8-[3-amino-piperidin-1-yl]-xanthines, The Preparation Thereof And Their Use As Pharmaceutical Compositions

  *US10202383B2*
  US010202383B2                                 
(12)United States Patent(10)Patent No.: US 10,202,383 B2
  et al. (45) Date of Patent:Feb.  12, 2019

(54)8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions 
    
(75)Inventor: Boehringer Ingelheim International GmbH,  Ingelheim am Rhein (DE) 
(73)Assignee:Boehringer Ingelheim International GmbH,  Ingelheim am Rhein (DE), Type: Foreign Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
(21)Appl. No.: 16/008,582 
(22)Filed: Jun.  14, 2018 
(65)Prior Publication Data 
 US 2018/0291025 A1 Oct.  11, 2018 
 Related U.S. Patent Documents 
(63) .
Continuation of application No. 15/801,442, filed on Nov.  2, 2017, now Pat. No. 10,023,574 , which is a continuation of application No. 15/366,019, filed on Dec.  1, 2016, now abandoned , which is a continuation of application No. 15/070,263, filed on Mar.  15, 2016, now Pat. No. 9,556,175 , which is a continuation of application No. 14/748,792, filed on Jun.  24, 2015, now Pat. No. 9,321,791 , which is a continuation of application No. 14/154,885, filed on Jan.  14, 2014, now Pat. No. 9,108,964 , which is a continuation of application No. 13/448,495, filed on Apr.  17, 2012, now Pat. No. 8,664,232 , which is a continuation of application No. 12/143,128, filed on Jun.  20, 2008, now Pat. No. 8,178,541 , which is a continuation of application No. 10/639,036, filed on Aug.  12, 2003, now Pat. No. 7,407,955 .
 
(60)Provisional application No. 60/461,752, filed on Apr.  10, 2003.
 
 Provisional application No. 60/409,312, filed on Sep.  9, 2002.
 
(30)Foreign Application Priority Data 
 Aug.  21, 2002     (DE)   102 38 243
 Mar.  20, 2003     (DE)   103 12 353
Jan.  1, 2013 C 07 D 473 04 F I Feb.  12, 2019 US B H C Jan.  1, 2013 C 07 D 473 06 L I Feb.  12, 2019 US B H C Jan.  1, 2013 C 07 D 473 08 L I Feb.  12, 2019 US B H C Jan.  1, 2013 C 07 D 519 00 L I Feb.  12, 2019 US B H C
(51)Int. Cl. C07D 473/04 (20060101); C07D 519/00 (20060101); C07D 473/08 (20060101); C07D 473/06 (20060101)
(58)Field of Search  None

 
(56)References Cited
 
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 2010//0074950  A1  3/2010    Sesha     
 2010//0092551  A1  4/2010    Nakamura et al.     
 2010//0173916  A1  7/2010    Himmelsbach et al.     
 2010//0179191  A1  7/2010    Himmelsbach et al.     
 2010//0183531  A1  7/2010    Johncock et al.     
 2010//0204250  A1  8/2010    Himmelsbach et al.     
 2010//0209506  A1  8/2010    Eisenreich     
 2010//0310664  A1  12/2010    Watson et al.     
 2010//0317575  A1  12/2010    Pinnetti et al.     
 2010//0330177  A1  12/2010    Pourkavoos     
 2011//0009391  A1  1/2011    Braun et al.     
 2011//0028391  A1  2/2011    Holst et al.     
 2011//0046076  A1  2/2011    Eickelmann et al.     
 2011//0065731  A1  3/2011    Dugi et al.     
 2011//0092510  A1  4/2011    Klein et al.     
 2011//0098240  A1  4/2011    Dugi et al.     
 2011//0112069  A1  5/2011    Himmelsbach et al.     
 2011//0144083  A1  6/2011    Himmelsbach et al.     
 2011//0144095  A1  6/2011    Himmelsbach et al.     
 2011//0190322  A1  8/2011    Klein et al.     
 2011//0195917  A1  8/2011    Dugi et al.     
 2011//0206766  A1  8/2011    Friedl et al.     
 2011//0212982  A1  9/2011    Christopher et al.     
 2011//0263493  A1  10/2011    Dugi et al.     
 2011//0263617  A1  10/2011    Mark et al.     
 2011//0275561  A1  11/2011    Graefe-Mody et al.     
 2011//0301182  A1  12/2011    Dugi     
 2012//0003313  A1  1/2012    Kohlrausch et al.     
 2012//0035158  A1  2/2012    Himmelsbach et al.     
 2012//0040982  A1  2/2012    Himmelsbach et al.     
 2012//0053173  A1  3/2012    Banno et al.     
 2012//0094894  A1  4/2012    Graefe-Mody et al.     
 2012//0107398  A1  5/2012    Schneider et al.     
 2012//0121530  A1  5/2012    Klein et al.     
 2012//0122776  A1  5/2012    Graefe-Mody et al.     
 2012//0129874  A1  5/2012    Sieger et al.     
 2012//0142712  A1  6/2012    Pfrengle et al.     
 2012//0165251  A1  6/2012    Klein et al.     
 2012//0208831  A1  8/2012    Himmelsbach et al.     
 2012//0219622  A1  8/2012    Kohlrausch et al.     
 2012//0219623  A1  8/2012    Meinicke     
 2012//0232004  A1  9/2012    Bachovchin et al.     
 2012//0252782  A1  10/2012    Himmelsbach et al.     
 2012//0252783  A1  10/2012    Himmelsbach et al.     
 2012//0296091  A1  11/2012    Sieger et al.     
 2013//0064887  A1  3/2013    Ito et al.     
 2013//0086076  A1  4/2013    Pandit et al.     
 2013//0122089  A1  5/2013    Kohlrausch et al.     
 2013//0172244  A1  7/2013    Klein et al.     
 2013//0184204  A1  7/2013    Pfrengle et al.     
 2013//0196898  A1  8/2013    Dugi et al.     
 2013//0236543  A1  9/2013    Ito et al.     
 2013//0303554  A1  11/2013    Klein et al.     
 2013//0310398  A1  11/2013    Mark et al.     
 2013//0315975  A1  11/2013    Klein et al.     
 2013//0317046  A1  11/2013    Johansen     
 2013//0324463  A1  12/2013    Klein et al.     
 2014//0100236  A1  4/2014    Busl et al.     
 2014//0274889  A1  9/2014    Johansen et al.     
 2014//0315832  A1  10/2014    Broedl et al.     
 2014//0343014  A1  11/2014    Klein et al.     
 2014//0371243  A1  12/2014    Klein et al.     
 2015//0196565  A1  7/2015    Klein et al.     
 2015//0246045  A1  9/2015    Klein et al.     
 2015//0265538  A1  9/2015    Balthes et al.     
 2016//0058769  A1  3/2016    Graefe-Mody et al.     
 2016//0082011  A1  3/2016    Klein et al.     
 2016//0106677  A1  4/2016    Boeck et al.     
 2016//0310435  A1  10/2016    Friedl et al.     
 2017//0020868  A1  1/2017    Dugi et al.     
 2017//0354660  A1  12/2017    Meinicke et al.     

 
 FOREIGN PATENT DOCUMENTS 
 
       AU       2003280680       A1                6/2004      
       AU       2009224546       A1                9/2009      
       CA       1123437       A1                5/1982      
       CA       2136288       A1                5/1995      
       CA       2375779                         5/2000      
       CA       2418656       A1                2/2002      
       CA       2435730       A1                9/2002      
       CA       2496249       A1                3/2004      
       CA       2496325       A1                3/2004      
       CA       2498423       A1                4/2004      
       CA       2505389       A1                5/2004      
       CA       2508233       A1                6/2004      
       CA       2529729       A1                12/2004      
       CA       2543074       A1                6/2005      
       CA       2555050       A1                9/2005      
       CA       2556064       A1                9/2005      
       CA       2558067       A1                10/2005      
       CA       2558446       A1                10/2005      
       CA       2561210       A1                10/2005      
       CA       2562859       A1                11/2005      
       CA       2576294       A1                3/2006      
       CA       2590912       A1                6/2006      
       CA       2599419       A1                11/2006      
       CA       2651019       A1                11/2007      
       CA       2651089       A1                11/2007      
       CA       2720450       A1                10/2009      
       CN       101234105       A                8/2008      
       DE       2205815       A1                8/1973      
       DE       2758025       A1                7/1979      
       DE       19705233       A1                8/1998      
       DE       10109021       A1                9/2002      
       DE       10117803       A1                10/2002      
       DE       10238243       A1                3/2004      
       DE       102004019540       A1                11/2005      
       DE       102004024454       A1                12/2005      
       DE       102004044221       A1                3/2006      
       DE       102004054054       A1                5/2006      
       EA       201300121                         10/2009      
       EP       0023032       A1                1/1981      
       EP       0149578       A2                7/1985      
       EP       0189941       A2                8/1986      
       EP       0223403       A2                5/1987      
       EP       0237608       A1                9/1987      
       EP       0248634       A2                12/1987      
       EP       0342675       A2                11/1989      
       EP       0412358       A1                2/1990      
       EP       0389282       A2                9/1990      
       EP       0399285       A1                11/1990      
       EP       0400974       A2                12/1990      
       EP       409281       A1                1/1991      
       EP       443983       A1                8/1991      
       EP       0475482       A1                3/1992      
       EP       0524482       A1                1/1993      
       EP       0638567       A1                2/1995      
       EP       0657454       A1                6/1995      
       EP       0775704       A1                5/1997      
       EP       0950658       A1                10/1999      
       EP       1054012       A1                11/2000      
       EP       1066265       A1                1/2001      
       EP       1310245       A1                5/2003      
       EP       1333033                         8/2003      
       EP       1338595       A2                8/2003      
       EP       1406873       A2                4/2004      
       EP       1500403       A1                1/2005      
       EP       1514552       A1                3/2005      
       EP       1523994       A1                4/2005      
       EP       1535906       A1                6/2005      
       EP       1537880       A1                6/2005      
       EP       1557165       A1                7/2005      
       EP       1586571       A1                10/2005      
       EP       1743655       A1                1/2007      
       EP       1760076                         3/2007      
       EP       1829877       A1                9/2007      
       EP       1852108       A1                11/2007      
       EP       1897892       A2                3/2008      
       EP       2143443       A1                1/2010      
       EP       2166007       A1                3/2010      
       ES       385302       A1                4/1973      
       ES       2256797       T3                7/2006      
       ES       2263057       T3                12/2006      
       FR       2707641       A1                1/1995      
       GB       2084580       A                4/1982      
       HU       9003243                         5/1990      
       HU       9902308       A2                7/2000      
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       JP       61030567                         2/1986      
       JP       770120                         3/1995      
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       JP       11193270                         7/1999      
       JP       2000502684       A                3/2000      
       JP       2001213770       A                8/2001      
       JP       2001278812       A                10/2001      
       JP       2001292388       A                10/2001      
       JP       2002348279       A                12/2002      
       JP       2003286287       A                10/2003      
       JP       2003300977       A                10/2003      
       JP       2004161749       A                6/2004      
       JP       2004196824       A                7/2004      
       JP       2004250336       A                9/2004      
       JP       2005511636       A                4/2005      
       JP       2005519059       A                6/2005      
       JP       2006503013       A                1/2006      
       JP       2006045156       A                2/2006      
       JP       2006137678       A                6/2006      
       JP       2007510059       A                4/2007      
       JP       2007522251       A                8/2007      
       JP       2007531780       A                11/2007      
       JP       2008513390       A                5/2008      
       JP       2008536881       A                9/2008      
       JP       2010500326       A                1/2010      
       JP       2010053576       A                3/2010      
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       JP       2010524580       A                7/2010      
       JP       2010535850       A                11/2010      
       JP       2010536734       A                12/2010      
       JP       2011088838       A                5/2011      
       JP       2011529945       A                12/2011      
       JP       2012502081       A                1/2012      
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       KR       20070111099       A                11/2007      
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       WO       199107945       A1                6/1991      
       WO       199205175       A1                4/1992      
       WO       199219227       A2                11/1992      
       WO       199402150       A1                2/1994      
       WO       199403456       A1                2/1994      
       WO       9532178       A1                11/1995      
       WO       199609045       A1                3/1996      
       WO       199611917       A1                4/1996      
       WO       199636638       A1                11/1996      
       WO       199718814       A1                5/1997      
       WO       199723447       A1                7/1997      
       WO       199723473       A1                7/1997      
       WO       199728808       A1                8/1997      
       WO       199746526       A1                12/1997      
       WO       1998007725                         2/1998      
       WO       199811893                         3/1998      
       WO       9818770       A1                5/1998      
       WO       199822464       A1                5/1998      
       WO       199828007       A1                7/1998      
       WO       199840069       A2                9/1998      
       WO       1998046082       A1                10/1998      
       WO       199856406       A1                12/1998      
       WO       199929695       A1                6/1999      
       WO       1999038501       A2                8/1999      
       WO       199950248       A1                10/1999      
       WO       199956561       A1                11/1999      
       WO       199967279       A1                12/1999      
       WO       200012064       A1                3/2000      
       WO       200072873                         5/2000      
       WO       200034241       A1                6/2000      
       WO       0069464       A1                11/2000      
       WO       0072799       A2                12/2000      
       WO       0078735       A1                12/2000      
       WO       200072973       A1                12/2000      
       WO       200073307       A2                12/2000      
       WO       200107441       A1                2/2001      
       WO       2001032158       A2                5/2001      
       WO       2001040180       A2                6/2001      
       WO       200152825                         7/2001      
       WO       200152852       A1                7/2001      
       WO       2001047514       A1                7/2001      
       WO       2001051919                         7/2001      
       WO       2001066548       A1                9/2001      
       WO       2001068603                         9/2001      
       WO       2001068646       A1                9/2001      
       WO       200177110       A1                10/2001      
       WO       2001072290       A2                10/2001      
       WO       200196301       A1                12/2001      
       WO       200197808       A1                12/2001      
       WO       200202560       A2                1/2002      
       WO       200214271       A1                2/2002      
       WO       200224698       A1                3/2002      
       WO       2002053516       A2                7/2002      
       WO       2002068420       A1                9/2002      
       WO       2003000241       A2                1/2003      
       WO       2003000250                         1/2003      
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     Primary Examiner —Deepak R Rao
     Assistant Examiner —Laura M Daniel
     Art Unit — 1624
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — David L. Kershner

(57)

Abstract

The present invention relates to substituted xanthines of general formula
[see pdf for image]
wherein R1 to R3 are as defined herein, the tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
6 Claims, Drawing Sheets, and Figures
 
 

FIELD OF INVENTION

[0001] The present invention relates to compounds having valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

DETAILED DESCRIPTION OF THE INVENTION

[0002] The present invention relates to new substituted xanthines of general formula
[0003]  [see pdf for image]
the tautomers, the stereoisomers, the mixtures, 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.
[0004] In the above formula I

R1 denotes a methyl group,

a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl-group,

a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or dimethylaminonaphthyl group,

a methyl group which is substituted by a 2-phenylethenyl or a biphenylyl group,

[0005] a methyl group which is substituted by a phenyloxadiazolyl, 5-methyl-3-phenyl-isoxazolyl, phenylpyridinyl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, methylisoquinolinyl, (methoxycarbonylmethylamino)-isoquinolinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, 1,2-dihydro-1-methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro-4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4-oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazolinyl or a 2-oxo-2H-chromenyl group,
a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyanoethyl group,
a phenylcarbonylmethyl or a 1-(phenylcarbonyl)-ethyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino)-carbonylamino or a 2-oxo-imidazolidin-1-yl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1-ylcarbonylmethoxy or morpholin-4-ylcarbonylmethoxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1-(methoxycarbonyl)-ethyloxy or a 1-(aminocarbonyl)-ethyloxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups, or
a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a —O—CH2—O, —O—CH2—CH2—O or a —N(CH3)—CO—O group,
R2 denotes a hydrogen atom,
a methyl, isopropyl, 2-propen-1-yl, 2-propyn-1-yl, or phenyl group or a cyanomethyl or methoxycarbonylmethyl group and
R3 denotes a 2-cyanobenzyl or 2,6-dicyanobenzyl group, a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-yl or 3-bromo-2-propen-1-yl group
a 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2,3-dimethyl-2-buten-1-yl group,
a 2-butyn-1-yl group,
a 1-cyclopenten-1-ylmethyl group or
a 2-furanylmethyl group.
[0006] 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,
[0007] 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).
[0008] Compounds which contain a group that can be cleaved in vivo are prodrugs of the corresponding compounds wherein this group that can be cleaved in vivo has been cleaved.
[0009] 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 C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, while a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-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 C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkyloxycarbonyl or C2-6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol with the proviso that no bonds to the oxygen atom start from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-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 C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
          Rp—CO—O—(RqCRr)—OH,
wherein
[0010] Rp denotes a C1-8-alkyl, C5-7-cycloalkyl, C1-8-alkyloxy, C5-7-cycloalkyloxy, phenyl or phenyl-C1-3-alkyl group,
[0011] Rq denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
[0012] Rr denotes a hydrogen atom or a C1-3-alkyl group,
by a group which is negatively charged under physiological conditions is meant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1-6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1-6-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 C1-3-alkyl or C1-3-alkoxy groups, while the substituents may be identical or different, a pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C1-16-alkoxycarbonyl or C1-16-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-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and the substituents may be identical or different, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, Rp—CO—O—(RqCRr)—O—CO, C1-6-alkyl-CO—NH—(RsCRt)—O—CO— or C1-6-alkyl-CO—O—(RsCRt)—(RsCRt)—O—CO— group, wherein Rp to Rr are as hereinbefore defined,
[0013] Rs and Rt, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups.
[0014] A first object of the invention relates to compounds of general formula (I) wherein

R1 denotes a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl group,

a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group,

a methyl group which is substituted by a 2-phenylethenyl or a biphenylyl group,

[0015] a methyl group which is substituted by a phenyl-oxadiazolyl, 5-methyl-3-phenyl-isoxazolyl, phenyl-pyridinyl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, methylisoquinolinyl, (methoxycarbonylmethylamino)-isoquinolinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, 1,2-dihydro-1-methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro-4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4-oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazolinyl or a 2-oxo-2H-chromenyl group,
a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyanoethyl group,
a phenylcarbonylmethyl or a 1-(phenylcarbonyl)-ethyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino)-carbonylamino or a 2-oxo-imidazolidin-1-yl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1-ylcarbonylmethoxy or morpholin-4-ylcarbonylmethoxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1-(methoxycarbonyl)-ethyloxy or a 1-(aminocarbonyl)-ethyloxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups or
a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a —O—CH2—O, —O—CH2—CH2—O or a —N(CH3)—CO—O group,
R2 denotes a methyl, isopropyl or phenyl group
and
R3 denotes a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-yl or 3-bromo-2-propen-1-yl group
a 2-buten-1-yl or 2,3-dimethyl-2-buten-1-yl group,
a 2-butyn-1-yl group,
a 1-cyclopenten-1-ylmethyl group or
a 2-furanylmethyl group,
as well as the compounds
[0016] 1-(2-cyano-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0017] 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0018] 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0019] 1-(2-{3-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0020] 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0021] 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperid in-1-yl)-xanthine,
[0022] 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0023] 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0024] 1-(2-{2-[(methyl aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0025] 1-(2-{2-[(dimethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0026] 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperid in-1-yl)-xanthine,
[0027] 1-methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0028] 1-methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0029] 1-methyl-3-(2-propyn-1-yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0030] 1-{2-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0031] 1-methyl-3-(2-propen-1-yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0032] 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0033] 1-methyl-3-phenyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0034] 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0035] 1-(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0036] 1-[(quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0037] 1-[(2-oxo-2H-chromen-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0038] 1-[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0039] 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0040] 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0041] 1-[(quinazolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0042] 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0043] 1-[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0044] 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0045] 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0046] 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0047] 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0048] 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0049] 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0050] 1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0051] 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0052] 1-[2-(3-meth oxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0053] 1-{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0054] 1-{2-[3-(dimethyl aminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0055] 1-{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0056] 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0057] 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0058] 1-{2-[2-(dimethyl aminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0059] 1-{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0060] 1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0061] 1-((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0062] 1-[(benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0063] 1-[(1H-indol-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0064] 1-[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0065] 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0066] 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0067] 1-({5-[(methoxycarbonyl)methylamino]-isoquinolin-1-yl}methyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0068] 1-(2-dimethyl amino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0069] 1-[2-(piperidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0070] 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0071] 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0072] 1-[2-(pyrrolidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0073] 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0074] 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0075] 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0076] 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0077] 1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0078] 1-[(isoquinolin-1-yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0079] 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0080] 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0081] 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0082] 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0083] 1-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0084] 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0085] 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0086] 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0087] 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0088] 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0089] 1-[2-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0090] 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-1-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0091] 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine,
[0092] 1-[2-(3-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine and
[0093] 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof.
[0094] A first preferred sub-group of the first object of the invention comprises compounds of general formula I wherein

R1 denotes a 4-methoxy-1-naphthylmethyl group,

a 2-quinolinylmethyl, 4-quinolinylmethyl or a 6-quinolinylmethyl group,

a 1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1-isoquinolinylmethyl or a 3-isoquinolinylmethyl group or

a 2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or a 4-quinazolinylmethyl group,

R2 denotes a methyl group and

R3 denotes a 2-buten-1-yl or a 2-butyn-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0095] A second preferred sub-group of the first object of the invention comprises compounds of general formula I, wherein

R1 denotes a [2-(methylcarbonylamino)-phenyl]-carbonylmethyl group,

a [2-(ethylcarbonylamino)-phenyl]-carbonylmethyl group or

a [2-(isopropylcarbonylamino)-phenyl]-carbonylmethyl group,

R2 denotes a methyl group and

R3 denotes a 2-buten-1-yl or a 2-butyn-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0096] A third preferred sub-group of the first object of the invention comprises compounds of general formula I, wherein

R1 denotes a [2-(aminocarbonylmethoxy)-phenyl]-carbonylmethyl group,

[2-(methylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group,

a [2-(ethylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group or

a [2-(isopropylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group,

R2 denotes a methyl group and

R3 denotes a 2-buten-1-yl group,

a 2-butyn-1-yl group or

a 1-cyclopenten-1-ylmethyl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0097] A second object of the invention relates to compounds of general formula I, wherein

R1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group,

a methyl group which is substituted by a phenanthrenyl group,

a methyl group which is substituted by a 2-phenylethenyl, 2-[(trifluoromethyl)-phenyl]-ethenyl, 2-(nitrophenyl)ethenyl, 2-(pentafluorophenyl)ethenyl or a biphenylyl group,

[0098] a methyl group which is substituted by a phenyloxadiazolyl, phenylpyridinyl, indolyl, methylindolyl, dimethyl-6,7-dihydro-5H-[2]pyrindinyl, benzimidazolyl, methylbenzimidazolyl, (cyanoethyl)-benzimidazolyl, (methylamino-carbonylmethyl)benzimidazolyl, benzylbenzimidazolyl, benzofuranyl, acetylbenzofuranyl, cyanobenzofuranyl, benzoxazolyl, nitrobenzoxazolyl, benzothiophenyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenylisoquinolinyl, methoxyisoquinolinyl, methoxy-chloro-isoquinolinyl, methoxy-bromo-isoquinolinyl, (methoxycarbonylmethylamino)-isoquinolinyl, dimethyl-5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropylquinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino)-quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1-ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, phenyl-oxyquinazolinyl, imidazo[1,2-a]pyridinyl, methylimidazo[1,2-a]pyridinyl, phenyl-imidazo[1,2-a]pyridinyl, benzylimidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, methylphthalazinyl, naphthyridinyl, 2,3-dihydro-benzo[1,4]-dioxinyl, 1,2-dihydro-2-oxo-quinolinyl, 1,2-dihydro-1-methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro-4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4-oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazolinyl or a 2-oxo-2H-chromenyl group,
a phenylcarbonylmethyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, (ethyloxycarbonylmethyl)amino, (methylaminocarbonyl)methylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, phenylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino)-carbonylamino or a 2-oxo-imidazolidin-1-yl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy, carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1-ylcarbonylmethoxy or morpholin-4-ylcarbonylmethoxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1-(ethyloxycarbonyl)-1-methyl-ethyloxy, 1-(methoxycarbonyl)-ethyloxy or a 1-(aminocarbonyl)-ethyloxy group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and a nitro group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and an amino group,
a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a —O—CH2—O, —O—CF2—O, —O—CH2—CH2—O, —NH—CO—NH, —N(CH3)—CO—NH, —N(CH3)—CO—N(CH3), —NH—CO—O— or a —N(CH3)—CO—O group,
a (2-phenylethyl)carbonylmethyl group,
a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or
a 2-cyanimino-2-phenyl-ethyl group,
R2 denotes a methyl, isopropyl, cyclopropyl, phenyl or fluorophenyl group and
R3 denotes a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-yl or 3-bromo-2-propen-1-yl group
a 1-buten-1-yl, 3-methyl-1-buten-1-yl, 2-buten-1-yl, 2-methyl-2-buten-1-yl- or 2,3-dimethyl-2-buten-1-yl group,
a 2-butyn-1-yl group,
a 1-cyclopenten-1-ylmethyl group or
a 2-furanylmethyl group,
the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof.
[0099] A preferred sub-group of the second object of the invention comprises compounds of general formula I wherein

R1 and R2 are as hereinbefore defined and

R3 denotes a 1-buten-1-yl, 2-buten-1-yl or 2-butyn-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0100] A particularly preferred sub-group of the second object of the invention comprises compounds of general formula I wherein

R1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl group,

a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group,

[0101] a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenylisoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropylquinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino)-quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1-ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1-methyl-2-oxo-quinolinyl group,
a phenylcarbonylmethyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group,
a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group,
a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a —O—CH2—O, —O—CF2—O, —O—CH2—CH2—O, —N(CH3)—CO—N(CH3) or a —N(CH3)—CO—O group,
a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or
a 2-cyanimino-2-phenyl-ethyl group,
R2 denotes a methyl, isopropyl, cyclopropyl, phenyl or 4-fluorophenyl group and
R3 denotes a 1-buten-1-yl, 2-buten-1-yl or a 2-butyn-1-yl group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0102] A second preferred sub-group of the second object of the invention comprises compounds of general formula I, wherein R1 and R2 are defined as immediately above and R3 denotes a 1-buten-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0103] A third preferred sub-group of the second object of the invention comprises compounds of general formula I wherein R1 and R2 are defined as immediately above and R3 denotes a 2-buten-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0104] A fourth preferred sub-group of the second object of the invention comprises compounds of general formula I wherein R1 and R2 are defined as immediately above and R3 denotes a 2-butyn-1-yl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0105] A third object of the invention relates to compounds of general formula I wherein

R1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl-group,

a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group, or

[0106] a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenylisoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropylquinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino)-quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1-ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1-methyl-2-oxo-quinolinyl group,
R2 denotes a methyl, isopropyl, cyclopropyl or phenyl group and
R3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2-cyanobenzyl group,
the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0107] A first preferred sub-group of the third object of the invention comprises compounds of general formula I wherein

R1 denotes a (3-methyl-isoquinolin-1-yl)methyl group,

R2 denotes a methyl group and

R3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2-cyanobenzyl group,

the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.

[0108] A second preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R1 and R2 are as hereinbefore defined and R3 denotes a 2-chlorobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0109] A third preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R1 and R2 are as hereinbefore defined and R3 denotes a 2-bromobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0110] A fourth preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R1 and R2 are as hereinbefore defined and R3 denotes a 2-ethynylbenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0111] A fifth preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R1 and R2 are as hereinbefore defined and R3 denotes a 2-cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0112] Most particularly preferred are the following compounds of general formula I:
[0113] (1) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0114] (2) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0115] (3) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0116] (4) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0117] (5) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0118] (6) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0119] (7) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0120] (8) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0121] (9) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
[0122] (10) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0123] (11) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0124] (12) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0125] (13) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
[0126] (14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0127] (15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0128] (16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,
[0129] (17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0130] (18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0131] (19) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0132] (20) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0133] (21) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0134] (22) 1-[(4-fluoro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0135] (23) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0136] (24) 1-[(3-trifluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0137] (25) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0138] (26) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0139] (27) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0140] (28) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
[0141] (29) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and
[0142] (30) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine
as well as the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
[0143] According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

a) reacting a compound of general formula

[0144]  [see pdf for image]
wherein
R1 to R3 are as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy group, with 3-aminopiperidine, the enantiomers thereof or the salts thereof.
[0145] The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, ethyleneglycol monomethylether, ethyleneglycol diethylether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Hünig base), while these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between −20 and 180° C., but preferably at temperatures between −10 and 120° C. The reaction may, however, also be carried out without a solvent or in an excess of the 3-aminopiperidine.

b) deprotecting a compound of general formula

[0146]  [see pdf for image]
wherein R1, R2 and R3 are as hereinbefore defined.
[0147] The tert.-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80° C.

c) In order to prepare a compound of general formula I wherein R1 according to the definition provided hereinbefore contains a carboxy group:

deprotecting a compound of general formula

[0148]  [see pdf for image]
wherein R2 and R3 are as hereinbefore defined and R1′ contains a carboxy group protected by a C1-4-alkyl group.
[0149] The protecting group is cleaved by hydrolysis, for example, using an acid such as hydrochloric acid or sulphuric acid or an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran or dioxane in the presence of water.
[0150] In the reactions described hereinbefore, any reactive groups present such as carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
[0151] For example, a protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
[0152] protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
[0153] Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
[0154] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100° C., but preferably at temperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
[0155] A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxan, methanol or diethylether.
[0156] A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120° C., or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
[0157] A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50° C.
[0158] 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.
[0159] 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.
[0160] 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 salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (−)-menthyloxycarbonyl.
[0161] 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, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
[0162] 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.
[0163] The compounds of general formulae II to IV used as starting materials are either known from the literature or may be obtained by methods known from the literature (cf. Examples I to LXXI).
[0164] 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.
[0165] The biological properties of the new compounds were investigated as follows:
[0166] 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 of for 30 minutes at 4° C. (to remove cell debris).
[0167] The DPP-IV assay was carried out as follows:
[0168] 50 μl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μM, were placed in black microtitre plates. 20 μl 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 μl of solubilised Caco-2 protein (final concentration 0.14 μg of protein per well). The test substances to be investigated were typically added prediluted in 20 μl, 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 IC50 values, was calculated from dosage/activity curves consisting of 11 measuring points in each case. The following results were obtained:
[0169] 
[00001] [TABLE-US-00001]
   
    Compound   DPP-IV inhibition
    (Example no.)IC50 [nM]
   
 
    2(3)   2160
    2(9)   264
    2(12)   16
    2(17)   32
    2(20)   12
    2(25)   4
    2(27)   9
    2(35)   5
    2(37)   5
    2(43)   6
    2(51)   6
    2(52)   9
    2(59)   250
    2(66)   22
    2(80)   1
    2(86)   2
    2(96)   2
    2(99)   1
    2(100)   3
    2(108)   3
    2(129)   3
    2(130)   3
    2(131)   3
    2(132)   1
    2(135)   3
    2(137)   13
    2(138)   8
    2(139)   4
    2(142)   1
    2(145)   4
    2(148)   1
    2(150)   1
    2(151)   3
    2(152)   4
    2(185)   3
    2(217)   4
    2(247)   2
    2(251)   12
    2(256)   8
    2(260)   13
    2(264)   6
    2(277)   6
    2(280)   5
    2(285)   3
    2(287)   11
    2(288)   14
   
[0170] The compounds prepared according to the invention are well tolerated, as for example when 10 mg/kg of the compound of Example 2(80) were administered to rats by oral route no changes in the animals' behaviour could be detected.
[0171] 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 1 and type 2 diabetes mellitus, diabetic complications (such as e.g. retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidaemias of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and calcitonin-induced 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 for favourably affecting catabolic states after operations or hormonal stress responses or reducing mortality or morbidity after myocardial infarct. They are also suitable for treating all conditions which are connected with the above mentioned effects and which are mediated by GLP-1 or GLP-2. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for preventing and treating acute renal failure. Furthermore, the compounds according to the invention may be used to treat inflammatory diseases of the respiratory tract. They are also suitable for the prevention and treatment of chronic inflammatory intestinal diseases such as e.g. irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis and also pancreatitis. It is also likely that they can be used for all kinds of damage to or impairment of the gastrointestinal tract such as colitis and enteritis, for example. It is also expected that DPP-IV inhibitors and hence also the compounds according to the invention may be used to treat infertility or to improve fertility in humans or mammals, particularly when the infertility is connected with insulin resistance or polycystic ovary syndrome. On the other hand these substances are suitable for affecting sperm motility and can thus be used as male contraceptives. The substances are also suitable for treating deficiencies of growth hormone which are associated with reduced stature, and may also be used to advantage in any indications in which growth hormone may be used. The compounds according to the invention are also suitable, on the basis of their inhibitory effect on DPP-IV, for treating various autoimmune diseases such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease, etc. They may also be used to treat viral diseases and also, for example, in HIV infections, for stimulating blood production, in benign prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease, for example. The compounds described may also be used for the treatment of tumours, particularly for modifying tumour invasion and also metastasisation; examples here are their use in treating T-cell lymphomas, acute lymphoblastic leukaemia, cell-based pancreatic carcinomas, basal cell carcinomas or breast cancers. Other indications are stroke, ischaemia of various origins, Parkinson's disease and migraine. In addition, further indications include follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophies, as well as psycho-somatic, depressive and neuropsychiatric diseases of all kinds.
[0172] 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. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Also, SGLT2 inhibitors such as T-1095, inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol-pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol resorption inhibitors such as for example ezetimibe, bile acid-binding substances such as for example cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as for example inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoidl receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ß3-agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.
[0173] 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, β-blockers, Ca-antagonists, etc., or combinations thereof.
[0174] The dosage required to achieve such an effect is expediently, by intravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
[0175] The Examples that follow are intended to illustrate the invention:

Preparation of the Starting Compounds

Example I

1,3-dimethyl-7-(2,6-dicyano-benzyl)-8-bromo-xanthine

[0176] A mixture of 555 mg of 8-bromotheophyllin and 0.39 ml of Hünig base in 9 ml N,N-dimethylformamide is combined with 600 mg of 2-bromomethyl-isophthalonitrile and stirred overnight at ambient temperature. For working up the reaction mixture is poured onto water. The precipitate formed is suction filtered, washed with water and dried.
[0177] Yield: 686 mg (83% of theory)
[0178] Rf value: 0.56 (silica gel, methylene chloride/methanol=95:5)
[0179] Mass spectrum (ESI+): m/z=399, 401 [M+H]+
[0180] The following compounds are obtained analogously to Example I:

(1) 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0181] Mass spectrum (ESI+): m/z=269, 271 [M+H]+

(2) 3-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0182] Mass spectrum (ESI+): m/z=316, 318 [M+H]+

(3) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0183] Mass spectrum (ESI+): m/z=415, 417 [M+H]+

(4) 3-methyl-7-[(2-trimethylsilanyl-ethoxy)methyl]-8-bromo-xanthine

[0184] (Carried out in the presence of potassium carbonate)
[0185] Mass spectrum (ESI+): m/z=375, 377 [M+H]+

(5) 3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0186] Mass spectrum (ESI+): m/z=313, 315 [M+H]+

(6) 3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-bromo-xanthine

[0187] Rf value: 0.43 (silica gel, methylene chloride/methanol=9:1)
[0188] Mass spectrum (ESI+): m/z=327, 329 [M+H]+

(7) 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0189] Rf value: 0.72 (silica gel, ethyl acetate)
[0190] Mass spectrum (ESI+): m/z=297/299 [M+H]+

(8) 3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0191] (The product is contaminated with approx. 10-20% of Z compound)
[0192] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/methanol=6:3:1)
[0193] Mass spectrum (ESI+): m/z=299, 301 [M+H]+

(9) 3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0194] Mass spectrum (ESI+): m/z=325, 327 [M+H]+

(10) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0195] Mass spectrum (ESI+): m/z=443, 445 [M+H]+

(11) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0196] (product contains approx. 25% of Z isomer)
[0197] Mass spectrum (ESI+): m/z=417, 419 [M+H]+

(12) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-methyl-allyl)-8-bromo-xanthine

[0198] Rf value: 0.71 (silica gel, methylene chloride/methanol=95:5)
[0199] Mass spectrum (ESI+): m/z=417, 419 [M+H]+

(13) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(3-bromo-allyl)-8-bromo-xanthine

[0200] Rf value: 0.68 (silica gel, methylene chloride/methanol=95:5)
[0201] Mass spectrum (ESI+): m/z=481, 483, 485 [M+H]+

(14) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(furan-2-yl)methyl]-8-bromo-xanthine

[0202] Rf value: 0.60 (silica gel, methylene chloride/methanol=95:5)
[0203] Mass spectrum (ESI+): m/z=443, 445 [M+H]+

(15) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-chloro-allyl)-8-bromo-xanthine

[0204] Rf value: 0.77 (silica gel, methylene chloride/methanol=95:5)
[0205] Mass spectrum (ESI+): m/z=437, 439, 441 [M+H]+

(16) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-methyl-2-buten-1-yl)-8-bromo-xanthine

[0206] Rf value: 0.77 (silica gel, methylene chloride/methanol=95:5)
[0207] Mass spectrum (ESI+): m/z=431, 433 [M+H]+

(17) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-methyl-2-buten-1-yl)-8-bromo-xanthine

[0208] Rf value: 0.77 (silica gel, methylene chloride/methanol=95:5)
[0209] Mass spectrum (ESI+): m/z=431, 433 [M+H]+

(18) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(1-phenylsulphanyl-butyl)-8-bromo-xanthine

[0210] Rf value: 0.83 (silica gel, methylene chloride/methanol=95:5)
[0211] Mass spectrum (ESI+): m/z=527, 529 [M+H]+

(19) 3-methyl-7-(3-methyl-1-phenylsulphanyl-butyl)-8-bromo-xanthine

[0212] (The [(1-chloro-3-methyl-butyl)sulphanyl]-benzene used as starting material for the reaction is obtained by chlorination of [(3-methyl-butyl)sulphanyl]-benzene with N-chloro-succinimide in carbon tetrachloride)
[0213] Rf value: 0.38 (silica gel, methylene chloride/methanol=95:5)
[0214] Mass spectrum (ESI+): m/z=423, 425 [M+H]+

(20) 1,3-dimethyl-7-(2-bromo-benzyl)-8-chloro-xanthine

[0215] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate=1:1)

(21) 1,3-dimethyl-7-(2-chloro-benzyl)-8-chloro-xanthine

[0216] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate=1:1)

(22) 3-cyclopropyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0217] Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0218] Mass spectrum (ESI+): m/z=223/225 [M+H]+

Example II

1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0219] 63 mg of ethyl bromoacetate are added to a mixture of 200 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 63 mg of potassium carbonate in 3 ml N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up it is combined with water and the precipitate formed is suction filtered, washed with water and dried for three hours at 80° C. in the drying cupboard.
[0220] Yield: 216 mg (94% of theory)
[0221] Mass spectrum (ESI+): m/z=653 [M+H]+
[0222] The following compounds are obtained analogously to Example II:

(1) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0223] Mass spectrum (ESI+): m/z=624 [M+H]+

(2) 1-(2-{3-[(methylsulphanyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0224] Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate=6:4)
[0225] Mass spectrum (ESI+): m/z=627 [M+H]+

(3) 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0226] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate=3:7)

(4) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0227] Mass spectrum (ESI+): m/z=638 [M+H]+

(5) 1-(2-{2-[(dimethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0228] Mass spectrum (ESI+): m/z=652 [M+H]+

(6) 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0229] Mass spectrum (ESI+): m/z=639 [M+H]+

(7) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0230] Mass spectrum (ESI+): m/z=636 [M+H]+

(8) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0231] Mass spectrum (ESI+): m/z=650 [M+H]+

(9) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-xanthine

[0232] Mass spectrum (ESI+): m/z=622 [M+H]+

(10) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0233] Mass spectrum (ESI+): m/z=608 [M+H]+

(11) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0234] Mass spectrum (ESI+): m/z=623 [M+H]+

(12) 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0235] Mass spectrum (ESI+): m/z=667 [M+H]+

(13) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0236] Mass spectrum (ESI+): m/z=622 [M+H]+

(14) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0237] (product contains some Z isomer)
[0238] Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[0239] Mass spectrum (ESI+): m/z=624 [M+H]+

(15) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0240] Mass spectrum (ESI+): m/z=636 [M+H]+

(16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0241] Mass spectrum (ESI+): m/z=622 [M+H]+

(17) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0242] Mass spectrum (ESI+): m/z=639 [M+H]+

(18) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0243] Mass spectrum (ESI+): m/z=638 [M+H]+

(19) 2-(2-acetyl-phenoxy)-N-ethyl-acetamide

[0244] Mass spectrum (ESI+): m/z=222 [M+H]+

(20) 1-{2-[2-(1-methoxycarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0245] Mass spectrum (ESI+): m/z=637 [M+H]+

(21) 1-{2-[2-(1-aminocarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0246] Mass spectrum (ESI+): m/z=622 [M+H]+

(22) 2-(2-acetyl-phenoxy)-N-methyl-acetamide

[0247] Mass spectrum (ESI+): m/z=208 [M+H]+

(23) 1-{2-[2-(2-oxo-propoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0248] Mass spectrum (ESI+): m/z=607 [M+H]+

(24) 1-{2-[2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0249] Mass spectrum (ESI+): m/z=665 [M+H]+

(25) 1-{2-[2-cyanomethoxy-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0250] Mass spectrum (ESI+): m/z=590 [M+H]+

(26) 1-(2-{2-[(methylsulphanyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0251] Mass spectrum (ESI+): m/z=611 [M+H]+

(27) 1-{[2-(tert.-butylcarbonyl)-benzofuran-3-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0252] (Formed as main product when 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine is reacted with 1-chloro-3,3-dimethyl-butan-2-one)
[0253] Mass spectrum (ESI+): m/z=631 [M+H]+

Example III

1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0254] 1.30 g of 3-tert.-butyloxycarbonylamino-piperidine are added to a mixture of 2.51 g of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulphoxide. The reaction mixture is stirred for 18 hours at 60° C. For working up it is combined with water and the precipitate formed is suction filtered. The solid crude product is dissolved in ethyl acetate, the solution is dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (10:1 to 1:1) as eluant.
[0255] Yield: 2.56 g (91% of theory)
[0256] Mass spectrum (ESI+): m/z=567 [M+H]+
[0257] The following compounds are obtained analogously to Example III:

(1) 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0258] Mass spectrum (ESI+): m/z=433 [M+H]+

(2) 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0259] Mass spectrum (ESI+): m/z=565 [M+H]+

(3) 3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0260] Rf value: 0.90 (silica gel, methylene chloride/methanol=9:1)
[0261] Mass spectrum (ESI): m/z=478 [M−H]

(4) 1-methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0262] Mass spectrum (ESI+): m/z=552 [M+H]+

(5) 1-methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0263] Mass spectrum (ESI+): m/z=519 [M+H]+

(6) 1-methyl-3-(2-propyn-1-yl)-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0264] Mass spectrum (ESI+): m/z=518 [M+H]+

(7) 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0265] Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate/methanol=7:2:1)
[0266] Mass spectrum (ESI+): m/z=596 [M+H]+

(8) 1-methyl-3-(2-propen-1-yl)-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0267] Mass spectrum (ESI+): m/z=520 [M+H]+

(9) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0268] Mass spectrum (ESI+): m/z=535 [M+H]+

(10) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0269] Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate=3:7)
[0270] Mass spectrum (ESI+): m/z=596 [M+H]+

(11) 1-methyl-3-phenyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0271] Mass spectrum (ESI+): m/z=556 [M+H]+

(12) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0272] Mass spectrum (ESI+): m/z=596 [M+H]+

(13) 1-[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine mixed with 1-[(1,4-dihydro-cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0273] Rf value: 0.62 (silica gel, ethyl acetate)

(14) 1-({4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1-yl}methyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0274] (Carried out with potassium carbonate in the presence of Hünig base)
[0275] Rf value: 0.27 (silica gel, cyclohexane/ethyl acetate=1:1)
[0276] Mass spectrum (ESI+): m/z=720 [M+H]+

(15) 1-[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0277] Rf value: 0.31 (silica gel, ethyl acetate/petroleum ether=7:3)
[0278] Mass spectrum (ESI+): m/z=574 [M+H]+

(16) 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0279] Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=95:5)
[0280] Mass spectrum (ESI+): m/z=605 [M+H]+

(17) 3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0281] (Carried out with potassium carbonate)
[0282] Rf value: 0.42 (silica gel, methylene chloride/methanol=20:1)
[0283] Mass spectrum (ESI+): m/z=447 [M+H]+

(18) 3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0284] (Carried out with potassium carbonate)
[0285] Melting point: 235-237° C.
[0286] Mass spectrum (ESI+): m/z=417 [M+H]+

(19) 1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0287] (Carried out with potassium carbonate)
[0288] Rf value: 0.36 (silica gel, ethyl acetate)
[0289] Mass spectrum (ESI+): m/z=558 [M+H]+

(20) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0290] (Carried out with potassium carbonate)
[0291] Rf value: 0.71 (silica gel, ethyl acetate)
[0292] Mass spectrum (ESI+): m/z=558 [M+H]+

(21) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0293] (Carried out with potassium carbonate; the product contains approx. 20% of Z isomer)
[0294] Rf value: 0.24 (silica gel, ethyl acetate/petroleum ether=1:1)
[0295] Mass spectrum (ESI+): m/z=560 [M+H]+

(22) 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0296] (Carried out with potassium carbonate)
[0297] Rf value: 0.64 (silica gel, ethyl acetate)
[0298] Mass spectrum (ESI+): m/z=417 [M+H]+

(23) 3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0299] (Carried out with potassium carbonate)
[0300] Rf value: 0.64 (silica gel, ethyl acetate)
[0301] Mass spectrum (ESI+): m/z=417 [M+H]+

(24) 3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0302] (product contains approx. 15% of Z isomer)
[0303] Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate=3:7)
[0304] Mass spectrum (ESI+): m/z=419 [M+H]+

(25) 3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0305] (product contains approx. 15% of Z isomer)
[0306] Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate=3:7)
[0307] Mass spectrum (ESI+): m/z=419 [M+H]+

(26) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0308] Mass spectrum (ESI+): m/z=551 [M+H]+

(27) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0309] Mass spectrum (ESI+): m/z=578 [M+H]+

(28) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0310] Mass spectrum (ESI+): m/z=563 [M+H]+

(29) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0311] Mass spectrum (ESI+): m/z=579 [M+H]+

(30) 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0312] Mass spectrum (ESI+): m/z=522 [M+H]+

(31) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0313] Mass spectrum (ESI+): m/z=551 [M+H]+

(32) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0314] (product contains approx. 10% of Z isomer)
[0315] Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate=1:1)
[0316] Mass spectrum (ESI+): m/z=552 [M+H]+

(33) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0317] (product contains approx. 25% of Z isomer)
[0318] Mass spectrum (ESI+): m/z=537 [M+H]+

(34) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

(35) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0319] (product contains some Z isomer)
[0320] Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate=4:6)
[0321] Mass spectrum (ESI+): m/z=553 [M+H]+

(36) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0322] Mass spectrum (ESI+): m/z=551 [M+H]+

(37) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0323] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0324] Mass spectrum (ESI+): m/z=550 [M+H]+

(38) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0325] Mass spectrum (ESI+): m/z=567 [M+H]+

(39) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0326] Mass spectrum (ESI+): m/z=535 [M+H]+

(40) 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0327] Mass spectrum (ESI+): m/z=610 [M+H]+

(41) 3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0328] (Carried out with potassium carbonate)
[0329] Rf value: 0.52 (silica gel, ethyl acetate)
[0330] Mass spectrum (ESI+): m/z=417 [M+H]+

(42) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-methyl-allyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0331] Rf value: 0.46 (silica gel, methylene chloride/methanol=95:5)

(43) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(3-bromo-allyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0332] Rf value: 0.22 (silica gel, methylene chloride/methanol=95:5)
[0333] Mass spectrum (ESI+): m/z=601, 603 [M+H]+

(44) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(furan-2-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0334] Rf value: 0.41 (silica gel, methylene chloride/methanol=95:5)

(45) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-chloro-allyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0335] Rf value: 0.49 (silica gel, methylene chloride/methanol=95:5)
[0336] Mass spectrum (ESI+): m/z=557, 559 [M+H]+

(46) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0337] Mass spectrum (ESI+): m/z=535 [M+H]+

(47) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0338] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=4:6)
[0339] Mass spectrum (ESI+): m/z=552 [M+H]+

(48) 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

[0340] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate=1:2)

(49) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0341] Mass spectrum (ESI+): m/z=582 [M+H]+

(50) 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0342] Mass spectrum (ESI+): m/z=626 [M+H]+

(51) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-benzooxazol-7-yl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0343] Mass spectrum (ESI+): m/z=738 [M+H]+

(52) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0344] Rf value: 0.48 (silica gel, methylene chloride/methanol=95:5)
[0345] Mass spectrum (ESI+): m/z=551 [M+H]+

(53) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0346] Mass spectrum (ESI+): m/z=551 [M+H]+

(54) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-benzooxazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0347] Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate=1:1)
[0348] Mass spectrum (ESI+): m/z=722 [M+H]+

(55) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0349] Mass spectrum (ESI+): m/z=615 [M+H]+

(56) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0350] Mass spectrum (ESI+): m/z=615 [M+H]+

(57) 1-[(1-methyl-1H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0351] Rf value: 0.80 (silica gel, methylene chloride/methanol=95:5)
[0352] Mass spectrum (ESI+): m/z=560 [M+H]+

(58) 1-[(quinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0353] Rf value: 0.50 (silica gel, ethyl acetate)
[0354] Mass spectrum (ESI+): m/z=558 [M+H]+

(59) 1-{[1-(tert.-butyloxycarbonylamino)-1H-indol-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0355] Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate=1:1)
[0356] Mass spectrum (ESI+): m/z=646 [M+H]+

(60) 1-[(2-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (mixed with 1-[(2-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine)

[0357] Rf value: 0.15 (silica gel, ethyl acetate)
[0358] Mass spectrum (ESI+): m/z=691 [M+H]+

(61) 1-[2-(quinolin-8-yl-]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0359] Rf value: 0.35 (silica gel, methylene chloride/methanol=95:5)
[0360] Mass spectrum (ESI+): m/z=586 [M+H]+

(62) 1-[(1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (mixed with 1-[(3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine)

[0361] Rf value: 0.23 (silica gel, ethyl acetate)
[0362] Mass spectrum (ESI+): m/z=677 [M+H]+

(63) 1-[(pyrazolo[1,5-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0363] Rf value: 0.46 (silica gel, methylene chloride/methanol=95:5)
[0364] Mass spectrum (ESI+): m/z=547 [M+H]+

(64) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-1-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0365] Rf value: 0.48 (silica gel, methylene chloride/methanol=95:5)
[0366] Mass spectrum (ESI+): m/z=537 [M+H]+

(65) 1-{2-[1-(tert.-butyloxycarbonyl)-1H-indol-7-yl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0367] Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate=1:1)

(66) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-1-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0368] Rf value: 0.40 (silica gel, methylene chloride/methanol=95:5)
[0369] Mass spectrum (ESI+): m/z=588 [M+H]+

(67) 1,3-dimethyl-7-(2-bromo-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0370] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=1:1)

(68) 1,3-dimethyl-7-(2-chloro-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0371] Rf value: 0.42 (silica gel, cyclohexane/ethyl acetate=1:1)

(69) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0372] Mass spectrum (ESI+): m/z=635 [M+H]+
[0373] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=3:7)

(70) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0374] Mass spectrum (ESI+): m/z=443 [M+H]+
[0375] Rf value: 0.70 (silica gel, ethyl acetate)

(71) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0376] Rf value: 0.35 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)
[0377] Mass spectrum (ESI+): m/z=443 [M+H]+

(72) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0378] Mass spectrum (ESI+): m/z=644, 646 [M+H]+
[0379] Rf value: 0.39 (silica gel, cyclohexane/ethyl acetate=1:1)

(73) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0380] Mass spectrum (ESI+): m/z=644, 646 [M+H]+

(74) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0381] Prepared by reacting (4-methyl-quinazolin-2-yl)-methylchloride and 3-methyl-7-(2-chlorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3-(tert.-butyloxycarbonylamino)-piperidine
[0382] Mass spectrum (ESI+): m/z=645, 647 [M+H]+

(75) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0383] Prepared by reacting (4-phenyl-quinazolin-2-yl)-methylchloride and 3-methyl-7-(2-chlorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3-(tert.-butyloxycarbonylamino)-piperidine
[0384] Mass spectrum (ESI+): m/z=707, 709 [M+H]+

Example IV

1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0385] Prepared by treating 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine with boron tribromide in methylene chloride. The desired product is contaminated with approx. 20% 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-bromo-3-methyl-butyl)-8-chloro-xanthine.
[0386] Mass spectrum (ESI+): m/z=403, 405 [M+H]+
[0387] The following compounds are obtained analogously to Example IV:

(1) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0388] (product is contaminated with approx. 20% 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-bromo-2-buten-1-yl)-8-bromo-xanthine)
[0389] Mass spectrum (ESI+): m/z=431, 433 [M+H]+

(2) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0390] Mass spectrum (ESI+): m/z=459, 461 [M+H]+

(3) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0391] (product contains some Z isomer)
[0392] Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate=4:6)
[0393] Mass spectrum (ESI+): m/z=433, 435 [M+H]+

(4) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0394] Mass spectrum (ESI+): m/z=447, 449 [M+H]+

Example V

1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0395] 1.71 g of 2-bromo-1-(2-methoxy-phenyl)-ethanone are added to a mixture of 2.00 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.38 mg of potassium carbonate in 15 ml of N,N-dimethylformamide. The reaction mixture is stirred for eight hours at ambient temperature. After aqueous working up the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (8:1 to 8:1) as eluant.
[0396] Yield: 2.61 g (84% of theory)
[0397] Mass spectrum (ESI+): m/z=417, 419 [M+H]+
[0398] The following compounds are obtained analogously to Example V:

(1) 1-[2-(3-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0399] (The reaction is carried out with 2-bromo-1-[3-(tert.-butyldimethylsilanyloxy)-phenyl]-ethanone)
[0400] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=3:7)
[0401] Mass spectrum (ESI+): m/z=567 [M+H]+

(2) 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0402] Mass spectrum (ESI+): m/z=401, 403 [M+H]+

(3) 1-(2-cyano-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0403] Mass spectrum (ESI+): m/z=391, 393 [M+Na]+

(4) 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0404] Rf value: 0.90 (silica gel, methylene chloride/methanol=9:1)
[0405] Mass spectrum (ESI+): m/z=600 [M+H]+

(5) 1-(2-phenyl-2-oxo-ethyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0406] Mass spectrum (ESI+): m/z=667 [M+H]+

(6) 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0407] Rf value: 0.90 (silica gel, methylene chloride/methanol=9:1)
[0408] Mass spectrum (ESI+): m/z=538 [M+H]+

(7) 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-xanthine

[0409] Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate=1:1)
[0410] Mass spectrum (ESI+): m/z=412 [M+H]+

(8) 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0411] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol=7:2:1)
[0412] Mass spectrum (ESI+): m/z=432, 434 [M+H]+

(9) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(2-trimethylsilanyl-ethoxy)methyl]-8-bromo-xanthine

[0413] Mass spectrum (ESI+): m/z=493, 495 [M+H]+

(10) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0414] Rf value: 0.64 (silica gel, cyclohexane/ethyl acetate=3:7)
[0415] Mass spectrum (ESI+): m/z=432, 434 [M+H]+

(11) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0416] Mass spectrum (ESI+): m/z=476, 478 [M+H]+

(12) 1-[(quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0417] Rf value: 0.45 (silica gel, ethyl acetate/petroleum ether=7:3)
[0418] Mass spectrum (ESI+): m/z=574 [M+H]+

(13) 1-[(2-oxo-2H-chromen-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0419] (The starting material 4-bromomethyl-chromen-2-one is prepared analogously to Kimura et al., Chem. Pharm. Bull. 1982, 30, 552-558.)
[0420] Rf value: 0.52 (silica gel, methylene chloride/methanol=95:5)
[0421] Mass spectrum (ESI+): m/z=591 [M+H]+

(14) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0422] Rf value: 0.54 (silica gel, methylene chloride/methanol=95:5)
[0423] Mass spectrum (ESI+): m/z=604 [M+H]+

(15) 1-[(quinazolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0424] Melting point: 195-197° C.
[0425] Mass spectrum (ESI+): m/z=575 [M+H]+

(16) 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0426] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=1:1)
[0427] Mass spectrum (ESI+): m/z=604 [M+H]+

(17) 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0428] Rf value: 0.18 (silica gel, petroleum ether/ethyl acetate=2:1)
[0429] Mass spectrum (ESI+): m/z=591 [M+H]+

(18) 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0430] Rf value: 0.53 (silica gel, methylene chloride/methanol=95:5)
[0431] Mass spectrum (ESI+): m/z=600 [M+H]+

(19) 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0432] Rf value: 0.73 (silica gel, ethyl acetate)
[0433] Mass spectrum (ESI+): m/z=600 [M+H]+

(20) 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0434] Rf value: 0.43 (silica gel, cyclohexane/ethyl acetate=1:1)
[0435] Mass spectrum (ESI+): m/z=597 [M+H]+

(21) 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0436] (Carried out in N-methylpyrrolidin-2-one at 60° C.)
[0437] Rf value: 0.27 (silica gel, methylene chloride/methanol=20:1)
[0438] Mass spectrum (ESI+): m/z=609 [M+H]+

(22) 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

[0439] (Carried out in N-methylpyrrolidin-2-one at 60° C.)
[0440] Rf value: 0.35 (silica gel, methylene chloride/methanol=20:1)
[0441] Mass spectrum (ESI+): m/z=623 [M+H]+

(23) 1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0442] (Carried out in N-methylpyrrolidin-2-one at 60° C.)
[0443] Rf value: 0.53 (silica gel, methylene chloride/methanol=20:1)
[0444] Mass spectrum (ESI+): m/z=611 [M+H]+

(24) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0445] (Carried out in N-methylpyrrolidin-2-one at 60° C.)
[0446] Rf value: 0.38 (silica gel, methylene chloride/methanol=20:1)
[0447] Mass spectrum (ESI+): m/z=565 [M+H]+

(25) 1-((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0448] Rf value: 0.54 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=95:5:0.1)
[0449] Mass spectrum (ESI+): m/z=549 [M+H]+

(26) 1-[(1-benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0450] Rf value: 0.75 (silica gel, methylene chloride/methanol=95:5)
[0451] Mass spectrum (ESI+): m/z=579 [M+H]+

(27) 1-{[1-(tert.-butyloxycarbonyl)-indol-3-yl]methyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0452] Rf value: 0.61 (silica gel, methylene chloride/methanol=9:1)
[0453] Mass spectrum (ESI+): m/z=662 [M+H]+

(28) 1-[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0454] Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate=1:1)
[0455] Mass spectrum (ESI+): m/z=599 [M+H]+

(29) 1-[(1-naphthyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0456] Rf value: 0.83 (silica gel, ethyl acetate/petroleum ether=4:1)
[0457] Mass spectrum (ESI+): m/z=557 [M+H]+

(30) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0458] Rf value: 0.25 (silica gel, ethyl acetate/petroleum ether=4:1)
[0459] Mass spectrum (ESI+): m/z=588 [M+H]+

(31) 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0460] Melting point: 163-165° C.
[0461] Mass spectrum (ESI+): m/z=557 [M+H]+

(32) 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0462] Rf value: 0.95 (silica gel, ethyl acetate/petroleum ether=4:1)
[0463] Mass spectrum (ESI+): m/z=531 [M+H]+

(33) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0464] Rf value: 0.40 (silica gel, ethyl acetate)
[0465] Mass spectrum (ESI+): m/z=559 [M+H]+

(34) 1-[(2-methyl-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0466] Rf value: 0.80 (silica gel, ethyl acetate)
[0467] Mass spectrum (ESI+): m/z=571 [M+H]+

(35) 1-[(5-nitro-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0468] Rf value: 0.54 (silica gel, methylene chloride/methanol=95:5)

(36) 1-(2-dimethylamino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0469] Rf value: 0.23 (silica gel, ethyl acetate)
[0470] Mass spectrum (ESI+): m/z=518 [M+H]+

(37) 1-[2-(piperidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0471] Rf value: 0.44 (silica gel, ethyl acetate)
[0472] Mass spectrum (ESI+): m/z=558 [M+H]+

(38) 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0473] Rf value: 0.25 (silica gel, ethyl acetate)
[0474] Mass spectrum (ESI+): m/z=588 [M+H]+

(39) 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0475] Rf value: 0.30 (silica gel, ethyl acetate)
[0476] Mass spectrum (ESI+): m/z=604 [M+H]+

(40) 1-[(2-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0477] Rf value: 0.75 (silica gel, ethyl acetate)
[0478] Mass spectrum (ESI+): m/z=587 [M+H]+

(41) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0479] Rf value: 0.80 (silica gel, ethyl acetate)
[0480] Mass spectrum (ESI+): m/z=587 [M+H]+

(42) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0481] Rf value: 0.56 (silica gel, methylene chloride/methanol=95:5)
[0482] Mass spectrum (ESI+): m/z=572 [M+H]+

(43) 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0483] Rf value: 0.83 (silica gel, ethyl acetate)
[0484] Mass spectrum (ESI+): m/z=611 [M+H]+

(44) 1-[(5-nitro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0485] Rf value: 0.78 (silica gel, ethyl acetate)
[0486] Mass spectrum (ESI+): m/z=602 [M+H]+

(45) 1-[2-(pyrrolidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0487] Rf value: 0.39 (silica gel, ethyl acetate)
[0488] Mass spectrum (ESI+): m/z=544 [M+H]+

(46) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0489] Rf value: 0.56 (silica gel, methylene chloride/methanol=95:5)
[0490] Mass spectrum (ESI+): m/z=572 [M+H]+

(47) 1-[(2-naphthyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0491] Rf value: 0.78 (silica gel, ethyl acetate)
[0492] Mass spectrum (ESI+): m/z=557 [M+H]+

(48) 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0493] Rf value: 0.80 (silica gel, ethyl acetate)
[0494] Mass spectrum (ESI+): m/z=456 [M+H]+

(49) 1-[(quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0495] Rf value: 0.40 (silica gel, ethyl acetate)
[0496] Mass spectrum (ESI+): m/z=558 [M+H]+

(50) 1-[(3-methoxy-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0497] Rf value: 0.83 (silica gel, ethyl acetate)
[0498] Mass spectrum (ESI+): m/z=587 [M+H]+

(51) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0499] Rf value: 0.38 (silica gel, ethyl acetate/petroleum ether=1:1)
[0500] Mass spectrum (ESI+): m/z=609 [M+H]+

(52) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1-yl]-xanthine

[0501] (Carried out with potassium-tert. butoxide in dimethylsulphoxide)
[0502] Rf value: 0.48 (silica gel, ethyl acetate/petroleum ether=2:1)
[0503] Mass spectrum (ESI+): m/z=622 [M+H]+

(53) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0504] Mass spectrum (ESI+): m/z=595 [M+H]+

(54) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0505] Mass spectrum (ESI+): m/z=559 [M+H]+

(55) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0506] Mass spectrum (ESI+): m/z=559 [M+H]+

(56) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0507] (product contains approx. 15% of Z isomer)
[0508] Rf value: 0.30 (silica gel, ethyl acetate/cyclohexane=8:2)
[0509] Mass spectrum (ESI+): m/z=561 [M+H]+

(57) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0510] (product contains approx. 15% of Z isomer)
[0511] Rf value: 0.30 (silica gel, ethyl acetate/cyclohexane=8:2)
[0512] Mass spectrum (ESI+): m/z=561 [M+H]+

(58) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0513] (product contains approx. 17% of Z isomer)
[0514] Rf value: 0.58 (silica gel, methylene chloride/methanol=95:5)
[0515] Mass spectrum (ESI+): m/z=574 [M+H]+

(59) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0516] (product contains approx. 17% of Z isomer)
[0517] Rf value: 0.58 (silica gel, methylene chloride/methanol=95:5)
[0518] Mass spectrum (ESI+): m/z=574 [M+H]+

(60) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0519] Mass spectrum (ESI+): m/z=445, 447 [M+H]+

(61) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0520] Mass spectrum (ESI+): m/z=488, 490 [M+H]+

(62) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0521] Mass spectrum (ESI+): m/z=473, 475 [M+H]+

(63) 1-[(isoquinolin-1-yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0522] Rf value: 0.35 (silica gel, methylene chloride/methanol=95:5)

(64) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0523] (product contains approx. 10% of Z isomer)
[0524] Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate=4:6)
[0525] Mass spectrum (ESI+): m/z=462, 464 [M+H]+

(65) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0526] (product contains some Z isomer)
[0527] Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate=1:1)
[0528] Mass spectrum (ESI+): m/z=447, 449 [M+H]+

(66) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0529] Rf value: 0.77 (silica gel, methylene chloride/methanol=95:5)
[0530] Mass spectrum (ESI+): m/z=460, 462 [M+H]+

(67) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0531] (product contains approx. 20% of Z isomer)
[0532] Mass spectrum (ESI+): m/z=537 [M+H]+

(68) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0533] Mass spectrum (ESI+): m/z=461, 463 [M+H]+

(69) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0534] Rf value: 0.61 (silica gel, cyclohexane/ethyl acetate=4:6)

(70) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0535] (product contains approx. 17% of Z isomer)
[0536] Mass spectrum (ESI+): m/z=638 [M+H]+

(71) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0537] (product contains approx. 18% of Z isomer)
[0538] Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate=6:4)
[0539] Mass spectrum (ESI+): m/z=537 [M+H]+

(72) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0540] Rf value: 0.60 (silica gel, methylene chloride/methanol=95:5)
[0541] Mass spectrum (ESI+): m/z=580 [M+H]+

(73) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0542] Rf value: 0.52 (silica gel, methylene chloride/methanol=95:5)
[0543] Mass spectrum (ESI+): m/z=572 [M+H]+

(74) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0544] Mass spectrum (ESI+): m/z=572 [M+H]+

(75) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0545] Mass spectrum (ESI+): m/z=572 [M+H]+

(76) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0546] Mass spectrum (ESI+): m/z=572 [M+H]+

(77) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0547] Rf value: 0.52 (silica gel, methylene chloride/methanol=95:5)
[0548] Mass spectrum (ESI+): m/z=574 [M+H]+

(78) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0549] Rf value: 0.52 (silica gel, methylene chloride/methanol=95:5)
[0550] Mass spectrum (ESI+): m/z=574 [M+H]+

(79) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0551] Rf value: 0.18 (silica gel, ethyl acetate/petroleum ether=1:1)
[0552] Mass spectrum (ESI+): m/z=593 [M+H]+

(80) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0553] Mass spectrum (ESI+): m/z=593 [M+H]+

(81) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0554] Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate=1:2)
[0555] Mass spectrum (ESI+): m/z=587 [M+H]+

(82) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0556] Mass spectrum (ESI+): m/z=587 [M+H]+

(83) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0557] Rf value: 0.86 (silica gel, ethyl acetate/petroleum ether=4:1)
[0558] Mass spectrum (ESI+): m/z=579 [M+H]+

(84) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0559] Rf value: 0.86 (silica gel, ethyl acetate/petroleum ether=4:1)
[0560] Mass spectrum (ESI+): m/z=579 [M+H]+

(85) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0561] Rf value: 0.48 (silica gel, methylene chloride/methanol=95:5)
[0562] Mass spectrum (ESI+): m/z=573 [M+H]+

(86) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0563] Rf value: 0.48 (silica gel, methylene chloride/methanol=95:5)
[0564] Mass spectrum (ESI+): m/z=573 [M+H]+

(87) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0565] Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate=1:2)
[0566] Mass spectrum (ESI+): m/z=622 [M+H]+

(88) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0567] Mass spectrum (ESI+): m/z=638 [M+H]+

(89) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0568] Mass spectrum (ESI+): m/z=624 [M+H]+

(90) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0569] Mass spectrum (ESI+): m/z=624 [M+H]+

(91) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0570] Rf value: 0.60 (silica gel, methylene chloride/methanol=95:5)

(92) 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0571] Mass spectrum (ESI+): m/z=506, 508 [M+H]+

(93) 1-[(4-dimethylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0572] (Carried out in the presence of caesium carbonate)
[0573] Rf value: 0.40 (silica gel, methylene chloride/methanol=95:5)
[0574] Mass spectrum (ESI+): m/z=602 [M+H]+

(94) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-benzooxazol-7-yl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-bromo-xanthine

[0575] Rf value: 0.75 (silica gel, ethyl acetate/petroleum ether=1:1)
[0576] Mass spectrum (ESI+): m/z=618, 620 [M+H]+

(95) 1-[(imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0577] Rf value: 0.44 (silica gel, methylene chloride/methanol=95:5)
[0578] Mass spectrum (ESI+): m/z=547 [M+H]+

(96) 1-[(quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0579] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0580] Mass spectrum (ESI+): m/z=559 [M+H]+

(97) 1-[2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0581] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0582] Mass spectrum (ESI+): m/z=619 [M+H]+

(98) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0583] Rf value: 0.35 (silica gel, ethyl acetate)
[0584] Mass spectrum (ESI+): m/z=559 [M+H]+

(99) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-benzooxazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0585] Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate=2:1)
[0586] Mass spectrum (ESI): m/z=600, 602 [M−H]

(100) 1-[(3-methyl-quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0587] Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate=1:2)
[0588] Mass spectrum (ESI+): m/z=573 [M+H]+

(101) 1-[(3-phenyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0589] Rf value: 0.85 (silica gel, ethyl acetate)
[0590] Mass spectrum (ESI+): m/z=634 [M+H]+

(102) 1-[(3,4-dimethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0591] Rf value: 0.60 (silica gel, ethyl acetate/methanol=3:1)
[0592] Mass spectrum (ESI+): m/z=586 [M+H]+

(103) 1-[(benzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-[(R)-3-(tert.-butyl-oxycarbonylamino)-piperidin-1-yl]-xanthine

[0593] Mass spectrum (ESI+): m/z=547 [M+H]+

(104) 1-{[4-(morpholin-4-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0594] (Carried out in the presence of caesium carbonate)
[0595] Rf value: 0.28 (silica gel, ethyl acetate)
[0596] Mass spectrum (ESI+): m/z=644 [M+H]+

(105) 1-{[4-(piperidin-1-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0597] (Carried out in the presence of caesium carbonate)
[0598] Rf value: 0.35 (silica gel, ethyl acetate)
[0599] Mass spectrum (ESI+): m/z=642 [M+H]+

(106) 1-({4-[4-(tert.-butyloxycarbonyl)-piperazin-1-yl]-quinazolin-2-yl}methyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0600] (Carried out in the presence of caesium carbonate)
[0601] Rf value: 0.50 (silica gel, ethyl acetate)
[0602] Mass spectrum (ESI+): m/z=743 [M+H]+

(107) 1-{[4-(pyrrolidin-1-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0603] (Carried out in the presence of caesium carbonate)
[0604] Rf value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=95:5:0.1)
[0605] Mass spectrum (ESI+): m/z=628 [M+H]+

(108) 1-[2-(1-ethoxycarbonyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0606] Rf value: 0.25 (silica gel, petroleum ether/ethyl acetate=1:2)
[0607] Mass spectrum (ESI+): m/z=677 [M+H]+

(109) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0608] Rf value: 0.77 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0609] Mass spectrum (ESI+): m/z=582 [M+H]+

(110) 1-[(imidazo[1,2-a]pyridine-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0610] Mass spectrum (ESI+): m/z=547 [M+H]+

(111) 1-[(8-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0611] Rf value: 0.25 (silica gel, ethyl acetate)
[0612] Mass spectrum (ESI+): m/z=561 [M+H]+

(112) 1-[(8-methoxy-quinolin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0613] Rf value: 0.60 (silica gel, ethyl acetate/methanol=9:1)
[0614] Mass spectrum (ESI+): m/z=588 [M+H]+

(113) 1-[(5-methoxy-quinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0615] Rf value: 0.40 (silica gel, methylene chloride/methanol=20:1)
[0616] Mass spectrum (ESI+): m/z=588 [M+H]+

(114) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0617] Mass spectrum (ESI+): m/z=635 [M+H]+

(115) 1-[(7-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0618] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0619] Mass spectrum (ESI+): m/z=561 [M+H]+

(116) 1-(2-oxo-4-phenyl-butyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0620] Mass spectrum (ESI+): m/z=563 [M+H]+

(117) 1-(2-{2-oxo-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-1H-benzoimidazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0621] Rf value: 0.50 (silica gel, ethyl acetate/petroleum ether=1:1)
[0622] Mass spectrum (ESI+): m/z=851 [M+H]+

(118) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (By-product of the reaction of 3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine with 1-chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline)

[0623] Rf value: 0.75 (aluminium oxide, petroleum ether/ethyl acetate=1:2)
[0624] Mass spectrum (ESI+): m/z=608 [M+H]+

(119) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0625] Mass spectrum (ESI+): m/z=495, 497 [M+H]+

(120) 1-[(3-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0626] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0627] Mass spectrum (ESI+): m/z=561 [M+H]+

(121) 1-[(5-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0628] Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0629] Mass spectrum (ESI+): m/z=561 [M+H]+

(122) 1-[(6-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0630] Rf value: 0.10 (silica gel, ethyl acetate/methanol=98:2)
[0631] Mass spectrum (ESI+): m/z=561 [M+H]+

(123) 1-[(3-benzyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0632] Rf value: 0.60 (silica gel, methylene chloride/methanol=95:5)
[0633] Mass spectrum (ESI+): m/z=637 [M+H]+

(124) 1-[(4-isopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0634] Rf value: 0.50 (silica gel, ethyl acetate/petroleum ether=8:2)
[0635] Mass spectrum (ESI+): m/z=601 [M+H]+

(125) 1-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0636] Rf value: 0.53 (silica gel, ethyl acetate/petroleum ether=3:2)

(126) 1-[(3-phenyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0637] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0638] Mass spectrum (ESI+): m/z=623 [M+H]+

(127) 1-[2-(naphthalen-1-yl]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0639] Rf value: 0.54 (silica gel, methylene chloride/methanol=95:5)
[0640] Mass spectrum (ESI+): m/z=585 [M+H]+

(128) 1-[(5-methoxy-isoquinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0641] Rf value: 0.50 (silica gel, ethyl acetate/methanol=24:1)
[0642] Mass spectrum (ESI+): m/z=588 [M+H]+

(129) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (By-product of the reaction of 3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine with 1-chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline)

[0643] Rf value: 0.75 (aluminium oxide, petroleum ether/ethyl acetate=1:2)
[0644] Mass spectrum (ESI+): m/z=608 [M+H]+

(130) 1-{[1-(1-cyano-1-methyl-ethyl)-isoquinolin-3-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0645] Rf value: 0.75 (silica gel, ethyl acetate)
[0646] Mass spectrum (ESI+): m/z=625 [M+H]+

(132) 1-methoxycarbonylmethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0647] Mass spectrum (ESI+): m/z=489 [M+H]+

(133) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0648] Mass spectrum (ESI+): m/z=635 [M+H]+

(134) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0649] (Carried out in the presence of caesium carbonate)
[0650] Rf value: 0.40 (silica gel, ethyl acetate)
[0651] Mass spectrum (ESI+): m/z=587 [M+H]+

(135) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0652] Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether=8:2)
[0653] Mass spectrum (ESI+): m/z=635 [M+H]+

(136) 1-[2-(quinolin-8-yl-]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0654] Rf value: 0.55 (silica gel, methylene chloride/methanol=95:5)
[0655] Mass spectrum (ESI+): m/z=466, 468 [M+H]+

(137) 1-[(3,4-dimethyl-6,7-dihydro-5H-[2]pyrindin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0656] Rf value: 0.65 (aluminium oxide, ethyl acetate/petroleum ether=3:1)
[0657] Mass spectrum (ESI+): m/z=576 [M+H]+

(138) 1-[(3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-xanthine

[0658] Rf value: 0.40 (aluminium oxide, methylene chloride/methanol=20:1)
[0659] Mass spectrum (ESI+): m/z=590 [M+H]+

(139) 1-{2-[1-(tert.-butyloxycarbonyl)-1H-indol-4-yl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0660] Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate=1:2)
[0661] Mass spectrum (ESI+): m/z=674 [M+H]+

(140) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0662] Mass spectrum (EI): m/z=587 [M]+

(141) 1-({1-[(2-trimethylsilanyl-ethoxy)methyl]-2-oxo-1,2-dihydro-quinolin-6-yl}methyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0663] Mass spectrum (ESI+): m/z=704 [M+H]+

(142) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0664] Mass spectrum (ESI+): m/z=601 [M+H]+

(143) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0665] Mass spectrum (ESI+): m/z=573 [M+H]+

(144) 1-[(4-methyl-phthalazin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0666] Rf value: 0.65 (silica gel, methylene chloride/methanol=9:1)
[0667] Mass spectrum (ESI+): m/z=573 [M+H]+

(145) 1-[(4-bromo-3-methoxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0668] Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate=1:1)
[0669] Mass spectrum (ESI+): m/z=666, 668 [M+H]+

(146) 1-[(4-difluoromethoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0670] Rf value: 0.80 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0671] Mass spectrum (ESI+): m/z=623 [M+H]+

(147) 1-{2-[1-(tert.-butyloxycarbonyl)-1H-indol-7-yl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0672] Rf value: 0.83 (silica gel, methylene chloride/methanol=95:5)

(148) 1-[(E)-3-(2-nitro-phenyl)-2-propen-1-yl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0673] Mass spectrum (ESI+): m/z=578 [M+H]+

(149) 1-((E)-3-pentafluorophenyl-2-propen-1-yl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0674] Mass spectrum (ESI+): m/z=623 [M+H]+

(150) 1-[(4-nitro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0675] Rf value: 0.41 (silica gel, methylene chloride/methanol=95:5)
[0676] Mass spectrum (ESI+): m/z=602 [M+H]+

(151) 1-[(benzooxazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0677] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate=3:7)
[0678] Mass spectrum (ESI+): m/z=548 [M+H]+

(152) 1-[(5-nitro-benzooxazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0679] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[0680] Mass spectrum (ESI+): m/z=593 [M+H]+

(153) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-1-buten-1-yl)-8-bromo-xanthine

[0681] Rf value: 0.65 (silica gel, methylene chloride/methanol=95:5)
[0682] Mass spectrum (ESI+): m/z=468, 470 [M+H]+

(154) 1-[(quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0683] Mass spectrum (ESI+): m/z=558 [M+H]+

(155) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0684] Mass spectrum (ESI+): m/z=559 [M+H]+

(156) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0685] Rf value: 0.45 (silica gel, methylene chloride/methanol=19:1)
[0686] Mass spectrum (ESI+): m/z=573 [M+H]+

(157) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0687] Rf value: 0.32 (silica gel, methylene chloride/methanol=96:4)
[0688] Mass spectrum (ESI+): m/z=601 [M+H]+

(158) 1-[([1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0689] Rf value: 0.20 (silica gel, ethyl acetate/methanol=98:2)
[0690] Mass spectrum (ESI+): m/z=559 [M+H]+

(159) 1-[([1,8]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0691] Rf value: 0.12 (silica gel, ethyl acetate/methanol=98:2)
[0692] Mass spectrum (ESI+): m/z=559 [M+H]+

(160) 1-[(4-fluoro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0693] Rf value: 0.47 (silica gel, petroleum ether/ethyl acetate=1:1)
[0694] Mass spectrum (ESI+): m/z=575 [M+H]+

(161) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0695] Rf value: 0.39 (silica gel, ethyl acetate)
[0696] Mass spectrum (ESI+): m/z=559 [M+H]+

(162) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0697] Rf value: 0.60 (silica gel, methylene chloride/methanol=95:5)
[0698] Mass spectrum (ESI+): m/z=606 [M+H]+

(163) 1-[(8-phenyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0699] Rf value: 0.48 (silica gel, methylene chloride/methanol=95:5)
[0700] Mass spectrum (ESI+): m/z=356 [M+H]+

(164) 1-[([1,5]naphthyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0701] Rf value: 0.25 (silica gel, ethyl acetate/petroleum ether=4:1)
[0702] Mass spectrum (ESI+): m/z=559 [M+H]+

(165) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0703] Mass spectrum (ESI+): m/z=623 [M+H]+

(166) 1-[(E)-3-(2-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0704] Mass spectrum (ESI+): m/z=601 [M+H]+

(167) 1-[(E)-3-(3-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0705] Mass spectrum (ESI+): m/z=601 [M+H]+

(168) 1-[(E)-3-(4-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0706] Mass spectrum (ESI+): m/z=601 [M+H]+

(169) 1-[(3-trifluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0707] Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate=3:7)
[0708] Mass spectrum (ESI+): m/z=626 [M+H]+

(170) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine

(171) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0709] Rf value: 0.38 (silica gel, cyclohexane/ethyl acetate=1:1)
[0710] Mass spectrum (ESI+): m/z=608 [M+H]+

(172) 1-[(4-chloro-3-methoxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0711] Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate=1:1)
[0712] Mass spectrum (ESI+): m/z=622, 624 [M+H]+

(173) 1-[(4-ethoxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0713] Rf value: 0.25 (silica gel, methylene chloride/ethyl acetate=1:1)
[0714] Mass spectrum (ESI+): m/z=603 [M+H]+

(174) 1-[(4-isopropyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0715] Rf value: 0.40 (silica gel, methylene chloride/ethyl acetate=1:1)
[0716] Mass spectrum (ESI+): m/z=617 [M+H]+

(175) 1-[(2-methyl-benzothiazol-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0717] Rf value: 0.56 (silica gel, methylene chloride/ethyl acetate=1:1)
[0718] Mass spectrum (ESI+): m/z=578 [M+H]+

(176) 1-[(3-phenyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0719] Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)
[0720] Mass spectrum (ESI+): m/z=634 [M+H]+

(177) 1-[(4-phenyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0721] Rf value: 0.35 (silica gel, methylene chloride/ethyl acetate=1:1)
[0722] Mass spectrum (ESI+): m/z=651 [M+H]+

(178) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0723] Rf value: 0.45 (silica gel, methylene chloride/ethyl acetate=1:1)
[0724] Mass spectrum (ESI+): m/z=661 [M+H]+

(179) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0725] Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate=1:1)
[0726] Mass spectrum (ESI+): m/z=598 [M+H]+

(180) 1-[2-(3-difluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0727] Rf value: 0.77 (silica gel, methylene chloride/ethyl acetate=1:1)
[0728] Mass spectrum (ESI+): m/z=601 [M+H]+

(181) 1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0729] Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate=1:1)
[0730] Mass spectrum (ESI+): m/z=635 [M+H]+

(182) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0731] Rf value: 0.57 (silica gel, methylene chloride/ethyl acetate=1:1)
[0732] Mass spectrum (ESI+): m/z=565 [M+H]+

(183) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0733] Rf value: 0.63 (silica gel, methylene chloride/ethyl acetate=1:1)
[0734] Mass spectrum (ESI+): m/z=565 [M+H]+

(184) 1-[2-(3-trifluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0735] Rf value: 0.64 (silica gel, methylene chloride/ethyl acetate=1:1)
[0736] Mass spectrum (ESI+): m/z=619 [M+H]+

(185) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0737] Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate=1:1)
[0738] Mass spectrum (ESI+): m/z=611 [M+H]+

(186) 1-[2-(biphenyl-3-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0739] Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)
[0740] Mass spectrum (ESI+): m/z=611 [M+H]+

(187) 1-[2-(3-isopropyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0741] Rf value: 0.66 (silica gel, methylene chloride/ethyl acetate=1:1)
[0742] Mass spectrum (ESI+): m/z=593 [M+H]+

(188) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0743] Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate=1:1)
[0744] Mass spectrum (ESI+): m/z=598 [M+H]+

(189) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0745] Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate=1:1)
[0746] Mass spectrum (ESI+): m/z=661 [M+H]+

(190) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0747] Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)
[0748] Mass spectrum (ESI+): m/z=608 [M+H]+

(191) 1-[2-(2-phenyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0749] Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate=1:1)
[0750] Mass spectrum (ESI+): m/z=627 [M+H]+

(192) 1-[2-(3-ethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0751] Rf value: 0.72 (silica gel, methylene chloride/ethyl acetate=1:1)
[0752] Mass spectrum (ESI+): m/z=579 [M+H]+

(193) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0753] Rf value: 0.67 (silica gel, methylene chloride/ethyl acetate=1:1)
[0754] Mass spectrum (ESI+): m/z=565 [M+H]+

(194) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl)-xanthine

[0755] Rf value: 0.57 (silica gel, methylene chloride/ethyl acetate=1:1)
[0756] Mass spectrum (ESI+): m/z=565 [M+H]+

(195) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-bromo-xanthine

(196) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

(197) 1-[(1,2,3,4-tetrahydro-phenanthridin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0757] Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether=2:1)
[0758] Mass spectrum (ESI+): m/z=612 [M+H]+

Example VI

1-(2-{3-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0759] To a solution of 402 mg of 1-(2-{3-[(methylsulphanyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 10 ml hexafluoroisopropanol are added 0.15 ml of a 35% hydrogen peroxide solution. The reaction mixture is stirred for half an hour at ambient temperature. Then 5 ml of a 10% sodium thiosulphate solution are added. The aqueous phase is extracted twice with 5 ml of methylene chloride. The combined extracts are dried over sodium sulphate and evaporated down. The yellow residue is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate/methanol (5:4:1) as eluant.
[0760] Yield: 299 mg (73% of theory)
[0761] Rf value: 0.28 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[0762] Mass spectrum (ESI+): m/z=643 [M+H]+
[0763] The following compounds are obtained analogously to Example VI:

(1) 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0764] Rf value: 0.05 (silica gel, ethyl acetate/cyclohexane=3:1)
[0765] Mass spectrum (ESI+): m/z=613 [M+H]+

(2) 1-(2-{2-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0766] Mass spectrum (ESI+): m/z=627 [M+H]+

Example VII

3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0767] 236 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are added dropwise to 630 mg of 7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 11 ml of acetonitrile. The solution is stirred for two hours at ambient temperature, then the acetonitrile is distilled off in vacuo. The flask residue is taken up in 11 ml of N,N-dimethylformamide and combined with 258 mg of (2-trimethylsilanyl-ethoxy)methyl chloride. The reaction mixture is stirred for three hours at 120° C. For working up water is added, the precipitate formed is filtered off and taken up in ethyl acetate. The solution is dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate/methanol (6:1:0 to 0:5:1) as eluant.
[0768] Yield: 435 mg (53% of theory)
[0769] Mass spectrum (ESI+): m/z=549 [M+H]+
[0770] The following compounds are obtained analogously to Example VII:

(1) 3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-xanthine

[0771] Mass spectrum (ESI): m/z=396 [M−H]

(2) 3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

[0772] Rf value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0773] Mass spectrum (ESI+): m/z=491 [M+H]+

Example VIII

7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0774] 510 mg of potassium-tert. butoxide are added to 2.32 g of 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(3-methyl-2-buten-1-yl)-4-ethoxycarbonyl-5-{[(ethoxycarbonylamino)carbonyl]amino}-3H-imidazole in 35 ml of ethanol. The yellow solution is refluxed for five hours. After cooling to ambient temperature it is diluted with methylene chloride. The organic phase is washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. methanolic ammonia (95:5:1 to 90:10:1) as eluant.
[0775] Yield: 630 mg (35% of theory)
[0776] Rf value: 0.24 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0777] Mass spectrum (ESI+): m/z=419 [M+H]+

Example IX

2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(3-methyl-2-buten-1-yl)-4-ethoxycarbonyl-5-{[(ethoxycarbonylamino)carbonyl]amino}-3H-imidazole

[0778] 2.97 ml of ethyl isocanatoformate are added to 4.00 g of 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(3-methyl-2-buten-1-yl)-4-ethoxycarbonyl-5-amino-3H-imidazole in 90 ml of 1,2-dimethoxyethane and the light brown solution is heated overnight at 120° C. in an oil bath. Then a further 0.6 ml of ethyl isocyanatoformate is added and heating is continued for a further four hours. For working up the reaction mixture is combined with saturated potassium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, evaporated down and purified through a silica gel column with methylene chloride/methanol/conc. methanolic ammonia (98:2:1 to 90:10:1) as eluant.
[0779] Yield: 2.27 g (45% of theory)
[0780] Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0781] Mass spectrum (ESI+): m/z=537 [M+H]+

Example X

2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(3-methyl-2-buten-1-yl)-4-ethoxycarbonyl-5-amino-3H-imidazole

[0782] Prepared by refluxing cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxy-carbonylmethyl)-amino]-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-methane with sodium in ethanol.
[0783] Rf value: 0.26 (aluminium oxide, ethyl acetate/petroleum ether=8:2)
[0784] Mass spectrum (ESI+): m/z=422 [M+H]+

Example XI

Cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxycarbonylmethyl)-amino]-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-methane

[0785] Prepared by reacting cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxy-carbonylmethyl)-amino]-phenyloxy-methane with 3-(tert.-butyloxycarbonylamino)-piperidine in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
[0786] Rf value: 0.10 (silica gel, petroleum ether/ethyl acetate=6:4)
[0787] Mass spectrum (ESI+): m/z=422 [M+H]+

Example XII

cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxycarbonylmethyl)-amino]-phenyloxy-methane

[0788] Prepared by reacting cyanimino-[(ethoxycarbonylmethyl)amino]-phenyloxy-methane with 1-bromo-3-methyl-2-butene in the presence of potassium carbonate in acetone at ambient temperature.
[0789] Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate=1:1)
[0790] Mass spectrum (ESI+): m/z=316 [M+H]+

Example XIII

cyanimino-[(ethoxycarbonylmethyl)amino]-phenyloxy-methan

[0791] Prepared by reacting diphenylcyanocarbonimidate with ethyl aminoacetate-hydrochloride in the presence of triethylamine in isopropanol at ambient temperature (analogously to R. Besse et al., Tetrahedron 1990, 46, 7803-7812).
[0792] Rf value: 0.73 (silica gel, petroleum ether/ethyl acetate=8:2)
[0793] Mass spectrum (ESI+): m/z=248 [M+H]+

Example XIV

1-methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-chloro-xanthine

[0794] Prepared by reacting 1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine with methyl bromoacetate in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
[0795] Rf value: 0.80 (silica gel, methylene chloride/methanol=9:1)
[0796] Mass spectrum (ESI+): m/z=388, 390 [M+H]+
[0797] The following compounds are obtained analogously to Example XIV:

(1) 1-methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0798] Mass spectrum (ESI+): m/z=355, 357 [M+H]+

(2) 1-methyl-3-(2-propyn-1-yl)-7-(2-cyano-benzyl)-8-chloro-xanthine

[0799] Rf value: 0.80 (silica gel, methylene chloride/methanol=95:5)
[0800] Mass spectrum (ESI+): m/z=354, 356 [M+H]+

(3) 1-methyl-3-(2-propen-1-yl)-7-(2-cyano-benzyl)-8-chloro-xanthine

[0801] Rf value: 0.90 (silica gel, methylene chloride/methanol=95:5)
[0802] Mass spectrum (ESI+): m/z=356, 358 [M+H]+

(4) 1-(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0803] Rf value: 0.78 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0804] Mass spectrum (ESI+): m/z=576 [M+H]+

(5) 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0805] Mass spectrum (ESI+): m/z=358, 360 [M+H]+

Example XV

1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0806] Prepared by treating 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-8-chloro-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature.
[0807] Rf value: 0.50 (silica gel, methylene chloride/methanol=9:1)
[0808] Mass spectrum (ESI+): m/z=316, 318 [M+H]+
[0809] The following compounds are obtained analogously to Example XV:

(1) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-8-bromo-xanthine

[0810] Rf value: 0.26 (silica gel, methylene chloride/methanol=95:5)
[0811] Mass spectrum (ESI): m/z=361, 363 [M−H]

(2) 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

[0812] (As the compound still contains impurities which cannot be removed by chromatography, the material is again converted into the BOC-protected derivative and then purified by chromatography, cf. Ex. XXV(1).)
[0813] Mass spectrum (ESI+): m/z=491 [M+H]+

Example XVI

1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-8-chloro-xanthine

[0814] Prepared by chlorination of 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-xanthine with N-chlorosuccinimide in dichloroethane while refluxing.
[0815] Mass spectrum (EI): m/z=445, 447 [M]+

Example XVII

7-(2-cyano-benzyl)-xanthine

[0816] Prepared by treating 16.68 g of 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50° C.
[0817] Yield: 8.46 g (50% of theory)
[0818] Mass spectrum (ESI+): m/z=268 [M+H]+

Example XVIII

2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one

[0819] Prepared by reacting 20.00 g of guanosine-hydrate with 22.54 g of 2-cyano-benzylbromide in dimethylsulphoxide at 60° C. and subsequent treatment with 57 ml of conc. hydrochloric acid.
[0820] Yield: 18.00 g (97% of theory)
[0821] Mass spectrum (ESI+): m/z=267 [M+H]+

Example XIX

1-{2-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0822] Prepared by treating 1-[2-(3-{[(2-chloro-ethylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine with potassium-tert. butoxide in N,N-dimethylformamide at ambient temperature.
[0823] Rf value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Example XX

1-[2-(3-{[(2-chloro-ethylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0824] Prepared by reacting 221 mg of 1-[2-(3-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 60 μl of 2-chloroethyl isocyanate in 3 ml methylene chloride at ambient temperature.
[0825] Yield: 163 mg (64% of theory)
[0826] Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate/methanol=6:3:1)
[0827] Mass spectrum (ESI+): m/z=671, 673 [M+H]+
[0828] The following compounds are obtained analogously to Example XX:

(1) 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0829] (Carried out in N,N-dimethylformamide at 30° C.)
[0830] Rf value: 0.26 (silica gel, cyclohexane/ethyl acetate=4:6)
[0831] Mass spectrum (ESI+): m/z=681 [M+H]+

Example XXI

1-[2-(3-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0832] Prepared by treating 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with iron powder in a mixture of ethanol, water and glacial acetic acid (80:25:10) at 100° C.
[0833] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/methanol/conc. aqueous ammonia=50:30:20:1)
[0834] Mass spectrum (ESI+): m/z=566 [M+H]+
[0835] The following compounds are obtained analogously to Example XXI:

(1) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0836] Mass spectrum (ESI+): m/z=566 [M+H]+

(2) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0837] Mass spectrum (ESI+): m/z=566 [M+H]+

(3) 1-[(5-amino-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0838] Rf value: 0.22 (silica gel, ethyl acetate)
[0839] Mass spectrum (ESI+): m/z=589 [M+H]+

(4) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-bromo-xanthine

[0840] Mass spectrum (ESI+): m/z=458, 460 [M+H]+

(5) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0841] (product contains approx. 10% of Z isomer)
[0842] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate=4:6)
[0843] Mass spectrum (ESI+): m/z=432, 434 [M+H]+

(6) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0844] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0845] Mass spectrum (ESI+): m/z=430, 432 [M+H]+

(7) 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

[0846] Mass spectrum (ESI+): m/z=552 [M+H]+

(8) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0847] Mass spectrum (ESI+): m/z=552 [M+H]+

(9) 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0848] Rf value: 0.82 (silica gel, ethyl acetate/petroleum ether=4:1)
[0849] Mass spectrum (ESI+): m/z=596 [M+H]+

Example XXII

1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0850] Prepared by reacting 248 mg of 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 40 μl of propionic acid chloride in the presence of 60 μl of pyridine in N,N-dimethylformamide at 80° C.
[0851] Yield: 168 mg (62% of theory)
[0852] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate=3:7)
[0853] Mass spectrum (ESI+): m/z=622 [M+H]+
[0854] The following compounds are obtained analogously to Example XXII:

(1) 1-({5-[(methoxycarbonyl)methylamino]-isoquinolin-1-yl}methyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0855] (Carried out with methyl bromoacetate and potassium carbonate)
[0856] Rf value: 0.42 (silica gel, methylene chloride/methanol=95:5)
[0857] Mass spectrum (ESI+): m/z=661 [M+H]+

(2) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0858] (product contains approx. 10% of Z isomer)
[0859] Mass spectrum (ESI+): m/z=594 [M+H]+

(3) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0860] (product contains approx. 10% of Z isomer)
[0861] Mass spectrum (ESI+): m/z=622 [M+H]+

(4) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0862] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate=3:7)
[0863] Mass spectrum (ESI+): m/z=608 [M+H]+

(5) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0864] Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate=3:7)
[0865] Mass spectrum (ESI+): m/z=592 [M+H]+

(6) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0866] Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate=1:1)
[0867] Mass spectrum (ESI+): m/z=636 [M+H]+

(7) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0868] Rf value: 0.44 (silica gel, methylene chloride/methanol=95:5)
[0869] Mass spectrum (ESI+): m/z=620 [M+H]+

(8) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0870] Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate=3:7)
[0871] Mass spectrum (ESI+): m/z=592 [M+H]+

(9) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0872] Rf value: 0.44 (silica gel, methylene chloride/methanol=95:5)
[0873] Mass spectrum (ESI+): m/z=620 [M+H]+

(10) 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0874] (Carried out in acetonitrile at 55° C.)
[0875] Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate=1:1)
[0876] Mass spectrum (ESI+): m/z=624 [M+H]+

(11) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0877] (Carried out in acetonitrile at 65° C.)
[0878] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/isopropanol=14:3:3)
[0879] Mass spectrum (ESI+): m/z=622 [M+H]+

(12) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0880] Mass spectrum (ESI+): m/z=608 [M+H]+

(13) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0881] Mass spectrum (ESI+): m/z=594 [M+H]+

(14) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0882] Rf value: 0.28 (silica gel, cyclohexane/ethyl acetate/isopropanol=8:1:1)
[0883] Mass spectrum (ESI+): m/z=594 [M+H]+

(15) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0884] Rf value: 0.90 (silica gel, methylene chloride/methanol=9:1)

(16) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl])-xanthine

[0885] (Carried out in 1,2-dichloroethane at 45° C.)
[0886] Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate/isopropanol=8:1:1)
[0887] Mass spectrum (ESI+): m/z=622 [M+H]+

(17) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0888] Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate/isopropanol=14:3:3)
[0889] Mass spectrum (ESI+): m/z=608 [M+H]+

(18) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0890] Mass spectrum (ESI+): m/z=606 [M+H]+

(19) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0891] Rf value: 0.22 (silica gel, methylene chloride/methanol=95:5)

(20) 1-(2-{2-[(phenylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0892] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/isopropanol=14:3:3)
[0893] Mass spectrum (ESI+): m/z=656 [M+H]+

(21) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0894] (Carried out with Hünig base and 4-dimethylamino-pyridine in methylene chloride)
[0895] Rf value: 0.60 (silica gel, methylene chloride/methanol=18:1)

Example XXIII

1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

[0896] Prepared by treating 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature.
[0897] Mass spectrum (ESI+): m/z=539 [M+H]+
[0898] The following compounds are obtained analogously to Example XXIII:

(1) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

[0899] Mass spectrum (ESI+): m/z=539 [M+H]+

Example XXIV

1-methyl-3-phenyl-7-(2-cyano-benzyl)-8-chloro-xanthine

[0900] A mixture of 829 mg of 1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine, 640 mg of phenylboric acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml methylene chloride is stirred for four days at ambient temperature in the presence of 100 mg of 4 Å molecular sieves. Then another 320 mg of phenylboric acid are added and the reaction mixture is stirred for another day at ambient temperature. For working up the mixture is filtered through talc and washed with ethyl acetate. The filtrate is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (7:3 to 1:1) as eluant.
[0901] Yield: 142 mg (14% of theory)
[0902] Mass spectrum (ESI+): m/z=392, 394 [M+H]+

Example XXV

1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0903] Prepared by reacting 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine with di-tert.butyl pyrocarbonate in the presence of Hünig base in methylene chloride at ambient temperature.
[0904] Rf value: 0.27 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0905] The following compounds are obtained analogously to Example XXV:

(1) 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

[0906] Rf value: 0.27 (silica gel, methylene chloride/methanol=95:5)
[0907] Mass spectrum : m/z=591 [M+H]+

(2) 7-acetyl-1-(tert.-butyloxycarbonyl)-1H-indole

[0908] Rf value: 0.82 (silica gel, methylene chloride/petroleum ether/ethyl acetate=5:4:1)
[0909] Mass spectrum (ESI+): m/z=260 [M+H]+

Example XXVI

1-[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1-[(1,4-dihydro-cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0910] 510 mg of a mixture of (cinnolin-4-yl)-methanol and (1,4-dihydro-cinnolin-4-yl)-methanol (see Ex. XXVII) are added to 830 mg of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.25 g of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture is combined with 0.92 ml diethyl azodicarboxylate and stirred overnight at ambient temperature. Then it is evaporated down and chromatographed through a silica gel column with ethyl acetate/petroleum ether (7:3 to 0:1) as eluant. A mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained.
[0911] Yield: 660 mg (52% of theory)
[0912] Rf value: 0.60 (silica gel, ethyl acetate/petroleum ether=7:3) The following compounds are obtained analogously to Example XXVI:

(1) 1-({4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1-yl}methyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0913] Rf value: 0.85 (silica gel, methylene chloride/methanol=95:5)
[0914] Mass spectrum (ESI+): m/z=557, 559 [M+H]+

(2) 1-[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0915] Melting point: 194-195° C.
[0916] Mass spectrum (ESI+): m/z=410, 412 [M+H]+

(3) 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine

[0917] Rf value: 0.66 (silica gel, ethyl acetate)
[0918] Mass spectrum (ESI+): m/z=441, 443 [M+H]+

(4) 1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0919] (Carried out with potassium carbonate)
[0920] Rf value: 0.45 (silica gel, ethyl acetate)
[0921] Mass spectrum (ESI+): m/z=438, 440 [M+H]+

(5) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0922] Rf value: 0.78 (silica gel, ethyl acetate)
[0923] Mass spectrum (ESI+): m/z=438, 440 [M+H]+

(6) 1-[(4-dimethylamino-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0924] Rf value: 0.80 (silica gel, ethyl acetate)
[0925] Mass spectrum (ESI+): m/z=600 [M+H]+

(7) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine

[0926] (The product contains approx. 20% of Z isomer)
[0927] Rf value: 0.71 (silica gel, ethyl acetate)
[0928] Mass spectrum (ESI+): m/z=440, 442 [M+H]+

(8) 1-[(1-methyl-1H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0929] Rf value: 0.95 (silica gel, methylene chloride/methanol=95:5)
[0930] Mass spectrum (ESI+): m/z=440, 442 [M+H]+

(9) 1-[(quinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0931] Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether=8:2)
[0932] Mass spectrum (ESI+): m/z=438, 440 [M+H]+

(10) 1-{[1-(tert.-butyloxycarbonylamino)-1H-indol-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0933] Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate=1:1)
[0934] Mass spectrum (ESI+): m/z=526, 528 [M+H]+

(11) 1-({2-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl}methyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (mixed with 1-({2-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl}methyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine)

[0935] Mass spectrum (ESI+): m/z=571, 573 [M+H]+

(12) 1-[(1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (mixed with 1-[(3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine)

[0936] Rf value: 0.50 (silica gel, methylene chloride/methanol=95:5)
[0937] Mass spectrum (ESI+): m/z=557, 559 [M+H]+

(13) 1-[(pyrazolo[1,5-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

[0938] Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate=1:2)
[0939] Mass spectrum (ESI+): m/z=427, 429 [M+H]+

Example XXVII

(cinnolin-4-yl)-methanol and (1,4-dihydro-cinnolin-4-yl)-methanol

[0940] A solution of 1.00 g of methyl cinnolin-4-carboxylate in 15 ml diethyl ether is added dropwise at 0° C. to a suspension of 222 mg of lithium aluminium hydride in 5 ml of diethyl ether. After 1.5 hours water is carefully added dropwise to the reaction mixture, this is stirred with methylene chloride and suction filtered through a glass fibre filter. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate and evaporated down. According to 1H-NMR a mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained as a yellow oil which is reacted further without any more purification.
[0941] Yield: 530 mg (62% of theory)
[0942] Rf value: 0.63 (silica gel, ethyl acetate)
[0943] Mass spectrum (ESI+): m/z=161 [M1+H]+ and 163 [M2+H]+
[0944] The following compounds are obtained analogously to Example XXVII:

(1) {2-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl}-methanol

[0945] (mixed with {2-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl}-methanol)
[0946] Mass spectrum (ESI+): m/z=293 [M+H]+

(2) (2,3,8-trimethyl-quinoxalin-6-yl)-methanol

[0947] Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:2)
[0948] Mass spectrum (ESI+): m/z=203 [M+H]+

(3) (8-methyl-quinoxalin-6-yl)-methanol

[0949] Rf value: 0.18 (silica gel, cyclohexane/ethyl acetate=1:1)
[0950] Mass spectrum (ESI+): m/z=175 [M+H]+

(4) (E)-3-pentafluorophenyl-2-propen-1-ol

[0951] (Carried out with diisobutylaluminium hydride in toluene)
[0952] Mass spectrum (EI): m/z=224 [M]+

(5) (E)-3-(2-trifluoromethyl-phenyl)-2-propen-1-ol

[0953] (Carried out with diisobutylaluminium hydride in toluene)

(6) (E)-3-(3-trifluoromethyl-phenyl)-2-propen-1-ol

[0954] (Carried out with diisobutylaluminium hydride in toluene)
[0955] Mass spectrum (EI): m/z=202 [M]+

(7) (E)-3-(4-trifluoromethyl-phenyl)-2-propen-1-ol

[0956] (Carried out with diisobutylaluminium hydride in toluene)

Example XXVIII

4-hydroxymethyl-2-[(2-trimethylsilanyl-ethoxy)methyl]-2H-phthalazin-1-one

[0957] Prepared by treating methyl 4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1-carboxylate with sodium borohydride in tetrahydrofuran at 40° C.
[0958] Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate 1:1)
[0959] Mass spectrum (ESI+): m/z=307 [M+H]+
[0960] The following compounds are obtained analogously to Example XXVIII:

(1) (3,4-dimethyl-isoquinolin-1-yl)-methanol

[0961] (Carried out with lithium borohydride in tetrahydrofuran)
[0962] Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate=2:1)
[0963] Mass spectrum (ESI+): m/z=188 [M+H]+

(2) (3-methyl-imidazo[1,2-a]pyridin-2-yl)-methanol

[0964] (Carried out with lithium borohydride in tetrahydrofuran)
[0965] Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[0966] Mass spectrum (ESI+): m/z=163 [M+H]+

(3) (3,4-dimethyl-6,7-dihydro-5H-[2]pyrindin-1-yl)-methanol

[0967] (Carried out with lithium borohydride in tetrahydrofuran)
[0968] Rf value: 0.40 (aluminium oxide, petroleum ether/ethyl acetate=1:1)
[0969] Mass spectrum (ESI+): m/z=178 [M+H]+

(4) (3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1-yl)-methanol

[0970] (Carried out with lithium borohydride in tetrahydrofuran)
[0971] Rf value: 0.45 (aluminium oxide, petroleum ether/ethyl acetate=3:1)
[0972] Mass spectrum (ESI+): m/z=192 [M+H]+

(5) 6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine

[0973] (Carried out with lithium borohydride in tetrahydrofuran at ambient temperature)
[0974] Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate=2:1)
[0975] Mass spectrum (ESI+): m/z=214 [M+H]+

Example XXIX

Methyl 4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1-carboxylate

[0976] Prepared by reacting methyl 4-oxo-3,4-dihydro-phthalazin-1-carboxylate with (2-trimethylsilanyl-ethoxy)methylchloride in the presence of Hünig base in methylene chloride at ambient temperature.
[0977] Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate 6:4)
[0978] Mass spectrum (ESI+): m/z=335 [M+H]+
[0979] The following compounds are obtained analogously to Example XXIX:

(1) 7-acetyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one

[0980] Mass spectrum (ESI+): m/z=308 [M+H]+

(2) 4-acetyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one

[0981] Rf value: 0.87 (silica gel, methylene chloride/methanol=99:1)

(3) 4-acetyl-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-1,3-dihydro-benzoimidazol-2-one

[0982] (Carried out with potassium-tert. butoxide in N,N-dimethylformamide)
[0983] Rf value: 0.90 (silica gel, petroleum ether/ethyl acetate=1:1)
[0984] Mass spectrum (ESI+): m/z=437 [M+H]+

(4) 6-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-quinolin-2-one

[0985] Rf value: 0.78 (silica gel, petroleum ether/ethyl acetate=1:1)
[0986] Mass spectrum (ESI+): m/z=290 [M+H]+

(5) methyl {2-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl}-carboxylate (mixed with methyl {2-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl}-carboxylate)

[0987] Mass spectrum (ESI+): m/z=321 [M+H]+

Example XXX

1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0988] 0.22 ml of a 35% hydrogen peroxide solution and 20 mg of sodium tungstate are added to 500 mg of 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 5 ml methylene chloride. The reaction mixture is stirred overnight at ambient temperature, then 1 ml of methanol is added. After another 48 hours a further 1.5 ml of 35% hydrogen peroxide solution, a spatula tip of sodium tungstate and two drops of water are added. The next morning, the oxidation is complete according to thin layer chromatography and the reaction mixture is diluted with 50 ml methylene chloride and washed twice with 30 ml of 10% sodium thiosulphate solution. The organic phase is dried over magnesium sulphate and evaporated down, leaving a viscous resin which is reacted further without any more purification.
[0989] Yield: 530 mg (100% of theory)
[0990] Rf value: 0.72 (silica gel, ethyl acetate)
[0991] Mass spectrum (ESI+): m/z=629 [M+H]+

Example XXXI

1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0992] Prepared by treating 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 3 M sodium hydroxide solution in methanol at ambient temperature.
[0993] Rf value: 0.34 (silica gel, methylene chloride/methanol=9:1)
[0994] Mass spectrum (ESI+): m/z=595 [M+H]+
[0995] The following compounds are obtained analogously to Example XXXI:

(1) 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

[0996] Rf value: 0.49 (silica gel, methylene chloride/methanol=9:1)

(2) 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0997] (Carried out with 4 M potassium hydroxide solution in tetrahydrofuran)
[0998] Mass spectrum (ESI+): m/z=609 [M+H]+

(3) 1-[2-(2-carboxymethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[0999] (Carried out with 4 M potassium hydroxide solution in tetrahydrofuran)
[1000] Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate=3:7)
[1001] Mass spectrum (ESI+): m/z=610 [M+H]+

(4) 1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1002] Mass spectrum (ESI+): m/z=475 [M+H]+

Example XXXII

1-{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1003] A mixture of 190 mg of 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine, 43 μl of a 40% aqueous methylamine solution, 103 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 43 mg of N-hydroxybenzotriazole and 45 μl of triethylamine in 3 ml of tetrahydrofuran is stirred for eight hours at ambient temperature. For working up the reaction mixture is diluted with ethyl acetate and washed with water, 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) as eluant.
[1004] Yield: 173 mg (89% of theory)
[1005] Rf value: 0.30 (silica gel, methylene chloride/methanol=20:1)
[1006] Mass spectrum (ESI+): m/z=608 [M+H]+
[1007] The following compounds are obtained analogously to Example XXXII:

(1) 1-{2-[3-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1008] Rf value: 0.28 (silica gel, methylene chloride/methanol=20:1)
[1009] Mass spectrum (ESI+): m/z=622 [M+H]+

(2) 1-{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1010] Rf value: 0.30 (silica gel, methylene chloride/methanol=20:1)
[1011] Mass spectrum (ESI+): m/z=664 [M+H]+

(3) 1-{2-[2-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1012] Rf value: 0.30 (silica gel, methylene chloride/methanol=20:1)
[1013] Mass spectrum (ESI+): m/z=622 [M+H]+

(4) 1-{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1014] Rf value: 0.30 (silica gel, methylene chloride/methanol=20:1)
[1015] Mass spectrum (ESI+): m/z=664 [M+H]+

(5) 1-(2-{2-[(isopropylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1016] (Carried out with Hünig base in N,N-dimethylformamide)
[1017] Mass spectrum (ESI+): m/z=650 [M+H]+

(6) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1018] (Carried out with Hünig base in N,N-dimethylformamide)
[1019] Mass spectrum (ESI+): m/z=636 [M+H]+

(7) 1-(2-{2-[2-oxo-2-(pyrrolidin-1-yl)-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-xanthine

[1020] (Carried out with Hünig base in N,N-dimethylformamide)
[1021] Mass spectrum (ESI+): m/z=662 [M+H]+

(8) 1-(2-{2-[2-(morpholin-4-yl)-2-oxo-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperid in-1-yl]-xanthine

[1022] (Carried out with Hünig base in N,N-dimethylformamide)
[1023] Mass spectrum (ESI+): m/z=678 [M+H]+

(9) 1-(2-{2-[(methylaminocarbonyl)methylamino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1024] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[1025] Mass spectrum (ESI+): m/z=623 [M+H]+

(10) 1-[(2-amino-phenylaminocarbonyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1026] Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[1027] Mass spectrum (ESI+): m/z=565 [M+H]+

Example XXXIII

1-chloromethyl-4-methyl-isoquinoline-hydrochloride

[1028] Prepared by treating (4-methyl-isoquinolin-1-yl)-methanol with thionyl chloride in methylene chloride.
[1029] Rf value: 0.76 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=95:5:0.1)
[1030] Mass spectrum (ESI+): m/z=192, 194 [M+H]+
[1031] The following compounds are obtained analogously to Example XXXIII:

(1) 1-chloromethyl-3,4-dimethyl-isoquinoline-hydrochloride

[1032] Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate=2:1)
[1033] Mass spectrum (ESI+): m/z=206, 208 [M+H]+

(2) 5-chloromethyl-8-methoxy-quinoline-hydrochloride

[1034] Mass spectrum (ESI+): m/z=208, 210 [M+H]+

(3) 8-chloromethyl-5-methoxy-quinoline-hydrochloride

[1035] Mass spectrum (EI): m/z=207, 209 [M]+

(4) 2-chloromethyl-3-methyl-imidazo[1,2-a]pyridine-hydrochloride

[1036] Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1)
[1037] Mass spectrum (ESI+): m/z=181, 183 [M+H]+

(5) 8-chloromethyl-5-methoxy-isoquinoline-hydrochloride

[1038] Mass spectrum (ESI+): m/z=208, 210 [M+H]+

(6) 1-chloromethyl-3,4-dimethyl-6,7-dihydro-5H-[2]pyridine-hydrochloride

[1039] Rf value: 0.50 (aluminium oxide, petroleum ether/ethyl acetate=10:1)
[1040] Mass spectrum (ESI+): m/z=196, 198 [M+H]+

(7) 1-chloromethyl-3,4-dimethyl-5,6,7,8-tetrahydro-isoquinoline-hydrochloride

[1041] Rf value: 0.50 (aluminium oxide, petroleum ether/ethyl acetate=10:1)
[1042] Mass spectrum (ESI+): m/z=210, 212 [M+H]+

(8) 6-chloromethyl-2,3,8-trimethyl-quinoxaline-hydrochloride

[1043] Mass spectrum (ESI+): m/z=221, 223 [M+H]+

(9) 6-chloromethyl-8-methyl-quinoxaline-hydrochloride

[1044] Mass spectrum (ESI+): m/z=193, 195 [M+H]+

(10) 6-chloromethyl-1,2,3,4-tetrahydro-phenanthridine-hydrochloride

[1045] Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate=5:1)
[1046] Mass spectrum (ESI+): m/z=232, 234 [M+H]+

Example XXXIV

1-[(4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1047] 0.5 ml of a 1 M sodium methoxide solution in methanol is added dropwise to a solution of 428 mg of 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 3 ml of methanol at ambient temperature. After about 20 minutes the thick suspension formed is heated gently in a water bath and diluted with 2 ml of methanol. As soon as the reaction to form the iminoester is complete according to thin layer chromatography, the reaction mixture is neutralised with 0.5 ml 1 M glacial acetic acid solution in methanol and combined with a solution of 130 mg of anthranilic acid in 2 ml of methanol. Gentle heating produces a clear solution, which is stirred for 2.5 hours at ambient temperature. Then the reaction mixture is gently refluxed for about 3.5 hours. After standing overnight at ambient temperature the methanol is distilled off and the residue is stirred with cold water, suction filtered and dried. The crude product is suspended in 5 ml of methanol, gently heated and after cooling suction filtered, washed with methanol and dried in the desiccator.
[1048] Yield: 302 mg (56% of theory)
[1049] Rf value: 0.55 (silica gel, ethyl acetate)
[1050] Mass spectrum (ESI+): m/z=575 [M+H]+
[1051] The following compounds are obtained analogously to Example XXXV:

(1) (4-difluoromethoxy-naphthalen-1-yl)-methanol

[1052] Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate=6:4)
[1053] Mass spectrum (ESI): m/z=223 [M−H]

Example XXXV

(4-dimethylamino-naphthalen-1-yl)-methanol

[1054] prepared by reduction of 4-dimethylamino-naphthalene-1-carbaldehyde with sodium borohydride in aqueous tetrahydrofuran.
[1055] Rf value: 0.67 (silica gel, cyclohexane/ethyl acetate=1:1)

Example XXXVI

2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone

[1056] prepared by bromination of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone in methylene chloride while cooling gently with an ice bath. The dibromo compound formed as a by-product is separated off by column chromatography.
[1057] Mass spectrum (ESI+): m/z=257, 259 [M+H]+
[1058] Rf value: 0.92 (silica gel, methylene chloride) The following compounds are obtained analogously to Example XXXVI:

(1) 7-(2-bromo-acetyl)-3-methyl-3H-benzooxazol-2-one

[1059] (bromination is carried out in dioxane at 40° C.; the product is contaminated with approx. 20% dibromo compound)
[1060] Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate=1:1)
[1061] Mass spectrum (ESI+): m/z=270, 272 [M+H]+

(2) 1-benzo[1,3]dioxol-4-yl-2-bromo-ethanone

[1062] Mass spectrum (ESI+): m/z=243, 245 [M+H]+
[1063] Rf value: 0.94 (silica gel, methylene chloride)

(3) 2-[2-(2-bromo-acetyl)-phenoxy]-N-ethyl-acetamide

[1064] (bromination is carried out with copper(II)bromide in dioxane)
[1065] Mass spectrum (ESI+): m/z=300, 302 [M+H]+

(4) 4-(2-bromo-acetyl)-3-methyl-3H-benzooxazol-2-one

[1066] Rf value: 0.67 (silica gel, methylene chloride/methanol=99:1)
[1067] Mass spectrum (ESI+): m/z=270, 272 [M+H]+

(5) 2-[2-(2-bromo-acetyl)-phenoxy]-N-methyl-acetamide

[1068] Mass spectrum (ESI+): m/z=386, 388 [M+H]+

(6) 7-(2-bromo-acetyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one

[1069] Rf value: 0.84 (silica gel, methylene chloride/methanol=99:1)
[1070] Mass spectrum (ESI+): m/z=384, 386 [M+H]+

(7) 4-(2-bromo-acetyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one

[1071] Rf value: 0.38 (silica gel, ethyl acetate/petroleum ether=1:1)
[1072] Mass spectrum (ESI+): m/z=283, 285 [M+H]+

(8) 4-(2-bromo-acetyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one

[1073] Rf value: 0.82 (silica gel, methylene chloride/methanol=99:1)

(9) 4-(2-bromo-acetyl)-1-ethoxycarbonyl-3-methyl-1,3-dihydro-benzoimidazol-2-one

[1074] Rf value: 0.39 (silica gel, petroleum ether/ethyl acetate=2:1)
[1075] Mass spectrum (ESI+): m/z=341, 343 [M+H]+

(10) 2-bromo-1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-ethanone

[1076] Mass spectrum (ESI): m/z=277, 279 [M−H]

Example XXXVII

(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone

[1077] Prepared by reacting 1-(2,3-dihydroxy-phenyl)-ethanone with 1,2-dibromoethane in the presence of potassium carbonate in N,N-dimethylformamide at 100° C.
[1078] Rf value: 0.43 (silica gel, ethyl acetate/petroleum ether=1:4)
[1079] Mass spectrum (ESI+): m/z=179 [M+H]+

Example XXXVIII

1-[(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1080] Prepared by reacting 1-[(4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with methyl iodide in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
[1081] Rf value: 0.50 (silica gel, ethyl acetate)
[1082] Mass spectrum (ESI+): m/z=589 [M+H]+
[1083] The following compounds are obtained analogously to Example XXXVIII:

(1) 7-acetyl-3-methyl-3H-benzooxazol-2-one

[1084] (The methylation is carried out in the presence of sodium carbonate in methanol)
[1085] Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate=1:1)
[1086] Mass spectrum (ESI+): m/z=192 [M+H]+

(2) 4-acetyl-3-methyl-3H-benzooxazol-2-one

[1087] (The methylation is carried out in the presence of sodium carbonate in methanol while refluxing)
[1088] Rf value: 0.67 (silica gel, methylene chloride/methanol=99:1)
[1089] Mass spectrum (ESI+): m/z=192 [M+H]+

(3) 4-acetyl-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one

[1090] (Carried out in the presence of potassium-tert. butoxide)
[1091] Rf value: 0.40 (silica gel, ethyl acetate/petroleum ether=2:1)
[1092] Mass spectrum (ESI+): m/z=205 [M+H]+

(4) 4-acetyl-1-ethoxycarbonyl-3-methyl-1,3-dihydro-benzoimidazol-2-one

[1093] Rf value: 0.23 (silica gel, petroleum ether/ethyl acetate=2:1)
[1094] Mass spectrum (ESI+): m/z=263 [M+H]+

(5) 1-[(1-methyl-1H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1095] Mass spectrum (ESI+): m/z=561 [M+H]+

(6) 1-{[1-(2-cyano-ethyl)-1H-benzoimidazol-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1096] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[1097] Mass spectrum (ESI+): m/z=600 [M+H]+

(7) 1-({1-[(methylaminocarbonyl)methyl]-1H-benzoimidazol-2-yl}methyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1098] Rf value: 0.45 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[1099] Mass spectrum (ESI+): m/z=618 [M+H]+

(8) 1-[(1-benzyl-1H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1100] Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol=5:4:1)
[1101] Mass spectrum (ESI+): m/z=637 [M+H]+

Example XXXIX

1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

[1102] Prepared by reacting 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(ter