 1H), 7.5-7.2 (m, 8H), 5.85 (s, 2H),
5.04 (d, 2H), 3.65 (m, 4H), 3.1 (m, 4H).
g.)4-Methoxy-N-(4-methoxvbenzoyl)-N-(6-(morpholin-4-yl)-4-
benzylamino-3-cyanoquinolin-2-yl)benzamide:
To the solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6-
(morpholin-4-yl)quinoline in 2 ml of pyridine, 0.4 ml of 4-
methoxybenzoyl chloride is added under stirring and cooling. The
reaction mixture is stirred at 80 °C for 8 hours, and then poured onto
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WO 2004/009969 PCT/HU2004/000080
5 ml of ice-water. The precipitated material is filtered off, washed twice
with 3 ml of water. After drying 0.53 g of the title compound is
obtained, m.p.: 157 °C.
1H-NMR(DMSO-d6) 8.92 ppm (t, 1H), 8.32 (m,4H), 7.61 (m, 3H),
7.38 (m, 5H), 7.12 (m, 4H), 5.1 (d, 2H), 3.82 (m, 8H).
h.) 4rMethoxv-N-[(6-(morpholin-4-yl)-4-ben2vlamino-3-cyanoquinolin-
2-yl]benzamide
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyI)-N-(6-
(morphoIin-4-yl)-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in
20 ml of acetonitrile, 5 ml of IN methanolic potassium hydroxide
solution is added. The reaction mixture is heated under reflux conditions
for 10 minutes, 1.5 ml of glacial acetic acid is added to it, then it is
neutralized with 15 ml of 1M sodium hydrogen carbonate solution. The
precipitate is filtered off, the yellow crystalline material is recrystallized
from the mixture of 5 ml of dimethylformamide and 40 ml of ethanol.
After drying 1.3 g of the title compound is obtained, m.p.: 260 °C.
1H-NMR (DMSO-d6) 10.5 pprn (s, 1H), 8.92 (t, 1H), 8.4 (m, 2H), 7.66
(m, 3H), 7.35 (m, 5H), 7.05 (, 2H), 5.1 (d, 2H), 3.82 (m, 8H).
Example 2.
4-MethoxY-N-[6-(4-methylpiperazin-l-yl)-4-benzylarnino-3-
cyanoquinolin-2-ylibenzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for
phenyl group, group a.) for 4-methylpiperazin-l-yl group, R6 for 4-
methoxyphenyl group.
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WO 2005/009969 PCT/H U12004/000080
a.) 2-Nitro-5-(4-methvlpiperazin-l-yl)benzoic acid:
The mixture of 10 g of 2-nitro-5-chlorobenzoic acid and 30 ml of N-
methylpiperazine is stirred at 120 °C for 6 hours. To the reaction
mixture 150 ml of ethyl acetate is added. The precipitated yellow
crystalline material is filtered off, dissolved in 15 nil of water. The pH
of the mixture is adjusted to 6 with acetic acid. The precipitated material
is filtered off, washed with water and dried, to obtain 11.2 g of the title
compound. Mp.: 212 °C.
1H-NMR (DMSO-d6) 7.89 ppm (d, 1H), 7.03-6.93 (m, 2H), 3.7-3.45 (m,
8H), 2.25 (s, 3H).
b.) 2-Amino-5-(4-methylpiperazin-l-yl)benzoic acid:
The mixture of 9 g of 2-nitro-5-(4-methylpiperazino)benzoic acid, 20 ml
of cyclohexene and 3.5 g of Pd/C (10%) is heated under reflux
conditions in 120 ml of ethanol for 6 hours. The hot reaction mixture is
filtered through celite filter. The filtrate is evaporated to obtain 3.5 g of
the title compound. M.p.: 212 °C
1H-NMR (DMSO-d6) 7.19 ppm (d, 1H), 7.06 (m, 1H), 6.69 (d, 1H), 2.9
(m, 4H), 2.43 (m, 4H), 2.22 (s, 3H).
c.) 5-(4-methvlpiperazin-l-yl)isatoic anhydride:
To the mixture of 5.3 g of 2-amino-5-(4-methylpiperazino)benzoic acid
in 30 ml of dioxane, under stirring and external cold water cooling 6 ml
of diphosgene is added dropwise. The mixture is heated under reflux
conditions for 4 hours. From the cold reaction mixture the solid material
is filtered off, washed with 50 ml of ether. The product is stirred for 5
minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine,
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WO2005/009969 PCT/HU2004/000080
filtered off, washed with 30 ml of methanol. After drying 5.4 g of the
title product is obtained, m.p.: 285 °C
1H-NMR (DMSO-d6) 7.81 ppm (m, 1H), 6.73 (m, 1H), 6.62 (m, IH),
3.73-2.92 (m,8H), 2.23 (s,3H).
d.)2-Amino-3-cyano-4-hvdroxy-6-(4-methylpiperazin-l-vl)quino1ine:
2 g of malonitrile is dissolved in 30 ml of.dimethylformamide. To the
solution, in several portions, 1.3 g of 60% oily dispersion of sodium
hydride are added. To the clear solution 6.5 g of 5-(4-
methylpiperazino)isatoic acid anhydride is added and the mixture is
stirred at room temperature for 10 hours. The reaction mixture is diluted
with 70 ml of water and extracted with 2 X 30 ml of ethyl acetate. The
aqueous phase is evaporated in vacuum, the solid residue is dissolved in
20 ml of water, the pH is adjusted to 6 with acetic acid. The precipitated
material is filtered off, washed with water. After drying 5.2 g of the title
compound is obtained, m.p.: 156 °C.
1H-NMR (DMSO-d6) 7.23 ppm (m, lH),7.12(m, lH),7.03(m, IH),
3.65-2.83 (m, 8), 2.1 (s,3H).
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WO 2005/009969 PCT/HU2004/000080
e.) 2-Amino-3-cyano-4-chloro-6-(4-methylpiperazin-1 -yl)quinoline:
The mixture of 2 g of 2-amino-3-cyano-4-hydroxy-6-(4-
methylpiperazino)quinoline and 4 ml of phosphoryl chloride is stirred at
120 °C for 4 hours. The cooled reaction mixture is poured onto 40 g of ice,
the pH of the mixture is adjusted to 8 with 10% sodium hydroxide
solution, and the precipitated material is filtered off. After drying 1.5 g of
the title compound is obtained, m.p.: 189 °C.
1H-NMR (DMSO-d6) 7.69 ppm (m, 1H), 7.49 (m, 1H), 7.08 (m, 1H), 6.83
(s, 2H), 3.25-2.57 (m, 8H), 2.29 (s, 3H).
f.) 2-Amino-3-cyano-4-benzylamino-6-(4-methylpiperazin-l-yl)quinoline:
3 g of 2-amino-3-cyano-4-chloro-6-(4-methylpiperazino)quinoline and
6 ml of benzylamine are stirred at 125 °C for 3 hours. The reaction
mixture is poured onto 30 ml of water. The.precipitated material is filtered
off, washed with 20 ml of water. After drying 2.3 g of the title compound
is obtained, m.p.: 176 °C.
1H-NMR (DMSO-d6) 8.5 ppm (t, 1H), 7.5-7.15 (m, 8H), 5.85 (s, 2H), 5.04
(d, 2H), 3.65-3.12 (m, 8H), 2.23 (s, 3H).
g.')4-Methoxy-N-(4-methoxybenzoyl)-N-[6-(4-methylpiperazin-l-yl)-4-
benzylamino-3-cvanoquinolin-2-yl]benzarnide:
To the solution of 0.6 g of 2-arnino-3-cyano-4-benzylamino-6-(4-
methylpiperazino)quinoline in 2 ml of pyridine, 0.6 ml of 4-
methoxybenzoyl chloride is added under stirring and cooling. The reaction
mixture is stirred at 80 °C for 8 hours, and then poured onto 5 ml of ice-
water. The precipitated material is filtered off, washed twice with 3 ml of
water. After drying 0.63 g of the title compound is obtained, m.p.: 176 °C.
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WO 2005/009969 PCT/HU2004/000080
1H-NMR (DMSO-d6) 8.39 ppm (m, 1H), 7.95 (m, 2H), 7.47 (m, 5H), 7.32
(m, 5H), 7.14 (m, 4H), 5.1 (m, 2H), 3.82 (s, 3H), 3.52-2.98 (m, 8H), 2.25
(s, 3H).
h.) 4-Methoxy-N-[6-(4-methyipiperazin-1 -yl]-4-benzylamino-3-
cyanoquinolin-2-yl]benzamide
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-(4-
methylpiperazino)-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in
. 15 ml of acetonkrile, 4 ml of 1N methanolic potassium hydroxide solution
is added. The reaction mixture is heated under reflux conditions for 10
minutes, 1 ml of glacial acetic acid is added to it, then it is neutralized
with 12 ml of 1M sodium hydrogen carbonate solution. The precipitate is
filtered off, the yellow crystalline material is recrystallized from the
mixture of 15 ml of methanol and 35 ml of water. After drying 1.1 g of the
title compound is obtained, m.p.: 173 °C.
1H-NMR (DMSO-d6) 10.53 ppm (m, 1H), 8.39 (m, 1H), 7.95 (m, 2H),
7.57 (m, 3H), 7.34 (m, 5H), 7.04 (m, 2H), 5.1 (m, 2H), 3.82 (s, 3H), 3.52-
2.98 (m, 8H), 2.25 (s, 3H).
Example 3.
4-Methoxy-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-
yl)benzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for
phenyl group, group a.) for dimethylamino group, R6 for 4-methoxyphenyl
group.
a.) 2-Nitro-5-dirnethyIarninobenzoic acid:
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WO 2005/009969 PCT/HU2004/000080
The mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 ml of 60%
aqueous dimethylamine solution is stirred at 100 °C for 6 hours. The
reaction mixture is evaporated, the residue dissolved in 15 ml of water.
The pH of the mixture is adjusted to 6 with acetic acid. The precipitated
yellow crystalline material is filtered off, washed with water and dried, to
obtain 3.4 g of the title compound. Mp.: 189 °C.
1H-NMR (DMSO-d6) 7.78 ppm (d, 1H), 6.59 (m, 1H), 6.48 (m, 1H), 3.0 (s,
6H).
b.) 2-Amino-5-dimethylaminobenzoic acid:
The mixture of 2.1 g of 2-nitro-5-dimethylaminobenzoic acid, 7 mi of
cyclohexene and 1.5 g of Pd/C (10%) is heated under reflux conditions in
60 ml of ethanol for 6 hours. The hot reaction mixture is filtered through
celite filter. The filtrate is evaporated to obtain 1.1 g of the title
compound. M.p.: 232 °C
'H-NMR (DMSO-d6) 7.01 ppm (m, 1H), 6.84 (m, 1H), 6.78 (m, 1H), 2.88
(s,-6H).
c.) 5-Dimethylaminoisatoic anhydride:
To the mixture of 8.9 g of 2-amino-5-dimethylaminobenzoic acid in 60 ml
of dioxane, under stirring and external cold water cooling 10 ml of
diphosgene is added dropwise. The mixture is heated under reflux
conditions for 4 hours. From the cold reaction mixture the solid material is
filtered off, washed with 50 ml of ether. The product is stirred for 5
minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine,
filtered off, washed with 30 ml of methanol. After drying 7 g of the title
product is obtained, m.p.: 258 °C
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WO 2005/009969 PCT/HU2004/0000800
IH-NMR(DMSO-d6)7.56ppm(m, 1H), 7.42 (m, 1H), 7.13 (m, 1H), 2.97
(s, 6H).
d.)2-Amino-3-cyano-4-hvdroxy-6-dimethylaminoquinoline:
To the solution of 4 g of malonitrile in 50 ml of dimethylformamide in
several portions 2.4 g of sodium hydride 60% oily dispersion is added. To
the clear solution 8 g of 5-dimethylaminoisatoic anhydride is added and
the mixture is stirred at room temperature for 10 hours. The mixture is
diluted with 70 ml of water and extracted with 2 X 30 ml of ethyl acetate.
The aqueous phase is evaporated in vacuum, the solid residue is dissolved
in 20 ml of water, the pH is adjusted to 6 with acetic acid. The precipitated
material is filtered off, washed with water. After drying 6.5 g of the title
compound is obtained, m.p.: 360 °C.
1H-NMR(DMSO-d6)7.43ppm(m, lH),7.23(m, 1H), 7.11(m, 1H), 2.95(s,
6H).
e.) 2-Amino-3-cyano-4-chloro-6-dimethylaminoquinoline:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-
dimethylaminoquinoline and 3.4 ml of phosphoryl chloride is stirred at
120 °C for 4 hours. The cooled reaction mixture is poured onto 30 g of ice,
the pH of the mixture is adjusted to 8 with 10% sodium hydroxide
solution and the precipitated material is filtered off. After drying 1.5 g of
the title compound is obtained, m.p.: 285 °C.
lH-NMR(DMSO-d6) 7.43 ppm(mm,lH), 7.21 (m, 1H), 7.05(m, 1H),
6.75(s,2H),2.99(s,6H).
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WO 2005/009969 PCT/HU2004/000080
f.) 2-Amino-3-cvano-4-benzvlamino-6-dimethylaminoquinoline:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 ml of
benzylamine are stirred at 125 °C for 3 hours. The reaction mixture is
poured onto 30 ml of water. The precipitated material is filtered off,
washed with 20 ml of water. After drying 2.3 g of the title compound is
obtained, m.p.: 265 °C.
'H-NMR (DMSO-d6) 8.55-8.45 ppm(m, 2H), 7.8(m, 1H), 7.5-7.23(m, 7H),
6.25(s, 2H), 5.08(d, 2H), 2.99(s, 6H).
g.)4-Methoxv-N-(4-methoxvbenzoyl)-N-(6-dimethylamino-4-
benzylamino-3-cyanoquinolin-2-yl)benzamide:
To the solution of 0.4 g of 2-amino-3-cyano-4-benzyIamino-6-
dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl
chloride is added under stirring and cooling. The reaction mixture is
stirred at 80 °C for 8 hours, then poured onto 5 ml of ice-water. The
precipitated material is filtered off, washed twice with 3 ml of water. After
drying 0.53 g of the title compound is obtained, m.p.: 156 °C.
1H-NMR (DMSO-d6) 8.35 ppm(m, 1H), 7.9(m, 2H), 7.47(m, 5H), 7.3(m,
5H), 7.1(m, 4H), 5.12(m, 2H), 3.82(s, 3H), 3.0(s, 6H).
h.)4-Methoxy-N-(6-dimethylamino-4-benzylamino-3-cvanoquinolin-2-
yl)benzamide
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-.N-(6-
dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 20 ml
of acetonitrile, 5 ml of IN methanolic potassium hydroxide solution is
added. The reaction mixture is heated under reflux conditions for 10
minutes, 1.5 ml of glacial acetic acid is added to it, then it is neutralized
with 15 ml of 1M sodium hydrogen carbonate solution. The precipitate is
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WO 2005/009969 PCT/HU2004/000080
filtered off, the yellow crystalline material is recrystallized from the
mixture of 5ml of dimethylformamide and 40 ml of ethanol. After drying
1.3 g of the title compound is obtained, m.p.: 185 °C.
1H-NMR (DMSO-d6) 10.5 ppm(m, 1H), 8.35(m, 1H), 7.91(m, 2H),
i 7.53(m, 3H), 7.3(m, 5H), 7.02(m, 2H), 5.1(m, 2H), 3.85(s, 3H), 3.0(s, 6H).
Example 4
4-Methoxy-N-(6-dimethylamino-4-[2-furylmethvlamino]-3-
cyanoquinolin-2-yl)benzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for 2-
furylamino group, group a.) for dimethylamino group, R6 for 4-
methoxyphenyl group.
a.)2-Amino-3-cvano-4-[2-furylmethylamino]-6-dimethylaminoquinoline:
3 g of 2-amino-3-cyano-4-chloro-6-dimethyIarninoquinoIine and 6 ml of
furfurylamine are stirred at 125 °C for 3 hours. The reaction mixture is
poured onto 30 ml of water. The precipitated material is filtered off,
washed with 20 ml of water. After drying 2.05 g of the title compound is
obtained, m.p.: 235 °C.
1H-NMR (DMSO-d6) 8.7 ppm(m, 1H), 7.6(m, 1H), 7.35-7.23(m, 3H), 6.8
(s, 2H), 6.4(m, 2H), 5.06(d, 2H), 2.96(s, 6H).
b.)4-Methoxy-.N-(4-methoxybenzoyl)-N-(6-dimethvlarnino-4-[2-
furylmethylamino1-3-cvanoquinolin-2-yl)benzamide:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-furylmethylamino]-6-
dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl
35

WO2005/00969 PCT/HU2004/000080
chloride is added under stirring and cooling. The reaction mixture is
stirred at 80 °C for 8 hours, then poured onto 5 ml of ice-water. The
precipitated material is filtered off, washed twice with 3 ml of water. After
drying 0.5 g of the title compound is obtained, m.p.: 143 °C.
1H-NMR (DMSO-d6) 8.35 ppm(m, 1H), 7.9-7.1(m, 14H), 5.12(m, 2H),
3.82(s,6H),3.0(s,6H).
c.)4-Methoxv-N-(6-dimethylamino-4-[2-furylmethylamino]-3-
cyanoquinolin-2-yl)benzamide
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-
dimethylamino-4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)benzamide
in 20 ml of acetonitrile, 5 ml of IN rnethanolic potassium hydroxide
solution is added. The reaction mixture is heated under reflux conditions
for 10 minutes, 1.5 ml of glacial acetic acid is added to it, then it is
neutralized with 15 ml of 1M sodium hydrogen carbonate solution. The
precipitate is filtered off, the yellow crystalline material is recrystallized
from the mixture of 5ml of dimethylformamide and 40 ml of ethanol. After
drying 1.1 g of the title compound is obtained, m.p.: 195 °C.
1H-NMR (DMSO-d6) 10.5 ppm(m, 1H), 8.25(t, 1H), 7.98(m, 2H), 7.63-
7.03(m, 7H), 6:42 (d, 1H), 5.04(d, 2H), 3.85(s, 3H), 3.05(s, 6H).
Example 5
4-Methoxv-N-(6-dirnethvlamino-4-[2-thienylmethylamino]-3-cvanoquinolin-
2-yl)benzamide
In the general formula (1) R1 and R2 stand for hydrogen atom, R3 for 2-
thienylmethylamino group, group a.) for dimethylamino group, R6 for 4-
methoxyphenyl group.
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WO 2005/U09969 PCT/HU2004/000080
a.)2-Amino-3-cvano-4-[2-thienyiniethylamino]-6-dimethylaminoquinoline:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 ml of 2-
thienylmethylamine are stirred at 125 oC for 3 hours. The reaction mixture is
poured onto 30 ml of water. The precipitated material is filtered off, washed
with 20 ml of water. After drying 1.9 g of the title compound is obtained,
m.p.:211 °C.
1H-NMR (DMSO-d6) 8.2 ppm(m, 1H), 7.46-6.95(m, 6H), 6.08(s, 2H), 5.18(d,.
2H), 2.94(s, 6H).
b.) 4-Methoxy-N-(4-methoxybenzoyl)-N-(6-dimethylamino-4-[2-
thienvlmethylamino]-3-cyanoquinolin-2-yl)benzamide:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-thienylmethylamino]-6-
dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl
chloride is added under stirring and cooling. The reaction mixture is stirred at
80 °C for 8 hours, then poured onto 5 ml of ice-water. The precipitated
material is filtered off, washed twice with 3 ml of water. After drying 0.43 g
of the title compound is obtained, m.p.: 171 °C.
1H-NMR (DMSO-d6) 8.35 ppm(m, 1H), 7.9-7.05(m, 14H), 5.12(m, 2H),
3.82(s,6H),3.0(s,6H).
c.) 4-Methoxv-N-(6-dimethvlamino-4-[2-thienylmethylamino]-3-
cyanoquinolin-2-yl)benzamide
To the solution of 2.3 g of 4-rnethoxy-N-(4-methoxybenzoyl)-.N-(6-

dimethylamino-4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzarnide
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WO 2005/009969 PCT/HU2004/000080
in 20 ml of acetonitrile, 5 ml of IN methanolic potassium hydroxide solution
is added. The reaction mixture is heated under reflux conditions for 10
minutes, 1.5 ml of glacial acetic acid is added to it, then it is neutralized with
15 ml of 1M sodium hydrogen carbonate solution. The precipitate is filtered
off, the yellow crystalline material is re crystallized from the mixture of 5ml
of dimethylformamide and 40 ml of ethanol. After drying 1.15 g of the title
compound is obtained, m.p.: 163 °C.
1H-NMR(DMSO-d6) 10.5 ppm(m, 1H), 8.3(t, 1H), 7.98(m, 2H), 7.63-6.96(m,
8H), 5.2(d, 2H), 3.85(s, 3H), 3.05(s, 6H).
Example 6
4-Methoxy-.N-[6-(piperazin-l-yl)-4-benzylamino-3-cyanoquinolin-2-
yl]benzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, group a.) for piperazino group, R6 for 4-methoxyphenyl group.
a.) 2-Nitro-5-(4-benzylpiperazin-1 -yl)benzoic acid:
The mixture of 20 g of 2-nitro-5-chlorobenzoic acid and 50 ml of N-
benzylpiperazine is stirred at 120 °C for 6 hours. To the reaction mixture
250 ml of ethyl acetate is added. The precipitated yellow crystalline material
is filtered off, dissolved in 200 ml of water. The pH of the mixture is adjusted
to 6 with acetic acid. The precipitated material is filtered off, washed with
water and dried, to obtain 30 g of the title compound. Mp.: 172 °C.
1H-NMR (DMSO-d6) 7.8-6.7 ppm (m, 8H), 3.5 (s, 2H), 3.5-2.8 (m, 8H).
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WO 2005/009969 PCT/HU2004/000080
b.) 2-Amino-5-(4-benzyIpiperazin-1 -yl)benzoic acid:
The mixture of 6 g of 2-nitro-5-(4-benzylpiperazin-l-yl)benzoic acid, 15 ml
of cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in
120 ml of ethanol for 6 hours. The hot reaction mixture is filtered through
celite filter. The filtrate is evaporated to obtain 4.8 g of the title compound.
M.p.:242°C.
1H-NMR (DMSO-d6) 7.5-6.8 ppm (m, 8H), 3.68 (s, 3H), 3.5-2.95 (m, 8H).
c.) 5-(4-benzvlpiperazin-1 -yl)isatoic anhydride:
To the mixture of 15 g of 2-amino-5-(4-benzylpiperazin-l-yl)benzoic acid in
90 ml of dioxane, under stirring and external cold water cooling 12.7 ml of
diphosgene is added dropwise. The mixture is heated under reflux conditions
for 4 hours. From the cold reaction mixture the solid material is filtered off,
washed with 120 ml of ether. The product is stirred for 5 minutes in the
mixture of 100 ml of methanol and 10 ml of triethylamine, it is filtered off
and washed with 50 ml of methanol. After drying 17 g of the title product is
obtained, m.p. 235 °C.
1H-NMR (DMSO-d6) 7.68-7.1 ppm (m, 8H), 3.6 (s, 2H), 3.5-2.5(m, 8H).
d.) 2-Amino-3-cyano-4-hydroxy-6-(4-benzylpiperazin-l-yl)quinoline:
6.1 g of malonitrile is dissolved in 100 ml of dimethylformamide. To the
solution, in several portions, 3.6 g of 60% oily dispersion of sodium hydride
are added. To the clear solution 18 g of 5-(4-benzylpiperazin-l-yl)isatoic
anhydride is added and the mixture is stirred at room temperature for 10
hours. The reaction mixture is diluted with 100 ml of water and extracted
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with 2 X 50 ml of ethyl acetate. The aqueous phase is evaporated in vacuum,
the solid residue is dissolved in 50 ml of water, the pH is adjusted to 6 with
acetic acid and refluxed for 5 hours. After cooling the precipitated material is
filtered off, washed with water. After drying 14.3 g of the title compound is
obtained, m.p.: 291 °C.
1H-NMR (DMSO-d6) 7.7-6.5 ppm (m, 10H), 4.2 (s, 2H), 3.5-2.5 (m, 8H),
e.) 2-Amino-3-cyano-4-chloro-6-(4-benzylpiperazin-l-yl)quinoline:
The mixture of 14 g of 2-amino-3-cyano-4-hydroxy-6-(4-benzylpiperazin-l-
yl)quinoline and 28 ml of phosphoryl chloride is stirred at 120 °C for 6 hours.
The cooled reaction mixture is poured onto 500 g of ice, the pH of the
mixture is adjusted to 8 with 10% sodium hydroxide solution, and the
precipitated material is filtered off. After drying 14.5 g of the title compound
is obtained, m.p.: 206 °C.
1H-NMR (DMSO-d6) 7.7-7.14 ppm (m, 8H), 6.9 (s, 2H), 3.7 (s, 2H), 3.5-2.5
(m, 8H).
f.) 2-Amino-3-cyano-4-benzylamino-6-(4-benzylpiperazin-l-yl)quinoline:
14 g of 2-amino-3-cyano-4-chloro-6-(4-benzylpiperazin-l-yl)quinoline and
28 ml of benzylamine are stirred at 125 °C for 4 hours. The reaction mixture
is poured onto 100 ml of water. The precipitated material is filtered off,
washed with 2 x 50 ml of water. After drying 8 g of the title compound is
obtained, m.p.: 202 °C.
1H-NMR (DMSO-d6) 8.1 ppm (m, 1H), 7.5-7.2 (m, 13H), 5.8 (s, 2H), 5.0 (d,
2H), 3.54 (s,2H), 3.5-2.5 (m, 8H).
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WO 2005/009969 PCT/HU2004/000080
g.) 4-Methoxy-N-(4-methoxybenzoyl)-N-(6-(4-ben2ylpiperazin-l-yl)-4-
benzylamino-3-cyanoquinolin-2-yl)benzamide:
To the solution of 0.9 g of 2-amino-3-cyano-4-benzylamino-6-(4-
benzylpiperazin-l-yl)quinoline in 5 ml of ethylacetate containing 0.3 ml of
triethylamine, 0.5 ml of 4-methoxybenzoyl chloride is added under stirring
and cooling. The reaction mixture is stirred at 80 °C for 8 hours, then poured
onto 10 ml of ice-water. The precipitated material is filtered off, washed
twice with 3 ml of water. After drying 0.53 g of the title compound is
obtained, m.p.: 157 °C.
1H-NMR(DMSO-d6) 8.92ppm(t, 1H), 8.32 (m, 4H), 7.61 (m, 3H), 7.38 (m,
5H), 7.12 (m, 4H), 5.1 (d, 2H), 3.82 (s, 6H), 3.56 (s, 2H), 3.5-2.5 (m, 8H).
h.) 4-Methoxy-N-[(6-(4-benzyIpiperazin-l-yl)-4-benzylamino-3-
cyanoquinolin-2-yl]benzamide
To the solution of 2.0 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-(4-
benzylpiperazin-1 -yl)-4-benzylamino-3-cyanoquinoIin-2-yl)benzamide in
20 ml of acetonitrile, 4 ml of 1N methanolic potassium hydroxide solution is
added. The reaction mixture is heated under reflux conditions for 10 minutes,
1.5 ml of glacial acetic acid is added to it, then it is neutralized with 15 ml of
1M sodium hydrogen carbonate solution. The precipitate is filtered off, the
yellow crystalline material is recrystallized from the mixture of 5 ml of
di methyl formamide and 40 ml of ethanol. After drying 1.3 g of the title
compound is obtained, m.p.: 260 °C.
1H-NMR(DMSO-d6) 10.5 ppm(s, 1H), 8.92 (t, 1H), 7.97-7.01 (m, 17H), 5.1
(d, 2H), 3.82 (s, 3H), 3.56 (s, 2H), 3.5-2.5 (m, 8H).
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WO 2005/009969 PCT/HU2004/000080
i.) 4-Methoxy-N-[(6-(piperazin-l-yl)-4-benzylamino-3-cyanoquinolin-2-
vlibenzamide
1 g of 4-methoxy-N-[(6-(4-benzylpiperazin-l-yl)-4-benzylamino-3-
cyanoquinolin-2-yl]benzamide was dissolved in dimethylformamide and
water, containing 0.5 ml of acetic acid and was hydrogenated in the presence
of 50 mg of Pd/C (10%) for 4 hours at 45 °C. After filtration of the catalyst
and evaporation of the solvent the crude product was purified by
chromathography to give 0.65 g of the title compound, mp: 145 °C.
1H-NMR (DMSO-d6) 10.5 ppm (s, 1H), 8.48 (m, 1H), 7.94 (m, 2H), 7.6-7.35
(m, 2H), 7.33 (s, 5H), 7.24 (m, 1H), 7.02 (m, 2H),, 5.08 (d, 2H), 3.83 (s, 3H),
3.22 (m,4H), 2.86 (m, 4H).
Example 7
N-[6-amino-4-(benzylamino)-3-cyanoquinolin-2-yl]-4-methoxybenzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, NR4R5 stands for NH2, R6 for 4-methoxyphenyl group.
a,) 5-Nitroisatoic anhydride:
To the mixture of 37 gof 2-amino-5-nitrobenzoic acid in 500 ml of dioxane,
under stirring 24.5 ml of diphosgene was added dropwise. The mixture was
heated under reflux conditions for 6 hours then it was evaporated to dryness.
The residue was suspended in 100 ml of diethyl ether and filtered off to give
41.4 g of the title product as HC1 salt, m.p.: 256-259 °C. LC-MS: MH* 209;
Ret. time: 5.00 min.
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1H-NMR (DMSO-d6) 8.54 (d, IH), 8.46 (dd, 1H), 7.37 (d, 1H) ppm.
b,) 2-Arnino-3-cyano-4-hydroxy-6-nitroquinoline:
To the solution of 47.25 g of 5-nitroisatoic anhydride in 230 ml ofDMF 15 g
of malonitrile and 63.3 ml of triethylamine were added and the reaction
mixture was stirred at 60 °C for 2 hours. The solvent was evaporated at
reduced pressure and the residue was mixed with 570 ml of acetonitrile and
114 ml of coned. HCI and the solution was stirred at room temperature
overnight. The precipitate was then filtered off, washed with water and
ethanol to give 49.7 g of product, m.p.: >360 °C. LC-MS: MH+ 231; Ret.
time: 4.78 min.
1H-NMR(DMSO-d6) 8.64 (d, 1H), 8.36 (dd, IH), 7.6 (s, 2H), 7.55 (d, IH)
ppm.
c,1 2-Amino-3-cyano-4-chloro-6-nitroquinoline:
The stirred mixture of 48.5 gof 2-amino-3-cyano-4-hydroxy-6-riitroquinoline
and 550 ml of phosphoryl chloride was refluxed for 4 hours. The reaction
mixture was concentrated to half of its volume and the residue was poured
onto 1500 g of ice. The yellow precipitate was filtered off, washed with water
to give 60.5 g of solid. 25 g of this solid was stirred at room temperature in
500 ml of 0.5 N HCI for 6 hours, then the precipitate was filtered off, washed
with water to give 18.5 g of product, m.p.: >360 °C. LC-MS: MH+ 249; Ret.
time: 5.94 min.
1H-NMR (DMSO-d6) 8.73 (d, 1H), 8.48 (dd, IH), 7.92 (d, IH) ppm.
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d,) 2-Amino-3-cvano-4-benzylamino-6-nitroquinoline:
A mixture of 7 g of 2-amino-3-cyano-4-chloro-6-nitroquinoline and 30 ml of
benzylamine was stirred at 55 °C for 1.5 hours. The reaction mixture is
poured onto 30 ml of water. The precipitated material is filtered off, washed
with water to give 7 g of the title compound, m.p.: 280-283 °C. LC-MS: MH+
2320; Ret. time: 5.19 min.
1H-NMR (DMSO-d6): 9.28 (d, 1H), 8.90 (t, 1H), 8.24 (dd, 1H), 7.3 (m, 5H),
6.98 (s,2H), 5.04 (d,2H) ppm.
e,) 4-Methoxy-N-(4-methoxybenzoyl)-N-(4-benzylamino-3-cyano-6-
nitroquinolin-2-yl)benzamide:
A suspension of 3.5 gof 2-amino-3-cyano-4-benzylamino-6-nitroquinoline in
50 ml of dry pyridine was refluxed with 5.6 g of 4-methoxybenzoyl chloride
for 3.5 hours. The solvent was evaporated in reduced pressure and the residue
was suspended in 30 ml of a saturated solution of Na2CO3 in water. The
suspension was extracted with 3 x 25 ml of CH2C12. The combined organic
extract was evaporated to dryness, the residue was dissolved in diethyl ether
and the solution was kept in a refrigerator for a night. The precipitate was
filtered off, washed with diethyl ether to give 6.25 g of the title compound,
m.p.: 145-148 °C. LC-MS: MH+ 588; Ret. time: 7.00 min.
f.)-N-[(4-Benzylamino-3-cvano-6-nitroquinolin-2-yl]-4-methoxy-benzamide
A suspension of 6.2 g of -N-(4-methoxybenzoyl)-N-(4-benzylamino-3-cyano-
6-nitroquinolin-2-yl)-4-methoxybenzamide in 75 ml of acetonitrile was
refluxed with 25.2 ml of 1N methanolic potassium hydroxide solution for 6
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min. 4.4 ml of glacial acetic acid was dropped to the solution while hot,
cooled and neutralized with 56.3 ml of 1M aqueous NaHC03 solution. The
precipitate was filtered off, washed with water to give 4.1 g of title
compound, m.p.: 264-266 °C.
1H-NMR (DMSO-d6) 10.9 (s, 1H), 9.55 (d, IH), 9.28 (t, 1H), 8.77 (d, 1H),
8.48 (dd, IH), 8.00 (d, 2H), 7.90 (d, IH), 7.4 (m, 4H), 7.29 (m, IH), 7.05 (d,
2H), 5.12 (d, 2H), 3.84 (s, 3H) ppm.
.g,) N-r6-amino-4-(benzylamino)-3-cyanoquinolin-2-yl]-4-methoxvbenzamide
A mixture of 320 ml of ethanol, 80 ml of water, 200 ml of THF, 7.6 g of Fe- .
powder, and 1 ml of coned. HC1 was refluxed for 10 min. 9 g of N-[(4-
benzylamino-3-cyano-6-nitroquinolin-2-yl]-4-methoxy-benzamide was then
added and the reaction mixture was intensively refluxed for 2 hours and it
was cooled to 35 °C. The precipitate was filtered off, washed with a 1:1
mixture of CH2C12 and ethanol. The combined organic solution was filtered
on charcoal and evaporated to dryness. The residue was suspended in a
mixture of 50 ml of water and 10 ml of ethanol, the solid material was filtered
off, washed with water to give 6.65 g of the title compound, mp: 228-230 °C.
LC-MS: MH+ 424; Ret. time: 5.33 min.
1H-NMR (DMSO-d6) 10.44 (s, IH), 8.0 (s+d, 3H), 7.50 (d, IH), 7.3-7.1 (m,
7H), 7.03 (d, 2H), 5.55 (s, 2H), 5.04 (d, 2H), 3.83 (s, 3H) ppm.
Example 8
N-{6-arnino-4-[(2-thienylrnethyl)arnino)1-3-cyanoquinolin-2-yl}-4-
methoxybenzamide

WO2005/009969 PCT/HU2004/000080
In the general formula (1) R1 and R2 stand for hydrogen atom, R3 for 2-thienyl
group, NR4 R5 stands for NH2, R6 for 4-methoxyphenyl group.
a,)2-Amino-3-cyano-4-(2-thienylmethyl)amino-6-nitroquinoline:
Applying the same procedure as given under Example 7d with the
modification that instead of benzylamine, (2-thienylmethyl)amine was used
to give 7.1 g of the title compound, m.p.: 277-280 °C. LC-MS: MH+ 326; Ret.
time: 5.25 min.
b,)N-(4-Methoxybenzoyl')-N-[3-cyano-6-nitro-4-(2--thienylmethyn-
aminoquinolin-2-yl]-4-methoxybenzamide:
Started the reaction from 2-amino-3-cyano-4-(2-thienylmethyl)amino-6-
nitroquinoline (3.6 g) and using the procedure as given for Example 7e, 6.3 g
of the title compound was prepared, m.p.: 174-177 °C. LC-MS: MH+ 595;
Ret. time: 7.16 min.
c) N-[3-Cyano-6-nitro-4-(2-thienylmethyl)aminoquinolin-2-yl]-4-
methoxybenzamide
Started the reaction from N-(4-methoxybenzoyl)-N-[3-cyano-6-nitro 4-(2-
thienyImethyl)amino]quinolin-2-yl)-4-methoxybenzamide (6.2 g) and using
the procedure as given for Example 7f, 4.3 g of the title compound was
prepared, m.p.: 217-220 °C. LC-MS: MH+ 460; Ret. time: 6.57 min.
1H-NMR (DMSO-d6): 11.0 (s, 1H), 9.50 (s, 1H), 9.29 (s, 1H), 8.48 (dd, 1H),
8.02 (d, 2H), 7.90 (d, 1H), 7.48 (dd, 1H), 7.21 (d, 1H), 7.0 (m, 3H), 5.27 (s,
2H), 3.85(s,3H)ppm
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d,)N-{6-amino-4-[(2-thienylmethyl)amino1-3-cvanoquinolin-2-yl}-4-
methoxybenzamide
Started the reaction from N-[4-(2-thienylmethyl)amino-3-cyano-6-
nitroquinolin-2-yl]-4-methoxybenzamide (10 g) and using the procedure as
given for Example 7g, 9.3 g of the title compound was prepared, mp: 200-203
°C. LC-MS: MH* 430; Ret. time: 5.52 min.
1H-NMR (DMSO-d6) 10.48 (s, 1H), 7.98 (s+d, 3H), 7.50 (d, 1H), 7.41 (dd,
1H), 7.21 (s, 1H), 7.16 (dd, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 6.98 (dd, 1H),
5.45 (s, 2H), 5.18 (d, 2H), 3.84 (s, 3H) ppm
Example 9
N-{4-(benzylamino)-3-cyano-6-(methylamino)quinolin-2-yl}-4-
methoxybenzamide
In the general formula (I) Rl and R2 stand for hydrogen atom, R3 for phenyl
group, R4 stands for Me, R5 stands for H and R6 for 4-methoxyphenyl group.
A suspension of 1 g of N-{4-(benzylamino)-3-cyano-6-aminoquinolin-2-yl}-
4-methoxybenzamide and 0.65 g of paraformaldehyde in a mixture of 48 ml
of ethanol and 48 mi of CH2C12 was refluxed with 0.5 ml of 54% HBF4
solution in diethyl ether for 1.5 hours. After addition of 0.3 g of NaBH4 the
reflux was continued for 1.5 hours followed by addition of a further amount
of 0.3 g of NaBH4 and reflux for 2 hours. After repeated addition of 0.25 ml
of 54% HBF4 solution in diethyl ether and 0.3 g of NaBH4 the reflux was
continued for additional 1.5 hours. The reaction mixture was filtered while
hot, the solid was washed with a 1:1 mixture of CH2C12 and ethanol. The
combined organic solution was concentrated and the residue was
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WO 2005/009969 PCT/HU2004/000080
chromatographed on silica gel with a 50:1 mixture of CHCI3 and ethyl acetate
to give the crude product. It was recrystallized from a 2:1 mixture of ethanol
and DMF to give 0.6 g of title compound, m.p.: 237-240 °C. LC-MS: MH+
438; Ret. time: 5.76 min.
1H-NMR (DMSO-d6) 10.43 (s, 1H), 8.18 (t, 1H), 7.94 (d, 2H), 7.50 (d, 1H),
7.3-7.0 (m, 9H), 6.24 (m, 1H), 5.08 (d, 2H), 3.83 (s, 3H), 2.83 (d, 3H) ppm.
Example 10
N-{3-Cyano-6-(formylanino)-4-[(2-thienvlmethynamino]quinolin-2-yl]-4-
methoxybenzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for 2-thienyl
group, R4 stands for Me, R5 stands for CHO and R6 for 4-methoxyphenyl
group.
A suspension of 0.32 gof N-{6-amino-4-[(2-thienylmethyl)amino]-3-
cyanoquinolin-2-yl}-4-methoxybenzamide was kept in 60 ml of methyl
formate at 100 °C in a closed apparatus (internal pressure: 10 bar) for 7 hours.
After cooling the solvent was evaporated and the residue was recrystallized
from CH2Cl2/MeOH to give 0.22 g of title compound, m.p.: 223-226 °C. LC-
MS: MH+ 458; Ret. time: 5.71 min.
Example 11
{4-(BenzylaminoV3-cyano-2-[(4-methoxybenzoynamino1quinolin-6-
yl}sulfamic acid
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WO 2005/009969 PCT/H U2004/000080
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, R4 stands for H, R5 stands for SO2OH and R6 for 4-methoxypheny!
group.
To a solution of 5.2 g of Na2S2O4 (purity: 85%) in 160 ml of water and
200 ml of ethanol was added 20 ml of aqueous INNaOH solution. The
solution was heat up to boiling then 2.27 g of iV-[(4-benzylamino-3-cyano-6-
nitroquinolin-2-yl]-4-methoxybenzamide was added and refluxing was
continued for 2 hours. The reaction mixture let stand at room temperature
overnight then it was concentrated to half of its volume. The residue was
made alkaline (pH=8) by addition of IN NaOH solution and was extracted
with CH2CI2. The aqueous solution was acidified to pH=5 by addition of
coned. HC1 solution and the precipitate was filtered off. The solid was
chromatographed on silica gel eluted first by a mixture of ethyl
acetate/methanol/25% ammonia = 220/30/2, then 200/80/2 to get 0.5 g of title
compound as ammonium salt, m.p.: 220-222 °C. LC-MS: MH+ 504; Ret.
time: 5.56 min.
1H-NMR (DMSO-d6) 10.48 (s, 1H), 8.21 (s, 1H), 8.09 (t, 1H), 7.95 (d, 2H),
7.70 (s, 1H), 7.62 (d, 1H), 7.56 (d, 1H), 7.3 (m, 4H), 7.25 (m, 1H), 7.03 (d,
2H), 5.05 (d, 2H), 3.83 (s, 3H) ppm
Example 12
{4-(Benzylamino)-3-cyano-2-[(4-methoxvbenzoyl)aminolquinolin-6-
yl}methylsulfamic acid
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WO2005/009969 PCT/HU2004/000080
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, R4 stands for Me, R5 stands for SO2OH and R6 for 4-methoxyphenyl
group.
A solution of 110 mg of N-{4-(benzyIamino)-3-cyano-6-
(methylamino)quinolin-2-yl}-4-methoxybenzamide in 10 ml of pyridine was
stirred at room temperature with 0.2 ml of DBU and 150 mg of pyridinium-
SO3 komplex for 2 hours. The reaction mixture was concentrated to dryness,
the residue was chromatographed on silica gel using a mixture of ethyl
acetate/methanol/25% ammonia = 200/80/2 as eluent to give 10 mg of title
compound as ammonium salt. LC-MS: MH+ 518; Ret. time: 6.22 min. .
Example 13
N-(4-(Benzylarnino)-3-cyano-6-[formyl(methyl)amino]quinolin-2-yI}-4-
methoxybenzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, R4 stands for Me, R5 stands for CHO and R6 for 4-methoxyphenyl
group.
A suspension of 110 mg of N-{4-(benzylamino)-3-cyano-6-
(methylamino)quinolin-2-yl}-4-rnethoxybenzamide was refluxed in 10 ml of
ethyl formate for 24 hours. After cooling the precipitated crystals were
filtered off, washed with ethyl formate and ethanol to give 30 mg of title
compound, m.p.: 237-240 °C. LC-MS: MH+ 465; Ret. time: 6.11 min.
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Example 14
4-Methoxv-N-[6-(4-formylpiperazin-l-yl)-4-benzylamino-3-cvanoquinolin-2-
yl]benzamide
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, group a.) for 4-formylpiperazino group, R6 for 4-methoxyphenyl
group.
A solution of 120 mg of 4-methoxy-N-[6-(piperazin-l-yl)-4-benzylamino-3-
cyanoquinolin-2-yl]benzamide in 5 ml of ethyl formate was refluxed for 2
hours. After cooling the solvent was evaporated and the residue was
recrystallysed from methanol to give 65 mg of the title compound, mp: 243°C
]H-NMR (DMSO-d6) 10.6 ppm (s, 1H), 8.48 (m, IH), 8.1 (s, 1H), 7.94 (m,
2H), 7.6-7.1 (m, 8H), 7.05 (m, 2H), 5.1 (d, 2H), 3.82 (s, 3H), 3.7-3.2 (m, 8H).
Example 15
4-r2-(Benzoylamino)-4-benzylamino)-3-cyanoquinolin-6-yl]piperazine-l-
sulfonic acid
In the general formula (I) R1 and R2 stand for hydrogen atom, R3 for phenyl
group, group a.) for 4-sulfonylpiperazino group, R6 for 4-methoxyphenyl
group.
A solution of 50 mg of 4-methoxy-N-[6-(piperazin-l-yl)-4-benzylamino-3-
cyanoquinolin-2-yl]benzamide in 0.5 ml pyridine and pyridinium-SO3
complex was refluxed for 2 hours and working up according to a procedure
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published in the literature (G.F. Smith and D.A. Taylor, Tetrahedron, 29, 669,
1973).
LC-MS: MH+ 572; Ret. time: 5.9 min.
52
Structure and physical characteristics of further compounds of the general
formula (I), wherein R1 and R2 stand for hydrogen atom, X stands for -NH-
group and n represents 1, are shown in Table I



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55
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WO 2005/009969 PCT/HU2004/000080


Example 40
Tablets of the following composition are prepared by known methods:
Active ingredient: 25 mg
Lactose 50 mg
Avicel 21 mg
Crospovidone 3 mg
Magnesium stearate 1 mg
Biology
Methods
Human adenosine A3 receptor binding
Preparing membrane suspension: ovarium cells of Chinese hamster
expressing cloned human A3 receptors (further: CHO-hA3) are appropriately
cultured and maintained. Achieving confluent cell layer, the medium is
removed from the cells by washing them with 37 °C PBS, then the cell are
suspended in ice cold PBS, centrifuged (1000 x g 10 min) (Sigma 3K30) and
homogenized using teflon homogenizer (B.Braun Potter S) at 1500/min
rotation speed, for 15 sec. in the following buffer: 50 mM Tris, 10 mM
MgCl2, I mM EDTA, pH 8.0. The suspension is centrifuged (43.000 g, 10
min). The pellet is suspended in the above buffer, protein concentration 0.1
mg/ml (Bradford method). Aliquots of the membrane preparation are stored
at -80 °C.
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Binding protocol: incubate CHO-hA3 membrane preparation (2 .g
protein content) in incubation buffer (50 mM Tris, 10 mM MgCl2, 1 mM
EDTA, 3 U/mL adenosine deaminase, pH 8.0), in the presence of 0.5 nM
[I]AB-MECA (p-amino-3-iodo-benzyl-5'-N-methylcarboxamido-
adenosine) (1,00.000 cpm) and 100 M R-PIA (N6-[L-2-
phenylisopropyl]adenosine) to define non-specific binding of test compound
in a total volume of 50 L for 1 hr at room temperature. Filter over Whatman
GF/B glass fibre filters (presoaked in 0.5% polyethylenimine for 3 hours),
wash 4x with 1 mL ice-cold 50 mM Tris, 10 mM MgCl2, 1 mM EDTA (pH
8.0) on 96-well Brandel Cell Harvester. Detection of activity: in gamma-
counter (1470 Wizard, Wallac). Inhibition [%] = 100-((activity in the
presence of test compound - non-specific activity)/(total activity - non-
specific activity))* 100
Human adenosine A1 receptor binding
Preparing membrane suspension: ovarium cells of Chinese hamster
expressing cloned human A1 receptors (further: CHO-hA1) are appropriately
cultured and maintained. Achieving confluent cell layer, the medium is
removed from the cells by washing them with 37 °C PBS, then the cell are
suspended in ice cold PBS, centrifuged (1000 x g 10 min) (Sigma 3K30) and
homogenized using teflon homogenizer (B.Braun Potter S) at 1500/min
rotation speed, for 15 sec. in the following buffer: 50 mM Tris, 10 mM HC1,
pH 7.4. The suspension is centrifuged (43.000 g, 10 min). The pellet is
suspended in the above buffer, protein concentration 5 mg/ml (Bradford
method). Aliquots of the membrane preparation are stored at -80 °C.
Binding protocol: incubate CHO-hA1 membrane preparation (50 g protein
content) in incubation buffer (50 mM Tris, 3 U/mL adenosine deaminase, pH
7.4), 10 nM [3H]CCPA (2-chloro-N6-cyclopenthyl-adenosine) (80.000 dpm)
and 10 M R-PIA (N6-[L-2-phenylisopropyl]adenosine) to define the non-
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WO 2005/009969 PCT/HU 2004/000080
specific binding or test compound in a total volume of 100 L for 3 hr at
room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in
0.5% polyethylenimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM Tris
(pH 7.4) on 96-well Brandel Cell Harvester, Detection of activity: in the
presence of 200 uL of HiSafe-3 coctail in beta-counter (1450 Microbeta,
Wallac). Inhibition [%] = 100-((activity in the presence of test compound -
non-specific activity)/(total activity - non-specific activity))* 100
Human adenosine A2a receptor binding
Binding protocol: Incubate 7 g of membranes (human A2a adenosine
receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.),
buffer (50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, 2 U/mL adenosine
deaminase, pH 7.4), 20 nM [3H]CGS-21680 (2-[p-(2-
'"carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamido-adenosine)'
(200.000 dpm) and 50 M NECA (5-N-ethyIcarboxamido-adenosine) to
define the non-specific binding of test compound, in a total volume of 100 l
for 90 min at room temperature. Filter in vacuum over Whatman GF/B glass
fibre filters (presoaked for 3 hours in 0.5% polyethylenimine), wash 4x with
1 mL ice-cold 50 mM Tris, 10 mM MgCl2, 1 mM EDTA, 0.9 % NaCl, pH
7.4) on 96-well Brandel Cell Harvester. Detection of activity: in beta-counter
(1450 Microbeta, Wallac) in the presence of 200 uL of HiSafe-3 coctail.
Inhibition [%] = 100-((activity in the presence of test compound - non-
specific activity)/(total activity - non-specific activity))* 100.
Human adenosine A2b receptor binding
Binding protocol: incubate 20.8 g of membranes (human A2b adenosine
receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.),
buffer (50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA, 0.1 mM benzamidine,
2 U/mL adenosine deaminase, pH 6.5), 32.4 nM [3H]DPCPX (8-
cyclopenthyl-l,3-dipropylxanthine) (800.000 dpm) and 100 uM NECA (5-
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WO2005/009969 PCT/HU2004/000080
N-ethylcarboxamido-adenosine) to define non-specific binding or test
compound in a total volume of 100 L for 30 min at room temperature. Filter
under 25 Hgmm vacuum over Whatman GF/C glass fibre filters (presoaked in
0.5% polyethylenimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM
Tris-HCl (pH 6.5) on 96-well Brandel Cell Harvester. Detection of activity:
in the presence of 200 L of HiSafe-3 coctail in beta-counter (1450
Microbeta, Wallac). Inhibition [%] = 100-((activity in the presence of test
compound - non-specific activity)/(total activity - non-specific activity))* 100
Results
We consider the compounds as biologically active ones if they inhibit
the binding of the radioligand on human adenosine A3 receptors with an
activity above 80 % at 1 uM in our experimental conditions.
The dissociation constant (Kd) of [125I]AB-MECA on CHO-hA3
membrane preparation is determined by isotope saturation studies with the
help of Scatchard analysis (G. Scatchard, Ann. N. Y. Acad. Sci. 51:660,
1949). The IC50 is converted to an affinity constant (Ki) by application of the
Cheng-Prusoff equation (Y. J. Cheng and W. H. Prusoff, Biochem.
Pharmacol. 22:3099, 1973).
A number of the compounds of the general formula (I) displayed
remarkable biological effects. The most active compounds of the general
formula (I) were those defined in claims 2-4. Especially advantageous are the
compounds given in the Examples, their Ki values are in the range of 0.5 nM
and 900 nM, preferably 0.5 nM and 700 nM. Ki values of the most
advantageous compounds are in the range of 0.5 nM 18 nM, most preferably
0.5 and 15nM.
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The compounds possess good bioavailability and a selectivity of at
least 3 order of magnitude, in respect to the human adenosine A1, A2a and A2b
receptor subtypes.
Further, the duration of their action at intravenous and oral
administration is long, their ED50 values are low, their toxicological and side-
effect profiles are advantageous.
These above data are favourable for the therapeutic application of the
compounds of the general formula (I).
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Claims
1. Compounds of the general formula (I), wherein
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or.branched C1-4 alkyl group,
straight or branched C1-4 alkoxy group, or halogen atom; a six- or five-
membered heteroaromatic ring containing one, two or three nitrogen
atoms, or a five-membered heteroaromatic ring containing one nitrogen
atom and one oxygen atom, or one nitrogen atom and one sulphur
atom, optionally substituted with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, or halogen
atom;
R4 and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an arnino
group, or an amino group substituted with one or two straight or
branched C1-4 alkyl group, a hydroxy group, a carboxy group, or an
alkoxy group substituted with a straight or branched C1-4 alkyl group -;
or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group or a
benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4 acyl group, or
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R4 and R5 , together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
R6 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with
methylenedioxy group, or with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy
group, trifluoromethyl group, cyano group or halogen atom; or a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one or
more straight or branched C1-4 alkyl group, straight or branched
C1-4 alicoxy group or halogen atom;
X stands for -CH2- group, -NH- group, -NR9- group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9 stands for
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z stands for oxygen atom sulphur atom, -CHR10-group or -NRl1-
group, wherein R10 stands for hydrogen atom, straight or branched
C1-4 alkyl group, or C3-6 cycloalkyl group and R11 stands for hydrogen
atom, straight or branched C1-4 alkyl group, C3-6 cycloalkyl group, -
SO2OH group or a straight or branched C1-4 acyl group ;
n represents zero, 1 or 2;
m represents 1,2, or 3;
o represents 1, 2, or 3;
p represents zero or 1;
r represents zero or 1,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates.
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2. Compounds of the general formula (I) according to claim 1., wherein
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or branched C1-4 alkyl group,
straight or branched C1-4 alkoxy group, or halogen atom;
R4 and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an amino
group, or an amino group substituted with one or two straight or
branched C1-4 alkyl group, a hydroxy group, a carboxy group, or an
alkoxy group substituted with a straight or branched C1-4 alkyl group -;
or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group or
a benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4 acyI group, or
R4 and R5, together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
R6 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with a
methylenedioxy group, or with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy
group, trifluoromethyl group, cyano group, or halogen atom; or a six-
or five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
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nitrogen atom and one sulphur atom, optionally substituted with one or
more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
X stands for -CH2- group, -NH- group, -NR9- group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9 represents a
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z stands for oxygen atom, sulphur atom, -CHR10-group or -NR11- group,
wherein R10 represents hydrogen atom, straight or branched C1-4 alkyl
group, or C3-6 cycloalkyl group and R11 represents hydrogen atom,
straight or branched C1-4 atkyl group, C3-6 cycloalkyl group, -SO2OH
group or a formyl group ;
n represents zero, 1 or 2;
m represents 1, 2, or 3;
o represents 1, 2, or 3;
p represents zero or 1;
r represents zero or 1,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates thereof.
3. Compounds of the general formula (I) according to claims 1.-2.,
wherein:
R1 stands for hydrogen atom or methyl group;
R2 stands for hydrogen atom or methyl group;
R3 stands for phenyl-, thienyl, or furyl group;
R4 and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an amino
group, or an amino group substituted with one or two straight or
branched C1-4 alkyl group, a hydroxy group, a carboxy group, or an
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alkoxy group substituted with a straight or branched C1-4 alkyl group -;
or
R4 stands for hydrogen atom or a straight or branched C1-4 alkyl alkyl
group or a benzyl group, and
R5 stands for hydrogen atom, -SO2OH group or a formyl group, or
R4 and R5 , together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
R6 stands for 4-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,4-
methylenedioxyphenyl group, 4-fluorophenyl, 2-thienyl or 2-furyl
group;
X stands for -NH- group, or oxygen atom;
Z stands for oxygen atom, sulphur atom, -CH2- group, -NH- group or
-NR11- group, wherein R11 represents a straight or branched C1-4 alkyl
group, C3-6 cycloalkyl group, -SO2OH group or formyl group and
n represents 1;
m represents 2;
o represents 2;
p represents zero;
r represents zero,
and their salts, solvates, isomers (tautomers, desmotrops, optically active
isomers) as well as the salts and solvates thereof.
4. The following compounds according to claims 1.-3.:
4-Methoxy-N-[6-fmorpholin-4-yl)-4-benzylamino-3-cyanoquinoiin-2-yl1-
benzamide
4-Methoxy-N-[6-(4-methylpiperazin-l-yl)-4-benzylamino-3-cyanoquinolin-
2-ylibenzamide
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_4-Methoxy-N-(6-dimethylamino-4-benzvlamino-3-cyanoquinolin-2-
ypbenzamide
3,4-Methylenedioxy-N-(6-dirnethylarnino-4-benzvlamino-3-cyanoquinolin-2-
yl)benzamide
4-Fluoro-N-(6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-
yl)benzamide
4-Methoxv-N-(6-(piperazin-l-yl)-4-benzylainino-3-cyanoquinolin-2-
yl)benzatnide
4-Methoxy-N-(6-amino-4-benzylamino-3-cyanoquinolin-2-yl)benzamide
N-[4-(benzylamino)-3-cyano-6-(4-formylpiperazin-l-yl)quinolin-2-yl]-4-
methoxybenzamide
4-{4-(Benzylamino)-3-cyano-2-[(4-methoxybenzoyl)amino]quinolin-6-
yl}piperazine-1 -sulfonic acid
N-{3-Cyano-6-(formylamino)-4-[(2-thienylmethyl)amino]quinolin-2-yl}-4-
methoxybenzamide
N-{3-Cyano-6-(formylamino)-4-[(2-thienylmethyl)amino]quinolin-2-yl}-l,3-
benzodioxole-5-carboxamide
N-[4-(Benzylamino)-3-cyano-6-(formylamino)quino]in-2-yn-U3-
benzodioxole-5-carboxamide
N-[4-(Benzylamino)-3-cyano-6-(formylamino)quinolin-2-yl]-4-
methoxybenzamide
N-4-(Benzylamino)-3-cyano-6-[formyl(methyl)amino]guinolin-2-yl}-4-
methoxybenzamide
N-{3-Cvano-6-[formyl(methyl)amimo]-4-[(2-thienylmethyl)amino]quinolin-2-
yl} -4-methoxybenzamide
{3-Cyano-2-[(4-methoxybenzoyl)amino]-4-[(2-
thienylmethynamino]quinolin-6-yl}methylsulfamic acid
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{4-(Benzvlamino)-3-cyano-2-[(4-methoxybenzoyl)amino]quinolin-6-
yl}methylsulfamic acid
{4-(Benzvlamino)-3-cvano-2-[(4-methoxvben2oynamino}quinolin-6-
yl}sulfamicacid
[2-[(l,3-Ben2odioxol-5-ylcarbonynamino]-4-(benzylamino)-3-
cyanoquinolin-6-ylisulfamic acid
{2-(l,3-Benzodioxol-5-yIcarbonyl)arnino]-3-cyano-4-[(2-
thienvlmethyl)amino]quinolin-6-yl}sulfamic acid
{3-Cyano-2-[(4-methoxybenzoyl)amino]-4-[(2-
thienylmethyl)amino]quinolin-6-yl}sulfamic acid
and their salts, solvates, isomers (tautomers, desmotrops), as well as
the salts and solvates thereof.
5. Process for the preparation of the compounds of the general formula (I)
and their salts, solvates and isomers, wherein in the formula the
meanings of R1, R2, R3, R4, R5, R6, R7, R8, X, Z, n, o, p, r and m are as
defined in claim 1., characterized in that,
v) a bis-carboxamide of the general formula (II"), wherein
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R2 stands for hydrogen atom or a straight or branched C1-4 alkyl group;
R3 stands for hydrogen atom, or a straight or branched C1-4 alkyl group,
C3-6 cycloalkyl group, a phenyl, thienyl, or furyl group, optionally
substituted with one or more straight or branched C1-4 alkyl group,
straight or branched C 1-4 alkoxy group, or halogen atom; a six- or five-
membered heteroaromatic ring containing one, two or three nitrogen
atoms, or a five-membered heteroaromatic ring containing one nitrogen
atom and one oxygen atom, or one nitrogen atom and one sulphur
atom, optionally substituted with one or more straight or branched
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C1-4 alkyl group, straight or branched C1-4 alkoxy group, or halogen
atom;
R4 and R5 independently stand for hydrogen atom, C3-6 cycloalkyl group,
straight or branched C1-4 alkyl group - optionally containing an amino
group, or an amino group substituted with one or two straight or
branched C1-4 alkyl group, a hydroxy group, a carboxy group, or an
alkoxy group substituted with a straight or branched C1-4 alkyl group -
or a protective group; or
' R4 stands for hydrogen atom or a straight or branched C1-4 alkyl group or a
benzyl group, and
,R5 stands for hydrogen atom, -SO2OH group or a straight or branched
C1-4 acyl group or a protective group, or
R4 and R5, together with the nitrogen atom, form a nitro group or a group of
the general formula a.), wherein R7 and R8 independently stand for
hydrogen atom, straight or branched C1-4 alkyl group or C3-6 cycloalkyl
group;
R6 stands for hydrogen atom or straight or branched C1-4 alkyl group,
phenyl, benzyl, thienyl, or furyl group, optionally substituted with
methylenedioxy group, or with one or more straight or branched
C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy
group, trifluoromethyl group, cyano group or halogen atom; or a six- or
five-membered heteroaromatic ring containing one, two or three
nitrogen atoms, or one nitrogen atom and one oxygen atom, or one
nitrogen atom and one sulphur atom, optionally substituted with one or
more straight or branched C1-4 alkyl group, straight or branched
C1-4 alkoxy group or halogen atom;
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X stands for -CH2- group, -NH- group, -NR9 group, or sulphur atom,
oxygen atom, sulpho group or sulphoxy group, wherein R9 stands for
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;
Z stands for oxygen atom sulphur atom, -CHR10 -group or -NR11-
group, wherein R10 stands for hydrogen atom, straight or branched .
C1-4 alkyl group, or C3-6 cycloalkyl group and R11 stands for hydrogen
atom, straight or branched C1-4 alkyl group, C3-6 cycloalkyl group, -
SO2OH group or a straight or branched C1-4 acyl group ;
n represents zero, 1 or 2;
m represents 1,2, or 3;
o represents 1, 2, or 3;
p represents zero or 1;
r represents zero or 1,
is selectively hydrolysed and if desired the protective group removed, or
v/i.) for the preparation of a compound of the general formula (I),
wherein R4 stands for hydrogen atom, a straight or branched C1-4 alkyl group
or benzyl group and R5 stands for a straight or branched C1-4 acyl group, or
R4 and R5 together with the nitrogen atom form a group of the general
formula a.), wherein Z stands for a -NR11 group, where R11 stands for a
straight or branched C1-4 acyl group and Rl, R2, R3, R6, R7, R8, R9, X, n, m, o,
p and r are as defined above,
a compound of the general formula (I), wherein R4 stands for hydrogen
atom, a straight or branched C1-4 alkyl group or benzyl group and R stands
for hydrogen atom, or R4 and R5 together with the nitrogen atom form a
group of the general formula a.), wherein Z stands for -NH group and R1 , R ,
R3, R6, R7, R8, R9, X, n, in, o, p and r are as defined above,
is acylated with a compound of the general formula R12 COY", wherein
R12 and Y" are as defined above, or
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WO 2005/009969 PCT/HU2004/000080
v/ii.) for the preparation of a compound of the general formula (I), wherein
R stands for hydrogen atom, a straight or branched C1-4 alkyl group or
benzyl group and R5 stands for -SO2OH group, or R4 and R5 together with
the nitrogen atom form a group of the general formula a.), wherein Z stands
for -NR11- group,where R11 stands for -SO2OH group and R1, R2, R3, R6, R7,
R8 , R9 , X, n, m, o, p and r are as defined above,
a compound of the general formula (I), wherein R4 stands for hydrogen
atom, a straight or branched C1-4 alkyl group or benzyl group and R5 stands
for hydrogen atom, or R4 and R5 together with the nitrogen atom form a
group of the general formula a.), wherein Z stands for-NH- group and R1 , R2 ,
R3, R6, R7, R8, R9, X, n, m, o, p and r are as defined above,
is reacted with a pyridine-SO3 complex, or with CISO3H, or
v/iii.) for the preparation of a compound of the general formula (I), wherein
R4 stands for hydrogen atom, a straight or branched C1-4 alkyl group or
benzyl group and R5 stands for -SO2OH group and R1, R2, R3, R6, R7, R8, R9,
X, Z, n, m, o, p and r are as defined above,
a compound of the general formula (XHI11), wherein R1, R2, R3, R6, R9,
X, and n are as defined above
is reacted with Na2S2O4 or NaHSO3,
or
is reduced and the compound of the general formula (XIV"), thus
obtained, wherein R4 stands for hydrogen atom and R1, Rr, R3, R6, R9, X",
and n", are as defined above, is sulphated with a pyridine-SO3 complex or
with CISO3H,
if desired after transforming the R4 hydrogen atom into a straight or
branched C1-4 alkyl group or a benzyl group, or
v/iv.) for the preparation of a compound of the general formula (I), wherein
R4 stands for hydrogen atom, C3-6 cycloalkyl group, benzyl group, straight or
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WO 2005/009969 PCT/HU2004/000080
branched C1-4 alkyl group - optionally containing an amino group, or an
amino group substituted with one or two straight or branched C1-4 alkyl
group, a hydroxy group, a carboxy group, or an alkoxy group substituted with
a straight or branched C1-4 alkyl group and R5 stands for hydrogen atom, or
R4 and R5 , together with the nitrogen atom, form a group of the general
formula a.), wherein R7 and R8 independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group and Z stands for
-NR11- group,where R11 stands for hydrogen atom,
removing the protective group of a compound of the general formula
(I"), wherein
R4 stands for hydrogen atom, C3-6 cycloalkyl group, benzyl group, straight or
branched C1-4 alkyl group - optionally containing an amino group, or an
amino group substituted with one or two straight or branched C1-4 alkyl
group, a hydroxy group, a carboxy group, or an alkoxy group substituted with
a straight or branched C1-4 alkyl group- and R5 stands for a protective group,
or
R4 and R5, together with the nitrogen atom, form a group of the general
1formula a .) wherein R and R independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group and Z stands for
-NR11 group, where R11 stands for a protecting group,
and-if desired- the substituents of the resulting compound of the general
formula (I) are transformed into each other by known methods, and/or the the
compound of the general formula (I) thus obtained is transformed into its salt
or solvate, or liberated from its salt or solvate and -if desired- resolved into
its optically active isomers and -if desired- a given desmotrop is transformed
into an other desmotropic form.
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WO 2005/009969 PCT/HU2004/000080
6. Process according to claim 5., characterized in that the
selective hydrolysis is effected with alkali hydroxide dissolved in alcoholic
medium, preferably with methanolic potassium- or sodium hydroxide
solution. .
7. Pharmaceutical composition, characterized in that it contains one or
more compounds of the general formula (I), -where in the formula R1 , R2 , R3 ,
R4, R5, R6, R7, R8, X, Z, n, m, o, p and r have the meaning as defined in Claim
1.,- and/or their salts, solvates, isomers (tautomers, desmotrops, optically
active isomers) the .salts, solvates thereof, and one or more auxiliary
materials, commonly used in the pharmaceutical industry.
8. Pharmaceutical composition as defined in claim 7., characterized in
that it contains as active substance one or more of the compounds defined in
claim 3.

9. Use of the compounds of the general formula (I), their salts, solvates and
isomers, -where in the formula R1, R2, R3, R4, R5, R6, R7, R8, X, Z, n, m,
o, p, and r have the meaning as defined in claim 1.- for the manufacture of
a pharmaceutical composition for the treatment of diseases in
development of which the receptor A3 plays a role.
10. Use of the compounds of the general formula (I) their salts, solvates and
isomers, -where in the formula R1, R2, R3, R4, R5, R6, R7, R8, X, Z, n, m,
o, p, and r have the meaning as defined in claim 1.- according to claim 9
as A3 ligand for the manufacture of a pharmaceutical composition for the
treatment of diseases of the heart, kidney, respiratory organs and central
nervous system, and for the inhibition of the protection of adenosine in
growing tumor cells, prevention of mast cell degranulation, inhibition of
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WO 2005/009969 PCT/HU2004/000080
the cytokine production, reduction of intraocular pressure, inhibition of
the TNF release, inhibition of eosinophil, neutrophil and other immune
cell migration., inhibition of bronchoconstriction and plasma
extravasation.
11.Use of the compounds of the general formula (I), their salts, solvates and
isomers, -where in the formula Rl, R2, R3, R4, R5, R6, R7, R8, X, Z, n, m, o,
p, and r have the meaning as defined in claim 1.- according to claim 10 as
A3 receptor antagonist for the manufacture of antiinflamatory,
antiasthmatic, antiischemic, antidepressant, antiarrhythmic, renal
protective, antitumor, antiparkinson and cognitive enhancing
pharmaceutical compositions and compositions for the treatment or
prevention of miocardial reperfusion injury, chronic obstructive
pulmonary disease (COPD) and adult respiratory distress syndrome
(ARDS) including chronic bronchitis, pulmonary emphysema or dyspnea,
allergic reactions (e.g. rhinitis, poison ivy induced responses, urticaria,
scleroderma, arthritis) other autoimmune diseases, inflammatory bowel
disease, Addison's disease, CrohrTs disease, psoriasis, rheumatism,
hypertension, neurogical function disorders, glaucoma and diabetes.
12.Use of the compounds of the general formula (I), their salts, solvates and
isomers, -where in the formula R1, R2, R3, R4, R5, R6, R7, R8, X, Z, n, m, o,
p, and r have the meaning as defined in claim 1.- according to claims 10
and 11 as A3 receptor antagonist for the manufacture of a pharmaceutical
composition for the treatment of diseases such as asthma, COPD and
ARDS, glaucoma, tumor, allergic reactions, inflammatory diseases,
ischemia, hypoxia, arrhytmia and renal diseases.
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13. Compounds of the general formula (I"), where in the formula the
meanings of Rr, R2", R3", R6", R7" R8" X", n", m", o", p", and r" are as defined
in claim 5. and
R4 stands for hydrogen atom, C3-6 cycloalkyl group, benzyl group, straight or
branched C1-4 alkyl group - optionally containing an amino group, or an
amino group substituted with one or two straight or branched C1-4 alkyl
group, a hydroxy group, a carboxy group, or an alkoxy group substituted with
a straight or branched C1-4 alkyl group- and R5 stands for a protective group,
or
R4 and R5, together with the nitrogen atom, form a group of the general
formula a .), wherein R and R independently stand for hydrogen atom,
straight or branched C1-4 alkyl group or C3-6 cycloalkyl group and Z stands for
-NR11 group, where R11 stands for a protecting group.
14. Compounds of the general formula (11"), where in the formula the
meanings of Rl", R2", R3", R4", R5", R6", R7" R8" X", Z", n" m", o", p", and r" are
as defined in claim 5.
15. Compounds of the general formula (III"), where in the formula the
meanings of R1", R2", R3", R4", R5", R7", R8", X", Z", n", m", o", p", and r11 are as
defined in claim 5.
16. Compounds of the general formula (IV") where in the formula the
meanings of R4", R5", R7", R8", Z", m", o", p", and r" are as defined
in claim 5.
17. Compounds of the general formula (V"), where in the formula the
meanings of R4", R5", R7", R8", Z", m", o", p", and r" are as defined in claim 5.
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WO 2005/009969 PCT/HU2004/000080
18. Compounds of the general formula (VI"), where in the formula the
meanings of R4", R5', R7", R8", Z", m", o", p", and r" are as defined in claim 5.,
with the proviso that R4 and R5' together with the nitrogen atom, have a
meaning different from dimethylamino- and amino group.
19. Compounds of the general formula (VII"), where in the formulae the
meanings of R4", R5", R7", R8", Z", m", o", p", and r" are as defined in claim 5.,
with the proviso that R4 and R5 together with the nitrogen, atom have a
meaning different from dimethylamino-, diethylamino-, and amino group.
20. Compounds of the general formula (VIII"), where in the formula R4
and R5 together with the nitrogen atom, represent a morpholino, N-
methylpiperazino, piperazino or 4-benzylpyperazino group.
21. Compounds of the general formula (XIH"), wherein the meanings of
the substituents R1", R2", R3", R6" and n" are as defined in claim 5.


Compounds of the general formula (I), and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) as well as the salts and solvates; are strong adenosine A3 receptor ligands preferably antagonists.

Documents:

02734-kolnp-2005-abstract.pdf

02734-kolnp-2005-claims.pdf

02734-kolnp-2005-description complete.pdf

02734-kolnp-2005-drawings.pdf

02734-kolnp-2005-form 1.pdf

02734-kolnp-2005-form 3.pdf

02734-kolnp-2005-form 5.pdf

02734-kolnp-2005-international publication.pdf

02734-kolnp-2005-priority document.pdf

2734-KOLNP-2005-CORRESPONDENCE 1.1.pdf

2734-KOLNP-2005-CORRESPONDENCE.pdf

2734-KOLNP-2005-FORM 27 1.1.pdf

2734-KOLNP-2005-FROM 27.pdf

2734-kolnp-2005-granted-abstract.pdf

2734-kolnp-2005-granted-assignment.pdf

2734-kolnp-2005-granted-claims.pdf

2734-kolnp-2005-granted-correspondence.pdf

2734-kolnp-2005-granted-description (complete).pdf

2734-kolnp-2005-granted-drawings.pdf

2734-kolnp-2005-granted-examination report.pdf

2734-kolnp-2005-granted-form 1.pdf

2734-kolnp-2005-granted-form 18.pdf

2734-kolnp-2005-granted-form 3.pdf

2734-kolnp-2005-granted-form 5.pdf

2734-kolnp-2005-granted-reply to examination report.pdf

2734-kolnp-2005-granted-specification.pdf

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Patent Number 235063
Indian Patent Application Number 2734/KOLNP/2005
PG Journal Number 26/2009
Publication Date 26-Jun-2009
Grant Date 24-Jun-2009
Date of Filing 27-Dec-2005
Name of Patentee SANOFI- AVENTIS
Applicant Address 174, AVENUE DE FRANCE, F-75013, PARIS, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 ARANYI, PETER BIMBO UT 216, H-1026 BUDAPEST
2 BATORI SANDOR RAKOCZI. E. 268/A, H-1214 BUDAPEST
3 TIMARI, GEZA ZOLDFA U. 8., H-2220 VEESES
4 BOER, KINGA TAS U. 16, H-2013 POMAZ
5 KAPUI, ZOLTAN ETELE 56/A, H-1115 BUDAPEST
6 MIKUS, ENDRE IDA U. 96, H-1162 BUDAPEST
7 URBAN-SZABO, KATALIN SZENT LASZLO U. 158, H-1131 BUDAPEST
8 GERBER, KATALIN KOS KAROLY TER 3., H-1192 BUDAPEST
9 VARGANE SZEREDI, JUDIT TELKES U. 12., H-1046 BUDAPEST
10 FINET, MICHEL SZENT ISTVAN U. 41, H-1023 BUDAPEST
PCT International Classification Number C07D 215/54
PCT International Application Number PCT/HU2004/000080
PCT International Filing date 2004-07-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 P 0401468 2004-07-21 Hungary
2 P 0302440 2003-07-31 Hungary
3 P 0401467 2004-07-21 Hungary