U.S. patent application number 12/706739 was filed with the patent office on 2010-06-10 for xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Matthias ECKHARDT, Frank HIMMELSBACH, Elke LANGKOPF, Ralf R. H. LOTZ, Roland MAIER, Michael MARK, Mohammad TADAYYON.
Application Number | 20100144703 12/706739 |
Document ID | / |
Family ID | 32718431 |
Filed Date | 2010-06-10 |
United States Patent
Application |
20100144703 |
Kind Code |
A1 |
HIMMELSBACH; Frank ; et
al. |
June 10, 2010 |
XANTHINE DERIVATIVES, THE PREPARATION THEREOF AND THEIR USE AS
PHARMACEUTICAL COMPOSITIONS
Abstract
Disclosed are substituted xanthines of general formula
##STR00001## wherein R.sup.1 to R.sup.4 are defined hereinbelow,
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).
Inventors: |
HIMMELSBACH; Frank;
(Mittelbiberach, DE) ; LANGKOPF; Elke;
(Warthausen, DE) ; ECKHARDT; Matthias; (Biberach,
DE) ; MAIER; Roland; (Biberach, DE) ; MARK;
Michael; (Biberach, DE) ; TADAYYON; Mohammad;
(Watford, DE) ; LOTZ; Ralf R. H.; (Schemmerhofen,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim am Rhein
DE
|
Family ID: |
32718431 |
Appl. No.: |
12/706739 |
Filed: |
February 17, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12331720 |
Dec 10, 2008 |
7696212 |
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12706739 |
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10695597 |
Oct 28, 2003 |
7482337 |
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12331720 |
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60429173 |
Nov 26, 2002 |
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Current U.S.
Class: |
514/211.08 ;
514/211.09; 514/211.11; 514/221; 514/263.34; 540/545; 540/547;
540/552; 540/569; 544/267 |
Current CPC
Class: |
C07D 473/06 20130101;
A61P 3/04 20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/211.08 ;
544/267; 514/263.34; 540/552; 514/211.09; 540/569; 514/221;
540/547; 514/211.11; 540/545 |
International
Class: |
A61K 31/553 20060101
A61K031/553; C07D 473/04 20060101 C07D473/04; A61K 31/522 20060101
A61K031/522; A61K 31/5513 20060101 A61K031/5513; A61K 31/554
20060101 A61K031/554 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 8, 2002 |
DE |
102 51 927 |
Claims
1. A Compound of general formula ##STR00102## wherein R.sup.1
denotes a C.sub.1-3-alkyl group substituted by a group R.sub.a,
wherein R.sub.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
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[f][1,4]oxazepinyl or
2,3-dihydro-benzo[b][1,4]oxazepinyl 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, 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 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 R.sub.x,
where R.sub.x denotes a hydrogen atom or a C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
hydroxy-C.sub.2-4-alkyl, C.sub.1-3-alkyloxy-C.sub.2-4-alkyl,
C.sub.3-6-cycloalkyloxy-C.sub.2-4-alkyl, amino-C.sub.2-4-alkyl,
C.sub.1-3-alkylamino-C.sub.2-4-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.2-4-alkyl,
C.sub.1-3-alkyl-carbonyl, C.sub.1-3-alkyloxy-carbonyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, aryl-carbonyl,
C.sub.1-3-alkyl-sulphonyl or aryl-sulphonyl group, a
phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl,
benzo[f]quinoxalinyl, 5H-dibenzo[d,t][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 wherein the above-mentioned
groups R.sub.a may be substituted by the groups R.sup.10 to
R.sup.13 and may additionally be substituted by a C.sub.1-3-alkyl
group and R.sup.10 denotes a hydrogen atom, a fluorine, chlorine,
bromine or iodine atom, a C.sub.1-4-alkyl, hydroxy, or
C.sub.1-4-alkyloxy group, a nitro, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)amino, cyano-C.sub.1-3-alkylamino,
[N-(cyano-C.sub.1-3-alkyl)-N-C.sub.1-3-alkyl-amino],
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkylamino, pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or
4-(C.sub.1-3-alkyl)-piperazin-1-yl group, a
C.sub.1-3-alkyl-carbonylamino, arylcarbonylamino,
aryl-C.sub.1-3-alkyl-carbonylamino,
C.sub.1-3-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-3-alkyl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
C.sub.1-3-alkyl-sulphonylamino,
bis-(C.sub.1-3-alkylsulphonyl)-amino, aminosulphonylamino,
C.sub.1-3-alkylamino-sulphonylamino,
di-(C.sub.1-3-alkyl)amino-sulphonylamino,
pyrrolidin-1-yl-sulphonylamino, piperidin-1-yl-sulphonylamino,
morpholin-4-yl-sulphonylamino, piperazin-1-yl-sulphonylamino or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulphonylamino,
(C.sub.1-3-alkylamino)thiocarbonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)-carbonylamino,
arylsulphonylamino or aryl-C.sub.1-3-alkyl-sulphonylamino group, an
N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N-(C.sub.1-3-alkyl)-arylcarbonylamino,
N-(C.sub.1-3-alkyl)-aryl-C.sub.1-3-alkyl-carbonylamino,
N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N-(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino,
N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulphonylamino,
N-(C.sub.1-3-alkyl)-arylsulphonylamino or
N-(C.sub.1-3-alkyl)-aryl-C.sub.1-3-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,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl group, a
C.sub.1-3-alkyl-carbonyl or an arylcarbonyl group, a
carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyl or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyl group,
a carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, aminocarbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy
group, a hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-C.sub.1-3-alkyl, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl, piperidin-1-yl-C.sub.1-3-alkyl,
morpholin-4-yl-C.sub.1-3-alkyl, piperazin-1-yl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl group, a
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-sulphanyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulphinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulphonyl-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkylamino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
piperazin-1-yl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy group, a
mercapto, C.sub.1-3-alkylsulphanyl, C.sub.1-3-alkylsulphinyl,
C.sub.1-3-alkylsulphonyl, C.sub.1-3-alkylsulphonyloxy,
arylsulphonyloxy, trifluoromethylsulphanyl,
trifluoromethylsulphinyl or trifluoromethylsulphonyl group, a
sulpho, aminosulphonyl, C.sub.1-3-alkyl-aminosulphonyl,
di-(C.sub.1-3-alkyl)-aminosulphonyl, pyrrolidin-1-yl-sulphonyl,
piperidin-1-yl-sulphonyl, morpholin-4-yl-sulphonyl,
piperazin-1-yl-sulphonyl or
4-(C.sub.1-3-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
C.sub.2-4-alkenyl or C.sub.2-4-alkynyl group, a
C.sub.3-4-alkenyloxy or C.sub.3-4-alkynyloxy group, a
C.sub.3-6-cycloalkyl or C.sub.3-6-cycloalkyloxy group, a
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl or
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy group or an aryl, aryloxy,
aryl-C.sub.1-3-alkyl or aryl-C.sub.1-3-alkyloxy group, R.sup.11 and
R.sup.12, which may be identical or different, in each case denote
a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, a
C.sub.1-3-alkyl, trifluoromethyl, hydroxy or C.sub.1-3-alkyloxy
group or a cyano group, or R.sup.11 together with R.sup.12, if they
are bound to adjacent carbon atoms, also denote a methylenedioxy,
difluoromethylenedioxy, ethylenedioxy or a straight-chain
C.sub.3-5-alkylene group and R.sup.13 denotes a hydrogen atom, a
fluorine, chlorine or bromine atom, a trifluoromethyl,
C.sub.1-3-alkyl or C.sub.1-3-alkyloxy group, R.sup.2 denotes a
hydrogen atom, a C.sub.1-6-alkyl group, a C.sub.2-4-alkenyl group,
a C.sub.3-4-alkynyl group, a C.sub.3-6-cycloalkyl group, a
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl group, a tetrahydrofuran-3-yl,
tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl
or tetrahydropyranylmethyl group, an aryl group, an
aryl-C.sub.1-4-alkyl group, an aryl-C.sub.2-3-alkenyl group, an
arylcarbonyl-C.sub.1-2-alkyl group, a heteroaryl-C.sub.1-3-alkyl
group, a furanylcarbonylmethyl, thienylcarbonylmethyl,
thiazolylcarbonylmethyl or pyridylcarbonylmethyl group, a
C.sub.1-4-alkyl-carbonyl-C.sub.1-2-alkyl group, a
C.sub.3-6-cycloalkyl-carbonyl-C.sub.1-2-alkyl group, an
aryl-A-C.sub.1-3-alkyl group, wherein A denotes an oxygen or
sulphur atom, an imino, C.sub.1-3-alkylimino, sulphinyl or
sulphonyl group, a C.sub.1-4-alkyl group substituted by a group
R.sub.b, wherein R.sub.b denotes a cyano, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkylamino-carbonyl, di-(C.sub.1-3-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 C.sub.2-4-alkyl group substituted by a group R.sub.c,
wherein R.sub.c denotes a hydroxy, C.sub.1-3-alkyloxy, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-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, R.sup.3 denotes a
C.sub.3-8-alkyl group, a C.sub.1-3-alkyl group substituted by a
group R.sub.d, wherein R.sub.d denotes a C.sub.3-7-cycloalkyl group
optionally substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.5-7-cycloalkenyl group optionally substituted by one or two
C.sub.1-3-alkyl groups, an aryl group or a furanyl, thienyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl-, pyridyl,
pyridazinyl, pyrimidyl or pyrazinyl group, wherein the
above-mentioned heterocyclic groups may be substituted in each case
by one or two C.sub.1-3-alkyl groups or by a fluorine, chlorine,
bromine or iodine atom or by a trifluoromethyl, cyano or
C.sub.1-3-alkyloxy group, a C.sub.3-8-alkenyl group, a
C.sub.3-6-alkenyl group substituted by a fluorine, chlorine or
bromine atom or a trifluoromethyl group, a C.sub.3-8-alkynyl group,
an aryl group or an aryl-C.sub.2-4-alkenyl group, and R.sup.4
denotes an azetidin-1-yl or pyrrolidin-1-yl group which is
substituted in the 3 position by an amino, C.sub.1-3-alkylamino or
a di-(C.sub.1-3-alkyl)amino group and may additionally be
substituted by one or two C.sub.1-3-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, C.sub.1-3-alkylamino or
a di-(C.sub.1-3-alkyl)amino group and may additionally be
substituted by one or two C.sub.1-3-alkyl groups, a
3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally substituted by an aminocarbonyl,
C.sub.1-2-alkyl-aminocarbonyl, di-(C.sub.1-2-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, a piperidin-1-yl or hexahydroazepin-1-yl group
substituted in the 3 position by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-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, wherein 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.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a piperazin-1-yl
or [1,4]diazepan-1-yl group optionally substituted on the carbon
skeleton by one or two C.sub.1-3-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.sub.1-3-alkyl groups, a
[1,4]diazepan-1-yl group optionally substituted by one or two
C.sub.1-3-alkyl groups, which is substituted by an amino group in
the 6 position, a C.sub.3-7-cycloalkyl group which is substituted
by an amino, C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino
group, a C.sub.3-7-cycloalkyl group which is substituted by an
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl group wherein the cycloalkyl
moiety is substituted by an amino, C
.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl group wherein the cycloalkyl
moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkylamino group wherein the cycloalkyl moiety is
substituted by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group, wherein the two nitrogen atoms on
the cycloalkyl moiety are separated from one another by at least
two carbon atoms, an
N-(C.sub.3-7-cycloalkyl)-N-(C.sub.1-3-alkyl)-amino group wherein
the cycloalkyl moiety is substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, wherein
the two nitrogen atoms on the cycloalkyl moiety are separated from
one another by at least two carbon atoms, a
C.sub.3-7-cycloalkylamino group wherein the cycloalkyl moiety is
substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
N-(C.sub.3-7-cycloalkyl)-N-(C.sub.1-3-alkyl)-amino group wherein
the cycloalkyl moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl-amino group wherein the
cycloalkyl moiety is substituted by an amino, C.sub.1-3-alkylamino
or di-(C.sub.1-3-alkyl)-amino group, an
N-(C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl)-N-(C.sub.1-2-alkyl)-amino
group wherein the cycloalkyl moiety is substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl-amino group wherein the
cycloalkyl moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
N-(C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl)-N-(C.sub.1-2-alkyl)-amino
group wherein the cycloalkyl moiety is substituted by an
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
R.sup.19--C.sub.2-4-alkylamino group wherein R.sup.19 is separated
from the nitrogen atom of the C.sub.2-4-alkylamino moiety by at
least two carbon atoms and R.sup.19 denotes an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, an
R.sup.19--C.sub.2-4-alkylamino group wherein the nitrogen atom of
the C.sub.2-4-alkylamino moiety is substituted by a C.sub.1-3-alkyl
group and R.sup.19 is separated from the nitrogen atom of the
C.sub.2-4-alkylamino moiety by at least two carbon atoms, wherein
R.sup.19 is as hereinbefore defined, an amino group substituted by
the group R.sup.20 wherein R.sup.20 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, wherein the groups mentioned for
R.sup.20 may each be substituted by one or two C.sub.1-3-alkyl
groups, an amino group substituted by the group R.sup.20 and a
C.sub.1-3-alkyl group wherein R.sup.20 is as hereinbefore defined,
wherein the groups mentioned for R.sup.20 may each be substituted
by one or two C.sub.1-3-alkyl groups, a R.sup.19--C.sub.3-4-alkyl
group wherein the C.sub.3-4-alkyl moiety is straight-chain and may
additionally be substituted by one or two C.sub.1-3-alkyl groups,
wherein R.sup.19 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.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)amino
group, or an azetidin-2-yl-C.sub.1-2-alkyl,
azetidin-3-yl-C.sub.1-2-alkyl, pyrrolidin-2-yl-C.sub.1-2-alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C.sub.1-2-alkyl,
piperidin-2-yl-C.sub.1-2-alkyl, piperidin-3-yl,
piperidin-3-yl-C.sub.1-2-alkyl, piperidin-4-yl or
piperidin-4-yl-C.sub.1-2-alkyl group, wherein the above-mentioned
groups may each be substituted by one or two C.sub.1-3-alkyl
groups, wherein 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.sub.h independently of one another,
where the substituents are identical or different and R.sub.h
denotes a fluorine, chlorine, bromine or iodine atom, a
trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino,
C.sub.1-3-alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy,
C.sub.1-3-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 R.sub.h, wherein the substituents may be identical
or different and R.sub.h is as hereinbefore defined, and, unless
otherwise specified, the above-mentioned alkyl, alkenyl and alkynyl
groups may be straight-chain or branched, or the tautomers,
enantiomers, diastereomers, the mixtures thereof, the prodrugs
thereof and the salts thereof.
2. The Compound according to claim 1, wherein R.sup.1 denotes a
methyl group substituted by a group R.sub.a, where R.sub.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, 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-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]naphthyridinyl, benzo[c][1,8]naphthyridinyl or
1,2,3,4-tetrahydro-phenanthridinyl group, 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 wherein the benzo groups of
the above-mentioned groups R.sub.a are substituted by the groups
R.sup.10 to R.sup.12 and the alkylene units of the above-mentioned
groups R.sub.a may be substituted by one or two C.sub.1-3-alkyl or
C.sub.1-3-alkyloxy-carbonyl groups, wherein the groups may be
identical or different, or by a trifluoromethyl group, and the
imino groups of the above-mentioned groups R.sub.a may be
substituted by a C.sub.1-3-alkyl group and R.sup.10 denotes a
hydrogen atom, a fluorine, chlorine, bromine or iodine atom, a
C.sub.1-3-alkyl or cyclopropyl group, a hydroxy, C.sub.1-3-alkyloxy
or cyclopropyloxy group, a nitro, amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)amino group, a C.sub.1-3-alkyl-carbonylamino or
C.sub.1-3-alkyl-sulphonylamino group, a cyano, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, a mercapto, C.sub.1-3-alkylsulphanyl,
C.sub.1-3-alkylsulphinyl or C.sub.1-3-alkylsulphonyl or
aminosulphonyl group or a difluoromethyl, trifluoromethyl,
difluoromethoxy or trifluoromethoxy group and R.sup.11 and
R.sup.12, 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.sup.2 denotes a
hydrogen atom, a C.sub.1-3-alkyl group, a C.sub.3-6-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.sub.1-3-alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy,
C.sub.1-3-alkyloxy, difluoromethoxy or trifluoromethoxy group,
wherein the substituents may be identical or different, R.sup.3
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 R.sup.4
denotes a (3-amino-piperidin-1-yl) group, wherein, unless otherwise
stated, the above-mentioned alkyl groups may be straight-chain or
branched.
3. The Compound according to claim 2, wherein R.sup.1 denotes a
methyl group substituted by a group R.sub.a, where R.sub.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, 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]thiazin-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[f][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, a
dibenzo[b,f][1,4]thiazepin-11-yl,
5-oxo-dibenzo[b,f][1,4]thiazepin-11-yl or
5,5-dioxo-dibenzo[b,f][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]naphthyridin-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,t][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 wherein the benzo groups of the above-mentioned groups
R.sub.a are substituted by the groups R.sup.10 to R.sup.12 and the
alkylene units of the above-mentioned groups R.sub.a may be
substituted by one or two methyl- or methoxy-carbonyl groups,
wherein the groups may be identical or different, or by a
trifluoromethyl group and the imino groups of the above-mentioned
groups R.sub.a may be substituted by a methyl group and R.sup.10
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.sup.11 and R.sup.12, which may be
identical or different, each represent a hydrogen atom, a fluorine,
chlorine or bromine atom, a methyl, trifluoromethyl or methoxy
group, R.sup.2 denotes a hydrogen atom or a methyl, ethyl, propyl,
isopropyl, phenyl or cyclopropyl group, R.sup.3 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 R.sup.4 denotes a
(3-amino-piperidin-1-yl) group.
4. The Compound according to claim 3, wherein R.sup.1 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, 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, R.sup.2 denotes a
methyl or cyclopropyl group, R.sup.3 denotes a 2-buten-1-yl,
3-methyl-2-buten-1-yl or 2-butyn-1-yl group and R.sup.4 denotes a
(3-amino-piperidin-1-yl) group, the tautomers, enantiomers,
diastereomers, the mixtures thereof and the salts thereof.
5. A compound chosen from: (1)
1-[(1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4H)methyl]-3-methyl-7-(3-m-
ethyl-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-met-
hyl-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-piper-
idin-1-yl)-xanthine, (5)
1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-y-
l)-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-am-
ino-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-am-
ino-piperidin-1-yl)-xanthine, (11)
1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-but-
yn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine, (12)
1-[(8-methyl-dibenzo[b,f][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-ami-
no-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-am-
ino-piperidin-1-yl)-xanthine, (16)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-p-
iperidin-1-yl)-xanthine, (17)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-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, (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-pi-
peridin-1-yl)-xanthine, (25)
1-[(benzo[f]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-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-p-
iperidin-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-b-
uten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine or the salts
thereof.
6. A Physiologically acceptable salt of a compound according to
claim 1 or 5 with inorganic or organic acids or bases.
7. A Pharmaceutical composition comprising a pharmaceutically
effective amount of a compound according to claim 1 optionally
together with one or more inert carriers and/or diluents.
8. A method of treating type I and type II diabetes mellitus,
arthritis, obesity, allograft transplantation and osteoporosis
caused by calcitonin, said method comprising administering to a
patient a pharmaceutically effective amount of a compound according
to claim 1.
Description
APPLICATION DATA
[0001] This application is a continuation of U.S. application Ser.
No. 12/331,720, filed Dec. 10, 2008, now allowed, which is a
continuation of U.S. application Ser. No. 10/695,597, filed Oct.
28, 2003, now U.S. Pat. No. 7,482,337, which claims the benefit of
German application No. DE 102 51 927 filed Nov. 8, 2002 and U.S.
Provisional Application No. 60/429,173, filed Nov. 26, 2002, the
content of each of the foregoing being incorporated by reference in
its entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0002] The present invention relates to new substituted xanthines
of general formula
##STR00002##
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.
[0003] 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.
[0004] In the above general formula I
R.sup.1 denotes a C.sub.1-3-alkyl group substituted by a group
R.sub.a, wherein [0005] R.sub.a denotes a 1,4-dihydro-quinazolinyl
or 3,4-dihydro-quinazolinyl group wherein in each case in the benzo
moiety [0006] one to three methyne groups may be replaced by
nitrogen atoms, [0007] a 3,4-dihydro-isoquinolinyl,
1H-benzo[d][1,2]oxazinyl, [0008] 4H-benzo[e][1,3]oxazinyl,
4H-benzo[d][1,3]oxazinyl or [0009] 2H-benzo[1,4]oxazinyl group,
wherein in each case [0010] 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, [0011] a 4H-benzo[e][1,3]thiazinyl,
4H-benzo[d][1,3]thiazinyl or 2H-benzo[1,4]thiazinyl group, wherein
in each case [0012] 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, [0013] 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 [0014] one to three methyne groups may be replaced
by nitrogen atoms, [0015] 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 [0016] 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, [0017] a
2,3-dihydro-benzo[f][1,4]oxazepinyl or
2,3-dihydro-benzo[b][1,4]oxazepinyl group wherein in each case
[0018] 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, [0019] a
2,3-dihydro-benzo[f][1,4]thiazepinyl or
2,3-dihydro-benzo[b][1,4]thiazepinyl group, wherein in each case
[0020] 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, [0021] a
5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl group wherein in the
benzo moiety [0022] one to three methyne groups may be replaced by
nitrogen atoms, [0023] an 11H-dibenzo[b,e]azepinyl or
5H-dibenzo[a,d]cycloheptenyl group, wherein in each case [0024] 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 R.sub.x,
where [0025] R.sub.x denotes a hydrogen atom or a C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, aryl, aryl-C.sub.1-3-alkyl,
hydroxy-C.sub.2-4-alkyl, C.sub.1-3-alkyloxy-C.sub.2-4-alkyl,
C.sub.3-6-cycloalkyloxy-C.sub.2-4-alkyl, amino-C.sub.2-4-alkyl,
C.sub.1-3-alkylamino-C.sub.2-4-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.2-4-alkyl,
C.sub.1-3-alkyl-carbonyl, C.sub.1-3-alkyloxy-carbonyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, aryl-carbonyl,
C.sub.1-3-alkyl-sulphonyl or aryl-sulphonyl group, [0026] a
phenanthridinyl, 1,2,3,4-tetrahydro-phenanthridinyl,
benzo[f]quinoxalinyl, 5H-dibenzo[d,t][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
[0027] in the benzo moiety one to three methyne groups may be
replaced by nitrogen atoms, [0028] a benzo[1,2,5]oxadiazolyl,
dibenzofuranyl, indolizinyl, 1H-perimidinyl, group, [0029] a
pyrazolo[1,5-c]quinazolinyl group or an imidazo[2,1-a]isoquinolinyl
or imidazo[1,2-a]isoquinolinyl group [0030] wherein the
above-mentioned groups R.sub.a may be substituted by the groups
R.sup.10 to R.sup.13 and may additionally be substituted by a
C.sub.1-3-alkyl group and [0031] R.sup.10 denotes a hydrogen atom,
[0032] a fluorine, chlorine, bromine or iodine atom, [0033] a
C.sub.1-4-alkyl, hydroxy, or C.sub.1-4-alkyloxy group, [0034] a
nitro, amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)amino,
cyano-C.sub.1-3-alkylamino,
[N-(cyano-C.sub.1-3-alkyl)-N-C.sub.1-3-alkyl-amino],
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkylamino, pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, or
4-(C.sub.1-3-alkyl)-piperazin-1-yl group, [0035] a
C.sub.1-3-alkyl-carbonylamino, arylcarbonylamino,
aryl-C.sub.1-3-alkyl-carbonylamino,
C.sub.1-3-alkyloxy-carbonylamino, aminocarbonylamino,
C.sub.1-3-alkyl-aminocarbonylamino,
di-(C.sub.1-3-alkyl)aminocarbonylamino,
pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,
morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonylamino,
C.sub.1-3-alkyl-sulphonylamino,
bis-(C.sub.1-3-alkylsulphonyl)-amino, aminosulphonylamino,
C.sub.1-3-alkylamino-sulphonylamino,
di-(C.sub.1-3-alkyl)amino-sulphonylamino,
pyrrolidin-1-yl-sulphonylamino, piperidin-1-yl-sulphonylamino,
morpholin-4-yl-sulphonylamino, piperazin-1-yl-sulphonylamino or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulphonylamino,
(C.sub.1-3-alkylamino)thiocarbonylamino,
(C.sub.1-3-alkyloxy-carbonylamino)-carbonylamino,
arylsulphonylamino or aryl-C.sub.1-3-alkyl-sulphonylamino group,
[0036] an N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-carbonylamino,
N-(C.sub.1-3-alkyl)-arylcarbonylamino,
N-(C.sub.1-3-alkyl)-aryl-C.sub.1-3-alkyl-carbonylamino,
N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyloxy-carbonylamino,
N-(aminocarbonyl)-C.sub.1-3-alkylamino,
N-(C.sub.1-3-alkyl-aminocarbonyl)-C.sub.1-3-alkylamino,
N-[di-(C.sub.1-3-alkyl)aminocarbonyl]-C.sub.1-3-alkylamino,
N-(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulphonylamino,
N-(C.sub.1-3-alkyl)-arylsulphonylamino or
N-(C.sub.1-3-alkyl)-aryl-C.sub.1-3-alkyl-sulphonylamino group,
[0037] 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, [0038] a cyano, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,
morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl group, [0039] a
C.sub.1-3-alkyl-carbonyl or an arylcarbonyl group, [0040] a
carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyl, cyano-C.sub.1-3-alkyl,
aminocarbonyl-C.sub.1-3-alkyl,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyl,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyl,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyl or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyl group,
[0041] a carboxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyloxy-carbonyl-C.sub.1-3-alkyloxy,
cyano-C.sub.1-3-alkyloxy, aminocarbonyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-aminocarbonyl-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
piperidin-1-yl-carbonyl-C.sub.1-3-alkyloxy,
morpholin-4-yl-carbonyl-C.sub.1-3-alkyl-oxy,
piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-carbonyl-C.sub.1-3-alkyloxy
group, [0042] a hydroxy-C.sub.1-3-alkyl,
C.sub.1-3-alkyloxy-C.sub.1-3-alkyl, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl,
pyrrolidin-1-yl-C.sub.1-3-alkyl, piperidin-1-yl-C.sub.1-3-alkyl,
morpholin-4-yl-C.sub.1-3-alkyl, piperazin-1-yl-C.sub.1-3-alkyl,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyl group, [0043] a
hydroxy-C.sub.1-3-alkyloxy, C.sub.1-3-alkyloxy-C.sub.1-3-alkyloxy,
C.sub.1-3-alkyl-sulphanyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulphinyl-C.sub.1-3-alkyloxy,
C.sub.1-3-alkylsulphonyl-C.sub.1-3-alkyloxy,
amino-C.sub.1-3-alkyloxy, C.sub.1-3-alkylamino-C.sub.1-3-alkyloxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyloxy,
pyrrolidin-1-yl-C.sub.1-3-alkyloxy,
piperidin-1-yl-C.sub.1-3-alkyloxy,
morpholin-4-yl-C.sub.1-3-alkyloxy,
piperazin-1-yl-C.sub.1-3-alkyloxy,
4-(C.sub.1-3-alkyl)-piperazin-1-yl-C.sub.1-3-alkyloxy group, [0044]
a mercapto, C.sub.1-3-alkylsulphanyl, C.sub.1-3-alkylsulphinyl,
C.sub.1-3-alkylsulphonyl, C.sub.1-3-alkylsulphonyloxy,
arylsulphonyloxy, trifluoromethylsulphanyl,
trifluoromethylsulphinyl or trifluoromethylsulphonyl group, [0045]
a sulpho, aminosulphonyl, C.sub.1-3-alkyl-aminosulphonyl,
di-(C.sub.1-3-alkyl)-aminosulphonyl, pyrrolidin-1-yl-sulphonyl,
piperidin-1-yl-sulphonyl, morpholin-4-yl-sulphonyl,
piperazin-1-yl-sulphonyl or
4-(C.sub.1-3-alkyl)-piperazin-1-yl-sulphonyl group, [0046] a methyl
or methoxy group substituted by 1 to 3 fluorine atoms, [0047] an
ethyl or ethoxy group substituted by 1 to 5 fluorine atoms, [0048]
a C.sub.2-4-alkenyl or C.sub.2-4-alkynyl group, [0049] a
C.sub.3-4-alkenyloxy or C.sub.3-4-alkynyloxy group, [0050] a
C.sub.3-6-cycloalkyl or C.sub.3-6-cycloalkyloxy group, [0051] a
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl or
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyloxy group or [0052] an aryl,
aryloxy, aryl-C.sub.1-3-alkyl or aryl-C.sub.1-3-alkyloxy group,
[0053] R.sup.11 and R.sup.12, which may be identical or different,
in each case denote a hydrogen atom, a fluorine, chlorine, bromine
or iodine atom, a C.sub.1-3-alkyl, trifluoromethyl, hydroxy or
C.sub.1-3-alkyloxy group or a cyano group, or [0054] R.sup.11
together with R.sup.12, if they are bound to adjacent carbon atoms,
also denote a methylenedioxy, difluoromethylenedioxy, ethylenedioxy
or a straight-chain C.sub.3-5-alkylene group and [0055] R.sup.13
denotes a hydrogen atom, a fluorine, chlorine or bromine atom, a
trifluoromethyl, C.sub.1-3-alkyl or C.sub.1-3-alkyloxy group,
R.sup.2 denotes a hydrogen atom, a C.sub.1-6-alkyl group, a
C.sub.2-4-alkenyl group, a C.sub.3-4-alkynyl group, a
C.sub.3-6-cycloalkyl group, a C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl
group, a tetrahydrofuran-3-yl, tetrahydropyran-3-yl,
tetrahydropyran-4-yl, tetrahydrofuranylmethyl or
tetrahydropyranylmethyl group, an aryl group, an
aryl-C.sub.1-4-alkyl group, an aryl-C.sub.2-3-alkenyl group, an
arylcarbonyl-C.sub.1-2-alkyl group, a heteroaryl-C.sub.1-3-alkyl
group, a furanylcarbonylmethyl, thienylcarbonylmethyl,
thiazolylcarbonylmethyl or pyridylcarbonylmethyl group, a
C.sub.1-4-alkyl-carbonyl-C.sub.1-2-alkyl group, a
C.sub.3-6-cycloalkyl-carbonyl-C.sub.1-2-alkyl group, an
aryl-A-C.sub.1-3-alkyl group, wherein A denotes an oxygen or
sulphur atom, an imino, C.sub.1-3-alkylimino, sulphinyl or
sulphonyl group, a C.sub.1-4-alkyl group substituted by a group
R.sub.b, wherein [0056] R.sub.b denotes a cyano, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkylamino-carbonyl, di-(C.sub.1-3-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 C.sub.2-4-alkyl group substituted by a group R.sub.c,
wherein [0057] R.sub.c denotes a hydroxy, C.sub.1-3-alkyloxy,
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-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, R.sup.3 denotes a
C.sub.3-8-alkyl group, a C.sub.1-3-alkyl group substituted by a
group R.sub.d, wherein [0058] R.sub.d denotes a
C.sub.3-7-cycloalkyl group optionally substituted by one or two
C.sub.1-3-alkyl groups, [0059] a C.sub.5-7-cycloalkenyl group
optionally substituted by one or two C.sub.1-3-alkyl groups, [0060]
an aryl group or [0061] a furanyl, thienyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl or
pyrazinyl group, wherein the above-mentioned heterocyclic groups
may be substituted in each case by one or two C.sub.1-3-alkyl
groups or by a fluorine, chlorine, bromine or iodine atom or by a
trifluoromethyl, cyano or C.sub.1-3-alkyloxy group, a
C.sub.3-8-alkenyl group, a C.sub.3-6-alkenyl group substituted by a
fluorine, chlorine or bromine atom or a trifluoromethyl group, a
C.sub.3-8-alkynyl group, an aryl group or an aryl-C.sub.2-4-alkenyl
group, and R.sup.4 denotes an azetidin-1-yl or pyrrolidin-1-yl
group which is substituted in the 3 position by an amino,
C.sub.1-3-alkylamino or a di-(C.sub.1-3-alkyl)amino group and may
additionally be substituted by one or two C.sub.1-3-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,
C.sub.1-3-alkylamino or a di-(C.sub.1-3-alkyl)amino group and may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
3-amino-piperidin-1-yl group wherein the piperidin-1-yl-moiety is
additionally substituted by an aminocarbonyl,
C.sub.1-2-alkyl-aminocarbonyl, di-(C.sub.1-2-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, a piperidin-1-yl or hexahydroazepin-1-yl group
substituted in the 3 position by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-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, wherein 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.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a piperazin-1-yl
or [1,4]diazepan-1-yl group optionally substituted on the carbon
skeleton by one or two C.sub.1-3-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.sub.1-3-alkyl groups, a
[1,4]diazepan-1-yl group optionally substituted by one or two
C.sub.1-3-alkyl groups, which is substituted by an amino group in
the 6 position,
a C.sub.3-7-cycloalkyl group which is substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, a
C.sub.3-7-cycloalkyl group which is substituted by an
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl group wherein the cycloalkyl
moiety is substituted by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl group wherein the cycloalkyl
moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkylamino group wherein the cycloalkyl moiety is
substituted by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group, wherein the two nitrogen atoms on
the cycloalkyl moiety are separated from one another by at least
two carbon atoms, an
N-(C.sub.3-7-cycloalkyl)-N-(C.sub.1-3-alkyl)-amino group wherein
the cycloalkyl moiety is substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, wherein
the two nitrogen atoms on the cycloalkyl moiety are separated from
one another by at least two carbon atoms, a
C.sub.3-7-cycloalkylamino group wherein the cycloalkyl moiety is
substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
N-(C.sub.3-7-cycloalkyl)-N-(C.sub.1-3-alkyl)-amino group wherein
the cycloalkyl moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl-amino group wherein the
cycloalkyl moiety is substituted by an amino, C.sub.1-3-alkylamino
or di-(C.sub.1-3-alkyl)-amino group, an
N-(C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl)-N-(C.sub.1-2-alkyl)-amino
group wherein the cycloalkyl moiety is substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, a
C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl-amino group wherein the
cycloalkyl moiety is substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
N-(C.sub.3-7-cycloalkyl-C.sub.1-2-alkyl)-N-(C.sub.1-2-alkyl)-amino
group wherein the cycloalkyl moiety is substituted by an
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or a
di-(C.sub.1-3-alkyl)amino-C.sub.1-3-alkyl group, an
R.sup.19--C.sub.2-4-alkylamino group wherein R.sup.19 is separated
from the nitrogen atom of the C.sub.2-4-alkylamino moiety by at
least two carbon atoms and [0062] R.sup.19 denotes an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group, an
R.sup.19--C.sub.2-4-alkylamino group wherein the nitrogen atom of
the C.sub.2-4-alkylamino moiety is substituted by a C.sub.1-3-alkyl
group and R.sup.19 is separated from the nitrogen atom of the
C.sub.2-4-alkylamino moiety by at least two carbon atoms, wherein
R.sup.19 is as hereinbefore defined, an amino group substituted by
the group R.sup.20 wherein [0063] R.sup.20 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, wherein the
groups mentioned for R.sup.20 may each be substituted by one or two
C.sub.1-3-alkyl groups, an amino group substituted by the group
R.sup.20 and a C.sub.1-3-alkyl group wherein R.sup.20 is as
hereinbefore defined, wherein the groups mentioned for R.sup.20 may
each be substituted by one or two C.sub.1-3-alkyl groups, a
R.sup.19--C.sub.3-4-alkyl group wherein the C.sub.3-4-alkyl moiety
is straight-chain and may additionally be substituted by one or two
C.sub.1-3-alkyl groups, wherein R.sup.19 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.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)amino
group, or an azetidin-2-yl-C.sub.1-2-alkyl,
azetidin-3-yl-C.sub.1-2-alkyl, pyrrolidin-2-yl-C.sub.1-2-alkyl,
pyrrolidin-3-yl, pyrrolidin-3-yl-C.sub.1-2-alkyl,
piperidin-2-yl-C.sub.1-2-alkyl, piperidin-3-yl,
piperidin-3-yl-C.sub.1-2-alkyl, piperidin-4-yl or
piperidin-4-yl-C.sub.1-2-alkyl group, wherein the above-mentioned
groups may each be substituted by one or two C.sub.1-3-alkyl
groups, wherein 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.sub.h independently of one another,
where the substituents are identical or different and R.sub.h
denotes a fluorine, chlorine, bromine or iodine atom, a
trifluoromethyl, cyano, nitro, amino, aminocarbonyl,
aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino,
C.sub.1-3-alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy,
C.sub.1-3-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, [0064] and the above-mentioned heteroaryl groups may be
mono- or disubstituted by R.sub.h, wherein the substituents may be
identical or different and R.sub.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.
[0065] Compounds of the above general formula I which contain one
or more groups that can be cleaved in vivo are so-called
prodrugs.
[0066] 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 et al. in International
Journal of Pharmaceutics 39, 75-85 (1987).
[0067] 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.sub.1-6-alkanol, a phenyl-C.sub.1-3-alkanol, a
C.sub.3-9-cycloalkanol, wherein a C.sub.5-8-cycloalkanol may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.5-8-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.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkyloxycarbonyl or
C.sub.2-6-alkanoyl group and the cycloalkanol moiety may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.4-7-cycloalkenol, a C.sub.3-5-alkenol, a
phenyl-C.sub.3-5-alkenol, a C.sub.3-5-alkynol or
phenyl-C.sub.3-5-alkynol with the proviso that no bonds to the
oxygen atom start from a carbon atom which carries a double or
triple bond, a C.sub.3-8-cycloalkyl-C.sub.1-3-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.sub.1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol
or an alcohol of formula
R.sub.p--CO--O--(R.sub.qCR.sub.r)--OH,
wherein [0068] R.sub.p denotes a C.sub.1-8-alkyl,
C.sub.5-7-cycloalkyl, C.sub.1-8-alkyloxy, C.sub.5-7-cycloalkyloxy,
phenyl or phenyl-C.sub.1-3-alkyl group, [0069] R.sub.q denotes a
hydrogen atom, a C.sub.1-3-alkyl, C.sub.5-7-cycloalkyl or phenyl
group and [0070] R.sub.r denotes a hydrogen atom or a
C.sub.1-3-alkyl group, by a group which is negatively charged under
physiological conditions is meant, for example, a tetrazol-5-yl,
phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl,
C.sub.1-6-alkylsulphonylamino, phenylsulphonylamino,
benzylsulphonylamino, trifluoromethylsulphonylamino,
C.sub.1-6-alkylsulphonylaminocarbonyl,
phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or
perfluoro-C.sub.1-6-alkylsulphonylaminocarbonyl group and by a
group which can be cleaved in vivo from an imino or amino group is
meant, for example, a hydroxy group, an acyl group such as a
phenylcarbonyl group optionally mono- or disubstituted by fluorine,
chlorine, bromine or iodine atoms, by C.sub.1-3-alkyl or
C.sub.1-3-alkyloxy groups, wherein the substituents may be
identical or different, a pyridinoyl group or a C.sub.1-16-alkanoyl
group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or
hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl
group, a C.sub.1-16-alkyloxycarbonyl or C.sub.1-16-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.sub.1-6-alkyloxycarbonyl group such as the
benzyloxycarbonyl, phenylethoxycarbonyl or phenyl propoxycarbonyl
group, a 3-amino-propionyl group wherein the amino group may be
mono- or disubstituted by C.sub.1-6-alkyl or C.sub.3-7-cycloalkyl
groups and the substituents may be identical or different, a
C.sub.1-3-alkylsulphonyl-C.sub.2-4-alkyloxycarbonyl,
C.sub.1-3-alkyloxy-C.sub.2-4-alkyloxy-C.sub.2-4-alkyloxycarbonyl,
R.sub.p--CO--O--(R.sub.qCR.sub.r)--O--CO,
C.sub.1-6-alkyl-CO--NH--(R.sub.sCR.sub.t)--O--CO or
C.sub.1-6-alkyl-CO--O--(R.sub.sCR.sub.t)--(R.sub.sCR.sub.t)--O--CO
group, wherein R.sub.p to R.sub.r are as hereinbefore defined,
[0071] R.sub.s and R.sub.t, which may be identical or different,
denote hydrogen atoms or C.sub.1-3-alkyl groups.
[0072] 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.
[0073] R.sup.2 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.
[0074] R.sup.3 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.
[0075] R.sup.4 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-[(methoxycarbonyl
methyl)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-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-ylcarbonyl
methyl)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-aminocyclopentyl)amino, (2-aminocyclohexyl)amino or
(3-aminocyclohexyl)amino group.
[0076] Preferred compounds of the above general formula I are those
wherein
R.sup.1 denotes a methyl group substituted by a group R.sub.a,
where [0077] R.sub.a denotes a 1,4-dihydro-quinazolinyl or
3,4-dihydro-quinazolinyl group, [0078] a 3,4-dihydro-isoquinolinyl
group, [0079] a 1H-benzo[d][1,2]oxazinyl or
1-oxo-1H-benzo[d][1,2]oxazinyl group, [0080] a
4H-benzo[e][1,3]oxazinyl or 4-oxo-4H-benzo[e][1,3]oxazinyl group,
[0081] a 4H-benzo[d][1,3]oxazinyl or 4-oxo-4H-benzo[d][1,3]oxazinyl
group, [0082] 2H-benzo[1,4]oxazinyl or 2-oxo-2H-benzo[1,4]oxazinyl
group, [0083] a 4H-benzo[e][1,3]thiazinyl or
4-oxo-4H-benzo[e][1,3]thiazinyl group, [0084] a
4H-benzo[d][1,3]thiazinyl or 2H-benzo[1,4]thiazinyl group, [0085] a
2-oxo-2H-benzo[e][1,3]oxazinyl or
2,2-dioxo-1H-benzo[c][1,2]thiazinyl group, [0086] a
2,3-dihydro-1H-benzo[e][1,4]diazepinyl or
2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepinyl group, [0087] a
4,5-dihydro-3H-benzo[b][1,4]diazepinyl or
4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepinyl group, [0088] a
5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepinyl group, [0089] a
2,3-dihydro-benzo[f][1,4]oxazepinyl or
2,3-dihydro-benzo[b][1,4]oxazepinyl group, [0090] a
2,3-dihydro-benzo[f][1,4]thiazepinyl-2,3-dihydro-benzo[b][1,4]thiazepinyl
group, [0091] a 5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepinyl
group, [0092] an 11H-dibenzo[b,e]azepinyl or
11-oxo-11H-dibenzo[b,e]azepinyl group, [0093] an
11H-benzo[e]pyrido[3,2-b]azepinyl group, [0094] a
5H-dibenzo[b,e][1,4]diazepinyl or dibenzo[b,f][1,4]oxazepinyl
group, [0095] 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, [0096]
5H-dibenzo[a,d]cycloheptenyl or 5H-dibenzo[b,f]azepinyl group,
[0097] a phenanthridinyl, benzo[c][1,5]naphthyridinyl,
benzo[h][1,6]naphthyridinyl, benzo[c][1,8]naphthyridinyl or
1,2,3,4-tetrahydro-phenanthridinyl group, [0098] a
benzo[f]quinoxalinyl group, [0099] 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, [0100] a
3-oxo-2,3-dihydro-isoindol-1-ylidene group, [0101] a
benzo[1,2,5]oxadiazolyl group, [0102] a dibenzofuranyl group,
[0103] an indolizinyl group, [0104] a 1H-perimidinyl group, [0105]
a pyrazolo[1,5-c]quinazolinyl group or [0106] an
imidazo[2,1-a]isoquinolinyl or imidazo[1,2-a]isoquinolinyl group
[0107] wherein the benzo groups of the above-mentioned groups
R.sub.a are substituted by the groups R.sup.10 to R.sup.12 and the
alkylene units of the above-mentioned groups R.sub.a may be
substituted by one or two C.sub.1-3-alkyl or
C.sub.1-3-alkyloxy-carbonyl groups, wherein the groups may be
identical or different, or by a trifluoromethyl group, and the
imino groups of the above-mentioned groups R.sub.a may be
substituted by a C.sub.1-3-alkyl group and [0108] R.sup.10 denotes
a hydrogen atom, [0109] a fluorine, chlorine, bromine or iodine
atom, [0110] a C.sub.1-3-alkyl or cyclopropyl group, [0111] a
hydroxy, C.sub.1-3-alkyloxy or cyclopropyloxy group, [0112] a
nitro, amino, C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)amino
group, [0113] a C.sub.1-3-alkyl-carbonylamino or
C.sub.1-3-alkyl-sulphonylamino group, [0114] a cyano, carboxy,
C.sub.1-3-alkyloxy-carbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, [0115] a mercapto, C.sub.1-3-alkylsulphanyl,
C.sub.1-3-alkylsulphinyl or C.sub.1-3-alkylsulphonyl or
aminosulphonyl group or [0116] a difluoromethyl, trifluoromethyl,
difluoromethoxy or trifluoromethoxy group and [0117] R.sup.11 and
R.sup.12, 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.sup.2 denotes a
hydrogen atom, a C.sub.1-3-alkyl group, a C.sub.3-6-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.sub.1-3-alkyl, cyclopropyl, ethenyl, ethynyl, hydroxy,
C.sub.1-3-alkyloxy, difluoromethoxy or trifluoromethoxy group,
wherein the substituents may be identical or different, R.sup.3
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 R.sup.4
denotes a (3-amino-piperidin-1-yl) group, wherein, 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.
[0118] Particularly preferred compounds of the above general
formula I are those wherein
R.sup.1 denotes a methyl group substituted by a group R.sub.a,
where [0119] R.sub.a denotes a 1,4-dihydro-quinazolin-2-yl or
3,4-dihydro-quinazolin-2-yl group, [0120] a
3,4-dihydro-isoquinolin-1-yl group, [0121] a
1H-benzo[d][1,2]oxazin-4-yl or 1-oxo-1H-benzo[d][1,2]oxazin-4-yl
group, [0122] a 4H-benzo[e][1,3]oxazin-2-yl or
4-oxo-4H-benzo[e][1,3]oxazin-2-yl group, [0123] a
4H-benzo[d][1,3]oxazin-2-yl or 4-oxo-4H-benzo[d][1,3]oxazin-2-yl
group, [0124] 2H-benzo[1,4]oxazin-3-yl or
2-oxo-2H-benzo[1,4]oxazin-3-yl group, [0125] a
4H-benzo[e][1,3]thiazin-2-yl or 4-oxo-4H-benzo[e][1,3]thiazin-2-yl
group, [0126] a 4H-benzo[d][1,3]thiazin-2-yl or
2H-benzo[1,4]thiazin-3-yl group, [0127] a
2-oxo-2H-benzo[e][1,3]oxazin-4-yl or
2,2-dioxo-1H-benzo[c][1,2]thiazin-4-yl group, [0128] 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, [0129] 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, [0130] a
5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-yl group, a
2,3-dihydro-benzo[f][1,4]oxazepin-5-yl or
2,3-dihydro-benzo[b]-[1,4]oxazepin-4-yl group, [0131] a
2,3-dihydro-benzo[f][1,4]thiazepin-5-yl or
2,3-dihydro-benzo[b]-[1,4]thiazepin-4-yl group, [0132] a
5-oxo-4,5-dihydro-benzo[f][1,3,4]oxadiazepin-2-yl group, [0133] an
11H-dibenzo[b,e]azepin-6-yl or 11-oxo-11H-dibenzo[b,e]azepin-6-yl
group, [0134] an 11H-benzo[e]pyrido[3,2-b]azepin-6-yl group [0135]
a 5H-dibenzo[b,e][1,4]diazepin-11-yl or
dibenzo[b,f][1,4]oxazepin-11-yl group, [0136] a
dibenzo[b,f][1,4]thiazepin-11-yl,
5-oxo-dibenzo[b,f][1,4]thiazepin-11-yl or
5,5-dioxo-dibenzo[b,f][1,4]thiazepin-11-yl group, [0137] a
5H-dibenzo[a,d]cyclohepten-10-yl or 5H-dibenzo[b,f]azepin-10-yl
group, [0138] a phenanthridin-6-yl, benzo[c][1,5]naphthyridin-6-yl,
benzo[h][1,6]naphthyridin-5-yl, benzo[c][1,8]naphthyridin-6-yl or
1,2,3,4-tetrahydrophenanthridin-6-yl group, [0139] a
benzo[f]quinoxalin-6-yl group, [0140] a
5H-dibenzo[d,f][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, [0141] a
3-oxo-2,3-dihydro-isoindol-1-ylidene group, [0142] a
benzo[1,2,5]oxadiazol-5-yl group, [0143] a dibenzofuran-2-yl group,
[0144] an indolizin-2-yl group, [0145] a 1H-perimidin-2-yl group,
[0146] a pyrazolo[1,5-c]quinazolin-5-yl group or [0147] an
imidazo[2,1-a]isoquinolin-2-yl or imidazo[1,2-a]isoquinolin-2-yl
group [0148] wherein the benzo groups of the above-mentioned groups
R.sub.a are substituted by the groups R.sup.10 to R.sup.12 and the
alkylene units of the above-mentioned groups R.sub.a may be
substituted by one or two methyl- or methoxy-carbonyl groups,
wherein the groups may be identical or different, or by a
trifluoromethyl group and the imino groups of the above-mentioned
groups R.sub.a may be substituted by a methyl group and [0149]
R.sup.10 denotes a hydrogen atom, [0150] a fluorine, chlorine,
bromine or iodine atom, [0151] a methyl or ethyl group, [0152] a
hydroxy, methoxy or ethoxy group or [0153] a difluoromethyl,
trifluoromethyl, difluoromethoxy or trifluoromethoxy group and
[0154] R.sup.11 and R.sup.12, which may be identical or different,
each represent a hydrogen atom, a fluorine, chlorine or bromine
atom, a methyl, trifluoromethyl or methoxy group, R.sup.2 denotes a
hydrogen atom or a methyl, ethyl, propyl, isopropyl, phenyl or
cyclopropyl group, R.sup.3 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 R.sup.4 denotes a
(3-amino-piperidin-1-yl) group, the tautomers, enantiomers,
diastereomers, the mixtures thereof and the salts thereof.
[0155] Most particularly preferred compounds of the above general
formula I are those wherein
R.sup.1 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, 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, R.sup.2 denotes a
methyl or cyclopropyl group, R.sup.3 denotes a 2-buten-1-yl,
3-methyl-2-buten-1-yl or 2-butyn-1-yl group and R.sup.4 denotes a
(3-amino-piperidin-1-yl) group, the tautomers, enantiomers,
diastereomers, the mixtures thereof and the salts thereof.
[0156] The following compounds of general formula I are
particularly preferred: [0157] (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, [0158]
(2)
1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-met-
hyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine, [0159]
(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, [0160]
(4)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piper-
idin-1-yl)-xanthine, [0161] (5)
1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-y-
l)-8-(3-amino-piperidin-1-yl)-xanthine, [0162] (6)
1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine, [0163] (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, [0164] (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, [0165] (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, [0166] (10)
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine, [0167] (11)
1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-but-
yn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine, [0168] (12)
1-[(8-methyl-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine, [0169] (13)
1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-ami-
no-piperidin-1-yl)-xanthine, [0170] (14)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3-amino--
piperidin-1-yl)-xanthine, [0171] (15)
1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine, [0172] (16)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-p-
iperidin-1-yl)-xanthine, [0173] (17)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine, [0174] (18)
1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)--
3-amino-piperidin-1-yl)-xanthine, [0175] (19)
1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)--
3-amino-piperidin-1-yl)-xanthine, [0176] (20)
1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine, [0177] (21)
1-[(pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine, [0178] (22)
1-[(benzo[c][1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine, [0179] (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, [0180] (24)
1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pi-
peridin-1-yl)-xanthine, [0181] (25)
1-[(benzo[f]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine, [0182] (26)
1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine, [0183] (27)
1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine, [0184] (28)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-p-
iperidin-1-yl)-xanthine, [0185] (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 [0186] (30)
1-[(3-oxo-2,3-dihydro-isoindol-1-ylidene)methyl]-3-methyl-7-(3-methyl-2-b-
uten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine and the salts
thereof.
[0187] 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
##STR00003##
wherein R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore defined
and R.sup.4'' denotes one of the groups mentioned for R.sup.4
hereinbefore which contain an imino, amino or alkylamino group,
wherein the imino, amino or alkylamino group is substituted by a
protective group.
[0188] 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.
[0189] 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.degree. C. and 80.degree.
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.degree. 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.degree. C. and the boiling
point of the solvent, by treating with boron tribromide in
methylene chloride at temperatures between -20.degree. C. and
ambient temperature, or by treating with aluminium chloride/anisol
at temperatures between 0.degree. C. and ambient temperature. b)
Deprotecting and cyclising a compound of general formula
##STR00004##
wherein R.sup.2 and R.sup.3 are as hereinbefore defined, R.sup.4''
denotes one of the groups mentioned for R.sup.4 hereinbefore which
contain an imino, amino or alkylamino group, wherein 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
R.sub.x, and the --CH.sub.2--CH.sub.2--X-phenyl unit is substituted
by R.sup.10 to R.sup.14 and may additionally be substituted by a
C.sub.1-3-alkyl group, wherein R.sub.x and R.sup.10 to R.sup.14 are
as hereinbefore defined, and PG also denotes one of the
above-mentioned protective groups, wherein 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.sup.1 denotes a
3-oxo-2,3-dihydro-isoindol-1-ylidenemethyl group optionally
substituted by a group as defined in claims 1 to 4:
[0190] Deprotecting and dehydrating a compound of general
formula
##STR00005##
wherein the benzo group is substituted by R.sup.10 to R.sup.14, and
R.sup.10 to R.sup.14 as well as R.sub.x, R.sup.2 and R.sup.3 are as
hereinbefore defined, and R.sup.4'' denotes one of the groups
mentioned for R.sup.4 hereinbefore which contain an imino, amino or
alkylamino group, wherein 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).
[0191] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers, as mentioned
hereinbefore. Thus, for example, cis/trans mixtures may be resolved
into their cis and trans isomers, and compounds with at least one
optically active carbon atom may be separated into their
enantiomers.
[0192] 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.
[0193] 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-yl)-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.
[0194] 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 maleic acid.
[0195] 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.
[0196] 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).
[0197] 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.
[0198] The biological properties of the new compounds were
investigated as follows:
[0199] 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 (10 mM Tris HCl, 0.15 M NaCl,
0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifuging at
35,000 g for 30 minutes at 4.degree. C. (to remove cell
debris).
[0200] The DPP-IV assay was carried out as follows:
[0201] 50 .mu.l substrate solution (AFC; AFC is
amido-4-trifluoromethylcoumarin), final concentration 100 .mu.M,
were placed in black microtitre plates. 20 .mu.l of assay buffer
(final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO)
was pipetted in. The reaction was started by adding 30 .mu.l of
solubilised Caco-2 protein (final concentration 0.14 .mu.g of
protein per well). The test substances to be investigated were
typically added prediluted in 20 .mu.l, 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 IC.sub.50 values, was
calculated from dosage/activity curves consisting of 11 measuring
points in each case. The following results were obtained:
TABLE-US-00001 Compound DPP IV inhibition (Example Nr.) IC.sub.50
[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 1(26) 7 1(27) 2 1(28) 2 1(29) 3 1(30)
3 1(32) 4 1(33) 4 2 6 3 20
[0202] 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.
[0203] 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 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.
[0204] 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
.beta..sub.3-agonists such as SB-418790 or AD-9677.
[0205] 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, .beta.-blockers, etc., or combinations
thereof.
[0206] 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 and/or diluents, e.g. with corn starch,
lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene
glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof into conventional galenic preparations
such as plain or coated tablets, capsules, powders, suspensions or
suppositories.
[0207] The Examples that follow are intended to illustrate the
invention:
PREPARATION OF THE STARTING COMPOUNDS
Example I
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-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xa-
nthine
[0208] A mixture of 260 mg of
3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-pi-
peridin-1-yl]-xanthine, 185 mg of
4-bromo-methyl-1-methyl-1H-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.degree. C. for 2 h and then stirred for another 15
h at 50.degree. 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.
[0209] Yield: 225 mg of (59% of theory)
[0210] R.sub.f value: 0.19 (silica gel, petroleum ether/ethyl
acetate=1:1)
[0211] Mass spectrum (ESI.sup.+): m/z=640 [M+H].sup.+
[0212] The following compounds are obtained analogously to Example
I: [0213] (1)
1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-met-
hyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xa-
nthine
[0214] R.sub.f value: 0.42 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=95:5)
[0215] Mass spectrum (ESI.sup.+): m/z=632 [M+H].sup.+ [0216] (2)
1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xa-
nthine
[0217] Mass spectrum (ESI.sup.+): m/z=445, 447 [M+H].sup.+ [0218]
(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.degree. C.)
[0219] R.sub.f value: 0.35 (silica gel, methylene
chloride/methanol=20:1)
[0220] Mass spectrum (ESI.sup.+): m/z=623 [M+H].sup.+ [0221] (4)
1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo--
xanthine
[0222] Mass spectrum (ESI.sup.+): m/z=462, 464 [M+H].sup.+ [0223]
(5)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-buty-
loxycarbonylamino)-piperidin-1-yl]-xanthine
[0224] R.sub.f value: 0.80 (silica gel, ethyl acetate)
[0225] Mass spectrum (ESI.sup.+): m/z=608 [M+H].sup.+ [0226] (6)
1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-y-
l)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0227] R.sub.f value: 0.55 (silica gel, ethyl acetate/petroleum
ether=2:1)
[0228] Mass spectrum (ESI.sup.+): m/z=612 [M+H].sup.+ [0229] (7)
1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(t-
ert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0230] R.sub.f value: 0.40 (silica gel, cyclohexane/ethyl
acetate=1:1)
[0231] Mass spectrum (ESI.sup.+): m/z=622 [M+H].sup.+ [0232] (8)
1-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[-
3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0233] R.sub.f value: 0.70 (silica gel, ethyl
acetate/cyclohexane=3:1)
[0234] Mass spectrum (ESI.sup.+): m/z=624 [M+H].sup.+ [0235] (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
[0236] R.sub.f value: 0.60 (aluminium oxide, petroleum ether/ethyl
acetate=1:1)
[0237] Mass spectrum (ESI.sup.+): m/z=628 [M+H].sup.+ [0238] (10)
1-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[-
(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0239] R.sub.f value: 0.75 (silica gel, ethyl acetate)
[0240] Mass spectrum (ESI.sup.+): m/z=624 [M+H].sup.+ [0241] (11)
1-[(3,3-dimethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-
-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0242] R.sub.f value: 0.50 (silica gel, ethyl acetate)
[0243] Mass spectrum (ESI.sup.+): m/z=588 [M+H].sup.+ [0244] (12)
1-[(methoxycarbonyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butylox-
ycarbonyl-amino)-piperidin-1-yl]-xanthine
[0245] Mass spectrum (ESI.sup.+): m/z=489 [M+H].sup.+ [0246] (13)
1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amin-
o)-piperidin-1-yl]-xanthine
[0247] Mass spectrum (ESI.sup.+): m/z=456 [M+H].sup.+ [0248] (14)
1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-but-
yn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0249] R.sub.f value: 0.60 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0250] Mass spectrum (ESI.sup.+): m/z=637 [M+H].sup.+ [0251] (15)
1-[(8-methyl-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0252] R.sub.f value: 0.65 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0253] Mass spectrum (ESI.sup.+): m/z=638 [M+H].sup.+ [0254] (16)
1-[(2-methyl-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0255] R.sub.f value: 0.70 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0256] Mass spectrum (ESI.sup.+): m/z=638 [M+H].sup.+ [0257] (17)
1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(te-
rt.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0258] R.sub.f value: 0.73 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0259] Mass spectrum (ESI.sup.+): m/z=549 [M+H].sup.+ [0260] (18)
1-[(2-chloro-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0261] R.sub.f value: 0.75 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0262] Mass spectrum (ESI.sup.+): m/z=658, 660 [M+H].sup.+ [0263]
(19)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-
-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0264] R.sub.f value: 0.55 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0265] Mass spectrum (ESI.sup.+): m/z=634 [M+H].sup.+ [0266] (20)
1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(t-
ert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0267] R.sub.f value: 0.67 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0268] Mass spectrum (ESI.sup.+): m/z=622 [M+H].sup.+ [0269] (21)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.--
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0270] R.sub.f value: 0.75 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0271] Mass spectrum (ESI.sup.+): m/z=608 [M+H].sup.+ [0272] (22)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(t-
ert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0273] R.sub.f value: 0.60 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0274] Mass spectrum (ESI.sup.+): m/z=634 [M+H].sup.+ [0275] (23)
1-[(dibenzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-b-
utyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0276] R.sub.f value: 0.85 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0277] Mass spectrum (ESI.sup.+): m/z=597 [M+H].sup.+ [0278] (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
[0279] R.sub.f value: 0.80 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0280] Mass spectrum (ESI.sup.+): m/z=622 [M+H].sup.+ [0281] (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
[0282] R.sub.f value: 0.85 (silica gel, methylene chloride/ethyl
acetate=1:1)
[0283] Mass spectrum (ESI.sup.+): m/z=622 [M+H].sup.+ [0284] (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
[0285] R.sub.f value: 0.54 (silica gel, methylene
chloride/methanol=94:6)
[0286] Mass spectrum (ESI.sup.+): m/z=609 [M+H].sup.+ [0287] (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
[0288] R.sub.f value: 0.67 (silica gel, ethyl acetate)
[0289] Mass spectrum (ESI.sup.+): m/z=598 [M+H].sup.+ [0290] (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
[0291] R.sub.f value: 0.40 (silica gel, methylene
chloride/methanol=95:5)
[0292] Mass spectrum (ESI.sup.+): m/z=609 [M+H].sup.+ [0293] (29)
1-[(benzo[c][1,5]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(-
R)-3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0294] R.sub.f value: 0.55 (silica gel, methylene
chloride/methanol=95:5)
[0295] Mass spectrum (ESI.sup.+): m/z=609 [M+H].sup.+ [0296] (30)
1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl--
amino)-piperidin-1-yl]-xanthine
[0297] R.sub.f value: 0.80 (silica gel, ethyl acetate)
[0298] Mass spectrum (ESI.sup.+): m/z=456 [M+H].sup.+ [0299] (31)
1-[(benzo[f]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(t-
ert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0300] R.sub.f value: 0.48 (silica gel, methylene
chloride/methanol=95:5)
[0301] Mass spectrum (ESI.sup.+): m/z=609 [M+H].sup.+ [0302] (32)
1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-
-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0303] R.sub.f value: 0.47 (silica gel, methylene
chloride/methanol=95:5)
[0304] Mass spectrum (ESI.sup.+): m/z=597 [M+H].sup.+ [0305] (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
[0306] R.sub.f value: 0.14 (silica gel, ethyl acetate)
[0307] Mass spectrum (ESI.sup.+): m/z=597 [M+H].sup.+ [0308] (34)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.--
butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0309] R.sub.f value: 0.20 (silica gel, cyclohexane/ethyl
acetate=1:1)
[0310] Mass spectrum (ESI.sup.+): m/z=608 [M+H].sup.+
Example II
4-Bromo-methyl-1-methyl-1H-benzo[c][1,2]thiazin-2,2-dioxide
[0311] 390 mg of 1,4-dimethyl-1H-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 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-1H-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.
[0312] Yield: 190 mg (35% of theory)
[0313] Mass spectrum (ESI.sup.+): m/z=288, 290 [M+H].sup.+
[0314] The following compounds are obtained analogously to Example
II: [0315] (1) 5-bromomethyl-benzo[h][1,6]naphthyridine
[0316] R.sub.f value: 0.76 (silica gel, ethyl acetate/petroleum
ether=1:1)
[0317] Mass spectrum (ESI.sup.+): m/z=273, 275 [M+H].sup.+ [0318]
(2) 6-chloromethyl-benzo[c][1,8]naphthyridine
[0319] (carried out with N-chlorosuccinimide in the presence of
benzoyl peroxide in carbon tetrachloride)
[0320] R.sub.f value: 0.47 (silica gel, ethyl
acetate/methanol=98:2) [0321] (3)
6-bromomethyl-benzo[c][1,5]naphthyridine
[0322] (carried out in the presence of benzoyl peroxide in carbon
tetrachloride)
[0323] R.sub.f value: 0.64 (silica gel, ethyl acetate/petroleum
ether=1:2)
[0324] Mass spectrum (ESI.sup.+): m/z=273, 275 [M+H].sup.+ [0325]
(4) 6-bromomethyl-benzo[f]quinoxaline
[0326] (carried out in the presence of benzoyl peroxide in carbon
tetrachloride)
[0327] R.sub.f value: 0.33 (silica gel, ethyl acetate/petroleum
ether=1:5)
[0328] Mass spectrum (ESI.sup.+): m/z=273, 275 [M+H].sup.+
Example III
3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-pipe-
ridin-1-yl]-xanthine
[0329] 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.degree. 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.degree. C. The cooled
reaction solution is poured onto 1 l of ice water, the precipitate
formed is suction filtered, washed with water and dried.
[0330] R.sub.f value: 0.60 (silica gel, ethyl acetate)
[0331] Mass spectrum (ESI.sup.+): m/z=433 [M+H].sup.+
[0332] The following compounds are obtained analogously to Example
III: [0333] (1)
3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1--
yl]-xanthine
[0334] melting point: 235-237.degree. C.
[0335] Mass spectrum (ESI.sup.+): m/z=417 [M+H].sup.+ [0336] (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
[0337] Mass spectrum (ESI.sup.+): m/z=551 [M+H].sup.+ [0338] (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
[0339] R.sub.f value: 0.50 (silica gel, cyclohexane/ethyl
acetate=1:2)
[0340] Mass spectrum (ESI.sup.+): m/z=582 [M+H].sup.+ [0341] (4)
3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidi-
n-1-yl]-xanthine
[0342] Mass spectrum (ESI.sup.+): m/z=417 [M+H].sup.+ [0343] (5)
3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperi-
din-1-yl]-xanthine
[0344] R.sub.f value: 0.70 (silica gel, ethyl acetate)
[0345] Mass spectrum (ESI.sup.+): m/z=443 [M+H].sup.+ [0346] (6)
3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonyl-amino)-piperid-
in-1-yl]-xanthine
[0347] R.sub.f value: 0.73 (silica gel, ethyl acetate)
[0348] Mass spectrum (ESI.sup.+): m/z=417 [M+H].sup.+ [0349] (7)
3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-amino)-pi-
peridin-1-yl]-xanthine
[0350] R.sub.f value: 0.35 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0351] Mass spectrum (ESI.sup.+): m/z=443 [M+H].sup.+ [0352] (8)
1-[(indolizin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-
carbonyl-amino)-piperidin-1-yl]-xanthine
[0353] R.sub.f value: 0.29 (silica gel, petroleum ether/ethyl
acetate=1:1)
[0354] Mass spectrum (ESI.sup.+): m/z=546 [M+H].sup.+
Example IV
3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine
[0355] 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.
[0356] Yield: 20.50 g (80% of theory)
[0357] Mass spectrum (ESI.sup.+): m/z=313, 315 [M+H].sup.+
[0358] The following compounds are obtained analogously to Example
IV: [0359] (1) 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine
[0360] R.sub.f value: 0.72 (silica gel, ethyl acetate)
[0361] Mass spectrum (ESI.sup.+): m/z=297, 299 [M+H].sup.+ [0362]
(2) 3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine
[0363] Mass spectrum (ESI.sup.+): m/z=299, 301 [M+H].sup.+ [0364]
(3) 3-cyclopropyl-7-(2-butyn-1-yl)-8-bromo-xanthine
[0365] R.sub.f value: 0.45 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0366] Mass spectrum (ESI.sup.+): m/z=323, 325 [M+H].sup.+
Example V
Methyl
1-chloromethyl-3-methyl-3,4-dihydro-isoquinolin-3-yl-carboxylate
[0367] Prepared from methyl
2-(2-chloro-acetylamino)-2-methyl-3-phenyl-propionate analogously
to Das et al., Indian J. Chem. 1985, 24B, 1302.
[0368] R.sub.f value: 0.52 (silica gel, petroleum ether/ethyl
acetate=2:1)
[0369] Mass spectrum (ESI.sup.+): m/z=252, 254 [M+H].sup.+
Example VI
1-(2-{2-[2-(tert.-butyloxycarbonylamino)-ethoxy]-phenyl}-2-oxo-ethyl)-3-me-
thyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]--
xanthine
[0370] 187 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added to
400 mg of
1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(t-
ert.-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.degree. C. Then a further 90 mg
of tert.-butyl 2-bromo-ethyl-carbaminate are added. After another
eight hours at 55.degree. C. the reaction is complete. The cooled
reaction mixture is combined with water, the precipitate formed is
suction filtered, washed with water and dried.
[0371] Yield: 368 mg (73% of theory)
[0372] Mass spectrum (ESI.sup.+): m/z=694 [M+H].sup.+
Example VII
1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xan-
thine
[0373] Prepared by treating
1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xa-
nthine with boron tribromide in the presence of 4 .ANG. molecular
sieve in methylene chloride at 4.degree. C.
[0374] Mass spectrum (ESI.sup.+): m/z=431, 433 [M+H].sup.+
Example VIII
1-[(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)methyl]-3-methyl-7-(3-met-
hyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xant-
hine
[0375] 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)-piperidin-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 .mu.l 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.
[0376] Yield: 160 mg (64% of theory)
[0377] R.sub.f value: 0.40 (silica gel, methylene
chloride/methanol=9:1)
[0378] Mass spectrum (ESI.sup.+): m/z=594 [M+H].sup.+
Example IX
1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8--
[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0379] 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.
[0380] Yield: 2.00 g (80% of theory)
[0381] R.sub.f value: 0.49 (silica gel, methylene
chloride/methanol=9:1)
[0382] Mass spectrum (ESI.sup.-): m/z=593 [M-H].sup.-
[0383] The following compound is obtained analogously to Example
IX: [0384] (1)
1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-am-
ino)-piperidin-1-yl]-xanthine
[0385] (The ester cleaving is carried out with 4 M potassium
hydroxide solution in a mixture of methanol and
tetrahydrofuran.)
[0386] Mass spectrum (ESI.sup.-): m/z=473 [M-H].sup.-
Example X
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-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xan-
thine
[0387] A mixture of 200 mg of
1-{2-[2-(2-chloro-acetylamino)-phenyl]-2-oxo-ethyl}-3-methyl-7-((E)-2-but-
en-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 down and chromatographed through a silica
gel column with ethyl acetate/methanol (10:0 to 8:2) as eluant.
[0388] Yield: 95 mg (51% of theory)
[0389] R.sub.f value: 0.25 (silica gel, cyclohexane/ethyl
acetate=2:8)
Example XI
1-{2-[2-(2-chloro-acetylamino)-phenyl]-2-oxo-ethyl}-3-methyl-7-((E)-2-bute-
n-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine
[0390] 51 .mu.l 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
.mu.l pyridine in 1 ml methylene chloride. The reaction mixture is
stirred for two hours at 35.degree. 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.
[0391] Yield: 210 mg (58% of theory)
[0392] R.sub.f value: 0.50 (silica gel, cyclohexane/ethyl
acetate/isopropanol=14:3:3)
[0393] Mass spectrum (ESI.sup.+): m/z=628, 630 [M+H].sup.+
[0394] The following compounds are obtained analogously to Example
XI: [0395] (1)
N-(1-benzyl-2,2,2-trifluoro-ethyl)-2-chloro-acetamide
[0396] (The reaction is carried out with chloroacetyl chloride in
diethyl ether in the presence of triethylamine).
[0397] R.sub.f value: 0.45 (aluminium oxide, petroleum ether/ethyl
acetate=5:1)
[0398] Mass spectrum (ESI.sup.+): m/z=266 [M+H].sup.+ [0399] (2)
2-chloro-N-(4-methyl-biphenyl-2-yl)-acetamide
[0400] (The reaction is carried out with chloroacetyl chloride in
the presence of diisopropylethylamine.)
[0401] R.sub.f value: 0.82 (silica gel, cyclohexane/ethyl
acetate=1:1)
[0402] Mass spectrum (ESI.sup.+): m/z=260, 262 [M+H].sup.+ [0403]
(3) 2-chloro-N-(6-methyl-biphenyl-2-yl)-acetamide
[0404] (The reaction is carried out with chloroacetyl chloride in
the presence of diisopropylethylamine.)
[0405] R.sub.f value: 0.60 (silica gel, cyclohexane/ethyl
acetate=3:1)
[0406] Mass spectrum (ESI.sup.+): m/z=260, 262 [M+H].sup.+ [0407]
(4) 2-chloro-N-(3-methyl-biphenyl-2-yl)-acetamide
[0408] (The reaction is carried out with chloroacetyl chloride in
the presence of diisopropylethylamine.)
[0409] R.sub.f value: 0.45 (silica gel, cyclohexane/ethyl
acetate=3:1)
Example XII
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
[0410] 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.
[0411] Yield: 5.38 g (90% of theory)
[0412] Mass spectrum (ESI.sup.+): m/z=552 [M+H].sup.+
Example XIII
6-chloromethyl-1,2,3,4-tetrahydro-phenanthridine-hydrochloride
[0413] Prepared by treating 110 mg of
6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine with 60 .mu.l of
thionyl chloride in 2.5 ml methylene chloride at 0.degree. C. to
ambient temperature.
[0414] Yield: 140 mg (100% of theory)
[0415] R.sub.f value: 0.50 (silica gel, petroleum ether/ethyl
acetate=5:1)
[0416] Mass spectrum (ESI.sup.+): m/z=232, 234 [M+H].sup.+
Example XIV
6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine
[0417] 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, wherein 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 wherein
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.
[0418] Yield: 120 mg (41% of theory)
[0419] R.sub.f value: 0.40 (silica gel, petroleum ether/ethyl
acetate=2:1)
[0420] Mass spectrum (ESI.sup.+): m/z=214 [M+H].sup.+
Example XV
Ethyl 1,2,3,4-tetrahydro-phenanthridin-6-yl-carboxylate
[0421] 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
product obtained is still somewhat contaminated but is further
reacted without any further purification.
[0422] Yield: 380 mg (8% of theory)
[0423] R.sub.f value: 0.55 (silica gel, petroleum ether/ethyl
acetate=2:1)
[0424] Mass spectrum (ESI.sup.+): m/z=256 [M+H].sup.+
Example XVI
1-chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline
[0425] 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.degree. 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.
[0426] Yield: 415 mg (84% of theory)
[0427] R.sub.f value: 0.55 (aluminium oxide, petroleum ether/ethyl
acetate=10:1)
[0428] Mass spectrum (ESI.sup.+): m/z=248, 250 [M+H].sup.+
Example XVII
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(te-
rt.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0429] A mixture of 280 mg of
1-[2-(2-amino-benzylamino)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(t-
ert.-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-(t-
ert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, deprotected
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine is also obtained.
[0430] Yield: 120 mg (44% of theory)
[0431] Mass spectrum (ESI.sup.+): m/z=561 [M+H].sup.+
Example XVIII
1-[2-(2-amino-benzylamino)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(te-
rt.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0432] A mixture of 397 mg of
1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-am-
ino)-piperidin-1-yl]-xanthine, 110 mg of 2-amino-benzylamine and
460 .mu.l 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 1M
sodium hydroxide solution and suction filtered. The filter cake is
washed with a little ethanol and diethyl ether and dried.
[0433] Yield: 400 mg (83% of theory)
[0434] R.sub.f value: 0.68 (silica gel, methylene
chloride/methanol=9:1)
[0435] Mass spectrum (ESI.sup.+): m/z=579 [M+H].sup.+
Example XIX
1-[(3-methyl-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-
-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0436] 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-amin-
o)-piperidin-1-yl]-xanthine in 5 ml of methanol. The reaction
mixture is stirred for two hours at ambient temperature, then a
further 150 .mu.l 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.
[0437] Yield: 250 mg (50% of theory)
[0438] Mass spectrum (ESI.sup.+): m/z=575 [M+H].sup.+
[0439] The following compound is obtained analogously to Example
XIX: [0440] (1)
1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-b-
utyloxycarbonyl-amino)-piperidin-1-yl]-xanthine
[0441] Mass spectrum (ESI.sup.+): m/z=597 [M+H].sup.+
Example XX
3-Cyclopropyl-8-bromo-xanthine
[0442] 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.degree. C. The
reaction mixture is stirred for six hours at this temperature, then
a further 100 .mu.l 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.degree. C. in the circulating air dryer.
[0443] Yield: 3.36 g (65% of theory)
[0444] R.sub.f value: 0.65 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0445] Mass spectrum (ESI.sup.+): m/z=271, 273 [M+H].sup.+
Example XXI
6-Chloromethyl-8-methyl-phenanthridine
[0446] 600 g of 2-chloro-N-(4'-methyl-biphenyl-2-yl)-acetamide are
heated in 3 ml phosphorus oxychloride to 100.degree. C. for about 6
hours. Then the phosphorus oxychloride is distilled off. The
residue is suspended in water and ethyl acetate and neutralised
with 3 M sodium hydroxide solution wherein 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.
[0447] Yield: 160 mg (29% of theory)
[0448] R.sub.f value: 0.45 (silica gel, cyclohexane/ethyl
acetate=1:1)
[0449] Mass spectrum (ESI.sup.+): m/z=242, 244 [M+H].sup.+
[0450] The following compounds are obtained analogously to Example
XXI: [0451] (1) 6-chloromethyl-1-methyl-phenanthridine
[0452] Mass spectrum (ESI.sup.+): m/z=242, 244 [M+H].sup.+ [0453]
(2) 6-chloromethyl-4-methyl-phenanthridine
[0454] Mass spectrum (ESI.sup.+): m/z=242, 244 [M+H].sup.+
Example XXII
1-[(indolizin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine
[0455] 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.
[0456] Yield: 405 mg (48% of theory)
[0457] R.sub.f value: 0.62 (silica gel, petroleum ether/ethyl
acetate=1:1)
[0458] Mass spectrum (ESI.sup.+): m/z=426, 428 [M+H].sup.+
Example XXIII
6-Methyl-benzo[c][1,8]naphthyridine
[0459] 8.7 ml glycerol and 4.38 g 3-amino-1-methyl-isoquinoline are
added to a mixture of 960 mg of iron(II)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 wherein cooling in the ice
bath. The viscous, sticky mass is heated to approx. 55.degree. C.,
combined with 15 ml of water and then stirred for three hours at
140.degree. C. The cooled reaction mixture is diluted with some
ice, made alkaline with 15 N sodium hydroxide solution wherein
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.
[0460] Yield: 2.05 g (38% of theory)
[0461] R.sub.f value: 0.15 (silica gel, ethyl acetate)
[0462] Mass spectrum (ESI.sup.+): m/z=195 [M+H].sup.+
[0463] The following compound is obtained analogously to Example
XXIII: [0464] (1) 6-methyl-benzo[c][1,5]naphthyridine
[0465] R.sub.f value: 0.52 (silica gel, methylene
chloride/methanol=95:5)
[0466] Mass spectrum (ESI.sup.+): m/z=195 [M+H].sup.+
Example XXIV
6-methyl-benzo[f]quinoxaline
[0467] 170 mg of 4-methyl-naphthalene-1,2-diamine and 114 .mu.l of
glyoxal are stirred in a mixture of 2 ml of water and 2 ml of
ethanol for half an hour at 75.degree. 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 purified by chromatography over a silica gel column with
methylene chloride/methanol (100:0 to 99:1) as eluant.
[0468] Yield: 140 mg (73% of theory)
[0469] R.sub.f value: 0.84 (silica gel, ethyl acetate)
[0470] Mass spectrum (ESI.sup.+): m/z=195 [M+H].sup.+
Example XXV
2-chloromethyl-imidazo[2,1-a]isoquinoline
[0471] 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.
[0472] Yield: 420 mg (39% of theory)
[0473] R.sub.f value: 0.65 (silica gel, methylene
chloride/methanol=95:5)
[0474] Mass spectrum (ESI.sup.+): m/z=217, 219 [M+H].sup.+
[0475] The following compound is obtained analogously to Example
XXV: [0476] (1) 2-chloromethyl-imidazo[1,2-a]isoquinoline
[0477] R.sub.f value: 0.64 (silica gel, methylene
chloride/methanol=95:5)
[0478] Mass spectrum (ESI.sup.+): m/z=217, 219 [M+H].sup.+
Example 1
##STR00006##
[0479]
1-[(1-methyl-2,2-dioxo-1H-benzo[c][1,2]thiazin-4H)methyl]-3-methyl--
7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
[0480] 3.5 ml isopropanolic hydrochloric acid (5-6 M) are added to
340 mg of
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-(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 1N 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.degree. C. in the drying gun.
[0481] Yield: 220 mg (77% of theory)
[0482] melting point: 205-208.degree. C. (decomposition)
[0483] Mass spectrum (ESI.sup.+): m/z=540 [M+H].sup.+
[0484] The following compounds are obtained analogously to Example
1: [0485] (1)
1-[(3-methoxycarbonyl-3-methyl-3,4-dihydro-isoquinolin-1-yl]methyl]-3-met-
hyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00007##
[0486] R.sub.f value: 0.42 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0487] Mass spectrum (ESI.sup.+): m/z=532 [M+H].sup.+ [0488] (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
##STR00008##
[0488] (carried out with trifluoroacetic acid in methylene
chloride)
[0489] R.sub.f value: 0.50 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:0.1)
[0490] Mass spectrum (ESI.sup.+): m/z=491 [M+H].sup.+ [0491] (3)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piper-
idin-1-yl)-xanthine-dihydrochloride
##STR00009##
[0492] R.sub.f value: 0.55 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0493] Mass spectrum (ESI.sup.+): m/z=508 [M+H].sup.+ [0494] (4)
1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-y-
l)-8-(3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid
##STR00010##
[0494] (carried out with trifluoroacetic acid in methylene
chloride)
[0495] R.sub.f value: 0.75 (aluminium oxide, methylene
chloride/methanol=10:1)
[0496] Mass spectrum (ESI.sup.+): m/z=512 [M+H].sup.+ [0497] (5)
1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine
##STR00011##
[0498] R.sub.f value: 0.45 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0499] Mass spectrum (ESI.sup.+): m/z=522 [M+H].sup.+ [0500] (6)
1-[(dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(-
3-amino-piperidin-1-yl)-xanthine
##STR00012##
[0501] Mass spectrum (ESI.sup.+): m/z=524 [M+H].sup.+ [0502] (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
##STR00013##
[0502] (carried out with trifluoroacetic acid in methylene
chloride)
[0503] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol=10:1)
[0504] Mass spectrum (ESI.sup.+): m/z=528 [M+H].sup.+ [0505] (8)
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
##STR00014##
[0506] Mass spectrum (ESI.sup.+): m/z=524 [M+H].sup.+
[0507] melting point: 128.degree. C.
(9)
1-[(3,3-dimethyl-3,4-dihydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bu-
tyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00015##
[0509] R.sub.f value: 0.55 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0510] Mass spectrum (ESI.sup.+): m/z=488 [M+H].sup.+ [0511] (10)
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine
##STR00016##
[0511] (carried out with trifluoroacetic acid in methylene
chloride)
[0512] Mass spectrum (ESI.sup.+): m/z=461 [M+H].sup.+ [0513] (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
##STR00017##
[0513] (carried out with trifluoroacetic acid in methylene
chloride)
[0514] Mass spectrum (ESI.sup.+): m/z=475 [M+H].sup.+ [0515] (12)
1-[(5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)methyl]-3-methyl-7-(2-but-
yn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00018##
[0516] R.sub.f value: 0.45 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0517] Mass spectrum (ESI.sup.+): m/z=537 [M+H].sup.+ [0518] (13)
1-[(8-methyl-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00019##
[0519] R.sub.f value: 0.60 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0520] Mass spectrum (ESI.sup.+): m/z=538 [M+H].sup.+ [0521] (14)
1-[(2-methyl-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00020##
[0522] R.sub.f value: 0.55 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0523] Mass spectrum (ESI.sup.+): m/z=538 [M+H].sup.+ [0524] (15)
1-[(benzo[1,2,5]oxadiazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-ami-
no-piperidin-1-yl)-xanthine
##STR00021##
[0525] R.sub.f value: 0.38 (silica gel, methylene
chloride/methanol=9:1)
[0526] Mass spectrum (ESI.sup.+): m/z=449 [M+H].sup.+ [0527] (16)
1-[(2-chloro-dibenzo[b,f][1,4]oxazepin-11-yl)methyl]-3-methyl-7-(2-butyn--
1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
##STR00022##
[0528] R.sub.f value: 0.50 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0529] Mass spectrum (ESI.sup.+): m/z=558, 560 [M+H].sup.+ [0530]
(17)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3-amino--
piperidin-1-yl)-xanthine
##STR00023##
[0531] R.sub.f value: 0.50 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0532] Mass spectrum (ESI.sup.+): m/z=534 [M+H].sup.+ [0533] (18)
1-[(8-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-am-
ino-piperidin-1-yl)-xanthine
##STR00024##
[0534] melting point: 200-205.degree. C.
[0535] Mass spectrum (ESI.sup.+): m/z=522 [M+H].sup.+ [0536] (19)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-p-
iperidin-1-yl)-xanthine
##STR00025##
[0537] R.sub.f value: 0.55 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0538] Mass spectrum (ESI.sup.+): m/z=508 [M+H].sup.+ [0539] (20)
1-[(phenanthridin-6-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine
##STR00026##
[0540] R.sub.f value: 0.50 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0541] Mass spectrum (ESI.sup.+): m/z=534 [M+H].sup.+ [0542] (21)
1-[(dibenzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pi-
peridin-1-yl)-xanthine
##STR00027##
[0543] R.sub.f value: 0.40 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0544] Mass spectrum (ESI.sup.+): m/z=497 [M+H].sup.+ [0545] (22)
1-[(1-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)--
3-amino-piperidin-1-yl)-xanthine
##STR00028##
[0546] R.sub.f value: 0.50 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0547] Mass spectrum (ESI.sup.+): m/z=522 [M+H].sup.+ [0548] (23)
1-[(4-methyl-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)--
3-amino-piperidin-1-yl)-xanthine
##STR00029##
[0549] R.sub.f value: 0.40 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0550] Mass spectrum (ESI.sup.+): m/z=522 [M+H].sup.+ [0551] (24)
1-[(indolizin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-
-1-yl)-xanthine
##STR00030##
[0552] R.sub.f value: 0.47 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0553] Mass spectrum (ESI.sup.+): m/z=446 [M+H].sup.+ [0554] (25)
1-[(benzo[h][1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine
##STR00031##
[0555] R.sub.f value: 0.49 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0556] Mass spectrum (ESI.sup.+): m/z=509 [M+H].sup.+ [0557] (26)
1-[(pyrazolo[1,5-c]quinazolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine
##STR00032##
[0558] R.sub.f value: 0.46 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0559] Mass spectrum (ESI.sup.+): m/z=498 [M+H].sup.+ [0560] (27)
1-[(benzo[c][1,8]naphthyridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine
##STR00033##
[0561] R.sub.f value: 0.48 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0562] Mass spectrum (ESI.sup.+): m/z=509 [M+H].sup.+ [0563] (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
##STR00034##
[0564] R.sub.f value: 0.51 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0565] Mass spectrum (ESI.sup.+): m/z=509 [M+H].sup.+ [0566] (29)
1-[(1H-perimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pi-
peridin-1-yl)-xanthine
##STR00035##
[0567] R.sub.f value: 0.47 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0568] Mass spectrum (ESI.sup.+): m/z=497 [M+H].sup.+ [0569] (30)
1-[(benzo[f]quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine
##STR00036##
[0570] R.sub.f value: 0.50 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0571] Mass spectrum (ESI.sup.+): m/z=509 [M+H].sup.+ [0572] (31)
1-[(imidazo[2,1-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine
##STR00037##
[0573] R.sub.f value: 0.54 (silica gel, methylene
chloride/methanol/conc. aqueous ammonia=90:10:1)
[0574] Mass spectrum (ESI.sup.+): m/z=497 [M+H].sup.+ [0575] (32)
1-[(imidazo[1,2-a]isoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
-amino-piperidin-1-yl)-xanthine
##STR00038##
[0576] melting point: 194-198.5.degree. C.
[0577] Mass spectrum (ESI.sup.+): m/z=497 [M+H].sup.+ [0578] (33)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-p-
iperidin-1-yl)-xanthine
##STR00039##
[0579] R.sub.f value: 0.55 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0580] Mass spectrum (ESI.sup.+): m/z=508 [M+H].sup.+
Example 2
##STR00040##
[0581]
1-[(2,3-dihydro-benzo[f][1,4]oxazepin-5-yl)methyl]-3-methyl-7-(2-bu-
tyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
[0582] 1.15 ml trifluoroacetic acid are added to 368 mg of
1-(2-{2-[2-(tert.-butyloxycarbonylamino)-ethoxy]-phenyl}-2-oxo-ethyl)-3-m-
ethyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-
-xanthine in 7 ml methylene chloride wherein 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.
[0583] Yield: 75 mg (30% of theory)
[0584] R.sub.f value: 0.20 (silica gel, methylene
chloride/methanol=9:1)
[0585] Mass spectrum (ESI.sup.+): m/z=476 [M+H].sup.+
Example 3
##STR00041##
[0586]
1-[(3-oxo-2,3-dihydro-isoindol-1-ylidene)methyl]-3-methyl-7-(3-meth-
yl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine
[0587] 150 mg of
1-[(1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)methyl]-3-methyl-7-(3-me-
thyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xan-
thine 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.
[0588] Yield: 50 mg (42% of theory)
[0589] R.sub.f value: 0.56 (Reversed phase ready-made TLC plate (E.
Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0590] Mass spectrum (ESI.sup.+): m/z=476 [M+H].sup.+
[0591] The following compounds may also be obtained analogously to
the foregoing Examples and other methods known from the
literature:
TABLE-US-00002 No. Name Structural formula (1)
1-[(1-methyl-1,4-dihydro-quinazolin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00042## (2)
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00043## (3) 1-[(3-methyl-3,4-dihydro-quinazolin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00044## (4)
1-[(3,4-dihydro-isoquinolin-1-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00045## (5) 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 ##STR00046## (6)
1-[(4,4-dimethyl-3,4-dihydro-isoquinolin-1-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00047## (7)
1-[(1H-benzo[d][1,2]oxazin-4-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00048## (8) 1-[(1-oxo-1H-benzo[d][1,2]oxazin-4-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00049## (9)
1-[(4H-benzo[e][1,3]oxazin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00050## (10) 1-[(4,4-dimethyl-4H-benzo[e][1,3]oxazin-
2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
(3-amino-piperidin-1-yl)-xanthine ##STR00051## (11)
1-[(4-oxo-4H-benzo[e][1,3]oxazin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00052## (12)
1-[(4H-benzo[d][1,3]oxazin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00053## (13) 1-[(4,4-dimethyl-4H-benzo[d][1,3]oxazin-
2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
(3-amino-piperidin-1-yl)-xanthine ##STR00054## (14)
1-[(4-oxo-4H-benzo[d][1,3]oxazin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00055## (15)
1-[(2H-benzo[1,4]oxazin-3-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00056## (16) 1-[(2-oxo-2H-benzo[1,4]oxazin-3-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00057## (17)
1-[(2,2-dimethyl-2H-benzo[1,4]oxazin-3-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00058## (18)
1-[4H-benzo[e][1,3]thiazin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00059## (19) 1-[4,4-dimethyl-4H-benzo[e][1,3]thiazin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00060## (20)
1-[4-oxo-4H-benzo[e][1,3]thiazin-2-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00061## (21)
1-[(4H-benzo[d][1,3]thiazin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00062## (22) 1-[(2H-benzo[1,4]thiazin-3-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00063## (23) 1-[(2-oxo-2H-benzo[e][1,3]oxazin-4-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00064## (24)
1-[(2,3-dihydro-1H-benzo[e][1,4]diazepin-
5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
(3-amino-piperidin-1-yl)-xanthine ##STR00065## (25)
1-[(1-methyl-2,3-dihydro-1H- benzo[e][1,4]diazepin-5-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00066## (26) 1-[(1-methyl-2-oxo-2,3-dihydro-1H-
benzo[e][1,4]diazepin-5-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00067## (27) 1-[(4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00068## (28) 1-[(5-methyl-4-oxo-4,5-dihydro-3H-
benzo[b][1,4]diazepin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00069## (29) 1-[5-oxo-4,5-dihydro-3H-
benzo[e][1,4]diazepin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00070## (30) 1-[4-methyl-5-oxo-4,5-dihydro-3H-
benzo[e][1,4]diazepin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00071## (31) 1-[(3,3-dimethyl-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
##STR00072## (32) 1-[(2,2-dimethyl-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
##STR00073## (33) 1-[(2,3-dihydro-benzo[b][1,4]oxazepin-4-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00074## (34)
1-[(6,6-dimethyl-2,3-dihydro- benzo[b][1,4]oxazepin-4-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00075## (35) 1-[(2,3-dihydro-benzo[b][1,4]thiazepin-4-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00076## (36)
1-[(2,2-dimethyl-2,3-dihydro-
benzo[b][1,4]thiazepin-4-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00077## (37) 1-[(2,3-dihydro-benzo[f][1,4]thiazepin-5-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00078## (38)
1-[(5-oxo-4,5-dihydro- benzo[f][1,3,4]oxadiazepin-2-yl)methyl]-3-
methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00079## (39) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-
3-ethyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00080## (40) 1-[(11H-dibenzo[b,e]azepin-6-yl)methyl]-
3-isopropyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00081## (41) 1-[(11-oxo-11H-dibenzo[b,e]azepin-6-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00082## (42)
1-[(11H-benzo[e]pyrido[3,2-b]azepin-6-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00083## (43) 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
##STR00084## (44) 1-[(dibenzo[b,f][1,4]thiazepin-11-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00085## (45)
1-[(5-oxo-dibenzo[b,f][1,4]thiazepin-11-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00086## (46)
1-[(5,5-dioxo-dibenzo[b,f][1,4]thiazepin-
11-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
(3-amino-piperidin-1-yl)-xanthine ##STR00087## (47)
1-[(5H-dibenzo[a,d]cyclohepten-10-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00088## (48)
1-[(5-methyl-5H-dibenzo[b,f]azepin-10-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00089## (49)
1-[(phenanthridin-6-yl)methyl]-3-methyl-7-
(3-methyl-2-buten-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00090## (50) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-
((E)-2-buten-1-yl)-8-(3-amino-piperidin-1- yl)-xanthine
##STR00091## (51) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-
((Z)-2-buten-1-yl)-8-(3-amino-piperidin-1- yl)-xanthine
##STR00092## (52) 1-[(phenanthridin-6-yl)methyl]-3-methyl-7-
[(1-cyclopenten-1-yl)methyl]-8-(3-amino- piperidin-1-yl)-xanthine
##STR00093## (53) 1-[(benzo[c][1,5]naphthyridin-6-yl)methyl]-
3-methyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00094## (54) 1-[(5H-dibenzo[d,f][1,3]diazepin-6-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00095## (55)
1-[(5H-benzo[e]pyrrolo[1,2-
a][1,4]diazepin-11-yl)methyl]-3-methyl-7-
(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)- xanthine ##STR00096##
(56) 1-[(thieno[3,2-b][1,4]benzoxazepin-9-
yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00097## (57)
1-[(3,4-dihydro-quinazolin-2-yl)methyl]-3-
phenyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00098## (58) 1-[(3,4-dihydro-isoquinolin-1-yl)methyl]-3-
phenyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yl)-xanthine
##STR00099## (59) 1-[(2,3-dihydro-benzo[f][1,4]oxazepin-5-
yl)methyl]-3-phenyl-7-(2-butyn-1-yl)-8-(3-
amino-piperidin-1-yl)-xanthine ##STR00100## (60)
1-[(2-oxo-2,3-dihydro-1H- benzo[e][1,4]diazepin-5-yl)methyl]-3-
phenyl-7-(2-butyn-1-yl)-8-(3-amino- piperidin-1-yI)-xanthine
##STR00101##
Example 4
Coated Tablets Containing 75 mg of Active Substance
1 Tablet Core Contains:
TABLE-US-00003 [0592] 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 mg
230.0 mg
Preparation:
[0593] The active substance is mixed with calcium phosphate, corn
starch, polyvinylpyrrolidone, 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.
[0594] Weight of core: 230 mg
[0595] die: 9 mm, convex
[0596] The tablet cores thus produced are coated with a film
consisting essentially of hydroxypropylmethylcellulose. The
finished film-coated tablets are polished with beeswax.
[0597] Weight of coated tablet: 245 mg.
Example 5
Tablets Containing 100 mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00004 [0598] active substance 100.0 mg lactose 80.0 mg
corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate
2.0 mg 220.0 mg
Method of Preparation:
[0599] 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.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets.
[0600] Weight of tablet: 220 mg
[0601] Diameter: 10 mm, biplanar, facetted on both sides and
notched on one side.
Example 6
Tablets Containing 150 mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00005 [0602] active substance 150.0 mg powdered lactose
89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
Preparation:
[0603] 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.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture.
[0604] Weight of tablet: 300 mg
[0605] die: 10 mm, flat
Example 7
Hard Gelatine Capsules Containing 150 mg of Active Substance
1 Capsule Contains:
TABLE-US-00006 [0606] active substance 150.0 mg corn starch (dried)
approx. 80.0 mg lactose (powdered) approx. 87.0 mg magnesium
stearate 3.0 mg approx. 420.0 mg
Preparation:
[0607] 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.
[0608] Capsule filling: approx. 320 mg
[0609] Capsule shell: size 1 hard gelatine capsule.
Example 8
Suppositories Containing 150 mg of Active Substance
1 Suppository Contains:
TABLE-US-00007 [0610] active substance 150.0 mg polyethyleneglycol
1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene
sorbitan monostearate 840.0 mg 2,000.0 mg.sup.
Preparation:
[0611] 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 mg of Active Substance
100 ml of Suspension Contain:
TABLE-US-00008 [0612] 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:
[0613] The distilled water is heated to 70.degree. 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.
[0614] 5 ml of suspension contain 50 mg of active substance.
Example 10
Ampoules Containing 10 mg Active Substance
Composition:
TABLE-US-00009 [0615] active substance 10.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 2.0 ml
Preparation:
[0616] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
Example 11
Ampoules Containing 50 mg of Active Substance
Composition:
TABLE-US-00010 [0617] active substance 50.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 10.0 ml
Preparation:
[0618] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
* * * * *