`(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'AMIN0'PIPERIDIN'1'YL]'XANTHINESs
`THE PREPARATION THEREOF AND THEIR
`
`(30)
`
`Foreign Application Priority Data
`
`USE AS PHARMACEUTICAL
`COMPOSITIONS
`
`Aug. 21, 2002
`Mar. 20, 2003
`
`(DE) ...................................... .. 102 38 243
`(DE) ...................................... .. 103 12 353
`
`(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. 0. BOX 368
`RIDGEFIELD, CT 06877 (US)
`(73) Assignee: Boehringer Ingelheim Pharma GmbH
`& Co. KG, Ingelheim (DE)
`10/639,036
`
`(21) Appl. No.:
`
`Publication Classification
`
`Int. Cl.7 .................... .. A61K 31/522; C07D 473/02
`(51)
`(52) U.S. Cl.
`............ .. 514/248; 514/263.21; 514/263.22;
`544/269; 544/237
`
`ABSTRACT
`(57)
`Th
`1
`t
`t
`t
`.
`t.
`b H t d
`e presen inven 10I1 re a es o su s 1u e
`general formula
`
`th.
`xan mes o
`
`f
`
`(1)
`
`NH»
`
`O
`
`/R3
`R1
`N
`l
`\N
`A /
`I|\I
`N
`R2
`
`O
`
`N
`
`(22)
`
`Filed:
`
`Aug. 12, 2003
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/409,312, filed on Sep.
`9, 2002. Provisional application No. 60/461,752, filed
`on Apr. 10, 2003.
`
`the
`wherein R1 to R3 are defined as in claims 1 to 16,
`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. 1003, Page 1
`
`MYLAN Ex. 1003, 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 benefit to U.S. provisional
`application serial No. 60/409,312 filed Sep. 9, 2002 and
`60/461,752 filed Apr. 10, 2003 and German application nos.
`DE 102 38 243.3 filed Aug. 21, 2002 and DE 103 12 353.9
`filed 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)
`
`NH2,
`
`0
`R1\N
`A '
`T
`R2
`
`0
`
`/R3
`N
`/>
`N
`
`N
`
`the tautomers, the stereoisomers, the mixtures, the
`[0004]
`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,
`
`a methyl group which is substituted by a dim-
`[0007]
`ethylaminocarbonyl, pyrrolidin-1-yl-carbonyl, piperi-
`din-1-ylcarbonyl, tert.-butylcarbonyl or a cycloheXyl-
`carbonylgroup,
`
`a methyl group which is substituted by a naph-
`[0008]
`thyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl
`or dimethylaminonaphthyl group,
`a methyl group
`which is substituted by a 2-phenylethenyl or a biphe-
`nylyl group,
`
`a methyl group which is substituted by a phe-
`[0009]
`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,
`
`a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyano-
`[0010]
`ethyl group,
`
`a phenylcarbonylmethyl or a 1-(phenylcarbo-
`[0011]
`nyl)-ethyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0012]
`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-
`[0013]
`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-
`[0014]
`nyl moiety is substituted by a methylsulphanyl, meth-
`ylsulphinyl or methylsulphonyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0015]
`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-
`[0016]
`nyl moiety is substituted by a 1-(methoXycarbonyl)-
`ethyloxy or a 1-(aminocarbonyl)-ethyloxy group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0017]
`nyl moiety is substituted by a methylsulphinylmethoxy
`group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0018]
`nyl moiety is substituted by two methoxy groups or
`
`a phenylcarbonylmethyl group wherein in the
`[0019]
`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,
`
`a methyl, isopropyl, 2-propen-1-yl, 2-propyn-1-
`[0021]
`yl or phenyl group or
`
`a
`[0022]
`group and
`
`cyanomethyl
`
`or methoxycarbonylmethyl
`
`[0023] R3 denotes a 2-cyanobenzyl or 2,6-dicyanoben-
`zyl group,
`
`a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-
`[0024]
`yl or 3-bromo-2-propen-1-yl group
`
`MYLAN Ex. 1003, Page 2
`
`MYLAN Ex. 1003, Page 2
`
`
`
`US 2004/0097510 A1
`
`May 20, 2004
`
`a 2-buten-1-yl, 3-methyl-2-buten-1-yl or 2,3-
`[0025]
`dimethyl-2-buten-1-yl group,
`
`[0026]
`
`a 2-butyn-1-yl group,
`
`[0027]
`
`a 1-cyclopenten-1-ylmethyl group or
`
`[0028]
`
`a 2-furanylmethyl group.
`
`[0029] The carboxy groups mentioned in the definition of
`the above mentioned groups may be replaced by a group
`which can be converted into a carboxy group in vivo or by
`a group which is negatively charged under physiological
`conditions,
`
`and furthermore the amino and imino groups men-
`[0030]
`tioned 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).
`
`[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 esterified with an alcohol wherein
`the alcohol moiety is preferably a C1_6alkanol, 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-cycloall<-
`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
`
`Rp—CO—O—(RqCR,)—OH,
`
`[0033] wherein
`
`[0034] RP denotes a C1_8-alkyl, C5_7-cycloalkyl, C1_8-
`alkyloxy, C5_7cycloall<yloxy, 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,
`
`by a group which is negatively charged under
`[0037]
`physiological conditions is meant, for example, a tetrazol-
`5-yl, phenylcarbonylaminocarbonyl,
`trifluoromethylcarbo-
`nylaminocarbonyl, C1_6-alkylsulphonylamino, phenylsul-
`phonylamino,
`benzylsulphonylamino,
`trifluoromethylsulphonylamino,
`C1_6-alkylsulphonylami-
`nocarbonyl, phenylsulphonylaminocarbonyl, benzylsulpho-
`nylaminocarbonyl
`or
`perfluoro-C1_6-alkylsulphonylami-
`nocarbonyl group
`
`and by a group which can be cleaved in vivo from
`[0038]
`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 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 CH6-alkanoyl group such as the formyl, acetyl, pro-
`pionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-
`trichloropropionyl or allyloxycarbonyl group,
`a C146-
`alkoxycarbonyl or CH6-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, 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-all<oxycar-
`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 defined,
`
`RS and Rt, which may be identical or different,
`[0039]
`denote hydrogen atoms or C1_3-alkyl groups.
`
`[0040] A first 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-1-ylcarbonyl,
`piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclo-
`hexylcarbonyl group,
`
`a methyl group which is substituted by a naph-
`[0042]
`thyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl
`or (dimethylamino)-naphthyl group,
`
`a methyl group which is substituted by a 2-phe-
`[0043]
`nylethenyl or a biphenylyl group,
`
`a methyl group which is substituted by a phenyl-
`[0044]
`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,
`
`a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyano-
`[0045]
`ethyl group,
`
`a phenylcarbonylmethyl or a 1-(phenylcarbo-
`[0046]
`nyl)-ethyl group,
`
`MYLAN Ex. 1003, Page 3
`
`MYLAN Ex. 1003, Page 3
`
`
`
`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,
`
`MYLAN Ex. 1003, Page 4
`
`MYLAN Ex. 1003, Page 4
`
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`US 2004/0097510 A1
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`May 20, 2004
`
`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. 1003, Page 5
`
`MYLAN Ex. 1003, Page 5
`
`
`
`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,
`[0133]
`1-[2-(2-nitro -3 -methoxy-phenyl)-2-oxo -ethyl]-
`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
`
`[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,
`
`[0151]
`[2-(ethylcarbonylamino)-phenyl]-carbonylm-
`a
`ethyl group or
`
`a [2-(isopropylcarbonylamino)-phenyl]-carbon-
`[0152]
`ylmethyl group,
`
`[0153] R2 denotes 3 methyl greup and
`
`[0154] R3 denotes 3 2'buten'1'Y1 Or 3 2'butYn'1'Y1
`group,
`[0155]
`the tautomers, enantiomers, diastereomers,
`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,
`
`1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-
`[0139]
`3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino-pip-
`eridin-Lyl)-Xamhine’
`the
`[0140]
`the tautomers, enantiomers, diastereomers,
`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
`
`the tautomers, enantiomers, diastereomers,
`[0165]
`mixtures thereof and the salts thereof.
`[0166] A second object of the invention relates to com-
`pounds of general formula 1, wherein
`
`the
`
`[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. 1003, Page 6
`
`MYLAN Ex. 1003, Page 6
`
`
`
`US 2004/0097510 A1
`
`May 20, 2004
`
`a methyl group which is substituted by a phenan-
`[0168]
`threnyl group,
`
`a methyl group which is substituted by a 2-phe-
`[0169]
`nylethenyl, 2-[(trifluoromethyl)phenyl]-ethenyl, 2-(ni-
`trophenyl)ethenyl, 2-(pentafluorophenyl)ethenyl or a
`biphenylyl group,
`
`a methyl group which is substituted by a phe-
`[0170]
`nyloxadiazolyl, phenyl-pyridinyl,
`indolyl, methylin-
`dolyl, dimethyl-6,7-dihydro-SH-[2]pyrindinyl, benz-
`imidazolyl, methylbenzimidazolyl,
`(cyanoethyl)-
`benzimidazolyl,
`(methylaminocarbonylmethyl)benzimidazolyl, benzyl-
`benzimidazolyl,
`benzofuranyl,
`acetylbenzofuranyl,
`cyanobenzofuranyl, benzoxazolyl, nitrobenzoxazolyl,
`benzothiophenyl, methylbenzothiazolyl, quinolinyl,
`methoxyquinolinyl,
`isoquinolinyl, methylisoquinoli-
`nyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-
`isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-me-
`thylethyl)isoquinolinyl,
`phenylisoquinolinyl,
`methoxyisoquinolinyl, methoXy-chloroisoquinolinyl,
`methoxy-bromo-isoquinolinyl,
`(methoXycarbonylm-
`ethylamino)isoquinolinyl,
`dimethyl-5,6,7,8-tetrahy-
`droisoquinolinyl,
`1,2,3,4-tetrahydrophenanthridinyl,
`cinnolinyl, quinazolinyl, methylquinazolinyl,
`isopro-
`pylquinazolinyl,
`cyclopropylquinazolinyl,
`phe-
`nylquinazolinyl, aminoquinazolinyl, (dimethylamino)-
`quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-
`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,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0172]
`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,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0173]
`nyl moiety is substituted by a phenyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0174]
`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-
`[0175]
`nyl moiety is substituted by a methylsulphanyl, meth-
`ylsulphinyl or methylsulphonyl group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0176]
`nyl moiety is
`substituted by a methoxy, difluo-
`romethoxy,
`trifluoromethoxy, ethyloxy,
`isopropyloxy
`or phenyloxy group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0177]
`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,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0178]
`nyl moiety is substituted by a 1-(ethyloXycarbonyl)-1-
`methyl-ethyloxy, 1-(methoXycarbonyl)-ethyloxy or a 1
`(aminocarbonyl)-ethyloxy group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0179]
`nyl moiety is substituted by two methoxy groups,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0180]
`nyl moiety is substituted by a methoxy group and a
`nitro group,
`
`a phenylcarbonylmethyl group wherein the phe-
`[0181]
`nyl moiety is substituted by a methoxy group and an
`amino group,
`
`a phenylcarbonylmethyl group wherein in the
`[0182]
`phenyl moiety two adjacent hydrogen atoms are
`replaced
`by
`a —O—CH2—O, —O—CF2—O,
`0 CH2 CH2 0,
`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,
`
`indolylcarbonylm-
`a naphthylcarbonylmethyl,
`[0184]
`ethyl or quinolinylcarbonylmethyl group or
`
`[0185]
`
`a 2-cyanimino-2-phenyl-ethyl group,
`
`isopropyl, cyclopropyl,
`[0186] R2 denotes a methyl,
`phenyl or fluorophenyl group and
`
`[0187] 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-
`[0188]
`1-yl, 2-methyl-2-buten-1-ylor 2,3-dimethyl-2-buten-1-
`yl group,
`
`[0189]
`
`a 2-butyn-1-yl group,
`
`[0190]
`
`a 1-cyclopenten-1-ylmethyl group or
`
`[0191]
`
`a 2-furanylmethyl group,
`
`the
`the tautomers, enantiomers, diastereomers,
`[0192]
`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
`
`[0194] R1 and R2 are as hereinbefore defined and
`
`[0195] R3 denotes a 1-buten-1-yl, 2-buten-1-yl or 2-bu-
`tyn-1-yl group,
`
`the tautomers, enantiomers, diastereomers,
`[0196]
`mixtures thereof and the salts thereof.
`
`the
`
`MYLAN Ex. 1003, Page 7
`
`MYLAN Ex. 1003, 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, fluoronaphthyl, methylnaphthyl, meth-
`oxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaph-
`thyl or nitronaphthyl group,
`
`a methyl group which is substituted by a 2-(pen-
`[0199]
`tafluorophenyl)ethenyl group,
`
`a me