EP1565468A1 - Derives de xanthine, leur production et leur utilisation en tant que medicaments - Google Patents

Derives de xanthine, leur production et leur utilisation en tant que medicaments

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Publication number
EP1565468A1
EP1565468A1 EP03782204A EP03782204A EP1565468A1 EP 1565468 A1 EP1565468 A1 EP 1565468A1 EP 03782204 A EP03782204 A EP 03782204A EP 03782204 A EP03782204 A EP 03782204A EP 1565468 A1 EP1565468 A1 EP 1565468A1
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EP
European Patent Office
Prior art keywords
group
alkyl
amino
substituted
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03782204A
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German (de)
English (en)
Inventor
Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Roland Maier
Michael Mark
Mohammad Tadayyon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1565468A1 publication Critical patent/EP1565468A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Definitions

  • the present invention relates to new substituted xanthines of the general formula
  • DPP-IV dipeptidyl peptidase-IV
  • DPP-IV dipeptidyl peptidase-IV
  • R 1 is an ABD group in which
  • A is a C ⁇ substituted by a phenyl group. 6 -alkyl group, where the C- ⁇ - 6 - alkyl group can be substituted by one to twelve fluorine atoms and wherein the phenyl ring can be substituted by the groups R 10 to R 14 and R 10 is a fluorine, chlorine, bromine or iodine atom,
  • N- (C ⁇ . 3 -alkyl) -C ⁇ - 3 -alkyl-carbonylamino- N- (C ⁇ - 3 -alkyl) -arylcarbonylamino-, N- (C ⁇ -3 -alkyl) -aryI-C ⁇ -3 -alkyl -carbonylamino-, N- (C 1, 3 -alkyl) -C ⁇ -3 -alkyloxy-carbonylamino-, N- (aminocarbonyl) -C ⁇ .
  • Methyl or ethyl group can be substituted
  • a C ⁇ -3 alkyl carbonyl or an arylcarbonyl group a carboxy-C 3 alkyl, C 3 alkyloxy carbonyl C 1 . 3- alkyl-, cyano-C 1 . 3 -alkyl-, aminocarbonyl-C ⁇ - 3 -alkyl-, C ⁇ .
  • hydroxy -C 3 alkyl C ⁇ . 3 -alkyloxy-C ⁇ - 3 -alkyl-, amino-C ⁇ - 3 -alkyl-, C ⁇ - 3 -alkyl-amino-C ⁇ - 3 -alkyl-, di- (C ⁇ . 3 -alkyl) -amino-C ⁇ . 3 -alkyl-, pyrrolidin-l-yl -CC 3 -alkyl-, piperidin-1-yI -CC. 3 -alkyl-. Morpholin-4-yl-C ⁇ - 3 -alkyl-, piperazin-1-yl-C ⁇ - 3 -alkyl-, 4- (C ⁇ . 3 -alkyl) -piperazin-1-yl-C ⁇ . 3 -alkyl group,
  • R 11 and R 12 which may be the same or different, each have a fluorine, chlorine, bromine or iodine atom, a C ⁇ . 3 alkyl, trifluoromethyl, hydroxy, or C 3 alkyloxy group or a cyano group, or
  • R 13 and R 14 which may be the same or different, each have a fluorine, chlorine or bromine atom, a trifluoromethyl, C ⁇ . 3 alkyl or C ⁇ . 3 alkyloxy group mean
  • R 10 a phenyl-C 2 - 3 alkynyl group in which the phenyl moiety by the groups R 10 may be substituted by R 14, where R 10 are defined as mentioned above to R 14,
  • B is an E-G group in which E is linked to group A and
  • E is an oxygen or sulfur atom
  • R a is a hydrogen atom, a C ⁇ . 6 -alkyl-, C 3 . 6 - alkenyl, C 3 . 6 alkynyl, C 3-7 cycloalkyl, phenyl, phenylmethyl, heteroaryl, heteroarylmethyl, amino, C ⁇ - 6 alkylamino, di- (C ⁇ -6-alkyl) amino, hydroxy, C Represents -6-alkyloxy group, where the aforementioned phenyl rings can each be substituted by the groups R 10 to R 11 , where R 10 to R 11 are defined as mentioned above,
  • R a is defined as mentioned above and the two radicals R a can be the same or different, an -NH-NH group in which the two hydrogen atoms are separated by a straight-chain C 3 . 5 alkylene bridge are replaced,
  • Oxygen atom is attached to group A and the nitrogen atom is attached to group G,
  • R b and R c which may be the same or different, represent a hydrogen or fluorine atom a C 1 - 6 - alkyl, C 3rd 7- Cycloalkyl-, phenyl-, phenylmethyl-, where the phenyl rings can each be substituted by the groups R 10 to R 14 , where R 10 to R 4 are defined as mentioned above, represent heteroaryl or heteroarylmethyl group 15 or R b and R c together form a straight-chain C 2 - 6 represent alkylene,
  • : 5 is a -SO 2 -CR b R c group in which the sulfur atom is attached to group A and the carbon atom is attached to group G and R b and R c , which may be the same or different, are as defined above .
  • G is a carbonyl or thiocarbonyl group
  • a methylene group substituted by an imino group in which the nitrogen atom is replaced by a C 6 alkyl, C 3 6 alkenyl, C 3 6 alkynyl, C 3 . 7- cycloalkyl-, phenyl-, phenylmethyl-, heteroaryl-, heteroarylmethyl-, amino-, C ⁇ -6-alkylamino-, di- (C ⁇ - 6 -alkyl) amino-, pyrrolidin-1-yl-, piperidine- 1-yl-, morpholin-4-yl-, C - 6 -alkyl-carbonylamino-, phenylcarbonylamino-, C ⁇ - 6 -alkyloxy-carbonyl-amino-, Ci- ⁇ -alkylsulfonylamino-, phenylsulfonylamino-, hydroxyl-, C ⁇ - 6 - alkyloxy, cyano or nitro group can be substituted, where the
  • a 1, 1-ethenylene group in which the exo-carbon atom by one or two chlorine or fluorine atoms or one or two C ⁇ . 6 alkyl, C ⁇ . 6 -perfluoroalkyl-, C 3 . 6 alkenyl, C 3 . 6 alkynyl, C 3-7 cycloalkyl, phenyl, phenylmethyl, heteroaryl, heteroarylmethyl, C ⁇ - 6 alkyl-carbonyl, C. 3 7 -cycloalkyl-carbonyl-, phenylcarbonyl-, heteroarylcarbonyl-, carboxy-, C ⁇ - 6 -alkyloxy-carbonyl-, aminocarbonyl-, C ⁇ .
  • a together with B represent a 1, 2,3,4-tetrahydroquinolinylcarbonyl, 1, 2,3,4-tetrahydroisoquinolinylcarbonyl, 2,3-dihydroindolylcarbonyl or 2,3-dihydroisoindolylcarbonyl group, in which the benzo groups in each case can be substituted by the groups R 10 to R 13 , R 10 to R 13 being defined as mentioned above and one or two carbon atoms of the benzo group can be replaced by nitrogen atoms and the alkylene parts of the groups mentioned above can each be substituted by one or two fluorine atoms, one or two methyl groups or an oxo group, where the substituents can be the same or different,
  • D is a C 6 alkylene group which can be substituted by one to twelve fluorine atoms
  • R 2 is a hydrogen atom
  • G is an oxygen or sulfur atom, a> imino, C ⁇ . 3 denotes alkylimino, sulfinyl or sulfonyl group,
  • R d a cyano, carboxy, C ⁇ . 3- alkyloxy-carbonyl-, aminocarbonyl-, C 1 - 3 - ⁇ alkylamino-carbonyl-, di- (C ⁇ -3- alkyl) -amino-carbonyl-, pyrrolidin-1 -ylcarbonyl-,
  • R e is hydroxy, C -3 alkyloxy, amino, C. 3 -Alkylamino-, di- (-C -3 alkyl) - amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazine Represents -1-yl or 4-ethyl-piperazin-1-yl group and is isolated by at least two carbon atoms from the ring nitrogen atom in the 3-position of the xanthine skeleton,
  • R 3 is a C 3 - 8 alkyl group, a C ⁇ substituted by a group R f . 3 alkyl group, wherein
  • R f an optionally by one or two C ⁇ . 3 alkyl groups substituted 5 C 3 . Cycloalkyl group or
  • R 4 is an azetidin-1-yl or pyrrolidin-1-yl group which is substituted in the 3-position by an amino, C ⁇ - 3 alkylamino or a di (C ⁇ . 3 alkyl) amino group and in addition by one or two C ⁇ . 3 -alkyl groups can be substituted,
  • a piperidin-1-yl or hexahydroazepin-1-yl group which is in the 3-position or in the 4-position by an amino, C ⁇ . 3 alkylamino or a di (C ⁇ - 3 alkyl) amino group is substituted and additionally by one or two C ⁇ . 3 -alkyl groups can be substituted,
  • an azetidin-1-yl, pyrrolidin-1yl, piperidin-1-yl or hexahydroazepin-1-yl group which by an amino -C ⁇ . 3 -alkyl-, C ⁇ . 3 -Alkylamino-C ⁇ . 3 -alkyl or a di- (C ⁇ . 3 -alkyl) - amino-C ⁇ . 3 -alkyl group is substituted,
  • group E is an oxygen atom and group G is a carbonyl group
  • group E is an oxygen atom and group G is a sulfonyl group
  • the group E is an -NR a group and the group G is a carbonyl group in which R a is defined as mentioned above
  • the group E is an -NR a group in which R a is defined as mentioned above
  • the group G a sulfonyl group or the group A optionally substituted by one of the above-mentioned groups
  • Phenyl or heteroaryl group and group E represent an oxygen atom and group G represent an ethenylene group
  • R 4 cannot assume the meaning of a piperazin-1-yl or [1, 4] diazepan-1-yl group which is optionally substituted on the carbon skeleton by one or two C 3 alkyl groups,
  • a C 3 - 7 cycloalkyl group by an amino-C ⁇ . 3 -alkyl-, C 1 . 3 -alkylamino-C 1 . 3 - alkyl or a di- (C ⁇ - 3 -alkyl) amino-C ⁇ - 3 alkyl group is substituted,
  • 5 is a C 3 . 7- Cycloalkyl-C ⁇ . 2 -alkyl-amino group, in which the cycloalkyl part by an amino -CC. 3 -alkyl-, C ⁇ _ 3 -alkylamino-C ⁇ . 3 -alkyl or a di- (C ⁇ - 3 -alkyl) amino-C ⁇ - 3 - alkyl group is substituted
  • C ⁇ _ 3 -alkyl amino-C ⁇ - 3 - alkyl group
  • R 19 an amino, C ⁇ . Represents 3 alkylamino or di (C 3 alkyl) amino group,
  • R 19 -C 2 - 4 alkylamino group in which the nitrogen atom of the C 2 - 4 alkylamino part is replaced by a C. 3 alkyl group is substituted and R by at least two carbon atoms from the nitrogen atom of the C 2 19 - is separated 4 alkylamino-part, wherein R 19 is as hereinbefore defined,
  • R 20 is an azetidin-3-yl, azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-3-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-3-yl Represents piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-ylmethyl group, the radicals mentioned for R 20 each being represented by one or two C1. 3 - alkyl groups can be substituted,
  • R 20 an amino group substituted by the radical R 20 and a C 3 alkyl group, in which R 20 is defined as mentioned above, where the radicals mentioned for R 20 can each be substituted by one or two C 3 alkyl groups,
  • R 19 -C 3-4 -alkyl group in which the C 3 - 4 -alkyl moiety is straight-chained and may additionally be substituted by one or two C -3 alkyl groups, wherein R 19 is as hereinbefore defined,
  • a pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, hexahydroazepin-3-yl or hexahydroazepin-4-yl group which is in the 1 position by an amino, C ⁇ . 3 -Alkylamino- or di- (-C ⁇ . 3 alkyl) amino group is substituted, or an azetidin-2-yl -CC. 2- alkyl, azetidin-3-yl -CC.
  • aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono- or disubstituted independently of one another by R h , where the substituents can be the same or different and R h is a fluorine, Chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, aminosulfonyl, methylsulfonyl, acetylamino, methylsulfonylamino, C - 4 alkyl, C ⁇ - 3 alkyl carbonyl -, Cyclopropyl, ethenyl, ethinyl, hydroxy, C ⁇ .
  • R h can be mono- or disubstituted by R h , where the substituents can be the same or different and R n is defined as mentioned above,
  • alkyl, alkenyl and alkynyl groups mentioned above can be straight-chain or branched
  • the carboxy groups mentioned in the definition of the abovementioned radicals can 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,
  • radicals can be substituted by a radical which can be split off in vivo.
  • 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).
  • a group that can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C 1 -C 6 -alkanol, a phenyl-C 1. 3- alkanol, a C 3 . 9 -cycloalkanol, where a Css-cycloalkanol can additionally be substituted by one or two C ⁇ - 3 alkyl groups, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a C ⁇ - 3 alkyl, phenyl-C ⁇ . 3 -alkyl-, phenyl-C ⁇ - -alkyloxy-carbonyl- or
  • R p is a C - 8 alkyl, C 5 - 7 cycloalkyl, C. 8 alkyloxy, C 5 . 7- Cycloalkyloxy-, phenyl or phenyl C ⁇ . 3 -alkyl group,
  • R q is a hydrogen atom, a C 3 alkyl, C 5 . 7- cycloalkyl or phenyl group and
  • R r represents a hydrogen atom or a C - 3 alkyl group
  • 3 -alkyloxy groups mono- or disubstituted phenylcarbonyl group, where the substituents can be the same or different, a pyridinoyl group or a C 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3.3 , 3-trichloropropionyl or allyloxycarbonyl group, a C ⁇ - 16 alkyloxy carbonyl or C ⁇ . ⁇ 6 alkyl carbonyloxy group, in which hydrogen atoms can be replaced in whole or in part by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl -, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, non
  • 6- alkyloxy-carbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group in which the amino group is mono- or disubstituted by Ci- ⁇ -alkyl or C 3 - 7 cycloalkyl groups and the substituents are the same or different can be a C 1 .
  • R s and Rt which may be the same or different, represent hydrogen atoms or C 3 alkyl groups
  • saturated alkyl and alkyloxy parts which contain more than 2 carbon atoms mentioned in the definitions above and below include unless otherwise stated, their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • R 1 , R 2 and R 3 are as defined above and
  • R 4 is a pyrrolidin-1 -yl group which is substituted in the 3-position by an amino group
  • alkyl, alkenyl and alkynyl groups can be straight-chain or branched
  • A is phenyl, phenylmethyl, 1-phenylethyl, pyridinyl, pyridinyimethyl, 1-pyridinylethyl, pyrimidinyl, pyrimidinylmethyl, pyrazinyl, pyrazinylmethyl, 1, 3,5-triazinyl, 1,3,5 Triazinylmethyl, 1, 2,4-triazinyl, 1, 2,4-triazinylmethyl, furanyl, thienyl, pyrrolyl, imidazolyl, 1, 3-oxazolyl group, the phenyl and heteroaryl groups mentioned Groups by a fluorine, chlorine or bromine atom or by a C 4 alkyl, C 4 alkoxy, trifluoromethyl, cyano, C 3 alkyl carbonyl, C 4 alkoxy carbonyl, methylsulfinyl -, Phenylsulfinyl-, Methylsulfonyl-, Phen
  • B is an E-G group in which E is linked to group A and
  • E is an oxygen atom, an -NH-, -N (CH 3 ) - or -NH-NH group or an - OCH 2 group in which the oxygen atom is linked to group A and the carbon atom is linked to group G, and
  • G is a carbonyl group
  • R 2 is a hydrogen atom
  • R 3 is a C 4 . 6 -alkenyl group
  • R 4 is a piperidin-1-yl group which is substituted in the 3-position by an amino group
  • a cyclohexyl group which is substituted in the 3-position by an amino group, or is a V- (2-aminoethyl) - / V-methylamino or an A / - (2-aminoethyl) - ⁇ / -ethylamino group,
  • alkyl, alkenyl and alkynyl groups mentioned above can be straight-chain or branched
  • R 1 is an ABD group in which
  • A is a phenyl, phenylmethyl, 1-phenylethyl, pyridinyl, pyridinyimethyl, 1-pyridinylethyl, pyrimidinyl or pyrimidinylmethyl group, the phenyl part being substituted by a fluorine, chlorine or bromine atom or by a C 4 alkyl group. , Trifluoromethyl, C. 4 -alkoxy, cyano, C ⁇ . 3 -alkyl-carbonyl-, C ⁇ .
  • B is an E-G group in which E is linked to group A and
  • E is an oxygen atom, an -NH group, -N (CH 3 ) group or -OCH 2 group in which the oxygen atom is linked to group A and the carbon atom is linked to group G, and
  • G represents a carbonyl group, or A and B together represent a 1, 2,3,4-tetrahydroquinolin-1 -ylcarbonyl or 1, 2,3,4-tetrahydroisoquinolin-2-ylcarbonyl group and
  • R 2 is a methyl group
  • R 3 is a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or
  • R 4 represents a (3-aminopiperidin-1-yl) group
  • R 1 is an ABD group in which
  • A is a phenyl, phenylmethyl, pyridinyl or pyridinylmethyl group, in which the phenyl rings can be substituted by an amino, methoxy, methyl, cyano or nitro group, and
  • B is an E-G group in which E is linked to group A and
  • E is an oxygen atom, an -NH group or -OCH 2 group in which the
  • Oxygen atom is linked to group A and the carbon atom is linked to group G, and
  • G represents a carbonyl group, or A and B together represent a 1,2,3,4-tetrahydroquinoline-1 -ylcarbonyl or 1, 2,3,4-tetrahydroisoquinolin-2-ylcarbonyl group and
  • R 2 is a methyl group
  • R 3 is a 2-buten-1-yl or 3-methyl-2-buten-1-yl group or o is a 2-butyn-1-yl group
  • R 4 represents a (3-aminopiperidin-1-yl) group
  • the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
  • R 1 to R 3 are defined as mentioned at the outset and
  • Z 1 represents a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulfinyl, sulfonyl or sulfonyloxy group, such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group, with an amine of the general formula R 4 '-H , in which R 4 'represents one of the radicals mentioned for R 4 , which is linked to the xanthine structure via a nitrogen atom.
  • a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulfinyl, sulfonyl or sulfonyloxy group, such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group, with an amine of the general formula R 4 '-H , in which R 4
  • the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base , for example triethylamine, or in the presence of N-ethyldiisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, and if appropriate 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.
  • a reaction accelerator such as an alkali metal halide or a palladium-based
  • R 1 , R 2 and R 3 are defined as mentioned at the outset and R 4 'is one of the groups mentioned at the outset for R 4 which contain an imino, amino or alkylamino group, the imino, amino or alkylamino group is substituted by a protective group, optionally followed by subsequent alkylation of the imino, amino or C 3 alkylamino group.
  • protecting groups include:
  • tert-butyloxycarbonyl group which can be obtained by treating 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 o diethyl ether at temperatures between 0 and split off at 80 ° C,
  • the 2.2.2-trichloroethoxycarbonyl group which can be split off by treatment with metals such as zinc or cadmium in a solvent such as acetic acid or a mixture of tetrahydrofuran and a weak aqueous acid at temperatures between 0 ° C and the boiling point of the solvent used and
  • the carbobenzyloxycarbonyl group which can be split off, for example, by hydrogenolysis in the presence of a noble metal catalyst, for example
  • the subsequent alkylation is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, for example with methyl iodide, ethyl bromide, dimethyl sulfate, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such
  • the subsequent reductive alkylation is advantageously carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a pH .0 value of 6-7 and at room temperature or in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
  • the methylation can also be carried out in the presence of formic acid as a reducing agent at elevated temperatures, e.g. at temperatures between 60 and 120 ° C.
  • any reactive groups present such as carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction, o
  • trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl groups come as protective residues for a carboxy group
  • an amino, alkylamino or imino group the formyl, acetyl, 5 trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.
  • the subsequent subsequent splitting off of a protective radical o is carried out, for example, hydrolytically in an aqueous solvent, for example 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 sulfuric acid or in the presence of one Alkali base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an aqueous solvent for example 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 sulfuric acid or in the presence of one Alkali base such as sodium hydroxide or potassium hydro
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon 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 room temperatures between 20 and 60 ° C, and at a hydrogen pressure of o 1 to 7 bar, but preferably from 3 to 5 bar.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably split off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C., or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • a phthalyl radical 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 dioxane at temperatures between 20 and 50 ° C.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be included in their ice and trans iso mers, and compounds with at least one optically active carbon atom are separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-O-p-toluoyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • suitable optically active alcohol are (+) - or (-) - menthol and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, Methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine, o
  • the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the enzyme DPP-IV.
  • the DPP-IV assay was carried out as follows: 50 ⁇ l substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 ⁇ M, were placed in black microtiter plates. 20 ⁇ l assay buffer (final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) were pipetted in. The reaction was started by adding 30 ⁇ l solubilized Caco-2 protein (final concentration 0.14 ⁇ g protein per well). The test substances to be checked were typically added pre-diluted in 20 ⁇ l, the assay buffer volume then being reduced accordingly. The reaction was carried out at room temperature, the incubation period was 60 minutes.
  • the compounds prepared according to the invention are well tolerated, since no changes in the behavior of the animals could be observed, for example, after oral administration of 10 mg / kg of the compound of Example 1 (3) to rats.
  • the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which can be influenced by inhibiting DPP-IV activity . It is therefore to be expected that the compounds according to the invention for the prevention or treatment of diseases or conditions such as diabetes mellitus type I and type II, diabetic complications, metabolic acidosis or ketosis, insulin resistance, dyslipidemias of various origins, arthritis, atherosclerosis and related diseases, obesity, Allograft transplantation and osteoporosis caused by calcitonin are suitable. In addition, these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells.
  • diseases or conditions such as diabetes mellitus type I and type II, diabetic complications, metabolic acidosis or ketosis, insulin resistance, dyslipidemias of various origins, arthritis, atherosclerosis and related diseases, obesity, Allograft transplantation and osteoporosis caused by calcitonin.
  • these substances are suitable
  • the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also increasing the number and size of pancreatic B cells.
  • the compounds according to the invention are suitable, inter alia, for achieving a sedative or anxiolytic effect to be able to influence catabolic conditions after operations or hormonal stress responses favorably or to reduce mortality and morbidity after myocardial infarction.
  • they are suitable for the treatment of all conditions which are related to the above-mentioned effects and are mediated by GLP-1 or GLP-2.
  • the compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute kidney failure. They are also suitable for the prevention and therapy of chronic inflammatory bowel diseases.
  • DPP-IV inhibitors and thus also the compounds according to the invention for the treatment of infertility or for the improvement of fertility in humans or in the mammalian organism can be used, especially if infertility is related to insulin resistance or polycystic ovarian syndrome.
  • the substances are suitable for influencing growth hormone deficiency states that are associated with short stature.
  • the compounds according to the invention can also be used in combination with other active ingredients.
  • Therapeutics suitable for such a combination include e.g. Antidiabetics, such as metformin, sulfonylurea substances (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. Gl 262570), alpha-glucosidase inhibitors (e.g.
  • Antidiabetics such as metformin, sulfonylurea substances (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.
  • acarbibose ), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. Exendin-4) or amylin.
  • inhibitors of protein tyrosine phosphatase 1 substances that influence deregulated glucose production in the liver, such as Inhibitors of glucose-6-phosphatase, or of fructose-1, 6-bisphosphatase, of glycogen-phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol-pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid-lowering agent, such as, for example, reducing glasase inhibitor, such as, for example, HMGase-reducing agent, such as, for example, HMG , Atorvastatin), fibrates (eg bezafibrate, fenofibrate), nicotinic acid and its derivatives,
  • the dosage required to achieve a corresponding effect is expediently 1 to 100 mg, preferably 1 to 30 mg for intravenous administration, and 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day for oral administration.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents mittein, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty acid Incorporate substances such as hard fat or their suitable mixtures into common galenical preparations such as tablets, coated tablets, capsules, powders, suspensions or suppositories.
  • a solution of 107 ⁇ l dimethyl sulfoxide in 0.5 ml methylene chloride is added dropwise to 64 ⁇ l oxalyl chloride in 2 ml methylene chloride with stirring at -60 ° C.
  • a solution of 345 mg of 1- (2-hydroxy-3-phenoxypropyl) -3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine was added dropwise in 1.5 ml of methylene chloride and after a further 15 minutes 0.42 ml of triethylamine were added.
  • Example VII 1-Carboxymethyl-3-methyl-7- (2-butyn-1-yl) -8- [3- (tert-butyloxycarbonylamino) iperidin-1-yl-xanthine prepared by saponification of 1-methoxycarbonylmethyl-3 -methyl-7- (2-butyn-1-yl) - 8- [3- (tert-butyloxycarbonylamino) -piperidin-1-yl] -xanthine with 4 N potassium hydroxide solution in a mixture of tetrahydrofuran and methanol (5: 1 ) at room temperature.
  • Mass spectrum (ESI + ): m / z 475 [M + H] +
  • the following compounds are obtained analogously to Example VII:
  • 1 coated tablet contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
  • the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
  • the finished film coated tablets are polished with beeswax. Drage weight: 245 mg.
  • 1 tablet contains:
  • Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinyl pyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C., sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets.
  • Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
  • 1 tablet contains:
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve
  • the granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes
  • 1 capsule contains: active ingredient 150.0 mg
  • the active ingredient is mixed with the excipients, through a sieve of
  • the final mix is filled into size 1 hard gelatin capsules.
  • Capsule shell hard gelatin capsule size 1.
  • 1 suppository contains: active ingredient 150.0 mg
  • Polyethylene glycol 1500 550.0 mg
  • Carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
  • 5 ml of suspension contain 50 mg of active ingredient.
  • the active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • composition active ingredient 50.0 mg
  • the active substance is dissolved in the required amount of 0.01 N HCl, isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

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Abstract

L'invention concerne des xanthines substituées de formule (I), dans laquelle R1 à R4 sont comme définies à la revendication 1, leurs tautomères, leurs stéréo-isomères, leurs mélanges, leurs promédicaments et leurs sels, lesquels ont des propriétés pharmacologiques intéressantes, notamment un effet inhibiteur sur l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).
EP03782204A 2002-11-21 2003-11-11 Derives de xanthine, leur production et leur utilisation en tant que medicaments Withdrawn EP1565468A1 (fr)

Applications Claiming Priority (3)

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DE10254304A DE10254304A1 (de) 2002-11-21 2002-11-21 Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10254304 2002-11-21
PCT/EP2003/012821 WO2004046148A1 (fr) 2002-11-21 2003-11-17 Derives de xanthine, leur production et leur utilisation en tant que medicaments

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EP (1) EP1565468A1 (fr)
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CA (1) CA2506720A1 (fr)
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US7560450B2 (en) 2009-07-14
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