DERIVES DE XANTHINE, LEUR PRODUCTION ET LEUR UTILISATION COMME MEDICAMENTS

PHENACYL XANTHINE DERIVATIVES AS DPP-IV INHIBITOR

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 1, ainsi que les tautomères, stéréoisomères, mélanges, promédicaments et sels de celles-ci. Ces composés possèdent des propriétés pharmacologiques avantageuses, notamment un effet inhibiteur sur l'activité de l'enzyme dipeptidyl peptidase IV (DPP-IV).

Abrégé anglais

The invention concerns substituted xanthines of general formula (I), wherein:
R1 to R4 are such as defined in Claim 1, and tautomers, stereoisomers,
mixtures, prodrugs and salts thereof. Said compounds have advantageous
pharmacological properties, in particular an inhibiting effect on the activity
of the dipeptidyl peptidase IV (DPP-IV) enzyme.

Revendications

46
Claims
1. Compounds of general formula
<IMG>
wherein
R1 denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by R10 and R11, where
R10 denotes a formylamino group,
a C3-7-cycloalkyl-carbonylamino or C3-7-cycloalkyl-C1-3-alkyl-carbonyl-
amino group,
a C6-9-bicycloalkyl-carbonylamino or C6-9-bicycloalkyl-C1-3-alkyl-
carbonylamino group,
a C5-7-cycloalkyl-carbonylamino group wherein
a methylene group is replaced by an oxygen or sulphur atom or
by an imino, sulphinyl or sulphonyl group,
a C5-7-cycloalkyl-carbonylamino group wherein a -CH2-CH2 group is
replaced by a -NH-CO or-NH-NH group,

47
a C5-7-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2 group
is replaced by a -NH-CO-NH, -NH-CO-O or-O-CH2-O group,
a C6-7-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2-CH2
group is replaced by a -NH-CH2-CH2-NH, -NH-CO-CH2-NH, -NH-CH2-
CH2-O, -NH-CO-CH2-O or-O-CH2-CH2-O group,
a cycloheptyl-carbonylamino group wherein a -CH2-CH2-CH2-CH2-CH2
group is replaced by a -NH-CH2-CH2-CH2-NH, -NH-CO-CH2-CH2-NH,
-NH-CH2-CH2-CH2-O, -NH-CO-CH2-CH2-O or-O-CH2-CH2-CH2-O
group,
a C5-7-cycloalkyl-carbonylamino group wherein one or two methylene
groups are replaced by carbonyl groups,
a C4-7-cycloalkenyl-carbonylamino or C4-7-cycloalkenyl-C1-3-alkyl-
carbonylamino group,
a C3-7-cycloalkyl-sulphonylamino, C3-7-cycloalkyl-C1-3-alkyl-
sulphonylamino, arylsulphonylamino or aryl-C1-3-alkyl-sulphonylamino
group or
a heteroarylcarbonylamino group,
while the imino groups contained in the above mentioned groups may
be substituted independently of one another by a C1-3-alkyl group,
and R11 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom
or
a C1-3-alkyl, C1-3-alkyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy or cyano group,
R2 denotes a hydrogen atom,

48
a C1-6-alkyl group,
a C2-4-alkenyl group,
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-D-C1-3-alkyl group, while D 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 a, where

49
R a denotes a cyano, carboxy, C1-3-alkyloxy-carbonyl, aminocarbonyl,
C1-3-alkylamino-carbonyl, di-(C1-3-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 C2-4-alkyl group substituted by a group R b, where
R b 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
skeleton by at least two carbon atoms,
R3 denotes a C3-8-alkyl group,
a C1-3-alkyl group substituted by a group R c, where
R c 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 each be substituted 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,

50
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 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 5 position by a hydroxy or methoxy group,
a 3-amino-piperidin-1-yl group wherein the methylene group in the 2 position
or 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, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, wherein in each case

51
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,
this bridge containing 2 to 5 carbon atoms if the two hydrogen atoms are on
the same carbon atom, or 1 to 4 carbon atoms if the hydrogen atoms are on
adjacent carbon atoms, or 1 to 4 carbon atoms if the hydrogen atoms are on
carbon atoms which are separated by one atom, or 1 to 3 carbon atoms if the
hydrogen atoms are 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 in the 6 position by an amino group,
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,
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,

52
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,
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-(C1-3-alkyl)amino-C1-3-alkyl group,

53
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,
where 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,
an R19-C3-4-alkyl group wherein the C3-4-alkyl moiety is straight-chained and
may additionally be substituted by one or two C1-3-alkyl groups, where R19 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, 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,

54
piperidin-3-yl-C1-2-alkyl, piperidin-4-yl or piperidin-4-yl-C1-2-alkyl group,
while
the abovementioned 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 R h
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,
or a 1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-
oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-
pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-
pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-
pyrazinyl, 2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-
oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-
quinolinyl, 1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl, 1,4-
dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl, 3,4-dihydro-4-oxo-
quinazolinyl, 1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl, 1,2-dihydro-2-
oxoquinoxalinyl, 1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl, 1,2-dihydro-1-oxo-
phthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl,

55
2,3-dihydro-benzo[1,4]dioxinyl or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl
group,
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 stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the
prodrugs thereof and the salts thereof.
2. Compounds of general formula I according to claim 1, wherein
R1, R2 and R3 are defined as in claim 1 and
R4 denotes a pyrrolidin-1-yl group which is substituted in the 3 position by
an
amino group,
a piperidin-1-yl group which is substituted in the 3 position by an amino
group,
a hexahydroazepin-1-yl group which is substituted in the 3 position or 4
position by an amino group,
a (2-aminocyclohexyl)amino group,
a cyclohexyl group which is substituted in the 3 position by an amino group,
or
an N-(2-aminoethyl)-methylamino or an N-(2-aminoethyl)-ethylamino group,
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,

56
the tautomers, enantiomers, diastereomers, the mixtures thereof and salts
thereof.
3. Compounds of general formula I according to claim 2, wherein
R1 denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by R10, while
R10 denotes a formylamino group,
a C3-7-cycloalkyl-carbonylamino or C3-7-cycloalkyl-C1-3-alkyl-
carbonylamino group,
a C6-9-bicycloalkyl-carbonylamino group,
a C5-7-cycloalkyl-carbonylamino group wherein
a methylene group is replaced by an oxygen or sulphur atom or
by an imino, sulphinyl or sulphonyl group,
a (1,3-dioxolanyl)-carbonylamino, (1,4-dioxanyl)-carbonylamino,
morpholin-2-yl-carbonylamino, morpholin-3-ylcarbonylamino or
piperazin-2-yl-carbonylamino group,
a C5-7-cycloalkyl-carbonylamino group wherein a -CH2-CH2 group is
replaced by an -NH-CO group,
a C5-7-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2 group
is replaced by an -NH-CO-O group,
a C5-7-cycloalkyl-carbonylamino group wherein a methylene group is
replaced by a carbonyl group,

57
a C5-7-cycloalkenyl-carbonylamino or C5-7-cycloalkenyl-C1-3-alkyl-
carbonylamino group,
a C3-7-cycloalkyl-sulphonylamino, phenylsulphonylamino or phenyl-C1-3-
alkyl-sulphonylamino group or
a pyridinylcarbonylamino group,
R2 denotes a hydrogen atom,
or a C1-3-alkyl group,
R3 denotes a C4-6-alkenyl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-yl-methyl group
and
R4 denotes a piperidin-1-yl group which is substituted in the 3 position by an
amino group,
a hexahydroazepin-1-yl group which is substituted in the 3 position or 4
position by an amino group,
a (2-aminocyclohexyl)amino group,
a cyclohexyl group which is substituted in the 3 position by an amino group,
or
an N-(2-aminoethyl)-methylamino or an N-(2-aminoethyl)-ethylamino group,

58
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
4. Compounds of general formula I according to claim 3, wherein
R1 denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by a formylamino, pyridinylcarbonylamino or
cyclopropylcarbonylamino group,
R2 denotes a methyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or
a 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.
5. Compounds of general formula I according to claim 4, wherein
R1 denotes a [2-(cyclopropylcarbonylamino)-phenyl]-carbonylmethyl or [2-
(pyridylcarbonylamino)-phenyl]-carbonylmethyl group,
R2 denotes a methyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or

59
a 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.
6. The following compounds of general formula I according to claim 1:
(1) 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-
yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(2) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
(3) 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(4) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(5) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
(6) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(7) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine and

60
(8) 1-[2-(2-{[(pyridin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
as well as the tautomers, enantiomers, diastereomers, the mixtures thereof
and the salts thereof.
7. Physiologically acceptable salts of the compounds according to at least one
of claims 1 to 6 with inorganic or organic acids or bases.
8. Pharmaceutical compositions containing a compound according to at least
one of claims 1 to 6 or a physiologically acceptable salt according to claim 7
optionally together with one or more inert carriers and/or diluents.
9. Use of a compound according to at least one of claims 1 to 7 for preparing
a pharmaceutical composition which is suitable for treating type I and type II
diabetes mellitus, arthritis, obesity, allograft transplantation and
calcitonin-
induced osteoporosis.
10. Process for preparing a pharmaceutical composition according to claim 8,
characterised in that a compound according to at least one of claims 1 to 7 is
incorporated in one or more inert carriers and/or diluents by a non-chemical
method.
11. Process for preparing the compounds of general formula I according to
claims 1 to 7, characterised in that
a) in order to prepare compounds of general formula I wherein R4 is one
of the groups mentioned in claim 1 linked to the xanthine skeleton via a
nitrogen atom:

61
a compound of general formula
<IMG>
wherein
R1 to R3 are defined as in claim 1 and
Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy,
mercapto, sulphinyl, sulphonyl or sulphonyloxy group,
is reacted with an amine of general formula R4'-H, wherein R4' denotes one of
the groups mentioned for R4 in claim 1 which is linked to the xanthine
skeleton via a nitrogen atom, or
b) a compound of general formula
<IMG>
wherein R1, R2 and R3 are defined as 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, is deprotected, and is
subsequently
optionally alkylated at the imino, amino or C1-3-alkylamino group, and/or

62
subsequently, if desired, any protecting groups used during the reaction are
cleaved and/or
the compounds of general formula I thus obtained are resolved into their
enantiomers or diastereomers and/or
the compounds of formula I thus obtained are converted into the salts thereof,
particularly for pharmaceutical use into the physiologically acceptable salts
thereof with inorganic or organic acids or bases.

Description

CA 02496325 2005-02-18
.. 1
81553fft
Boehringer Ingelheim Pharma GmbH & Co. KG Case 111386
D-55216 IngelheimlRhein Foreign filing text
New xanthine derivatives, the preparation thereof and their use
as pharmaceutical compositions
The present invention relates to new substituted xanthines of general formula
O Rs
R~\ N
N a ~I~~
y ,~--R
O N N
R2
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, parkicularly 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.
In the above formula I
R' denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by R~° and R1~, where

2
R'° denotes a formylamino group,
a C3_~-cycloalkyl-carbonylamino or C3_~-cycloalkyl-C~_3-alkyl-carbonyl-
amino group,
a C6_9-bicycloalkyl-carbonylamino or Cs_9-bicycloalkyl-C~.3-alkyl-
carbonylamino group,
a C5_7-cycloalkyl-carbonylamino group wherein
a methylene group is replaced by an oxygen or sulphur atom or
by an imino, sulphinyl or sulphonyl group,
a C5_~-cycloalkyl-carbonylamino group wherein a -CH2-CH2 group is
replaced by a -NH-CO or-NH-NH group,
a C5_~-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2 group
is replaced by a -NH-CO-NH, -NH-CO-O or -O-CHz-O group,
a C6_~-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2-CH2
group is replaced by a -NH-CH2-CH2-NH, -NH-CO-CH2-NH, -NH-CH2-
CH2-O, -NH-CO-CH2-O or-O-CH2-CH2-O group,
a cycloheptyl-carbonylamino group wherein a -CH2-CH2-CH2-CH2-CH2
group is replaced by a -NH-CH2-CH2-CH2-NH, -NH-CO-CH2-CH2-NH,
-NH-CH2-CH2-CH2-O, -NH-CO-CH2-CH2-O or-O-CH2-CH2-CH2-O
group,
a C5_7-cycloalkyl-carbonylamino group wherein one or two methylene
groups are replaced by carbonyl groups,
a C4_~-cycloalkenyl-carbonylamino or C4_~-cycloalkenyl-C~_3-alkyl-
carbonylamino group,
CA 02496325 2005-02-18

3
a C3_7-cycloalkyl-sulphonylamino, C3_~-cycloalkyl-C~_3-alkyl-
sulphonylamino, arylsulphonylamino or aryl-C~_3-alkyl-sulphonylamino
group or
a heteroarylcarbonylamino group,
while the imino groups contained in the above mentioned groups may
be substituted independently of one another by a C~_3-alkyl group,
and R~' denotes a hydrogen, fluorine, chlorine, bromine or iodine atom
or
a C~_3-alkyl, C~_3-alkyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy or cyano group,
R2 denotes a hydrogen atom,
a C~_6-alkyl group,
a C2~-alkenyl group,
a C3_4-alkynyl group,
a C3_6-cycloalkyl group,
a C3_6-cycloalkyl-C~_3-alkyl group,
a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl or tetrahydropyranylmethyl group,
an aryl group,
an aryl-C~_4-alkyl group,
an aryl-C2_3-alkenyl group,
CA 02496325 2005-02-18

an arylcarbonyl-C,_2-alkyl group,
a heteroaryl-C~_3-alkyl group,
a furanylcarbonylmethyl, thienylcarbonylmethyl, thiazolylcarbonylmethyl or
pyridylcarbonylmethyl group,
a C~_4-alkyl-carbonyl-C~_2-alkyl group,
a C3_6-cycloalkyl-carbonyl-C~_2-alkyl group,
an aryl-D-C~_3-alkyl group, while D denotes an oxygen or sulphur atom, an
imino, C~_3-alkylimino, sulphinyl or sulphonyl group,
a C~_4-alkyl group substituted by a group Ra, where
Ra 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 CZ_4-alkyl group substituted by a group Rb, where
Rb denotes a hydroxy, C~_3-alkyloxy, amino, C~_3-alkylamino, dl-(C~_3-
alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-
yl, 4-methyl-piperazin-1-y1 or 4-ethyl-piperazin-1-yl group and is
isolated from the cyclic nitrogen atom in the 3 position of the xanthine
skeleton by at least two carbon atoms,
R3 denotes a C3_$-alkyl group,
a C~_3-alkyl group substituted by a group R~, where
CA 02496325 2005-02-18

5
R~ denotes a C3_7-cycloalkyl group optionally substituted by one or two
C~_3-alkyl groups,
a C5_T-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 each be substituted 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_$-alkenyl group,
a C3_6-alkenyl group substituted by a fluorine, chlorine or bromine atom, or a
trifluoromethyl group,
a C3_$-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, C~_3-alkylamino or a di-(C~_3-alkyl)amino group and
may additionally be substituted by one or two C~_3-alkyl groups,
CA 02496325 2005-02-18

6
a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3
position or 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~_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 5 position by a hydroxy or methoxy group,
a 3-amino-piperidin-1-yl group wherein the methylene group in the 2 position
or 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,
this bridge containing 2 to 5 carbon atoms if the two hydrogen atoms are on
the same carbon atom, or 1 to 4 carbon atoms if the hydrogen atoms are on
adjacent carbon atoms, or 1 to 4 carbon atoms if the hydrogen atoms are on
carbon atoms which are separated by one atom, or 1 to 3 carbon atoms if the
hydrogen atoms are on carbon atoms which are separated by two atoms,
an azetidin-1-yi, 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,
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,
CA 02496325 2005-02-18

CA 02496325 2005-02-18
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 in the 6 position by an amino group,
a C3_~-cycloalkyl group which is substituted by an amino, C~_3-alkylamino or
di-
(C~_3-alkyl)-amino group,
a C3_7-cycloalkyl group which is substituted by an amino-C~_3-alkyl, C,-a-
alkylamino-C1_3-alkyl or a di-(C~_3-alkyl)amino-C~_3-alkyl group,
a C3_7-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-(Cs_7-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,
a C3_~-cycloalkylamino 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)-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 dl-
(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_7-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_7-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 dl-(C~_3'
alkyl)amino-C~_3-alkyl group,
an N-(C3_7-cycloalkyl-C~_2-alkyl)-N-(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 R'9-C2~-alkylamino group wherein R'9 is separated from the nitrogen atom
of the C2_4-alkylamino moiety by at least two carbon atoms and
R'9 denotes an amino, C~_3-alkylamino or di-(C,_3-alkyl)-amino group,
an R'9-C2_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_4-alkylamino moiety by at least two carbon atoms,
where R'9 is as hereinbefore defined,
an amino group substituted by the group R2° wherein
R2° denotes an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-
ylmethyl,
pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl,
piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-
CA 02496325 2005-02-18

9
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
R2° is as hereinbefore defined, while the groups mentioned for
R2° may each
be substituted by one or two C~_3-alkyl groups,
an R'9-Cs~-alkyl group wherein the C3_4-alkyl moiety is straight-chained and
may additionally be substituted by one or two C~_3-alkyl groups, where R'g 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,
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, pyridyf, indolyl, benzofuranyl,
benzothiophenyl, quinolinyl or isoquinolinyl group,
CA 02496325 2005-02-18

10
CA 02496325 2005-02-18
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,
or a 1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-
oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-
pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-
pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-
pyrazinyl, 2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-
oxo-1 H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-
quinolinyl, 1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl, 1,4-
dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl, 3,4-dihydro-4-oxo-
quinazolinyl, 1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl, 1,2-dihydro-2-
oxoquinoxafinyl, 1,2,3,4-tetrahydro-2,3-dioxo-quinoxaiinyl, 1,2-dihydro-1-oxo-
phthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, cumarinyl,
2,3-dihydro-benzo[1,4]dioxinyl or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl
group,
and the above mentioned heteroaryl groups may be mono- or
disubstituted by R,,, while the substituents may be identical or different
and Rh is as hereinbefore defined,
and, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the
prodrugs thereof and the salts thereof.
Compounds which contain a group that can be cleaved in vivo are prodrugs of
the corresponding compounds in which this graup that can be cleaved in vivo
has been cleaved.

11
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
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 ef al. in International Journal of Pharmaceutics 39, 75-85 (1987).
By a group which can be converted in vivo into a carboxy group is meant, for
example, a hydroxymethyl group, a carboxy group esterified with an alcohol
wherein the alcohol moiety is preferably a C~_6-alkanol, a phenyl-C~_3-
alkanol,
a C3_9-cycloalkanof, white a C5_8-cycioalkanol may additionally be substituted
by one or two C~_3-alkyl groups, a C5_$-cycloalkanol wherein a methylene
group in the 3 or 4 position is replaced by an oxygen atom or by an imino
group optionally substituted by a C,_3-alkyl, phenyl-C~_3-alkyl, phenyl-
C~_3-alkyloxycarbonyl or C2_6-alkanoyl group and the cycloalkanol moiety may
additionally be substituted by one or two C~.3-alkyl groups, a C4_~-
cycloalkenol,
a C3_5-alkenol, a phenyl-C~_5-alkenol, a Ca_5-alkynol or phenyl-C3_5-alkynol
with
the proviso that no bonds to the oxygen atom start from a carbon atom which
carries a double or triple bond, a C3_8-cycloalkyl-C~_3-alkanol, a
bicycloalkanol
with a total of 8 to 10 carbon atoms which may additionally be substituted in
the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-dihydro-3-oxo-1-
isobenzofuranol or an alcohol of formula
Rp-CO-O-(RqCRr)-OH,
wherein
Rp denotes a C~_$-alkyl, C5_~-cycloalkyl, C~_8-aikyfoxy, C5a-
cycloalkyloxy, phenyl or phenyl-C~_3-alkyl group,
CA 02496325 2005-02-18

12
CA 02496325 2005-02-18
Rq denotes a hydrogen atom, a C,_3-alkyl, C5_7-cycloalkyl or phenyl
group and
Rr 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_7-cycloalkyl groups and the substituents may

13
be identical or different, a C~_3-alkylsulphonyl-C2_4-alkyloxycarbonyl,
C~_3-alkyloxy-C2~-alkyloxy-C2_4-alkyloxycarbonyl, Rp-CD-O-(RqCR~)-O-CO,
C~_6-alkyl-CO-NH-(RSCRt)-O-CO- or C~_6-alkyl-CO-O-(RSCRt)-(RSGRt)-O-CO-
group, wherein Rp to R~ are as hereinbefore defined,
RS and Rt, which may be identical or different, denote hydrogen atoms or
C~_3-alkyl groups.
Moreover, 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.
Preferred compounds of general formula I are those wherein
R', R2 and R3 are as hereinbefore defined and
R4 denotes a pyrrolidin-1-yl group which is substituted in the 3 position by
an
amino group,
a piperidin-1-yl group which is substituted in the 3 position by an amino
group,
a hexahydroazepin-1-yl group which is substituted in the 3 position or 4
position by an amino group,
a (2-aminocyclohexyl)amino group,
a cyclohexyl group which is substituted in the 3 position by an amino group,
or
an N-(2-aminoethyl)-methylamino or an N-(2-aminoethyl)-ethylamino group,
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,
CA 02496325 2005-02-18

14
CA 02496325 2005-02-18
the tautomers, enantiomers, diastereomers, the mixtures thereof and salts
thereof.
Particularly preferred compounds of general formula I are those wherein
R' denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by R'°, while
R'° denotes a formylamino group,
a C3_~-cycloalkyl-carbonylamino or C3_~-cycloalkyl-C~_3-alkyl-
carbonylamino group,
a C6_9-bicycloalkyl-carbonylamino group,
a C5_~-cycloalkyl-carbonylamino group wherein
a methylene group is replaced by an oxygen or sulphur atom or
by an imino, sulphinyl or sulphonyl group,
a (1,3-dioxolanyl)-carbonylamino, (1,4-dioxanyl)-carbonylamino,
morpholin-2-yl-carbonylamino, morpholin-3-ylcarbonylamino or
piperazin-2-yl-carbonylamino group,
a C5_~-cycloalkyl-carbonylamino group wherein a -CH2-CH2 group is
replaced by an -NH-CO group,
a C5_~-cycloalkyl-carbonylamino group wherein a -CH2-CH2-CH2 group
is replaced by an -NH-CO-O group,
a C5_~-cycloalkyl-carbonylamino group wherein a methylene group is
replaced by a carbonyl group,

15
CA 02496325 2005-02-18
a C5_~-cycloalkenyl-carbonylamino or C5_7-cycloalkenyl-C~_3-alkyl-
carbonylamino group,
a C3_~-cycloalkyl-sulphonylamino, phenylsulphonylamino or phenyl-C~_3-
alkyl-sulphonylamino group or
a pyridinylcarbonylamino group,
R2 denotes a hydrogen atom,
or a C~_3-alkyl group,
R3 denotes a C4_6-alkenyl group,
a 2-butyn-1-yl group or
a 1-cyclopenten-1-yl-methyl group
and
R4 denotes a piperidin-1-yl group which is substituted in the 3 position by an
amino group,
a hexahydroazepin-1-yl group which is substituted in the 3 position or 4
position by an amino group,
a (2-aminocyclohexyl)amino group,
a cyclohexyl group which is substituted in the 3 position by an amino group,
or
an N-(2-aminoethyl)-methylamino or an N-(2-aminoethyl)-ethylamino group,
while, unless otherwise stated, the above mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched,

16
CA 02496325 2005-02-18
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts
thereof.
Most particularly preferred compounds of general formula I are those wherein
R' denotes a phenylcarbonylmethyl group wherein the phenyl moiety is
substituted by a formylamino, pyridinylcarbonylamino or
cyclopropylcarbonylamino group,
R2 denotes a methyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or
a 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,
but particularly those compounds of general formula I wherein
R' denotes a [2-(cyclopropylcarbonylamino)-phenyl]-carbonylmethyl or [2-
(pyridylcarbonylamino)-phenyl]-carbonylmethyl group,
R2 denotes a methyl group,
R3 denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or
a 2-butyn-1-yl group

17
CA 02496325 2005-02-18
and
R4 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-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-
y1)-8-(3-amino-piperidin-1-yl)-xanthine,
(2) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl )-xanthine,
(3) 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine,
(4) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(5) 1-(2-{2-[(cyclopropyfcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
(6) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
(7) 1-(2-{2-[(cyciopropylcarbonyf)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine and
(8) 1-[2-(2-{[(pyridin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

18
CA 02496325 2005-02-18
as well as the tautomers, enantiomers, diastereomers, the mixtures thereof
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) In order to prepare compounds of general formula I wherein R4 is one of
the above mentioned groups linked to the xanthine skeleton via a nitrogen
atom:
reacting a compound of general formula
3
R' ~N N
~~Z'
O N N
R2
wherein
R' to R3 are as hereinbefore defined and
Z' denotes a leaving group such as a halogen atom, a substituted hydroxy,
mercapto, sulphinyl, sulphonyl or sulphonyloxy group, such as for example a
chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy
group,
with an amine of general formula R4'-H, wherein R4~ denotes one of the
groups mentioned hereinbefore for R4 which is linked to the xanthine skeleton
via a nitrogen atom.
The reaction is expediently carried out in a solvent such as isopropanol,
butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide,
ethyleneglycol monomethylether, ethyleneglycol diethylether or sulpholane,
optionally in the presence of an inorganic or tertiary organic base, e.g.
sodium
carbonate, potassium carbonate or potassium hydroxide, a tertiary organic

19
CA 02496325 2005-02-18
base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine
(Hunig
base), while these organic bases may simultaneously also serve as solvent,
and optionally in the presence of a reaction accelerator such as an alkali
metal halide or a palladium-based catalyst at temperatures between -20 and
180°C, but preferably at temperatures between -10 and 120°C. The
reaction
may however also be carried out without a solvent or in an excess of the
amine of general formula R4'-H.
b) deprotecting a compound of general formula
R3
Rv. N /1 -N
Ra"
O N N
R2 (111),
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, while the imino, amino or alkylamino
group is substituted by a protective group, optionaNy followed by subsequent
alkylation of the imino, amino or C~_3-alkylamino 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.
The following are examples of protective groups:

20
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 chloridelanisol at temperatures
between 0°C and ambient temperature.
The optional subsequent introduction of a C~.3-alkyl group may be done by
alkylation or reductive alkylation.
The subsequent alkylation is optionally carried out in a solvent or mixture of
solvents such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzeneltetrahydrofuran or dioxane with an
alkylating agent such as a corresponding halide or sulphonic acid ester, e.g.
with methyl iodide, ethyl bromide, dimethyl sulphate, optionally in the
presence of a tertiary organic base or in the presence of an inorganic base,
conveniently at temperatures between 0 and 150°C, preferably at
temperatures between 0 and 100°C.
The subsequent reductive alkylation is carried out with a corresponding
carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde or
CA 02496325 2005-02-18

CA 02496325 2005-02-18
21
acetone in the presence of a complex metal hydride such as sodium
borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium
cyanoborohydride, conveniently at a pH of 6-7 and at ambient temperature or
in the presence of a hydrogenation catalyst, e.g. with hydrogen in the
presence of palladium/charcoal, under a hydrogen pressure of 1 to 5 bar. The
methylation may also be carried out in the presence of formic acid as reducing
agent at elevated temperatures, e.g. at temperatures between 60 and
120°C.
In the reactions described hereinbefore, any reactive groups present such as
carboxy, amino, alkylamino or imino groups may be protected during the
reaction by conventional protecting groups which are cleaved again after the
reaction.
For example, a protecting group for a carboxy group may be a trimethylsilyl,
methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group,
protecting groups for an amino, alkylamino or imino group may be a formyl,
acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl,
benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the
amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by
hydrolysis in an aqueous solvent, e.g. in water, isopropanollwater, acetic
acidlwater, tetrahydrofuranlwater or dioxan/water, in the presence of an acid
such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the
presence of an alkali metal base such as sodium hydroxide or potassium
hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 120°C, preferably at temperatures between 10
and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for
example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst
such as palladiumlcharcoal in a suitable solvent such as methanol, ethanol,
ethyl acetate or glacial acetic acid, optionally with the addition of an acid
such

22
as hydrochloric acid at temperatures between 0 and 100°C, but
preferably at
temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7
bar,
but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably
cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating
with
an acid such as trifluoroacetic acid or hydrochloric acid or by treating with
iodotrimethylsilane, optionally using a solvent such as methylene chloride,
dioxan, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as
hydrochloric acid, optionally in the presence of a solvent such as acetic acid
at
temperatures between 50 and 120°C, or by treating with sodium hydroxide
solution, optionally in the presence of a solvent such as tetrahydrofuran at
temperatures between 0 and 50°C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a
primary amine such as methylamine, ethylamine or n-butylamine in a solvent
such as methanol, ethanol, isopropanol, toluenelwater or dioxan at
temperatures between 20 and 50°C.
Moreover, the compounds of general formula I obtained may be resolved into
their enantiomers andlor diastereomers, as mentioned hereinbefore. Thus, for
example, cisltrans mixtures may be resolved into their cis and trans isomers,
and compounds with at least one optically active carbon atom may be
separated into their enantiomers.
Thus, for example, the cisltrans mixtures 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
~CA 02496325 2005-02-18

23
methods known per se, e.g. by chromatography andlor 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-tolyltartaric acid, malic acid, mandelic
acid,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An
optically
active alcohol may be for example (+) or (-)-menthol and an optically active
acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts
thereof, particularly for pharmaceutical use into the physiologically
acceptable
salts with inorganic or organic acids. Acids which may be used for this
purpose
include for example hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic
acid, citric acid, tartaric acid or malefic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy
group, they may subsequently, if desired, be converted into the salts thereof
with inorganic or organic bases, particularly for pharmaceutical use into the
physiologically acceptable salts thereof. Suitable bases for this purpose
include for example sodium hydroxide, potassium hydroxide, arginine,
cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
CA 02496325 2005-02-18

24
The compounds ofi general formulae II and III 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 VII).
As already mentioned hereinbefore, the compounds of general formula I
according to the invention and the physiologically acceptable salts thereof
have valuable pharmacological properties, particularly an inhibiting effect on
the enzyme DPP-IV.
The biological properties of the new compounds were investigated as follows:
The ability of the substances and their corresponding salts to inhibit the DPP-
IV activity can be demonstrated in 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).
The DPP-IV assay was carried out as follows:
50 pl substrate solution (AFC; AFC is amido-4-trifiuoromethylcoumarin), 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 pl 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
CA 02496325 2005-02-18

25
CA 02496325 2005-02-18
(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 ICSO values, was
calculated from dosagelactivity curves consisting of 11 measuring points in
each case. The following results were obtained:
Compound DPP IV inhibition
(Example No.) ICSO [nM)
1 5
1(1) 11
1(2) 3
1(3) 4
1 (4) 3
1(5) 3
1(6) 5
1(7) 8
The compounds prepared according to the invention are well tolerated, as for
example when 10 mglkg of the compound of Example 1 (5) 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 far 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 1 and type 2 diabetes mellitus, diabetic complications (such as e.g.
retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis,
reactive hypoglycaemia, insulin resistance, metabolic syndrome,
dyslipidaemias of various origins, arthritis, atherosclerosis and related
diseases, obesity, allograft transplantation and calcitonin-induced

26
CA 02496325 2005-02-18
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 ceNs 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 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. Furthermore, the compounds
according to the invention may be used to treat inflammatory diseases of the
respiratory tract. They are also suitable for the prevention and treatment of
chronic inflammatory intestinal diseases such as e.g. irritable bowel syndrome
(IBS), Crohn's disease or ulcerative colitis and also pancreatitis. It is also
likely that they can be used for all kinds of damage to or impairment of the
gastrointestinal tract such as colitis and enteritis, for example. 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. On the other hand these substances are
suitable for affecting sperm motility and can thus be used as male
contraceptives. The substances are also suitable for treating deficiencies of
growth hormone which are associated with reduced stature, and may also be
used to advantage in any indications in which growth hormone may be used.
The compounds according to the invention are also suitable, on the basis of
their inhibitory effect on DPP IV, for treating various autaimmune diseases
such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis and
Basedow's
disease, etc. They may also be used to treat viral diseases and also, for
example, in HIV infections, for stimulating blood production, in benign
prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal

27
defects and neurodegenerative diseases such as Alzheimer's disease, for
example. The compounds described may also be used for the treatment of
tumours, particularly for modifying tumour invasion and also metastasisation;
examples here are their use in treating T-cell lymphomas, acute lymphoblastic
leukaemia, cell-based pancreatic carcinomas, basal cell carcinomas or breast
cancers. Other indications are stroke, ischaemia of various origins, Parkin-
son's disease and migraine. In addition, further indications include
follicular
and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis,
encephalomyelitis, glomerulonephritis, lipodystrophies, as well as psycho-
somatic, depressive and neuropsychiatric diseases of all kinds.
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, tolbutamid, glimepiride), nateglinide,
repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma
agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators
(e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other
DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1
and GLP-1 analogues (e.g. exendin-4) or amylin. Also, SGLT2 inhibitors such
as T-1095, inhibitors of protein tyrosine phosphatase 1, substances which
influence deregulated glucose production in the liver, such as e.g. inhibitors
of
glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen -
phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol -
pyruvate carboxykinase, glycogen synthase kinase or pyruvate
dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase inhibitors
(e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate),
nicotinic
acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT
inhibitors (e.g. avasimibe) or cholesterol resorption inhibitors such as for
example ezetimibe, bile acid-binding substances such as for example
cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds
such as for example inhibitors of CETP or regulators of ABC1 or active
substances for the treatment of obesity, such as e.g. sibutramine or
tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the
CA 02496325 2005-02-18

28
cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists,
NPY5 or NPY2 antagonists or f~3-agonists such as SB-418790 or AD-9677 as
well as agonists of the 5HT2c receptor.
It is also possible to combine the compounds with drugs for treating high
blood pressure such as e.g. All antagonists or ACE inhibitors, diuretics,
(3-blockers, Ca-antagonists, etc., or combinations thereof.
The dosage required to achieve such an effect is expediently, by intravenous
route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg,
preferably 1 to 100 mg, in each case 1 to 4 a day. For this purpose, the
compounds of formula I prepared according to the invention, optionally
combined with other active substances, may be incorporated together with
one or more inert conventional carriers andlor diluents, e.g. with corn
starch,
lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water, waterlethanol,
water/glycerol, waterlsorbitol, waterlpolyethylene 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:
CA 02496325 2005-02-18

29
CA 02496325 2005-02-18
Preparation of the starting compounds:
Example I
1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]- 3-methyl-7-(3-methyl-2-buten-1-yl)-
8-f3-(tert.-butyloxycarbonylamino)-piperidin-1-yll-xanthine
A mixture of 1.2 ml of formic acid and 2 ml of acetic acid anhydride is heated
to 60°C for 10 minutes. Then 1 ml of this mixture is added to 226 mg of
1-[2-
(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine and the reaction mixture is
stirred for 15 minutes at 80°C. For working up, the reaction mixture is
combined with methylene chloride and slowly made alkaline with saturated
potassium carbonate solution. The aqueous phase is extracted with
methylene chloride and the combined organic phases are dried over sodium
sulphate and evaporated down. The crude product is further reacted without
any more purification.
Yield: 186 mg (78 % of theory)
Rf value: 0.40 (silica gel, cyclohexanelethyl acetate = 3:7)
Mass spectrum (ESI+): m/z = 594 [M+H]+
The following compounds are obtained analogously to Example I:
(1 ) 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.23 (silica gel, cyclohexane/ethyl acetate = 3:7)
Mass spectrum (ESI+): m/z = 578 [M+H]+
Example II
1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1-yll-xanthine
Prepared by treating von 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-

~o
CA 02496325 2005-02-18
xanthine with powdered iron in a mixture of ethanol, water and glacial acetic
acid (150:50:14) at 90°C.
Mass spectrum (ESI+): mlz = 566 [M+H]+
The following compounds are obtained analogously to Example II:
(1 ) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-
xanthine
Mass spectrum (ESI+): mlz = 430, 432 [M+H]+
(2) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-({E)-2-buten-1-yl)-8-[(R)-3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Mass spectrum (ESl+): mlz = 552 [M+H]+
(3) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-
xanthine
Rf value: 0.62 (silica gel, cyclohexane/ethyl acetate = 4:6)
Mass spectrum (ESI+): mlz = 432, 434 [M+H)+
Example III
1-[2-(2-vitro-phenyl )-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-
(tert.-butyloxycarbonylamino)-piperidin-1~r11-xanthine
2.20 g of 3-tert.-butyloxycarbonylamino-piperidine are added at 65°C to
4.40
g of 1-[2-(2-vitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-
chloro-xanthine and 1.30 g of sodium carbonate in 50 ml of
dimethylsulphoxide. The reaction mixture is stirred for approx. 16 h at
65°C.
After cooling to ambient temperature it is poured onto a mixture of 600 ml of
water and 100 g of ice. The precipitate formed is suction filtered and washed
with water. The filter cake is dissolved in diethyl ether, the solution is
dried
and evaporated down. The brown resinous flask residue is brought to
crystallisation with diisopropylether.
Yield: 3.30 g (54 °!o of theory)

31
CA 02496325 2005-02-18
Rf value: 0.52 (silica gel, cyclohexanelethyl acetate = 3:7)
Mass spectrum (ESI+): m/z = 596 [M+H]+
The following compounds are obtained analogously to Example III:
(1 ) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rt value: 0.50 (silica gel, methylene chloridelmethanol = 95:5)
Mass spectrum (ESI+): mlz = 550 [M+H]+
(2) 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)
(3) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-
(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 4:6)
Mass spectrum (ESI+): mlz = 552 [M+H]+
(4) 3-methyl-7-{2-butyn-1-yl)-8-j(R)-3-(tert.-butyloxycarbonylamino)-piperidin-
1-yl]-xanthine
Melting point: 197-200°C
Mass spectrum (ESI+): mlz = 417 [M+H]+
(5) 3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-
1-yl]-xanthine
Rf value: 0.52 {silica gel, ethyl acetate)
Mass spectrum (ESI+): mlz = 417 [M+H]+
(6) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-
(tert:-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.20 (silica gel, cyclohexanelethyl acetate = 1:1 )
Mass spectrum (ESI+): mlz = 552 [M+H]+

32
CA 02496325 2005-02-18
Example IV
1-f2-(2-n itro-phenyl)-2-oxo-ethyll-3-methyl-7-(3-methyl-2-buten-1-yl)-8-
chloro-
xanthine
A mixture of 6.02 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine,
5.86 g of 2-bromo-1-(2-vitro-phenyl)-ethanone and 5.00 g of potassium
carbonate in 150 ml of N,N-dimethylformamide is stirred for approx. 26 h at
60°C. For working up the cooled reaction mixture is poured onto a
mixture of
500 ml of 1 N sodium hydroxide solution and 200 g of ice. The precipitate
formed is suction filtered and dried.
Yield: 6.32 g (65 °f° of theory)
Rf value: 0.50 (silica gel, cyclohexanelethyl acetate = 4:6)
Mass spectrum (ESI+): mlz = 432, 434 [M+H]+
The following compounds are obtained analogously to Example IV:
(1 ) 1-[2-(2-vitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-
xanthine
Rf value: 0.77 (silica gel, methylene chloridelmethanol = 95:5)
Mass spectrum (ESl+): mlz = 460, 462 jM+H]+
(2) 1-[2-(2-vitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-
xanthine
Rf value: 0.50 (silica gel, cyclohexanelethyl acetate = 1:1 )
Mass spectrum (ESI+): mlz = 462, 464 [M+H]+
(3) 1-[2-(2-vitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-
(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.60 (silica gel, methylene chloridelmethanol = 95:5)
(4) 1-[2-(2-vitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-
(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.60 (silica gel, methylene chloridelmethanol = 95:5)

33
CA 02496325 2005-02-18
Mass spectrum (ESI+): mlz = 580 [M+H]+
Example V
3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine
5.87 ml of 1-bromo-3-methyl-2-butene are added to 10.56 g of 3-methyl-8-
chloro-xanthine and 17 ml of Hunig base in 100 ml of N,N-dimethylformamide.
The reaction mixture is stirred for approx. 10 minutes at ambient temperature
and then combined with 800 ml of water. The light-coloured precipitate formed
is suction filtered, washed with ethanol and diethyl ether and dried.
Yield: 10.56 g (81 % of theory)
Mass spectrum (ESI+): mlz = 269, 271 [M+H]+
The following compounds are obtained analogously to Example V:
(1 ) 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine
Rf value: 0.72 (silica gel, ethyl acetate)
Mass spectrum (ESI+): mlz = 297, 299 [M+H]+
(2) 3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine
Mass spectrum (ESI+): mlz = 299, 301 [M+H]+
Example VI
1-(2-f2-f(cyclopropylcarbonyl)aminol-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-8-f 3-(tert.-butyloxycarbonylamino)-piperid in-1-yll-
xanthine
A mixture of 242 mg of 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-
xanthine and 44 NI of pyridine in N,N-dimethylformamide is combined with 39
NI of cyclopropanecarboxylic acid chloride and stirred for 2 h at
80°C. Then
another 20 pl of pyridine and 30 NI of cyclopropanecarboxylic acid chloride
are

34
CA 02496325 2005-02-18
added. After a further 10 h at 80°C the cooled reaction mixture is
diluted with
methylene chloride and combined with water. The aqueous phase is extracted
with methylene chloride and the combined organic phases are evaporated
down. The crude product is purified through a silica gel column with
cyclohexanelethyl acetate (7:3 to 4:6) as eluant.
Yield: 90 mg (33 % of theory)
Rf value: 0.60 (silica gel, cyclohexanelethyl acetate = 3:7)
The following compounds are obtained analogously to Example VI:
(1 ) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyiamino)-piperid in-1-yl]-xanth
ine
Rf value: 0.30 (silica gel, cyclohexanelethyl acetatelisopropanol = 8:1:1 )
Mass spectrum (ESI+): mlz = 620 [M+H]+
(2) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.53 (silica gel, cyclohexane/ethyl acetate/isopropanol = 14:3:3)
Mass spectrum (ESI+): mlz = 620 [M+H]+
(3) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.35 (silica gel, methylene chloridelmethanol = 95:5)
Mass spectrum (ESI+): mlz = 618 [M+H]+
(4) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-xanth ine
Rf value: 0.35 (silica gel, methylene chloridelmethanol = 95:5)
Mass spectrum (ESI+): mlz = 618 [M+H]+
(5) 1-[2-(2-{[(pyridin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-
xanthine
Rf value: 0.55 (silica gel, cyclohexanelethyl acetatelisopropanol = 14:3:3)
Mass spectrum (ESI+): m/z = 657 [M+H]+

35
CA 02496325 2005-02-18
Example VII
1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-
butyloxycarbonylamino)-piperidin-1-yll-xanthine
Prepared by reduction of 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-
butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
with
sodium dithionite in a mixture of methylglycol and water (3:2) at
100°C.
Rf value: 0.50 (silica gel, cyclohexanelethyl acetate = 4:6)
The following compounds are obtained analogously to Example VII:
(1 ) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-
(tert.-
butyloxycarbonylamino)-piperidin-1-yl]-xanthine
Rf value: 0.34 (silica gel, methylene chloride/methanol = 95:5)
Preparation of the final compounds:
Examale 1
1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-
8-(3-amino-piperidin-1-yl)-xanthine
A solution of 180 mg of 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]- 3-methyl-7-
(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-
xanthine in 4 ml of methylene chloride is combined with 1 ml of
trifluoroacetic
acid and stirred for half an hour at ambient temperature. For working up the
reaction mixture is made slightly alkaline with 1 N sodium hydroxide solution
and the aqueous phase is extracted with methylene chloride. The combined
organic phases are evaporated down and purified through a silica gel
column.
Yield: 130 mg (87 % of theory)

36
CA 02496325 2005-02-18
Rf value: 0.38 (Ready-made reversed phase TLC plate (E. Merck),
acetonitrilelwater/ trifluoroacetic acid = 100:100:0.1 )
Mass spectrum (ESI+): mlz = 494 [M+H]+
The following compounds are obtained analogously to Example 1:
{1 ) 1-(2-{2-[(cyclopropyicarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
Rf value: 0.35 (Ready-made reversed phase TLC plate (E. Merck),
acetonitrilelwaterl trifluoroacetic acid = 100:100:0.1 )
Mass spectrum (ESI+): mlz = 534 [M+H]+
(2) 1-[2-(2-formylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine
Rf value: 0.20 (silica gel, methylene chloridelmethanol/conc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): mlz = 478 [M+H]+
(3) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine
Rf value: 0.50 (Ready-made reversed phase TLC plate (E. Merck),
acetonitrilelwaterl trifluoroacetic acid = 50:50:0.1 )
Mass spectrum (ESI+): mlz = 520 [M+H]+
(4) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-({S)-3-amino-piperidin-1-yl)-xanthine
Rf value: 0.50 (Ready-made reversed phase TLC plate (E. Merck),
acetonitrilelwaterl trifluoroacetic acid = 50:50:0.1 )
Mass spectrum (ESI+): mlz = 520 [M+H]+
(5) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine
Mass spectrum (ESI+): mlz = 518 [M+H]+

37
CA 02496325 2005-02-18
(6) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine
Rf value: 0.14 (silica gel, methylene chloride/methanollconc. aqueous
ammonia = 90:10:1 )
Mass spectrum (ESI+): m/z = 518 [M+H]+
(7) 1-[2-(2-{[(pyridin-2-yi)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
Mass spectrum (ESI+): m/z = 557 [M+H]+
The following compounds may also be obtained analogously to the foregoing
Examples and other methods known from the literature:
(1 ) 1-(2-{2-[(cyclobutylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl )-xanthine
(2) 1-(2-{2-[(cyclopentylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-
methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(3) 1-(2-{2-[(cyclohexylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-
2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(4) 1-(2-{2-[(cycloheptylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(5) 1-[2-(2-{[(bicyclo[2.2.1]heptan-1-yl)carbonyl)amino}-phenyl)-2-oxo-ethyl]-
3-
methyl-7-(3-methyl-2-buten-1-yl)-8-{3-amino-piperidin-1-yl)-xanthine
(6) 1-[2-(2-{[(bicyclo[2.2.2]octan-1-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(7) 1-[2-(2-{[(1-cyclobuten-1-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-
7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

38
CA 02496325 2005-02-18
(8) 1-[2-(2-{[(1-cyclopenten-1-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-[( 1-cyclopenten-1-yl)methyl]-8-(3-amino-piperidin-1-yl)-xanthine
(9) 1-[2-(2-{[(1-cyclohexen-1-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(10) 1-[2-(2-{[(2-oxo-cyclohexane-1-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-[( 1-cyclopenten-1-yl)methyl]-8-(3-amino-piperidin-1-yl )-xanthine
(11 ) 1-[2-(2-{[(2,6-dioxo-cyclohexane-1-yl)carbonyl]amino}-phenyl)-2-oxo-
ethyl]-3-methyl-7-[( 1-cyclopenten-1-yl)methyl]-8-(3-amino-piperidin-1-yl)-
xanthine
(12) 1-[2-(2-{[(tetrahydro-furan-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(13) 1-[2-(2-{[(tetrahydro-furan-3-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(14) 1-[2-(2-{[(tetrahydro-thiophen-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]
3-methyl-7-[(1-cyciopenten-1-yl)methyl]-8-(3-amino-piperidin-1-yl)-xanthine
(15) 1-[2-(2-{[(tetrahydro-thiophen-3-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-
3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(16) 1-[2-(2-{[(1-oxo-tetrahydro-thiophen-2-yl)carbonyl)amino}-phenyl)-2-oxo-
ethyl]-3-methyl-7-[( 1-cyclopenten-1-yl )methyl]-8-(3-amino-piperidin-1-yl)-
xanthine
(17) 1-[2-(2-{[(1,1-dioxo-tetrahydro-thiophen-2-yl)carbonyl]amino}-phenyl)-2-
oxo-ethyl]-3-methyl-7-[( 1-cyclopenten-1-yl)methyl]-8-(3-amino-piperid in-1-
yl)-
xanthine

39
CA 02496325 2005-02-18
(18) 1-[2-(2-{[(pyrrolidin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-
7-
(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(19) 1-[2-(2-{[(pyrrolidin-3-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-
7-
((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(20) 1-[2-(2-{[(tetrahydro-pyran-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(21 ) 1-[2-(2-{[([1,3]dioxolan-4-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-((E )-1-buten-1-yl)-8-(3-amino-piperid in-1-yl)-xanthine
(22) 1-[2-(2-{[([1,4]dioxane-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(23) 1-[2-(2-{[(morpholin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-
7-((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(24) 1-[2-(2-{[(piperazin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(25) 1-[2-(2-{[(5-oxo-pyrrolidin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-[(1-cyclopenten-1-yl)methyl]-8-(3-amino-piperidin-1-yl)-xanthine
(26) 1-[2-(2-{[(6-oxo-piperidin-2-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(27) 1-[2-(2-{[(2-oxo-oxazolidin-4-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-((E)-1-buten-1-yl)-8-(3-amino-piperidin-1-yi)-xanthine
(28) 1-[2-(2-{[(cyclopropylmethyl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

~o
CA 02496325 2005-02-18
(29) 1-[2-(2-{[(pyridin-3-yl)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-
(2-
butyn-1-yl)-8-(3-amino-piperid in-1-yl)-xanthine
(30) 1-(2-{2-[(cyclopropylsulphonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(31) 1-(2-{2-[(phenylsulphonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
(32) 1-(2-{2-[(benzylsulphonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-
butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
Example 2
Coated tablets containing 75 ma 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
hydroxypropylmethylcellulose 15.0 mg
magnesium stearate 1.5 ma
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.

41
CA 02496325 2005-02-18
Weight of core: 230 mg
die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially
of
hydroxypropylmethylcellulose. The finished film-coated tablets are polished
with beeswax.
Weight of coated tablet: 245 mg.
Example 3
Tablets containing 100 ma of active substance
Composition:
1 tablet contains:
active substance 100.0 mg
lactose 80.0 mg
corn starch 34.0 mg
polyvinylpyrrolidone 4.0 mg
magnesium stearate 2._ 0 ma
220.0 mg
Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly
moistened with an aqueous solution of the polyvinylpyrrolidone. After the
moist
composition has been screened (2.0 mm mesh size) and dried in a rack-type
drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant
is
added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar, facetted on both sides and notched on one
side.

42
CA 02496325 2005-02-18
Example 4
Tablets containing 150 ma of active substance
Composition:
1 tablet contains:
active substance 150.0 mg
powdered lactose 89.0 mg
corn starch 40.0 mg
colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg
magnesium stearate 1.0 ma
300.0 mg
Preparation:
The active substance mixed with lactose, corn starch and silica is moistened
with a 20% aqueous polyvinylpyrrolidone solution and passed through a
screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are
passed
through the same screen again and mixed with the specified amount of
magnesium stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg
die: 10 mm, flat
Example 5
Hard Gelatine capsules containing 150 ma 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 ma
approx. 420.0 mg

43
CA 02496325 2005-02-18
Preparation:
The active substance is mixed with the excipients, passed through a screen
with a mesh size of 0.75 mm and homogeneously mixed using a suitable
apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg
Capsule shell: size 1 hard gelatine capsule.
Example 6
Suppositories containing 150 ma of active substance
1 suppository contains:
active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg
polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 ma
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 7
Suspension containing 50 ma 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

44
CA 02496325 2005-02-18
Preparation:
The distilled water is heated to 70°C. The methyl and propyl
p-hydroxybenzoates together with the glycerol and sodium salt of
carboxymethylcellulose are dissolved therein with stirring. The solution is
cooled to ambient temperature and the active substance is added and
homogeneously dispersed therein with stirring. After the sugar, the sorbitol
solution and the flavouring have been added and dissolved, the suspension is
evacuated with stirring to eliminate air.
ml of suspension contain 50 mg of active substance.
Example 8
Ampoules containing 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
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 9
Ampoules containing 50 ma of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml

45
CA 02496325 2005-02-18
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.

Dessin représentatif