NOUVEAUX DERIVES DE XANTHINE, LEUR PRODUCTION ET LEUR UTILISATION COMME MEDICAMENTS

XANTHINE DERIVATIVES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

Abrégé français

La présente invention concerne des xanthines substituées de formule générale (I), dans laquelle R?1¿ à R?4¿ sont tels que définis dans la revendication n·1, ainsi que les tautomères, stéréoisomères, mélanges, promédicaments et sels de celles-ci. Ces composés possèdent des propriétés pharmacologiques avantageuses, notamment une action inhibitrice sur l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).

Abrégé anglais

The present invention relates to substituted xanthines of general formula
(see formula I),
wherein R1 to R4 are defined as in claim 1, the tautomers, the stereoisomers,
the mixtures thereof, the prodrugs thereof and the salts thereof, which have
valuable pharmacological properties, particularly an inhibitory effect on the
activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

Revendications

91
Claims
1. Compounds of general formula
<IMG>
wherein
R1 denotes a C1-3-alkyl group substituted by a group R a, while
R a denotes a 1,4-dihydro-quinazolinyl or 3,4-dihydro-quinazolinyl group
wherein in each case in the benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
a 3,4-dihydro-isoquinolinyl, 1H-benzo[d][1,2]oxazinyl,
4H-benzo[e][1,3]oxazinyl, 4H-benzo[d][1,3]oxazinyl or
2H-benzo[1,4]oxazinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group,
a 4H-benzo[e][1,3]thiazinyl, 4H-benzo[d][1,3]thiazinyl or 2H-
benzo[1,4]thiazinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a

92
methylene group may be replaced by a carbonyl group and a
sulphur atom may be replaced by a sulphinyl or sulphonyl group,
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl
group, wherein in each case in the benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl, 4,5-dihydro-3H-benzo[b]-
[1,4]diazepinyl or 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group,
wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group ,
a 2,3-dihydro-benzo[1[1,4]oxazepinyl or 2,3-dihydro-benzo[b)[1,4]oxa-
zepinyl group wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[f][1,4]thiazepinyl or 2,3-dihydro-
benzo[b][1,4]thiazepinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group and a
sulphur atom may be replaced by a sulphinyl or sulphonyl group,

93
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl group wherein in the
benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
an 11 H-dibenzo[b,e]azepinyl or 5H-dibenzo[a,d]cycloheptenyl group,
wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and a methylene group in the
heterocyclyl moiety may be replaced by an oxygen or sulphur
atom, a carbonyl, sulphinyl, sulphonyl or an imino group
substituted by R x, where
R x denotes a hydrogen atom or a C1-4-alkyl, C2-4-alkenyl,
C2-4-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, aryl,
aryl-C1-3-alkyl, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl,
C3-6-cycloalkyloxy-C2-4-alkyl, amino-C2-4-alkyl, C1-3-
alkylamino-C2-4-alkyl, di-(C1-3-alkyl)-amino-C2-4-alkyl, C1-3-
alkyl-carbonyl, C1-3-alkyloxy-carbonyl, C1-3-alkyloxy-
carbonyl-C1-3-alkyl, aryl-carbonyl, C1-3-alkyl-sulphonyl or
aryl-sulphonyl group,
a phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl, benzo[f]quino-
xalinyl, 5H-dibenzo[d,f][1,3]diazepinyl, 5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl or a 3-oxo-2,3-
dihydro-isoindol-1-ylidene group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms,

94
a benzo[1,2,5]oxadiazolyl, dibenzofuranyl, Indolizinyl or 1H-perimidinyl,
group,
a pyrazolo[1,5-c]quinazolinyl group or an imidazo[2,1-a]isoquinolinyl or
imidazo[1,2-a]isoquinolinyl group
while the above-mentioned groups R a may be substituted by the
groups R10 to R13 and may additionally be substituted by a C1-3-alkyl
group and
R10 denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C1-4-alkyl, hydroxy, or C1-4-alkyloxy group,
a nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, cyano-C1-3-
alkylamino, [N-(cyano-C1-3-alkyl)-N-C1-3-alkyl-amino], C1-3-
alkyloxy-carbonyl-C1-3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl,
morpholin-4-yl, piperazin-1-yl, or 4-(C1-3-alkyl)-piperazin-1-yl
group,
a C1-3-alkyl-carbonylamino, arylcarbonylamino, aryl-C1-3-alkyl-
carbonylamino, C1-3-alkyloxy-carbonylamino,
aminocarbonylamino, C1-3-alkyl-aminocarbonylamino, di-(C1-3-
alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,
piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,
piperazin-1-yl-carbonylamino or 4-(C1-3-alkyl)-piperazin-1-yl-
carbonylamino, C1-3-alkyl-sulphonylamino, bis-(C1-3-
alkylsulphonyl)-amino, aminosulphonylamino, C1-3-alkylamino-
sulphonylamino, di-(C1-3-alkyl)amino-sulphonylamino, pyrrolidin-
1-yl-sulphonylamino, piperidin-1-yl-sulphonylamino, morpholin-4-
yl-sulphonylamino, piperazin-1-yl-sulphonylamino or 4-(C1-3-

95
alkyl)-piperazin-1-yl-sulphonylamino, (C1-3-
alkylamino)thiocarbonylamino, (C1-3-alkyloxy-carbonylamino)-
carbonylamino, arylsulphonylamino or aryl-C1-3-alkyl-
sulphonylamino group,
an N-(C1-3-alkyl)-C1-3-alkyl-carbonylamino, N-(C1-3-alkyl)-
arylcarbonylamino, N-(C1-3-alkyl)-aryl-C1-3-alkyl-carbonylamino,
N-(C1-3-alkyl)-C1-3-alkyloxy-carbonylamino, N-(aminocarbonyl)-
C1-3-alkylamino, N-(C1-3-alkyl-aminocarbonyl)-C1-3-alkylamino,
N-[di-(C1-3-alkyl)aminocarbonyl]-C1-3-alkylamino, N-(C1-3-alkyl)-
C1-3-alkyl-sulphonylamino, N-(C1-3-alkyl)-arylsulphonylamino or
N-(C1-3-alkyl)-aryl-C1-3-alkyl-sulphonylamino group,
a 2-oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl, 2,5-dioxo-
imidazolidin-1-yl or 2-oxo-hexahydropyrimidin-1-yl group wherein
the nitrogen atom in the 3 position may be substituted in each
case by a methyl or ethyl group,
a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-
alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, pyrrolidin-1-
yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,
piperazin-1-yl-carbonyl or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl
group,
a C1-3-alkyl-carbonyl or an arylcarbonyl group,
a carboxy-C1-3-alkyl, C1-3-alkyloxy-carbonyl-C1-3-alkyl, cyano-
C1-3-alkyl, aminocarbonyl-C1-3-alkyl, C1-3-alkyl-aminocarbonyl-
C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, pyrrolidin-1-yl-
carbonyl-C1-3-alkyl, piperidin-1-yl-carbonyl-C1-3-alkyl, morpholin-
4-yl-carbonyl-C1-3-alkyl, piperazin-1-yl-carbonyl-C1-3-alkyl or 4-
(C1-3-alkyl)-piperazin-1-yl-carbonyl-C1-3-alkyl group,

96
a carboxy-C1-3-alkyloxy, C1-3-alkyloxy-carbonyl-C1-3-alkyloxy,
cyano-C1-3-alkyloxy, aminocarbonyl-C1-3-alkyloxy, C1-3-alkyl-
aminocarbonyl-Cl-3-alkyloxy, di-(C1-3-alkyl)-aminocarbonyl-C1-3-
alkyloxy, pyrrolidin-1-yl-carbonyl-C1-3-alkyloxy, piperidin-1-yl-
carbonyl-C1-3-alkyloxy, morpholin-4-yl-carbonyl-C1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C1-3-alkyloxy or 4-(C1-3-alkyl)-piperazin-1-
yl-carbonyl-C1-3-alkyloxy group,
a hydroxy-C1-3-alkyl, C1-3-alkyloxy-C1-3-alkyl, amino-C1-3-alkyl,
C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl,
pyrrolidin-1-yl-C1-3-alkyl, piperidin-1-yl-C1-3-alkyl, morpholin-4-yl-
C1-3-alkyl, piperazin-1-yl-C1-3-alkyl or 4-(C1-3-alkyl)-piperazin-1-yl-
C1-3-alkyl group,
a hydroxy-C1-3-alkyloxy, C1-3-alkyloxy-C1-3-alkyloxy, C1-3-alkyl-
sulphanyl-C1-3-alkyloxy, C1-3-alkylsulphinyl-C1-3-alkyloxy, C1-3-
alkylsulphonyl-C1-3-alkyloxy, amino-C1-3-alkyloxy, C1-3-
alkylamino-C1-3-alkyloxy, di-(C1-3-alkyl)-amino-C1-3-alkyloxy,
pyrrolidin-1-yl-C1-3-alkyloxy, piperidin-1-yl-C1-3-alkyloxy,
morpholin-4-yl-C1-3-alkyloxy, piperazin-1-yl-C1-3-alkyloxy or4-(C1-3-
alkyl)-piperazin-1-yl-C1-3-alkyloxy group,
a mercapto, C1-3-alkylsulphanyl, C1-3-alkylsulphinyl, C1-3-
alkylsulphonyl, C1-3-alkylsulphonyloxy, arylsulphonyloxy,
trifluoromethylsulphanyl, trifluoromethylsulphinyl or
trifluoromethylsulphonyl group,
a sulpho, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-
alkyl)-aminosulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1-yl-
sulphonyl, morpholin-4-yl-sulphonyl, piperazin-1-yl-sulphonyl or
4-(C1-3-alkyl)-piperazin-1-yl-sulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms,

97
an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a C2-4-alkenyl or C2-4-alkynyl group,
a C3-4-alkenyloxy or C3-4-alkynyloxy group,
a C3-6-cycloalkyl or C3-6-cycloalkyloxy group,
a C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkyl-C1-3-alkyloxy group
or
an aryl, aryloxy, aryl-C1-3-alkyl or aryl-C1-3-alkyloxy group,
R11 and R12, which may be identical or different, in each case
denote a hydrogen atom, a fluorine, chlorine, bromine or iodine
atom, a C1-3-alkyl, trifluoromethyl, hydroxy or C1-3-alkyloxy group
or a cyano group, or
R11 together with R12, if they are bound to adjacent carbon
atoms, also denote a methylenedioxy, difluoromethylenedioxy,
ethylenedioxy or a straight-chain C3-5-alkylene group
and
R13 denotes a hydrogen atom, a fluorine, chlorine or bromine
atom, a trifluoromethyl, C1-3-alkyl or C1-3-alkyloxy group,
R2 denotes a hydrogen atom,
a C1-6-alkyl group,
a C2-4-alkenyl group,

98
a C3-4-alkynyl group,
a C3-6-cycloalkyl group,
a C3-6-cycloalkyl-C1-3-alkyl group,
a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl or tetrahydropyranylmethyl group,
an aryl group,
an aryl-C1-4-alkyl group,
an aryl-C2-3-alkenyl group,
an arylcarbonyl-C1-2-alkyl group,
a heteroaryl-C1-3-alkyl group,
a furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl or
pyridylcarbonylmethyl group,
a C1-4-alkyl-carbonyl-C1-2-alkyl group,
a C3-6-cycloalkyl-carbonyl-C1-2-alkyl group,
an aryl-A-C1-3-alkyl group, while A denotes an oxygen or sulphur atom, an
imino, C1-3-alkylimino, sulphinyl or sulphonyl group,
a C1-4-alkyl group substituted by a group R b, while
R b denotes a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl,
C1-3-alkylamino-carbonyl, di-(C1-3-alkyl)-amino-carbonyl, pyrrolidin-1-

99
ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-
ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl or 4-ethylpiperazin-1-
ylcarbonyl group,
or a C2-4-alkyl group substituted by a group R c,, while
R c denotes a hydroxy, C1-3-alkyloxy, amino, C1-3-alkylamino, di-(C1-3-
alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-
yl, 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl group and is
isolated from the cyclic nitrogen atom in the 3 position of the xanthine
structure by at least two carbon atoms,
R3 denotes a C3-8-alkyl group,
a C1-3-alkyl group substituted by a group R d, while
R d denotes a C3-7-cycloalkyl group optionally substituted by one or two
C1-3-alkyl groups,
a C5-7-cycloalkenyl group optionally substituted by one or two C1-3-alkyl
groups,
an aryl group or
a furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl-,
pyridyl, pyridazinyl, pyrimidyl or pyrazinyl group, while the above-
mentioned heterocyclic groups may be substituted in each case by one
or two C1-3-alkyl groups or by a fluorine, chlorine, bromine or iodine
atom or by a trifluoromethyl, cyano or C1-3-alkyloxy group,
a C3-8-alkenyl group,

100
a C3-6-alkenyl group substituted by a fluorine, chlorine or bromine atom or a
trifluoromethyl group,
a C3-8-alkynyl group,
an aryl group or
an aryl-C2-4-alkenyl group,
and
R4 denotes an azetidin-1-yl or pyrrolidin-1-yl group which is substituted in
the
3 position by an amino, C1-3-alkylamino or a di-(C1-3-alkyl)amino 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, C1-3-alkylamino or a di-(C1-3-
alkyl)amino group and may additionally be substituted by one or two C1-3-alkyl
groups,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally
substituted by an aminocarbonyl, C1-2-alkyl-aminocarbonyl, di-(C1-2-
alkyl)aminocarbonyl, pyrrolidin-1-yl-carbonyl, (2-cyano-pyrrolidin-1-yl)-
carbonyl, thiazolidin-3-yl-carbonyl, (4-cyano-thiazolidin-3-yl)carbonyl,
piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl group,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally
substituted in the 4 position or in the 5 position by a hydroxy or methoxy
group,
a 3-amino-piperidin-1-yl group wherein the methylene group in 2 position or in
6 position is replaced by a carbonyl group,

101
a piperidin-1-yl or hexahydroazepin-1-yl group substituted in the 3 position
by
an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, wherein in each case
two hydrogen atoms on the carbon skeleton of the piperidin-1-yl or
hexahydroazepin-1-yl group are replaced by a straight-chain alkylene bridge,
while this bridge contains 2 to 5 carbon atoms, if the two hydrogen atoms are
located on the same carbon atom, or contains 1 to 4 carbon atoms if the
hydrogen atoms are located on adjacent carbon atoms, or contains 1 to 4
carbon atoms, if the hydrogen atoms are located on carbon atoms which by
are separated by one atom, or contains 1 to 3 carbon atoms if the two
hydrogen atoms are located on carbon atoms which are separated by two
atoms,
an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl
group
which is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a
di-
(C1-3-alkyl)amino-C1-3-alkyl group,
a piperazin-1-yl or [1,4]diazepan-1-yl group optionally substituted on the
carbon skeleton by one or two C1-3-alkyl groups,
a 3-imino-piperazin-1-yl, 3-imino-[1,4]diazepan-1-yl or 5-imino-[1,4]diazepan-
1-yl group optionally substituted on the carbon skeleton by one or two C1-3-
alkyl groups,
a [1,4]diazepan-1-yl group optionally substituted by one or two C1-3-alkyl
groups, which is substituted by an amino group in the 6 position,
a C3-7-cycloalkyl group which is substituted by an amino, C1-3-alkylamino or
di-
(C1-3-alkyl)-amino group,
a C3-7-cycloalkyl group which is substituted by an amino-C1-3-alkyl, C1-3-
alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-C1-3-alkyl group,

102
a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is
substituted
by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
a C3-7-cycloalkyl-C1-2-alkyl group wherein the cycloalkyl moiety is
substituted
by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-
C1-3-
alkyl group,
a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, while the two
nitrogen atoms on the cycloalkyl moiety are separated from one another by at
least two carbon atoms,
an N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino group wherein the cycloalkyl
moiety
is substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
while the two nitrogen atoms on the cycloalkyl moiety are separated from one
another by at least two carbon atoms,
a C3-7-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-alkyl)amino-C1-3-
alkyl group,
an N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino group wherein the cycloalkyl
moiety
is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-
3-
alkyl)amino-C1-3-alkyl group,
a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is
substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an N-(C3-7-cycloalkyl-C1-2-alkyl)-N-(C1-2-alkyl)-amino group wherein the
cycloalkyl moiety is substituted by an amino, C1-3-alkylamino or di-(C1-3-
alkyl)-
amino group,

103
a C3-7-cycloalkyl-C1-2-alkyl-amino group wherein the cycloalkyl moiety is
substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or a di-(C1-3-
alkyl)amino-C1-3-alkyl group,
an N-(C3-7-cycloalkyl-C1-2-alkyl)-N-(C1-2-alkyl)-amino group wherein the
cycloalkyl moiety is substituted by an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-
alkyl or a di-P-3-alkyl)amino-C1-3-alkyl group,
an R19-C2-4-alkylamino group wherein R19 is separated from the nitrogen atom
of the C2-4-alkylamino moiety by at least two carbon atoms and
R19 denotes an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an R19-C2-4-alkylamino group wherein the nitrogen atom of the C2-4-alkylamino
moiety is substituted by a C1-3-alkyl group and R19 is separated from the
nitrogen atom of the C2-4-alkylamino moiety by at least two carbon atoms,
while R19 is as hereinbefore defined,
an amino group substituted by the group R20 wherein
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 group R20 and a C1-3-alkyl group wherein
R20 is as hereinbefore defined, while the groups mentioned for R20 may each
be substituted by one or two C1-3-alkyl groups,
a R19-C3-4-alkyl group wherein the C3-4-alkyl moiety is straight-chain and may
additionally be substituted by one or two C1-3-alkyl groups, while R19 is as
hereinbefore defined,

104
a 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl group,
a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl or
hexahydroazepin-4-yl group which is substituted in the 1 position by an
amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group,
or an azetidin-2-yl-C1-2-alkyl, azetidin-3-yl-C1-2-alkyl, pyrrolidin-2-yl-C1-2-
alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C1-2-alkyl, piperidin-2-yl-C1-2-alkyl,
piperidin-3-yl,
piperidin-3-yl-C1-2-alkyl, piperidin-4-yl or piperidin-4-yl-C1-2-alkyl group,
while
the above-mentioned groups may each be substituted by one or two C1-3-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- or disubstituted by Rh
independently of one another, where the substituents are identical or
different
and R h denotes a fluorine, chlorine, bromine or iodine atom, a
trifluoromethyl,
cyano, nitro, amino, aminocarbonyl, aminosulphonyl, methylsulphonyl,
acetylamino, methylsulphonylamino, C1-3-alkyl, cyclopropyl, ethenyl, ethynyl,
hydroxy, C1-3-alkyloxy, difluoromethoxy or trifluoromethoxy group,
by the heteroaryl groups mentioned in the definitions of the above mentioned
groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,
benzothiophenyl, quinolinyl or isoquinolinyl group,
or a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two methyne
groups are replaced by nitrogen atoms,
or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl
group
wherein one to three methyne groups are replaced by nitrogen atoms,

105
and the above-mentioned heteroaryl groups may be mono- or
disubstituted by R h, while the substituents may be identical or different
and R h is as hereinbefore defined,
and, unless otherwise specified, 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 denotes a methyl group substituted by a group R a, where
R a denotes a 1,4-dihydro-quinazolinyl or 3,4-dihydro-quinazolinyl
group,
a 3,4-dihydro-isoquinolinyl group,
a 1H-benzo[d][1,2]oxazinyl or 1-oxo-1H-benzo[d][1,2]oxazinyl group,
a 4H-benzo[e][1,3]oxazinyl or 4-oxo-4H-benzo[e][1,3]oxazinyl group,
a 4H-benzo[d][1,3]oxazinyl or 4-oxo-4H-benzo[d][1,3]oxazinyl group,
2H-benzo[1,4]oxazinyl or 2-oxo-2H-benzo[1,4]oxazinyl group,
a 4H-benzo[e][1,3]thiazinyl or 4-oxo-4H-benzo[e][1,3]thiazinyl group,
a 4H-benzo[d][1,3]thiazinyl or 2H-benzo[1,4]thiazinyl group,
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1H-benzo[c][1,2]thiazinyl
group,

106
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl or 2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepinyl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepinyl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepinyl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group,
a 2,3-dihydro-benzo[f][1,4]oxazepinyl or 2,3-dihydro-
benzo[b][1,4]oxazepinyl group,
a 2,3-dihydro-benzo[f][1,4]thiazepinyl or 2,3-dihydro-
benzo[b][1,4]thiazepinyl group,
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl group,
an 11H-dibenzo[b,e]azepinyl or 11-oxo-11H-dibenzo[b,e]azepinyl
group,
an 11H-benzo[e]pyrido[3,2-b]azepinyl group,
a 5H-dibenzo[b,e][1,4]diazepinyl or dibenzo[b,f][1,4]oxazepinyl group,
a dibenzo[b,f][1,4]thiazepinyl, 5-oxo-dibenzo[b,f][1,4]thiazepinyl or 5,5-
dioxo-dibenzo[b,f][1,4]thiazepinyl group,
5H-dibenzo[a,d]cycloheptenyl or 5H-dibenzo[b,f]azepinyl group,
a phenanthridinyl, benzo[c][1,5]naphthyridinyl, benzo[h][1,6]naphthyri-
dinyl, benzo[c][1,8]naphthyridinyl or 1,2,3,4-tetrahydro-phenanthridinyl
group,

107
a benzo[f]quinoxalinyl group,
a 5H-dibenzo[d,f][1,3]diazepinyl, 5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepinyl or thieno[3,2-b][1,4]benzoxazepinyl group,
a 3-oxo-2,3-dihydro-isoindol-1-ylidene group,
a benzo[1,2,5]oxadiazolyl group,
a dibenzofuranyl group,
an indolizinyl group,
a 1H-perimidinyl group,
a pyrazolo[1,5-c]quinazolinyl group or
an imidazo[2,1-a]isoquinolinyl or imidazo[1,2-a]isoquinolinyl group
while the benzo groups of the above-mentioned groups R a are
substituted by the groups R10 to R12 and the alkylene units of the
above-mentioned groups R a may be substituted by one or two C1-3-
alkyl or C1-3-alkyloxy-carbonyl groups, while the groups may be
identical or different, or by a trifluoromethyl group, and the imino groups
of the above-mentioned groups R a may be substituted by a C1-3-alkyl
group and
R10 denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C1-3-alkyl or cyclopropyl group,

108
a hydroxy, C1-3-alkyloxy or cyclopropyloxy group,
a nitro, amino, C1-3-alkylamino or di-(C1-3-alkyl)amino group,
a C1-3-alkyl-carbonylamino or C1-3-alkyl-sulphonylamino group,
a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl, C1-3-
alkyl-aminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a mercapto, C1-3-alkylsulphanyl, C1-3-alkylsulphinyl or C1-3-
alkylsulphonyl or aminosulphonyl group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or
trifluoromethoxy group and
R" and R12, which may be identical or different, in each case
represent a hydrogen atom, a fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl or methoxy group,
R 2 denotes a hydrogen atom,
a C1-3-alkyl group,
a C3-6-cycloalkyl group or
a phenyl group optionally mono- or disubstituted by a fluorine, chlorine,
bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C1-3-
alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy, C1-3-alkyloxy, difluoromethoxy
or
trifluoromethoxy group, while the substituents may be identical or different,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,

109
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
while, unless otherwise stated, the above-mentioned alkyl groups may be
straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
3. Compounds of general formula I according to claim 2, wherein
R1 denotes a methyl group substituted by a group R a, where
R a denotes a 1,4-dihydro-quinazolin-2-yl or 3,4-dihydro-quinazolin-2-yl
group,
a 3,4-dihydro-isoquinolin-1-yl group,
a 1H-benzo[d][1,2]oxazin-4-yl or 1-oxo-1H-benzo[d][1,2]oxazin-4-yl
group,
a 4H-benzo[e][1,3]oxazin-2-yl or 4-oxo-4H-benzo[e][1,3]oxazin-2-yl
group,
a 4H-benzo[d][1,3]oxazin-2-yl or 4-oxo-4H-benzo[d][1,3]oxazin-2-yl
group,
2H-benzo[1,4]oxazin-3-yl or 2-oxo-2H-benzo[1,4]oxazin-3-yl group,

110
a 4H-benzo[e][1,3]thiazin-2-yl or 4-oxo-4H-benzo[e][1,3]thiazin-2-yl
group,
a 4H-benzo[d][1,3]thiazin-2-yl or 2H-benzo[1,4]thiazin-3-yl group,
a 2-oxo-2H-benzo[e][1,3]oxazin-4-yl or 2,2-dioxo-1H-benzo[c][1,2]thia-
zin-4-yl group,
a 2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl or 2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepin-5-yl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-yl group,
a 2,3-dihydro-benzo[1[1,4]oxazepin-5-yl or 2,3-dihydro-benzo[b]-
[1,4]oxazepin-4-yl group,
a 2,3-dihydro-benzo[f][1,4]thiazepin-5-yl or 2,3-dihydro-benzo[b]-
[1,4]thiazepin-4-yl group,
a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepin-2-yl group,
an 11H-dibenzo[b,e]azepin-6-yl or 11-oxo-11H-dibenzo[b,e]azepin-6-yl
group,
an 11H-benzo[e]pyrido[3,2-b]azepin-6-yl group
a 5H-dibenzo[b,e][1,4]diazepin-11-yl or dibenzo[b,f][1,4]oxazepin-11-yl
group,

111
a dibenzo[b,1[1,4]thiazepin-11-yl, 5-oxo-dibenzo[b,1[1,4]thiazepin-11-yl
or 5,5-dioxo-dibenzo[b,1[1,4]thiazepin-11-yl group,
a 5H-dibenzo[a,d]cyclohepten-10-yl or 5H-dibenzo[b,f]azepin-10-yl
group,
a phenanthridin-6-yl, benzo[c][1,5]naphthyridin-6-yl, benzo[h][1,6]naph-
thyridin-5-yl, benzo[c][1,8]naphthyridin-6-yl or 1,2,3,4-tetrahydro-
phenanthridin-6-yl group,
a benzo[f]quinoxalin-6-yl group,
a 5H-dibenzo[d,1[1,3]diazepin-6-yl, 5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepin-11-yl or thieno[3,2-b][1,4]benzoxazepinyl-9-yl group,
a 3-oxo-2,3-dihydro-isoindol-1-ylidene group,
a benzo[1,2,5]oxadiazol-5-yl group,
a dibenzofuran-2-yl group,
an indolizin-2-yl group,
a 1H-perimidin-2-yl group,
a pyrazolo[1,5-c]quinazolin-5-yl group or
an imidazo[2,1-a]isoquinolin-2-yl or imidazo[1,2-a]isoquinolin-2-yl group
while the benzo groups of the above-mentioned groups Ra are
substituted by the groups R10 to R12 and the alkylene units of the
above-mentioned groups R a may be substituted by one or two methyl-
or methoxy-carbonyl groups, while the groups may be identical or

112
different, or by a trifluoromethyl group and the imino groups of the
above-mentioned groups R a may be substituted by a methyl group and
R10 denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a methyl or ethyl group,
a hydroxy, methoxy or ethoxy group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or
trifluoromethoxy group and
R11 and R12, which may be identical or different, each represent
a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl,
trifluoromethyl or methoxy group,
R2 denotes a hydrogen atom or
a methyl, ethyl, propyl, isopropyl, phenyl or cyclopropyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,

113
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
4. Compounds of general formula I according to claim 3, wherein
R1 denotes a 3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-ylmethyl
group,
a 1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4-ylmethyl group,
a 2,3-dihydro-benzo[f][1,4]oxazepin-5-ylmethyl group,
a 2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-ylmethyl group,
a phenanthridin-6-ylmethyl or 1,2,3,4-tetrahydro-phenanthridin-6-ylmethyl
group,
an 11H-dibenzo[b,e]azepin-6-ylmethyl group,
a dibenzo[b,f][1,4]oxazepin-11-ylmethyl group,
a 3-oxo-2,3-dihydro-isoindol-1-ylidenemethyl group,
a 3-trifluoromethyl-3,4-dihydro-isoquinolin-1-ylmethyl group,
a 3,4-dihydro-quinazolin-2-ylmethyl group,
a 5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylmethyl group,
an 8-methyl-dibenzo[b,f][1,4]oxazepin-11-ylmethyl group,
a benzo[1,2,5]oxadiazol-5-ylmethyl group,

114
an 8-methyl-phenanthridin-6-ylmethyl group,
a 1-methyl-phenanthridin-6-ylmethyl group,
a 4-methyl-phenanthridin-6-ylmethyl group,
a benzo[h][1,6]naphthyridin-5-ylmethyl group,
a pyrazolo[1,5-c]quinazolin-5-yl group,
a benzo[c][1,8]naphthyridin-6-ylmethyl group,
a benzo[c][1,5]naphthyridin-6-ylmethyl group,
a 1H-perimidin-2-ylmethyl group,
a benzo[f]quinoxalin-6-ylmethyl group or
an imidazo[2,1-a]isoquinolin-2-ylmethyl or imidazo[1,2-a]isoquinolin-2-
ylmethyl group,
R2 denotes a methyl or cyclopropyl group,
R3 denotes a 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.

115
5. The following compounds of general formula I according to claim 1:
(1) 1-[(1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(2) 1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(3) 1-[(2-oxo-2,3-dihydro-1 H-benzo[e][1,4]diazepin-5-yl)methyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(4) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine,
(5) 1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-
8-(3-amino-piperidin-1-yl)-xanthine,
(6) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(7) 1-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(8) 1-[(3-trifluoromethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(9) 1-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine,
(10) 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,

116
(11) 1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(12) 1-[(8-methyl-dibenzo[b,1[1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthino,
(13) 1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(14) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine,
(15) 1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(16) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-
piperidin-1-yl)-xanthine,
(17) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine,
(18) 1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine,
(19) 1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine,
(20) 1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(21) 1-[(pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,

117
(22) 1-[(benzo[c][1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(23) 1-[(benzo[c][1,5]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine,
(24) 1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine,
(25) 1-[(benzo[f]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine,
(26) 1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(27) 1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(28) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine,
(29) 1-[(2,3-dihydro-benzo[f][1,4]oxazepin-5-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-8-(3-amino-piperidin-1-yl)-xanthine, and
(30) 1-[(3-oxo-2,3-dihydro-isoindol-1-ylidene)methyl]-3-methyl-7-(3-methyl-2-
buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
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 or bases.

118
7. Pharmaceutical composition containing a compound according to at
least one of claims 1 to 5 or a physiologically acceptable salt according to
claim 6
together with one or more inert carriers and/or diluents.
8. Use of a compound according to at least one of claims 1 to 5 or a
physiologically acceptable salt according to claim 6 for preparing a
pharmaceutical
composition for use in the treatment of type I or type II diabetes mellitus,
arthritis,
obesity or osteoporosis caused by calcitonin or for use following allograft
transpantation.
9. Process for preparing a pharmaceutical composition according to
claim 7, comprising incorporating a compound according to at least one of
claims
1 to 5 or a physiologically acceptable salt according to claim 6 in one or
more inert
carriers and/or diluents by a non-chemical method.
10. Process for preparing a compound according to at least one of
claims 1 to 5 or a physiologically acceptable salt according to claim 6
comprising
a) deprotecting a compound of general formula
<IMG>
wherein R1, R2 and R3 are defined as mentioned in claim 1 and
R4" denotes one of the groups mentioned for R4 hereinbefore which contain an
imino, amino or alkylamino group, while the imino, amino or alkylamino group
is
substituted by a protective group, or

119
b) deprotecting and cyclizing a compound of general formula
<IMG>
wherein R2 and R3 are defined as mentioned in claim 1,
R4" denotes one of the groups mentioned for R4 hereinbefore which contain an
imino, amino or alkylamino group, while the imino, amino or alkylamino group
is
substituted by a protective group,
X denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or an imino group
substituted by R x, and
the -CH2-CH2-X-phenyl unit is substituted by R10 to R14 and may additionally
be
substituted by a C1-3-alkyl group,
while R x and R10 to R14 are as hereinbefore defined, and
PG also denotes a protective group,
while the two protective groups may be cleaved simultaneously or one after the
other, or
c) in order to prepare a compound of general formula I wherein R1
denotes a 3-oxo-2,3-dihydro-isoindol-1-ylidenemethyl group optionally
substituted
by a group as defined in any one of claims 1 to 5,
deprotecting and dehydrating a compound of general formula

120
<IMG>
wherein the benzo group is substituted by R10 to R14
and R10 to R14 as well as R, R2 and R3 are as hereinbefore defined, and
R4" denotes one of the groups mentioned for R4 hereinbefore which contain an
imino, amino or alkylamino group, while the imino, amino or alkylamino group
is
substituted by a protective group, and
the dehydration is carried out under the same reaction conditions as the
cleaving
of the protective group,
the compounds of general formula I thus obtained in (a), (b) or (c) are
resolved
into their enantiomers and/or diastereomers and/or
the compounds of formula I obtained are converted into their salts.
11. Process according to claim 10, wherein the compounds of formula I
obtained are converted into their salts physiologically acceptable salts with
inorganic or organic acids or bases.

Description

CA 02505389 2005-05-06
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1410
55216 Ingelheim Foreign filing text
1
82433fft
Xanthine derivatives, the preparation thereof and their use
as pharmaceutical compositions
The present invention relates to new substituted xanthines of general formula
3
R1~N N
R4
O N N
Rz
the tautomers, enantiomers, diastereomers, the mixtures thereof, the
prodrugs 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 the prevention or treatment of diseases or
conditions associated 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
as well as processes for the preparation thereof.
The present invention thus relates to the above compounds of general
formula I which have valuable pharmacological properties, the pharmaceutical
compositions containing the pharmacologically effective compounds, the use
thereof and processes for the preparation thereof.
In the above general formula I
R' denotes a C~_3-alkyl group substituted by a group Ra, while

CA 02505389 2005-05-06
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1410
55216 Ingelheim Foreign filing tent
2
Ra denotes a 1,4-dihydro-quinazolinyl or 3,4-dihydro-quinazolinyl group
wherein in each case in the benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
a 3,4-dihydro-isoquinolinyl, 1 H-benzo[dJ[1,2]oxazinyl,
4H-benzo[e][1,3]oxazinyl, 4H-benzo[dj[1,3]oxazinyl or
2H-benzo[1,4]oxazinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group,
a 4H-benzo[e][1,3]thiazinyl, 4H-benzo[dJ[1,3]thiazinyl or 2H-
benzo[1,4]thiazinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group and a
sulphur atom may be replaced by a sulphinyl or sulphonyl group,
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1 H-benzo[c][1,2]thiazinyl
group, wherein in each case in the benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl, 4,5-dihydro-3H-benzo[b]-
[1,4]diazepinyl or 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group,
wherein in each case

CA 02505389 2005-05-06
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1410
55216 Ingelheim Foreign filing text
3
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group ,
a 2,3-dihydro-benzo[tJ[1,4]oxazepinyl or 2,3-dihydro-benzo[b][1,4]oxa-
zepinyl group wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group,
a 2,3-dihydro-benzo[tj[1,4]thiazepinyl or 2,3-dihydro-
benzo[b][1,4]thiazepinyl group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and in the heterocyclyl moiety a
methylene group may be replaced by a carbonyl group and a
sulphur atom may be replaced by a sulphinyl or sulphonyl group,
a 5-oxo-4,5-dihydro-benzo[t][1,3,4]oxadiazepinyl group wherein in the
benzo moiety
one to three methyne groups may be replaced by nitrogen
atoms,
an 11H-dibenzo[b,e]azepinyl or 5H-dibenzo[a,d]cycloheptenyl group,
wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms and the methylene group in the
heterocyclyl moiety may be replaced by an oxygen or sulphur
atom, a carbonyl, sulphinyl, sulphonyl or an imino group
substituted by RX, where

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RX denotes a hydrogen atom or a C»-alkyl, C2~-alkenyl,
C2_4-alkynyl, C3_s-cycloalkyl, C3~-cycloalkyl-C~_3-alkyl, aryl,
aryl-C~_3-alkyl, hydroxy-C2_4-alkyl, C~_3-alkyloxy-CZ~-alkyl,
C3_6-cycloalkyloxy-C2_4-alkyl, amino-C2_4-alkyl, C,_3-
alkylamino-C2~-alkyl, di-(C~_3-alkyl)-amino-CZ_4-alkyl, C~_3-
alkyl-carbonyl, C~_3-alkyloxy-carbonyl, C~_3-alkyloxy-
carbonyl-C~_3-alkyl, aryl-carbonyl, C~_3-alkyl-sulphonyl or
aryl-sulphonyl group,
a phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl, benzo[t]quino-
xalinyl, 5H-dibenzo[d,tJ[1,3]diazepinyl, 5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepinyl, thieno[3,2-b][1,4]benzoxazepinyl or a 3-oxo-2,3-
dihydro-isoindol-1-ylidene group, wherein in each case
in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms,
a benzo[1,2,5]oxadiazolyl, dibenzofuranyl, indolizinyl, 1H-perimidinyl,
group,
a pyrazolo[1,5-c]quinazolinyl group or an imidazo[2,1-a]isoquinolinyl or
imidazo[1,2-a]isoquinolinyl group
while the above-mentioned groups Ra may be substituted by the
groups R'° to R'3 and may additionally be substituted by a C~_3-alkyl
group and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C,~-alkyl, hydroxy, or C~~-alkyloxy group,

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a nitro, amino, C,_3-alkylamino, di-(C~_3-alkyl)amino, cyano-C~_3-
alkylamino, [N-(cyano-C~_3-alkyl)-N-C~_3-alkyl-amino], C~_3-
alkyloxy-carbonyl-C~_3-alkylamino, pyrrolidin-1-yl, piperidin-1-yl,
morpholin-4-yl, piperazin-1-yl, or 4-(C~_3-alkyl)-piperazin-1-yl
group,
a C~_3-alkyl-carbonylamino, arylcarbonylamino, aryl-C~_3-alkyl-
carbonylamino, C~_3-alkyloxy-carbonylamino,
aminocarbonylamino, C,_3-alkyl-aminocarbonylamino, dl-(C~_3-
alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,
piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,
piperazin-1-yl-carbonylamino or 4-(C~_3-alkyl)-piperazin-1-yl-
carbonylamino, C,_3-alkyl-sulphonylamino, bIS-(C~-3-
alkylsulphonyl)-amino, aminosulphonylamino, C~_3-alkylamino-
sulphonylamino, di-(C~_3-alkyl)amino-sulphonylamino, pyrrolidin-
1-yl-sulphonylamino, piperidin-1-yl-sulphonylamino, morpholin-4-
yl-sulphonylamino, piperazin-1-yl-sulphonylamino or 4-(C~_3-
alkyl)-piperazin-1-yl-sulphonylamino, (C~-3-
alkylamino)thiocarbonylamino, (C~_3-alkyloxy-carbonylamino)-
carbonylamino, arylsulphonylamino or aryl-C~_3-alkyl-
sulphonylamino group,
an N-(C~_3-alkyl)-C~_3-alkyl-carbonylamino, N-(C~_3-alkyl)-
arylcarbonylamino, N-(C~_3-alkyl)-aryl-C~_3-alkyl-carbonylamino,
N-(C~_3-alkyl)-C~_3-alkyloxy-carbonylamino, N-(aminocarbonyl)-
C,_3-alkylamino, N-(C~_3-alkyl-aminocarbonyl)-C~_3-alkylamino ,
N-[di-(C~_3-alkyl)aminocarbonyl]-C~_3-alkylamino, N-(C~_3-alkyl)-
C~_3-alkyl-sulphonylamino, N-(C~_3-alkyl)-arylsulphonylamino or
N-(C~_3-alkyl)-aryl-C~_3-alkyl-sulphonylamino group,
a 2-oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl, 2,5-dioxo-
imidazolidin-1-yl or 2-oxo-hexahydropyrimidin-1-yl group wherein

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the nitrogen atom in the 3 position may be substituted in each
case by a methyl or ethyl group,
a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-
alkyl-aminocarbonyl, di-(C,_3-alkyl)-aminocarbonyl, pyrrolidin-1-
yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,
piperazin-1-yl-carbonyl or 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl
group,
a C~_3-alkyl-carbonyl or an arylcarbonyl group,
a carboxy-C~_3-alkyl, C~_3-alkyloxy-carbonyl-C~_3-alkyl, cyano-
C,_3-alkyl, aminocarbonyl-C~_3-alkyl, C~_3-alkyl-aminocarbonyl-
C~_3-alkyl, di-(C~_3-alkyl)-aminocarbonyl-C~_3-alkyl, pyrrolidin-1-yl-
carbonyl-C~_3-alkyl, piperidin-1-yl-carbonyl-C~_3-alkyl, morpholin-
4-yl-carbonyl-C,_3-alkyl, piperazin-1-yl-carbonyl-C~_3-alkyl or 4-
(C~_3-alkyl)-piperazin-1-yl-carbonyl-C~_3-alkyl group,
a carboxy-C~_3-alkyloxy, C,_3-alkyloxy-carbonyl-C,_3-alkyloxy,
cyano-C~_3-alkyloxy, aminocarbonyl-C~_3-alkyloxy, C~_3-alkyl-
aminocarbonyl-C~_3-alkyloxy, di-(C,_3-alkyl)-aminocarbonyl-C~_3-
alkyloxy, pyrrolidin-1-yl-carbonyl-C~_3-alkyloxy, piperidin-1-yl-
carbonyl-C~_3-alkyloxy, morpholin-4-yl-carbonyl-C~_3-alkyl-oxy,
piperazin-1-yl-carbonyl-C~_3-alkyloxy or 4-(C,_3-alkyl)-piperazin-1-
yl-carbonyl-C~_3-alkyloxy group,
a hydroxy-C~_3-alkyl, C~_3-alkyloxy-C~_3-alkyl, amino-C~_3-alkyl,
C~_3-alkylamino-C~_3-alkyl, di-(C~_3-alkyl)-amino-C~_3-alkyl,
pyrrolidin-1-yl-C,_3-alkyl, piperidin-1-yl-C~_3-alkyl, morpholin-4-yl-
C~_3-alkyl, piperazin-1-yl-C~_3-alkyl, 4-(C,_3-alkyl)-piperazin-1-yl-
C~_3-alkyl group,

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a hydroxy-C~_3-alkyloxy, C,_3-alkyloxy-C~_3-alkyloxy, C~_3-alkyl-
sulphanyl-C~_3-alkyloxy, C~_3-alkylsulphinyl-C,_3-alkyloxy, C~_3-
alkylsulphonyl-C~_3-alkyloxy, amino-C~_3-alkyloxy, C~_3-
alkylamino-C1_3-alkyloxy, di-(C~_3-alkyl)-amino-C~_3-alkyloxy,
pyrrolidin-1-yl-C~_3-alkyloxy, piperidin-1-yl-C~_3-alkyloxy,
morpholin-4-yl-C,_3-alkyloxy, piperazin-1-yl-C~_3-alkyloxy, 4-(C,_3-
alkyl)-piperazin-1-yl-C~_3-alkyloxy group,
a mercapto, C~_3-alkylsulphanyl, C~_3-alkylsulphinyl, C~_3-
alkylsulphonyl, C~_3-alkylsulphonyloxy, arylsulphonyloxy,
trifluoromethylsulphanyl, trifluoromethylsulphinyl or
trifluoromethylsulphonyl group,
a sulpho, aminosulphonyl, C~_3-alkyl-aminosulphonyl, di-(C,_3-
alkyl)-aminosulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1-yl-
sulphonyl, morpholin-4-yl-sulphonyl, piperazin-1-yl-sulphonyl or
4-(C,_3-alkyl)-piperazin-1-yl-sulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a C2~-alkenyl or CZ~-alkynyl group,
a C3_4-alkenyloxy or C3~,-alkynyloxy group,
a C3_6-cycloalkyl or C3_s-cycloalkyloxy group,
a C3_6-cycloalkyl-C~_3-alkyl or C3_6-cycloalkyl-C~_3-alkyloxy group
or
an aryl, aryloxy, aryl-C,_3-alkyl or aryl-C,_3-alkyloxy group,

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R" and R'2, which may be identical or different, in each case
denote a hydrogen atom, a fluorine, chlorine, bromine or iodine
atom, a C~_3-alkyl, trifluoromethyl, hydroxy or C~_3-alkyloxy group
or a cyano group, or
R" together with R'Z, if they are bound to adjacent carbon
atoms, also denote a methylenedioxy, difluoromethylenedioxy,
ethylenedioxy or a straight-chain C3_5-alkylene group
and
R'3 denotes a hydrogen atom, a fluorine, chlorine or bromine
atom, a trifluoromethyl, C~_3-alkyl or C~_3-alkyloxy group,
RZ denotes a hydrogen atom,
a C~_6-alkyl group,
a C2~-alkenyl group,
a C3~-alkynyl group,
a C3~-cycloalkyl group,
a C3~-cycloalkyl-C1_3-alkyl group,
a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl or tetrahydropyranylmethyl group,
an aryl group,
an aryl-C~~-alkyl group,
an aryl-C2_3-alkenyl group,

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an arylcarbonyl-C,_2-alkyl group,
a heteroaryl-C~_3-alkyl group,
a furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl or
pyridylcarbonylmethyl group,
a C~.~-alkyl-carbonyl-C~_2-alkyl group,
a C3_6-cycloalkyl-carbonyl-C,_z-alkyl group,
an aryl-A-C~_3-alkyl group, while A denotes an oxygen or sulphur atom, an
imino, C~_3-alkylimino, sulphinyl or sulphonyl group,
a C»-alkyl group substituted by a group Rb, while
Rb denotes a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl,
C~_3-alkylamino-carbonyl, di-(C~_3-alkyl)-amino-carbonyl, pyrrolidin-1-
ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-
ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl or 4-ethylpiperazin-1-
ylcarbonyl group,
or a C2~-alkyl group substituted by a group R~, while
R~ denotes a hydroxy, C~_3-alkyloxy, amino, C~_3-alkylamino, di-(C~_3-
alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-
yl, 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl group and is
isolated from the cyclic nitrogen atom in the 3 position of the xanthine
structure by at least two carbon atoms,
R3 denotes a C3_8-alkyl group,

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a C,_3-alkyl group substituted by a group Rd, while
Rd denotes a C3_~-cycloalkyl group optionally substituted by one or two
C~_3-alkyl groups,
a C5_~-cycloalkenyl group optionally substituted by one or two C~_3-alkyl
groups,
an aryl group or
a furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyridyl, pyridazinyl, pyrimidyl or pyrazinyl group, while the above-
mentioned heterocyclic groups may be substituted in each case by one
or two C~_3-alkyl groups or by a fluorine, chlorine, bromine or iodine
atom or by a trifluoromethyl, cyano or C,_3-alkyloxy group,
a C3_a-alkenyl group,
a C3~-alkenyl group substituted by a fluorine, chlorine or bromine atom or a
trifluoromethyl group,
a C3_8-alkynyl group,
an aryl group or
an aryl-C2~-alkenyl group,
and
R4 denotes an azetidin-1-yl or pyrrolidin-1-yl group which is substituted in
the
3 position by an amino, C~_3-alkylamino or a di-(C~_3-alkyl)amino group and
may additionally be substituted by one or two C,_3-alkyl groups,

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a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position or in the 4 position by an amino, C~_3-alkylamino or a di-(C~_3-
alkyl)amino group and may additionally be substituted by one or two C~_3-alkyl
groups,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally
substituted by an aminocarbonyl, C~_2-alkyl-aminocarbonyl, di-(C~_Z-
alkyl)aminocarbonyl, pyrrolidin-1-yl-carbonyl, (2-cyano-pyrrolidin-1-yl)-
carbonyl, thiazolidin-3-yl-carbonyl, (4-cyano-thiazolidin-3-yl)carbonyl,
piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl group,
a 3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally
substituted in the 4 position or in the 5 position by a hydroxy or methoxy
group,
a 3-amino-piperidin-1-yl group wherein the methylene group in 2 position or in
6 position is replaced by a carbonyl group,
a piperidin-1-yl or hexahydroazepin-1-yl group substituted in the 3 position
by
an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group, wherein in each case
two hydrogen atoms on the carbon skeleton of the piperidin-1-yl or
hexahydroazepin-1-yl group are replaced by a straight-chain alkylene bridge,
while this bridge contains 2 to 5 carbon atoms, if the two hydrogen atoms are
located on the same carbon atom, or contains 1 to 4 carbon atoms if the
hydrogen atoms are located on adjacent carbon atoms, or contains 1 to 4
carbon atoms, if the hydrogen atoms are located on carbon atoms which by
are separated by one atom, or contains 1 to 3 carbon atoms if the two
hydrogen atoms are located on carbon atoms which are separated by two
atoms,
an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl
group
which is substituted by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a
di-
(C~_3-alkyl)amino-C,_3-alkyl group,

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a piperazin-1-yl or [1,4]diazepan-1-yl group optionally substituted on the
carbon skeleton by one or two C,_3-alkyl groups,
a 3-imino-piperazin-1-yl, 3-imino-[1,4]diazepan-1-yl or 5-imino-[1,4]diazepan-
1-yl group optionally substituted on the carbon skeleton by one or two C~_3-
alkyl groups,
a [1,4]diazepan-1-yl group optionally substituted by one or two C~_3-alkyl
groups, which is substituted by an amino group in the 6 position,
a C3_~-cycloalkyl group which is substituted by an amino, C~_3-alkylamino or
di-
(C~_3-alkyl)-amino group,
a C3_~-cycloalkyl group which is substituted by an amino-C,_3-alkyl, C,_3-
alkylamino-C~_3-alkyl or a di-(C,_3-alkyl)amino-C,_3-alkyl group,
a C3_~-cycloalkyl-C~_2-alkyl group wherein the cycloalkyl moiety is
substituted
by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group,
a C3_~-cycloalkyl-C~_2-alkyl group wherein the cycloalkyl moiety is
substituted
by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-(C~_3-alkyl)amino-
C~_3-
alkyl group,
a C3_~-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group, while the two
nitrogen atoms on the cycloalkyl moiety are separated from one another by at
least two carbon atoms,
an N-(C3_~-cycloalkyl)-N-(C,_3-alkyl)-amino group wherein the cycloalkyl
moiety
is substituted by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group,
while the two nitrogen atoms on the cycloalkyl moiety are separated from one
another by at least two carbon atoms,

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a C3_~-cycloalkylamino group wherein the cycloalkyl moiety is substituted by
an amino-C~_3-alkyl, C1_3-alkylamino-C~_3-alkyl or a di-(C~_3-alkyl)amino-C~_3-
alkyl group,
an N-(C3_~-cycloalkyl)-N-(C~_3-alkyl)-amino group wherein the cycloalkyl
moiety
is substituted by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-
(C,_3-
alkyl)amino-C~_3-alkyl group,
a C3_~-cycloalkyl-C~_2-alkyl-amino group wherein the cycloalkyl moiety is
substituted by an amino, C,_3-alkylamino or di-(C~_3-alkyl)-amino group,
an N-(C3_~-cycloalkyl-C~_2-alkyl)-N-(C~_2-alkyl)-amino group wherein the
cycloalkyl moiety is substituted by an amino, C~_3-alkylamino or di-(C~_3-
alkyl)-
amino group,
a C3_~-cycloalkyl-C~_2-alkyl-amino group wherein the cycloalkyl moiety is
substituted by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl or a di-(C~_3-
alkyl)amino-C~_3-alkyl group,
an N-(C3_~-cycloalkyl-C~_2-alkyl)-N-(C~_Z-alkyl)-amino group wherein the
cycloalkyl moiety is substituted by an amino-C~_3-alkyl, C~_3-alkylamino-C~_3-
alkyl or a di-(C,_3-alkyl)amino-C~_3-alkyl group,
an R'9-C2_4-alkylamino group wherein R'9 is separated from the nitrogen atom
of the C2~-alkylamino moiety by at least two carbon atoms and
R'9 denotes an amino, C,_3-alkylamino or di-(C~_3-alkyl)-amino group,

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an R'9-CZ_4-alkylamino group wherein the nitrogen atom of the C2~,-alkylamino
moiety is substituted by a C~_3-alkyl group and R'9 is separated from the
nitrogen atom of the C2~-alkylamino moiety by at least two carbon atoms,
while R'9 is as hereinbefore defined,
an amino group substituted by the group R2° wherein
RZ° 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 group R2° and a C,_3-alkyl group
wherein
RZ° is as hereinbefore defined, while the groups mentioned for
RZ° may each
be substituted by one or two C~_3-alkyl groups,
a R'9-C3~-alkyl group wherein the C3~-alkyl moiety is straight-chain and may
additionally be substituted by one or two C~_3-alkyl groups, while R'9 is as
hereinbefore defined,
a 3-amino-2-oxo-piperidin-5-yl or 3-amino-2-oxo-1-methyl-piperidin-5-yl group,
a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl or
hexahydroazepin-4-yl group which is substituted in the 1 position by an
amino, C,_3-alkylamino or di-(C~_3-alkyl)amino group,
or an azetidin-2-yl-C~_2-alkyl, azetidin-3-yl-C~_2-alkyl, pyrrolidin-2-yl-C~_2-
alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C~_2-alkyl, piperidin-2-yl-C~_2-alkyl,
piperidin-3-yl,
piperidin-3-yl-C,_2-alkyl, piperidin-4-yl or piperidin-4-yl-C~_2-alkyl group,
while
the above-mentioned groups may each be substituted by one or two C~_3-alkyl
groups,

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while by the aryl groups mentioned in the definition of the above groups are
meant phenyl or naphthyl groups, which may be mono- or disubstituted by R,,
independently of one another, where the substituents are identical or
different
and Rh denotes a fluorine, chlorine, bromine or iodine atom, a
trifluoromethyl,
cyano, nitro, amino, aminocarbonyl, aminosulphonyl, methylsulphonyl,
acetylamino, methylsulphonylamino, C~_3-alkyl, cyclopropyl, ethenyl, ethynyl,
hydroxy, C~_3-alkyloxy, difluoromethoxy or trifluoromethoxy group,
by the heteroaryl groups mentioned in the definitions of the above mentioned
groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,
benzothiophenyl, quinolinyl or isoquinolinyl group,
or a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two methyne
groups are replaced by nitrogen atoms,
or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl
group
wherein one to three methyne groups are replaced by nitrogen atoms,
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,
and, unless otherwise specified, 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.
Compounds of the above general formula I which contain one or more groups
that can be cleaved in vivo are so-called prodrugs.
The carboxy groups mentioned in the definition of the above mentioned
groups may be replaced by a group which can be converted into a carboxy

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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
above mentioned 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~_s-alkanol, a phenyl-C~_3-
alkanol,
a C3_9-cycloalkanol, while a C5_8-cycloalkanol may additionally be substituted
by one or two C,_3-alkyl groups, a C5_s-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-alkyloxycarbonyl or CZ~-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 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~_8-alkyl, C5_,-cycloalkyl, C~_8-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

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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~_s-alkylsulphonylamino,
phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino,
C~_s-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl,
benzylsulphonylaminocarbonyl or perfluoro-C~_s-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-alkyloxy groups, while the substituents may be
identical or different, a pyridinoyl group or a C~_~s-alkanoyl group such as
the
formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-
trichloropropionyl or allyloxycarbonyl group, a C~_~s-alkyloxycarbonyl or
C,_~s-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,
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~_s-alkyloxycarbonyl 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,_s-alkyl or C3_~-cycloalkyl groups and the substituents may
be identical or different, a C~_3-alkylsulphonyl-C2~-alkyloxycarbonyl,

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C~_3-alkyloxy-C2_4-alkyloxy-C2~-alkyloxycarbonyl, Rp-CO-O-(RqCRr)-O-CO,
C~_6-alkyl-CO-NH-(RSCR,)-O-CO or C~_6-alkyl-CO-O-(RSCRt)-(RSCRt)-O-CO
group, wherein RP to Rr are as hereinbefore defined,
RS and Rt, which may be identical or different, denote hydrogen atoms or
C~_3-alkyl groups.
Moreover, the saturated alkyl and alkyloxy moieties which contain more than
2 carbon atoms mentioned in the foregoing definitions and those that follow,
unless otherwise stated, also include the branched isomers thereof such as,
for example, the isopropyl, tert.butyl, isobutyl group, etc.
R2 for example in each case denotes a hydrogen atom, 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-(piperidino)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,
(pyrrolidinocarbonyl)methyl, (piperidinocarbonyl)methyl, (morpholinocarbonyl)-
methyl, 2-(aminocarbonyl)ethyl, 2-(methylaminocarbonyl)ethyl, 2-
(dimethylaminocarbonyl)ethyl, 2-(pyrrolidinocarbonyl)ethyl, 2-(piperidino-
carbonyl)ethyl, 2-(morpholinocarbonyl)ethyl, cyanomethyl or 2-cyanoethyl
group.

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R3 for example may denote a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-
methylpropyl, pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,
cyclopropylmethyl, (1-methylcyclopropyl)methyl, (2-methylcyclopropyl)methyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-(cyclopropyl)ethyl-,
2-propen-1-yl, 2-methyl-2-propen-1-yl, 3-phenyl-2-propen-1-yl, 2-buten-1-yl,
4,4,4-trifluoro-2-buten-1-yl, 3-buten-1-yl, 2-chloro-2-buten-1-yl, 2-bromo-2-
buten-1-yl, 3-chloro-2-buten-1-yl, 3-bromo-2-buten-1-yl, 2-methyl-2-buten-1-
yl,
3-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 3-trifluoromethyl-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-(1-cyclopenten-1-yl)ethyl, 2-propyn-1-
yl, 2-butyn-1-yl, 3-butyn-1-yl, phenyl, methylphenyl, benzyl, a fluorobenzyl,
chlorobenzyl, bromobenzyl, methylbenzyl, methoxybenzyl, 1-phenylethyl, 2-
phenylethyl, 3-phenylpropyl, 2-furanylmethyl, 3-furanylmethyl, 2-thienylmethyl
or 3-thienylmethyl group.
R4 for example may denote a 3-aminopyrrolidin-1-yl, 3-aminopiperidin-1-yl,
3-(methylamino)-piperidin-1-yl, 3-(ethylamino)-piperidin-1-yl,
3-(dimethylamino)-piperidin-1-yl, 3-(diethylamino)-piperidin-1-yl, 3-[(2-
hydroxyethyl)amino]-piperidin-1-yl, 3-[N-methyl-N-(2-hydroxyethyl)-amino]-
piperidin-1-yl, 3-((3-hydroxypropyl)amino]-piperidin-1-yl, 3-[N-methyl-N-(3-
hydroxypropyl)-amino]-piperidin-1-yl, 3-[(carboxymethyl)amino]-piperidin-1-yl,
3-[(methoxycarbonylmethyl)amino]-piperidin-1-yl,
3-[(ethoxycarbonylmethyl)amino]-piperidin-1-yl, 3-[N-methyl-N-
(methoxycarbonylmethyl)-amino]-piperidin-1-yl,
3-[N-methyl-N-(ethoxycarbonylmethyl)-amino]-piperidin-1-yl, 3-[(2-
carboxyethyl)amino]-piperidin-1-yl, 3-{[2-(methoxycarbonyl)ethyl]amino}-
piperidin-1-yl, 3-{[2-(ethoxycarbonyl)ethyl]amino}-piperidin-1-yl, 3-{N-methyl-
N-[2-(methoxycarbonyl)ethyl]-amino}-piperidin-1-yl, 3-{N-methyl-N-[2-
(ethoxycarbonyl)ethyl]-amino}-piperidin-1-yl, 3-[(aminocarbonylmethyl)amino]-
piperidin-1-yl, 3-[(methylaminocarbonylmethyl)amino]-piperidin-1-yl,
3-[(dimethylaminocarbonylmethyl)amino]-piperidin-1-yl,
3-[(ethylaminocarbonylmethyl)amino]-piperidin-1-yl,
3-[(diethylaminocarbonylmethyl)amino]-piperidin-1-yl, 3-[(pyrrolidin-1-

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ylcarbonylmethyl)amino]-piperidin-1-yl, 3-[(2-cyanopyrrolidin-1-
ylcarbonylmethyl)amino]-piperidin-1-yl,
3-[(4-cyanothiazolidin-3-ylcarbonylmethyl)amino]-piperidin-1-yl, 3-[(2-
aminocarbonylpyrrolidin-1-ylcarbonylmethyl)amino]-piperidin-1-yl, 3-[(2-
carboxypyrrolidin-1-ylcarbonylmethyl)amino]-piperidin-1-yl, 3-[(2-
methoxycarbonylpyrrolidin-1-ylcarbonylmethyl)amino]-piperidin-1-yl, 3-[(2-
ethoxycarbonylpyrrolidin-1-ylcarbonylmethyl)amino]-piperidin-1-yl,
3-[(piperidin-1-ylcarbonylmethyl)amino]-piperidin-1-yl,
3-[(morpholin-4-ylcarbonylmethyl)amino]-piperidin-1-yl, 3-amino-2-methyl-
piperidin-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,
2-amino-8-aza-bicyclo[3.2.1 ]oct-8-yl, 6-amino-2-aza-bicyclo[2.2.2]oct-2-yl,
4-aminopiperidin-1-yl, 3-amino-hexahydroazepin-1-yl, 4-amino-
hexahydroazepin-1-yl, piperazin-1-yl, [1,4]diazepan-1-yl, 3-aminocyclopentyl,
3-aminocyclohexyl, 3-(methylamino)-cyclohexyl, 3-(ethylamino)-cyclohexyl,
3-(dimethylamino)-cyclohexyl, 3-(diethylamino)-cyclohexyl,
4-aminocyclohexyl, (2-aminocyclopropyl)amino, (2-aminocyclobutyl)amino,
(3-aminocyclobutyl)amino, (2-aminocyclopentyl)amino, (3-amino-
cyclopentyl)amino, (2-aminocyclohexyl)amino or (3-aminocyclohexyl)amino
group.
Preferred compounds of the above general formula I are those wherein
R' denotes a methyl group substituted by a group Ra, where
Ra denotes a 1,4-dihydro-quinazolinyl or 3,4-dihydro-quinazolinyl
group,
a 3,4-dihydro-isoquinolinyl group,
a 1H-benzo[dj[1,2]oxazinyl or 1-oxo-1H-benzo[d][1,2]oxazinyl group,
a 4H-benzo[e][1,3]oxazinyl or 4-oxo-4H-benzo[e][1,3]oxazinyl group,

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a 4H-benzo[dJ[1,3]oxazinyl or 4-oxo-4H-benzo[d][1,3]oxazinyl group,
2H-benzo[1,4]oxazinyl or 2-oxo-2H-benzo[1,4]oxazinyl group,
a 4H-benzo[e][1,3]thiazinyl or 4-oxo-4H-benzo[e][1,3]thiazinyl group,
a 4H-benzo[dJ[1,3]thiazinyl or 2H-benzo[1,4]thiazinyl group,
a 2-oxo-2H-benzo[e][1,3]oxazinyl or 2,2-dioxo-1 H-benzo[c][1,2]thiazinyl
group,
a 2,3-dihydro-1H-benzo[e][1,4]diazepinyl or 2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepinyl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepinyl or 4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepinyl group,
a 5-oxo-4,5-dihydro-3H-benzo[eJ[1,4]diazepinyl group,
a 2,3-dihydro-benzo[t][1,4]oxazepinyl or 2,3-dihydro-
benzo[b][1,4]oxazepinyl group,
a 2,3-dihydro-benzo[t][1,4]thiazepinyl- 2,3-dihydro-
benzo[b][1,4]thiazepinyl group,
a 5-oxo-4,5-dihydro-benzo[~[1,3,4]oxadiazepinyl group,
an 11H-dibenzo[b,e]azepinyl or 11-oxo-11H-dibenzo[b,e]azepinyl
group,
an 11 H-benzo[e]pyrido[3,2-b]azepinyl group,

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a 5H-dibenzo[b,e][1,4]diazepinyl or dibenzo[b,f][1,4]oxazepinyl group,
a dibenzo[b,t][1,4]thiazepinyl, 5-oxo-dibenzo[b,t][1,4]thiazepinyl or 5,5-
dioxo-dibenzo[b,fJ[1,4]thiazepinyl group,
5H-dibenzo[a,d]cycloheptenyl or 5H-dibenzo[b,fJazepinyl group,
a phenanthridinyl, benzo[c][1,5]naphthyridinyl, benzo[h][1,6]naphthyri-
dinyl, benzo[c][1,8]naphthyridinyl or 1,2,3,4-tetrahydro-phenanthridinyl
group,
a benzo[fjquinoxalinyl group,
a 5H-dibenzo[d,t][1,3]diazepinyl, 5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepinyl or thieno[3,2-b][1,4]benzoxazepinyl group,
a 3-oxo-2,3-dihydro-isoindol-1-ylidene group,
a benzo[1,2,5]oxadiazolyl group,
a dibenzofuranyl group,
an indolizinyl group,
a 1 H-perimidinyl group,
a pyrazolo[1,5-c]quinazolinyl group or
an imidazo[2,1-a]isoquinolinyl or imidazo[1,2-a]isoquinolinyl group
while the benzo groups of the above-mentioned groups Ra are
substituted by the groups R'° to R'2 and the alkylene units of the
above-mentioned groups Ra may be substituted by one or two C1-s-

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alkyl or C~_3-alkyloxy-carbonyl groups, while the groups may be
identical or different, or by a trifluoromethyl group, and the imino groups
of the above-mentioned groups Ra may be substituted by a C,_3-alkyl
group and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a C~_3-alkyl or cyclopropyl group,
a hydroxy, C~_3-alkyloxy or cyclopropyloxy group,
a nitro, amino, C,_3-alkylamino or di-(C~_3-alkyl)amino group,
a C~_3-alkyl-carbonylamino or C~_3-alkyl-sulphonylamino group,
a cyano, carboxy, C~_3-alkyloxy-carbonyl, aminocarbonyl, C~_3-
alkyl-aminocarbonyl or di-(C,_3-alkyl)-aminocarbonyl group,
a mercapto, C~_3-alkylsulphanyl, C~_3-alkylsulphinyl or C~_3-
alkylsulphonyl or aminosulphonyl group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or
trifluoromethoxy group and
R" and R'2, which may be identical or different, in each case
represent a hydrogen atom, a fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl or methoxy group,
RZ denotes a hydrogen atom,
a C,_3-alkyl group,

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a C3_6-cycloalkyl group or
a phenyl group optionally mono- or disubstituted by a fluorine, chlorine,
bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C~_3-
alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy, C~_3-alkyloxy, difluoromethoxy
or
trifluoromethoxy group, while the substituents may be identical or different,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
while, unless otherwise stated, the above-mentioned alkyl groups may be
straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
Particularly preferred compounds of the above general formula I are those
wherein
R' denotes a methyl group substituted by a group Ra, where
Ra denotes a 1,4-dihydro-quinazolin-2-yl or 3,4-dihydro-quinazolin-2-yl
group,

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a 3,4-dihydro-isoquinolin-1-yl group,
a 1 H-benzo[dJ[1,2]oxazin-4-yl or 1-oxo-1 H-benzo[d][1,2]oxazin-4-yl
group,
a 4H-benzo[e][1,3]oxazin-2-yl or4-oxo-4H-benzo[e][1,3]oxazin-2-yl
group,
a 4H-benzo[d][1,3]oxazin-2-yl or 4-oxo-4H-benzo[d][1,3]oxazin-2-yl
group,
2H-benzo[1,4]oxazin-3-yl or 2-oxo-2H-benzo[1,4]oxazin-3-yl group,
a 4H-benzo[e][1,3]thiazin-2-yl or 4-oxo-4H-benzo[e][1,3]thiazin-2-yl
group,
a 4H-benzo[dJ[1,3]thiazin-2-yl or 2H-benzo[1,4]thiazin-3-yl group,
a 2-oxo-2H-benzo[e][1,3]oxazin-4-yl or 2,2-dioxo-1H-benzo[c][1,2]thia-
zin-4-yl group,
a 2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl or2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepin-5-yl group,
a 4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl or 4-oxo-4, 5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl group,
a 5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-yl group,
a 2,3-dihydro-benzo[t][1,4]oxazepin-5-yl or 2,3-dihydro-benzo[b]-
[1,4]oxazepin-4-yl group,

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a 2,3-dihydro-benzo[t][1,4]thiazepin-5-yl or 2,3-dihydro-benzo[b]-
[1,4]thiazepin-4-yl group,
a 5-oxo-4,5-dihydro-benzo[t](1,3,4]oxadiazepin-2-yl group,
an 11H-dibenzo[b,ejazepin-6-yl or 11-oxo-11H-dibenzo[b,e]azepin-6-yl
group,
an 11H-benzo[e]pyrido[3,2-b]azepin-6-yl group
a 5H-dibenzo[b,e][1,4]diazepin-11-yl or dibenzo[b,t][1,4]oxazepin-11-yl
group,
a dibenzo[b,t](1,4]thiazepin-11-yl, 5-oxo-dibenzo[b,t][1,4]thiazepin-11-yl
or 5,5-dioxo-dibenzo[b,t][1,4]thiazepin-11-yl group,
a 5H-dibenzo[a,djcyclohepten-10-yl or 5H-dibenzo[b,t]azepin-10-yl
group,
a phenanthridin-6-yl, benzo[cj[1,5]naphthyridin-6-yl, benzo[h][1,6]naph-
thyridin-5-yl, benzo[c][1,8]naphthyridin-6-yl or 1,2,3,4-tetrahydro-
phenanthridin-6-yl group,
a benzo[t]quinoxalin-6-yl group,
a 5H-dibenzo[d,~[1,3]diazepin-6-yl, 5H-benzo[e]pyrrolo[1,2-
a][1,4jdiazepin-11-yl or thieno[3,2-b][1,4]benzoxazepinyl-9-yl group,
a 3-oxo-2,3-dihydro-isoindol-1-ylidene group,
a benzo[1,2,5]oxadiazol-5-yl group,
a dibenzofuran-2-yl group,

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an indolizin-2-yl group,
a 1 H-perimidin-2-yl group,
a pyrazolo[1,5-c]quinazolin-5-yl group or
an imidazo[2,1-a]isoquinolin-2-yl or imidazo[1,2-a]isoquinolin-2-yl group
while the benzo groups of the above-mentioned groups Ra are
substituted by the groups R'° to R'Z and the alkylene units of the
above-mentioned groups Ra may be substituted by one or two methyl-
or methoxy-carbonyl groups, while the groups may be identical or
different, or by a trifluoromethyl group and the imino groups of the
above-mentioned groups Ra may be substituted by a methyl group and
R'° denotes a hydrogen atom,
a fluorine, chlorine, bromine or iodine atom,
a methyl or ethyl group,
a hydroxy, methoxy or ethoxy group or
a difluoromethyl, trifluoromethyl, difluoromethoxy or
trifluoromethoxy group and
R" and R'2, which may be identical or different, each represent
a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl,
trifluoromethyl or methoxy group,
R2 denotes a hydrogen atom or

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a methyl, ethyl, propyl, isopropyl, phenyl or cyclopropyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-ylmethyl group
and
R4 denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
Most particularly preferred compounds of the above general formula I are
those wherein
R' denotes a 3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-ylmethyl
group,
a 1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4-ylmethyl group,
a 2,3-dihydro-benzo[tJ[1,4]oxazepin-5-ylmethyl group,
a 2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-ylmethyl group,
a phenanthridin-6-ylmethyl or 1,2,3,4-tetrahydro-phenanthridin-6-ylmethyl
group,
an 11H-dibenzo[b,e]azepin-6-ylmethyl group,
a dibenzo[b,fJ[1,4]oxazepin-11-ylmethyl group,

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a 3-oxo-2,3-dihydro-isoindol-1-ylidenemethyl group,
a 3-trifluoromethyl-3,4-dihydro-isoquinolin-1-ylmethyl group,
a 3,4-dihydro-quinazolin-2-ylmethyl group,
a 5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylmethyl group,
an 8-methyl-dibenzo[b,tj[1,4]oxazepin-11-ylmethyl group,
a benzo[1,2,5]oxadiazol-5-ylmethyl group,
an 8-methyl-phenanthridin-6-ylmethyl group,
a 1-methyl-phenanthridin-6-ylmethyl group,
a 4-methyl-phenanthridin-6-ylmethyl group,
a benzo[h][1,6]naphthyridin-5-ylmethyl group,
a pyrazolo(1,5-c]quinazolin-5-yl group,
a benzo[c][1,8]naphthyridin-6-ylmethyl group,
a benzo[c][1,5]naphthyridin-6-ylmethyl group,
a 1H-perimidin-2-ylmethyl group,
a benzo[f]quinoxalin-6-ylmethyl group or
an imidazo[2,1-a]isoquinolin-2-ylmethyl or imidazo[1,2-a]isoquinolin-2-
ylmethyl group,

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R2 denotes a methyl or cycfopropyf group,
R3 denotes a 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2-butyn-1-yl group
and
R' denotes a (3-amino-piperidin-1-yl) group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
The following compounds of general formula I are particularly preferred:
(1) 1-[(1-methyl-2,2-dioxo-1H-benzo[cJ[1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(2) 1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(3) 1-[(2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)methyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(4) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine,
(5) 1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-
8-(3-amino-piperidin-1-yl)-xanthine,
(6) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yf)-xanthine,

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(7) 1-[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(8) 1-[(3-trifluoromethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(9) 1-[(dibenzo[b,tJ[1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine,
(10) 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(11) 1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(12) 1-[(8-methyl-dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(13) 1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(14) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine,
(15) 1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(16) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-
piperidin-1-yl)-xanthine ,
(17) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine,

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(18) 1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine,
(19) 1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine,
(20) 1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(21) 1-((pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(22) 1-[(benzo[c][1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(23) 1-[(benzo(c][1,5]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine,
(24) 1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine,
(25) 1-[(benzo[fJquinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine,
(26) 1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(27) 1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(28) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine,

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(29) 1-[(2,3-dihydro-benzo[tJ[1,4]oxazepin-5-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-8-(3-amino-piperidin-1-yl)-xanthine and
(30) 1-[(3-oxo-2,3-dihydro-isoindol-1-ylidene)methyl]-3-methyl-7-(3-methyl-2-
buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
and the salts thereof.
According to the invention the compounds of general formula I are obtained
by methods known per se, for example by the following methods:
a) Deprotecting a compound of general formula
~3
R~'~N I ~N
/ Ra"
O N N
Rz
(ll),
wherein R', R2 and R3 are as hereinbefore defined and
R4~' denotes one of the groups mentioned for R4 hereinbefore which contain
an imino, amino or alkylamino group, white the imino, amino or alkylamino
group is substituted by a protective group.
The liberating of an amino group from a protected precursor is a standard
reaction in synthetic organic chemistry. There are many examples of suitable
protective groups. A summary of the chemistry of protective groups can be
found in Theodora W. Greene and Peter G. M. Wuts, Protective Groups in
Organic Synthesis, Second Edition, 1991, published by John Wiley and Sons,
and in Philip J. Kocienski, Protecting Groups, published by Georg Thieme,
1994.

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The following are examples of protective groups:
the tert.-butyloxycarbonyl group which can be cleaved by treating with an acid
such as for example 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
diethylether at temperatures between 0°C and 80°C,
the 2,2,2-trichloroethoxycarbonyl group which can be cleaved by treating with
metals such as for example zinc or cadmium in a solvent such as acetic acid
or a mixture of tetrahydrofuran and a weak aqueous acid at temperatures
between 0°C and the boiling temperature of the solvent used and
the carbobenzyloxycarbonyl group which can be cleaved for example by
hydrogenolysis in the presence of a noble metal catalyst such as for example
palladium-charcoal and a solvent such as for example alcohols, ethyl acetate,
dioxane, tetrahydrofuran or mixtures of these solvents at temperatures
between 0°C and the boiling point of the solvent, by treating with
boron
tribromide in methylene chloride at temperatures between -20°C and
ambient
temperature, or by treating with aluminium chloride/anisol at temperatures
between 0°C and ambient temperature.
b) Deprotecting and cyclising a compound of general formula
~3
N NN
~~R4,~
HN~X O O N N
PG
R2
(III),
wherein R2 and R3 are as hereinbefore defined,

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R4~' denotes one of the groups mentioned for R4 hereinbefore which contain
an imino, amino or alkyiamino group, while the imino, amino or alkylamino
group is substituted by one of the above-mentioned protective groups,
X denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or an imino
group substituted by RX, and
the -CHZ-CH2-X-phenyl unit is substituted by R'° to R'4 and may
additionally
be substituted by a C,_3-alkyl group,
while RX and R'° to R'4 are as hereinbefore defined, and
PG also denotes one of the above-mentioned protective groups,
while the two protective groups may be cleaved simultaneously or one after
the other (cf. Example 2).
c) In order to prepare a compound of general formula I wherein R' denotes a
3-oxo-2,3-dihydro-isoindol-1-ylidenemethyl group optionally substituted by a
group as defined in claims 1 to 4:
Deprotecting and dehydrating a compound of general formula
O R3
O I~H
N N
NR ~ ~ ~~R4,~
N N
O
R2
(IV),
wherein the benzo group is substituted by R'° to R'4,
and R'° to R'a as well as Rx, RZ and R3 are as hereinbefore defined,
and
R4~' denotes one of the groups mentioned for R4 hereinbefore which contain
an imino, amino or alkylamino group, while the imino, amino or alkylamino
group is substituted by one of the above-mentioned protective groups and
the dehydration is carried out under the same reaction conditions as the
cleaving of the protective group (cf. Example 3).
Moreover, the compounds of general formula I obtained may be resolved into
their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for

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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 cis/trans mixtures may be resolved by chromatography
into the cis and trans isomers thereof, 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
Interscience, 1971 ) into their optical antipodes 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 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 active substance which forms racemic salts or derivatives
such as e.g. esters or amides of an optically active substance, 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 suitable agents.
Optically active acids in common use are e.g. the D- and L-forms of tartaric
acid or dibenzoyltartaric acid, di-O-p-toluoyltartaric 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 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

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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.
The compounds of general formulae II, III and IV used as starting materials
are either known from the literature in some cases or may be obtained by
methods known from the literature (cf. Examples I to XV).
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 a test set-up in which an extract of 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 as described 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, pages 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 centrifuging at 35,000 g for 30 minutes at
4°C
(to remove cell debris).

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The DPP-IV assay was carried out as follows:
50 pl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final
concentration 100 NM, 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 adding 30 NI of solubilised Caco-
2 protein (final concentration 0.14 Ng of protein per well). The test
substances
to be investigated were typically added prediluted in 20 NI, and the volume of
assay buffer was then reduced accordingly. The reaction was carried out at
ambient temperature, incubating for 60 minutes. Then the fluorescence was
measured in a Victor 1420 Multilabel Counter, the excitation wavelength being
405 nm and the emission wavelength being 535 nm. Blank readings
(corresponding to 0 % activity) were obtained in mixtures without any Caco-2
protein (volume replaced by assay buffer), control values (corresponding to
100 % activity) were obtained in mixtures with no substance added. The
potency of the test substances in question, expressed as IC5o values, was
calculated from dosage/activity curves consisting of 11 measuring points in
each case. The following results were obtained:
Compound DPP IV inhibition
(Example Nr.) lCSO [nM]
1 13
1(1) 32
1(2) 6
1(3) 5
1(4) 5
1 (7) 11
1(8) 4
1 (10) 8
1 (12) 14
1(15) 11
1 (20) 10
1 (25) 7

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1 (26~
1 (27) 2
1 (28) 2
1 (29) 3
1 (30) 3
1 (32)
1 (33)
2 6
3 20
The compounds prepared according to the invention are well tolerated, as for
example when 10 mg/kg of the compound of Example 1 (2) were administered
to rats by oral route no changes in the animals' behaviour could be detected.
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 treating all those conditions or
illnesses which can be influenced 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, metabolic
acidosis
or ketosis, insulin resistance, dyslipidaemias of various origins, arthritis,
atherosclerosis and related diseases, obesity, allograft transplantation and
calcitonin-induced osteoporosis. In addition these substances are capable of
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 also increasing the number and size of
pancreatic B-cells. Additionally, and 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 likely that the compounds according to the invention are
suitable for achieving, inter alia, a sedative or anxiety-relieving effect and
also
of favourably affecting catabolic states after operations or hormonal stress
responses or of reducing mortality or morbidity after myocardial infarct. They

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are also suitable for treating all conditions which are connected with the
above
mentioned effects and which are 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 renal
failure. They are also suitable for the prevention and treatment of chronic
inflammatory intestinal diseases. It is also expected that DPP-IV inhibitors
and
hence also the compounds according to the invention may be used to treat
infertility or to improve fertility in humans or mammals, particularly when
the
infertility is connected with insulin resistance or polycystic ovary syndrome.
The substances are also suitable for treating deficiencies of growth hormone
which are associated with reduced stature.
The compounds according to the invention may also be used in conjunction
with other active substances. Therapeutic agents which are suitable for such
combinations include, for example, antidiabetics, such as metformin,
sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride), nateglinide,
repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma
agonists (e.g. GI 262570), alpha-glucosidase inhibitors (e.g. acarbose,
voglibose), alpha2 antagonists, insulin and insulin analogues, GLP-1 and
GLP-1 analogues (e.g. exendin-4) or amylin. Also, 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, cholesterol
absorption inhibitors such as for example ezetimibe, bile acid-binding
substances such as for example cholestyramine, 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, or f33-agonists such as SB-418790 or AD-9677.

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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, 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 a day. For this purpose, the
compounds of formula l 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,
polyvinylpyrrofidone, 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:
Examale I
1-[(1-methyl-2,2-dioxo-1 H-benzo[c][1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-
xanthine
A mixture of 260 mg of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy-
carbonylamino)-piperidin-1-yl]-xanthine, 185 mg of 4-bromo-methyl-1-methyl-
1 H-benzo[c][1,2]thiazine-2,2-dioxide and 550 mg of potassium carbonate in 4
ml N,N-dimethylformamide is stirred for about 40 h at ambient temperature.
As no reaction of any note can be detected by thin layer chromatography, the
mixture is heated to 60° C for 2 h and then stirred for another 15 h at
50°C
until the reaction is virtually complete. Then 30 ml of water are added, the
precipitate formed is suction filtered and dried. The crude product is
purified
by chromatography over a silica gel column with petroleum ether/ethyl acetate
(1:1) as eluant.
Yield: 225 mg of (59 % of theory)
Rf value: 0.19 (silica gel, petroleum ether/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 640 [M+H]+
The following compounds are obtained analogously to Example I:
(1) 1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-
methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-
xanthine
Rf value: 0.42 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 95:5)
Mass spectrum (ESI+): m/z = 632 [M+H]+
(2) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-
xanthine
Mass spectrum (ESI+): m/z = 445, 447 [M+H]+

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(3) 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-
1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
(carried out in N-methylpyrrolidin-2-one at 60°C)
Rfvalue: 0.35 (silica gel, methylene chloride/methanol = 20:1)
Mass spectrum (ESI+): m/z = 623 [M+H]+
(4) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-
xanthine
Mass spectrum (ESI+): m/z = 462, 464 [M+H]+
(5) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rr value: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 608 (M+H]+
(6) 1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-
8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
R, value: 0.55 (silica gel, ethyl acetate/ petroleum ether = 2:1 )
Mass spectrum (ESI+): m/z = 612 [M+H]+
(7) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 622 [M+H]+
(8) 1-[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.70 (silica gel, ethyl acetate/cyclohexane = 3:1 )
Mass spectrum (ESI+): m/z = 624 [M+H]+
(9) 1-[(3-trifluoromethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)- 8-(3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

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Rf value: 0.60 (aluminium oxide, petroleum ether/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 628 [M+H]+
(10) 1-[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.75 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 624 [M+H]+
(11) 1-[(3,3-dimethyl-3,4-dihydro-isoquinoiin-1-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.50 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 588 [M+H]+
(12) 1-[(methoxycarbonyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Mass spectrum (ESI+): m/z = 489 [M+H]+
(13) 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-(3-(tert.-butyloxycarbonyl-
amino)-piperidin-1-yl]-xanthine
Mass spectrum (ESI+): m/z = 456 [M+H]+
(14) 1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 637 [M+H]+
(15) 1-[(8-methyl-dibenzo[b,tJ[1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 638 [M+H]+
(16) 1-[(2-methyl-dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

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Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 638 [M+H]+
(17) 1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.73 (silica gel, methylene chloride/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 549 [M+H]+
(18) 1-[(2-chloro-dibenzo[b,tj[1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 658, 660 [M+H]+
(19) 1-((phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.55 (silica gel, methylene chloride/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 634 [M+H]+
(20) 1-((8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.67 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 622 [M+H]+
(21) 1-((phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 608 (M+H]+
(22) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 634 [M+H]+

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(23) 1-[(dibenzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 597 [M+H]+
(24) 1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-
3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.80 (silica gel, methylene chloride/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 622 [M+H]+
(25) 1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-
3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 622 [M+H]+
(26) 1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.54 (silica gel, methylene chloride/methanol = 94:6)
Mass spectrum (ESI+): m/z = 609 (M+H]+
(27) 1-[(pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
R, value: 0.67 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 598 [M+H]+
(28) 1-[(benzo[c](1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 609 [M+H]+
(29) 1-[(benzo[c][1,5]naphthyridin-6-yl)methylJ-3-methyl-7-(2-butyn-1-yl)-8-
[(R)-3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5)

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Mass spectrum (ESI+): m/z = 609 [M+H]+
(30) 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-
amino)-piperidin-1-yl]-xanthine
Rf value: 0.80 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 456 [M+H]+
(31) 1-[(benzo[f)quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 609 [M+H]+
(32) 1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-ylJ-xanthine
Rf value: 0.47 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESl+): m/z = 597 [M+H]+
(33) 1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.14 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 597 [M+H]+
(34) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 608 [M+H]+
Example II
4-Bromo-methyl-1-methyl-1 H-benzoL]f 1.2]thiazin-2.2-dioxide
390 mg of 1,4-dimethyl-1 H-benzo[c][1,2]thiazin-2,2-dioxide in 20 ml 1,2-
dichloroethane are combined with 332 mg of N-bromosuccinimide and 50 mg
of 2,2'-azodiisobutyronitrile. The yellow solution is refluxed for a total of
10 h
and then left to stand for another two days at ambient temperature. The

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reaction mixture is distributed between water and methylene chloride, the
organic phase is washed with water, dried over magnesium sulphate and
evaporated down. A yellowish resin is left which is purified through a silica
gel
column with petroleum ether/ethyl acetate (5:1 to 4:1 ) as eluant. A mixture
of
4-bromo-methyl-1-methyl-1 H-benzo[c][1,2]thiazin-2,2-dioxide and 3-bromo-
1,4-dimethyl-1H-benzo[c][1,2]thiazin-2,2-dioxide is obtained, which is further
reacted as it is.
Yield: 190 mg (35 % of theory)
Mass spectrum (ESI+): m/z = 288, 290 [M+H]+
The following compounds are obtained analogously to Example II:
(1) 5-bromomethyl-benzo[h][1,6]naphthyridine
Rf value: 0.76 (silica gel, ethyl acetate/petroleum ether = 1:1 )
Mass spectrum (ESI+): m/z = 273, 275 [M+H]+
(2) 6-chloromethyl-benzo[c][1,8]naphthyridine
(carried out with N-chlorosuccinimide in the presence of benzoyl peroxide in
carbon tetrachloride)
Rf value: 0.47 (silica gel, ethyl acetate/methanol = 98:2)
(3) 6-bromomethyl-benzo[c][1,5]naphthyridine
(carried out in the presence of benzoyl peroxide in carbon tetrachloride)
Rf value: 0.64 (silica gel, ethyl acetate/petroleum ether = 1:2)
Mass spectrum (ESI+): m/z = 273, 275 [M+H]+
(4) 6-bromomethyl-benzo[tjquinoxaline
(carried out in the presence of benzoyl peroxide in carbon tetrachloride)
Rf value: 0.33 (silica gel, ethyl acetate/petroleum ether = 1:5)
Mass spectrum (ESI+): m/z = 273, 275 [M+H]+

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Example III
3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-
piperidin-1-yll-xanthine
A mixture of 20.50 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine,
13.64 g of 3-tert.-butyloxycarbonylamino-piperidine and 20.27 g of potassium
carbonate in 100 ml dimethylsulphoxide is stirred for 4 h at 115°C.
Then a
further 2.50 g of 3-tert.-butyloxycarbonylamino-piperidine are added and the
reaction mixture is stirred for a further 2 h at 115°C. The cooled
reaction
solution is poured onto 1 I of ice water, the precipitate formed is suction
filtered, washed with water and dried.
Rf value: 0.60 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 433 [M+H]+
The following compounds are obtained analogously to Example 111:
(1) 3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-
yl]-
xanthine
melting point: 235-237°C
Mass spectrum (ESI+): m/z = 417 [M+H]+
(2) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Mass spectrum (ESI+): m/z = 551 [M+H]+
(3) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:2)
Mass spectrum (ESI+): m/z = 582 [M+H]+
(4) 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-
1-yl]-xanthine
Mass spectrum (ESI+): m/z = 417 [M+H]+

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(5) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-
piperidin-1-yl]-xanthine
Rf value: 0.70 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 443 [M+H]+
(6) 3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonyl-amino)-
piperidin-
1-yl]-xanthine
Rf value: 0.73 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 417 [M+H]+
(7) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-amino)-
piperidin-1-yl]-xanthine
Rf value: 0.35 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 443 [M+H]+
(8) 1-[(indolizin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Rf value: 0.29 (silica gel, petroleum ether/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 546 [M+H]+
Example IV
3-methyl-7-(3-methyl-2-buten-1-yl~-8-bromo-xanthine
15.37 ml of Hunig base and 9.98 ml of 3,3-dimethylallylbromide are added to
20.00 g of 3-methyl-8-bromo-xanthine in 200 ml of N,N-dimethylformamide.
The reaction mixture is stirred for about half an hour at ambient temperature
and then diluted with 500 ml of water. The precipitate formed is suction
filtered, washed with water and dried.
Yield: 20.50 g (80 % of theory)
Mass spectrum (ESI+): m/z = 313, 315 [M+H]+
The following compounds are obtained analogously to Example IV:

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(1) 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine
Rf value: 0.72 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 297, 299 [M+H]+
(2) 3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine
Mass spectrum (ESI+): m/z = 299, 301 [M+H]+
(3) 3-cyclopropyl-7-(2-butyn-1-yl)-8-bromo-xanthine
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 323, 325 [M+H]+
Example V
Methyl 1-chloromethyl-3-methyl-3,4-dihydro-isoq_uinolin-3-yl-carboxylate
Prepared from methyl 2-(2-chloro-acetylamino)-2-methyl-3-phenyl-propionate
analogously to Das et al., Indian J. Chem. 1985, 248, 1302.
Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate = 2:1 )
Mass spectrum (ESI+): m/z = 252, 254 [M+H]+
Example VI
1-(2-{2-[2-(tert.-butyloxycarbonylamino)-ethoxy]-phenyl}-2-oxo-ethyl)-3-
methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-
xanthine
187 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added to 400 mg of 1-[2-
(2-hyd roxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine and 150 mg of potassium
carbonate in 6 ml N,N-dimethylformamide and the reaction mixture is stirred
overnight at 55°C. Then a further 90 mg of tert.-butyl 2-bromo-ethyl-
carbaminate are added. After another eight hours at 55°C the reaction
is
complete. The cooled reaction mixture is combined with water, the precipitate
formed is suction filtered, washed with water and dried.
Yield: 368 mg (73 % of theory)

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Mass spectrum (ESI+): m/z = 694 [M+H]+
Example VII
1-[2-(2-hyd roxy-phenyl )-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-
xanthine
Prepared by treating 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-
butyn-1-yl)-8-bromo-xanthine with boron tribromide in the presence of 4A
molecular sieve in methylene chloride at 4°C.
Mass spectrum (ESI+): m/z = 431, 433 [M+H]+
Examale VIII
1-[(1-hydroxy-3-oxo-2,3-dihydro-1 H-isoindol-1-yl)methyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-
xanthine
A mixture of 250 mg of 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-pi perid in-1-yl]-
xanthine, 404 mg of ammonium carbonate, 135 mg of O-(benzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium-tetrafluoroborate, 57 mg of
hydroxybenzotriazole and 59 pl of triethylamine in 3 ml of tetrahydrofuran is
stirred for eight hours at ambient temperature. For working up the reaction
mixture is diluted with 30 ml of ethyl acetate and washed with 10 % citric
acid
solution, 10 % potassium carbonate solution and saturated sodium chloride
solution. The organic phase is evaporated down and chromatographed
through a silica gel column with methylene chloride/methanol (98:2 to 80:20).
The cyclised compound is obtained as the main product.
Yield: 160 mg (64 % of theory)
R, value: 0.40 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 594 [M+H]+

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Examale IX
1-[2-(2-ca rboxy-phenyl )-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1-yll-xanthine
A mixture of 2.60 g of 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-
(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-
xanthine and 8 ml of 3 N sodium hydroxide solution in 25 ml of methanol is
stirred for two hours at ambient temperature. For working up the reaction
mixture is neutralised with 24 ml of 1 N hydrochloric acid, acidified slightly
by
the addition of 20 ml of 10 % citric acid solution and extracted with ethyl
acetate. The combined extracts are washed with saturated sodium chloride
solution, dried over magnesium sulphate and evaporated down.
Yield: 2.00 g (80 % of theory)
Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI~): m/z = 593 [M-H]~
The following compound is obtained analogously to Example IX:
(1) 1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-
amino)-piperidin-1-yl]-xanthine
(The ester cleaving is carried out with 4 M potassium hydroxide solution in a
mixture of methanol and tetrahydrofuran.)
Mass spectrum (ESI-): m/z = 473 [M-H]-
Example X
1-[(2-oxo-2, 3-dihydro-1 H-benzo[e][ 1,4]diazepin-5-yl)methyl]-3-methyl-7-((E)-
2-
buten-1-yl)-8-((R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yll-xanthine
A mixture of 200 mg of 1-{2-[2-(2-chloro-acetylamino)-phenyl]-2-oxo-ethyl}-3-
methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-
yl]-xanthine, 5 ml of conc. ammonia, 2 ml of tetrahydrofuran and 2 ml of
methanol is stirred at ambient temperature for about a week. Then the dark
reaction mixture is added to a pack of 14 g of Extrelut and after 20 minutes
washed out thoroughly with methylene chloride. The filtrate is evaporated

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down and chromatographed through a silica gel column with ethyl
acetate/methanol (10:0 to 8:2) as eluant.
Yield: 95 mg (51 % of theory)
Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate = 2:8)
Example XI
1-{2-[2-(2-ch loro-acetyl amino)-phenyl]-2-oxo-ethyl}-3-methyl-7-((E)-2-buten-
1-
Y~-8-f(R)-3-(tert.-butylox carbonylamino)-piperidin-1~r11-xanthine
51 NI of bromoacetyl chloride are added to 319 mg of 1-[2-(2-amino-phenyl)-2-
oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-
amino)-piperidin-1-yl]-xanthine and 60 NI pyridine in 1 ml methylene chloride.
The reaction mixture is stirred for two hours at 35°C and after
cooling to
ambient temperature, combined with 0.5 M citric acid. The organic phase is
separated off and the aqueous phase is extracted with methylene chloride.
The combined organic phases are evaporated down and chromatographed
through a silica gel column with cyclohexane/ethyl acetate (6:4) as eluant.
Yield: 210 mg (58 % of theory)
Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/isopropanol = 14:3:3)
Mass spectrum (ESI+): m/z = 628, 630 [M+H]+
The following compounds are obtained analogously to Example XI:
(1) N-(1-benzyl-2,2,2-trifluoro-ethyl)-2-chloro-acetamide
(The reaction is carried out with chloroacetyl chloride in diethyl ether in
the
presence of triethylamine).
R, value: 0.45 (aluminium oxide, petroleum ether/ethyl acetate = 5:1 )
Mass spectrum (ESI+): m/z = 266 [M+H]+
(2) 2-chloro-N-(4-methyl-biphenyl-2-yl)-acetamide
(The reaction is carried out with chloroacetyl chloride in the presence of
diisopropylethylamine. )
Rf value: 0.82 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 260, 262 [M+H]+

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(3) 2-chloro-N-(6-methyl-biphenyl-2-yl)-acetamide
(The reaction is carried out with chloroacetyl chloride in the presence of
diisopropylethylamine. )
R, value: 0.60 (silica gel, cyclohexane/ethyl acetate = 3:1)
Mass spectrum (ESI+): m/z = 260, 262 (M+H]+
(4) 2-chloro-N-(3-methyl-biphenyl-2-yl)-acetamide
(The reaction is carried out with chloroacetyl chloride in the presence of
diisopropylethylamine.)
Rf value: 0.45 (silica gel, cyclohexane/ethyl acetate = 3:1)
Example XII
1-[2-(2-a m i no-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Prepared by reduction of 6.34 g 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-
xanthine with 5.15 g iron powder in a mixture of 260 ml of ethanol, 85 ml of
water and 33 ml glacial acetic acid at reflux temperature.
Yield: 5.38 g (90 % of theory)
Mass spectrum (ESI+): m/z = 552 [M+H]+
Example XIII
6-chloromethvl-1 2 3 4-tetrahydro-phenanthridine-hydrochloride
Prepared by treating 110 mg of 6-hydroxymethyl-1,2,3,4-tetrahydro-
phenanthridine with 60 NI of thionyl chloride in 2.5 ml methylene chloride at
0°C to ambient temperature.
Yield: 140 mg (100 % of theory)
Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 5:1 )
Mass spectrum (ESI+): m/z = 232, 234 [M+H]+

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Example XIV
6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine
A solution of 350 mg of ethyl 1,2,3,4-tetrahydro-phenanthridin-6-yl-
carboxylate
in 10 ml of tetrahydrofuran is added dropwise within five minutes to a
suspension of 37 mg of lithium borohydride in 15 ml of tetrahydrofuran, while
cooling with an ice bath. Then the ice bath is removed and the reaction
mixture is stirred for a further 2.5 hours at ambient temperature. For working
up, 2 ml of 1 M citric acid are added to the brown reaction solution while
cooling with an ice bath. The mixture is stirred with 100 ml of ethyl acetate
and 50 ml of water and adjusted to pH 10 with 4 N sodium hydroxide solution.
The organic phase is separated off, washed with water, dried over
magnesium sulphate and evaporated down. The flask residue is
chromatographed through a silica gel column with ethyl acetate/petroleum
ether (1:4 to 1:1) as eluant.
Yield: 120 mg (41 % of theory)
R, value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1 )
Mass spectrum (ESI+): m/z = 214 [M+H]+
Example XV
Ethvl 1.2,3,4-tetrahydro-ahenanthridin-6-vl-carboxylate
Analogously to the method described by Gonsalves et al. (Tetrahedron 1992,
48, 6821) a solution of 3.90 g of ethyl 5,6,7,8-tetrahydro-
benzo[1,2,4]triazine-
3-carboxylate (Sagi et al., Heterocycles 1989, 29, 2253) is refluxed in 20 ml
of dioxane. Then 8.22 g anthranilic acid and 7.02 g isoamyl nitrite, in each
case dissolved in 20 ml dioxane, are simultaneously added dropwise within 25
minutes using two dropping funnels. The reaction mixture is refluxed for a
further 30 minutes. For working up the cooled dark brown reaction solution is
diluted with 150 ml diethyl ether, washed with 100 ml of 2 N sodium hydroxide
solution and with water, dried over magnesium sulphate and evaporated
down. The brown, oily flask residue is chromatographed through a silica gel
column with ethyl acetate/petroleum ether (20:80 to 50:50) as eluant. The

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product obtained is still somewhat contaminated but is further reacted without
any further purification.
Yield: 380 mg (8 % of theory)
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:1 )
Mass spectrum (ESI+): m/z = 256 [M+H]+
Example XVI
1-chloromethyl-3-trifluoromethvl-3,4-dihvdro-isoauinoline
0.74 ml of phosphorus oxychloride and 530 mg of N-(1-benzyl-2,2,2-trifluoro-
ethyl)-2-chloro-acetamide are added to 4.00 g of warm polyphosphoric acid
and the viscous reaction mixture is stirred for 1.5 h at 130°C. After
cooling to
ambient temperature the reaction mixture is stirred with ice water and suction
filtered. The filter cake is dissolved in ethyl acetate, the solution is dried
over
magnesium sulphate and evaporated down. A white solid is left.
Yield: 415 mg (84 % of theory)
Rf value: 0.55 (aluminium oxide, petroleum ether/ethyl acetate = 10:1 )
Mass spectrum (ESI+): m/z = 248, 250 [M+H]+
Example XVII
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yll-xanthine
A mixture of 280 mg of 1-(2-(2-amino-benzylamino)-2-oxo-ethyl]-3-methyl-7-
(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
and
4 ml glacial acetic acid is heated to boiling for two hours. Then the reaction
mixture is evaporated down and the flask residue is purified through a column
of aluminium oxide (activity stage III) with methylene chloride/ethyl
acetate/methanol (5:5:0 to 5:4:1 ) as eluant. In addition to the desired 1-
[(3,4-
dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, deprotected 1-[(3,4-dihydro-
quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-
xanthine is also obtained.

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Yield: 120 mg (44 % of theory)
Mass spectrum (ESI+): m/z = 561 [M+H]+
Example XVIII
1-[2-(2-ami no-benzylami no)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-
but~ycarbonyl-amino)-piperidin-1-~1-xanthine
A mixture of 397 mg of 1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, 110 mg of 2-amino-
benzylamine and 460 pl of diisopropylethylamine in 3 ml of N,N-
dimethylformamide is combined with 272 mg of (benzotriazol-1-yl)-N-
tetramethyl-uronium-tetrafluoroborate and stirred for two hours at ambient
temperature. Then the reaction mixture is evaporated down, the residue is
triturated with 15 ml 1 M sodium hydroxide solution and suction filtered. The
filter cake is washed with a little ethanol and diethyl ether and dried.
Yield: 400 mg (83 % of theory)
Rf value: 0.68 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 579 [M+H]+
Example XIX
1-((3-methyl-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
I3-(tert.-butylox~carbon rLl-amino)-piperidin-1-yl]-xanthine
0.5 ml of 1 M sodium methoxide solution are added to 400 mg of 1-
cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-
piperidin-1-yl]-xanthine in 5 ml of methanol. The reaction mixture is stirred
for
two hours at ambient temperature, then a further 150 NI of 1 M sodium
methoxide solution are added. After another two hours the reaction to form
the iminoester is complete and the reaction mixture is neutralised with 1 M
acetic acid in methanol. Then a solution of 130 mg of 2-methylaminomethyl-
phenylamine in 3 ml of methanol is added and the reaction mixture is refluxed
for three hours. Then the methanol is distilled off and the residue is stirred
with water, suction filtered and dried.
Yield: 250 mg (50 % of theory)

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Mass spectrum (ESI+): m/z = 575 [M+H]+
The following compound is obtained analogously to Example XIX:
(1) 1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
Mass spectrum (ESI+): m/z = 597 [M+H]+
Example XX
3-Cyclopropyl-8-bromo-xanthine
1.08 ml bromine are slowly added dropwise to a mixture of 3.67 g of 3-
cyclopropyl-xanthine and 3.40 g potassium carbonate in 60 ml acetonitrile at
an oil bath temperature of 60 °C. The reaction mixture is stirred for
six hours
at this temperature, then a further 100 NI bromine are added. After another
three hours the acetonitrile is distilled off in vacuo and the residue is
dissolved
in 100 ml of water. Then 10 ml of saturated sodium thiosulphate solution are
added and the mixture is extracted with ethyl acetate. The aqueous phase is
acidified with 1 M hydrochloric acid, whereupon a fine precipitate is formed.
The precipitate is suction filtered, washed with water and diethyl ether and
dried at 80°C in the circulating air dryer.
Yield: 3.36 g (65 % of theory)
Rf value: 0.65 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 271, 273 [M+H]+
Example XXI
6-Chloromethvl-8-methyl-phenanthridine
600 g of 2-chloro-N-(4'-methyl-biphenyl-2-yl)-acetamide are heated in 3 ml
phosphorus oxychloride to 100 °C for about 6 hours. Then the phosphorus
oxychloride is distilled off. The residue is suspended in water and ethyl

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acetate and neutralised with 3 M sodium hydroxide solution while cooling with
an ice bath. The aqueous phase is extracted with ethyl acetate and the
combined organic phases are washed with saturated sodium chloride
solution, dried over magnesium sulphate and evaporated down. The residue
is triturated with diisopropylether, suction filtered and dried.
Yield: 160 mg (29 % of theory)
Rf value: 0.45 (silica gel, cyclohexane/ethyl acetate = 1:1 )
Mass spectrum (ESI+): m/z = 242, 244 [M+H]+
The following compounds are obtained analogously to Example XXI:
(1) 6-chloromethyl-1-methyl-phenanthridine
Mass spectrum (ESI+): m/z = 242, 244 [M+H]+
(2) 6-chloromethyl-4-methyl-phenanthridine
Mass spectrum (ESI+): m/z = 242, 244 [M+H]+
Example XXII
1-f(indolizin-2-yllmethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine
0.61 ml of diisopropyl azodicarboxylate are added to a mixture of 594 mg of 3
methyl-7-(2-butyn-1-yl)-8-bromo-xanthine, 353 mg of (indolizin-2-yl)-methanol
and 826 mg of triphenylphosphine in 30 ml of tetrahydrofuran. The reaction
mixture is stirred for two hours at ambient temperature. For working up it is
diluted with methylene chloride, added to 6 g silica gel and chromatographed
through a silica gel column with petroleum ether/ethyl acetate (7:3 to 1:5) as
eluant.
Yield: 405 mg (48 % of theory)
Rf value: 0.62 (silica gel, petroleum ether/ethyl acetate = 1:1)
Mass spectrum (ESI+): m/z = 426, 428 [M+H]+

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Example XXIII
6 Methyl benzol'clf 1 8lnaphthyridine
8.7 ml glycerol and 4.38 g 3-amino-1-methyl-isoquinoline are added to a
mixture of 960 mg of iron(11)sulphate-heptahydrate, 12.00 g of 3-nitro-
benzosulphonic acid sodium salt, 15 ml of conc. sulphuric acid and 1.70 g of
boric acid while cooling in the ice bath. The viscous, sticky mass is heated
to
approx. 55°C, combined with 15 ml of water and then stirred for three
hours at
140°C. The cooled reaction mixture is diluted with some ice, made
alkaline
with 15 N sodium hydroxide solution white cooling with an ice bath and
extracted with methylene chloride. The combined organic phases are washed
with saturated sodium chloride solution, dried over magnesium sulphate and
evaporated down. The flask residue is chromatographed through a silica gel
column with ethyl acetate/methanol (99:1 to 94:6) as eluant. The crude
product thus obtained is stirred with tert.-butylmethylether and some ethyl
acetate, suction filtered and dried.
Yield: 2.05 g (38 % of theory)
Rf value: 0.15 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 195 [M+H]+
The following compound is obtained analogously to Example XXIII:
(1) 6-methyl-benzo[c][1,5]naphthyridine
Rr value: 0.52 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 195 [M+H]+
Example XXIV
6-methyl-benzoLJf puinoxaline
170 mg of 4-methyl-naphthalene-1,2-diamine and 114 Nl of glyoxal are stirred
in a mixture of 2 ml of water and 2 ml of ethanol for half an hour at
75°C. For
working up the cooled reaction mixture is diluted with methylene chloride and
water. The organic phase is washed with saturated sodium chloride solution,
dried over magnesium sulphate and evaporated down. The crude product is

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purified by chromatography over a silica gel column with methylene
chloride/methanol (100:0 to 99:1) as eluant.
Yield: 140 mg (73 % of theory)
R, value: 0.84 (silica gel, ethyl acetate)
Mass spectrum (ESI+): m/z = 195 [M+H]+
Example XXV
2-chloromethyl-imidazo[2,1-alisoquinoline
1.47 g of 1-amino-isoquinoline and 635 mg of 1,3-dichloroacetone are
refluxed for one hour in 10 ml acetonitrile. For working up the reaction
mixture
is combined with methanol, added to approx. 5 g silica gel and
chromatographed through a silica gel column with methylene
chloride/methanol (98:2 to 96:4) as eluant.
Yield: 420 mg (39 % of theory)
Rf value: 0.65 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 217, 219 [M+H]+
The following compound is obtained analogously to Example XXV:
(1) 2-chloromethyl-imidazo[1,2-a]isoquinoline
Rf value: 0.64 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 217, 219 [M+H]+

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Preparation of the final compounds:
Example 1
o /
O
.N .N I N~N
/ \ O~N N
I NHZ
1-[( 1-methyl-2,2-dioxo-1 H-benzo[c][1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
3.5 ml isopropanolic hydrochloric acid (5-6 M) are added to 340 mg of 1-[(1-
methyl-2, 2-dioxo-1 H-benzo[c][1,2]thiazin-4-yl)methyl]-3-methyl-7-(3-methyl-2-
buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 15
ml
methylene chloride and the reaction mixture is stirred for three hours at
ambient temperature. For working up it is diluted with water and methylene
chloride and combined with 18 ml 1 N sodium hydroxide solution. The
aqueous phase is extracted with methylene chloride and the combined
organic phases are washed with water, dried over magnesium sulphate and
evaporated down. The yellowish, foamy flask residue is stirred with tert.-
butyl-
methylether and a little diethyl ether, the light-coloured precipitate formed
is
suction filtered and dried at 60°C in the drying gun.
Yield: 220 mg (77 % of theory)
melting point: 205-208°C (decomposition)
Mass spectrum (ESI+): m/z = 540 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) 1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
o-
0
N O
N N
~~ N
O~ N ~''~N
I N HZ

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Rf value: 0.42 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 532 [M+H]+
(2) 1-[(2-oxo-2,3-dihydro-1H-benzo[e][1,4)diazepin-5-yl)methyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine
H O
N
/N O
N N
O~N I N~N
( NHz
(carried out with trifluoroacetic acid in methylene chloride)
R, value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:0.1 )
Mass spectrum (ESI+): m/z = 491 [M+H]+
(3) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine-dihydrochloride
I
i
I
I ~ ~N O
N
N
z ~~-N~--~
O N N
NHz x 2 HCI
Rf value: 0.55 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 508 [M+H]+

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(4) 1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-8-(3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid
N O
N
~ ~ I ~~-N
O N N
I NHz x CF3COOH
(carried out with trifluoroacetic acid in methylene chloride)
Rf value: 0.75 (aluminium oxide, methylene chloride/methanol = 10:1 )
Mass spectrum (ESI+): m/z = 512 [M+H]+
(5) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
I ~ o
N N
I ~~--N
N p~N N
I NHz
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 522 [M+H]+
(6) 1-[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
I~ o
N N
1 ~ I i~ N
O N O~N N
I NHz
Mass spectrum (ESI+): m/z = 524 [M+H]+

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(7) 1-[(3-trifluoromethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid
F
F F
N O
_ ~N N
I N~ N~--
O~N
I NHZ x CF3COOH
(carried out with trifluoroacetic acid in methylene chloride)
Rf value: 0.30 (silica gel, methylene chloride/methanol = 10:1 )
Mass spectrum (ESI+): m/z = 528 [M+H]+
(8) 1-[(dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine
0
N N
O N O~N N
1 I ~~-N
I NHz
Mass spectrum (ESI+): m/z = 524 [M+H]+
melting point: 128°C
(9) 1-[(3,3-dimethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
N O
~N N
I ~~ N
O~N '~N
NHZ
R, value: 0.55 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 488 [M+H]+

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(10) 1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
H O
N~N N
I I ~~N'-(
I N p~N N
I NHZ
(carried out with trifluoroacetic acid in methylene chloride)
Mass spectrum (ESI+): m/z = 461 [M+H]+
(11) 1-[(3-methyl-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-
yl)-8-(3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid
I o
N~N N
I N O~N N
I I ~~-N '--
I NHz x CF3COOH
(carried out with trifluoroacetic acid in methylene chloride)
Mass spectrum (ESI+): m/z = 475 (M+H]+
(12) 1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
/ 1
N O
\ I N ~ I N~N
O N N
I NHZ
Rf value: 0.45 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 537 [M+H]+

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(13) 1-[(8-methyl-dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
0
O N
N ~ I i~ N \
O N N
I NHZ
Rf value: 0.60 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI'): m/z = 538 [M+H]+
(14) 1-[(2-methyl-dibenzo[b,tj[1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
0
O / N N
i N ~ I i~ N
O N N
I NHz
R, value: 0.55 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 538 [M+H]+
(15) 1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
0
O I /~ N
,N, / ~ N
O N
I NHz
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 449 [M+H]+

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(16) 1-[(2-chloro-dibenzo[b,t][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
CI
o
O N
N ~ I i~ N
O N N
I NHZ
Rf value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 558, 560 [M+H]+
(17) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3-amino-
piperidin-1-yl)-xanthine
~N
O
N N
/~-N
O~N N
NHZ
Rf value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 534 [M+H]+
(18) 1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
I~ o
i~ N N
~ /~-N
I ~ N p i 'N N
I NHZ
melting point: 200-205°C
Mass spectrum (ESI+): m/z = 522 [M+H]+

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(19) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-
piperidin-1-yl)-xanthine
I
~N O
N N
O~N ~ ~~N~
N
I ~NHZ
Rf value: 0.55 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 508 [M+H]+
(20) 1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine
i
i
i ~N O
N
O~N~ /~N~
~N
NHZ
Rf value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI+): m/z = 534 [M+H]+
(21) 1-[(dibenzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine

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li li o
N N
/~' N
O~N N
I NHZ
Rf value: 0.40 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 497 [M+H]+
(22) 1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine
i
I _
~N O
N \
O~N~ /~N~
~.~(~N
I NHZ
R, value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 522 [M+HJ+
(23) 1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-
3-amino-piperidin-1-yl)-xanthine
w
i
I
~N O
N
N
~. z /~-N~
O N N
I NHz
Rf value: 0.40 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 522 [M+H]+

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(24) 1-[(indolizin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-
1-
yl)-xanthine
O
N ~ N N
O~N~ ~~N~
N
I NHz
Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 446 [M+H]+
(25) 1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
I~ O i
N ~ N N
~ N ~ I ~~ N
~N
( / O N NHz
Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): mlz = 509 [M+H]+
(26) 1-[(pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
-N O
\ N~N N
w N O~N N
I I />-N
I NHz
Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 498 [M+H]+

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(27) 1-[(benzo[c][1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
N N O i
N
~N
I ~~ N,
/ ~ O~ i NN
NH2
Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 509 [M+H]+
(28) 1-[(benzo[c][1,5]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
((R)-3-amino-piperidin-1-yl)-xanthine
~I o
N
~~-N,
N' I N O N ~N
I NHz
Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 509 [M+H]+
(29) 1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine
O
N~N N \
N ~ I i~ N,
~N
0 N NHz
Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 497 [M+H]+

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(30) 1-[(benzo[t]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-
amino-piperidin-1-yl)-xanthine
o ~.~_-
N
/~--N
N O N N
I NHZ
Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 509 [M+H]+
(31) 1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
O
I N~ N
O N
I NH2
Rf value: 0.54 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 497 [M+H]+
(32) 1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
o r=_--
N
N~ N \ >
/~-N
,N O~N N
I NHZ
melting point: 194-198.5°C
Mass spectrum (ESI+): m/z = 497 [M+H]+

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(33) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
piperidin-1-yl)-xanthine
i
I I
/N O
N
N \
O~N~ /~N~
~('N
I NHz
Rf value: 0.55 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1 )
Mass spectrum (ESI+): m/z = 508 [M+H]+
Example 2
\ ~ _
NO i
N N
~ y--N
O "N N
I NHz
1-[(2,3-dihydro-benzo[tJ[1,4]oxazepin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
(3-amino-piperidin-1-yl)-xanthine
1.15 ml trifluoroacetic acid are added to 368 mg of 1-(2-{2-[2-(tert.-
butyloxycarbonylamino)-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-
yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-ylj-xanthine in 7 ml
methylene chloride while cooling with an ice bath. The reaction mixture is
stirred for about three hours at ambient temperature and then added to cooled
potassium carbonate solution. The organic phase is washed with saturated
sodium chloride solution, dried over magnesium sulphate and evaporated
down. The crude product is purified through a silica gel column with
methylene chloride/methanol (10:0 to 7:3) as eluant.
Yield: 75 mg (30 % of theory)
Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1 )
Mass spectrum (ESI+): m/z = 476 [M+HJ+

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Example 3
o /
\ i N N
~ ~~-N
O H O "N N
( NHz
1-[(3-oxo-2,3-dihydro-isoindol-1-ylidene)methyl]-3-methyl-7-(3-methyl-2-
buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
150 mg of 1-[(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)methyl]-3-methyl-
7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-
xanthine are stirred for four hours in a mixture of 0.4 ml trifluoroacetic
acid
and 1.2 ml methylene chloride. For working up the reaction mixture is diluted
with 30 ml methylene chloride, combined with 10 ml 10 % potassium
carbonate solution and stirred vigorously. The organic phase is separated off,
dried over magnesium sulphate and evaporated down.
Yield: 50 mg (42 % of theory)
Rf value: 0.56 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI+): m/z = 476 [M+H]+

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The following compounds may also be obtained analogously to the foregoing
Examples and other methods known from the literature:
No. Name Structural formula
1-[(1-methyl-1,4-dihydro-quinazolin-2- ~ N o
(1) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- ' ~ N N ~~ N~N
O~N~N
amino-plpendln-1-yl)-xanthine I NHz
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3- ~ N o
(2) methyl-7-(2-butyn-1-yl)-8-(3-amino- I -~ NH N~ ~I N~-N
p~N~N
plpendln-1-yl)-xanthme ~ NH
z
1-[(3-methyl-3,4-dihydro-quinazolin-2- ( o
N N
(3) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- ~~ ~ ,~--N
p N N
amino-piperidin-1-yl)-xanthine ~ ~ ~ NH
z
1-[(3,4-dihydro-isoquinolin-1-y1)methyl]-3- N o
(4) methyl-7-(2-butyn-1-yl)-8-(3-amino- \ N N
piperidin-1-yl)-xanthine o ~ N NH
z
P
N O ~ NHz
1-[(3,3-dimethyl-3,4-dihydro-isoquinolin-1- N N
(5) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- ! ~ ~ ~~N~
amino-piperidin-1-yl)-xanthine ~ / o N N
1-[(4,4-dimethyl-3,4-dihydro-isoquinolin-1- N o
(6) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- N ~ N~--N
amino-piperidin-1-yl)-xanthine ~'/ o~N N NH
z

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1-[(1H-benzo[dJ[1,2]oxazin-4-yl)methyl]-3- o-N o
(7) methyl-7-(2-butyn-1-yl)-8-(3-amino- \ N
/ \ ~ I ~~N~
piperidin-1-yl)-xanthine o i N
NHZ
1-[(1-oxo-1H-benzo[d][1,2]oxazin-4- o-N o
O N
(8) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
/ \ ~ ~ ~~-N
amino-piperidin-1-yl)-xanthine o i N
NHZ
1-[(4H-benzo[e][1,3]oxazin-2-yl)methyl]-3- o /-
O~
(9) methyl-7-(2-butyn-1-yl)-8-(3-amino- I ~ IN N ( N~-N
piperidin-1-yl)-xanthine o~N N
I NHZ
O
1-[(4,4-dimethyl-4H-benzo[e][1,3]oxazin- o
(10) 2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- I ~ ~~ I N~--N
O N N
(3-amino-piperidin-1-yl)-xanthine ~ I NHZ
1-[(4-oxo-4H-benzo[e][1,3]oxazin-2- o
0
(11) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- I ~ ~~ I N>--N
O N
amino-piperidin-1-yl)-xanthine ~ N
O I NHZ
O
1-[(4H-benzo[dJ[1,3]oxazin-2-yl)methyl]-3- ~ N\
(12) methyl-7-(2-butyn-1-yl)-8-(3-amino- I ~ ~N I ~N
O~N N
piperidin-1-yl)-xanthine ~ NHz
1-[(4,4-dimethyl-4H-benzo[dJ[1,3]oxazin- o
N
(13) 2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- I ~ ~~ I N~-N
(3-amino-piperidin-1-yl)-xanthine ~ o N N
I NHZ
1-[(4-oxo-4H-benzo[c~[1,3]oxazin-2- o
N
(14) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- I ~ ~~ I N~--N
aml o N N
no-pipendin-1-yl)-xanthine o I NHZ

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1-[(2H-benzo[1,4]oxazin-3-yl)methyl]-3- o
N N
(15) methyl-7-(2-butyn-1-yl)-8-(3-amino- I ~ ~~ I ~~--N
piperidin-1-yl)-xanthine o o N N
I NHz
1-[(2-oxo-2H-benzo[1,4]oxazin-3- o 0
(16) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- o~N ~ N N
amino-piperidin-1-yl)-xanthine I N o~N~N
\ ~ NHZ
1-[(2,2-dimethyl-2H-benzo[1,4]oxazin-3- ~ o
17 I meth I - - _ o II N N
( ) y ) y ] 3 methyl-7-(2-butyn 1-yl)-8-(3- N ~ ~ ,~N
amino-piperidin-1-yl)-xanthine ~ I o j N ~ H
z
o
1-[4H-benzo[e][1,3]thiazin-2-yl)methyl]-3-
(18) methyl-7-(2-butyn-1-yl)-8-(3-amino- ~ ~ S~NI I ,~-N
N o~N N
piperidin-1-yl)-xanthine I
NH2
1-[4,4-dimethyl-4H-benzo[e][1,3]thiazin-2- o
S N
(19) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- I \ ~ N ' >
~~--N
amino-piperidin-1-yl)-xanthine ~ N O~N N
I N HZ
1-[4-oxo-4H-benzo[e][ 1, 3]thiazin-2- o
(20) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- I j S j~~ I NON
amino-piperidin-1-yl)-xanthine ~ o N N
p I NHZ
1-[(4H-benzo[dJ[1,3]thiazin-2-yl)methyl]-3- o
N
(21) methyl-7-(2-butyn-1-yl)-8-(3-amino- I \ ~N I N~--N
- ~s
piperidm-1-yl) xanthlne o N N
I NHZ
1-[(2H-benzo[1,4]thiazin-3-yl)methyl]-3- o
(22) methyl-7-(2-butyn-1-yl)-8-(3-amino- I ,~N
\ N~~ N
piperidin-1-yl)-xanthine ~ S o N N
I NHz

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O
1-[(2-oxo-2H-benzo[e][1,3]oxazin-4- ~N o
(23) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- ~ ~ N I N~--N
amino- i eridin-1- I -xanthine o~N~N
PP Y)
NHZ
1-[(2,3-dihydro-1H-benzo[e][1,4]diazepin- ~ ~ o
N
(24) 5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- HN ~N ~ ~ N~--N
(3-amino-piperidin-1-yl)-xanthine U o N N
I N HZ
1-[(1-methyl-2,3-dihydro-1H- I ~ o
(25) benzo[a][1,4]diazepin-5-yl)methylJ-3- ~ 1 N
N I ~~ N
methyl-7-(2-butyn-1-yl)-8-(3-ammo- ~N~N O~N
N
piperidin-1-yl)-xanthine I NHZ
1-[(1-methyl-2-oxo-2,3-dihydro-1H- I ~ o
(26) benzo[a][1,4]diazepin-5-yl)methyl]-3- ~ 1 N N
methyl-7-(2-butyn-1-yl)-8-(3-amino- ~ ~ N~--N
rN~N O%\N
piperidin-1-yl)-xanthine O I NHZ
1-[(4-oxo-4, 5-dihydro-3H- p
benzo[b][1,4]diazepin-2-yl)methyl]-3- ~'
(27) meth I-7- 2-but n-1- I -8- 3- mi ~ / N\ ~ I NON
Y ( Y Y) ( a no- O N N
piperidin-1-yl)-xanthine H O I NHZ
1-[(5-methyl-4-oxo-4, 5-d ihydro-3H- p
(2$) benzo[b][1,4]diazepin-2-yl)methyl]-3- ~ ~ N~ N N N
meth I-7= 2-but n-1- I -8- 3-amino-
Y ( Y Y) ( N O N N
piperidin-1-yl)-xanthine ~ p ~ NHZ
1-[5-oxo-4, 5-di hyd ro-3H- O
9 benzo[a][1,4]diazepin-2-yl)methyl]-3- ~ N N
( ) methyl-7-(2-butyn-1-yl)-8-(3-amino- ~ ~ ~~ ~ NON
O N
piperidin-1-yl)-xanthine O H ( NHZ

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1-[4-methyl-5-oxo-4, 5-d ihyd ro-3H- p
(30) benzo[a][1,4]diazepin-2-yl)methyl]-3- \ /
meth I-7- 2-but n-1- I -8- 3-amino- N~~ N N
Y ( Y Y) ( O
N N
piperidin-1-yl)-xanthine p \ I NHz
1-[(3, 3-d i methyl-2, 3-d i hyd ro-
benzo[fJ[1,4]oxazepin-5-yl)methyl]-3- N o
N
(31) methyl-7-(2-butyn-1-yl)-8-(3-amino- p - ~ ~ ~~N~
'-~N
piperidin-1-yl)-xanthine \ / p N NHZ
1-[(2,2-dimethyl-2,3-dihydro- ~N O
(32) benzo[tj[1,4]oxazepin-5-yl)methyl]-3- 'p~' ~ N I NON
methyl-7-(2-butyn-1-yl)-8-(3-amino- ~ / p~~N~N
piperidin-1-yl)-xanthine \ I NHz
1-[(2,3-dihydro-benzo[b][1,4]oxazepin-4- p
N~ ~ N
(33) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- \ / \ ~ ,~-N
amino-piperidin-1-yl)-xanthine O 0 N N
I NHz
1-[(6, 6-d imethyl-2, 3-d i hyd ro- p
34 benzo[b][1,4]oxazepin-4-yl)methyl]-3- ~N~ N N
\ \ i
( ) methyl-7-(2-butyn-1-yl)-8-(3-amino- / p~N I NON
piperidin-1-yl)-xanthine p I NHz
1-[(2,3-dihydro-benzo[b][1,4]thiazepin-4- p
N~ N N
(35) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- \ / ~ ~ ,~-N
amino-piperidin-1-yl)-xanthine S p N N
I NHz
1-[(2,2-dimethyl-2,3-dihydro- p
36 benzo[b][1,4]thiazepin-4-yl)methyl]-3- ~ N~ N N
( ) meth I-7- 2-but n-1- I -8- 3-amino- \ / ~ ~ ~~N
Y ( Y Y) ( S O N N
piperidin-1-yl)-xanthine ( NHZ

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1-[(2,3-dihydro-benzo[t][1,4]thiazepin-5- ~ ~ o
N N
(37) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- S I ~ ,~N~
~--~ N 0 i 'N N
amino-piperidin-1-yl)-xanthine
I NHZ
1-[(5-oxo-4, 5-d ihyd ro- o
38 benzo[tj[1,3,4]oxadiazepin-2-yl)methyl]-3- \ ~ o~N N
( ) methyl-7-(2-butyn-1-yl)-8-(3-amino- 'IIN o~N I NON
piperidin-1-yl)-xanthine o H I ~--~NHz
1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]- ~ ~ o
(39) 3-ethyl-7-(2-butyn-1-yl)-8-(3-amino- ~~~ ~ i~-N
piperidin-1-yl)-xanthine - o ~ N
\ / NHz
1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]- ~ ~ o
N
(40) 3-isopropyl-7-(2-butyn-1-yl)-8-(3-amino- l~~ I i~--N
piperidin-1-yl)-xanthine -- o N N
\ / NHZ
I \ o
1-[(11-oxo-11H-dibenzo[b,e]azepin-6- ~ _ N
(41) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- o N ~ ~ ~~N~
O N N
amino-piperidin-1-yl)-xanthine \ ~ I NHZ
1-[(11H-benzo[e]pyrido[3,2-b]azepin-6- I ~ o
(42) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- IN ~ ~ ~~N
N
amino-piperidin-1-yl)-xanthine N - O N NHZ
\ /
1-[(5-methyl-5H- I ~ o
(43) dibenzo[b,a][1,4]diazepin-11-yl)methyl]-3- N~ ~ N ~ N~-N
methyl-7-(2-butyn-1-yl)-8-(3-amino- _ N O~N N
I NHz
piperidin-1-yl)-xanthine \ /

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I\ o
1-[(dibenzo[b,t][1,4]thiazepin-11-
(44) yl)meth I -3-meth I-7- 2-but n-1- I -8- 3 N
v ) y ( v v > ( - s 'N ~ I N~ N
O N
amino-piperidin-1-yl)-xanthine \ ~ I NHz
I\ O =
1-[(5-oxo-dibenzo[b,tJ[1,4]thiazepin-11- ~ N
(45) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- O:S 'N O~N~ ~~N~
\N
amino-piperidin-1-yl)-xanthine \ ~ I NHZ
I\ O =
1-[(5,5-dioxo-dibenzo[b,t][1,4]thiazepin- ~ N
(46) 11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- o~g ~N o~N~ ~~N~
''~~N
(3-amino-piperidin-1-yl)-xanthine o~ \ ~ I NHZ
I\ O
1-[(5H-dibenzo[a,dJcyclohepten-10- ~ _ N
(47) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- 1 o~N~ ~~-N\
'~N
amino-pipendin-1-yl)-xanthine \ ~ I NHZ
I\ o
1-[(5-methyl-5H-dibenzo[b,t]azepin-10- ~ N
(48) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- .N 1 O~N~N~N
amino-piperidin-1-yl)-xanthine - I ~--~NHz
\ /
1-[(phenanthridin-6-yl)methyl]-3-methyl-7- I I
i ~N O
(49) (3-methyl-2-buten-1-yl)-8-(3-amino-
N N
piperidin-1-yl)-xanthine \ >
/~-N
O~N N
I N Hz

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i
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-
0
(50) ((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-
yl)-xanthine N ~ N N
O~N N
I NH2
w
1-[(phenanthridin-6-yl)methyl]-3-methyl-7- ~
(51) ((Z)-2-buten-1-yl)-8-(3-amino-piperidin-1- ~ o
yl)-xanthine N ~ N N
O~N N
N HZ
w
1-[(phenanthridin-6-yl)methyl]-3-methyl-7- ~ I
/ ~N O
(52) [(1-cyclopenten-1-yl)methyl]-8-(3-amino-
piperidin-1-yl)-xanthine N N N
O~N N
I NHZ
1 benzo c 1,5 na hth ridin-6- I meth I ~ \ o N
-[( [ 1[ ] p Y Y ) Y ]-
(53) 3-methyl-7-(2-butyn-1-yl)-8-(3-amino- ~ \ \N I ~~-N
. . ~ N O ~ N~ '---~N
pipendin-1-yl)-xanthine N~ I NHZ
O
1-[(5H-dibenzo[d,t][1,3]diazepin-6-
N
(54) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- \ / ~~ ~ ~~N
O N N
amino-piperidin-1-yl)-xanthine ~ I NH2
1-[(5H-benzo[e]pyrrolo[1,2- / ~ p
(55) a][1,4]diazepin-11-yl)methyl]-3-methyl-7- N I N ( NON
(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)- ._ N O~'N N
xanthine ~ / I NHz

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1-[(thieno[3,2-b][1,4]benzoxazepin-9- ~ \ o
(56) yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3- o N N I N~-N
~N N
amino-piperidin-1-yl)-xanthine o
\ S ~ NHz
O i
I \ N N
1-[(3,4=dihydro-quinazolin-2=yl)methyl]-3- ~ NH ~ I ~~N
(57) phenyl 7 (2 butyn 1 yl) 8 (3 amino- o N N
NHz
piperidin-1-yl)-xanthine
~I
N O i
1-[(3,4-dihydro-isoquinolin-1-yl)methyl]-3- ~ \ ~N I N
N
(58) phenyl-7-(2-butyn-1-yl)-8-(3-amino- o~'N N ~--(~
NHz
piperidin-1-yl)-xanthine
I
I\ o
1-[(2,3-dihydro-benzo[f][1,4]oxazepin-5- ~ 1 N N
~ ~~N~
(59) yl)methyl]-3-phenyl-7-(2-butyn-1-yl)-8-(3- O~N O!\N NN
amino-piperidin-1-yl)-xanthine ~ I NH2
H O
N
1-[(2-oxo-2,3-dihydro-1 H- \. ~ ' N o
benzo[a][1,4]diazepin-5-yl)methyl]-3-
N
(60) phenyl-7-(2-butyn-1-yl)-8-(3-amino- ~ ( N~--N~
piperidin-1-yl)-xanthine o N NH2
i I

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Example 4
Coated tablets containing 75 mg of active substance
1 tablet core contains:
active substance 75.0 mg
calcium phosphate 93.0 mg
corn starch 35.5 mg
polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose15.0 mg
magnesium stearate 1.5 mp
230.0 mg
Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvin-
ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of
magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-
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.

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Example 5
Tablets containing 100 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 m4
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.
Example 6
Tablets containing 150 mq 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
polyvinylpyrrolidone10.0 mg
magnesium stearate 1.0 mp
300.0 mg

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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
Example 7
Hard gelatine capsules containing 150 m4 of active substance
1 capsule contains:
active substance 150.0 mg
corn starch (dried) approx. 80.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 mp
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.

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89
Example 8
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 monostearate840.0 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.
Example 9
Suspension containing 50 mgi 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

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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 10
Ampoules containing 10 m~ active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 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 2 ml
ampoules.
Example 11
Ampoules containing 50 mg of active substance
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.

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