PIPERIDINE-DIHYDROTHIENOPYRIMIDINE SULFOXIDE COMPOUNDS AND SAID COMPOUND FOR USE AS A MEDICINAL PRODUCT IN THE TREATMENT OF A DISEASE THAT CAN BE TREATED BY INHIBITING THE PDE4 ENZYME

Abstract

Piperidino-dihydrothienopyrimidine sulfoxides of formula (1), wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is Cl and wherein R may be located in the para, meta or ortho position of Ring A, wherein S* is a sulfur atom representing a chiral center, and all salts acceptable for pharmaceutical use, enantiomers and racemates, hydrates and solvates thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma.

Description

PIPERIDINE-DIHYDROTHIENOPYRIMIDINE SULFOXIDES AND THEIR USE IN TREATING COPD AND ASTHMA The invention relates to novel piperidino-dihydrothienopyrimidine sulfoxides of formula I, wherein Ring A is a 6-membered aromatic ring that may optionally comprise one or two nitrogen atoms and wherein R is Cl and wherein R may be located in the para, meta or ortho position of Ring A, wherein S* is a sulfur atom representing a chiral center, and all salts, enantiomers and racemates, hydrates and solvates acceptable for pharmaceutical use thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma. PREVIOUS ART WO 2006 / 111549 and WO 2007 / 118793 each disclose dihydrothienopyrimidine sulfoxides that are substituted with piperazine instead of piperidine. WO 2009 / 050248 discloses piperidino-dihydrothienopyrimidines that differ from the compounds of the invention in their substitution pattern. Due to their particular substitution pattern, the compounds of the invention are both more potent PDE4 inhibitors than the compounds disclosed in WO 2009 / 050248 and exhibit a minimized potential for the development of undesirable gastrointestinal side effects. DESCRIPTION OF THE INVENTION Surprisingly, the compounds of the invention, due to their particular substitution pattern, have been found to be particularly suitable for the treatment of inflammatory disease. The compounds of the invention also 1724223 of 64 are superior to the corresponding piperazine-dihydrothienopyrimidine sulfoxides of prior art document WO 2009 / 050248. The present invention therefore relates to compounds of formula I wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is Cl and wherein R may be located in the para, meta or ortho position of Ring A, wherein S* represents a sulfur atom which is a chiral center, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates and polymorphs thereof. The invention also relates to the compounds of formula I mentioned above, wherein R is Cl and wherein R is preferably located in the para position of Ring A, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates and polymorphs thereof. The invention further relates to the compounds of formula I mentioned above, wherein Ring A is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates, and polymorphs thereof. The invention preferably relates to the compounds of formula I mentioned above, wherein Ring A is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl, and wherein R is a substituent of Cl in the para position, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates, and polymorphs thereof. In particular, the invention relates to the compound of formula II, 1724223 of 64 and all salts acceptable for pharmaceutical use thereof, enantiomers and racemates thereof, hydrates, solvates and polymorphs thereof. In particular, the invention relates to the compound of formula III, III, and all salts acceptable for pharmaceutical use thereof, enantiomers and racemates thereof, hydrates, solvates and polymorphs thereof. The invention further relates to the compounds mentioned above according to one of formula I, II or III, wherein S* represents a sulfur atom representing a chiral center that is in the R configuration. The invention further relates to the compounds mentioned above according to one of formula I, II or III, wherein S* represents a sulfur atom representing a chiral center that is in the S configuration. For the compound of formula III, three different polymorphs have been identified, two different anhydrous forms and one dihydrated form, and have been characterized by X-ray powder diffraction (XRPD), by thermogravimetric analysis (TGA) and by differential scanning calorimetry (DSC). Figure 3a shows the X-ray powder diffraction pattern of the anhydrous form A of formula III (see Example 2). The following 2Θ and d values ​​were observed in this XRPD pattern of the anhydrous form A of formula III. 1724223 of 64 (Table 1). Table 1: All observable peaks for the anhydrous form A: 2-Theta d(A) I / Io 4.48 19.70 27 8.76 10.09 46 9.54 9.26 11 12.98 6.82 69 13.44 6.58 9 15.50 5.71 2 16.56 5.35 8 17.94 4.94 35 18.54 4.78 20 19.18 4.62 100 20.36 4.36 15 20.64 4.30 10 21.48 4.13 23 22.62 3.93 38 22.98 3.87 15 23.65 3.76 4 24.46 3.64 15 24.76 3.59 21 26.61 3.35 5 27.34 3.26 13 27.92 3.19 28 29.14 3.06 15 30.68 2.91 11 31.05 2.88 17 32.34 2.77 8 32.65 2.74 3 33.28 2.69 20 33.54 2.67 17 The main peaks of the XRPD diagram of the anhydrous form A of the compound of formula III are detailed in Table 2. Table 2: Main peaks for the anhydrous form A: 2-Theta d(A) I / Io 4.48 19.70 27 8.76 10.09 46 12.98 6.82 69 17.94 4.94 35 19.18 4.62 100 21.48 4.13 23 22.62 3.93 38 24.76 3.59 21 27.92 3.19 28 The most prominent peaks in the XRPD diagram of the anhydrous form A of 1724223 of 64 compound of formula III are detailed in Table 3. Table 3: Prominent peaks for the anhydrous form A: 2-Theta d(A) I / Io 8.76 10.09 46 12.98 6.82 69 19.18 4.62 100 Figure 3b shows the X-ray powder diffraction pattern of the anhydrous form B of formula III (see Example 2). In this XRPD pattern of the anhydrous form B of formula III, the following 2Θ values ​​and d values ​​were observed (Table 4). Table 4: All observable peaks for the anhydrous form B: 2-Theta d(A) I / Io 4.78 18.47 46 9.78 9.04 25 14.56 6.08 5 15.14 5.85 17 16.96 5.22 43 17.48 5.07 14 19.18 4.62 100 19.74 4.49 41 20.80 4.27 38 21.30 4.17 71 21.72 4.09 28 23.82 3.73 50 24.28 3.66 55 24.58 3.62 35 25.53 3.49 4 26.64 3.34 21 27.12 3.29 2 27.61 3.23 13 27.90 3.20 31 28.48 3.13 8 28.78 3.10 18 29.74 3.00 8 30.92 2.89 18 31.75 2.82 6 32.04 2.79 10 32.78 2.73 2 34.55 2.59 8 The main peaks of the XRPD diagram of the anhydrous form B of the compound of formula III are detailed in Table 5. 1724223 of 64 Table 5: Main peaks for the anhydrous form B: 2-Theta d(A) I / Io 4.78 18.47 46 9.78 9.04 25 15.14 5.85 17 16.96 5.22 43 19.18 4.62 100 19.74 4.49 41 20.80 4.27 38 21.30 4.17 71 21.72 4.09 28 23.82 3.73 50 24.28 3.66 55 27.90 3.20 31 The most prominent peaks of the XRPD diagram of the anhydrous form B of the compound of formula III are detailed in Table 6. Table 6: Prominent peaks for the anhydrous form B 2-Theta d(A) I / Io 4.78 18.47 46 16.96 5.22 43 19.18 4.62 100 21.30 4.17 71 24.28 3.66 55 23.82 3.73 50 Accordingly, the invention relates to an anhydrous crystalline compound of formula III that shows a reflected peak in the X-ray powder diffraction pattern with a d-value of 4.62 A. Furthermore, the invention relates to an anhydrous crystalline compound of formula III that shows reflected peaks in the X-ray powder diffraction pattern with d values ​​of 4.62 A, 6.82 A and 10.09 A. Furthermore, the invention relates to an anhydrous crystalline compound of formula III, which shows reflected peaks in the X-ray powder diffraction pattern with d values ​​of 4.62 A, 4.17 A and 3.66 A. Additionally, the invention relates to an anhydrous crystalline compound of formula III, which shows reflected peaks in the X-ray powder diffraction pattern with d values ​​of 4.62 A, 6.82 A, 10.09 A, 3.93 A and 4.94 A. Additionally, the invention relates to an anhydrous crystalline compound of formula III, which shows reflected peaks in the X-ray powder diffraction pattern with d values ​​of 4.62 A, 4.17 A, 3.66 A, 3.73 A and 18.47 A. 1724223 of 64 Fig. 3c shows the X-ray powder diffraction pattern of the dihydrate form C of formula III (see Example 2). In this XRPD pattern of the dihydrate form C of formula III, the following 2Θ values ​​and d values ​​could be observed (Table 7). Table 7: All observable peaks for the dihydrate form C: 2-Theta d(A) I / Io 8.60 10.27 4 9.78 9.04 15 10.28 8.60 28 11.10 7.97 6 12.96 6.83 8 13.72 6.45 16 14.72 6.01 5 15.46 5.73 9 17.20 5.15 70 18.72 4.74 21 19.10 4.64 29 19.70 4.50 33 20.04 4.43 26 20.70 4.29 75 21.54 4.12 100 22.48 3.95 61 23.00 3.86 5 23.78 3.74 5 24.26 3.67 7 24.62 3.61 15 24.98 3.56 19 26.50 3.36 41 27.92 3.19 8 28.62 3.12 20 29.21 3.05 9 29.64 3.01 15 30.18 2.96 19 30.66 2.91 16 31.88 2.80 4 33.00 2.71 12 33.94 2.64 9 The main peaks of the XRPD diagram of the dihydrate form C of the compound of formula III are detailed in Table 8. Table 8: Main peaks for the dihydrate form C: 2-Theta d(A) I / Io 10.28 8.60 28 17.20 5.15 70 18.72 4.74 21 19.10 4.64 29 1724223 of 64 2-Theta d(A) I / Io 19.70 4.50 33 20.04 4.43 26 20.70 4.29 75 21.54 4.12 100 22.48 3.95 61 26.50 3.36 41 28.62 3.12 20 The most prominent peaks of the XRPD diagram of the dihydrate form C of the compound of formula III are detailed in Table 9. Table 9: Prominent peaks for the dihydrate form C: 2-Theta d(A) I / Io 17.20 5.15 70 20.70 4.29 75 21.54 4.12 100 22.48 3.95 61 26.50 3.36 41 Accordingly, the invention relates to a crystalline dihydrate compound of formula III, which shows a reflected peak in the X-ray powder diffraction pattern with a d value of 4.12 A. The invention also relates to a crystalline dihydrate compound of formula III, which shows reflective peaks in the X-ray powder diffraction pattern with d values ​​of 4.12 A, 4.29 A and 5.15 A. The invention further relates to a crystalline dihydrate compound of formula III, which shows reflective peaks in the X-ray powder diffraction pattern with d values ​​of 4.12 A, 4.29 A, 5.15 A, 3.95 A and 3.36 A. In another aspect, the invention relates to the compounds mentioned above for use as a medicament. Another aspect of the invention relates to a method for treating a disease that can be treated by inhibiting the PDE4 enzyme, comprising the step of administering one of the above-mentioned compounds in accordance with at least one of formulas I, II, or III to a patient in need thereof. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II or III to prepare a medicament for the treatment and / or prevention of a disease that can be treated by inhibiting the PDE4 enzyme. 1724223 of 64 Furthermore, the invention relates to one of the compounds mentioned above in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a disease that can be treated by inhibiting the PDE4 enzyme. The invention further relates to the above-mentioned method for treating a disease treatable by inhibiting the PDE4 enzyme, comprising the step of administering one of the above-mentioned compounds in accordance with at least one of formulas I, II, or III to a patient in need thereof, characterized in that the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, skin, or eyes, cancer, and a disease of the central or peripheral nervous system. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II, or III to prepare a medicament for the treatment and / or prevention of a disease that can be treated by inhibiting the PDE4 enzyme, wherein the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, skin, or eyes, cancer, and a disease of the central or peripheral nervous system. Furthermore, the invention relates to one of the above-mentioned compounds in accordance with at least one of formulas I, II, or III for the treatment and / or prevention of a disease that can be treated by inhibiting the PDE4 enzyme, wherein the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, skin, or eyes, cancer, and a disease of the central or peripheral nervous system. The invention further relates to the method mentioned above for treating a disease selected from the group consisting of a respiratory or pulmonary disease that is accompanied by an increase in mucus production, inflammations and / or obstructive diseases of the respiratory tract, comprising the step of administering one of the compounds mentioned above in accordance with at least one of formulas I, II or III to a patient who needs it. Furthermore, the invention relates to the use of one of the compounds mentioned above in accordance with at least one of formulas I, II or III to prepare a 1724223 of 64 drug for the treatment and / or prevention of a selected disease from the group consisting of a respiratory or pulmonary disease that is accompanied by an increase in mucus production, inflammations and / or obstructive diseases of the respiratory tract, comprising the step of administering one of the above-mentioned compounds in accordance with at least one of formulas I, II or III to a patient who needs it. Furthermore, the invention relates to one of the compounds mentioned above in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a selected disease from the group consisting of a respiratory or pulmonary disease that is accompanied by an increase in mucus production, inflammation and / or obstructive diseases of the respiratory tract, comprising the step of administering one of the compounds mentioned above in accordance with at least one of formulas I, II or III. The invention further relates to the method mentioned above for treating a disease selected from the group consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, asthma, and chronic bronchitis, comprising the step of administering one of the compounds mentioned above in accordance with at least one of formulas I, II, or III to a patient in need thereof. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II or III to prepare a medicament for the treatment and / or prevention of a selected disease from the group consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, asthma and chronic bronchitis. Furthermore, the invention relates to one of the above-mentioned compounds in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a selected disease from the group consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, asthma and chronic bronchitis. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II or III to prepare a medicament for the treatment and / or prevention of a selected disease from the group consisting of rheumatoid arthritis, sarcoidosis, glaucoma and dry eye syndrome. Furthermore, the invention relates to one of the aforementioned compounds plus 1724223 of 64 above in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a selected disease from the group consisting of rheumatoid arthritis, sarcoidosis, glaucoma and dry eye syndrome. The invention further relates to the method mentioned above for treating a disease selected from the group consisting of Crohn's disease and ulcerative colitis, comprising the step of administering one of the compounds mentioned above in accordance with at least one of formulas I, II or III to a patient in need thereof. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II or III to prepare a medicament for the treatment and / or prevention of a selected disease from the group consisting of Crohn's disease and ulcerative colitis. Furthermore, the invention relates to one of the compounds mentioned above in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a selected disease from the group consisting of Crohn's disease and ulcerative colitis. The invention further relates to the method mentioned above for treating a disease selected from the group consisting of depression, manic or bipolar depression, chronic and acute anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, chronic and acute multiple sclerosis, or chronic and acute pain and brain damage caused by stroke, hypoxia, or head trauma, comprising the step of administering one of the compounds mentioned above in accordance with at least one of formulas I, II, or III to a patient in need thereof. Furthermore, the invention relates to the use of one of the above-mentioned compounds in accordance with at least one of formulas I, II, or III to prepare a medicament for the treatment and / or prevention of a selected disease from the group consisting of depression, manic or bipolar depression, chronic and acute anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, chronic and acute multiple sclerosis, or chronic and acute pain and brain damage caused by stroke, hypoxia, or head trauma. Furthermore, the invention relates to one of the compounds mentioned above in accordance with at least one of formulas I, II or III for the treatment and / or prevention of a selected disease from the group consisting of depression, manic or bipolar depression, chronic and acute anxiety states, schizophrenia, 1724223 of 64 Alzheimer's disease, Parkinson's disease, chronic and acute multiple sclerosis or chronic and acute pain and brain damage caused by stroke, hypoxia or head trauma. In another aspect, the invention relates to a pharmaceutical composition comprising at least one of the compounds mentioned above in accordance with at least one of formulas I, II or III. In another aspect, the invention relates to a pharmaceutical composition characterized in that it contains at least one of the above-mentioned compounds of at least one of formulas I, II or III in combination with one or more active substances selected from the group consisting of beta-mimetics, corticosteroids, anticholinergics, other PDE4 inhibitors, NSAIDs, COX2 inhibitors, EP4 receptor antagonists, EGFR inhibitors, LTD4 antagonists, CCR3 inhibitors, iNOS inhibitors, MRP4 inhibitors and SYK inhibitors. In another aspect, the invention relates to a method for manufacturing compound A A wherein HX is an acid acceptable for pharmaceutical use, comprising steps a) and b), wherein in step a) compound B HY B, wherein HY is a pharmaceutically acceptable acid, is reduced by borane and wherein in step b) a pharmaceutically acceptable acid HX is added to obtain compound A. In one embodiment of the method mentioned above for making compound A, the borane for reduction in step a) is added directly. In another embodiment of the method mentioned above for manufacturing compound A, the borane for reduction in step a) is generated in situ. In a preferred embodiment of the method mentioned above for manufacturing compound A, the borane for reduction in step a) is generated in situ from 12 1724223 of 64 the combination of NaBH4 and I2 or from the combination of NaBH4 and BF3-OEt2. In another preferred embodiment of the above-mentioned method of a compound A, to manufacture the acid HX, either tosylic acid or hydrochloric acid is selected. In another embodiment of the method mentioned above, compound A is used to manufacture the pharmaceutically acceptable acid HY, where compound B is HCl. In another aspect, the invention relates to a method for manufacturing compound C H Cl C, wherein HX is tosylic acid, hydrochloric acid, or sulfuric acid, comprising steps i), ii), and iii), wherein in step i) 4-cyano-piperidine is first contacted with an acid and then reacted with ammonia to obtain intermediate E E and wherein in step ii) the intermediate E is reacted with compound D in the presence of a base (PF6)- D and where in step iii) the acid HX is added. In a preferred embodiment of the above-mentioned method for manufacturing the compound C4-cyano-piperidine, it is contacted with hydrochloric acid and then reacted with ammonia to obtain intermediate E in step i). In a preferred embodiment of the method mentioned above for manufacturing 1724223 of 64 compound C, intermediate E is reacted with compound D in the presence of sodium methanolate in step ii). In another aspect, the invention relates to formula VIII intermediaries VIII and its salts. In another aspect, the invention relates to formula IX intermediaries and its salts, where S* signifies a sulfur atom representing a chiral center. Compounds of general formulas I, H, and III contain basic groups. Therefore, compounds of general formulas I, II, and III can form salts with inorganic acids acceptable for pharmaceutical use, such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfonic acid, or with organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid, or acetic acid). As described above, the compounds of formulas I, II, and III can be transformed into their salts acceptable for pharmacological use as pharmaceutical products. For example, these compounds can form acidic addition salts acceptable for pharmacological and physiological use with inorganic or organic acids. To produce these acidic addition salts of the compounds of formulas I, II, and III, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methylsulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid can be used. Mixtures of the acids mentioned above can also be used. Compounds of formulas I, II, and III may also be present in the form of their individual optical isomers or enantiomers, in mixtures of individual enantiomers or in the form of their racemates, and in the form of their free bases or in the form 1724223 of 64 of its acid addition salts with acids acceptable for pharmacological use (for example, acid addition salts with hydrohalogenic acids such as hydrochloric acid or hydrobromic acid or with organic acids such as oxalic acid, fumaric acid, diglycolic acid or methyl sulfonic acid. The compounds of the invention may also be present in their racemic forms, but they may also be present in the form of a pure enantiomer, meaning in their (R) form or in their (S) form. As mentioned above, pharmaceutically acceptable salts of the compounds of formulas I, II, and III are also a preferred aspect of the present invention. These pharmaceutically acceptable salts of the compounds of formulas I, II, and III may also be present in the form of their hydrates (e.g., mono- or dihydrates) and / or in the form of their solvates. A solvate of a compound of formula I, II or III is hereby defined as a crystalline salt of the respective compound of formula I, II or III that contains solvent molecules (e.g. ethanol, methanol, etc.) within its crystal lattice. A hydrate of a compound of formula I, II or III is hereby defined as a crystalline salt of a compound of formula I, II or III that contains crystalline water in its crystal lattice. SYNTHESIS METHODS Generating Examples 1 and 2: Scheme 1: .N. XI p-TsOH Example 1 R = 4-chlorophenyl; or Example 2 R = 5-chloropyrimidin-2-yl 1724223 of 64 3.1. Generation of the Vile Compound: Scheme 2: either II — CO2Me g CO2Me III Cl Vile POCI3 Dletylaniline T¡(O'Pr)CI3 Et3N MeOH HCI OH VI H2O NaOH V 3.1.1 Synthesis of dimethyl-3-thiadipate (Compound III) SH Piperidine (0.02 equiv) i—CO2Me g CO 2 Μ s I II III Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052 mol) were charged into an inert jacketed reactor equipped with an addition funnel, mechanical stirrer, N2 line, and thermocouple thermometer. Methyl acylate (250 g, 2.87 mol) was then slowly added over a period of 30 minutes, maintaining the temperature at approximately 45 °C. After the addition was complete, the mixture was stirred at 45 °C for 30 minutes. Piperidine (17.9 g, 210 mmol) was added, and stirring at 45 °C continued for 30 minutes (to remove excess acylate). tert-Butyl methyl ether (MTBE) (251 mL) was charged, the mixture was cooled to 15 °C, and 1 M HCl (251 mL) was added. The mixture was stirred for 5 minutes, and the organic layer was collected and washed with water (251 ml). The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50 °C. Dichloromethane (251 ml) was added, and the mixture was concentrated again under reduced pressure by distillation at 40–45 °C.The crude product III (480 g) was used in the next step without further purification. 3.1.2 Synthesis of methyl-3-oxo-tetrahydrothiophene-2-carboxylate (Compound IV) I—CO2Me Ti(O'Pr)CI3O ^ / -co MeS\s / -CO2Me III IV 1724223 of 64 T1Cl4 (CH2Cl2 1.0 M, 1.16 L; 1.16 mol) was charged into a dry, inert, jacketed reactor equipped with a temperature probe, mechanical stirrer, and a dropping funnel. The reactor contents were cooled to -10°C, and isopropanol (89.6 mL, 1.16 mol) was charged at or below -10°C. The mixture was stirred at -10°C for 30 minutes, and dimethyl 3-thiaadipate (200 g, 1.01 mol) was charged slowly over 1 hour, maintaining the internal temperature at or below -10°C. The reaction was stirred for an additional 30 minutes at -10°C, and Et3N (489 mL, 3.49 mol) was charged slowly over 1.5 hours, maintaining the internal temperature at or below -10°C. The mixture was stirred at a temperature below -10°C for 1.5 hours. 3 N HCl (1.01 L; 3.03 mol) was slowly added while maintaining the internal temperature below 10°C. The temperature was then increased to 30°C and the mixture was stirred for 1 hour.The mixture was allowed to settle, the organic layer was collected, and the aqueous layer was extracted twice with dichloromethane (1.5 L per extraction). The combined organic portions were washed twice with water (1.5 L per wash) and dried with MgSO4 (40 g). The resulting solution was concentrated to a minimum volume under reduced pressure at 25–35°C to produce crude IV (148.6 g). The IV spectral data are consistent with values ​​reported in the literature (Liu, H.-J.; Teng, K.N. Can. J. Chem. 1982, 60, 437). 3.1.3 Synthesis of methyl ester of 3-ureido-4,5-dihydro-thiophene-2-carboxylic acid (Compound V) CO2Me IV U area, MeOH / HCl V Urea (2.16 kg, 35.9 mol) was charged into a dry, jacketed reactor equipped with a stirrer, N2 line, and thermocouple thermometer. 3-oxo-tetrahydro-thiophene-2-carboxylic acid methyl ester (Compound IV, 3.0 kg) was charged, followed by methanol (4.5 L). Concentrated HCl (297 mL, 3.59 mol) was charged at 20–25 °C, and the mixture was stirred under reflux for 4–6 hours. The reaction mixture was cooled to 0 °C, and the resulting solid was collected by filtration. The cake was washed with water twice (2 l water per wash) and dried in a vacuum oven at 50 °C to produce 4.17 kg (83 %w / w) of compound V (95% yield),1H NMR (500 MHz, (CD3)2SO) δ 3.10 (dd, 2 H, J = 8.5, 8.5 Hz), 3.50 (dd, 2 H, J = 8.5, 8.5 Hz), 3.73 (s, 3 H), 6.50-7.20 (bs, 2 H), 9.47 (s, 1 H);13C NMR (125 MHz, (CD3)2SO) δ 28.7, 37.8, 52.4, 100.0, 151.6, 154.7, 165.7; LCMS (EI) for C7H11N2O3S, (M+H)+ calculated 203.0, measured 203.0. 1724223 of 64 3.1.4 Synthesis of 6,7-dihydro-thieno[3,2-dipyrimidine-2,4-diol (Compound VI) NaOH H2O OH VI Compound V (2.0 kg, 9.47 mol) was added to a solution of water (6.0 L) and NaOH (379 g, 9.47 mol) at room temperature. The mixture was stirred at 85 °C for 3 hours. After cooling to 0 °C, concentrated HCl (861 mL, 10.4 mol) was slowly added until the pH of the solution was 0–1. The mixture was cooled to 0 °C, stirred for 5–10 minutes, and the resulting solid was collected by filtration. The cake was thoroughly washed with water twice (1 l per rinse), air dried for 2-3 hours (suction) and then further dried in a vacuum oven at 50 °C for 12-16 hours to produce 1.67 kg of compound VI.1H NMR (500 MHz, (CD3)2SO) δ 3,11 (dd, 2 H, J = 8.5, 8.5 Hz), 3,31 (dd, 2 H, J = 8.5, 8.5 Hz), 11,14 (s, 1 H), 11,38 (s, 1 H);13C NMR (125 MHz, (CD3)2SO) δ 29,3, 35,4, 108,5, 150,5, 152,4, 160,4; LCMS (EI) for C6H7N2O2S, (M+H)+calculated 171.0, measured 171.0. 3.1.5 Synthesis of 2,4-dichloro-thiene[3,2-dlpyrimidine (Compound VII): OH POCl3^^N^Cl -----* < HER SN OHCl VIVII 800 g of solid Compound VI (4.66 mol) were loaded into a dry, inert, jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer, and dropping funnel. 1.5 liters (9.31 mol) of diethylaniline were added over 30 minutes to 1 hour, maintaining the temperature at or below 25°C. The internal temperature was raised to 105–110°C, and 0.68 equivalents (868 mL, 34% of the total) of phosphorus oxychloride were added to the reactor (reactor 1) over 5–10 minutes. When the internal temperature began to decrease, it was maintained at 110°C, and the addition of the remaining POCl3 (1.32 equivalents, or 66% of the total) was resumed over a period of 30–40 minutes. The internal temperature was adjusted to 105–110°C and the mixture was stirred for 18–24 hours or until completion (analysis by HPLC). The mixture was cooled to 45°C and charged with THF (400 mL) at 45°C. The crude mixture was then placed in a reactor or 18 1724223 of 64 secondary dry vessel (vessel or reactor 2). 4.8 liters of water were charged into reactor 1 and cooled to 5 °C. The crude reaction mixture (in reactor or vessel 2) was then slowly charged into reactor 1 containing water, maintaining the temperature at 5–10 °C. The mixture was stirred at 5 °C for 30 minutes to 1 hour, and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 L per rinse) and air-dried in a funnel for 6–8 hours to produce 964 g (92% w / w; 88% yield) of crude Compound Vil. Dichloromethane (4.6 L) was charged into a 10-liter reactor. Crude Compound Vil and activated carbon (46.2 g) were loaded into the reactor, the mixture was heated to 40°C and stirred for 20 minutes. The resulting solution was collected by filtration through a filter medium to remove the carbon. The cake was rinsed with dichloromethane twice (175 ml per rinse).The solution was concentrated under reduced pressure to a minimum agitable volume, and the remaining dichloromethane was removed by distillation with a minimal amount of petroleum ether. Additional petroleum ether (1.3 L) was charged into the reactor, the mixture was cooled to 10°C, and stirred for 1 hour. The resulting solid was collected by filtration, and the cake was rinsed twice with petroleum ether (150 mL per rinse). The cake was dried with air in a funnel (suction) until it appeared dry. The resulting solid Vile Compound was transferred to a suitable tared container and dried in an oven at 50 °C for 6 hours to obtain the final product:1H NMR (400 MHz, DMSO-d6) δ 3.45-3.56 (m, 4H);13C NMR (400 MHz, DMSO-d6) δ 29.3, 36.5, 134.8, 151.0, 154.1, 175.9. 3.2 Generation of Example 1: Scheme 3: * chiral c X- = CI-o Tso HSO419 1724223 of 64 3.2.1 Synthesis of Compound A 1. I2 / NaBH4 2. p-TsOH OH BA NaBH4 (28.6 g, 757 mmol, 2.87 equivalents) and THF (500 mL) were loaded into a 2-liter reactor under nitrogen, and the mixture was cooled to -5 °C. A solution of I2 (63.6 g, 251 mmol, 0.95 equivalents) was prepared in 125 mL of THF and added to the reactor slowly over 45 minutes, maintaining an internal temperature of -5 to 5 °C. The addition funnel was then rinsed with 42 mL of THF. Compound B (50 g, 264 mmol, 1 equivalent) was then loaded at -6 °C, and the temperature was subsequently raised to approximately 5 °C. The reaction mixture was then heated to 65 °C for 23 hours (Note: The reaction conversion was analyzed by GC / FID by deactivating 0.1 ml of the reaction mixture with MeOH, then derivatizing with 0.5 ml of a 5 / 2 / 2 mixture of THF / acetic anhydride / TEA). Afterwards, 83 ml of MeOH was slowly charged into the reaction mixture over 20 minutes, maintaining the temperature between 20-27 °C.The reaction mixture was concentrated to a minimum stirable volume, and 500 mL of 2-methyltetrahydrofuran (MeTHF) was added. Then, 485 g of 25 wt% aqueous NaOH (11.5 equivalents) were added, and the solids dissolved. The layers were separated, and the aqueous phase was extracted twice with 500 mL of 2-methyltetrahydrofuran (MeTHF). The organic extracts were then filtered through a celite and MgSO4 pad and rinsed with 50 mL of 2-methyltetrahydrofuran (MeTHF). A solution of p-toluenesulfonic acid monohydrate (51 g, 264 mmol, 1 equivalent) in MeTHF (100 mL) was prepared and added to the organic extracts (alternatively, HCl can be used to obtain the HCl salt of compound A). A homogeneous, light yellow solution resulted. The solution was concentrated to approximately 275–300 mL and the water content was monitored. Additional MeTHF was added and the solution was concentrated back to the original volume until the water content was <0.1%.The resulting solid was filtered and rinsed with 50 ml of MeTHF, left to dry in the funnel overnight, and then further dried in the vacuum oven at 50 °C. 61.71 g of compound A:1H NMR (DMSO-d6, 400 MHz) were collected δ 1.70-1.92 (m, 2H), 1.94-2.03 (m, 2H), 2.04-2.18 (m, 2H), 2.29 (s, 3H), 3.55 (s, 3H), 5.47 (br s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.95 (br s, 3H);13C NMR (DMSO-d6, 100 MHz) δ 13.3, 20.8, 56.4, 63.5, 125.5, 128.1, 137.8, 145.4. 1724223 of 64 3.2.2 Synthesis of Compound VIII Intermediates Vil (180 g, 852 mmol) and A (129 g, 937 moles) were sequentially loaded into a multi-necked vessel equipped with a condenser, thermocouple thermometer, and nitrogen line. Acetonitrile (900 mL) and triethylamine (594 mL, 4.26 moles) were then added at 22 °C, and the mixture was stirred at 75–77 °C for 12 hours. Water (1.2 L) was slowly added over 20 minutes, and the mixture was seeded with Compound VIII crystals (0.3 g) at 40 °C and then cooled to 25 °C for 2 hours. The mixture was stirred for an additional 12 hours at normal room temperature, and the resulting solid was collected by filtration. The filter cake was rinsed with a 2:1 mixture of water / MeCN (400 ml) followed by water (200 ml).The resulting solid was vacuum dried at 50 °C for 12 hours to produce 132 g (57% yield) of compound VIII:1H NMR (400 MHz, CDCI3) δ 1.85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J = 8.0, 8.4 Hz, 2H), 3.43 (dd, J = 8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1H);13C NMR (CDCI3, 100 MHz) δ 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1, 156.2, 168.0. 3.2.3 Synthesis of Compound IX: chiral Compound VIII (122 g, 429 mmol), S-(-)-1,1'-bi-2-naphthol (S-(-)BINOL) (12.4 g, 42.9 mmol), dichloromethane (608 mL), Ti(O₂Pr)₄ (6.54 mL, 21.4 mmol), and water (7.72 mL, 429 mmol) were loaded into a 2-liter multi-necked flask at 20 °C under nitrogen and shaken for 1 hour. tert-butyl hydroperoxide (70% on 21 1724223 of 64 water, 62.3 ml, 472 mmol) all at once at 21 °C; the mixture became completely homogeneous and the temperature was raised to approximately 40 °C. The mixture was allowed to reach normal room temperature, stirred for 1.5 hours, and filtered. The cake was rinsed twice with isopropyl acetate (243 ml per rinse) and the cake was air-dried on the filter for > 6 hours to produce 114.4 g of compound IX. Ή NMR (400 MHz, DMSO-d6) δ 1.70-1.85 (m, 2H), 2.14-2.34 (m, 4H), 2.98-3.08 (m, 1H), 3.09-3.19 (m, 1H), 3.30-3.40 (m darkened, 1H), 3.50-3.62 (m, 1H), 3.65-3.77 (m, 2H), 4.91 (t, J= 6 Hz, 1H), 8.63 (s, 1H);13C NMR (100 MHz, DMSO-d6) δ 14.5, 29.6, 29.8, 32.6, 48.6, 59.2, 62.8, 119.0, 157.8, 161.4, 175.3. The other enantiomer of compound IX can be produced when S-(-)-1,1'-Bi-2-naphthol is replaced by R-(+)-1,1'-Bi-2-naphthol. A racemate of compound IX can be produced by methods known to those skilled in the art that exclude chiral agents and conditions. An example of such a procedure for producing racemic sulfoxides is provided in WO 06 / 111549. 3.2.4 Summary of Example 1 IX sulfoxide (6.48 g; 22.5 mmol), 4-(4-chlorophenyl)piperidine hydrochloride C (5.75 g; 24.8 mmol) (alternatively the p-TsOH- or H₂SO₄ salt of compound C), and N,N-diisopropylethylamine (12.4 mL; 72.1 mmol) were mixed in 47 mL of dioxane. The resulting mixture was loaded into three 20 mL vials, which were heated to 120 °C for 25 minutes in a microwave oven. After cooling to room temperature, the reaction mixtures were poured onto ice water. The resulting precipitate was filtered, collected in 500 mL of ethyl acetate, and heated to reflux. After reflux, the mixture was cooled in an ice bath and the resulting precipitate was filtered and dried in a dry box at 50 °C under reduced pressure 22 1724223 of 64 producing 7.57 g of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 1.43-1.57 (m, 2H), 1.67-1.85 (m, 4H), 2.11-2.21 (m, 2H), 2.26-2.43 (m, 2H), 2.80-3.01 (m, 5H), 3.17-3.47 (m, water peak committed integration), 3.67-3.76 (m, 2H), 4.74-4.86 (m, 3H), 7.25-7.36 (m, 5H). 13C NMR (100 MHz, DMSO-d6) δ 14.3, 29.4, 29.6, 32.3, 32.5, 41.4, 44.2, 48.5, 58.4, 63.6, 109.2, 128.2, 128.6, 130.5, 144.7, 157.6, 161.5, 174.7 3.3 Generation of Example 2: Scheme 4: chiral X-=CI-o Ts-o HSO4- 3.3.1 Generation of compound G: Scheme 5: 3.3.1.1 Synthesis of Compound E: N H 1. MeOH, HCl / Dioxane 2. NH3 / MeOH AND 1724223 of 64 4M HCl in dioxane (225 mL, 3 equivalents, 900 mmol) was charged into a 500 mL three-necked jacketed reactor equipped with a mechanical stirrer, temperature probe, and argon line. The solution was cooled to 0 °C, and 4M cyanopiperidine (33.04 g, 300 mmol) was charged, followed by methanol (36.4 mL, 900 mmol, 3 equivalents) over approximately 30 minutes, while maintaining the temperature below 10 °C (elevated temperature). The mixture was stirred for 6–8 hours at normal room temperature until complete conversion to D₂O was observed by 1H NMR analysis of an aliquot (the clear solution turned into a white suspension after 30 minutes). The mixture was cooled to 5 °C and charged with 25 wt% NaOMe in methanol (129.6 g, 600 mmol, 2 equivalents) while maintaining the temperature below 15 °C. The mixture was then stirred for 1 hour.7.0 N ammonia in methanol (64.2 mL, 1.5 equivalents, 450 mmol) was added to the above mixture and stirred for 2 hours at normal room temperature. The mixture was concentrated under reduced pressure at 60 °C to a volume of ~250 mL to produce a solution of crude compound E, which was used without isolation. 1H NMR (400 MHz, D2O) δ 1.80-1.95 (m, 2H), 2.15 (br d, J = 4.4 Hz, 2H), 2.79-2.90 (m, 1H), 3.02 (ddd, J = 13.2, 13.2, 3.0 Hz, 2H), 3.48 (m, 2H). 3.3.1.2 Synthesis of Compound G: E DG The previous solution of intermediate compound E was cooled to ~20 °C and charged with 25 wt% NaOMe in methanol (162 g, 2.5 equivalents, 750 mmol). The mixture was then stirred for 30 minutes. Compound D (=(Z)-N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethane-amino(V) hexafluorophosphate) (82.3 g, 95 wt% purity, 0.85 equivalents, 255 mmol) was charged to the previous mixture in two portions at normal room temperature for ~30 minutes and stirred for 3 hours at room temperature. The mixture was concentrated under reduced pressure at 60 °C to a volume of ~200 mL. 2-Methyltetrahydrofuran (400 mL) was added, and the mixture was further concentrated to a volume of ~150 mL under reduced pressure at 60 °C. 250 mL of 2-Methyltetrahydrofuran was added, the mixture was cooled to ~20 °C, water (150 mL) was added, and the mixture was stirred for 5 minutes. The components were then separated. 1724223 of 64 layers and the organic layer was collected. The organic layer was washed with 30% aqueous NaOH (120 mL) and the layers were separated. The organic extracts were concentrated to a minimum shakeable volume (~150 mL) and n-propanol (350 mL) was added. A solution of p-toluenesulfonic acid monohydrate in n-propanol (0.85 equivalents, 255 mmol, 48.4 g in 100 mL of n-propanol) was added to the above clear solution for 10 minutes at ~65 °C. The above mixture was concentrated at ~65 °C under reduced pressure to maintain ~350 mL and <1.0% water (a water content below 1.0% is recommended to avoid product losses to the mother liquor). The batch was cooled to 20 °C with stirring for 3 hours. The solids were filtered, rinsed with the filtrate and then with n-propanol (120 ml) to produce 111 g (68% w / w per test, 75.48 g) of compound G after vacuum drying at 65 °C in a vacuum oven for 12 hours. Ή RMN (DMSO-d6, 400 MHz) δ 1.83-1.99 (m, 2H), 2.13 (d, J = 12 Hz, 2H), 2.97 (s, 3H), 3.0-3.11 (m, 2H), 3.13-3.23 (m, 1H), 3.30-3.42 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 8.47 (br, 2H), 8.91 (s, 2H);13C RMN (DMSO-d6, 100 MHz) δ 20.7, 27.0, 40.8, 42.8, 125,5, 128.1, 128.8, 137.9, 145.2, 155.8, 169.0. 3.3.2 Síntesis del Ejemplo 2: * quiral G con HX siendo HCI, TsOH o H2SO4 Compound IX (86.5 g, 291 mmol, 1 equivalent), compound G (160 g, 305 mmol, 1.05 equivalents), tetrahydrofuran (THF) (484 mL), water (121 mL), and DIPEA (N,N-diisopropylethylamine, 127 mL, 727 mmol, 2.5 equivalents) were all loaded into a 3-liter round-bottom flask under nitrogen and heated to 65 °C for 3 hours. Water (1125 mL, 13 mL / g compound IX) was then added at 65 °C, and the mixture was stirred for 2 hours while cooling to 20 °C. The mixture was filtered, and the cake was washed twice with 173 mL of acetone. The cake was then allowed to dry in the 1724223 of 64 funnel overnight to produce 116.7 g of Example 2: 1H NMR (400 MHz, CDCh) δ 1.75-1.95 (m, 4H), 2.02-2.11 (m, 2H), 2.12-2.26 (m, 2H), 2.38 (q, J = 9.6 Hz, 2H), 2.93-3.12 (m, 4H), 3.12-3.22 (m, 1H), 3.28-3.39 (m, 1H), 3.533.65 (m, 1H), 3.80 (d, J = 5.6 Hz, 2H), 4.42 (t, J = 5.2 Hz, 1H), 4.82 (br d, J = 11.2 Hz, 2H), 6.47 (s, 1H), 8.62 (s, 2H);13C NMR (100 MHz, CDCh) δ 14.8, 30.0, 30.1, 30.6, 32.7, 44.3, 49.4, 59.1,68.2, 107.5, 129.1, 155.5, 159.0, 162.3, 170.5, 174.6. 3.3.2.1 Crystallization to give the anhydrous form A of Example 2 Preparation of seed crystals (anhydrous form A) Small amounts of crude Example 2 (1–2 mg) were suspended in approximately 0.1 mL of the following solvents: ethanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1-propanol, 2-butanol, and acetonitrile. After a heating / cooling cycle, the samples resulted in suspensions of the anhydrous crystalline form A as analyzed by X-ray powder diffraction. a. Crystallization from acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone: Approximately 1 g of the crude Example 2 is dissolved in 10 mL of a polar organic solvent such as acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone at a temperature >60°C. The solution is cooled to 30–40°C, and an antisolvent (approximately 5–10 mL) such as isopropyl alcohol, ethyl alcohol, or acetone is added. The solution is seeded with crystals of the anhydrous form A from Example 2 and cooled to 20°C. An additional amount of antisolvent (5–10 mL) is added to increase the yield. The resulting suspension is filtered within 1 hour of cooling, and the wet cake is dried at 60°C under vacuum. Anhydrous form A is obtained as a white solid, as confirmed by X-ray powder diffraction (XRPD) of the standard anhydrous form A on file. b. Crystallization from tetrahydrofuran / water: Approximately 1 g of the crude Example 2 is dissolved in 10 mL of a tetrahydrofuran / water mixture (8:2, v / v) at a temperature >60°C. The solution is cooled to 40–50°C, seeded with crystals of the anhydrous form A of Example 2, and further cooled to 20°C in less than 1 hour. Approximately 5–10 mL of antisolvent (an organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is filtered within 1 hour of the addition of the antisolvent, and the wet cake is dried at 60°C under vacuum. The anhydrous form A is obtained as a white solid, as confirmed by diffraction. 1724223 of 64 in X-ray powder (XRPD) of the standard anhydrous form A on file. c. Drying from the dihydrate: Approximately 1 g of the dihydrate form from Example 2 is washed with approximately 5 mL of an anhydrous solvent such as ethanol, methanol, isopropanol, or acetone in a Büchner funnel. The wet cake is then dried at 60 °C under vacuum. Anhydrous form A is obtained as a white solid, as confirmed by X-ray powder diffraction (XRPD) of standard anhydrous form A on file. 3.3.2.2 Crystallization to give the anhydrous form B of Example 2 Preparation of seed crystals of the anhydrous form B Small amounts of crude Example 2 (1–2 mg) were suspended in approximately 0.1 mL of mixtures of 2-propanol and water (one with 3.3% water and the other with 6.6% water). After a heating / cooling cycle, the samples resulted in suspensions of the crystalline anhydrous Form B by X-ray powder diffraction analysis. Samples in anhydrous 2-propanol subjected to the same conditions resulted in a mixture of Form A and Form B as analyzed by X-ray powder diffraction. A mixture of Form A and Form B, suspended at 20°C for 4 days in mixtures of water and the following solvents: methanol, ethanol, 2-propanol, 1-propanol, and acetone (all with approximately 9% water), resulted in Form B as analyzed by X-ray powder diffraction. a. Crystallization from n-propanol / water: g of crude Example 2 are dissolved in 160 mL of n-propanol / water mixture (9:1, v / v) at a temperature >65°C. The solution is cooled to 60°C, seeded with crystals of the anhydrous form B of Example 2, and allowed to stand for 0.5 hours. The suspension is then cooled to 30°C for at least 5 hours. Optionally, the suspension is distilled at 30°C under reduced pressure to reduce the volume to approximately 80–100 mL to maximize yield. The suspension is further cooled to 0°C and allowed to stand for at least 8 hours or until the anhydrous form A is no longer detectable. The suspension is filtered, and the wet cake is dried at 60°C under vacuum. The anhydrous form B of Example 2 is obtained as a white solid in 90% yield. X-ray powder diffraction (XRPD) corresponds to the standard anhydrous form B on file. b. Crystallization from tetrahydrofuran / water: Approximately 1 g of the crude Example 2 is dissolved in 10 ml of tetrahydrofuran / water mixture (8:2, v / v) at a temperature >60°C. The solution is cooled The slurry is seeded with crystals of anhydrous form B from Example 2, and then cooled to 20°C for 2 hours. Approximately 10 mL of antisolvent (an organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is allowed to stand for at least 8 hours or until anhydrous form A is no longer detectable. The slurry is then filtered, and the wet cake is dried at 60°C under vacuum. Anhydrous form B from Example 2 is obtained as a white solid. The X-ray powder diffraction (XRPD) corresponds to the standard anhydrous form B on file. c. Conversion from the dihydrate: Approximately 1 g of the Dihydrate of Example 2 is suspended in 5–10 mL of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with crystals of the anhydrous form B of Example 2 and stirred at 20–40 °C for at least 4 hours or until conversion to the anhydrous form B is complete, as monitored by X-ray powder diffraction (XRPD) analysis. d. Conversion from the anhydrous form A: Approximately 1 g of the anhydrous form A of Example 2 is suspended in 5–10 mL of an anhydrous solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with crystals of the anhydrous form B of Example 2 and stirred at 20–40 °C for at least 4 hours or until conversion to the anhydrous form B is complete, as monitored by X-ray powder diffraction (XRPD) analysis. 3.3.2.3 Crystallization to give the dihydrate form of Example 2 Preparation of seed crystals of the dihydrate form Mixing the crystals of anhydrous form A and anhydrous form B from Example 2, suspended at 20°C for 4 days in 2-butanone / water (with 9% water), resulted in the dihydrate crystals as confirmed by X-ray powder diffraction analysis. a. Crystallization from n-propanol / water: g of crude Example 2 are dissolved in 120 mL of an n-propanol / water mixture (8:2, v / v) at a temperature >65°C. The solution is cooled to 50°C, seeded with the dihydrate crystals from Example 2, and allowed to stand for 0.5 hours. Water (approximately 60–100 mL) is added to the slurry. The slurry is cooled to 20°C for at least 5 hours and then allowed to stand for at least 8 hours. The slurry is filtered, and the wet cake is washed with water and then dried. 1724223 of 64 with air. b. Crystallization in THF / water: Approximately 1 g of crude Example 2 is dissolved in 10 mL of tetrahydrofuran / water mixture (8:2, v / v) at a temperature >60°C. The solution is cooled to 30–50°C, seeded with the dihydrate crystals from Example 2, and further cooled to 20°C for 2 hours. Approximately 10 mL of water is added to the slurry. The resulting slurry is allowed to stand for at least 8 hours. The slurry is filtered, and the wet cake is washed with water and then air-dried. X-ray powder diffraction (XRPD) of the product shows the pattern of the dihydrate. c. Conversion from anhydrous form A or from anhydrous form B: Approximately 1 g of either anhydrous form A or anhydrous form B from Example 2 is suspended in approximately 5–10 mL of a mixture of at least 30% water and an organic solvent such as ethanol, methanol, isopropanol, acetone, or tetrahydrofuran. The suspension is seeded with the dihydrate crystals from Example 2 and stirred at 20°C for at least 4 hours or until conversion to the dihydrate form is complete, as monitored by X-ray powder diffraction (XRPD) analysis. The suspension is filtered, and the wet cake is washed with water and then air-dried. The polymorphs from Example 2 were characterized by X-ray powder diffraction (XRPD) as shown in Figures 3a, 3b, and 3c, which display the X-ray powder diffraction patterns and tables of all observable reflected peaks. A Rigaku Miniflex II instrument with a Power 450 W (30 kV-15 mA) X-ray generator (optics: variable divergence slit) was used for the X-ray powder diffraction analysis. The goniometer range was 3.0–35.0° 2θ, and the scan rate was 0.02° 2θ / minute with an accuracy of better than 0.01°. A foil / graphite filter was used as the monochromator, and a 23.0 mm diameter Nal scintillation counter was used as the detector. The sample was analyzed on a low-background Si(510) sample holder. The polymorphs from Example 2 were further classified by differential scanning calorimetry (DSC) using a TA Instruments DSC Q1000, as shown in Figures 4a, 5a, and 6a. The samples were analyzed in an unsealed aluminum crucible under a flow of N2. The ramp used for the measurements was 10°C / min from 20°C to 300°C. The polymorphs from Example 2 were further classified by thermogravimetric analysis (TGA) using a TA Instruments TGA Q500 as shown in the 1724223 of 64 Figures 4b, 5b, and 6b. The samples were analyzed in an open platinum sample crucible under N2 flow. The ramp used for the measurements was 10°C / minute from 20°C to 300°C. FIGURES: Fig. 1a: Gastric emptying for rats that had received Example 1 Fig. 1b: intestinal transit for rats that had received Example 1 Fig. 2a: Gastric emptying for rats that had received Example 2 Fig. 2b: intestinal transit for rats that had received Example 2 Fig. 3a: X-ray powder diffraction pattern of the anhydrous form A of Example 2 Fig. 3b: X-ray powder diffraction pattern of the anhydrous form B of Example 2 Fig. 3c: X-ray powder diffraction pattern of the dihydrate form C of Example 2 Fig. 4a: Differential scanning calorimetry (DSC) of the anhydrous form A of Example (DSC indicates a melting endotherm at approximately 235°C, followed by decomposition with continuous heating above the melting point) Fig. 4b: Thermogravimetric analysis (TGA) of the anhydrous Form A from Example 2 (TGA indicates unsolved form as shown by the negligible volatile content (minimal weight loss of (0.145%) up to the melting temperature) Fig. 5a: Differential scanning calorimetry (DSC) of the anhydrous form B of the Example (DSC indicates a simultaneous solid-solid transition or melting / recrystallization occurring at approximately 218°C. The resulting form is the most probable anhydrous form A as indicated by the melting exotherm at 235°C, corresponding to the melting point of form A. After melting of form A, the compound decomposes when heated above 240°C) Fig. 5b: Thermogravimetric analysis (TGA) of the anhydrous form B of Example 2 (TGA shows the negligible volatile content for form B (indicated unsolvated form) as shown by the minimal weight loss (0.057%) up to the melting temperature) Fig. 6a: Differential scanning calorimetry (DSC) of the dihydrate form C of Example 2 (DSC indicates low temperature dehydration according to the 1724223 of 64 indicated by the broad endotherm at <100°C. The dehydrated solid is most likely form A as indicated by the melt endotherm occurring at approximately 236°C characteristic of form A. Form A then decomposes when heated above the melting temperature). Fig. 6b: Thermogravimetric analysis (TGA) of the dihydrate form C from Example 2 (TGA shows a large weight loss for form C indicating dehydration by heating to <100°C. The dehydrated material (probably form A) shows almost no weight loss until melting (from 100°C to 236°C) consistent with previous observations for form A) EXAMPLES: The following examples were prepared in a manner analogous to the synthesis methods described from here on. Table A: Chemical structures of the example compounds in this 1724223 of 64 The following compounds A to D of the prior art are the structurally closest compounds disclosed in WO 2009 / 050248, which is the closest prior art document. Table B: Chemical structures of the structurally closest compounds disclosed in WO 2009 / 050248. Prior art compound Chemical structure Prior art compound A (=Example 2 of WO 2009 / 050248) ci / N \ / N \ XT x —< .ONS* h T o 1 HN. 7\ OH where S* means a sulfur atom representing a chiral center Prior art compound B (=Example 27 of WO 2009 / 050248) H ___ N Γ / > \ NN<^j / NX / ' Λ NS* T o 1 H N. / XOH where S* means a sulfur atom representing a chiral center Prior art compound C (=Example 34 of WO 2009 / 050248) NNNJ x NS* T o 1 HNK / \ OH where S* means a sulfur atom representing a chiral center 1724223 of 64 BIOLOGICAL EXPERIMENTS 5.1 Determination of ICsode PDE4B values ​​(in vitro): The IC50 values ​​of the compounds of the invention (Compounds 1 and 2 of the Examples) and of compounds A to D of the above-mentioned prior art with respect to their PDE4B inhibition ability have been determined by a Scintillation Proximity Assay (SPA) (GE Healthcare, No. TRKQ7090). The Scintillation Proximity Assay (SPA) is based on the detection of the different affinities of cyclic 3'-5'-adenosine monophosphate (cAMP, low affinity) and linear 5'-adenosine monophosphate (AMP, high affinity) for yttrium silicate scintillator beads. The cAMP-specific phosphodiesterase (PDE) PDE4B cleaves the 3'-phosphodiester bond of the yttrium-labeled [3H]AMP to [3H]5'-AMP. This [3H]5'-AMP associates with the scintillator beads due to its higher affinity and causes scintillations (bright flashes) that can be measured on a Wallac Microbeta Scintillation Counter. 1 pl of a [3H]cAMP solution (0.05 pCi in H2O, 10 - 30 Ci / mmol) are added to 89 pl of a PDE4B enzyme solution (site-active fragment comprising amino acids 152 - 484; 0.15 - 0.18 ng) in assay buffer (Tris HCl 50 mM pH 7.5; MgCl2 8.3 mM; 1.7 mM ethylene glycol tetraacetic acid (EGTA); 0.25 mg / ml bovine serum albumin (BSA)) and this mixture is incubated at 30 °C for one hour a) without the compound to be tested (in the presence of 1 pl of dimethyl sulfoxide (DMSO), corresponding to 1% DMSO) and b) in the presence of the compound to be tested at a concentration of 125 pM, 25 pM, 5 pM, 1 pM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM, 0.0128 nM (5-step dilution series starting from 125 pM down to 0.0128 nM, in the presence of 1% DMSO). 1724223 of 64 After this incubation, the reaction is stopped by adding 50 µL of bead solution (500 mg of beads / 35 mL of H₂O, 18 mM sulfate). Over the next 45 minutes, the beads have the opportunity to form a sediment. After this, the scintillations are measured using a scintillation counter. If the tested compound is able to inhibit the enzymatic activity of PDE4B, less [3H]AMP is produced, depending on the concentration of the tested compound, and fewer scintillations are measurable. These results are expressed as IC50 values. The IC50 value represents the concentration of the compound at which the enzymatic activity of PDE4B is inhibited to half its maximum value. Therefore, the lower the IC50 value, the better the inhibition of PDE4B. Table C: Experimentally determined IC50 values ​​with respect to PDE4B inhibition for the compounds of the invention and for the compounds of the prior art as disclosed in WO 2009 / 050248 Compound Experimentally determined IC50 value for PDE4B inhibition [nM] Example 1 4.3 Example 2 7.2 Prior art Compound A 3.3 Prior art Compound B 66 Prior art Compound C 44 Prior art Compound D 7.3 Only compounds A and D from the prior art have IC50 values ​​in the same potency range as Examples 1 and 2. Consequently, all other experiments have been carried out only with Examples 1 and 2 and with compounds A and D from the prior art. 5.2 Determination of the dose-response relationship and calculation of the mean maximum effective dose with respect to LPS-induced inhibition of neutrophil influx in the bronchoalveolar lavage fluid of male Wistar rats The anti-inflammatory activity of Examples 1 and 2 and of compounds A and D from the prior art was evaluated in an in vivo LPS-induced lung inflammation model in rats. As a measure of the pharmacological potency of the compounds mentioned above, the median maximum effective dose (ED50) with respect to the inhibition of lipopolysaccharide-induced neutrophil influx (LPS-induced) in bronchoalveolar lavage fluid (BALF) was determined by evaluating the dose-response relationship. Bacterial endotoxins (lipopolysaccharides [LPS]) are components of the membrane.34 1724223 of 64 external bacterial cells that play an important role in the pathogenesis of gram-negative bacterial infections. Inhalation of such aerosolized LPS is known to induce a dose-dependent increase in neutrophils in lung tissue and air spaces in rats, which can be detected by analyzing the number of neutrophils in bronchoalveolar lavage fluid (BALF). However, this dose-dependent increase in neutrophils in BALF should be reduced in a dose-dependent manner in the presence of an effective PDE4 inhibitor. Male Wistar rats (HanWistar) from an approved local distributor were used for the experiments. The ordered weight of the animals ranged from 200 to 250 g. The animals were fasted overnight before the experiment. A total of 32 animals were used for each experiment. Eight animals (n=8) per dose were used for the treatment groups, two animals were used for the LPS control (positive control), and two animals for the negative control. The animals in the LPS control and negative control groups received "vehicle only" ("vehicle only" corresponds to 10 ml / kg body weight of 0.5% Natrosol solution). The other groups were treated with different doses of Example Compound 1, Example Compound 2, prior art Compound A, or prior art Compound D, respectively (see Table D). The amount of compound for the highest concentration tested for each compound was suspended in 10 ml of 0.5% Natrosol solution (Hydroxyethylcellulose) and then diluted to the respective concentrations as shown in Table D. The respective compound suspension or “vehicle only” (10 ml / kg body weight of 0.5% Natrosol solution) was administered orally by gag feeding. The resulting dosage for the individual compounds corresponded to Table D. Table D: Compounds tested and their respective doses Compound Dose (mg / kg) Stock Solution Concentration (mg / ml) Example 1 0.3 1.0 3.0 0.3 Example 2 0.01 0.10 1.00 0.1 Prior Art Compound A 0.3 1.0 3.0 0.3 Prior Art Compound D 0.3 1.0 3.0 0.3 The above doses were determined based on previous trials in the LPS TNF ex vivo mouse model. One hour (0.5 hours for compound A of the prior art and for compound D) (1724223 of 64 of the prior art) After application of the compound (time set to allow sufficient exposure as instructed by previous pharmacokinetic experiments), the animals were exposed to nebulized / aerosolized LPS. Whole-body exposure of 12 animals each was carried out in a Plexiglas chamber. The animals were separated / individualized with perforated metal plates. The aerosol was generated with a commercially available nebulizer (PARI Master + PARI LL nebulizer (Pari GmbH)). The concentration of the nebulized LPS solution was 1 mg / ml of air. The duration of LPS exposure was 30 minutes. Hours after the completion of LPS exposure, the animals were anesthetized with isoflurane and subsequently euthanized by cervical dislocation. The trachea was cannulated, and BALF was performed using 2 x 5 ml of wash buffer (phosphate-buffered saline (PBS) + 2% BSA). The neutrophil content of the BALF was determined using an ADVIA 120 blood hematometer (Bayer Diagnostics). Neutrophil data were normalized (Positive Control (=LPS treatment only) = 100%, Negative Control (no LPS treatment, administration of the “vehicle only”) = 0%) and expressed as a percentage of the LPS control. The ED50 was calculated using a nonlinear device (with GraphPad Prism software and a sigmoidal dose-response device). The ED50 value is the median maximum effective dose of the compound in question with respect to its inhibition of LPS-induced neutrophil influx in BALF. Consequently, a very small ED50 value indicates a good ability of the respective compound to prevent neutrophil influx into lung tissue after LPS exposure and, therefore, a good ability of the respective compound to prevent lung tissue inflammation. Because the ED50 value, unlike the IC50 value, is not the result of an in vitro assay but rather the result of an in vivo assay conducted in rats, and because it measures not only the direct inhibition of the PDE4B enzyme but also the neutrophil influx into lung tissue after LPS exposure, the ED50 value is a highly sensitive parameter for assessing a compound's suitability as a therapeutic agent in inflammatory airway diseases such as COPD and asthma (both of which are inflammatory diseases). Exposure of rats to LPS led to a different influx of neutrophils into the BALF. Pretreatment of rats with compounds Example 1, Example 2, prior art compound A, and prior art compound D led to inhibition of 1724223 of 64 LPS-induced neutrophil influx in BALF. The calculated ED50 values ​​for the various compounds are provided in Table E. Table E: ED50 values ​​of the tested compounds calculated from the experimental data: Compound ED50 (mg / kg body weight) Example 1 0.31 Example 2 0.1 Prior art Compound A 1.13 Prior art Compound D 6.66 The experimentally determined ED50 values ​​for the compounds of the invention - meaning for Example 1 (ED50 = 0.31 mg / kg body weight) and for Example 2 (ED50 = 0.1 mg / kg body weight) - demonstrate that these compounds of the invention, Example 1 and Example 2, are between 3 and 66 times more potent in this assay than compounds A and D of the prior art. Therefore, the compounds of the invention show a better potency to prevent the influx of neutrophils into lung tissue and are thus much more appropriate to be used as a therapeutic agent to treat inflammatory respiratory diseases such as asthma and COPD. 5.3 Gastric emptying and gastrointestinal transit in conscious rats In order to identify an active agent that is appropriate to serve as a therapeutic inhibitor of PDE4, it is necessary to determine whether the compound in question is effective at a dose that does not cause significant gastrointestinal side effects. Gastrointestinal side effects are known to be prominent within the field of PDE4 inhibitors (see Diamant, Z., Spina, D.; “PDE4-inhibitors: a novel targeted therapy for obstructive airways disease”, Pulm. Pharmacol. Ther. 2011, 24 (4), pages 353-360 and Press, NJ; Banner, KH; “PDE4 Inhibitors - A Review of the Current Field”; Progress in Medicinal Chemistry 2009, 47; pages 3774). Experiments 1.1 and 1.2 above have shown that the compounds of the invention are clearly more potent with respect to the enzymatic inhibition of PDE4B and / or more potent with respect to the prevention of neutrophil influx into lung tissue and are therefore advantageous with respect to the structurally related compounds disclosed in WO 2009 / 050248, in particular in comparison with Compounds A, B, C and D. In order to evaluate whether the compounds of the present invention lead to effects 1724223 of 64 gastrointestinal collaterals The compounds of the invention were administered to rats 30 minutes before the rats were fed a test meal comprising barium sulfate. After this, it was tested whether gastric emptying and / or gastrointestinal transit in these rats was affected by the presence of these compounds. The effects of compounds Example 1 and Example 2 on gastric emptying and gastrointestinal transit in conscious rats have been investigated as described below. Wistar rats of both sexes, weighing 130–160 g (ages: male 7 weeks, female 8 weeks), were used. The animals were obtained from an approved local distributor and required a minimum four-day quarantine period prior to use, during which time they were kept under routine animal care procedures. Groups of up to five animals were housed in cages in a temperature- and humidity-controlled room with a light / dark cycle, with lights on from 6:00 a.m. to 6:00 p.m. The animals had access to standard rodent food and water ad libitum. The animals were transported to the laboratory on the day of the experiment. Gastric emptying as well as small bowel propulsion are determined using a barium sulfate test meal. Five Crl:WI(Han) rats of each sex (n=10) were used. The animals were deprived of food 17 hours before the experiment but were allowed free access to water. The investigational drug (drug was suspended to a concentration of 10 ml / kg body weight in 0.5% Natrosol solution) or the negative control (vehicle only, 10 ml / kg body weight was provided) was administered 30 minutes (orally) before the trial meal in doses calculated to be 3 times, 10 times, or 30 times the ED50 found in the rat efficacy studies. Compound Dose 3 times ED50 [mg / kg body weight orally] Dose 10 times ED50 [mg / kg body weight orally] Dose 30 times ED50 [mg / kg body weight orally] Example 1 (ED50 = 0.31 mg / kg body weight) 1.0 3.0 10.0 Example 2 (ED50 = 0.1 mg / kg body weight) 0.3 1.0 3.0 1724223 of 64 The test meal (a suspension of 7.5 g of barium sulfate in 10 ml of salt-free water) was administered orally by feeding at a dose of 2 ml / 100 g of body weight. Thirty minutes after administration of the test meal, the animals were euthanized under deep isoflurane anesthesia by cervical dislocation. The stomach and intestine were then exposed by laparotomy and removed. The removed stomach was weighed, then an incision was made, the contents were removed, and the empty stomach was weighed again. The length of the intestines traversed with barium sulfate in relation to the total length of the intestines is determined by direct measurements using a ruler. Gastric emptying assessment Gastric contents were calculated from the weight difference between the full and empty stomach and normalized to 100 g of body weight. Thus, an increase in the weight difference indicated impaired gastric emptying, while a reduction in the weight difference indicated improved gastric emptying. Intestinal transit assessment The length of the intestines traversed with barium sulfate (according to the criterion of visual inspection) in relation to the complete length of the intestines (from the pylorus to the rectum) is determined by direct measurements using a ruler. Intestinal transit time is calculated as the percentage movement of barium sulfate in the intestine relative to the total length of the intestines. Consequently, an increase in intestinal transit time indicates an acceleration of intestinal transit, while a reduction in intestinal transit time indicates a deceleration of intestinal transit. Statistics Data are expressed as mean ± standard deviation (SD). For each dose, comparisons were made using analysis of variance (ANOVA) and a subsequent Dunnett test to compare the various groups with controls when ANOVA was significant. p < 0.05 was considered significant. Consequently, the compounds of the invention do not show any statistically significant gastrointestinal side effects, even at doses up to 30 times the ED50 dose, because, as shown in Fig. 1a and 2b, none of the rats that received Example 1 or 2 showed substantial improvement or deterioration. 1724223 of 64 in gastric emptying nor a substantial acceleration or deceleration in intestinal transit even at doses up to 30 times the ED50 dose. For Example 1, gastric emptying showed no relevant difference at a dose 3 times ED50 and at a dose 10 times ED50, and only a very moderate improvement in the weight-for-body-weight difference at a dose 30 times ED50. However, intestinal transits for the corresponding animals that received the compound from Example 1 showed no significant difference compared to those intestinal transits of the negative controls even up to a dose of 30 times ED50. For Example 2, both gastric emptying and intestinal transit showed no relevant difference compared to the negative control during all tested doses of the compound in Example 2, not even at the dose 30 times ED50. Consequently, the compounds of the invention are not only more potent with respect to the inhibition of PDE4B than the compounds disclosed in WO 2009 / 050248 (as shown in Experiments 1.1 and 1.2), but they also do not show any relevant gastrointestinal side effects. 6. INSTRUCTIONS The compounds of formula I have broad potential in various therapeutic fields. Particular mention should be made of those applications for which the compounds according to the invention of formula I are particularly suitable due to their pharmaceutical efficacy as PDE4 inhibitors. Examples include respiratory or gastrointestinal diseases or ailments, inflammatory diseases of the joints, skin, or eyes, cancers, and also diseases of the central or peripheral nervous system. Special mention should be made of the prevention and treatment of airway and lung diseases accompanied by increased mucus production, inflammation, and / or obstructive airway diseases. Examples include acute, allergic, or chronic bronchitis, chronic obstructive bronchitis (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways, infectious bronchitis or pneumonitis, pediatric asthma, bronchiectasis, pulmonary fibrosis, ARDS (acute respiratory distress syndrome in adults), bronchial edema, pulmonary edema, bronchitis, pneumonia, or interstitial pneumonia driven by various causes, such as aspiration. 1724223 of 64 inhalation of toxic gases, or bronchitis, pneumonia or interstitial pneumonia as a result of heart failure, radiation, chemotherapy, cystic fibrosis or mucoviscidosis, or alpha1-antitrypsin deficiency. Also worthy of special mention is the treatment of inflammatory diseases of the gastrointestinal tract. Examples include acute or chronic inflammatory changes such as gallbladder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, deep cystic colitis, pneumatosis cystoides intestinalis, diseases of the bile duct and gallbladder (e.g., gallstones and gallbladder conglomerates), inflammatory diseases of the joints such as rheumatoid arthritis, and inflammatory diseases of the skin and eyes. Special mention should also be made of the treatment of sarcoidosis. Special mention should also be made of the treatment of cancers. Examples include all forms of acute and chronic leukemias, such as acute myeloid and acute lymphoblastic leukemia, chronic myeloid and chronic lymphoblastic leukemia, as well as bone tumors such as osteosarcoma and all types of gliomas, such as oligodendroglioma and glioblastoma. Special attention should also be given to the prevention and treatment of diseases of the central and peripheral nervous systems. Examples include depression, manic or bipolar depression, chronic and acute anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, chronic and acute multiple sclerosis, chronic and acute pain, and brain injuries caused by stroke, hypoxia, or traumatic brain injury. The present invention particularly relates to the use of compounds of formula I to prepare a pharmaceutical composition for the treatment of obstructive or inflammatory diseases of the upper and lower respiratory tract including the lungs, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, alpha-1-antitrypsin deficiency, particularly COPD, chronic bronchitis and asthma. It is much more preferable to use the compounds of formula I for the treatment of obstructive and inflammatory diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, particularly COPD, chronic bronchitis and asthma. 1724223 of 64 It is also preferable to use the compounds of formula I for the treatment of diseases of the central or peripheral nervous system such as depression, manic or bipolar depression, chronic and acute anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, chronic and acute multiple sclerosis or chronic and acute pain as well as brain injuries caused by stroke, hypoxia or head trauma. It is also preferable to use the compounds of formula I for the treatment of inflammatory eye diseases, particularly for the treatment of “dry eye” syndrome and glaucoma. Individuals with “dry eye” syndrome suffer from ocular discomfort (dry, gritty sensation; itching; burning / stinging; pain / irritation) and blurred vision. Phosphodiesterase 4 (PDE4) enzymes regulate a host's biological processes by degrading the second messenger cAMP. PDE4 inhibitors have been intensively investigated as anti-inflammatory therapies because increases in cAMP levels are known to attenuate inflammatory responses in multiple cell types (see Govek et al., Bioorganic & Med. Chem. Lett. 20, (2010), pp. 2928–2932). Furthermore, it is also preferable to use the compounds of formula I for the treatment of eye diseases, particularly for the treatment of glaucoma, since an increase in AMPs has been shown to protect retinal ganglion cells from cell death induced by high intracellular pressure (IOP) (see Seki T. et al, J Mol Neurosci. 2011 Jan;43(1):30-4.), and an increase in cAMP is involved in the reduction of IOP (see Naveh N. et al., Br J Ophthalmol. 2000 Dec;84(12):1411-4), the main reason for the development of glaucoma. 7. Combinations The compounds of formula I can be used alone or in conjunction with other active substances of formula I according to the invention. If desired, the compounds of formula I can also be used in combination with other pharmacologically active substances. It is preferable to use for this purpose active substances selected, for example, from among beta-mimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, MRP4 inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3-kinase inhibitors, NSAIDs, COX-2 inhibitors, EP4 receptor antagonists, DPP4 inhibitors, or double or triple combinations thereof, such as, for example, combinations of the compounds of formula I with one or two compounds selected from among 1724223 of 64 • EP4 receptor antagonists, DPP4 inhibitors, NSAIDs, inhibitors of COX-2 inhibitors and corticosteroids, • beta-mimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, and LTD4 antagonists, • anticholinergics, beta-mimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, and LTD4 antagonists, • PDE4 inhibitors, corticosteroids, EGFR inhibitors, and LTD4 antagonists LTD4 • EGFR inhibitors, PDE4 inhibitors and LTD4 antagonists • EGFR inhibitors and LTD4 antagonists • CCR3 inhibitors, iNOS inhibitors (inducible nitric oxide synthase inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as BH4) and derivatives thereof as referred to in WO 2006 / 120176 and SYK inhibitors (spleen tyrosine kinase inhibitors) • anticholinergics, beta-mimetics, corticosteroids, PDE4 inhibitors and MRP4 inhibitors. The invention also relates to combinations of three active substances, each chosen from one of the categories of compounds mentioned above. The betamimics used are preferentially selected compounds among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharina, isoprenalina, levosalbutamol, mabuterol, meluadrina, metaproterenol, orciprenalina, pirbuterol, procaterol, reproterol, rimiterol, ritodrina, salmeterol, salmefamol, soterenol, sulfonterol, tiaramida, terbutalina, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hidroxy-2-(4-hidroxy-3-hidroxymetil-phenyl)-ethylamino]hexiloxy}-butyl)-bencil-sulfonamida, 5-[2-(5,6-dietyl-indan-2-ilamino)-1-hidroxy-etil]-8hidroxy-1H-quinolin-2-ona, 4-hidroxy-7-[2-{[2-{[3-(2-phenyletoxy)propyl]sulfonil}etil]amino}etil]-2(3H)-benzotiazolona, ​​1-(2-fluoro-4-hidroxyfenil)-2-[4-(1-benzimidazolyl)-2metil-2-butylamino]etanol, 1-[3-(4-metoxibencil-amino)-4-hidroxyfenil]-2-[4-(1benzimidazolyl)-2-methyl-2-butylamino]etanol, 1-[2H-5-hidroxy-3-oxo-4H-1,4-benzoxazin8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-methyl-2-propilamino]etanol, 1-[2H-5-hidroxi-3-oxo4H-1,4-benzoxazin-8-il]-2-[3-(4-metoxifenil)-2-methyl-2-propilamino]etanol, 1-[2H-5hidroxi-3-oxo-4H-1,4-benzoxazin-8-il]-2-[3-(4-n-butiloxifenil)-2-metil-243, 1724223 of 64 propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5trifluoromethylphenyl)-2-tert-butylamino)ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(ethyl 4phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1hydroxy-2-[2-(ácido 4-phenoxy-acetico)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4Hbenzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1 -hydroxy-2-[2-(4-isopropyl-phenyl)1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethylethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, acid 4-(4-{2[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methylpropyl}-phenoxy)-butyric, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6hydroxy-4H-benzo[1,4]oxazin-3-one and 1 -(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2(tert-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of acidic addition salts acceptable for pharmacological use, solvates or hydrates thereof. According to the invention, the acidic addition salts of the beta-mimetics are preferably selected from among hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate. Of the acidic addition salts mentioned above, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid, and acetic acid are particularly preferred according to the invention. The anticholinergics used are preferably compounds selected from among the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3',4,4'-tetrafluorobenzylate methobromide, scopine 3,3',4,4'-tetrafluorobenzylate methobromide, tropenol 4,4'-difluorobenzylate methobromide, methobromide of 1724223 of 64 scopine 4,4'-difluorobenzylate, tropenol methobromide 3,3'-difluorobenzylate, scopine methobromide 3,3'-difluorobenzylate, tropenol methobromide 9-hydroxyfluorene-9-carboxylate, tropenol methobromide 9-fluorofluorene-9-carboxylate, scopine methobromide 9-hydroxyfluorene-9-carboxylate, scopine methobromide 9fluorofluorene-9-carboxylate, tropenol methobromide 9-methylfluorene-9-carboxylate, scopine methobromide 9-methylfluorene-9-carboxylate, cyclopropyltropine methobromide benzylate, cyclopropyltropine methobromide 2,2-diphenylpropionate, cyclopropyltropine methobromide 9-hydroxy-xanthene-9-carboxylate, cyclopropyltropine methobromide 9-methyl-fluorene-9-carboxylate, cyclopropyltropine methobromide 9methyl-xanthene-9-carboxylate, cyclopropyltropine methobromide 9-hydroxy-fluorenecarboxylate, cyclopropyltropine methobromide methyl 4,4'difluorobenzylate, tropenol methobromide 9-hydroxy-xanthene-carboxylate,Scopine methobromide 9-hydroxy-xanthene-9-carboxylate, tropenol methobromide 9-methyl-xanthene-9-carboxylate, scopine methobromide 9-methyl-xanthene-9-carboxylate, tropenol methobromide 9-ethyl-xanthene-9-carboxylate, tropenol methobromide 9-difluoromethyl-xanthene-9-carboxylate, scopine methobromide 9-hydroxymethyl-xanthene-9-carboxylate, optionally in the form of solvates or hydrates thereof. In the salts mentioned above, the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium, and trospium are the pharmacologically active ingredients. As anions, the salts mentioned above may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, or p-toluenesulfonate, while chloride, bromide, iodide, sulfate, methanesulfonate, or p-toluenesulfonate are preferred as counterions. Of all the salts, chlorides, bromides, iodides, and methanesulfonate are particularly preferred. Tiotropium bromide is of particular importance. In the case of tiotropium bromide, the pharmaceutical combinations according to the invention preferably contain it in the form of crystalline tiotropium bromide monohydrate, which is known from WO 02 / 30928. If tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03 / 000265. The corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butyxocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, 1724223 of 64 rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, (S)fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and / or hydrates thereof. Particularly preferred is the steroid selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl 6,9-difluoro-17-[(2furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxiandrosta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and / or hydrates thereof. Any reference to steroids includes a reference to any salt, derivative, hydrate, or solvate thereof. Examples of possible steroid salts and derivatives include: alkali metal salts, such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates thereof. Other PDE4 inhibitors that can be used are preferably made up of enprofilin, theophilin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrine, lirimilast, arofilin, atizoram, D-4396 (Sch-351591), AWD-12281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370,N-(3,5-dichloro1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamida, (-)p-[(4aR*,10bS*)-9etoxi-1,2,3,4,4a,10b-hexahidro-8-methoxi-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,Ndiisopropylbenzamida, (R)-(+)-1-(4-bromobencyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2pyrrolidona, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methylisothioureido]bencyl)-2-pyrrolidona, metoxiphenil)ciclohexano-1-carboxílico], difluorometoxiphenil)ciclohexano-1-ona, difluorometoxifenil)ciclohexan-1-ol], metoxiphenil)pyrrolidin-2-ylideno]acetate, metoxiphenil)pirrolidin-2-ylideno]acetate, cis[ácido 4-cyano-4-(3-cyclopentyloxy-4 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4cis[4-cyano-4-(3-cyclopropylmethoxy-4(R)-(+)-ethyl[4-(3-cyclopentyloxy-4(S)-(-)-ethyl[4-(3-cyclopentyloxy-49-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H 1724223 of 64 pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the acidic addition salts acceptable for pharmacological use, solvates and / or hydrates thereof. By acidic addition salts with acids acceptable for pharmacological use that the above-mentioned PDE4 inhibitors could be in a position to form, for example, salts selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. The EP4 receptor antagonists that can be used are preferably compounds selected from [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinoline-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide]; 5-butyl-2,4-dihydro-4-[[2'-[N-(3-methyl-2-thiophene-carbonyl)sulfamoyl]biphenyl-4-yl]methyl]-2-[(2trifluoromethyl)phenyl]-1,2, 4-triazol-3-on; (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid; N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4methylbenzolsulfonamide; 4-[[4-(5-methoxy-2-pyridinyl)phenoxy]methyl]-5-methyl-N-[(2-methylphenyl)sulfonyl]-2-furan carboxamide; 11alpha,15alpha-dihydroxy-16-(3-methoxymethylphenyl)-9-oxo-17,18,19,20-tetranor-5-thia-13(E) prostanoic acid methyl ester; 4-Cyano-2-[[2-(4-fluoro-1-naphthalenyl)-1-oxopropyl]amino]-benzene butyric acid and N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulfonamide. The NSAIDS that can be used are preferably compounds selected from among Aceclofenac, Acemetacin, Acetylsalicylic acid, Alclofenac, Alminoprofen, Amphenac, Ampiroxicam, Antolmethingoacil, Anirolac, Anthrafenin, Azapropazone, Benorilat, Bermo, Biprofen, Buprofen, Bromfenac Bucolom, Bufexamac, Bumadizon, Butibufen, Butixirate, Carbasalatecalcium, Carprofen, Choline Trisalicylate of Magnesium, Celecoxib, Cinmethacin, Cinnoxicam, Clidanac, Clobuzarit, 1724223 of 64 Deboxamet, Dexibuprofeno, Dexketoprofeno, Diclofenac, Diflunisal, Droxicam, Eltenac, Enfenaminsaure, Etersalato, Etodolac, Etofenamato, Etoricoxib, Feclobuzon, Felbinac, Fenbufeno, Fenclofenac, Fenoprofeno, Fentiazac, Fepradinol, Feprazon, Flobufeno, Floctafenina, Flufenaminsaure, Flufenisal, Flunoxaprofeno, Flurbiprofeno, Flurbiprofenaxetil, Furofenac, Furprofeno, Glucametacina, Ibufenac, Ibuprofeno, Indobufeno, Indometacina, Indometacinfarnesil, Indoprofeno, Isoxepac, Isoxicam, Ketoprofeno, Ketorolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofeno, Lumiracoxib, Meclofenaminsaure, Meclofeno, Mefenaminsaure, Meloxicam, Mesalazina, Miroprofeno, Mofezolac, Nabumeton, Naproxeno, Nifluminsaure, Olsalazin, Oxaprozina, Oxipinac, Oxifenbutazona, Parecoxib, Fenilbutazona, Pelubiprofeno, Pimeprofeno, Pirazolac, Priroxicam, Pirprofeno, Pranoprofeno, Prifelona, Prinomod, Proglumetacina, Proquazona, Protizininsaure, Rofecoxib, Romazarit, Salicilamid, Salicylsaure, Salmistein, Salnacedina, Salsalat,Sulindac, Sudoxicam, Suprofen, Talniflumate, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensaure, Taramid, Tilnoprofenarbamel, Timegadine, Tinoridine, Tiopinac, Tolfenaminsaure, Tolmetin, Ufenamate, Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen. The COX2 inhibitors (Coxibes) that can be used are preferably compounds selected from Celecoxib, Meloxicam, Etoricoxib, Lumiracoxib, Parecoxib, Rofecoxib, and Valdecoxib. The LTD4 antagonists that can be used are preferably compounds selected from montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid, 1-(((1(R)-3(3-(2-(2,3-dichlorothiene[3,2b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-ethylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid, and [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the acidic addition salts acceptable for pharmacological use and optionally in the form of the salts and derivatives, solvates and / or hydrates thereof. By acidic addition salts with acids acceptable for pharmacological use that LTD4 antagonists may be able to form means, for example, salts selected from among hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, 1724223 of 64 hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. By salts or derivatives that LTD4 antagonists may be able to form means, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. The EGFR inhibitors used are preferably composed of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2buten-1-yl]amino}-7-cyclopentyloxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxi]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxomorfolin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7cyclopentyloxy-quinazoline, 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis-(2-methoxyethyl)amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, 4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, 4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, 4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4, 1724223 of 64 fluorofenil)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)(tetrahidrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxyethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hidroxy-phenyl)-7H-pyrrolo[2,3d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-bencyloxy)-phenyl]amino}-6-(5{[(2-methanesulfonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynyl-fenil)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2buten-1-yl]amino}-quinazolina, 4-[(3-chloro-4-fluoro-fenil)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazolina, 4-[(3-chloro-4-fluoro-fenil)amino]-6-[2-(2,2dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazolina, 4-[(3cloro-4-fluoro-fenil)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)(tetrahydrofuran-2-yl)methoxy]-quinazolina, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxomorpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(2-acetylamino-ethyl)piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro, 1724223 de 64 phenyl)amino]-6-(tetrahidropyran-4-iloxi)-7-(2-acetylamino-ethoxi)-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-(tetrahidropyran-4-iloxi)-7-(2-methanesulfonylamino-ethoxy)quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4iloxi}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethylpiperidin-4-iloxi)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohexan-1-iloxi)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-iloxi)-7ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline, 4-[(3-cloro-4-fluoro-fenil)amino]-6-(cis-4{N-[(piperidin-1-yl)carbonyl]-N-metil-amino}-ciclohexan-1-yloxy)-7-methoxy-quinazolina, 4[(3-chloro-4-fluoro-fenil)amino]-6-(cis-4-{N-[(4-metil-piperazin-1-yl)carbonyl]-N-metilamino}-ciclohexan-1-yloxy)-7-methoxy-quinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{cis4-[(morpholin-4-yl)carbonylamino]-ciclohexan-1-yloxy}-7-methoxy-quinazolina, 4-[(3-cloro-4fluoro-fenil)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxyquinazolina,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylaminocyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynylphenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynylphenyl)amino]-6-(1-(2methoxy-acetyl)-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy51, 1724223 of 64 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-iloxi)-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]piperidin-4-iloxi}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3methoxypropyl-amino)-carbonyl]-piperidin-4-iloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-iloxy]-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)cyclohexan-1-iloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-Nmethyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the acidic addition salts acceptable for pharmacological use thereof,the solvates and / or hydrates thereof. By acidic addition salts with acids acceptable for pharmacological use that EGFR inhibitors may be able to form means, for example, salts selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. Examples of dopamine agonists that may be used preferentially include compounds selected from bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride, and viozan. Any reference to the above-mentioned dopamine agonists within the scope of the present invention includes a reference to 1724223 of 64 any of the acidic addition salts acceptable for pharmacological use and optionally hydrates thereof that may exist. By acidic addition salts acceptable for physiological use that may be formed from the dopamine agonists mentioned above, it is meant, for example, salts acceptable for pharmaceutical use that are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid. Examples of H1 antihistamines preferably include compounds selected from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine, and meclizine. Any reference to the above-mentioned H1 antihistamines within the scope of the present invention includes a reference to any of the pharmacologically acceptable acidic addition salts that may exist. Examples of PAF antagonists preferably include compounds selected from 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6Hthiene-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thiene-[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepines. The MRP4 inhibitors used are preferably compounds selected from N-acetyldinitrophenylcysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulfate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide, estradiol 3,17-disulfate, estradiol 3-glucuronide, estradiol 3-sulfate, estrone 3-sulfate, flurbiprofen, folate, N5-formyltetrahydrofolate, glycocholate, lithocholic acid sulfate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulfate, methotrexate, MK571 ((E )-3-[[[3-[2(acid 7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]propanoic acid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulfate, topotecan, trequinsine and zaprinast, dipyridamole, optionally in the form of the racemates,enantiomers, diastereomers and the acidic addition salts acceptable for pharmacological use and hydrates thereof. 1724223 of 64 By acid addition salts with acids acceptable for pharmacological use means, for example, salts selected from among hydrochlorides, hydrobromides, hydroiodides, hydrosulfates, hydrophosphates, hydromethanesulfonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydroxalates, hydrosuccinates, hydrobenzoates and hydrop-toluenesulfonates, preferably hydrochlorides, hydrobromides, hydrosulfates, hydrophosphates, hydrofumarates and hydromethanesulfonates. The compounds that can be used as iNOS inhibitors are compounds selected from among: S-(2-aminoethyl)isothiourea, aminoguanidine, 2aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, Smethylisothiourea, S-ethylisothiourea,; S-methylthiocitrulline, S-ethylthiocitrulline, L-NA (N“-nitro-Larginine), L-NAME (N“-nitro-L-arginine methyl ester), L-NMMA (NG-monomethyl-L-arginine), L-NIO (N“-iminoethyl-L-ornithine), L-NIL (N“-iminoethyl-lysine), acid (S)-6acetymidoylamino-2-amino-hexanoic (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45, 1686-1689), 1400W, (S)-4-(2-acetymidoylamino-ethylsulfanyl)-2-aminobutyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600), 2-[2-(4-methoxypyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) (Mol. Pharmacol. 2006, 69, 69). 328-337), 2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO 01 / 62704), 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile (WO 2004 / 041794), 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-4-chlorobenzonitrile (WO 2004 / 041794), 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)5-chlorobenzonitrile (WO 2004 / 041794), (2S,4R)-2-amino-4-(2-chloro-5-trifluoromethylphenylsulfanyl)-4-thiazol-5-yl-butan-1-ol (WO 2004 / 041794), 2-((1R,3S)-3-amino-4-hidroxi1-thiazol-5-yl-butylsulfanyl)-5-chloro-nicotinonitrile (WO 2004 / 041794), 4-((S)-3-amino-4hidroxi-1-phenyl-butylsulfanyl)-6-methoxy-nicotinonitrile (WO 02 / 090332), 3-phenyl-3,4-dihydro1-isoquinolinamine replaced as follows by example AR-C102222 (J. Med. Chem. 2003, 46, 913-916), (1S,5S,6R)-7-chloro-5-methyl-2-aza-bicyclo[4,1,0]hept-2-en-3-ylamine (ONO1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R,5R)-5-ethyl-4-methylthiazolidin-2-ylidenoamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methylselenazolidin-2-ylidenoamine (Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4aminotetrahidrobiopterin (Curr. Drug Metabol. 2002, 3, 119-121), (E)-3-(4-chloro-phenyl)N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin2-yl-ethyl)-acrylamida (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2,4-difluorophenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine (PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl 3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4. 1724223 de 64 (2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), acid (R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidina-2-carboxílico (2benzo[1,3]dioxol-5-yl-ethyl)-amida (BBS-2) (Drugs Future 2004, 29, 45-52) and sales faracéuticas, profármacos o solvatos de los mismos. Examples of iNOS inhibitors within the scope of the present invention may also include antisense oligonucleotides, particularly those antisense oligonucleotides that bind to nucleic acids encoding iNOS. For example, WO 01 / 52902 describes antisense oligonucleotides, particularly antisense oligonucleotides, that bind to nucleic acids encoding iNOS to modulate iNOS expression. The iNOS antisense oligonucleotides as described in WO 01 / 52902 may therefore also be combined with the PDE4 inhibitors of the present invention due to their similar effect on iNOS inhibition. The compounds that can be used as SYK inhibitors are preferably selected compounds of: 2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide; 2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl]amino]-3-pyridinecarboxamide; 6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2b]-1,4-oxazin-3(4H)-one; N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine 7-(4-methoxyphenyl)-N-methyl-1,6-naphthyridin-5-amine; N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-(2-thienyl)-1,6-naphthiridin-5-yl-1,3-propanediamine; N-[7-[4-(dimethylamino)fenil]-1,6-naphthiridin-5-yl]-1,2-ethanediamine; N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridin-5-yl]- 1,3-propanediamine; N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-(7-phenyl-1,6-naphthiridin-5-yl)-1,3-propanediamine; N-[7-(3-fluorophenyl)-1,6-naphthiridin-5-yl]-1,3-propanediamine; N-[7-(3-chlorophenyl)-1,6-naphthiridin-5-yl]-1,3-propanediamine; N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4'-methyl[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-1,3-propanodiamine; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; 1724223 of 64 N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(4-methylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-(methylthio)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-(1-methylethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; 7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridine-5-amine; 7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridine-5-amine; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanodiamine; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,5-pentanodiamine; 3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1-propanol; 4-[5-(4-aminobutoxy)-1,6-naphthyridin-7-yl]-N,N-dimethylbenzenamine; 4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-1-butanol; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N-methyl-1,3-propanodiamine; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N'-methyl-1,3-propanodiamine; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N,N'-dimethyl-1,3-propanodiamine; 1-amino-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol; N-[7-[4-(dimethylamino)fenil]-1,6-naphthiridin-5-yl]-2,2-dimethyl-1,3-propanodiamine; 7-[4-(dimethylamino)fenil]-N-(3-pyridinylmethyl)-1,6-naphthyridin-5-amine; N-[(2-aminofenil)metil]-7-[4-(dimethylamino)fenil]-1,6-naphthyridin-5-amine; N-[7-[6-(dimethylamino)[1,1'-bifenil]-3-yl]-1,6-naphthiridin-5-yl]-1,3-propanodiamine, ; N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthiridin-5-yl]-1,3-propanediamine; N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-[4-(diethylamino)phenyl]-3-methyl-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-(3'-fluoro[1,1'-biphenyl]-3-yl)-1,6-naphthyridin-5-yl]-1,2-ethanediamine, N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,6-naphthyridin-1,3-propanediamine; N,N'-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamina; N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridin-5-yl]-1,6-naphthyridin-1,3propanediamine; N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine; N-[7-(2-naphthalenyl)-1,6-naphtiridin-5-yl]-1,3-propanediamine; N-[7-(2'-fluoro[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(3,4-dimethylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; 1724223 of 64 1-amino-3-[[7-(2-naphthalenyl)-1,6-naphtiridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(2'-fluoro[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(4'-methoxy[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol; N-[7-(4'-methoxy[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine; 1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol; 2-[[2-[[7-[4-(dimethylamino)fenil]-1,6-naphthiridin-5-yl]amino]ethyl]thio]-ethanol; 7-[4-(dimethylamino)fenil]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridin-5-amine; 7-[4-(dimethylamino)fenil]-N-4-pyrimidinyl-1,6-naphthyridin-5-amine; N-[7-[4-(dimethylamino)fenil]-1,6-naphthiridin-5-yl]-1,3-cyclohexanodiamine; N,N-dimethyl-4-[5-(1-piperazinyl)-1,6-naphthiridin-7-yl]-benzenamine; 4-[5-(2-methoxyethoxy)-1,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine; 1-[7-[4-(dimethylamino)phenyl]-1,6-naphthiridin-5-yl]-4-piperidinol; 1-[7-[4-(dimethylamino)phenyl]-1,6-naphthiridin-5-yl]-3-pyrrolidinol; 7-[4-(dimethylamino)fenil]-N-(2-furanylmethyl)-1,6-naphthyridin-5-amine; 7-[4-(dimethylamino)fenil]-N-[3-(1H-imidazol-1-yl)propyl]-1,6-naphthyridin-5-amine; 1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-4-piperidinecarboxamida; 1-[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphtiridin-5-yl]amino]propyl]-2-pyrrolidinone; N-[3'-[5-[(3-aminopropyl)amino]-1,6-naphtiridin-7-yl][1,1'-biphenyl]-3-yl]-acetamida; N-[7-(4'-fluoro[1,1'-biphenyl]-4-yl)-1,6-naphtiridin-5-yl]-1,3-propanediamine; N-[4'-[5-[(3-aminopropyl)amino]-1,6-naphthyridin-7-yl][1,1'-biphenyl]-3-yl]-acetamida; N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-(2-thienyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; 7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridin-5-amine; 3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]methylamino]-propanonitrile; 7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1,6-naphthyridine-5-amine; (1R,2S)-N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-cyclohexanodiamine, N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-bencenodimethanamine; N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine; N-[7-[3',5'-bis(trifluoromethyl)[1,1'-biphenyl]-4-yl]-1,6-naphthyridin-5-yl],3-propanodiamine; 1724223 of 64 N-[7-(3'-methoxy[1,1'-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(3'-fluoro[1,1'-biphenyl]-4-yl)-1,6-naphtiridin-5-yl]-1,3-propanodiamine; 4-[[7-[4-(dimethylamino)phenyl]-1,6-naphtiridin-5-yl]oxi]-1-butanol; N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]- 1,4-cyclohexanediamine; 7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-naphthyridin-5-amine; N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanodiamine; N-[7-(1-methyl-1H-indol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4cyclohexanediamine; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4cyclohexanediamine; N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanodiamine; N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanodiamine; N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthiridin-5-yl]-1,4-cyclohexanodiamine; 4-[[7-[4-[[2-(dimethylamino)ethyl]metilamino]fenil]-1,6-naphthiridin-5-yl]oxy]-cyclohexanol; N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthiridin-5-yl]-1,3-propanediamine; N,N-dimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthiridin-7-yl]-benzenamina; 4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamina; [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridin-2-yl]amino]propyl]carbamate de 1,1-dimethylethyl. The invention further relates to pharmaceutical preparations containing a triple combination comprising a compound of formula I, II, or III and two additional active agents, both independently selected from the groups of active agents mentioned above, such as another PDE4B inhibitor, an anticholinergic, a beta-mimetic, a corticosteroid, an EGFR inhibitor, an MRP4 inhibitor, a LTD4 antagonist, an iNOS inhibitor, a PAF antagonist, an H1 antihistamine, a dopamine agonist, or a SYK inhibitor. The invention further relates to the preparation of such a double or triple combination and its use for treating respiratory ailments. 8. Formulations Appropriate forms of administration include, for example, tablets, 1724223 of 64 capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case must be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the total composition, i.e., in quantities that are sufficient to achieve the dosage range specified hereinafter. The preparations can be administered orally as a tablet, as a powder, as a powder in a capsule (e.g., a hard gelatin capsule), as a solution, or as a suspension. When administered by inhalation, the combination of active substances can be provided as a powder, as an aqueous or ethanolic solution, or using a propellant gas formulation. Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula I in accordance with the above preferred embodiments. It is particularly preferable if the compounds of formula I are administered orally, and also particularly preferable if they are administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance(s) with known excipients, such as inert diluents like calcium carbonate, calcium phosphate, or lactose; disintegrants like corn starch or alginic acid; thickeners like starch or gelatin; lubricants like magnesium stearate or talc; and / or release-delaying agents like carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise multiple layers. Coated tablets can be prepared accordingly by coating cores produced analogously to tablets with substances normally used for tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or avoid incompatibilities, the core may also comprise a series of layers. Similarly, the tablet coating may comprise a series of layers to achieve delayed release, possibly using the excipients mentioned above for tablets. Syrups containing the active substances or combinations thereof according to the invention may further contain a sweetener such as saccharin, cyclamate, glycerol, or sugar, and a flavor enhancer, for example, a flavoring agent such as vanillin or orange extract. They may also contain adjuvants or thickeners such as sodium carboxymethylcellulose, agents 1724223 of 64 humectants such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Capsules containing one or more active substances or combinations of substances can be prepared, for example, by mixing the active substances with inert vehicles such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories can be prepared, for example, by mixing with vehicles provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. Excipients that may be used include, for example, water, organic solvents acceptable for pharmaceutical use such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), vehicles such as, for example, natural mineral powders (e.g. kaolin, clays, talc, limestone), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, sulfite residual liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate). For oral administration, the tablets may, of course, contain, in addition to the aforementioned vehicles, additives such as sodium citrate, calcium carbonate, and calcium diphosphate, along with various other additives such as starch, preferably potato starch, gelatin, and similar materials. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used during the tablet manufacturing process. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorants in addition to the excipients mentioned above. It is also preferable that the Formula I compounds be administered by inhalation, particularly preferably once or twice daily. For this purpose, the Formula I compounds must be available in forms suitable for inhalation. Inhalable preparations include inhalable powders, metered-dose aerosols containing propellants, or propellant-free inhalable solutions, which may be mixed with excipients acceptable for conventional physiological use. 1724223 of 64 Within the scope of the present invention, the term propellant-free inhalable solutions also includes sterile ready-to-use inhalable concentrates or solutions. Preparations that may be used in accordance with the invention are described in more detail in the following part of the specification. Inhalable Powders If the active substances of Formula I are present mixed with excipients acceptable for physiological use, the following excipients acceptable for physiological use may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, sucrose, maltose), oligosaccharides and polysaccharides (e.g., dextran), polyalcohols (e.g., sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate), or mixtures of these excipients. Preferably, monosaccharides or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is even more particularly preferred.The methods for preparing inhalable powders in accordance with the invention by grinding and micronizing and finally mixing the components together are known from the prior art. Inhalable aerosols containing propellants Inhalable aerosols containing propellants that can be used in accordance with the invention may contain the compounds of formula I dissolved in the propellant gas or in dispersed form. The propellant gases that can be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane, or isobutane and halohydrocarbons such as, preferably, fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane. The aforementioned propellant gases can be used alone or in mixtures thereof. In particular, the preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane), and mixtures thereof.Propellant-driven inhalation aerosols used within the scope of use in accordance with the invention may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art. 1724223 of 64 Propellant-free inhalable solutions The compounds of formula I according to the invention are preferably used to prepare propellant-free inhalable solutions and inhalable suspensions. The solvents used for this purpose include aqueous or alcoholic solutions, preferably ethanolic. The solvent may be water alone or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic sources. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and / or propionic acid, etc.The preferred inorganic acids are hydrochloric and sulfuric acids. It is also possible to use acids that have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid, and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids that have other properties besides their acidifying qualities, for example, as flavoring agents, antioxidants, or complexing agents, such as citric acid or ascorbic acid. In accordance with the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. Cosolvents and / or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred cosolvents are those containing hydroxyl groups or other polar groups, for example, alcohols—particularly isopropyl alcohol—glycols, particularly propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols, and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any substance acceptable for pharmacological use that is not an active substance but that can be formulated with the active substance or substances in the pharmacologically appropriate solvent to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least undesirable pharmacological effect.Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates. 1724223 of 64 polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or extend the shelf life of the finished pharmaceutical formulation, flavorings, vitamins and / or other additives known in the art. Additives also include salts acceptable for pharmacological use such as sodium chloride as isotonic agents. Preferred excipients include antioxidants such as ascorbic acid, for example, provided it has not already been used to adjust pH, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins that are in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Appropriate preservatives are those known in the art, particularly cetylpyridinium chloride, benzalkonium chloride, or benzoic acid, or benzoates such as sodium benzoate at the concentration known from the prior art. For the forms of treatment described above, ready-to-use packages of a medicinal product for the treatment of respiratory ailments are provided, containing an attached description including, for example, the words respiratory disease, COPD, or asthma, together with dihydrothienopyrimidine and one or more combination auxiliaries selected from those described above.

Claims

1. A compound characterized in that it has formula I (FORMULA I) wherein Ring A is a 6-membered aromatic ring optionally comprising one or two nitrogen atoms and wherein R is Cl and wherein R may be located in the para, meta, or ortho position of Ring A, wherein S* is a sulfur atom representing a chiral center, and all pharmaceutically acceptable salts, enantiomers, and racemates thereof. 26 Claims follow