AU2003253418A1 - 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments - Google Patents

8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments Download PDF

Info

Publication number
AU2003253418A1
AU2003253418A1 AU2003253418A AU2003253418A AU2003253418A1 AU 2003253418 A1 AU2003253418 A1 AU 2003253418A1 AU 2003253418 A AU2003253418 A AU 2003253418A AU 2003253418 A AU2003253418 A AU 2003253418A AU 2003253418 A1 AU2003253418 A1 AU 2003253418A1
Authority
AU
Australia
Prior art keywords
methyl
xanthine
piperidin
amino
oxo
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.)
Granted
Application number
AU2003253418A
Other versions
AU2003253418B2 (en
Inventor
Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Ralf Richard Hermann Lotz
Roland Maier
Michael Mark
Mohammad Tadayyon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
BOEHRINGER INGELHEIM PHARMA
Boehringer Ingelheim Pharma GmbH and Co KG
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=31947613&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AU2003253418(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from DE10238243A external-priority patent/DE10238243A1/en
Priority claimed from DE10312353A external-priority patent/DE10312353A1/en
Application filed by BOEHRINGER INGELHEIM PHARMA, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical BOEHRINGER INGELHEIM PHARMA
Publication of AU2003253418A1 publication Critical patent/AU2003253418A1/en
Priority to AU2010201384A priority Critical patent/AU2010201384C1/en
Application granted granted Critical
Publication of AU2003253418B2 publication Critical patent/AU2003253418B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07D473/12—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

Description

au-if il COMMONWEALTH OF AUSTRALIA PATENTS ACT 1990 IN THE MATTER of a Patent Application by Boehringer Ingelheim Pharma GmbH & Co.KG VERIFICATION OF TRANSLATION Patent Application No.: PCT/EP2003/009127 (WO 2004/018468) I, JANE ROBERTA MANN, B.A., of Frank B. Dehn & Co., 59 St Aldates, Oxford OXI 1ST, am the translator of the documents attached and I state that the following is a true translation to the best of my knowledge and belief of the specification as published of International Patent Application No. PCT/EP2003/009127 (WO 2004/018468) of Boehringer Ingelheim Pharma GmbH & Co.KG. Signature of translator Dated: 3rd February 2005 WO 2004/018468 1 PCT/EP2003/009127 81690pct.211 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions The present invention relates to new substituted xanthines of general formula 0 NH 2 RON N 0 'N N the tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an increased DPP-IV activity or capable of being prevented or alleviated by reducing the DPP-IV activity, particularly type I or type 11 diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (1) or a physiologically acceptable salt thereof as well as processes for the preparation thereof. In the above formula I
R
1 denotes a methyl group, a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1 ylcarbonyl, piperidin-1-ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl group, WO 2004/018468 2 PCT/EP2003/009127 a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or dimethylaminonaphthyl group, a methyl group which is substituted by a 2-phenylethenyl or a biphenylyl group, a methyl group which is substituted by a phenyloxadiazolyl, 5-methyl-3 phenyl-isoxazolyl, phenylpyridinyl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, methylisoquinolinyl, (methoxycarbonylmethylamino) isoquinolinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, 1,2-dihydro-1 methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro 4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4 oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazolinyl or a 2-oxo-2H chromenyl group, a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyanoethyl group, a phenylcarbonylmethyl or a 1-(phenylcarbonyl)-ethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino) carbonylamino or a 2-oxo-imidazolidin-1-yl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, WO 2004/018468 3 PCT/EP2003/009127 aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1 -ylcarbonylmethoxy or morpholin 4-ylcarbonylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1 -(methoxycarbonyl)-ethyloxy or a 1 -(aminocarbonyl)-ethyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups or a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -0-CH 2 -0, -O-CH 2
-CH
2 -0 or a -N(CH 3
)
CO-0 group,
R
2 denotes a hydrogen atom, a methyl, isopropyl, 2-propen-1-yl, 2-propyn-1-yl or phenyl group or a cyanomethyl or methoxycarbonylmethyl group and
R
3 denotes a 2-cyanobenzyl or 2,6-dicyanobenzyl group, a 2-methyl-2-propen-1 -yl, 2-chloro-2-propen-1 -yl or 3-bromo-2-propen-1 -yl group a 2-buten-1 -yl, 3-methyl-2-buten-1 -yl or 2,3-dimethyl-2-buten-1 -yl group, a 2-butyn-1 -yl group, a 1-cyclopenten-1-ylmethyl group or WO 2004/018468 4 PCT/EP2003/009127 a 2-furanylmethyl group. The carboxy groups mentioned in the definition of the above mentioned groups may be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, and furthermore the amino and imino groups mentioned in the definition of the above mentioned groups may be substituted by a group which can be cleaved in vivo. Such groups are described for example in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987). Compounds which contain a group that can be cleaved in vivo are prodrugs of the corresponding compounds wherein this group that can be cleaved in vivo has been cleaved. By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C1--alkanol, a phenyl-C 1
.
3 -alkanol, a C 3
.
9 -cycloalkanol, while a C 5 s 8 -cycloalkanol may additionally be substituted by one or two C1- 3 -alkyl groups, a C 5 s 8 -cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C1- 3 -alkyl, phenyl-C 1
.
3 -alkyl, phenyl
C
1
-
3 -alkyloxycarbonyl or C 2
-
6 -alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C 1
-
3 -alkyl groups, a C 4
.
7 -cycloalkenol, a C3- 5 -alkenol, a phenyl-C 3
-
5 -alkenol, a C 3
-
5 -alkynol or phenyl-C 3
-
5 -alkynol with the proviso that no bonds to the oxygen atom start from a carbon atom which carries a double or triple bond, a C 3
-
8 -cycloalkyl-C 1
-
3 -alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C 1
-
3 -alkyl groups, a 1,3-dihydro-3-oxo-1 isobenzofuranol or an alcohol of formula WO 2004/018468 5 PCT/EP2003/009127 Rp-CO-O-(RqCRr)-OH, wherein Rp denotes a C1.
8 -alkyl, C 5
.
7 -cycloalkyl, C 1
-
8 -alkyloxy, C 5 7 cycloalkyloxy, phenyl or phenyl- C1.
3 -alkyl group, Rq denotes a hydrogen atom, a C1- 3 -alkyl, C 5
.
7 -cycloalkyl or phenyl group and Rr denotes a hydrogen atom or a C 1
-
3 -alkyl group, by a group which is negatively charged under physiological conditions is meant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C 1
.
6 -alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino,
C
1
.
6 -alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C 1
.
6 -alkylsulphonylaminocarbony group and by a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as a phenylcarbonyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1
.
3 -alkyl or C1- 3 -alkoxy groups, while the substituents may be identical or different, a pyridinoyl group or a C1.
16 -alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3 trichloropropionyl or allyloxycarbonyl group, a C 1
.
1 -alkoxycarbonyl or C1.
16 -alkylcarbonyloxy group, wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy, WO 2004/018468 6 PCT/EP2003/009127 pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C 1
.
6 -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C1.
6 -alkyl or C 3
.
7 -cycloalkyl groups and the substituents may be identical or different, a Cl- 3 -alkylsulphonyl-C 2 4-alkoxycarbonyl, C 1
-
3 -alkoxy
C
2 4-alkoxy-C24-alkoxycarbonyl, Rp-CO-O-(RqCRr)-O-CO, C1.
6 -alkyl-CO-NH
(R
3 CRt)-O-CO- or C1.
6 -alkyl-CO-O-(RCRt)-(RCRt)-O-CO- group, wherein R, to R, are as hereinbefore defined, R, and Rt, which may be identical or different, denote hydrogen atoms or
C
1
.
3 -alkyl groups. A first object of the invention relates to compounds of general formula (1) wherein
R
1 denotes a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl group, a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group, a methyl group which is substituted by a 2-phenylethenyl or a biphenylyl group, a methyl group which is substituted by a phenyl-oxadiazolyl, 5-methyl-3 phenyl-isoxazolyl, phenyl-pyridinyl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, methylisoquinolinyl, (methoxycarbonylmethylamino) isoquinolinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, 1,2-dihydro-1 methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro 4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4- WO 2004/018468 7 PCT/EP2003/009127 oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazolinyl or a 2-oxo-2H chromenyl group, a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyanoethyl group, a phenylcarbonylmethyl or a 1 -(phenylcarbonyl)-ethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino) carbonylamino or a 2-oxo-imidazolidin-1 -yl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1 -ylcarbonylmethoxy or morpholin 4-ylcarbonylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1 -(methoxycarbonyl)-ethyloxy or a 1 -(aminocarbonyl)-ethyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy group, WO 2004/018468 8 PCT/EP2003/009127 a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups or a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -0-CH 2 -0, -O-CH 2
-CH
2 -0 or a -N(CH 3
)
CO-0 group,
R
2 denotes a methyl, isopropyl or phenyl group and
R
3 denotes a 2-methyl-2-propen-1 -yl, 2-chloro-2-propen-1 -yI or 3-bromo-2 propen-1-yl group a 2-buten-1 -yl or 2,3-dimethyl-2-buten-1 -yl group, a 2-butyn-1 -yl group, a 1 -cyclopenten-1 -ylmethyl group or a 2-furanylmethyl group, as well as the compounds 1-(2-cyano-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 9 PCT/EP2003/009127 1 -(2-{3-[(methanesulphinyl)methoxy] -phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -(1 -methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine, 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(dimethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1 -methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1 -methyl-3-(2- propyn-1 -yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, WO 2004/018468 10 PCT/EP2003/009127 1 -{2-[3-(2-oxo-imidazoiidin- 1 -yi)-phenyl]-2 -oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yi)-8-(3-amino-piperidin-1 -yI)-xanthine, 1 -methyl-3-(2-propen- 1 -yI)-7-(2-cyano-benzyl )-8-(3-amino-piperid in-i -yI ) xanthine, 1 -(2-{2-[(ethylcarbonyl)ami no]-phenyl}-2 -oxo-ethyl )-3-methyl-7-(3-methyl-2 buten-1 -yI)-8-(3-amino-piperidin-1 -yI)-xanthine, 1 -methyl-3-phenyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yI)-xanthine, 1 -[2-(2-amino-phenyl )-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yI )-8-((S) 3-amino-piperidin-1 -yi)-xanthine, 1 -(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7 -(3-methyl-2-buten-1 -yI)-8-(3-amino piperidin-1 -yI)-xanthine, 1 -[(q u ioi n-2-yI )methyl]-3-methyl-7-(3-methyl-2-buten- 1 -yI)-8-(3-amino piperidin-1 -yI)-xanthine, 1 -[(2-oxo-2H-chromen-4-y )methyl]-3-methyl-7-(3-methyl-2-buten-1 -yI )-8-(3 amino-piperidin-1 -yI)-xanthine, 1 -[(cinnolin-4-yI)methyl]-3-methyi-7-(3-methyl-2-buten-1 -yI)-8-(3-amino piperidin-1 -yI)-xanthine, 1 -[(1 -methyl-2-oxo-1 ,2-dihydro-quinolin-4-yI)methyl]-3-methyl-7-(3-methy-2 buten-1 -yI)-8-(3-amino-piperidin-1 -yI)-xanthine, 1 -[(4-oxo-3,4-dihydro-phthalazin-1 -yI)methyl]-3-methyl-7-(3-methyl-2-buten-1 yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(quinazolin-4-yI)methyl]-3-methyI-7-(3-methyl-2-buten-1 -yI)-8-(3-amino piperidin-1 -yI)-xanthine, WO 2004/018468 11 PCT/EP2003/009127 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yi) 8-(3-amino-piperidin-1 -yl)-xanthine, 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1 -yl)methyl]-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yi)-8-(3-amino-piperidin-1 -yi)-xanthine, 1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 12 PCT/EP2003/009127 1 -{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[3-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten- 1 yl)-8-(3-amino-piperidin-1 -yi)-xanthine, 1 -{2-[2-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-(3-amino-piperidin-1 -yl)-xanthine, 1 -((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin 1 -yl)-xanthine, 1 -[(benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1 -[(1 H-indol-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, WO 2004/018468 13 PCT/EP2003/009127 1 -[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -({5-[(methoxycarbonyl)methylamino]-isoquinolin-1 -yl}methyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-dimethylamino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(piperidin-1 -yi)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(2-methyl-1 -oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(pyrrolidin-1 -yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yi)-xanthine, WO 2004/018468 14 PCT/EP2003/009127 1-[2-(benzo[1,3]dioxol-4-yI)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8 (3-amino-piperidin-1 -yi)-xanthine, 1 -methyl-3-isopropyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(isoquinolin-1 -yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2 -oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)- 8 ((S)-3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, 1 -methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 15 PCT/EP2003/009127 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten- 1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(3-methyl-1 -buten-1 -yl)- 8 ((R)-3-amino-piperidin-1 -yl)-xanthine, 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-cyano-benzy)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[2-(3-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine and 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof. A first preferred sub-group of the first object of the invention comprises compounds of general formula I wherein
R
1 denotes a 4-methoxy-1-naphthylmethyl group, a 2-quinolinylmethyl, 4-quinolinylmethyl or a 6-quinolinylmethyl group, a 1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1 isoquinolinylmethyl or a 3-isoquinolinylmethyl group or WO 2004/018468 16 PCT/EP2003/009127 a 2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or a 4-quinazolinyl methyl group,
R
2 denotes a methyl group and
R
3 denotes a 2-buten-1-yl or a 2-butyn-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A second preferred sub-group of the first object of the invention comprises compounds of general formula 1, wherein
R
1 denotes a [2-(methylcarbonylamino)-phenyl]-carbonylmethyl group, a [2-(ethylcarbonylamino)-phenyl]-carbonylmethy group or a [2-(isopropylcarbonylamino)-phenyl]-carbonylmethy group,
R
2 denotes a methyl group and
R
3 denotes a 2-buten-1 -yl or a 2-butyn-1 -yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A third preferred sub-group of the first object of the invention comprises compounds of general formula I according to claim 1, wherein
R
1 denotes a [2-(aminocarbonylmethoxy)-phenyl]-carbonylmethy group, [2-(methylaminocarbonylmethoxy)-phenyl]-carbonylmethy group, WO 2004/018468 17 PCT/EP2003/009127 a [2-(ethylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group or a [2-(isopropylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group,
R
2 denotes a methyl group and
R
3 denotes a 2-buten-1-yl group, a 2-butyn-1-yl group or a 1 -cyclopenten-1 -ylmethyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A second object of the invention relates to compounds of general formula 1, wherein
R
1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group, a methyl group which is substituted by a phenanthrenyl group, a methyl group which is substituted by a 2-phenylethenyl, 2-[(trifluoromethyl) phenyl]-ethenyl, 2-(nitrophenyl)ethenyl, 2-(pentafluorophenyl)ethenyl or a biphenylyl group, a methyl group which is substituted by a phenyloxadiazolyl, phenylpyridinyl, indolyl, methylindolyl, dimethyl-6,7-dihydro-5H-[2]pyrindinyl, benzimidazolyl, methylbenzimidazolyl, (cyanoethyl)-benzimidazolyl, (methylamino carbonylmethyl)benzimidazolyl, benzylbenzimidazolyl, benzofuranyl, acetylbenzofuranyl, cyanobenzofuranyl, benzoxazolyl, nitrobenzoxazolyl, benzothiophenyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, WO 2004/018468 18 PCT/EP2003/009127 isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl ethyl)isoquinolinyl, phenylisoquinolinyl, methoxyisoquinolinyl, methoxy-chloro isoquinolinyl, methoxy-bromo-isoquinolinyl, (methoxycarbonylmethylamino) isoquinolinyl, dimethyl-5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro phenanthridinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropylquinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino)-quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1-ylquinazolinyl, morpholin-4 ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, phenyl oxyquinazolinyl, imidazo[1,2-a]pyridinyl, methylimidazo[1,2-a]pyridinyl, phenyl imidazo[1,2-a]pyridinyl, benzylimidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, methylphthalazinyl, naphthyridinyl, 2,3-dihydro-benzo[1,4] dioxinyl, 1,2-dihydro-2-oxo-quinolinyl, 1,2-dihydro-1-methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro-4-oxo-phthalazinyl, 3,4 dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4-oxo-quinazolinyl, 3,4 dihydro-3-methyl-4-oxo-quinazoliny or a 2-oxo-2H-chromenyl group, a phenylcarbonylmethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, (ethyloxycarbonylmethyl)amino, (methylaminocarbonyl)methylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, phenylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino)-carbonylamino or a 2-oxo imidazolidin-1-yl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, WO 2004/018468 19 PCT/EP2003/009127 methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy, carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylamino carbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1 ylcarbonylmethoxy or morpholin-4-ylcarbonylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1 -(ethyloxycarbonyl)-1 -methyl-ethyloxy, 1 -(methoxycarbonyl)-ethyloxy or a 1 (aminocarbonyl)-ethyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and a nitro group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and an amino group, a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -O-CH 2 -0, -O-CF 2 -0, -O-CH 2
-CH
2 -0, -NH CO-NH, -N(CH 3 )-CO-NH, -N(CH 3
)-CO-N(CH
3 ), -NH-CO-0- or a -N(CH 3
)
CO-0 group, WO 2004/018468 20 PCT/EP2003/009127 a (2-phenylethyl)carbonylmethyl group, a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or a 2-cyanimino-2-phenyl-ethyl group,
R
2 denotes a methyl, isopropyl, cyclopropyl, phenyl or fluorophenyl group and
R
3 denotes a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-y or 3-bromo-2 propen-1-yl group a 1 -buten-1 -yl, 3-methyl-1 -buten-1 -yl, 2-buten-1 -yl, 2-methyl-2-buten-1 -yl or 2,3-dimethyl-2-buten-1 -yl group, a 2-butyn-1-yI group, a 1-cyclopenten-1-ylmethyl group or a 2-furanylmethyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof. A preferred sub-group of the second object of the invention comprises compounds of general formula I wherein
R
1 and R 2 are as hereinbefore defined and
R
3 denotes a 1-buten-1-yl, 2-buten-1-yl or 2-butyn-1-y group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
WO 2004/018468 21 PCT/EP2003/009127 A particularly preferred sub-group of the second object of the invention comprises compounds of general formula I wherein
R
1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl group, a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group, a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenyl isoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropyl quinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino) quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1 ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1 methyl-2-oxo-quinolinyl group, a phenylcarbonylmethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group, WO 2004/018468 22 PCT/EP2003/009127 a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -O-CH 2 -0, -O-CF 2 -0, -O-CH 2
-CH
2 -0, N(CH 3
)-CO-N(CH
3 ) or a -N(CH 3 )-CO-O group, a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or a 2-cyanimino-2-phenyl-ethyl group,
R
2 denotes a methyl, isopropyl, cyclopropyl, phenyl or 4-fluorophenyl group and
R
3 denotes a 1-buten-1-yl, 2-buten-1-yl or a 2-butyn-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A second preferred sub-group of the second object of the invention comprises compounds of general formula 1, wherein R 1 and R 2 are defined as immediately above and R 3 denotes a 1 -buten-1 -yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A third preferred sub-group of the second object of the invention comprises compounds of general formula I wherein R' and R 2 are defined as immediately above and R 3 denotes a 2-buten-1 -yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A fourth preferred sub-group of the second object of the invention comprises compounds of general formula I wherein R 1 and R 2 are defined as immediately above and R 3 denotes a 2-butyn-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
WO 2004/018468 23 PCT/EP2003/009127 A third object of the invention relates to compounds of general formula I wherein
R
1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl- group, a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group, or a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenyl isoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropyl quinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino) quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1 ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1 methyl-2-oxo-quinolinyl group,
R
2 denotes a methyl, isopropyl, cyclopropyl or phenyl group and
R
3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2 cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
WO 2004/018468 24 PCT/EP2003/009127 A first preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R' denotes a (3-methyl-isoquinolin-1 -yl)methyl group,
R
2 denotes a methyl group and
R
3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2 cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A second preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R 1 and R 2 are as hereinbefore defined and R 3 denotes a 2-chlorobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A third preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R 1 and R 2 are as hereinbefore defined and R 3 denotes a 2-bromobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A fourth preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R 1 and R 2 are as hereinbefore defined and R 3 denotes a 2-ethynylbenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. A fifth preferred sub-group of the third object of the invention comprises compounds of general formula I wherein R 1 and R 2 are as hereinbefore defined and R 3 denotes a 2-cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
WO 2004/018468 25 PCT/EP2003/009127 Most particularly preferred are the following compounds of general formula 1: (1) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine, (2) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3 -methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (3) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2 -oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (4) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine, (5) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine, (6) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (7) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine, (8) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (9) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-(3-(R)-amino-piperidin-1 -yl)-xanthine, (10) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine, (11) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, WO 2004/018468 26 PCT/EP2003/009127 (12) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine, (13) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R) amino-piperidin-1 -yl)-xanthine, (14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, (15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, (17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (19) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (20) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (21) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (22) 1-[(4-fluoro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine , WO 2004/018468 27 PCT/EP2003/009127 (23) 1 -((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine , (24) 1-[(3-trifluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, (25) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, (26) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (27) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, (28) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (29) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R) 3-amino-piperidin-1-yl)-xanthine and (30) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine as well as the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods: a) reacting a compound of general formula WO 2004/018468 28 PCT/EP2003/009127 0 R3 RN NZi (lI), ON N wherein
R
1 to R 3 are as hereinbefore defined and Z' denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy group, with 3-aminopiperidine, the enantiomers thereof or the salts thereof. The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, ethyleneglycol monomethylether, ethyleneglycol diethylether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Honig base), while these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 1800C, but preferably at temperatures between -10 and 120'C. The reaction may, however, also be carried out without a solvent or in an excess of the 3 aminopiperidine.
WO 2004/018468 29 PCT/EP2003/009127 b) deprotecting a compound of general formula RI 0 R 3 H R2 NN N 0 wherein R 1 , R 2 and R 3 are as hereinbefore defined. The tert.-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 0 C. c) In order to prepare a compound of general formula I wherein R 1 according to the definition provided hereinbefore contains a carboxy group: deprotecting a compound of general formula O R3 N-1 R
NH
2 N wherein R 2 and R 3 are as hereinbefore defined and Rfcontains a carboxy group protected by a C14-alkyl group. The protecting group is cleaved by hydrolysis, for example, using an acid such as hydrochloric acid or sulphuric acid or an alkali metal hydroxide such WO 2004/018468 30 PCT/EP2003/009127 as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran or dioxane in the presence of water. In the reactions described hereinbefore, any reactive groups present such as carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. For example, a protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group. Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 1200C, preferably at temperatures between 10 and 100C. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 10000, but preferably at temperatures between 20 and 600C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
WO 2004/018468 31 PCT/EP2003/009127 A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxan, methanol or diethylether. A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 1200C, or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50*C. A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 500C. Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers. Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
WO 2004/018468 32 PCT/EP2003/009127 The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycarbonyl. Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compounds of general formulae 11 to IV used as starting materials are either known from the literature or may be obtained by methods known from the literature (cf. Examples I to LXXI). As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof WO 2004/018468 33 PCT/EP2003/009127 have valuable pharmacological properties, particularly an inhibiting effect on the enzyme DPP-IV. The biological properties of the new compounds were investigated as follows: The ability of the substances and their corresponding salts to inhibit the DPP IV activity can be demonstrated in a test set-up in which an extract of human colon carcinoma cell line Caco-2 is used as the DPP-IV source. The differentiation of the cells in order to induce the DPP-IV expression was carried out as described by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2" , which appeared in Proc. NatI. Acad. Sci. Vol. 90, pages 5757-5761 (1993). The cell extract was obtained from cells solubilised in a buffer (10mM Tris HCl, 0.15 M NaCI, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifuging at 35,000 g of for 30 minutes at 40C (to remove cell debris). The DPP-IV assay was carried out as follows: 50 pl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 pM, were placed in black microtitre plates. 20 pl of assay buffer (final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1 % DMSO) was pipetted in. The reaction was started by adding 30 pl of solubilised Caco 2 protein (final concentration 0.14 pg of protein per well). The test substances to be investigated were typically added prediluted in 20 pl, and the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient temperature, incubating for 60 minutes. Then the fluorescence was measured in a Victor 1420 Multilabel Counter, the excitation wavelength being 405 nm and the emission wavelength being 535 nm. Blank readings (corresponding to 0 % activity) were obtained in mixtures without any Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100 % activity) were obtained in mixtures with no substance added. The potency of the test substances in question, expressed as IC5o values, was calculated from dosage/activity curves consisting of 11 measuring points in each case. The following results were obtained: WO 2004/018468 34 PCT/EP2003/009127 Compound DPP-IV inhibition (Example no.) IC 50 [nM] 2(3) 2160 2(9) 264 2(12) 16 2(17) 32 2(20) 12 2(25) 4 2(27) 9 2(35) 5 2(37) 5 2(43) 6 2(51) 6 2(52) 9 2(59) 250 2(66) 22 2(80) 1 2(86) 2 2(96) 2 2(99) 1 2(100) 3 2(108) 3 2(129) 3 2(130) 3 2(131) 3 2(132) 1 2(135) 3 2(137) 13 2(138) 8 2(139) 4 2(142) 1 2(145) 4 2(148) 1 WO 2004/018468 35 PCT/EP2003/009127 2(150) 1 2(151) 3 2(152) 4 2(185) 3 2(217) 4 2(247) 2 2(251) 12 2(256) 8 2(260) 13 2(264) 6 2(277) 6 2(280) 5 2(285) 3 2(287) 11 2(288) 14 The compounds prepared according to the invention are well tolerated, as for example when 10 mg/kg of the compound of Example 2(80) were administered to rats by oral route no changes in the animals' behaviour could be detected. In view of their ability to inhibit DPP-IV activity, the compounds of general formula I according to the invention and the corresponding pharmaceutically acceptable salts thereof are suitable for treating all those conditions or illnesses which can be influenced by the inhibition of the DPP-IV activity. It is therefore to be expected that the compounds according to the invention will be suitable for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as e.g. retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidaemias of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and calcitonin-induced osteoporosis. In addition these substances are capable of preventing B-cell degeneration such as e.g. apoptosis or necrosis of pancreatic B-cells. The WO 2004/018468 36 PCT/EP2003/009127 substances are also suitable for improving or restoring the function of pancreatic cells and also increasing the number and size of pancreatic B cells. Additionally, and on the basis of the role of the Glucagon-Like Peptides, such as e.g. GLP-1 and GLP-2 and their link with DPP-IV inhibition, it is likely that the compounds according to the invention are suitable for achieving, inter alia, a sedative or anxiety-relieving effect and also for favourably affecting catabolic states after operations or hormonal stress responses or reducing mortality or morbidity after myocardial infarct. They are also suitable for treating all conditions which are connected with the above mentioned effects and which are mediated by GLP-1 or GLP-2. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for preventing and treating acute renal failure. Furthermore, the compounds according to the invention may be used to treat inflammatory diseases of the respiratory tract. They are also suitable for the prevention and treatment of chronic inflammatory intestinal diseases such as e.g. irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis and also pancreatitis. It is also likely that they can be used for all kinds of damage to or impairment of the gastrointestinal tract such as colitis and enteritis, for example. It is also expected that DPP-IV inhibitors and hence also the compounds according to the invention may be used to treat infertility or to improve fertility in humans or mammals, particularly when the infertility is connected with insulin resistance or polycystic ovary syndrome. On the other hand these substances are suitable for affecting sperm motility and can thus be used as male contraceptives. The substances are also suitable for treating deficiencies of growth hormone which are associated with reduced stature, and may also be used to advantage in any indications in which growth hormone may be used. The compounds according to the invention are also suitable, on the basis of their inhibitory effect on DPP-IV, for treating various autoimmune diseases such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease, etc. They may also be used to treat viral diseases and also, for example, in HIV infections, for stimulating blood production, in benign prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease, for example. The compounds described may also be used for the treatment of WO 2004/018468 37 PCT/EP2003/009127 tumours, particularly for modifying tumour invasion and also metastasisation; examples here are their use in treating T-cell lymphomas, acute lymphoblastic leukaemia, cell-based pancreatic carcinomas, basal cell carcinomas or breast cancers. Other indications are stroke, ischaemia of various origins, Parkin son's disease and migraine. In addition, further indications include follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophies, as well as psycho somatic, depressive and neuropsychiatric diseases of all kinds. The compounds according to the invention may also be used in conjunction with other active substances. Therapeutic agents which are suitable for such combinations include, for example, antidiabetics, such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. Also, SGLT2 inhibitors such as T-1095, inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents, such as HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol resorption inhibitors such as for example ezetimibe, bile acid-binding substances such as for example cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as for example inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, WO 2004/018468 38 PCT/EP2003/009127 NPY5 or NPY2 antagonists or R 3 -agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor. It is also possible to combine the compounds with drugs for treating high blood pressure such as e.g. All antagonists or ACE inhibitors, diuretics, B-blockers, Ca-antagonists, etc., or combinations thereof. The dosage required to achieve such an effect is expediently, by intravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. The Examples that follow are intended to illustrate the invention: WO 2004/018468 39 PCT/EP2003/009127 Preparation of the starting compounds: Example I 1,3-dimethyl-7-(2,6-dicyano-benzyl)-8-bromo-xanthine A mixture of 555 mg of 8-bromotheophyllin and 0.39 ml of Hinig base in 9 ml N,N-dimethylformamide is combined with 600 mg of 2-bromomethyl isophthalonitrile and stirred overnight at ambient temperature. For working up the reaction mixture is poured onto water. The precipitate formed is suction filtered, washed with water and dried. Yield: 686 mg (83 % of theory) Rf value: 0.56 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 399, 401 [M+H]* The following compounds are obtained analogously to Example I: (1) 3-methyl-7-(3-methyl-2-buten-1 -yl)-8-chloro-xanthine Mass spectrum (ESl*): m/z = 269, 271 [M+H]* (2) 3-methyl-7-(2-cyano-benzyl)-8-ch loro-xanthine Mass spectrum (ESl*): m/z = 316, 318 [M+H]* (3) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Mass spectrum (ESl*): m/z = 415, 417 [M+H]* (4) 3-methyl-7-[(2-trimethylsilanyl-ethoxy)methyl]-8-bromo -xa nth i ne (Carried out in the presence of potassium carbonate) Mass spectrum (ESl*): m/z = 375, 377 [M+H]* (5) 3-methyl-7-(3-methyl-2-buten-1 -yl)-8-bromo-xanthine Mass spectrum (ESl*): m/z = 313, 315 [M+H]* (6) 3-methyl-7-(2,3-dimethyl-2-buten-1 -yl)-8-bromo-xanthine Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 327, 329 [M+H]* WO 2004/018468 40 PCT/EP2003/009127 (7) 3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine Rf value: 0.72 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 297/299 [M+H]* (8) 3-methyl-7-((E)-2-buten-1 -yl)-8-bromo-xanthine (The product is contaminated with approx. 10-20 % of Z compound) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/methanol = 6:3:1) Mass spectrum (ESl*): m/z = 299, 301 [M+H]* (9) 3-methyl-7-[(1 -cyclopenten-1 -yl)methyl] -8-bromo-xanthine Mass spectrum (ESl*): m/z = 325, 327 [M+H]* (10) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8 bromo-xanthine Mass spectrum (ESl*): m/z = 443, 445 [M+H]* (11) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1 -yl)-8-bromo-xanthine (product contains approx. 25 % of Z isomer) Mass spectrum (ESI*): m/z = 417, 419 [M+H]* (12) 1 -(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-methyl-al lyl)-8-bromo-xanthine Rf value: 0.71 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 417, 419 [M+H]* (13) 1 -(2-phenyl-2-oxo-ethyl)-3-methyl-7-(3-bromo-allyl)-8-bromo-xanth i ne Rf value: 0.68 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI): m/z = 481, 483, 485 [M+H]* (14) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(furan-2-yl)methyl]-8-bromo xanthine Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 443, 445 [M+H]* WO 2004/018468 41 PCT/EP2003/009127 (15) 1 -(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-chloro-aIlyl)-8-bromo-xanthine Rf value: 0.77 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 437, 439, 441 [M+H]* (16) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-methyl-2-buten-1-yl)-8-bromo xanthine Rf value: 0.77 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 431, 433 [M+H]* (17) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-methyl-2-buten-1-yl)-8-bromo xanthine Rf value: 0.77 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 431, 433 [M+H]* (18) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(1 -phenylsulphanyl-butyl)-8-bromo xanthine Rf value: 0.83 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 527, 529 [M+H]* (19) 3-methyl-7-(3-methyl-1 -phenylsulphanyl-butyl)-8-bromo-xanthine (The [(1-chloro-3-methyl-butyl)sulphanyl]-benzene used as starting material for the reaction is obtained by chlorination of [(3-methyl-butyl)sulphanyl] benzene with N-chloro-succinimide in carbon tetrachloride) Rf value: 0.38 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 423, 425 [M+H] (20) 1,3-dimethyl-7-(2-bromo-benzyl)-8-chloro-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:1) (21) 1,3-dimethyl-7-(2-chloro-benzyl)-8-chloro-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:1) (22) 3-cyclopropyl-7-(2-butyn-1 -yl)-8-bromo-xanthine WO 2004/018468 42 PCT/EP2003/009127 Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 223/225 [M+H]* Example 11 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine 63 mg of ethyl bromoacetate are added to a mixture of 200 mg of 1-[2-(2 hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine and 63 mg of potassium carbonate in 3 ml N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up it is combined with water and the precipitate formed is suction filtered, washed with water and dried for three hours at 800C in the drying cupboard. Yield: 216 mg (94 % of theory) Mass spectrum (ESl*): m/z = 653 [M+H]* The following compounds are obtained analogously to Example 11: (1) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl)-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESl*): m/z = 624 [M+H]* (2) 1-(2-{3-[(methylsulphanyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate = 6:4) Mass spectrum (ESI*): m/z = 627 [M+H]* (3) 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 3:7) WO 2004/018468 43 PCT/EP2003/009127 (4) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yi] xanthine Mass spectrum (ESI*): m/z = 638 [M+H]* (5) 1-(2-{2-[(dimethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 652 [M+H]* (6) 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 639 [M+H]* (7) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yi)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine Mass spectrum (ESI*): m/z = 636 [M+H]* (8) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 [(1 -cyclopenten-1 -yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 650 [M+H]* (9) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2 -oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 622 [M+H]* (10) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 608 [M+H]* WO 2004/018468 44 PCT/EP2003/009127 (11) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 623 [M+H]* (12) 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl] xanthine Mass spectrum (ESI*): m/z = 667 [M+H]* (13) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 622 [M+H]* (14) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains some Z isomer) Rf value: 0.35 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESI'): m/z = 624 [M+H]* (15) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 636 [M+H]* (16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 622 [M+H]* (17) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESl*): m/z = 639 [M+H]* WO 2004/018468 45 PCT/EP2003/009127 (18) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 638 [M+H]* (19) 2-(2-acetyl-phenoxy)-N-ethyl-acetamide Mass spectrum (ESI*): m/z = 222 [M+H]* (20) 1 -{2-[2-(1 -methoxycarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yI)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 637 [M+H]* (21) 1-{2-[2-(1-aminocarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 622 [M+H]* (22) 2-(2-acetyl-phenoxy)-N-methyl-acetamide Mass spectrum (ESI*): m/z = 208 [M+H]* (23) 1-{2-[2-(2-oxo-propoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESIl): m/z = 607 [M+H]* (24) 1 -{2-[2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-phenyl]-2-oxo-ethyl}-3 methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin- 1-yl] xanthine Mass spectrum (ESI*): m/z = 665 [M+H]* (25) 1-{2-[2-cyanomethoxy-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 590 [M+H]* (26) 1-(2-{2-[(methylsulphanyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yi)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 46 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 611 [M+H]* (27) 1-{[2-(tert.-butylcarbonyl)-benzofuran-3-yl]methyl}-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Formed as main product when 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl 7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine is reacted with 1-chloro-3,3-dimethyl-butan-2-one) Mass spectrum (ESI*): m/z = 631 [M+H]* Example I1 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine 1.30 g of 3-tert.-butyloxycarbonylamino-piperidine are added to a mixture of 2.51 g of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-chloro-xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulphoxide. The reaction mixture is stirred for 18 hours at 60 0 C. For working up it is combined with water and the precipitate formed is suction filtered. The solid crude product is dissolved in ethyl acetate, the solution is dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (10:1 to 1:1) as eluant. Yield: 2.56 g (91 % of theory) Mass spectrum (ESl*): m/z = 567 [M+H]* The following compounds are obtained analogously to Example IlIl: (1) 3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 433 [M+H]* (2) 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 565 [M+H]* WO 2004/018468 47 PCT/EP2003/009127 (3) 3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1-yl]-xanthine Rf value: 0.90 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI-): m/z = 478 [M-H]~ (4) 1-methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 552 [M+H]* (5) 1 -methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl amino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 519 [M+H]* (6) 1 -methyl-3-(2-propyn-1 -yl)-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl amino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 518 [M+H]* (7) 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-l-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate/methanol = 7:2:1) Mass spectrum (ESI*): m/z = 596 [M+H]* (8) 1-methyl-3-(2-propen-1-yl)-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonyl amino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 520 [M+H]* (9) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 535 [M+H]* (10) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 596 [M+H]* WO 2004/018468 48 PCT/EP2003/009127 (11) 1 -methyl-3-phenyl-7-(2-cyano-benzyl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 556 [M+H]* (12) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 596 [M+H]* (13) 1-[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine mixed with1-[(1,4-dihydro cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.62 (silica gel, ethyl acetate) (14) 1-({4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1 yl}methyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with potassium carbonate in the presence of HOnig base) Rf value: 0.27 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 720 [M+H]* (15) 1-[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.31 (silica gel, ethyl acetate/petroleum ether = 7:3) Mass spectrum (ESl*): m/z = 574 [M+H]* (16) 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5) Mass spectrum (ESI*): m/z = 605 [M+H]* WO 2004/018468 49 PCT/EP2003/009127 (17) 3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine (Carried out with potassium carbonate) Rf value: 0.42 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI*): m/z = 447 [M+H]* (18) 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 yl]-xanthine (Carried out with potassium carbonate) Melting point: 235-237*C Mass spectrum (ESI*): m/z = 417 [M+H]* (19) 1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with potassium carbonate) Rf value: 0.36 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 558 [M+H]* (20) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with potassium carbonate) Rf value: 0.71 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 558 [M+H]* (21) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with potassium carbonate; the product contains approx. 20 % of Z isomer) Rf value: 0.24 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESI): m/z = 560 [M+H]* (22) 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin 1 -yl]-xanthine (Carried out with potassium carbonate) WO 2004/018468 50 PCT/EP2003/009127 Rf value: 0.64 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 417 [M+H]* (23) 3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin 1 -yl]-xanthine (Carried out with potassium carbonate) Rf value: 0.64 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 417 [M+H]* (24) 3-methyl-7-((E)-2-buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine (product contains approx. 15 % of Z isomer) Rf value: 0.35 (silica gel, cyclohexane/ ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 419 [M+H]* (25) 3-methyl-7-((E)-2-buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine (product contains approx. 15 % of Z isomer) Rf value: 0.35 (silica gel, cyclohexane/ ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 419 [M+H]* (26) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 551 [M+H]* (27) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 578 [M+H]* (28) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten-1-yl)methyl]-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 563 [M+H]* WO 2004/018468 51 PCT/EP2003/009127 (29) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 579 [M+H]* (30) 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 522 [M+H]* (31) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 551 [M+H]* (32) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 10 % of Z isomer) Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate =1:1) Mass spectrum (ESl*): m/z = 552 [M+H]* (33) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 25 % of Z isomer) Mass spectrum (ESl*): m/z = 537 [M+H]* (34) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (35) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains some Z isomer) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESl*): m/z = 553 [M+H]* (36) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 52 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 551 [M+H]* (37) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 550 [M+H]* (38) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 567 [M+H]* (39) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 535 [M+H]* (40) 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 610 [M+H]* (41) 3-methyl-7-(2-butyn-1 -yl)-8-[(S)- 3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine (Carried out with potassium carbonate) Rf value: 0.52 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 417 [M+H]* (42) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-methyl-allyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.46 (silica gel, methylene chloride/methanol = 95:5) (43) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(3-bromo-allyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.22 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI'): m/z = 601, 603 [M+H]* WO 2004/018468 53 PCT/EP2003/009127 (44) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(furan-2-yl)methyl]-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol = 95:5) (45) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-chloro-allyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.49 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 557, 559 [M+H]* (46) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 535 [M+H]* (47) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESI): m/z = 552 [M+H]* (48) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:2) (49) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 582 [M+H]* (50) 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 626 [M+H]* (51) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro benzooxazol-7-yl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 738 [M+H]* WO 2004/018468 54 PCT/EP2003/009127 (52) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI): m/z = 551 [M+H]* (53) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 551 [M+H]* (54) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro benzooxazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 722 [M+H]* (55) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 615 [M+H]* (56) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 615 [M+H]* (57) 1 -[(1-methyl-1 H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxy-carbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 560 [M+H]* (58) 1-[(quinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonyl-amino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 558 [M+H]* WO 2004/018468 55 PCT/EP2003/009127 (59) 1-{[1-(tert.-butyloxycarbonylamino)-1H-indol-2-yl]methyl}-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI'): m/z = 646 [M+H]* (60) 1-[(2-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5 yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1-yl]-xanthine (mixed with1-[(2-methyl-3-[(2-trimethylsilanyl ethoxy)methyl]-3H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine) Rf value: 0.15 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 691 [M+H]* (61) 1-[2-(quinolin-8-yl-]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxy-carbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 586 [M+H]* (62) 1-[(1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl)methyl]-3 methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl] xanthine (mixed with1-[(3-[(2-trimethylsilanyl-ethoxy)methyl]-3H benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine) Rf value: 0.23 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 677 [M+H]* (63) 1-[(pyrazolo[1,5-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.46 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI'): m/z = 547 [M+H]* (64) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-1-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) WO 2004/018468 56 PCT/EP2003/009127 Mass spectrum (ESl*): m/z = 537 [M+H]* (65) 1-{2-[1-(tert.-butyloxycarbonyl)-1H-indol-7-yl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.38 (silica gel, petroleum ether/ethyl acetate = 1:1) (66) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(3-methyl-1 -buten-1 -yl) 8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 588 [M+H]* (67) 1,3-dimethyl-7-(2-bromo-benzyl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1) (68) 1,3-dimethyl-7-(2-chloro-benzyl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Rf value: 0.42 (silica gel, cyclohexane/ethyl acetate = 1:1) (69) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 635 [M+H]* Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 3:7) (70) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 443 [M+H]* Rf value: 0.70 (silica gel, ethyl acetate) (71) 3-cyclopropyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Rf value: 0.35 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 443 [M+H]* WO 2004/018468 57 PCT/EP2003/009127 (72) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 644, 646 [M+H]* Rf value: 0.39 (silica gel, cyclohexane/ethyl acetate = 1:1) (73) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 644, 646 [M+H]* (74) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Prepared by reacting (4-methyl-quinazolin-2-yl)-methylchloride and 3-methyl 7-(2-chlorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3 (tert.-butyloxycarbonylamino)-piperidine Mass spectrum (ESI*): m/z = 645, 647 [M+H]* (75) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Prepared by reacting (4-phenyl-quinazolin-2-yl)-methylchloride and 3-methyl 7-(2-ch lorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3 (tert.-butyloxycarbonylamino)-piperidine Mass spectrum (ESl*): m/z = 707, 709 [M+H]* Example IV 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 chloro-xanthine Prepared by treating 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1-yl)-8-chloro-xanthine with boron tribromide in methylene chloride. The desired product is contaminated with approx. 20 % 1-[2-(2 hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-bromo-3-methyl-butyl)-8-chloro xanthine. Mass spectrum (ESl*): m/z = 403, 405 [M+H]* WO 2004/018468 58 PCT/EP2003/009127 The following compounds are obtained analogously to Example IV: (1) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine (product is contaminated with approx. 20 % 1-[2-(2-hydroxy-phenyl)-2-oxo ethyl]-3-methyl-7-(3-bromo-2-buten-1 -yl)-8-bromo-xanthine) Mass spectrum (ESI*): m/z = 431, 433 [M+H]* (2) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-bromo-xanthine Mass spectrum (ESI*): m/z = 459, 461 [M+H]* (3) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8 bromo-xanthine (product contains some Z isomer) Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESl*): m/z = 433, 435 [M+H]* (4) 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 bromo-xanthine Mass spectrum (ESI*): m/z = 447, 449 [M+H]* Example V 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8 chloro-xanthine 1.71 g of 2-bromo-1 -(2-methoxy-phenyl)-ethanone are added to a mixture of 2.00 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.38 mg of potassium carbonate in 15 ml of N,N-dimethylformamide. The reaction mixture is stirred for eight hours at ambient temperature. After aqueous working up the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (8:1 to 8:1) as eluant. Yield: 2.61 g (84 % of theory) Mass spectrum (ESl*): m/z = 417, 419 [M+H]* WO 2004/018468 59 PCT/EP2003/009127 The following compounds are obtained analogously to Example V: (1) 1-[2-(3-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)- 8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (The reaction is carried out with 2-bromo-1 -[3-(tert.-butyldimethylsilanyloxy) phenyl]-ethanone) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESI'): m/z = 567 [M+H]* (2) 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8 chloro-xanthine Mass spectrum (ESI*): m/z = 401, 403 [M+H] (3) 1 -(2-cya no-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-chloro-xa nth i ne Mass spectrum (ESI'): m/z = 391, 393 [M+Na]* (4) 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.90 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 600 [M+H]* (5) 1-(2-phenyl-2-oxo-ethyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(3-methyl 2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 667 [M+H]* (6) 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.90 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 538 [M+H]* (7) 1 -methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2 -cyano-benzyl)-xanth i ne Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI'): m/z = 412 [M+H]* WO 2004/018468 60 PCT/EP2003/009127 (8) 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 chloro-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol = 7:2:1) Mass spectrum (ESl*): m/z = 432, 434 [M+H]* (9) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(2-trimethylsilanyl-ethoxy)methyl]-8 bromo-xanthine Mass spectrum (ESl*): m/z = 493, 495 [M+H]* (10) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8 chloro-xanthine } Rf value: 0.64 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESI*): m/z = 432, 434 [M+H]* (11) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8 bromo-xanthine Mass spectrum (ESl*): m/z = 476, 478 [M+H]* (12) 1-[(quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.45 (silica gel, ethyl acetate/petroleum ether = 7:3) Mass spectrum (ESI*): m/z = 574 [M+H]* (13) 1-[(2-oxo-2H-chromen-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-l-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (The starting material 4-bromomethyl-chromen-2-one is prepared analogously to Kimura et al., Chem. Pharm. Bull. 1982, 30, 552-558.) Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 591 [M+H]* (14) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) WO 2004/018468 61 PCT/EP2003/009127 Mass spectrum (ESl*): m/z = 604 [M+H]* (15) 1-[(quinazolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Melting point: 195-1970C Mass spectrum (ESI*): m/z = 575 [M+H]* (16) 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 604 [M+H]* (17) 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.18 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI*): m/z = 591 [M+H]* (18) 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.53 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 600 [M+H]* (19) 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.73 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 600 [M+H]* (20) 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.43 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 597 [M+H]* (21) 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 62 PCT/EP2003/009127 (Carried out in N-methylpyrrolidin-2-one at 600C) Rf value: 0.27 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI*): m/z = 609 [M+H]* (22) 1-[2-(2- ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in N-methylpyrrolidin-2-one at 60*C) Rf value: 0.35 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 623 [M+H]* (23) 1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in N-methylpyrrolidin-2-one at 600C) Rf value: 0.53 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI'): m/z = 611 [M+H]* (24) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in N-methylpyrrolidin-2-one at 600C) Rf value: 0.38 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 565 [M+H]* (25) 1 -((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 549 [M+H]* (26) 1-[(1-benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 579 [M+H]* WO 2004/018468 63 PCT/EP2003/009127 (27) 1-{[1-(tert.-butyloxycarbonyl)-indol-3-yl]methyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.61 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI): m/z = 662 [M+H]* (28) 1-[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 599 [M+H]* (29) 1-[(1-naphthyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.83 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESI*): m/z = 557 [M+H]* (30) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn 1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESl*): m/z = 588 [M+H]* (31) 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Melting point: 163-165*C Mass spectrum (ESI*): m/z = 557 [M+H]* (32) 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.95 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESl*): m/z = 531 [M+H]* (33) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 559 [M+H]* WO 2004/018468 64 PCT/EP2003/009127 (34) 1-[(2-methyl-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 571 [M+H]* (35) 1-[(5-nitro-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) (36) 1-(2-dimethylamino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.23 (silica gel, ethyl acetate) Mass spectrum (ESI'): m/z = 518 [M+H]* (37) 1-[2-(piperidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.44 (silica gel, ethyl acetate) Mass spectrum (ESI'): m/z = 558 [M+H]* (38) 1-[(2-methyl-1 -oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(2-butyn-1 -yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 588 [M+H]* (39) 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.30 (silica gel, ethyl acetate) Mass spectrum (ESI): m/z = 604 [M+H]* (40) 1-[(2-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 587 [M+H]* WO 2004/018468 65 PCT/EP2003/009127 (41) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 587 [M+H]* (42) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.56 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 572 [M+H]* (43) 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.83 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 611 [M+H]* (44) 1-[(5-nitro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.78 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 602 [M+H]* (45) 1-[2-(pyrrolidin-1-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.39 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 544 [M+H]* (46) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.56 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 572 [M+H]* (47) 1-[(2-naphthyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.78 (silica gel, ethyl acetate) WO 2004/018468 66 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 557 [M+H]* (48) 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl amino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESIf): m/z = 456 [M+H]* (49) 1-[(quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 558 [M+H]* (50) 1-[(3-methoxy-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.83 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 587 [M+H]* (51) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.38 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 609 [M+H]* (52) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1 -yl]-xanthine (Carried out with potassium-tert. butoxide in dimethylsulphoxide) Rf value: 0.48 (silica gel, ethyl acetate/petroleum ether = 2:1) Mass spectrum (ESI*): m/z = 622 [M+H]* (53) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten- 1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 595 [M+H]* WO 2004/018468 67 PCT/EP2003/009127 (54) 1 -[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 559 [M+H]* (55) 1 -[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI'): m/z = 559 [M+H]* (56) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 15 % of Z isomer) Rf value: 0.30 (silica gel, ethyl acetate/cyclohexane = 8:2) Mass spectrum (ESl*): m/z = 561 [M+H]* (57) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 15 % of Z isomer) Rf value: 0.30 (silica gel, ethyl acetate/cyclohexane = 8:2) Mass spectrum (ESl*): m/z = 561 [M+H]* (58) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 17 % of Z isomer) Rf value: 0.58 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 574 [M+H]* (59) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 17 % of Z isomer) Rf value: 0.58 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 574 [M+H]* (60) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo xanthine WO 2004/018468 68 PCT/EP2003/009127 Mass spectrum (ESI): m/z = 445, 447 [M+H]* (61) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1-yl)methyl] 8-bromo-xanthine Mass spectrum (ESI): m/z = 488, 490 [M+H]* (62) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-bromo-xanth i ne Mass spectrum (ESI*): m/z = 473, 475 [M+H]* (63) 1-[(isoquinolin-1-yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.35 (silica gel, methylene chloride/methanol = 95:5) (64) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo xanthine (product contains approx. 10 % of Z isomer) Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESI*): m/z = 462, 464 [M+H]* (65) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8 bromo-xanthine (product contains some Z isomer) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 447, 449 [M+H]* (66) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo xanthine Rf value: 0.77 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 460, 462 [M+H]* (67) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 20 % of Z isomer) WO 2004/018468 69 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 537 [M+H]* (68) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-bromo-xanthine Mass spectrum (ESIf): m/z = 461, 463 [M+H]* (69) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Rf value: 0.61 (silica gel, cyclohexane/ethyl acetate = 4:6) (70) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine (product contains approx. 17 % of Z isomer) Mass spectrum (ESI*): m/z = 638 [M+H]* (71) 1 -(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten- 1-yl)-8-[(S)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 18 % of Z isomer) Rf value: 0.35 (silica gel, cyclohexarie/ethyl acetate = 6:4) Mass spectrum (ESl*): m/z = 537 [M+H]* (72) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 580 [M+H]* (73) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI): m/z = 572 [M+H]* (74) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 572 [M+H]* WO 2004/018468 70 PCT/EP2003/009127 (75) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 572 [M+H]* (76) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 572 [M+H]* (77) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8-[(S) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 574 [M+H]* (78) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 574 [M+H]* (79) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.18 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 593 [M+H]* (80) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 593 [M+H]* (81) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.56 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESIl): m/z = 587 [M+H]* WO 2004/018468 71 PCT/EP2003/009127 (82) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 587 [M+H]* (83) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.86 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESI*): m/z = 579 [M+H]* (84) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.86 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESl*): m/z = 579 [M+H]* (85) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 573 [M+H]* (86) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 573 [M+H]* (87) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1 -yl]-xanthine Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 622 [M+H]* (88) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 638 [M+H]* WO 2004/018468 72 PCT/EP2003/009127 (89) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 624 [M+H]* (90) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Mass spectrum (ESI*): m/z = 624 [M+H]* (91) 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) (92) 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-bromo-xanthine Mass spectrum (ESI*): m/z = 506, 508 [M+H]* (93) 1-[(4-dimethylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 602 [M+H]* (94) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro benzooxazol-7-yl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-bromo xanthine Rf value: 0.75 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESI*): m/z = 618, 620 [M+H]* (95) 1-[(imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.44 (silica gel, methylene chloride/methanol = 95:5) WO 2004/018468 73 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 547 [M+H]* (96) 1-[(quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonyl-amino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 559 [M+H]* (97) 1-[2-(1,3-dimethyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yl)-2-oxo-ethyl] 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 619 [M+H]* (98) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 559 [M+H]* (99) 1-(2-{2-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro benzooxazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI~): m/z = 600, 602 [M-H] (100) 1-[(3-methyl-quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 573 [M+H]* (101) 1-[(3-phenyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 634 [M+H]* WO 2004/018468 74 PCT/EP2003/009127 (102) 1-[(3,4-dimethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, ethyl acetate/methanol = 3:1) Mass spectrum (ESl*): m/z = 586 [M+H]* (103) 1-[(benzofuran -2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-[(R)-3-(tert.-butyl oxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 547 [M+H]* (104) 1-{[4-(morpholin-4-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl) 8-[3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.28 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 644 [M+H]* (105) 1-{[4-(piperidin-1-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 642 [M+H]* (106) 1 -({4-[4-(tert.-butyloxycarbonyl)-piperazin-1 -yl]-quinazolin-2-yl}methyl) 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI): m/z = 743 [M+H]* (107) 1 -{[4-(pyrrolidin-1 -yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1 -yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI'): m/z = 628 [M+H]* WO 2004/018468 75 PCT/EP2003/009127 (108) 1-[2-(1-ethoxycarbonyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4 yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI*): m/z = 677 [M+H]* (109) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.77 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 582 [M+H]* (110) 1 -[(imidazo[1,2-a]pyridine-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 547 [M+H]* (111) 1-[(8-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, ethyl acetate) Mass spectrum (ESI): m/z = 561 [M+H]* (112) 1-[(8-methoxy-quinolin-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI*): m/z = 588 [M+H]* (113) 1-[(5-methoxy-quinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI*): m/z = 588 [M+H]* (114) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 76 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 635 [M+H]* (115) 1-[(7-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 561 [M+H]* (116) 1-(2-oxo-4-phenyl-butyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 563 [M+H]* (117) 1-(2-{2-oxo-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-2,3-dihydro-1 H benzoimidazol-4-yl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 851 [M+H]* (118) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (By-product of the reaction of 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine with 1 -chloromethyl-3-trifluoromethyl 3,4-dihydro-isoquinoline) Rf value: 0.75 (aluminium oxide, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI*): m/z = 608 [M+H]* (119) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-bromo-xanthine Mass spectrum (ESI*): m/z = 495, 497 [M+H]* (120) 1-[(3-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 561 [M+H]* WO 2004/018468 77 PCT/EP2003/009127 (121) 1-[(5-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 561 [M+H]* (122) 1-[(6-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.10 (silica gel, ethyl acetate/methanol = 98:2) Mass spectrum (ESI*): m/z = 561 [M+H]* (123) 1-[(3-benzyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESIl): m/z = 637 [M+H]* (124) 1-[(4-isopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate/petroleum ether = 8:2) Mass spectrum (ESI*): m/z = 601 [M+H]* (125) 1-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-[3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine Rf value: 0.53 (silica gel, ethyl acetate/petroleum ether = 3:2) (126) 1-[(3-phenyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 623 [M+H]* (127) 1-[2-(naphthalen-1 -yl]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 585 [M+H]* WO 2004/018468 78 PCT/EP2003/009127 (128) 1-[(5-methoxy-isoquinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate/methanol = 24:1) Mass spectrum (ESl*): m/z = 588 [M+H]* (129) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)- 8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (By-product of the reaction of 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine with 1 -chloromethyl-3-trifluoromethyl 3,4-dihydro-isoquinoline) Rf value: 0.75 (aluminium oxide, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 608 [M+H]* (130) 1 -{[1 -(1 -cyano-1 -methyl-ethyl)-isoquinolin-3-yl]methyl}-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 625 [M+H]* (132) 1-methoxycarbonylmethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonyl-amino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 489 [M+H]* (133) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 635 [M+H]* (134) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in the presence of caesium carbonate) Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 587 [M+H]* WO 2004/018468 79 PCT/EP2003/009127 (135) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether = 8:2) Mass spectrum (ESl*): m/z = 635 [M+H]* (136) 1-[2-(quinolin-8-yl-]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine Rf value: 0.55 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 466, 468 [M+H]* (137) 1-[(3,4-dimethyl-6,7-dihydro-5H-[2]pyrindin-1 -yl)methyl]-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (aluminium oxide, ethyl acetate/petroleum ether = 3:1) Mass spectrum (ESI*): m/z = 576 [M+H]* (138) 1-[(3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1-yl)methyl]-3-methyl-7 (2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (aluminium oxide, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 590 [M+H]* (139) 1 -{2-[1 -(tert.-butyloxycarbonyl)-1 H-indol-4-yl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 674 [M+H]* (140) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)methyl]-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (El): m/z = 587 [M]* (141) 1-({1-[(2-trimethylsilanyl-ethoxy)methyl]-2-oxo-1,2-dihydro-quinolin-6 yl}methyl)-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 704 [M+H]* WO 2004/018468 80 PCT/EP2003/009127 (142) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8
-[
3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 601 [M+H]* (143) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 573 [M+H]* (144) 1-[(4-methyl-phthalazin -1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 573 [M+H]* (145) 1-[(4-bromo-3-methoxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 666, 668 [M+H]* (146) 1-[(4-difluoromethoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 623 [M+H]* (147) 1 -{2-[1 -(tert.-butyloxycarbonyl)-1 H-indol-7-yl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-bromo-xanthine Rf value: 0.83 (silica gel, methylene chloride/methanol = 95:5) (148) 1 -[(E)-3-(2-nitro-phenyl)-2-propen-1 -yl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 578 [M+H]* (149) 1 -((E)-3-pentafluorophenyl-2-propen-1 -yl)-3-methyl-7-(2-butyn-1 -yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 81 PCT/EP2003/009127 Mass spectrum (ESI): m/z = 623 [M+H]* (150) 1-[(4-nitro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 602 [M+H]* (151) 1-[(benzooxazol-2-y)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbo-nylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 548 [M+H]* (152) 1-[(5-nitro-benzooxazol-2-y)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESl*): m/z = 593 [M+H]* (153) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(3-methyl-1 -buten-1 -yl) 8-bromo-xanthine Rf value: 0.65 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 468, 470 [M+H]* (154) 1-[(quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonyl-amino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 558 [M+H]* (155) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 559 [M+H]* (156) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.45 (silica gel, methylene chloride/methanol = 19:1) Mass spectrum (ESl*): m/z = 573 [M+H]* WO 2004/018468 82 PCT/EP2003/009127 (157) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.32 (silica gel, methylene chloride/methanol = 96:4) Mass spectrum (ESI*): m/z = 601 [M+H]* (158) 1-[([1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.20 (silica gel, ethyl acetate/methanol = 98:2) Mass spectrum (ESl*): m/z = 559 [M+H]* (159) 1-[([1,8]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.12 (silica gel, ethyl acetate/methanol = 98:2) Mass spectrum (ESl*): m/z = 559 [M+H]* (160) 1-[(4-fluoro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.47 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 575 [M+H]* (161) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.39 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 559 [M+H]* (162) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-y)-2-oxo-ethyl]-3 methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.60 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 606 [M+H]* (163) 1-[(8-phenyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 83 PCT/EP2003/009127 Rf value: 0.48 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 356 [M+H]* (164) 1-[([1,5]naphthyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESl*): m/z = 559 [M+H]* (165) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 623 [M+H]* (166) 1-[(E)-3-(2-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 601 [M+H]* (167) 1-[(E)-3-(3-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 601 [M+H]* (168) 1 -[(E)-3-(4-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl'): m/z = 601 [M+H]* (169) 1-[(3-trifluoromethyl-isoquinolin- 1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)- 8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.68 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 626 [M+H]* (170) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8 chloro-xanthine (171) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 84 PCT/EP2003/009127 Rf value: 0.38 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 608 [M+H]* (172) 1-[(4-chloro-3-methoxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 622, 624 [M+H]* (173) 1-[(4-ethoxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.25 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 603 [M+H]* (174) 1-[(4-isopropyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 617 [M+H]* (175) 1-[(2-methyl-benzothiazol-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.56 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 578 [M+H]* (176) 1-[(3-phenyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 634 [M+H]* (177) 1-[(4-phenyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.35 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 651 [M+H]* WO 2004/018468 85 PCT/EP2003/009127 (178) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.45 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 661 [M+H]* (179) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 598 [M+H]* (180) 1-[2-(3-difluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl) 8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.77 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 601 [M+H]* (181) 1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 635 [M+H]* (182) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.57 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 565 [M+H]* (183) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.63 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 565 [M+H]* (184) 1-[2-(3-trifluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl) 8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.64 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 619 [M+H]* WO 2004/018468 86 PCT/EP2003/009127 (185) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 611 [M+H]* (186) 1-[2-(biphenyl-3-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 611 [M+H]* (187) 1-[2-(3-isopropyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.66 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 593 [M+H]* (188) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 598 [M+H]* (189) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI): m/z = 661 [M+H]* (190) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESIl): m/z = 608 [M+H]* (191) 1-[2-(2-phenyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate = 1:1) WO 2004/018468 87 PCT/EP2003/009127 Mass spectrum (ESI'): m/z = 627 [M+H]* (192) 1-[2-(3-ethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.72 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 579 [M+H]* (193) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.67 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 565 [M+H]* (194) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl)-xanthine Rf value: 0.57 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI'): m/z = 565 [M+H]* (195) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8 bromo-xanthine (196) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (197) 1 -[(1,2,3,4-tetrahydro-phenanthridin -6-yl)methyl]-3-methyl-7-(2-butyn- 1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.55 (silica gel, ethyl acetate/ petroleum ether = 2:1) Mass spectrum (ESl*): m/z = 612 [M+H]* Example VI 1-(2-{3-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll xanthine WO 2004/018468 88 PCT/EP2003/009127 To a solution of 402 mg of 1-(2-{3-[(methylsulphanyl)methoxy]-phenyl}-2-oxo ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1-yl]-xanthine in 10 ml hexafluoroisopropanol are added 0.15 ml of a 35 % hydrogen peroxide solution. The reaction mixture is stirred for half an hour at ambient temperature.Then 5 ml of a 10 % sodium thiosulphate solution are added. The aqueous phase is extracted twice with 5 ml of methylene chloride. The combined extracts are dried over sodium sulphate and evaporated down. The yellow residue is purified by chromatography through a silica gel column with cyclohexane/ ethyl acetate/methanol (5:4:1) as eluant. Yield: 299 mg (73 % of theory) Rf value: 0.28 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESI): m/z = 643 [M+H]* The following compounds are obtained analogously to Example VI: (1) 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.05 (silica gel, ethyl acetate/cyclohexane = 3:1) Mass spectrum (ESI*): m/z = 613 [M+H]* (2) 1-(2-{2-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI'): m/z = 627 [M+H]* Example VII 3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine 236 pl of 1,8-diazabicyclo[5.4.0]undec-7-ene are added dropwise to 630 mg of 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine in 11 ml of acetonitrile. The solution is stirred for two hours at ambient temperature, then the acetonitrile is distilled off in vacuo. The flask residue is taken up in 11 ml of N,N-dimethylformamide and combined with 258 mg of (2-trimethylsilanyl-ethoxy)methy chloride. The reaction mixture is WO 2004/018468 89 PCT/EP2003/009127 stirred for three hours at 120 0 C. For working up water is added, the precipitate formed is filtered off and taken up in ethyl acetate. The solution is dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate/methanol (6:1:0 to 0:5:1) as eluant. Yield: 435 mg (53 % of theory) Mass spectrum (ESl*): m/z = 549 [M+H]* The following compounds are obtained analogously to Example VII: (1) 3-[(2-trimethylsilanyl-ethoxy)methyl]-7-(2-cyano-benzyl)-xanthine Mass spectrum (ESI-): m/z = 396 [M-H] (2) 3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 491 [M+H]* Example VIII 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll xanthine 510 mg of potassium-tert. butoxide are added to 2.32 g of 2-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-3-(3-methyl-2-buten-1 -yl)-4 ethoxycarbonyl-5-{[(ethoxycarbonylamino)carbonyl]amino}-3H-imidazole in 35 ml of ethanol. The yellow solution is refluxed for five hours. After cooling to ambient temperature it is diluted with methylene chloride. The organic phase is washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. methanolic ammonia (95:5:1 to 90:10:1) as eluant. Yield: 630 mg (35 % of theory) WO 2004/018468 90 PCT/EP2003/009127 Rf value: 0.24 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 419 [M+H]* Example IX 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(3-methyl-2-buten-1-yl)-4 ethoxycarbonyl-5-{[(ethoxycarbonylamino)carbonyl]amino}-3H-imidazole 2.97 ml of ethyl isocanatoformate are added to 4.00 g of 2-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-3-(3-methyl-2-buten-1 -yl)-4 ethoxycarbonyl-5-amino-3H-imidazole in 90 ml of 1,2-dimethoxyethane and the light brown solution is heated overnight at 120 0 C in an oil bath. Then a further 0.6 ml of ethyl isocyanatoformate is added and heating is continued for a further four hours. For working up the reaction mixture is combined with saturated potassium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, evaporated down and purified through a silica gel column with methylene chloride/methanol/conc. methanolic ammonia (98:2:1 to 90:10:1) as eluant. Yield: 2.27 g (45 % of theory) Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 537 [M+H] Example X 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-3-(3-methyl-2-buten-1 -yl)- 4 ethoxycarbonyl-5-amino-3H-imidazole Prepared by refluxing cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxy carbonylmethyl)-amino]-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] methane with sodium in ethanol. Rf value: 0.26 (aluminium oxide, ethyl acetate/petroleum ether = 8:2) Mass spectrum (ESl*): m/z = 422 [M+H]* Example XI Cyanimino-[N-(3-methyl-2-buten-1 -yl)-N-(ethoxycarbonylmethyl)-amino]-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yll-methane WO 2004/018468 91 PCT/EP2003/009127 Prepared by reacting cyanimino-[N-(3-methyl-2-buten-1-yl)-N-(ethoxy carbonylmethyl)-amino]-phenyloxy-methane with 3-(tert.
butyloxycarbonylamino)-piperidine in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature. Rf value: 0.10 (silica gel, petroleum ether/ethyl acetate = 6:4) Mass spectrum (ESl*): m/z = 422 [M+H]* Example XII cyanimino-[N-(3-methyl-2-buten-1 -yl)-N-(ethoxycarbonylmethyl)-amino] phenyloxy-methane Prepared by reacting cyanimino-[(ethoxycarbonylmethyl)amino]-phenyloxy methane with 1 -bromo-3-methyl-2-butene in the presence of potassium carbonate in acetone at ambient temperature. Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 316 [M+H]* Example X111 cVanimino-[(ethoxVcarbonVlmethVl)aminol-phenVloxV-methan Prepared by reacting diphenylcyanocarbonimidate with ethyl aminoacetate hydrochloride in the presence of triethylamine in isopropanol at ambient temperature (analogously to R. Besse et al., Tetrahedron 1990, 46, 7803 7812). Rf value: 0.73 (silica gel, petroleum ether/ethyl acetate = 8:2) Mass spectrum (ESl*): m/z = 248 [M+H]* Example XIV 1 -methyl-3-[(methoxycarbonyl)methyll-7-(2-cVano-benzVl)-8-chloro-xanthine Prepared by reacting 1 -methyl-7-(2-cyano-benzyl)-8-chloro-xanth ine with methyl bromoacetate in the presence of potassium carbonate in N,N dimethylformamide at ambient temperature.
WO 2004/018468 92 PCT/EP2003/009127 Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 388, 390 [M+H]* The following compounds are obtained analogously to Example XIV: (1) 1-methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-chloro-xanthine Mass spectrum (ESI*): m/z = 355, 357 [M+H]* (2) 1-methyl-3-(2-propyn-1-yl)-7-(2-cyano-benzyl)-8-ch loro-xanthine Rf value: 0.80 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 354, 356 [M+H]* (3) 1 -methyl-3-(2-propen-1 -yl)-7-(2-cyano-benzyl)-8-ch loro-xanthine Rf value: 0.90 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 356, 358 [M+H]* (4) 1-(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.78 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 576 [M+H]* (5) 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-chloro-xanthine Mass spectrum (ESI*): m/z = 358, 360 [M+H]* Example XV 1 -methyl-7-(2-cyano-benzyl)-8-ch loro-xa nthine Prepared by treating 1 -methyl-3-[(2-trimethylsilanyl-ethoxy)methyl] -7-(2 cyano-benzyl)-8-chloro-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature. Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI'): m/z = 316, 318 [M+H]* WO 2004/018468 93 PCT/EP2003/009127 The following compounds are obtained analogously to Example XV: (1) 1 -(2-phenyl-2-oxo-ethyl)-3-methyl-8-bromo-xanthine Rf value: 0.26 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI-): m/z = 361, 363 [M-H] (2) 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7 -(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (As the compound still contains impurities which cannot be removed by chromatography, the material is again converted into the BOC-protected derivative and then purified by chromatography, cf. Ex. XXV(1).) Mass spectrum (ESI*): m/z = 491 [M+H]* Example XVI 1 -methyl-3-[(2-trimethylsilanyl-ethoxy)methyll-7-(2-cyano-benzyl)-8-chloro xanthine Prepared by chlorination of 1-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-7 (2-cyano-benzyl)-xanthine with N-chlorosuccinimide in dichloroethane while refluxing. Mass spectrum (El): m/z = 445, 447 [M]* Example XVII 7-(2-cyano-benzyl)-xanthine Prepared by treating 16.68 g of 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin 6-one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50*C. Yield: 8.46 g (50 % of theory) Mass spectrum (ESl*): m/z = 268 [M+H]* Example XVIII 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one Prepared by reacting 20.00 g of guanosine-hyd rate with 22.54 g of 2-cyano benzylbromide in dimethylsulphoxide at 600C and subsequent treatment with 57 ml of conc. hydrochloric acid.
WO 2004/018468 94 PCT/EP2003/009127 Yield: 18.00 g (97% of theory) Mass spectrum (ESI'): m/z = 267 [M+H]* Example XIX 1 -{2-[3-(2-oxo-imidazolidin-1 -yl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by treating 1-[2-(3-{[(2-chloro-ethylamino)carbonyl]amino}-phenyl) 2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine with potassium-tert. butoxide in N,N dimethylformamide at ambient temperature. Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1) Example XX 1-[2-(3-{[(2-chloro-ethylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll xanthine Prepared by reacting 221 mg of 1-[2-(3-amino-phenyl)-2-oxo-ethyl]-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine with 60 pl of 2-chloroethyl isocyanate in 3 ml methylene chloride at ambient temperature. Yield: 163 mg (64 % of theory) Rf value: 0.20 (silica gel, cyclohexane/ethyl acetate/methanol = 6:3:1) Mass spectrum (ESl*): m/z = 671, 673 [M+H]* The following compounds are obtained analogously to Example XX: (1) 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1 -yl]-xanthine (Carried out in N,N-dimethylformamide at 300C) Rf value: 0.26 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESl*): m/z = 681 [M+H]* Example XXI WO 2004/018468 95 PCT/EP2003/009127 1-[2-(3-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by treating 1-[2-(3-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine with iron powder in a mixture of ethanol, water and glacial acetic acid (80:25:10) at 1000C. Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/methanol/conc. aqueous ammonia = 50:30:20:1) Mass spectrum (ESI*): m/z = 566 [M+H]* The following compounds are obtained analogously to Example XXI: (1) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI'): m/z = 566 [M+H]* (2) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI): m/z = 566 [M+H]* (3) 1-[(5-amino-isoquinolin-1-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.22 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 589 [M+H]* (4) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1 -cyclopenten-1 yl)methyl]-8-bromo-xanth i ne Mass spectrum (ESl*): m/z = 458, 460 [M+H]* (5) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo xanthine (product contains approx. 10 % of Z isomer) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESl*): m/z = 432, 434 [M+H]* WO 2004/018468 96 PCT/EP2003/009127 (6) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-l-yl)-8-bromo xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 430, 432 [M+H]* (7) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 552 [M+H]* (8) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(S)-3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 552 [M+H]* (9) 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.82 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESl*): m/z = 596 [M+H]* Example XXII 1-(2-{2-[(ethylcarbonyl)aminol-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 248 mg of 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine with 40 pl of propionic acid chloride in the presence of 60 pl of pyridine in N,N-dimethylformamide at 80*C. Yield: 168 mg (62 % of theory) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 622 [M+H]* The following compounds are obtained analogously to Example XXII: WO 2004/018468 97 PCT/EP2003/009127 (1) 1-({5-[(methoxycarbonyl)methylamino]-isoquinolin-1-yl}methyl)-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine (Carried out with methyl bromoacetate and potassium carbonate) Rf value: 0.42 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 661 [M+H]* (2) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 10 % of Z isomer) Mass spectrum (ESl*): m/z = 594 [M+H]* (3) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (product contains approx. 10 % of Z isomer) Mass spectrum (ESI*): m/z = 622 [M+H]* (4) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-[(S)- 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 608 [M+H]* (5) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 592 [M+H]* (6) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 636 [M+H]* WO 2004/018468 98 PCT/EP2003/009127 (7) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.44 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 620 [M+H]* (8) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESI*): m/z = 592 [M+H]* (9) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.44 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 620 [M+H]* (10) 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine (Carried out in acetonitrile at 55 0 C) Rf value: 0.25 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 624 [M+H]* (11) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out in acetonitrile at 650C) Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/isopropanol = 14:3:3) Mass spectrum (ESl*): m/z = 622 [M+H]* (12) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine Mass spectrum (ESI*): m/z = 608 [M+H]* (13) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine WO 2004/018468 99 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 594 [M+H]* (14) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1 -yl)-8 [(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.28 (silica gel, cyclohexane/ethyl acetate/isopropanol = 8:11:1) Mass spectrum (ESI): m/z = 594 [M+H]* (15) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine Rf value: 0.90 (silica gel, methylene chloride/methanol = 9:1) (16) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl])-xanthine (Carried out in 1,2-dichloroethane at 450C) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate/isopropanol = 8:1:1) Mass spectrum (ESl*): m/z = 622 [M+H]* (17) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate/isopropanol = 14:3:3) Mass spectrum (ESl*): m/z = 608 [M+H]* (18) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn 1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 606 [M+H]* (19) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn 1 -yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.22 (silica gel, methylene chloride/methanol = 95:5) (20) 1-(2-{2-[(phenylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate/isopropanol = 14:3:3) Mass spectrum (ESl*): m/z = 656 [M+H]* WO 2004/018468 100 PCT/EP2003/009127 (21) 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-[(1 cyclopenten-1 -yl)methyl]-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine (Carried out with HOnig base and 4-dimethylamino-pyridine in methylene chloride) Rf value: 0.60 (silica gel, methylene chloride/methanol = 18:1) Example XXIII 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2- buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Prepared by treating 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-{3-(tert.-butyloxycarbonylamino) piperidin-1 -yl]-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature. Mass spectrum (ESI*): m/z = 539 [M+H]* The following compounds are obtained analogously to Example XXIII: (1) 1-(2-{2-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 539 [M+H]* Example XXIV 1 -methyl-3-phenyl-7-(2-cyano-benzyl)-8-chloro-xanthine A mixture of 829 mg of 1 -methyl-7-(2-cyano-benzyl)-8-chloro-xanthine, 640 mg of phenylboric acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml methylene chloride is stirred for four days at ambient temperature in the presence of 100 mg of 4A molecular sieves.Then another 320 mg of phenylboric acid are added and the reaction mixture is stirred for another day at ambient temperature. For working up the mixture is filtered through talc and washed with ethyl acetate. The filtrate is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (7:3 to 1:1) as eluant.
WO 2004/018468 101 PCT/EP2003/009127 Yield: 142 mg (14 % of theory) Mass spectrum (ESI*): m/z = 392, 394 [M+H]* Example XXV 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonyl-amino)-piperidin-1 -yll-xanthine Prepared by reacting 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1-yl)-xanthine with di-tert.butyl pyrocarbonate in the presence of Hinig base in methylene chloride at ambient temperature. Rf value: 0.27 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) The following compounds are obtained analogously to Example XXV: (1) 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1 -yl]-xanthine Rf value: 0.27 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 591 [M+H]* (2) 7-acetyl-1 -(tert.-butyloxycarbonyl)-1 H-indole Rf value: 0.82 (silica gel, methylene chloride/petroleum ether/ethyl acetate= 5:4:1) Mass spectrum (ESl*): m/z = 260 [M+H]* Example XXVI 1 -[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-chloro-xanthine and 1-[(1,4-dihydro-cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 chloro-xanthine 510 mg of a mixture of (cinnolin-4-yl)-methanol and (1,4-dihydro-cinnolin-4 -yl) methanol (see Ex. XXVII) are added to 830 mg of 3-methyl-7-(3-methyl-2 buten-1-yl)-8-chloro-xanthine and 1.25 g of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture is combined with 0.92 ml diethyl azodicarboxylate and stirred overnight at ambient temperature.Then it is evaporated down and chromatographed through a silica gel column with ethyl WO 2004/018468 102 PCT/EP2003/009127 acetate/petroleum ether (7:3 to 0:1) as eluant. A mixture of cinnoline and 1,4 dihydro-cinnoline compound is obtained. Yield: 660 mg (52 % of theory) Rf value: 0.60 (silica gel, ethyl acetate/petroleum ether = 7:3) The following compounds are obtained analogously to Example XXVI: (1) 1-({4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1 yl}methyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-chloro-xanthine Rf value: 0.85 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI'): m/z = 557, 559 [M+H]* (2) 1-[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro xanthine Melting point: 194-195 0 C Mass spectrum (ESl*): m/z = 410, 412 [M+H]* (3) 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-chloro-xanthine Rf value: 0.66 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 441, 443 [M+H]* (4) 1 -[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine (Carried out with potassium carbonate) Rf value: 0.45 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 438, 440 [M+H]* (5) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Rf value: 0.78 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 438, 440 [M+H]* (6) 1-[(4-dimethylamino-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) WO 2004/018468 103 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 600 [M+H]* (7) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-bromo-xanthine (The product contains approx. 20 % of Z isomer) Rf value: 0.71 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 440, 442 [M+H]* (8) 1 -[(1 -methyl-1 H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine Rf value: 0.95 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 440, 442 [M+H]* (9) 1-[(quinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether = 8:2) Mass spectrum (ESl*): m/z = 438, 440 [M+H]* (10) 1 -{[1 -(tert.-butyloxycarbonylamino)-1 H-indol-2-yl]methyl}-3-methyl-7-(2 butyn-1 -yl)-8-bromo-xanthine Rf value: 0.74 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 526, 528 [M+H]* (11) 1 -({2-methyl-1 -[(2-trimethylsilanyl-ethoxy)methyl]-1 H-benzoimidazol-5 yl}methyl)-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine (mixed with -({2 methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol-5-yl}methyl)-3 methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine) Mass spectrum (ESl*): m/z = 571, 573 [M+H]* (12) 1-[(1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-benzoimidazol-5-yl)methyl]-3 methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (mixed with1-[(3-[(2-trimethylsilanyl ethoxy)methyl]-3H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 bromo-xanthine) Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI): m/z = 557, 559 [M+H]* WO 2004/018468 104 PCT/EP2003/009127 (13) 1-[(pyrazolo[1,5-a]pyridin -2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo xanthine Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESI*): m/z = 427, 429 [M+H]* Example XXVII (cinnolin-4-yl)-methanol and (1,4-dihydro-cinnolin-4-yl)-methanol A solution of 1.00 g of methyl cinnolin-4-carboxylate in 15 ml diethyl ether is added dropwise at 0*C to a suspension of 222 mg of lithium aluminium hydride in 5 ml of diethyl ether. After 1.5 hours water is carefully added dropwise to the reaction mixture, this is stirred with methylene chloride and suction filtered through a glass fibre filter. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate and evaporated down. According to 1 H-NMR a mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained as a yellow oil which is reacted further without any more purification. Yield: 530 mg (62 % of theory) Rf value: 0.63 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 161 [M1+H]* and 163 [M2+H]* The following compounds are obtained analogously to Example XXVII: (1) {2-methyl-1 -[(2-trimethylsilanyl-ethoxy)methyl]-1 H-benzoimidazol-5-yl} methanol (mixed with {2-methyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzoimidazol 5-yl}-methanol) Mass spectrum (ESI*): m/z = 293 [M+H]* (2) (2,3,8-trimethyl-quinoxalin-6-yl)-methanol Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 203 [M+H]* (3) (8-methyl-quinoxalin-6-yl)-methano Rf value: 0.18 (silica gel, cyclohexane/ethyl acetate = 1:1) WO 2004/018468 105 PCT/EP2003/009127 Mass spectrum (ESl*): m/z = 175 [M+H]* (4) (E)-3-pentafluorophenyl-2-propen-1 -ol (Carried out with diisobutylaluminium hydride in toluene) Mass spectrum (El): m/z = 224 [M]* (5) (E)-3-(2-trifluoromethyl-phenyl)-2-propen-1-ol (Carried out with diisobutylaluminium hydride in toluene) (6) (E)-3-(3-trifluoromethyl-phenyl)-2-propen-1-ol (Carried out with diisobutylaluminium hydride in toluene) Mass spectrum (El): m/z = 202 [M]* (7) (E)-3-(4-trifluoromethyl-phenyl)-2-propen-1-ol (Carried out with diisobutylaluminium hydride in toluene) Example XXVIII 4-hydroxymethyl-2-[(2-trimethylsilanyl-ethoxy)methyl]-2H-phthalazin-1 -one Prepared by treating methyl 4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4 dihydro-phthalazin-1-carboxylate with sodium borohydride in tetrahydrofuran at 40 0 C. Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum (ESl*): m/z = 307 [M+H]* The following compounds are obtained analogously to Example XXVIII: (1) (3,4-dimethyl-isoquinolin-1-yl)-methanol (Carried out with lithium borohydride in tetrahydrofuran) Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI*): m/z = 188 [M+H]* (2) (3-methyl-imidazo[1,2-a]pyridin-2-yl)-methanol (Carried out with lithium borohydride in tetrahydrofuran) WO 2004/018468 106 PCT/EP2003/009127 Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 163 [M+H]* (3) (3,4-dimethyl-6,7-dihydro-5H-[2]pyrindin-1 -yl)-methanol (Carried out with lithium borohydride in tetrahydrofuran) Rf value: 0.40 (aluminium oxide, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 178 [M+H]* (4) (3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1 -yl)-methanol (Carried out with lithium borohydride in tetrahydrofuran) Rf value: 0.45 (aluminium oxide, petroleum ether/ethyl acetate = 3:1) Mass spectrum (ESI): m/z = 192 [M+H]* (5) 6-hydroxymethyl-1,2,3,4-tetrahydro-phenanthridine (Carried out with lithium borohydride in tetrahydrofuran at ambient temperature) Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 214 [M+H]* Example XXIX Methyl 4-oxo-3-[(2-trimethylsilanyl-ethoxy)methyl]-3,4-dihydro-phthalazin-1 carboxylate Prepared by reacting methyl 4-oxo-3,4-dihydro-phthalazin-1 -carboxylate with (2-trimethylsilanyl-ethoxy)methylchloride in the presence of Honig base in methylene chloride at ambient temperature. Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate 6:4) Mass spectrum (ESl*): m/z = 335 [M+H]* The following compounds are obtained analogously to Example XXIX: (1) 7-acetyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one Mass spectrum (ESl*): m/z = 308 [M+H]* WO 2004/018468 107 PCT/EP2003/009127 (2) 4-acetyl-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol-2-one Rf value: 0.87 (silica gel, methylene chloride/methanol = 99:1) (3) 4-acetyl-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-1,3-dihydro benzoimidazol-2-one (Carried out with potassium-tert. butoxide in N,N-dimethylformamide) Rf value: 0.90 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 437 [M+H]* (4) 6-methyl-1-[(2-trimethylsilanyl-ethoxy)methyl]-1H-quinolin -2-one Rf value: 0.78 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 290 [M+H]* (5) methyl {2-methyl-1 -[(2-trimethylsilanyl-ethoxy)methyl]-1 H-benzoimidazol-5 yl}-carboxylate (mixed with methyl {2-methyl-3-[(2-trimethylsilanyl ethoxy)methyl]-3H-benzoimidazo-5-yl}-carboxylate) Mass spectrum (ESl*): m/z = 321 [M+H]* Example XXX 1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine 0.22 ml of a 35 % hydrogen peroxide solution and 20 mg of sodium tungstate are added to 500 mg of 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin 1-yl]-xanthine in 5 ml methylene chloride. The reaction mixture is stirred overnight at ambient temperature, then 1 ml of methanol is added. After another 48 hours a further 1.5 ml of 35 % hydrogen peroxide solution, a spatula tip of sodium tungstate and two drops of water are added. The next morning, the oxidation is complete according to thin layer chromatography and the reaction mixture is diluted with 50 ml methylene chloride and washed twice with 30 ml of 10 % sodium thiosulphate solution. The organic phase is dried over magnesium sulphate and evaporated down, leaving a viscous resin which is reacted further without any more purification. Yield: 530 mg (100 % of theory) WO 2004/018468 108 PCT/EP2003/009127 Rf value: 0.72 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 629 [M+H]* Example XXXI 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by treating 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine with 3 M sodium hydroxide solution in methanol at ambient temperature. Rf value: 0.34 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI*): m/z = 595 [M+H]* The following compounds are obtained analogously to Example XXXI: (1) 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1) (2) 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8 [3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with 4 M potassiuim hydroxide solution in tetrahydrofuran) Mass spectrum (ESl*): m/z = 609 [M+H]* (3) 1-[2-(2-carboxymethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten 1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with 4 M potassium hydroxide solution in tetrahydrofuran) Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 610 [M+H]* (4) 1-carboxymethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 475 [M+H]* WO 2004/018468 109 PCT/EP2003/009127 Example XXXII 1 -{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine A mixture of 190 mg of 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine, 43 pl of a 40 % aqueous methylamine solution, 103 mg of 0 (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 43 mg of N-hydroxybenzotriazole and 45 pl of triethylamine in 3 ml of tetrahydrofuran is stirred for eight hours at ambient temperature. For working up the reaction mixture is diluted with ethyl acetate and washed with water, 10 % citric acid solution, 10 % potassium carbonate solution and saturated sodium chloride solution. The organic phase is evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (98:2 to 80:20) as eluant. Yield: 173 mg (89 % of theory) Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI*): m/z = 608 [M+H]* The following compounds are obtained analogously to Example XXXII: (1) 1-{2-[3-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.28 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESI*): m/z = 622 [M+H]* (2) 1-{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESIl): m/z = 664 [M+H]* WO 2004/018468 110 PCT/EP2003/009127 (3) 1 -{2-[2-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 622 [M+H]* (4) 1-{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 664 [M+H]* (5) 1-(2-{2-[(isopropylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with HOnig base in N,N-dimethylformamide) Mass spectrum (ESl*): m/z = 650 [M+H]* (6) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with HOnig base in N,N-dimethylformamide) Mass spectrum (ESl*): m/z = 636 [M+H]* (7) 1-(2-{2-[2-oxo-2-(pyrrolidin-1-yl)-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with HOnig base in N,N-dimethylformamide) Mass spectrum (ESI'): m/z = 662 [M+H]* (8) 1-(2-{2-[2-(morpholin-4-yl)-2-oxo-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (Carried out with HUnig base in N,N-dimethylformamide) Mass spectrum (ESl*): m/z = 678 [M+H]* WO 2004/018468 111 PCT/EP2003/009127 (9) 1-(2-{2-[(methylaminocarbonyl)methylamino]-phenyl}-2-oxo-ethyl)-3 methyl-7-((E)-2-buten-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESI*): m/z = 623 [M+H]* (10) 1-[(2-amino-phenylaminocarbonyl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESl*): m/z = 565 [M+H]* Example XXXIII 1 -chloromethyl-4-methyl-isoquinoline-hydrochloride Prepared by treating (4-methyl-isoquinolin-1 -yl)-methanol with thionyl chloride in methylene chloride. Rf value: 0.76 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 192,194 [M+H]* The following compounds are obtained analogously to Example XXXIII: (1) 1-chloromethyl-3,4-dimethyl-isoquinoline-hydrochloride Rf value: 0.65 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 206, 208 [M+H]* (2) 5-chloromethyl-8-methoxy-quinoline-hydrochloride Mass spectrum (ESl*): m/z = 208, 210 [M+H]* (3) 8-chloromethyl-5-methoxy-quinoline-hydrochloride Mass spectrum (El): m/z = 207, 209 [M]* (4) 2-chloromethyl-3-methyl-imidazo[1,2-a]pyridine-hydrochloride Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) WO 2004/018468 112 PCT/EP2003/009127 Mass spectrum (ESl*): m/z = 181, 183 [M+H]* (5) 8-chloromethyl-5-methoxy-isoquinoline-hydrochloride Mass spectrum (ESl*): m/z = 208, 210 [M+H]* (6) 1-chloromethyl-3,4-dimethyl-6,7-dihydro-5H-[2]pyridine-hydrochloride Rf value: 0.50 (aluminium oxide, petroleum ether/ethyl acetate = 10:1) Mass spectrum (ESl*): m/z = 196,198 [M+H]* (7) 1-chloromethyl-3,4-dimethyl-5,6,7,8-tetrahydro-isoquinoline-hydrochloride Rf value: 0.50 (aluminium oxide, petroleum ether/ethyl acetate = 10:1) Mass spectrum (ESl*): m/z = 210, 212 [M+H]* (8) 6-chloromethyl-2,3,8-trimethyl-quinoxaline-hydrochloride Mass spectrum (ESl*): m/z = 221, 223 [M+H]* (9) 6-chloromethyl-8-methyl-quinoxaline-hydrochloride Mass spectrum (ESl*): m/z = 193,195 [M+H]* (10) 6-chloromethyl-1,2,3,4-tetrahydro-phenanthridine-hydrochloride Rf value: 0.50 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESl*): m/z = 232, 234 [M+H]* Example XXXIV 1-[(4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine 0.5 ml of a 1 M sodium methoxide solution in methanol is added dropwise to a solution of 428 mg of 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine in 3 ml of methanol at ambient temperature. After about 20 minutes the thick suspension formed is heated gently in a water bath and diluted with 2 ml of methanol. As soon as the reaction to form the iminoester is complete according to thin layer chromatography, the reaction mixture is neutralised with 0.5 ml 1 M glacial acetic acid solution in methanol and combined with a solution of 130 mg of WO 2004/018468 113 PCT/EP2003/009127 anthranilic acid in 2 ml of methanol. Gentle heating produces a clear solution, which is stirred for 2.5 hours at ambient temperature. Then the reaction mixture is gently refluxed for about 3.5 hours. After standing overnight at ambient temperature the methanol is distilled off and the residue is stirred with cold water, suction filtered and dried. The crude product is suspended in 5 ml of methanol, gently heated and after cooling suction filtered, washed with methanol and dried in the desiccator. Yield: 302 mg (56 % of theory) Rf value: 0.55 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 575 [M+H]* The following compounds are obtained analogously to Example XXXV: (1) (4-difluoromethoxy-naphthalen-1-yl)-methanol Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate = 6:4) Mass spectrum (ESI-): m/z = 223 [M-H] Example XXXV (4-dimethylamino-naphthalen-1 -yl)-methanol prepared by reduction of 4-dimethylamino-naphthalene-1 -carbaldehyde with sodium borohydride in aqueous tetrahydrofuran. Rf value: 0.67 (silica gel, cyclohexane/ethyl acetate = 1:1) Example XXXVI 2-bromo-1 -(2,3-dihydro-benzo[1,41dioxin-5-yl)-ethanone prepared by bromination of 1 -(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone in methylene chloride while cooling gently with an ice bath. The dibromo compound formed as a by-product is separated off by column chromatography. Mass spectrum (ESl*): m/z = 257, 259 [M+H]* Rf value: 0.92 (silica gel, methylene chloride) The following compounds are obtained analogously to Example XXXVI: WO 2004/018468 114 PCT/EP2003/009127 (1) 7-(2-bromo-acetyl)-3-methyl-3H-benzooxazol-2-one (bromination is carried out in dioxane at 40*C; the product is contaminated with approx. 20 % dibromo compound) Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 270, 272 [M+H]* (2) 1 -benzo[1,3]dioxol-4-yl-2-bromo-ethanone Mass spectrum (ESI*): m/z = 243, 245 [M+H]* Rf value: 0.94 (silica gel, methylene chloride) (3) 2-[2-(2-bromo-acetyl)-phenoxy]-N-ethyl-acetamide (bromination is carried out with copper(II)bromide in dioxane) Mass spectrum (ESI*): m/z = 300, 302 [M+H]* (4) 4-(2-bromo-acetyl)-3-methyl-3H-benzooxazol-2-one Rf value: 0.67 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESl*): m/z = 270, 272 [M+H]* (5) 2-[2-(2-bromo-acetyl)-phenoxy]-N-methyl-acetamide Mass spectrum (ESl*): m/z = 386, 388 [M+H]* (6) 7-(2-bromo-acetyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol 2-one Rf value: 0.84 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESI*): m/z = 384, 386 [M+H]* (7) 4-(2-bromo-acetyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one Rf value: 0.38 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 283, 285 [M+H]* (8) 4-(2-bromo-acetyl)-3-[(2-trimethylsilanyl-ethoxy)methyl]-3H-benzooxazol 2-one Rf value: 0.82 (silica gel, methylene chloride/methanol = 99:1) WO 2004/018468 115 PCT/EP2003/009127 (9) 4-(2-bromo-acetyl)-1 -ethoxycarbonyl-3-methyl-1,3-dihydro-benzoimidazol 2-one Rf value: 0.39 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESI*): m/z = 341, 343 [M+H]* (10) 2-bromo-1 -(2,2-difluoro-benzo[1,3]dioxol-4-yl)-ethanone Mass spectrum (ES[): m/z = 277, 279 [M-H] Example XXXVII (2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone Prepared by reacting 1 -(2,3-dihydroxy-phenyl)-ethanone with 1,2 dibromoethane in the presence of potassium carbonate in N,N dimethylformamide at 100*C. Rf value: 0.43 (silica gel, ethyl acetate/petroleum ether = 1:4) Mass spectrum (ESl*): m/z = 179 [M+H]* Example XXXVIII 1-[(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 1-[(4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl 7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine with methyl iodide in the presence of potassium carbonate in N,N dimethylformamide at ambient temperature. Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 589 [M+H]* The following compounds are obtained analogously to Example XXXVIII: (1) 7-acetyl-3-methyl-3H-benzooxazol-2-one (The methylation is carried out in the presence of sodium carbonate in methanol) Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 192 [M+H]* WO 2004/018468 116 PCT/EP2003/009127 (2) 4-acetyl-3-methyl-3H-benzooxazol-2-one (The methylation is carried out in the presence of sodium carbonate in methanol while refluxing) Rf value: 0.67 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESl*): m/z = 192 [M+H]* (3) 4-acetyl-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Carried out in the presence of potassium-tert. butoxide) Rf value: 0.40 (silica gel, ethyl acetate/petroleum ether = 2:1) Mass spectrum (ESl*): m/z = 205 [M+H]* (4) 4-acetyl-1 -ethoxycarbonyl-3-methyl-1,3-dihydro-benzoimidazol-2-one Rf value: 0.23 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 263 [M+H]* (5) 1-[(1-methyl-1H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 561 [M+H]* (6) 1 -{[1 -(2-cyano-ethyl)-1 H-benzoimidazol-2-yl]methyl}-3-methyl-7-(2-butyn 1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESI*): m/z = 600 [M+H]* (7) 1-({1-[(methylaminocarbonyl)methyl]-1H-benzoimidazol-2-yl}methyl)-3 methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine Rf value: 0.45 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESl*): m/z = 618 [M+H]* (8) 1 -[(1 -benzyl-1 H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate/methanol = 5:4:1) Mass spectrum (ESI*): m/z = 637 [M+H]* WO 2004/018468 117 PCT/EP2003/009127 Example XXXIX 1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine with paraformaldehyde and potassium cyanide in the presence of zinc chloride in glacial acetic acid at 400C. Rf value: 0.45 (silica gel, cyclohexane/ethyl acetate = 3:7) Mass spectrum (ESl*): m/z = 605 [M+H]* Example XL 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)- 3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine prepared by reduction of 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-[(S)- 3-(tert.-butyloxycarbonylamino)-piperidin- 1 -yl]-xanthine with sodium dithionite in a mixture of methylglycol and water (2:1) at 1000C. Rf value: 0.34 (silica gel, methylene chloride/methanol = 95:5) The following compounds are obtained analogously to Example XL: (1) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 4:6) Example XLI 2-chloromethyl-4-methyl-quinazoline prepared by treatment of 2.95 g of 2-chloromethyl-4-methyl-quinazoline-3 oxide with 6 ml phosphorus trichloride in 150 ml chloroform while refluxing. Yield: 1.75 g (57 % of theory) Rf value: 0.81 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI): m/z = 193,195 [M+H]* Example XLII WO 2004/018468 118 PCT/EP2003/009127 2-chloromethyl-4-dimethylamino-quinazoline A freshly prepared solution of 202 mg of dimethylamine in 3.2 ml of tetrahydrofuran is added dropwise to 500 mg of 4-chloro-2-chloromethyl quinazoline in 5 ml of tetrahydrofuran while cooling with an ice bath. Then the reaction mixture is stirred for another 3.5 hours while cooling with an ice bath and then for a further 30 minutes at ambient temperature. The solvent is then gently distilled off using a rotary evaporator and the residue is taken up in methylene chloride. The solution is washed with saturated sodium hydrogen carbonate solution and with water, dried over magnesium sulphate and evaporated down. The solid residue is stirred with a little tert.-butylmethylether, suction filtered, washed with petroleum ether and dried in vacuo. Yield: 323 mg (62 % of theory) Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 222, 224 [M+H]* The following compounds are obtained analogously to Example XLIl: (1) 2-chloromethyl-4-(morpholine-4-yl)-quinazoline Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 264, 266 [M+H]* (2) 2-chloromethyl-4-(piperidin-1 -yl)-quinazoline Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 262, 264 [M+H]* (3) 4-[4-(tert.-butyloxycarbonyl)-piperazin-1 -yl]-2-chloromethyl-quinazoline Rf value: 0.57 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI): m/z = 363, 365 [M+H]* (4) 2-chloromethyl-4-(pyrrolidin-1 -yl)-quinazoline Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 248, 250 [M+H]* WO 2004/018468 119 PCT/EP2003/009127 (5) 2-chloromethyl-4-ethoxy-quinazoline (The reaction is carried out with sodium ethoxide in ethanol at ambient temperature.) Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESl*): m/z = 223, 225 [M+H]* (6) 2-chloromethyl-4-isopropyloxy-quinazoline (The reaction is carried out with sodium isopropoxide in isopropanol at ambient temperature.) Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESIl): m/z = 237, 239 [M+H]* (7) 2-chloromethyl-4-phenyloxy-quinazoline (The reaction is carried out with sodium hydride and phenol in tetrahydrofuran at ambient temperature.) Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI*): m/z = 271, 273 [M+H]* Example XLIII 1-(2-{2-[(ethoxycarbonyl)methylamino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine A solution of 110 pL of ethyl diazoacetate in 0.5 ml of toluene is added dropwise to 531 mg of 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2 buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine and 10 mg of methyltrioxorhenium in 4.5 ml of toluene at ambient temperature under an argon atmosphere. The reaction mixture is stirred for 15 hours at ambient temperature.Then approx. another 5 mg of methyltrioxorhenium and 20 pL ethyl diazoacetate are added and the reaction mixture is heated to 500C for two hours. After cooling to ambient temperature another 5 mg of methyltrioxorhenium and 20 pL ethyl diazoacetate are added. After another 16 hours at ambient temperature the reaction mixture is combined with 5 ml of conc. aqueous ammonia, shaken thoroughly and added to an Extrelut pack. After 15 min it is rinsed with 200 ml methylene chloride. The methylene chloride solution is evaporated down and chromatographed through a silica WO 2004/018468 120 PCT/EP2003/009127 gel column with cyclohexane/ethyl acetate/isopropanol (8:2:0 to 8:1:1) as eluant. Yield: 220 mg (36 % of theory) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 638 [M+H]* Example XLIV 1-[(2-cyano-benzofuran-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine A mixture of 215 mg of 1-{2-[2-cyanomethoxy-phenyl]-2-oxo-ethyl}-3-methyl 7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine and 244 mg of caesium carbonate in 4 ml of N,N-dimethylformamide is stirred for two hours at 500C, then a further three hours at 700C. For working up the reaction mixture is combined with water and the precipitate formed is suction filtered and dried. Yield: 130 mg (62 % of theory) Mass spectrum (ESl*): m/z = 572 [M+H]* Example XLV 1-[2-(3-methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yl)-2-oxo-ethyl]-3 methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll xanthine Prepared by treating 1-[2-(1 -ethoxycarbonyl-3-methyl-2-oxo-2,3-dihydro-1 H benzoimidazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxy carbonylamino)-piperidin-1-yli]-xanthine with 1 N sodium hydroxide solution in methanol at ambient temperature. Rf value: 0.36 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 605 [M+H]* Example XLVI 4-acetyl-1 -ethoxycarbonyl-1,3-dihydro-benzoimidazol-2-one 5.29 g of diethyldicarbonat and 611 mg of dimethylaminopyridine are added to 1.50 g of 1-(2,3-diamino-phenyl)-ethanone in 75 ml methylene chloride. The reaction mixture is stirred for three hours at ambient temperature, then WO 2004/018468 121 PCT/EP2003/009127 another 100 mg of dimethylaminopyridine and 1 ml of diethyldicarbonate are added and the mixture is stirred for a further 20 hours at ambient temperature. For working up the reaction mixture is diluted with methylene chloride, washed with 2 N citric acid solution as well as saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The residue is chromatographed through a silica gel column with petroleum ether/ethyl acetate (3:1 to 1:2) as eluant. The desired product is stirred with a little tert.-butylmethylether, suction filtered, nachwashed with a little ethyl acetate and tert.-butylmethylether and dried. Yield: 900 mg (36 % of theory) Rf value: 0.15 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 249 [M+H]* Example XLVII 1-[(4-amino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine 501 mg of 1 -cyanomethyl-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine are added to a mixture of 17 mg of potassium-tert. butoxide in 10 ml of methanol. After brief heating with stirring a clear solution is formed and after about 20 minutes the nitrile has largely reacted to form the iminoester according to thin layer chromatography. 206 mg of 2-amino-benzamidine-hydrochloride are then added and the reaction mixture is refluxed for four hours. After cooling to ambient temperature the precipitate formed is suction filtered, washed with methanol and dried. Yield: 143 mg (23 % of theory) Rf value: 0.15 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 574 [M+H]* Example XLVIII 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-buten-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl-xanthine WO 2004/018468 122 PCT/EP2003/009127 150 mg of 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine are hydrogenated in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol in the presence of 30 mg of 5 %m palladium on activated charcoal (contaminated with quinoline) at ambient temperature, until the calculated amount of hydrogen has been taken up. Then a spatula tip of activated charcoal is added and the mixture is suction filtered. The filtrate is evaporated down and the crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (7:3 to 4:6). Yield: 120 mg (85 % of theory) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 4:6) Mass spectrum (ESl*): m/z = 537 [M+H]* Example XLIX 8-hydroxymethyl-5-methoxy-quinoline 148 mg of sodium hydride (approx. 60 % in mineral oil) are added batchwise to a solution of 640 mg of 8-hydroxymethyl-quinolin-5-ol in N,N dimethylformamide while cooling with an ice bath and the reaction mixture is slowly heated to ambient temperature. After the development of gas has ended, 230 pl methyl iodide are added dropwise while cooling with an ice bath, then the reaction mixture is stirred for approx. another two hours at ambient temperature. For working up it is poured onto ice water, saturated with sodium chloride and extracted with a mixture of diethyl ether and ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The flask residue is triturated with petroleum ether and the supernatant is decanted. The crude product is purified through a silica gel column with ethyl acetate as eluant. Yield: 470 mg (68 % of theory) Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 190 [M+H]* The following compounds are obtained analogously to Example XLIX: WO 2004/018468 123 PCT/EP2003/009127 (1) 8-hydroxymethyl-5-methoxy-isoquinoline Rf value: 0.40 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESl*): m/z = 190 [M+H]* Example L 8-hydroxymethyl-quinolin-5-ol 3.40 g of quinolin-5-ol is combined with 8 ml of conc. hydrochloric acid and 8 ml of 37 % formalin solution while cooling with an ice bath. Then hydrogen chloride gas is piped through the reaction mixture for about two hours, while the temperature slowly rises. The reaction mixture is stirred first overnight while cooling with an ice bath, then at ambient temperature and then evaporated down in vacuo. The flask residue is taken up in water, covered with a layer of diethyl ether and adjusted to pH 10 while cooling with an ice bath and vigorously stirring with dilute ammonia solution. After another two hours' vigorous stirring at ambient temperature the organic phase is separated off and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (20:1) as eluant. Yield: 660 mg (16 % of theory) Mass spectrum (ESl*): m/z = 176 [M+H]* The following compounds are obtained analogously to Example L: (1) 8-hydroxymethyl-isoquinolin-5-ol Rf value: 0.50 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESl*): m/z = 176 [M+H]* Example LI 1-[(2-cyclopropyl-quinazolin-4-yl)methyl]-3-methyl-7-[(1 -cyclopenten-1 yl)methyll-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yll-xanthine A mixture of 250 mg of 1-(2-{2-[(cyclopropylcarbonyl)amino]-phenyl}-2-oxo ethyl)-3-methyl-7-[(1 -cyclopenten-1 -yl)methyl] -8-[3-(tert.- WO 2004/018468 124 PCT/EP2003/009127 butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 7.5 ml of ethanolic ammonia solution (6 M) is heated to 150 *C for seven hours in a bomb. For working up the reaction mixture is evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant. The contaminated product fraction is evaporated down and again purified through a reversed phase HPLC column with water/ acetonitrile/trifluoroacetic acid (65:15:0.08 to 0:100:0.1) as eluant. The product fractions are evaporated down, made alkaline with dilute sodium hydroxide solution and extracted with methylene chloride. The combined extracts are dried over magnesium sulphate and evaporated down. Yield: 40 mg (14 % of theory) Rf value: 0.40 (silica gel, methylene chloride /ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 627 [M+H]* Example LIl 4-(2-bromo-acetyl)-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-1,3-dihydro benzoimidazol-2-one 520 mg of 2-pyrrolidinone-hydrotribromide and 89 mg of 2-pyrrolidinone are added to 420 mg of 4-acetyl-1,3-bis-[(2-trimethylsilanyl-ethoxy)methyl]-1,3 dihydro-benzoimidazol-2-one in 5 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is refluxed for two hours and then suction filtered while still warm. The filter cake is washed with tetrahydrofuran and the filtrate is evaporated down, leaving 660 mg of a yelllowish-brown solid. This is stirred with a little methanol, suction filtered, washed with some methanol and dried. The crude product is reacted further without any more purification. Yield: 430 mg (87 % of theory) Rf value: 0.23 (silica gel, petroleum ether/ethyl acetate = 9:1) Mass spectrum (El): m/z = 514, 516 [M]* The following compounds are obtained analogously to Example LIl: (1) 7-(2-bromo-acetyl)-1 -(tert.-butyloxycarbonyl)-1 H-indole Rf value: 0.33 (silica gel, petroleum ether/ethyl acetate = 9:1) Mass spectrum (ESl*): m/z = 338, 340 [M+H]* WO 2004/018468 125 PCT/EP2003/009127 (2) 2-bromo-1-(3-isopropyloxy-phenyl)-ethanone (Carried out with phenyltrimethylammonium tribromide in methylene chloride) Rf value: 0.39 (silica gel, cyclohexane/ethyl acetate = 9:1) (3) 2-bromo-1 -(3-difluoromethoxy-phenyl)-ethanone (Carried out with phenyltrimethylammonium tribromide in methylene chloride) Rf value: 0.24 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Example LIII methyl 3-methyl-imidazo[1,2-alpyridine-2-carboxylate A mixture of 1.91 g of 2-aminopyridine and 4.40 g of methyl 3-bromo-2-oxo butyrate in 40 ml of ethanol is refluxed for 6 hours and then left to stand for 2 days at ambient temperature. The solvent is distilled off using the rotary evaporator and the crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/methanolic ammonia solution (95:4:1 to 90:9:1) as eluant. 560 mg of the ethyl ester are isolated as the by product. Yield: 2.09 g (54 % of theory) Rf value: 0.20 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 191 [M+H]* Example LIV 2-chloromethyl-4-isopropyl-quinazoline Dry hydrogen chloride gas is piped through a solution of 2.86 g of 1-(2-amino phenyl)-2-methyl-propan-1 -one and 1.33 ml of chloroacetonitrile in 14 ml dioxane with stirring at ambient temperature for approx. five hours. Then the dioxane is largely distilled off in a water jet vacuum. The honey-like residue is combined with ice water and the resulting suspension is made alkaline with saturated potassium carbonate solution while cooling with an ice bath. The precipitate is suction filtered, washed with water and dried. The crude product is purified by chromatography over a silica gel column with petroleum ether/methylene chloride (8:2 to 0:1) as eluant.
WO 2004/018468 126 PCT/EP2003/009127 Yield: 1.80 g (58 % of theory) Rf value: 0.30 (silica gel, methylene chloride/petroleum ether = 1:1) Mass spectrum (ESI*): m/z = 221, 223 [M+H]* Example LV 1 -chloromethyl-3-trifluoromethyl-3,4-dihydro-isoquinoline 530 mg of N-(1-benzyl-2,2,2-trifluoro-ethyl)-2-chloro-acetamide (prepared by reacting 1-benzyl-2,2,2-trifluoro-ethylamine with chloroacetyl chloride in the presence of triethylamine) and 0.74 ml of phosphorus oxychloride are added to 4.00 g of polyphosphoric acid. The viscous mixture is stirred for 1.5 hours at 130 0 C. For working up the reaction mixture is cooled and combined with ice water, stirred vigorously for ten minutes and suction filtered. The filter cake is dissolved in ethyl acetate and the solution is dried over magnesium sulphate and evaporated down, leaving a white solid. Yield: 415 mg (84 % of theory) Rf value: 0.55 (aluminium oxide, petroleum ether/ethyl acetate = 10:1) Mass spectrum (ESl'): m/z = 248, 250 [M+H]* The following compound is obtained analogously to Example LV: (1) 1-methyl-3-trifluoromethyl-3,4-dihydro-isoquinoline (The starting material N-(1 -benzyl-2,2,2-trifluoro-ethyl)-acetamide is obtained by reacting 1 -benzyl-2,2,2-trifluoro-ethylamine with acetic anhydride.) Example LVI 3-bromomethyl-1 -(1 -cyano-1 -methyl-ethyl)-isoquinoline A mixture of 375 mg of 1 -(1 -cyano-1 -methyl-ethyl)-3-methyl-isoquinoline and 321 mg of N-bromosuccinimide in 5 ml carbon tetrachloride is combined with a spatula tip of 2,2-azoisobutyric acid dinitrile and refluxed for about six hours. The cooled reaction mixture is filtered and evaporated down. The flask residue is reacted further without any more purification. Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) The following compounds are obtained analogously to Example LVI: WO 2004/018468 127 PCT/EP2003/009127 (1) 6-bromomethyl-1 -[(2-trimethylsilanyl-ethoxy)methyl]-1 H-quinolin-2-one (2) 1-bromomethyl-4-bromo-3-methoxy-isoquinoline (3) 2-bromomethyl-[1,5]naphthyridine Mass spectrum (ESI+): m/z = 223, 225 [M+H]+ (4) 5-bromomethyl-[1,6]naphthyridine Rf value: 0.48 (silica gel, ethyl acetate/methanol = 98:2) (5) 7-bromomethyl-5-phenyl-quinoxaline Rf value: 0.85 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 299, 301 [M+H]* (6) 4-bromomethyl-[1,5]naphthyridine Rf value: 0.56 (silica gel, methylene chloride/ethyl acetate = 7:3) Mass spectrum (ESl*): m/z = 223, 225 [M+H]* (7) 1-bromomethyl-3-trifluoromethyl-isoquinoline Mass spectrum (ESl*): m/z = 290, 292 [M+H]* (8) 1 -bromomethyl-3-difluoromethyl-isoquinoline Mass spectrum (ESI*): m/z = 272, 274 [M+H]* (9) 1-bromomethyl-4-chloro-3-methoxy-isoquinoline Example LVII 1 -(1 -cyano-1 -methyl-ethyl)-3-methyl-isoquinoline 3.30 g of 2,2-azoisobutyric acid dinitrile are added to 1.60 g of 3-methyl isoquinoline-N-oxide in 30 ml of toluene. The reaction mixture is stirred for six hours at 85 0 C and then left to stand for two days at ambient temperature. For working up the reaction mixture is extracted with 20% hydrochloric acid. The combined aqueous phases are diluted with methylene chloride, made alkaline WO 2004/018468 128 PCT/EP2003/009127 with saturated potassium carbonate solution while cooling with an ice bath and extracted with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulphate and evaporated down. The residue is chromatographed through a silica gel column with cyclohexane as eluant. Yield: 375 mg (18 % of theory) Mass spectrum (ESl*): m/z = 211 [M+H]* Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 3:1) Example LVIII 1-(2-cyanoimino-2-phenyl-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine (E/Z-mixture) 0.48 ml of a 1 M solution of titaniium tetrachloride in methylene chloride are added dropwise to 244 mg of 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 7 ml of methylene chloride. Then 88 pl of 1,3-bis(trimethylsilyl)carbodiimide are added and the mixture is stirred for four hours at ambient temperature. For working up the reaction mixture is diluted with methylene chloride and poured onto ice water. The organic phase is washed with 0.5 N citric acid, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (98:2 to 95:5) as eluant. Yield: 206 mg (97 % of theory) Mass spectrum (ESI-): m/z = 557 [M-H] Rf value: 0.16 (silica gel, cyclohexane/ethyl acetate = 1:1) Example LIX 1 -[(1 H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1 -yll-xanthine 350 mg of 1-[(2-amino-phenylaminocarbonyl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine are refluxed in 3 ml glacial acetic acid for two hours. Then the reaction mixture is evaporated down, the flask residue is combined with 5 ml of 1 M sodium hydroxide solution and washed with methylene chloride. Then the aqueous phase is WO 2004/018468 129 PCT/EP2003/009127 acidified with 1 M hydrochloric acid and extracted with methylene chloride. The combined extracts are evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate/methanol (6:4:0 to 5:4:1) as eluant. Yield: 250 mg of (74 % of theory) Mass spectrum (ESl*): m/z = 547 [M+H]* Example LX Ethyl 3,4-dimethyl-6,7-dihydro-5H-[2]pyrindin-1-carboxylate Prepared by treating 1.16 g of ethyl 3,4-dimethyl-4a-(pyrrolidin-1 -yl)-5,6,7,7a tetrahydro-4aH-[2]pyrindin-1 -carboxylate with 1.08 g of 70 % 3-chloro perbenzoic acid in 50 ml methylene chloride at ambient temperature. Yield: 850 mg (97 % of theory) Rf value: 0.30 (aluminium oxide, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESl*): m/z = 220 [M+H]* The following compounds are obtained analogously to Example LX: (1) ethyl 3,4-dimethyl-5,6,7,8-tetrahydro-isoquinoline-1-carboxylate Rf value: 0.35 (aluminium oxide, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESl*): m/z = 234 [M+H]* Example LXI Ethyl 3,4-dimethyl-4a-(pyrrolidin-1-yl)-5,6,7,7a-tetrahydro-4aH-[2]pyrindin-1 carboxylate Prepared by reacting 2.50 g of ethyl 5,6-dimethyl-[1,2,4]triazin-3-carboxylate with 2.74 g of 1-(cyclopenten-1-yl)-pyrrolidine in 25 ml chloroform at ambient temperature. Yield: 3.00 g (75 % of theory) Rf value: 0.60 (aluminium oxide, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI*): m/z = 291 [M+H]* The following compounds are obtained analogously to Example LXI: WO 2004/018468 130 PCT/EP2003/009127 (1) ethyl 3,4-dimethyl-4a-(pyrrolidin-1-yl)-4a,5,6,7,8,8a-hexahydro isoquinoline-1 -carboxylate Rf value: 0.60 (aluminium oxide, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESl*): m/z = 305 [M+H]* Example LXII Methyl 2,3,8-trimethyl-quinoxalin-6-carboxylate Prepared by reacting 1.60 g of methyl 3,4-diamino-5-methyl-benzoate with 0.86 ml diacetyl in a mixture of water and ethanol while refluxing. Yield: 1.53 g (80 % of theory) Rf value: 0.63 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 231 [M+H]* The following compounds are obtained analogously to Example LXII: (1) methyl 8-methyl-quinoxalin-6-carboxylate (reaction is carried out with glyoxal in water.) Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 203 [M+H]* (2) 5-bromo-7-methyl-quinoxaline (reaction is carried out with glyoxal in a water/ethanol mixture.) Rf value: 0.75 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 223, 225 [M+H]* Example LXIII Methyl 3,4-diamino-5-methyl-benzoate Prepared by reduction of methyl 3-nitro-4-amino-5-methyl-benzoate at a partial hydrogen pressure of 50 psi in the presence of Raney nickel in methanol at ambient temperature. Rf value: 0.40 (silica gel, tert.-butylmethylether) Example LXIV WO 2004/018468 131 PCT/EP2003/009127 Methyl 3-nitro-4-amino-5-methyl-benzoate Prepared by treating 3-nitro-4-acetylamino-5-methyl-benzoic acid with hydrogen chloride gas in methanol at ambient temperature and subsequently heating while refluxing. Mass spectrum (ESI*): m/z = 211 [M+H]* Rf value: 0.75 (silica gel, tert.-butylmethylether/acetic acid = 99:1) Example LXV 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-1 -buten-1 -yl)-8-bromo-xanthine 0.13 ml 35 % hydrogen peroxide solution are added to 290 mg of 1-(2-phenyl 2-oxo-ethyl)-3-methyl-7-(1 -phenylsulphanyl-butyl)-8-bromo-xanthine in 6 ml hexafluoroisopropanol. The reaction mixture is stirred for one hour at ambient temperature, diluted with methylene chloride and washed with sodium thiosulphate solution. The organic phase is dried over magnesium sulphate and evaporated down. The flask residue is taken up in 6 ml of toluene and refluxed for eight hours. Then the toluene is distilled off in vacuo and the crude product is purified through a silica gel column with methylene chloride/methanol (100:0 to 95:5) as eluant. Yield: 104 mg (45 % of theory) Rf value: 0.61 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 417, 419 [M+H]* The following compounds are obtained analogously to Example LXV: (1) 3-methyl-7-(3-methyl-1 -buten-1 -yl)-8-bromo-xanthine Rf value: 0.24 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 313, 315 [M+H]* Example LXVI 1 -methanesulphonyloxymethyl-4-difluoromethoxy-naphthalene Prepared by reacting (4-difluoromethoxy-naphthalen-1-yl)-methanol with methanesulphonic acid chloride in methylene chloride in the presence of triethylamine.
WO 2004/018468 132 PCT/EP2003/009127 The following compounds are obtained analogously to Example LXVI: (1) (E)-1-methanesulphonyloxy-3-(2-nitro-phenyl)-2-propene (2) (E)-1 -methanesulphonyloxy-3-pentafluorophenyl-2-propene (3) (E)-1-methanesulphonyloxy-3-(2-trifluoromethyl-phenyl)-2-propene (4) (E)-1-methanesulphonyloxy-3-(3-trifluoromethyl-phenyl)-2-propene (5) (E)-1 -methanesulphonyloxy-3-(4-trifluoromethyl-phenyl)-2-propene Example LXVII 7-methyl-5-phenyl-quinoxaline A mixture of 400 mg of 5-bromo-7-methyl-quinoxaline, 244 mg of phenylboric acid and 100 mg of tetrakis(triphenylphosphine)palladium in 12 ml dioxane, 4 ml of methanol and 3.6 ml 1 M aqueous sodium carbonate solution is refluxed for three hours under an argon atmosphere. Then the reaction mixture is evaporated down and the residue is distributed between ethyl acetate and water. The ethyl acetate phase is separated off, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (85:15 to 70:30) as eluant. Yield: 390 mg (66% of theory) Rf value: 0.36 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI*): m/z = 221 [M+H]* Example LXVIII 1 -methyl-3-trifluoromethyl-isoquinoline WO 2004/018468 133 PCT/EP2003/009127 Prepared by treating 905 mg of 1 -chloromethyl-3-trifluoromethyl-3,4-dihydro isoquinoline with 420 mg of potassium-tert. butoxide in 10 ml of tetrahydrofuran at ambient temperature. Yield: 755 mg of (98% of theory) Mass spectrum (ESI*): m/z = 212 [M+H]* The following compounds are obtained analogously to Example LXVIII: (1) 1-methyl-3-difluoromethyl-isoquinoline (Prepared from 1-methyl-3-trifluoromethyl-3,4-dihydro-isoquinoline) Mass spectrum (ESI*): m/z = 194 [M+H]* Example LXIX 4-chloro-3-methoxy-1 -methyl-isoguinoline Prepared by treating 3-methoxy-1 -methyl-isoquinoline with sulphuryl chloride in methylene chloride. Rf value: 0.30 (silica gel, cyclohexane) Mass spectrum (ESI*): m/z = 208, 210 [M+H]* Example LXX 3-cyclopropyl-8-bromo-xanthine Prepared by reacting 3-cyclopropyl-xanthine with bromine in the presence of potassium carbonate in acetonitrile at 600C. Rf value: 0.65 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 271, 273 [M+H]* Example LXXI Ethyl 1,2,3,4-tetrahydro-phenanthridin-6-yl-carboxylate Analogously to the method described by Gonsalves et al. (Tetrahedron 1992, 48, 6821) a solution of 3.90 g of ethyl 5,6,7,8-tetrahydro-benzo[1,2,4]triazin-3 carboxylate (Sagi et al., Heterocycles 1989, 29, 2253) in 20 ml dioxane is refluxed. Then 8.22 g of anthranilic acid and 7.02 g of isoamylnitrite, in each case dissolved in 20 ml dioxane, are simultaneously added dropwise within 25 WO 2004/018468 134 PCT/EP2003/009127 minutes by means of two dropping funnels. The reaction mixture is refluxed for a further 30 minutes. For working up the cooled deep-brown reaction solution is diluted with 150 ml diethyl ether, washed with 100 ml of 2 N sodium hydroxide solution and with water, dried over magnesium sulphate and evaporated down. The brown, oily flask residue is chromatographed through a silica gel column with ethyl acetate/petroleum ether (20:80 to 50:50) as eluant. The product obtained is still somewhat contaminated, but is reacted further without any more purification. Yield: 380 mg (8 % of theory) Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 256 [M+H]* WO 2004/018468 135 PCT/EP2003/009127 Preparation of the final compounds: Example 1 1,3-dimethyl-7-(2,6-dicyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine 129 mg of 3-amino-piperidine-dihydrochloride are added to a mixture of 298 mg of 1,3-dimethyl-7-(2,6-dicyano-benzyl)-8-bromo-xanthine and 420 mg of potassium carbonate in 9 ml of N,N-dimethylformamide. The reaction mixture is stirred for three hours at 800C. For working up the mixture is diluted with methylene chloride and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. methanolic ammonia (95:5:1 to 80:20:1) as eluant. Yield: 43 mg (14 % of theory) Rf value: 0.67 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 80:20:1) Mass spectrum (ESl*): m/z = 419 [M+H]* The following compounds are obtained analogously to Example 1: (1) 1-(2-cyano-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl) xanthine Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI*): m/z = 433 [M+H]* Example 2 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine A solution of 209 mg of 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-[3-(tert.-butyloxycarbonylamino) piperidin-1-yl]-xanthine in 4 ml methylene chloride is combined with 1 ml of trifluoroacetic acid and stirred for half an hour at ambient temperature. For working up the reaction mixture is diluted with methylene chloride and washed with saturated potassium carbonate solution. The organic phase is dried, WO 2004/018468 136 PCT/EP2003/009127 evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (1:0 to 4:1) as eluant. Yield: 153 mg of (87 % of theory) Mass spectrum (ESl*): m/z = 553 [M+H]* The following compounds are obtained analogously to Example 2: (1) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 524 [M+H]* (2) 1-(2-{3-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.58 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 100:100:0.1) Mass spectrum (ESl*): m/z = 543 [M+H]* (3) 1-(1-methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 465 [M+H]* (4) 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI): m/z = 500 [M+H]* (5) 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1-yl)-8-(3-amino-piperidin-1 yl)-xanthine Rf value: 0.58 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 80:20:1) Mass spectrum (ESI-): m/z = 435 [M-H] (6) 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 137 PCT/EP2003/009127 Mass spectrum (ESl*): m/z = 553 [M+H]* (7) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methy-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 538 [M+H]* (8) 1-(2-{2-[(dimethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 552 [M+H]* (9) 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 438 [M+H]* (10) 1-methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 452 [M+H]* (11) 1 -methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 419 [M+H]* (12) 1 -methyl-3-(2-propyn-1 -yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 418 [M+H]I (13) 1-{2-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 138 PCT/EP2003/009127 Rf value: 0.54 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 100:100:0.1) Mass spectrum (ESI*): m/z = 535 [M+H]* (14) 1 -methyl-3-(2-propen-1 -yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI*): m/z = 420 [M+H]* (15) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1 yl)-xanthine Mass spectrum (ESl*): m/z = 435 [M+H]* (16) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 100:100:0.1) Mass spectrum (ESl*): m/z = 522 [M+H]* (17) 1-methyl-3-phenyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI*): m/z = 456 [M+H]* (18) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 ((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 466 [M+H]* (19) 1-(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Rf value: 0.07 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 476 [M+H]* WO 2004/018468 139 PCT/EP2003/009127 (20) 1-[(quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* (21) 1-[(2-oxo-2H-chromen-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-l-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 491 [M+H]* Rf value: 0.16 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) (22) 1-[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (1:1 mixture with 1-[(1,4-dihydro-cinnolin-4-yl)methyl] 3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine) (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 475 [M+H]* (23) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 178-181 0 C Mass spectrum (ESI*): m/z = 504 [M+H]* (24) 1-[(4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.06 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) WO 2004/018468 140 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 491 [M+H]* (25) 1-[(quinazolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 475 [M+H]* (26) 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methyl-2 buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 504 [M+H]* (27) 1-[(isoquinoline-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 474 [M+H]J (28) 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:1) Mass spectrum (ESl*): m/z = 491 [M+H]* (29) 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) WO 2004/018468 141 PCT/EP2003/009127 Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 500 [M+H]* (30) 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.58 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 500 [M+H]* (31) 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)methyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product precipitated as the hydrochloride) Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 505 [M+H]* (32) 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.34 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 497 [M+H]* (33) 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine Rf value: 0.21 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 513 [M+H]* (34) 1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 142 PCT/EP2003/009127 Rf value: 0.66 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI): m/z = 529 [M+H]* (35) 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product precipitated as the hydrochloride) Rf value: 0.54 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI): m/z = 495 [M+H]* (36) 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product precipitated as the hydrochloride) Rf value: 0.47 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 509 [M+H]* (37) 1-{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 508 [M+H]* (38) 1-{2-[3-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) WO 2004/018468 143 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 522 [M+H]* (39) 1-{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 564 [M+H]* (40) 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl) 8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 495 [M+H]* (41) 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.41 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 523 [M+H]* (42) 1 -{2-[2-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 522 [M+H]* WO 2004/018468 144 PCT/EP2003/009127 (43) 1-{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.53 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI): m/z = 564 [M+H]* (44) 1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.44 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI'): m/z = 511 [M+H]* (45) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2,3-dimethyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; product obtained as the hydrochloride) Rf value: 0.68 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 465 [M+H]* (46) 1 -((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI*): m/z = 449 [M+H]* (47) 1-[(benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) WO 2004/018468 145 PCT/EP2003/009127 Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 479 [M+H]* (48) 1-[(1H-indol-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 462 [M+H]* (49) 1 -[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 499 [M+H]* (50) 1 -[(1 -naphthyl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.56 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 457 [M+H]* (51) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 488 [M+H]* (52) 1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1 yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) WO 2004/018468 146 PCT/EP2003/009127 Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 458 [M+H]* (53) 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 457 [M+H]* (54) 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 431 [M+H]* (55) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin 1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 459 [M+H]* (56) 1-[(2-methyl-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.25 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 471 [M+H]* (57) 1-({5-[(methoxycarbonyl)methylamino]-isoquinolin-1 -yl}methyl)-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 147 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 561 [M+H]* (58) 1-(2-dimethylamino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 418 [M+H]* (59) 1-[2-(piperidin-1 -yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 458 [M+H]* (60) 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinoline-4-yl)methyl]-7-(2-butyn-1-yl) 8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.17 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 488 [M+H]* (61) 1-[(2-methyl-1-oxo-1,2-dihydro-isoquinoline-4-yl)methyl]-7-(3-methyl-2 buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.13 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI): m/z = 504 [M+H]* WO 2004/018468 148 PCT/EP2003/009127 (62) 1-[(2-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.17 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI*): m/z = 487 [M+H]* (63) 1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.42 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 458 [M+H]* (64) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.14 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 487 [M+H]* (65) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 155-158 0 C Mass spectrum (ESl*): m/z = 472 [M+H]* (66) 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 511 [M+H]* WO 2004/018468 149 PCT/EP2003/009127 (67) 1-[(5-nitro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 502 [M+H]* (68) 1-[2-(pyrrolidin-1 -yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.56 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 444 [M+H]* (69) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-( 3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 472 [M+H]* (70) 1-[(2-naphthyl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 457 [M+H]* (71) 1-[(4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 475 [M+H]* WO 2004/018468 150 PCT/EP2003/009127 (72) 1-[(quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1 yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 458 [M+H]* (73) 1-[(4-dimethylamino-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.18 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 500 [M+H]* (74) 1 -[(isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; the product still contains approx. 20 % of Z isomer) Rf value: 0.66 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 460 [M+H]* (75) 1-[(3-methoxy-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.25 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESl*): m/z = 487 [M+H]* (76) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 509 [M+H]* WO 2004/018468 151 PCT/EP2003/009127 (77) 1-[(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)methyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI'): m/z = 489 [M+H]* (78) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 522 [M+H]* (79) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESI*): m/z = 495 [M+H]* (80) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESI): m/z = 459 [M+H]* (81) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 459 [M+H]* (82) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; the product still contains approx. 20 % of Z isomer) WO 2004/018468 152 PCT/EP2003/009127 Rf value: 0.12 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI*): m/z = 461 [M+H]* (83) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; the product still contains approx. 15 % of Z isomer) Rf value: 0.12 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI*): m/z = 461 [M+H]* (84) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; the product still contains approx. 17 % of Z isomer) Rf value: 0.54 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* (85) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8-((S) 3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride; the product still contains approx. 17 % of Z isomer) Rf value: 0.54 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* (86) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 536 [M+H]* (87) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 153 PCT/EP2003/009127 Mass spectrum (ESI'): m/z = 478 [M+H]* (88) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(1-cyclopenten -1-yl)methyl]-8-(3 amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 463 [M+H]* (89) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 [(1 -cyclopenten-1 -yl)methyl]-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 550 [M+H]* (90) 1-methyl-3-isopropyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl) xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 422 [M+H]* (91) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 522 [M+H]* (92) 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 508 [M+H]* (93) 1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 505 [M+H]* (94) 1-(2-{2-[(isopropylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3 methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 550 [M+H]* WO 2004/018468 154 PCT/EP2003/009127 (95) 1-[(isoquinolin-1-yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.21 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 532 [M+H]* (96) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (product contains approx. 10 % of Z isomer) Mass spectrum (ESI*): m/z = 494 [M+H]* (97) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine (product contains approx. 25 % of Z isomer) Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 437 [M+H]* (98) 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 567 [M+H]* (99) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 522 [M+H]* (100) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (product contains approx. 10 % of Z isomer) Mass spectrum (ESl*): m/z = 522 [M+H]* (101) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-((E)-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (product contains approx. 8 % of Z isomer) WO 2004/018468 155 PCT/EP2003/009127 Rf value: 0.51 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 524 [M+H]* (102) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ES I): m/z = 536 [M+H]* (103) 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 581 [M+H]* (104) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Rf value: 0.54 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 452 [M+H]* (105) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.48 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 508 [M+H]* (106) 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Rf value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 450 [M+H]* (107) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(2-butyn-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 522 [M+H]* WO 2004/018468 156 PCT/EP2003/009127 (108) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (product contains approx. 22 % of Z isomer) Mass spectrum (ESI*): m/z = 437 [M+H]* (109) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI*): m/z = 536 [M+H]* (110) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Rf value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 492 [M+H]* (111) 1-(2-{2-[2-oxo-2-(pyrrolidin-1 -yl)-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.20 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 562 [M+H]* (112) 1 -(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(3-methyl-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 538 [M+H]* (113) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 435 [M+H]* (114) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (product contains approx. 30 % of Z isomer) Mass spectrum (ESl*): m/z = 538 [M+H]* WO 2004/018468 157 PCT/EP2003/009127 (115) 1 -methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 380 [M+H]* (116) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.40 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 536 [M+H]* (117) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1 -yl)-8-((S)-3-amino piperidin-1 -yl)-xanthine (product contains approx. 23 % of Z isomer) Rf value: 0.42 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 437 [M+H]* (118) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 520 [M+H]* (119) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 492 [M+H]* (120) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 520 [M+H]* (121) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-methyl-allyl)-8-(3-amino piperidin-1 -yl)-xanthine WO 2004/018468 158 PCT/EP2003/009127 Rf value: 0.21 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 437 [M+H]* (122) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(3-bromo-allyl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.14 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 501, 503 [M+H]* (123) 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo -ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.42 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 524 [M+H]* (124) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-[(furan-2-yl)methyl]-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 463 [M+H]* (125) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-chloro-allyl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.18 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) (126) 1-{2-[2-(1-methoxycarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 537 [M+H]* (127) 1 -{2-[2-(1 -aminocarbonyl-ethoxy)-phenyl]-2-oxo-ethyl}-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 522 [M+H]* WO 2004/018468 159 PCT/EP2003/009127 (128) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 435 [M+H]* (129) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 155-156.5 0 C Mass spectrum (ESl*): m/z = 472 [M+H]* (130) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 472 [M+H]* (131) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 472 [M+H]* (132) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 472 [M+H]* (133) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8 ((S)-3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 160 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* (134) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-((E)-2-buten-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 167.5-1720C Mass spectrum (ESl*): m/z = 474 [M+H]* (135) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-(R)-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.34 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 493 [M+H]* (136) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-(S)-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 493 [M+H]* (137) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S) 3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 487 [M+H]* (138) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) WO 2004/018468 161 PCT/EP2003/009127 Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 487 [M+H]* (139) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)- 8 ((R)-3-amino-piperidin-1-yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 479 [M+H]* (140) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((S)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 479 [M+H]* (141) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(S) amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 473 [M+H]* (142) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 198-202 0 C Mass spectrum (ESI'): m/z = 473 [M+H]* (143) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.53 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) WO 2004/018468 162 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 522 [M+H]* (144) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 538 [M+H]* (145) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.49 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 522 [M+H]* (146) 1 -(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 508 [M+H]* (147) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 494 [M+H]* (148) 1 -(2-{2-[(methylaminocarbonyl)methoxy] -phenyl}-2-oxo-ethyl)-3-methyl 7-((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 524 [M+H]* (149) 1 -[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1 -yl) 8-((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.49 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 494 [M+H]* (150) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-((E)-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 524 [M+H]* WO 2004/018468 163 PCT/EP2003/009127 (151) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 520 [M+H]* (152) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 522 [M+H]* (153) 1-(2-{2-[2-(morpholin-4-yl)-2-oxo-ethoxy]-phenyl}-2-oxo-ethyl)-3-methyl 7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 578 [M+H]* (154) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 508 [M+H]* (155) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn 1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 506 [M+H]* (156) 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn 1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 506 [M+H]* (157) 1-[2-(2-acetylamino-phenyl)-2-oxo-ethylj-3-methyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 492 [M+H]* (158) 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 164 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 526 [M+H]* (159) 1-(2-{2-[(phenylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2 buten-1-yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.49 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 556 [M+H]* (160) 1-[(2-acetyl-benzofuran-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Obtained as main product when 1-{2-[2-(2-oxo-propoxy)-phenyl]-2-oxo-ethyl} 3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl] xanthine is treated with trifluoroacetic acid in methylene chloride) Mass spectrum (ESl*): m/z = 489 [M+H]* (161) 1 -{2-[2-(1 -ethoxycarbonyl-1 -methyl-ethoxy)-phenyl]-2-oxo-ethyl}-3 methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 565 [M+H]* (162) 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 496 [M+H]* (163) 1-[(4-dimethylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 (3-amino-piperidin-1 -yl)-xanthine Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 502 [M+H]* WO 2004/018468 165 PCT/EP2003/009127 (164) 1-[2-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf value: 0.42 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 508 [M+H]* (165) 1-(2-{2-[(ethoxycarbonyl)methylamino]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.51 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 538 [M+H]* (166) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-methyl-2-buten-1-yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 451 [M+H]* (167) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-methyl-2-buten-1 -yl)- 8
-(
3 amino-piperidin-1 -yl)-xanthine Rf value: 0.59 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 80:20:1) Mass spectrum (ESl*): m/z = 451 [M+H]* (168) 1-[(imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 447 [M+H]* (169) 1-[(quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine Wo 2004/018468 166 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 459 [M+H]* (170) 1-[2-(1,3-dimethyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yl)-2-oxo ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 519 [M+H]* (171) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 459 [M+H]* (172) 1-[(2-cyano-benzofuran-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 472 [M+H]* (173) 1-[2-(2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 492 [M+H]* Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) (174) 1-[(3-methyl-quinoxalin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Melting point: 188.5-191 0 C Mass spectrum (ESl*): m/z = 473 [M+H]* (175) 1-[(3-phenyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine WO 2004/018468 167 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 534 [M+H]* (176) 1-(2-{2-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Mass spectrum (ESI*): m/z = 527 [M+H]* (177) 1-[(benzofuran-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Produced when 1 -{[2-(tert.-butylcarbonyl)-benzofu ran -3-yl]methyl}-3-methyl 7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine is treated with trifluoroacetic acid in methylene chloride) Mass spectrum (ESI*): m/z = 447 [M+H]* (178) 1-[(3,4-dimethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-( 3 amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.75 (aluminium oxide, methylene chloride/methanol = 10:1) Mass spectrum (ESI*): m/z = 486 [M+H]* (179) 1-[(benzofuran-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 447 [M+H]* (180) 1-{[4-(morpholin-4-yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1-yl) 8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 544 [M+H]* WO 2004/018468 168 PCT/EP2003/009127 (181) 1 -{[4-(piperidin-1 -yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1 -yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 542 [M+H]* (182) 1 -{[4-(piperazin-1 -yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1 -yl)- 8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 543 [M+H]* (183) 1 -{[4-(pyrrolidin-1 -yl)-quinazolin-2-yl]methyl}-3-methyl-7-(2-butyn-1 -yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 528 [M+H]* (184) 1-[2-(3-methyl-2-oxo-2,3-dihydro-1 H-benzoimidazol-4-yl)-2-oxo-ethyl]-3 methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 505 [M+H]* (185) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine Rf value: 0.27 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 482 [M+H]* WO 2004/018468 169 PCT/EP2003/009127 (186) 1-[(imidazo[1,2-a]pyridine-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 447 [M+H]* (187) 1-[(8-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 461 [M+H]* (188) 1-[(4-amino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 474 [M+H]* (189) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((Z)-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 437 [M+H]* (190) 1-[(8-methoxy-quinolin-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-( 3 amino-piperidin-1 -yl)-xanthine x 2 trifluoroacetic acid Rf value: 0.45 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESl*): m/z = 488 [M+H]* (191) 1-[(5-methoxy-quinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.20 (silica gel, ethyl acetate/methanol = 1:1) Mass spectrum (ESl*): m/z = 488 [M+H]* WO 2004/018468 170 PCT/EP2003/009127 (192) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 535 [M+H]* (193) 1-[(7-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 461 [M+H]* (194) 1-[(2-cyclopropyl-quinazolin-4-yl)methyl]-3-methyl-7-[(1-cyclopenten-1 yl)methyl]-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 527 [M+H]* (195) 1-(2-oxo-4-phenyl-butyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine x trifluoroacetic acid Mass spectrum (ESI): m/z = 463 [M+H]* (196) 1-(2-{2-[(methylaminocarbonyl)methylamino]-phenyl}-2-oxo-ethyl)-3 methyl-7-((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.52 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 523 [M+H]* (197) 1-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-2-oxo-ethyl]-3-methyl-7 (2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 171 PCT/EP2003/009127 Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 491 [M+H]* (198) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)- 8 (3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.75 (silica gel, methylene chloride/methanol = 10:1) Mass spectrum (ESl*): m/z = 508 [M+H]* (199) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.80 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 96:4:0.5) Mass spectrum (ESl*): m/z = 515 [M+H]* (200) 1-[(3-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine Rf-Wet: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 461 [M+H]* (201) 1-[2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2 butyn-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESI*): m/z = 515 [M+H]* (202) 1-[(5-methyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.53 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 461 [M+H]* WO 2004/018468 172 PCT/EP2003/009127 (203) 1-[(6-methyl-imidazo[1,2-ajpyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yi)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 176.5-178*C Mass spectrum (ESI*): m/z = 461 [M+H]* (204) 1-[(3-benzyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 201-2040C Mass spectrum (ESl*): m/z = 537 [M+H]* (205) 1-[(4-isopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 501 [M+H]* (206) 1-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.65 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 465 [M+H]* (207) 1 -[(1 -methyl-1 H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 460 [M+H]* WO 2004/018468 173 PCT/EP2003/009127 (208) 1 -[(quinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin 1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 458 [M+H]* (209) 1-[(3-phenyl-imidazo[1,2-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 523 [M+H]* (210) -[(1 H-indol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin 1 -yl)-xanthine-hydrochloride Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI'): m/z = 446 [M+H]* (211) 1-[2-(naphthalen-1-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 485 [M+H]* (212) 1-[(5-methoxy-isoquinolin-8-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.50 (silica gel, methylene chloride/methanol = 5:1) Mass spectrum (ESl*): m/z = 488 [M+H]* (213) 1 -{[1 -(1 -cyano-1 -methyl-ethyl)-isoquinolin-3-yl]methyl}-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine WO 2004/018468 174 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.25 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 525 [M+H]* (214) 1-(2-cyanoimino-2-phenyl-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine x trifluoroacetic acid (E/Z-mixture) Mass spectrum (ESl*): m/z = 459 [M+H]* (215) 1-[(1H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine x trifluoroacetic acid Mass spectrum (ESI*): m/z = 447 [M+H]* (216) 1 -[(1-methyl-1 H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 (3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 461 [M+H]* (217) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 535 [M+H]* (218) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 487 [M+H]* (219) 1-[(2-methyl-1H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 461 [M+H]* WO 2004/018468 175 PCT/EP2003/009127 (220) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)- 3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 535 [M+H]* (221) 1-[2-(quinolin-8-yl-]-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 486 [M+H]* (222) 1-[(3,4-dimethyl-6,7-dihydro-5H-[2]pyridin-1-yl)methyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.25 (aluminium oxide, methylene chloride/methanol = 20:1) Mass spectrum (ESI): m/z = 476 [M+H]* (223) 1-[(3,4-dimethyl-5,6,7,8-tetrahydro-isoquinolin-1-yl)methyl]-3-methyl-7 (2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.50 (aluminium oxide, methylene chloride/methanol = 20:1) Mass spectrum (ESl*): m/z = 490 [M+H]* (224) 1-[2-(1H-indol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 474 [M+H]* (225) 1 -[(1 H-benzoimidazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 447 [M+H]* WO 2004/018468 176 PCT/EP2003/009127 (226) 1 -[(pyrazolo[1,5-a]pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.47 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 447 [M+H]* (227) 1-[(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)methyl]-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 488 [M+H]* (228) 1-[(2-oxo-1,2-dihydro-quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine Rf value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* (229) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 501 [M+H]* (230) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 473 [M+H]* WO 2004/018468 177 PCT/EP2003/009127 (231) 1-[(4-methyl-phthalazin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 473 [M+H]* (232) 1-[(4-bromo-3-methoxy-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 566, 568 [M+H]* (233) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-1 -buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine Rf value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 437 [M+H]* (234) 1-[(4-difluoromethoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.08 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 95:5:1) Mass spectrum (ESl*): m/z = 523 [M+H]* (235) 1-[2-(1 H-indol-7-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 474 [M+H]* WO 2004/018468 178 PCT/EP2003/009127 (236) 1-[(E)-3-(2-nitro-phenyl)-2-propen-1-yl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 478 [M+H]* (237) 1-((E)-3-pentafluorophenyl-2-propen-1-yl)-3-methyl-7-(2-butyn-1-yl)- 8 (3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 523 [M+H]* (238) 1-[(4-nitro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 502 [M+H]* (239) 1 -{[1 -(2-cyano-ethyl)-1 H-benzoimidazol-2-yl]methyl}-3-methyl-7-(2 butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine-hydrochloride (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 500 [M+H]* (240) 1 -({ 1 -[(methylaminocarbonyl)methyl] -1 H-benzoimidazol-2-yl}methyl)-3 methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Mass spectrum (ESI'): m/z = 518 [M+H]* (241) 1 -[(1 -benzyl-1 H-benzoimidazol-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 (3-amino-piperidin-1 -yl)-xanthine Rf value: 0.47 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 537 [M+H]* (242) 1-[(benzooxazol-2-y)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine x trifluoroacetic acid WO 2004/018468 179 PCT/EP2003/009127 Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESI*): m/z = 448 [M+H]* (243) 1-[(5-nitro-benzooxazol-2-y)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine Rf value: 0.49 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 493 [M+H]* (244) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(3-methyl-1 -buten-1 -yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.21 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 488 [M+H]* (245) 1 -[(quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino-piperidin 1-yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 458 [M+H]* (246) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.51 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 459 [M+H] (247) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) WO 2004/018468 180 PCT/EP2003/009127 Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 473 [M+H]* (248) 1-[(2,3,8-trimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin- 1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 501 [M+H]* (249) 1-[([1,6]naphthyridin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 459 [M+H]* (250) 1-[([1,8]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 459 [M+H]* (251) 1-[(4-fluoro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 475 [M+H]* (252) 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine WO 2004/018468 181 PCT/EP2003/009127 (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESI*): m/z = 459 [M+H]* (253) 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3 methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 187-189 0 C Mass spectrum (ESI): m/z = 506 [M+H]* (254) 1-[(8-phenyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 535 [M+H]* (255) 1-[([1,5]naphthyridine-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 459 [M+H]* (256) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 523 [M+H]* (257) 1 -[(E)-3-(2-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI*): m/z = 501 [M+H]* (258) 1-[(E)-3-(3-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 501 [M+H]* WO 2004/018468 182 PCT/EP2003/009127 (259) 1 -[(E)-3-(4-trifluoromethyl-phenyl)-allyl]-3-methyl-7-(2-butyn-1-yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI): m/z = 501 [M+H]* (260) 1-[(3-trifluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8 ((R)-3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Mass spectrum (ESI*): m/z = 526 [M+H]* (261) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-isopropyl-7-(2-butyn-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine (262) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-(4-fluorophenyl)-7-(2-butyn-1 -yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine (263) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.51 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 535 [M+H]* (264) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 508 [M+H]* (265) 1-[(4-chloro-3-methoxy-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Mass spectrum (ESl*): m/z = 522, 524 [M+H]* Rf value: 0.40 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) WO 2004/018468 183 PCT/EP2003/009127 (266) 1-[(4-ethoxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 1 M ethereal hydrochloric acid) Rf value: 0.60 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI): m/z = 503 [M+H]* (267) 1-[(4-isopropyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 517 [M+H]* (268) 1-[(2-methyl-benzothiazol-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 1670C Mass spectrum (ESl*): m/z = 478 [M+H]* (269) 1-[(3-phenyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 534 [M+H]* (270) 1-[(4-phenyloxy-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.60 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 551 [M+H]* WO 2004/018468 184 PCT/EP2003/009127 (271) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 561 [M+H]* (272) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 498 [M+H]* (273) 1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 535 [M+H]* (274) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 465 [M+H]* (275) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.27 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 465 [M+H]* WO 2004/018468 185 PCT/EP2003/009127 (276) 1-[2-(3-trifluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 519 [M+H]* (277) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.35 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 511 [M+H]* (278) 1-[2-(biphenyl-3-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.35 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 511 [M+H]* (279) 1-[2-(3-isopropyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin-1-yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 493 [M+H]* (280) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-cyclopropyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.50 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) WO 2004/018468 186 PCT/EP2003/009127 Mass spectrum (ESI*): m/z = 498 [M+H]* (281) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.45 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 561 [M+H]* (282) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Melting point: 191*C Mass spectrum (ESI*): m/z = 508 [M+H]* (283) 1-[2-(2-phenyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.40 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 527 [M+H]* (284) 1-[2-(3-ethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.29 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 479 [M+H]* (285) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.28 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) WO 2004/018468 187 PCT/EP2003/009127 Mass spectrum (ESI'): m/z = 465 [M+H]* (286) 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.34 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI): m/z = 465 [M+H]* (287) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 544, 546 [M+H]* (288) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8 ((R)-3-amino-piperidi n-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 588, 590 [M+H]* (289) 1 -[(1,2,3,4-tetrahydro-phenanthridin -6-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid Rf value: 0.75 (aluminium oxide, methylene chloride/methanol = 10:1) Mass spectrum (ESl*): m/z = 512 [M+H]* (290) 1-[2-(3-difluoromethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl) 8-((R)-3-amino-piperidin-1 -yl)-xanthine (Carried out with 5-6 M isopropanolic hydrochloric acid in methylene chloride) Rf value: 0.28 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 501 [M+H]* (291) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-ethynyl-benzyl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine (292) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-phenyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine WO 2004/018468 188 PCT/EP2003/009127 (293) 1 -[(phenanthren-9-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (294) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine Rf value: 0.35 (silica gel, methylene chloride/methanol/triethylamine = 90:10:1) Mass spectrum (ESl*): m/z = 545, 547 [M+H]* (295) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8 ((R)-3-amino-piperidin-1-yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol/triethylamine = 90:10:1) Mass spectrum (ESl*): m/z = 607, 609 [M+H]* Example 3 1-[2-(3-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yI)-8-(3-amino-piperidin-1 -yl)-xanthine Prepared by saponifying 70 mg of 1-(2-{3-[(methoxycarbonyl)methoxy] phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin 1 -yl)-xanthine with 0.10 ml of 4 M potassium hydroxide solution in a mixture of 1 ml of tetrahydrofuran and 0.5 ml of methanol at ambient temperature. Yield: 57 mg (84 % of theory) Rf value: 0.55 (ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:0.1) Mass spectrum (ESl*): m/z = 525 [M+H]* The following compounds are obtained analogously to Example 3: (1) 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine (Carried out with sodium hydroxide solution) Mass spectrum (ESI-): m/z = 523 [M-H]- WO 2004/018468 189 PCT/EP2003/009127 Example 4 Coated tablets containing 75 mg of active substance 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation: The active substance is mixed with calcium phosphate, corn starch, polyvin ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. Weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax. Weight of coated tablet: 245 mg. Example 5 Tablets containing 100 mg of active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg WO 2004/018468 190 PCT/EP2003/009127 corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation: The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 500C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side. Example 6 Tablets containing 150 mg of active substance Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mq 300.0 mg Preparation: The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 450C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
WO 2004/018468 191 PCT/EP2003/009127 Weight of tablet: 300 mg die: 10 mm, flat Example 7 Hard gelatine capsules containing 150 mg of active substance 1 capsule contains: active substance 150.0 mg corn starch (dried approx. 80.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation: The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule. Example 8 Suppositories containing 150 mg of active substance 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation: After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds. Example 9 WO 2004/018468 192 PCT/EP2003/009127 Suspension containing 50 mg of active substance 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation: The distilled water is heated to 70 0 C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air. 5 ml of suspension contain 50 mg of active substance. Example 10 Ampoules containing 10 mg active substance Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml Preparation: WO 2004/018468 193 PCT/EP2003/009127 The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules. Example 11 Ampoules containing 50 mg of active substance Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml Preparation: The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Claims (17)

1. Compounds of general formula N NH /R N 0 'N N R2 wherein R 1 denotes a methyl group which is substituted by a dimethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, tert.-butylcarbonyl or a cyclohexylcarbonyl group, a methyl group which is substituted by a naphthyl, methylnaphthyl, methoxynaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group, a methyl group which is substituted by a 2-phenylethenyl or a biphenylyl group, a methyl group which is substituted by a phenyl-oxadiazolyl, 5-methyl-3 phenyl-isoxazolyl, phenyl-pyridinyl, indolyl, benzothiophenyl, quinolinyl, isoquinolinyl, methylisoquinolinyl, (methoxycarbonylmethylamino) isoquinolinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, 1,2-dihydro-1 methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro
4-oxo-phthalazinyl, 3,4-dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4 oxo-quinazolinyl, 3,4-dihydro-3-methyl-4-oxo-quinazoliny or a 2-oxo-2H chromenyl group, a 2-methoxyethyl, 2-phenyloxyethyl or 2-cyanoethyl group, a phenylcarbonylmethyl or a 1 -(phenylcarbonyl)-ethyl group, WO 2004/018468 195 PCT/EP2003/009127 a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino) carbonylamino or a 2-oxo-imidazolidin-1 -yl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylaminocarbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1 -ylcarbonylmethoxy or morpholin 4-ylcarbonylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1 -(methoxycarbonyl)-ethyloxy or a 1 -(aminocarbonyl)-ethyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups or a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -O-CH 2 -0, -O-CH 2 -CH 2 -0 or a -N(CH 3 ) CO-0 group, WO 2004/018468 196 PCT/EP2003/009127 R 2 denotes a methyl, isopropyl or phenyl group and R 3 denotes a 2-methyl-2-propen-1 -yl, 2-chloro-2-propen-1 -yl or 3-bromo-2 propen-1-yl group a 2-buten-1 -yl or 2,3-dimethyl-2-buten-1 -yl group, a 2-butyn-1 -yl group, a 1-cyclopenten-1-ylmethyl group or a 2-furanylmethyl group, as well as the compounds 1-(2-cyano-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-{2-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methy-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(aminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{3-[(methanesulphinyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -(1 -methyl-2-oxo-2-phenyl-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-(2-phenoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, WO 2004/018468 197 PCT/EP2003/009127 1-(2-phenyl-2-oxo-ethyl)-7-(3-methyl-2-buten-1 -yi)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-{3-[(ethoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(dimethylaminocarbonyl)methoxy]- phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-methoxy-ethyl)-3-methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1 -methyl-3-[(methoxycarbonyl)methyl]-7-(2-cyano-benzyl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -methyl-3-cyanomethyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-methyl-3-(2- propyn-1-yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1-yl) xanthine, 1 -{2-[3-(2-oxo-imidazolidin-1 -yl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -methyl-3-(2-propen-1 -yl)-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl) xanthine, 1-(2-{2-[(ethylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 198 PCT/EP2003/009127 1 -methyl-3-phenyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-((S) 3-amino-piperidin-1 -yl)-xanthine, 1-(2-phenyl-2-oxo-ethyl)-3-cyanomethyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -[(quinolin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[(2-oxo-2H-chromen-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1 -[(cinnolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -[(1 -methyl-2-oxo-1,2-dihydro-quinolin-4-yl)methyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[(4-oxo-3,4-dihydro-phthalazin-1 -yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(quinazolin-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[(5-methyl-3-phenyl-isoxazol-4-yl)methyl]-3-methyl-7-(3-methy-2-buten- 1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(isoquinolin-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)
8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 199 PCT/EP2003/009127 1-[(4-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(5-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(3-methyl-4-oxo-3,4-dihydro-phthalazin-1 -yl)methyl]-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methylsulphanyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methanesulphinyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methanesulphonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yi)-xanthine, 1 -{2-[3-(methylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[3-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[3-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 200 PCT/EP2003/009127 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(2-ethoxycarbonyl-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-{2-[2-(dimethylaminocarbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -{2-[2-(morpholin-4-yl-carbonyl)-phenyl]-2-oxo-ethyl}-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[2-(2,6-d imethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 -buten-1 -yl) 8-(3-amino-piperidin-1 -yl)-xanthine, 1 -((E)-3-phenyl-allyl)-3-methyl-7-(3-methyl-2-buten-1 -yi)-8-(3-amino-piperidin 1 -yl)-xanthine, 1 -[(benzo[b]thiophen-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1 -[(1 H-indol-3-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1 -[(biphenyl-4-yl)methyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-(2-cyclohexyl-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-(3,3-dimethyl-2-oxo-butyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3-amino piperidin-1 -yl)-xanthine, WO 2004/018468 201 PCT/EP2003/009127 1 -({5-[(methoxycarbonyl)methylamino]-isoquinolin-1 -yl}methyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-dimethylamino-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yi)-xanthine, 1-[2-(piperidin-1 -yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[(2-methyl-1 -oxo-1,2-dihydro-isoquinolin-4-yl)methyl]-7-(3-methyl-2-buten-1 yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2,3-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl) 8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(pyrrolidin-1 -yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yi)-8-(3 amino-piperidin-1 -yl)-xanthine, 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2 buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)- 8 (3-amino-piperidin-1 -yl)-xanthine, 1 -methyl-3-isopropyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-cyanomethylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1 -[(isoquinolin-1 -yl)methyl]-3-[(methoxycarbonyl)methyl]-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 202 PCT/EP2003/009127 1-(2-{2-[(isopropyloxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-{[(ethoxycarbonylamino)carbonyl]amino}-phenyl)-2 -oxo-ethyl]-3 methyl-7-(3-methyl-2-buten-1 -yi)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 -yl)- 8 ((S)-3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3 methyl-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, 1 -methyl-7-(2-cyano-benzyl)-8-(3-amino-piperidin-1 -yi)-xanthine, 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-(2-{2-[(methoxycarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-4-yl)-2-oxo-ethyl]-3-methyl-7 (3-methyl-2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-nitro-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten- 1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, 1-[2-(2-amino-3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten 1 -yl)-8-(3-amino-piperidin-1 -yi)-xanthine, 1-[2-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-2-oxo-ethyl]-3-methyl-7-(3-methyl 2-buten-1 -yl)-8-(3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 203 PCT/EP2003/009127 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(3-methyl-1 -buten-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-cyano-benzyl)-8-(3-amino piperidin-1 -yl)-xanthine, 1-[2-(3-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methy-2-buten-1 yl)-8-(3-amino-piperidin-1-yl)-xanthine and 1-[2-(2-carboxymethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1 yl)-8-(3-amino-piperidin-1 -yl)-xanthine, the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof. 2. Compounds of general formula I according to claim 1, wherein R 1 denotes a 4-methoxy-1-naphthylmethyl group, a 2-quinolinylmethyl, 4-quinolinylmethyl or a 6-quinolinylmethyl group, a 1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1 isoquinolinylmethyl or a 3-isoquinolinylmethyl group or a 2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or a 4-quinazolinyl methyl group, R 2 denotes a methyl group and R 3 denotes a 2-buten-1 -yl or a 2-butyn-1 -yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. WO 2004/018468 204 PCT/EP2003/009127 3. Compounds of general formula I according to claim 1, wherein R 1 denotes a [2-(methylcarbonylamino)-phenyl]-carbonylmethyl group, a [2-(ethylcarbonylamino)-phenyl]-carbonylmethy group or a [2-(isopropylcarbonylamino)-phenyl]-carbonylmethy group, R 2 denotes a methyl group and R 3 denotes a 2-buten-1 -yl or a 2-butyn-1 -yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. 4. Compounds of general formula I according to claim 1, wherein R 1 denotes a [2-(aminocarbonylmethoxy)-phenyl]-carbonylmethy group, [2-(methylaminocarbonylmethoxy)-phenyl]-carbonylmethyl group, a [2-(ethylaminocarbonylmethoxy)-phenyl]-carbonylmethy group or a [2-(isopropylaminocarbonylmethoxy)-phenyl]-carbonylmethy group, R 2 denotes a methyl group and R 3 denotes a 2-buten-1-yl group, a 2-butyn-1-yl group or a 1-cyclopenten-1-ylmethyl group, WO 2004/018468 205 PCT/EP2003/009127 the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. 5. Compounds of general formula I wherein R 1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl, nitronaphthyl or (dimethylamino)-naphthyl group, a methyl group which is substituted by a phenanthrenyl group, a methyl group which is substituted by a 2-phenylethenyl, 2-[(trifluoromethyl) phenyl]-ethenyl, 2-(nitrophenyl)ethenyl, 2-(pentafluorophenyl)ethenyl or a biphenylyl group, a methyl group which is substituted by a phenyloxadiazolyl, phenylpyridinyl, indolyl, methylindolyl, dimethyl-6,7-dihydro-5H-[2]pyrindinyl, benzimidazolyl, methylbenzimidazolyl, (cyanoethyl)-benzimidazolyl, (methylamino carbonylmethyl)benzimidazolyl, benzylbenzimidazolyl, benzofuranyl, acetylbenzofuranyl, cyanobenzofuranyl, benzoxazolyl, nitrobenzoxazolyl, benzothiophenyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl ethyl)isoquinolinyl, phenylisoquinolinyl, methoxyisoquinolinyl, methoxy-chloro isoquinolinyl, methoxy-bromo-isoquinolinyl, (methoxycarbonylmethylamino) isoquinolinyl, dimethyl-5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro phenanthridinyl, cinnolinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropylquinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino)-quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1-ylquinazolinyl, morpholin-4 ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, phenyl oxyquinazolinyl, imidazo[1,2-a]pyridinyl, methylimidazo[1,2-a]pyridinyl, phenyl imidazo[1,2-a]pyridinyl, benzylimidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, WO 2004/018468 206 PCT/EP2003/009127 phenylquinoxalinyl, methylphthalazinyl, naphthyridinyl, 2,3-dihydro-benzo[1,4] dioxinyl, 1,2-dihydro-2-oxo-quinolinyl, 1,2-dihydro-1-methyl-2-oxo-quinolinyl, 1,2-dihydro-2-methyl-1-oxo-isoquinolinyl, 3,4-dihydro-4-oxo-phthalazinyl, 3,4 dihydro-3-methyl-4-oxo-phthalazinyl, 3,4-dihydro-4-oxo-quinazolinyl, 3,4 dihydro-3-methyl-4-oxo-quinazoliny or a 2-oxo-2H-chromenyl group, a phenylcarbonylmethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by an amino, cyanomethylamino, (ethyloxycarbonylmethyl)amino, (methylaminocarbonyl)methylamino, methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, phenylcarbonylamino, methoxycarbonylamino, (ethyloxycarbonylamino)-carbonylamino or a 2-oxo imidazolidin-1-yl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a carboxy, methoxycarbonyl, ethyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or morpholin-4-ylcarbonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphanyl, methylsulphinyl or methylsulphonyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methylsulphinylmethoxy, carboxymethoxy, ethyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, isopropylamino- WO 2004/018468 207 PCT/EP2003/009127 carbonylmethoxy, dimethylaminocarbonylmethoxy, pyrrolidin-1 ylcarbonylmethoxy or morpholin-4-ylcarbonylmethoxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a 1 -(ethyloxycarbonyl)-1 -methyl-ethyloxy, 1 -(methoxycarbonyl)-ethyloxy or a 1 (aminocarbonyl)-ethyloxy group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by two methoxy groups, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and a nitro group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy group and an amino group, a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -O-CH 2 -0, -O-CF 2 -0, -O-CH 2 -CH 2 -0, -NH CO-NH, -N(CH 3 )-CO-NH, -N(CH 3 )-CO-N(CH 3 ), -NH-CO-0- or a -N(CH 3 ) CO-0 group, a (2-phenylethyl)carbonylmethyl group, a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or a 2-cyanimino-2-phenyl-ethyl group, R 2 denotes a methyl, isopropyl, cyclopropyl, phenyl or fluorophenyl group and R 3 denotes a 2-methyl-2-propen-1-yl, 2-chloro-2-propen-1-yl or 3-bromo-2 propen-1-yl group a 1 -buten-1 -yl, 3-methyl-1 -buten-1 -yl, 2-buten-1 -yl, 2-methyl-2-buten-1 -yl- WO 2004/018468 208 PCT/EP2003/009127 or 2,3-dimethyl-2-buten-1 -yl group, a 2-butyn-1 -yl group, a 1-cyclopenten-1-ylmethyl group or a 2-furanylmethyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof. 6. Compounds of general formula I according to claim 5, wherein R 1 and R 2 are defined as in claim 5 and R 3 denotes a 1-buten-1-yl, 2-buten-1-yl or 2-butyn-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. 7. Compounds of general formula I according to claim 6, wherein R 1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl group, a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group, a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenyl isoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropyl- WO 2004/018468 209 PCT/EP2003/009127 quinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino) quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1 ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1 methyl-2-oxo-quinolinyl group, a phenylcarbonylmethyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a phenyl group, a phenylcarbonylmethyl group wherein the phenyl moiety is substituted by a methoxy, difluoromethoxy, trifluoromethoxy, ethyloxy, isopropyloxy or phenyloxy group, a phenylcarbonylmethyl group wherein in the phenyl moiety two adjacent hydrogen atoms are replaced by a -O-CH 2 -0, -O-CF 2 -0, -O-CH 2 -CH 2 -0, N(CH 3 )-CO-N(CH 3 ) or a -N(CH 3 )-CO-O group, a naphthylcarbonylmethyl, indolylcarbonylmethyl or quinolinylcarbonylmethyl group or a 2-cyanimino-2-phenyl-ethyl group, R 2 denotes a methyl, isopropyl, cyclopropyl, phenyl or 4-fluorophenyl group and R 3 denotes a 1 -buten-1 -yl, 2-buten-1 -yl or a 2-butyn-1 -yI group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof. WO 2004/018468 210 PCT/EP2003/009127 8. Compounds of general formula I according to claim 5, wherein R 1 and R 2 are defined as in claim 7 and R 3 denotes a 1-buten-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
9. Compounds of general formula I according to claim 5, wherein R 1 and R 2 are defined as in claim 7 and R 3 denotes a 2-buten-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
10. Compounds of general formula I according to claim 5, wherein R 1 and R 2 are defined as in claim 7 and R 3 denotes a 2-butyn-1-yl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
11. Compounds of general formula I wherein R 1 denotes a methyl group which is substituted by a naphthyl, fluoronaphthyl, methylnaphthyl, methoxynaphthyl, (difluoromethoxy)-naphthyl, cyanonaphthyl or nitronaphthyl- group, a methyl group which is substituted by a 2-(pentafluorophenyl)ethenyl group, or a methyl group which is substituted by a benzofuranyl, methylbenzothiazolyl, quinolinyl, methoxyquinolinyl, isoquinolinyl, methylisoquinolinyl, (difluoromethyl)-isoquinolinyl, (trifluoromethyl)-isoquinolinyl, dimethylisoquinolinyl, (1-cyano-1-methyl-ethyl)isoquinolinyl, phenyl isoquinolinyl, methoxyisoquinolinyl, 1,2,3,4-tetrahydrophenanthridinyl, quinazolinyl, methylquinazolinyl, isopropylquinazolinyl, cyclopropyl quinazolinyl, phenylquinazolinyl, aminoquinazolinyl, (dimethylamino) quinazolinyl, pyrrolidin-1-ylquinazolinyl, piperidin-1-ylquinazolinyl, piperazin-1 ylquinazolinyl, morpholin-4-ylquinazolinyl, ethoxyquinazolinyl, WO 2004/018468 211 PCT/EP2003/009127 isopropyloxyquinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl, [1,5]naphthyridinyl, [1,6]naphthyridinyl, [1,8]naphthyridinyl or a 1,2-dihydro-1 methyl-2-oxo-quinolinyl group, R 2 denotes a methyl, isopropyl, cyclopropyl or phenyl group and R 3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2 cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
12. Compounds of general formula I according to claim 11, wherein R 1 denotes a (3-methyl-isoquinolin-1 -yl)methyl group, R 2 denotes a methyl group and R 3 denotes a 2-chlorobenzyl, 2-bromobenzyl, 2-ethynylbenzyl or 2 cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
13. Compounds of general formula I according to claim 11, wherein R 1 and R 2 are defined as in claim 11 and R 3 denotes a 2-chlorobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
14. Compounds of general formula I according to claim 11, wherein WO 2004/018468 212 PCT/EP2003/009127 R 1 and R 2 are defined as in claim 11 and R 3 denotes a 2-bromobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
15. Compounds of general formula I according to claim 11, wherein R 1 and R 2 are defined as in claim 11 and R 3 denotes a 2-ethynylbenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
16. Compounds of general formula I according to claim 11, wherein R 1 and R 2 are defined as in claim 11 and R 3 denotes a 2-cyanobenzyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
17. The following compounds of general formula I according to claims 1, 5 and 11: (1) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine, (2) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3 -methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (3) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 (2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (4) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine, (5) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine, WO 2004/018468 213 PCT/EP2003/009127 (6) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (7) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((S)-3 amino-piperidin-1 -yl)-xanthine, (8) 1-[(4-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (9) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn 1 -yl)-8-(3-(R)-amino-piperidin-1 -yl)-xanthine, (10) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3 amino-piperidin-1 -yi)-xanthine, (11) 1-[(4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (12) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine, (13) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R) amino-piperidin-1 -yl)-xanthine, (14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, (15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7 ((E)-2-buten-1 -yl)-8-((S)-3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 214 PCT/EP2003/009127 (17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2 butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E) 2-buten-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine, (19) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (20) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (21) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (22) 1-[(4-fluoro-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine , (23) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine , (24) 1-[(3-trifluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, (25) 1-[(3-difluoromethyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, (26) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yi)-xanthine, (27) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8 ((R)-3-amino-piperidin-1 -yl)-xanthine, WO 2004/018468 215 PCT/EP2003/009127 (28) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine, (29) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R) 3-amino-piperidin-1-yl)-xanthine and (30) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-((R) 3-amino-piperidin-1 -yl)-xanthine as well as the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
18. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 17 with inorganic or organic acids or bases.
19. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 17 or a physiologically acceptable salt according to claim 18 optionally together with one or more inert carriers and/or diluents.
20. Use of a compound according to at least one of claims 1 to 18 for preparing a pharmaceutical composition which is suitable for treating type I and type 11 diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis.
21. Process for preparing a pharmaceutical composition according to claim 19, characterised in that a compound according to at least one of claims 1 to 18 is incorporated in one or more inert carriers and/or diluents by a non chemical method. WO 2004/018468 216 PCT/EP2003/009127
22. Process for preparing the compounds of general formula I according to claims 1 to 18, characterised in that a) a compound of general formula 0 R3 R2 CN 0AN N wherein R 1 to R 3 are defined as in claims 1 to 16 and Z' denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group, is reacted with 3-aminopiperidine, the enantiomers or the salts thereof, or b) a compound of general formula o R 3 H /> N0 Ri N wherein R 1 , R 2 and R 3 are defined as in claims 1 to 16, is deprotected, or c) to prepare a compound of general formula I wherein R 1 according to the definition mentioned in claim 1 contains a carboxy group: a compound of general formula WO 2004/018468 217 PCT/EP2003/009127 0 R3 NH-1 1/ NH 2 N 0~N I >N (IV), O N wherein R 2 and R 3 are defined as in claims 1 to 16 and Rfcontains a carboxy group protected by a C14-alkyl group, is deprotected and/or subsequently, if desired, any protecting groups used during the reaction are cleaved and/or the compounds of general formula I thus obtained are resolved into their enantiomers or diastereomers and/or the compounds of formula I thus obtained are converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids or bases.
AU2003253418A 2002-08-21 2003-08-18 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments Active 2026-11-01 AU2003253418B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2010201384A AU2010201384C1 (en) 2002-08-21 2010-04-07 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10238243A DE10238243A1 (en) 2002-08-21 2002-08-21 New 8-(3-amino-piperidin-1-yl)-xanthine derivatives are dipeptidylpeptidase-IV inhibitors useful for, e.g. treating diabetes mellitus, arthritis or obesity
DE10238243.3 2002-08-21
DE10312353A DE10312353A1 (en) 2003-03-20 2003-03-20 New 8-(3-amino-piperidin-1-yl)-xanthine derivatives are dipeptidylpeptidase-IV inhibitors useful for, e.g. treating diabetes mellitus, arthritis or obesity
DE10312353.9 2003-03-20
PCT/EP2003/009127 WO2004018468A2 (en) 2002-08-21 2003-08-18 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2010201384A Division AU2010201384C1 (en) 2002-08-21 2010-04-07 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Publications (2)

Publication Number Publication Date
AU2003253418A1 true AU2003253418A1 (en) 2004-03-11
AU2003253418B2 AU2003253418B2 (en) 2010-04-22

Family

ID=31947613

Family Applications (2)

Application Number Title Priority Date Filing Date
AU2003253418A Active 2026-11-01 AU2003253418B2 (en) 2002-08-21 2003-08-18 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
AU2010201384A Active 2028-05-21 AU2010201384C1 (en) 2002-08-21 2010-04-07 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Family Applications After (1)

Application Number Title Priority Date Filing Date
AU2010201384A Active 2028-05-21 AU2010201384C1 (en) 2002-08-21 2010-04-07 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Country Status (38)

Country Link
EP (6) EP2308878A3 (en)
JP (6) JP4233524B2 (en)
KR (2) KR101111101B1 (en)
CN (4) CN100522962C (en)
AR (3) AR041025A1 (en)
AT (1) ATE453644T1 (en)
AU (2) AU2003253418B2 (en)
BE (1) BE2011C038I2 (en)
BR (2) BR122012026540B8 (en)
CA (1) CA2496249C (en)
CY (3) CY1109928T1 (en)
DE (2) DE50312295D1 (en)
DK (1) DK1532149T3 (en)
EA (3) EA024251B1 (en)
EC (2) ECSP055617A (en)
EG (1) EG25011A (en)
ES (1) ES2339112T3 (en)
FR (1) FR11C0052I2 (en)
HK (6) HK1081552A1 (en)
HR (2) HRP20050157B1 (en)
HU (1) HUS1100028I1 (en)
IL (1) IL166964A (en)
IN (2) IN2015DN01133A (en)
LU (2) LU91889I2 (en)
ME (1) ME00396B (en)
MX (1) MXPA05001684A (en)
MY (2) MY165643A (en)
NO (4) NO333970B1 (en)
PE (1) PE20040897A1 (en)
PL (2) PL216134B1 (en)
PT (1) PT1532149E (en)
RS (2) RS52142B (en)
SA (1) SA03240448B1 (en)
SI (1) SI1532149T1 (en)
TW (3) TWI469783B (en)
UA (1) UA84275C2 (en)
UY (1) UY27946A1 (en)
WO (1) WO2004018468A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008290582B2 (en) * 2007-08-17 2014-08-14 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases

Families Citing this family (173)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100497336C (en) * 2002-05-31 2009-06-10 先灵公司 Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof
GB0215293D0 (en) 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
PL216134B1 (en) * 2002-08-21 2014-03-31 Boehringer Ingelheim Pharma 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US7482337B2 (en) * 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10251927A1 (en) * 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New 1,7,8-trisubstituted xanthine derivatives, are dipeptidylpeptidase-IV inhibitors useful e.g. for treating diabetes mellitus type I or II, arthritis or obesity
DE10254304A1 (en) 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
JP4806628B2 (en) 2003-05-05 2011-11-02 プロビオドルグ エージー Glutaminyl cyclase inhibitor
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10355304A1 (en) 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 8- (piperazin-1-yl) and 8 - ([1,4] diazepan-1-yl) xanthines, their preparation and their use as pharmaceuticals
JP4970048B2 (en) 2003-12-22 2012-07-04 カトリーケ・ウニフェルジテイト・ルーベン・カー・イュー・ルーベン・アール・アンド・ディ Imidazo [4,5-c] pyridine compounds and methods of antiviral therapy
DE10360835A1 (en) 2003-12-23 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg New bicyclic imidazole derivatives are dipeptidylpeptidase-IV inhibitors useful to treat e.g. arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis
AU2012202850B2 (en) * 2004-02-18 2015-08-20 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor
CN102199151A (en) * 2004-02-18 2011-09-28 贝林格尔.英格海姆国际有限公司 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004009039A1 (en) * 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- [3-Amino-piperidin-1-yl] xanthines, their preparation and use as pharmaceuticals
US7393847B2 (en) 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
BRPI0418639B8 (en) 2004-03-15 2021-05-25 Takeda Pharmaceutical dipeptidyl peptidase inhibitor compounds, as well as pharmaceutical composition containing the same
US7439370B2 (en) 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
DE102004030502A1 (en) 2004-06-24 2006-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel imidazoles and triazoles, their preparation and use as medicines
US7790730B2 (en) 2004-07-27 2010-09-07 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
DE102004043944A1 (en) * 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 8- (3-amino-piperidin-1-yl) -7- (but-2-ynyl) -xanthines, their preparation and their use as pharmaceuticals
DE102004044221A1 (en) 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg New 3-methyl-7-butynyl xanthines, their preparation and their use as pharmaceuticals
AU2012205240B2 (en) * 2004-11-05 2015-03-26 Boehringer Ingelheim International Gmbh Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines
DE102004054054A1 (en) * 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
PL1841765T3 (en) 2004-12-21 2009-08-31 Gilead Sciences Inc Imidazo[4,5-c]pyridine compound and method of antiviral treatment
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
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
DE102005035891A1 (en) * 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
HRP20140091T4 (en) † 2005-09-14 2021-12-24 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
CN101374523B (en) 2005-09-14 2012-04-11 武田药品工业株式会社 Dipeptidyl peptidase inhibitors for treating diabetes
JP5122462B2 (en) 2005-09-16 2013-01-16 武田薬品工業株式会社 Dipeptidyl peptidase inhibitor
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
EP1968947A1 (en) * 2005-12-23 2008-09-17 AstraZeneca AB Gaba-b receptor modulators
TW200803855A (en) * 2006-02-24 2008-01-16 Kalypsys Inc Quinolones useful as inducible nitric oxide synthase inhibitors
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
CN101437823B (en) 2006-05-04 2014-12-10 勃林格殷格翰国际有限公司 Polymorphs
PE20110235A1 (en) * 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
DK2038275T3 (en) 2006-07-07 2010-05-10 Gilead Sciences Inc New pyridazine compound and its use
US8071583B2 (en) 2006-08-08 2011-12-06 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
JP5379692B2 (en) 2006-11-09 2013-12-25 プロビオドルグ エージー 3-Hydroxy-1,5-dihydro-pyrrol-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcers, cancer and other diseases
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US9126987B2 (en) 2006-11-30 2015-09-08 Probiodrug Ag Inhibitors of glutaminyl cyclase
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
DK2142514T3 (en) 2007-04-18 2015-03-23 Probiodrug Ag Thiourea derivatives as glutaminyl cyclase inhibitors
UA99466C2 (en) 2007-07-06 2012-08-27 Гилиад Сайенсиз, Инк. Crystalline pyridazine compound
PE20090938A1 (en) * 2007-08-16 2009-08-08 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL
UY31291A1 (en) * 2007-08-16 2009-03-31 PHARMACEUTICAL COMPOSITION THAT INCLUDES A DERIVATIVE OF PIRAZOL-0-GLUCOSIDO
PE20091730A1 (en) 2008-04-03 2009-12-10 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
EP2108960A1 (en) 2008-04-07 2009-10-14 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditons modulated by PYY
PE20100156A1 (en) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int NAFLD TREATMENT
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
BRPI0916997A2 (en) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh DPP-4 INHIBITOR AND ITS USE
JP5906086B2 (en) * 2008-08-15 2016-04-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Purine derivatives for use in the treatment of FAB-related diseases
KR20110067096A (en) * 2008-09-10 2011-06-21 베링거 인겔하임 인터내셔날 게엠베하 Combination therapy for the treatment of diabetes and related conditions
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
UY32177A (en) * 2008-10-16 2010-05-31 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH INSUFFICIENT GLUCEMIC CONTROL TO WEIGHT THERAPY WITH DRUG, ORAL OR NOT, ANTIDIABÉTICO
KR20110103968A (en) * 2008-12-23 2011-09-21 베링거 인겔하임 인터내셔날 게엠베하 Salt forms of organic compound
AR074990A1 (en) * 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
AR075204A1 (en) 2009-01-29 2011-03-16 Boehringer Ingelheim Int DPP-4 INHIBITORS AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM, USEFUL TO TREAT METABOLIC DISEASES IN PEDIATRIC PATIENTS, PARTICULARLY MELLITUS DIABETES TYPE 2
LT2395983T (en) * 2009-02-13 2020-07-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
MX2011008416A (en) 2009-02-13 2011-09-08 Boehringer Ingelheim Int Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics.
UY32427A (en) * 2009-02-13 2010-09-30 Boheringer Ingelheim Internat Gmbh PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM, PROCEDURE FOR PREPARATION, METHODS OF TREATMENT AND USES OF THE SAME
AR077642A1 (en) 2009-07-09 2011-09-14 Arena Pharm Inc METABOLISM MODULATORS AND THE TREATMENT OF DISORDERS RELATED TO THE SAME
JP5934645B2 (en) 2009-09-11 2016-06-15 プロビオドルグ エージー Heterocyclic derivatives as glutaminyl cyclase inhibitors
CA2775961C (en) 2009-09-30 2017-11-07 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene
DK2486029T3 (en) 2009-09-30 2015-08-24 Boehringer Ingelheim Int Methods of making of glucopyranosyl-substituted benzyl-benzene derivatives.
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2011039367A2 (en) 2009-10-02 2011-04-07 Boehringer Ingelheim International Gmbh Therapeutic uses of pharmaceutical compositions
EA034869B1 (en) 2009-11-27 2020-03-31 Бёрингер Ингельхайм Интернациональ Гмбх Treatment of genotyped diabetic patients with dpp-4 inhibitors such as linagliptin
JP6026284B2 (en) 2010-03-03 2016-11-16 プロビオドルグ エージー Inhibitors of glutaminyl cyclase
CN102791704B (en) 2010-03-10 2015-11-25 前体生物药物股份公司 The heterocycle inhibitor of glutaminyl cyclase (QC, EC 2.3.2.5)
JP2013522279A (en) 2010-03-18 2013-06-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Combination of GPR119 agonist and DDP-IV inhibitor linagliptin for use in the treatment of diabetes and related conditions
BR112012025592A2 (en) 2010-04-06 2019-09-24 Arena Pharm Inc gpr119 receptor modulators and the treatment of disorders related thereto
EP2560953B1 (en) 2010-04-21 2016-01-06 Probiodrug AG Inhibitors of glutaminyl cyclase
BR112012028136A2 (en) * 2010-05-05 2016-08-09 Boehringer Ingelheim Int combination therapy
US20120107398A1 (en) 2010-05-05 2012-05-03 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
KR20130093012A (en) * 2010-06-24 2013-08-21 베링거 인겔하임 인터내셔날 게엠베하 Diabetes therapy
PE20131371A1 (en) 2010-09-22 2013-11-25 Arena Pharm Inc GPR119 RECEPTOR MODULATORS AND THE TREATMENT OF RELATED DISORDERS
US9034883B2 (en) * 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
KR102117282B1 (en) * 2010-11-15 2020-06-01 베링거 인겔하임 인터내셔날 게엠베하 Vasoprotective and cardioprotective antidiabetic therapy
US20130035281A1 (en) 2011-02-09 2013-02-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
UY33937A (en) 2011-03-07 2012-09-28 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS
JP6050264B2 (en) 2011-03-16 2016-12-21 プロビオドルグ エージー Benzimidazole derivatives as inhibitors of glutaminyl cyclase
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
JP6028016B2 (en) * 2011-05-10 2016-11-16 サンド・アクチエンゲゼルシヤフト Polymorphs of linagliptin benzoate
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
EP2731947B1 (en) 2011-07-15 2019-01-16 Boehringer Ingelheim International GmbH Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20130123282A1 (en) 2011-11-16 2013-05-16 Leonid Metsger Solid state forms of linagliptin
US20130172244A1 (en) 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
CN103254192B (en) * 2012-02-15 2015-12-02 上海医药工业研究院 Xanthine derivative, its salt, intermediate, preparation method and application
CN103254193B (en) * 2012-02-15 2015-04-22 上海医药工业研究院 Xanthine compound intermediate and preparation method thereof
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2825539A1 (en) * 2012-03-12 2015-01-21 Cadila Healthcare Limited Amorphous form of linagliptin and process for preparation thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN103373999B (en) * 2012-04-28 2016-01-13 上海医药工业研究院 purine compound, intermediate, preparation method and application thereof
JP6224084B2 (en) * 2012-05-14 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Xanthine derivatives as DPP-4 inhibitors for the treatment of glomerular epithelial cell related disorders and / or nephrotic syndrome
EP2849754B1 (en) 2012-05-14 2022-09-14 Boehringer Ingelheim International GmbH Linagliptin, a xanthine derivative as dpp-4 inhibitor, for use in the treatment of sirs and/or sepsis
JP6374862B2 (en) 2012-05-24 2018-08-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Xanthine derivatives as DPP-4 inhibitors for use in the treatment of autoimmune diabetes, particularly LADA
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
EP2854824A1 (en) 2012-05-25 2015-04-08 Boehringer Ingelheim International GmbH Use of keratinocytes as a biologically active substance in the treatment of wounds, such as diabetic wounds, optionally in combination with a dpp-4 inhibitor
CN103509023B (en) * 2012-06-20 2014-08-27 成都苑东药业有限公司 Xanthine derivative
CN103509022B (en) * 2012-06-20 2015-04-01 成都苑东药业有限公司 Xanthine derivative
CN104540498A (en) 2012-08-13 2015-04-22 桑多斯股份公司 Stable pharmaceutical composition containing 8-[(3r)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1h-purine-2,6-dione or a pharmaceutically acceptable salt thereof
WO2014045266A1 (en) 2012-09-24 2014-03-27 Ulf Eriksson Treatment of type 2 diabetes and related conditions
CN103709163B (en) * 2012-09-29 2016-12-21 齐鲁制药有限公司 Xanthine derivative, Preparation Method And The Use
UA116217C2 (en) 2012-10-09 2018-02-26 Санофі Exendin-4 derivatives as dual glp1/glucagon agonists
CN103319483B (en) 2012-10-19 2016-08-03 药源药物化学（上海）有限公司 A kind of preparation method of important intermediate of linagliptin
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
EP2935266A1 (en) * 2012-12-17 2015-10-28 Mylan Laboratories Ltd. An improved process for the preparation of linagliptin
LT2934568T (en) 2012-12-21 2018-02-12 Sanofi Dual glp1/gip or trigonal glp1/gip/glucagon agonists
CN103936738B (en) * 2013-01-23 2016-11-23 成都苑东生物制药股份有限公司 Xanthine derivative
CN103936739B (en) * 2013-01-23 2016-08-31 成都苑东生物制药股份有限公司 Xanthine derivative
CN103936737B (en) * 2013-01-23 2016-09-14 成都苑东生物制药股份有限公司 Xanthine derivative
CN106008507B (en) * 2013-01-23 2017-11-28 成都苑东生物制药股份有限公司 Xanthine derivative
HUE041709T2 (en) 2013-04-05 2019-05-28 Boehringer Ingelheim Int Therapeutic uses of empagliflozin
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
DK2986304T3 (en) 2013-04-18 2022-04-04 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION, TREATMENT PROCEDURES AND USES.
EP3007701A1 (en) * 2013-06-14 2016-04-20 Boehringer Ingelheim International GmbH Dpp-4 inhibitors for treating diabetes and its complications
CN104292228B (en) * 2013-07-16 2016-03-30 成都苑东生物制药股份有限公司 Polymorphic of a kind of Xanthine compounds and preparation method thereof, purposes
WO2015011609A1 (en) 2013-07-23 2015-01-29 Ranbaxy Laboratories Limited Process for the preparation of linagliptin and an intermediate thereof
CN104418857A (en) * 2013-08-22 2015-03-18 北京蓝丹医药科技有限公司 Amorphous linagliptin and preparation method thereof
EP3080149A1 (en) 2013-12-13 2016-10-19 Sanofi Dual glp-1/glucagon receptor agonists
TW201609799A (en) 2013-12-13 2016-03-16 賽諾菲公司 Dual GLP-1/GIP receptor agonists
EP3080150B1 (en) 2013-12-13 2018-08-01 Sanofi Exendin-4 peptide analogues as dual glp-1/gip receptor agonists
TW201609796A (en) 2013-12-13 2016-03-16 賽諾菲公司 Non-acylated EXENDIN-4 peptide analogues
CN104725379A (en) * 2013-12-24 2015-06-24 杭州民生药物研究院有限公司 Preparation method and application of purine ketone derivatives and composition thereof
ES2950384T3 (en) * 2014-02-28 2023-10-09 Boehringer Ingelheim Int Medical use of a DPP-4 inhibitor
TW201625669A (en) 2014-04-07 2016-07-16 賽諾菲公司 Peptidic dual GLP-1/glucagon receptor agonists derived from Exendin-4
TW201625670A (en) 2014-04-07 2016-07-16 賽諾菲公司 Dual GLP-1/glucagon receptor agonists derived from EXENDIN-4
TW201625668A (en) 2014-04-07 2016-07-16 賽諾菲公司 Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
CN104557935B (en) * 2015-01-27 2016-08-17 江苏嘉逸医药有限公司 Preparation (R)-8-(3-amino piperidine-1-base)-xanthic method of purification
WO2016144862A1 (en) 2015-03-09 2016-09-15 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
AR105319A1 (en) 2015-06-05 2017-09-27 Sanofi Sa PROPHARMS THAT INCLUDE A DUAL AGONIST GLU-1 / GLUCAGON CONJUGATE HIALURONIC ACID CONNECTOR
EP3313841A1 (en) * 2015-06-25 2018-05-02 Boehringer Ingelheim International GmbH Process for the preparation of a xanthine-based compound
AR105284A1 (en) 2015-07-10 2017-09-20 Sanofi Sa DERIVATIVES OF EXENDINA-4 AS SPECIFIC DUAL PEPTIDE AGONISTS OF GLP-1 / GLUCAGÓN RECEPTORS
AU2016335082A1 (en) 2015-10-09 2018-04-12 Hexal Ag Pharmaceutical composition containing 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof
EP3156048A1 (en) 2015-10-13 2017-04-19 Galenicum Health S.L. Stable pharmaceutical composition of linagliptin in the form of immediate release tablets
CN105566271B (en) * 2015-12-03 2019-09-13 福建医科大学 The purposes of biflavone compound and its drug of preparation treating cancer
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US11285180B2 (en) 2016-12-06 2022-03-29 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods of enhancing the potency of incretin-based drugs in subjects in need thereof
EP3606527A1 (en) 2017-04-03 2020-02-12 Coherus Biosciences, Inc. Ppar-gamma agonist for treatment of progressive supranuclear palsy
KR102469957B1 (en) 2017-06-30 2022-11-24 한미약품 주식회사 Pharmaceutical composition comprising linagliptin and metformin with improved stability
CN107325114B (en) * 2017-07-04 2019-06-11 吉林省爱诺德生物工程有限公司 A kind of preparation method of Ceftaroline Fosamil intermediate
DK3461819T3 (en) 2017-09-29 2020-08-10 Probiodrug Ag GLUTAMINYL CYCLASE INHIBITORS
KR102500835B1 (en) 2017-10-24 2023-02-17 한미약품 주식회사 Complex Preparations Comprising Lingliptin and Metformin as an active ingredients and preparing method thereof
CN108299436B (en) * 2018-02-09 2020-01-17 上海慈瑞医药科技股份有限公司 Xanthine compound and pharmaceutical composition and application thereof
KR102208009B1 (en) * 2018-04-26 2021-01-28 주식회사 경보제약 Preparation methode of 5-phenyl pentyl hexahydro cyclopentafuran compounds and cycloheptanoate compounds
KR102647472B1 (en) 2018-07-31 2024-03-14 한미약품 주식회사 Solid composite formulation for oral administration comprising dipeptidyl peptidase-4 inhibitor and metformine, and a process for the preparation thereof
HU231374B1 (en) 2018-08-06 2023-04-28 Richter Gedeon Nyrt. Process for the preparation of boc-linagliptin
CN113543852A (en) 2019-03-06 2021-10-22 第一三共株式会社 Pyrrolopyrazole derivatives
CN110305131B (en) * 2019-07-03 2021-12-31 山东百诺医药股份有限公司 Novel crystal form of linagliptin and preparation method thereof
EP3811930A1 (en) 2019-10-24 2021-04-28 Authenda Pharmaceuticals AG Oral gliptin compositions and method for preparation thereof
CN113423404B (en) * 2019-12-02 2023-09-29 成都苑东生物制药股份有限公司 Xanthine derivative pharmaceutical composition and preparation method thereof
CA3170233A1 (en) 2020-02-13 2021-08-19 Zaklady Farmaceutyczne Polpharma S.A. Pharmaceutical composition comprising linagliptin and metformin
CN112876409A (en) * 2021-01-20 2021-06-01 都创(上海)医药科技股份有限公司 Synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof
WO2023002036A1 (en) 2021-07-22 2023-01-26 Krka, D.D., Novo Mesto Process for preparing a pharmaceutical composition comprising linagliptin and metformin hydrochloride
KR20230055762A (en) 2021-10-19 2023-04-26 한미약품 주식회사 Pharmaceutical composite formulation comprising metformin, linagliptin and meglumine
WO2023156675A1 (en) 2022-02-21 2023-08-24 Krka, D.D., Novo Mesto Process for purification of linagliptin
KR20230126664A (en) 2022-02-23 2023-08-30 주식회사 제뉴원사이언스 Pharmaceutical combination of controlled drug delivery comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof
CN114989147A (en) * 2022-06-20 2022-09-02 佛山市晨康生物科技有限公司 Benzopyrimidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
EP4349837A1 (en) 2022-10-05 2024-04-10 Zaklady Farmaceutyczne "Polpharma" S.A. A pharmaceutical intermediate

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061753A (en) * 1976-02-06 1977-12-06 Interx Research Corporation Treating psoriasis with transient pro-drug forms of xanthine derivatives
FR2558162B1 (en) * 1984-01-17 1986-04-25 Adir NOVEL XANTHINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4968672A (en) * 1987-01-02 1990-11-06 The United States Of America As Represented By The Department Of Health And Human Services Adenosine receptor prodrugs
FR2654935B1 (en) * 1989-11-28 1994-07-01 Lvmh Rech USE OF XANTHINES, WHICH MAY BE INCORPORATED IN LIPOSOMES, TO PROMOTE PIGMENTATION OF THE SKIN OR HAIR.
US5965555A (en) * 1996-06-07 1999-10-12 Hoechst Aktiengesellschaft Xanthine compounds having terminally animated alkynol side chains
ATE297904T1 (en) 1997-04-15 2005-07-15 Genentech Inc HALO-ALKOXYCARBONYL COMPOUNDS
DE19828114A1 (en) * 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs of unstable inhibitors of dipeptidyl peptidase IV
PT1741447E (en) * 2000-01-21 2013-12-11 Novartis Ag Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents
GB0008694D0 (en) * 2000-04-07 2000-05-31 Novartis Ag Organic compounds
GB0014969D0 (en) * 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
AU2001268958B2 (en) * 2000-07-04 2006-03-09 Novo Nordisk A/S Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv
KR100883277B1 (en) * 2001-02-24 2009-02-12 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 Pharmaceutical composition comprising xanthine derivative and process for the preparation thereof
ATE388951T1 (en) * 2001-07-03 2008-03-15 Novo Nordisk As DPP-IV INHIBITING PURINE DERIVATIVES FOR THE TREATMENT OF DIABETES
JP2005509603A (en) * 2001-09-19 2005-04-14 ノボ　ノルディスク　アクティーゼルスカブ Heterocyclic compounds that are inhibitors of the DPP-IV enzyme
WO2003057200A2 (en) * 2002-01-11 2003-07-17 Novo Nordisk A/S Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes
PL216134B1 (en) * 2002-08-21 2014-03-31 Boehringer Ingelheim Pharma 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
DE10251927A1 (en) * 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New 1,7,8-trisubstituted xanthine derivatives, are dipeptidylpeptidase-IV inhibitors useful e.g. for treating diabetes mellitus type I or II, arthritis or obesity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008290582B2 (en) * 2007-08-17 2014-08-14 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases

Also Published As

Publication number Publication date
CY1109928T1 (en) 2014-09-10
CY2012001I2 (en) 2016-12-14
AU2003253418B2 (en) 2010-04-22
NO20140234L (en) 2005-03-03
JP2009079061A (en) 2009-04-16
TW200944209A (en) 2009-11-01
EP2058311A2 (en) 2009-05-13
DE122011100059I1 (en) 2012-04-05
TW201304782A (en) 2013-02-01
LU91889I9 (en) 2019-01-03
EA200500302A1 (en) 2005-10-27
PE20040897A1 (en) 2005-01-31
NO20130968L (en) 2005-03-03
AR077875A2 (en) 2011-09-28
RS52142B (en) 2012-08-31
TWI469783B (en) 2015-01-21
SI1532149T1 (en) 2010-05-31
EA010303B1 (en) 2008-08-29
AU2010201384C1 (en) 2013-09-26
ATE453644T1 (en) 2010-01-15
EA024251B1 (en) 2016-08-31
LU91889I2 (en) 2011-12-21
BE2011C038I2 (en) 2022-08-09
KR101150449B1 (en) 2012-06-01
CN102964347A (en) 2013-03-13
CY2013002I1 (en) 2020-05-29
EP2070539A1 (en) 2009-06-17
JP2009001565A (en) 2009-01-08
RS20050137A (en) 2007-11-15
JP5623459B2 (en) 2014-11-12
NO333970B1 (en) 2013-11-04
IN2015DN01133A (en) 2015-06-26
HRP20050157A2 (en) 2006-05-31
JP4971251B2 (en) 2012-07-11
RS20120139A3 (en) 2015-02-27
PL403104A1 (en) 2013-05-13
HK1134076A1 (en) 2010-04-16
HRP20050157B1 (en) 2013-01-31
BRPI0313648B1 (en) 2018-07-17
IL166964A (en) 2011-02-28
EG25011A (en) 2011-05-25
HUS1100028I1 (en) 2016-07-28
NO20050069L (en) 2005-03-03
TW200404542A (en) 2004-04-01
NO2014008I1 (en) 2014-06-02
KR20050058375A (en) 2005-06-16
HK1081552A1 (en) 2006-05-19
JP5351486B2 (en) 2013-11-27
HRP20090665A2 (en) 2010-07-31
MEP59708A (en) 2011-05-10
AU2010201384A1 (en) 2010-04-29
MY165643A (en) 2018-04-18
DE50312295D1 (en) 2010-02-11
UY27946A1 (en) 2004-03-31
CN102964347B (en) 2015-11-18
CN100522962C (en) 2009-08-05
SA03240448B1 (en) 2009-06-07
HK1215439A1 (en) 2016-08-26
EP2060573A3 (en) 2011-04-13
HK1183028A1 (en) 2013-12-13
UA84275C2 (en) 2008-10-10
EA016166B1 (en) 2012-02-28
JP4233524B2 (en) 2009-03-04
TWI319320B (en) 2010-01-11
CN105001222B (en) 2017-11-07
BR0313648A (en) 2007-05-08
JP2012162555A (en) 2012-08-30
ME00396B (en) 2011-05-10
PL375342A1 (en) 2005-11-28
ECSP12005617A (en) 2012-04-30
EP2308878A2 (en) 2011-04-13
IN2015DN01132A (en) 2015-06-26
HK1134077A1 (en) 2010-04-16
EP1532149A2 (en) 2005-05-25
DK1532149T3 (en) 2010-05-10
EA200702022A1 (en) 2008-06-30
EP2060573A2 (en) 2009-05-20
JP6114231B2 (en) 2017-04-12
JP6139004B2 (en) 2017-05-31
BR122012026540B8 (en) 2021-05-25
KR20090047560A (en) 2009-05-12
PL216134B1 (en) 2014-03-31
LU92128I2 (en) 2013-03-11
CA2496249A1 (en) 2004-03-04
EP2308878A3 (en) 2011-10-26
EP3424926A1 (en) 2019-01-09
FR11C0052I1 (en) 2012-01-06
EP1532149B1 (en) 2009-12-30
KR101111101B1 (en) 2012-06-13
PT1532149E (en) 2010-02-17
BR122012026540B1 (en) 2019-04-24
JP2006503013A (en) 2006-01-26
CN105001222A (en) 2015-10-28
ECSP055617A (en) 2005-05-30
AR041025A1 (en) 2005-04-27
NO2014008I2 (en) 2014-04-08
NO336641B1 (en) 2015-10-12
MY137619A (en) 2009-02-27
BRPI0313648B8 (en) 2021-05-25
WO2004018468A2 (en) 2004-03-04
JP2014177485A (en) 2014-09-25
AU2010201384B2 (en) 2013-05-02
HK1250708A1 (en) 2019-01-11
EA201001167A1 (en) 2011-02-28
JP2016199572A (en) 2016-12-01
EP2058311A3 (en) 2011-04-13
EP1532149B9 (en) 2011-04-20
AR087287A2 (en) 2014-03-12
CA2496249C (en) 2012-01-24
CY2012001I1 (en) 2016-12-14
CN107674077A (en) 2018-02-09
WO2004018468A3 (en) 2004-04-08
ES2339112T3 (en) 2010-05-17
TWI388325B (en) 2013-03-11
RS20120139A2 (en) 2012-10-31
FR11C0052I2 (en) 2013-01-11
CN1675212A (en) 2005-09-28
MXPA05001684A (en) 2005-04-19

Similar Documents

Publication Publication Date Title
US10202383B2 (en) 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
AU2010201384C1 (en) 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
AU2013202252B2 (en) 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
AU2013251292B2 (en) 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments
NZ564768A (en) 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
NC Extension of term for standard patent requested (sect. 70)

Free format text: PRODUCT NAME: TRAJENTA LINAGLIPLIN

Filing date: 20111101

NDA Extension of term for standard patent accepted (sect.70)

Free format text: PRODUCT NAME: TRAJENTA LINAGLIPTIN

Filing date: 20111101

NDB Extension of term for standard patent granted (sect.76)

Free format text: PRODUCT NAME: TRAJENTA LINAGLIPTIN

Filing date: 20111101

Extension date: 20261101