AU2012205240B2 - Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines - Google Patents

Abstract

C:\NRPortbl\UCC\REC\4479582_1 DOC-19/07/2012 Abstract The invention relates to an improved method for producing enantiomer-free 8-(3 amino-piperidin-1 -yl)-xanthenes.

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Method for producing chiral 8-(3-amino-piperidin- I -yl)-xanthines" The following statement is a full description of this invention, including the best method of performing it known to me/us: C \NRPmrhl\)CC\RiC\4479388_I DOC - 19/7/12 C:\NRPortb1\DCC\REC\44795B2_1 DOC-19/D'/2012 Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines This application is a divisional of Australian Patent Application No. 2005300559, the entire content of which is incorporated herein by reference. The invention relates to an improved process for preparing chiral 8-(3 aminopiperidin-1-yl)-xanthines, their enantiomers and their physiologically tolerated salts. 8-(3-aminopiperidin-1-yl)-xanthines of the following general structure O NH R N R N (I) in which R' is, for example, an optionally substituted arylmethyl group or an optionally substituted heteroarylmethyl group, R 2 is, for example, an alkyl group and R 3 is, for example, an optionally substituted benzyl group or a straight-chain or branched alkenyl or alkinyl group are already known from the international applications WO 02/068420, WO 04/018468, WO 04/018467, WO 2004/041820 and WO 2004/046148, in which compounds having valuable pharmacological properties are described, which include in particular an inhibiting action on the activity of the enzyme dipeptidylpeptidase IV (DPP-IV). Therefore, compounds of this type are suitable for preventing or treating disorders or states which are connected with an increased DPP-IV activity or which can be prevented or alleviated by reduction in the DPP-IV activity, especially of diabetes mellitus type I or type 11, prediabetes, or reduction of glucose tolerance. WO 04/018468 discloses a preparation process in which 8-(3-aminopiperidin-1-yl) xanthines are prepared by deprotecting a corresponding tert.-butyloxycarbonyl protected derivative of the general formula (11).

H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _.ocx-24/02/2015 -2 ORO O R3 H /X N 0 / N O N N NZ (I 1) In this process, impurities which were difficult to remove, especially on the industrial scale, occurred, and are attributable to the protecting group used. The process was therefore unsuitable for the industrial preparation of 8-(3-aminopiperidin-1-yl)-xanthines, especially for medicament production with its strict demands on purity. Furthermore, the method had the disadvantage that the preparation of the enantiomerically pure precursor 3-(tert-butyloxycarbonylamino) piperidine is complicated and expensive. However, enantiomerically pure active ingredients are to be preferred for the pharmaceutical application owing to the risk of side effects and for the reduction of the dose to a minimum. These circumstances count against the suitability of the known process for the industrial preparation of enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthines. In the light of the above-described disadvantages of the known preparation process, the present invention provides a process which allows the preparation of enantiomerically pure 8-(3-am inopiperidin-1 -yl)-xanthines using readily obtainable starting materials in high chemical and optical purity and without great technical cost and inconvenience. This novel process should also be suitable for synthesis on the industrial scale and thus for commercial application. In one aspect the invention provides a process for preparing chiral 8-(3 aminopiperidin-1-yl)-xanthines. In addition to high yield industrial performance, very good chemical and optical purities are further advantages of the inventive synthetic route. According to the process of the present invention, the appropriate xanthine precursor (111) is reacted according to scheme 1 with enantiomerically pure or racemic 3-(phthalimido)piperidine in suitable solvents at temperatures of 20 to C:\NRPortbl\DCC\REC\44795821.DOC- 19/02/2012 -3 160 0 C; preferably of 8 to 140 0 C. The solvents used may, for example, be tetrahydrofuran (THF), dioxane, N,N-dimethylformamide (DMF), dimethyl acetamide (DMA), N-methyl-2-pyrrolidone (NMP) or dimethyl sulphoxide (DMSO). Preference is given to using NMP. Subsequently, the phthalyl protecting group is detached by processes known per se. Possible detachment methods are described, for example, by T.W. Greene in "Protective Groups in Organic Synthesis", Wiley 1981 on page 265 (for example hydrazine in ethanol). 0 R 3 N o 0 R 3 O N O R 0 N N 0 NH Ik I

R

2 R R3 NH, N N N 0 NN (I) In the abovementioned formulae, X is a leaving group selected from the group of the halogens, for example a fluorine, chlorine or bromine atom, or of the sulphonic esters, for example a phenylsulphonyloxy, p-toluenesulphonyloxy, methylsulphonyloxy or trifluoromethylsulphonyloxy group, R' is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinyl methyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinyl methyl, naphthyridinylmethyl or phenanthridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by Ra, where the substituents may be identical or different and Ra is a hydrogen, fluorine, chlorine or bromine atom or a cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or C:\NHPortb1\DCC\REC\4479582_1.DOC-19/0 7 /2012 -4 ethoxy group, or two Ra radicals, when they are bonded to adjacent carbon atoms, may also be an -O-CH 2 -0- or -O-CH 2

-CH

2 -0- group,

R

2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group and

R

3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group. The process is preferable for those compounds in which X is a chlorine or bromine atom,

R

1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinyl methyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinyl methyl or naphthyridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by Ra, where the substituents may be identical or different and Ra is a hydrogen, fluorine or chlorine atom or a cyano, methyl, ethyl, methoxy or ethoxy group,

R

2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group and

R

3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group. The process is more preferable for those compounds in which X is a chlorine or bromine atom,

R

1 is a cyanobenzyl, (cyanopyridinyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinolinylmethyl, (methylisoquinolinyl)methyl, quinazolinylmethyl, (methylquinazolinyl)methyl, quinoxazinylmethyl, C:\NRPortbl\DCC\RF.C\4429582_..DOC-19/07/2012 -5 (methylquinoxalinyl)methyl, (dimethylquinoxalinyl)methyl or naphthyridinylmethyl group, R2 is a methyl, cyclopropyl or phenyl group and

R

3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-chlorobenzyl, 2 bromobenzyl or 2-cyanobenzyl group, but in particular for the compounds 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl 7-(2-butyn-1 -yl)-8-(3-(R)-aminopiperidin-1 -yl)-xanthine, 1-[(3-methylisoquinolin-1 yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-aminopiperidin-1 -yI)-xanthine and 1-[(3-cyanopiperidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino piperidin-1-yl)-xanthine, where X is bromine. Preference is given in each case to using (R)-3-(phthalimido)piperidine as a reagent. The preparation of the compounds of the formula (Ill) has been described in the literature which has already been cited above and is effected by processes known per se. The invention further provides a process for preparing optically active 3-(phthalimido)piperidine. In this process, 3-aminopyridine is initially hydrogenated by means of processes known per se. The thus obtained racemic 3-aminopiperidine is then converted to the corresponding phthalimide by means of phthalic anhydride. The (R) enantiomer can be precipitated selectively out of the solution of the racemic, crude phthalimide (IV) by means of D-tartaric acid. It is also possible to obtain the (S) enantiomer of (IV) in a simple manner from the mother liquor of this salt precipitation by adding L-tartaric acid, without preceding removal of the excess of D-tartaric acid still present in the mother liquor. This extremely simple enantiomeric separation of the compound of the formula (IV) is surprising to those skilled in the art. The racemic base from the hydrogen ation reaction does not have to be purified beforehand for this purpose. The process works without any problem even on the industrial scale.

H:\sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 -6 In addition, the unexpectedly clean reaction of 3-aminopiperidine with phthalic anhydride is surprising per se, since, according to the literature (for example US patent US 4,005,208, especially Example 27), mixtures would be expected which, in addition to the desired product, comprise derivatives in which the ring nitrogen atom is acylated. 0 N - HNN N+ 3H2---~- H 0 phthalic anhydride

NH

2 NH 2 0 3-aminopyridine rac-3-aminopiperidine e OH ONH N 0 R)-3-phthalimidopiperidine tartrate O [R)-IV)H D-)-tartaric acid 0 According to one embodiment of the present invention there is provided a compound of the general formula (II) 0 R3 N R 0 N N/ o N N

R

2 or an enantiomer thereof, H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 6A in which

R

1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or phenanthridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by Ra, where the substituents may be the same or different and Ra is a hydrogen, fluorine, chlorine or bromine atom or a cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy group, or two Ra radicals, when they are bonded to adjacent carbon atoms, may also be an -O-CH 2 -0- or -O-CH 2

-CH

2 -0- group,

R

2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group and

R

3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.

H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _.ocx-24/02/2015 - 6B The examples which follow will illustrate the invention in greater detail: Example 1 D-Tartaric acid salt of the R enantiomer of 3-(phthalimido)piperidine a. Hydrogenation: /M N ~H 2 H EI

NH

2 NH 2 3-aminopiperidine rac-3-aminopiperidine C:\R~otblDCCREC4475821.DC-19/07/2012 -7 10.00 kg (106.25 mol) of 3-aminopyridine, 500 g of technical-grade activated carbon and 65 litres of acetic acid are initially charged in a hydrogenation reactor. 50 g of Nishimura catalyst (a commercially available rhodium/platinum mixed catalyst) are added slurried in 2.5 litres of acetic acid and flushed in with 2.5 litres of acetic acid. Hydrogenation is effected at 500C and 100 bar of hydrogen pressure until hydrogen uptake stops and post-hydrogenation is subsequently effected at 500C for 30 minutes. The catalyst and the activated carbon are filtered off and washed with 10 litres of acetic acid. The product solution is reacted further without purification. The reaction also proceeds under less severe pressures. b. Acylation 0 HN HNQ 0 O phthalic anhydride N

NH

2 o 15.74 kg (106.25 mol) of phthalic anhydride are initially charged in the reactor and admixed with the filtrate from the hydrogenation. It is flushed in with 7.5 litres of acetic acid and the reaction mixture is subsequently heated to reflux, in the course of which approx. 30% of the acetic acid used is distilled off within one hour. The reaction solution is cooled to 90'C. The product solution is reacted further without purification.

C:\NRPortbl\CCC\REC\4479582_1.DOC:-1/07/2012 c. Optical resolution OH CM OH HNQ HO o H NQ TD N OH N 0 D(-)-tartaric acid 0 (R)-3-phthallmldo piperidine tartrate [(R)-(IV)] A solution, heated to 500C, of 11.16 kg of D(-)-tartaric acid (74.38 mol) in 50 litres of absolute ethanol is metered into the acylation reaction solution at 90 C. It is flushed in with 10 litres of absolute ethanol and stirred at 900C for 30 minutes, in the course of which the product crystallizes. After cooling to 50C, the product was centrifuged off and washed with absolute ethanol. The product solution is reacted further without purification. d. Recrystallisation The moist crude product is heated to reflux in a mixture of 50 litres of acetone and 90 litres of water until a solution has formed. Subsequently, the solution is cooled to 5 0 C, in the course of which the product crystallizes out. The suspension is stirred at 50C for 30 minutes, and the product is centrifuged off and finally washed with a mixture of 20 litres of acetone and 10 litres of water. The mixture is dried at 450C in a drying cabinet under inertization. Yields: 11.7-12.5 kg (29-31% of theory) Example 2 Synthesis of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-(3-(R)-aminopiperidin-1 -yl)-xanthine C \NRPortbl\DCC\REC\4479582_1 DOC- 19/07/2012 a. 2-Chloromethyl-4-methvlquinazoline N 0 10.00 kg (73.98 mol) of 2-aminoacetophenone are initially charged and 24.5 litres of 1,4-dioxane are added. The solution, cooled to 10'C, is admixed with 16.72 kg (458.68 mol) of hydrogen chloride by blanketing. The reaction mixture warms up to 22-25 0 C. At this temperature, further hydrogen chloride is blanketed in. From about half of the total blanketing amount, the mixture is cooled to -10 0 C and blanketing is continued. Subsequently, the suspension formed is left to stand at -10*C overnight. A solution of 6.70 kg (88.78 mol) of chloroacetonitrile in 2.5 litres of 1,4-dioxane is added at -1 0 0 C within one hour. The feed vessel is flushed with 2 litres of 1,4 dioxane. Afterwards, the reactor contents are warmed to 6 0 C and stirred for a further approx. 2 hours. A further reactor is initially charged with a mixture of 122 litres of water and 62.04 kg (775.31 mol) of sodium hydroxide solution (50%) and cooled to 6*C. The reaction mixture from the first reactor is added in portions. The internal temperature is not more than 11 C. Subsequently, the first reactor is flushed first with 6 litres of 1,4-dioxane and then with 6 litres of water. The resulting suspension is stirred at 50C for a further 30 minutes. The product is centrifuged off, washed with 41 litres of water and dried at 350C in a drying cabinet under inertization. Yield: 10.5-12.1 kg (74-85% of theory) b. 1-[(4-Methylquinazolin-2-vl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine 0 0,N 0 r i + N NaC N. / ~>- Na 2

CO

3 N1 N ( X . -NO " N -N 0 N N 10.00 kg (33.66 mol) of 3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine, 7.13 kg (37.02 mol) of 2-chloromethyl-4-methylquinazoline, 3.92 kg (37.02 mol) of anhydrous sodium carbonate and 30 litres of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 1400C and stirred at 1400C for 2 hours. After the reaction has ended, the reaction mixture is cooled to C:\NRPortbl\DCC\REC\449582_1.DOC-19/07/2012 - 10 80*C and diluted with 60 litres of 96% ethanol and subsequently at 700C with 55 litres of water. At 600C, 4.04 kg (67.32 mol) of acetic acid are metered in and flushed in with 5 litres of water. The resulting suspension is stirred at 60'C for 30 minutes, then cooled to 23*C and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed first with a mixture of 20 litres of 96% ethanol and 20 litres of water, then with 40 litres of 96% ethanol and 40 litres of water. Drying is effected at 45*C in a drying cabinet under inertization. Yield: 11.6-12.6 kg (76-83% of theory) c. 1-[(4-Methylquinazolin-2-yl)methyll-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) phthalimidopiperidin-1 -yl)-xanthine N N N. Nm Br N N 10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 yl)-8-bromoxanthine, 12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5 litres of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 1400C. After the temperature has been attained, 11.41 kg (88.24 mol) of diisopropylethylamine are metered in within 20 minutes. The feed vessel is flushed with 2.5 litres of N-methyl-2-pyrrolidone and the reaction mixture is subsequently stirred at 140*C for 2 hours. After the reaction has ended, the reaction mixture is cooled to 600C and diluted with 80 litres of methanol. The resulting suspension is stirred at 500C for 30 minutes, then cooled to 230C and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed 3 times with 20 litres each time of methanol. Drying is effected at 45*C in a drying cabinet under inertization. Yield: 12.0-12.5 kg (90-94% of theory) C+\NRPortbl\DCC\REC\4479582_1.DOC-19/07/2012 - 11 d. 1-[(4-Methylquinazolin-2-yl)methVll-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) aminopiperidin-1 -yl)-xanthine 0 0 N N O N NH , N K 0 1800 kg (3 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8 (3-(R)-phthalimidopiperidin-1-yl)-xanthine are heated to 80-85'C in 18 litres of toluene. Subsequently, 1.815 litres (30 mol) of ethanolamine are added to the suspension at 75-80'C. To complete the reaction, the mixture is stirred at 80-85'C for 2 hours, in the course of which the solids go into solution. Subsequently, the phases are separated. The ethanolamine phase is washed twice with warm toluene (4 litres each time). The combined toluene phases are washed twice with 8 litres each time of water at 75-800C. From the toluene phase, 22 litres of toluene are distilled off under reduced pressure. 4 litres of tert.-butyl methyl ether are metered at 40-500C to the resulting suspension and subsequently cooled to 0-50C. The product is isolated by filtration, washed with tert.-butyl methyl ether and suction-dried. The moist crude substance is subsequently heated to reflux with 5 times the amount of absolute ethanol and the hot solution is clarified by filtration through activated carbon. After the filtrate has been cooled to 200C and crystallization has set in, it is diluted to double the volume with tert.-butyl methyl ether. The suspension is cooled to 20C, stirred for a further 2 hours, filtered with suction and dried at 450C in a vacuum drying cabinet. Yield: 1174 g (83.2% of theory) Alternative process for step d: 1400 g (2.32 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine are initially charged in 4.9 1 of tetrahydrofuran and subsequently heated to 55-65 0 C. Subsequently, 350 ml of water and 1433 g (2.32 mol) of ethanolamine are added to the suspension. To complete the reaction, the mixture is stirred at 60-63'C for a further 3 hours. Subsequently, 619 ml of 45% sodium hydroxide solution and 3.85 1 of water are added and the mixture is stirred at 55-65'C for 30 min.

C:\NRPortb1\DCC\RCC\4479582 1 DOC-19/02/2012 - 12 5.6 I of toluene are then added to the reaction mixture, the mixture is stirred for 15 min and the phases are subsequently separated. The organic phase is washed with 2.8 1 of water at 55-650C and subsequently removed. From the organic phase, 4.2 1 are distilled off under reduced pressure. Subsequently, 1.4 1 of methylcyclohexane are added at 65-75'C, in the course of which the product crystallizes. The suspension is stirred at 15-25'C for 8-16 h and subsequently cooled to 0-5*C. The product is isolated by filtration, washed with 4.2 I of methylcyclohexane, suction-dried and dried at 350C under reduced pressure. The dried crude substance (991 g) is subsequently heated to reflux with 5 times the amount of methanol, activated carbon is added and the mixture is filtered. The filtrate is reduced to a volume of 1.5 I by distilling off methanol. After the filtrate has been cooled to 45-550C, it is diluted to four times the volume with tert.-butyl methyl ether. The suspension is cooled to 0-50C, stirred for 2 hours, filtered with suction, washed with tert.-butyl methyl ether and dried at 350C in a vacuum drying cabinet. Yield: 899 g (81.9% of theory) Example 3 1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) aminopiperidin-1 -yl)-xanthine a. 3-Cyano-2-(chloromethyl)-pyridine 165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridinecarboxamide are heated together with 270 ml of phosphorus oxychloride to 90-100'C for 1 hour. The reaction mixture is cooled to room temperature and subsequently added dropwise to approx. 800 ml of water at 50-60*C. After the phosphorus oxychloride has been hydrolyzed, the mixture is neutralized with sodium hydroxide solution with cooling, in the course of which the product precipitates out. It is filtered off, washed with 300 ml of water and subsequently dried at 35-40*C. Yield: 122.6 g (82% of theory) Variant to process step a: 3-cyano-2-(chloromethyl)pyridine 20.0 g (131.45 mmol) of 2-hydroxymethyl-3-pyridinecarboxamide are suspended in 110 ml of acetonitrile and heated to 78*C. Within 15 minutes, 60.65 g C:\NRPortbl\DCC\REC\4479582_1.DOC-19/07/2012 - 13 (395.52 mmol) of phosphorus oxychloride are metered in and the mixture is heated to 81*C for 2 hours. After cooling at 22*C, the reaction mixture is stirred into 200 ml of water at 4 0 'C. After 100 ml of toluene have been added, the mixture is neutralized with sodium hydroxide solution with cooling. After phase separation, the organic phase is washed with 100 ml of water. Removal of the organic phase and evaporation of the solvent under reduced pressure gives rise initially to an oily residue which crystallizes on standing. Yield: 16.66 g (83% of theory) b. 1- (3-Cyanopyridin-2-yl)methyll-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine N N N ON B N N c1 202 g (0.68 mol) of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthifne, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 litres of N-methyl-2-pyrrolidone are initially charged in the reactor and heated to 700C. Subsequently, 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP) are added dropwise. The reactor contents are stirred at 70'C for 19 hours. After the reaction has ended, 2.8 litres of water are added to the reaction mixture and it is cooled to 250C. The product is filtered off, washed with 2 litres of water and dried at 700C in a drying cabinet under inertization. Yield: 257.5 g (91% of theory) c. 1-[(3-Cyanopyridin-2-yl)methyll-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) phthalimidopiperidin-1 -yl)-xanthine N 0 0I N N Br N O 0 N N ON o- t7 yn ) NI 230 g (0.557 mol) of 1 -[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-l -yl)-8 bromoxanthine, 318 g (0.835 mol) of 3-(phthalimido)piperidine D-tartrate and 1.15 litres of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor C:\NPortbl\DCC\REC\4479582_1 DOC-19/07/2012 - 14 contents are heated to 1400C. After the temperature has been attained, 478 ml (2.78 mol) of diisopropylethylamine are metered in within 20 minutes and the reaction mixture is subsequently stirred at 140*C for 2 hours. Subsequently, the reaction mixture is cooled to 75'C and diluted with 720 ml of methanol. Afterwards, 2.7 litres of water are added at 68-60'C and the mixture is cooled to 25 0 C. The product is filtered off and washed with 2 litres of water. Drying is effected at 700C in a drying cabinet under inertization. The crude product thus obtained is subsequently stirred at boiling in 1 litre of methanol, hot-filtered, washed with 200 ml of methanol and subsequently dried at 700C under inertization. Yield: 275 g (88% of theory) d. 1-[(3-cyanopyridin-2-Vl)methyll-3-methyl-7-(2-butyn-1-yl)-8-(3-(R) aminopiperidin-1-yl)-xanthine N 0I 0 N O NQ N N O 11N N'0 0 j, K N N, N

NH

2 0 412.5 g (0.733 mol) of 1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 (3-(R)-phthalimidopiperidin-1-yl)-xanthine are heated to 800C in 4125 ml of toluene. Subsequently, 445 ml of ethanolamine (7.33 mol) are added to the suspension at 75-800C. To complete the reaction, the mixture is stirred at 80-85 C for a further 2 hours, in the course of which the solids go into solution. Subsequently, the phases are separated. The ethanolamine phase is extracted twice with warm toluene (1 litre each time). The combined toluene phases are washed twice with 2 litres each time of water at 75-800C. The toluene phases are dried with sodium sulphate, filtered and subsequently reduced to a volume of approx. 430 ml by distillation under reduced pressure. Subsequently, 1 litre of tert.

butyl methyl ether is metered in at 50-55*C and the mixture is then cooled to 0 50C. The product is isolated by filtration, washed with tert.-butyl methyl ether and dried at 600C in a drying cabinet.

C:\NRPortbl\DCC\REC\4479582_1.DOC-19/07/2012 - 15 Yield: 273 g (86% of theory) Melting point: 188 ± 3 0 C Analogously to Examples 2 and 3, 1-[(3-methylisoquinolin-1-yl)methyl]-3-methyl-7 (2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)-xanthine is also prepared. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (20)

1. A compound of the general formula (II) 0 0 R3 N R 0 N 0 N N or an enantiomer thereof, in which R 1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or phenanthridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by Ra, where the substituents may be the same or different and Ra is a hydrogen, fluorine, chlorine or bromine atom or a cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy group, or two Ra radicals, when they are bonded to adjacent carbon atoms, may also be an -O-CH 2 -0- or -O-CH 2 -CH 2 -0- group, R2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group and H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 17 R 3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl,

2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group. 2. The compound of the general formula (II) according to Claim 1, in which R 1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl or naphthyridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by Ra, where the substituents may be the same or different and Ra is a hydrogen, fluorine or chlorine atom or a cyano, methyl, ethyl, methoxy or ethoxy group, R2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group and R 3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.

3. The compound of the general formula (II) according to Claim 2, in which R 1 is a cyanobenzyl, (cyanopyridinyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinolinylmethyl, (methylisoquinolinyl)methyl, quinazolinylmethyl, (methylquinazolinyl)methyl, quinoxazinylmethyl, (methylquinoxalinyl)methyl, (dimethylquinoxalinyl)m ethyl or naphthyridinylmethyl group, R2 is a methyl, cyclopropyl or phenyl group and H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 18 R 3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl group.

4. The compound of the general formula (II) according to Claim 3, in which R 1 is a (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1 -yl)methyl or (3-cyanopyridin-2-yl)methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group.

5. A compound according to Claim 4 which is of the general formula O R3 N N O N N / N 0 N R 2 in which R 1 is a (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1 -yl)methyl or (3-cyanopyridin-2-yl) methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group.

6. The compound according to claim 5 in which R 1 is a (4-methylquinazolin-2-yl)methyl group. H:\sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 19

7. A method of preparing a compound of the general formula 0 R3 RiN N O N N I NH 2 or a physiologically tolerated salt thereof, in which R 1 is a (4-methylquinazolin-2-yl)methyl group, (3-methylisoquinolin-1 -yl)methyl or (3-cyanopyridin-2-yl) methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group, said method comprising deprotecting a compound of Claim 5.

8. A method of preparing a compound of the following formula O R3 -N A N N NH2 R 2 2 in which R 1 is a (4-methylquinazolin-2-yl)methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group, wherein the phthalyl protecting group of the compound according to Claim 6 is detached. H:\sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 20

9. The method according to Claim 8, wherein the phthalyl protecting group is detached in the presence of ethanolamine, either in the presence of toluene or a mixture of tetrahydrofuran and water.

10. The method according to Claim 8 or Claim 9, further comprising crystallizing the deprotected compound from ethanol or methanol.

11. The method according to Claim 8 or Claim 9, wherein the deprotected compound is crystallized from ethanol.

12. A medicament comprising a compound obtained by the method according to any one of Claims 7 to 11 as well as one or more inert carriers and/or diluents.

13. Use of a compound obtained by the method according to any one of Claims 7 to 11 for producing a medicament which is suitable for treating diabetes mellitus type I or II, prediabetes, or reduction of glucose tolerance.

14. A method for producing a medicament by using a compound of the following general formula 0 R3 RI N NN ON N I NH 2 R2 in which R 1 is a (4-methylquinazolin-2-yl)methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group, H:\sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 21 prepared by a process according to any one of Claims 8 to 11, and combining with one or more inert carriers and/or diluents.

15. A method for producing a medicament by using a compound of the following general formula o R 3 R N NN O N C NH 2 R2" in which R 1 is a (4-methylquinazolin-2-yl)methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group, prepared by a process according to Claim 11, and combining with one or more inert carriers and/or diluents.

16. A compound of the following formula 0 R3 RI N O N J]:N I NH 2 R2 in which R 1 is a (4-methylquinazolin-2-yl)methyl group, R2 is a methyl group and R 3 is a 2-butyn-1 -yl group, obtained by deprotecting the compound according to claim 6. H:sxd\lnterwoven\NRPortbl\DCC\SXD\7483224 _docx-24/02/2015 - 22

17. A compound according to claim 16 obtained by detaching the phthalyl protecting group from the compound according to Claim 6 in the presence of ethanolamine, either in the presence of toluene or a mixture of tetrahydrofuran and water.

18. A compound according to Claim 16 or Claim 17, obtained by crystallizing the deprotected compound from ethanol or methanol.

19. A method of treating diabetes mellitus type I or II, prediabetes, or reduction of glucose tolerance comprising administering an effective amount of a compound according to any one of Claims 7 to 11 to a subject in need thereof.

20. Compound according to any one of Claims 1 to 6, method according to any one of Claims 7 to 11, 14 and 15, medicament according to Claim 12, use according to Claim 13, product obtained according to any one of Claims 16 to 18, or method of treatment according to Claim 19, substantially as hereinbefore described with reference to any one of the examples.