IL176920A - 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 inhibitorInfo
- Publication number
- IL176920A IL176920A IL176920A IL17692006A IL176920A IL 176920 A IL176920 A IL 176920A IL 176920 A IL176920 A IL 176920A IL 17692006 A IL17692006 A IL 17692006A IL 176920 A IL176920 A IL 176920A
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- IL
- Israel
- Prior art keywords
- methyl
- cyano
- benzyl
- xanthine
- piperidin
- Prior art date
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Description
DPP ys ¾> mm \t»tt¾» i*iiist» / wvp-[i» -i- »i>*a-M»tt -3]-8 8-[3-Amino-piperidin-l-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor Boehringer Ingelheim International GmbH C.167361 -amino-piperidin-1 -yl]-xanthine, the production thereof and the use in the form of a DPP-IV inhibitor The present invention relates to new substituted xanthines of general formula 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 II diabetes mellitus, the pharmaceutical compositions containing a compound of general formula (I) 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.
WO02068420A relates to substituted xanthines of general formula (I) wherein R1 -R4 are defined as cited in the invention, the tautomers, stereoisomers, mixtures, prodrugs and salts thereof which exhibit valuable pharmacological properties, particularly an inhibitory effect on the activity of the dipeptidylpeptidase-IV enzyme.
In the above formula I R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difiuoro-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, a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-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-3-methoxy-benzylI 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 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 group, a (benzo[1 ,3]dioxol-5-yl)methyl group, a [(4-cyano-benzo[1 ,3]dioxol-5-yl)methyl 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 (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, 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-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl 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 (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2-yl)methyl group, a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, a [(1-meihyl-1 H-benzotriazol-5-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, (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-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, 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- yl)methyl, (4-phenylamino-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.
Preferred are compounds of general formula ( la ), wherein R is as hereinbefore defined, as well as their tautomers and salts.
Also preferred are compounds of general formula 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: a) reacting a compound of general formula wherein R is as hereinbefore defined and Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group such as a chlorine or bromine atom, a methanesulphonyl or methanesulphonyloxy group, with 3-aminopiperidine, the enantiomers or the salts thereof.
The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, ethyleneglycol monomethylether, ethyleneglycol diethylether or sulpholane, optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyl-diisopropylamine (Hiinig base), while these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180°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. b) deprotecting a compound of general formula wherein R is as hereinbefore defined.
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°C.
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.
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.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 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.
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.
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 120°C or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine, ethanolamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures obtained may be separated by chromatography into their c/'s 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, 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 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 the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be, for example, (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I 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 maleic acid.
The compounds of general formulae II and III 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).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on the enzyme DPP-IV.
The biological properties of the new compounds were investigated as follows: The ability of the substances and their corresponding salts to inhibit the DPP-IV activity can be demonstrated in 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 description by Reiher et al. in an article entitled "Increased expression of intestinal cell line Caco-2" , which appeared in Proc. Natl. 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 NaCI, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4°C (to remove cell debris).
The DPP-IV assay was carried out as follows: 50 μΙ of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μΜ, were placed in black microtitre plates. 20 pi of assay buffer (final concentrations 50 mM Tris HCI pH 7.8, 50 mM NaCI, 1 % DMSO) was pipetted in. The reaction was started by the addition of 30 μΙ 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 μΙ, while the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient 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 % 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 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 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 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 II diabetes mellitus, pre-diabetes, reduced glucose tolerance or changes in the fasting blood sugar, diabetic 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, 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 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 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 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 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 which growth hormone may be used. The compounds according to the invention are also suitable, on the basis of their inhibitory effect on DPP-IV, for treating various autoimmune diseases such as e.g. rheumatoid arthritis, multiple sclerosis, thyroiditis and Basedow's disease, etc. They may also be used to treat viral diseases and also, for example, in HIV infections, for stimulating blood production, in benign prostatic hyperplasia, gingivitis, as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease, for example. The compounds described may also be used for the treatment of 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 include follicular and epidermal hyperkeratoses, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophies, as well as psychosomatic, depressive and neuropsychiatric diseases of all kinds.
The compounds according to the invention may also be used in conjunction with 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. Gl 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), PPAR-gamma/alpha/delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, 11 β-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-1095 or 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 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 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 substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoidl receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3^οηϊ5ΐ3 such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.
It is also possible to combine the compounds with drugs for treating high blood pressure such as e.g. All antagonists or ACE inhibitors, diuretics, β-blockers, Ca-antagonists, etc., or combinations thereof.
The dosage required to achieve such an effect is expediently, by intravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples that follow are intended to illustrate the invention: Preparation of the starting compounds Example I 1-f(4-phenylamino-quinazolin-2-vnmethvn-3-methyl-7-(2-butvn-1-vn-8-i3-(tert.-butyloxycarbonylamino)-piperidin-1-vn-xanthine A mixture of 416 mg 3-methyl-7-(2-butyn-1-yl)-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 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 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 (ESI+): m/z = 650 [M+H]+ 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 Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 664 [M+H]+ (2) 1 -[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1 ) Mass spectrum (ESI+): m/z = 572 [M+H]+ (3) 1 -[(3-cyano-naphthalen-1 -yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(ter - butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.67 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 582 [M+H]+ (4) 1 -[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 635 [M+H]+ (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 ) Mass spectrum (ESI+): m/z = 583 [M+H]+ (6) 1 -[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 583 [M+H]+ (7) 1 -[2-(3-cyclopropyloxy-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, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 591 [M+H]+ (8) 1 -[2-(3-cyclopropylmethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.65 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 605 [M+Hf (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 Rf value: 0.85 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 605 [M+H]+ (10) 1 -[(1 -cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI*): m/z = 583 [M+H]+ (11 ) 1 -[(2,4-methoxy-naphthalen-l -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) Mass spectrum (ESI+): m/z = 617 [M+H]+ (12) 1 -[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 587 [M+H]+ (13) 1 -[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine 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 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 559 [M+H]+ (15) 1 -[(6-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(ft)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 588 [M+H]+ (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]+ (17) 1-{[(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3- (tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (18) 1 -[(7-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.24 (silica gel, ethyl acetate/petroleum ether = 1 :1 ) Mass spectrum (ESI+): m/z = 576 [M+H]+ (19) 1 -[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.63 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 603 [M+H]+ (20) 1 -[(6-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert-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.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 613, 615 [M+H]+ (22) 1 -cyanomethyl-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 = 456 [M+H]+ (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 (ESI+): m/z = 588 [M+H]+ (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 (ESI+): m/z = 585 [M+H]+ (25) 1 -[([1 ,5]naphthyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.28 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 559 [M+H]+ (26) 1 -[(3-cyano-4-methyl-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1 :1) Mass spectrum (ESI+): m/z = 597 [M+H]+ (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 (ESI+): m/z = 587 [M+H]+ (28) 1 -[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[( ?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.42 (silica gel, petroleum ether/ethyl acetate = 1 :2) Mass spectrum (ESI+): m/z = 583 [M+H]+ (29) 1 -[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[( ?)-3-(tert-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) (30) 1 -[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(K)-3-(tert- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.46 (silica gel, ethyl acetate) (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 (ESI+): m/z = 580 [M+H]+ (32) 1-[(1 ,4-dicyano-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.54 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 607 [M+Hf (33) 1 -[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(K)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.36 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 618 [M+H]+ (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]+ (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 (ESI+): m/z = 584 [M+H]+ (36) 1 -[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 559 [M+H]+ (37) 1 -(2-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- 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-[( ?)-3-(tert.- butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.58 (silica gel, methylene chloride/ethyl acetate = 1 :1) Mass spectrum (ESI+): m/z = 532 [M+H]+ (39) 1 -(4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.61 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 532 [M+H]+ (40) 1-[(pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 508 [M+H]+ (41 ) 1 -benzyl-3-methyl-7-(2-butyn-1 -yl)-8-[( )-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 507 [M+H]+ (42) 1 -(4-methoxy-benzyl)-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 (ESI+): m/z = 537 [M+H]+ (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]+ (44) 1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectnjm (ESI+): m/z = 557 [M+H]+ (45) 1 -(2-cyano-4-bromo-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 610, 612 [M+H]+ (46) 1 -(3-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 (ESI+): m/z = 525 [M+H]+ (47) 1-(3,5-dimethoxy-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 = 567 [M+H]+ (48) 1 -(2-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert-butyloxycarbonylamino)-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-[(fi)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1 :1) Mass spectrum (ESI+): m/z = 533 [M+H]+ (50) 1 -[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.60 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 533 [M+H]+ (51 ) 1 -(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[( ?)-3-(teit-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 566, 568 [M+H]+ (52) 1 -(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(ter -butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESf ): m/z = 525 [M+Hf (53) 1 -(4-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(K)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 541 , 543 [M+H]+ (54) 1 -(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 550 [M+H]+ (55) 1 -(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(fl)-3-(ter -butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 550 [M+Hf (56) 1 -(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 566, 568 [M+H]+ (57) 1 -[(5-methoxycarbonyl-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 = 555 [M+H]+ (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 (ESI+): m/z = 600 [M+H]+ (59) 1 -(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 557 [M+H]+ (60) 1 -(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): 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 ) 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-(teit-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.70 (silica gel, methylene chloride/ethyl acetate = 1 :1) Mass spectrum (ESI+): m/z = 562 [M+H]+ (63) 1 -(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(ter -butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.75 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 562 [M+H]+ (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 (ESI+): m/z = 537 [M+H]+ (65) 1 -(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 575 [M+H]+ (66) 1 -(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(ter - butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 567 [M+H]+ (67) 1 -(3-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESf): m/z = 541 , 543 [M+H]+ (68) 1 -(4-trifluoromethyl-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 (ESI+): m/z = 575 [M+H]+ (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+Hf (70) 1 -(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.65 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 585 [M+H]+ (71 ) 1 -[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert- butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 526 [M+H]+ (72) 1 -[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 563 [M+H]+ (73) 1 -(2,6-Difluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(fl)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.62 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 543 [M+H]+ (74) 1 -(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.67 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 591 [M+H]+ (75) 1 -(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.62 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 591 [M+H]+ (76) 1 -[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.55 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 533 [M+H]+ (77) 1 -[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(fl)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.55 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 533 [M+H]+ (78) 1 -[(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 (ES!+): m/z = 509 [M+H]+ (79) 1 -[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(ter -butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1 ) Mass spectrum (ESf ): m/z = 523 [M+H]+ (80) 1-[(4I6-dimethyl^yrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[( ?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+): m/z = 537 [M+H]+ (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 (ESI+): m/z = 439, 441 [M+H]+ (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]+ (83) 1 -(3,4-difluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[( ?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.75 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 543 [M+H]+ (84) 1 -(2-fluoro-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.55 (silica gel, ethyl acetate/petroleum ether = 3:2) Mass spectrum (ESI+): m/z = 555 [M+H]+ (85) 1 -(2-fluoro-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine 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 -yl)-8-[(f?)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine 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-[(ft)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.48 (silica gel, ethyl acetate/petroleum ether = 1 :1 ) Mass spectrum (ESI+): m/z = 555 [M+H]+ (88) 1 -[(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(/?)-3-(tert-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 497 [M+H]+ (89) 1 -(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(fl)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 557 [M+H]+ (90) 1 -(4-cyano-2-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 550 [M+H]+ (91 ) (1 -(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(fi)-3-(tert.- butyloxycarbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): 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)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 525 [M+H]+ (93) 1 -(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(fl)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine (94) 1 -(4-cyano-3-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(ft)-3-(tert-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Mass spectrum (ESI+): m/z = 550 [M+H]+ (95) 1 -(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESI+): 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) Mass spectrum (ESI+): m/z = 583 [M+H]+ (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 ) Mass spectrum (ESI+): m/z = 533 [M+H]+ (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+H]+ (99) 1 -[(1 -methyl-1 H-benzotriazol-5-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 (ESI+): m/z = 562 [M+H]+ (100) 1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[( ?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine Rf value: 0.30 (silica gel, methylene chloride/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 533 [M+H]+ (101 ) 1 -[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo-xanthine 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-(tert.-butyloxycarbonylamino)-piperidin-l -yl]-xanthine Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 576 [M+H]+ Example II 3-methyl-7-(2-butvn-1-vn-8-r(ff)-3-(tert.-butyloxycarbQnylamino)-piperidin-1-vn-xanthine 1 1.00 g of (/?)-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 a mechanical stirrer at approx. 114°C. Then another 900 mg of (f?)-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 114°C. After 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 60°C.
Yield: 19.73 g (94 % of theory) Rf value: 0.64 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 417 [M+H]+ The following compound is obtained analogously to Example II: (1 ) 3-methyl-7-(2-butyn-1-yl)-8-[(3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine melting point: 235-237X Mass spectrum (ESf): m/z = 417 [M+H]+ (2) 1 -[(quinoxalin-6-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) Mass spectrum (ESI+): 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]+ (4) 1 -(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-[(R)-3-(ter -butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 562 [M+H]+ (5) 1 -[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(S)-3-(tett-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.50 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 533 [M+H]+ Example III 3-methyl-7-(2-butvn-1-yl)-8-bromo-xanthine 17.06 g 1-bromo-2-butyn are added to 30.17 g of 3-methyl-8-bromo-xanthine and 27.00 ml Hunig 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 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) Rf value: 0.24 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 297, 299 [M+H]+ Example IV 2-chloromethyl-4-phenylamino-quinazoline 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) Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1 :1) Mass spectrum (ESI+): m/z = 270, 272 [M+H]+ The following compound is obtained analogously to Example IV: (1 ) 2-chloromethyl-4-benzylamino-quinazoline Rf value: 0.60 (silica gel, cyclohexane/ethyl acetate = 1 :1 ) Mass spectrum (ESI+): m/z = 284, 286 [M+H]+ Example V 1-bromomethyl-4-cvano-isoquinoline Prepared by bromination of 1-methyl-4-cyano-isoquinoline with N-bromosuccinimide in the presence of azobisisobutyronitrlle 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: (1 ) 2-bromomethyl-4-cyano-quinoline Mass spectrum (ESI+): m/z = 247, 249 [M+H]+ (2) 3-bromomethyl-1 -cyano-isoquinoline Mass spectrum (ESI+): 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 ) (4) 2-bromomethyl-4-methoxy-quinoline Mass spectrum (ESI+): m/z = 252, 254 [M+H]+ (5) 3-bromomethyl-[1 ,5]naphthyridine Mass spectrum (ESI+): m/z = 223, 225 [M+H]+ (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]+ (7) 2-bromomethyl-3-cyano-quinoline Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1 ) (8) 2-bromomethyl-4-phenyl-pyrimidine Rf value: 0.88 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 249, 251 [M+H]+ (9) 2-bromomethyl-1 ,4-dicyano-naphthalene Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate = 9:1 ) Mass spectrum (ΕΓ): m/z = 270, 272 [M]+ (10) 2-bromomethyl-6,7-dimethoxy-quinoline Rf value: 0.70 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 282, 284 [M+H]+ (11 ) 2-bromomethyl-4-cyano-quinazoline Rf value: 0.85 (silica gel, methylene chloride/methanol = 99:1 ) Mass spectrum (ΕΓ): m/z = 247, 249 [M]+ (12) 7-bromomethyl-quinazoline Rf value: 0.15 (silica gel, methylene chloride/methanol = 99:1 ) Mass spectrum (ESI+): m/z = 223, 225 [M+H]+ (13) 2-trifluoromethyl-4-cyano-benzylbromide (14) 2-bromomethyl-5-cyano-6-methoxy-pyridine Mass spectrum (ESI+): m/z = 227, 229 [M+H]+ (15) 3-bromomethyl-4-cyano-isoquinoline Rf value: 0.43 (silica gel, petroleum ether/ethyl acetate = 7:3) (16) 7-bromomethyl-8-cyano-quinoline Rf value: 0.25 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 247, 249 [M+H]+ (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]+ Example VI 2-bromo-1-(3-cvclopropyloxy-phenyl)-ethanone Prepared by bromination of 1-(3-cyclopropyloxy-phenyl)-ethanone with phenyltrimethylammonium tribromide in methylene chloride at reflux temperature. Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 3:1 ) Mass spectrum (ESI+): m/z = 255, 257 [M+H]+ The following compounds are obtained analogously to Example VI: (1 ) 2-bromo-1-(3-cyclopropylmethoxy-phenyl)-ethanone 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 ) Example VII 1-(3-cvclopropyloxy-phenyl)-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°C.
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 : (1 ) 1 -(3-cyclopropylmethoxy-phenyl)-ethanone Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 3:1 ) Mass spectrum (ESI+): m/z = 191 [M+H]+ (2) 1 -(3-cyclobutyloxy-phenyl)-ethanone Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate = 3:1 ) Mass spectrum (ESI+): m/z = 191 [M+H]+ Example VIII 1-chloromethyl-2.4-dimethoxy-naDhthalene Prepared by chlorinating 1-hydroxymethyl-2,4-dimethoxy-naphthalene with thionyl chloride in methylene chloride at ambient temperature.
Rf value: 0.78 (silica gel, cyclohexane/ethyl acetate = 1 :1) Mass spectrum (El): m/z = 236, 238 [M]+ Example IX 1-hvdroxymethyl-2,4-dimethoxy-naphthalene 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 1-i(6-amino-quinolin-2-yl)methvn-3-methyl-7-(2-butvn-1-yl)-8-r(ffl-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl1-xanthine Prepared by treating 1-[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[( ?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with sodium dithionite in a mixture of ethanol/water (5:2) at 55-60°C.
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5) Mass spectrum (ESI+): m/z = 573 [M+H]+ Example XI 1 -methyl-4-( pyridin-2-yl)-isoquinoline Prepared by reacting 4-bromo-1-methyl-isoquinoline with lithium-triisopropoxy-2-pyridinyl-boronate in the presence of tetrakis(triphenylphosphine)palladium, triphenylphosphine, sodium carbonate and copper(l)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]+ Example XII 1-r(8-amino-quinolin-2-yl)methvn-3-methyl-7-(2-butvn-1-vh-8-i(ffl-3-(tert.-butyloxy-carbonylamino)-piperidin-1-vn-xanthine Prepared by treating 1-[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[( ?)-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]+ Example XIII 1-(2-oxo-2-i2-(pyridin-3-vn-phenvn-ethyl)-3-methyl-7-(2-butvn-1-yl)-8-r( )-3-(tert.-butyloxycarbonylamino)-piperidin-1-vn-xanthine Prepared by reacting 1-[2-oxo-2-(2-bromo-phenyl)-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[( ^^-(tert.-butyloxycarbonylaminoj-piperidin-l-yll-xanthine with pyridine-3-boric acid 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]+ 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 -yl)-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)-pyridine).
Rf value: 0.40 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z = 612 [M+H]+ Example XIV 1-r(4-ethyl-quinazolin-2-yl)methyl1-3-methvW butyloxycarbonylamino)-piperidin-1-vn-xanthine Prepared by treating 1 -cyanomethyl-3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-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) Mass spectrum (ESI+): m/z = 587 [M+H]+ The following compound is obtained analogously to Example XIV: (1) 1 -[(4-cyclopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[(ft)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 599 [M+H]+ Example XV 2-chloromethyl-3-cvano-4-methyl-quinoline Prepared by reacting 3-cyano-2,4-dimethyl-1-oxy-quinoline with benzosulphonic acid chloride in toluene at 80°C.
Rf value: 0.55 (silica gel, cyclohexane/ethyl acetate = 2:1) Mass spectrum (ESI+): m/z = 217, 219 [M+H]+ Example XVI 3-cvano-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.
Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 199 [M+H]+ Example XVII 2-chloromethyl-4.5-dimethyl-guinazoline Prepared by reacting 1-(2-amino-6-methyl-phenyl)-ethanone with chloroacetonitriie in dioxane while piping in hydrogen chloride at 30-38°C.
Mass spectrum (ESI+): m/z = 207, 209 [M+H]+ Example XVIII 1-rf2-methyl-guinazolin-4-yl)methvn-3-methv(-7-(2-butvn-1-vn-8-r(ffl-3-(tert.-butyloxycarbonylamino)-piperidin-1-vn-xanthine Prepared by reacting 1-[2-(2-acetylamino-phenyl)-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°C.
Rf value: 0.35 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 573 [M+H]+ Example XIX 1-f2-(2-acetylamino-phenvn-2-oxo-ethvn-3-methyl-7-(2-butvn-1-yl)-8-r(ffl-3-(tert.-butyloxycarbonylamino)-piperidin-1-vn-xanthine Prepared by reacting 1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[( )-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-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 (ESI+): m/z = 592 [M+H]+ Example XX 1-r2-(2-amino-phenyl)-2-oxo-ethvn-3-methyl-7-(2-butvn-1-yl)-8-f(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl1-xanthine Prepared by reducing 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine with tin(ll)chloride dihydrate in tetrahydrofuran at ambient temperature.
Rf value: 0.85 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z = 550 [M+H]+ Example XXI 1-f(furan-3-vnmethvn-3-methyl-7-(2-butvn-1-yl)-8-i(/:?)-3-(tert.-butyloxycarbonyl- amino)-piperidin-1 -yll-xanthine A mixture of 300 mg of 3-methyl-7-(2-butyn-1 -yl)-8-[(f?)-3-(tert.-butyloxycarbonyl- amino)-piperidin-1-yl]-xanthine, 95 μΙ furan-3-yl-methanol, 302 mg triphenylphosphine and 226 μΙ diisopropyl azodicarboxylate in 4 ml tetrahydrofuran is stirred overnight at ambient temperature . For working up the reaction mixture is combined with saturated potassium carbonate solution and extracted with ethyl acetate . The 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]+ 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 (ESI+): m/z = 391 , 393 [M+Hf (2) 1 -[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-[( ?)-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine Mass spectrum (ESI+): m/z = 575, 577 [M+H]+ Example XXII 1-r(5-cvano-furan-2-yl)methyl1-3-methyl-7-(2-butvn-1-yl)-8-r(ffl-3-(tert.-butyloxy-carbonylamino)-piperidin-1 -yll-xanthine Prepared by reacting 1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(f?)-3-(tert.-butyloxycarbonylamino)-piperidin-1 -yl]-xanthine with hydroxylamine-O-sulphonic acid and pyridine in toluene at reflux temperature.
Example XXIII -(methanesulphonyloxymethyl)-2-furan-carboxaldehvde Prepared by reacting 5-(hydroxymethyl)-2-furan-carboxaldehyde with methanesulphonic acid chloride in the presence of triethylamine in methylene chloride at ambient temperature. The crude product is further reacted without any more purification.
Example XXIV 2-chloromethyl-3-cvano-pyridine 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-methyl)-nicotinamide with phosphorus oxychloride.
Rf value: 0.85 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+): m/z = 153, 155 [M+H]+ Example XXV 8-cvano-7-methyl-quinoline Prepared by reacting 8-bromo-7-methyl-quinoline with zinc cyanide in the presence of tetrakis(triphenylphosphine)palladium in N-methylpyrrolidinone under a protective gas atmosphere at 100-105°C.
Rf value: 0.35 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESI+): m/z = 169 [M+H]+ Example XXVI 2-methyl-8-cvano-quinoline Prepared by reacting 2-methyl-8-bromo-quinoline with copper(l)cyanide in N-methylpyrrolidinone under a protective gas atmosphere at 180°C.
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 7:3) Mass spectrum (ESf ): m/z = 169 [M+H]+ Preparation of the final compounds Example 1 1-rf4-phenylamino-quinazolin-2-vnmethyl1-3-methyl-7-(2-butvn-1-yl)-8-(3-amino-piperidin-1 -vD-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 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, 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]+ 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 Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 564 [M+H]+ (2) 1 -[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI+): m/z = 472 [M+H]+ (3) 1-[(3-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn^ piperidin-1 -yl)-xanthine Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): 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/ 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 Rf value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 483 [M+H]+ (6) 1 -[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Mass spectrum (ESI+): m/z = 483 [M+H]+ (7) 1 -[2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl]-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/ 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-((f?)-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) Mass spectrum (ESI+): m/z = 505 [M+H]+ (9) 1 -[2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3- amino-piperidin-1 -yl)-xanthine Rf value: 0.40 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 505 [M+H]+ (10) 1 -[(1 -cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino- piperidin-1-yl)-xanthine Mass spectrum (ESI+): 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 Rf value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESf): m/z = 517 [M+H]+ (12) 1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine Rf value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 487 [M+H]+ (13) 1-[(6-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((/?)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 473 [M+H]+ (14) 1-[(quinoxalin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((f?)-3-amino-piperidin-1-yl)-xanthine-hydrochloride Mass spectrum (ESI+): m/z = 459 [M+H]+ (15) 1-[(6-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((f?)-3-amino- piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 488 [M+H]+ (16) 1-[(6-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(( )-3-amino-piperidin-1-yl)-xanthine Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 484 [M+Hf (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]+ (18) 1 -[(7-f luoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.58 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) 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 = 90:10:1 ) Mass spectrum (ESI+): m/z = 473 [M+H]+ (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 ) Mass spectrum (ESI+): m/z = 476 [M+H]+ (21 ) 1 -{2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1 -yl)-8-((fl)-3- amino-piperidin-1-yl)-xanthine Rf value: 0.55 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50: 1 ) Mass spectrum (ESI+): 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 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-cyclopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-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 ) Mass spectrum (ESI+): m/z = 499 [M+H]+ (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 (ESI+): m/z = 488 [M+H]+ (25) 1 -[(2-phenyl-pyrimidin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 485 [M+H]+ (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 (ESI+): m/z = 459 [M+H]+ (27) 1 -[(3-cyano-4-methyl-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-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/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): 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 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 487 [M+H]+ (29) 1 -[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(( ?)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 483 [M+H]+ (30) 1 -[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 483 [M+H]+ (31 ) 1 -[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-3-amino- piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 485 [M+H]+ (32) 1 -[(2-methyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-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 = 90:10:1 ) Mass spectrum (ESI+): m/z = 473 [M+Hf (33) 1 -[(1 ,4-dicyano-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-hydrochloride Rf value: 0.86 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESf): m/z = 507 [M+H]+ (34) 1 -{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.55 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 512 [M+Hf (35) 1-[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine R value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 518 [M+H]+ (36) 1 -[(quinazolin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(( ?)-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]+ (37) 1 -[(4-cyano-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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 = 90:10:1 ) Mass spectrum (ESI+): m/z = 484 [M+H]+ (38) 1 -[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 459 [M+Hf (39) 1 -(2-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-3-amino-piperidin-1 -yl)-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]+ (40) 1 -(3-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 432 [M+H]+ (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 = 90:10:1 ) Mass spectrum (ESI+): m/z = 432 [M+H]+ (42) 1-[(pyridin-2-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 (ESI+): m/z = 408 [M+H]+ (43) 1 -benzyl-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (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)-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]+ (45) 1 -(2-chloro-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 ) Mass spectrum (ESI+): m/z = 441 , 443 [M+H]+ (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 (ESI+): m/z = 457 [M+H]+ (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 (ESI+): m/z = 510, 512 [M+H]+ (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) Mass spectrum (ESI+): 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) Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 467 [M+H]+ (50) 1 -(2-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 ) Mass spectrum (ESI+): m/z = 425 [M+H]+ (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 (ESI+): m/z = 433 [M+H]+ (52) 1 -[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 433 [M+H]+ (53) 1 -(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 466, 468 [M+H]+ (54) 1 -(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((K)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 425 [M+H]+ (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]+ (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) Mass spectrum (ESI+): m/z = 450 [M+H]+ (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 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 450 [M+H]+ (58) 1 -(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin- 1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 466, 468 [M+H]+ (59) 1 -[(5-methoxycarbonyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(( ?)-3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 455 [M+H]+ (60) 1 -(2-trifluoromethyl-4-cyano-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 (ESf): 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 (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 457 [M+H]+ (62) 1 -(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 477 [M+H]+ (63) 1 -[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 433 [M+H]+ (64) 1 -(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-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/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 462 [M+H]+ (65) 1 -(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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 ) Mass spectrum (ESI+): m/z = 462 [M+H]+ (66) 1 -(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((fl)-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 ) 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 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 475 [M+H]+ (68) 1 -(3,4-dimethoxy-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: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1) Mass spectrum (ESI+): m/z = 467 [M+H]+ (69) 1 -(3-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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 ) Mass spectrum (ESI+): m/z = 441 , 443 [M+H]+ (70) 1 -(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-(( ?)-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 ) Mass spectrum (ESI+): m/z = 475 [M+H]+ (71 ) 1-[([2,2']bipyridinyl-6-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 (ESI+): m/z = 485 [M+H]+ (72) 1 -(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino- piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 485 [M+H]+ (73) 1 -[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino- piperidin-1 -yl)-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 426 [M+H]+ (74) 1 -[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine 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)-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 443 [M+Hf (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 (ESI+): m/z = 491 [M+H]+ (77) 1 -(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-3-amino-piperidin-1-yl)-xanthine Rf value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 491 [M+H]+ (78) 1 -[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -y\)-8-{(R)-3-am\r\o- piperidin-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 ) Mass spectrum (ESI+): m/z = 433 [M+H]+ (79) 1 -[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-3-amino-piperidin-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 ) Mass spectrum (ESI+): m/z = 433 [M+H]+ (80) 1 -[(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: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 409 [M+H]+ (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/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 423 [M+H]+ (82) 1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((/?)-3-am piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) melting point: 202-204°C Mass spectrum (ESI+): m/z = 437 [M+H]+ (83) 1 -[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 459 [M+H]+ (84) 1 -(3-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-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) Mass spectrum (ESI+): m/z = 455 [M+H]+ (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 ) Mass spectrum (ESI+): m/z = 443 [M+H]+ (86) 1 -(2-fluoro-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.39 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 455 [M+H]+ (87) 1 -(2-fluoro-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino- piperidin-1 -yl)-xanthine Rf value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1) Mass spectrum (ESI+): m/z = 455 [M+H]+ (88) 1 -[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino- piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 483 [M+H]+ (89) 1 -(2-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((fl)-3-amino-piperidin-1-yl)-xanthine Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1 ) Mass spectrum (ESI+): m/z = 455 [M+H]+ (90) 1 -[(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 397 [M+H]+ (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 (ESI+): m/z = 457 [M+H]+ (92) 1 -[(f uran-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) Mass spectrum (ESI+): m/z = 397 [M+H]+ (93) 1 -[(5-methyl-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 = 411 [M+H]+ (94) 1 -[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino- piperidin-1-yl)-xanthine x trifluoroacetic acid (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-((f?)-3-amino-piperidin-1-yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 450 [M+Hf (96) 1 -(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 450 [M+H]+ (97) 1 -[(5-cyano-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((ft)-3-amino-piperidin-1-yl)-xanthine x trifluoroacetic acid (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESf): m/z = 422 [M+Hf (98) 1 -(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-3-amino-piperidin-1 -yl)-xanthine (BOC cleaving carried out with trifluoroacetic acid) Mass spectrum (ESI+): m/z = 450 [M+H]+ (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 (ESI+): m/z = 450 [M+H]+ (100) 1 -(2-cyano-3-methoxy-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 ) Mass spectrum (ESI+): m/z = 462 [M+H]+ (101 ) 1-[(8-cyano-quinolin-7-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 = 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) melting point: 166°C Mass spectrum (ESI+): m/z = 433 [M+H]+ (103) 1 -[(8-cyano-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 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 483 [M+H]+ (104) 1 -[(1 -methyl-1 H-benzotriazol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((f?)-3-amino-piperidin-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 ) Mass spectrum (ESI+): m/z = 462 [M+H]+ (105) 1 -[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((/?)-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) 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) Rf value: 0.60 (reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/ trifluoroacetic acid = 50:50:1 ) Mass spectrum (ESI+): m/z = 433 [M+H]+ (107) 1 -[(4-cyano-benzo[1 ,3]dioxol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((K)-3-amino-piperidin-1 -yl)-xanthine Rf value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:0.1 ) Mass spectrum (ESI+): m/z = 476 [M+H]+ 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-yl)-xanthine (2) 1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1- yl)-xanthine (3) 1 -(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 - yl)-xanthine (4) 1 -(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 - yl)-xanthine (5) 1 -(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (6) 1 -(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (7) 1 -(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (8) 1 -(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (9) 1 -(2-fluoro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (10) 1-(2-trifluoromethyl-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (11 ) 1-[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amin piperidin-1 -yl)-xanthine (12) 1 -[(4-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (13) 1 -[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino- piperidin-1 -yl)-xanthine (14) 1 -[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino- piperidin-1 -yl)-xanthine (15) 1 -[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino- piperidin-1 -yl)-xanthine (16) 1-[(2-cyano^yridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amin piperidin-1 -yl)-xanthine (17) 1 -[(5-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (18) 1-[(6-cyano^yridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (19) 1 -(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (20) 1 -(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (21 ) 1-[([2,2 bipyridinyl-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-( piperidin-1 -yl)-xanthine (22) 1 -[(5-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (23) 1-[(6-fluoro^yridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino- piperidin-1 -yl)-xanthine (24) 1 -[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (25) 1 -(2-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (26) 1 -(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (27) 1 -(3-chloro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (28) 1 -(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (29) 1 -(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (30) 1 -(2-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (31 ) 1 -(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (32) 1 -(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine (33) 1 -[(benzo[1 ,3]dioxol-5-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-amino-piperidin-1 -yl)-xanthine 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, 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. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg.
Example 3 Tablets containing 100 mq of active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 ma 220.0 mg Method of Preparation: The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
Example 4 Tablets containing 150 ma of active substance Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation: The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen 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 Example 5 Hard gelatine capsules containing 150 mq of active substance 1 capsule contains: active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation: The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.
Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 6 Suppositories containing 150 mq of active substance 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mq 2,000.0 mg Preparation: After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
Example 7 Suspension containing 50 mq of active substance 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation: The distilled water is heated to 70°C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air. ml of suspension contain 50 mg of active substance.
Example 8 Ampoules containing 10 ma 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 HCI, 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.
Claims (16)
1. Compounds of general formula : ( I ). wherein 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, a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-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-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-cya no-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, 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 group, a (benzo[l,3]dioxol-5-yl)methyl group, a [(4-cyano-benzo[ l,3]dioxol-5-yl)methyl 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-l-yl)methyl, (1,4-dicyano-naphthalen-2-yl)methyl or (2,4-dimethoxy-naphthalen-l-yl)methyl group, 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, 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- 16-01X01673615 72 176920/2 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, 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, a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, a [(1-methyl-l H-benzotriazol-5-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, (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-yl)methyl or (8-cyano-quinolin-7-yl)methyl group, a (1-cyano-isoquinolin-3-yl)methyl, (4-cyano-isoquinolin-l-yl)methyl, (4-cyano-isoquinolin-3-yl)methyl or [(4-(pyridin-2-yl)-isoquinolin-l-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, (2-phenyl-quinazolin-4-yl)methyl, (4-cyano-quinazolin-2-yl)methyl, (4-phenylamino-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 ([l,5]naphthyridin-3-yl)methyl group, the tautomers, enantiomers, diastereomers, the mixtures and the salts thereof.
2. A compound of general formula wherein R is defined as in claim 1, and the tautomers and salts thereof.
3. A compound of general formula 16-01X01673615 73 176920/2 wherein R is defined as in claim 1, and the tautomers and salts thereof.
4. Physiologically acceptable salts of the compounds according to one of claims 1 to 3 with inorganic or organic acids.
5. Pharmaceutical compositions containing a compound according to at least 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 at least one of claims 1 to 4 for preparing a pharmaceutical composition which is suitable for treating type I and II diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis.
7. Process for preparing a pharmaceutical composition according to claim 5, characterised in that a compound according to at least one of claims 1 to 4 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
8. Process for preparing the compounds of general formula I according to claims 1 to 4, characterised in that • a) a compound of general formula 16-01\01673615 74 176920/3 wherein R is defined as in claim 1 and Z1 denotes a leaving group such as a halogen atom, a substituted hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group, is reacted with 3-aminopiperidine, the enantiomers or the salts thereof, or • b) a compound of general formula
9. A compound of general formula wherein R denotes a (3-cyanopyridin-2-yl)methyl group, or a physiologically acceptable salt thereof with an inorganic or organic acid.
10. Pharmaceutical composition containing a compound of general formula 16-01X01673615 75 176920/3 ( la ), wherein R denotes a (3-cyanopyridin-2-yl)methyl group, or a physiologically acceptable salt thereof with an inorganic or organic acid, optionally together with one or more inert carriers and/or diluents.
11. Use of a compound of general formula wherein R denotes a (3-cyanopyridin-2-yl)methyl group, or a physiologically acceptable salt thereof with an inorganic or organic acid, for preparing a pharmaceutical composition which is suitable for treating type II diabetes mellitus or obesity.
12. Process for preparing a pharmaceutical composition according to claim 10, characterised in that a compound of general formula wherein R denotes a (3-cyanopyridin-2-yl)methyl group, or a physiologically acceptable salt thereof with an inorganic or organic acid, is incorporated in one or more inert carriers and/or diluents by a non-chemical method. 16-01X01673615 76 176920/3
13. The compound l-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-((R)-3-amino-piperidin-l-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid.
14. Pharmaceutical composition containing l-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-((R)-3-amino-piperidin-l-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid, optionally together with one or more inert carriers and/or diluents.
15. Use of the compound l-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-((R)-3-amino-piperidin-l-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid for preparing a pharmaceutical composition which is suitable for treating type II diabetes mellitus or obesity.
16. Process for preparing a pharmaceutical composition according to claim 14, characterised in that l-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l-yl)-8-((R)-3-amino-piperidin-l-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid is incorporated in one or more inert carriers and/or diluents by a non-chemical method. For the Applicants, REINHOLD COHN AND PARTNERS 16-01X01673615
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DE102004008112A DE102004008112A1 (en) | 2004-02-18 | 2004-02-18 | New 8-aminopiperidinyl-xanthine derivatives, useful for treating e.g. diabetes, arthritis and osteoporosis, are inhibitors of dipeptidylpeptidase-IV |
DE102004012921A DE102004012921A1 (en) | 2004-03-17 | 2004-03-17 | New 7-butynyl-8-(3-amino-1-piperidinyl)xanthine derivatives useful as dipeptidyl peptidase IV inhibitors, e.g. for treating diabetes, arthritis, obesity and osteoporosis |
DE102004032263A DE102004032263A1 (en) | 2004-07-03 | 2004-07-03 | New 7-butynyl-8-(3-amino-1-piperidinyl)xanthine derivatives useful as dipeptidyl peptidase IV inhibitors, e.g. for treating diabetes, arthritis, obesity and osteoporosis |
PCT/EP2005/001427 WO2005085246A1 (en) | 2004-02-18 | 2005-02-12 | 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a dpp inhibitor |
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IL217268A IL217268A0 (en) | 2004-02-18 | 2011-12-29 | 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a dpp inhibitor |
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Families Citing this family (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7569574B2 (en) | 2002-08-22 | 2009-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US7495005B2 (en) | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US7482337B2 (en) | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10254304A1 (en) | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New xanthine derivatives, their production and their use as medicines |
US7566707B2 (en) | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10355304A1 (en) | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel 8- (piperazin-1-yl) and 8 - ([1,4] diazepan-1-yl) xanthines, their preparation and their use as pharmaceuticals |
US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
EP2119717B1 (en) * | 2004-02-18 | 2018-01-17 | Boehringer Ingelheim International GmbH | 8-[3-amino-piperidin-1-yl]-xanthins, their production and utilisation as DPP IV inhibitors |
DE102004009039A1 (en) | 2004-02-23 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8- [3-Amino-piperidin-1-yl] xanthines, their preparation and use as pharmaceuticals |
US7393847B2 (en) | 2004-03-13 | 2008-07-01 | Boehringer Ingleheim International Gmbh | Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions |
US7439370B2 (en) | 2004-05-10 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides |
DE102004030502A1 (en) | 2004-06-24 | 2006-01-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel imidazoles and triazoles, their preparation and use as medicines |
DE102004043944A1 (en) * | 2004-09-11 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel 8- (3-amino-piperidin-1-yl) -7- (but-2-ynyl) -xanthines, their preparation and their use as pharmaceuticals |
DE102004044221A1 (en) | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New 3-methyl-7-butynyl xanthines, their preparation and their use as pharmaceuticals |
DE102004054054A1 (en) * | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines |
AU2012205240B2 (en) * | 2004-11-05 | 2015-03-26 | Boehringer Ingelheim International Gmbh | Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines |
DE102005035891A1 (en) * | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals |
GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
JP2009533393A (en) | 2006-04-12 | 2009-09-17 | プロビオドルグ エージー | Enzyme inhibitor |
EP1852108A1 (en) * | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
PE20080251A1 (en) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | USES OF DPP IV INHIBITORS |
EP2540725A1 (en) | 2006-05-04 | 2013-01-02 | Boehringer Ingelheim International GmbH | Polymorphs of 1-((4-Methyl-chinazolin-2-yl)methyl)-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-amino-piperidin-1-yl)xanthin |
US8071583B2 (en) | 2006-08-08 | 2011-12-06 | Boehringer Ingelheim International Gmbh | Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus |
JP5379692B2 (en) | 2006-11-09 | 2013-12-25 | プロビオドルグ エージー | 3-Hydroxy-1,5-dihydro-pyrrol-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcers, cancer and other diseases |
US9126987B2 (en) | 2006-11-30 | 2015-09-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
DK2142514T3 (en) | 2007-04-18 | 2015-03-23 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
BRPI0701664A2 (en) * | 2007-05-28 | 2009-01-13 | Fundacao Universidade Fed De Sco Carlos | 4-quinolinones and quinolines, preparation process, pharmaceutical formulations and their use |
CN101357922B (en) * | 2007-08-02 | 2011-05-18 | 山东轩竹医药科技有限公司 | New DPP-IV inhibitor |
PE20090938A1 (en) | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL |
PE20090597A1 (en) * | 2007-08-16 | 2009-06-06 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION INCLUDING A DERIVATIVE OF PIRAZOL-O-GLUCOSIDE |
EP3542801A1 (en) * | 2007-08-17 | 2019-09-25 | Boehringer Ingelheim International GmbH | Purin derivatives for use in the treatment of fap-related diseases |
WO2009107571A1 (en) | 2008-02-27 | 2009-09-03 | 住友化学株式会社 | Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor |
JP2009256298A (en) | 2008-03-26 | 2009-11-05 | Sumitomo Chemical Co Ltd | Optical resolution method for piperidin-3-ylcarbamate compound, and its intermediate |
PE20140960A1 (en) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | FORMULATIONS INVOLVING A DPP4 INHIBITOR |
EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
KR20190016601A (en) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment for diabetes in patients inappropriate for metformin therapy |
UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
PE20110297A1 (en) * | 2008-08-15 | 2011-05-26 | Boehringer Ingelheim Int | DPP-4 INHIBITORS FOR WOUND HEALING |
RU2011113823A (en) | 2008-09-10 | 2012-10-20 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED CONDITIONS |
UY32177A (en) * | 2008-10-16 | 2010-05-31 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH INSUFFICIENT GLUCEMIC CONTROL TO WEIGHT THERAPY WITH DRUG, ORAL OR NOT, ANTIDIABÉTICO |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
BRPI0920699A2 (en) * | 2008-10-16 | 2020-09-01 | Boehringer Ingelheim International Gmbh | use of a dpp-4 inhibitor in the treatment of diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
JP2012512848A (en) | 2008-12-23 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Salt forms of organic compounds |
TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
TWI466672B (en) | 2009-01-29 | 2015-01-01 | Boehringer Ingelheim Int | Treatment for diabetes in paediatric patients |
CA2752437C (en) | 2009-02-13 | 2017-07-11 | Boehringer Ingelheim International Gmbh | Antidiabetic medications |
NZ594487A (en) | 2009-02-13 | 2013-11-29 | Boehringer Ingelheim Int | Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof |
EA022007B1 (en) | 2009-09-11 | 2015-10-30 | Пробиодруг Аг | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
CN102596191B (en) | 2009-10-02 | 2016-12-21 | 勃林格殷格翰国际有限公司 | Comprise the pharmaceutical composition of BI 1356 and metformin |
NZ599298A (en) | 2009-11-27 | 2014-11-28 | Boehringer Ingelheim Int | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
EP2542549B1 (en) | 2010-03-03 | 2016-05-11 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
EA022420B1 (en) | 2010-03-10 | 2015-12-30 | Пробиодруг Аг | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011113947A1 (en) | 2010-03-18 | 2011-09-22 | Boehringer Ingelheim International Gmbh | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
EP2368552A1 (en) | 2010-03-25 | 2011-09-28 | Boehringer Ingelheim Vetmedica GmbH | 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(r)-amino-piperidin-1-yl]-xanthine for the treatment of a metabolic disorder of a predominantly carnivorous non-human animal |
JP5945532B2 (en) | 2010-04-21 | 2016-07-05 | プロビオドルグ エージー | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
EA201201509A1 (en) | 2010-05-05 | 2013-04-30 | Бёрингер Ингельхайм Интернациональ Гмбх | PHARMACEUTICAL COMPOSITIONS CONTAINING PIOGLITAZONE AND LINAGLIPTIN |
JP6034781B2 (en) | 2010-05-05 | 2016-11-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Combination therapy |
EP3725325B1 (en) | 2010-06-24 | 2023-05-31 | Boehringer Ingelheim International GmbH | Diabetes therapy |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
IT1403282B1 (en) * | 2010-12-23 | 2013-10-17 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF LINAGLIPTIN |
CN102617566B (en) * | 2011-01-30 | 2015-03-04 | 山东轩竹医药科技有限公司 | Pyrazolo alkylimidazole derivative |
UY33937A (en) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS |
US8530670B2 (en) | 2011-03-16 | 2013-09-10 | Probiodrug Ag | Inhibitors |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
DK2731947T3 (en) | 2011-07-15 | 2019-04-23 | Boehringer Ingelheim Int | SUBSTITUTED DIMERIC QUINAZOLINE DERIVATIVE, PREPARATION AND USE thereof IN PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF TYPE I AND TYPE II DIABETES |
BR112014003061A2 (en) | 2011-08-12 | 2017-02-21 | Boehringer Ingelheim Vetmedica Gmbh | masked flavor pharmaceutical composition |
US20130172244A1 (en) | 2011-12-29 | 2013-07-04 | Thomas Klein | Subcutaneous therapeutic use of dpp-4 inhibitor |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
ES2929025T3 (en) * | 2012-05-14 | 2022-11-24 | Boehringer Ingelheim Int | Linagliptin, a xanthine derivative as a dpp-4 inhibitor, for use in the treatment of SIRS and/or sepsis |
EP2849755A1 (en) | 2012-05-14 | 2015-03-25 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
WO2013174768A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
EP2854824A1 (en) | 2012-05-25 | 2015-04-08 | Boehringer Ingelheim International GmbH | Use of keratinocytes as a biologically active substance in the treatment of wounds, such as diabetic wounds, optionally in combination with a dpp-4 inhibitor |
WO2014045266A1 (en) | 2012-09-24 | 2014-03-27 | Ulf Eriksson | Treatment of type 2 diabetes and related conditions |
US20140303098A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
ES2906115T3 (en) | 2013-04-18 | 2022-04-13 | Boehringer Ingelheim Int | Pharmaceutical composition, treatment methods and uses thereof |
MX2015015103A (en) * | 2013-04-29 | 2016-02-11 | Archer Daniels Midland Co | 5-(hydroxymethyl) furan-2-carbaldehyde (hmf) sulfonates and process for synthesis thereof. |
JP6615109B2 (en) | 2014-02-28 | 2019-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Medical use of DPP-4 inhibitors |
CN106188058B (en) * | 2015-05-29 | 2020-11-06 | 江苏天士力帝益药业有限公司 | Xanthine derivatives |
CA3022202A1 (en) | 2016-06-10 | 2017-12-14 | Boehringer Ingelheim International Gmbh | Combinations of linagliptin and metformin |
EP3551202B1 (en) | 2016-12-06 | 2024-01-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
ES2812698T3 (en) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Glutaminyl cyclase inhibitors |
WO2019191776A1 (en) | 2018-03-31 | 2019-10-03 | Hall John L | Selective anti-cancer agent effective for prevention and treatment |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6895801A (en) | 2000-07-04 | 2002-01-14 | Novo Nordisk As | Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv |
DK1953162T3 (en) | 2001-02-24 | 2012-09-10 | Boehringer Ingelheim Pharma | Xanthine derivatives, their preparation and their use as a drug. |
JP2005502624A (en) * | 2001-07-03 | 2005-01-27 | ノボ ノルディスク アクティーゼルスカブ | Purine derivatives inhibiting DPP-IV for the treatment of diabetes |
JP2005509603A (en) | 2001-09-19 | 2005-04-14 | ノボ ノルディスク アクティーゼルスカブ | Heterocyclic compounds that are inhibitors of the DPP-IV enzyme |
JP2004043429A (en) * | 2002-02-25 | 2004-02-12 | Eisai Co Ltd | New xanthine derivative and dppiv inhibitor |
DE60304911D1 (en) | 2002-02-25 | 2006-06-08 | Eisai Co Ltd | Xanthine derivatives as DPP-IV inhibitors |
JP2003300977A (en) | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | Xanthine derivative |
NZ536794A (en) * | 2002-06-06 | 2007-04-27 | Eisai Co Ltd | Condensed imidazole derivatives |
EP3424926A1 (en) * | 2002-08-21 | 2019-01-09 | Boehringer Ingelheim Pharma GmbH & Co. KG | 8-[3-amino-piperidin-1-yl]-xanthins, their production and utilisation as medicine |
AU2003280680A1 (en) | 2002-11-01 | 2004-06-18 | Sumitomo Pharmaceuticals Co., Ltd. | Xanthine compound |
EP2119717B1 (en) * | 2004-02-18 | 2018-01-17 | Boehringer Ingelheim International GmbH | 8-[3-amino-piperidin-1-yl]-xanthins, their production and utilisation as DPP IV inhibitors |
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