EP1778689A1 - Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv - Google Patents

Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv

Info

Publication number
EP1778689A1
EP1778689A1 EP05775003A EP05775003A EP1778689A1 EP 1778689 A1 EP1778689 A1 EP 1778689A1 EP 05775003 A EP05775003 A EP 05775003A EP 05775003 A EP05775003 A EP 05775003A EP 1778689 A1 EP1778689 A1 EP 1778689A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkylene
aryl
cycloalkyl
heterocyclyl
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.)
Withdrawn
Application number
EP05775003A
Other languages
German (de)
French (fr)
Inventor
Karl Schoenafinger
Gerhard Jaehne
Elisabeth Defossa
Guenter Billen
Christian Buning
Georg Tschank
Ulrich Werner
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of EP1778689A1 publication Critical patent/EP1778689A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D473/12—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, 3, and 7, e.g. caffeine
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • 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
    • C07D473/10—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 3 and 7, e.g. theobromine

Definitions

  • the invention relates to substituted 8-aminoalkylthio-xanthines and their physiologically acceptable salts and physiologically functional derivatives.
  • the invention had the object of providing compounds that develop a therapeutically useful blood sugar lowering effect. 5
  • the invention therefore relates to compounds of the formula I,
  • Rl, R2, R3 are independently H, (C, -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C i O) alkynyl, (C 6 -C) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (d-
  • R7, R8 are independently H, (Ci-C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 6 -C i o) aryl,
  • R9, RIO each independently H, (Ci-C 6) -alkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (Ci- C 6) -alkylene-heterocyclyl;
  • R4, R5 independently of one another are hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl, where (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl may be substituted by F , Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (Ci-C6) - alkyl, N ((C r C6) alkyl) 2, OH, O (C, -C6) - Alkyl, O-aryl, OHeteroaryl, S (C, -C 6 ) -alkyl, S (O) (C r C 6 ) -alkyl,
  • Rl 1, R12, R13, R14, R15, R16 independently of one another H, (Ci-C6) - alkyl, aryl, heterocyclyl, (C 3 -C 8) -cycloalkyl, (C 1 -C 4) - alkylene-0 Alkyl, (C 1 -C 4 ) -alkylene
  • S is alkyl, (C 1 -C 4 ) -alkylene-NH-alkyl, (C 1 -C 4 ) -alkylene-N (alkyl) 2 , (C 1 -C 4 ) -alkylene-aryl, (C 1 -C 4 ) -alkylene-heterocyclyl, F , Cl, Br, I, CN, COOH, COO (C 1 -C 6 ) -alkyl, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON ((C 1 -C 6 ) -alkyl) 2 , CF 3, or two of the radicals R4, R5, Rl 1, R12, R13, R14, R15, R16 together form a (C 2 -C 6) - alkylene, where a (C 6 -C i o) aryl or a (C 6 -C i 0) can be fused -Heterocycl
  • n O, 1, or 2;
  • n O or 1;
  • Rl, R2, R3 are independently H, (Ci-Cio) alkyl, (C 3 -C io) cycloalkyl, (C 2 -C 10) - alkenyl, (C 2 -C 10) -alkynyl, (C 6 -C 10) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR 7,
  • R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl,
  • R9, RIO each independently H, (Ci-C6) - alkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (C 1 - C 6) -alkylene-heterocyclyl; * -
  • R4, R5 are independently hydrogen, (Ci-C6) - alkyl or (C 3 -C 8) -cycloalkyl, where (Cj-C6) alkyl or (C 3 -C 8) -cycloalkyl may be substitiuert with the by F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((CC 6 ) -
  • Alkyl) 2 OH, O (C r C6) alkyl, O-aryl, OHeteroaryl, S (Ci-C 6) -alkyl, S (O) (CC 6) - alkyl, S (O) 2 (C, - C 6 ) alkyl;
  • R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-O alkyl, C 4 ) -alkylene-alkyl, (CC 4 ) -alkylene
  • n 0, 1, or 2;
  • n O or 1;
  • Rl, R2, R3 are independently H, (Ci -C 0) - alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C io) alkynyl, (C 6 -C i O) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, SF 5, OH, (Ci- C 6) alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, 0R7 .
  • R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, aryl,
  • R4, R5 are independently hydrogen, (Ci-C 6) -alkyl or (C 3 -C 8) -cycloalkyl, where (Ci-C 6) - alkyl or (C 3 -C 8) -cycloalkyl may be with the substitiuert by F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (C, -C6) - alkyl, N ((Ci-C 6) - alkyl) 2, OH, 0 (C 1 -Co ) -AuCyI, OAryl, OHeteroaryl, S (C ! -C 6 ) -alkyl, S (O) (C 1 -C 6 ) -
  • R 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -
  • n 0, 1 or 2;
  • Rl, R2, R3 are independently (Ci-C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 2 -C i O) -alkenyl, (C 2 -C 0) -alkynyl, (C 6 -C i O ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -
  • R7, R8 are independently H, (C 1 -C 6) - alkyl, (C 3 -C] 0) cycloalkyl, aryl,
  • Heterocyclyl (Ci-C 4) -alkylene- (C 6 -C 0) aryl or (CrC 4) -alkylene-heterocyclyl;
  • R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl or C 3 -C 7 -cycloalkyl;
  • Rl, R2, R3 are independently (C 1 -C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 0) -alkynyl, (C 6 -Ci 0 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl,
  • Alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted by F, Cl, CN, SF 5 , (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , ( C 2 -C 4) - Alkenyl, (C 2 -C 4) alkynyl, OR 7, NR 7 R 8, NR 7 CONR 7 R 8, COR 7, COOR 7, CONR 7 R 8, (C 1 -C 4) alkylene-OR 7, (C 1 -C 4) alkylene-NR 7 R 8, (C 1 -C 4) alkylene NR7SO 2 R7, (Ci-C 6) -alkylene-SR7, alkylene-S (0) R7, alkylene-CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (Ci-C 6)
  • Cycloalkyl (C 6 -C] 0) -aryl or heterocyclyl;
  • R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, aryl,
  • R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 4) -alkyl;
  • the invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • radicals or substituents can occur several times in the compounds of the formula I, they may all independently , have the meanings given to one another and be identical or different.
  • suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethane sulfone, fumaric acid, Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid
  • organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethane sulfone, fumaric acid, Gluconic, glyco
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxyrnethyl-l, 3-propanediol), diethanolamine, lysine, or ethylenediamine ,
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
  • physiologically functional derivative denotes any physiologically acceptable derivative of a compound of the formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
  • the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
  • prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
  • the compounds of the invention may also be in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
  • the alkyl radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C] -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C !
  • suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C] -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2
  • NH (CH 2) n -aryl, SO 2 -NH (CH 2) n heterocycle, SO 2 -N (C 1 -C 6) - alkyl) (CH 2) n - aryl, SO 2 -N (C 1 - C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n 0 - 6 can be and the aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C r C 6 ) alkyl, (Ci -C 6 ) - alkyl, NH 2 may be substituted, C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl,
  • alkenyl radical is meant a straight or branched hydrocarbon chain having two or more carbons and one or more double bonds, e.g. Vinyl, AHyI, pentenyl.
  • the alkenyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( Ci -C 6) alkyl, CON [(Ci-C 6) alkyl] 2, cycloalkyl, (C 1 -C 0) - alkyl, (C 2 -C 6) -alkynyl, 0- (C 1 -C 6) - alkyl 0-CO- (C 1 -C 6) - alkyl, 0-CO- (Ci-C6) - aryl, O-CO- (Ci-C 6) -heterocycle ,;
  • suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6
  • alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as ethynyl, propynyl, hexynyl.
  • the alkynyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( C, -C 6) alkyl, CON [!
  • aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
  • the aryl radicals may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C, -C 6) alkyl, CON [(C r C6) alkyl] 2i cycloalkyl, (C -C 10!) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, 0- (C, - C 6) -alkyl O-CO- (C r C6) alkyl, 0-CO- (C 1 -Ce) -ATyI, O-CO- (Ci-C 6) - heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -al
  • a cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, e.g. Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the Cycloalkylrestereste may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 - C 6) alkyl, conf (C 1 -C 6) alkyl] 2, cycloalkyl, (C, -C10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, 0- (C, -C 6) - alkyl 0-CO- (C, -C6) - alkyl, 0-CO- (C, -C6) - aryl, O-CO- (CrC 6) heterocycle ,; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S-
  • Heterocycle or heterocyclic radical is understood as meaning rings and ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic or the heterocyclic radical is condensed with benzene nuclei.
  • Suitable "heterocyclic rings” or “heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl
  • Pyridyl is both 2-, 3- and 4-pyridyl.
  • Thienyl is both 2- and 3-thienyl.
  • Furyl is both 2- and 3-furyl. >
  • N-oxides of these compounds e.g. l-oxy-2-, 3- or 4-pyridyl.
  • heterocyclic rings or heterocyclic radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C, -C 6 ) alkyl , CONH 2, CONH (C r C6) alkyl, CON [(C r C6) alkyl] 2, cycloalkyl, (C 1 -C 10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 - C 6) aryl, 0-CO- ( C, -C 6 ) heterocycle;
  • suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C, -C
  • N (heterocycle) -CO-N ((C 1 -C 6 ) alkyl) aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO-N- (aryl) 2 , aryl , O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n 0-6, where the aryl radical or heterocyclic radical can be monosubstituted to trisubstituted by F, Cl, Br , I, OH, CF 3, NO 2, CN, OCF 3, O- (Ci-C 6) alkyl, (C, -C 6) - alkyl, NH 2, NH (C 1 -C 6) - alkyl , N ((C, -C6) - alkyl) 2, SO 2 -CH 3, COOH, COO- (C 6 -C! - alkyl, CONH. 2
  • the compound (s) of formula (I) may also be administered in combination with other active ingredient.
  • the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
  • an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • the active ingredient for example, from 1 mg to 100 mg
  • the compounds according to formula I can themselves be used as compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition.
  • the carrier must, of course, be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient's health.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may likewise be present, including further compounds of the formula I.
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable administration in each individual case is of the type and The severity of the condition to be treated and the type of compound used in each case according to formula I is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
  • Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert Base such as gelatin and glycerin or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can be preferably prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • Suitable pharmaceutical compositions for transdermal applications may be present as individual patches suitable for long-term close contact with the epidermis of the patient.
  • patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation.
  • Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US No. 6,221,633), GLP-I derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
  • the orally active hypoglycemic agents preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, Glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, 5 fat metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents.
  • the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, or with a compound as described in PCT / EP 2004/00269, PCT / EP 2003/05815, PCT / EP 2003/05814, PCT / EP 2003/05816, EP 0114531, US Pat. No. 6,498,156.
  • a cholesterol absorption inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside
  • the compounds of formula I are used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • the compounds of formula I in combination with PPAR alpha agonist e.g. GW 9578, GW 7647.
  • the compounds of formula I are used in combination with a mixed PPAR alpha / gamma agonist such as GW 1536, AVE 30 8042, AVE 8134, AVE 0847 or as described in PCT / US 2000/11833, PCT / US 2000/11490, DE10142734.4 described.
  • the compounds of formula I are administered in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate.
  • the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
  • an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757.
  • the compounds of formula I are used in combination with bile acid resorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), e.g. HMR 1741 administered.
  • the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
  • a CETP inhibitor e.g. JTT-705.
  • the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
  • a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
  • the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586.
  • the compounds of formula I are administered in combination with an ACAT inhibitor, e.g. Avasimibe, administered.
  • an ACAT inhibitor e.g. Avasimibe
  • the compounds of formula I are used in combination with an antioxidant, e.g. OPC-14117 administered.
  • the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor such as NO-1886. In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor, such as SB-204990.
  • the compounds of formula I in combination with a squalene synthetase inhibitor, such as e.g. BMS-188494.
  • the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
  • a lipoprotein (a) antagonist e.g. CI-1027 or nicotinic acid.
  • the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
  • a lipase inhibitor e.g. Orlistat
  • the compounds of the formula I are administered in combination with insulin.
  • the compounds of the formula I are used in combination with a
  • Sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compounds of the formula I are used in combination with a
  • Biguanide e.g. Metformin
  • administered e.g. Metformin
  • the compounds of formula I are used in combination with a meglitinide, e.g. Repaglinide, administered.
  • the compounds of the formula I are used in combination with a
  • Thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, especially 5 - [[4-]
  • the compounds of formula I are administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a ⁇ -
  • Adenosine Al agonists such as for example, those described in EP 0912520 or PCT / EP06749.
  • the compounds of formula I are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with one
  • Sulphonylurea and metformin a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg Naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A)), MC4 agonists (eg 1-amino-1,2,3 , 4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine) 5-yl) -1- (4-ch
  • (Melanocyte-stimulating hormone) agonists CCK-A agonists (eg ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl ] -5,7-dimethyl-indol-1-yl ⁇ -acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (eg dexfenfluramine), mixed sertonine and noradrenergic compounds (eg WO 00/71549), 5HT Agonists, for example, 1- (3-ethylbenzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1 - (2- diisopropy
  • Drugs of the Future (2001), 26 (9), 873-881) , DA agonists (bromocriptine, doprexine), lipase / amylase inhibitors (eg, WO 00/40569), PPAR modulators (eg, WO 00/78312), RXR modulators, or TR-j3 agonists.
  • DA agonists bromocriptine, doprexine
  • lipase / amylase inhibitors eg, WO 00/40569
  • PPAR modulators eg, WO 00/78312
  • RXR modulators eg, TR-j3 agonists.
  • the further active ingredient is leptin; , see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
  • the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine.
  • the other active ingredient is rimonabant.
  • the compounds of formula I in combination with bulking agents preferably insoluble bulking agents
  • bulking agents preferably insoluble bulking agents
  • Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
  • Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
  • Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars. It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.
  • the compounds of the formula I can be prepared by suitable starting materials of the formula II in which R 1, R 2 and R 3 have the abovementioned meaning and X is a leaving group such as chlorine, bromine, iodine, sulfonyloxide, sulfinyl, sulfoxyl, with a compound of formula V optionally in the presence of suitable bases to the compounds of formula FV, wherein X is a suitable leaving group such as chlorine, bromine, iodine, Sulfonyloxi, sulfinyl or sulfoxyl.
  • R4 or R5 is hydrogen
  • R4 or R5 it may be appropriate to use the radical - NR4R5 protected in the nitrogen function form and to split off the protective group at a suitable point of the reaction again.
  • suitable protecting groups and the methods of introduction and cleavage are known (See: Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., New York, 1999)
  • the thioether function in IV can then be oxidized by known methods to the substances of the formula I according to the invention, wherein n is a number 1 or 2.
  • Suitable halogenating agents may be, for example, halogens, such as chlorine and bromine, N-bromosuccinimide, phosphorus pentoxide or phosphorus oxychloride.
  • the compounds of formula III can be obtained by reaction of the halogen compounds of formula II with suitable reagents such as hydrogen sulfide or thiourea by known methods.
  • the radicals R 1 to R 3 can be prepared by methods known per se by alkylating appropriate precursors, the sequence being able to be varied. In some cases, however, they can also be introduced by selecting appropriate precursors in the preparation of the xanthine skeleton.
  • the compounds of the formula I have favorable effects on the lipid and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidaemias and the metabolic syndrome / syndrome X. Furthermore, the compounds are suitable for the prophylaxis and treatment of arteriosclerotic phenomena.
  • the compounds may be used alone or in combination with other blood sugar lowering agents.
  • the compounds act as DPP-IV (dipeptidyl peptidase IV) inhibitors and are also useful in the treatment of disorders of sensation and other psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia, and the treatment of disorders associated with the circadian rhythm Weight reduction in mammals, for the treatment of immune disorders, and for the treatment of substance abuse.
  • H-Ala-Pro-AFC (15 ⁇ M final concentration) in Tris / HCl (40 mM, pH 7.4), total volume 0.2 ml
  • the reaction was carried out at room temperature for various periods of time (typically 10 minutes) and stopped at the end of the reaction by addition of 20 ⁇ l of ZnCl 2 (1 M).
  • the conversion of H-Ala-Pro-AFC was determined fluorimetrically by measuring the emission at 5,535 nm after excitation at 405 nm. In the case of addition of inhibitors, the added buffer volume was adjusted so that a total volume of the test mixture of 200 ⁇ l was maintained.
  • IC50 values for inhibitors were determined by varying the inhibitor concentrations at the stated substrate concentration of 15 ⁇ M. Ki and Km values were determined by corresponding substrate and inhibitor concentration variation as described (Dixon, M. and Webb, E.C. (1979) Enzymes, third edition, pp. 47-206, Academic Press). The Km, IC50 and Ki values were calculated using a commercially available software package (Leatherbarrow, RJ. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, U.K.). 5
  • 2,6-dione 5 The mixture of 80 mg 8-bromo-3-methyl-7- (3-methyl-but-2-enyl) -3,7-dmydropurine-2,6-dione, 90 mg 1 -Amino-2-methyl-2-propanethiol hydrochloride, 2 ml of DMF and 200 mg
  • Cesium carbonate was stirred at 70 ° C for 5 hours.

Abstract

The invention relates to substituted 8-aminoalkylthio-xanthines, to the physiologically compatible salts thereof and to the physiologically functional derivatives thereof. The invention also relates to compounds of formula (I), wherein the groups have the meaning cited in the description, in addition to the physiologically compatible salts thereof. The compounds can be used, for example, as medicaments for the prevention and treatment of type 2 diabetes.

Description

Beschreibung description
SUBSTITUIERTE 8-AMINOALKYLTHIO-XANTHINE UND IHRE VERWENDUNG ALS INHIBITOREN DER DIPEPTIDYL PEPTIDASE IVSUBSTITUTED 8-AMINOALKYLTHIO-XANTHINES AND THEIR USE AS INHIBITORS OF DIPEPTIDYL PEPTIDASE IV
55
Die Erfindung betrifft substituierte 8-Aminoalkylthio-xanthine sowie deren physiologisch verträgliche Salze und physiologisch funktionelle Derivate.The invention relates to substituted 8-aminoalkylthio-xanthines and their physiologically acceptable salts and physiologically functional derivatives.
Es ist bereits das 8-(2-Amino-ethylsulfanyl)-l,3,7-trimethyl-3,7-dihydro-purin-2,6-dion in der 0 Literatur beschrieben. Diese Verbindung wirkt auf das Zentralnervensystem ( J. Med. Chem. (1966), 9 500-6).There is already described the 8- (2-aminoethylsulfanyl) -1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione in the literature. This compound acts on the central nervous system (J. Med. Chem. (1966), 9 500-6).
Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Verfügung zu stellen, die eine therapeutisch verwertbare Blutzucker senkende Wirkung entfalten. 5The invention had the object of providing compounds that develop a therapeutically useful blood sugar lowering effect. 5
Die Erfindung betrifft daher Verbindungen der Formel I,The invention therefore relates to compounds of the formula I,
0 worin bedeuten ,0 in which
Rl, R2, R3 unabhängig voneinander H, (C,-C10)-Alkyl, (C3-C 10)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-C iO)-Alkinyl, (C6-Cio)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder 5 mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (d-Rl, R2, R3 are independently H, (C, -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C i O) alkynyl, (C 6 -C) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (d-
C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (CrC6)-Alkylen-OR7, (C,-C6)-Alkylen-NR7R8, (Cr C6)-Alkylen-NR7SO2R7, (CrC6)-Alkylen-SR7, Alkylen-S(0)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (d-C6)-Alkylen-(C3- Cio)-Cycloalkyl, (Ci-C6)-Alkylen-(C6-Cio)-Aryl, (C1-C6)-Alkylen-Heterocyclyl, (C3-C]o)-Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein dürfen;C 6 ) alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, OP (O) (OR 7) 2 , NR 7 R 8 , NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C r C 6 ) -alkylene-OR7, (C, -C 6 ) -alkylene-NR7R8, (C r C 6) -alkylene-NR7SO 2 R7, (C r C 6) -alkylene-SR7, alkylene-S (0) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, ( dC 6) alkylene- (C 3 - Cio) cycloalkyl, (Ci-C 6) alkylene- (C 6 -Cio) aryl, (C 1 -C 6) alkylene-heterocyclyl, (C 3 -C ] o) cycloalkyl, (C 6 -C 0) aryl or heterocyclyl, where not all of the radicals Rl, R2 and R3 simultaneously be hydrogen or methyl;
R7, R8 unabhängig voneinander H, (Ci-C6)- Alkyl, (C3-C io)-Cycloalkyl, (C6-C iO)-Aryl,R7, R8 are independently H, (Ci-C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 6 -C i o) aryl,
Heterocyclyl, (Ci-C6)-Alkylen-CONR9R10, (d-C6)-Alkylen-COOR9, , (C1-C6)- Alkylen-COR9, (Ci-C6)-Alkylen-OR9, (Ci-C6)-Alkylen-NR9R10, (C]-C6)-Heterocyclyl, (Ci-C 6) -alkylene-CONR9R10, (dC 6) alkylene-COOR 9, (C 1 -C 6) - alkylene-COR 9, (Ci-C 6) -alkylene-OR9, (Ci-C 6) -alkylene-NR9R10, (C] -C6) -
Alkylen-SR9, (CrC6)-Alkylen-S(O)R9, (C,-C6)-Alkylen-S(O)2R9 , (Ci-C4)- Alkylen-(C6-Cio)-Aryl oder (Ci-C4)-Alkylen-Heterocyclyl;Alkylene-SR9, (C r C6) alkylene-S (O) R9, (C, -C 6) -alkylene-S (O) 2 R9, (Ci-C 4) - alkylene (C 6 -Cio ) -Aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R9, RIO unabhängig voneinander H, (Ci-C6)-Alkyl, (Ci-C6)-Alkylen-(C6-C10)-Aryl, (Ci- C6)-Alkylen-Heterocyclyl;R9, RIO each independently H, (Ci-C 6) -alkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (Ci- C 6) -alkylene-heterocyclyl;
R4, R5 unabhängig voneinander Wasserstoff, (Ci-C6)-Alkyl oder (C3-C8)-Cykloalkyl, wobei (Ci-C6)-Alkyl oder (C3-C8)-Cykloalkyl substitiuert sein können mit F, Cl, Br, I, CN, Aryl, Heterocyclyl, NH2, NH(Ci -C6)- Alkyl, N((CrC6)-Alkyl)2, OH, O(C, -C6)- Alkyl, OAryl, OHeteroaryl, S(C,-C6)-Alkyl, S(O)(CrC6)-Alkyl,R4, R5 independently of one another are hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl, where (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl may be substituted by F , Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (Ci-C6) - alkyl, N ((C r C6) alkyl) 2, OH, O (C, -C6) - Alkyl, O-aryl, OHeteroaryl, S (C, -C 6 ) -alkyl, S (O) (C r C 6 ) -alkyl,
S(O)2(C1-C6)- Alkyl, wobei diese Alkylgruppen wiederum mit F, Cl, Br, I substituiert sein können;S (O) 2 (C 1 -C 6 ) -alkyl, where these alkyl groups may in turn be substituted by F, Cl, Br, I;
Rl 1, R12, R13, R14, R15, R16 unabhängig voneinander H, (Ci -C6)- Alkyl, Aryl, Heterocyclyl, (C3-C8)-Cykloalkyl, (C1 -C4)- Alkylen-0 Alkyl, (Ci -C4)-Alkylen-Rl 1, R12, R13, R14, R15, R16 independently of one another H, (Ci-C6) - alkyl, aryl, heterocyclyl, (C 3 -C 8) -cycloalkyl, (C 1 -C 4) - alkylene-0 Alkyl, (C 1 -C 4 ) -alkylene
S Alkyl, (Ci-C4)-Alkylen-NHAlkyl, (d-C4)-Alkylen-N(Alkyl)2, (Ci-C4)-Alkylen- Aryl, (Ci-C4)-Alkylen-Heterocyclyl, F, Cl, Br, I, CN, COOH, COO(Ci-C6)- Alkyl, CONH2, CONH(C ,-C6)- Alkyl, CON((C,-C6)-Alkyl)2, CF3, oder zwei der Reste R4, R5, Rl 1, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)- Alkylenrest, an dem ein (C6-C iO)-Arylrest oder ein (C6-C i0)-Heterocyclylrest ankondensiert sein kann, wobei der (C2-C6)- Alkylenrest und die ankondensierten Arylreste oder Heterocyclylreste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, OCF3, CF3, CN, (Ci-C6)-Alkyl, Aryl, Heterocyclyl, (C3-C8)- Cykloalkyl, (Ci-C4)-Alkylen-OAlkyl, (Ci-C4)-Alkylen-SAlkyl, (C,-C4)-Alkylen- NHAlkyl, (Ci-C4)-Alkylen-N(Alkyl)2, (Ci-C4)-Alkylen-Aryl, (Ci-C4)-Alkylen- Heterocyclyl, COOH, COO(Ci -C6)- Alkyl, CONH2, CONH(C1 -C6)- Alkyl, CON((CrC6)-Alkyl)2, OH, 0-(Ci -C6)- Alkyl, O-(C3-C6)-Cycloalkyl, S-(C1-C6)-S is alkyl, (C 1 -C 4 ) -alkylene-NH-alkyl, (C 1 -C 4 ) -alkylene-N (alkyl) 2 , (C 1 -C 4 ) -alkylene-aryl, (C 1 -C 4 ) -alkylene-heterocyclyl, F , Cl, Br, I, CN, COOH, COO (C 1 -C 6 ) -alkyl, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON ((C 1 -C 6 ) -alkyl) 2 , CF 3, or two of the radicals R4, R5, Rl 1, R12, R13, R14, R15, R16 together form a (C 2 -C 6) - alkylene, where a (C 6 -C i o) aryl or a (C 6 -C i 0) can be fused -Heterocyclylrest, wherein the (C 2 -C 6) - alkylene mono- and fused aryl or heterocyclyl groups may be substituted or polysubstituted by F, Cl, Br, I, OCF 3 , CF 3 , CN, (C 1 -C 6 ) -alkyl, aryl, heterocyclyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-O-alkyl, (Ci-C 4) -alkylene-SAlkyl, (C, -C 4) alkylene- NHalkyl, (Ci-C 4) -alkylene-N (alkyl) 2, (Ci-C 4) -alkylene-aryl, ( Ci-C 4) -alkylene- heterocyclyl, COOH, COO (Ci-C6) - alkyl, CONH 2, CONH (C 1 -C 6) - alkyl, CON ((C r C6) alkyl) 2, OH , 0- (Ci-C6) - alkyl, O- (C 3 -C 6) cycloalkyl, S- (C 1 -C 6) -
Alkyl, S-(C3-C6)-Cycloalkyl, SO-(Ci -C6)- Alkyl, SO-(C3-C6)-Cycloalkyl, SO2- (d-C6)-Alkyl, SO2-(C3-C6)-Cycloalkyl, SO2-NH2, SO2-NH-(C1-C6)- Alkyl, SO2- > NH-SO2-(C3-C6)-Cycloalkyl substituiert sein können; wobei die Aryl- und Heterocyclylreste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SF5, OH, (C1 -C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)- Alkenyl, (C2-Alkyl, S- (C 3 -C 6) cycloalkyl, SO- (Ci-C6) - alkyl, SO- (C 3 -C 6) -cycloalkyl, SO 2 - (dC 6) -alkyl, SO 2 - (C 3 -C 6 ) -cycloalkyl, SO 2 -NH 2 , SO 2 -NH- (C 1 -C 6 ) -alkyl, SO 2 - > NH-SO 2 - (C 3 -C 6 ) -cycloalkyl could be; where the aryl and heterocyclyl radicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -
C6)-Alkinyl, 0(Ci-C4)- Alkyl, NH2, NH(Ci -C4)- Alkyl, N((CrC4)-Alkyl)2, NR7C0NH(Ci -C4)- Alkyl , CO(CrC4)-Alkyl, OCO(Ci -C4)- Alkyl, OCOO(C1- C4)-Alkyl, COO(Ci-C4)-Alkyl, CONH2, CONH(Ci -C4)- Alkyl, CON((Ci-C4)- Alkyl)2, (d-C6)-Alkylen-O(Ci-C4)-Alkyl , (C i-C6)-Alkylen-NH(C, -C4)- Alkyl, (C,-C6)-Alkylen-NH2, (C,-C6)-Alkylen-N((C,-C4)-Alkyl)2, (CrC6)-Alkylen-C 6) alkynyl, 0 (Ci-C4) - alkyl, NH 2, NH (Ci-C4) - alkyl, N ((C r C 4) alkyl) 2, NR7C0NH (Ci-C4) - alkyl, CO (C r C 4) -alkyl, OCO (Ci-C4) - alkyl, OCOO (C 1 - C 4) -alkyl, COO (Ci-C 4) -alkyl, CONH 2, CONH (Ci - C 4) - alkyl, CON ((Ci-C4) - alkyl) 2, (dC 6) -alkylene-O (Ci-C 4) -alkyl, (C iC 6) alkylene-NH (C, -C 4) - alkyl, (C, -C 6) -alkylene-NH 2, (C, -C 6) -alkylene-N ((C, -C 4) alkyl) 2, (C r C6) alkylene -
NHSO2(Ci-C4)-Alkyl, (Ci-C6)- Alkylen-S(Ci-C4)- Alkyl, Alkylen-S(0)-(Cl-C4)- Alkyl, Alkylen-CONH2, Alkylen-CONH(Ci -C4)- Alkyl, Alkylen-CON((CrC4)- Alkyl)2, S(Ci -C4)- Alkyl, SO(C ,-C4)- Alkyl, SO2(Ci-C4)-Alkyl, SO2NH2, SO2NH(CrC4)-Alkyl, SO2N((Ci-C4)-Alkyl)2, NRTSO2(C1 -C4)-Alkyl , (Ci-C6)- Alkylen-(C3-Cio)-Cycloalkyl, (C3-C i0)-Cycloalkyl;NHSO 2 (C 1 -C 4 ) -alkyl, (C 1 -C 6 ) -alkylene-S (C 1 -C 4 ) -alkyl, alkylene-S (0) - (C 1 -C 4 ) -alkyl, alkylene-CONH 2 , alkylene-CONH (Ci-C4) - alkyl, alkylene-CON ((C r C 4) - alkyl) 2, S (Ci-C4) - alkyl, SO (C, -C4) - alkyl, SO 2 (Ci-C 4) alkyl, SO 2 NH 2, SO 2 NH (C r C 4) -alkyl, SO 2 N ((Ci-C 4) alkyl) 2, NRTSO 2 (C 1 -C 4) alkyl, (Ci-C 6) - alkylene- (C 3 -Cio) cycloalkyl, (C 3 -C i 0) cycloalkyl;
m O, 1, oder 2;m is O, 1, or 2;
n O oder 1 ;n is O or 1;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
Bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben: Rl , R2, R3 unabhängig voneinander H, (Ci-Cio)-Alkyl, (C3-C io)-Cycloalkyl, (C2-C10)- Alkenyl, (C2-C10)-Alkinyl, (C6-C io)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (C1- C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7,Preference is given to compounds of the formula I in which one or more radicals have the following meaning: Rl, R2, R3 are independently H, (Ci-Cio) alkyl, (C 3 -C io) cycloalkyl, (C 2 -C 10) - alkenyl, (C 2 -C 10) -alkynyl, (C 6 -C 10) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR 7,
OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (CrC6)-Alkylen-OR7, (C,-C6)-Alkylen-NR7R8, (C1- C6)-Alkylen-NR7SO2R7, (Ci-C6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (C,-C6)-Alkylen-(C3- Ci0)-Cycloalkyl, (Ci-C6)-Alkylen-(C6-C10)-Aryl, (Ci-C6)-Alkylen-Heterocyclyl,OP (O) (OR7) 2 , NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C r C 6 ) -alkylene-OR7, (C, -C 6 ) -alkylene-NR7R8, (C 1 - C 6) -alkylene-NR7SO 2 R7, (Ci-C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, R7 NR7SO 2 , (C, -C 6) alkylene- (C 3 - Ci 0) cycloalkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (Ci-C 6) -alkylene-heterocyclyl .
(C3-Cio)-Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein dürfen;(C 3 -Cio) cycloalkyl, (C 6 -C 0) aryl or heterocyclyl, where not all of the radicals Rl, R2 and R3 simultaneously be hydrogen or methyl;
R7, R8 unabhängig voneinander H, (C1 -C6)- Alkyl, (C3-C10)-Cycloalkyl, (C6-C10)- Aryl,R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl,
Heterocyclyl, (Ci-C6)-Alkylen-CONR9R10, (C-C6)-Alkylen-COOR9, (C1-C6)- Alkylen-COR9, (CrC6)-Alkylen-OR9, (C-C6)-Alkylen-NR9R10, (C1-C4)- Alkylen-(C6-C10)-Aryl oder (CrC4)-Alkylen-Heterocyclyl;Heterocyclyl, (Ci-C 6) -alkylene-CONR9R10, (CC 6) alkylene-COOR 9, (C 1 -C 6) - alkylene-COR 9, (C r C 6) -alkylene-OR9, (CC 6) - Alkylene-NR9R10, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R9, RIO unabhängig voneinander H, (Ci -C6)- Alkyl, (Ci-C6)-Alkylen-(C6-C10)-Aryl, (C1- C6)-Alkylen-Heterocyclyl; *-R9, RIO each independently H, (Ci-C6) - alkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (C 1 - C 6) -alkylene-heterocyclyl; * -
R4, R5 unabhängig voneinander Wasserstoff, (Ci -C6)- Alkyl oder (C3-C8)-Cykloalkyl, wobei (Cj-C6)-Alkyl oder (C3-C8)-Cykloalkyl substitiuert sein können mit die durch F, Cl, Br, I, CN,Aryl, Heterocyclyl, NH2, NH(Ci -C6)- Alkyl, N((C-C6)-R4, R5 are independently hydrogen, (Ci-C6) - alkyl or (C 3 -C 8) -cycloalkyl, where (Cj-C6) alkyl or (C 3 -C 8) -cycloalkyl may be substitiuert with the by F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((CC 6 ) -
Alkyl)2, OH, O(CrC6)-Alkyl, OAryl, OHeteroaryl, S(Ci-C6)-Alkyl, S(O)(C-C6)- Alkyl, S(O)2(C,-C6)-Alkyl;Alkyl) 2, OH, O (C r C6) alkyl, O-aryl, OHeteroaryl, S (Ci-C 6) -alkyl, S (O) (CC 6) - alkyl, S (O) 2 (C, - C 6 ) alkyl;
RI l, R12, R13, R14, R15, R16 unabhängig voneinander H, (Ci -C6)- Alkyl, (C3-C8)- Cykloalkyl, (Ci -C4)- Alkylen-O Alkyl, (Ci-C4)-Alkylen-SAlkyl, (C-C4)-Alkylen-RI 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-O alkyl, C 4 ) -alkylene-alkyl, (CC 4 ) -alkylene
NHAlkyl, (C,-C4)-Alkylen-N(Alkyl)2, F, Cl, Br, I, CN, COOH, COO(C-C6)- Alkyl, CONH2, CONH(C -C6)- Alkyl, CON((C-C6)-Alkyl)2, CF3, oder zwei der Reste R4, R5, Rl 1, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)- Alkylenrest; wobei der (C2-C6)- Alkylenrest ein- oder mehrfach substituiert sein kann mit F, Cl, Br, I, CN, NO2, SF5, OH, (C !-C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O(Ci-C4)-Alkyl, NH2, NH(C1 -C4)-Alkyl, N((C1-C4)-Alkyl)2, NRTCONH(C1 -C4)- Alkyl , CO(C1 -C4)- Alkyl, OCO(C1-C4)-NH alkyl, (C 1 -C 4 ) alkylene-N (alkyl) 2 , F, Cl, Br, I, CN, COOH, COO (CC 6 ) alkyl, CONH 2 , CONH (C 6 -C 6 ) alkyl , CON ((CC 6 ) -alkyl) 2 , CF 3 , or two of the radicals R4, R5, Rl 1, R12, R13, R14, R15, R16 form a (C 2 -C 6) together - alkylene radical; wherein the (C 2 -C 6) - alkylene radical mono- or may be multiply substituted with F, Cl, Br, I, CN, NO 2, SF 5, OH, (C 6 -C!) - alkyl, -CF 3 , -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, O (Ci-C 4) -alkyl, NH 2, NH (C 1 -C 4) -Alkyl, N ((C 1 -C 4 ) -alkyl) 2 , NRTCONH (C 1 -C 4 ) -alkyl, CO (C 1 -C 4 ) -alkyl, OCO (C 1 -C 4 ) -
Alkyl, OCOO(C1 -C4)-Alkyl, COO(Ci -C4)- Alkyl, CONH2, CONH(C !-C4)- Alkyl, CON((C]-C4)-Alkyl)2, (C rC6)-Alkylen-O(C, -C4)- Alkyl , (d-C6)-Alkylen- NH(CrC4)-Alkyl, (C1-C6)- Alkylen-NH2, (CrC6)-Alkylen-N((Ci-C4)-Alkyl)2, (C1-C6)-Alkylen-NHSO2(C,-C4)-Alkyl, (C,-C6)-Alkylen-S(Ci-C4)-Alkyl, Alkylen-S(0)-(Cl-C4)-Alkyl, Alkylen-CONH2, Alkylen-CONH(d-C4)-Alkyl,Alkyl, OCOO (C 1 -C 4) -alkyl, COO (Ci-C4) - alkyl, CONH 2, CONH (C 4 -C?) - alkyl, CON ((C] -C4) alkyl) 2 , (C rC 6) -alkylene-O (C, -C 4) - alkyl, (dC 6) -alkylene- NH (CrC 4) alkyl, (C 1 -C 6) - alkylene-NH 2, (C r C 6 ) -alkylene-N ((C 1 -C 4 ) -alkyl) 2 , (C 1 -C 6 ) -alkylene-NHSO 2 (C 1 -C 4 ) -alkyl, (C, -C 6 ) - Alkylene-S (C 1 -C 4 ) -alkyl, alkylene-S (O) - (C 1 -C 4 ) -alkyl, alkylene-CONH 2 , alkylene-CONH (C 1 -C 4 ) -alkyl,
Alkylen-CON((C,-C4)-Alkyl)2, S(C,-C4)-Alkyl, SO(CrC4)-Alkyl, SO2(Ci-C4)- Alkyl, SO2NH2, SO2NH(C, -C4)-Alkyl, SO2N((Ci-C4)-Alkyl)2, NR7SO2(d-C4)- Alkyl , (C,-C6)-Alkylen-(C3-Ci0)-Cycloalkyl, (C3-C10)-Cycloalkyl;Alkylene-CON ((C, -C 4) alkyl) 2, S (C, -C 4) alkyl, SO (C r C 4) alkyl, SO 2 (Ci-C 4) - alkyl, SO 2 NH 2, SO 2 NH (C, -C 4) -alkyl, SO 2 N ((Ci-C 4) alkyl) 2, NR7SO 2 (dC 4) - alkyl, (C, -C 6) alkylene- (C 3 -C 0) cycloalkyl, (C 3 -C 10) cycloalkyl;
m 0, 1, oder 2;m is 0, 1, or 2;
n O oder 1 ;n is O or 1;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
Besonders bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben:Particular preference is given to compounds of the formula I in which one or more radicals have the following meaning:
Rl, R2, R3 unabhängig voneinander H, (Ci -Ci0)- Alkyl, (C3-C 10)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-C io)-Alkinyl, (C6-C iO)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (Ci- C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0R7,Rl, R2, R3 are independently H, (Ci -C 0) - alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C io) alkynyl, (C 6 -C i O) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, SF 5, OH, (Ci- C 6) alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, 0R7 .
OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, C00R7, CONR7R8, OCONR7R8, (C,-C6)-Alkylen-OR7, (Ci-C6)-Alkylen-NR7R8, (Ci- C6)-Alkylen-NR7SO2R7, (C,-C6)-Alkylen-SR7, Alkylen-S(0)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (CrC6)-Alkylen-(C3- C io)-Cycloalkyl, (C i -C6)- Alkylen-(C6-C 10)- Aryl, (C1 -C6)- Alkylen-Heterocyclyl, (C3-C10)-Cycloalkyl, (C6-Cio)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein dürfen;OP (O) (OR7) 2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, C00R7, CONR7R8, OCONR7R8, (C, -C 6) -alkylene-OR7, (Ci-C 6) -alkylene-NR7R8, (C - C 6) -alkylene-NR7SO 2 R7, (C, -C 6) -alkylene-SR7, alkylene-S (0) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (C r C6) -alkylene- (C 3 - C io) cycloalkyl, (C i -C 6) - alkylene- (C 6 -C 1 0) - aryl, (C 1 -C 6) - alkylene Heterocyclyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl, where not all radicals R 1, R 2 and R 3 may be simultaneously hydrogen or methyl;
R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-Ci0)-Cycloalkyl, Aryl,R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, aryl,
Heterocyclyl, (Ci-C4)-Alkylen-(C6-C10)-Aryl oder (Ci-C4)-Alkylen- Heterocyclyl;Heterocyclyl, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R4, R5 unabhängig voneinander Wasserstoff, (Ci-C6)-Alkyl oder (C3-C8)-Cykloalkyl, wobei (Ci-C6)- Alkyl oder (C3-C8)-Cykloalkyl substitiuert sein können mit die durch F, Cl, Br, I, CN,Aryl, Heterocyclyl, NH2, NH(C ,-C6)- Alkyl, N((Ci-C6)- Alkyl)2, OH, 0(C1-Co)-AuCyI, OAryl, OHeteroaryl, S(C!-C6)-Alkyl, S(O)(C1-C6)-R4, R5 are independently hydrogen, (Ci-C 6) -alkyl or (C 3 -C 8) -cycloalkyl, where (Ci-C 6) - alkyl or (C 3 -C 8) -cycloalkyl may be with the substitiuert by F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (C, -C6) - alkyl, N ((Ci-C 6) - alkyl) 2, OH, 0 (C 1 -Co ) -AuCyI, OAryl, OHeteroaryl, S (C ! -C 6 ) -alkyl, S (O) (C 1 -C 6 ) -
Alkyl, S(O)2(C,-C6)-Alkyl;Alkyl, S (O) 2 (C, -C 6 ) -alkyl;
Rl 1, R12, R13, R14, R15, R16 unabhängig voneinander H, (Ci -C6)- Alkyl, (C3-C8)-R 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -
Cykloalkyl,cycloalkyl,
oder zwei der Reste R4, R5, Rl 1, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)-or two of the radicals R 4, R 5, R 11, R 12, R 13, R 14, R 15, R 16 together form a (C 2 -C 6 )
Alkylenrest;alkylene;
m 0, 1 oder 2;m is 0, 1 or 2;
n 0;n 0;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
Weiterhin besonders bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben: Rl , R2, R3 unabhängig voneinander (Ci-C6)- Alkyl, (C3-C io)-Cycloalkyl, (C2-C iO)-Alkenyl, (C2-Ci0)-Alkinyl, (C6-C iO)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, CN, NO2, SF5, OH, (Ci-C6)-Alkyl, -CF3, -OCF3, -Particular preference is furthermore given to compounds of the formula I in which one or more radicals have the following meanings: Rl, R2, R3 are independently (Ci-C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 2 -C i O) -alkenyl, (C 2 -C 0) -alkynyl, (C 6 -C i O ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -
SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (Ci-C6)-Alkylen-OR7, (Ci-C6)-Alkylen-NR7R8, (C,-C6)-Alkylen-NR7SO2R7, (CrC6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (CrC6)-Alkylen-(C3- Cio)-Cycloalkyl, (C1 -C6)- Alkylen-(C6-Ci0)- Aryl, (C,-C6)-Alkylen-Heterocyclyl,SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (Ci-C 6) -alkylene-OR7, (Ci-C 6) -alkylene-NR7R8, (C, -C 6) -alkylene-NR7SO 2 R7, (C r C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R7, SO 2 NR7R8, NR7SO 2 R7, (C r C6) alkylene- (C3 - Cio) cycloalkyl, (C 1 -C 6) - alkylene- (C 6 -C 0) - aryl, (C , -C 6 ) -alkylene heterocyclyl,
(C3-C10)-Cycloalkyl, (C6-C10)- Aryl oder Heterocyclyl;(C 3 -C 10) cycloalkyl, (C 6 -C 10) - aryl or heterocyclyl;
R7, R8 unabhängig voneinander H, (C1 -C6)- Alkyl, (C3-C ]0)-Cycloalkyl, Aryl,R7, R8 are independently H, (C 1 -C 6) - alkyl, (C 3 -C] 0) cycloalkyl, aryl,
Heterocyclyl (Ci-C4)-Alkylen-(C6-Ci0)-Aryl oder (CrC4)-Alkylen-Heterocyclyl;Heterocyclyl (Ci-C 4) -alkylene- (C 6 -C 0) aryl or (CrC 4) -alkylene-heterocyclyl;
R4, R5 Wasserstoff;R4, R5 hydrogen;
Rl 1, R12, R13, R14 unabhängig voneinander H, (Ci-C6)-Alkyl oder C3-C7-Cycloalkyl;R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl or C 3 -C 7 -cycloalkyl;
m 0;m 0;
n 0;n 0;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
Weiterhin besonders bevorzugt sind Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben:Particular preference is furthermore given to compounds of the formula I in which one or more radicals have the following meanings:
Rl, R2, R3 unabhängig voneinander (C1 -C6)- Alkyl, (C3-C io)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-Ci0)-Alkinyl, (C6-Ci0)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-,Rl, R2, R3 are independently (C 1 -C 6) - alkyl, (C 3 -C io) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 0) -alkynyl, (C 6 -Ci 0 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl,
Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, CN, SF5, (Ci -C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C4)- Alkenyl, (C2-C4)-Alkinyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (C,-C4)-Alkylen-OR7, (C]-C4)-Alkylen-NR7R8, (Ci-C4)-Alkylen- NR7SO2R7, (Ci-C6)-Alkylen-SR7, Alkylen-S(0)R7, Alkylen-CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (Ci-C6)- Alkylen-(C3-C,0)-Cycloalkyl, (Ci-C6)-Alkylen-(C6-Ci0)-Aryl, (Ci-C6)-Alkylen-Heterocyclyl, (C3-Ci0)-Alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted by F, Cl, CN, SF 5 , (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , ( C 2 -C 4) - Alkenyl, (C 2 -C 4) alkynyl, OR 7, NR 7 R 8, NR 7 CONR 7 R 8, COR 7, COOR 7, CONR 7 R 8, (C 1 -C 4) alkylene-OR 7, (C 1 -C 4) alkylene-NR 7 R 8, (C 1 -C 4) alkylene NR7SO 2 R7, (Ci-C 6) -alkylene-SR7, alkylene-S (0) R7, alkylene-CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (Ci-C 6) - alkylene- (C 3 -C, 0) cycloalkyl, (Ci-C 6) alkylene- (C 6 -C 0) aryl, (Ci-C6) alkylene-heterocyclyl, (C 3 - Ci 0 ) -
Cycloalkyl, (C6-C]0)-Aryl oder Heterocyclyl;Cycloalkyl, (C 6 -C] 0) -aryl or heterocyclyl;
R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-Ci0)-Cycloalkyl, Aryl,R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, aryl,
Heterocyclyl, (Ci-C4)-Alkylen-(C6-Ci0)-Aryl oder (CrC4)-Alkylen- Heterocyclyl;Heterocyclyl, (Ci-C 4) -alkylene- (C 6 -C 0) aryl or (C r C 4) -alkylene- heterocyclyl;
R4, R5 Wasserstoff;R4, R5 hydrogen;
Rl 1, R12, R13, R14 unabhängig voneinander H, (Ci-C4)-Alkyl;R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 4) -alkyl;
m 0;m 0;
n 0;n 0;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
Die Erfindung bezieht sich auf Verbindungen der Formel I, in Form ihrer Racemate, racemischen Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.The invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
Können Reste oder Substituenten mehrfach in den Verbindungen der Formel I auftreten, so können sie alle unabhängig, voneinander die angegebenen Bedeutungen haben und gleich oder verschieden sein.If radicals or substituents can occur several times in the compounds of the formula I, they may all independently , have the meanings given to one another and be identical or different.
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter- und Schwefelsäure sowie organischer Säuren, wie z.B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isethion-, Milch-, Lactobion-, Malein-, Äpfel-, Methansulfon-, Bernstein-, p-Toluolsulfon- und Weinsäure. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze), Erdalkali salze (wie Magnesium- und Calciumsalze), Trometamol (2-Amino-2-hydroxyrnethyl-l,3-propandiol), Diethanolamin, Lysin, oder Ethylendiamin.Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethane sulfone, fumaric acid, Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxyrnethyl-l, 3-propanediol), diethanolamine, lysine, or ethylenediamine ,
Salze mit einem nicht pharmazeutisch verträglichen Anion, wie zum Beispiel Trifluoracetat, gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nicht-therapeutischen, zum Beispiel in-vitro-Anwendungen.Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiolo¬ gisch verträgliche Derivat einer erfindungsgemäßen Verbindung der Formel I, z.B. einen Ester, der bei Verabreichung an einen Säuger, wie z.B. den Menschen, in der Lage ist, (direkt oder indirekt) eine Verbindung der Formel I oder einen aktiven Metaboliten hiervon zu bilden.The term "physiologically functional derivative" as used herein denotes any physiologically acceptable derivative of a compound of the formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
Zu den physiologisch funktionellen Derivaten zählen auch Prodrugs der erfmdungsgemäßen Verbindungen. Solche Prodrugs können in vivo zu einer erfmdungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z.B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.The compounds of the invention may also be in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel I" auf Verbin- dung(en) der Formel I wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktionellen Derivate wie hierin beschrieben. Unter einem Alkylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit einem oder mehreren Kohlenstoffen verstanden, wie z.B. Methyl, Ethyl, iso-Propyl, tert.-Butyl, Hexyl.Hereinafter, all references to "compound (s) according to formula I" refer to compound (s) of formula I as described above, as well as their salts, solvates and physiologically functional derivatives as described herein. An alkyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having one or more carbons, such as, for example, methyl, ethyl, isopropyl, tert-butyl, hexyl.
Die Alkylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1 -C6) Alkyl, CONH2, CONH(C] -C6) Alkyl, CON[(C,-C6)Alkyl]2) Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0-(C !-C6)- Alkyl 0-C0- (Ci-C6)-Alkyl, 0-CO-(Ci -C6)- Aryl, O-CO-(Ci-C6)-Heterocyclus,;The alkyl radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C] -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C ! C 6 ) - alkyl 0-C0- (C 1 -C 6 ) -alkyl, 0-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
PO3H2, SO3H, SO2-NH2, SO2NH(Ci-C6)-Alkyl, SO2NC(C1 -C6)- Alkyl]2 , S-(C !-C6)- Alkyl, S- (CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(Ci-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, S O2-(Ci -C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus , SO2-PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (Ci-C 6) -alkyl, SO 2 NC (C 1 -C 6) - alkyl] 2, S- (C 6 -C! ) - alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n - heterocycle, SO 2 - (Ci-C6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n heterocycle, SO 2 -
NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1 -C6)- Alkyl)(CH2)n- Aryl, SO2-N(C1- C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(CrC6)-Alkyl, (Ci -C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(Ci -C6)- Alkyl, N((C,-C6)-Alkyl)2, NH(Ci -C7)- Acyl, NH-CO-(Ci-C6)- Alkyl, NH-C00-(Ci-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-C00- Aryl, NH- COO-Heterocyclus, NH-CO-NH-(Ci -C6)- Alkyl, NH-CO-NH- Aryl, NH-CO-NH-Heterocyclus, N(C 1-C6)- Alkyl -CO-(C ,-C6)- Alkyl, N(C, -C6)- Alkyl -COO-(C, -C6)- Alkyl, N(C, -C6)- Alkyl - CO- Aryl, N(Ci -C6)- Alkyl -CO-Heterocyclus, N(Ci -C6)- Alkyl -COO-Aryl, N(C ,-C6)- Alkyl - COO-Heterocyclus, N(Ci -C6)- Alkyl -CO-NH-(C, -C6)- Alkyl), N(C,-C6)-Alkyl -CO-NH-Aryl, N(C ,-C6)- Alkyl -CO-NH-Heterocyclus, N((Ci-C6)-Alkyl)-CO-N-(Ci-C6)-Alkyl)2, N((Ci-C6)- Alkyl)-CO-N((Ci-C6)-Alkyl)-Aryl, N((Ci-C6)-Alkyl)-CO-N((Ci-C6)-Alkyl)-Heterocyclus, N((Ci-C6)-Alkyl)-CO-N-(Aryl)2, N((C1-C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-CO-(C,- C6)- Alkyl, N(Heterocyclus)-CO-(Ci-C6)-Alkyl, N(Aryl)-COO-(C, -C6)- Alkyl, N(Heterocyclus)- COO-(Ci-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)-Alkyl), N(Heterocyclus)-CO-NH-(C1- C6)- Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(C,-C6)- Alkyl)2, N(Heterocyclus)-CO-N-(C,-C6)-Alkyl)2, N(Aryl)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Heterocyclus)-CO-N((Ci-C6)- Alkyl)- Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, 0-(CH2)π-Aryl, O-(CH2)n-Heterocyclus, wobei n = O - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-Alkyl, (Ci-C6)-Alkyl, NH2, NH(C1 -C6)- Alkyl, N((C,-C6)- Alkyl)2, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.NH (CH 2) n -aryl, SO 2 -NH (CH 2) n heterocycle, SO 2 -N (C 1 -C 6) - alkyl) (CH 2) n - aryl, SO 2 -N (C 1 - C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0 - 6 can be and the aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C r C 6 ) alkyl, (Ci -C 6 ) - alkyl, NH 2 may be substituted, C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 -C 4 ) -alkyl C 7 ) - acyl, NH-CO- (C 1 -C 6 ) -alkyl, NH-C00- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-C00--aryl, NH- COO-heterocycle, NH-CO-NH- (Ci-C6) - alkyl, NH-CO-NH- aryl, NH-CO-NH-heterocycle, N (C 1 -C 6) - alkyl -CO (C 1 -C 6 ) -alkyl, N (C 1 -C 6 ) -alkyl-COO- (C 1 -C 6 ) -alkyl, N (C 1 -C 6 ) -alkyl-CO-aryl, N ( C 1 -C 6 ) - alkyl -CO-heterocycle, N (C 1 -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl-COO heterocycle, N (C 1 -C 6 ) -alkyl -CO-NH- (C, -C6) - alkyl), N (C, -C6) -alkyl -CO-NH-aryl, N (C, -C6) - alkyl - CO-NH-heterocycle, N ((Ci-C 6) -alkyl) -CO-N- (Ci-C 6) alkyl) 2, N ((Ci-C 6) - alkyl) -CO-N (( C 1 -C 6 ) -alkyl) -aryl, N ((C 1 -C 6 ) -alkyl) -CO-N ((C 1 -C 6 ) -alkyl) -heterocycle, N ((C 1 -C 6 ) -alkyl) -CO-N- (aryl) 2, N ((C 1 -C 6) -alkyl) -CO-N- (heterocycle) 2, N (aryl) -CO- (C, - C 6) - alkyl, N (Heterocyclic) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N ( Aryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) - Alkyl), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocyclic) -CO-NH-aryl, N (aryl) - CO-N- (C, -C 6) - alkyl) 2, N (heterocycle) -CO-N- (C, -C 6) alkyl) 2, N (aryl) -CO-N ((Ci-C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO- N- (aryl) 2, aryl, 0- (CH 2) π -aryl, O- (CH 2) n -heterocycle, wherein n = O - 6 may be, where the aryl radical or heterocyclic radical may be substituted up to 3-fold may be with F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (C r C6) alkyl, (Ci-C 6) -alkyl, NH 2, NH (C 1 -C 6) - alkyl, N ((C, -C 6 ) -alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 .
Unter einem Alkenylrest wird eine geradkettige oder verzweigte Kohlenwasserstofϊkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Doppelbindungen verstanden, wie z.B. Vinyl, AHyI, Pentenyl.By an alkenyl radical is meant a straight or branched hydrocarbon chain having two or more carbons and one or more double bonds, e.g. Vinyl, AHyI, pentenyl.
Die Alkenylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci -C6) Alkyl, CONH2, CONH(Ci -C6) Alkyl, CON[(Ci-C6)Alkyl]2, Cycloalkyl, (C1 -Ci0)- Alkyl, (C2-C6)-Alkinyl, 0-(C1 -C6)- Alkyl 0-CO- (C 1-C6)- Alkyl, 0-CO-(Ci -C6)- Aryl, O-CO-(Ci-C6)-Heterocyclus,;The alkenyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( Ci -C 6) alkyl, CON [(Ci-C 6) alkyl] 2, cycloalkyl, (C 1 -C 0) - alkyl, (C 2 -C 6) -alkynyl, 0- (C 1 -C 6) - alkyl 0-CO- (C 1 -C 6) - alkyl, 0-CO- (Ci-C6) - aryl, O-CO- (Ci-C 6) -heterocycle ,;
PO3H2, SO3H, SO2-NH2, SO2NH(C ,-C6)- Alkyl, SO2N[(Ci-C6)-Alkyl]2 , S-(C !-C6)- Alkyl, S- (CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(Ci-C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, SO2-(Ci-C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus , SO2- NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1-C6)-Alkyl)(CH2)n-Aryl, SO2-N(C1- C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C 1-C6)- Alkyl, (d -C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(Ci-C6)- Alkyl, N((C !-Ce)-AIk^)2, NH(C, -C7)- Acyl, NH-CO-(C-C6)- Alkyl, NH-C00-(CrC6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH- COO-Heterocyclus, NH-CO-NH-(Ci -C6)- Alkyl, NH-CO-NH- Aryl, NH-CO-NH-Heterocyclus, N(Ci -C6)- Alkyl -CO-(Ci -C6)- Alkyl, N(Ci -C6)- Alkyl -COO-(Ci -C6)- Alkyl, N(C,-C6)-Alkyl - CO-Aryl, N(C ,-C6)- Alkyl -CO-Heterocyclus, N(C ,-C6)- Alkyl -COO- Aryl, N(Ci -C6)- Alkyl - COO-Heterocyclus, N(C, -C6)- Alkyl -CO-NH-(Ci -C6)- Alkyl), N(Ci -C6)- Alkyl -CO-NH-Aryl, N(C,-C6)-Alkyl -CO-NH-Heterocyclus, N((Ci-C6)-Alkyl)-CO-N-(Ci-C6)-Alkyl)2, N((C,-C6)- Alkyl)-CO-N((Ci-C6)-Alkyl)-Aryl, N((C,-C6)-Alkyl)-CO-N((C,-C6)-Alkyl)-Heterocyclus, N((C1-C6)-Alkyl)-CO-N-(Aryl)2, N((C1-C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-CO-(Cr C6)-Alkyl, N(Heterocyclus)-CO-(Ci -C6)- Alkyl, N(Aryl)-COO-(C, -C6)- Alkyl, N(Heterocyclus)- COO-(C, -C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO- Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl), N(Heterocyclus)-CO-NH-(Ci- C6)-Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(C-C6)- Alkyl)2, N(Heterocyclus)-CO-N-(Ci -C6)-Alkyl)2, N(Aryl)-CO-N((C, -C6)-Alkyl)-Aryl, N(Heterocyclus)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0 - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (C,-C6)-Alkyl, NH2, NH(Ci -C6)- Alkyl, NC(C1-C6)- Alkyl)2, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N [(Ci-C 6) -alkyl] 2, S- (C -C! 6 ) - alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2) n - heterocycle, SO 2 - (Ci-C 6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n heterocycle, SO 2 - NH (CH 2 n) - Aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical of up to two times by F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - substituted alkyl, NH 2 - alkyl, (d-C6) can be C (NH) (NH 2), NH 2, NH- (Ci-C 6) - alkyl, N 2, NH (C, -C 7) - acyl ((C -Ce) -AIk ^!) , NH-CO- (CC 6 ) -alkyl, NH-C00- (C r C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH -CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C 1 -C 6 ) - Alkyl -CO- (Ci-C6) - alkyl, N (Ci-C6) - alkyl -COO (Ci-C6) - alkyl, N (C, -C6) -alkyl - CO-aryl, N (C 1 -C 6 ) -alkyl -CO-heterocycle, N (C 1 -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl-COO heterocycle, N (C, -C 6 ) - alkyl -CO-NH- (Ci-C6) - alkyl), N (Ci-C6) - alkyl -CO-NH-aryl, N (C, -C6) -alkyl -CO-NH-heterocycle , N ((Ci-C 6) -alkyl) -CO-N- (Ci-C 6) alkyl) 2, N ((C, -C6) - alkyl) -CO-N ((Ci-C 6 ) -alkyl) -aryl, N ((C, -C6) -alkyl) -CO-N ((C, -C 6) -alkyl) -heterocycle, N ((C 1 -C 6) alkyl) - CO-N- (aryl) 2 , N ((C 1 -C 6 ) -alkyl) -CO-N- (heterocycle) 2 , N (aryl) -CO- (C 1 -C 6 ) -alkyl, N (heterocycle) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocyclic) -COO- (C 1 -C 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl) , N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocyclic) -CO-NH-aryl, N (aryl) -CO-N - (CC 6 ) - alkyl) 2 , N (heterocycle) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N ((C, -C 6 ) -Al kyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO-N- (Aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical may be substituted one to three times with F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, C 6) - alkyl, NC (C 1 -C 6) - alkyl) 2, SO 2 -CH 3, COOH, COO- (Ci-C6) - alkyl, CONH. 2
Unter einem Alkinylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Dreifachbindungen verstanden, wie z.B. Ethinyl, Propinyl, Hexinyl. Die Alkinylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci -C6) Alkyl, CONH2, CONH(C, -C6) Alkyl, CON[(C!-C6)Alkyl]2> Cycloalkyl, (C2-C6)-Alkenyl, (d-C10)-Alkyl, 0-(C J-C6)- Alkyl 0-C0- (Ci -C6)- Alkyl, 0-CO-(C !-C6)- Aryl, O-CO-(Ci-C6)-Heterocyclus; PO3H2, SO3H, SO2-NH2, SO2NH(Ci-C6)- Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C1 -C6)- Alkyl, S- (CH2)n- Aryl, S-(CH2)n-Heterocyclus, SO-(C1 -C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, SO2-(CrC6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus , SO2- NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C,-C6)-Alkyl)(CH2)n-Aryl, SO2-N(Cr C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C1 -C6)- Alkyl, (Ci -C6)- Alkyl, NH2 substituiert sein kann;An alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as ethynyl, propynyl, hexynyl. The alkynyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( C, -C 6) alkyl, CON [! (C-C6) alkyl] 2> cycloalkyl, (C 2 -C 6) alkenyl, (dC 10) alkyl, 0- (C J-C6) - (! C-C6) - alkyl-C0 0 (Ci-C6) alkyl, 0-CO- - aryl, O-CO- (Ci-C 6) heterocyclic; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (Ci-C 6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C 1 -C 6) - alkyl, S- (CH 2) n - aryl, S- (CH 2) n -heterocycle, SO- (C 1 -C 6) - alkyl, SO- (CH 2) n -aryl, SO- ( CH 2 ) n - heterocycle, SO 2 - (C r C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 - NH (CH 2 ) n -Aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl) ( CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or substituted alkyl, NH 2 - alkyl, (Ci-C6) - up to two times by F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) heterocyclic group can;
C(NH)(NH2), NH2, NH-(C1 -C6)- Alkyl, N((d-C6)-Alkyl)2, NH(Ci-C7)-Acyl, NH-CO-(C-C6)- Alkyl, NH-C00-(Ci-C6)-Alkyl, NH-CO- Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH- COO-Heterocyclus, NH-CO-NH-(C1 -C6)- Alkyl, NH-CO-NH- Aryl, NH-CO-NH-Heterocyclus, N(Ci-C6)- Alkyl -CO-(Ci -C6)- Alkyl, N(Ci -C6)- Alkyl -COO-(CrC6)-Alkyl, N(C,-C6)-Alkyl - CO-Aryl, N(C ,-C6)- Alkyl -CO-Heterocyclus, N(Ci -C6)- Alkyl -COO-Aryl, N(Ci -C6)- Alkyl - COO-Heterocyclus, N(C ,-C6)- Alkyl -CO-NH-(Ci -C6)-Alkyl), N(C ,-C6)- Alkyl -CO-NH-Aryl, N(Ci-C6)-Alkyl -CO-NH-Heterocyclus, N((C1-C6)-Alkyl)-CO-N-(C1-C6)-Alkyl)2, N((CrC6)- Alkyl)-CO-N((C, -C6)- Alkyl)- Aryl, N((Ci-C6)-Alkyl)-CO-N((CrC6)-Alkyl)-Heterocyclus, N((C , -C6)- Alkyl)-CO-N-(Aryl)2, N((Ci -C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-C0-(C - C6)-Alkyl, N(Heterocyclus)-CO-(C, -C6)- Alkyl, N(Aryl)-COO-(CrC6)-Alkyl, N(Heterocyclus)- COO-(CrC6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(C,-C6)-Alkyl), N(Heterocyclus)-CO-NH-(Ci- C6)-Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(CrC6)- Alkyl)2, N(Heterocyclus)-CO-N-(C1-C6)-Alkyl)2, N(Aryl)-CO-N((C1-C6)-Alkyl)-Aryl, N(Heterocyclus)-CO-N((C1-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0 - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-Alkyl, (C,-C6)-Alkyl, NH2, NH(C1 -C6)- Alkyl, N((C,-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C1 -C6)- Alkyl, CONH2.C (NH) (NH 2), NH 2, NH- (C 1 -C 6) - alkyl, N ((dC 6) alkyl) 2, NH (Ci-C7) -acyl, NH-CO- ( CC 6 ) - alkyl, NH-C00- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- ( C 1 -C 6) - alkyl, NH-CO-NH- aryl, NH-CO-NH-heterocycle, N (Ci-C6) - alkyl -CO (Ci-C6) - alkyl, N (Ci - C 6) - alkyl -COO (C r C6) alkyl, N (C, -C6) -alkyl - CO-aryl, N (C, -C6) - alkyl -CO-heterocycle, N (Ci -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl-COO-heterocycle, N (C 1 -C 6 ) -alkyl-CO-NH- (C 1 -C 6 ) -alkyl), N (C, -C6) - alkyl -CO-NH-aryl, N (Ci-C6) -alkyl -CO-NH-heterocycle, N ((C 1 -C 6) -alkyl) -CO-N- (C 1 -C 6) alkyl) 2, N ((C r C6) - alkyl) -CO-N ((C, -C6) - alkyl) - aryl, N ((Ci-C 6) - alkyl) -CO-N ((C r C6) -alkyl) -heterocycle, N ((C, -C6) - alkyl) -CO-N- (aryl) 2, N ((Ci-C6) - alkyl) -CO-N- (heterocycle) 2, N (aryl) -C0- (C - C 6) -alkyl, N (heterocycle) -CO- (C, -C 6) - alkyl, N (aryl) - COO- (C r C6) alkyl, N (heterocycle) - COO- (C r C6) alkyl, N (aryl) -CO-aryl, N (Heterocyc lus) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C, -C 6 ) -alkyl), N (heterocycle) - CO-NH- (Ci C 6 ) alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (C r C 6 ) -alkyl) 2 , N (Heterocyclic) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) alkyl) aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocyclic) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl radical or heterocyclic radical may be monosubstituted to trisubstituted by F, Cl, Br, I, OH, CF 3 , NO 2, CN, OCF 3, O- (C r C6) alkyl, (C, -C 6) alkyl, NH 2, NH (C 1 -C 6) - alkyl, N ((C, - C 6 ) - alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 .
Unter einem Arylrest wird ein Phenyl, Naphthyl-, Biphenyl-, Tetrahydronaphthyl-, alpha- oder beta-Tetralon-, Indanyl- oder Indan-1-on-ylrest verstanden.An aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
Die Arylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C, -C6) Alkyl, CONH2, CONH(C ,-C6) Alkyl, CON[(CrC6)Alkyl]2i Cycloalkyl, (C !-C10)- Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0-(C,- C6)-Alkyl O-CO-(CrC6)-Alkyl, 0-CO-(C 1-Ce)-ATyI, O-CO-(Ci-C6)-Heterocyclus,; PO3H2, SO3H, SO2-NH2, SO2NH(Ci -C6)- Alkyl, SO2N[(Ci-C6)-Alkyl]2 , S-(Ci-C6)- Alkyl, S- (CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C, -C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, SO2-(Ci-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)π-Heterocyclus , SO2- NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1 -C6)- Alkyl)(CH2)n- Aryl, SO2-N(C,- C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C ,-C6)- Alkyl, (C ,-C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(C ,-C6)- Alkyl, N((Ci-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C-C6)- Alkyl, NH-COO-(C,-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH- COO-Heterocyclus, NH-CO-NH-(Ci -C6)- Alkyl, NH-CO-NH- Aryl, NH-CO-NH-Heterocyclus, N(Ci -C6)- Alkyl -CO-(C ,-C6)- Alkyl, N(Ci -C6)- Alkyl -COO-(C i-C6)-Alkyl, N(Ci-C6)-Alkyl - CO-Aryl, N(C ,-C6)- Alkyl -CO-Heterocyclus, N(C, -C6)- Alkyl -COO- Aryl, N(Ci -C6)- Alkyl - COO-Heterocyclus, N(Ci -C6)- Alkyl -CO-NH-(C,-C6)-Alkyl), N(Ci -C6)- Alkyl -CO-NH-Aryl, N(C,-C6)-Alkyl -CO-NH-Heterocyclus, N((C,-C6)-Alkyl)-CO-N-(C,-C6)-Alkyl)2, N((CrC6)- Alkyl)-CO-N((C , -C6)- Alkyl)- Aryl, N((C , -C6)- Alkyl)-CO-N((C , -C6)- Alkyl)-Heterocyclus, N((Ci-C6)-Alkyl)-CO-N-(Aryl)2, N((Ci-C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-CO-(Ci- C6)-Alkyl, N(Heterocyclus)-CO-(C,-C6)-Alkyl, N(Aryl)-COO-(C,-C6)-Alkyl, N(Heterocyclus)- COO-(Ci-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl), N(Heterocyclus)-CO-NH-(Cr C6)-Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(Ci-C6)- Alkyl)2, N(HeICrOCyClUs)-CO-N-(C1 -C6)- Alkyl)2, N(Aryl)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Heterocyclus)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0 - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (C ,-C6)- Alkyl, NH2, NH(C1 -C6)- Alkyl, N((CrC6)- Alkyl)2, SO2-CH3, COOH, COO-(C, -C6)- Alkyl, CONH2.The aryl radicals may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C, -C 6) alkyl, CON [(C r C6) alkyl] 2i cycloalkyl, (C -C 10!) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, 0- (C, - C 6) -alkyl O-CO- (C r C6) alkyl, 0-CO- (C 1 -Ce) -ATyI, O-CO- (Ci-C 6) - heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 -C 6 ) - alkyl, S- (CH 2) n -aryl, S- (CH 2) n -heterocycle, SO- (C, -C6) - alkyl, SO- (CH 2) n -aryl, SO- (CH 2 ) n - heterocycle, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) π -heterocycle, SO 2 --NH (CH 2 ) n -aryl , SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl) ( CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or Heterocyclic radical substituted up to two times by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C, -C 7 ) acyl , NH-CO- (CC 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C 1 -C 6 ) - Alkyl -CO- (C 1 -C 6 ) -alkyl, N (C 1 -C 6 ) -alkyl, -COO- (C 1 -C 6 ) -alkyl, N (C 1 -C 6 ) -alkyl-CO-aryl, N ( C, -C 6 ) -alkyl-CO-heterocycle, N (C, -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl-COO-heterocycle, N (C 1 -C 6 ) - Alkyl -CO-NH- (C 1 -C 6 ) -alkyl), N (C 1 -C 6 ) -alkyl, -CO-NH-aryl, N (C 1 -C 6 ) -alkyl, -CO-NH-heterocycle, N ((C 1 -C 6 ) alkyl) -CO-N- (C 1 -C 6 ) alkyl) 2 , N ((C r C 6 ) alkyl) -CO-N ((C, -C 6) - alkyl) - aryl, N ((C, -C6) - alkyl) -CO-N ((C, -C6) - alkyl) -heterocycle, N ((Ci-C 6) -alkyl) - CO-N- (aryl) 2 , N ((C 1 -C 6 ) -alkyl) -CO-N- (heterocycle) 2 , N (aryl) -CO- (ci) C 6 ) -alkyl, N (heterocycle) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO- (C 1 -C 4 ) -alkyl; C 6 ) alkyl, N (aryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclic) -COO-aryl, N (aryl) -CO-NH - (Ci-C 6) - alkyl), N (heterocycle) -CO-NH- (Cr C6) alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl , N (aryl) -CO-N- (Ci-C 6) - alkyl) 2, N (HeICrOCyClUs) -CO-N- (C 1 -C 6) - alkyl) 2, N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (heterocycle) -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N ( Heterocycle) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, wherein the aryl radical or heterocyclic radical is a may be substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2, NH (C 1 -C 6) - alkyl, N ((C r C6) - alkyl) 2, SO 2 -CH 3, COOH, COO- (C, -C 6) - alkyl, CONH. 2
Unter einem Cycloalkylrest wird ein einen oder mehrere Ringe enthaltendes Ringssystem, welches gesättigt oder partiell ungesättigt (mit einer oder zwei Doppelbindungen) vorliegt, verstanden, das ausschließlich aus Kohlenstoffatomen aufgebaut ist, wie z.B. Cyclopropyl, Cyclopentyl, Cyclopentenyl, Cyclohexyl oder Adamantyl.A cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, e.g. Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
Die Cycloalkylrestereste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C ,-C6) Alkyl, CONH2, CONH(C1- C6)Alkyl, CONf(C1 -C6) Alkyl]2, Cycloalkyl, (C ,-C10)- Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0-(C, -C6)- Alkyl 0-CO-(C ,-C6)- Alkyl, 0-CO-(C ,-C6)- Aryl, O-CO-(CrC6)-Heterocyclus,; PO3H2, SO3H, SO2-NH2, S O2NH(C ,-C6)- Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C1-Co)-AUCyI, S- (CH2)n-Aryl, S-(CH2)n-Heterocyclus, SO-(C1 -C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, SO2-(C, -C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus , SO2- NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C1 -C6)- Alkyl)(CH2)n- Aryl, SO2-N(C,- C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)π-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C 1-C6)- Alkyl, (C ,-C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(C,-C6)-Alkyl, N((C,-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(Ci-C6)- Alkyl, NH-COO-(Ci -C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO- Aryl, NH- COO-Heterocyclus, NH-CO-NH-(C ,-C6)- Alkyl, NH-CO-NH- Aryl, NH-CO-NH-Heterocyclus, N(C,-C6)-Alkyl -CO-(C, -C6)- Alkyl, N(C ,-C6)- Alkyl -COO-(C,-C6)-Alkyl, N(C1 -C6)- Alkyl - CO-Aryl, N(C ,-C6)- Alkyl -CO-Heterocyclus, N(C ,-C6)- Alkyl -COO-Aryl, N(Ci -C6)- Alkyl - COO-Heterocyclus, N(Ci -C6)- Alkyl -CO-NH-(C1 -C6)- Alkyl), N(Ci -C6)- Alkyl -CO-NH-Aryl, N(C1-Ce)-AIlCyI -CO-NH-Heterocyclus, N((Ci-C6)-Alkyl)-CO-N-(C]-C6)-Alkyl)2, N((C,-C6)- Alkyl)-CO-N((Ci-C6)-Alkyl)-Aryl, N((Ci-C6)-Alkyl)-CO-N((C1-C6)-Alkyl)-Heterocyclus, N((C,-C6)-Alkyl)-CO-N-(Aryl)2, N((Ci-C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-CO-(Ci- C6)-Alkyl, N(Heterocyclus)-CO-(C,-C6)-Alkyl, N(Aryl)-COO-(Ci -C6)- Alkyl, N(Heterocyclus)- COO-(Ci-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl), N(Heterocyclus)-CO-NH-(Ci- C6)- Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(CrC6)- Alkyl)2, N(Heterocyclus)-CO-N-(Ci-C6)-Alkyl)2, N(Aryl)-CO-N((C1-C6)-Alkyl)-Aryl, N(Heterocyclus)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0 - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(CrC6)-Alkyl, (C ,-C6)- Alkyl, NH2, NH(C ,-C6)- Alkyl, N((d-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C, -C6)- Alkyl, CONH2.The Cycloalkylrestereste may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 - C 6) alkyl, conf (C 1 -C 6) alkyl] 2, cycloalkyl, (C, -C10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, 0- (C, -C 6) - alkyl 0-CO- (C, -C6) - alkyl, 0-CO- (C, -C6) - aryl, O-CO- (CrC 6) heterocycle ,; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C 1 - Co) -AUCyI, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocycle, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- ( CH 2 ) n - heterocycle, SO 2 - (C, -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocycle, SO 2 - NH (CH 2 ) n -aryl, SO 2 -NH (CH 2) n heterocycle, SO 2 -N (C 1 -C 6) - alkyl) (CH 2 n) - aryl, SO 2 -N (C, - C 6) - Alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) π- aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical having up to two times by F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - alkyl, (C, -C 6) - alkyl, NH 2 (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C, -C 7 ) - acyl, NH-CO- (Ci-C 6 ) - alkyl, NH-COO- (Ci -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH - COO heterocycle, NH-CO-NH- (C, -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C, -C 6 ) -Alkyl -CO- (C, -C 6) - alkyl, N (C, -C6) - alkyl -COO (C, -C 6) alkyl, N (C 1 -C 6) - alkyl - CO-aryl, N (C, -C 6 ) -alkyl-CO-heterocycle, N (C, -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl- COO-heterocycle, N (Ci-C6) - alkyl -CO-NH- (C 1 -C 6) - alkyl), N (Ci-C6) - alkyl -CO-NH-aryl, N (C 1 - Ce) -alkyl -CO-NH-heterocycle, N ((Ci-C 6) -alkyl) -CO-N- (C] -C6) alkyl) 2, N ((C, -C6) - alkyl ) -CO-N ((Ci-C 6) -alkyl) -aryl, N ((Ci-C 6) -alkyl) -CO-N ((C 1 -C 6) -alkyl) -heterocycle, N (( C, -C 6 ) -alkyl) -CO-N- (aryl) 2 , N ((C 1 -C 6 ) -alkyl) -CO-N- (heterocycle) 2 , N (aryl) -CO- (ci) C 6 ) -alkyl, N (heterocycle) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocycle) -COO- (C 1 -C 4 ) -alkyl 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl), N (heterocycle) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl , N (aryl) -CO-N- (C r C 6 ) -alkyl) 2 , N (heterocycle) -CO-N- (C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N ( (C 1 -C 6) -alkyl) -aryl, N (heterocycle) -CO-N ((Ci-C 6) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2, N ( Heterocycle) -CO-N- (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6 n, where the aryl radical or heterocyclic radical may be substituted up to 3 times by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (C r C6) alkyl, ( C, -C 6 ) alkyl, NH 2 , NH (C, -C 6 ) alkyl, N ((dC 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C, -C 6 ) - alkyl, CONH 2 .
Unter Heterocyclus bzw. Heterocyclischer Rest werden Ringe und Ringsysteme verstanden, die außer Kohlenstoff noch Heteroatome, wie zum Beispiel Stickstoff, Sauerstoff oder Schwefel enthalten. Ferner gehören auch Ringsysteme zu dieser Definition, worin der Heterocylus bzw. der Heterocyclische Rest mit Benzolkernen kondensiert ist.Heterocycle or heterocyclic radical is understood as meaning rings and ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic or the heterocyclic radical is condensed with benzene nuclei.
Geeignete "Heterocyclische Ringe" bzw. "Heterocyclische Reste" sind Acridinyl, Azocinyl, Benzimidazolyl, Benzofuryl, Benzothienyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Benzimidazalinyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Decahydrochinolinyl, 2H,6H- 1,5,2- Dithiazinyl, Dihydrofuro[2,3-b]-Tetrahydrofuran, Furyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, lH-Indazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-Indolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolyl, Isoxazolyl, Moφholinyl, Naphthyridinyl,Suitable "heterocyclic rings" or "heterocyclic radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H Indazinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, monochlorinyl, naphthyridinyl,
Octahydroisochinolinyl, Oxadiazolyl, 1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pyridooxazole, Pyridoimidazole, Pyridothiazole, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, 6H-1,2,5-Thiadazinyl, Thiazolyl, 1,2,3- Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thienyl, Triazolyl, Tetrazolyl und Xanthenyl.Octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, Phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H- Pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3, 4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.
Pyridyl steht sowohl für 2-, 3- als auch 4-Pyridyl. Thienyl steht sowohl für 2- als auch 3- Thienyl. Furyl steht sowohl für 2- als auch 3-Furyl. >Pyridyl is both 2-, 3- and 4-pyridyl. Thienyl is both 2- and 3-thienyl. Furyl is both 2- and 3-furyl. >
Umfasst sind weiterhin die entsprechenden N-Oxide dieser Verbindungen, also z.B. l-Oxy-2-, 3- oder 4-pyridyl.Also included are the corresponding N-oxides of these compounds, e.g. l-oxy-2-, 3- or 4-pyridyl.
Umfasst sind weiterhin ein oder mehrfach benzoannelierte Derivate dieser Heterocyclen.Also included are one or more benzoannelated derivatives of these heterocycles.
Die Heterocyclischen Ringe bzw. Heterocyclische Reste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C, -C6) Alkyl, CONH2, CONH(CrC6)Alkyl, CON[(CrC6)Alkyl]2, Cycloalkyl, (C1-C10)- Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0-(C, -C6)- Alkyl 0-CO-(Ci -C6)- Alkyl, 0-CO-(C1- C6)-Aryl, 0-CO-(C, -C6)-Heterocyclus;The heterocyclic rings or heterocyclic radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C, -C 6 ) alkyl , CONH 2, CONH (C r C6) alkyl, CON [(C r C6) alkyl] 2, cycloalkyl, (C 1 -C 10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 - C 6) aryl, 0-CO- ( C, -C 6 ) heterocycle;
PO3H2, SO3H, SO2-NH2, SO2NH(C-C6)- Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C1 -C6)- Alkyl, S- (CH2)n-Aryl, S-(CH2)n-Heterocyclus, S 0-(Ci -C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n- Heterocyclus, SO2-(C1-C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocyclus , SO2- NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterocyclus, SO2-N(C, -C6)-Alkyl)(CH2)n-Aryl, SO2-N(C,- C6)-Alkyl)(CH2)n-Heterocyclus, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterocyclus)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterocyclische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (C,-C6)-Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(C,-C6)-Alkyl, N((C,-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C-C6)- Alkyl, NH-COO-(C, -C6)- Alkyl, NH-CO-Aryl, NH-CO-Heterocyclus, NH-COO-Aryl, NH- COO-Heterocyclus, NH-CO-NH-(C-C6)- Alkyl, NH-CO-NH-Aryl, NH-CO-NH-Heterocyclus, N(C,-C6)-Alkyl -CO-(C, -C6)- Alkyl, N(C,-C6)-Alkyl -COO-(C, -C6)- Alkyl, N(C,-C6)-Alkyl - CO-Aryl, N(Ci -C6)- Alkyl -CO-Heterocyclus, N(Ci -C6)- Alkyl -COO-Aryl, N(Ci -C6)- Alkyl - COO-Heterocyclus, N(Ci -C6)- Alkyl -CO-NH-(Ci -C6)-Alkyl), N(C, -C6)- Alkyl -CO-NH-Aryl, N(C,-C6)-Alkyl -CO-NH-Heterocyclus, N((CrC6)-Alkyl)-CO-N-(Ci-C6)-Alkyl)2, N((Ci-C6> Alkyl)-CO-N((C i -C6)- Alkyl)- Aryl, N((C , -C6)- Alkyl)-CO-N((C, -C6)- Alkyl)-Heterocyclus, N((C,-C6)-Alkyl)-CO-N-(Aryl)2, N((Ci-C6)-Alkyl)-CO-N-(Heterocyclus)2, N(Aryl)-CO-(Ci- C6)- Alkyl, N(Heterocyclus)-CO-(Ci-C6)-Alkyl, N(ATyI)-COO-(C1 -C6)- Alkyl, N(Heterocyclus)- COO-(Ci -C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocyclus)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterocyclus)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)-Alkyl), N(Heterocyclus)-CO-NH-(Ci- C6)- Alkyl), N(Aryl)-CO-NH-Aryl, N(Heterocyclus)-CO-NH-Aryl, N(Aryl)-CO-N-(Ci-C6)- Alkyl)2, N(Heterocyclus)-CO-N-(CrC6)-Alkyl)2, N(ATyI)-CaNt(C1-C6)- Alkyl)- Aryl,PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (CC 6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C 1 -C 6) - alkyl, S- (CH 2) n -aryl, S- (CH 2) n -heterocycle, S 0- (Ci-C6) - alkyl, SO- (CH 2) n -aryl, SO- (CH 2 ) n - heterocycle, SO 2 - (C 1 -C 6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n heterocycle, SO 2 - NH (CH 2) n - Aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocycle) 2 where n = 0-6 and the aryl radical or heterocyclic radical substituted up to two times by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C, -C 7 ) - Acyl, NH-CO- (CC 6 ) -alkyl, NH-COO- (C, -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle , NH-CO-NH- (CC 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N (C, -C 6 ) -alkyl-CO- ( C, -C 6) - alkyl, N (C, -C6) -alkyl -COO- (C, -C 6) - alkyl, N (C, -C6) alkyl - CO-aryl, N (C 1 -C 6 ) -alkyl-CO-heterocycle, N (C 1 -C 6 ) -alkyl-COO-aryl, N (C 1 -C 6 ) -alkyl-COO-heterocycle, N (C 1 -C 6 ) -alkyl C 6) - alkyl -CO-NH- (Ci-C6) alkyl), N (C, -C6) - alkyl -CO-NH-aryl, N (C, -C6) -alkyl -CO- NH-heterocycle, N ((C r C6) -alkyl) -CO-N- (Ci-C 6) alkyl) 2, N ((Ci-C6> alkyl) -CO-N ((C i - C 6) - alkyl) - aryl, N ((C, -C6) - alkyl) -CO-N ((C, -C6) - alkyl) -heterocycle, N ((C, -C 6) alkyl ) -CO-N- (aryl) 2 , N ((C 1 -C 6 ) -alkyl) -CO-N- (heterocycle) 2 , N (aryl) -CO- (C 1 -C 6 ) -alkyl, N ( heterocycle) -CO- (Ci-C 6) -alkyl, N (ATyI) -COO- (C 1 -C 6) - alkyl, N (heterocycle) - COO- (Ci-C6) -alkyl, N (aryl ) -CO-aryl, N (heterocyclic) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl ), N (heterocyclic) -CO-NH- (C 1 -C 6 ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocyclic) -CO-NH-aryl, N (aryl) -CO- N- (Ci-C 6) - alkyl) 2, N (heterocycle) -CO-N- (C r C6) alkyl) 2, N (ATyI) -CaNt (C 1 -C 6) - alkyl) - aryl,
N(Heterocyclus)-CO-N((Ci-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl)2, N(Heterocyclus)-CO-N- (Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterocyclus, wobei n = 0 - 6 sein kann, wobei der Arylrest oder Heterocyclische Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (C ,-C6)- Alkyl, NH2, NH(C1 -C6)- Alkyl, N((C,-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C !-C6)- Alkyl, CONH2.N (heterocycle) -CO-N ((C 1 -C 6 ) alkyl) aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO-N- (aryl) 2 , aryl , O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n = 0-6, where the aryl radical or heterocyclic radical can be monosubstituted to trisubstituted by F, Cl, Br , I, OH, CF 3, NO 2, CN, OCF 3, O- (Ci-C 6) alkyl, (C, -C 6) - alkyl, NH 2, NH (C 1 -C 6) - alkyl , N ((C, -C6) - alkyl) 2, SO 2 -CH 3, COOH, COO- (C 6 -C!) - alkyl, CONH. 2
Die Verbindung(en) der Formel (I) können auch in Kombination mit weiteren Wirkstoff verabreicht werden.The compound (s) of formula (I) may also be administered in combination with other active ingredient.
Die Menge einer Verbindung gemäß Formel I, die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z.B. der ge¬ wählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg und 50 mg) pro Tag pro Kilogramm Kör- pergewicht, z.B. 3-10 mg/kg/Tag. Eine intravenöse Dosis kann z.B. im Bereich von 0,3 mg bis 1,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. Geeignete Infusionslösungen für diese Zwecke können z.B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z.B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Ampullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisfor¬ mulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Zur Therapie der oben genannten Zustände können die Verbindungen gemäß Formel I selbst als Verbindung verwendet werden, vor¬ zugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muss natürlich verträglich sein, in dem Sinne, dass er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheits- schädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel I. Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesentlichen darin bestehen, dass die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen gemischt werden.The amount of a compound of formula I required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound selected, the intended use, the mode of administration, and the clinical condition of the patient , In general, the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day. For example, an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, for example, from 1 mg to 100 mg, ampoules for injections, and orally administrable single dose formulations, such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the treatment of the above conditions For example, the compounds according to formula I can themselves be used as compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition. The carrier must, of course, be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient's health. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including further compounds of the formula I. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z.B. sublinguale) und parenterale (z.B. subkutane, intramuskuläre, intra¬ dermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabrei¬ chungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel I abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Poylvinylacetatphthalat, Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable administration in each individual case is of the type and The severity of the condition to be treated and the type of compound used in each case according to formula I is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tablet¬ ten, die jeweils eine bestimjnte Menge der Verbindung gemäß Formel I enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wässrigen oder nicht-wässrigen Flüssig¬ keit; oder als eine Öl-in- Wasser- oder Wasser-in-Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfasst, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allge- meinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpresst oder geformt wird, gegebe- nenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepresste Tabletten können durch tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients). In general In other words, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary. For example, a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung ge¬ eignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel I mit einem Ge- schmackssto ff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert Base such as gelatin and glycerin or sucrose and gum arabic.
Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wässrige Zubereitungen einer Verbindung gemäß Formel I, die vor¬ zugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. Diese Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich die Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann. Diese Zubereitungen können vor¬ zugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die er- haltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungsgemäße Zusammensetzungen enthalten im allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can be preferably prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vor¬ zugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel I mit einem oder mehreren herkömmlichen festen Trägern, bei¬ spielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt. Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglykole, Alkohole und Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der Wirkstoff ist im allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%.Suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier. The active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammen¬ setzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wässrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine ge¬ eignete Wirkstoff-Konzentration beträgt ca. 1% bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondere Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder Iontophorese freigesetzt werden.Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be present as individual patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
Als weitere Wirkstoffe für die Kombinationspräparate sind geeignet:As further active ingredients for the combination preparations are suitable:
Alle Antidiabetika, die in der Roten Liste 2004, Kapitel 12 genannt sind. Sie können mit den erfindungsgemäßen Verbindungen der Formel I insbesondere zur synergistischenAll antidiabetic medicines mentioned in the Red List 2004, chapter 12. In particular, they can be synergistic with the compounds of the formula I according to the invention
Wirkungsverbesserung kombiniert werden. Die Verabreichung der Wirkstoffkombination kann entweder durch getrennte Gabe der Wirkstoffe an den Patienten oder in Form von Kombinationspräparaten, worin mehrere Wirkstoffe in einer pharmazeutischen Zubereitung vorliegen, erfolgen. Die meisten der nachfolgend aufgeführten Wirkstoffe sind in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001, offenbart.Impact improvement can be combined. The administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetika umfassen Insulin und Insulinderivate, wie z.B. Lantus® (siehe www.lantus.com) oder HMR 1964, schnell wirkende Insuline (siehe US 6,221,633), GLP-I -Derivate wie z.B. diejenigen die in WO 98/08871 von Novo Nordisk A/S offenbart wurden, sowie oral wirksame hypoglykämische Wirkstoffe.Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US No. 6,221,633), GLP-I derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweise Sulphonylfharnstoffe, Biguanidine, Meglitinide, Oxadiazolidindione, Thiazolidindione, Glukosidase- Inhibitoren, Glukagon- Antagonisten, GLP-1-Agonisten, Kaliumkanalöffher, wie z.B. diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden, Insulin-Sensitizer, Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind, Modulatoren der Glukoseaufhahme, 5 den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe,. Verbindungen, die die Nahrungsmitteleinnahme verringern, PPAR- und PXR-Agonisten und Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal der Betazellen wirken.The orally active hypoglycemic agents preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, Glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, 5 fat metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents. Compounds that reduce food intake, PPAR and PXR agonists and drugs that act on the ATP-dependent potassium channel of beta cells.
10 Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem HMGCoA-Reduktase Inhibitor wie Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Cerivastatin, Rosuvastatin verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
15 Bei einer Ausfuhrungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Cholesterinresorptionsinhibitor, wie z.B. Ezetimibe, Tiqueside, Pamaqueside, oder mit einer Verbindung, wie in PCT/EP 2004/00269, PCT/EP 2003/05815, PCT/EP 2003/05814, PCT/EP 2003/05816, EP 0114531, US 6,498,156 beschrieben, verabreicht.In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, or with a compound as described in PCT / EP 2004/00269, PCT / EP 2003/05815, PCT / EP 2003/05814, PCT / EP 2003/05816, EP 0114531, US Pat. No. 6,498,156.
2020
Bei einer Ausfuhrungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem PPAR gamma Agonist, wie z.B. Rosiglitazon, Pioglitazon, JTT-501, Gl 262570, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
25 Bei einer Ausführungsform der Erfindung werden die Verbindungen deF Formel I in Kombination mit PPAR alpha Agonist, wie z.B. GW 9578, GW 7647, verabreicht.In one embodiment of the invention, the compounds of formula I in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem gemischten PPAR alpha/gamma Agonisten, wie z.B. GW 1536, AVE 30 8042, AVE 8134, AVE 0847, oder wie in PCT/US 2000/11833, PCT/US 2000/11490, DEl 0142734.4 beschrieben verabreicht. Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Fibrat, wie z.B. Fenofibrat, Clofibrat, Bezafibrat, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a mixed PPAR alpha / gamma agonist such as GW 1536, AVE 30 8042, AVE 8134, AVE 0847 or as described in PCT / US 2000/11833, PCT / US 2000/11490, DE10142734.4 described. In one embodiment of the invention, the compounds of formula I are administered in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem MTP-Inhibitor, wie z.B. Implitapide , BMS-201038, R-103757, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit Gallensäureresorptionsinhibitor (siehe z.B. US 6,245,744 oder US 6,221,897), wie z.B. HMR 1741, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with bile acid resorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), e.g. HMR 1741 administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem CETP-Inhibitor, wie z.B. JTT-705 , verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem polymeren Gallensäureadsorber, wie z.B. Cholestyramin, Colesevelam, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem LDL-Rezeptorinducer (siehe US 6,342,512), wie z.B. HMRl 171, HMRl 586, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ACAT-Inhibitor, wie z.B. Avasimibe, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, e.g. Avasimibe, administered.
Bei einer Ausführungsforrn der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Antioxidans, wie z.B. OPC-14117, verabreicht.In one embodiment of the invention, the compounds of formula I are used in combination with an antioxidant, e.g. OPC-14117 administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein-Lipase Inhibitor, wie z.B. NO-1886, verabreicht. Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ATP-Citrat-Lyase Inhibitor, wie z.B. SB-204990, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor such as NO-1886. In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor, such as SB-204990.
Bei einer Ausfuhrungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Squalen Synthetase Inhibitor, wie z.B. BMS-188494, verabreicht.In one embodiment of the invention, the compounds of formula I in combination with a squalene synthetase inhibitor, such as e.g. BMS-188494.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein(a) antagonist, wie z.B. CI- 1027 oder Nicotinsäure, verabreicht.In one embodiment of the invention, the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipase Inhibitor, wie z.B. Orlistat, verabreicht.In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
Bei einer Ausfuhrungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit Insulin verabreicht.In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einemIn one embodiment, the compounds of the formula I are used in combination with a
Sulphonylharnstoff, wie z.B. Tolbutamid, Glibenclamid, Glipizid oder Glimepirid verabreicht.Sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einemIn one embodiment, the compounds of the formula I are used in combination with a
Biguanid, wie z.B. Metformin, verabreicht.Biguanide, e.g. Metformin, administered.
Bei wieder einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Meglitinid, wie z.B. Repaglinid, verabreicht.In yet another embodiment, the compounds of formula I are used in combination with a meglitinide, e.g. Repaglinide, administered.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einemIn one embodiment, the compounds of the formula I are used in combination with a
Thiazolidindion, wie z.B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[[4-Thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, especially 5 - [[4-
[(3,4-Dihydro-3-methyl-4-oxo-2-chinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidindion, verabreicht.[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem α-Glukosidase-Inhibitor, wie z.B. Miglitol oder Acarbose, verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einemIn one embodiment, the compounds of formula I are administered in combination with an α-glucosidase inhibitor, e.g. Miglitol or acarbose, administered. In one embodiment, the compounds of the formula I are used in combination with a
Adenosin Al Agonisten, wie z. B. solchen, die in EP 0912520 oder PCT/EP06749beschrieben sind, verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Wirkstoff verabreicht, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, wie z.B. Tolbutamid, Glibenclamid, Glipizid, Glimepirid oder Repaglinid.Adenosine Al agonists, such as For example, those described in EP 0912520 or PCT / EP06749. In one embodiment, the compounds of formula I are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z.B. in Kombination mit einemIn one embodiment, the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with one
Sulphonylhamstoff und Metformin, einem Sulphonylharnstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulphonylharnstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht.Sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
Bei einer weiteren Ausführungsform werden die Verbindungen der Formel I in Kombination mit CART-Modulatoren (siehe "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolie Research (2001), 33(9), 554-558), NPY-Antagonisten z.B. Naphthalin-1- sulfonsäure-{4-[(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amid Hydrochlorid (CGP 71683A)), MC4-Agonisten (z.B. 1-Amino- 1,2,3, 4-tetrahydro-naphthalin-2- carbonsäure [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5- yl)-l-(4-chlor-phenyl)-2-oxo-ethyl]-amid; (WO 01/91752)) , Orexin-Antagonisten (z.B. l-(2- Methyl-benzoxazol-6-yl)-3-[ 1 ,5]naphthyridin-4-yl-hamstoff Hydrochlorid (SB-334867-A)), H3-Agonisten (3-Cyclohexyl-l-(4,4-dimethyl-l,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)- propan-1-on Oxalsäuresalz (WO 00/63208)); TNF-Agonisten, CRF- Antagonisten (z.B. [2- Methyl-9-(2,4,6-trimethyl-phenyl)-9H-l,3,9-triaza-fluoren-4-yl]-dipropyl-amin (WO 00/66585)), CRF BP- Antagonisten (z.B. Urocortin), Urocortin-Agonisten, /33-Agonisten (z.B. l-(4-Chlor-3-methanesulfonylmethyl-phenyl)-2-[2-(2,3-dimethyl-lH-indol-6-yloxy)- ethylamino]-ethanol Hydrochlorid (WO 01/83451)), CBl (Cannabinoid Rezeptor 1) Rezeptor Antagonisten (zB. Rimonabant oder die in WO 02/28346 genannten Wirkstoffe, MSHIn a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg Naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A)), MC4 agonists (eg 1-amino-1,2,3 , 4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine) 5-yl) -1- (4-chlorophenyl) -2-oxo-ethyl] -amide; (WO 01/91752)), orexin antagonists (eg 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-) tetrahydro-imidazo [4,5-c] pyridin-5-yl) propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (eg, [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, / 33 agonists (eg, 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl -lH-indol-6-yloxy) -ethylamino] -ethanol hydrochloride (WO 01/83451), CBl (cannabinoid receptor 1) receptor antagonists (eg rimonabant or the active substances mentioned in WO 02/28346, MSH
(Melanocyt-stimulierendes Hormon)-Agonisten, CCK-A Agonisten (z.B. {2-[4-(4-Chlor-2,5- dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethyl-indol-l-yl}- essigsäure Trifluoressigsäuresalz (WO 99/15525)), Serotonin- Wiederaufnahme-Inhibitoren (z.B. Dexfenfluramine), gemischte Sertonin- und noradrenerge Verbindungen (z.B. WO 00/71549), 5HT-Agonisten z.B. l-(3-Ethyl-benzofuran-7-yl)-piperazin Oxalsäuresalz (WO 01/09111), Bombesin-Agonisten, Galanin-Antagonisten, Wachstumshormon (z.B. humanes Wachstumshormon), Wachstumshormon freisetzende Verbindungen (6-Benzyloxy-l-(2- diisopropylamino-ethylcarbamoyl)-3,4-dihydro-lH-isochinolin-2-carbonsäuretertiärbutylester (WO 01/85695)), TRH-Agonisten (siehe z.B. EP 0 462 884) entkoppelnde Protein 2- oder 3- Modulatoren, Leptinagonisten (siehe z.B. Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya- Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase-Inhibitoren (z.B. WO 00/40569), PPAR-Modulatoren (z.B. WO 00/78312), RXR-Modulatoren oder TR-j3-Agonisten verabreicht.(Melanocyte-stimulating hormone) agonists, CCK-A agonists (eg {2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl ] -5,7-dimethyl-indol-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (eg dexfenfluramine), mixed sertonine and noradrenergic compounds (eg WO 00/71549), 5HT Agonists, for example, 1- (3-ethylbenzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1 - (2- diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see eg EP 0 462 884) decoupling protein 2- or 3-modulators, leptin agonists (see eg Lee, Daniel W., Leinung, Matthew C; Rozhavskaya Arena, Marina; Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity. Drugs of the Future (2001), 26 (9), 873-881) , DA agonists (bromocriptine, doprexine), lipase / amylase inhibitors (eg, WO 00/40569), PPAR modulators (eg, WO 00/78312), RXR modulators, or TR-j3 agonists.
Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff Leptin; . siehe z.B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.In one embodiment of the invention, the further active ingredient is leptin; , see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
Bei einer Ausführungsform ist der weitere Wirkstoff Dexamphetamin oder Amphetamin. Bei einer Ausführungsform ist der weitere Wirkstoff Fenfluramin oder Dexfenfluramin. Bei noch einer Ausführungsform ist der weitere Wirkstoff Sibutramin. Bei einer Ausführungsform ist der weitere Wirkstoff Orlistat. Bei einer Ausführungsform ist der weitere Wirkstoff Mazindol oder Phentermin.In one embodiment, the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine.
Bei einer weiteren Ausführungsform ist der weitere Wirkstoff Rimonabant.In another embodiment, the other active ingredient is rimonabant.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit Ballaststoffen, vorzugsweise unlöslichen Ballaststoffen (siehe z.B. Carob/ Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax ist ein Carob enthaltendes Produkt der Fa. Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) verabreicht. Die Kombination mit Caromax® kann in einer Zubereitung erfolgen, oder durch getrennte Gabe von Verbindungen der Formel I und Caromax®. Caromax® kann dabei auch in Form von Lebensmitteln, wie z.B. in Backwaren oder Müsliriegeln, verabreicht werden. Es versteht sich, dass jede geeignete Kombination der erfindungsgemäßen Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird. In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6.) Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) administered. Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®. Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars. It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.
JTT-501 Die Verbindungen der Formel I lassen sich dadurch herstellen, dass man geeignete Ausgangsstoffe der Formel II, worin Rl, R2 und R3 die oben angegebene Bedeutung besitzen und X eine Austrittsgruppe, wie Chlor, Brom, Jod, Sulfonyloxid, Sulfinyl, Sulfoxyl, bedeutet, mit einer Verbindung der Formel V ggf. in Gegenwart von geeigneten Basen zu den Verbindungen der Formel FV umsetzt, wobei X für eine geeignete Austrittsgruppe wie beispielsweise Chlor, Brom, Jod, Sulfonyloxi, Sulfinyl oder, Sulfoxyl steht. Alternativ setzt man Verbindungen der Formel III, worin Rl, R2 und R3 die oben angegebene Bedeutung besitzen, mit Alkylierungsmittel der Formel VI zu den Verbindungen der Formel FV um, wobei X für eine geeignete Austrittsgruppe wie beispielsweise Chlor, Brom, Jod, Sulfonyloxi, Sulfinyl oder, Sulfoxyl steht.JTT-501 The compounds of the formula I can be prepared by suitable starting materials of the formula II in which R 1, R 2 and R 3 have the abovementioned meaning and X is a leaving group such as chlorine, bromine, iodine, sulfonyloxide, sulfinyl, sulfoxyl, with a compound of formula V optionally in the presence of suitable bases to the compounds of formula FV, wherein X is a suitable leaving group such as chlorine, bromine, iodine, Sulfonyloxi, sulfinyl or sulfoxyl. Alternatively, compounds of formula III in which R1, R2 and R3 are as defined above, with alkylating agent of formula VI to the compounds of formula FV, wherein X is a suitable leaving group such as chlorine, bromine, iodine, sulfonyloxy, sulfinyl or, sulfoxyl.
In den Fällen, wo R4 oder R5 Wasserstoff bedeutet, kann es zweckmäßig sein, den Rest - NR4R5 in an der Stickstofffunktion geschützter Form einzusetzen und die Schutzgruppe an geeigneter Stelle der Reaktion wieder abzuspalten. Solche geeignete Schutzgruppen und die Verfahren der Einführung und Abspaltung sind bekannt (Siehe:Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., New York, 1999 )In cases where R4 or R5 is hydrogen, it may be appropriate to use the radical - NR4R5 protected in the nitrogen function form and to split off the protective group at a suitable point of the reaction again. Such suitable protecting groups and the methods of introduction and cleavage are known (See: Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., New York, 1999)
Die Thioetherfunktion in IV kann dann nach bekannten Methoden oxidiert werden zu den erfindungsgemäßen Stoffen der Formel I, worin n eine Zahl 1 oder 2 bedeutet. Die Halogenverbindungen der Formel II können nach bekannten Verfahren wie beispielsweise durch Halogenierung der entsprechenden H-oder OH- Verbindung (Formel 2, X = H, OH) erhalten werden. Geeignete Halogenierungsmittel können beispielhaft Halogene, wie Chlor und Brom, N-Bromsuccinimid, Phosphorpentoxid oder Phosphoroxichlorid sein. Die Verbindungen der Formel III können durch Umsetzung der Halogenverbindungen der Formel II mit geeigneten Reagentien wie beispielsweise Schwefelwasserstoff oder Thiohamstoff nach bekanntenMethoden erhalten werden.The thioether function in IV can then be oxidized by known methods to the substances of the formula I according to the invention, wherein n is a number 1 or 2. The halogen compounds of the formula II can be obtained by known processes, for example by halogenation of the corresponding H or OH compound (formula 2, X =H, OH). Suitable halogenating agents may be, for example, halogens, such as chlorine and bromine, N-bromosuccinimide, phosphorus pentoxide or phosphorus oxychloride. The compounds of formula III can be obtained by reaction of the halogen compounds of formula II with suitable reagents such as hydrogen sulfide or thiourea by known methods.
Die Synthese von Verbindungen der Formel II und Illist mehrfach in der Literatur beschrieben (siehe Houben Weyl E9b/2, S. 331 ff). Sie können beispielsweise ausgehend von Diaminopyrimidinderivaten oder Aminoimidazolcarbonsäureamiden durch Umsetzung mit geeigneten Reagentien erhalten und durch gezielte chemische Modifikationen wie Hydrolyse, Alkylierung, Halogenierung in die gewünschten Ausgangsverbindungen der Formel II oder III umgewandelt werden.The synthesis of compounds of the formula II and IIIb has been described several times in the literature (see Houben Weyl E9b / 2, p. 331 ff). They can be obtained, for example, starting from Diaminopyrimidinderivaten or Aminoimidazolcarbonsäureamiden by reaction with suitable reagents and converted by targeted chemical modifications such as hydrolysis, alkylation, halogenation in the desired starting compounds of formula II or III.
Die Reste Rl bis R3 lassen sich nach an sich bekannten Methoden durch Alkylierung entsprechender Vorstufen herstellen, wobei die Reihenfolge variiert werden kann. Zum Teil können sie aber auch durch die Auswahl entsprechender Vorstufen bei der Herstellung des Xanthingerüstes eingeführt werden.The radicals R 1 to R 3 can be prepared by methods known per se by alkylating appropriate precursors, the sequence being able to be varied. In some cases, however, they can also be introduced by selecting appropriate precursors in the preparation of the xanthine skeleton.
Die nachfolgend aufgeführten Beispiele dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken. Tabellel:The following examples serve to illustrate the invention, but without limiting it. Sheetl:
OO
Die Verbindungen der Formel I zeichnen sich durch günstige Wirkungen auf den Lipid-und Kohlenhydratstoffwechsel aus, sie senken insbesondere den Blutzuckerspiegel und sind zur Behandlung von Typ 2 Diabetes, von Insulinresistenz, von Dyslipidämien und des metabolischen Syndroms / Syndrom X geeignet. Weiterhin sind die Verbindungen zur Prophylaxe und Behandlung von arteriosklerotischen Erscheinungen geeignet. Die Verbindungen können allein oder in Kombination mit weiteren Blutzucker senkenden Wirkstoffen eingesetzt werden. Die Verbindungen wirken als DPP-IV (Dipeptidyl Peptidase IV) Inhibitoren und eignen sich auch zur Behandlung von Störungen des Empfindens und anderer psychiatrischen Indikationen, wie zum Beispiel Depressionen, Angstzuständen, Angstneurosen, Schizophrenie sowie zur Behandlung von Störungen assoziiert mit dem zirkadianen Rhythmus, zur Gewichtsreduktion bei Säugetieren, zur Behandlung von Immunstörungen, und zur Behandlung von Drogenmissbrauch.The compounds of the formula I have favorable effects on the lipid and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidaemias and the metabolic syndrome / syndrome X. Furthermore, the compounds are suitable for the prophylaxis and treatment of arteriosclerotic phenomena. The compounds may be used alone or in combination with other blood sugar lowering agents. The compounds act as DPP-IV (dipeptidyl peptidase IV) inhibitors and are also useful in the treatment of disorders of sensation and other psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia, and the treatment of disorders associated with the circadian rhythm Weight reduction in mammals, for the treatment of immune disorders, and for the treatment of substance abuse.
Weiterhin eignen sie sich zur Behandlung von Krebs, Arthritis, Osteoarthritis, Osteoporose, Schlafstörungen, Schlaf Apnoe, weiblicher und männlicher Sexualstörungen, Entzündungen, Akne, Pigmentierung der Haut, Störungen des Steroidstoffwechsels, Hautkrankheiten, Psoriasis, Mykosen, neurodegenerativer Krankheiten, Multiple Sklerose und Alzheimer- Krankheit.They are also useful in the treatment of cancer, arthritis, osteoarthritis, osteoporosis, sleep disorders, sleep apnea, female and male sexual disorders, inflammation, acne, skin pigmentation, steroid metabolism disorders, skin diseases, psoriasis, mycoses, neurodegenerative diseases, multiple sclerosis and Alzheimer's disease - Illness.
Die Wirksamkeit der Verbindungen wurde wie folgt getestet:The effectiveness of the compounds was tested as follows:
Messung der DPP-IV Aktivität:Measurement of DPP-IV activity:
Material:Material:
DPP-FV aus Schweineniere (Sigma, München)DPP-FV from pig kidney (Sigma, Munich)
H-Ala-Pro-AFC (Bachern, Weil am Rhein)H-Ala-Pro-AFC (Bachern, Weil am Rhein)
Testbedingungen:Test conditions:
DPP-IV (1 mU/ml, Endkonzentratio)DPP-IV (1 mU / ml, final concentration)
H-Ala-Pro-AFC (15μM Endkonzentration) in Tris/HCl (40 mM, pH 7.4), Gesamtvolumen 0,2 ml Die Reaktion wurde bei Raumtemperatur für unterschiedliche Zeiträume (typischerweise 10 min) durchgeführt und am Ende der Reaktion durch Zugabe von 20μl ZnCl2 (1 M) gestoppt . Der Umsatz von H-Ala-Pro-AFCwurde fluorimetrisch durch Messung der Emission bei 5 535nm nach Anregung bei 405 nm bestimmt. Im Falle der Zugabe von Inhibitoren wurde das zugegebene Puffervolumen so angepasst, dass ein Gesamtvolumen der Testmischung von 200μl eingehalten wurde.H-Ala-Pro-AFC (15 μM final concentration) in Tris / HCl (40 mM, pH 7.4), total volume 0.2 ml The reaction was carried out at room temperature for various periods of time (typically 10 minutes) and stopped at the end of the reaction by addition of 20 μl of ZnCl 2 (1 M). The conversion of H-Ala-Pro-AFC was determined fluorimetrically by measuring the emission at 5,535 nm after excitation at 405 nm. In the case of addition of inhibitors, the added buffer volume was adjusted so that a total volume of the test mixture of 200 μl was maintained.
IC50 Werte für Inhibitoren wurden durch Variation der Inhibitorkonzentrationen bei der angegebenen Substratkonzentration von 15μM bestimmt. Ki und Km Werte wurden durch 0 enstsprechende Variation von Substrat- und Inhibitorkonzentration wie beschrieben (Dixon, M. and Webb, E.C.(1979) Enzymes , third edition, pp. 47-206, Academic Press) ermittelt. Die Werte für Km, IC50 and Ki wurden mit einem kommerziell erhältlichen Software-Paket errechnet ( Leatherbarrow, RJ. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, U.K.). 5IC50 values for inhibitors were determined by varying the inhibitor concentrations at the stated substrate concentration of 15 μM. Ki and Km values were determined by corresponding substrate and inhibitor concentration variation as described (Dixon, M. and Webb, E.C. (1979) Enzymes, third edition, pp. 47-206, Academic Press). The Km, IC50 and Ki values were calculated using a commercially available software package (Leatherbarrow, RJ. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, U.K.). 5
Tabelle 2: Biologische AktivitätTable 2: Biological activity
Aus der Tabelle ist abzulesen, dass die Verbindungen der Formel I die Aktivität der DPP-IV (Dipeptidyl Peptidase IV) hemmen und dadurch zur Senkung des Blutzuckerspiegels gut geeignet sind.From the table it can be seen that the compounds of the formula I inhibit the activity of DPP-IV (dipeptidyl peptidase IV) and are therefore well suited for lowering the blood sugar level.
Nachfolgend wird die Herstellung einiger Beispiele detailliert beschrieben, die übrigen Verbindungen der Formel I wurden analog erhalten:The preparation of some examples is described in detail below, the remaining compounds of the formula I were obtained analogously:
Beispiel 1example 1
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion8- (2-amino-1, 1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3, 7-dihydro-purine-2,6-dione
Die Mischung aus 80 mg 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-The mixture of 80 mg 8-bromo-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -
3,7-dihydro-purin-2,6-dion, 53 mg l-Amino-2-methyl-2-propanthiol-hydrochlorid, 2 ml DMF und 77 μl Triethylamin wurde 6 Stunden bei 80°C gerührt.3,7-Dihydro-purine-2,6-dione, 53 mg of 1-amino-2-methyl-2-propanethiol hydrochloride, 2 ml of DMF and 77 μl of triethylamine were stirred at 80 ° C. for 6 hours.
Nach dem Einengen wurde der ölige Rückstand säulenchromatografisch (Kieselgel, Laufmittel:After concentration, the oily residue was purified by column chromatography (silica gel, mobile phase:
Methylenchlorid: Methanol = 9:1) gereinigt. Ausbeute: 25 mg Fp.: Öl MS: M+l = 456Methylene chloride: methanol = 9: 1). Yield: 25 mg mp: oil MS: M + l = 456
Analog wurden hergestellt:Analog were produced:
Beispiel 2 8-(2-Amino-ethylsulfanyl)-l-ethyl-3-methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purine-2,6- dion Fp.: Öl MS: M+l = 338Example 2 8- (2-Amino-ethylsulfanyl) -l-ethyl-3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro-purene-2,6-dione M.p .: Oil MS: M + l = 338
Beispiel 3Example 3
8-(2-Amino-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion Fp.: Harz MS: M+l = 428 Beispiel 48- (2-aminoethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine 2,6-dione mp: resin MS: M + l = 428 Example 4
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid8- (2-amino-1, 1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3, 7-dihydro-purine-2,6-dione hydrochloride
5 100 mg von 8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2- oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion wurden in 2 ml Essigester gelöst und mit überschüssiger Lösung von Chlorwasserstoff in Essigester behandelt. Nach dem Einengen unter Vakuum bei Raumtemperatur wurde der Rückstand mit 5 ml Diisopropylether verrührt und das Produkt abgesaugt und im Vakuum getrocknet. 0 Ausbeute: 96 mg Fp.: MS: M+l = 4565 100 mg of 8- (2-amino-1,1'-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl ) -3,7-dihydro-purine-2,6-dione were dissolved in 2 ml of ethyl acetate and treated with excess solution of hydrogen chloride in ethyl acetate. After concentration under vacuum at room temperature, the residue was stirred with 5 ml of diisopropyl ether and the product was filtered off with suction and dried in vacuo. 0 Yield: 96 mg M.p .: MS: M + l = 456
Beispiel 5Example 5
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-8- (2-amino-1, 1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro-purine
2,6-dion 5 Die Mischung aus 80 mg 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-3,7-dmydro-purin-2,6- dion, 90 mg l-Amino-2-methyl-2-propanthiol-hydrochlorid, 2 ml DMF und 200mg2,6-dione 5 The mixture of 80 mg 8-bromo-3-methyl-7- (3-methyl-but-2-enyl) -3,7-dmydropurine-2,6-dione, 90 mg 1 -Amino-2-methyl-2-propanethiol hydrochloride, 2 ml of DMF and 200 mg
Cäsiumcarbonat wurde 5 Stunden bei 70°C gerührt.Cesium carbonate was stirred at 70 ° C for 5 hours.
Nach dem Einengen wurde der ölige Rückstand säulenchromatografisch (Kieselgel, Laufmittel:After concentration, the oily residue was purified by column chromatography (silica gel, mobile phase:
Methylenchlorid: Methanol = 9:1) gereinigt. 0 Ausbeute: 85 mg Fp.: Öl MS: M+l = 338Methylene chloride: methanol = 9: 1). 0 Yield: 85 mg Mp: oil MS: M + l = 338
Beispiel 6Example 6
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-[2-(l,l,2,3,3,3-hexafluor-propoxy)-ethyl]-3- methyl- 7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid 5 wurde analog ausgehend von 8-Brom-l-[2-(l,l,2,3,3,3-hexafluor-propoxy)-ethyl]-3-methyl-7- (3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion erhalten und durch Umsetzen mit einer Lösung von Chlorwasserstoff in Essigester ins Hydrochlorid überführt. Fp.: MS: M+l = 5328- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- [2- (1,1,2,3,3,3-hexafluoro-propoxy) -ethyl] -3-methyl-7- (3 -methyl-but-2-enyl) -3,7-dihydro-purine-2,6-dione hydrochloride 5 was prepared analogously from 8-bromo-1- [2- (1, 1, 2, 3, 3, 3-hexafluoro-propoxy) -ethyl] -3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro-purine-2,6-dione and by reacting with a solution of hydrogen chloride converted into hydrochloride in ethyl acetate. Mp: MS: M + l = 532
0 Beispiel 70 Example 7
3-Methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-8-[2-(l,7,7-trimethyl- bicyclo[2.2.1]hept-2-ylamino)-ethylsulfanyl]-3,7-dihydro-purin-2,6-dion-hydrochlorid wurde analog ausgehend von 2-(l,7,7-Trimethyl-bicyclo[2.2.1]hept-2-ylamino)-ethanethiol- hydrochlorid in Gegenwart von Cäsiumcarbonat und abschließender Behandlung mit Chlorwasserstoff erhalten. Fp.: MS: M+l = 5643-Methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -8- [2- (1,7,7-trimethyl-bicyclo [2.2. 1] hept-2-ylamino) -ethylsulfanyl] -3,7-dihydro-purine-2,6-dione hydrochloride was obtained analogously from 2- (l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylamino) -ethanethiol hydrochloride in the presence of cesium carbonate and subsequent treatment with hydrogen chloride. Mp: MS: M + l = 564
55
Beispiel 8Example 8
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -(4-fluor-benzyl)-3-methyl-7-(3-methyl-but-2- enyl)- 3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 4468- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1- (4-fluoro-benzyl) -3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro- purine-2,6-dione hydrochloride MS: M + 1 = 446
10 Beispiel 910 Example 9
2-[8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo- 2,3,6,7-tetrahydro-purin-l-yl]-N-(4-chlor-phenyl)-acetamid-hydrochlorid MS: M+l =5052- [8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -2,6-dioxo-2,3,6,7 tetrahydro-purin-1-yl] -N- (4-chloro-phenyl) -acetamide hydrochloride MS: M + l = 505
Beispiel 10Example 10
15 8-(2-Amino-2-methyl-propylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 45615 8- (2-Amino-2-methyl-propylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7 dihydro-purine-2,6-dione MS: M + 1 = 456
a) 8-Mercapto-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purin- 2,6-diona) 8-mercapto-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine 2,6- dion
20 50 mg 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purin- 2,6-dion wurden in 1 ml Dimethylformamid gelöst, mit 24 mg L-Cysteinmethylester- hydrochlorid und 37 mg Pottasche versetzt und die Mischung unter Umrühren 1 Stunde auf 9O0C erhitzt. Nach dem Erkalten auf Raumtemperatur wurde mit 10 ml Wasser verstzt und mit Eisessig schwach sauer gestellt. Beim Verrühren fiel ein Niederschlag aus, der abfiltriert und20 50 mg of 8-bromo-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine-2,6 Dione were dissolved in 1 ml of dimethylformamide, treated with 24 mg of L-Cysteinmethylester- hydrochloride and 37 mg of potash and the mixture with stirring for 1 hour at 9O 0 C heated. After cooling to room temperature was quenched with 10 ml of water and made slightly acidic with glacial acetic acid. On stirring, a precipitate fell out, which was filtered off and
25 im Vakuum getrocknet wurde.25 was dried in vacuo.
Ausbeute: 40 mg Fp.: 182,7°C MS: M+l = 385Yield: 40 mg mp: 182.7 ° C MS: M + l = 385
b) 8-(2-Amino-2-methyl-propylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dionb) 8- (2-amino-2-methyl-propylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3, 7-dihydro-purine-2,6-dione
30 30 mg 8-Mercapto-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro- purin- 2,6-dion wurden in 2 ml Dimethylformamid vorgelegt, mit 37 mg Pottasche versetzt und 15 Minuten gerührt. Dann wurden 13,5 mg Schwefelsäure-mono-(2-amino-2-methyl-propyl)- ester zugefügt und 29 Stunden bei 80°C gerührt. Die flüchtigen Anteile wurden im Vakuum bei 40°C entfernt und der Rückstand säulenchromatografisch (Kieselgel, Laufmittel: Methylenchlorid: Methanol = 95:5) gereinigt. Ausbeute: 12 mg Fp.: Harz MS: M+l = 45630 30 mg of 8-mercapto-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine-2,6 Dione were initially charged in 2 ml of dimethylformamide, mixed with 37 mg of potash and stirred for 15 minutes. Then 13.5 mg of sulfuric acid mono- (2-amino-2-methyl-propyl) - ester and stirred at 80 ° C for 29 hours. The volatiles were removed in vacuo at 40 ° C and the residue purified by column chromatography (silica gel, eluent: methylene chloride: methanol = 95: 5). Yield: 12 mg mp: resin MS: M + l = 456
Beispiel 11Example 11
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-l-(2-oxo-2-ρhenyl-ethyl)-7-(3,3,3- trifluor- propyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 4848- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-1- (2-oxo-2-phenyl-ethyl) -7- (3,3,3-trifluoropropyl) -3, 7-dihydro-purine-2,6-dione hydrochloride MS: M + l = 484
Beispiel 12Example 12
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-(5-cyclopropyl-[l,3,4]thiadiazol-2-ylmethyl)-3- methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4768- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- (5-cyclopropyl- [l, 3,4] thiadiazol-2-ylmethyl) -3-methyl-7- (3-methyl-butanol) 2-enyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 476
Beispiel 13 8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-l57-bis-(3,3,3-trifluor-propyl)-3,7- dihydro- purin-2,6-dion-hydrochlorid MS: M+l = 462Example 13 8- (2-amino-l, l-dimethyl-ethylsulfanyl) -3-methyl-l 7 5-bis- (3,3,3-trifluoro-propyl) -3,7-dihydro-purine-2, 6-dione hydrochloride MS: M + 1 = 462
Beispiel 14Example 14
8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -cyclohexylmethyl-3-methyl-7-(3,3,3-trifluor- propyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 4628- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1-cyclohexylmethyl-3-methyl-7- (3,3,3-trifluoropropyl) -3,7-dihydro-purine-2,6- dione hydrochloride MS: M + 1 = 462
Beispiel 15Example 15
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-[3-(4-chlor-ρhenyl)-allyl]-3-methyl-7-(3,3,3- trifluor-propyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 5168- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- [3- (4-chloro-phenyl) -allyl] -3-methyl-7- (3,3,3-trifluoro-propyl) - 3,7-dihydro-purine-2,6-dione hydrochloride MS: M + 1 = 516
Beispiel 16Example 16
8-(2-Amino-l,l-dimethyl-eithylsulfanyl)-l-(4-fluor-benzyl)-3-methyl-7-(3,3,3-trifluor- propyl)- 3,7-dihydro-purin-2,6-dion-hydrochlorid MSW: M+l = 4748- (2-amino-l, l-dimethyl-e i thylsulfanyl) -l- (4-fluoro-benzyl) -3-methyl-7- (3,3,3-trifluoro-propyl) - 3,7- dihydro-purine-2,6-dione hydrochloride MSW: M + 1 = 474
Beispiel 17Example 17
2-Amino-3-[3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo-l-(2-oxo-2-phenyl-ethyl)-2,3,6,7- tetrahydro-lH-purin-8-ylsulfanyl]-propionsäure-methylester-hydrochlorid MS: M+l = 486 Beispiel 182-Amino-3- [3-methyl-7- (3-methyl-but-2-enyl) -2,6-dioxo-l- (2-oxo-2-phenyl-ethyl) -2,3,6 , 7-tetrahydro-lH-purin-8-ylsulfanyl] -propionic acid methyl ester hydrochloride MS: M + l = 486 Example 18
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(3-chlor-3-methyl-butyl)- 1 -(5-fluor- benzothiazol-2- ylmethyl)-3-methyl-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 5398- (2-amino-1, 1-dimethyl-ethylsulfanyl) -7- (3-chloro-3-methylbutyl) -1- (5-fluoro-benzothiazol-2-ylmethyl) -3-methyl-3, 7-dihydro-purine-2,6-dione hydrochloride MS: M + 1 = 539
Beispiel 19Example 19
8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -(5 -fluor-benzothiazol-2-ylmethyl)-3 -methyl-7-(3 - methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l : 5038- (2-amino-1,1-dimethyl-ethylsulfanyl) -1- (5-fluorobenzothiazol-2-ylmethyl) -3-methyl-7- (3-methyl-but-2-enyl) -3, 7-dihydro-purine-2,6-dione MS: M + 1: 503
Beispiel 20Example 20
3-Methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-8-(pyrrolidin-2- ylmethylsulfanyl)- 3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 4683-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -8- (pyrrolidin-2-ylmethylsulfanyl) -3,7-dihydro-purine 2,6-dione hydrochloride MS: M + l = 468
Beispiel 21 8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(5-methyl- isoxazol-3-ylmethyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 433Example 21 8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (5-methyl-isoxazol-3-ylmethyl) - 3,7-Dihydro-purine-2,6-dione hydrochloride MS: M + 1 = 433
Beispiel 22Example 22
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2,2,2- trifluor- ethyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 4208- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2,2,2-trifluoroethyl) -3, 7-Dihydro-purine-2,6-dione hydrochloride MS: M + 1 = 420
Beispiel 23Example 23
8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-ethyl-7-(3 -methyl-but-2-enyl)- 1 -(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4708- (2-amino-1,1-dimethyl-ethylsulfanyl) -3-ethyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3, 7-dihydro-purine-2,6-dione MS: M + 1 = 470
Beispiel 24Example 24
8-(2- Amino- l,l-dimethyl-e>thylsulfanyl)-3-cyclopropyl-7-(3-methyl-but-2-enyl)-l -(2-0X0-2- ρhenyl-ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4828- (2- amino-l, l-dimethyl-e> thylsulfanyl) -3-cyclopropyl-7- (3-methyl-but-2-enyl) -l - (2-0X0-2- ρhenyl-ethyl) - 3,7-dihydro-purine-2,6-dione MS: M + 1 = 482
Beispiel 25Example 25
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-cyclopropyl-7-(3-methyl-but-2-enyl)-l-phenethyl- 3,7-dihydro-purin-2,6-dion MS: M+l = 468 Beispiel 268- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-cyclopropyl-7- (3-methyl-but-2-enyl) -l-phenethyl-3,7-dihydro-purine-2,6- dion MS: M + l = 468 Example 26
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-7-but-2-ynyl-3-methyl-l-(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion MS: M+l = 4408- (2-Amino-1,1-dimethyl-ethylsulfanyl) -7-but-2-ynyl-3-methyl-1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine 2,6-dione MS: M + 1 = 440
Beispiel 27Example 27
8-(2-Amino-l , 1 -dimethyl-ethylsulfanyl)-7-but-2-ynyl- 1 -(3,3-dimethyl-2-oxo-butyl)-3-methyl- 3,7-dihydro-purin-2,6-dion MS: M+l = 4208- (2-Amino-1,1-dimethyl-ethylsulfanyl) -7-but-2-ynyl-1- (3,3-dimethyl-2-oxo-butyl) -3-methyl-3,7-dihydro- purine-2,6-dione MS: M + 1 = 420
Beispiel 28Example 28
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-ethyl- 1 -(3-hydroxy-3-methyl-butyl)-7-(3-methyl- but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4388- (2-amino-1, 1-dimethyl-ethylsulfanyl) -3-ethyl-1- (3-hydroxy-3-methyl-butyl) -7- (3-methyl-but-2-enyl) -3, 7-dihydro-purine-2,6-dione MS: M + 1 = 438
Beispiel 29 8-(2-Amino-ethanesulfinyl)-3-methyl-7-(3-methyl-but-2-enyl)-l -(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion MS: M+l = 444Example 29 8- (2-Amino-ethanesulfinyl) -3-methyl-7- (3-methyl-but-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro- purine-2,6-dione MS: M + 1 = 444
Beispiel 30 8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2-chlor-4-fluor-benzyl)- 1 ,3-dimethyl-3 ,7- dihydro- purin-2,6-dion MS: M+l = 426Example 30 8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (2-chloro-4-fluoro-benzyl) -1,3-dimethyl-3,7-dihydro-purine-2,6- dion MS: M + 1 = 426
Beispiel 31Example 31
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 ,3-dimethyl-7-(2-oxo-2-phenyl-ethyl)-3,7-dihydro- purin-2,6-dion MS: M+l = 4028- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1,3-dimethyl-7- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine-2,6-dione MS : M + 1 = 402
Beispiel 32Example 32
8-(2-Amino-l , 1 -dimethyl-ethylsulfanyl)- 1 -(I -benzyl- 1 H-imidazol-2-ylmethyl)-3-methyl-7- (3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 5088- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- (1-benzyl-1H-imidazol-2-ylmethyl) -3-methyl-7- (3-methyl-but-2-enyl) 3,7-dihydro-purine-2,6-dione MS: M + 1 = 508
Beispiel 33 8-(l -Aminomethyl-cyclohexylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 496Example 33 8- (1-Aminomethylcyclohexylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine 2,6-dione MS: M + 1 = 496
70 mg (0.162 mmol) 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)- 3,7-dihydro-purin-2,6- dion wurden mit 57.3 mg (0.243 mmol) 1-Aminomethyl- cyclohexanthiol Hydrochlorid (hergestellt nach F. I. Carroll et al., J. Org. Chem 28, 1240- 1243 (1963) oder alternativ nach B. Roy et al., J. Org. Chem. 59, 7019-7026 (1994)) in 1 ml Dimethylformamid suspendiert, mit 158.6 mg (0.487 mmol) Cäsiumcarbonat versetzt und 6 h bei 7O0C gerührt. Danach wurde die Reaktionsmischung im Vakuum eingeengt, in Wasser/ Acetonitril gelöst und chromatographisch (Abimed; Purospher STAR RPl 8e, 10 μ; [Acetonitril : (Wasser + 0.05% Trifluoressigsäure) = 5:95 (0 min) nach 95:5 (40 min)]) gereinigt. Man erhielt 59 mg 8-(l-Aminomethyl-cyclohexylsulfanyl)-3-methyl-7-(3-methyl- but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purin-2,6-dion. HPLC/MS [(Acetonitril + 0.05% Trifluoressigsäure) : (Wasser + 0.05% Trifluoressigsäure) = 5:95 (0 min) nach 95:5 (3 min)]: 496.24 (MH+), RT = 1.55 min.70 mg (0.162 mmol) of 8-bromo-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro-purine 2,6-dione was treated with 57.3 mg (0.243 mmol) of 1-aminomethylcyclohexanethiol hydrochloride (prepared according to FI Carroll et al., J. Org. Chem 28, 1240-1243 (1963) or alternatively according to B. Roy et al. , J. Org. Chem. 59, 7019-7026 (1994)) in 1 ml of dimethylformamide, mixed with 158.6 mg (0.487 mmol) of cesium carbonate and stirred at 7O 0 C for 6 h. The reaction mixture was then concentrated in vacuo, dissolved in water / acetonitrile and chromatographed (Abimed; Purospheric STAR RPl 8e, 10 μ; [acetonitrile: (water + 0.05% trifluoroacetic acid) = 5:95 (0 min) at 95: 5 (40 min)]). 59 mg of 8- (1-aminomethylcyclohexylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7- dihydro-purine-2,6-dione. HPLC / MS [(acetonitrile + 0.05% trifluoroacetic acid): (water + 0.05% trifluoroacetic acid) = 5:95 (0 min) at 95: 5 (3 min)]: 496.24 (MH + ), rt = 1.55 min.
Beispiel 34Example 34
2-[8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 ,3-dimethyl-2,6-dioxo- 1 ,2,3,6-tetrahydro-purin- 7- ylmethyl]-benzonitril MS: M+l = 3992- [8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl] -benzonitrile MS : M + l = 399
Beispiel 35Example 35
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l,3-dimethyl-7-(3-phenyl-allyl)-3,7-dihydro-purine- 2,6-dion MS: M+l = 4008- (2-Amino-1,1-dimethyl-ethylsulfanyl) -l, 3-dimethyl-7- (3-phenyl-allyl) -3,7-dihydro-purine-2,6-dione MS: M + l = 400
Beispiel 36Example 36
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(3-methyl-but-2-enyl)- 1 -(2-oxo-2-phenyl-ethyl)-3- (2,2,2-trifluor-ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 5248- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (3-methyl-but-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3- (2,2 , 2-trifluoro-ethyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 524
Beispiel 37 8-(l-Aminomethyl-cyclohexylsulfanyl)-l-[2-(4-chlor-benzenesulfonyl)-ethyl]-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 580 Beispiel 38Example 37 8- (1-Aminomethylcyclohexylsulfanyl) -1- [2- (4-chlorobenzenesulfonyl) ethyl] -3-methyl-7- (3-methyl-but-2-enyl) -3,7- dihydro-purine-2,6-dione trifluoroacetate MS: M + 1 = 580 Example 38
(S)-8-(l-Aminomethyl-cyclohexylsulfanyl)-l-(2-fluor-2-phenyl-ethyl)-3-methyl-7-(3-methyl- but- 2-enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 580(S) -8- (1-aminomethylcyclohexylsulfanyl) -1- (2-fluoro-2-phenyl-ethyl) -3-methyl-7- (3-methyl-but-2-enyl) -3,7- dihydro-purine-2,6-dione trifluoroacetate MS: M + 1 = 580
Beispiel 39Example 39
8-(2-Amino-l , 1 -dimethyl-ethylsulfanyl)-7-but-2-ynyl-l -(2-oxo-2-phenyl-ethyl)-3-(2,2,2- trifluor-ethyl)-3,7-dihydro-purin-2,6-dion-hydrochlorid MS: M+l = 5088- (2-Amino-1,1-dimethyl-ethylsulfanyl) -7-but-2-ynyl-1- (2-oxo-2-phenyl-ethyl) -3- (2,2,2-trifluoro-ethyl ) -3,7-dihydro-purine-2,6-dione hydrochloride MS: M + 1 = 508
Beispiel 40 8-(l-Aminomethyl-cyclohexylsulfanyl)-l-[2-(4-chlor-phenylmethanesulfonyl)-ethyl]-3- methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 594Example 40 8- (1-Aminomethylcyclohexylsulfanyl) -1- [2- (4-chloro-phenylmethanesulfonyl) -ethyl] -3-methyl-7- (3-methyl-but-2-enyl) -3,7- dihydro-purine-2,6-dione trifluoroacetate MS: M + 1 = 594
Beispiel 41Example 41
8-( 1 - Aminomethyl-cyclohexylsulfanyl)-7-benzyl-3 -methyl- 1 -(2-oxo-2-phenyl-ethyl)-3 ,7- dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5188- (1-Aminomethylcyclohexylsulfanyl) -7-benzyl-3-methyl-1- (2-oxo-2-phenylethyl) -3, 7-dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 518
Beispiel 42Example 42
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -[2-(2-chlor-phenyl)-2-oxo-ethyl]-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4908- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1- [2- (2-chloro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-but-2 -nyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 490
Beispiel 43Example 43
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -[2-(3-chlor-phenyl)-2-oxo-ethyl]-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4908- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -1- [2- (3-chloro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methyl-but-2 -nyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 490
Beispiel 44Example 44
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-[2-(4-chlor-phenyl)-2-oxo-ethyl]-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4908- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- [2- (4-chloro-phenyl) -2-oxo-ethyl] -3-methyl-7- (3-methylbut-2-yl) -nyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 490
Beispiel 45 8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-methyl-3-oxo- 3-phenyl-propyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 484 Beispiel 46Example 45 8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-methyl-3-oxo-3-phenyl -propyl) -3,7-dihydro-purine-2,6-dione MS: M + l = 484 Example 46
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-[2-(4-fluor-benzyl)-2H-tetrazol-5-ylmethyl]-3- methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 5288- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- [2- (4-fluoro-benzyl) -2H-tetrazol-5-ylmethyl] -3-methyl-7- (3-methyl-but -2-enyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 528
Beispiel 47Example 47
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)- 1 -[ 1 -(4-fluor-benzyl)- 1 H-tetrazol-5-ylmethyl]-3- methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 5288- (2-Amino-1, 1-dimethylethylsulfanyl) -1- [1- (4-fluoro-benzyl) -1 H -tetrazol-5-ylmethyl] -3-methyl-7- (3-methyl- but-2-enyl) -3,7-dihydro-purine-2,6-dione MS: M + 1 = 528
Beispiel 48 8-(l-Aminomethyl-cyclohexylsulfanyl)-l-benzthiazol-2-ylmethyl-7-benzyl-3-methyl-3,7- dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 547Example 48 8- (1-aminomethylcyclohexylsulfanyl) -1-benzthiazol-2-ylmethyl-7-benzyl-3-methyl-3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + 1 = 547
Beispiel 49Example 49
8-(l-Aminomethyl-cyclohexylsulfanyl)-7-benzyl-3-methyl-l-(5-nitro-benzoxazol-2-ylinethyl)- 3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5768- (1-aminomethylcyclohexylsulfanyl) -7-benzyl-3-methyl-1- (5-nitro-benzoxazol-2-ylin-ethyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 576
Beispiel 50Example 50
8-(l-Aminomethyl-cyclohexylsulfanyl)-7-benzyl-l-(5-chlor-benzooxazol-2-ylmethyl)-3- methyl-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5658- (1-aminomethylcyclohexylsulfanyl) -7-benzyl-1- (5-chloro-benzoxazol-2-ylmethyl) -3-methyl-3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 565
Beispiel 51Example 51
8-(l-Aminomethyl-cyclohexylsulfanyl)-l-benzothiazol-2-ylmethyl-3-methyl-7-(3-methyl-but-8- (l-Aminomethyl-cyclohexylsulfanyl) -l-benzothiazol-2-ylmethyl-3-methyl-7- (3-methyl-but-
2- enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5252-enyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + 1 = 525
Beispiel 52 8-(l-Aminomethyl-cyclohexylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(5-nitro- benzoxazol-2-ylmethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 554Example 52 8- (1-Aminomethylcyclohexylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (5-nitrobenzoxazol-2-ylmethyl) -3,7-dihydro- purine-2,6-dione trifluoroacetate MS: M + 1 = 554
Beispiel 53Example 53
8-(l-Aminomethyl-cyclohexylsulfanyl)-l-(5-chlor-benzoxazol-2-ylmethyl)-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5438- (1-aminomethylcyclohexylsulfanyl) -1- (5-chloro-benzoxazol-2-ylmethyl) -3-methyl-7- (3-methylbut-2-enyl) -3,7-dihydro-purine 2,6-dione trifluoroacetate MS: M + 1 = 543
Beispiel 54 8-( 1 - Aminomethyl-cyclohexylsulfany^-T-benzyl- 1 -(5 -fluor-benzothiazol-2-ylmethyl)-3 - methyl-3,7-dihydro-purin-2,6-dion MS: M+l = 565Example 54 8- (1-Aminomethylcyclohexylsulfinyl) -T-benzyl-1- (5-fluorobenzothiazol-2-ylmethyl) -3-methyl-3,7-dihydro-purine-2,6-dione MS: M + 1 = 565
Beispiel 55Example 55
8-( 1 -Aminomethyl-cyclohexylsulfanyl)- 1 -(5-fluor-benzothiazol-2-ylmethyl)-3-methyl-7-(3- methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5438- (1-Aminomethylcyclohexylsulfanyl) -1- (5-fluoro-benzothiazol-2-ylmethyl) -3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro-purine 2,6-dione trifluoroacetate MS: M + 1 = 543
Beispiel 56 [8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo- 2,3,6,7- tetrahydro-purin-l-yl]-acetonitril MS: M+l = 377Example 56 [8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -2,6-dioxo-2,3,6,7 - tetrahydro-purin-1-yl] -acetonitrile MS: M + l = 377
Beispiel 57Example 57
8-(l-Aminomethyl-cycloheptylsulfanyl)-7-benzyl-3-methyl-l-(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5328- (1-aminomethylcycloheptylsulfanyl) -7-benzyl-3-methyl-1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 532
Beispiel 58Example 58
8-(l-Aminomethyl-cycloheptylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 510 ' 8- (1-aminomethylcycloheptylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine 2,6-dione trifluoroacetate MS: M + l = 510 '
Beispiel 59Example 59
2-[8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo- 2,3,6,7-tetrahydro-purin-l-yl]-acetamid , MS: M+l = 3952- [8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -2,6-dioxo-2,3,6,7 tetrahydro-purin-1-yl] -acetamide, MS: M + 1 = 395
Beispiel 60Example 60
8-(l-Aminomethyl-l-ethyl-propylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l -(2-0X0-2- phenyl-ethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 4848- (1-aminomethyl-1-ethyl-propylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-0X0-2-phenyl-ethyl) -3,7- dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 484
Beispiel 61 8-(l-Aminomethyl-l-ethyl-propylsulfanyl)-7-benzyl-3-methyl-l-(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 506 Beispiel 62Example 61 8- (1-Aminomethyl-1-ethyl-propylsulfanyl) -7-benzyl-3-methyl-1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine-2,6- dione trifluoroacetate MS: M + 1 = 506 Example 62
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(2-methyl-2H-tetrazol-5-ylmethyl)- 1 - (2- oxo-2-phenyl-ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4848- (2-Amino-1, 1-dimethylethylsulfanyl) -3-methyl-7- (2-methyl-2H-tetrazol-5-ylmethyl) -1- (2-oxo-2-phenyl-ethyl) - 3,7-dihydro-purine-2,6-dione MS: M + 1 = 484
Beispiel 63Example 63
8-(l-Aminomethyl-cyclopentylsulfanyl)-7-benzyl-3-methyl-l-(2-oxo-2-phenyl-ethyl)-3,7- dihydro-purin-2,6-dion-trifluoracetat - MS: M+l = 5048- (1-aminomethylcyclopentylsulfanyl) -7-benzyl-3-methyl-1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate - MS: M + 1 = 504
Beispiel 64 8-(l-Aminomethyl-cyclopentylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 482Example 64 8- (1-Aminomethyl-cyclopentylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -3,7-dihydro- purine-2,6-dione trifluoroacetate MS: M + l = 482
Beispiel 65Example 65
8-(l-Aminomethyl-cyclooctylsulfanyl)-7-benzyl-3-methyl-l -(2-0X0-2 -phenyl-ethyl)-3, 7- dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5468- (1-aminomethyl-cyclooctylsulfanyl) -7-benzyl-3-methyl-1- (2-0X0-2-phenyl-ethyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate MS: M + l = 546
Beispiel 66Example 66
8-(l-Aminomethyl-cyclooctylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat MS: M+l = 5248- (1-aminomethylcyclooctylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine 2,6-dione trifluoroacetate MS: M + 1 = 524
Beispiel 67Example 67
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(5-phenyl-8- (2-amino-1, 1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methylbut-2-enyl) -1- (5-phenyl-
[l,3,4]oxadiazol-2-ylmethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 496[l, 3,4] oxadiazol-2-ylmethyl) -3,7-dihydro-purine-2,6-dione MS: M + l = 496
Beispiel 68Example 68
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl-7-(5-methyl-[ 1 ,3 ,4]oxadiazol-2-ylmethyl)- l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 4848- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (5-methyl- [1,3,3-oxadiazol-2-ylmethyl] -1- (2-oxo-2-) phenyl-ethyl) -3,7-dihydro-purine-2,6-dione MS: M + l = 484
Beispiel 69Example 69
2-{2-[8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo- 2,3,6, 7-tetrahydro-purin-l -yl]-acetyl} -benzoesäure-ethylester MS: M+l = 5282- {2- [8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-7- (3-methyl-but-2-enyl) -2,6-dioxo-2,3, 6,7-tetrahydro-purin-1-yl] -acetyl} -benzoic acid ethyl ester MS: M + 1 = 528
Beispiel 70Example 70
8-(2-Amino-l , 1 -dimethyl-ethylsulfanyl)-3-methyl- 1 ,7-bis-(2,4,5-trifluor-benzyl)-3,7- dihydro- purin-2,6-dion MS: M+l = 5588- (2-Amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-1, 7-bis (2,4,5-trifluoro-benzyl) -3,7-dihydro-purine-2,6- dion MS: M + l = 558
Beispiel 71Example 71
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l,7-bis-(2,5-difluor-benzyl)-3-methyl-3,7-dihydro- purin-2,6-dion MS: M+l = 5228- (2-Amino-1,1-dimethyl-ethylsulfanyl) -l, 7-bis (2,5-difluoro-benzyl) -3-methyl-3,7-dihydro-purine-2,6-dione MS : M + 1 = 522
Beispiel 72Example 72
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2-chlor-benzyl)- 1 ,3-dimethyl-3,7-dihydro- purin- 2,6-dion8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (2-chloro-benzyl) -1,3-dimethyl-3,7-dihydro-purine-2,6-dione
MS: M+l = 408MS: M + 1 = 408
Beispiel 73Example 73
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2-chlor-4-fluor-benzyl)-3-methyl- 1 -(2-oxo-2- phenyl-ethyl)-3 ,7-dihydro-purin-2,6-dion MS: M+l = 5308- (2-amino-1, 1-dimethyl-ethylsulfanyl) -7- (2-chloro-4-fluoro-benzyl) -3-methyl-1- (2-oxo-2-phenyl-ethyl) -3, 7-dihydro-purine-2,6-dione MS: M + 1 = 530
Beispiel 74Example 74
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2,5-difluor-benzyl)-3-methyl- 1 -(2-oxo-2-phenyl- ethyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 5148- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (2,5-difluoro-benzyl) -3-methyl-1- (2-oxo-2-phenyl-ethyl) -3,7- dihydro-purine-2,6-dione MS: M + 1 = 514
Beispiel 75Example 75
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-3-methyl- 1 -(2-oxo-2-phenyl-ethyl)-7-(2,4,5- trifluor- benzyl)-3,7-dihydro-purin-2,6-dion MS: M+l = 532 Beispiel 768- (2-amino-1,1-dimethyl-ethylsulfanyl) -3-methyl-1- (2-oxo-2-phenyl-ethyl) -7- (2,4,5-trifluorobenzyl) -3, 7-dihydro-purine-2,6-dione MS: M + 1 = 532 Example 76
2-[8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-3-methyl-2,6-dioxo-l-(2-oxo-2-phenyl-ethyl)- l,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitril2- [8- (2-Amino-1,1'-dimethyl-ethylsulfanyl) -3-methyl-2,6-dioxo-1- (2-oxo-2-phenylethyl) -1,3,3,6 tetrahydro-purin-7-ylmethyl] -benzonitrile
MS: M+l = 503MS: M + 1 = 503
Beispiel 77Example 77
8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(4-fluor-benzyl)- 1 -methyl-3-(2,2,2-trifluor- ethyl)-8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (4-fluoro-benzyl) -1-methyl-3- (2,2,2-trifluoro-ethyl) -
3,7-dihydro-purin-2,6-dion-trifluoracetat3,7-dihydro-purine-2,6-dione trifluoroacetate
MS: M+l = 460MS: M + 1 = 460
Beispiel 78Example 78
8-(2- Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2-chlor-benzyl)- 1 -methyl-3-(2,2,2-trifluor- ethyl)-8- (2-amino-1,1-dimethyl-ethylsulfanyl) -7- (2-chloro-benzyl) -1-methyl-3- (2,2,2-trifluoro-ethyl) -
3,7-dihydro-purin-2,6-dion-trifluoracetat3,7-dihydro-purine-2,6-dione trifluoroacetate
MS: M+l - 476MS: M + 1-476
Beispiel 79Example 79
8-(2-Amino-l,l-dimethyl-ethylsulfanyl)-l-(2-morpholin-4-yl-2-oxo-ethyl)-7-oxazol-2- ylmethyl-3-(2,2,2-trifluor-ethyl)-3,7-dihydro-purin-2,6-dion-trifluoracetat8- (2-Amino-1,1-dimethyl-ethylsulfanyl) -1- (2-morpholin-4-yl-2-oxo-ethyl) -7-oxazol-2-ylmethyl-3- (2,2,2 trifluoro-ethyl) -3,7-dihydro-purine-2,6-dione trifluoroacetate
MS: M+l = 546MS: M + 1 = 546
Beispiel 80Example 80
8-(2-Amino- 1 , 1 -dimethyl-ethylsulfanyl)-7-(2-chlor-benzyl)-3-[2-(4-fluor-phenyl)-ethyl]- 1 - methyl-3,7-dihydro-purin-2,6-dion-trifluoracetat8- (2-Amino-1, 1-dimethyl-ethylsulfanyl) -7- (2-chloro-benzyl) -3- [2- (4-fluoro-phenyl) -ethyl] -1-methyl-3,7- dihydro-purine-2,6-dione trifluoroacetate
MS: M+l = 516MS: M + 1 = 516
Die Beispiele 81 bis 83 erläutern die Herstellung der Ausgangsstoffe:Examples 81 to 83 illustrate the preparation of the starting materials:
Beispiel 81 8-Brom-3-methyl-3,7-dihydro-purin-2,6-dion 100g 3-Methyl-3,7-dihydro-purin-2,6-dion und 49g Natriumacetat werden in 800ml Eisessig suspendiert, auf 9O0C Innentemperatur erhitzt und langsam (ca. 3-4Stunden) mit 33,3ml Brom versetzt. Die Suspension wird noch 3 Stunden bei dieser Temperatur nachgerührt, laut DC (DCM/MeOH = 10:1) ist die Reaktion vollständig. Die Reaktionslösung wird abgekühlt und abgesaugt. Der Rückstand wird mit 100ml Eisessig und 500ml Wasser gewaschen und im Vakuum bei 50°C getrocknet. Ausbeute: 145 g Fp.: >300°C (Zers.)Example 81 8-Bromo-3-methyl-3,7-dihydro-purine-2,6-dione 100 g of 3-methyl-3,7-dihydro-purine-2,6-dione and 49 g of sodium acetate are suspended in 800 ml of glacial acetic acid, heated to 9O 0 C internal temperature and slowly (about 3-4 hours) with 33.3 ml of bromine. The suspension is stirred for 3 hours at this temperature, according to TLC (DCM / MeOH = 10: 1), the reaction is complete. The reaction solution is cooled and filtered with suction. The residue is washed with 100 ml of glacial acetic acid and 500 ml of water and dried in vacuo at 50 ° C. Yield: 145 g mp.> 300 ° C (decomp.)
Beispiel 82 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dionExample 82 8-Bromo-3-methyl-7- (3-methylbut-2-enyl) -3,7-dihydro-purine-2,6-dione
50g 8-Brom-3-methyl-3,7-dihydro-purin-2,6-dion werden in 900ml DMF vorgelegt und mit 14,1g Kaliumcarbonat versetzt. Die Suspension wird auf 600C Innentemperatur erhitzt und langsam mit 31,7g l-Brom-3-methyl-2-buten versetzt. Es wird noch für 3 Stunden bei dieser Temperatur nachgerührt und anschließend mit 1,2L Wasser versetzt. Der Feststoff wird abgesaugt, gut mit Wasser gewaschen und bei 45°C im Vakuum getrocknet. Ausbeute: 63,9 g Fp.: 223,3°C50 g of 8-bromo-3-methyl-3,7-dihydro-purine-2,6-dione are initially charged in 900 ml of DMF and admixed with 14.1 g of potassium carbonate. The suspension is heated to 60 0 C internal temperature and slowly added 3-methyl-2-buten-l-bromo with 31,7g. It is stirred for 3 hours at this temperature and then treated with 1.2 liters of water. The solid is filtered off, washed well with water and dried at 45 ° C in a vacuum. Yield: 63.9 g mp. 223.3 ° C
Beispiel 83 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-l-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purin-2,6- dionExample 83 8-Bromo-3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2-phenylethyl) -3,7-dihydro-purine-2,6- dion
30 g 8-Brom-3-methyl-7-(3-methyl-but-2-enyl)-3,7-dihydro-purin-2,6-dion, 20,6 g Phenacylbromid und 25,4 g Pottasche werden in 400ml DMF vorgelegt und für 3 Stunden auf 800C Innentemperatur erhitzt. Die Lösung wird auf ca. 500C abgekühlt und langsam mit 400ml Wasser versetzt. Anschließend wird über Nacht gerührt und vom ausgefallenen Feststoff abgesaugt. Nach dem Waschen mit Wasser wird der hellbraune Feststoff aus 300ml Isopropanol umkristallisiert. Ausbeute: 39,7 g Fp.: 90,4° 30 g of 8-bromo-3-methyl-7- (3-methyl-but-2-enyl) -3,7-dihydro-purine-2,6-dione, 20.6 g of phenacyl bromide and 25.4 g of potash presented in 400 ml of DMF and heated for 3 hours at 80 0 C internal temperature. The solution is cooled to about 50 0 C and slowly added with 400ml of water. The mixture is then stirred overnight and filtered with suction from the precipitated solid. After washing with water, the light brown solid is recrystallized from 300 ml of isopropanol. Yield: 39.7 g. Mp. 90.4 °

Claims

Patenansprüche: Patent claims:
1. Verbindungen der Formel I,1. Compounds of the formula I,
I worin bedeutenI mean
Rl, R2, R3 unabhängig voneinander H, (C1-C10)- Alkyl, (C3-C10)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-C10)-Alkinyl, (C6-C]0)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (Ci- C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7,Rl, R2, R3 are independently H, (C 1 -C 10) - alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 10) -alkynyl, ( C 6 -C] 0 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2, SH, SF 5, OH, (Ci- C 6) alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, OR7,
OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (Ci-C6)-Alkylen-OR7, (C,-C6)-Alkylen-NR7R8, (Cr C6)-Alkylen-NR7SO2R7, (C,-C6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (C,-C6)-Alkylen-(C3- Ci0)-Cycloalkyl, (Ci-C6)-Alkylen-(C6-Ci0)-Aryl, (CrC6)-Alkylen-Heterocyclyl,OP (O) (OR7) 2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (Ci-C 6) -alkylene-OR7, (C, -C 6) -alkylene-NR7R8, (C r C 6) -alkylene-NR7SO 2 R7, (C, -C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, R7 NR7SO 2 , (C, -C 6) alkylene- (C 3 - Ci 0) cycloalkyl, (Ci-C 6) alkylene- (C 6 -C 0) aryl, (C r C6) alkylene-heterocyclyl .
(C3-Cio)-Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein dürfen;(C 3 -Cio) cycloalkyl, (C 6 -C 0) aryl or heterocyclyl, where not all of the radicals Rl, R2 and R3 simultaneously be hydrogen or methyl;
R7, R8 unabhängig voneinander H, (Ci -C6)- Alkyl, (C3-C io)-Cycloalkyl, (C6-Ci0)- Aryl,R7, R8 are independently H, (Ci-C6) - alkyl, (C 3 -C io) cycloalkyl, (C 6 -C 0) - aryl,
Heterocyclyl, (CrC6)-Alkylen-CONR9R10, (CrC6)-Alkylen-COOR9, , (C]-C6)- Alkylen-COR9, (C!-C6)-Alkylen-OR9, (CrC6)-Alkylen-NR9R10, (Ci-C6)- Alkylen-SR9, (Ci-C6)-Alkylen-S(O)R9, (Ci-C6)-Alkylen-S(O)2R9 , (C1-C4)- Alkylen-(C6-Cio)-Aryl oder (Ci-C4)-Alkylen-Heterocyclyl;Heterocyclyl, (C r C 6) -alkylene-CONR9R10, (C r C6) alkylene-COOR 9, (C] -C6) - (! C-C6) alkylene-COR 9, -alkylene-OR9, ( C r C 6 ) -alkylene NR9R10, (Ci-C 6 ) - Alkylene-SR9, (Ci-C 6) -alkylene-S (O) R9, (Ci-C 6) -alkylene-S (O) 2 R9, (C 1 -C 4) - alkylene (C 6 -Cio ) -Aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R9, RIO unabhängig voneinander H, (C]-C6)-Alkyl, (C]-C6)-Alkylen-(C6-Cio)-Aryl, (Ci- C6)-Alkylen-Heterocyclyl;R 9, R 10, independently of one another, are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10) -aryl, (C 1 -C 6 ) -alkylene heterocyclyl;
R4, R5 unabhängig voneinander Wasserstoff, (CrC6)-Alkyl oder (C3-C8)-Cykloalkyl, wobei (Ci-Cö)-Alkyl oder (C3-C8)-Cykloalkyl substitiuert sein können mit F, Cl, Br, I, CN, Aryl, Heterocyclyl, NH2, NH(Ci -C6)- Alkyl, N((C,-C6)-Alkyl)2, OH, 0(C1 -C6)- Alkyl, OAryl, OHeteroaryl, S(Ci-C6)-Alkyl, S(O)(Ci-C6)-Alkyl,R4, R5 are independently hydrogen, (C r C6) alkyl or (C 3 -C 8) -cycloalkyl, where (C ö) alkyl or (C 3 -C 8) -cycloalkyl may be substitiuert with F , Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (Ci-C6) - alkyl, N ((C, -C 6) alkyl) 2, OH, 0 (C1-C6) Alkyl, O-aryl, OHeteroaryl, S (C 1 -C 6 ) -alkyl, S (O) (C 1 -C 6 ) -alkyl,
S(O)2(C]-C6)- Alkyl, wobei diese Alkylgruppen wiederum mit F, Cl, Br, I substituiert sein können;S (O) 2 (C] -C6) - alkyl, where these alkyl groups may in turn be substituted by F, Cl, Br, I;
Rl 1, R12, R13, R14, R15, R16 unabhängig voneinander H, (Ci -C6)- Alkyl, Aryl, Heterocyclyl, (C3-C8)-Cykloalkyl, (C, -C4)- Alkylen-0 Alkyl, (C,-C4)-Alkylen-R 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl, heterocyclyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-O Alkyl, (C 1 -C 4 ) -alkylene
SAlkyl, (Ci-C4)-Alkylen-NHAlkyl, (Ci-C4)-Alkylen-N(Alkyl)2, (Ci-C4)-Alkylen- Aryl, (Ci-C4)-Alkylen-Heterocyclyl, F, Cl, Br, I, CN, COOH, COO(Ci-C6)- Alkyl, CONH2, CONH(C1 -C6)-Alkyl, CON((C,-C6)-Alkyl)2, CF3, oder zwei der Reste R4, R5, Rl 1, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)- Alkylenrest, an dem ein (C6-CiO)-Arylrest oder ein (C6-C]0)-Heterocyclylrest ankondensiert sein kann, wobei der (C2-C6)- Alkylenrest und die ankondensierten Arylreste oder Heterocyclylreste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, OCF3, CF3, CN, (Ci-C6)-Alkyl, Aryl, Heterocyclyl, (C3-C8)- Cykloalkyl, (Ci -C4)- Alkylen-0 Alkyl, (Ci -C4)- Alkylen-S Alkyl, (d-C4)-Alkylen- NHAlkyl, (Ci-C4)-Alkylen-N(Alkyl)2, (Ci-C4)-Alkylen-Aryl, (C,-C4)-Alkylen-SAlkyl, (C 1 -C 4 ) -alkylene-NHalkyl, (C 1 -C 4 ) -alkylene-N (alkyl) 2 , (C 1 -C 4 ) -alkylene-aryl, (C 1 -C 4 ) -alkylene-heterocyclyl, F, Cl, Br, I, CN, COOH, COO (Ci-C 6) - alkyl, CONH 2, CONH (C 1 -C 6) -alkyl, CON ((C, -C 6) alkyl) 2, CF 3, or two of the radicals R4, R5, Rl 1, R12, R13, R14, R15, R16 together form a (C 2 -C 6) - alkylene, where a (C 6 -C O) -aryl or (C 6 -C] 0 ) -Heterocyclylrest may be fused, wherein the (C 2 -C 6 ) - alkylene radical and the fused aryl radicals or heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, OCF 3 , CF 3 , CN, (C 1 -C 6 ) -alkyl, aryl, heterocyclyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-0-alkyl, (C 1 -C 4 ) -alkylene-S alkyl, (dC 4) alkylene- NHalkyl, (Ci-C 4) -alkylene-N (alkyl) 2, (Ci-C 4) -alkylene-aryl, (C, -C 4) alkylene-
Heterocyclyl, COOH, COO(Ci -C6)- Alkyl, CONH2, CONH(Ci -C6)- Alkyl, CON((d-C6)-Alkyl)2, OH, 0-(C, -C6)- Alkyl, O-(C3-C6)-Cycloalkyl, S-(Ci-C6)- Alkyl, S-(C3-C6)-Cycloalkyl, SO-(C ,-C6)- Alkyl, SO-(C3-C6)-Cycloalkyl, SO2- (C1-C6)- Alkyl, SO2-(C3-C6)-Cycloalkyl, SO2-NH2, SO2-NH-(C ,-C6)- Alkyl, SO2- NH-SO2-(C3-C6)-Cycloalkyl; wobei die Aryl- und Heterocyclylreste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SF5, OH, (Ci-C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)- Alkenyl, (C2-C6)- Alkinyl, 0(C, -C4)- Alkyl, NH2, NH(Ci -C4)- Alkyl, N((CrC4)-Alkyl)2, NRVCONH(C1 -C4)- Alkyl , CO(C1- C4)-Alkyl, OCO(Ci-C4)-Alkyl, OCOO(C, -C4)- Alkyl, COO(Ci -C4)- Alkyl, CONH2, CONH(CrC4)-Alkyl, CON((Ci-C4)-Alkyl)2, (CrC6)-Alkylen-O(Ci-C4)- Alkyl , (Ci-C6)- Alkylen-NH(C,-C4)- Alkyl, (Ci-C6)-Alkylen-NH2, (Ci-C6)- 5 Alkylen-N((C,-C4)-Alkyl)2, (Ci -C6)- Alkylen-NHSO2(C, -C4)- Alkyl, (C1-C6)-Heterocyclyl, COOH, COO (C 1 -C 6 ) -alkyl, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON ((C 1 -C 6 ) -alkyl) 2 , OH, O- (C, -C 6 ) - alkyl, O- (C 3 -C 6) cycloalkyl, S- (Ci-C 6) - alkyl, S- (C 3 -C 6) cycloalkyl, SO- (C, -C6) - alkyl, SO - (C 3 -C 6 ) -cycloalkyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (C 3 -C 6 ) -cycloalkyl, SO 2 -NH 2 , SO 2 -NH- (C , -C 6 ) -alkyl, SO 2 -NH-SO 2 - (C 3 -C 6 ) -cycloalkyl; where the aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , - SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O (C 1 -C 4 ) -alkyl, NH 2, NH (Ci-C4) - alkyl, N ((C r C 4) alkyl) 2, NRVCONH (C 1 -C 4) - alkyl, CO (C 1 - C 4) alkyl, OCO ( Ci-C 4) alkyl, OCOO (C, -C 4) - alkyl, COO (Ci-C4) - alkyl, CONH 2, CONH (C r C 4) -alkyl, CON ((Ci-C 4) alkyl) 2, (C r C6) -alkylene-O (Ci-C4) - alkyl, (Ci-C 6) - alkylene-NH (C, -C 4) - alkyl, (Ci-C 6) -alkylene-NH2, (Ci-C 6) - 5 alkylene-N ((C, -C 4) alkyl) 2, (Ci-C6) - alkylene-NHSO2 (C, -C 4) - alkyl , (C 1 -C 6 ) -
Alkylen-S(Ci -C4)- Alkyl, Alkylen-S(O)-(C 1 -C4)- Alkyl, Alkylen-CONH2, Alkylen-CONH(Ci-C4)-Alkyl, Alkylen-CON((Ci-C4)-Alkyl)2, S(C1 -C4)- Alkyl, SO(Ci-C4)-Alkyl, SO2(Ci-C4)-Alkyl, SO2NH2, SO2NH(Ci-C4)-Alkyl, SO2N((C,- C4)-Alkyl)2, NR7SO2(Ci-C4)- Alkyl , (C,-C6)-Alkylen-(C3-C10)-Cycloalkyl, (C3- 10 Ci0)-Cycloalkyl; . -Alkylene-S (C 1 -C 4 ) -alkyl, alkylene-S (O) - (C 1 -C 4 ) -alkyl, alkylene-CONH 2 , alkylene-CONH (C 1 -C 4 ) -alkyl, alkylene-CON (( Ci-C 4) alkyl) 2, S (C 1 -C 4) - alkyl, SO (Ci-C 4) -alkyl, SO2 (Ci-C 4) alkyl, SO 2 NH 2, SO 2 NH (Ci-C 4) -alkyl, SO 2 N ((C, - C 4) alkyl) 2, NR7SO 2 (Ci-C 4) - alkyl, (C, -C 6) alkylene- (C 3 - C 10 ) -cycloalkyl, (C 3 - 10 Ci 0 ) -cycloalkyl; , -
m O, 1, oder 2;m is O, 1, or 2;
15 n O oder 1 ;15 n O or 1;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
20 2. Verbindungen der Formel I, gemäß Anspruch 1, dadurch gekennzeichnet, dass darin bedeuten20 2. Compounds of formula I, according to claim 1, characterized in that mean
Rl , R2, R3 unabhängig voneinander H, (Ci -Ci0)- Alkyl, (C3-C i0)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-Cio)-Alkinyl, (C6-C iO)-Aryl, Heterocyclyl, wobei die Alkyl-, - 25 Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (Ci- C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0R7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, 0C0R7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (Ci-C6)-Alkylen-OR7, (CrC6)-Alkylen-NR7R8, (Cr 30 C6)-Alkylen-NR7SO2R7, (Ci-C6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen-Rl, R2, R3 are independently H, (Ci -C 0) - alkyl, (C 3 -C i 0) cycloalkyl, (C 2 -C 0) - alkenyl, (C2 -Cio) alkynyl, (C i -C 6 O) -aryl, heterocyclyl, where the alkyl, - Inputs 25 cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals can be monosubstituted or polysubstituted by F, Cl, Br, I, CN NO 2, SH, SF 5, OH, (Ci- C 6) alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl , 0R7, OP (O) (OR7) 2, NR7R8, NR7CONR7R8, COR7, 0C0R7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (Ci-C 6) -alkylene-OR7, (C r C6) alkylene-NR7R8, (Cr 30 C 6 ) -alkylene-NR 7 SO 2 R 7, (C 1 -C 6 ) -alkylene-SR 7, alkylene-S (O) R 7, alkylene-
CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (CrC6)-Alkylen-(C3- C 10)-Cycloalkyl , (C ] -C6)- Alkylen-(C6-C i O)-Aryl, (C i -C6)- Alkylen-Heterocyclyl,CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (C r C6) -alkylene- (C 3 - C 10) cycloalkyl, (C] -C6) - alkylene (C 6 -C i o) aryl, (C i -C 6) - alkylene-heterocyclyl,
(C3-C io)-Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein dürfen;(C 3 -C io) cycloalkyl, (C 6 -C 0) aryl or heterocyclyl, where not all of the radicals Rl, R2 and R3 simultaneously be hydrogen or methyl;
R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-C10)-Cycloalkyl, (C6-C ]0)-Aryl,R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 10) cycloalkyl, (C 6 -C] 0) aryl,
Heterocyclyl, (Ci-C6)-Alkylen-CONR9R10, (C1-C6)-Alkylen-COOR9, (C1-C6)-Heterocyclyl, (Ci-C 6) -alkylene-CONR9R10, (C 1 -C 6) alkylene-COOR 9, (C 1 -C 6) -
Alkylen-COR9, (Ci-C6)-Alkylen-OR9, (C1-C6)-Alkylen-NR9R10, (C1-C4)-Alkylene-COR 9, (Ci-C 6) -alkylene-OR9, (C 1 -C 6) -alkylene-NR9R10, (C 1 -C 4) -
Alkylen-(C6-Cio)-Aryl oder (Ci-C4)-Alkylen-Heterocyclyl;Alkylene- (C 6 -C 10) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R9, RIO unabhängig voneinander H, (Ci-C6)-Alkyl, (Ci-C6)-Alkylen-(C6-Cio)-Aryl, (C,-R9, R10 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10) -aryl, (C 1 -C 6 ) -alkyl,
C6)-Alkylen-Heterocyclyl;C 6 ) -alkylene heterocyclyl;
R4, R5 unabhängig voneinander Wasserstoff, (C]-C6)-Alkyl oder (C3-C8)-Cykloalkyl, wobei (CrC6)-Alkyl oder (C3-Cg)-Cykloalkyl substitiuert sein können mit die durch F, Cl, Br, I, CN,Aryl, Heterocyclyl, NH2, NH(C1 -C6)- Alkyl, N((C,-C6)- Alkyl)2, OH, 0(C1 -C6)- Alkyl, OAryl, OHeteroaryl, S (Ci -C6)- Alkyl, S(O)(C1-C6)- Alkyl, S(O)2(C1-C6)-Alkyl;R4, R5 independently of one another hydrogen, (C] -C6) alkyl or (C 3 -C 8) -cycloalkyl, where (CrC 6) alkyl or (C3 -CG) -cycloalkyl may be substitiuert with the through F , Cl, Br, I, CN, aryl, heterocyclyl, NH 2, NH (C 1 -C 6) - alkyl, N ((C, -C6) - alkyl) 2, OH, 0 (C1-C6 ) - alkyl, O-aryl, OHeteroaryl, S (Ci-C6) - alkyl, S (O) (C 1 -C 6) - alkyl, S (O) 2 (C 1 -C 6) alkyl;
Rl 1, R12, R13, R14, R15, R16 unabhängig voneinander H, (C !-C6)- Alkyl, (C3-C8)-Rl 1, R12, R13, R14, R15, R16 independently of one another H, (C 6 -C!) - alkyl, (C 3 -C 8) -
Cykloalkyl, (C1 -C4)- Alkylen-0 Alkyl, (C1 -C4)- Alkylen-S Alkyl, (C,-C4)-Alkylen- NHAlkyl, (C,-C4)-Alkylen-N(Alkyl)2, F, Cl, Br, I, CN, COOH, COO(Ci-C6)- Alkyl, CONH2, CONH(C, -C6)- Alkyl, CON((Ci-C6)-Alkyl)2, CF3, oder zwei der Reste R4, R5, Rl 1, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)- Alkylenrest; wobei der (C2-C6)-Alkylenrest ein- oder mehrfach substituiert sein kann mit F, Cl, Br, I, CN, NO2, SF5, OH, (Ci -C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, 0(C ,-C4)- Alkyl, NH2, NH(CrC4)-Alkyl, N((Ci-C4)-Alkyl)2, NR7C0NH(C, -C4)- Alkyl , CO(C ,-C4)- Alkyl, OCO(Ci-C4)- Alkyl, OCOO(Ci-C4)-Alkyl, COO(Ci -C4)- Alkyl, CONH2, CONH(C ,-C4)-Alkyl, CON((C,-C4)-Alkyl)2, (C ,-C6)-Alkylen-O(Ci -C4)- Alkyl , (d-C6)-Alkylen-Cycloalkyl, (C 1 -C 4) - alkylene-0 alkyl, (C 1 -C 4) - alkylene-S alkyl, (C, -C 4) alkylene- NHalkyl, (C, -C 4) alkylene- N (alkyl) 2 , F, Cl, Br, I, CN, COOH, COO (C 1 -C 6 ) -alkyl, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON (C 1 -C 6 ) -Alkyl) 2 , CF 3 , or two of the radicals R 4, R 5, R 11, R 12, R 13, R 14, R 15, R 16 together form a (C 2 -C 6 ) -alkylene radical; wherein the (C 2 -C 6) alkylene mono- or may be multiply substituted with F, Cl, Br, I, CN, NO 2, SF 5, OH, (Ci-C6) - alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, 0 (C, -C 4) - alkyl, NH 2, NH (C r C 4) - alkyl, N ((Ci-C4) alkyl) 2, NR7C0NH (C, -C 4) - alkyl, CO (C, -C 4) - alkyl, OCO (Ci-C4) - alkyl, OCOO (C -C4) -alkyl, COO (Ci-C4) - alkyl, CONH 2, CONH (C, -C 4) -alkyl, CON ((C, -C 4) alkyl) 2, (C, -C 6 ) -alkylene-O (C 1 -C 4 ) -alkyl, (C 1 -C 6 ) -alkylene
NH(C, -C4)- Alkyl, (C!-C6)-Alkylen-NH2, (Ci-C6)-Alkylen-N((Ci-C4)-Alkyl)2, (Ci-C6)- Alkylen-NHSO2(C,-C4)- Alkyl, (C1-C6)- Alkylen-S(Ci-C4)-Alkyl, Alkylen-S(O)-(Cl-C4)-Alkyl, Alkylen-CONH2, Alkylen-CONH(C,-C4)-Alkyl, Alkylen-CON((CrC4)-Alkyl)2, S(d-C4)-Alkyl, SO(C!-C4)-Alkyl, SO2(C-C4)- Alkyl, SO2NH2, SO2NH(Ci-C4)-Alkyl, SO2N((Ci-C4)-Alkyl)2, NR7SO2(C,-C4)- Alkyl , (C1-C6)- Alkylen-(C3-C10)-Cycloalkyl, (C3-Ci0)-Cycloalkyl;NH (C, -C 4) - alkyl, -alkylene-NH 2, (Ci-C 6) -alkylene-N ((Ci-C 4) alkyl) 2, (Ci-C (C 6 -C!) 6) - alkylene-NHSO2 (C, -C4) - alkyl, (C 1 -C 6) - alkylene-S (Ci-C 4) -alkyl, Alkylene-S (O) - (Cl-C4) -alkyl, -alkylene-CONH 2, alkylene-CONH (C, -C4) alkyl, alkylene-CON ((C r C 4) alkyl) 2, S ( dC 4) -alkyl, SO (C -C 4) alkyl, SO 2 (CC 4) - alkyl, SO 2 NH 2, SO 2 NH (Ci-C 4) -alkyl, SO 2 N ((Ci- 4 C 2) alkyl) 2, NR7SO (C, -C 4) - alkyl, (C 1 -C 6) - alkylene- (C 3 -C 10) cycloalkyl, (C 3 -C 0) cycloalkyl;
m 0, 1, oder 2;m is 0, 1, or 2;
10 n O oder 1;10n O or 1;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
15 3. Verbindungen der Formel I, gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass darin bedeuten15 3. Compounds of formula I, according to claim 1 or 2, characterized in that mean
Rl , R2, R3 unabhängig voneinander H, (C]-Cio)-Alkyl, (C3-C10)-Cycloalkyl, (C2-Ci0)- Alkenyl, (C2-Ci0)-Alkinyl, (C6-C1O)-ATyI, Heterocyclyl, wobei die Alkyl-, 20 Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, I, CN, NO2, SH, SF5, OH, (C1- C6)-Alkyl, -CF3, -OCF3, -SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (CrC6)-Alkylen-OR7, (CrC6)-Alkylen-NR7R8, (C- _ 25 C6)-Alkylen-NR7SO2R7, (C,-C6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen-Rl, R2, R3 are independently H, (C] -Cio) -alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 0) alkynyl, (C 6 -C 10 ) -ATyI, heterocyclyl, where the alkyl, 20 cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR7, OP (O) (OR7) 2 , NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C r C 6 ) -alkylene-OR7, (C r C 6 ) -alkylene-NR7R8, ( C 1-25 C 6 ) -alkylene-NR 7 SO 2 R 7, (C 1 -C 6 ) -alkylene-SR 7, alkylene-S (O) R 7, alkylene-
CONR7R8, SR7, SOR7, SO2R7, SO2NR7R8, NR7SO2R7, (C,-C6)-Alkylen-(C3- C io)-Cycloalkyl, (C i -C6)- Alkylen-(C6-C i o)- Aryl, (C i -C6)- Alkylen-Heterocyclyl, (C3-C i0)-Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl, wobei nicht alle Reste Rl, R2 und R3 gleichzeitig Wasserstoff oder Methyl sein 30 dürfen; R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-C]0)-Cycloalkyl, Aryl,CONR7R8, SR7, SOR7, SO2 R7, SO 2 NR7R8, NR7SO 2 R7, (C, -C 6) alkylene- (C 3 - C io) cycloalkyl, (C i -C 6) - alkylene (C 6 -C io) - aryl, (C i -C 6) - alkylene-heterocyclyl, (C 3 -C i 0) cycloalkyl, (C 6 -C 0) aryl or heterocyclyl, where not all of the radicals Rl, R2 and R3 may be simultaneously hydrogen or methyl; R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C] 0) cycloalkyl, aryl,
Heterocyclyl, (Ci-C4)-Alkylen-(C6-Ci0)-Aryl oder (Ci-C4)-Alkylen- Heterocyclyl;Heterocyclyl, (Ci-C 4) -alkylene- (C 6 -C 0) aryl or (Ci-C 4) -alkylene- heterocyclyl;
R4, R5 unabhängig voneinander Wasserstoff, (C1-Co)-AUCyI oder (C3-Cg)-Cykloalkyl, wobei (Ci-C6)- Alkyl oder (C3-C8)-Cykloalkyl substituiert sein können mit die durch F, Cl, Br, I, CN,Aryl, Heterocyclyl, NH2, NH(Ci -C6)- Alkyl, N((CrC6)- Alkyl)2, OH, 0(Ci -C6)- Alkyl, OAryl, OHeteroaryl, S(C!-C6)-Alkyl, S(O)(C1-C6)- Alkyl, S(O)2(C1-C6)-Alkyl;R4, R5 are independently hydrogen, (C 1 -Co) -AUCyI or (C3 -CG) -cycloalkyl, where (Ci-C 6) - alkyl or (C 3 -C 8) -cycloalkyl may be substituted with by F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C r C 6 ) -alkyl) 2 , OH, 0 (C 1 -C 6 ) - (! C-C6) alkyl, O-aryl, OHeteroaryl, S-alkyl, S (O) (C 1 -C 6) - alkyl, S (O) 2 (C 1 -C 6) alkyl;
Rl 1, R12, R13, R14, R15, R16 unabhängig voneinander H, (C1 -C6)- Alkyl, (C3-C8)- Cykloalkyl,R 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl,
oder zwei der Reste R4, R5, RIl, R12, R13, R14, R15, R16 bilden gemeinsam einen (C2-C6)- Alkylenrest;or two of the radicals R 4, R 5, R 11, R 12, R 13, R 14, R 15, R 16 together form a (C 2 -C 6 ) -alkylene radical;
m 0, 1 oder 2;m is 0, 1 or 2;
n 0; ' sowie deren physiologisch verträglichen Salze.n 0; ' and their physiologically acceptable salts.
4. Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben:4. Compounds of the formula I in which one or more radicals have the following meaning:
Rl , R2, R3 unabhängig voneinander (Ci-C6)-Alkyl, (C3-C i0)-Cycloalkyl, (C2-C 10)-Alkenyl, (C2-Ci0)-Alkinyl, (C6-Ci0)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, Br, CN, NO2, SF5, OH, (C, -C6)- Alkyl, -CF3, -OCF3, -Rl, R2, R3 are independently (Ci-C 6) -alkyl, (C 3 -C i 0) cycloalkyl, (C 2 -C 10) alkenyl, (C 2 -C 0) -alkynyl, (C 6 -Ci 0 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN, NO 2 , SF 5 , OH, (C, -C 6 ) -alkyl, -CF 3 , -OCF 3 , -
SCF3, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (C,-C6)-Alkylen-OR7, (C,-C6)-Alkylen-NR7R8, (d-C6)-Alkylen-NR7SO2R7, (d-C6)-Alkylen-SR7, Alkylen-S(0)R7, Alkylen- CONR7R8, SR7, S0R7, SO2R7, SO2NR7R8, NR7SO2R7, (C1-C6)-Alkylen-(C3- C10)-Cycloalkyl, (Ci-C6)-Alkylen-(C6-C10)-Aryl, (Ci-C6)-Alkylen-Heterocyclyl, (C3-Cio)-Cycloalkyl, (C6-C10)- Aryl oder Heterocyclyl; 5 R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-C10)-Cycloalkyl, Aryl,SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (C, -C 6) -alkylene-OR7, (C -C 6 ) -alkylene NR7R8, (dC 6) -alkylene-NR7SO 2 R7, (dC 6) -alkylene-SR7, alkylene-S (0) R7, alkylene CONR7R8, SR7, S0R7, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (C 1 -C 6) alkylene- (C 3 - C 10) cycloalkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (Ci-C6) alkylene-heterocyclyl, (C 3- Cio) -cycloalkyl, (C 6 -C 10 ) -aryl or heterocyclyl; 5 R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, aryl,
Heterocyclyl (C1 -C4)- Alkylen-(C6-C10)- Aryl oder (C]-C4)-Alkylen-Heterocyclyl;Heterocyclyl (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R4, R5 Wasserstoff;R4, R5 hydrogen;
1010
Rl 1, R12, R13, R14 unabhängig voneinander H, (Ci-C6)- Alkyl oder C3-C7-Cycloalkyl;R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl or C 3 -C 7 -cycloalkyl;
m 0;m 0;
15 n 0;15 n 0;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
20 5. Verbindungen der Formel I, worin ein oder mehrere Reste die folgende Bedeutung haben:5. Compounds of the formula I in which one or more radicals have the following meaning:
Rl , R2, R3 unabhängig voneinander (Ci -C6)- Alkyl, (C3-C io)-Cycloalkyl, (C2-C10)- Alkenyl, (C2-C I0)- Alkinyl, (C6-Ci0)-Aryl, Heterocyclyl, wobei die Alkyl-, Cycloalkyl-, - 25 Alkenyl-, Alkinyl-, Aryl- und Heterocyclyl Reste ein- oder mehrfach substituiert sein können mit F, Cl, CN, SF5, (Ci -C6)- Alkyl, -CF3, -OCF3, -SCF3, (C2-C4)- Alkenyl, (C2τC4)-Alkinyl, OR7, NR7R8, NR7CONR7R8, COR7, COOR7, CONR7R8, (Ci-C4)-Alkylen-OR7, (CrC4)-Alkylen-NR7R8, (CrC4)-Alkylen- NR7SO2R7, (Ci-C6)-Alkylen-SR7, Alkylen-S(O)R7, Alkylen-CONR7R8, SR7, 30 SOR7, SO2R7, SO2NR7R8, NR7SO2R7, (Ci-C6)-Alkylen-(C3-Cio)-Cycloalkyl,Rl, R2, R3 are independently (Ci-C6) - alkyl, (C 3 -C io) cycloalkyl, (C 2 -C 10) - alkenyl, (C 2 -C I0) - alkynyl, (C 6 - Ci 0 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, - 25 alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, CN, SF 5 , (Ci -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 4) -alkenyl, (C 2τ C 4 ) -alkynyl, OR 7, NR 7 R 8, NR 7CONR 7 R 8, COR 7, COOR 7, CONR 7 R 8, (C 1 -C 4 ) alkylene-OR7, (C r C4) -alkylene-NR7R8, (C r C4) alkylene- NR7SO 2 R7, (Ci-C 6) -alkylene-SR7, alkylene-S (O) R7, alkylene-CONR7R8 , SR7, SOR7 30, SO 2 R 7, SO 2 NR7R8, NR7SO 2 R7, (Ci-C 6) alkylene- (C 3 -Cio) cycloalkyl,
(Ci-C6)-Alkylen-(C6-Ci0)-Aryl, (CrC6)-Alkylen-Heterocyclyl, (C3-Ci0)- Cycloalkyl, (C6-Ci0)-Aryl oder Heterocyclyl; R7, R8 unabhängig voneinander H, (Ci-C6)-Alkyl, (C3-Cio)-Cycloalkyl, Aryl,(Ci-C 6) alkylene- (C 6 -C 0) aryl, (C r C6) alkylene-heterocyclyl, (C 3 -C 0) - cycloalkyl, (C 6 -C 0) aryl, or heterocyclyl; R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10) -cycloalkyl, aryl,
Heterocyclyl, (Ci-C4)-Alkylen-(C6-C10)-Aryl oder (Ci-C4)-Alkylen- Heterocyclyl;Heterocyclyl, (C 1 -C 4 ) -alkylene- (C 6 -C 10 ) -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
R4, R5 Wasserstoff;R4, R5 hydrogen;
Rl 1, R12, R13, R14 unabhängig voneinander H, (Ci-C4)-Alkyl;R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 4) -alkyl;
m 0;m 0;
n 0;n 0;
sowie deren physiologisch verträglichen Salze.and their physiologically acceptable salts.
6. Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Anwendung als Arzneimittel.6. Compounds according to one or more of claims 1 to 5 for use as medicaments.
7. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5.7. A medicament containing one or more of the compounds according to one or more of claims 1 to 5.
8. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 und mindestens einen weiteren Wirkstoff.8. Medicaments containing one or more of the compounds according to one or more of claims 1 to 5 and at least one further active ingredient.
9. Arzneimittel, gemäß Anspruch 8, dadurch gekennzeichnet, dass es als weiteren Wirkstoff eine oder mehrere Antidiabetika, hypoglykämischen Wirkstoffe, HMGCoA- Reduktase Inhibitoren, Cholesterinresorptionsinhibitoren, PPAR gamma Agonisten, PPAR alpha Agonisten, PPAR alpha/gamma Agonisten, Fibrate, MTP-Inhibitoren, Gallensäureresorptionsinhibitoren, CETP-Inhibitoren, polymere Gallensäureadsorber, LDL- Rezeptorinducer, ACAT-Inhibitoren, Antioxidantien, Lipoprotein-Lipase Inhibitoren, ATP- Citrat-Lyase Inhibitoren, Squalen synthetase inhibitoren, Liρoprotein(a) antagonisten, Lipase Inhibitoren, Insuline, Sulfonylharnstoffe, Biguanide, Meglitinide, Thiazόlidindione, a- Glukosidase-Inhibitoren, auf den ATP-abhängigen Kaliumkanal der Betazellen wirkende Wirkstoffe, CART-Agonisten, NPY-Agonisten, MC4-Agonisten, Orexin-Agonisten, H3- Agonisten, TNF-Agonisten, CRF-Agonisten, CRF BP-Antagonisten, Urocortin-Agonisten, 03- Agonisten, , CBl -Rezeptor Antagonisten ,MSH (Melanocyt-stimulierendes Hormon)- Agonisten, CCK- Agonisten, Serotonin- Wiederaufnahme-Inhibitoren, gemischte Sertonin- und noradrenerge Verbindungen, 5HT-Agonisten, Bombesin-Agonisten, Galanin-Antagonisten, Wachstumshormone, Wachstumshormon freisetzende Verbindungen, TRH- Agonisten, entkoppelnde Protein 2- oder 3 -Modulatoren, Leptinagonisten, DA-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase- Inhibitoren, PPAR-Modulatoren, RXR-Modulatoren oder TR-/?- Agonisten oder Amphetamine enthält.9. Medicament, according to claim 8, characterized in that it contains as further active ingredient one or more antidiabetics, hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol resorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, fibrates, MTP inhibitors , Bile acid resorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, lipase Inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazoledinediones, a-glucosidase inhibitors, beta-cell ATP-dependent potassium channel drugs, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF Agonists, CRF agonists, CRF BP antagonists, urocortin agonists, 03 agonists, CB1 receptor antagonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors , PPAR modulators, RXR modulators or TR - /? - agonists or amphetamines.
10. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Herstellung eines Medikamentes zur Blutzuckersenkung.10. Use of the compounds according to one or more of claims 1 to 5 for the manufacture of a medicament for lowering blood sugar.
11. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Herstellung eines Medikamentes zur Behandlung des Typ II Diabetes.11. Use of the compounds according to one or more of claims 1 to 5 for the manufacture of a medicament for the treatment of type II diabetes.
12. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Herstellung eines Medikamentes zur Behandlung von Lipid- und12. Use of the compounds according to one or more of claims 1 to 5 for the manufacture of a medicament for the treatment of lipid and
Kohlenhydratstoffwechselstörungen.Carbohydrate metabolism disorders.
13. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Herstellung eines Medikaments zur Behandlung arteriosklerotischer Erscheinungen.13. Use of the compounds according to one or more of claims 1 to 5 for the manufacture of a medicament for the treatment of arteriosclerotic phenomena.
14. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5 zur Herstellung eines Medikaments zur Behandlung von Insulin Resistenz.14. Use of the compounds according to one or more of claims 1 to 5 for the manufacture of a medicament for the treatment of insulin resistance.
15. Verfahren zur Herstellung eines Arzneimittels enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass der Wirkstoff mit einem pharmazeutisch geeigneten Träger vermischt wird und diese Mischung in eine für die Verabreichung geeignete Form gebracht wird. 15. A process for preparing a pharmaceutical composition comprising one or more of the compounds according to one or more of claims 1 to 5, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture is brought into a suitable form for administration.
EP05775003A 2004-08-03 2005-07-19 Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv Withdrawn EP1778689A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004037554A DE102004037554A1 (en) 2004-08-03 2004-08-03 Substituted 8-aminoalkylthio-xanthines, process for their preparation and their use as medicaments
PCT/EP2005/007821 WO2006015691A1 (en) 2004-08-03 2005-07-19 Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv

Publications (1)

Publication Number Publication Date
EP1778689A1 true EP1778689A1 (en) 2007-05-02

Family

ID=34993242

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05775003A Withdrawn EP1778689A1 (en) 2004-08-03 2005-07-19 Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv

Country Status (10)

Country Link
US (1) US8236810B2 (en)
EP (1) EP1778689A1 (en)
JP (1) JP2008508331A (en)
AU (1) AU2005270509A1 (en)
BR (1) BRPI0514091A (en)
CA (1) CA2575904A1 (en)
DE (1) DE102004037554A1 (en)
IL (1) IL180872A0 (en)
MX (1) MX2007000609A (en)
WO (1) WO2006015691A1 (en)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004039507A1 (en) * 2004-08-14 2006-03-02 Sanofi-Aventis Deutschland Gmbh Substituted 8-aminoalkoxi-xanthines, process for their preparation and their use as medicaments
DOP2006000008A (en) 2005-01-10 2006-08-31 Arena Pharm Inc COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED AFFECTIONS AND FOR THE TREATMENT OF AFFECTIONS THAT IMPROVE THROUGH AN INCREASE IN THE BLOOD CONCENTRATION OF GLP-1
PE20071221A1 (en) 2006-04-11 2007-12-14 Arena Pharm Inc GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS
DE102007005045B4 (en) 2007-01-26 2008-12-18 Sanofi-Aventis Phenothiazine derivatives, process for their preparation and their use as medicines
EP2025674A1 (en) 2007-08-15 2009-02-18 sanofi-aventis Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs
EP2146210A1 (en) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
US8397733B2 (en) * 2010-01-15 2013-03-19 Celanese Acetate Llc Degradable cigarette filter: pill with multilayered coating
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
EP2683700B1 (en) 2011-03-08 2015-02-18 Sanofi Tetra-substituted oxathiazine derivatives, method for their preparation, their usage as medicament and medicament containing same and its use
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
EP2760862B1 (en) 2011-09-27 2015-10-21 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
IN2015DN03795A (en) 2012-10-24 2015-10-02 Inserm Inst Nat De La Santé Et De La Rech Médicale
EP3273981B1 (en) 2015-03-24 2020-04-29 INSERM - Institut National de la Santé et de la Recherche Médicale Method and pharmaceutical composition for use in the treatment of diabetes

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2688618A (en) 1952-01-03 1954-09-07 Bristol Lab Inc Basic caffeine derivatives
DE1005517B (en) 1955-12-30 1957-04-04 Cassella Farbwerke Mainkur Ag Process for the production of new xanthine compounds containing mercury
DE3232883A1 (en) 1982-09-02 1984-03-08 Josef Dipl.-Chem. Dr.Rer.Nat. Klosa NEW SALTS OF BASIC COFFEINE-8-ETHERS AND THEIR USE IN PHARMACEUTICAL PREPARATIONS
EP0430300A3 (en) 1989-12-01 1992-03-25 Takeda Chemical Industries, Ltd. Xanthine derivatives, their production and use
GB9020959D0 (en) 1990-09-26 1990-11-07 Beecham Group Plc Novel compounds
US5290801A (en) * 1992-05-29 1994-03-01 The Du Pont Merck Pharmaceutical Company Benzimidazoles for the treatment of atherosclerosis
CN1268137A (en) * 1997-07-03 2000-09-27 杜邦药品公司 Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
JP2002542245A (en) 1999-04-16 2002-12-10 ノボ ノルディスク アクティーゼルスカブ Substituted imidazoles, their manufacture and use
SI1757606T1 (en) * 2001-02-24 2009-10-31 Boehringer Ingelheim Pharma Xanthinderivatives for use as medical agents and the preparation thereof
WO2004048379A1 (en) 2002-11-01 2004-06-10 Sumitomo Pharmaceuticals Co., Ltd. Xanthine compound
DE102004039507A1 (en) * 2004-08-14 2006-03-02 Sanofi-Aventis Deutschland Gmbh Substituted 8-aminoalkoxi-xanthines, process for their preparation and their use as medicaments
CA2631885A1 (en) * 2005-12-07 2007-06-14 Ucb Pharma, S.A. Xanthine derivatives, processes for preparing them and their uses
JP2011507910A (en) * 2007-12-21 2011-03-10 ユニバーシティー オブ ロチェスター Methods for changing the lifetime of eukaryotes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006015691A1 *

Also Published As

Publication number Publication date
DE102004037554A1 (en) 2006-03-16
US20070265284A1 (en) 2007-11-15
BRPI0514091A (en) 2008-05-27
JP2008508331A (en) 2008-03-21
IL180872A0 (en) 2007-07-04
AU2005270509A1 (en) 2006-02-16
MX2007000609A (en) 2007-03-30
US8236810B2 (en) 2012-08-07
WO2006015691A1 (en) 2006-02-16
CA2575904A1 (en) 2006-02-16

Similar Documents

Publication Publication Date Title
WO2006015691A1 (en) Substituted 8-aminoalkylthio-xanthines, and the use thereof as inhibitors of the dipeptidyl peptidase iv
EP1778690B1 (en) Substituted 8-aminoalkoxi-xanthines, method for the production thereof and use thereof as medicaments
DE102005017605B4 (en) Substituted 2-aminoalkylthio-benzimidazoles, process for their preparation and their use as medicaments
EP1863789B1 (en) Aminocarbonyl-substituted 8-n-benzimidazoles, method for their production and their use as medicaments
EP1863790B1 (en) Amide-substituted 8-n-benzimidazoles, method for the production thereof, and use of the same as medicaments
EP1776372A1 (en) Substituted, bicyclic 8-pyrrolidinoxanthines, method for the production thereof and their use as medicaments
EP1778697A1 (en) Substituted bicyclic 8-pyrrolidino-xanthines and use thereof as inhibitors of the dipeptidyl peptidase iv
EP1651649B1 (en) Novel cyanopyrrolidides, methods for the production thereof, and use of the same as medication
WO2006015700A1 (en) Substituted, bicyclic 8-piperidinoxanthines, method for the production thereof and their use as medicaments
DE10333935A1 (en) New bicyclic cyano-heterocycles, process for their preparation and their use as pharmaceuticals
EP1720870B1 (en) Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, method for the production thereof and their use as medicaments
EP1863488B1 (en) Use of amino-substituted 8-n-benzimidazoles
DE102004004971B3 (en) Cycloalkyl substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as Arnzeimittel
EP1863817B1 (en) Substituted, bicyclic 8-pyrrolidino-benzimidazoles, method for their production and their use as medicaments
DE10302452B4 (en) Carbonylamino-substituted acyl-phenyl-urea derivatives, processes for their preparation and their use
DE10335092B3 (en) Substituted benzoylureido-o-benzoylamides, process for their preparation and their use

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070305

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20130419

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20130604