IMIDAZOPYRIDAZINE DIONES, THE PRODUCTION THEREOF, AND THE USE OF THE SAME AS A MEDICAMENT

IMIDAZOPYRIDAZINDIONE, SA FABRICATION ET SON UTILISATION COMME MEDICAMENT

English Abstract

The invention relates to substituted imidazopyridazine diones of general
formula (I) wherein R1 to R4 have the designation defined in patent claim 1.
The invention also relates to the tautomers, enantiomers, diastereomers,
mixtures and salts of said diones, comprising valuable pharmacological
properties, especially an inhibitive effect on the activity of the enzyme
dipeptidylpeptidase-IV (DPP-IV).

French Abstract

L'invention concerne une imidazopyridazindione de formule générale (I) dans laquelle R?1¿ à R?4¿ sont tels que définis dans la revendication 1. L'invention concerne également les énantiomères, les diastéréoisomères de ce composé, ainsi que leurs mélanges et leurs sels, lesquels présentent des propriétés pharmacologiques précieuses, en particulier, un effet inhibiteur de l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).

Claims

56
Claims
1. Compounds of general formula
<IMG>
wherein
R1 denotes an arylmethyl group,
a heteroarylmethyl group,
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group or
an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the propenyl chain
may
be substituted by 1 to 4 fluorine atoms or a cyano, C1-3-alkyloxy-carbonyl or
nitro
group,
R2 denotes a C1-6-alkyl group,
an aryl or heteroaryl group,
a C1-6-alkyl group substituted by a group R a, where
R a denotes a fluorine, chlorine or bromine atom,

57
a C3-7-cycloalkyl group wherein one or two methylene groups independently of
one another may each be replaced by an oxygen or sulphur atom or by an -NH
or -N(C1-3-alkyl)- group, or by a carbonyl, sulphinyl or sulphonyl group,
or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-amino-carbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,
piperazin-
1-ylcarbonyl, 4-(C1-3-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, C1-3-alkylsulphinyl or C1-3-alkylsulphonyl group,
a C2-6-alkyl group substituted by a group R b, where
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms and
R b denotes a hydroxy, C1-3-alkoxy, C1-3-alkylsulphanyl, amino, C1-3-
alkylamino or
di-(C1-3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,
piperazin-1-yl
or 4-(C1-3-alkyl)-piperazin-1-yl group,
a C3-6-cycloalkyl group or
a C3-6-alkenyl or C3-6-alkynyl group, while the multiple bond is isolated from
the cyclic
nitrogen atom by at least one carbon atom,
R3 denotes a C5-7-cycloalkenylmethyl group optionally substituted by a C1-3-
alkyl
group,
an arylmethyl or heteroarylmethyl group,
a straight-chain or branched C2-6-alkenyl group which may be substituted by 1
to 15
fluorine atoms or by a cyano, nitro or C1-3-alkoxy-carbonyl group,
or a straight-chain or branched C3-6-alkynyl group which may be substituted by
1 to 9
fluorine atoms or by a cyano, nitro or C2-8-alkoxy-carbonyl group,

58
and
R4 denotes a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in
the 3
position by an amino or C1-3-alkylamino group and may additionally be
substituted by
one or two C1-3-alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position
or in the 4 position by an amino group or C1-3-alkylamino group and may
additionally
be substituted by one or two C1-3-alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one
or two
C1-3-alkyl groups,
an amino group substituted by the groups R15 and R16 wherein
R15 denotes a hydrogen atom, a C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-
3-
alkyl, aryl or aryl-C1-3-alkyl group and
R16 denotes a R17 -C2-3-alkyl group, while the C2-3-alkyl moiety is straight-
chain
and may be substituted by 1 to 4 C1-3-alkyl groups, which may be identical or
different, and
R17 denotes an amino or C1-3-alkylamino group,
an amino group substituted by the groups R15 and R18, wherein
R15 is as hereinbefore defined and R18 denotes a C3-6-cycloalkyl-methyl group
substituted by R19 in the 1 position of the cycloalkyl group or a C3-6-
cycloalkyl
group substituted by a R19-CH2- group in the 1 position, while R19 denotes an
amino or C1-3-alkylamino group,

59
an amino group substituted by the groups R15 and R20 wherein
R15 is as hereinbefore defined and R20 denotes an azetidin-3-yl, azetidin-2-
ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl,
pyrrolidin-3-
ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-
ylmethyl
or piperidin-4-ylmethyl group, while the groups mentioned for R20 may each be
substituted by one or two C1-3-alkyl groups,
an amino group substituted by the groups R15 and R21 wherein
R15 is as hereinbefore defined and R21 denotes a C3-7-cycloalkyl group
substituted in the 2 or 3 position by an amino or C1-3-alkylamino group, which
may additionally be substituted by one or two C1-3-alkyl groups,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs
thereof and the salts thereof.
2. Compounds of general formula (I) according to claim 1, wherein
R1 and R2 are defined as in claim 1,
R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-
methyl,
furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl,
methoxybenzyl
or cyanobenzyl group, and
R4 denotes an N-(2-aminoethyl)-N-methyl-amino group which may be substituted
in
the ethyl moiety by one or two C1-3-alkyl groups, or

60
a 3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl group, while the
above-
mentioned groups may each additionally be substituted by one or two C1-3-alkyl
groups,
the enantiomers, the diastereomers, the mixtures thereof and the salts
thereof.
3. Compounds of general formula (I) according to claim 2, wherein
R1 denotes a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl,
pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl,
isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl,
phenanthridinylmethyl,
naphthyridinylmethyl or benzotriazolylmethyl group, while all the above-
mentioned
aryl and heteroaryl groups may be substituted by one or two fluorine,
chlorine,
bromine atoms or one or two cyano, nitro, amino, C1-3-alkyl, C1-3-alkyloxy and
morpholinyl groups, while the substituents are identical or different,
R2 denotes a C1-6-alkyl group which may be substituted by a fluorine atom or a
cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-
alkylaminocarbonyl,
C1-3-alkylsulphonyl, aryl or heteroaryl group, while the aryl or heteroaryl
group is as
hereinbefore defined,
C2-6-alkyl group a substituted by a group R b, where
R b is isolated from the cyclic nitrogen atom by at least two carbon atoms and
R b
denotes a hydroxy or C1-3-alkyloxy group,
or a C3-6-alkenyl or C3-6-alkynyl group, while the multiple bond is isolated
from the
cyclic nitrogen atom by at least one carbon atom,
R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-
methyl,
furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl or
cyanobenzyl
group and

61
R4 denotes an N-(2-aminoethyl)-N-methylamino, N-(2-aminopropyl)-N-methyl-
amino,
3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl group,
the enantiomers, the diastereomers, the mixtures thereof and the salts
thereof.
4. Compounds of general formula (I) according to claim 3, wherein
R1 denotes a cyanobenzyl, phenylcarbonylmethyl, methylquinazolinylmethyl,
methyl-
isoquinolinylmethyl, naphthylmethyl or quinolinylmethyl group,
R2 denotes a methyl, prop-2-enyl, prop-2-ynyl, 2-fluoroethyl, cyanomethyl,
carboxy-
methyl, aminocarbonylmethyl, pyridinylmethyl or phenylmethyl group,
R3 denotes a 2-butyn-1-yl group and
R4 denotes a 3-aminopiperidin-1-yl or piperazin-1-yl group,
the enantiomers, the diastereomers, the mixtures and salts thereof.
5. The following compounds of general formula (I) according to claim 1:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-
yl-
methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-
ylmethyl)-5,6-
dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(3) (R)-1-(1-but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-
(quinolin-2-yl-
methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,

62
(4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-
2-yl-
methyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-
ylmethyl)-5,6-
dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(6) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-
dihydro-1H-
imidazo[4,5-d]pyridazine-4,7-dione,
(7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-
(naphth-
1-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(naphth-1-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-
isoquinolin-1-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-
(phenylcarbonylmethyl)-
5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-
quinazolin-2-
ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,

63
(15) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-
5,6-
dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
(16) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-
methyl-
quinazolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione,
and the salts thereof.
6. Physiologically acceptable salts of the compounds according to at least one
of
claims 1 to 5 with inorganic or organic acids.
7. Pharmaceutical compositions containing a compound according to at least one
of
claims 1 to 5 or a physiologically acceptable salt according to claim 6,
optionally
together with one or more inert carriers and/or diluents.
8. Use of a compound according to at least one of claims 1 to 6 for preparing
a
pharmaceutical composition which is suitable for treating type I and II
diabetes
mellitus, arthritis, obesity, allograft transplantation and calcitonin-induced
osteoporosis.
9. Process for preparing a pharmaceutical composition according to claim 7,
characterised in that a compound according to at least one of claims 1 to 6 is
incorporated in one or more inert carriers and/or diluents by a non-chemical
method.
10. Process for preparing the compounds of general formula (I) according to
claims
1 to 6, characterised in that
a) a compound of general formula

64
<IMG>
wherein
R1 to R3 are defined as in claim 1 and
Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy,
mercapto, sulphinyl, sulphonyl or sulphonyloxy group,
is reacted with a compound of general formula
H - R4 ,(III)
wherein
R4 is as hereinbefore defined; or
b) in order to prepare a compound of general formula I wherein R4 according to
the
definition given in claim 1 contains an amino group or an alkylamino group
optionally
substituted in the alkyl moiety:
a compound of general formula
<IMG>
wherein R1, R2 and R3 are defined as in claim 1 and

65
R4' contains an N-tert.-butyloxycarbonylamino group or an N-tert.-
butyloxycarbonyl-
N-alkylamino group, where the alkyl moiety of the N-tert.-butyloxycarbonyl-N-
alkyl-
amino group may be substituted as mentioned hereinbefore, is deprotected;
and any protecting groups used during the reaction are then cleaved and/or
the compounds of general formula I thus obtained are resolved into their
enantiomers and/or diastereomers and/or
the compounds of formula I thus obtained are converted into their salts,
particularly
for pharmaceutical use into the physiologically acceptable salts thereof with
inorganic or organic acids.

Description

,.
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Boehringer Ingelheim Case 1/1658
Foreign filing text
Imidazopyridazinediones, their preparation and their use as pharmaceutical
compositions
The present invention relates to substituted imidazopyridazinediones of
general
formula
O /R3
R~\N /N
/~ R4
R2/ ' N
O
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof,
particularly the physiologically acceptable salts thereof with inorganic or
organic
acids or bases which have valuable pharmacological properties, particularly an
inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-
IV), the
preparation thereof, the use thereof for preventing or treating illnesses or
conditions
connected with an increased DPP-IV activity or capable of being prevented or
alleviated by reducing the DPP-IV activity, particularly type I or type II
diabetes
mellitus, the pharmaceutical compositions containing a compound of general
formula
(I) or a physiologically acceptable salt thereof and processes for the
preparation
thereof.
In the above formula I
R~ denotes an arylmethyl group,
a heteroarylmethyl group,

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2
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group or
an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the propenyl chain
may
be substituted by 1 to 4 fluorine atoms or a cyano, C~_3-alkyloxy-carbonyl or
nitro
group,
R2 denotes a C~_6-alkyl group,
an aryl or heteroaryl group,
a C~_6-alkyl group substituted by a group Ra, where
Ra denotes a fluorine, chlorine or bromine atom,
a C3_~-cycloalkyl group wherein one or two methylene groups independently of
one another may each be replaced by an oxygen or sulphur atom or by an -NH
or -N(C~_3-alkyl)- group, or by a carbonyl, sulphinyl or sulphonyl group,
or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C~_3-alkoxy-carbonyl,
aminocarbonyl, C~_3-alkylamino-carbonyl or di-(C~_3-alkyl)-amino-carbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,
piperazin-
1-ylcarbonyl, 4-(C~_3-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, C~_3-alkylsulphinyl or C~_3-alkylsulphonyl group,
a C2_6-alkyl group substituted by a group Rb, where
Rb is isolated from the cyclic nitrogen atom by at least two carbon atoms and
Rb denotes a hydroxy, C~_3-alkoxy, C~_3-alkylsulphanyl, amino, C~_3-alkylamino
or
di-(C~_3-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,
piperazin-1-yl
or 4-(C~_3-alkyl)-piperazin-1-yl group,

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3
a C3_6-cycloalkyl group or
a C3_6-alkenyl or C3_6-alkynyl group, while the multiple bond is isolated from
the cyclic
nitrogen atom by at least one carbon atom,
R3 denotes a C5_~-cycloalkenylmethyl group optionally substituted by a C~_3-
alkyl
group,
an arylmethyl or heteroarylmethyl group,
a straight-chain or branched C2_$-alkenyl group which may be substituted by 1
to 15
fluorine atoms or by a cyano, nitro or C~_3-alkoxy-carbonyl group,
or a straight-chain or branched C3_6-alkynyl group which may be substituted by
1 to 9
fluorine atoms or by a cyano, nitro or C2_$-alkoxy-carbonyl group,
and
R4 denotes a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in
the 3
position by an amino or C~_3-alkylamino group and may additionally be
substituted by
one or two C~_3-alkyl groups,
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position
or in the 4 position by an amino group or C~_3-alkylamino group and may
additionally
be substituted by one or two C~_3-alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group which may be substituted by one
or two
C~_3-alkyl groups,
an amino group substituted by the groups R~5 and R~6 wherein

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R'5 denotes a hydrogen atom, a C~_6-alkyl, C3_6-cycloalkyl, C3_6-cycloalkyl-
C~_3-
alkyl, aryl or aryl-C~_3-alkyl group and
R~6 denotes a R~'-C2_3-alkyl group, while the C2_3-alkyl moiety is straight-
chain
and may be substituted by 1 to 4 C~_3-alkyl groups, which may be identical or
different, and
R" denotes an amino or C~_3-alkylamino group,
an amino group substituted by the groups R'S and R'$, wherein
R~5 is as hereinbefore defined and R'$ denotes a C3_6-cycloalkyl-methyl group
substituted by R'9 in the 1 position of the cycloalkyl group or a C3_6-
cycloalkyl
group substituted by a R'9-CH2- group in the 1 position, while R'9 denotes an
amino or C~_3-alkylamino group,
an amino group substituted by the groups R'S and R2° wherein
R~5 is as hereinbefore defined and R2° denotes an azetidin-3-yl,
azetidin-2-
ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl,
pyrrolidin-3-
ylmethyl, piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-
ylmethyl
or piperidin-4-ylmethyl group, while the groups mentioned for R2° may
each be
substituted by one or two C~_3-alkyl groups,
an amino group substituted by the groups R'5 and RZ' wherein
R~5 is as hereinbefore defined and R2~ denotes a C3_~-cycloalkyl group
substituted in the 2 or 3 position by an amino or C~_3-alkylamino group, which
may additionally be substituted by one or two C~_3-alkyl groups,
while by the aryl groups mentioned in the definition of the above groups are
meant
phenyl or naphthyl groups, which may be mono-, di- or trisubstituted by Rh
independently of one another, while the substituents may be identical or
different

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and Rh denotes a fluorine, chlorine, bromine or iodine atom, a
trifluoromethyl, cyano,
nitro, amino, aminocarbonyl, C~_3-alkoxy-carbonyl, aminosulphonyl,
methylsulphonyl,
acetylamino, methylsulphonylamino, C~_3-alkyl, cyclopropyl, ethenyl, ethynyl,
morpholinyl, hydroxy, C~_3-alkyloxy, difluoromethoxy or trifluoromethoxy
group, and
5 wherein additionally each hydrogen atom may be replaced by a fluorine atom,
by the heteroaryl groups mentioned in the definition of the above groups are
meant a
pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,
phenanthridinyl, quinolinyl or isoquinolinyl group,
or a pyrrolyl, furanyl, thienyl or pyridyl group is meant, wherein one or two
methyne
groups are replaced by nitrogen atoms,
or a indolyl, benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl or
isoquinolinyl group is meant, wherein one to three methyne groups are replaced
by
nitrogen atoms,
or a 1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-
oxo-
pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-
pyrimidinyl,
3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, 1,2-
dihydro-
2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-
indolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-
oxo-
benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl, 1,2-
dihydro-
1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-
quinazolinyl, 3,4-
dihydro-4-oxo-quinazolinyl, 1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl, 1,2-
dihydro-2-
oxoquinoxalinyl, 1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl, 1,2-dihydro-1-oxo-
phthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl,
2,3-
dihydro-benzo[1,4]dioxinyl or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl group is
meant,

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and the above-mentioned heteroaryl groups may be mono- or disubstituted by
Rh, while the substituents may be identical or different and Rh is as
hereinbefore defined,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl- and
alkynyl
groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs
thereof and the salts thereof.
The carboxy groups mentioned in the definition of the abovementioned groups
may
be replaced by a group which can be converted into a carboxy group in vivo or
by a
group which is negatively charged under physiological conditions,
and furthermore the amino and imino groups mentioned in the definition of the
abovementioned groups may be substituted by a group which can be cleaved in
vivo. Such groups are described for example in WO 98/46576 and by N.M. Nielsen
et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
By a group which can be converted in vivo into a carboxy group is meant, for
example, a hydroxymethyl group, a carboxy group esterified with an alcohol
wherein
the alcohol moiety is preferably a C~_6-alkanol, a phenyl-C~_3-alkanol, a
C3_9-cycloalkanol, while a C5_$-cycloalkanol may additionally be substituted
by one or
two C~_3-alkyl groups, a C5_$-cycloalkanol wherein a methylene group in the 3
or 4
position is replaced by an oxygen atom or by an imino group optionally
substituted
by a C~_3-alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkoxycarbonyl or C2_6-
alkanoyl group
and the cycloalkanol moiety may additionally be substituted by one or two C~_3-
alkyl
groups, a C4_~-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-
alkynol or
phenyl-C3_5-alkynol, with the proviso that no bonds to the oxygen atom start
from a
carbon atom which carries a double or triple bond, a C3_$-cycloalkyl-C~_3-
alkanol, a
bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be

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substituted in the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-
dihydro-
3-oxo-1-isobenzofuranol or an alcohol of formula
RP-CO-O-(RqCR~)-OH,
wherein
Rp denotes a C~_$-alkyl, C5_~-cycloalkyl, C~_$-alkyloxy, C5_~-cycloalkyloxy,
phenyl or
phenyl- C~_3-alkyl group,
Rq denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and
R~ denotes a hydrogen atom or a C~_3-alkyl group,
by a group which is negatively charged under physiological conditions is
meant, for
example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl,
trifluoromethylcarbonylaminocarbonyl, C~_6-alkylsulphonylamino,
phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino,
C~_6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl,
benzylsulphonylaminocarbonyl or perfluoro-C~_6-alkylsulphonylaminocarbonyl
group
and by a group which can be cleaved in vivo from an imino or amino group is
meant,
for example, a hydroxy group, an acyl group such as a phenylcarbonyl group
optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine
atoms, by
C~_3-alkyl or C~_3-alkoxy groups, while the substituents may be identical or
different, a
pyridinoyl group or a C~_~6-alkanoyl group such as the formyl, acetyl,
propionyl,
butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or
allyloxycarbonyl
group, a C~_~6-alkoxycarbonyl or C~_~6-alkylcarbonyloxy group, wherein
hydrogen
atoms may be wholly or partially replaced by fluorine or chlorine atoms such
as the
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl,
octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,

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.,
8
dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy,
2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy,
butylcarbonyloxy, tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy,
octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy,
dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C~_6-alkoxycarbonyl
group such as the benzyloxycarbonyl, phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group
may be mono- or disubstituted by C~_6-alkyl or C3_~-cycloalkyl groups and the
substituents may be identical or different, a C~_3-alkylsulphonyl-C2_4-
alkoxycarbonyl,
C~_3-alkoxy-C2_4-alkoxy-C2_4-alkoxycarbonyl, RP-CO-O-(RqCR~)-O-CO, C~_6-alkyl-
CO-
NH-(RSCRt)-O-CO- or C~_6-alkyl-CO-O-(RSCRt)-(RSCRt)-O-CO- group, wherein Rp to
R~ are as hereinbefore defined,
RS and Rt, which may be identical or different, denote hydrogen atoms or
C~_3-alkyl groups.
Moreover, unless otherwise stated, the saturated alkyl and alkoxy moieties
containing more than 2 carbon atoms mentioned in the definitions above also
include
the branched isomers thereof such as the isopropyl, tert.butyl, isobutyl
group, etc.
R' may denote, for example, a 2-cyanobenzyl, 3-fluorobenzyl, 3-methoxybenzyl,
4-
bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl, 2-cyano-4-fluorobenzyl, 2-cyano-6-
fluorobenzyl, 3,5-dimethoxybenzyl, 2,6-dicyanobenzyl, 5-cyanofuranylmethyl,
oxazolylmethyl, isoxazolylmethyl, 5-methoxycarbonylthienylmethyl,
pyridinylmethyl,
3-cyanopyridin-2-ylmethyl, 3-cyanopyridin-4-ylmethyl, 4-cyanopyridin-3-
ylmethyl, 6-
cyanopyridin-2-ylmethyl, 6-fluoropyridin-2-ylmethyl, pyrimidin-2-ylmethyl, 4-
methyl-
pyrimidin-2-ylmethyl, 4,6-dimethyl-pyrimidin-2-ylmethyl, 3-(2-cyanophenyl)-
prop-2-
enyl, 3-(pyridin-2-yl)-prop-2-enyl, 3-(pentafluorophenyl)-prop-2-enyl, phenyl-
carbonylmethyl, 3-methoxyphenylcarbonylmethyl, naphth-1-ylmethyl, naphth-2-
ylmethyl, 4-cyanonaphth-1-ylmethyl, quinolin-1-ylmethyl, quinolin-2-ylmethyl,
quinolin-6-ylmethyl, 4-cyanoquinolin-1-ylmethyl, isoquinolin-1-ylmethyl, 4-
cyano-
isoquinolin-1-ylmethyl, 4-cyano-isoquinolin-3-ylmethyl, 3-methylisoquinolin-1-

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9
ylmethyl, quinazolin-2-ylmethyl, 4-methylquinazolin-2-ylmethyl,
[1,5]naphthiridin-2-yl,
[1,5]naphthiridin-3-yl, 1-methyl-benzotriazol-5-ylmethyl, phenanthridin-6-
ylmethyl,
quinoxalin-6-ylmethyl or 2,3-dimethyl-quinoxalin-6-ylmethyl group.
R2 may denote, for example, a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl,
2-
methylpropyl, 2-propen-1-yl, 2-propyn-1-yl, cyclopropylmethyl, benzyl, 2-
phenylethyl,
phenylcarbonylmethyl, 3-phenylpropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-
ethoxyethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-
(pyrrolidino)ethyl, 2-
(piperidino)ethyl, 2-(morpholino)ethyl, 2-(piperazino)ethyl, 2-(4-
methylpiperazino)ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-
(dimethylamino)propyl, 3-(diethylamino)propyl, 3-(pyrrolidino)propyl, 3-
(piperi-
dino)propyl, 3-(morpholino)propyl-,3-(piperazino)propyl, 3-(4-
methylpiperazino)-
propyl, carboxymethyl, (methoxycarbonyl)methyl, (ethoxycarbonyl)methyl, 2-
carboxyethyl, 2-(methoxycarbonyl)ethyl, 2-(ethoxycarbonyl)ethyl, 3-
carboxypropyl, 3-
(methoxycarbonyl)propyl, 3-(ethoxycarbonyl)propyl, (aminocarbonyl)methyl,
(methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrroli-
dinocarbonyl)methyl, (piperidinocarbonyl)methyl, (morpholinocarbonyl)methyl, 2-
(aminocarbonyl)ethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbo-
nyl)ethyl, 2-(pyrrolidinocarbonyl)ethyl, 2-(piperidinocarbonyl)ethyl, 2-
(morpholino-
carbonyl)ethyl, cyanomethyl, 2-cyanoethyl, 2-fluoroethyl, pyridin-3-ylmethyl
or
pyridin-4-ylmethyl group.
R3 may denote, for example, a 2-propen-1-yl, 2-methyl-2-propen-1-yl, 1-buten-1-
yl,
2-buten-1-yl, 3-buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-buten-1-yl, 2,3-
dimethyl-2-buten-1-yl, 3-methyl-3-buten-1-yl, 1-cyclopenten-1-ylmethyl, (2-
methyl-1-
cyclopenten-1-yl)methyl, 1-cyclohexen-1-ylmethyl, 2-propyn-1-yl, 2-butyn-1-yl,
3-
butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-cyanobenzyl, 3-
fluorobenzyl, 2-methoxybenzyl, 2-furanylmethyl, 3-furanylmethyl, 2-
thienylmethyl or
3-thienylmethyl group.
R4 may denote, for example, a 3-aminopyrrolidin-1-yl, 3-aminopiperidin-1-yl, 3-
(methylamino)-piperidin-1-yl, 3-(ethylamino)-piperidin-1-yl, 3-amino-2-methyl-
piperi-

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din-1-yl, 3-amino-3-methyl-piperidin-1-yl, 3-amino-4-methyl-piperidin-1-yl, 3-
amino-5-
methyl-piperidin-1-yl, 3-amino-6-methyl-piperidin-1-yl, 4-aminopiperidin-1-yl,
3-amino-hexahydroazepin-1-yl, 4-amino-hexahydroazepin-1-yl, (2-aminocyclo-
propyl)amino, (2-aminocyclobutyl)amino, (3-aminocyclobutyl)amino,
5 (2-aminocyclopentyl)amino, (3-aminocyclopentyl)amino, (2-
aminocyclohexyl)amino,
(3-aminocyclohexyl)amino, piperazin-1-yl, homopiperazin-1-yl, N-(2-aminoethyl)-
N-
methylamino, N-(2-aminopropyl)-N-methylamino or N-(2-amino-2-methyl-propyl)-N-
methylamino group.
10 Preferred compounds of the above general formula I are those wherein
R~ and R2 are as hereinbefore defined,
R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-
methyl,
furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl,
methoxybenzyl
or cyanobenzyl group, and
R4 denotes an N-(2-aminoethyl)-N-methyl-amino group which may be substituted
in
the ethyl moiety by one or two C~_3-alkyl groups, or
a 3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl group, while the
above-
mentioned groups may each additionally be substituted by one or two C~_3-alkyl
groups,
the enantiomers, the diastereomers, the mixtures thereof and the salts
thereof.
Particularly preferred compounds of the above general formula I are those
wherein
R' denotes a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl,
pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl,
isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl,
phenanthridinylmethyl,
naphthyridinylmethyl or benzotriazolylmethyl group, while all the above-
mentioned

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11
aryl and heteroaryl groups may be substituted by one or two fluorine,
chlorine,
bromine atoms or one or two cyano, nitro, amino, C~_3-alkyl, C~_3-alkyloxy and
morpholinyl groups, while the substituents are identical or different,
Rz denotes a C~_6-alkyl group which may be substituted by a fluorine atom or a
cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-
alkylaminocarbonyl,
C~_3-alkylsulphonyl, aryl or heteroaryl group, while the aryl or heteroaryl
group is as
hereinbefore defined,
C2_6-alkyl group a substituted by a group Rb, where
Rb is isolated from the cyclic nitrogen atom by at least two carbon atoms and
Rb
denotes a hydroxy or C~_3-alkyloxy group,
or a C3_6-alkenyl or C3_6-alkynyl group, while the multiple bond is isolated
from the
cyclic nitrogen atom by at least one carbon atom,
R3 denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-
methyl,
furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl or
cyanobenzyl
group and
R4 denotes an N-(2-aminoethyl)-N-methylamino, N-(2-aminopropyl)-N-methyl-
amino,
3-aminopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl group,
the enantiomers, the diastereomers, the mixtures thereof and the salts
thereof.
Most particularly preferred compounds of the above general formula I are those
wherein
R~ denotes a cyanobenzyl, phenylcarbonylmethyl, methylquinazolinylmethyl,
methyl-
isoquinolinylmethyl, naphthylmethyl or quinolinylmethyl group,

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12
R2 denotes a methyl, prop-2-enyl, prop-2-ynyl, 2-fluoroethyl, cyanomethyl,
carboxy-
methyl, aminocarbonylmethyl, pyridinylmethyl or phenylmethyl group,
R3 denotes a 2-butyn-1-yl group and
R4 denotes a 3-aminopiperidin-1-yl or piperazin-1-yl group,
the enantiomers, the diastereomers, the mixtures thereof and salts.
The following preferred compounds may be mentioned by way of example:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-
yl-
methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(3) (R)-1-(1-but-2-ynyl )-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-
(quinolin-2-yl-
methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-
2-yl-
methyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(6) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-2-ylmethyl)-5,6-
dihydro-1 H-
imidazo[4,5-d]pyridazine-4,7-dione,
(7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-
(naphth-
1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,

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13
(8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-
(naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-
isoquinolin-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-
(phenylcarbonylmethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-
quinazolin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(15) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-
5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
(16) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-
methyl-
quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione,
and the salts thereof.

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14
According to the invention the compounds of general formula I are obtained by
methods known per se, for example by the following methods:
a) reacting a compound of general formula
O /R3
R1\N N
/~Z' ( II ),
R2/ ' N
O
wherein
R' to R3 are as hereinbefore defined and
Z' denotes a leaving group such as a halogen atom, a substituted hydroxy,
mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as for example a
chlorine
or bromine atom, a methanesulphonyl or methanesulphonyloxy group,
with a compound of general formula
H - R4 ,(III)
wherein
R4 is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as isopropanol,
butanol,
tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide,
dimethylsulphoxide, methylene chloride, ethyleneglycolmonomethylether,
ethyleneglycoldiethylether or sulpholane, optionally in the presence of an
inorganic
or tertiary organic base, e.g. sodium carbonate or potassium hydroxide, a
tertiary
organic base, e.g. triethylamine, or in the presence of N-ethyl-
diisopropylamine
(Hunig base), while these organic bases may simultaneously also serve as
solvent,
and optionally in the presence of a reaction accelerator such as an alkali
metal
halide or a palladium-based catalyst, at temperatures between -20 and
180°C, but

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preferably at temperatures between -10 and 120°C. However, the reaction
may also
be carried out without a solvent or in an excess of the compound of general
formula
IV used.
5 b) In order to prepare a compound of general formula I wherein R4 according
to the
definition provided hereinbefore contains an amino group or an alkylamino
group
optionally substituted in the alkyl moiety:
deprotecting a compound of general formula
O /R3
R \N N
/~R4 ( IV ),
R2/ ' N
O
wherein R', R2 and R3 are as hereinbefore defined and
R4' contains an N-tert.-butyloxycarbonylamino group or an N-tert.-
butyloxycarbonyl-
N-alkylamino group, while the alkyl moiety of the N-tert.-butyloxycarbonyl-N-
alkyl-
amino group may be substituted as mentioned hereinbefore.
The tert.-butyloxycarbonyl group is preferably cleaved by treating with an
acid such
as trifluoroacetic acid or hydrochloric acid or by treating with
bromotrimethylsilane or
iodotrimethylsilane, optionally using a solvent such as methylene chloride,
ethyl
acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures
between 0
and 80°C.
If according to the invention a compound of general formula I is obtained
which
contains an amino, alkylamino or imino group, this may be converted by
acylation or
sulphonylation into a corresponding acyl or sulphonyl compound of general
formula I
or

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16
if a compound of general formula I is obtained which contains an amino,
alkylamino
or imino group, this may be converted by alkylation or reductive alkylation
into a
corresponding alkyl compound of general formula I or
if a compound of general formula I is obtained which contains a carboxy group,
this
may be converted by esterification into a corresponding ester of general
formula I or
if a compound of general formula I is obtained which contains a carboxy or
ester
group, this may be converted by reaction with an amine into a corresponding
amide
of general formula I.
The subsequent esterification is optionally carried out in a solvent or
mixture of
solvents such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or most
advantageously in a corresponding alcohol, optionally in the presence of an
acid
such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in
the
presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane,
sulphuric
acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole
and
optionally additionally in the presence of 4-dimethylamino-pyridine,
N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride,
conveniently at
temperatures between 0 and 150°C, preferably at temperatures between 0
and 80°C.
The subsequent ester formation may also be carried out by reacting a compound
which contains a carboxy group with a corresponding alkyl halide.
The subsequent acylation or sulphonylation is conveniently carried out in a
solvent
or mixture of solvents such as methylene chloride, dimethylformamide, benzene,
toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane
with a
corresponding acyl or sulphonyl derivative, optionally in the presence of a
tertiary
organic base or in the presence of an inorganic base or in the presence of a

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17
dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl
chloride,
trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-
toluenesulphonic
acid, phosphorus trichloride, phosphorus pentoxide, N,N'-
dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole
and
optionally also in the presence of 4-dimethylamino-pyridine,
N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride,
expediently at
temperatures between 0 and 150°C, preferably at temperatures between 0
and
80°C.
The subsequent alkylation is optionally carried out in a solvent or mixture of
solvents
such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane with an alkylating agent
such
as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide,
ethyl
bromide, dimethyl sulphate or benzyl chloride, optionally in the presence of a
tertiary
organic base or in the presence of an inorganic base, expediently at
temperatures
between 0 and 150°C, preferably at temperatures between 0 and
100°C.
The subsequent reductive alkylation is carried out with a corresponding
carbonyl
compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or
butyraldehyde in the presence of a complex metal hydride such as sodium
borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium
cyanoborohydride, expediently at a pH of 6-7 and at ambient temperature or in
the
presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of
palladium/charcoal, at a hydrogen pressure of 1 to 5 bar. The methylation can
also
be carried out in the presence of formic acid as reduction agent at elevated
temperatures, e.g. at temperatures between 60 and 120°C.
The subsequent amide formation is carried out by reacting a corresponding
reactive
carboxylic acid derivative with a corresponding amine, optionally in a solvent
or
mixture of solvents such as methylene chloride, dimethylformamide, benzene,
toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane,
whilst
the amine used may simultaneously serve as solvent, optionally in the presence
of a

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18
tertiary organic base or in the presence of an inorganic base or with a
corresponding
carboxylic acid in the presence of a dehydrating agent, e.g. in the presence
of
isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus
trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole
and
optionally also in the presence of 4-dimethylamino-pyridine,
N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride,
expediently at
temperatures between 0 and 150°C, preferably at temperatures between 0
and
80°C.
15
In the reactions described hereinbefore, any reactive groups present such as
hydroxy, carboxy, amino, alkylamino or imino groups may be protected during
the
reaction by conventional protecting groups which are cleaved again after the
reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl,
acetyl,
benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl,
tert.butyl, benzyl or tetrahydropyranyl group,
protecting groups for an amino, alkylamino or imino group may be a formyl,
acetyl,
trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl,
benzyl,
methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino
group, a
phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by
hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic
acid/water,
tetrahydrofuran/water or dioxane/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence
of an alkali
metal base such as sodium hydroxide or potassium hydroxide or aprotically,
e.g. in
the presence of iodotrimethylsilane, at temperatures between 0 and
120°C,
preferably at temperatures between 10 and 100°C.

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19
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for
example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst
such as
palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl
acetate or
glacial acetic acid, optionally with the addition of an acid such as
hydrochloric acid at
temperatures between 0 and 100°C, but preferably at ambient
temperatures
between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but
preferably from
3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in
trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating
with an
acid such as trifluoroacetic acid or hydrochloric acid or by treating with
iodotrimethylsilane optionally using a solvent such as methylene chloride,
dioxane,
methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as
hydrochloric acid, optionally in the presence of a solvent such as acetic acid
at
temperatures between 50 and 120°C or by treating with sodium hydroxide
solution,
optionally in the presence of a solvent such as tetrahydrofuran, at
temperatures
between 0 and 50°C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a
primary
amine such as methylamine, ethylamine or n-butylamine in a solvent such as
methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures
between
20 and 50°C.
Moreover, the compounds of general formula I obtained may be resolved into
their
enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for
example,
cis/trans mixtures may be resolved into their cis and trans isomers, and
compounds
with at least one optically active carbon atom may be separated into their
enantiomers.
Thus, for example, the cisltrans mixtures obtained may be separated by
chromatography into their cis and trans isomers, the compounds of general
formula I
obtained which occur as racemates may be separated by methods known per se
(cf.
Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley

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Interscience, 1971) into their optical enantiomers and compounds of general
formula
I with at least 2 asymmetric carbon atoms may be resolved into their
diastereomers
on the basis of their physical-chemical differences using methods known per
se, e.g.
by chromatography and/or fractional crystallisation, and, if these compounds
are
5 obtained in racemic form, they may subsequently be resolved into the
enantiomers
as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases
or
by recrystallisation from an optically active solvent or by reacting with an
optically
10 active substance which forms salts or derivatives such as e.g. esters or
amides with
the racemic compound, particularly acids and the activated derivatives or
alcohols
thereof, and separating the diastereomeric mixture of salts or derivatives
thus
obtained, e.g. on the basis of their differences in solubility, whilst the
free antipodes
may be released from the pure diastereomeric salts or derivatives by the
action of
15 suitable agents. Optically active acids in common use are e.g. the D- and L-
forms of
tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An
optically active
alcohol may be, for example, (+) or (-)-menthol and an optically active acyl
group in
amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be converted into the
salts
thereof, particularly for pharmaceutical use into the physiologically
acceptable salts
with inorganic or organic acids. Acids which may be used for this purpose
include for
example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic
acid,
phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or
malefic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy
group,
they may subsequently, if desired, be converted into the salts thereof with
inorganic
or organic bases, particularly for pharmaceutical use into the physiologically
acceptable salts thereof. Suitable bases for this purpose include for example
sodium
hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.

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21
The compounds of general formulae II and IV used as starting compounds are
either
known from the literature or may be prepared by methods known from the
literature
(see Examples I to VII).
As already mentioned hereinbefore, the compounds of general formula I
according
to the invention and the physiologically acceptable salts thereof have
valuable
pharmacological properties, particularly an inhibiting effect on the enzyme
DPP-IV.
The biological properties of the new compounds were investigated as follows:
The ability of the substances and their corresponding salts to inhibit the DPP-
IV
activity can be demonstrated in an experiment in which an extract of the human
colon carcinoma cell line Caco-2 is used as the DPP IV source. The
differentiation of
the cells in order to induce the DPP-IV expression was carried out in
accordance
with the description by Reiher et al. in an article entitled "Increased
expression of
intestinal cell line Caco-2" , which appeared in Proc. Natl. Acad. Sci. Vol.
90, pp.
5757-5761 (1993). The cell extract was obtained from cells solubilised in a
buffer
(10mM Tris HCI, 0.15 M NaCI, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0)
by
centrifugation at 35,000 g for 30 minutes at 4°C (to remove cell
debris).
The DPP-IV assay was carried out as follows:
50 NI of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin),
final
concentration 100 uM, were placed in black microtitre plates. 20 pl of assay
buffer
(final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCI, 1 % DMSO) was
pipetted in. The reaction was started by the addition of 30 pl of solubilised
Caco-2
protein (final concentration 0.14 pg of protein per well). The test substances
under
investigation were typically added prediluted to 20 pl, while the volume of
assay
buffer was then reduced accordingly. The reaction was carried out at ambient
temperature, the incubation period was 60 minutes. Then the fluorescence was
measured in a Victor 1420 Multilabel Counter, with the excitation wavelength
at 405
nm and the emission wavelength at 535 nm. Dummy values (corresponding to 0
activity) were obtained in mixtures with no Caco-2 protein (volume replaced by
assay
buffer), control values (corresponding to 100 % activity) were obtained in
mixtures
without any added substance. The potency of the test substances in question,

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22
expressed as IC5o values, were calculated from dosage/activity curves
consisting of
11 measured points in each case. The following results were obtained:
Compound DPP IV inhibition
(Example no.) ICSO [nM]
1 1
1(1) 4
1(2) 6
1 (3) 14
1 (4) 52
The compounds prepared according to the invention are well tolerated as no
toxic
side effects could be detected in rats after the oral administration of 10
mg/kg of the
compound of Example 1 (1 ), for example.
In view of their ability to inhibit DPP-IV activity, the compounds of general
formula I
according to the invention and the corresponding pharmaceutically acceptable
salts
thereof are suitable for influencing any conditions or diseases which can be
affected
by the inhibition of the DPP-IV activity. It is therefore to be expected that
the
compounds according to the invention will be suitable for the prevention or
treatment
of diseases or conditions such as type I and type II diabetes mellitus,
diabetic
complications (e.g. retinopathy, nephropathy or neuropathies), metabolic
acidosis or
ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome,
dyslipidaemias of various origins, arthritis, atherosclerosis and related
diseases,
obesity, allograft transplantation and osteoporosis caused by calcitonin. In
addition,
these substances are suitable for preventing B-cell degeneration such as e.g.
apoptosis or necrosis of pancreatic B-cells. The substances are also suitable
for
improving or restoring the function of pancreatic cells and additionally
increasing the
size and number of pancreatic B-cells. Additionally, on the basis of the role
of the
glucagon-like peptides such as e.g. GLP-1 and GLP-2 and their link with DPP-IV
inhibition, it is expected that the compounds according to the invention will
be
suitable for achieving, inter alia, a sedative or tranquillising effect, as
well as having
a favourable effect on catabolic states after operations or hormonal stress
responses
or possibly reducing mortality and morbidity after myocardial infarct.
Moreover, they

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23
are suitable for treating any conditions connected with the effects mentioned
above
and mediated by GLP-1 or GLP-2. The compounds according to the invention may
also be used as diuretics or antihypertensives and are suitable for preventing
and
treating acute kidney failure. The compounds according to the invention may
also be
used to treat inflammatory complaints of the respiratory tract. They are also
suitable
for preventing and treating chronic inflammatory bowel diseases such as e.g.
irritable
bowel syndrome (IBS), Crohn's disease or ulcerative colitis and also
pancreatitis. It
is also expected that they can be used for all kinds of injury or damage to
the
gastrointestinal tract such as may occur in colitis and enteritis, for
example.
Moreover, it is expected that DPP-IV inhibitors and hence the compounds
according
to the invention can be used to treat infertility or to improve fertility in
humans or
mammals, particularly if the infertility is connected with insulin resistance
or with
polycystic ovary syndrome. On the other hand these substances are suitable for
influencing sperm motility and are thus suitable for use as male
contraceptives. In
addition, the substances are suitable for treating growth hormone deficiencies
connected with restricted growth, and may reasonably be used for all
indications for
which growth hormone may be used. The compounds according to the invention are
also suitable, on the basis of their inhibitory effect on DPP-IV, for treating
various
autoimmune diseases such as e.g. rheumatoid arthritis, multiple sclerosis,
thyroiditis
and Basedow's disease, etc. They may also be used to treat viral diseases and
also, for example, in HIV infections, for stimulating blood production, in
benign
prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal
defects and
neurodegenerative diseases such as Alzheimer's disease, for example. The
compounds described may also be used for the treatment of tumours,
particularly for
modifying tumour invasion and also metastasisation; examples here are their
use in
treating T-cell lymphomas, acute lymphoblastic leukaemia, cell-based
pancreatic
carcinomas, basal cell carcinomas or breast cancers. Other indications are
stroke,
ischaemia of various origins, Parkinson's disease and migraine. In addition,
further
indications include follicular and epidermal hyperkeratoses, increased
keratinocyte
proliferation, psoriasis, encephalomyelitis, glomerulonephritis,
lipodystrophies, as
well as psychosomatic, depressive and neuropsychiatric diseases of all kinds.
The compounds according to the invention may also be used in conjunction with
other active substances. Suitable therapeutic agents for such combinations
include
for example antidiabetic agents such as metformin, sulphonylureas (e.g.
glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide,
thiazolidinediones
(e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and

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antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase
inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2
antagonists,
insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or
amylin. Also, SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors
of
protein tyrosine phosphatase 1, substances which influence deregulated glucose
production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or
fructose-
1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and
inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or
pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase
inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate,
fenofibrate),
nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists,
ACAT
inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as for
example
ezetimibe, bile acid-binding substances such as for example cholestyramine,
inhibitors of ileac bile acid transport, HDL-raising compounds such as for
example
inhibitors of CETP or regulators of ABC1 or active substances for the
treatment of
obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine,
axokine,
antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4
receptor agonists, NPY5 or NPY2 antagonists or f33-agonists such as SB-418790
or
AD-9677 as well as agonists of the 5HT2c receptor.
It is also possible to combine the compounds with drugs for treating high
blood
pressure such as e.g. All antagonists or ACE inhibitors, diuretics, f3-
blockers, Ca-
antagonists, etc., or combinations thereof.
The dosage required to achieve such an effect is expediently, by intravenous
route,
1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably
1 to
100 mg, in each case 1 to 4 times a day. For this purpose, the compounds of
formula I prepared according to the invention, optionally combined with other
active
substances, may be incorporated together with one or more inert conventional
carriers and/or diluents, e.g. with corn starch, lactose, glucose,
microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol,
propylene
glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such
as hard
fat or suitable mixtures thereof into conventional galenic preparations such
as plain
or coated tablets, capsules, powders, suspensions or suppositories.
The Examples that follow are intended to illustrate the invention:

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Preparation of the starting compounds:
Example I
4-methyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarboxylate
5
a dimethyl 2-bromo-1 H-imidazole-4,5-dicarboxylate
9.50 g bromine in 100 ml dichloromethane are added dropwise to a mixture of
9.90 g
methyl 1 H-imidazole-4,5-dicarboxylate and 7.46 g potassium carbonate in 200
ml
dichloromethane and 80 ml acetonitrile. The mixture is stirred for 12 h at
ambient
10 temperature in the dark and then added to a saturated aqueous solution of
sodium
thiosulphate and sodium chloride. The organic phase is separated off and the
aqueous phase is extracted several times with ethyl acetate. The combined
organic
phases are dried over sodium sulphate and the solvent is removed.
Yield: 12.31 g (87% of theory)
15 Mass spectrum (ESI+): m/z = 263/265 (Br) [M+H]+
b) dimethyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarbox I~~ ate
3.06 g 1-bromo-2-butyne are added dropwise to a mixture of 6.00 g of dimethyl
2-
bromo-1 H-imidazole-4,5-dicarboxylate and 3.80 g of potassium carbonate in 40
ml of
20 dimethylformamide. The mixture is stirred for 12 h at ambient temperature
and then
added to an aqueous saturated solution of sodium thiosulphate. The organic
phase
is separated off and the aqueous phase is extracted three times with ethyl
acetate.
The combined organic phases are dried over sodium sulphate, the solvent is
removed and the residue is chromatographed over silica gel (cyclohexane/ethyl
25 acetate 4:1 > 1:1 ).
Yield: 5.28 g (74% of theory)
Mass spectrum (ESI+): m/z = 315/317 (Br) [M+H]+
c) 4-methyl 2-bromo-1~but-2-ynyl)-1 H-imidazole-4,5-dicarbox ly ate
65 ml 1 M sodium hydroxide solution are added to a solution of 22.00 g
dimethyl 2-
bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-dicarboxylate in 120 ml of a mixture of
water,
tetrahydrofuran and methanol (1:1:1). After 15 min stirring at ambient
temperature

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the organic solvents are removed and the residue is adjusted to pH 1 with 1 M
hydrochloric acid. The aqueous phase is extracted four times with ethyl
acetate, the
combined organic phases are dried over sodium sulphate, and the solvent is
removed. The residue is triturated with diisopropylether, separated off by
means of a
paper filter and dried.
Yield: 15.00 g (71 % of theory)
Mass spectrum (ESI+): m/z = 301/303 (Br) [M+H]+
Example II
Tert-butyl N'-(auinolin-2-yl)methylene-hydrazine carboxylate
A solution of 10.70 g 2-quinolinecarboxaldehyde and 9.00 g tert-butyl
hydrazinecarboxylate in 200 ml of ethanol is refluxed for 2 h with stirring.
Then the
solution is evaporated to dryness and the residue is triturated with
diisopropylether,
separated off and dried at 50°C .
Yield: 16.00 g (87% of theory)
Mass spectrum (ESI+): m/z = 272 [M+H]+
The following compound is obtained analogously to Example II:
(1) tert-butyl N'-(naphth-1-yl)methylene-hydrazinecarboxylate
Mass spectrum (ESI+): m/z = 293 [M+Na]+
Example III
Tert-but I~quinolin-2-ylmethyl)-hydrazinecarboxylate
0.5 g 10% Pd/C are added to a solution of 15.00 g tert-butyl N'-(quinolin-2-
yl)methylene-hydrazinecarboxylate in 200 ml of methanol. The resulting mixture
is
then shaken for 6 h at ambient temperature under 1 atm H2 pressure. Then the
precipitate and the catalyst are separated from the solvent, the precipitate
is
dissolved in tetrahydrofuran, filtered again and in this way the catalyst is
separated
off. The THF solution is evaporated down and the residue is triturated with
tert-
butylmethylether, separated off and dried at 50°C . The tert-
butylmethylether phase
is evaporated down again and the residue is triturated this time with diethyl
ether,

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27
separated off and dried at 50°C. The two solid fractions from the
purification with
tert-butylmethylether and diethyl ether are combined.
Yield: 9.00 g (60% of theory)
Mass spectrum (ESI+): m/z = 274 [M+H]+
The following compound is obtained analogously to Example III:
(1) tert-butyl N'-(naphth-1-ylmethyl)-hydrazinecarboxylate
Mass spectrum (ESI+): m/z = 273 [M+H]+
Example IV
Tert-butyl N'-(2-phenylsulphonyl-ethyl-hydrazinecarboxylate
A solution of 0.79 g tent-butyl hydrazinecarboxylate and 1.00 g
phenylvinylsulphone
in 8 ml of ethanol is refluxed for 5 h with stirring. Then the solvent is
removed
completely and the residue is chromatographed over silica gel
(cyclohexane/ethyl
acetate).
Yield: 1.00 g (56% of theory)
Mass spectrum (ESI+): m/z = 301 [M+H]+
Example V
Methyl 5-[N'-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-hydrazinocarbonyl]-1-
(but-2-
ynyl)- 2-chloro-1 H-imidazol-4-carboxylate
1.2 ml of thionyl chloride and lastly 0.2 ml of dimethylformamide are added to
a
solution of 4.50 g of 4-methyl 2-bromo-1-(but-2-ynyl)-1 H-imidazole-4,5-
dicarboxylate
in 20 ml dichloromethane. The solution is stirred for 17 h at ambient
temperature.
Then 30 ml of toluene are added and the solution is evaporated to dryness. The
residue is dissolved in 10 ml of dimethylformamide, then 4.02 g of tert-butyl
N'-
(quinolin-2-ylmethyl)-hydrazinecarboxylate and 4 ml Hunig base are added. The
solution is stirred for 0.5 h at ambient temperature and then evaporated down.
The
residue is chromatographed over silica gel (cyclohexane/ethyl acetate 3:2).
Yield: 2.00 g (26% of theory)
Mass spectrum (ESI+): m/z = 512/514 (CI) [M+H]+

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The following compounds are obtained analogously to Example V:
(1) methyl 5-[N'-tert-butoxycarbonyl-N-(naphth-1-ylmethyl)-hydrazinocarbonyl]-
1-
(but-2-ynyl)-2-chloro-1 H-imidazole-4-carboxylate mixed with methyl 2-bromo-5-
[N'-
tert-butoxycarbonyl-N-(naphth-1-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-1
H-
imidazole-4-carboxylate
Mass spectrum (ESI+): m/z = 555/557 (Br); m/z = 512/514 (CI) [M+H]+
(2) methyl 5-[N'-tert-butoxycarbonyl-N-(2-phenylsulphonyl-ethyl)-
hydrazinocarbonyl]-
1-(but-2-ynyl)-2-chloro-1 H-imidazole-4-carboxylate
Mass spectrum (ESI+): m/z = 539/541 (CI) [M+H]+
Example VI
1-(but-2-ynyl)-2-chloro-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-
d]=
pyridazine-4,7-dione
2.80 g methyl 2-chloro-5-[N'-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-
hydrazinocarbonyl]-1-(but-2-ynyl)-1 H-imidazol-4-carboxylate are dissolved in
50 ml
of ethyl acetate. Then 1.5 ml of 4 M hydrochloric acid in dioxane are added,
and the
solution is stirred for 2 h at 50°C. Then the solution is cooled to
ambient
temperature, the precipitate formed is separated off, washed with ethyl
acetate and
diethyl ether and dried in the drying cupboard at 50°C.
Yield: 1.60 g (77% of theory)
Mass spectrum (ESI+): m/z = 380/382 (CI) [M+H]+
The following compounds are obtained analogously to Example VI:
(1) 1-(but-2-ynyl)-2-chloro-6-(naphth-1-ylmethyl)-5,6-dihydro-1H-imidazo[4.5d]-
pyridazine-4,7-dione mixed with 2-bromo-1-(but-2-ynyl)-6-naphth-1-ylmethyl-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 423/425 (Br); m/z = 379/381 (CI) [M+H]+

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(2) 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-
imidazo[4,5-
d]-pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 407/409 (CI) [M+H]+
Example VII
1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-
imidazof4,5-dlp.,hridazine-4,7-dione
0.20 g 1-(but-2-ynyl)-2-chloro-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-
imidazo[4,5-d]-
pyridazine-4,7-dione and 0.25 g potassium carbonate are placed in 4 ml of
dimethylformamide. Then 53 pl of bromoacetonitrile are added and the mixture
is
stirred for 2 h at 40°C. After the addition of aqueous saturated sodium
chloride
solution the mixture is extracted three times with ethyl acetate, the combined
organic
phases are dried over sodium sulphate, and then the solvent is removed. The
residue is purified over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 0,14 g (42% of theory)
Mass spectrum (ESI+): m/z = 419/421 (CI) [M+H]+
The following compounds are obtained analogously to Example VII:
(1) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-
imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 394/396 (CI) [M+H]+
(2) 1-(but-2-ynyl)-2-chloro-5-(prop-2-enyl)-6-(quinolin-2-ylmethyl)-5,6-
dihydro-1 H-
imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 420/422 (CI) [M+H]+
(3) 1-(but-2-ynyl)-2-chloro-5-(phenylmethyl)-6-(quinolin-2-ylmethyl)-5,6-
dihydro-1 H-
imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 470/472 (CI) [M+H]+

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(4) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(naphth-1-ylmethyl)-5,6-dihydro-1 H-
imidazo[4,5-d]pyridazine-4,7-dione mixed with 1-(but-2-ynyl)-2-bromo-5-methyl-
6-
(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 437/439 (Br); m/z = 393/395 (CI) [M+H]+
5
(5) 1-(but-2-ynyl)-2-chloro-5-(tert-butoxycarbonylmethyl)-6-(quinolin-2-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 494/496 (CI) [M+H]+
10 (6) 1-(but-2-ynyl)-2-chloro-5-aminocarbonylmethyl-6-(quinolin-2-ylmethyl)-
5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 437/439 (CI) [M+H]+
(7) 1-(but-2-ynyl)-2-chloro-5-(pyridin-3-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-
dihydro-
15 1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 471/473 (CI) [M+H]+
(8) 1-(but-2-ynyl)-2-chloro-5-(prop-2-ynyl)-6-(quinolin-2-ylmethyl)-5,6-
dihydro-1 H-
imidazo[4,5-d]pyridazine-4,7-dione
20 Mass spectrum (ESI+): m/z = 418/420 (CI) [M+H]+
(9) 1-(but-2-ynyl)-2-chloro-5-(pyridin-4-ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-
dihydro-
1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 471/473 (CI) [M+H]+
(10) 1-(but-2-ynyl)-2-chloro-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-
1 H-
imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 421/423 [M+H]+
The starting materials used are 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-
ethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and methyl iodide.

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31
(11) 1-(but-2-ynyl)-2-chloro-5-(2-fluoro-ethyl)-6-(2-phenylsulphonyl-ethyl)-
5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 453/455 [M+H]+
The starting materials used are 1-(but-2-ynyl)-2-chloro-6-(2-phenylsulphonyl-
ethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and 2-
methylsulphonyloxyethyl
fluoride.
Example VIII
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperid in-1-yl)-5-
cyanomethyl-6-
(auinolin-2-ylmethyl -5) 6-dihydro-1 H-imidazof4,5-dlpyridazine-4,7-dione
A solution of 0.14 g 1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-
ylmethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione, 0.15 g potassium carbonate
and
0.07 g (R)-3-tert-butoxycarbonylaminopiperidine in 2 ml dimethylsulphoxide is
stirred
for 5 h at 60°C. Then water is added and the mixture is extracted three
times with
ethyl acetate. The combined organic phases are dried over sodium sulphate, and
then the solvent is removed. The residue is purified by chromatography on
silica gel
(cyclohexane/ethyl acetate 1:1 ).
Yield: 0.13 g (75% of theory)
Mass spectrum (ESI+): m/z = 583 [M+H]+
The following compounds are obtained analogously to Example VIII:
(1) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-
(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 558 [M+H]+
(2) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(prop-2-
enyl)-6-
(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 584 [M+H]+
(3) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-
(phenylmethyl)-
6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione

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Mass spectrum (ESI+): m/z = 634 [M+H]+
(4) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-
(naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 557 [M+H]+
(5) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-(tent-
butoxy-
carbonylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-
d]pyridazine-4,7-
dione
Mass spectrum (ESI+): m/z = 658 [M+H]+
(6) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-
aminocarbonyl-
methyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
Mass spectrum (ESI+): m/z = 601 [M+H]+
(7) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-
(pyridin-3-
ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
Mass spectrum (ESI+): m/z = 635 [M+H]+
(8) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(prop-2-
ynyl)-6-
(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 582 [M+H]+
(9) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-
(pyridin-4-
ylmethyl)-6-(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
Mass spectrum (ESI+): m/z = 635 [M+H]+
(10) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-(2-
phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 585 [M+H]+

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(11) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-
fluoro-
ethyl)-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-
4,7-dione
Mass spectrum (ESI+): m/z = 617 [M+H]+
Example IX
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-5,6-
dihydro-
1 H-imidazof4,5-dlpyridazine-4,7-dione
0.11 g potassium-tent-butoxide are added to a solution of 0.52 g of (R)-1-(but-
2-ynyl)-
2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-phenylsulphonyl-
ethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione in 5 ml of tetrahydrofuran.
The
solution is stirred for 10 min at ambient temperature and then diluted with
water. It is
extracted three times with ethyl acetate, the combined organic phases are
dried over
sodium sulphate, and the solvent is then removed. The residue is purified by
chromatography on silica gel (cyclohexane/ethyl acetate).
Yield: 0.31 g (85% of theory)
Mass spectrum (ESI+): m/z = 417 [M+H]+
The following compound is obtained analogously to Example IX:
(1) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-
fluoro-ethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 449 [M+H]+
Example X
(R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(3-
methyl-isoauinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
0.20 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-
methyl-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione and 0.10 g potassium
carbonate
are placed in 2 ml of dimethylformamide. Then 0.10 g of 3-methyl-isoquinolin-1-
yl-
methylchloride are added and the mixture is stirred for 5 h at 50°C.
After the addition
of water the mixture is extracted three times with ethyl acetate, the combined
organic

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phases are dried over sodium sulphate, and the solvent is removed. The residue
is
purified over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 0.06 g (22% of theory)
Mass spectrum (ESI+): m/z = 572 [M+H]+
The following compounds are obtained analogously to Example X:
(1) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-
(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 535 [M+H]+
(2) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-(4-
methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
Mass spectrum (ESI+): m/z = 573 [M+H]+
(3) (R)-1-(but-2-ynyl)-2-(3-tent-butoxycarbonylamino-piperidin-1-yl)-5-methyl-
6-(2-
cyano-benzyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 532 [M+H]+
(4) (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-(2-
fluoro-ethyl)-
6-(4-methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-
4,7-
dione
Mass spectrum (ESI+): m/z = 605 [M+H]+

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Preparation of the end compounds:
Example 1
(R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-
ylmethyl)-
5 5 6-dihydro-1 H-imidazof4 5-dlpVridazine-4,7-dione x 2 trifluoroacetic acid
I
N / O i
N
N ~N I ~~--N
N
O NHz
1 ml of trifluoroacetic acid is added to a solution of 0.13 g of (R)-1-(but-2-
ynyl)-2-(3-
tert-butoxycarbonylamino-piperidin-1-yl)-5-cyanomethyl-6-(quinolin-2-ylmethyl)-
5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione in 2 ml dichloromethane. The
solution
10 is stirred for 4 h at ambient temperature, then diluted with 5 ml of
toluene and
evaporated to dryness. The residue is stirred with diethyl ether, separated
off using a
filter paper and dried at 50°C .
Yield: 100 mg (63% of theory)
Mass spectrum (ESI+): m/z = 483 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(quinolin-2-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2 trifluoroacetic acid
Mass spectrum (ESI+): m/z = 458 [M+H]+
I
N / O i
N
N ~ /~- N
/N N
O NHz

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(2) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)- 5-(prop-2-enyl)-6-(quinolin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2
trifluoroacetic acid
Mass spectrum (ESI+): m/z = 484 [M+H]+
I \
N / O i
N
I /~---N
~N N
O NHz
(3) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(phenylmethyl)-6-(quinolin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2
trifluoroacetic acid
Mass spectrum (ESI+): m/z = 534 [M+H]+
N
O i
N
I /~N
'N
O NHz
(4) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(naphth-1-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 1 trifluoroacetic acid
Mass spectrum (ESI+): m/z = 457 [M+H]+
I
/ / o
N N
I I /~ N
/N N
O NHz
(5) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-hydroxycarbonylmethyl-6-
(quinolin-
2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 2
trifluoroacetic acid
Mass spectrum (ESI+): m/z = 502 [M+H]+

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I
N / O i
N
/~- N
HO~ N
O NHz
(6) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-aminocarbonylmethyl-6-
(quinolin-
2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 501 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium
carbonate solution)
I~
I
N / O i
N
/~ N
H N 'N
O NHz
(7) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-ylmethyl)-6-
(quinolin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 535 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium
carbonate solution)
I I
N / O i
N
N \ N I /~-- N
'N
O NH2

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(8) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(quinolin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 482 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium
carbonate solution)
I~
I \
N / O i
N
/~-N
'N
O NHz
(9) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-
(quinolin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x 3
trifluoroacetic acid
Mass spectrum (ESI+): m/z = 535 [M+H]+
I
I
N / O %
N~ N N
I /~--N
'N
O NHz
(10) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(3-methyl-
isoquinolin-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x trifluoroacetic
acid
Mass spectrum (ESI+): m/z = 472 [M+H]+
I~
/ ~N O i
N N
I I /~ N
/N N
O NHz

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(11) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-
(phenylcarbonylmethyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x trifluoroacetic acid
Mass spectrum (ESI+): m/z = 435 [M+H]+
i o0
N
/~ N
/N N
O NH2
(12) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-
quinazolin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 473 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium
carbonate solution and the product was purified over silica gel with
dichloromethane/methanol)
I\
N' / N O i
N
/~ N
/N N
O NHz
(13) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-cyano-benzyl)-
5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
Mass spectrum (ESI+): m/z = 432 [M+H]+
(reaction solution was worked up under aqueous conditions with potassium
carbonate solution and the product was purified over silica gel with
dichloromethane/methanol)

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O i
N
N
/~ N
/N N
O NHz
(14) (R)-1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(4-
methyl-
5 quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione x
2
trifluoroacetic acid
Mass spectrum (ESI+): m/z = 505 [M+H]+
I\
N' //N O i
N
N ~ ~~-N
F~/N N
O NHz
Example 2
1-(but-2-ynyl)-2-(piperazin-1-yl)-5-methyl-6-(quinolin-4-ylmethyl)-5,6-dihydro-
1 H-
imidazof4,5-dlpyridazine-4,7-dione
I
N ~ O i
N
/~--N NH
/N N
A mixture of 80 mg of 1-(but-2-ynyl)-2-chloro-5-methyl-6-(quinolin-2-ylmethyl)-
5,6-
dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione and 85 mg of 1,4-piperazine in 2
ml
of dimethylformamide is stirred for 18 h at 65°C. The reaction mixture
is diluted with

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water and extracted three times with ethyl acetate. The combined organic
phases
are dried over sodium sulphate, the solvent is evaporated and the residue is
chromatographed over silica gel (cyclohexane/ethyl acetate 1:1 ).
Yield: 30 mg (33% of theory)
Mass spectrum (ESI+): m/z = 444 [M+H]+
The following compounds may also be obtained analogously to the foregoing
Examples and other methods known from the literature:
(1) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanoethyl-6-(4-cyano-naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(2) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(4-fluoro-naphth-
1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(3) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(3-methyl-
isoquinolin-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(4) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-carboxymethyl-6-(2-cyano-
benzyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(5)1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-fluoro-benzyl)-5,6-
dihydro-
1 H-imidazo[4,5-d]pyridazine-4,7-dione
(6) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methylaminocarbonylmethyl)-6-
(4-
methyl-quinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(7) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-
(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(8) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(2-nitrophenyl-prop-2-
enyl)-
5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(9) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methoxycarbonylmethyl)-6-(3-
methoxy-phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(10) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-carboxy-ethyl)-6-(3-cyano-
pyridin-
2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(11) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxy-ethyl)-6-
([1.5]naphthyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione

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(12) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxy-ethyl)-6-
(quinoxalin-6-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(13) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(1-methyl-1 H-
benzotriazol-
5-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(14) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-3-yl)-6-(quinazolin-
7-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(15) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-cyano-quinazolin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(16) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoro-ethyl)-6-(1-cyano-
isoquinolin-3-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(17) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-phenyl-pyrimidin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(18) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxy-ethyl)-6-(4-cyano-
isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(19) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-[4-(morpholin-4-
yl)quinazolin-2-ylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(20) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-cyano-ethyl)-6-
([1.5]naphthyridin-
3-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(21) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxy-ethyl)-6-(2,3-
dimethyl-
quinoxalin-6-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(22) 1-(3,3-dimethylprop-2-enyl)-2-(3-amino-piperidin-1-yl)-5-(2-
methylsulphonyl-
ethyl)-6-(4-cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-
4,7-
dione
(23) 1-(but-1-enyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-(4-fluoro-
naphth-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(24) 1-(cyclopent-1-enylmethyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(3-
methyl-isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(25) 1-(2-chloro-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-ethyl-6-(2-cyano-
phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(26) 1-(2-bromo-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-ynyl)-6-(2-
fluoro-
phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione

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(27) 1-(but-2-enyl)-2-(3-amino-piperidin-1-yl)-5-cyanomethyl-6-(4-methyl-
quinazolin-
2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(28) 1-(thien-3-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(prop-2-enyl)-6-
(phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(29) 1-(thien-2-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-phenylethyl)-6-[3-
(2,3,4,5,6-
pentafluorophenyl)-prop-2-enyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(30) 1-(furan-3-ylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-methoxyethyl)-6-[(3-
methoxy-phenyl)carbonylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(31) 1-(cyclopent-1-enylmethyl)-2-(3-amino-piperidin-1-yl)-5-(2-cyano-ethyl)-6-
(4-
cyano-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(32) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(methoxycarbonylmethyl)-6-(4
methoxy-naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(33) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(cyclopropylmethyl)-6-(3-
methyl-
isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(34) 1-( but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(aminomethylcarbonylmethyl)-
6-(4-
bromo-2-cyano-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(35) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-fluoroethyl)-6-(3,5-
dimethoxyphenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(36) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-[2-(methylaminocarbonyl)-
ethyl]-6
(4,5-dimethylquinazolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-
4,7
dione
(37) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(2-methylsulphonyl-ethyl)-6-
(3-
isopropoxy-phenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-
dione
(38) 1-(3,3-dimethylprop-2-enyl)-2-(3-amino-piperidin-1-yl)-5-(2-hydroxethyl)-
6-[3-
(pyridin-2-yl)-prop-2-enyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(39) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(3-methylbutyl)-6-(2-
aminophenylcarbonylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(40) 1-(but-2-ynyl)-2-(2-aminoethyl-methylamino)-5-cyanomethyl-6-[4-(morpholin-
4-
yl)-quinazolin-2-ylmethyl]-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(41) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-propyl-6-([1.5]naphthyridin-3-
ylmethyl)-5,6-
dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione

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(42) 1-(but-2-ynyl)-2-[N-(2-aminopropyl)-N-methyl-amino]-5-methyl-6-(2,3-
dimethyl-
quinoxalin-6-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(43) 1-(3,3-dimethylprop-2-enyl)-2-(homopiperazin-1-yl)-5-cyanomethyl-6-(4-
cyano-
naphth-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(44) 1-(but-1-enyl)-2-[N-(2-aminoethyl]-N-methyl-amino]-5-
(methoxycarbonylmethyl)-
6-(2-cyano-4-fluoro-phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7
dione
(45) 1-(cyclopent-1-enylmethyl)-2-(piperazin-1-yl)-5-(prop-2-ynyl)-6-(3-methyl-
isoquinolin-1-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(46) 1-(2-iodo-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-hexyl-6-(3-chloro-4-
cyano-
phenylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(47) 1-(2-cyano-phenylmethyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(6-cyano-
pyridin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(48) 1-(but-2-ynyl)-2-(piperazin-1-yl)-5-(2-hydroxy-ethyl)-6-(3-methyl-
isoquinolin-1-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(49) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(pyridin-4-ylmethyl)-6-
(quinolin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(50) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(tetrahydrofuran-3-ylmethyl)-
6-
(quinolin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(51) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(carboxymethyl)-6-(4-cyano-
quinolin-
2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(52) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4,6-dimethyl-
pyrimidin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(53) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(cyanomethyl)-6-(4,6-dimethyl-
pyrimidin-2-ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(54) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(4-methyl-pyrimidin-
2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(55) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-methyl-6-(6-cyano-pyridin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione
(56) 1-(but-2-ynyl)-2-(3-amino-piperidin-1-yl)-5-(carboxymethyl)-6-(3-cyano-
pyridin-2-
ylmethyl)-5,6-dihydro-1 H-imidazo[4,5-d]pyridazine-4,7-dione

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Ex. Structure Ex. Structure
(1) li (2) F
I \ \
I \ \ / / o
/ / o
N
N N N\ N ~ /~N
I I /~ N ~ N
N ~N N O NHz
O NHz
(3) \ \~ (4) \
/ iN O i i I / p i
N ~
N ~N I N~N ~N I N~N
HO
O NHz O NHz
(5) ~ \ (6) I \
F / O i ~ \
N I N~N N~N O i
/ N O N N
O NHz W ~N I /~N~
N 'N
O NHz
(7) / ~ (8) ( \
\ O O ~ O N~ /
N O \ p i
N ~ N ~ N' N N N
I ~ ~~ N,
O NHz /N NN
O NHz
(9) o/ (10) I \
i ~N O i
_ N~
N
\ O O HO N I /~N
N N
N~-N ~ O NHz
O
O NHZ

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(11) I ~N (12) ~N
I w N w
N
/ O i / O i
/~ N N I /~ N
\O~/ ~N HO~/ ~N
IOI NHz ~O~ NHz
(13) ~N_N~ (14) ~N~
N INI
I~ I
/ O i / O i
N N
I N~-N ~ I N I /~-N
/ ~N ~N
O NH2 O ~NHz
(15) I w ~ N (16) I w
N
i ~ ~i
N iN O ~ I ~N O i
/~N N I /~N
/N N F~/N N
O NH2 O NHz
(17) / I (18) N
II
I
N\/N O ~ I
/ ~N O i
N
N
/N I N~N N I /~--N
O NH2 HO~ N
O NHz
(19) I w ~ (20) NI w
I y I sN
N\ /'N O ~ / O i
N\ N I N N I /~'N
y ~ ~N
O ~NHz N O NHz

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(21) (22) II
~N
N \ \ \
I / ~ I / / o I
O ~N N
N N O I I /~ N
I /~N ~~S~/N ~/\N
~O~/ N ~--~ I I NH
Q NHz O O z
(23) F (24) \ \
\ \ I / ~NO /
I ~ /
0 ~ 'N N
N~ N ~ I I N~ N
N I / N w N
~N N ~ NH2
NHZ
(25) \ cl (26) \ Br
I ~ I
N ~ / O ~ I F / O
/~--N N I /~-N
~N~N ~N~N
O NHz O NHz
(27) I \ (2$) / I s
\ \ o0
NI ~ N N
O I N /
I I /~- N
N N ~N N
N ~N I /~N~ O NHz
'N
O NHz
(29) F F F (30) o~
/
I\
w
F / F \ I O / O
g ~ O /
\ O N N
I I /~- N
N I /~N ~O~/N N
\ N II N O NHz
/ O NHz

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(31 ) INI (32) o ~
\ \ \ \
I
I / / o ~ / / o
N
N
/~ N N I /~ N
~N~ N
N / O N NH2 \ ~\ O NHz
O O
(33) I \ \ (34) Br
iN O ~ I \
N N N i, / O i
/~-N o N N
N ~--~ I I /~--N
O NHz \N~N~N
O NHz
(35) ~ (36) I \
I \ °\
_ \
/ O / NI ~N O i
N N
FAN I N~N~ O N I N~N
O NHz ~ N
/NI H ~ NHz
(37) ~ (38) I \
O i IV
\ I o O i O
N N
N~ I I /~ N
O N I / N HON N
\\S~\/N N O NHz
O O NHz
(39) / I NHz (4p) I \ o
\ O i
0 ~ I \
I N~N N~N O i
N
" N NH N~ N I / N/
O z ~N N
NH2

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(41 ) I \ (42)
N I ~N I ~N
N
/ O i I
N / O i
~NH N N
/~ N
O N N
O NHz
(43) II (44) F
I~
I \ \
/ o
/ / o / N~
\O N N
N ~ ~~ I / N
N~~N I /~N~ H O N N
,N ~ O NHz
O
(45) I \ \ (46) ci I \ i
/ ~N ~ /
O ~ Ni / O
N N ~ \N N
I /~N NH N I /~N~
N ~--~ / NN
O O NHZ
(47) I ~ ~iN N~\ (48) I \ \
iN O / / / ~N O i
N
N N I />-N~NH
I N N HON N
NHZ O
(49) I \ (50) I \
I \ I \
N / O i N /
O i
N\ININN O NI/~--N
N
p NHz ~ NHZ

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(5~ ) ~ \ ~ N (52)
\ ~ N~N O i
NI / O j N N
I I /~ N
N /N N
/~-N\ > o NHZ
HO 'N
O NHz
(53) ~ (54) I
N /N O i N\ /N O i
N N N
N
N ~ I I />--N I I />---N~
N N /N N
O NHz O NHz
(55) \ ~~N (56) I \
I / ~N O i
~N O i N
N N
N
N I /~ N / I fV~---N
/ N O NHz
0 NHz
Example 3
Coated tablets containing 75 mq of active substance
5
1 tablet core contains:
active substance 75.0 mg
calcium phosphate 93.0 mg
corn starch 35.5 mg
10 polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose 15.0 mg
magnesium stearate 1.5 ma
230.0 mg
15 Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-
ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of
magnesium stearate. Blanks about 13 mm in diameter are produced in a tablet-

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51
making machine and these are then rubbed through a screen with a mesh size of
1.5
mm using a suitable machine and mixed with the rest of the magnesium stearate.
This granulate is compressed in a tablet-making machine to form tablets of the
desired shape.
weight of core: 230 mg
die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially
of
hydroxypropylmethylcellulose. The finished film-coated tablets are polished
with
beeswax.
Weight of coated tablet: 245 mg.
Example 4
Tablets containin 1q 00 mg of active substance
Composition:
1 tablet contains:
active substance 100.0 mg
lactose 80.0 mg
corn starch 34.0 mg
polyvinylpyrrolidone 4.0 mg
magnesium stearate 2.0 ma
220.0 mg
Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly
moistened with an aqueous solution of the polyvinylpyrrolidone. After the
moist
composition has been screened (2.0 mm mesh size) and dried in a rack-type
drier at
50°C it is screened again (1.5 mm mesh size) and the lubricant is
added. The
finished mixture is compressed to form tablets.
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

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Example 5
Tablets containingi 150 mg of active substance
Composition:
1 tablet contains:
active substance 150.0 mg
powdered lactose 89.0 mg
corn starch 40.0 mg
colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg
magnesium stearate 1.0 mg
300.0 mg
Preparation:
The active substance mixed with lactose, corn starch and silica is moistened
with a
20% aqueous polyvinylpyrrolidone solution and passed through a screen with a
mesh
size of 1.5 mm. The granules, dried at 45°C, are passed through the
same screen
again and mixed with the specified amount of magnesium stearate. Tablets are
pressed from the mixture.
Weight of tablet: 300 mg
die: 10 mm, flat

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Example 6
Hard gelatine capsules containing 150 mg of active substance
1 capsule contains:
active substance 150.0 mg
corn starch (dried) approx. 180.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 mg
approx. 420.0 mg
Preparation:
The active substance is mixed with the excipients, passed through a screen
with a
mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The
finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg
Capsule shell: size 1 hard gelatine capsule.
Example 7
Suppositories containing 150 mg of active substance
1 suppository contains:
active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg
polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
After the suppository mass has been melted the active substance is
homogeneously
distributed therein and the melt is poured into chilled moulds.

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Example 8
Suspension containing 50 mg of active substance
100 ml of suspension contain:
active substance 1.00 g
carboxymethylcellulose-Na-salt 0.10 g
methyl p-hydroxybenzoate 0.05 g
propyl p-hydroxybenzoate 0.01 g
glucose 10.00 g
glycerol 5.00 g
70% sorbitol solution 20.00 g
flavouring 0.30 g
dist. water ad 100 ml
Preparation:
The distilled water is heated to 70°C. The methyl and propyl p-
hydroxybenzoates
together with the glycerol and sodium salt of carboxymethylcellulose are
dissolved
therein with stirring. The solution is cooled to ambient temperature and the
active
substance is added and homogeneously dispersed therein with stirring. After
the
sugar, the sorbitol solution and the flavouring have been added and dissolved,
the
suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example 9
Ampoules containing 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml

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Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made
isotonic with common salt, filtered sterile and transferred into 2 ml
ampoules.
5
Example 10
Ampoules containing 50 ma of active substance
10 Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI, made
isotonic with common salt, filtered sterile and transferred into 10 ml
ampoules.