(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0097510 A1
`Himmelsbach et al.
`(43) Pub. Date:
`May 20, 2004
`
`US 20040097510A1
`
`(54) 8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES,
`THE PREPARATION THEREOF AND THEIR
`USE AS PHARMACEUTICAL
`COMPOSITIONS
`
`(75) Inventors: Frank Himmelsbach, Mittelbiberach
`(DE); Elke Langkopf, Warthausen
`(DE); Matthias Eckhardt, Biberach
`(DE); Michael Mark, Biberach (DE);
`Roland Maier, Biberach (DE); Ralf
`R.H. LotZ, Schemmerhofen (DE);
`Mohammad Tadayyon, Ulm (DE)
`
`Correspondence Address:
`BOEHRINGER INGELHEIM CORPORATION
`900 RIDGEBURY ROAD
`P. O. BOX 368
`RIDGEFIELD, CT 06877 (US)
`
`(73) Assignee: Boehringer Ingelheim Pharma GmbH
`& Co. KG, Ingelheim (DE)
`
`(21) Appl. No.:
`
`10/639,036
`
`(22) Filed:
`
`Aug. 12, 2003
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/409,312, ?led on Sep.
`9, 2002. Provisional application No. 60/461,752, ?led
`on Apr. 10, 2003.
`
`(30)
`
`Foreign Application Priority Data
`
`. . . . .. 102 38 243
`Aug. 21, 2002 (DE) . . . . . .
`Mar. 20, 2003 (DE) ...................................... .. 103 12 353
`
`PubliCatiOn Classi?cation
`
`7
`(51) Int. Cl. .................... .. A61K 31/522; C07D 473/02
`(52) U.S. Cl. ............ .. 514/248; 514/263.21; 514/263.22;
`544/269; 544/237
`
`ABSTRACT
`(57)
`The present invention relates to substituted Xanthines of
`general formula
`
`0
`
`NH2>
`
`N
`
`N
`
`o
`
`/R3
`R1
`:
`\ N
`)\ I / N
`N
`|
`R2
`
`Wherein R1 to R3 are de?ned as in claims 1 to 16, the
`tautomers, the stereoisomers, the mixtures, the prodrugs
`thereof and the salts thereof Which have valuable pharma
`cological properties, particularly an inhibiting effect on the
`activity of the enzyme dipeptidylpeptidase-IV (DPI-IV).
`
`Mylan EX 1012, Page 1
`
`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE
`PREPARATION THEREOF AND THEIR USE AS
`PHARMACEUTICAL COMPOSITIONS
`
`APPLICATION DATA
`
`[0001] This application claims bene?t to US. provisional
`application serial No. 60/409,312 ?led Sep. 9, 2002 and
`60/461,752 ?led Apr. 10, 2003 and German application nos.
`DE 102 38 243.3 ?led Aug. 21, 2002 and DE 103 12 353.9
`?led Mar. 20, 2003.
`
`FIELD OF INVENTION
`
`[0002] The present invention relates to compounds having
`valuable pharmacological properties, particularly an inhib
`iting effect on the activity of the enZyme dipeptidylpepti
`dase-IV (DPP-IV).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0003] The present invention relates to neW substituted
`Xanthines of general formula
`
`(1)
`
`NHZ,
`
`0
`
`R1\N
`A I
`0
`I?
`R2
`
`R3
`/
`N
`/>
`N
`
`N
`
`[0004] the tautomers, the stereoisomers, the miXtures, the
`prodrugs thereof and the salts thereof, particularly the physi
`ologically acceptable salts thereof With inorganic or organic
`acids or bases Which have valuable pharmacological prop
`erties, 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 contain
`ing a compound of general formula (I) or a physiologically
`acceptable salt thereof as Well as processes for the prepara
`tion thereof.
`
`[0005] In the above formula I
`[0006] R1 denotes a methyl group,
`[0007] a methyl group Which is substituted by a dim
`ethylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperi
`din-1-ylcarbonyl, tert.-butylcarbonyl or a cycloheXyl
`carbonylgroup,
`[0008] a methyl group Which is substituted by a naph
`thyl, methylnaphthyl, methoXynaphthyl, nitronaphthyl
`or dimethylaminonaphthyl group, a methyl group
`Which is substituted by a 2-phenylethenyl or a biphe
`nylyl group,
`[0009] a methyl group Which is substituted by a phe
`nyloXadiaZolyl, 5-methyl-3-phenyl-isoXaZolyl, phe
`nylpyridinyl, indolyl, benZothiophenyl, quinolinyl, iso
`
`methylisoquinolinyl,
`quinolinyl,
`(methoXycarbonylmethylamino)isoquinolinyl, cinnoli
`nyl, 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,
`
`[0010] a 2-methoXyethyl, 2-phenyloXyethyl or 2-cyano
`ethyl group,
`
`[0011] a phenylcarbonylmethyl or a 1-(phenylcarbo
`nyl)-ethyl group,
`
`[0012] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by an amino, cyanomethy
`lamino, methylcarbonylamino, ethylcarbonylamino,
`isopropylcarbonylamino,
`methoXycarbonylamino,
`(ethyloXycarbonylamino)carbonylamino or a 2-oXo
`imidaZolidin-1-yl group,
`
`[0013] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a carboXy, methoXycarbo
`nyl, ethyloXycarbonyl, aminocarbonyl, methylami
`nocarbonyl, dimethylaminocarbonyl or morpholin-4
`yl-carbonyl group,
`
`[0014] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methylsulphanyl, meth
`ylsulphinyl or methylsulphonyl group,
`
`[0015] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a carboXymethoXy, ethy
`loXycarbonylmethoXy, isopropyloXycarbonylmethoXy,
`aminocarbonylmethoXy,
`methylaminocarbonyl
`methoXy, ethylaminocarbonylmethoXy, isopropylami
`nocarbonylmethoXy, dimethylaminocarbonylmethoXy,
`pyrrolidin-1-ylcarbonylmethoXy or morpholin-4-ylcar
`bonylmethoXy group,
`
`[0016] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a 1-(methoXycarbonyl)
`ethyloXy or a 1-(aminocarbonyl)-ethyloXy group,
`
`[0017] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methylsulphinylmethoXy
`group,
`
`[0018] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by tWo methoXy groups or
`
`[0019] 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,
`
`[0020] R2 denotes a hydrogen atom,
`[0021] a methyl, isopropyl, 2-propen-1-yl, 2-propyn-1
`yl or phenyl group or
`
`[0022] a cyanomethyl or methoXycarbonylmethyl
`group and
`
`[0023] R3 denotes a 2-cyanobenZyl or 2,6-dicyanoben
`Zyl group,
`
`[0024] a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1
`yl or 3-bromo-2-propen-1-yl group
`
`Mylan EX 1012, Page 2
`
`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`a l-cyclopenten-l-ylmethyl group or
`
`a 2-furanylmethyl group.
`
`a 2-butyn-1-yl group,
`
`[0025] a 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2,3
`dimethyl-2-buten-1-yl group,
`[0026]
`[0027]
`[0028]
`[0029] The carboXy groups mentioned in the de?nition 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,
`[0030] and furthermore the amino and imino groups men
`tioned in the de?nition 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).
`[0031] Compounds Which contain a group that can be
`cleaved in vivo are prodrugs of the corresponding com
`pounds Wherein this group that can be cleaved in vivo has
`been cleaved.
`
`[0032] By a group Which can be converted in vivo into a
`carboXy group is meant, for eXample, a hydroXymethyl
`group, a carboXy group esteri?ed With an alcohol Wherein
`the alcohol moiety is preferably a C1_6alkanol, a phenyl-C1_
`a-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 C 4_7-cycloalk
`enol, 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
`
`[0034] Rp denotes a C1_8-alkyl, C5_7-cycloalkyl, C1_8
`alkyloXy, C5_7cycloalkyloXy, phenyl or phenyl-C1_3
`alkyl group,
`[0035] Rq denotes a hydrogen atom, a C1_3-alkyl,
`C5_7-cycloalkyl or phenyl group and
`
`[0036] RI denotes a hydrogen atom or a C1_3-alkyl
`group,
`[0037] by a group Which is negatively charged under
`physiological conditions is meant, for eXample, a tetraZol
`S-yl, phenylcarbonylaminocarbonyl, tri?uoromethylcarbo
`nylaminocarbonyl, C1_6-alkylsulphonylamino, phenylsul
`phonylamino,
`benZylsulphonylamino,
`tri?uoromethylsulphonylamino,
`C1_6-alkylsulphonylami
`nocarbonyl, phenylsulphonylaminocarbonyl, benZylsulpho
`nylaminocarbonyl or per?uoro-C1_6-alkylsulphonylami
`nocarbonyl group
`
`[0038] 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 option
`ally mono- or disubstituted by ?uorine, 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, pro
`pionyl, 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
`?uorine or chlorine atoms such as the methoXycarbonyl,
`ethoXycarbonyl, propoXycarbonyl, isopropoXycarbonyl,
`butoXycarbonyl, tert.butoXycarbonyl, pentoXycarbonyl, heX
`oXycarbonyl, octyloXycarbonyl, nonyloXycarbonyl, decy
`loXycarbonyl, undecyloXycarbonyl, dodecyloXycarbonyl,
`heXadecyloXycarbonyl, methylcarbonyloXy, ethylcarbony
`loXy, 2,2,2-trichloroethylcarbonyloXy, propylcarbonyloXy,
`isopropylcarbonyloXy, butylcarbonyloXy, tert.butylcarbony
`loXy, pentylcarbonyloXy, heXylcarbonyloXy, octylcarbony
`loXy, nonylcarbonyloXy, decylcarbonyloXy, undecylcarbo
`nyloXy, dodecylcarbonyloXy or heXadecylcarbonyloXy
`group, a phenyl-C1_6-alkoXycarbonyl group such as the
`benZyloXycarbonyl, phenylethoXycarbonyl or phenylpro
`poXycarbonyl 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-alkoXycar
`bonyl,
`C1_3-alkoXyC2_4-alkoXy-C2_4-alkoXycarbonyl,
`Rp—CO—O—(RqCRr)—O—CO, C1_6alkyl-CO—NH(R
`SCRt)—O—CO— or
`C1_6-alkyl-CO—O—(RSCRt)—
`(RSCRQ—O—CO— group, Wherein Rp to RI are as herein
`before de?ned,
`[0039] RS and R, Which may be identical or different,
`denote hydrogen atoms or C1_3-alkyl groups.
`[0040] A ?rst object of the invention relates to compounds
`of general formula (I) Wherein
`[0041] R1 denotes a methyl group Which is substituted
`by a dimethylaminocarbonyl, pyrrolidin-l-ylcarbonyl,
`piperidin-l-ylcarbonyl, tert.-butylcarbonyl or a cyclo
`heXylcarbonyl group,
`[0042] a methyl group Which is substituted by a naph
`thyl, methylnaphthyl, methoXynaphthyl, nitronaphthyl
`or (dimethylamino)-naphthyl group,
`[0043] a methyl group Which is substituted by a 2-phe
`nylethenyl or a biphenylyl group,
`[0044] a methyl group Which is substituted by a phenyl
`oXadiaZolyl, 5-methyl-3-phenyl-isoXaZolyl, phenyl-py
`ridinyl, indolyl, benZothiophenyl, quinolinyl, isoquino
`linyl,
`methylisoquinolinyl,
`(methoXycarbonylmethylamino)isoquinolinyl, cinnoli
`nyl, 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,
`[0045] a 2-methoXyethyl, 2-phenyloXyethyl or 2-cyano
`ethyl group,
`[0046] a phenylcarbonylmethyl or a l-(phenylcarbo
`nyl)-ethyl group,
`
`Mylan EX 1012, Page 3
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`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`a phenylcarbonylmethyl group wherein the phe-
`[0047]
`nyl moiety is substituted by an amino, cyanomethy-
`lamino, methylcarbonylamino,
`ethylcarbonylamino,
`isopropylcarbonylamino,
`methoxycarbonylamino,
`(ethyloXycarbonylamino)carbonylamino or a 2-oXo-
`imidazolidin-1-yl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0048]
`nyl moiety is substituted by a carboxy, methoXycarbo-
`nyl, ethyloxycarbonyl, aminocarbonyl, methylami-
`nocarbonyl, dimethylaminocarbonyl or morpholin-4-
`yl-carbonyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0049]
`nyl moiety is substituted by a methylsulphanyl, meth-
`ylsulphinyl or methylsulphonyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0050]
`nyl moiety is substituted by a carboxymethoxy, ethy-
`loxycarbonylmethoxy,
`isopropyloXycarbonylmethoxy,
`aminocarbonylmethoxy,
`methylaminocarbonyl-
`methoxy, ethylaminocarbonylmethoxy,
`isopropylami-
`nocarbonylmethoxy, dimethylaminocarbonylmethoxy,
`pyrrolidin-1-ylcarbonylmethoxy or morpholin-4-ylcar-
`bonylmethoxy group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0051]
`nyl moiety is substituted by a 1-(methoXycarbonyl)-
`ethyloxy or a 1-(aminocarbonyl)-ethyloxy group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0052]
`nyl moiety is substituted by a methylsulphinylmethoxy
`gfO1lp,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0053]
`nyl moiety is substituted by two methoxy groups or
`
`a phenylcarbonylmethyl group wherein in the
`[0054]
`phenyl moiety two adjacent hydrogen atoms are
`replaced by a
`0 CH2 0,
`0 CH2 CH2 0
`or a —N(CH3)CO—O group,
`
`[00551] R2 denotes a methyl, isopropyl or phenyl group
`an
`
`1-(1 -methyl-2-oxo -2-phenyl-ethyl)-3-methyl-7-
`[0066]
`(3 -methyl-2-buten- 1-yl)-8-(3-amino -piperidin-1 -yl)-
`Xanthine,
`
`1-(2-phenoxy-ethyl) -3-methyl-7-(2-cyano -ben-
`[0067]
`zyl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-
`[0068]
`1-yl) -8 -(3-amino-piperidin-1 -yl)-Xanthine,
`
`1-(2-{3-[(ethoXycarbonyl)methoXy]-phenyl} -2-
`[0069]
`oxo -ethyl) -3 -methyl-7-(3 -methyl-2-buten- 1-yl)-8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`1-(2-{2-[(methylaminocarbonyl)methoXy] -phe-
`[0070]
`nyl} -2-oXo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -
`yl)-8-(3-amino -piperidin-1 -yl) -Xanthine,
`
`1-(2-{2-[(dimethylaminocarbonyl)methoXy]-
`[0071]
`phenyl} -2-oXo-ethyl)-3-methyl-7-(3-methyl-2-buten-
`1-yl) -8 -(3-amino-piperidin-1 -yl)-Xanthine,
`
`1-(2-methoXy-ethyl)-3-methyl-7-(2-cyano-ben-
`[0072]
`zyl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-methyl-3-[(methoXycarbonyl)methyl]-7-(2-
`[0073]
`cyano -benzyl) -8 -(3-amino -piperidin- 1-yl)-Xanthine,
`
`1-methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-
`[0074]
`(3-amino -piperidin-1 -yl) -Xanthine,
`
`1-methyl-3 -(2-propyn-1 -yl)-7-(2-cyano -ben-
`[0075]
`zyl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1- {2-[3 -(2-oxo-imidazolidin-1 -yl)-phenyl] -2-
`[0076]
`oxo -ethyl} -3-methyl-7-(3 -methyl-2-buten-1 -yl) -8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`1-methyl-3 -(2-propen-1 -yl)-7-(2-cyano -ben-
`[0077]
`zyl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-(2-{2-[(ethylcarbonyl) amino]-phenyl} -2-oXo-
`[0078]
`ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl) -8 -(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`[0056] R3 denotes a 2-methyl-2-propen-1-yl, 2-chloro-
`2-propen-1-yl or 3-bromo-2-propen-1-yl group
`
`1-methyl-3-phenyl-7-(2-cyano-benzyl)-8-(3-
`[0079]
`amino-piperidin-1 -yl)-Xanthine,
`
`[0057]
`group,
`
`a 2-buten-1-yl or 2,3-dimethyl-2-buten-1-yl
`
`[0058]
`
`a 2-butyn-1-yl group,
`
`[0059]
`
`a 1-cyclopenten-1-ylmethyl group or
`
`[0060]
`
`a 2-furanylmethyl group,
`
`[0061]
`
`as well as the compounds
`
`1-(2-cyano -ethyl) -3 -methyl-7-(2-cyano -ben-
`[0062]
`zyl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-(2-{2-[(ethoXycarbonyl)methoXy]-phenyl} -2-
`[0063]
`oxo-ethyl) -3 -methyl-7-(3-methyl-2-buten- 1 -yl) -8 -(3-
`amino-piperidin- 1-yl)-Xanthine,
`
`1-(2-{2-[(aminocarbonyl)methoXy] -phenyl} -2-
`[0064]
`oxo-ethyl) -3 -methyl-7-(3-methyl-2-buten- 1 -yl) -8 -(3-
`amino-piperidin- 1-yl)-Xanthine,
`
`1-[2-(2- amino -phenyl)-2-oxo -ethyl] -3 -methyl-
`[0080]
`7-(3-methyl-2-buten- 1-yl)-8-((S)3-amino -piperidin-1 -
`yl)-Xanthine,
`
`1-(2-phenyl-2-oxo -ethyl) -3 -cyanomethyl-7-(3-
`[0081]
`methyl-2-buten- 1 -yl) -8 -(3-amino-piperidin- 1-yl)-Xan-
`thine,
`
`1-[(quinolin-2-yl)methyl]-3-methyl-7-(3-me-
`[0082]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -yl) -Xan-
`thine,
`
`1-[(2-oxo -2H-chromen-4-yl)methyl]-3-methyl-
`[0083]
`7-(3-methyl-2-buten- 1-yl)-8-(3-amino-piperidin-1 -yl)-
`Xanthine,
`
`1-[(cinnolin-4-yl)methyl] -3-methyl-7-(3-me-
`[0084]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -yl) -Xan-
`thine,
`
`1-(2-{3-[(methanesulphinyl)methoXy]-phenyl} -
`[0065]
`2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl) -8-
`(3-amino -piperidin-1 -yl) -Xanthine,
`
`1-[(1-methyl-2-oXo- 1 ,2-dihydro -quinolin-4-yl-
`[0085]
`)methyl] -3 -methyl-7-(3 -methyl-2-buten- 1-yl)-8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
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`US 2004/0097510 A1
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`
`1-[(4-OX0-3,4-dihydr0-phtha1azin-1 -y1)methy1]-
`[0086]
`3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-pip-
`eridin- 1-yl)-Xanthine,
`
`1- {2-[2-(dimethylaminocarbonyl) -phenyl] -2-
`[0104]
`OX0 -ethyl} -3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`1-[(quinaz01in-4-y1)methy1]-3-methyl-7-(3 -me-
`[0087]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -y1)-Xan-
`thine,
`
`1- {2-[2-(morpholin-4-yl-Carb0ny1)-pheny1]-2-
`[0105]
`OX0 -ethyl} -3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`1-[(5-rnethyl-3 -phenyl-is0Xaz01-4-y1)methy1]-3-
`[0088]
`methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1-[(is0quin0lin-3-y1)methy1] -3 -methy1-7-(3-me-
`[0089]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -y1)-Xan-
`thine,
`
`1-[(3-phenyl-[1,2,4]0Xadiaz01-5-y1)methy1]-3-
`[0090]
`methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1-[(4-phenyl-pyridin-2-y1)methy1] -3-methy1-7-
`[0091]
`(3-methy1-2-buten- 1-yl)-8-(3-amino-piperidin-1 -y1)-
`Xanthine,
`
`1-[(5-phenyl-pyridin-2-y1)methy1] -3-methy1-7-
`[0092]
`(3-methy1-2-buten- 1-yl)-8-(3-amino-piperidin-1 -y1)-
`Xanthine,
`
`1-[(3-methyl-4-OX0 -3,4-dihydro -phtha1azin- 1-
`[0093]
`y1)methy1] -3-methy1-7-(3-methy1-2-buten- 1 -y1)-8-(3-
`amin0-piperidin- 1-yl)-Xanthine,
`
`1-[2-(3 -methylsulphanyl-phenyl)-2-OX0-ethy1]-
`[0094]
`3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-pip-
`eridin- 1-yl)-Xanthine,
`
`1-[2-(3 -methanesulphinyl-phenyl) -2-OX0 -ethy1]-
`[0095]
`3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-pip-
`eridin- 1-yl)-Xanthine,
`
`1-[2-(3 -methanesulphonyl-phenyl)-2-OX0-
`[0096]
`ethyl]-3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-
`amin0-piperidin- 1-yl)-Xanthine,
`
`1-[2-(3-carboxy-phenyl)-2-OX0-ethy1]-3-me-
`[0097]
`thyl-7-(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-
`1 -yl) -Xanthine,
`
`1-[2-(3 -methoxycarbonyl-phenyl) -2-OX0 -ethy1]-
`[0098]
`3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-pip-
`eridin- 1-yl)-Xanthine,
`
`1- {2-[3-(methylaminocarbonyl)-pheny1]-2-0X0-
`[0099]
`ethyl} -3 -methyl-7-(3-methy1-2-buten- 1-yl)-8-(3-
`amin0-piperidin- 1-yl)-Xanthine,
`
`1- {2-[3-(dimethylaminocarbonyl)-phenyl] -2-
`[0100]
`OX0-ethyl} -3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-
`amin0-piperidin- 1-yl)-Xanthine,
`
`1- {2-[3-(morpholin-4-yl-carbonyl)-pheny1]-2-
`[0101]
`OX0-ethyl} -3-methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-
`amin0-piperidin- 1-yl)-Xanthine,
`
`1-[2-(2-Carboxy-phenyl)-2-OX0-ethy1]-3-me-
`[0102]
`thyl-7-(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-
`1 -yl) -Xanthine,
`
`1-[2-(2-ethoxycarbonyl-phenyl) -2-0X0-ethy1]-3-
`[0103]
`methyl-7-(3 -methy-2-buten- 1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1-[2-(2,6-dimethoxy-phenyl) -2-OX0 -ethy1]-3-
`[0106]
`methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1-((E) -3 -pheny1- allyl) -3 -methy1-7-(3-methy1-2-
`[0107]
`buten-1 -yl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-[(benz0[b]thi0phen-3 -y1)methy1]-3-methy1-7-
`[0108]
`(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-1 -y1)-
`Xanthine,
`
`1-[(1H-indol-3-y1)methy1]-3-methy1-7-(3-me-
`[0109]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -y1)-Xan-
`thine,
`
`1 -[(biphenyl-4-y1)methy1]-3-methyl-7-(3-me-
`[0110]
`thyl-2-buten-1 -yl)-8-(3-amino -piperidin- 1 -y1)-Xan-
`thine,
`
`1 -(2-cyclohexyl-2-OX0-ethy1)-3-methy1-7-(3-
`[0111]
`methy1-2-buten- 1 -yl) -8 -(3-amin0-piperidin- 1-y1)-Xan-
`thine,
`
`1 -(3,3 -dirnethyl-2-OX0 -buty1)-3-methy1-7-(3-
`[0112]
`methy1-2-buten- 1 -yl) -8 -(3-amin0-piperidin- 1-y1)-Xan-
`thine,
`
`1 -({5 -[(rnethoXycarb0ny1)methy1amin0]-is0-
`[0113]
`quinolin-1 -y1}methy1) -3 -methyl-7-(3 -methy1-2-buten-
`1-yl) -8 -(3-amino-piperidin-1 -yl)-Xanthine,
`
`1 -(2-dimethylamino -2-OX0 -ethy1)-3-methy1-7-
`[0114]
`(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-1 -y1)-
`Xanthine,
`
`1 -[2-(piperidin-1 -yl)-2-OX0-ethy1]-3-methy1-7-
`[0115]
`(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-1 -y1)-
`Xanthine,
`
`1 -[(2-methyl-1 -0X0- 1 ,2-dihydro -is0quin01in-4-
`[0116]
`y1)methy1] -7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-pip-
`eridin- 1-yl)-Xanthine,
`
`1 -[2-(2,3-dimethoxy-phenyl)-2-0X0-ethy1]-3-
`[0117]
`methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1 -[2-(pyrr01idin- 1 -yl) -2-0X0-ethy1]-3-methy1-7-
`[0118]
`(3 -methy1-2-buten- 1-yl)-8-(3-amino -piperidin-1 -y1)-
`Xanthine,
`
`1 -[2-(2,3-dihydro-benz0[ 1,4]di0Xin-5 -yl) -2-
`[0119]
`OX0 -ethyl] -3 -methyl-7-(3 -methy1-2-buten- 1-yl)-8-(3-
`amino-piperidin-1 -yl)-Xanthine,
`
`1-[2-(3-rnethyl-2-OX0 -2,3 -dihydro -benz00X-
`[0120]
`azol-7-yl)-2-OX0-ethyl] -3 -methy1-7-(3-methy1-2-
`buten-1 -yl)-8-(3-amino -piperidin- 1 -yl) -Xanthine,
`
`1-[2-(benz0[1,3]di0X01-4-yl)-2-0X0-ethy1]-3-
`[0121]
`methyl-7-(3 -methyl-2-buten-1 -y1)-8-(3-amin0-piperi-
`din-1 -yl) -Xanthine,
`
`1-methyl-3 -isopropyl-7-(2-cyano-benzyl) -8-(3-
`[0122]
`amino-piperidin-1 -yl)-Xanthine,
`
`Mylan EX 1012, Page 5
`
`Mylan EX 1012, Page 5
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`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`1-[2-(2-cyanomethylamino -phenyl) -2-oxo-
`[0123]
`ethyl]-3-methyl-7-(3 -methyl-2-buten-1 -yl)-8-(3-
`amino-piperidin- 1-yl)-xanthine,
`
`1-[(isoquinolin- 1-yl)methyl] -3 -[(methoxycarbo-
`[0124]
`nyl)methyl] -7-(3-methyl-2-buten-1 -yl) -8 -(3-amino -pi-
`peridin-1 -yl)-xanthine,
`
`1-(2-{2-[(isopropyloxycarbonyl)methoxy] -phe-
`[0125]
`nyl} -2-oxo-ethyl)-3-methyl-7-(3 -methyl-2-buten-1 -
`yl)-8-(3-amino-piperidin-1 -yl)-xanthine,
`
`1-[2-(2-{[(ethoxycarbonylamino)carbonyl]
`[0126]
`amino} -phenyl)-2-oxo -ethyl] -3 -methyl-7-(3-methyl-2-
`buten- 1-yl)-8-(3-amino -piperidin-1 -yl) -xanthine,
`
`1-[2-(2-acetylamino -phenyl) -2-oxo -ethyl]-3-
`[0127]
`methyl-7-(3 -methyl-2-buten-1 -yl)-8-((S) -3-amino -pip-
`eridin- 1-yl)-xanthine,
`
`1-(2-{2-[(methylaminocarbonyl)methoxy] -phe-
`[0128]
`nyl} -2-oxo-ethyl)-3-methyl-7-(3 -methyl-2-buten-1 -
`yl)-8-((S)-3-amino-piperidin- 1-yl)-xanthine,
`
`1-methyl-7-(2-cyano-benzyl)-8-(3-amino-pip-
`[0129]
`eridin- 1-yl)-xanthine,
`
`1-(2-{2-[(isopropylcarbonyl)amino]-phenyl} -2-
`[0130]
`oxo-ethyl) -3 -methyl-7-(3-methyl-2-buten- 1 -yl) -8 -(3-
`amino-piperidin- 1-yl)-xanthine,
`
`1-(2-{2-[(methoxyarbonyl)amino]-phenyl} -2-
`[0131]
`oxo-ethyl) -3 -methyl-7-(3-methyl-2-buten- 1 -yl) -8 -(3-
`amino-piperidin- 1-yl)-xanthine,
`
`1-[2-(3 -methyl-2-oxo -2,3-dihydro -benzoox-
`[0132]
`azol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-
`buten- 1-yl)-8-(3-amino -piperidin-1 -yl) -xanthine,
`
`1-[2-(2-nitro -3 -methoxy-phenyl)-2-oxo -ethyl]-
`[0133]
`3-methyl-7-(3 -methyl-2-buten-1 -yl)-8-(3-amino -pip-
`eridin- 1-yl)-xanthine,
`
`1-[2-(2-amino -3 -methoxy-phenyl)-2-oxo-
`[0134]
`ethyl]-3-methyl-7-(3 -methyl-2-buten-1 -yl)-8-(3-
`amino-piperidin- 1-yl)-xanthine,
`
`1-[2-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-
`[0135]
`oxo-ethyl] -3 -methyl-7-(3-methyl-2-buten- 1 -yl) -8 -(3-
`amino-piperidin- 1-yl)-xanthine,
`
`1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-me-
`[0136]
`thyl-7-(3 -methyl- 1 -buten- 1-yl)-8-((R)-3-amino-piperi-
`din-1 -yl) -xanthine,
`
`1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-me-
`[0137]
`thyl-7-(2-cyano -benzyl)-8-(3-amino-piperidin-1 -yl)-
`xanthine,
`
`1-[2-(3-carboxymethoxy-phenyl)-2-oxo-ethyl]-
`[0138]
`3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-pip-
`eridin-1-yl)-xanthine and
`
`1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-
`[0139]
`3-methyl-7-(3 -methyl-2-buten-1 -yl)-8-(3-amino -pip-
`eridin- 1-yl)-xanthine,
`
`the
`the tautomers, enantiomers, diastereomers,
`[0140]
`mixtures thereof, the prodrugs thereof and the salts thereof.
`
`[0141] A first preferred sub-group of the first object of the
`invention comprises compounds of general
`formula I
`wherein
`
`[0142] R1
`group,
`
`denotes
`
`a
`
`4-methoxy-1 -naphthylmethyl
`
`a 2-quinolinylmethyl, 4-quinolinylmethyl or a
`[0143]
`6-quinolinylmethyl group,
`
`a 1-isoquinolinylmethyl, 3-methyl-1-isoquinoli-
`[0144]
`nylmethyl, 4-methyl-1 isoquinolinylmethyl or a 3-iso-
`quinolinylmethyl group or
`
`a 2-quinazolinylmethyl, 4-methyl-2-quinazoli-
`[0145]
`nylmethyl or a 4-quinazolinylmethyl group,
`
`[0146] R2 denotes a methyl group and
`
`[0147] R3 denotes a 2-buten-1-yl or a 2-butyn-1-yl
`group,
`
`the tautomers, enantiomers, diastereomers,
`[0148]
`mixtures thereof and the salts thereof.
`
`the
`
`[0149] A second preferred sub-group of the first object of
`the invention comprises compounds of general formula 1,
`wherein
`
`[0150] R1 denotes a [2-(methylcarbonylamino)-phe-
`nyl]-carbonylmethyl group,
`
`[2-(ethylcarbonylamino)-phenyl]-carbonylm-
`a
`[0151]
`ethyl group or
`
`a [2-(isopropylcarbonylamino)-phenyl]-carbon-
`[0152]
`ylmethyl group,
`
`[0153] R2 denotes a methyl group and
`
`[0154] R3 denotes a 2-buten-1-yl or a 2-butyn-1-yl
`group,
`
`the tautomers, enantiomers, diastereomers,
`[0155]
`mixtures thereof and the salts thereof.
`
`the
`
`[0156] Athird preferred sub-group of the first object of the
`invention comprises compounds of general
`formula I
`according to claim 1, wherein
`
`[0157] R1 denotes a [2-(aminocarbonylmethoxy)-phe-
`nyl]-carbonylmethyl group,
`
`[2-(methylaminocarbonylmethoxy)-phenyl]-
`[0158]
`carbonylmethyl group,
`
`a[2-(ethylaminocarbonylmethoxy)-phenyl]-car-
`[0159]
`bonylmethyl group or
`
`[2-(isopropylaminocarbonylmethoxy)-phe-
`a
`[0160]
`nyl]-carbonylmethyl group,
`
`[0161] R2 denotes a methyl group and
`
`[0162] R3 denotes a 2-buten-1-yl group,
`
`[0163]
`
`a 2-butyn-1-yl group or
`
`[0164]
`
`a 1-cyclopenten-1-ylmethyl group,
`
`the tautomers, enantiomers, diastereomers,
`[0165]
`mixtures thereof and the salts thereof.
`
`the
`
`[0166] A second object of the invention relates to com-
`pounds of general formula 1, wherein
`
`[0167] R1 denotes a methyl group which is substituted
`by a naphthyl, fluoronaphthyl, methylnaphthyl, meth-
`oxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaph-
`thyl, nitronaphthyl or (dimethylamino)-naphthyl group,
`
`Mylan EX 1012, Page 6
`
`Mylan EX 1012, Page 6
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`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`[0168] a methyl group Which is substituted by a phenan
`threnyl group,
`[0169] a methyl group Which is substituted by a 2-phe
`nylethenyl, 2-[(tri?uoromethyl)phenyl]-ethenyl, 2-(ni
`trophenyl)ethenyl, 2—(penta?uorophenyl)ethenyl or a
`biphenylyl group,
`[0170] a methyl group Which is substituted by a phe
`nyloXadiaZolyl, phenyl-pyridinyl, indolyl, methylin
`dolyl, dimethyl-6,7-dihydro-5H-[2]pyrindinyl, benZ
`imidaZolyl,
`methylbenZimidaZolyl,
`(cyanoethyl)
`benZimidaZolyl,
`(methylaminocarbonylmethyl)benZimidaZolyl, benZyl
`benZimidaZolyl, benZofuranyl, acetylbenZofuranyl,
`cyanobenZofuranyl, benZoXaZolyl, nitrobenZoXaZolyl,
`benZothiophenyl, methylbenZothiaZolyl, quinolinyl,
`methoXyquinolinyl, isoquinolinyl, methylisoquinoli
`nyl, (di?uoromethyl)-isoquinolinyl, (tri?uoromethyl)
`isoquinolinyl, dimethylisoquinolinyl, (l-cyano-l-me
`thylethyl)isoquinolinyl,
`phenylisoquinolinyl,
`methoXyisoquinolinyl, methoXy-chloroisoquinolinyl,
`methoXy-bromo-isoquinolinyl, (methoXycarbonylm
`ethylamino)isoquinolinyl,
`dimethyl-S,6,7,8-tetrahy
`droisoquinolinyl,
`1,2,3,4-tetrahydrophenanthridinyl,
`cinnolinyl, quinaZolinyl, methylquinaZolinyl, isopro
`pylquinaZolinyl,
`cyclopropylquinaZolinyl,
`phe
`nylquinaZolinyl, aminoquinaZolinyl, (dimethylamino)
`quinaZolinyl, pyrrolidin-l-ylquinaZolinyl, piperidin-l
`ylquinaZolinyl, piperaZin-1-ylquinaZolinyl, morpholin
`4-ylquinaZolinyl,
`ethoXyquinaZolinyl,
`isopropyloXyquinaZolinyl,
`phenyloXyquinaZolinyl,
`imidaZo[1,2-a]pyridinyl, methylimidaZo[1,2-a]pyridi
`nyl, phenylimidaZo[1,2-a]pyridinyl, benZylimidaZo[1,
`2-a]pyridinyl, pyraZolo[1,5-a]pyridinyl, quinoXalinyl,
`methylquinoXalinyl, dimethylquinoXalinyl, trimeth
`ylquinoXalinyl, phenylquinoXalinyl, methylphthalaZi
`nyl, 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-iso
`quinolinyl, 3,4-dihydro-4-oXo-phthalaZinyl, 3,4-dihy
`dro-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,
`[0171]
`a phenylcarbonylmethyl group,
`[0172] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by an amino, cyanomethy
`lamino, (ethyloXycarbonylmethyl)amino, (methylami
`nocarbonyl)methylamino,
`methylcarbonylamino,
`ethylcarbonylamino, isopropylcarbonylamino, phenyl
`carbonylamino, methoXycarbonylamino, (ethyloXycar
`bonylamino)-carbonylamino or a 2-oXo-imidaZolidin
`1-yl group,
`[0173] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a phenyl group,
`
`[0174] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a carboXy, methoXycarbo
`nyl, ethyloXycarbonyl, aminocarbonyl, methylami
`nocarbonyl, dimethylaminocarbonyl or morpholin-4
`yl-carbonyl group,
`
`[0175] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methylsulphanyl, meth
`ylsulphinyl or methylsulphonyl group,
`
`[0176] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methoXy, di?uo
`romethoXy, tri?uoromethoXy, ethyloXy, isopropyloXy
`or phenyloXy group,
`
`[0177] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methylsulphinylmethoXy,
`carboXymethoXy, ethyloXycarbonylmethoXy, isopropy
`loXycarbonylmethoXy, aminocarbonylmethoXy, methy
`laminocarbonylmethoXy, ethylaminocarbonylmethoXy,
`isopropylaminocarbonylmethoXy, dimethylaminocar
`bonylmethoXy, pyrrolidin-1-ylcarbonylmethoXy or
`morpholin-4-ylcarbonylmethoXy group,
`[0178] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a 1-(ethyloXycarbonyl)-1
`methyl-ethyloXy, 1-(methoXycarbonyl)-ethyloXy or a 1
`(aminocarbonyl)-ethyloXy group,
`[0179] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by tWo methoXy groups,
`[0180] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methoXy group and a
`nitro group,
`
`[0181] a phenylcarbonylmethyl group Wherein the phe
`nyl moiety is substituted by a methoXy group and an
`amino group,
`
`[0182] 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, —NHCO—NH, —N(CH3)—
`CO—NH, —N(CH3)—CO—N(CH3), —NH—CO—
`O— or a —N(CH3)CO—O group,
`[0183]
`a (2-phenylethyl)carbonylmethyl group,
`[0184] a naphthylcarbonylmethyl, indolylcarbonylm
`ethyl or quinolinylcarbonylmethyl group or
`[0185]
`a 2-cyanimino—2-phenyl-ethyl group,
`[0186] R2 denotes a methyl, isopropyl, cyclopropyl,
`phenyl or ?uorophenyl group and
`
`a 2-butyn-1-yl group,
`
`[0187] R3 denotes a 2-methyl-2-propen-1-yl, 2-chloro
`2-propen-1-yl or 3-bromo-2-propen-1-yl group
`[0188] a 1-buten-1-yl, 3-methyl-1-buten-1-yl, 2-buten
`1-yl, 2-methyl-2-buten-1-ylor 2,3-dimethyl-2-buten-1
`yl group,
`[0189]
`[0190]
`[0191]
`[0192] the tautomers, enantiomers, diastereomers, the
`mixtures thereof, the prodrugs thereof and the salts thereof.
`[0193] A preferred sub-group of the second object of the
`invention comprises compounds of general formula I
`Wherein
`
`a l-cyclopenten-l-ylmethyl group or
`
`a 2-furanylmethyl group,
`
`[0194] R1 and R2 are as hereinbefore de?ned and
`
`[0195] R3 denotes a 1-buten-1-yl, 2-buten-1-yl or 2-bu
`tyn-1-yl group,
`
`[0196] the tautomers, enantiomers, diastereomers, the
`mixtures thereof and the salts thereof.
`
`Mylan EX 1012, Page 7
`
`

`
`US 2004/0097510 A1
`
`May 20, 2004
`
`[0197] A particularly preferred sub-group of the second
`object of the invention comprises compounds of general
`formula I Wherein
`
`[0198] R1 denotes a methyl group Which is substituted
`by a naphthyl, ?uoronaphthyl, methylnaphthyl, meth
`oxynaphthyl, (di?uoromethoxy)-naphthyl, cyanonaph
`thyl or nitronaphthyl