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AU2012202850B2 - 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor - Google Patents

8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor Download PDF

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AU2012202850B2
AU2012202850B2 AU2012202850A AU2012202850A AU2012202850B2 AU 2012202850 B2 AU2012202850 B2 AU 2012202850B2 AU 2012202850 A AU2012202850 A AU 2012202850A AU 2012202850 A AU2012202850 A AU 2012202850A AU 2012202850 B2 AU2012202850 B2 AU 2012202850B2
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methyl
cyano
xanthine
benzyl
butyn
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Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Mohammad Tadayyon
Leo Thomas
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Abstract

Abstract The invention relates to substituted xanthines of general formula (I), wherein R is such as defined in claim 1, and to the tautomers, stereoisomers, mixtures and the salts thereof, said products exhibiting precious pharmacological properties, in particular an inhibiting effect on a dipeptidylpeptidase-IV (DPP-IV) enzyme activity. o N'

Description

A ustralian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor" The following statement is a full description of this invention, including the best method of performing it known to us:- 8-[3-amino-piperidin-1 -yl]-xanthine, the production thereof and the use in the form of a DPP-IV inhibitor This is a divisional of Australian patent application No. 2005219508, the entire contents of which are incorporated herein by reference. The present invention relates to new substituted xanthines of general formula 0 N ( i), N/> N
INH
2 the tautomers, the enantiomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids 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 preventing or treating illnesses or conditions connected 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 and processes for the preparation thereof. Xanthine derivatives with an inhibiting effect on DPP-IV are already known from WO 02/068420, WO 02/02560, WO 03/004496, WO 03/024965, WO 04/018468, WO 04/048379, JP 2003300977 and EP 1 338 595. In the above formula I R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group, 2 a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group, 5 a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4 cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4 methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5 fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 10 2-cyano-4-bromobenzyl group, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl 15 group, a (benzo[1,3]dioxol-5-yl)methyl group, a [(4-cyano-benzo[1,3]dioxol-5-yl)methyl group, 20 a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl, 2-(3-cyclopropylmethoxy-phenyl)-2-oxo ethyl or 2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl group, a 2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or 2-oxo-2-[2-(pyrdin-4-yl)-phenyl]-ethyl 25 group, a (3-cyano-naphthalen-1-yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4 dimethoxy-naphthalen-1-yl)methyl group, 30 a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan 2-yl)methyl, (5-cyano-furan-2-yl)methyl or (5-methoxycarbonyl-furan-2-yl)methyl group, 3 a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group, 5 a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2 yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5 cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or (5-cyano-6-methoxy pyridin-2-yl)methyl group, 10 a (6-phenyl-pyridin-2-yl)methyl or a ([2,2]bipyridinyl-6-yl)methyl group, a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2 yl)methyl group, 15 a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, a [(1-methyl-1 H-benzotriazol-5-yl)methyl] group, 20 a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl, (2-methyl-quinolin-4 yl)methyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-4-methyl-quinolin-2-yl)methyl, (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl, (8-cyano-quinolin-2 yl)methyl, (6-amino-quinolin-2-yl)methyl, (8-amino-quinolin-2-yl)methyl, (4-methoxy quinolin-2-yl)methyl, (6-methoxy-quinolin-2-yl)methyl, (6,7-dimethoxy-quinolin-2 25 yl)methyl or (8-cyano-quinolin-7-yl)methyl group, a (1 -cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-1 -yl)methyl- (4-cyano isoquinolin-3-yl)methyl or [(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl group, 30 a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl, (2-methyl-quinazolin-4-yl)methyl, (4,5-dimethyl-quinazolin-2-yl)methyl, (4-ethyl-quinazolin-2-yl)methyl, (4-cyclopropyl quinazolin-2-yl)methyl, (2-phenyl-quinazolin-4-yl)methyl, (4-cyano-quinazolin-2- H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 -4 yl)methyl, (4-phenylam ino-quinazolin-2-yl)methyl or (4-benzylamino-quinazolin-2 yl)methyl group, a (quinoxalin-5-yl)methyl- (quinoxalin-6-yl)methyl or (2,3-dimethyl-quinoxalin-6 yl)methyl group, or a ([1,5]naphthyridin-3-yl)methyl group, the tautomers, enantiomers, diastereomers, the mixtures and the salts thereof. In one aspect, the present invention relates to a compound of general formula R-L N N I) R/> N NN 0 NN I
NH
2 wherein R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4 cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5 methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6- H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 - 4A fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3 chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group, a (benzo[1,3]dioxol-5-yl)m ethyl group, a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl, 2-(3-cyclopropylmethoxy-phenyl)-2 oxo-ethyl or 2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl group, a 2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or 2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group, a (3-cyano-naphthalen-1 -yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4 dimethoxy-naphthalen-1-yl)methyl group, a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2 yl)methyl group, a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2 yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5 cyano-pyrid in-3-yl)m ethyl, (6-cyano-pyrid in-3-yl)m ethyl or (5-cyano-6-methoxy pyridin-2-yl)methyl group, a (6-phenyl-pyridin-2-yl)methyl or a ([2,2']bipyridinyl-6-yl)methyl group, a (2-phenyl-pyrim idin-4-yl)methyl or (4-phenyl-pyrim idin-2-yl)methyl group, a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl, (2-methyl-quinolin-4 yl)methyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-4-methyl-quinolin-2-yl)methyl, H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 -4B (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl, (6-amino-quinolin-2 yl)methyl, (8-am ino-quinolin-2-yl)methyl, (6-methoxy-quinolin-2-yl)methyl or (6,7 dimethoxy-quinolin-2-yl)methyl group, a (1 -cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-1 -yl)methyl, or [(4-(pyridin 2-yl)-isoquinolin-1-yl]methyl group, a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl, (2-methyl-quinazolin-4-yl)methyl, (4,5-dimethyl-quinazolin-2-yl)methyl, (4-ethyl-quinazolin-2-yl)methyl, (4 cyclopropyl-quinazolin-2-yl)methyl, (4-cyano-quinazolin-2-yl)methyl, (4 phenylam ino-quinazolin-2-yl)methyl or (4-benzylam ino-quinazolin-2-yl)methyl group, a (quinoxalin-5-yl)methyl, group, or a ([1,5]naphthyridin-3-yl)methyl group, or a tautomer, enantiomer, diastereomer, a mixture or a salt thereof. Preferred are compounds of general formula o O N N I
NH
2 wherein R is as hereinbefore defined, as well as their tautomers and salts. Also preferred are compounds of general formula H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 -4C R-, N O<N (Ilb), O N N I
NH
2 wherein R is as hereinbefore defined, as well as their tautomers and salts. According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods: 5 a) reacting a compound of general formula 0 N N 5 wherein R is 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 10 atom, a methanesulphonyl or methanesulphonyloxy group, with 3-aminopiperidine, the enantiomers 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 15 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 (Hunig 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 20 temperatures between -20 and 180 0 C, but preferably at temperatures between -10 and 120*C. The reaction may, however, also be carried out without solvent or in an excess of the 3-aminopiperidine. 25 b) deprotecting a compound of general formula 6 RN N 00 N\N wherein R is as hereinbefore defined. 5 The tert.-butyloxycarbonyl group is preferably cleaved by treating with an acid -such as trifluoroacetic acid or hydrochloric acid or by treating 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. 10 In the reactions described hereinbefore, any reactive groups present such as amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. 15 For example, a protecting group 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. 20 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 25 the presence of iodotrimethylsilane, at temperatures between 0 and 120*C, preferably at temperatures between 10 and 100"C.
7 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 5 temperatures between 0 and 100*C, but preferably at ambient temperatures between 20 and 60*C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole. 10 A 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, dioxane, methanol or diethyl ether. 15 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. 20 A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine, ethanolamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50"C. 25 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 30 enantiomers.
8 Thus, for example, the cis/trans mixtures obtained may be separated by chromatography into their cis and trans isomers, 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, 5 1971) into their optical enantiomers 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 10 as mentioned above. 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 15 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 20 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. 25 Furthermore, the compounds of formula I obtained 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, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or 30 maleic acid.
9 The compounds of general formulae i and IlI used as starting compounds are either known from the literature or may be prepared by methods known from the literature (see Examples I to XXV). 5 As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharma cological properties, particularly an inhibiting effect on the enzyme DPP-IV. The biological properties of the new compounds were investigated as follows: 10 The ability of the substances and their corresponding salts to inhibit the DPP-IV activity can be demonstrated in an experiment in which an extract of the 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 in accordance with the 15 description 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, pp. 5757-5761 (1993). The cell extract was obtained from cells solubilised in a buffer (10mM Tris HCI, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 40C (to remove cell debris). 20 The DPP-IV assay was carried out as follows: 50 pl of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 pM, were placed in black microtitre plates. 20 pl of assay buffer 25 (final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCl, 1 % DMSO) was pipetted in. The reaction was started by the addition of 30 pl of solubilised Caco-2 protein (final concentration 0.14 pg of protein per well). The test substances under investigation were typically added prediluted to 20 pl, while the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient 30 temperature, the incubation period was 60 minutes. Then the fluorescence was measured in a Victor 1420 Multilabel Counter, with the excitation wavelength at 405 nm and the emission wavelength at 535 nm. Dummy values (corresponding to 0 % 10 activity) were obtained in mixtures with no Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100 % activity) were obtained in mixtures without any added substance. The potency of the test substances in question, expressed as IC50 values, were calculated from dosage/activity curves consisting of 5 11 measured points in each case. The following results were obtained: Compound DPP IV inhibition (Example No.) IC50 [nM] 1 6 1(3) 6 1(4) 9 1(6) 2 1(7) 5 1(12) 2 1(21) 2 1(26) 2 1(30) 2 1(31) 3 1(38) 1 1(39) 2 The compounds prepared according to the invention are well tolerated as no toxic side effects could be detected in rats after the oral administration of 10 mg/kg of the 10 compound of Example 1 (30), for example. 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 influencing any conditions or diseases which can be affected 15 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 I and type 11 diabetes mellitus, pre-diabetes, reduced glucose tolerance or changes in the fasting blood sugar, diabetic 11 complications (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 osteoporosis caused by calcitonin. In addition, 5 these substances are suitable for preventing B-cell degeneration such as e.g. apoptosis or necrosis of pancreatic B-cells. The substances are also suitable for improving or restoring the function of pancreatic cells and additionally increasing the size and number of pancreatic B-cells. Additionally, 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 10 inhibition, it is expected that the compounds according to the invention will be suitable for achieving, inter alia, a sedative or tranquillising effect, as well as having a favourable effect on catabolic states after operations or hormonal stress responses or possibly reducing mortality and morbidity after myocardial infarct. Moreover, they are suitable for treating any conditions connected with the effects mentioned above 15 and 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 kidney failure. The compounds according to the invention may also be used to treat inflammatory complaints of the respiratory tract. They are also suitable for preventing and treating chronic inflammatory bowel diseases such as e.g. irritable 20 bowel syndrome (IBS), Crohn's disease or ulcerative colitis and also pancreatitis. It is also expected that they can be used for all kinds of injury or damage to the gastrointestinal tract such as may occur in colitis and enteritis, for example. Moreover, it is expected that DPP-IV inhibitors and hence the compounds according to the invention can be used to treat infertility or to improve fertility in humans or 25 mammals, particularly if the infertility is connected with insulin resistance or with polycystic ovary syndrome. On the other hand these substances are suitable for influencing sperm motility and are thus suitable for use as male contraceptives. In addition, the substances are suitable for treating growth hormone deficiencies connected with restricted growth, and may reasonably be used for all indications for 30 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 12 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 neuro degenerative diseases such as Alzheimer's disease, for example. The compounds 5 described may also be used for the treatment of 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, Parkinson's disease and migraine. In addition, further indications 10 include follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psorasis, 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 15 other active substances. Suitable therapeutic agents for such combinations include for example antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), PPAR 20 gamma/alpha/delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, 115-HSD inhibitors, FGF19 agonists or mimetics, 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, combinations with SGLT2 inhibitors such as T-1 095 or 25 KGT-1251 (869682), 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 30 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 13 absorption 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 LXRalpha antagonists, LXRbeta agonists or LXRalpha/beta regulators or active 5 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, NPY5 or NPY2 antagonists or (1 3 -agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor. 10 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, lB-blockers, Ca antagonists, etc., or combinations thereof. 15 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 20 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 25 or coated tablets, capsules, powders, suspensions or suppositories. The Examples that follow are intended to illustrate the invention: 14 Preparation of the starting compounds Example I 1-[(4-phenylamino-auinazolin-2-vl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-[3-(tert.
5 butyloxvcarbonlamino)-iperidin-1-ll-xanthine A mixture of 416 mg 3-methyl-7-(2-butyn-1-y )8-[3-(tert.-butyloxycarbonylamino) piperidin-1-yl]-xanthine and 456 mg caesium carbonate in 4 ml N,N dimethylformamide is stirred for 10 minutes at 80*C, then 324 mg 2-chloromethyl-4 phenylamino-quinazoline are added and the reaction mixture is stirred for two hours 10 at 80*C. Then another 50 mg caesium carbonate and 50 mg chloromethyl-4 phenylamino-quinazoline are added and the mixture is stirred for a further 1.5 hours at 80*C. Then the solvent is distilled off and the residue is distributed between water and ethyl acetate. The organic phase is washed with dilute citric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated 15 down. The crude product is purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (8:2 to 10:0) as eluant . Yield: 425 mg (65 % of theory) Rf value: 0.33 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 650 [M+H}* 20 The following compounds are obtained analogously to Example I: (1) 1-[(4-benzylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine 25 Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 664 [M+H]* (2) 1-[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine 30 Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 572 [M+H]I 15 (3) 1-[(3-cyano-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.67 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 582 [M+H]* 5 (4) 1-[(2-phenyl-quinazolin-4-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 (ESlI): m/z = 635 [M+H]* 10 (5) 1-[(4-cyano-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/methanol/conc. aqueous ammonia = 90:10:1) 15 Mass spectrum (ESl*): m/z = 583 [M+H]* (6) 1-[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 583 [M+H]* 20 (7) 1 -[2-(3-cyclo propyloxy-phenyl)-2-oxo-ethyl]- 3 -m ethyl-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 = 591 [M+H]* 25 (8) 1-[2-(3-cyclopropyl m ethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yI)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 605 [M+H]+ 30 (9) 1-[2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine 16 Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 605 [M+HI) (10) 1-[(1-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
5 butyloxycarbonylamino)-piperidin-1-y]-xanthine Mass spectrum (ESl*): m/z = 583 [M+H]* (11) 1-[(2,4-methoxy-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 10 Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 617 [M+H]+ (12) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidifn-1 -yl]-xanthine 15 Rt value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ES 1+): m/z = 587 [M+H]* (13) 1-[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-ylI]-xanthine 20 Rf value: 0.45 (silica gel, ethyl acetate/petroleum ether = 7:3) Mass spectrum (ESI*): m/z = 603 [M+H] (14) 1-[(quinoxalin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yI)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine 25 Mass spectrum (ESI'): m/z = 559 [M+H] * (15) 1-[(6-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, ethyl acetate) 30 Mass spectrum (ESI'): m/z = 588 [M+H]* 17 (16) 1-[(6-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.43 (silica gel, methylene chloride/methanol = 96:4) Mass spectrum (ESI*): m/z = 584 [M+H]* 5 (17) 1-{[(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperdin-1 -yl]-xanthine (18) 1-[(7-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
10 butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.24 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 576 [M+H]* (19) 1-[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
15 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.63 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 603 [M+H]) (20) 1-[(6-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
20 butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.47 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI*): m/z = 576 [M+H]' (21) 1-[2-oxo-2-(2-bromo-phenyl)ethyl]-3-methyl-7-(2-butyn-1-yl)- 8 -[(R)-3-(tert.
25 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 613, 615 [M+H]+ (22) 1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino) 30 piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 456 [M+H]* 18 (23) 1-[(4-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 588 [M+H]* 5 (24) 1-[(2-phenyl-pyrimidin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.39 (silica gel, methylene chloride/methanol = 96:4) Mass spectrum (ESl*): m/z = 585 [M+H] I0 (25) 1-[([1,5]naphthyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.28 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 559 [M+H]* 15 (26) 1-[(3-cyano-4-methyl-quinolin-2-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 = 597 [M+H]* 20 (27) 1-[(4,5-dimethyl-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 = 587 [M+H]* 25 (28) 1-[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.42 (silica gel, petroleum ether/ethyl acetate = 1:2) Mass spectrum (ESl*): m/z = 583 [M+H]l 30 (29) 1-[(3-cyano-quinolin-2-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/ethyl acetate = 1:1) 19 (30) 1-[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.46 (silica gel, ethyl acetate) 5 (31) 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: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 580 [M+H]' 10 (32) 1-[(1,4-dicyano-naphthalen-2-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 607 [M+H]* 15 (33) 1-[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.36 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 618 [M+H]* 20 (34) 1-[(quinazolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 559 [M+H]I 25 (35) 1-[(4-cyano-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, methylene chloride/ethyl acetate = 7:3) Mass spectrum (ESl*): m/z = 584 [M+H]* 30 (36) 1-[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine 20 Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 559 [M+H]+ (37) 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
5 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, methylene chloride/ethyl acetate = 7:3) Mass spectrum (ESI*): m/z = 532 [M+H]* (38) 1-(3-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
10 butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.58 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 532 [M+H]* (39) 1-(4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yI)-8-[(R)-3-(tert.
15 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.61 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 532 [M+H]I (40) 1-[(pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
20 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 508 [M+H]* (41) 1-benzyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)3-(tert.-butyloxycarbonylamino) piperidin-1-yl]-xanthine 25 Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 507 [M+H]* (42) 1-(4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yli]-xanthine 30 Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 537 [M+H]* 21 (43) 1-(2-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 541, 543 [M+H] 4 5 (44) 1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 557 [M+H]* 10 (45) 1-(2-cyano-4-bromo-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 610, 612 [M+H]I (46) 1-(3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
15 butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 525 [M+H]* (47) 1-(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
20 butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 567 [M+H]+ (48) 1-(2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
25 butyloxycarbonyla mino)-piperidin-1 -yl]-xanthine Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 525 [M+H]+ (49) 1-[(6-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
30 butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rr value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESI*): m/z = 533 [M+H]* 22 (50) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1:1) 5 Mass spectrum (ESI*): m/z = 533 [M+H]J (51) 1-(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ES I): m/z = 566, 568 [M+H]* 10 (52) 1-(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80"(silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 525 [M+H]* 15 (53) 1-(4-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 541, 543 [M+H]1 20 (54) 1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 550 [M+H]* 25 (55) 1-(3-cyano-4-fluoro-benzy)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 550 [M+H]* (56) 1-(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
30 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 566, 568 [M+H]I 23 (57) 1-[(5-methoxycarbonyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yI8-[(R)-3 (tert.-butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 555 [M+H] 5 (58) 1-(2-trifluoromethyl-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 600 [M+H]* (59) 1-(3,5-dicyano-benzy)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
0 butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 557 [M+H]* (60) 1-(3-nitro-4-cyano-benzyI)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 15 Mass spectrum (ESl*): m/z = 577 [M+H]* (61) 1-[(2-cyano-pyridin-3-yl)methyl]-3-methyl-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) 20 Mass spectrum (ESI'): m/z = 533 [M+H]* (62) 1-(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)- 8 -[(R)-3-(tert.
butyloxycarbonylamino)-pipeidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1:1) 25 Mass spectrum (ESI*): m/z = 562 [M+H]I (63) 1-(2-cyano-5-methoxy-benzyl)-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) 30 Mass spectrum (ESI'): m/z = 562 [M+H]* 24 (64) 1-(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 537 [M+H]* 5 (65) 1-(3-trifluoromethyl-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 575 [M+H1* 10 (66) 1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 567 [M+H]* 15 (67) 1-(3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 541, 543 [M+H]* 20 (68) 1-(4-trfluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 575 [M+H]* 25 (69) 1-[([2,2']bipyridinyl-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.53 (aluminium oxide, methylene chloride/methanol = 98:2) Mass spectrum (ESI*): m/z = 585 [M+H]* 30 (70) 1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine 25 R, value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 585 [M+H]1 (71) 1-[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
5 butyloxycarbonylaminoy-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 526 [M+H]* (72) 1-[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yt)-8-[(R)-3 (tert.-butyloxycarbonylaminoy-piperidin-1 -yl]-xanthine 10 Mass spectrum (ESl*): m/z = 563 [M+H]* (73) 1-(2,6-Difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.62 (silica gel, ethyl acetate) 15 Mass spectrum (ESl*): m/z = 543 [M+H]* (74) 1-(3-trfluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.67 (silica gel, ethyl acetate) 20 Mass spectrum (ESl*): m/z = 591 [M+H]* (75) 1-(4-trfluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)- 8 -[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Ri value: 0.62 (silica gel, ethyl acetate) 25 Mass spectrum (ESI*): m/z = 591 [M+H] (76) 1-[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rr value: 0.55 (silica gel, methylene chloride/ethyl acetate = 1:1) 30 Mass spectrum (ESl*): m/z = 533 [M+H]+ 26 (77) 1-[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.55 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 533 [M+H]I 5 (78) 1-[(pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylaminoy-piperidin-1-yl]-xanthine Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI*): m/z = 509 [M+HJ 10 (79) 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESl*): m/z = 523 [M+H]* 15 (80) 1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI*): m/z = 537 [M+H]+ 20 (81) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Rf value: 0.55 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 439, 441 [M+H]* 25 (82) 1-(3-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 555 [M+H] 30 (83) 1-(3,4-difluoro-benzy)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.75 (silica gel, ethyl acetate) 27 Mass spectrum (ESl*): m/z = 543 [M+H] (84) 1-(2-fluoro-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 5 Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether = 3:2) Mass spectrum (ESl*): m/z = 555 [M+H]* (85) 1-(2-fluoro-3-methoxy-benzy)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1-yl]-xanthine 10 Rf value: 0.48 (silica gel, ethyl acetate/petroleum ether = 3:2) Mass spectrum (ESI*): m/z = 555 [M+H]* (86) 1-[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yI)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 15 Rf value: 0.55 (silica gel, methylene chloride/methanol= 95:5) Mass spectrum (ESI*): m/z = 583 [M+H] (87) 1-(2-fluoro-4-methoxy-benzyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine 20 Rf value: 0.48 (silica gel, ethyl acetate/petroleum ether = 1:1) Mass spectrum (ESl*): m/z = 555 [M+H]* (88) 1-[(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine 25 Mass spectrum (ESI*): m/z = 497 [M+H]+ (89) 1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-pipeidin-1 -yl]-xanthine Mass spectrum (ESIl): m/z = 557 [M+H]* 30 (90) 1-(4-cyano-2-fluoro-benzyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 28 Mass spectrum (ESI*): m/z = 550 [M+H]* (91) (1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-1 -yl]-xanthine 5 Mass spectrum (ESl*): m/z = 550 [M+H]* (92) 1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)8-[(R)-3-(tert.
butyloxycarbonylamino)-piperdin-I -yl]-xanthine Mass spectrum (ESl*): m/z = 525 [M+H]* 10 (93) 1-(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (94) 1-(4-cyano-3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
15 butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 550 [M+HI* (95) 1 -(2-cya no-3-methoxy-be nzyl)-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xa nthi ne Rf value: 0.85 (silica gel, ethyl acetate) 20 Mass spectrum (ESl*): m/z = 442, 444 [M+H]* (96) 1-[(8-cyano-quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate) 25 Mass spectrum (ESI'): m/z = 583 [M+HI* (97) 1-[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, ethyl acetate/cyclohexane = 3:1) 30 Mass spectrum (ESl*): m/z = 533 [M+H] 29 (98) 1-[(8-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.40 (silica gel, ethyl acetate/petroleum ether = 4:1) Mass spectrum (ESI*): m/z = 583 [M+Hj 5 (99) 1 -[(1-methyl-1 H-benzotrazol-5-yl)methyl-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3 (tert.-butyloxycarbonylamino)-piperdin-1 -yl]-xanthine Rf value: 0.30 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 562 [M+H]* 10 (100) 1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.30 (silica gel, methylene chloride/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 533 [M+HI* 15 (101) 1 -[(3-cya no-pyridi n-2-yl)methyl]-3-m ethyl-7-(2-butyn-1 -yl)-8-bromo-xanthifne Mass spectrum (ESI*): m/z = 413, 415 [M+H]* (102) 1-[(4-cyano-benzo[1,3]dioxol-5-yl)methyl]-3-methyl-7(2-butyn-1-yl)-8-[(R)-3 20 (tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 576 [M+H]* Example i 25 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperdin-1-vll xanthine 11.00 g of (R)-3-tert.-butyloxycarbonylamino-piperidine are added to 15.00 g of 3 methyl-7-(2-butyn-1-yl)-8-bromo-xanthine and 16.00 g potassium carbonate in 100 ml dimethylsulphoxide and the thick light beige suspension is stirred for four hours with 30 a mechanical stirrer at approx. 1 14'C. Then another 900 mg of (R)-3-tert.
butyloxycarbonylamino-piperidine, dissolved in 10 ml dimethylsulphoxide, are added to the reaction mixture and this is stirred for a further two hours at 11 4C. After 30 cooling to ambient temperature the reaction mixture is liberally diluted with water. The precipitate formed is thoroughly triturated until there are no lumps left and suction filtered. The light-coloured solid is again suspended with water, suction filtered, washed with water and diethyl ether and dried in the circulating air dryer at 5 60 0 C. Yield: 19.73 g (94 % of theory) Rt value: 0.64 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 417 [M+H] 10 The following compound is obtained analogously to Example ll: (1) 3-methyl-7-(2-butyn-1 -yl)8-[(3-(tert.-butyloxycarbonylamino-pipeidin-1 -yl] xanthine melting point: 235-237*C 15 Mass spectrum (ESI*): m/z = 417 [M+HI* (2) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rr value: 0.40 (silica gel, ethyl acetate) 20 Mass spectrum (ESl*): m/z = 559 [M+H]* (3) 1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 511 [M+H]* 25 (4) 1-(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 562 [M+H]+ 30 (5) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yl]-xanthine 31 Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 533 [M+H]* Example Ill 5 3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine 17.06 g 1-bromo-2-butyn are added to 30.17 g of 3-methyl-8-bromo-xafnthifne and 27.00 ml HOnig base in 370 ml N,N-dimethylformamide. The reaction mixture is stirred for two hours at ambient temperature, then another 1 ml of 1-bromo-2-butyne is added and the mixture is stirred for a further hour at ambient temperature. For 10 working up the reaction mixture is diluted with approx. 300 ml water. The light coloured precipitate formed is suction filtered and washed with water. The filter cake is washed with a little ethanol and diethyl ether and dried at 60*C in the circulating air dryer. Yield: 30.50 g (84 % of theory) 15 Rr value: 0.24 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 297, 299 [M+H]* Example IV 2-chloromethyl-4-phenylamino-quinazoline 20 Prepared by reacting 500 mg 4-chloro-2-chloromethyl-quinazoline with 438 mg aniline in 12 ml methylene chloride at ambient temperature. Yield: 518 mg (82 % of theory) Ri value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (ESl*): m/z = 270, 272 [M+H]I 25 The following compound is obtained analogously to Example IV: (1) 2-chloromethyl-4-benzylamino-quinazoline Rr value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1:1) 30 Mass spectrum (ESl*): m/z = 284, 286 [M+H]* 32 Example V 1-bromomethyl-4-cyano-isoquinoline Prepared by bromination of 1-methyl-4-cyano-isoquinoline with N-bromosuccinimide 5 in the presence of azobisisobutyronitrile in carbon tetrachloride at 80*C. Rf value: 0.51 (silica gel, methylene chloride) Mass spectrum (El): m/z = 246, 248 [M]* The following compounds are obtained analogously to Example V: 10 (1) 2-bromomethyl-4-cyano-quinoline Mass spectrum (ESl*): m/z = 247, 249 [M+H]* (2) 3-bromomethyl-1-cyano-isoquinoline 15 Mass spectrum (ESl*): m/z = 247, 249 [M+H]+ (3) 1-bromomethyl-4-(pyridin-2-yl)-isoquinoline Rf value: 0.47 (silica gel, methylene chloride/methanol = 9:1) 20 (4) 2-bromomethyl-4-methoxy-quinoline Mass spectrum (ESl*): m/z = 252, 254 [M+H]* (5) 3-bromomethyl-[1,5]naphthyridine Mass spectrum (ESI*): m/z = 223, 225 [M+H]j 25 (6) 2-bromomethyl-5-cyano-quinoline Rf value: 0.28 (silica gel, petroleum ether/ethyl acetate = 5:1) Mass spectrum (ESI*): m/z = 247, 249 [M+H]* 30 (7) 2-bromomethyl-3-cyano-quinoline Rj value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) 33 (8) 2-bromomethyl-4-phenyl-pyrimidine Rf value: 0.88 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 249, 251 [M+H]* 5 (9) 2-bromomethyl-1,4-dicyano-naphthalefne Rr value: 0.48 (silica gel, petroleum ether/ethyl acetate = 9:1) Mass spectrum (El*): m/z = 270, 272 [M]+ (10) 2-bromomethyl-6,7-dimethoxy-quinoline 10 Rr value: 0.70 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 282, 284 [M+H]* (11) 2-bromomethyl-4-cyano-quinazoline Rf value: 0.85 (silica gel, methylene chloride/methanol = 99:1) 15 Mass spectrum (El+): m/z = 247, 249 [M]* (12) 7-bromomethyl-quinazoline Rf value: 0.15 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESl*): m/z = 223, 225 [M+H]+ 20 (13) 2-trifluoromethyl-4-cyano-benzylbromide (14) 2-bromomethyl-5-cyano-6-methoxy-pyridine Mass spectrum (ESl*): m/z = 227, 229 [M+H]+ 25 (15) 3-bromomethyl-4-cyano-isoquinoline Rf value: 0.43 (silica gel, petroleum ether/ethyl acetate = 7:3) (16) 7-bromomethyl-8-cyano-quinoline 30 Rf value: 0.25 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI*): m/z = 247, 249 [M+H]* 34 (17) 2-bromomethyl-8-cyano-quinoline Rf value: 0.75 (silica gel, methylene chloride/methanol = 99:1) Mass spectrum (ESI*): m/z = 247, 249 [M+H]j 5 Example VI 2-bromo-1 -(3-cyclopropvloxy-phenvi)-ethanone Prepared by bromination of 1-(3-cyclopropyloxy-phenyl)-ethanone with phenyltrimethylammoniumn tribromide in methylene chloride at reflux temperature. Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 3:1) 10 Mass spectrum (ESl*): m/z = 255, 257 [M+H]* The following compounds are obtained analogously to Example VI: (1) 2-bromo--1-(3-cyclopropylmethoxy-phenyl)-ethanone 15 Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) (2) 2-bromo-1-(3-cyclobutyloxy-phenyl)-ethanone Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) 20 Example Vil 1-(3-cyclopropyloxy-phenvl)-ethanone Prepared by reacting 3-hydroxyacetophenone with bromocyclopropane in the presence of potassium iodide and potassium-tert.butoxide in N,N-dimethylformamide in the microwave at 220 0 C. 25 Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESI*): m/z = 177 [M+H]+ The following compounds are obtained analogously to Example VII: 30 (1) 1 -(3-cyclopropylmethoxy-phenyl)-ethanone Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESl*): m/z = 191 [M+H]* 35 (2) 1 -(3-cyclobutyloxy-phenyl)-ethanone Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1) Mass spectrum (ESl*): m/z = 191 [M+H]I 5 Example VIII 1 -chloromethyl-2,4-dimethoxy-naphthalene Prepared by chlorinating 1 -hydroxymethyl-2,4-dimethoxy-naphthalene with thionyl chloride in methylene chloride at ambient temperature. 10 Rf value: 0.78 (silica gel, cyclohexane/ethyl acetate = 1:1) Mass spectrum (El): m/z = 236, 238 [M]' Example IX 1-hydroxymethyl-2.4-dimethoxy-naphthalene 15 Prepared by reducing2,4-dimethoxy-naphthalene-1-carboxaldehyde with sodium borohydride in a mixture of dioxane and water (3:1) at ambient temperature. Rf value: 0.48 (silica gel, cyclohexane/ethyl acetate = 1:1) Example X 20 1-[(6-amino-quinolin-2-yl)methyll-3-methyl-7-(2-butv-1 -vl)-8-RR)-3-(tert.-butyloxV carbonylamino)-piperidin-1 -vll-xanthine Prepared by treating 1-[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R) 3-(tert.-butyloxycarbonylamino)piperidin-1-yl]-xanthine with sodium dithionite in a mixture of ethanol/water (5:2) at 55-60*C. 25 Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESl*): m/z = 573 [M+H]+ Example X 1 -methyl-4-(pvridin-2-vl)-isoquinoline 30 Prepared by reacting 4-bromo-1-methyl-isoquinoline with lithium-triisopropoxy- 2 pyridinyl-boronate in the presence of tetrakis(triphenylphosphine)palladium, 36 triphenylphosphine, sodium carbonate and copper(I)iodide in 1,4-dioxane at reflux temperature. Rf value: 0.22 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI *): m/z = 221 [M+H]I 5 Example XII 1-[(8-amino-quinolin-2-vl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-(R)-3-(tert.-butloxY carbonylamino)-piperidin-1 -yll-xanthine Prepared by treating 1-[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R) 10 3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with iron powder in a mixture of glacial acetic acid, ethanol and water (2:20:5) at reflux temperature. Rf value: 0.50 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI'): m/z = 573 [M+H]* 15 Example XIII 1-{2-oxo-2-[2-(pyridin-3-vl)-phenyll-ethvl}-3-methyl-7-(2-butvn-l-vl)-8-I(R)-3-(tert.
butyloxvcarbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 1-[2-oxo-2-(2-bromo-phenyl)ethyl]-3-methyl-7-(2-butyn-1-yl)- 8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with pyridine-3-boric acid 20 in the presence of tetrakis(triphenylphosphine)palladium, tetra-n-butylammonium bromide and sodium carbonate in a mixture of toluene/ethanol (1:1) at 105"C. Rf value: 0.55 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 612 [M+H]* 25 The following compound is obtained analogously to Example XII: (1) 1-{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1-yI)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1 -yl]-xanthine (The reaction is carried out with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 30 pyridine). Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 612 [M+H]* 37 Example XIV 1 -(4-ethyl-uinazolin-2-v)methyll-3-methyl-7R-3rt.
butyloxvcarbonvlamino)-piperidin-1 -vll-xanthine 5 Prepared by treating 1-cyanomethyl-3-methyl-7-(2-butyn-1-yI)-8-[(R)-3-(tert.
butyloxycarbonylamino)-piperidin-1-yll-xanthine with potassium-tert.-butoxide in methanol and subsequently reacting the resulting iminoester with 2-amino-propio phenone in the presence of glacial acetic acid. Rf value: 0.60 (silica gel, ethyl acetate) 10 Mass spectrum (ESl): m/z = 587 [M+H]+ The following compound is obtained analogously to Example XIV: (1) 1 -[(4-cyclo propyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.
15 butyloxycarbonylanmino)-piperid in-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 599 [M+H]* Example XV 20 2-chloromethyl-3-cyano-4-methyl-quinoline Prepared by reacting 3-cyano-2,4-dimethyl-l-oxy-quinoline with benzosulphonic acid chloride in toluene at 80 0 C. Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 2:1) Mass spectrum (ESl*): m/z = 217, 219 [M+H]* 25 Example XVI 3-cyano-2,4-dimethyl-1 -oxy-quinoline Prepared by treating 3-cyano-2,4-dimethyl-quinoline with aqueous hydrogen peroxide solution (35 %) in glacial acetic acid at 60*C. 30 Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 199 [M+H]* 38 Example XVII 2-chloromethyl-4,5-dimethyl-qui nazoline Prepared by reacting 1-(2-amino-6-methyl-phenyl)-ethanone with chloroacetonitrile in dioxane while piping in hydrogen chloride at 30-38*C. 5 Mass spectrum (ESl*): m/z = 207, 209 [M+H]* Example XVIII 1-[(2-methyl-quinazolin-4-vl)methyll-3-methyl-7-(2-butyn-I -yl)-8-f(Rj-3-tert.
butvloxvcarbonvlamino)-piperidin-1 -vil-xanthine 10 Prepared by reacting 1-[2-(2-acetylamino-pheny)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 yl)8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with ethanolic ammonia (6 M) and ammonium chloride in the autoclave at 150 0 C. Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 573 [M+H]* 15 Example XIX 1-[2-(2-acetylamino-phenyl)-2-oxo-ethyll-3-methyl-7-(2-butvn-1l)- 8 -[ CRh-tert butvloxvcarbonylamino)-piperidin-1 -vIl-xanthine Prepared by reacting 1-[2-(2-amino-pheny)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yI)-8 20 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yI]-xanthine with acetyl chloride in the presence of pyridine in methylene chloride at ambient temperature. Rf value: 0.79 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 592 [M+H]j 25 Example XX 1-[2-(2-amino-phenl2-oxo-ethyll-3-m -)-8-[(R)-3-(tert.
butyloxvcarbonviamino)-piperidin-1 -vil-xanthine Prepared by reducing 1-[2-(2-nitro-phenyl-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8 [(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with tin(ll)chloride 30 dihydrate in tetrahydrofuran at ambient temperature. Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESl*): m/z = 550 [M+H]* 39 Example XXI 1 -f(furan-3-vl)methyll-3-methyl-7-(2-butvn-1-vi)-8-[(R)-3-(tert.-butvloxvcarbonyl amino)-piperidin-1 -yll-xanthine 5 A mixture of 300 mg of 3-methyl-7-(2-butyn-1-yl)8-[(R)-3-(tert.-butyloxycarbonyl amino)-piperidin-1 -yl)-xanthine, 95 pl furan-3-yi-methanol, 302 mg triphenylphosphine and 226 pl diisopropyl azodicarboxylate in 4 ml tetrahydrofuran is stirred ovemight at ambient temperature . For working up the reaction mixture is combined with saturated potassium carbonate solution and extracted with ethyl acetate . The 10 combined organic phases are dried over magnesium sulphate and evaporated down. The flask residue is chromatographed over a silica gel column with cyclohexane/ethyl acetate (1:1 to 3:7). Yield: 330 mg (92 % of theory) Mass spectrum (ESI*): m/z = 497 [M+H] 15 The following compounds are obtained analogously to Example XXI: (1) 1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine Mass spectrum (ESl*): m/z = 391, 393 [M+H]I 20 (2) 1-[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)8-[(R)-3-(tert.-butyloxy carbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESl*): m/z = 575, 577 [M+H] 4 25 Example XXII 1 -f(5-cyano-furan-2-vl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butvloxV carbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yi)-8-[(R) 3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine with hydroxylamine-O 30 sulphonic acid and pyridine in toluene at reflux temperature.
40 Example XXIII 5-(methanesulphonvioxvmethyl)-2-furan-carboxaldehyde Prepared by reacting 5-(hydroxymethyl)-2-furan-carboxaldehyde with methanesulphonic acid chloride in the presence of triethylamine in methylene 5 chloride at ambient temperature. The crude product is further reacted without any more purification. Example XXIV 2-chloromethyl-3-cyano-pdrdine 10 Prepared from 2-(hydroxymethyl)-nicotinamide by reaction with thionyl chloride in acetonitrile and subsequent dehydration of the 2-(chloromethyl)-nicotinamide thus obtained with trifluoroacetic acid anhydride in the presence of triethylamine in methylene chloride. Alternatively the compound is also obtained in one step by refluxing 2-(hydroxy 15 methyl)-nicotinamide with phosphorus oxychloride. Rf value: 0.85 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESl*): m/z = 153, 155 [M+H]* Example XXV 20 8-cyano-7-methyl-quinoline Prepared by reacting 8-bromo-7-methyl-quinoline with zinc cyanide in the presence of tetrakis(triphenylphosphi ne)palladium in N-methylpyrrolidinone under a protective gas atmosphere at 100-105 0 C. Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 7:3) 25 Mass spectrum (ESI'): m/z = 169 [M+H]* Example XXVI 2-methyl-8-cyano-quinoline Prepared by reacting 2-methyl-8-bromo-quinoline with copper(I)cyanide in N 30 methylpyrrolidinone under a protective gas atmosphere at 180*C. Rr value: 0.40 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESl*): m/z = 169 [M+H]* 41 Preparation of the final compounds Example 1 5 1-[(4-phenvlamino-auinazolin-2-vl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-(3-amino piperidin-1 -vi)-xanthine A mixture of 400 mg 1-[(4-phenylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn 1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 10 ml methylene chloride is combined with 2 ml isopropanolic hydrochloric acid (5-6 M) and stirred for 10 three hours at ambient temperature. Then the reaction mixture is diluted with methylene chloride, combined with ice water and made alkaline with 3 M potassium carbonate solution. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried over magnesium sulphate and evaporated down. The flask residue is stirred with diethyl ether, suction filtered, 15 washed with diethyl ether and dried in vacuo . Yield: 274 mg (81 % of theory) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 550 [M+H]* 20 The following compounds are obtained analogously to Example 1: (1) 1-[(4-benzylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino piperidin-1 -yl)-xanthine 25 Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 564 [M+H]* (2) 1-[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino 30 piperidin-1-yl)-xanthine Mass spectrum (ESli): m/z = 472 [M+H] 42 (3) 1-[(3-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) 5 Mass spectrum (ESl*): m/z = 482 [M+H]+ (4) 1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.45 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ 10 trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 535 [M+H]* (5) 1-[(4-cyano-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine 15 Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 483 [M+H]* (6) 1-[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino 20 piperidin-1 -yl)-xanthine Mass spectrum (ESI'): m/z = 483 [M+H]* (7) 1-[2-(3-cyclopropyloxy-pheny)2-o xo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine 25 Rf value: 0.45 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 491 [M+H]* (8) 1-[2-(3-cyclopropylmethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R) 30 3-amino-piperidin-1 -yl)-xanthine Rf value: 0.35 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) 43 Mass spectrum (ESIl): m/z = 505 [M+H] 4 (9) 1-[2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine 5 Rf value: 0.40 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ tnfluoroacetic acid = 50:50:1) Mass spectrum (ESl+): mlz = 505 [M+H]+ (10) 1-[(1-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino 10 piperidin-1-yl)-xanthine Mass spectrum (ESl*): m/z = 483 [M+H]* (11) 1-[(2,4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine 15 Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 517 [M+H]* (12) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3 20 amino-piperidin-1 -yl)-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:0.1) Mass spectrum (ESl*): m/z = 487 [M+H]* 25 (13) 1-[(6-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:0.1) Mass spectrum (ESl*): m/z = 473 [M+H]+ 30 (14) 1 -[(quinoxalin-5-yl)methyl]-3-m ethyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine-hydrochloride 44 Mass spectrum (ESl*): m/z = 459 [M+H]* (15) 1-[(6-methoxy-quinolin-2-yl)methyl-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino piperidin-1-yl)-xanthine 5 Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 488 [M+H]* (16) 1-[(6-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino 10 piperidin-1-yl)-xanthine Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ES l*): m/z = 484 [M+H]* 15 (17) 1-{[(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 80:20:1) Mass spectrum (ESI*): m/z = 535 [M+H]* 20 (18) 1-[(7-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.58 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) 25 Mass spectrum (ESI*): m/z = 476 [M+H]+ (19) 1-[(8-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 30 90:10:1) Mass spectrum (ESl*): m/z = 473 [M+H]1 45 (20) 1-[(6-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) 5 Mass spectrum (ESl*): m/z = 476 [M+H]+ (21) 1-{2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethy}-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine Rf value: 0.55 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ 10 trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 512 [M+H]+ (22) 1-[(4-ethyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8 -((R)-3-amino piperidin-1-yl)-xanthine 15 Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 487 [M+H]* (23) 1 4-cyclo propyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 20 amino-piperidin-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 499 [M+H]* 25 (24) 1-[(4-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Mass spectrum (ESl*): m/z = 488 [M+H] 30 (25) 1-[(2-phenyl-pyrimidin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine 46 Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 485 [M+H]+ 5 (26) 1-[([1,5]naphthyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ESl*): m/z = 459 [M+H]* 10 (27) 1-[(3-cyano-4-methyl-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ 15 trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 497 [M+H]* (28) 1-[(4,5-dimethyl-quinazolin- 2 -yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine 20 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 487 [M+H]* (29) 1-[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine 25 Rf value: 0.50 (sitica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 483 [M+H]+ (30) 1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino 30 piperidin-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 47 Rf value: 0.50 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 483 [M+H]* 5 (31) 1-[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-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 = 485 [M+H]* 10 (32) 1-[(2-methyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 15 90:10:1) Mass spectrum (ESl*): m/z = 473 [M+H]* (33) 1 -[(1,4-d icyano-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine-hydrochloride 20 Rf value: 0.86 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 507 [M+H] (34) 1-{2-oxo-2-[2-(pyridin-4-ylphenyl]-ethyl}-3-methyl-7-(2-butyn-1-yI)-8-((R)-3 25 amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.55 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 512 [M+H]j 30 (35) 1-[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine 48 Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI 4 ): m/z = 518 [M+H]* 5 (36) 1-[(quinazolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine-hydrochloride Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 459 [M+H]* 10 (37) 1-[(4-cyano-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 15 90:10:1) Mass spectrum (ESI*): m/z = 484 [M+H]* (38) 1-[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-y-)-8-((R)3-amino-piperdin-1 yl)-xanthine 20 Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 459 [M+H]I (39) 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) 25 xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 432 [M+H]* 30 (40) 1-(3-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 -yl) xanthine 49 (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 432 [M+H]+ 5 (41) 1-(4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 10 90:10:1) Mass spectrum (ESl*): m/z = 432 [M+H]+ (42) 1-[(pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am ino-piperidin-1-yl) xanthine 15 Rf value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 408 [M+H]+ (43) 1-benzyl-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperdin-1-yl)-xanthine 20 (BOC cleaving carried out with trifluoroacetic acid) melting point: 207-209*C Mass spectrum (ESI*): m/z = 407 [M+H]* (44) 1-(4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) 25 xanthine-hydrochloride Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 437 [M+H]* 30 (45) 1-(2-chloro-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine 50 Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 441, 443 [M+H]* 5 (46) 1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 457 [M+H]* 10 (47) 1-(2-cyano-4-bromo-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin 1 -yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 510, 512 [M+H]+ 15 (48) 1-(3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) 20 Mass spectrum (ESl*): m/z = 425 [M+H]* (49) 1 -(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 25 Rf value: 0.45 (silica gel, methylene chlorde/methanol/conc. aqueous ammonia 90:10:0.1) Mass spectrum (ESl*): m/z = 467 [M+H]* (50) 1-(2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yi)-8-((R)-3-amino-piperidin-1-yl) 30 xanthine (BOC cleaving carried out with trifluoroacetic acid) 51 Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI*): m/z = 425 [M+H]* 5 (51) 1-{(6-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 433 [M+H] 10 (52) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI 4 ): m/z = 433 [M+H]+ 15 (53) 1-(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn--1-yl)-8-((R)-3-amino-piperidin 1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 466, 468 [M+H]+ 20 (54) 1-(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 425 [M+H]* 25 (55) 1(4-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 441, 443 [M+H]+ 30 (56) 1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) 52 Mass spectrum (ESIl): m/z = 450 [M+HI* (57) 1-(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine x trifluoroacetic acid 5 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 450 [M+H]* (58) 1-(2-chloro-4-cyano-benzy)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin 1-yi)-xanthine x trifluoroacetic acid 10 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 466, 468 [M+H]j (59) 1-[(5-methoxycarbonyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1-yl)-xanthine x trifluoroacetic acid 15 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI'): m/z = 455 [M+H]* (60) 1-(2-trifluoromethyl-4-cyano-benzy)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine x trifluoroacetic acid 20 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 500 [M+H]* (61) 1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine 25 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z 457 [M+H]* (62) 1-(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine x trifluoroacetic acid 30 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 477 [M+H]+ 53 (63) 1-[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ 5 trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 433 [M+H]+ (64) 1-(2-cyano-4-methoxy-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine 10 (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 462 [M+H]+ 15 (65) 1-(2-cyano-5-methoxy-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.45 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) 20 Mass spectrum (ESl*): m/z = 462 [M+H] (66) 1-(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-l-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) 25 Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI'): m/z = 437 [M+H]+ (67) 1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 30 yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 54 Rf value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 475 [M+H]' 5 (68) 1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-l yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) 10 Mass spectrum (ESl*): m/z = 467 [M+H]* (69) 1-(3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) 15 Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:0.1) Mass spectrum (ESl*): m/z = 441, 443 [M+H]j (70) 1-(4-trfluoromethyl-benzyl)3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidinl 20 yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rr value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 475 [M+H]+ 25 (71) 1-[([2,2']bipyridinyl-6-yl)methyl]-3-methyl-7-( 2 -butyn-1-yI)-8-((R)-3-amino piperidin-1-yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) 30 Mass spectrum (ESl*): m/z = 485 [M+H]
.
55 (72) 1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) 5 Mass spectrum (ESl*): m/z = 485 [M+H]' (73) 1-[(6-fluoro-pyidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-y-((R)-3-ammino piperidin-1 -yl)-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 10 90:10:1) Mass spectrum (ESl*): m/z = 426 [M+H]* (74) 1-[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine 15 Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI*): m/z = 463 [M+H]* (75) 1-(2,6-difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) 20 xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 443 [M+H] 25 (76) 1-(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)8-((R)-3-amino-piperidin 1 -yl)-xanthine Rf value: 0.36 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ESl*): m/z = 491 [M+H]+ 30 (77) 1-(4-trifluoromethoxy-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino-piperidin 1 -yl)-xanthine 56 Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESl*): m/z = 491 [M+H]* 5 (78) 1-[(2-cyano-pyrdin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidir-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) 10 Mass spectrum (ESl*): m/z = 433 [M+H]* (79) 1-[(5-cyano-pydin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8 -((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 15 Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 433 [M+H]1 (80) 1-[(pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 20 yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 409 [M+H]+ 25 (81) 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.65 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/Water/ 30 trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 423 [M+H]+ 57 (82) 1-[(4,6-dimethyl-pyrimidin-2-yl)methyll-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) melting point: 202-204 0 C 5 Mass spectrum (ESIi): m/z = 437 [M+H]+ (83) 1 -[(quinoxaIin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-a mino-piperidin-1 yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 10 90:10:0.1) Mass spectrum (ESI*): m/z = 459 [M+H]I (84) 1-(3-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine 15 (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 455 [M+H]* 20 (85) 1-(3,4-difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:0.1) 25 Mass spectrum (ESl*): m/z = 443 [M+H]* (86) 1-(2-fluoro-5-methoxy-benzyl)-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rr value: 0.39 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 30 90:10:1) Mass spectrum (ESl*): m/z = 455 {M+H]* 58 (87) 1-(2-fluoro-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) 5 Mass spectrum (ESI*): m/z = 455 [M+H]* (88) 1-[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 10 Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 483 [M+H}* (89) 1-(2-fluoro-4-methoxy-benzy)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino 15 piperidin-1-yl)-xanthine Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ESl*): m/z = 455 [M+H]* 20 (90) 1 [(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl) xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 397 [M+H] 25 (91) 1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 457 [M+H]+ 30 (92) 1 -[(furan-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl) xanthine (BOC cleaving carried out with. trifluoroacetic acid) 59 Mass spectrum (ESl*): m/z = 397 [M+H]1 (93) 1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-( 2 -butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine 5 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 411 [M+H]* (94) 1-[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine x trifluoroacetic acid 10 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI'): m/z = 475, 477 [M+H]* (95) 1-(4-cyano-2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine 15 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI*): m/z = 450 [M+H]+ (96) 1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)- 8 -((R)-3-amino-piperidin-1 yl)-xanthine 20 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESIl): m/z = 450 [M+H]* (97) 1-[(5-cyano-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine x trifluoroacetic acid 25 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESIl): m/z = 422 [M+H]* (98) 1-(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine 30 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 450 [M+H] 60 (99) 1-(4-cyano-3-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESl*): m/z = 450 [M+H]* 5 (100) 1-(2-cyano-3-methoxy-benzyl)-3-methyl-7-( 2 -butyn-1-yI)-8-((R)-3-amino piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) 10 Mass spectrum (ESl*): m/z = 462 [M+H]* (101) 1-[(8-cyano-quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yyl)-8-((R)-3-amino piperidin-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 15 Mass spectrum (ESI*): m/z = 483 [M+H]* (102) 1-[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 20 melting point: 1660C Mass spectrum (ESl*): m/z = 433 [M+H]+ (103) 1-[(8-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-y8-((R)-3-amino piperidin-1-yl)-xanthine 25 (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:0.1) Mass spectrum (ESl*): m/z = 483 [M+Hj 30 (104) 1 -(1 -methyl-1 H-benzotriazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3 amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 61 Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESI*): m/z = 462 [M+H]* 5 (105) 1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino piperidin-1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.65 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) 10 Mass spectrum (ESI*): m/z = 433 [M+H]* (106) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) 15 Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1) Mass spectrum (ESl*): m/z = 433 [M+H]* (107) 1-[(4-cyano-benzo[1,3]dioxol-5-yl)methyll-3-methyl-7-(2-butyn-1-yl)-8-((R)-3 20 amino-piperidin-1-yl)-xanthine Rf value: 0.45 (silica gel, methylene chlorde/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESl*): m/z = 476 [M+H]* 25 The following compounds may also be obtained analogously to the foregoing Examples and other methods known from the literature: (1) 1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 30 yl)-xanthine 62 (2) 1 -(2-cyano-5-fluoro-benzyI-3-methy-7-(2-butyfl-1 -yI)-8-(R)-3-amiflo-Pipefdil-1 yI)-xanthine (3) 1 -(2-cya no-6-fl uo ro-benzyl)-3-methyl-7-(2-b utyfl-l -yI)- 8 (R)-3-a m i no-pi pe rid in- 1 5 yI)-xanthine (4) 1 -(3-cyano-4-fluoro-benzyI-3-methyI-7-(2-butyfl-1 -yl)- 8 -(( R)-3-am ino-pi peridin-1 yI)-xanthine 10 (5) 1 -(3,5-dicyano-benzy)-3-methyl-7-(2-butyl-1 -yI)-8-((R)-3-amino-piperddin-i -yI) xanthine (6) 1 -(3,4-dicyano-benzyI)-3-methy-7-(2-butyfl-1 -yI)-8-((R)-3-amino-pipeidil-1 -yI) xanthine 15 (7) 1 -(3-nitro-4-cyano-benzyl)-3-nlethyl-7-(2-butyfl- yI)-8-((R)-3-amino-piperldifl yI)-xanthine (8) 1 -(2-chloro-4-cyano-benzyI-3-methyI-7-(2-butyfl-l-yI)-8-((R)-3-amliflo-piperdifll 20 yI)-xanthine (9) 1 -(2-fluoro-4-cyano-benzyl )3-methyl-7-(2-butyn-1 -yI)- 8 -(( R)-3-am ino-piperidin- 1 yI)-xanthine 25 (10) 1 -(2-trfuoromethy-4-cyano-benzyI)-3-methyI- 7
-(
2 -butyfll -yI)-8-((R)-3-amiflo piperidin-1 -yi)-xanthine (11) 1 -[(5-cyano-pyridin-2-yl)methyI]-3-methyI-7-(2-butyfll -yI)-8-((R)-3-amiflo piperidin-1 -yI)-xanthine 30 (12) 1 -1(4-cyano-pyrid in-2-yI )methyl]-3-methyl-7-(2-butyl- 1-yI )-8-(( R)-3-a mino piperidin-1 -yI)-xanthine 63 (13) 1 -[(4-cya no-pyridin-3-y)methy]-3-methy--( 2 -butyn-1-yI)-8-((R)-3-amino piperidin-1 -yI)-xanthine 5 (14) 1 -[(3-cyano-pynd n4y)methy]-3-methyI-7-(2-butyfl I-yI)-8-(R)-3-amiflo piperidin-1 -yI)-xanthine (15) 1 -[(2-cyano-pyridi n-3-yl)methyI]-3-methyI-7-(2-butyfll -yI)- 8 -(( R)-3-amino piperdin-i -yI)-xanthine 10 (16) 1 -[(2-cyano-pyrid in-4-yl)m ethyll-3-methyl-7-(2-butyfli -yI )-8-((R)-3-a mino piperidin-1 -yI)-xanthine (17) 1 -[(5-cyano-pyri -lmthl--ety--2-uy--yI)-8-((R)-3-a mino 15 piperidin-1 -yI)-xanthine (18) 1 -[(6-cyano-pyridi n-3-y)methyII-3-methyI-7-(2-butyfll -yi)-8-((R)-3-amiflo piperid in-I -yI)-xanthine 20 (19) 1 -(2-cyano-4-methoxy-benzyI)-3-methyI--7-(2-butyrn-l-y1)-8-(( R)-3-amino piperidin-1 -yI)-xanthine (20) 1 -(2-cyano-5-m ethoxy-benzy)-3-mlethy-7-(2-butyfll-yI)-8-(R)-3-amino piperidin-1 -yI)-xanthine 25 (21) 1 -[([2 ,2'lbipyridi nyl-6-yI )methyl]-3-methyl-7-(2-butyfl-l-yI )-8-(( R)3-a mino piperidin-1 -yI)-xanthine (22) 1 -[(5-methoxy-pyrid in-2-y)methyI]-3-methyI-7-(2-butyfll -yI)-8-((R)-3-amino 30 piperidin-1 -yI)-xanthifle 64 (23) 1 -[(6-fluoro-pyrddin-2-yI)m ethyI1-3-methyI-7-(2-butyfll -yI)-8-((R)-3-amiflo piperidin-1 -yI)-xanthifle (24) 1 -[(5-cyano-6-methoxy-pyridin2y ehy]3mty-7(-uy--yI)- 8 -(R)-3 5 amino-piperidifl-1 -yI)-xanthine (25) 1 -(2-methoxy-benzy)-3-ml ethyl-7-(2-butyn-1 -yI)-8-((R)-3-a i no-pi pe rid i n-1 -yI) xanthine 10 (26) 1 -(3-methoxy-benzY)3-methyl-7-(2-butYfl-1 yY-(Y3aiopieii--yI) xanthine (27) 1 -(3-chloro-benzyl )-3-methyl-7-(2-butyl-1 -yI)-8-(( R)3-amino-piperid in-i -yI) xanthine 15 (28) 1 -(4-trifluoromethyl-beflzyt 3-methyl-7-(2-butyfl-l-yI )8-(( R)3-amiflo-pipefdif-l yI)-xanthine (29.) 1 (-dlooehy-ezI3mthl7(-uy--yI )-8-((R)-3-amino-pipefldil-l 20 yI)-xanthine (30) 14-trifluoromethyI-beflzyYI3-methy-7( 2 butyn-1-yI)-8-((R)-3-amiflo-piperid in-i yI)-xanthine 25 (31) 1 -(3,4-dirnethoxy-benzy)3methyI-7( 2 butyn-1 -yI)-8-((R)-3-amino-pipefldifl-1 yI)-xanthine (32) 1 (,-iehxy6fur-eny)3mtyl7(-uy--yI)-8-((R)-3-amio piperidin-1 -yI)-xanthine 30 (33) 1 -[(benzo[1 ,3]ixl5y mtyl3mtyl7(-uy--yI)-8-((R)-3-amiflo piperidin-1 -yI)-xanthine 65 Example 2 Coated tablets containing 75 ma of active substance 5 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg 10 hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mq 230.0 mg Preparation: 15 The active substance is mixed with calcium phosphate, com starch, polyvin ylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks about 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. 20 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 25 hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax. Weight of coated tablet: 245 mg.
66 Example 3 Tablets containing 100 mq of active substance 5 Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg 10 com starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg 15 Method of PreDaration: 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 50 0 C it is 20 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. 25 67 Example 4 Tablets containing 150 mq of active substance 5 Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg 10 colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 15 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 45*C, are passed through the same screen 20 again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Weight of tablet: 300 mg die: 10 mm, flat 68 Example 5 Hard gelatine capsules containing 150 mq of active substance 5 1 capsule contains: active substance 150.0 mg com starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 ma 10 approx. 420.0 mg Preparation: The active substance is mixed with the excipients, passed through a screen with a 15 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. 20 Example 6 Suppositories containing 150 ma of active substance 1 suppository contains: 25 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 30 69 Preparation: After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds. 5 Example 7 Suspension containing 50 mq of active substance 10 100 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 15 glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml 20 Preparation: The distilled water is heated to 700C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved 25 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. 30 ""WT *"""""'"""- " 70 Example 8 Ampoules containing 10 mq active substance Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 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 2 ml ampoules. Example 9 Ampoules containing 50 mq 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 HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
C.% T """"1 -3c-"""" 70A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (13)

1. A compound of general formula R-, N N (I 0O:k N N NH 2 wherein R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl,
3-chlorobenzyl or 4-chlorobenzyl group, a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4 cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5 methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6 fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3 chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group, a (benzo[1,3]dioxol-5-yl)m ethyl group, H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 - 72 a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl, 2-(3-cyclopropylmethoxy-phenyl)-2 oxo-ethyl or 2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl group, a 2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or 2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group, a (3-cyano-naphthalen-1 -yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4 dimethoxy-naphthalen-1-yl)methyl group, a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2 yl)methyl group, a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2 yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5 cyano-pyrid in-3-yl)m ethyl, (6-cyano-pyrid in-3-yl)m ethyl or (5-cyano-6-methoxy pyridin-2-yl)methyl group, a (6-phenyl-pyridin-2-yl)methyl or a ([2,2']bipyridinyl-6-yl)methyl group, a (2-phenyl-pyrim idin-4-yl)methyl or (4-phenyl-pyrim idin-2-yl)methyl group, a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl, (2-methyl-quinolin-4 yl)methyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-4-methyl-quinolin-2-yl)methyl, (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl, (6-amino-quinolin-2 yl)methyl, (8-am ino-quinolin-2-yl)methyl, (6-methoxy-quinolin-2-yl)methyl or (6,7 dimethoxy-quinolin-2-yl)methyl group, a (1 -cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-1 -yl)methyl, or [(4-(pyridin 2-yl)-isoquinolin-1-yl]methyl group, H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 - 73 a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl, (2-methyl-quinazolin-4-yl)methyl, (4,5-dimethyl-quinazolin-2-yl)methyl, (4-ethyl-quinazolin-2-yl)methyl, (4 cyclopropyl-quinazolin-2-yl)methyl, (4-cyano-quinazolin-2-yl)methyl, (4 phenylam ino-quinazolin-2-yl)methyl or (4-benzylam ino-quinazolin-2-yl)methyl group, a (quinoxalin-5-yl)methyl, group, or a ([1,5]naphthyridin-3-yl)methyl group, or a tautomer, enantiomer, diastereomer, a mixture or a salt thereof. 2. A compound of general formula 0 R-, N N N (la), O N I NH 2 wherein R is defined as in claim 1, or a tautomer or a salt thereof. 3. A compound of general formula R-, N N (1b), O N N I NH 2 wherein R is defined as in claim 1, or a tautomer or a salt thereof.
4. A physiologically acceptable salt of the compound according to any one of claims 1 to 3 with an inorganic or organic acid. H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 - 74 5. A pharmaceutical composition containing a compound according to any one of claims 1 to 3 or a physiologically acceptable salt according to claim 4, optionally together with one or more inert carriers and/or diluents.
6. Use of a compound according to any one of claims 1 to 4 in the preparation of a pharmaceutical composition for treating type I or II diabetes mellitus, arthritis, obesity, allograft transplantation, a diabetic complication or calcitonin-induced osteoporosis.
7. A process for preparing a pharmaceutical composition according to claim 5, wherein a compound according to any one of claims 1 to 4 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
8. A process for preparing the compound of general formula I according to any one of claims 1 to 4, wherein a) a compound of general formula R,, N Zi (II), N O NN wherein R is defined as in claim 1 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, an enantiomer or a salt thereof, or b) a compound of general formula H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 -75 R-, N O N N N O N4 OX wherein R is defined as in claim 1, is deprotected, and/or any protecting groups used during the reaction are then cleaved and/or the compound of general formula I thus obtained is resolved into its enantiomers and/or diastereomers and/or the compound of formula I thus obtained is converted into a salt thereof, particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid.
9. A method of treating type I or II diabetes mellitus, arthritis, obesity, allograft transplantation, a diabetic complication or calcitonin-induced osteoporosis, said method comprising administering to a subject a compound according to any one of claims 1 to 4.
10. Use of a compound according to any one of claims 1 to 4 in the preparation of a pharmaceutical composition for preventing or treating illnesses or conditions connected with an increased DPP-IV activity or capable of being influenced by inhibition of the DPP-IV activity, optionally wherein said composition is used in conjunction with another active substance.
11. Use according to claim 10, wherein the active substance is an antidiabetic. H: \ec\Interwoven\NRPortbl\DCC\REC\811785 1_doc-30/07/2015 - 76 12. Use according to claim 11, wherein the antidiabetic is metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist, an alpha-glucosidase inhibitor, insulin or an insulin analogue, or GLP-1 or a GLP-1 analogue.
13. A method of preventing or treating illnesses or conditions connected with an increased DPP-IV activity or capable of being influenced by inhibition of the DPP IV activity, said method comprising administering to a subject a compound according to any one of claims 1 to 4, optionally in conjunction with another active substance.
14. The method according to claim 13, wherein the active substance is an antidiabetic.
15. The method according to claim 14, wherein the antidiabetic is metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist, an alpha-glucosidase inhibitor, insulin or an insulin analogue, or GLP-1 or a GLP-1 analogue.
16. The compound according to any one of claims 1 to 3; the pharmaceutical composition according to claim 5; the use according to claim 6 or 10; the process according to claim 7 or 8; or the method according to claim 9 or 13; substantially as hereinbefore described and/or exemplified.
AU2012202850A 2004-02-18 2012-05-16 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor Expired AU2012202850B2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002068420A1 (en) * 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivative, production and use thereof as a medicament
WO2004018468A2 (en) * 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002068420A1 (en) * 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivative, production and use thereof as a medicament
WO2004018468A2 (en) * 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments

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