MX2008008961A - Trihydrochloride forms of a dihydropteridinone derivative and processes for preparation - Google Patents

Abstract

The present invention relates to a specific salt of a dihydropteridione derivative, namely the trihydrochloride salt of the compound N-[trans-4-[4-(cyclopropylmethyl)-1- piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6- oxo-2-pteridinyl]amino]-3-methoxy-benzamide, to its crystallisation in the form of an hydrate with water, to a process for the manufacture thereof, and to the use thereof in a pharmaceutical composition.

Description

TRIH1DROCHLORIDE FORMS OF A DERIVATIVE OF DIHYDROPTERIDINONE AND PREPARATION PROCEDURES The present invention relates to a specific salt of a dihydropteridione derivative, namely the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl)] -1-piperazinyl] -cyclohexy (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide, to its anhydrous form, upon its crystallization in the form of a hydrate with water, a a process for its manufacture, and its use in a pharmaceutical composition. BACKGROUND OF THE INVENTION A number of dihydropteridione derivatives are already known in the prior art. Thus, for example, International Patent Applications WO 03/020722 and WO 2004/076454 describe dihydropteridione derivatives, a process for their manufacture and their use in a pharmaceutical composition for treating diseases related to the activity of specific and characterized cellular cyclokinase. by excessive or abnormal cell proliferation. The compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8 - (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide and a process for its manufacture are specifically described in WO 2004/076454. However, the aforementioned patent applications do not disclose any salt form or specific crystalline form of any of the compounds exemplified therein. Although the pharmacologically valuable properties of the dihydropteridinone derivatives described in the art and mentioned above are the basic prerequisite for the effective use of the compounds as pharmaceutical compositions, an active substance must, in any case, satisfy additional needs to be accepted for use as a drug These parameters are largely related to the physicochemical nature of the active substance. Therefore, it continues to be a necessity for new saline and crystalline forms of active substances, which can be conveniently formulated for administration to patients, and which are pure and highly crystalline to meet the demanding needs and pharmaceutical specifications. Preferably, said compounds will be easily formed and will have favorable overall characteristics. Examples of favorable overall characteristics are drying times, filtration capacity, solubility, intrinsic dissolution rate, stability in general and especially thermal stability and hygroscopic capacity. An absence of breakdown products in the pharmaceutical composition to be used is also favorable, since if breakdown products are present in the pharmaceutical composition, the content of active substance present in the pharmaceutical formulation would be lower than specified. Another critical parameter to control is the hygroscopic capacity, since the absorption of moisture reduces the content of pharmaceutically active substance as a result of the weight increase caused by the absorption of water. Pharmaceutical compositions with a tendency to absorb moisture have to be protected from moisture during storage, for example by the addition of suitable drying agents or by preserving the drug in a medium in which it is protected from moisture. In addition, moisture absorption can reduce the content of pharmaceutically active substance during manufacture if the pharmaceutical substance is exposed to the environment without being protected from moisture in any way. Preferably, therefore, the hygroscopic capacity of a pharmaceutically active substance should be well characterized, and if possible also stabilized. As the crystal modification of an active substance is important for the reproducible active substance content of a preparation, there is a need to clarify as much as possible any existing polymorphism of an active substance present in crystalline form. If there are different polymorphic modifications of an active substance, care must be taken to ensure that the crystalline modification of the substance does not change in the pharmaceutical preparation after producing it. Otherwise, this would have a damaging effect on the reproducible potency of the drug. Against this background, active substances characterized only by light polymorphism are preferred. Minor levels of organic solvents in the crystal lattice are also favorable, due in part to the potential toxicity of the solvent to the vessel as a function of the solvent. Another criterion that may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of the manufacturing process, is the solubility of the active substance. If for example pharmaceutical solutions are prepared (for example, for infusions), it is essential that the active substance be sufficiently soluble in physiologically acceptable solvents. For drugs that have to be taken orally, it is generally very important that the active substance be sufficiently soluble and bioavailable.

In addition, the process for preparing said compound also needs to be conveniently carried out on a commercial scale. Therefore, without being restrictive, examples of the parameters that need to be controlled are the stability of the initial substance under various environmental conditions, the stability during the production of the pharmaceutical formulation and the stability in the final compositions of the drug. The pharmaceutically active substance used to prepare the pharmaceutical compositions should therefore have great stability, which is ensured even under all kinds of environmental conditions. The problem of the present invention is thus to provide a pharmaceutically active substance which is not only characterized by high pharmacological potency, but also satisfies the physicochemical needs mentioned above as much as possible. THE INVENTION Surprisingly, it has been found that the problem outlined above is solved by the trihydrochloride salt and by the crystalline form of the trihydrochloride hydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide, whose structure is represented below in the form of the free base as formula (I). (i) The trihydrochloride salt and the crystalline form of the trihydrochloride hydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-eti l-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide offers numerous advantages over the free base and the anhydrous form of this compound. Therefore, on the anhydrous form, the crystalline form of the trihydrochloride hydrate has, for example, an advantage of stability under ambient conditions. In addition, when compared to the salt of the base, the trihydrochloride salt has a water solubility advantage, where the trihydrochloride is much more soluble than the free base. Finally, when compared to other common builders of salt forms, the trihydrochloride salt form also has advantages as regards the yield, purity and reproducibility of the synthesis of the salt form. Thus, a first object of the present invention is the trihydrochloride salt form of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl- 5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention is the anhydrous form of trihydrochloride of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5, 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention are the crystalline forms of the trihydrochloride hydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -l-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl- 5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention is the crystalline form of the trihydrochloride trihydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl- 5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention is an improved process for the manufacture of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5 , 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention is an improved process for the manufacture of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) - 7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. A further object of the present invention is a pharmaceutical composition comprising the trihydrochloride salt, a crystalline form of trihydrochloride hydrate or the crystalline form of the trihydrochloride trihydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl] -5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide, together with one or more carriers, diluents or pharmaceutically acceptable excipients. A further object of the present invention is the use of the trihydrochloride salt, a crystalline form of trihydrochloride hydrate or the crystalline form of trihydrochloride trihydrate of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] ] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3 -methoxy-benzamide, in a method to treat diseases characterized by excessive or abnormal cell proliferation, 0 to prepare a pharmaceutical composition that is suitable for treating diseases characterized by excessive or abnormal cell proliferation. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the X-ray powder diffractogram of the crystalline trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl. l] -4 - [[(7R) -7-ethyl-5,6J 2-pteridinyl] amino] -3-methoxy-benzamide, recorded using an Advanced Bruker D8 diffractometer equipped with a position sensitive detector (OED) and an anode of Cu as an X-ray source (Cradiation,? = 1, 54056 A, 40 kV, 40 mA). Figure 2 shows an optical microscopy photograph of crystals of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl] 5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. Figure 3 shows the thermoanalysis and determination of the melting point (DSC TG) of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[( 7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide, recorded using a DSC and evaluated by the initial peak (heating rate: 10 ° C / min). The given value is determined using a DSC 821 e made by Mettler Toledo. DETAILED DESCRIPTION OF THE INVENTION As already mentioned above, the compound N- [trans -4- [4- (cyclopropylmethyl) -l -piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6, 7,8-Tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide is specifically described in WO 2004/076454, in addition to a process for its preparation. For details of a process for making this compound, reference is made to this patent application. For an alternative procedure to the manufacture of this compound, the following procedure is referred to. Abbreviations used. TLC Thin layer chromatography. DSC Differential Scanning Calorimeter TG ThermoGravimetry The starting materials trans-4-aminocyclohexanol 10, 3-methoxy-4-nitrobenzoic acid 2, N- (cyclopropylmethyl) piperazine 12c. and 4-acetamido-cyclohexanone 18, are known compounds that are commercially available. This method is a convergent process, which includes the steps of: (i) synthesis of a compound of formula 15c (i) synthesis of a compound of formula 16 16 and (ü) reacting the compound of formula 15c with the compound of formula 16. In the foregoing, the synthesis of a compound of formula 15c and the synthesis of a compound of formula 16 are described (i) Synthesis of a compound of formula 15c 2 11 260 g (1.32 moles) of 3-methoxy-4-nitrobenzoic acid 2 were placed in 1.5 L of toluene. 300 mL of toluene was distilled. 5 mL of dimethylformamide was added dropwise to the residue and 123 mL (1.7 moles) of thionyl chloride was added thereto. The reaction solution was refluxed for 2 hours. The solvent was concentrated by evaporation using the rotary evaporator under reduced pressure. The residue was dissolved in 500 mL of tetrahydrofuran and added dropwise to a suspension of 202 g (1.33 mol) of trans-4-aminocyclohexanol 10 in 1.5 L of tetrahydrofuran and 1.38 L of a 30% potassium carbonate solution, that the temperature stayed between 5o and 13 ° C. The mixture was stirred for 1 hour at 20 ° C and 5 L of demineralized water was added. The precipitate was filtered by suction and washed with demineralized water. The solid was dried at 70 ° C in the circulating air dryer. 380 g (98% of theory) of product H were obtained. TLC (methylene chloride / ethanol = 9: 1) Rf = 0.47 1 g of ruthenium chloride hydrate (III) in fine powder was added to 185 g (0.63 mole) of H and 234 g of N-methylmorpholine-N-oxide in 1.8 L of acetonitrile and the mixture was refluxed for 1 hour. hour. Under reduced pressure, 1.6 L of acetonitrile was evaporated. 1.5 L of demineralized water was added to the residue and the suspension was cooled to 5 ° C. The precipitate was filtered by suction and washed with a lot of demineralized water. The solid was dried at 70 ° C in the circulating air dryer. 168 g (91% of theory) of product 13 were obtained. TLC (methylene chloride / ethanol = 9: 1) Rf = 0.64 112 g (383 mmoles) of product 13, 108 g (770 mmoles) of N- (cyclopropylmethyl) piperazine 12c and 4.5 mL of methanesulfonic acid in toluene were refluxed for 3 hours using the water separator (approximately 76 mL of water separated). Under reduced pressure, 900 mL of toluene was evaporated and the residue was suspended in 1.2 L of ethanol. 15 g of sodium borohydride were added in one batch to this suspension at a temperature of 15 ° to 25 ° C in one hour. The mixture was stirred for 3 hours at 20 ° C and another 4 g of sodium borohydride was added. The mixture was stirred for 16 hours at 20 ° C. At reduced pressure, 650 mL of acetonitrile were evaporated. 2 L of demineralized water and 300 mL of cyclohexane were added. The mixture was cooled to 5 ° C and the suspension was filtered by suction. The residue was dissolved in normal hydrochloric acid. 5 g of active carbon was added and the mixture was filtered by suction. 400 mL of tert-butyl methyl ether was added to the filtrate and made alkaline with ammonia solution. It was cooled to 4 ° C, the precipitate was filtered by suction and washed with demineralized water. The residue was refluxed in 400 mL of tert-butyl methyl ether. After cooling, the solid was filtered by suction and washed with tert-butyl methyl ether. After drying in the circulating air dryer at 60 ° C, 73 g (46% of theory) of product 14c were obtained. TLC (methylene chloride / ethanol = 9: 1) Rf = 0.2 Compound 14c can also be prepared alternatively by the following method. 22 g (142 mmol) of 4-acetamido-cyclohexanone 18, 39.7 g (283 mmol) of N-cyclopropylmethylpiperazine 12c and 0.71 mL of methanesulfonic acid in 175 mL of toluene were refluxed using the water separator until precipitated more water. The mixture was allowed to cool and at 50 ° C, 175 mL of ethanol was added and the resulting mixture was cooled to 20 ° C. 5.37 g (142 mmol) of sodium borohydride was added in a batch with thorough stirring and the mixture was stirred for 16 hours at 20 ° C. 200 mL of a normal 4-hydrochloric acid in droplets was added to the reaction mixture. Under reduced pressure, 200 mL of solvent was evaporated. 100 mL of saturated potassium carbonate solution and 200 mL of methyl isobutyl ketone were added to the residue. The two-phase mixture was cooled to 5 ° C with thorough stirring. The product was filtered by suction and dissolved at reflux temperature in 90 mL of methyl isobutyl ketone. After the addition of the activated carbon, it was filtered hot. The mixture was allowed to cool and the precipitate was removed by suction filtration. After drying, 16.2 g (41% of the theoretical value) of the trans form of compound 19 were obtained. TLC (methylene chloride / ethanol / ammonia = 9: 1: 0.1) Rf = 0.39 A solution of 44 g (157 mmol) of product 19 in 500 mL of 24% hydrochloric acid was refluxed for 6 hours. The solvent was concentrated by evaporation under reduced pressure and the residue was crystallized from 700 mL of isopropanol. The precipitate was filtered by suction, washed with tert-butyl methyl ether and dried at 60 ° C in the vacuum drying cabinet. 54.7 g of product 20 were obtained as the trihydrochloride (contains 5% water). 33 g (90.4 mmoles) of 3-methoxy-4-nitrobenzoic acid 2 were suspended in 80 L of toluene. 0.5 mL of dimethylformamide and 16 g (134 mmoies) of thionyl chloride were added. The mixture was refluxed for 1 hour. The solution was concentrated by evaporation under reduced pressure and the crude acid chloride was dissolved in 50 mL of tetrahydrofuran. The solution was added dropwise to a suspension of 18.7 g (94.9 mmoies, 95%) of the trihydrochloride 20 and 49 g (397 mmoies) of diisopropylethylamine in 150 mL of tetrahydrofuran while cooling in the ice bath. TLC was used to verify that the reaction was complete. After the reaction had ended, water was added to the suspension and the pH was adjusted to 10 by the addition of sodium hydroxide solution. The organic phase was separated and washed with saturated saline. The combined aqueous phases were extracted once with tetrahydrofuran. The combined organic phases were concentrated by evaporation under reduced pressure. The residue was refluxed in 300 mL of tert-butyl methyl ether. The mixture was allowed to cool to 20 ° C and the precipitate was filtered by suction. After drying in the vacuum drying cabinet at 45 ° C, 31.3 g (83% of theory) of product 14c were obtained.

A solution of 72.5 g (174 mmoies) of product 14c in 700 mL of methanol and 145 mL of dimethylformamide was hydrogenated in the presence of 10 g of Raney nickel at a temperature of 20 ° C and a hydrogen pressure of 50 psi.

The catalyst was filtered and the methanol was evaporated under reduced pressure. 500 ml_ of demineralized water was added to the residue and the suspension was cooled to 5 ° C. The precipitate was filtered by suction and washed with demineralized water. After drying in the circulating air dryer at 60 ° C, 60.5 g (90% of theory) of product 15c were obtained. TLC (methylene chloride / ethanol / ammonia = 9: 1: 0.1) Rf = 0.58 (i) Synthesis of a compound of formula 16 The synthesis of 2-chloro-7-ethyl-7,8-dihydro-5-methyl -8- (1-methylethyl) - (7f?) - 6 (5 -) -pteridinone 16 is generally described in WO 2004/076454, to which reference is made. The present invention provides an alternative route of synthesis of 2-chloro-7-ethyl-7,8-dihydro-5-methyl-8- (1-methylethyl) - (7f?) - 6 (5H) -pteridinone 16, which is described in the following. The following starting materials are known and commercially available: (R) -2-amino-butyric acid 2J. and 2,4-dichloro-5-nitropyrimidine 5. 21 22 A suspension of 25 g (242 mmol) of (R) -2-amino-butyric acid 21 and 32 mL (290 mmol) of trimethylortoformate in 150 mL of methanol was heated to 50 ° C. At this temperature 26.5 mL (364 mmol) of thionyl chloride were added in 30 minutes. With the evolution of gas, the temperature increased to 60 ° C. The reaction mixture was refluxed for 3 hours. 125 mL of methanol were distilled and 100 mL of toluene was added. 75 mL of solvent was removed by distillation. A suspension of 77 g (364 mmoles) of sodium triacetoxyborohydride in 175 mL of toluene was added to the reaction mixture at 60 ° C. 22 mL of acetone was added at 40 ° C. The reaction mixture was stirred at room temperature for 16 hours. Under cooling, 73 mL of ammonia (25%) was added. After the addition of 50 mL of demineralized water, the mixture was heated to 50 ° C. The organic phase was separated and washed with demineralized water. 24 mL of a 10 molar solution of hydrogen chloride in ethanol was added. 125 mL of solvent was removed by distillation. 175 mL of tetrahydrofuran was added and the suspension was cooled to 2 ° C. The suspension was filtered by suction and washed with cold tetrahydrofuran. After drying in the vacuum drying oven at 50 ° C, 42.9 g (90% of theory) of product 22 were obtained as hydrochloride. 9.3 mL of a 50% aqueous sodium hydroxide solution was added to a stirred mixture of 33.3 g (170 mmol) of hydrochloride 22 in 60 mL of cyclohexane and 60 mL of demineralized water. The aqueous phase was separated and the organic phase was added dropwise to a refluxing suspension of 30 g (155 mmol) of 5 and 52 g (619 mmol) of sodium hydrogen carbonate in 230 mL of cyclohexane. The suspension was refluxed for 5 hours using a water separator to remove the water formed. 75 mL of solvent was distilled. At 75 ° C, the suspension was filtered by suction to remove the salts. The solvent was distilled. The residue was dissolved in 240 mL of 2-propanol and 90 mL of solvent was distilled again. The solution was cooled slowly to 2 ° C. The suspension was filtered by suction and washed with cold 2-propanol. After drying in a vacuum drying oven at 50 ° C, 38.9 g (79% of theory) of product £ 3 were obtained. The lipophilic solvents such as, for example, cyclohexane, methylcyclohexane, toluene and mixtures thereof, are particularly suitable for achieving high regioselectivity in the nucleophilic substitution reaction with compound 5. 23 24 50 g of 23 were hydrogenated in 375 mL of tetrahydrofuran in the presence of 5 g of Platinum in Carbon (5%) at a hydrogen pressure of 3 bar and at 35 ° C until no more hydrogen was consumed. 2.5 g of vanadyl acetylacetonate was added and the hydrogenation was continued. The suspension was filtered to remove the catalyst. The solvent was removed under reduced pressure. 150 mL of 2-propanol was added to the residue and heated to reflux. 300 ml of demineralized water was added. The suspension was cooled slowly to 2 ° C. The suspension was filtered by suction and washed with a cold mixture of 2-propanol and demineralized water. After drying in a vacuum drying oven at 50 ° C, 36 g (90% of the theoretical value) of product 24 were obtained. 16 A suspension of 7 g (27.5 mmoles) of product 25 and 5.7 g (41 mmoles) of potassium carbonate in 30 mL of dimethyl carbonate was heated at 130 ° C in an autoclave for 5 hours. The mixture was allowed to cool and 25 mL of demineralized water and 15 mL of ethyl acetate were added with stirring. The organic phase was distilled under reduced pressure. A mixture of 25 mL of ethanol and 45 mL of demineralized water was added to the residue and heated to 60 ° C. The solution was allowed to cool to room temperature. The precipitate was filtered by suction and washed with a mixture of demineralized water and ethanol (2: 1). The product was dried at 50 ° C in the vacuum drying cabinet. 6 g (82% of theory) of product 16 were obtained. (Iii) Reaction of a compound of formula 15c with a compound of formula 16. 15c 16 (I) A solution of 23 g (59.5 mmoles) of compound 15c. 16.8 g (62.5 mmol) of 2-chloro-7-ethyl-7,8-dihydro-5-methyl-8- (1-methylethyl) - (7?) - 6 (5H) -pteridinone 16 and 28.3 g (149 mmoles) of para-toluenesulfonic acid hydrate in 350 mL of 2-methyl-4-pentanol was refluxed for 22 hours using the water separator. After the addition of 1 g of compound 16,. the mixture was refluxed for an additional 2 hours. 300 mL of solvent was distilled and the viscous oil was allowed to cool to 60 ° C. 300 mL of methylene chloride and 300 mL of demineralized water were added, and the pH was raised by adding about 20 mL of normal sodium hydroxide solution to pH = 9. The organic phase was washed twice with water and dried over sulfate. sodium The solvent was evaporated under reduced pressure and the residue was dissolved at 65 ° C in 200 mL of ethyl acetate. The mixture was allowed to cool slowly to 20 ° C, the precipitate was filtered by suction and washed with cold ethyl acetate. After drying at 60 ° C in the vacuum drying cabinet, 24.4 g (66% of theory) of product (I) were obtained (mp = 182 ° C, DSC: 10 K / min, additional endothermic effects in the DSC diagram before the merger). Thus, it is an object of the present invention to provide a process for the manufacture of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7- etl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I). it is reacted with a compound of formula 16, 16 wherein the compound of formula 16 is prepared by methylation of a compound of formula 8 8 in the presence of dimethyl carbonate. The present invention further provides a process for the manufacture of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl- 5,6,7,8-tetrahydro-5-methyl-8 (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), said process comprising the steps of in contact, at elevated temperature or room temperature, N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8 -tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo ^ 2-pteridinyl] amino] -3-methoxy-benzamide dissolved in a suitable solvent or in a mixture of solvents, with hydrochloric acid or hydrogen chloride gaseous dissolved in an organic solvent, optionally in the presence of para-toluenesulfonic acid, and collecting the formed precipitate. Suitable solvents for dissolving N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6J, 8-tetrahydro-5-methyl-8 - (1-Methylethyl) -6-oxo-2-pteridinyl] amino] -3-m-benzamide for the formation of salts, are alcohols such as methanol, ethanol, 1- or 2-propanol, isomeric alcohols of butanol, isomeric alcohols of pentanol, isomeric hexanol alcohols, such as 2-methyl-4-pentanol, ketones such as acetone, dialkyl ethers such as tetrahydrofuran, esters of acetic acid such as ethyl acetate, organic acids such as acetic acid, amides such as N-methylpyrrolidinone and nitriles such as acetonitrile. An alternative manufacturing procedure is illustrated by the following experiment, in which the trihydrochloride salt is obtained by the addition of concentrated hydrochloric acid to the reaction medium after completion of the acid-mediated nucleophilic aromatic substitution reaction of compound 15c with compound 16. The following example is illustrative of the present invention and, therefore, it is not considered as a limitation within its scope. A suspension of 143 g (0.37 mol) of 15c and 110 g (0.41 mol) of 16 in 2 L 2 -methyl-4-pentanol was heated to 60 ° C. 176 g (0.93 mol) of para-toluenesulfonic acid monohydrate were added and the mixture was heated to reflux for 24 hours using a water separator. The solution was cooled to 100 ° C. 183 g of concentrated hydrochloric acid were added. 1.5 L of acetone was added at 60 ° C. The suspension was stirred at room temperature for 16 hours. The precipitate was filtered by suction and washed with acetone. The product was dried at 60 ° C in the vacuum drying cabinet. 267 g (92% of theory) of compound (I) were obtained as trihydrochloride. A further object of the present invention is the following step of purification of the trihydrochloride salt by means of crystallization, wherein: the compound (I) as the trihydrochloride is suspended in a suitable organic solvent, such as ethanol; the reaction medium is heated to reflux; water is added; after cooling, the precipitate is collected, washed with a suitable solvent, such as ethanol, and dried. The following example of purification by means of crystallization is illustrative of the present invention and, therefore, is not considered as a limitation within its scope. Example of purification of the trihydrochloride salt of the compound of formula (I) by means of crystallization. A suspension of 15.5 g of compound (I) as trihydrochloride in 160 ml_ of dry ethanol was heated to reflux. 5.5 ml of demineralized water was added. The solution was allowed to cool slowly to 20 ° C and was stirred 16 hours at 20 ° C. The precipitate was filtered by suction and washed with ethanol. After drying in the vacuum drying cabinet at 50 ° C, 13.3 g (86% of theory) of compound (I) was obtained as trihydrochloride. A further object of the present invention is a process for making a hydrated crystal form of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[( 7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula ( I), said method comprising the steps of: dissolving the compound (I) as a base in a suitable organic solvent, such as ethanol, at room temperature or elevated temperature; add hydrochloric acid to the reaction medium; cooling the reaction medium; Collect the precipitate, wash the precipitate with, for example, ethanol, and dry. The following manufacturing example of a hydrated crystal form of the crude trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) - 7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo ^ 2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), is illustrative of the present invention and therefore is not considered as a limitation within its scope. Example of manufacturing a hydrated crystalline form of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5, 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I). 1.1 g of concentrated hydrochloric acid was added to a solution of 2 g of the free base of (1) in 30 mL of ethanol. After stirring for 2 hours at 20 ° C, the suspension was cooled to 2 ° C. The precipitate was filtered by suction and washed with ethanol. After drying in the vacuum drying cabinet, 2.15 g (91% of theory) of product (I) was obtained as trihydrochloride. The trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -l-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5 -methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), is represented by the following Formula.

C34H50N8O3 3 HCI MW = 728.21 The present invention also provides a process for the manufacture of an anhydrous form of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl ] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy -benzamide of formula (I), in which a preparation of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7] -ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) is dried to a temperature above 130 ° C and maintained in a dry atmosphere. The following solubility and solid state characteristics of a hydrated form of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7- ethyl-5,6) 7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), are related to present invention. The solubility properties of a hydrated form of the N- [trans-4- [4- (cyclopropylmethyl] -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5-trihydrochloride salt] , 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. Solubility in aqueous media Table I shows the solubility values of a hydrated form of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohe (1-methylethyl ) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) in different aqueous media.

Table I n.d. = not determined From the above results, it can be concluded that this hydrated form of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 ^ (1 -methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) has a pH that depends on the solubility profile in aqueous media with high solubility in acidic and neutral media and solubility strongly reduced in basic media due to the lower solubility of the free base. Solubility in organic media The hydrated form of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5.6 , 7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) is highly soluble (> 10 mg / ml ) in propylene glycol, glycofurol, Cremofor RH40 (30% aqueous solution), Poloxamer 188 (20% aqueous solution), Solutol HS 15 (20% aqueous solution) in addition to ?? - β-cyclodextrin (20% aqueous solutions), 10%, and 5%). The properties of the solid state of a hydrated form of the N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5-trihydrochloride salt, 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide. Appearance In the solid state, this hydrated form of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7- ethyl-5 , 6,7,8-tetrahydro-5-methyl-8- (1-m-benzamide of formula (I) appears as a white-colored raw-crystal powder.) Crystallinity and polymorphism This hydrated form of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1- Methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) is highly crystalline The powder diffraction diagram of X-rays is shown in Figure 1. Reflection and intensities of the powder X-rays (standardized) are shown in the following Table II Table II In Table II above, the value "2 T [°]" indicates the diffraction angle in degrees and the value "dhki [A]" indicates the distances specified in A between the planes of the network. According to the results shown in Table II, the present invention relates more to the crystalline salt form of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl trihydrochloride trihydrate] - 4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide , characterized in that in the X-ray powder diagram, it has, among others, the characteristic values d = 3.73 A, 4.13 A, 4.52 A, 4.53 A, 6.55 A, 7.14 A, 7.73 A, 9.01 A and 11.21 A (the most prominent peaks in the diagram). The material crystallizes in rod-shaped crystals as shown in Figure 2 attached. Under standard conditions, the crystalline salt form of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7 trihydrochloride, 8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide according to the invention, is present in the form of a hydrate and is obtainable after drying with a changing stoichiometry (1-3 equivalents of water). The hydrate with a stoichiometry close to a trihydrate appears to be the hydrated form stable under ambient conditions and can be obtained after conditioning the dried material. The crystalline water is strongly bound. Decrease humidity below 10% of h.r. does not result in a significant loss of weight. Thus, the present invention also relates to the crystalline salt of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5-trihydrochloride, 6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide, characterized in that it is in a trihydrated form. Thermoanalysis of the crystalline form of the crystalline salt of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6-trihydrochloride, 7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide according to the invention shows a Tfus = 245 ± 5 ° C (DSC: 10 K-min "1 heating rate), under decomposition, and a general endothermic effect between 60 - 140 ° C, which corresponds to the release of water.The DSC / TG diagram is shown in Figure 3. A more detailed look on the TG trace shows a weight loss of approximately 7.5 ± 0.5% by weight between 60 and 140 ° C. This weight loss can be attributed to the release of occluded crystalline water, correlating the observed weight loss with the molecular weight of the N- [trans-4- [4- (cyclopropylmethyl) -1- piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl trihydrochloride salt] -8- (1-methylethyl-2-pteridinyl] amino] -3-methoxy-benzamide reveals an stequiometry of the respective hydrated form close to the trihydrate.

C34H50N8O3 x 3 HCI x 3 H2O M = 782.26 - 3 H2O Am = - 6.9% C34H50N8O3 x 3 HCI M = 728.21 At approximately 260 ° C another strong endothermic peak can be observed in the DSC diagram, indicating the fusion of the dehydrated form. The start of this fusion event is approximately 245 ° C. The fusion occurs, however, under decomposition, indicated by the loss of weight that accompanies it in the fusion. When a TG-IR coupling experiment is performed, it can be seen that the hydrochloric acid is released in the decomposition. The respective anhydrous form, obtained by heating a sample to 140 ° C, is not stable. Thus, the present invention also relates to the crystalline salt of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-Se trihydrochloride. e-Tetrahydro-S-methyl-e-l-methylethi-e-oxo ^ -pteridinyljaminol-S-methoxy-benzamide, characterized by a melting point of Tm.p. = 245 + 5 ° C (determined by DSC, evaluation using maximum peak, heating rate: 10 ° C / min). Stability of the solid state When the stability of the hydrated crystalline salt form of N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl) hydrated hydrochloride is tested -5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl-2-pteridinyl] amino] -3-methoxy-benzamide under severe pressure conditions (24 hours at 105 ° C, 72 hours at 70 ° C and >; 90% relative humidity, or 24 hours in a Xenotester (? = 300 - 800 nm, 250 W m "2)), the results show that the hydrated salt of N- [trans-4- [4- (cyclopropylmethyl) trihydrochloride] ) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl) ] amino] -3-methoxy-benzamide is very stable in the solid state.No significant decomposition or impurities (? <2.4%) can be observed under the applied pressure conditions.From the above data, it can be concluded that the hydrated form of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8 -tetrahydro-5-methyl (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) is characterized by its high solubility in acidic and neutral media and its high crystallinity The crystalline polymorph form is characterized as a trihydrate.The crystalline form is very stable under severe stress conditions and is easily soluble in physiologically acceptable solvents. Physiologically acceptable solvents are known to the person skilled in the art and include, without limitation, for example isotonic solutions containing a salt or a sugar, such as a 0.9% NaCl solution, a 5% glucose or mannitol solution or a Ringer / lactate solution.

The present invention also relates to the metabolites of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7, 8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), to prodrugs of this compound or of these metabolites obtained by means of of, for example, chemical or non-chemical derivatization of the entire molecule or of one or more chemical groups of the molecule, to conjugates of this compound or of these metabolites with a natural or artificial polymer (for example, an oligopeptide, a protein or a chemical polymer), and to the use thereof in a pharmaceutical composition. The "metabolites" are thought to include compounds that are generated from the parent active drug according to formula (I) or other formulas or compounds of the present invention in vivo when said parent drug is administered to a mammalian subject. The metabolites provide the same pharmacological effect and include compounds of the present invention in which, for example, an alkyl-amino group is replaced by an unsubstituted amino group or the corresponding N-oxide, an ester group is replaced by the corresponding carboxylate , or a methyl group has been transformed into a hydroxymethyl or carbonyl group. The "prodrugs" are intended to include any covalently bonded vehicle that releases the parent active drug according to formula (I) or other formulas or compounds of the present invention in vivo when said parent prodrug is administered to a mammalian subject. The prodrugs of a compound of the present invention, for example the compound of formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are separated, either in routine handling or in vivo, to the compound father. The "conjugated compounds" are thought to include any covalently linked natural or artificial polymer (eg, an oligopeptide, a protein or a chemical polymer) that releases the parent active drug according to formula (I) or other formulas or compounds of the present invention. invention in vivo when said conjugate compound is administered to a mammalian subject. The conjugates of a compound of the present invention, for example the formula (I), are prepared by linking functional groups present in the compound to an oligopeptide, a protein or a polymer in such a way that the modifications are separated in vivo by a biomolecule, which is normally found in the neighborhood of white, to the parent compound. As the dihydropteridinone derivatives mentioned in WO 2004/076454, the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7] -ethyl-5, ^ 2-pteridinyl] amino] -3-methoxy-benzamide also has, in particular, an inhibitory effect on specific cellular cyclokinase. Thus, this compound can be used, for example, to treat diseases related to the activity of specific cellular cyclokinase and characterized by excessive or abnormal cell proliferation, and especially to treat diseases related to the activity of the polo-type kinase, PLK-1. Such diseases include, for example: viral infections (e.g., HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasite infections; leukemias, lymphoma and solid tumors; cutaneous diseases (for example, psoriasis); bone diseases; cardiovascular diseases (for example, restenosis and hypertrophy). This compound is also suitable to protect cells from proliferation (i.e., hair, intestinal, blood or stem cells) from damage to their DNA caused by radiation, UV treatment and / or cytostatic treatment (Davis et al., 2001) . It can be used for the prevention, short or long term treatment of the diseases mentioned above, also in combination with other active substances used for the same indications, for example, cytostatic. In addition, the compounds according to the present invention can be used by themselves or in conjunction with other pharmacologically active substances. Suitable preparations for the pharmaceutical compositions according to the present invention include, for example, tablets, capsules, suppositories, solutions, - particularly solutions for injection (s.c., i.v., i.m.) and infusion -, syrups, emulsions or dispersible powders. The proportion of the pharmaceutically active compound (s) should be in the range of 0.01 to 90% by weight, preferably 0.1 to 50% by weight of the composition as a whole, i.e., in quantities that are sufficient to reach the dose necessary to achieve a therapeutic effect. The specified doses, if necessary, can be given several times a day. Suitable tablets can be obtained, for example, by mixing the active substance (s) with known excipients, for example with inert diluents such as calcium carbonate, calcium phosphate or lactose, with disintegrants such as corn starch or acid. alginic, with binders such as starch or gelatin, with lubricants such as magnesium stearate or talc and / or with agents for delaying administration, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets can be prepared accordingly, by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example, collidone or shellac, gum arabic, talcum, titanium dioxide or sugar. To achieve a delayed release or to avoid incompatibilities, the core may also consist of a series of layers. Similarly, the tablet coating may consist of a series of layers to achieve a delayed release, possibly using the excipients mentioned above for the tablets. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer for example a flavoring such as vanillin or orange extract . They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates. The solutions for injection and infusion are prepared in the usual manner, for example, by the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediamine-tetraacetic acid, optionally using emulsifiers and / or dispersants, while if water is used as a diluent, for example, organic solvents such as solvating agent or dissolution aids can optionally be used, and transferred to vials or ampoules for injection or infusion bottles. For example, capsules containing one or more active substances or combinations of active substances can be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packaging them in gelatin capsules. Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. Excipients which can be used include, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), vegetable oils (for example peanut or sesame oil), mono- or poly-functional alcohols (for example example ethanol or glycerol), supports, such as, for example, natural mineral powders (for example kaolins, clays, talc, chalk), synthetic mineral powders (for example highly disperse silicic acid and silicates), sugars (for example cane sugar, lactose and glucose) , emulsifiers (for example lignin, spent sulfite liquids, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate). The preparations are administered by normal methods, preferably by oral route, by injection or transdermally. For oral administration, the tablets can, of course, contain, apart from the aforementioned vehicles, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with different additives such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time for the tabletting process. In the case of aqueous suspensions, the active substances can be combined with different flavor enhancers or colorants in addition to the excipients mentioned above. For parenteral use, solutions of the active substances can be used with suitable liquid carriers. The dose for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour. However, it may sometimes be necessary to deviate from the specified amounts, depending on the body weight, the route of administration, the individual response to the medication, the nature of its formulation and the time or interval during which the drug is administered. Thus, in some cases, it may be sufficient to use less than the minimum dose specified above, while in other cases the specified upper limit will have to be exceeded. When administering large amounts it may be advisable to divide them into a number of smaller doses throughout the day. The following examples of formulations illustrate the present invention without limiting its scope. A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinyl pyrrolidone 15 mg magnesium stearate 5 mg 500 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the rest of the corn starch and the maium stearate are sieved and mixed. The mixture is compressed to produce tablets of suitable shape and size. Tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinyl pyrrolidone 15 mg sodium carboxymethylstarch 23 mg maium stearate 2 mg 400 mg The finely divided active substance, part of the corn starch, the lactose, the microcrystalline cellulose and the polyvinylpyrrolidone are mixed, the mixture is sifted and the rest of the corn starch and the water is used to form a granulate that dries and it is sifted. Sodium carboxymethyl starch and maium stearate are added and mixed, and the mixture is compressed to form tablets of a suitable size. C) Ampoule solution active substance 50 mg sodium chloride 900 mg sodium hydroxide until pH 4.0 water for injection until 100 ml The active substance is dissolved in water at its own pH and sodium chloride is added to make the solution isotonic. The pH is then adjusted to 4.0 by the addition of 1 N sodium hydroxide. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions to ampoules which are then sterilized and hot sealed. The ampoules may contain 5 mg, 25 mg and 50 mg of active substance.

Claims (12)

1. CLAIMS 1.- Procedure for the manufacture of the compound N- [trans-4- [4- (cyclopropylmethyl) -l-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8 -tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) (") characterized in that a compound of formula 15c it reacts with a compound of formula 16 16 wherein the compound of formula 16 is prepared by methylation of a compound of formula 8 in the presence of dimethyl carbonate.
2. 2. - Trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -l-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro -5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), according to claim 1.
3. 3. Hydrated crystalline forms of trihydrochloride of the compound N- [trans -4- [4- (Cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- ( 1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), according to claim 1.
4. 4. - Trihydrate crystalline form of trihydrochloride of the compound N- [trans-4- [ 4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6 -oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I), according to claim 1.
5. 5. Process for the manufacture of the trihydrochloride salt of the compound N- [trans-4- [ 4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8 - (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, said process comprising the steps of contacting N- [trans-4- [ 4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo -2-pteridinyl] amino] -3-methoxy-benzamide dissolved in a suitable solvent or in solvent mixtures, with hydrochloric acid or gaseous hydrogen chloride dissolved in an organic solvent and collecting the formed precipitate.
6. 6.- Process for the manufacture of the trihydrochloride salt of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl- SeTS-tetrahydro S-methyl-S-l-methylethi-e-oxo ^ -pteridinylJaminoJ-S-methoxybenzamide of formula (I) according to claim 1, said process comprising the step of adding hydrochloric acid to the reaction medium used for the reaction of compound 15c with compound 16 16
7. 7. - Process according to claims 5 or 6, comprising an additional step of purification by means of crystallization of the trihydrochloride salt of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4- [[(7R) -7-etl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, comprising the steps of: suspending the compound of formula (I) as trihydrochloride in a suitable organic solvent, heating the reaction medium to reflux, adding water to the reaction medium, collecting the precipitate , washing and drying it.
8. 8. Process for the manufacture of a hydrated crystalline form of the trihydrochloride of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5 , 6,7,8-tetrahydro-5-methyl-8- (1-methyl-ethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, said method comprising the steps of: dissolving the compound (I) as a base in a suitable organic solvent at room temperature or elevated temperature, adding hydrochloric acid to the reaction medium, cooling the reaction medium, collecting the precipitate, washing the precipitate and drying the precipitate.
9. 9. The process according to claim 8, wherein the hydrated crystalline form is the trihydrate.
10. 10. - Pharmaceutical composition containing the trihydrochloride salt, a hydrated crystalline form of trihydrochloride or the trihydrated crystalline form of trihydrochloride of the compound N- [trans-4- [4- (cyclopropylmethyl) -1-piperazinyl] cyclohexyl] -4- [[(7R) -7-ethyl-5, 6,7,8-tetrahydro-5-methyl ^ (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
11. 11. - Process for preparing a pharmaceutical composition according to claim 6, characterized in that the trihydrochloride salt, a hydrated crystalline form of trihydrochloride or the trihydrated crystalline form of trihydrochloride of the compound N- [trans-4- [4- (cyclopropylmethyl) - 1- piperazinyl] cyclohexyl] -4 - [[(7R) -7-ethyl-5,6,7,8-tete 2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, it is incorporated in one or more inert carriers and / or diluents by a non-chemical method.
12. 12. Use of the trihydrochloride salt, a hydrated crystalline form of trihydrochloride or the trihydrated crystalline form of trihydrochloride of the compound N- [trans -4- [4- (cyclopropylmethyl) -1-piperazin] cyclohexyl] - 4 - [[(7R) -7-ethyl-5,6,7,8-tetrahydro-5-methyl-8- (1-methylethyl) -6-oxo-2-pteridinyl] amino] -3-methoxy-benzamide of formula (I) according to claim 1, for preparing a pharmaceutical composition which is suitable for treating excessive or abnormal cell proliferation.