NZ620199B2 - Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating copd and asthma - Google Patents

Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating copd and asthma Download PDF

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NZ620199B2
NZ620199B2 NZ620199A NZ62019912A NZ620199B2 NZ 620199 B2 NZ620199 B2 NZ 620199B2 NZ 620199 A NZ620199 A NZ 620199A NZ 62019912 A NZ62019912 A NZ 62019912A NZ 620199 B2 NZ620199 B2 NZ 620199B2
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amino
phenyl
compound
acid
compounds
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NZ620199A
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NZ620199A (en
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Rogelio P Frutos
Soojin Kim
Jason Alan Mulder
Peter Nickolaus
Nitinchandra Patel
Pascale A J Pouzet
Chris H Senanayake
Thomas G Tampone
Xudong Wei
Ulrike Werthmann
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Boehringer Ingelheim International Gmbh
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Priority claimed from PCT/EP2012/066104 external-priority patent/WO2013026797A1/en
Publication of NZ620199A publication Critical patent/NZ620199A/en
Publication of NZ620199B2 publication Critical patent/NZ620199B2/en

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Abstract

The disclosure relates to novel piperidino-dihydrothienopyrimidine sulfoxides 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 CI and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, 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. erein S* is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, 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

PC T/EP2012/066104 NOVEL PIPERIDINO-DIHYDROTHIENOPYRIMIDINE SULFOXIDES AND THEIR USE FOR TREATING COPD AND ASTHMA The invention relates to novel piperidino-dihydrothienopyrimidine sulfoxides of formula HN OH wherein Ring A is a 6-membered aromatic ring which optionally comprise one or two atoms and nitrogen wherein R is Cl and meta- wherein R be located either in the para-, or ortho-position of Ring may A, wherein is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, 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. 1 PRIOR ART 2006/111549 and 2007/118793 each disclose WO WO dihydrothieno-pyrimidinesulfoxides which are substituted instead of discloses piperazine piperidine. piperidino-dihydrothienopyrimidines which differ from the compounds of the invention in their substitution pattern. Due to their particular substitution pattern the compounds of the invention are at the same time more potent PDE4 inhibitors than the compounds disclosed in and show a minimized potential for the development of unwanted gastrointestinal side effects. 2013/026797 T/EP2012/066104 WO PC 2 DESCRIPTION OF THE INVENTION it has been found that the compounds of the invention are due to their particular Surprisingly substitution pattern particularly suitable for the treatment of inflammatory disease. The compounds of the invention are further superior to the corresponding piperazino- sulfoxides of the art document 2009/050248. dihydrothienopyrimidine prior WO The present invention therefore relates to compounds of formula I HN OH 6-membered wherein Ring A is a aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is Cl and meta- wherein R be located either in the para-, or ortho-position of Ring may A, wherein represents a sulphur atom that is a chiral center, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, solvates and thereof. hydrates, polymorphs The invention further relates to the above-mentioned compounds of formula wherein R is Cl and wherein R is preferably located in the para-position of Ring and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates and thereof. polymorphs PC T/EP2012/066104 above-mentioned The invention further relates to the compounds of formula wherein Ring A is selected from the of and and all group consisting phenyl, pyridinyl pyrimidinyl, pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates and thereof. The invention preferably relates to the above-mentioned polymorphs compounds of formula wherein Ring A is selected from the consisting of I, group phenyl, Cl-substituent pyridinyl and pyrimidinyl and wherein R is a in the para-position, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvates and polymorphs thereof.
In the invention concerns the of formula particular compound II, HN OH and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, solvates and thereof. hydrates, polymorphs In particular the invention concerns the compound of formula III, 2013/026797 T/EP2012/066104 WO PC HN OH and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, solvates and thereof. hydrates, polymorphs The invention further relates to the above-mentioned compounds according of one of formula II or III, wherein represents a sulphur atom which represents a chiral center being in the R-configuration.
The invention further relates to the above-mentioned of one of formula compounds according II or III, wherein respresents a sulphur atom which represents a chiral center being in the S-configuration.
For the of formula III three different two different forms compound polymorphs, anhydrous and one form have been identified and characterized X-ray diffraction dihydrate powder thermogravimetric analysis and differential scanning calorimetry (XRPD), by (TGA) by (DSC).
Fig. 3a shows the X-ray powder diffraction diagram of the anhydrous form A of formula III Example In this XRPD diagram ofthe anhydrous form A of formula III the (see 2). -values d-values followingthe and could be observed (Table Table 1:All observable eaks for the anh drate Form A: 2013/026797 T/EP2012/066104 WO PC 2-Theta I/lo 4.48 19.70 27 8.76 10.09 46 9.54 9.26 12. 6.82 98 69 13.44 6.58 .50 5.71 16.56 5.35 17.94 4.94 35 18.54 4.78 20 19.18 4.62 100 .36 4.36 15 .64 4.30 10 21.48 4.13 23 22.62 3. 93 38 22.98 3.87 15 23.65 3.76 24.46 3.64 15 24.76 3.59 21 26.61 3.35 27.34 3.26 13 27.92 3.19 28 29.14 3.06 15 .68 2.91 31. 2. 17 05 88 32.34 2.77 32.65 2.74 33.28 2.69 20 33.54 2.67 17 2013/026797 T/EP2012/066104 WO PC The of the XRPD diagram of anhydrous Form A of the of formula III major peaks compound are listed in Table 2.
Ma'or Table 2: eaks for the anh drate Form A: 2-Theta I/lo 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 of the XRPD diagram of anhydrous Form A of the compound of formula III are listed in Table 3.
Table 3: Prominent eaks for the anh drate Form A: 2-Theta I/lo 8.76 10. 46 12.98 6.82 69 19.18 4.62 100 shows the X-ray diffraction of the form B of formula III Fig. 3b powder diagram anhydrous Example In this XRPD diagram of the anhydrous form B of formula III the following (see 2). -values d-values and could be observed (Table 2013/026797 T/EP2012/066104 WO PC Table 4: All observable eaks for the anh drate Form B: 2-Theta 4.78 18.47 46 9.78 9.04 25 14.56 6.08 .14 5. 17 16.96 5.22 43 17.48 5.07 14 19.18 4.62 100 19.74 4.49 41 . 4.27 80 38 21.30 4.17 71 21.72 4.09 28 23.82 3.73 50 24.28 3. 66 55 24. 3.62 58 35 .53 3.49 26.64 3.34 21 27.12 3.29 27.61 3.23 13 27.90 3.20 31 28.48 3.13 28.78 3.10 18 29.74 3.00 .92 2.89 18 31.75 2.82 32.04 2.79 10 32.78 2.73 34.55 2.59 2013/026797 T/EP2012/066104 WO PC The major peaks of the XRPD diagram of anhydrous Form B of the compound of formula III are listed in Table Ma'or Table 5: eaks for the anh drate Form B: 2-Theta I/lo d(A) 4.78 18.47 46 9.78 9.04 25 .14 5.85 17 16.96 5.22 43 19.18 4.62 100 19.74 4.49 41 . 4.27 80 38 21.30 4.17 71 21.72 4.09 28 23.82 3.73 50 24.28 3.66 55 27. 3.20 31 The most prominent peaks of the XRPD diagram of anhydrous Form B of the compound of formula III are listed in Table 6.
Table 6: Prominent eaks for the anh drate Form B 2-Theta I/lo 4.78 18.47 46 16. 5.22 43 19.18 4.62 100 21.30 4.17 71 2013/026797 T/EP2012/066104 WO PC 24.28 3. 66 55 23.82 3.73 50 the invention concerns a crystalline anhydrous of formula III which Consequently compound d-value shows a reflex peak in the X-ray powder diffraction diagram with a of 4.62 A.
Further the invention concerns a crystalline anhydrous compound of formula III which shows d-values reflex peaks in the X-ray powder diffraction diagram with of 4.62 6.82 A and .09 A.
Further the invention concerns a crystalline anhydrous compound of formula III, which d-values shows reflex peaks in the X-ray powder diffraction diagram with of 4.62 4.17 A and 3.66 A.
Additionally the invention relates to a crystalline anhydrous compound of formula III, which d-values shows reflex peaks in the X-ray powder diffraction diagram with of 4.62 6.82 A, A, .09 3.93 A and 4.94 A.
Additionally the invention relates to a crystalline anhydrous of formula which compound III, d-values shows reflex peaks in the X-ray powder diffraction diagram with of 4.62 4.17 A, A, A and 18.47 A. 3.66 A, 3.73 3c shows the X-ray diffraction diagram of the dihydrate form C of formula III Fig. powder Example In this XRPD diagram of the dihydrate form C of formula III the following (see 2). -values d-values and could be observed (Table 7).
Table 7: All observable eaks for the dih drate Form C: 2013/026797 T/EP2012/066104 WO PC 2-Theta I/lo 8.60 10.27 9.78 9.04 15 .28 8.60 28 11.10 7.97 12.96 6.83 13.72 6.45 16 14.72 6.01 .46 5.73 17.20 5.15 70 18.72 4.74 21 19.10 4.64 29 19.70 4.50 33 .04 4.43 26 .70 4.29 75 21.54 4.12 100 22.48 3.95 61 23.00 3.86 23.78 3.74 24.26 3.67 24.62 3.61 15 24.98 3.56 19 26.50 3.36 41 27.92 3.19 28.62 3.12 20 29.21 3. 29.64 3.01 15 .18 2.96 19 .66 2.91 16 2013/026797 T/EP2012/066104 WO PC 31. 2. 88 80 33.00 2.71 12 33.94 2.64 The major peaks of the XRPD diagram of dihydrate Form C of the compound of formula III are listed in Table 8.
Ma'or Table 8: eaks for the dih drate Form C: 2-Theta I/lo .28 8. 28 17.20 5.15 70 18.72 4.74 21 19.10 4.64 29 19.70 4.50 33 .04 4.43 26 .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 of the XRPD of Form of the of prominent peaks diagram dihydrate C compound formula III are listed in Table 9.
Table Prominent eaks for the dih drate Form 9: C: 2-Theta I/lo 17.20 5.15 70 .70 4.29 75 2013/026797 T/EP2012/066104 WO PC 21.54 4.12 100 22.48 3.95 61 26.50 3.36 41 the invention relates to a crystalline dihydrate of formula which Consequently, compound III, d-value shows a reflex peak in the X-ray powder diffraction diagram with a of 4.12 A.
The invention also relates to a of formula which shows crystalline dihydrate compound III, reflex in the X-ray diffraction diagram with d-values of 4.12 4.29 A and peaks powder A, .15 A.
The invention further relates to a of formula which shows crystalline dihydrate compound III, reflex in the X-ray diffraction with d-values of 4.12 4.29 15 peaks powder diagram A, A, 5. A, 3.95 A and 3.36 A.
In another aspect the invention relates to the above-mentioned compounds for use as a medicament.
Another of the invention concerns a method of treating a disease which can be treated aspect the inhibition of the PDE4-enzyme comprising the of administering one of the by step aforementioned compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for a medicament for the treatment and/or I, preparing prevention of a disease which can be treated the inhibition of the PDE4-enzyme.
Further the invention concerns one of the aforementioned compounds according to at least one of formulas II or III for the treatment and/or of a disease which can I, prevention be treated the inhibition of the PDE4-enzyme. 2013/026797 T/EP2012/066104 WO PC The invention further relates to the above-mentioned method of treating a disease which can be treated the inhibition of the PDE4-enzyme the of administering one of by comprising step the aforementioned compounds according to at least one of formulas II or III to a patient in need characterised in that the disease to treated is selected from the thereof, be group consisting of a disease, a gastrointestinal disease, an inflammatory disease of the respiratory the skin or the cancer and a disease of the peripheral or central nervous system. joints, eyes, Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for preparing a medicament for the treatment and/or of a disease which can treated the inhibition of the PDE4-enzyme, wherein prevention be the disease to be treated is selected from the consisting of a disease, a group respiratory gastrointestinal disease, an inflammatory disease of the the skin or the cancer and joints, eyes, a disease of the or central nervous peripheral system.
Further the invention concerns one of the aforementioned compounds according to at least one of formulas II or III for the treatment and/or prevention of a disease which can be treated the inhibition of the PDE4-enzyme, wherein the disease to be treated is selected from the consisting of a respiratory disease, a gastrointestinal disease, an inflammatory group disease of the joints, the skin or the cancer and a disease of the peripheral or central eyes, nervous system.
The invention further relates to the above-mentioned method of treating a disease which is selected from the group consisting of a respiratory or pulmonary disease which is accompanied increased mucus inflammations and/or obstructive diseases of production, the respiratory tract, comprising the of administering one of the aforementioned step compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns the of one of the aforementioned to use compounds according at least one of formulas II or III for a medicament for the treatment and/or I, preparing prevention of a disease selected from the consisting of a or group respiratory pulmonary disease which is accompanied increased mucus production, inflammations and/or 2013/026797 T/EP2012/066104 WO PC obstructive diseases of the the of one of the respiratory tract, comprising step administering aforementioned compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns one of the aforementioned compounds according to at least one of formulas II or III for the treatment and/or of a disease selected from the I, prevention consisting of a or disease which is accompanied increased group respiratory pulmonary mucus inflammations and/or obstructive diseases of the tract, production, respiratory comprising the of administering one of the aforementioned compounds according to at step least one of formulas II or II.
The invention further relates to the above-mentioned method of treating a disease which is selected from the consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, group alpha 1 antitrypsin deficiency, asthma and chronic bronchitis, comprising the step of administering one of the aforementioned compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for a medicament for the treatment and/or I, preparing of a disease selected from the of chronic prevention group consisting COPD, sinusitis, idiopathic fibrosis, 1 asthma and chronic bronchitis. pulmonary alpha antitrypsin deficiency, Further the invention concerns one of the aforementioned compounds according to at least one of formulas II or III for the treatment and/or prevention of a disease selected from the consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1 group asthma and chronic bronchitis. antitrypsin deficiency, Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for a medicament for the treatment and/or I, preparing prevention of a disease selected from the consisting of rheumatoid arthritis, sarcoidosis, group and the glaucoma dry eyes syndrome.
Further the invention concerns one of the aforementioned to at least compounds according one of formulas II or III for the treatment and/or prevention of a disease selected from the consisting of rheumatoid arthritis, sarcoidosis, glaucoma and the eyes syndrome. group dry 2013/026797 T/EP2012/066104 WO PC The invention further relates to the above-mentioned method of treating a disease which is Crohn's selected from the consisting of disease and ulcerative colitis, comprising the group step of administering one of the aforementioned compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for a medicament for the treatment and/or I, preparing Crohn's prevention of a disease selected from the group consisting of disease and ulcerative colitis.
Further the invention concerns one of the aforementioned to at least compounds according one of formulas II or III for the treatment and/or prevention of a disease selected from the of Crohn's disease and ulcerative colitis. group consisting The invention further relates to the above-mentioned method of a disease which is treating selected from the consisting of bipolar or manic acute and group depression, depression, Alzheimer's Parkinson's chronic anxiety states, schizophrenia, disease, disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused stroke, or cranio-cerebral the of one of the hypoxia trauma, comprising step administering aforementioned compounds according to at least one of formulas II or III to a patient in need thereof.
Further the invention concerns the use of one of the aforementioned compounds according to at least one of formulas II or III for preparing a medicament for the treatment and/or of a disease selected from the of or manic prevention group consisting depression, bipolar acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson' s depression, disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused stroke, or cranio-cerebral trauma. hypoxia Further the invention concerns one of the aforementioned to at least compounds according one of formulas II or III for the treatment and/or prevention of a disease selected from the consisting of depression, bipolar or manic depression, acute and chronic anxiety states, group 2013/026797 T/EP2012/066104 WO PC Alzheimer's Parkinson's acute and chronic sclerosis schizophrenia, disease, disease, multiple or acute and chronic and brain caused stroke, or cranio-cerebral pain damage hypoxia trauma.
In another aspect the invention concerns a pharmaceutical composition comprising at least one of the aforementioned compounds according to at least one of formulas II or III.
In a further aspect the invention relates to a pharmaceutical composition characterised in that it contains at least one of the aforementioned compounds of at least one of formulas II or III in combination with one or more active substances selected from the of group consisting other PDE4 inhibitors, COX2 betamimetics, corticosteroids, anticholinergics, NSAIDS, inhibitors, EP4 receptor antagonists, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, MRP4-inhibitors and SYK inhibitors.
In another the invention relates to a method of manufacturing the A aspect compound wherein HX is a pharmaceutically acceptable acid, the and wherein in comprising steps a) b), step a) compound wherein HY is a pharmaceutically acceptable acid, is reduced borane and wherein in 2013/026797 T/EP2012/066104 WO PC a pharmaceutically acceptable acid HX is added in order to obtain A. step compound In one embodiment of the above-mentioned method of manufacturing compound A the borane for the reduction in step is added directly.
In another embodiment of the above-mentioned method of manufacturing A the compound borane for the reduction in is generated in-situ. step a) above-mentioned In a preferred embodiment of the method of manufacturing compound A the borane for the reduction in step is generated in situ either from the combination ofNaBH4 and or from the combination of NaBH4 and BF~-OEt2.
In another preferred embodiment of the above-mentioned method of one of manufacturing A the acid HX is selected from acid or acid. compound tosylic hydrochloric In a further embodiment of the above-mentioned method of one of manufacturing compound A the pharmaceutically acceptable acid HY in compound B is HCI.
In another the invention relates to a method of aspect manufacturing compound C wherein HX is tosylic acid, hydrochloric acid or sulphuric acid, comprising the steps ii) and iii), 2013/026797 T/EP2012/066104 WO PC wherein in is contacted first with an acid and is then reacted with step 4-cyano-piperidine ammonia in order to obtain intermediate E and wherein in intermediate E is reacted with D in the of a base step ii) compound presence („, ) and wherein in the acid HX is added. step iii) In a preferred embodiment of the above-mentioned method of manufacturing C compound cyano-piperidine is contacted with hydrochloric acid and is then reacted with ammonia in order to obtain intermediate E in step i).
In a embodiment of the above-mentioned method of the preferred manufacturing compound C intermediate E is reacted with compound D in the presence of sodium methanolate in step ii).
In a further the invention relates to intermediates of formula VIII aspect Vill and their salts. 2013/026797 T/EP2012/066104 WO PC In a further the invention relates to intermediates of formula IX aspect and their salts, wherein stands for a sulphur atom that represents a chiral center.
Compounds of the general formulas II und III contain basic Therefore compounds I, groups. of the general formulas II und III form salts with pharmaceutically acceptable I, may inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or with organic acids as for instance maleic fumaric citric tartaric acid or (such acid, acid, acid, acetic acid).
As described above the of formulas II and III transformed into their compounds I, may be salts for their as For instance these pharmacologically acceptable use pharmaceutics. form and acid addition salts compounds may physiologically pharmacologically acceptable with or with acids. In order to these acid addition salts of the inorganic organic produce compounds of formulas II and III for instance hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methyl sulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid may be used. Further it is possible to mixtures of the aforementioned acids.
The compounds of formulas II and III also be present in the form of their individual I, may optic isomers or enantiomers, in mixtures of the individual enantiomers or in the form of their racemates, and in the form of their free bases or in the form of their acid addition salts with acceptable acids instance acid addition salts with hydrohalogenic acids pharmacologically (for such as hydrochloric acid or hydrobromic acid or with organic acids such as oxalic acid, fumaric acid, diglycolic acid or methyl sulfonic acid. 2013/026797 T/EP2012/066104 WO PC The compounds of the invention also be present in their racemic forms, but also be may may present in the form of one pure enantiomers, that means in their (R)- or in their (S)-forms.
As mentioned before the pharmacologically acceptable salts of the compounds of formula II and III are also a preferred of the instant invention. These pharmaceutically aspect acceptable salts of the compounds of formulas II and III also be in the form of I, may present mono- their hydrates instance or dihydrates) and/or in the form of their solvates. (for A solvate of a of formula II or III is defined herein as a salt of the compound I, crystalline of formula II or III which contains solvent molecules instance respective compound I, (for ethanol, methanol etc. within its crystal lattice.
A of a of formula II or III is defined herein as a salt of a hydrate compound I, crystalline of formula II or III which contains crystalline water in its crystal lattice. compound I, 2013/026797 T/EP2012/066104 WO PC METHODS OF SYNTHESIS Generation of Exam les 1 and 2: Scheme 1: +OH +OH VI I VII I chiral Example 1 R 4-chlorophenyl; OH X H2N~ or Example 2 p-TsOH = -chloropyrimidineyl X Cl or Ts or HSO, C: R 4-Chlorophenyl Cq R 5-Chloropyrimidineyl 1. Generation of Com ound VII: Scheme 2 Me Ti(0'Pr)CI3 0 Piperidine ~ 0~ 0~ EtsN 0 CO, Me MeOH NaOH Ithiaadi 3.1.1 S nthesis of Dimeth ate Com ound III Piperidine (0.02 oiv) 2013/026797 T/EP2012/066104 WO PC 2.61 and 43 0.052 were to an Methyl thioglycolate (292 mol) piperidine (4. mol) charged g, g, inerted jacketed reactor with an addition funnel, mechanical stirrer, line and equipped N~ thermocouple thermometer. Methyl acrylate (250 2.87 mol) was then added slowly over a of min the at 45 period 30 keeping temperature approximately Upon complete addition, the mixture was stirred at 45 for 30 min. Piperidine 9 210 was added and (17. mmol) stirring at 45 continued for 30 min order to of excess Tert- (in scavenge acrylate). butylmethylether was charged, the mixture was cooled to 15 and 1 M (MTBE) (251 ml) HC1 (251 ml) was added. The mixture was stirred for 5 min and the organic layer was collected and washed with water The mixture was concentrated to a minimum (251 ml). volume distillation under reduced at 50 Dichloromethane was pressure (251 ml) charged and the mixture was again concentrated under reduced pressure distillation at 45 Crude III was in the next without further product (480 used step purification. 1.2 nthesis of Meth Ioxo-tetrah drothio henecarbox late 3. S Com ound IV Me 0 CO, Ti(O'Pr)CI, TiC4 0 M 1.16 1.16 was charged to an inerted and dried jacketed reactor (1. CH~CI~, L; mol) with temperature probe, mechanical stirrer and a funnel. The reactor equipped dropping contents were cooled to -10 and 6 1.16 was charged at or below— isopropanol (89. ml, mol) 'C. -10 The mixture was stirred at for 30 min and dimethyl 3-thiaadipate 1.01 (200 was charged slowly over 1 h the internal temperature at or below The mol) keeping reaction was stirred for an additional 30 min at and EtqN (489 mL, 3.49 mol) was over 1. hours the internal at or below -10 The slowly charged 5 keeping temperature mixture was stirred at or below -10 for 1. hours. HC1 01 was 3 N (1. L; 3.03 mol) slowly charged the internal temperature below 10 The temperature was increased to keeping and the mixture was stirred for 1 hour. The mixture was allowed to settle, the organic was collected and the was extracted with dichloromethane twice 1 layer aqueous layer (1.5 per 2013/026797 T/EP2012/066104 WO PC The combined were washed twice with water 1 extraction). organic portions (1.5 per wash) and dried with The resulting solution was concentrated to a minimum volume MgSO~ (40 -35 under reduced pressure at to afford crude IV (148.6 The spectral data of IV is consistent with literature values H.-J. K. Can.
(Liu, Teng, N. J. Chem. 19S2, 60, 437). 3-Ureido-4 5-dih dro-thio henecarbox 3.1.3 S nthesis of lic acid meth I ester Com oundV Urea, MeOH/HCI Urea 16 35.9 mol) was charged into a jacketed reactor with a stirrer, Nz (2. kg, dry, equipped line and thermometer. 3-oxo-tetrahydro-thiophenecarboxylic acid thermocouple methyl ester 3.0 was followed methanol 5 Conc.
(Compound IV, charged by (4. I). HC1(297 ml, was at 20-25 and the mixture stirred at reflux for 4-6 hours. The 3.59 mol) charged reaction mixture was cooled to 0 and the resulting solid was collected filtration. The cake was washed with water twice 1 water wash) and dried in a vacuum oven at 50 (2 per "/„) to afford 4.17 % of compound V (95% NMR (500 MHz, 6 kg (83 yield), (CD~)~SO) 2 2 50-7.20 2 3. (dd, H, J 8.5, 8.5 Hz), 3.50 (dd, H, J 8.5, 8.5 Hz), 3.73 3 6. (bs, (s, H), 9.47 1 NMR MHz, 6 28. 37. 52. 100. 151. 154.
H), (s, H); (125 (CD~)~SO) 7, 8, 4, 0, 6, 7, 165. LCMS for C7Hi (M+H)+ calcd. 203. measd. 203.0. 7; (EI) iN~O~S, 0, 7-Dih dro-thieno rimidine-2 4-dipl 3.1.4 S nthesis of 6 3 Com ound VI N~OH NaOH 2013/026797 T/EP2012/066104 WO PC 47 was added to a solution of water and NaOH Compound V (2.0 9. mol) (6.0 (379 kg, I) 9.47 at normal room temperature. The above mixture was stirred at 85 for 3 hours. mol) After cooling to 0 conc. HC1 (861 ml, 10.4 mol) was added slowly until the of the solution was 0-1. The mixture was cooled to 0 stirred for 5-10 min and the resulting solid was collected filtration. The cake was washed thoroughly with water twice 1 rinse), by (I per air-dried for hours and then dried further in a vacuum oven at 50 for 12-16 (suction) 'H = hours to afford 1.67 of compound VI. NMR (500 MHz, 6 3.11 2 J kg (CD~)~SO) (dd, H, 31 2 11.14 1 11. 1 NMR 8.5, 8.5 Hz), 3. H, J 8.5, 8.5 Hz), 38 C (125 (dd, (s, H), (s, H); 29. 108. 150. 152. 160. LCMS for MHz, (CD~)~SO) 6 3, 35.4, 5, 5, 4, 4; (EI) C~H7N~O~S, (M+H)+ calcd. 171. measd. 171.0. 3.1.5 S nthesis of 2.4-dichloro-thieno 3 rimidine Com ound VII N OH POCI~ NyCI VI VI I of solid VI was into to an inert and reactor 800 Compound (4.66 mol) charged dry jacketed (reactor with a temperature mechanical stirrer and a funnel. 1.5 I) equipped probe, dropping litre 31 Diethylaniline was charged over 30 min to 1 h the temperature at or (9. mol) keeping below 25 The internal temperature was brought to 105-110 and 0.68 equiv. (868 34% of the of was added into the reactor over 5- m1, total) phosphorus oxychloride (reactor min. When the inside temperature to decrease, the internal temperature was began maintained at 110 and addition of the remaining POClq 32 or 66% of the (1. equiv. total) -40 resumed over a period of min. The internal temperature was adjusted to 105-110 and 18-24 the mixture was stirred for h or until complete (HPLC analysis). The mixture was cooled to 45 and THF was charged at 45 The above crude mixture was (400 mL) into a secondary vessel or reactor or reactor 4.8 1 of water was charged placed dry (vessel 2). into the reactor 1 and cooled to 5 The crude reaction mixture reactor or vessel is (in 2) -10 then slowly charged into reactor 1 containing water keeping the temperature at The 2013/026797 T/EP2012/066104 WO PC mixture was stirred at for min to 1 h and the solid was collected filtration. 30 resulting The cake was rinsed with water twice 6 1 and the cake was air dried in the funnel (1. per rinse) for h to afford 964 88% of crude Compound VII. Dichloromethane (92%w/w; yield) 6 is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 (4. L) 40'C were into the the mixture is heated to and stirred for 20 min. The charged reactor, solution was collected filtration a filter media to remove charcoal. The resulting through cake was rinsed with dichloromethane twice ml rinse). The solution was (175 per concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased distillation with a minimum amount of ether. away petroleum Additional ether was into the the mixture was cooled to petroleum (1.3 charged reactor, 'C and stirred for 1 hr. The resulting solid was collected filtration and the cake was rinsed with petroleum ether twice ml rinse). The cake was air dried in the funnel (150 per until it The solid VII was transferred to a suitable (suction) appeared dry. resulting Compound 'C 'H tared container and dried in an oven at for hr to final NMR 50 6 get product: (400 DMSO-d6) 6 3.45-3.56 C NMR DMSO-d6) 6 29. 36. 134.
MHz, 4H); (400 MHz, 3, 5, 8, 151. 154. 175.9. 0, 1, 3.2 Generation of Exam Ie I: Scheme chiral N CI DIPEA, dioxane EtsN microwave Y S-(-)-Binaphthol CH CN Y ~N Ti(oiPr)4 (65%) ~OH H&O t-BuOOH CH~CI~, 22 VI II Example 1 H~N. 1. /NaBH4 ~OH I, X OH 2. p-TsOH HCI- p-TsOH (66%) X- = Cl-or Ts-or HSO4- 2013/026797 T/EP2012/066104 WO PC 3.2.1 S nthesis of Com ound A 1. /NaBH4 2. p-TsOH p-TsOH HCI- NaBH4 6 757 mmol, 2.87 and THF were charged to a 2 L reactor under (28. (500 ml) g, eq) nitrogen and the mixture was cooled to A solution of I~ (63.6 251 mmol, 0.95 in 125 mL THF was and added to the reactor over 45 min an prepared slowly maintaining -5 'C. internal of to The addition funnel was then rinsed with 42 mL THF. temp 5 Compound -6 'C, B 264 mmol, 1 was then at then the temperature rose to (50 charged approx. g, eq) 'C. 'C The reaction mixture was then heated to 65 for 23 h (Note: Reaction conversion was GC/FID 1 mL reaction mixture with then analyzed quenching 0. MeOH, derivatizing by by with mL of a 5/2/2 mixture of THF/acetic mL MeOH were then 0.5 anhydride/TEA). 83 charged to the reaction mixture over 20 min maintaining the temperature between slowly 27 The reaction mixture was concentrated to a minimum stirrable volume and 500 mL methyltetrahydrofurane (MeTHF) were added. 485 of 25 wt% aq. NaOH (11. 5 were then solids were dissolved. The were and the was added, layers separated aqueous phase extracted twice with 500 ml 2-methyltetrahydrofurane The organics were then (MeTHF). filtered through a of celite and and rinsed with 50 mL 2-methyltetrahydrofurane pad MgSO4 (MeTHF). A solution of p-toluenesulfonic acid monohydrate 264 mmol, 1 in (51 eq) MeTHF (100 ml) was prepared and added to the organics (alternatively HC1 may be used to obtain the HC1-salt of A homogeneous solution resulted. The compound A). light yellow 300 solution was concentrated to mL and the water content was checked. Additional MeTHF was added and concentrated to the original volume until the water content was 1 %. The resulting solid was filtered and rinsed with 50 ml MeTHF, leA to in the funnel and then dried further in the vacuum oven at 61.71 of A were overnight 50 compound collected: 2013/026797 T/EP2012/066104 WO PC NMR 400 1.70-1.92 1.94-2. 2.04-2. 18 (DMSO-d6, MHz) 6 2H), 03 2H), 2H), (m, (m, (m, 2.29 3.55 5.47 7.13 J 8.0 7.49 J 8.0 3H), 3H), (br s, IH), Hz, 2H), Hz, 2H), (s, (s, (d, (d, 7.95 NMR (DMSO-d6, 100 MHz) 6 13. 20. 56. 63. 125. 128. (br s, 3H); 3, 8, 4, 5, 5, 1, 137. 145.4 3.2.2 S nthesis of Com ound VIII p-TsOH Et~N CH~CN VI I VI I I Intermediates VII 852 and A were into a (180 mmol) (129 937 mol) sequentially charged g, g, multi-neck vessel with a condenser, thermocouple thermometer and nitrogen line. equipped Acetonitrile and triethylamine ml, 4.26 were then added at 22 and the (900 ml) (594 mol) 75-77 mixture was stirred at for 12 h. Water 2 was charged slowly over 20 min, the (1. I) 'C 'C mixture was seeded with Compound VIII crystals 3 at 40 and then cooled to 25 over 2 h. The mixture was stirred for an additional 12h at normal room temperature and the resulting solid was collected filtration. The filter cake was rinsed with 2:1 mixture of water/MeCN (400 mL) followed water (200 ml). The resulting solid was dried under 'C 'H vacuum at 50 for 12 h to afford 132 (57% of compound VIII: NMR (400 MHz, yield) 1.85-2. 2.10-2.21 2.32-2.41 27 4 CDClq) 6 05 2H), 2H), 2H), 3. J 8.0, 8. Hz, (m, (m, (m, (dd, 3.43 J 8. 8.4 3.91 4.67 C NMR 100 6 2H), (dd, 0, Hz, 2H), (s, 2H), (s, IH); (CDClq, MHz) 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1, 156.2, 168.0. 2013/026797 T/EP2012/066104 WO PC 3.2.3 S nthesis of Com ound IX: chiral N CI NyCI S-(-)-Binaphthol ~N ~N Ti(OIPr)4 t-BuOOH CH~CI~, VII I 1'-Binaphthol Compound VIII (122 429 S-(-)-1, (S-(-)-BINOL) 4 42.9 mmol), (12. g, g, dichloromethane 54 mL, 21.4 and water 72 ml, 429 mmol), (608 mL), Ti(OiPr)4 (6. mmol), (7. were to a 2 1 multi-neck flask at 20 under and stirred for 1 h. tert- mmol) charged nitrogen in water, 62.3 472 was added at once at 21 the Butyl hydroperoxide (70% ml, mmol) mixture became completely homogeneous and the temperature rose to 40 The approx. mixture was allowed to reach normal room temperature, was stirred for 1.5 h and filtered. The air-dried cake was twice rinsed with acetate (243 ml rinse) and the cake was in isopropyl per the filter for 6 h to afford 114.4 of IX. compound NMR DMSO-d6) 6 1.70-1.85 2.14-2.34 2.98-3.08 (400 MHz, 2H), 4H), IH), (m, (m, (m, 3.09-3.19 3.30-3.40 (obscured 3.50-3.62 3.65-3.77 4.91 (m, IH), m, IH), (m, IH), (m, 2H), (t, J 6 Hz, IH), 8.63 IH); C NMR (100 MHz, DMSO-d6) 6 14.5, 29.6, 29.8, 32.6, 48.6, 59. 62. 119. 157. 161. 175.3. 2, 8, 0, 8, 4, 1'-Binaphthol The other enantiomer of compound IX be produced when S-(-)-1, is 1'-Binaphthol. replaced R-(+)-1, A racemate of compound IX be produced methods by may known those skilled in the art that exclude chiral agents and conditions. An example for such a procedure to produce racemic sulfoxides is given in WO 06/111549. 2013/026797 T/EP2012/066104 WO PC 2.4 nthesis of Exam le 1 3. S 1. dioxane DIPEA, NYCI microwave // ~N Example 1 chiral Sulfoxide IX 48 22.5 mmol), 4-(4-Chlorophenyl)-piperidine hydrochloride C 75 (6. (5. g; g; 24. the p-TsOH-salt or the H~SO~-salt of and 8 mmol) (alternatively compound N, 4 72. 1 were mixed in 47 ml of dioxane. The resulting diisopropylethylamine (12. ml; mmol) mixture was to three 20 ml vials which were heated to 120 for 25 min. in a charged microwave oven. After cooling to room temperature, the reaction mixtures were poured on ice water. The resulting precipitate was filtered off, taken in 500 ml ethyl acetate and heated to reflux. After the mixture was cooled in an ice bath and the resulting was refluxing, precipitate filtered off and dried in a box at 50 at reduced pressure yielding 7.57 of Example 1.
'H — 67-1. 11-2.
NMR (400 MHz, DMSO-d6) 6 1.43 1.57 1. 85 2. 21 (m, 2H), (m, 4H), (m, 2H), 26-2. 80-3. 17-3. 2. 43 2. 01 3. 47 integration compromised water (m, 2H), (m, 5H), (m, by peak), 3.67-3.76 4.74-4.86 7.25-7.36 2H), 3H), 5H). (m, (m, (m, C NMR DMSO-d6) 6 14. 29. 29. 32. 32. 41. 44. 48. 58. 63. (100 MHz, 3, 4, 6, 3, 5, 4, 2, 5, 4, 6, 109. 128. 128. 130. 144. 157. 161. 174.7 2, 2, 6, 5, 7, 6, 5, 2013/026797 T/EP2012/066104 WO PC Generation of Exam le 2: Scheme 4: chiral N CI S-(-)-Binaphthol Ti(oipr)4 / t-BuOOH VI I I Example 2 N~OH p-TsOH X Cl or Ts or HSO4 ~N~xN~ 3.3.1 Generation of Com ound G: Scheme 5: 1. NaOMe MeOH 1. MeOH, HCI HCI 2. HX 2. /MeOH Cl HN H x &N~ X Ts-or Cl or HSO4- 2013/026797 T/EP2012/066104 WO PC 3.3.1.1 S nthesis of Com ound E: 1. MeOH, HCI/ Dioxane 2. /MeOH N NH, 4M HC1 in dioxane 3 900 was to a 500 ml 3-neck jacketed (225 ml, mmol) charged reactor with a mechanical stirrer, temperature probe and argon line. The solution equipped was cooled to 0 and 4-cyanopiperidine (33.04 300 mmol) was charged followed methanol 4 over -30 min while the below 10 (36. ml, 900 mmol, 3 equiv) keeping temperature The above mixture was stirred for h at normal room temperature (temperature rose). until complete conversion was observed NMR analysis of an aliquot in D20 clear by (the solution turned into a white slurry aAer 30 min). The mixture was cooled to 5 and 25 wt% NaOMe in methanol (129. 600 mmol, 2 was charged while maintaining the 6g, eq) temperature below 15 The mixture was then stirred for 1 h. 7.0 N ammonia in methanol 2 ml, 1.5 450 mmol) was charged to the above mixture and stirred for 2 h at normal (64. eq, room temperature. The mixture was concentrated under reduced pressure at 60 to a volume of -250 ml to afford a solution of crude E that was without isolation: compound used 'H = NMR 1.80-1. 2.15 4.4 2.79-2. (400 MHz, D20) 6 95 2H), (br d, J Hz, 2H), 90 (m, (m, 3.02 J 13. 13. 3.0 Hz, 3.48 1H), (ddd, 2, 2, 2H), (m, 2H). 2013/026797 T/EP2012/066104 WO PC 1.2 nthesis of Com ound 3.3. S G: NaOMe MeOH pTsOH ~N &N~ The above solution of intermediate compound E was cooled to and 25 wt% NaOMe in methanol 2. was The mixture was then stirred for min. (162 5eq, 750 mmol) charged. 30 Compound D (= (Z)-N-(2-chloro(dimethylamino)allylidene)-N-methylmethan-aminium hexafluorophosphate of 95 wt % 0.85 255 mmol) was charged to the (82.3g purity, eq, (V)), above mixture in two portions at normal room temperature over min and stirred for 3 h at room The mixture was concentrated under reduced at to a volume temperature. pressure 60 of -200 ml. 2-Methyltetrahydrofuran was and the mixture was concentrated (400 ml) charged further to a volume of -150 ml under reduced pressure at 60 2-methyltetrahydrofuran -20 'C, (250 ml) was charged, the mixture was cooled to water (150 ml) was added and the mixture was stirred for min. The were and the was collected. layers separated organic layer The organic was washed with 30 % NaOH and the were layer aqueous (120 ml) layers separated. The organics were concentrated to a minimum stirrable volume (-150 and was charged. A solution of p-toluenesulfonic acid monohydrate in propanol (350 ml) 255 48.4 in 100 ml was to the above clear propanol (0.85 equiv. mmol, n-propanol) charged -65 'C. -65 solution over 10 min at The above mixture was concentrated at under reduced to maintain -350 ml and (LO % water is recommended to have a water content pressure (it below 1.0 % to avoid product losses to the mother The batch was cooled to 20 liquor). with stirring over 3 h. The solids were filtered, rinsed with the filtrate and then with to afford 111 48 of after propanol (120 mL) (68 % w/w assay, 75. compound G g g) vacuum at 65 in a vacuum oven for 12 h. drying 'H = 83-1.
NMR (DMSO-d6, 400 MHz) 6 1. 99 2.13 J 12 Hz, 2.97 (m, 2H), (d, 2H), (s, 3H), 0-3. 13-3. 3. 11 3. 23 3.30-3.42 7.14 J 8.0 Hz, 7.52 J (m, 2H), (m, 1H), (m, 2H), (d, 2H), (d, 47 91 NMR 100 20. 27. 40. 8.0 Hz, 2H), 8. 2H), 8. 2H); C (DMSO-d6, MHz) 6 7, 0, 8, (br, (s, 42. 125. 128. 128. 137. 145. 155. 169.0. 8, 5, 1, 8, 9, 2, 8, 2013/026797 T/EP2012/066104 WO PC 3.3.2 S nthesis of Exam le 2: chiral N DIPEA, THF/ water // 2. THF/water/IPA ~N crystallization Example 2 G with HX being HCI, TsOH or H, SO4 Compound IX (86.5 291 mmol, 1 compound G (160 305 mmol, 1.05 eq), eq), g, g, water and DIPEA 127 tetrahydrofuran (THF) (484 ml), (121 ml) N-diisopropylethylamine, 727 mmol, 2.5 were all to a 3 1 round bottom flask under nitrogen and heated ml, charged to 65 for 3 h. Water (1125 ml, 13 compound was then charged at the temperature mVg IX) 'C 'C. 65 and stirred for 2 h while cooling to 20 The mixture was filtered and the cake was washed twice with 173 ml acetone. The cake was then left to on the funnel to dry overnight afford 116.7 of Example 2: NMR MHz, 6 1.75-1.95 2.02-2. 11 2.12-2.26 2.38 (400 CDClq) (m, 4H), (m, 2H), (m, 2H), 93-3. 12-3. 28-3. 53-3.
J 9.6 Hz, 2. 12 3. 22 3. 39 3. 65 2H), (m, 4H), (m, IH), (m, IH), (m, = = = 4.42 2 4.82 11.2 47 IH), 3.80 J 5.6 Hz, 2H), J 5. Hz, IH), (br d, J Hz, 2H), 6. (d, (t, (s, 62 NMR 14. 32. 44. 49.
IH), 8. 2H); C (100 MHz, CDClq) 6 8, 30.0, 30.1, 30.6, 7, 3, 4, 59. 68. 107. 129. 155. 159. 162. 170. 174.6. 1, 2, 5, 1, 5, 0, 3, 5, 3.3.2.1 C stallization to anh drous Form A of Exam le 2 Pre aration of seeder stals anh drous FormA Small amounts of crude Example 2 (1-2 were suspended in approximately 0.1 ml of the following solvents: ethanol, acetone, 2-butanone, ethyl acetate, acetate, isopropyl 2013/026797 T/EP2012/066104 WO PC 2-butanol, and acetonitrile. AAer a the tetrahydrofuran, 1-propanol, heating/cooling cycle, resulted in suspensions of crystalline anhydrous Form A as analysed X-ray samples powder diffraction. 1 orN-meth a. Cr stallization fromacetic acid dimeth 1sulfoxide olidone: 1 of crude 2 is dissolved in 10 ml of a solvent such Approximately Example polar organic of&60'C. as acetic acid, dimethyl sulfoxide, or N-methylpyrrolidone at a temperature The -40'C 5-10 solution is cooled to and an antisolvent such as (approximately ml) isopropyl alcohol, ethyl alcohol, or acetone is added. The solution is seeded with anhydrous Form A 'C. of 2 and cooled to An additional amount of antisolvent (5-10 is crystals Example ml) added to increase the The resulting is filtered within 1 hr of and the wet yield. slurry cooling cake is dried at 60 under vacuum. Anhydrous Form A is obtained as a white solid as confirmed X-ray powder diffraction (XRPD) of the anhydrous Form A standard on file. b. Cr stallization from tetrah drofuran/water: Approximately 1 of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture &60'C. 40-50'C, at a temperature of The solution is cooled to seeded with (8:2, v/v) 'C anhydrous Form A crystals of Example 2, and further cooled to in less than 1 hr. -10 ml of antisolvent organic solvent such as alcohol, Approximately (an isopropyl ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is filtered within 1 hr after the antisolvent addition and the wet cake is dried at 60 under vacuum. Anhydrous Form A is obtained as a white solid as confirmed X-ray powder diffraction (XRPD) of the anhydrous Form A standard on file. c. Dr in fromDih drate: Approximately 1 of the Dihydrate form of Example 2 is washed with approximately 5 ml of an solvent such as or acetone on a buchner funnel. anhydrous ethanol, methanol, isopropanol, The wet cake is then dried at 60 under vacuum. Anhydrous Form A is obtained as a white solid as confirmed X-ray diffraction of the anhydrous Form A standard on by powder (XRPD) 2013/026797 T/EP2012/066104 WO PC 2.2 stallization to anh drous Form B of Exam le 2 3.3. C Pre aration of seed cr stals ofanh drous Form B Small amounts of crude Example 2 (1-2 were suspended in approximately 0.1 ml of propanol and water mixtures with 3.3% of water and another with 6.6% water). AAer a (one heating/cooling cycle, the samples resulted in suspensions of crystalline anhydrous Form B X-ray diffraction The in to the powder analysis. samples anhydrous 2-propanol subjected same conditions resulted in the mixture of Form A and Form B as analysed X-ray powder 'C diffraction. The mixture of Form A and Form slurried at for 4 in mixtures of B, days water and the following solvents: methanol, ethanol, 2-propanol, 1-propanol, and acetone (all with 9% resulted in Form B as analysed X-ray diffraction. approximately water), powder a. Cr stallization fromn- ro anoVwater: of crude Example 2 is dissolved in 160 ml of n-propanoVwater mixture v/v) at a (9:1, &65'C. of The solution is cooled to 60'C, with Form B temperature seeded anhydrous crystals 'C of and for hr. The is cooled to over at least hrs.
Example 2, aged 0.5 slurry 5 Optionally 'C the is distilled at under reduced to reduce the volume to slurry pressure approximately 80-100 ml in order to maximize the yield. The slurry is further cooled to C and the slurry is for at least hrs or until Form A is no detected. The is filtered aged 8 anhydrous longer slurry and the wet cake is dried at under vacuum. Form B of 2 is 60 Anhydrous Example obtained as a white solid in a 90% X-ray diffraction conforms to the yield. powder (XRPD) anhydrous Form B standard on file. b. Cr stallization from tetrah drofuran/water: 1 of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture Approximately &60'C. 40-50'C, at a temperature of The solution is cooled to seeded with (8:2, v/v) 'C anhydrous Form B crystals of Example and is further cooled to over 2 hrs. ml of antisolvent solvent such as Approximately (an organic isopropyl alcohol, ethyl or is added to the The is for at least hrs or alcohol, acetone) slurry. resulting slurry aged 8 until anhydrous Form A is no longer detected. The slurry is then filtered and the wet cake is dried at 60 under vacuum. Anhydrous Form B of Example 2 is obtained as a white solid.
X-ray diffraction conforms to the Form B standard on file. powder (XRPD) anhydrous 2013/026797 T/EP2012/066104 WO PC Conversion from Dih drate: 1 of Dihydrate of Example 2 is in 5-10 ml of an anhydrous Approximately suspended solvent such as ethanol, methanol, isopropanol, acetone, ethyl acetate, acetate, isopropyl tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form B crystals of 2 and stirred at 20-40 for at least 4 hrs or until the conversion to Form Example anhydrous B is as checked X-ray diffraction complete powder (XRPD) analysis.
Conversion from anh drous Form A: 1 of Form A of 2 is in 5-10 ml an Approximately anhydrous Example suspended of anhydrous solvent such as ethanol, methanol, acetone, acetate, isopropanol, ethyl isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form B of 2 and stirred at 20-40 for at least 4 hrs or until the conversion to crystals Example Form B is as checked X-ray diffraction anhydrous complete powder (XRPD) analysis. 3.3.2.3 C stallization to Dih drate Form of Exam le 2 Pre arationofseed cr stals ofthe Dih drate Form The mixture of Form A and Form B of slurried at anhydrous anhydrous crystals Example 2, 'C for 4 in 2-butanone/water 9 lo resulted in the Dihydrate crystals as days (with water), confirmed X-ray powder diffraction analysis. a. Cr stallization fromn- ro anoVwater: of crude Example 2 is dissolved in 120 ml of n-propanoVwater mixture at a (8:2, v/v) &65'C. temperature of The solution is cooled to 50'C, seeded with Dihydrate crystals of Example and aged for 0.5 hr. Water (approximately 60-100 ml) is added to the slurry. The 'C is cooled to over at least hrs and then for at least hrs. The is slurry 5 aged 8 slurry filtered, and the wet cake is washed with water and then air-dried. 2013/026797 T/EP2012/066104 WO PC Cr stallization in THF/water: 1 of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture Approximately &60'C. 30-50'C, at a temperature of The solution is cooled to seeded with (8:2, v/v) 'C Dihydrate crystals of Example and further cooled to over 2 hrs. Approximately 10 ml of water is added to the The is for at least hrs. The is slurry. resulting slurry aged 8 slurry and the wet cake is washed with water and then air-dried. X-ray diffraction filtered, powder of the product shows the Dihydrate pattern.
(XRPD) Conversion from anh drous Form A or from anh drous Form B: 1 of Form A or of Form B of 2 is Approximately anhydrous anhydrous Example suspended in 5-10 ml of a mixture of at least 30% water and an organic solvent such as approximately ethanol, methanol, isopropanol, acetone, or tetrahydrofuran. The suspension is seeded with 'C of 2 and stirred at for at least 4 hrs or until the conversion to Dihydrate crystals Example the Form is as checked X-ray diffraction Dihydrate complete powder (XRPD) analysis.
The is filtered, and the wet cake is washed with water and then air-dried. slurry The polymorphs of Example 2 were characterized X-ray powder diffraction (XRPD) as shown in Figures 3a, 3b and 3c showing the X-ray powder diffraction diagrams and the tables with all observable reflex For the performance of the X-ray diffraction analysis peaks. powder a Rigaku Miniflex II instrument was used with an X-ray generator of the Power 450 W type kV-15 mA) (Optics: variable divergence slit). The Goniometer range was 3.0 35.0 2 0 02' 01'. and the scan speed was 0. 2 0/min with an accuracy of more than 0. As a monochromator a foil was and as a detector the scintillation counter Nal filter/graphite used 23.0 mm diameter was used. The sample was analysed on a low background Si sample (510) holder.
The of 2 were further characterized differential polymorphs Example scanning calorimetry with a TA Instruments DSC as shown in Figures 5a and 6a. The samples (DSC) Q1000 4a, were analyzed in an unsealed Aluminium under an flow. The ramp that was used for pan Nz 'C/min 20'C 300'C. the measurements was from to The of Example 2 were further characterized thermogravimetric analysis polymorphs with a TA Instruments TGA as shown in Figures 5b and 6b. The samples (TGA) Q500 4b, 2013/026797 T/EP2012/066104 WO PC were in an under flow. The that was for the analyzed open platinum sample pan Nz ramp used 'C/min 20'C 300'C. measurements was from to FIGURES: 1a: gastric for rats that had received Example 1 Fig. emptying Fig. 1b: intestinal transit for rats that had received Example 1 2a: for rats that had received 2 Fig. gastric emptying Example 2b: intestinal transit for rats that had received 2 Fig. Example 3a: X-ray diffraction diagram of anhydrous form A of Example 2 Fig. powder 3b: X-ray powder diffraction diagram of anhydrous form B of Example 2 Fig.
X-ray diffraction of form of 2 Fig. 3c: powder diagram dihydrate C Example 4a: Differential Calorimetric of the Form A of Fig. Scanning (DSC) anhydrous Example 2 indicates a melt endotherm at about 235'C, followed a (DSC decomposition when heating continued above melting) Fig. 4b: Thermogravimetric Analysis of the anhydrous Form A of Example 2 (TGA) non-solvated (TGA indicates form as shown negligible volatile content (minimal loss of 145 to the melting weight (0. temperature) %) up 5a: Differential Scanning Calorimetric of the anhydrous Form B of Fig. (DSC) solid-solid Example 2 (DSC indicates either a transition or a simultaneous 218'C. melt/recrystallization occuring at about The resulting form is most form A as indicated the melt exotherm at 235'C, likely anhydrous corresponding to the melting point of form A. After the melting of form A the 240'C) compound is decomposed when heated above Fig. 5b: Thermogravimetric Analysis of the anhydrous form B of Example 2 (TGA) shows volatile content for form B non-solvated (TGA negligible (indicated as shown the minimal loss 057 to the melting form) weight (0. by %) up temperature) Fig. 6a: Differential Scanning Calorimetric of the dihydrate Form C of Example (DSC) 2 indicates low as indicated the broad (DSC temperature dehydration &100'C. endotherm at The dehydrated solid is most form A as indicated likely 236'C the melt endotherm occuring at about characteristic of form A. Form A is then decomposed when heated above melting temperature), 2013/026797 T/EP2012/066104 WO PC Thermogravimetric of the form of 2 Fig. 6b: Analysis (TGA) dihydrate C Example shows a loss for form C indicating the dehydration (TGA large weight &100'C. heating at The dehydrated material form shows almost no (likely A) 100'C 236'C) weight loss to melting (from to consistent with the previous observations for form 2013/026797 T/EP2012/066104 WO PC 4 Exam les: The following Examples were to the methods of synthesis described prepared analogously hereinbefore.
Table A: Chemical structures of the example compounds of the instant invention Example No. Chemical Structure wherein stands for a sulphur atom which represents a chiral center wherein stands for a atom which a chiral sulphur represents center The following Prior Art compounds A to D are the structurally closest compounds disclosed in which is the closest piece of prior art. 2013/026797 T/EP2012/066104 WO PC Table B: Chemical structures of the closest disclosed in structurally compounds WO 2009/050248.
Prior art Chemical Structure compound Prior art compound A (= 2 of Example Ol-I wherein stands for a sulphur atom which represents a chiral center Prior art compound B Example 27 of wherein stands for a sulphur atom which represents a chiral center Prior art compound C (= 34 of Example wherein stands for a sulphur atom which represents a chiral 2013/026797 T/EP2012/066104 WO PC center Prior art D compound (=Example 39 of wherein stands for a sulphur atom which represents a chiral center 2013/026797 T/EP2012/066104 WO PC BIOLOGICAL EXPERIMENTS .1 Determination of the PDE4B IC~0-values in vitro The IC50-values of the compounds of the invention (Example Compounds 1 and and of the above-mentioned art A to D with to their PDE4B-inhibiting prior compounds respect ability have been determined with a Scintillation Proximity (SPA) Assay (GE Healthcare, No.
TRKQ7090).
The Scintillation Proximity Assay is based on the detection of the different affinities of (SPA) 3'-5 '-adenosine 5'-adenosine the cyclic monophosphate (cAMP, low affinity) and the linear to yttrium-silicate-scintilator beads. The cAMP-specific monophosphate (AMP, high affinity) PDE4B cleaves the 3'-phosphodiester bond of the tritium-labelled- phosphodiesterase (PDE) H]5'-AMP. H]5'-AMP H]cAMP to the This associates with the scintillator beads [ [ [ because of their higher affinity and causes scintillations (light flashes) which can be measured in a Wallac Microbeta Scintillation Counter. of a H]cAMP-solution 05 in 10 30 Ci/mmol) are added to 89 of a pl (0. pCi H20, pl PDE4B-enzyme-solution (active site fragment comprising the amino acids 152 484; 0. 0.18 in assay buffer mM Tris HC1 7. 8.3 mM 7 mM ethylene glyclol ng) (50 pH 5; MgC12, 1, tetraacetic acid 25 ml bovine serum albumin and this mixture is (EGTA); 0. / mg (BSA)) incubated at 30 for one hour without the compound to be tested the presence of 1 dimethylsulfoxide a) (in pl (DMSO), to 1% and corresponding DMSO) in the of the to tested in a concentration of 125 25 presence compound be b) pM, pM, 5@M, 200 40 8 1.6 0.32 0.064 0.0128 nM (dilution series in 5er- I@M, nM, nM, nM, nM, nM, nM, steps beginning from 125 until 0.0128 nM, in the presence of 1% DMSO). bead-solution Afler this incubation the reaction is stopped the addition of 50 of (500 by pl mg beads / 35 ml H20, 18 mM zinc sulfate). In the following 45 minutes the beads have the to form a sediment. Afler that the scintillations are measured in the scintillation opportunity 2013/026797 T/EP2012/066104 WO PC counter. Ifthe tested is able to inhibit the of the PDE4B- compound enzymatic activity less ['H]AMP on the concentration of the tested is enzyme, depending compound produced and less scintillations are measurable. These results are expressed as IC50-values. The IC50- value stands for the compound concentration at which the PDE4B enzyme activity is inhibited to a half maximal value. Therefore the lower the IC50-value is the better is the PDE4B inhibition.
Table C: Experimentally determined IC50-values with respect to PDE4B inhibition for the of the invention and for the Prior art as disclosed in 2009/050248 compounds compounds WO Compound Experimentally determined IC50-value for PDE4B inhibition [nM] Example 1 4.3 Example 2 7.2 Prior art A compound 3.3 Prior art compound B 66 Prior art compound C 44 Prior art D 7.3 compound art A and D have values in the same as 1 Only prior compounds IC50 potency range Examples and 2. all further experiments have been performed with Examples 1 and 2 Consequently just and with prior art compounds A and D. 2013/026797 T/EP2012/066104 WO PC half- .2 Determination of the dose response relationship and calculation of the maximal effective in to the inhibition of LPS-induced dose regard neutrophil influx into bronchoalveolar lavage fluid of male Wistar rats The anti-inflammatory of 1 and 2 and of Prior art A and D was activity Examples compounds assessed in an in vivo LPS-induced inflammation model in rats. lung half- As a measure of the pharmacological of the above mentioned compounds the potency maximal effective dose in regard to the inhibition of lipopolysaccharide-induced (LPS- (ED5o) neutrophil influx into the bronchoalveolar fluid was determined induced) lavage (BALF) assessing the dose response relationship. Bacterial endotoxins (lipopolysaccharides are [LPS]) components of the outer bacterial cell membrane which an important role in the play pathogenesis of infections with gram-negative bacteria. It is known that inhalation of such aerosolized LPS induces a dose-dependent increase in to tissues and neutrophils lung airspaces in rats which be detected the amount of neutrophils in the may by analyzing bronchoalveolar lavage fluid However, this dose-dependent increase of neutrophils (BALF). in the BALF should be diminished in a dose-dependent in the presence of an effective PDE4-inhibitor.
Male Wistar rats from an local distributor were used for the (HanWistar) approved experiments. The ordered weight of the animals was in the range of 200-250 Animals were fasted before the A total number of 32 animals were for each overnight experiment. used experiment. animals dose were used for the treatment two animals Eight (n=8) per groups, were used for the LPS-control control) and two animals for the negative control. (positive LPS-control received"vehicle only" The animals of the and of the negative control groups vehicle only" to 10 Natrosol The other corresponds mVkg body weight 0,5 % solution). were treated with the different doses of either Example Example groups compound 1, compound Prior art compound A or Prior art compound D respectively Table 2, (see D).
The amount of for the concentration tested for each was compound highest compound in 10 ml Natrosol solution and then diluted to the suspended 0.5% (Hydroxyethylcellulose) respective concentrations as shown in Table D. The respective compound suspension or 2013/026797 T/EP2012/066104 WO PC "vehicle only" Natrosol was administered (10 mVkg body weight 0.5 % solution) orally The resulting doses of the individual compounds corresponded to Table D: gavage.
Table D: Tested com ounds and their res ective doses Concentration of the Compound Dose (mg/kg) Stock Solution (mg/mi) Example 1 0.3 1.0 3.0 0.3 Example 2 0.01 0.10 1.00 0.
Prior art compound A 0.3 1.0 3.0 0.3 Prio art compound D 0.3 1.0 3.0 0.3 The above doses were determined due to previous tests in the LPS TNF Ex vivo mouse model.
One hour 5 hour for Prior art compound A and for Prior art compound aAer compound (0. D) application (time set to allow for sufficient exposure as guided prior pharmacokinetic the animals were to nebulised/aerosolized LPS. The whole experiments) exposed body exposure of 12 animals each was performed in a plexi chamber. Animals were glas separated/individualized with perforated metal plates. The aerosol was generated with a commercially available nebuliser (PARI Master PARI LL nebuliser (Pari GmbH). The concentration of the nebulized LPS-solution was 1 air. The duration of the LPS mg/ml was 30 minutes. exposure 4 hours aAer the end of LPS exposure animals were anesthetised with Isoflorane and euthanised thereaAer cervical dislocation. The trachea was cannulated and BALF was performed 2x 5mL buffer buffered saline 2% using lavage (phosphate (PBS) BSA). 2013/026797 T/EP2012/066104 WO PC Determination of content of the BALF was an ADVIA 120 blood neutrophil performed using hemacytometer Neutrophil data were normalised (Positive Control (Bayer Diagnostics).
(=LPS treatment alone) 100%, Negative Control LPS treatment, administration of "vehicle only" )= and expressed as percent of LPS control. The ED50 was calculated using a nonlinear fit the Pad Prism Aware and a (with Graph so sigmoidal dose response fit).
The ED50-value is the half-maximal effective dosis of the compound in question with respect LPS-induced to its inhibition of an neutrophil influx into BALF. Consequently a very small ED50-value stands for a of the to good capability respective compound prevent neutrophil influx into the tissue aAer LPS and therefore for a of the lung exposure good capacity respective to inflammation of the tissue. Since the ED50-value is compound prevent lung unlike the IC50 value not the result of an in vitro assay, but the result of an in vivo assay in rats and since here not the direct inhibition of the PDE4B but the performed only enzyme, influx into the tissue aAer LPS-exposure is the ED50 value is neutrophil lung measured, already a sensitive parameter for a compound's suitability to serve as a therapeutic very agent in inflammatory airway diseases like COPD and asthma (which are both inflammatory diseases).
Exposure of rats with LPS led to a distinct neutrophil influx into the BALF.
Pretreatment of rats with compounds Example Example Prior art compound A and Prior 1, 2, art D led to an inhibition of the LPS-induced influx into the BALF. The compound neutrophil calculated values for the various compounds are given in Table E.
ED50 Table E: ED50 values of the tested com ounds which were calculated from the ex erimental data: ED»(mg/kg body Compound weight) Example 1 0.31 Example 2 0.1 Prior art A 1.13 compound Prior art D compound 6.66 2013/026797 T/EP2012/066104 WO PC The experimentally determined ED5p-values for the compounds of the invention that means for 1 31 and for 2 1 Example (ED5p 0. mg/kg body weight) Example (ED5p 0. mg/kg body demonstrate that these compounds of the invention, Example 1 and Example are weight) 2, between 3 to 66 times more potent in this assay than prior art compounds A and D.
Therefore the compounds of the invention show a better to prevent the influx of potency into the tissue and are therefore a lot more suitable to as a neutrophils lung be used therapeutic to treat inflammatory respiratory diseases such as asthma and COPD. 2013/026797 T/EP2012/066104 WO PC .3 Gastric em t in and astrointestinal transit in conscious rats In order to identify an active which is suitable to serve as a therapeutic PDE4 inhibitor it agent 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 within the field of PDE4 inhibitors be prominent "PDE4-inhibitors: Diamant, Z. D. a novel targeted for obstructive (see Spina, therapy airways disease", Pulm. Pharmacol. Ther. 2011, 24 353-360 and Press, N.J. Banner, (4), pp. ; "PDE4 Field"; K.H. Inhibitors A Review of the Current Progress in Medicinal Chemistry 37-74). 2009, 47; The experiments 1.1 and 1.2 above have shown that the compounds of the invention are clearly more potent with respect to PDE4B enzyme inhibition and/or more potent with respect to preventing neutrophil influx into the lung tissue and are therefore advantageous over the structurally related compounds disclosed in , in particular in comparison to Compounds C and D.
A, B, In order to evaluate whether the compounds of the present invention lead to gastrointestinal side effects the compounds of the invention have been administered to rats 30 minutes before the rats were fed with a test meal barium sulfate. AAer that it was tested whether comprising gastric and/or gastrointestinal transit in these rats was affected the of emptying by presence these compounds.
The effects of the compounds Example 1 and Example 2 on gastric and emptying gastrointestinal transit in concious rats has been as described below. investigated Wistar rats of both sexes 130-160 male female were The animals weighing (ages: 7 wk, 8 wk) used. are obtained from an local a minimum of four is before approved distributor, days quarantine required which time the animals are maintained under routine animal care of use, during procedures. Groups to animals are housed in in a room with controlled and and a cages temperature humidity light/dark with the on from a.m. to m. The animals have access to normal rodent chow and cycle lights 6 6 . water ad libitum. The animals are to the on the of experimentation. transported laboratory day Gastric as well as small intestinal are determined a barium sulfate test meal. emptying propulsion using 2013/026797 T/EP2012/066104 WO PC Five rats Crl:WI(Han) of each sex (n=10) were used. The animals were deprived of food 17 h prior to the experiment but allowed free access to water.
The under investigation was suspended to the concentration of 10 mV weight in 0.5 drug (drug kg body % Natrosol solution) or the negative control (vehicle alone was given 10 mVkg body weight was -fold 30-fold administered 30 min. o. before the test meal at doses calculated to be 3-fold, or the ED5o found in efficacy studies in the rat.
Compound Dose 3-fold Dose 10-fold Dose 30-fold ED5O ED5O ED5O o. o. o. [mg/kg body weight p. [mg/kg body weight p. [mg/kg body weight p.
] ] ] Example 1 31 1.0 3.0 10.0 (ED5p 0, mg/kg Example 1 1.
(ED5p 0, 0.3 0 3.0 mg/kg BW) The test meal of 7.5 barium sulfate in 10 ml salt-free is orally at a (suspension water) given by gavage dose of 2 mV100 weight. Thirty minutes after the administration of the test meal the animals body were killed in isoflurane anaesthesia cervical dislocation. The stomach and the intestine were deep by then and removed. exposed by laparatomy The removed stomach was then incised, the contents removed and the stomach is weighed, empty weighed again.
The length of traversed with barium sulfate in relation to the whole length of the is determined gut gut direct measurements a ruler. by using Evaluation of gastric emptying The gastric content was calculated from the weight difference between the filled and stomach empty and normalized to 100 body weight. Thus, an increase in weight difference indicated an impaired gastric whereas a decrease in weight difference indicated an enhanced gastric emptying. emptying, 2013/026797 T/EP2012/066104 WO PC Evaluation of intestinal transit The length of traversed with barium sulphate visual inspection) in relation to the gut (as judged by whole length of the (from the to the rectum) is determined direct measurements using a gut pylorus by ruler.
Intestinal transit is calculated as the percentage movement of barium sulphate in the intestine in relation to the whole length of the Consequently an increased intestinal transit length indicated an gut. accelerated intestinal transit whereas a decreased intestinal transit length indicated decelerated intestinal transit.
Statistics Data are expressed as mean standard deviation For each comparisons were performed (SD). dose, an analysis of variance and a hoc Dunnett test to compare the various to using (ANOVA) post groups the controls when the ANOVA was significant. 0.05 was considered significant.
Consequently the compounds of the invention show no statistically relevant gastrointestinal side effects, even at doses which are to the 30-fold ED5o-dosis, because as shown in 1a up Fig. and b and 2a and b rats which had received either example 1 or 2 neither showed a substantially enhanced or impaired gastric nor a substantially accelerated or emptying -fold decelerated intestinal transit even at doses to ED5o-dose.
For Example 1 the gastric shows no relevant differences at a 3-fold ED5o dose and emptying at a 10-fold and a moderate enhancement of the difference ED5o dose, only very weight per at a 30-fold the intestinal transits for the body weight ED5o dose. However, corresponding animals which received Example 1 showed no significant differences compared to compound -fold those intestinal transits of the negative controls even to the ED5o dose.
For Example 2 both the gastric and the intestinal transit showed no relevant emptying differences to the control all tested of compared negative during doses Example compound 2, not even at the 30-fold dose.
ED5o Consequently the compounds of the invention are not only more potent with respect to PDE4B inhibition than the compounds disclosed in shown in Experiments 1.1 and 1. but also show no relevant gastrointestinal side effects. 2013/026797 T/EP2012/066104 WO PC 6. INDICATIONS The of formula I have a broad in different fields. Particular compounds potential therapeutic mention should made of those for which the to the be applications compounds according invention of formula I are preferably suited on account of their pharmaceutical efficacy as PDE4 inhibitors. Examples include respiratory or gastrointestinal diseases or complaints, inflammatory diseases of the joints, skin or cancers, and also diseases of the peripheral eyes, or central nervous system.
Particular mention should be made of the prevention and treatment of diseases of the airways and of the which are accompanied increased mucus production, inflammations and/or lung by obstructive diseases of the airways. Examples include acute, allergic or chronic bronchitis, chronic obstructive bronchitis pulmonary allergic or non- (COPD), coughing, emphysema, Farmer's allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, disease, infectious bronchitis or pneumonitis, paediatric asthma, hyperreactive airways, bronchiectases, fibrosis, ARDS adult distress pulmonary (acute respiratory syndrome), bronchial oedema, oedema, bronchitis, pneumonia or interstitial pneumonia pulmonary various such as inhalation of toxic or triggered causes, aspiration, gases, bronchitis, or interstitial as a result of heart irradiation, pneumonia pneumonia failure, chemotherapy, fibrosis or mucoviscidosis, or alphal-antitrypsin deficiency. cystic Also deserving special mention is the treatment of inflammatory diseases of the gastrointestinal tract. Examples include acute or chronic inflammatory changes in gall Crohn's bladder inflammation, disease, ulcerative colitis, inflammatory pseudopolyps, juvenile colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the polyps, bile duct and gall bladder, e. gallstones and conglomerates, inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.
Preferential mention should also be made to the treatment of sarcoidosis.
Preferential mention should also be made of the treatment of cancers. Examples include all forms of acute and chronic leukaemias such as acute and acute leukaemia, lymphatic myeloid chronic and chronic leukaemia as well as bone tumours such as e. lymphatic myeloid osteosarcoma and all kinds of gliomas such as e. oligodendroglioma and glioblastoma. 2013/026797 T/EP2012/066104 WO PC Preferential mention should also be made of the prevention and treatment of diseases of the peripheral or central nervous system. Examples of these include depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson' s disease, acute and chronic multiple sclerosis or acute and chronic as well as injuries to pain the brain caused stroke, or craniocerebral trauma. by hypoxia Particularly the invention relates to the use of compounds of formula I for preferably present a pharmaceutical composition for the treatment of inflammatory or obstructive preparing diseases of the and lower tract including the such as for example upper respiratory lungs, chronic allergic rhinitis, rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, chronic chronic Crohn's fibrosing alveolitis, COPD, bronchitis, sinusitis, asthma, disease, ulcerative alphaantitrypsin chronic bronchitis and colitis, deficiency, particularly COPD, asthma.
It is most preferable to use the compounds of formula for the treatment of inflammatory and Crohn's obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, disease, ulcerative colitis, rheumatoid arthritis, particularly COPD, chronic bronchitis and asthma.
It is also preferable to use the compounds of formula for the treatment of diseases of the or central nervous such as bipolar or manic acute peripheral system depression, depression, and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic as well as injuries to the brain caused pain stroke, or craniocerebral trauma. hypoxia It is also preferable to use the compounds of formula for the treatment of inflammatory "dry eyes" diseases of the in particular for the treatment of the syndrome and for the eyes, "dry eyes" treatment of glaucoma. Individuals with the syndrome suffer from ocular discomfort feeling; itching; stinging/burning; pain/soreness) and blurred vision. (dry, gritty The phosphodiesterase 4 enzymes regulate the biological processes of a host (PDE4) by degrading the second messenger cAMP. PDE4 inhibitors have been intensively investigated as antiinflammatory therapies because increases in cAMP levels are known to attentuate inflammatoy responses in multiple cell Govek et Bioorganic k Med. Chem. Lett types (see al, 2928-2932). , (2010), 2013/026797 T/EP2012/066104 WO PC Furthermore it is also preferable to use the compounds of formula for the treatment of diseases of the in particular for the treatment of glaucoma, since it has been shown that eyes, an increase in cAMP protects retinal ganglion cells from high intracellular pressure (IOP) induced cell death Seki T. et al, J Mol Neurosci. 2011 Jan;43(1):30-4. and an increase in (see cAMP is involved in the reduction of IOP Naveh N. et al. Br J Ophthalmol. 2000 (see Dec;84(12):1411-4),the main reason for the development of glaucoma. 2013/026797 T/EP2012/066104 WO PC 7. Combinations The compounds of formula be used on their own or in conjunction with other active substances of formula according to the invention. If desired the compounds of formula 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 other PDE4-inhibitors, LTD4-antagonists, betamimetics, anticholinergics, corticosteroids, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists, Hl-antihistamines, PAF-antagonists and PI3-kinase inhibitors, NSAIDS, COX 2 inhibitors, EP 4-receptor antagonists or double or triple combinations thereof, such as for example combinations of compounds of formula with one or two compounds selected from among EP 4-receptor antagonists, NSAIDS, COX 2 inhibitors and corticosteroids, ~ EGFR-inhibitors betamimetics, corticosteroids, PDE4-inhibitors, and LTD4-antagonists, PDE4-inhibitors, EGFR-inhibitors and anticholinergics, betamimetics, corticosteroids, LTD4-antagonists, PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists EGFR-inhibitors and LTD4-antagonists iNOS-inhibitors CCR3-inhibitors, (inducible nitric oxide synthase-inhibitors), (6R)-L- "BH4") erythro-5, 6,7,8-tetrahydrobiopterin (hereinafter referred to as and the derivatives thereof as mentioned in and SYK-inhibitors tyrosine kinase (spleen inhibitors) PDE4-inhibitors MRP4-inhibitors. anticholinergics, betamimetics, corticosteroids, and The invention also relates to combinations of three active substances, each chosen from one of the above-mentioned categories of compounds.
Suitable betamimetics used are preferably compounds selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, rimiterol, pirbuterol, procaterol, reproterol, 2013/026797 T/EP2012/066104 WO PC ritodrine, salmeterol, salmefamol, soterenol, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-(6-[2-hydroxy(4-hydroxyhydroxymethyl- 6-diethyl-indan phenyl)-ethylamino]-hexyloxy) -butyl)-benzyl-sulphonamide, 5-[2-(5. linone, 4-hydroxy[2- ylamino)hydroxy-ethyl]hydroxy-1H-quino [2- [3-(2- 1-(2-fluoro phenylethoxy)propyl]sulphonyl)ethyl]-amino)ethyl]-2(3H)-benzothiazolone, lyl)methylbutylamino] ethano 1-[3-(4- hydroxyphenyl)[4-(1-benzimidazo 1, methoxybenzyl-amino)hydroxyphenyl][4-(1-benzimidazo lyl)methyl 1-[2Hhydroxyoxo-4H- L4-benzoxazinyl][3-(4-N, N- butylamino] ethanol, 1-[2Hhydroxyoxo-4H-1, dimethylaminophenyl)methylpropylamino] ethanol, benzoxazinyl][3-(4-methoxyphenyl)methylpropylamino]ethanol, 1-[2H hydroxyoxo-4H-1, 4-benzoxazinyl][3-(4-n-butyloxyphenyl)methyl ethanol, 1-[2Hhydroxyoxo-4H-1, 4-benzoxazinyl] (4-[3-(4- propylamino] 4-triazo1yl]methylbutylamino)ethanol, 5-hydroxy(1- methoxyphenyl)-1, 2, 4-benzoxazin(4H)-one, 1-(4-aminochloro hydroxyisopropylaminobutyl)-2H-1, trifluoromethylphenyl)tert. -butylamino) ethanol, 6-hydroxy (1-hydroxy[2-(4- -4H-benzo methoxy-phenyl)-1, 1-dimethyl-ethylamino]-ethyl) 4]oxazinone, 6-hydroxy (1-hydroxy[2-( ethyl 4-phenoxy-acetate)-1, 1-dimethyl-ethylamino]-ethyl)-4H- 6-hydroxy 1-dimethyl- benzo[1, 4]oxazinone, (1-hydroxy[2-(4-phenoxy-acetic acid)-1, 8- 6- -4H-benzo 4]oxazinone, 1-dimethyl(2, ethylamino]-ethyl) (2-[1, 4, trimethylphenyl)-ethylamino]hydroxy-ethyl) hydroxy-4H-benzo 4]oxazinone, hydroxy (1-hydroxy[2-(4-hydroxy-phenyl)-1, 1-dimethyl-ethylamino]-ethyl)-4H- 6-hydroxy 1-dimethyl- benzo[1, 4]oxazinone, (1-hydroxy[2-(4-isopropyl-phenyl)-1, -4H-benzo 4]oxazinone, 1-dimethyl- ethylamino]-ethyl) (2-[2-(4-ethyl-phenyl)-1, ethylamino]hydroxy-ethyl) hydroxy-4H-benzo 4]oxazinone, (2-[2-(4-ethoxy- phenyl)-1, 1-dimethyl-ethylamino]hydroxy-ethyl)hydroxy-4H-benzo 4]oxazinone, 4-(4- 4-dihydro-2H-benzo (2-[2-hydroxy(6-hydroxyoxo-3. 4]oxazinyl)- 8- 1- 4-difluoro-phenyl)-1, ethylamino]methyl-propyl)-phenoxy)-butyric acid, (2-[2-(3. dimethyl-ethylamino]hydroxy-ethyl) hydroxy-4H-benzo 4]oxazinone and 1-(4- ethoxy-carbonylaminocyanofluorophenyl)(tert. -butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the acceptable acid addition salts, solvates or hydrates thereof. pharmacologically 2013/026797 T/EP2012/066104 WO PC to the invention the acid addition salts of the betamimetics are selected According preferably from the hydrochloride, hydrobromide, among hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, fumarate and Of the above-mentioned acid hydrophosphate, hydro hydromethanesulphonate. addition salts the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are to the invention. particularly preferred according The are selected from the anticholinergics used preferably compounds among tiotropium salts, oxitropium salts, flutropium salts, salts, salts, trospium ipratropium glycopyrronium salts, tropeno12, 2-diphenylpropionate methobromide, scopine 2-diphenylpropionate 2-fluoro-2, 2-fluoro-2, 2- methobromide, scopine 2-diphenylacetate methobromide, tropeno1 4'-tetrafluorobenzilate diphenylacetate methobromide, tropeno1 3, 4, methobromide, scopine 4'-tetrafluorobenzilate methobromide, tropeno1 4'-difluorobenzilate methobromide, 3, 4, 4, 4'-difluorobenzilate 3'-difluorobenzilate scopine methobromide, tropeno13, methobromide, 3'-difluorobenzilate scopine methobromide, tropeno 1 9-hydroxy-fluorenecarboxylate- methobromide, tropeno19-fluoro-fluorenecarboxylate -methobromide, scopine 9-hydroxy- fluorencarboxylate methobromide, 9-fluoro-fluorenecarboxylate methobromide, scopine tropeno1 9-methyl-fluorenecarboxylate methobromide, scopine 9-methyl-fluorene carboxylate methobromide, benzilate methobromide, cyclopropyltropine cyclopropyltropine 9-hydroxy-xanthene 2-diphenylpropionate methobromide, cyclopropyltropine 9-methyl-fluorenecarboxylate carboxylate methobromide, cyclopropyltropine methobromide, 9-methyl-xanthenecarboxylate methobromide, cyclopropyltropine 9-hydroxy-fluorenecarboxylate methobromide, methyl- cyclopropyltropine 4'-difluorobenzilate 9-hydroxy-xanthene cyclopropyltropine methobromide, tropeno 1 -methobromide, 9-hydroxy-xanthenecarboxylate carboxylate scopine methobromide, tropeno1 9-methyl-xanthenecarboxylate methobromide, 9-methyl-xanthene scopine carboxylate methobromide, tropeno19-ethyl-xanthenecarboxylate methobromide, tropenol 9-difluoromethyl-xanthenecarboxylate methobromide, scopine 9-hydroxymethyl-xanthene- 9-carboxylate methobromide, in the form of the solvates or hydrates thereof. optionally 2013/026797 T/EP2012/066104 WO PC In the above-mentioned salts the cations tiotropium, oxitropium, flutropium, ipratropium, and trospium are the active ingredients. As anions, the glycopyrronium pharmacologically above-mentioned salts preferably contain chloride, bromide, iodide, sulphate, may phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or while p-toluenesulphonate, chloride, bromide, iodide, sulphate, or are as counter-ions. Of all the the methanesulphonate p-toluenesulphonate preferred salts, chlorides, bromides, iodides and methanesulphonate are particularly preferred.
Of particular importance is tiotropium bromide. In the case of tiotropium bromide the combinations to the invention contain it in the form of pharmaceutical according preferably the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. Ifthe 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.
Corticosteroids used here are compounds selected from prednisolone, preferably among prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, RPR-106541, NS-126, 9-difluoro[(2- deflazacort, (S)-fluoromethyl 6, furanylcarbonyl)oxy]hydroxymethyloxo-androsta-1, 4-dienecarbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 9-difluorohydroxymethyloxo 4-dienecarbothionate, propionyloxy-androsta-1, 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 among flunisolide, beclomethasone, triamcino lone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, NS-126, 9-difluoro[(2-furanylcarbonyl)oxy] dexamethasone, (S)-fluoromethyl 6, hydroxymethyloxo-androsta-1, 4-dienecarbothionate and (S)-(2-oxo-tetrahydro- 4-diene- furan-3S-yl) 9-difluorohydroxymethyloxopropionyloxy-androsta-1, 17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers 2013/026797 T/EP2012/066104 WO PC thereof and in the form of the salts and solvates and/or optionally derivatives, hydrates thereof. reference to steroids includes a reference to salts or derivatives, hydrates or solvates Any any thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal such as for sodium or salts, example potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen palmitates, pivalates or furoates phosphates, thereof.
Other PDE4 inhibitors which are selected from may be used preferably compounds among roflumilast, ariflo tofimilast, lirimilast, enprofyllin, theophyllin, (cilomilast), pumafentrin, arofyllin, atizoram, D-4396 (Sch-351591),AWD281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 5-dichloro-l-oxo-pyridinyl)difluoromethoxy N-(3, 10bS*)ethoxy-1, 10b-hexahydro cyclopropylmethoxybenzamide, (-)p-[(4aR*. 2,3,4,4a, methoxymethylbenzo[s][1. 6]naphthyridinyl]-N, N-diisopropylbenzamide, (R)-(+)(4- bromobenzyl)[(3-cyclopentyloxy)methoxyphenyl]pyrrolidone, 3-(cyclopentyloxy methoxyphenyl)(4-N'-[Ncyano-S-methyl-isothioureido]benzyl)pyrrolidone, cis[4- cyano(3-cyclopentyloxymethoxyphenyl)cyclohexanecarboxylic acid], carbomethoxycyano(3-cyclopropylmethoxydifluoromethoxyphenyl) hexane cyclo one, cis[4-cyano(3-cyclopropylmethoxydifluoromethoxyphenyl)cyclohexan-l-ol], (R)- (+)-ethyl[4-(3-cyclopentyloxymethoxyphenyl)pyrrolidinylidene] acetate, (S)-(-)-ethyl[4- 6-dihydro- (3-cyclopentyloxymethoxyphenyl)pyrro lidinylidene] acetate, 9-cyclopenty1-5, 7-ethyl(2-thienyl)-9H-pyrazo lo 4-c]-1, 4-triazolo and 9-cyclopenty1-5, 2, 3-a]pyridine [3, [4, dihydroethyl(tert-butyl)-9H-pyrazolo[3, 4-c]-1, 4-triazolo[4, 3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the acceptable acid addition salts, solvates and/or hydrates thereof. pharmacologically acid addition salts with pharmacologically acceptable acids which the above-mentioned PDE4-inhibitors might be in a position to form are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, 2013/026797 T/EP2012/066104 WO PC hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, fumarate and hydrophosphate, hydro hydromethanesulphonate.
EP 4 receptor antagonists which may be used are preferably compounds selected from among [N- 9-diethoxyoxo-6, 8-dihydro-7H-pyrro lo quino line-7yl) [4-(5, [3,4-g] methylbenzyl] sulfonyl) (2-methoxyphenyl) acetamide]; -butyl-2, 4-dihydro[[2'-[N-(3-methylthiophene-carbonyl) sulfamoyl]biphenyl yl]methyl][(2-trifluoromethyl)phenyl]-1, 4-triazoleon; (4-((IS)-I-[((5-chloro[(4-fluorophenyl)oxy]phenyl)carbonyl)amino]ethyl)benzoic acid; (2-[4-(2-ethyl-4, 6-dimethyl- IH-imidazo N-[( 5-c]pyridinyl)phenyl] ethyl) amino) carbonyl]methylbenzo1 sulfonamide; sulfonyl] 4-[[4-(5-methoxypyridinyl)phenoxy]methyl]methyl-N-[(2-methylphenyl) furane carboxamide; -tetranor 11alpha, 15alpha-dihydroxy(3-methoxymethylphenyl)oxo-17, 18,19, acid thia-13(E) prostanoic methyl ester; 4-cyano[[2-(4-fluoro-I-naphthalenyl)-I-oxopropyl]amino]-benzene butyric acid and (2-[4-(4,9-diethoxyoxo-1, 3-dihydro-2H-benzo iso indo Iyl)phenyl] acetyl) benzene sulphonamide.
NSAIDS which be used are preferably compounds selected from among Aceclofenac, Acemetacin, Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin, Benorilat, Bermoprofen, Bindarit, Azapropazon, Bromfenac, Bucloxinsaure, Bucolom, Bufexamac, Bumadizon, Butibufen, Butixirat, Carbasalatcalcium, Cholin Magnesium Trisalicylat, Celecoxib, Cinmetacin, Carprofen, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Enfenaminsaure, Etofenamat, Droxicam, Eltenac, Etersalat, Etodolac, Etoricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac, Fenoprofen, Fentiazac, Fepradinol, Feprazon, Floctafenin, Flufenaminsaure, Flufenisal, Flobufen, Flunoxaprofen, Flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac, Ibuprofen, Indobufen, 2013/026797 T/EP2012/066104 WO PC Indometacin, Indometacinfarnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsaure, Meclofen, Mefenaminsaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton, Naproxen, Nifluminsaure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon, Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, Pranoprofen, Pirprofen, Prifelon, Prinomod, Proglumetacin, Protizininsaure, Rofecoxib, Romazarit, Proquazon, Salicylamid, Salicylsaure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenosal, Tenoxicam, Tiaprofensaure, Taramid, Tenidap, Tepoxalin, Tolfenaminsaure, Tilnoprofenarbamel, Timegadin, Tinoridin, Tiopinac, Tolmetin, Ufenamat, Valdecoxib, Zaltoprofen and Zoliprofen.
Ximoprofen, COX2-inhibitors which are selected from (Coxibe) may be used preferably compounds among Celecoxib, Meloxicam, Etoricoxib, Lumiracoxib, Parecoxib, Rofecoxib and Valdecoxib.
LTD4-antagonists which be used are compounds selected from may preferably among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM- VUF-K-8707, 7-difluoro 1507), VUF-5078, L-733321, 1-(((R)-(3-(2-(6, quinolinyl)ethenyl)phenyl)(2-(2- hydroxypropyl)phenyl)thio)methylcyclopropane-acetic 3-dichlorothieno 2-b]pyridinyl)-(E)-ethenyl)phenyl)(2-(1- acid, 1-(((1(R)-3(3-(2-(2. acid and [2-[[2-(4- hydroxy-I-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic tert-butylthiazolyl)benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the enantiomers or in the form of the racemates, diastereomers, optionally pharmacologically acceptable acid addition salts and in the form of the salts and derivatives, solvates optionally and/or hydrates thereof. acid addition salts with pharmacologically acceptable acids which the LTD4-antagonists of are for salts selected from the may be capable forming meant, example, among hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, fumarate and salts or derivatives which hydrophosphate, hydro hydromethanesulphonate. By 2013/026797 T/EP2012/066104 WO PC the LTD4-antagonists of are for alkali metal may be capable forming meant, example: salts, such for sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, as, example, isonicotinates, acetates, propionates, dihydrogen palmitates, pivalates phosphates, phosphates, or furo ates.
The EGFR-inhibitors are selected from 4-[(3-chloro used preferably compounds among fluorophenyl) amino] [4-(morpho linyl)oxobutenyl] amino cyclopropylmethoxy-quinazoline, 4-[(3-chlorofluorophenyl)amino]([4-(N, diethylamino)oxobutenyl] 4-[(3-chloro- amino cyclopropylmethoxy-quinazo line, amino] N-dimethylamino)oxobutenyl] amino 4-fluorophenyl) [4-(N, 4-[(R)-(1-phenyl-ethyl)amino] ([4-(morpholinyl)- cyclopropylmethoxy-quinazoline, 1-oxobutenyl] amino cyclopentyloxy-quinazo line, 4-[(3-chlorofluoro- amino] linyl)oxobutenyl] [4-((R)methyloxo-morpho amino phenyl) 4-[(3-chlorofluoro-phenyl)amino] cyclopropylmethoxy-quinazoline, ([4-((R)methyl- 2-oxo-morpho linyl)oxobutenyl]amino [(S)-(tetrahydrofuranyl)oxy]- quinazoline, 4-[(3-chlorofluoro-phenyl)amino]([4-((R)methoxymethyloxo- morpholinyl)oxobutenyl] amino cyclopropylmethoxy-quinazo line, 4-[(3- chlorofluoro-phenyl) amino][2-((S)methyloxo-morpho linyl)-ethoxy] methoxy-quinazoline, 4-[(3-chlorofluorophenyl)amino]((4-[N-(2-methoxy-ethyl)-N- methyl-amino]oxobutenyl) amino)cyclopropylmethoxy-quinazoline, 4-[(3-chloro- 4-fluorophenyl) amino] N-dimethylamino)oxobutenyl] amino [4-(N, N-bis-(2-methoxy- cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino] ([4-(N, ethyl)-amino)oxobutenyl] amino cyclopropylmethoxy-quinazo line, 4-[(R)-(1- phenyl-ethyl) amino]((4-[N-(2-methoxy-ethyl)-N-ethyl-amino]oxobuten amino)cyclopropylmethoxy-quinazo line, 4-[(R)-(1-phenyl-ethyl) amino]( (4-[N-(2- methoxy-ethyl)-N-methyl-amino]oxobutenyl) amino)cyclopropylmethoxy- amino]( quinazo line, 4-[(R)-(1-phenyl-ethyl) (4-[N-(tetrahydropyranyl)-N-methyl- amino]oxobutenyl) amino)cyclopropylmethoxy-quinazoline, 4-[(3-chloro amino] N-dimethylamino)oxobutenyl] amino ((R)- fluorophenyl) [4-(N, amino] N- tetrahydro furanyloxy)-quinazo line, 4-[(3-chlorofluorophenyl) [4-(N, dimethylamino)oxobutenyl] amino ((S)-tetrahydro furanyloxy)-quinazo line, [(3-chlorofluorophenyl) amino]( (4-[N-(2-methoxy-ethyl)-N-methyl-amino]oxo butenyl) amino)cyclopentyloxy-quinazoline, 4-[(3-chlorofluorophenyl)amino] ([4- 2013/026797 T/EP2012/066104 WO PC (N-cyclopropyl-N-methyl-amino)oxobutenyl] amino cyclopentyloxy-quinazo line, 4-[(3-chlorofluorophenyl) amino] N-dimethylamino)oxobutenyl] amino )— [4-(N, 7-[(R)-(tetrahydro furanyl)methoxy]-quinazo line, 4-[(3-chlorofluorophenyl) amino] N-dimethylamino)oxobutenyl]amino [4-(N, )[(S)-(tetrahydrofuranyl)methoxy]- 7-bis-(2-methoxy-ethoxy)-quinazo 4-[(3- quinazo line, 4-[(3-ethynyl-phenyl) amino]-6, line, amino]- chlorofluorophenyl) amino][3-(morpho linyl)-propyloxy][(vinylcarbonyl) quinazoline, 4-[(R)-(1-phenyl-ethyl)amino](4-hydroxy-phenyl)-7H-pyrrolo[2, N-dimethylamino) d]pyrimidine, 3-cyano[(3-chlorofluorophenyl)amino] ([4-(N, oxobutenyl] amino ethoxy-quino [3-chloro(3-fluoro-benzyloxy)- line, amino (5- -furanyl) phenyl] [(2-methanesulphonyl-ethyl) amino]methyl) quinazo line, [(R)-(1-phenyl-ethyl)amino] ([4-((R)methyloxo-morpholinyl)oxobuten lin amino methoxy-quinazo line, 4-[(3-chlorofluorophenyl) amino] [4-(morpho yl)oxobutenyl] amino 4-[(3-chloro- [(tetrahydro furanyl)methoxy]-quinazo line, amino]( N-bis-(2-methoxy-ethyl)-amino]oxobuten 4-fluorophenyl) (4-[N, amino)[(tetrahydrofuranyl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino] -dimethyloxo-morpho linyl)oxobutenyl] amino -quinazo line, 4-[(3- [4-(5, 2-dimethyloxo-morpho chlorofluoro-phenyl) amino][2-(2, linyl)-ethoxy] 2-dimethyloxo- methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) amino][2-(2, morpholinyl)-ethoxy][(R)-(tetrahydrofuranyl)methoxy]-quinazoline, 4-[(3-chloro fluoro-phenyl) amino][2-(2, 2-dimethyloxo-morpho linyl)-ethoxy][(S)- (tetrahydrofuranyl)methoxy]-quinazoline, 4-[(3-chlorofluoro-phenyl)amino] (2-[4-(2- 4-[(3-chlorofluoro- oxo-morpholinyl)-piperidin-l-yl]-ethoxy)methoxy-quinazoline, phenyl)amino][1-(tert. -butyloxycarbonyl)-piperidinyloxy]methoxy-quinazoline, [(3-chlorofluoro-phenyl) amino](transamino-cyclohexanyloxy)methoxy- quinazoline, 4-[(3-chlorofluoro-phenyl)amino](transmethanesulphonylamino- amino] cyclohexanyloxy)methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) 4-[(3-chlorofluoro-phenyl)amino](1- (tetrahydropyranyloxy)methoxy-quinazoline, methyl-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro-phenyl)amino] linyl) carbonyl]-piperidinyloxy) methoxy-quinazo line, 4-[(3-chloro (1-[(morpho fluoro-phenyl)amino] (1-[(methoxymethyl)carbonyl]-piperidinyloxy)methoxy- 4-[(3-chlorofluoro-phenyl)amino](piperidinyloxy)methoxy- quinazoline, quinazoline, 4-[(3-chlorofluoro-phenyl)amino][1-(2-acetylamino-ethyl)-piperidin yloxy]methoxy-quinazoline, 4-[(3-chlorofluoro-phenyl)amino](tetrahydropyran yloxy)ethoxy-quinazoline, 4-[(3-chlorofluoro-phenyl)amino]((S)-tetrahydrofuran 2013/026797 T/EP2012/066104 WO PC 4-[(3-chlorofluoro-phenyl) amino](tetrahydropyran yloxy)hydroxy-quinazo line, yloxy)(2-methoxy-ethoxy)-quinazoline, 4-[(3-chlorofluoro-phenyl)amino] (trans [(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy)methoxy-quinazoline, 4-[(3- amino] hexan chlorofluoro-phenyl) (trans[(morpho linyl) carbonylamino]-cyclo 4-[(3-chlorofluoro-phenyl)amino] (trans[(morpholin- yloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- 4-yl)sulphonylamino]-cyclohexan-l-yloxy)methoxy-quinazoline, phenyl)amino](tetrahydropyranyloxy)(2-acetylamino-ethoxy)-quinazoline, 4-[(3- chlorofluoro-phenyl) amino](tetrahydropyranyloxy)(2-methanesulphonylamino- 4-[(3-chlorofluoro-phenyl)amino] ethoxy)-quinazoline, (1-[(piperidinyl)carbonyl]- 4-[(3-chlorofluoro-phenyl)amino](1- piperidinyloxy)methoxy-quinazoline, aminocarbonylmethyl-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- phenyl)amino](cis(N-[(tetrahydropyranyl)carbonyl]-N-methyl-amino)-cyclohexan- 1-yloxy)methoxy-quinazo 4-[(3-chlorofluoro-phenyl) amino](cis line, (N- linyl) carbonyl]-N-methyl-amino -cyclohexanyloxy)methoxy-quinazo [(morpho line, 4-[(3-chlorofluoro-phenyl) amino](cis linyl) sulphonyl]-N-methyl- (N-[(morpho amino)-cyclohexanyloxy)methoxy- quinazoline, 4-[(3-chlorofluoro-phenyl)amino]- 4-[(3-chloro 6-(transethansulphonylamino-cyclohexan-l-yloxy)methoxy-quinazoline, fluoro-phenyl)amino](1-methanesulphonyl-piperidinyloxy)ethoxy-quinazoline, 4-[(3- chlorofluoro-phenyl) amino](1-methanesulphonyl-pip eridinyloxy)(2-methoxy- ethoxy)-quinazoline, 4-[(3-chlorofluoro-phenyl)amino][1-(2-methoxy-acetyl)-piperidin- amino](cis 4-yloxy](2-methoxy-ethoxy)-quinazo line, 4-[(3-chlorofluoro-phenyl) acetylamino-cyclohexan-l-yloxy)methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino][1- (tert. -butyloxycarbonyl)-piperidinyloxy]methoxy-quinazo line, 4-[(3-ethynyl- phenyl)amino](tetrahydropyranyloxy]methoxy-quinazoline, 4-[(3-chlorofluoro- amino](cis hexan (N-[(piperidinyl) carbonyl]-N-methyl-amino -cyclo phenyl) yloxy)methoxy-quinazoline, 4-[(3-chlorofluoro-phenyl)amino](cis (N-[(4-methyl- piperazin-l-yl)carbonyl]-N-methyl-amino)-cyclohexan-l-yloxy)methoxy-quinazoline, hexan [(3-chlorofluoro-phenyl) amino] (cis[(morpho linyl) carbonylamino]-cyclo yloxy)methoxy-quinazoline, 4-[(3-chlorofluoro-phenyl)amino] (1-[2-(2- oxopyrrolidin-l-yl)ethyl]-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- amino] linyl) (2-methoxy-ethoxy)- phenyl) (1-[(morpho carbonyl]-piperidinyloxy) quinazoline, 4-[(3-ethynyl-phenyl)amino](1-acetyl-piperidinyloxy)methoxy- quinazoline, 4-[(3-ethynyl-phenyl)amino](1-methyl-piperidinyloxy)methoxy- quinazoline, 4-[(3-ethynyl-phenyl)amino](1-methanesulphonyl-piperidinyloxy) 2013/026797 T/EP2012/066104 WO PC 4-[(3-chlorofluoro-phenyl)amino](I-methyl-piperidinyloxy)- methoxy-quinazoline, 7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chlorofluoro-phenyl)amino](1- isopropyloxycarbonyl-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- phenyl)amino](cismethylamino-cyclohexan- l-yloxy)methoxy-quinazoline, 4-[(3- chlorofluoro-phenyl)amino] (cis[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexan-l-yloxy)methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino](piperidin yloxy)methoxy-quinazo line, 4-[(3-ethynyl-phenyl) amino][ I -(2-methoxy-acetyl)- piperidinyloxy]methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino] I-[(morpholin 4-[(3-chlorofluoro- yl)carbonyl]-piperidinyloxy)methoxy-quinazoline, 6-dimethyl-morpholinyl)carbonyl]-piperidinyloxy) phenyl)amino] (1-[(cis-2, lin methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) amino] I -[(2-methyl-morpho yl)carbonyl]-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- amino] I S)-(2-oxaaza-bicyclo carbonyl]-piperidin phenyl) -[(S, 2, 1]heptyl) 4-[(3-chlorofluoro-phenyl)amino] I-[(N-methyl-N yloxy)methoxy-quinazoline, methoxyethyl-amino) carbonyl]-piperidinyloxy) methoxy-quinazo line, 4-[(3-chloro fluoro-phenyl) amino](I -ethyl-piperidinyloxy)methoxy-quinazo line, 4-[(3-chloro fluoro-phenyl)amino] I-[(2-methoxyethyl)carbonyl]-piperidinyloxy)methoxy- amino] quinazo line, 4-[(3-chlorofluoro-phenyl) I -[(3-methoxypropyl-amino)-carbonyl]- methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) amino][cis(N- piperidinyloxy) methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]methoxy-quinazoline, 4-[(3- hexanyloxy] chlorofluoro-phenyl) amino][cis(N-acetyl-N-methyl-amino)-cyclo amino](transmethylamino- methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) cyclohexanyloxy)methoxy-quinazo 4-[(3-chlorofluoro-phenyl) amino][trans- line, 4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]methoxy-quinazoline, amino](transdimethylamino-cyclohexan- [(3-chlorofluoro-phenyl) I-yloxy) amino](trans lin methoxy-quinazo line, 4-[(3-chlorofluoro-phenyl) (N-[(morpho 4-[(3-chloro yl)carbonyl]-N-methyl-amino)-cyclohexan-l-yloxy)methoxy-quinazoline, amino][2-(2, 2-dimethyloxo-morpho linyl)-ethoxy][(S)- fluoro-phenyl) (tetrahydrofuranyl)methoxy]-quinazoline, 4-[(3-chlorofluoro-phenyl)amino](1- methanesulphonyl-piperidinyloxy)methoxy-quinazoline, 4-[(3-chlorofluoro- phenyl)amino](l-cyano-piperidinyloxy)methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, in the form of the racemates, optionally enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof. 2013/026797 T/EP2012/066104 WO PC acid addition salts with acceptable acids which the EGFR-inhibitors By pharmacologically be capable of forming are meant, for salts selected from the may example, among hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, hydrochloride, hydrobromide, preferably hydrosulphate, hydrophosphate, hydro fumarate and hydromethanesulphonate. of which include selected Examples dopamine agonists may be used preferably compounds from bromocriptine, lisuride, among cabergoline, alpha-dihydroergocryptine, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan. reference to the above- mentioned dopamine agonists within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which exist. the acceptable acid addition salts which be formed the may By physiologically may above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric tartaric acid and maleic acid. acid, Examples of Hl-antihistamines preferably include compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, chlorophenoxamine, dimenhydrinate, promethazine, ebastine, doxylamine, diphenhydramine, desloratidine and meclozine. reference to the above-mentioned Hl-antihistamines within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts which exist.
Examples of PAF-antagonists include compounds selected from 4-(2- preferably among 2-fJ- chlorophenyl)methyl[3(4-morpho linyl)propanon-l-yl]-6H-thieno-[3, 2013/026797 T/EP2012/066104 WO PC lo 3-a] 9-dihydromethyl[(4- 2,4]triazo diazepines, 6-(2-chlorophenyl)-8, [1, [4, [1,4] carbonyl]-4H, 7H-cyclo-penta-[4, 5]thieno-[3, 2-f] 4]triazo lo morpho linyl) 2, [1, [4, diazepines. a][1,4] MRP4-inhibitors used are preferably compounds selected from among ¹cetyl- dinitrophenyl-cysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, 17-beta- dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol glucuronide, estradio13, 17-disulphate, estradio13-glucuronide, estradio13-sulphate, estrone sulphate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acid indomethacin, lithocholic acid sulphate, ibuprofen, indoprofen, ketoprofen, sulphate, methotrexate, MK571 ((E)[[[3-[2-(7-chloroquino linyl) ethenyl]phenyl]-[[3- dimethylamino)oxopropyl]thio]methyl]thio]-propanoic alpha-naphthyl-beta-D- acid), glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, PSC833, sildenafil, taurocho tauro litho cho sulfinpyrazone, taurochenodeoxycho late, late, taurodeoxycho late, late, taurolithocholic acid trequinsin and in sulphate, topotecan, zaprinast, dipyridamole, optionally the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof. acid addition salts with acids are for salts pharmacologically acceptable meant, example, selected from the hydrochlorides, hydrobromides, among hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulphonates, preferably the hydrochlorides, hydrobromides, hydrofumarates and hydrosulphates, hydrophosphates, hydro methanesulphonates.
Compounds which may be used as iNOS inhibitors are compounds selected from among: L-canavanine, (2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT, iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, L-NA L-NAME (N"-nitro-L- methyltiocitrullin, S-ethylthiocitrulline, (N"-nitro-L-arginine), L-NMMA L-NIO (N"-iminoethyl-L- argininemethylester), -monomethyl-L-arginine), 2013/026797 T/EP2012/066104 WO PC L-NIL (N"-iminoethyl-lysine), (S)acetimidoylaminoamino-hexanoic acid ornithine), (1H-tetrazolyl)-amide Med. Chem. 1686-1689), 1400W, (S)(2- (SC-51) (J. 2002, 45, acetimidoylamino-ethylsulphanyl)amino-butyric acid (GW274150) Med. Chem.
(Bioorg.
Lett. 2000, 10, 597-600), 2-[2-(4-methoxy-pyridinyl)-ethyl]-3H-imidazo 5-b]pyridine Pharmacol. 2-((R)amino- (BYK191023)(Mol. 2006, 69, 328-337), I-phenyl-propoxy) chlorofluorobenzonitrile 3S)aminohydroxy-l-thiazo1yl- (WO 01/62704), 2-((1R, butylsulphanyl)trifluoromethyl-nicotinonitrile 2004/041794), 2-((1R.3S)amino hydroxy-I-thiazolyl-butylsulphanyl)chloro-benzonitrile 2004/041794), 3S)aminohydroxy-l-thiazo1yl-butylsulphanyl)chloro-benzonitrile ((1R. (WO 4R)amino(2-chlorotrifluoromethyl-phenylsulphanyl)thiazo1 2004/041794), (2S. yl-butanol 2004/041794), 3S)aminohydroxy-l-thiazo1yl- (WO 2-((1R. butylsulphanyl)chloro-nicotinonitrile 2004/041794), 4-((S)aminohydroxy- substituted phenyl-butylsulphanyl)methoxy-nicotinonitrile (WO 02/090332), 3-phenyl-3, dihydroisoquinolinamine such as AR-C102222 Med. e. (J. Chem. 2003, 46, 913-916), 5S.6R)chloromethylaza-bicyclo 1.0]heptenylamine (ONO-1714) (1S. [4.
(Biochem. Res. Commun. 2000, 270, 663-667), 5R)ethylmethyl- Biophys. (4R, thiazolidinylideneamine 5R)ethylmethyl- (Bioorg. Med. Chem. 2004, 12, 4101), (4R, selenazolidinylideneamine (Bioorg. Med. Chem. Lett. 2005, 15, 1361), aminotetrahydrobiopterine Metabol. 119-121),(E)(4-chloro-phenyl)- (Curr. Drug 2002, 3, N-(I- (2-oxo[4-(6-trifluoromethyl-pyrimidinyloxy)-piperidin-I-yl]-ethylcarbamoyl) pyridinyl-ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2, difluoro-phenyl)[2-(4-imidazol-I-ylmethyl-phenoxy)-ethoxy]phenyl-pyridine (PPA250) Pharmacol. Ther.
(J. Exp. 2002, 303, 52-57), methyl 3-([(benzo[1,3]dioxo1ylmethyl)- carbamoyl]-methyl)(2-imidazol-I-yl-pyrimidinyl)-piperazine-I-carboxylate (BBS-I) (Drugs Future 2004, 29, 45-52), (R)-I-(2-imidazol-I-ylmethyl-pyrimidinyl)- pyrrolidinecarboxylic acid (2-benzo[1, 3]dioxo1yl-ethyl)-amide (BBS-2)(Drugs Future 45-52) and the pharmaceutical salts, or solvates thereof. 2004, 29, prodrugs Examples of iNOS-inhibitors within the of the invention also include scope present may iNOS- antisense oligonucleotides, particularly those antisense oligonucleotides which bind nucleic acids. For 01/52902 describes antisense coding example, WO oligonucleotides, particularly antisense oligonucleotides, which bind iNOS nucleic acids, for modulating coding the expression of iNOS. iNOS-antisense oligonucleotides as described particularly in WO 2013/026797 T/EP2012/066104 WO PC 01/52902 therefore also combined with the PDE4-inhibitors of the invention may be present on account of their similar effect to the iNOS-inhibitors.
Compounds which be used as SYK-inhibitors are preferably compounds selected from among: 2-[(2-amino amino][(3-bromophenyl) amino]pyrimidinecarboxamide; ethyl) 2-[[7-(3,4-dimethoxyphenyl) imidazo 2-c]pyrimidinyl] amino]pyridinecarboxamide; 6-[[5-fluoro[3, amino]pyrimidinyl]amino]-2, 2-dimethyl-2H- 4,5-trimethoxyphenyl) 2-b]-1,4-oxazin-3(4H)-one; pyrido N-[3-bromo(4-methoxyphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine 7-(4-methoxyphenyl)-N-methyl-1, 6-naphthyridinamine; N-[7-(4-methoxyphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(2-thienyl)-1, 6-naphthyridiny1-1, 3-propanediamine; 6-naphthyridinyl]-1, 2-ethanediamine; N-[7-[4-(dimethylamino)phenyl]-1, N-[7-(4-methoxyphenyl)(trifluoromethyl)-1, 6-naphthyridinyl]- 3-propanediamine; N-[7-(4-methoxyphenyl)phenyl-1, 6-naphthyridinyl]-1, 3-propanediamine; N-(7-phenyl-1, 6-naphthyridinyl)-1, 3-propanediamine; N-[7-(3-fluorophenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 6-naphthyridinyl]-1, N-[7-(3-chlorophenyl)-1, 3-propanediamine; N-[7-[3-(trifluoromethoxy)phenyl]-1, 6-naphthyridin-5yl]-1, 3-propanediamine; N-[7-(4-fluorophenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(4-fluorophenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(4-chlorophenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(4'-methyl[1, 1'-biphenyl]yl)-1, 6-naphthyridin-1, 3-propanediamine; 2013/026797 T/EP2012/066104 WO PC N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(diethylamino)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(4-morpho linyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-[[2-(dimethylamino) ethyl]methylamino]phenyl]-1, 6-naphthyridinyl]-1, anediamine; prop N-[7-(4-bromophenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(4-methylphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(methylthio)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; 6-naphthyridinyl]-1, N-[7-[4-(1-methylethyl)phenyl]-1, 3-propanediamine; 6-naphthyridinamine; 7-[4-(dimethylamino)phenyl]-N-methyl-1, N-dimethyl-1, 6-naphthyridinamine; 7-[4-(dimethylamino)phenyl]-N, N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 4-butanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 5-pentanediamine; 3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]oxy]propano1; 4-[5-(4-aminobutoxy)-1, 6-naphthyridinyl]-N, N-dimethyl-benzenamine; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl] amino]butano N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-N-methyl-1, 3-propanediamine; 6-naphthyridinyl]-N'-methyl-1, N-[7-[4-(dimethylamino)phenyl]-1, 3-propanediamine; 6-naphthyridinyl]-N, N'-dimethyl-1, N-[7-[4-(dimethylamino)phenyl]-1, 3-propanediamine; 6-naphthyridinyl] 1-amino[[7-[4-(dimethylamino)phenyl]-1, amino]propano1; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-2, 2-dimethyl-1, 3-propanediamine; 7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1, 6-naphthyridinamine; N-[(2-aminophenyl)methyl][4-(dimethylamino)phenyl]-1, 6-naphthyridinamine; 2013/026797 T/EP2012/066104 WO PC N-[7-[6-(dimethylamino) 1'-biphenyl]yl]-1, 6-naphthyridinyl]-1, 3-propanediamine, [1, ; N-[7-[3-chloro(diethylamino)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(dimethylamino)methoxyphenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; 6-naphthyridinyl]-1, N-[7-[4-(diethylamino)phenyl]methyl-1, 3-propanediamine; N-[7-(3'-fluoro 1'-biphenyl]yl)-1, 6-naphthyridinyl]-1, 2-ethanediamine, N-[7-(4-methoxyphenyl)-1, 6-naphthyridinyl]-1, 6-naphthyridine-1, 3-propanediamine; N'-bis(3-aminopropyl)(4-methoxyphenyl)-2, 5-diamine; N-[7-(4-methoxyphenyl)(phenylmethoxy)-1, 6-naphthyridinyl]-1, 6-naphthyridine-1, anediamine; prop -diamine; N5-(3-aminopropyl)(4-methoxyphenyl)-N2-(phenylmethyl)-2, N-[7-(2-naphthalenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(2'-fluoro 1'-biphenyl]yl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(3, 5-trimethoxyphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(3,4-dimethylphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 1-amino[[7-(2-naphthalenyl)-1, 6-naphthyridinyl] amino]propano1; 1-amino[[7-(2'-fluoro 1'-biphenyl]yl)-1, 6-naphthyridinyl]amino]propanol; 1-amino[[7-(4'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridinyl] amino]propano 1-amino[[7-(3, 5-trimethoxyphenyl)-1, 6-naphthyridinyl] amino]propano1; 1-amino[[7-(4-bromophenyl)-1, 6-naphthyridinyl] amino]propano1; N-[7-(4'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridinyl]-2, 2-dimethyl-1, anediamine; prop 1-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl] amino]propano1; 2-[[2-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl] amino] ethyl]thio]-ethano 2013/026797 T/EP2012/066104 WO PC 7-[4-(dimethylamino)phenyl]-N-(3-methylisoxazolyl)-1, 6-naphthyridinamine; 7-[4-(dimethylamino)phenyl]-Npyrimidiny1-1, 6-naphthyridinamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 3-cyclo hexanediamine; 6-naphthyridinyl]-benzenamine; N, N-dimethyl[5-(1-piperazinyl)-1, 6-naphthyridinyl]-N, N-dimethyl-benzenamine; 4-[5-(2-methoxyethoxy)-1, 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]pip eridino 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]pyrro lidino 7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1, 6-naphthyridinamine; 7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazo 1yl)propyl]-1, 6-naphthyridinamine; 6-naphthyridinyl]pip eridinecarboxamide; 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl] lidinone; 1-[3-[[7-[4-(dimethylamino)phenyl]-1, amino]propyl]pyrro N-[3'-[5-[(3-aminopropyl) amino]-1, 6-naphthyridinyl] 1'-biphenyl]yl]-acetamide; N-[7-(4'-fluoro 1'-biphenyl]yl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 6-naphthyridinyl] 1'-biphenyl]yl]-acetamide; N-[4'-[5-[(3-aminopropyl) amino]-1, 3-benzodioxo 6-naphthyridinyl]-1, N-[7-[4-(1, 1yl)phenyl]-1, 3-propanediamine; N-[7-[4-(2-thienyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-fluoro(trifluoromethyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(3-pyridinyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; 3-benzodioxo N-[7-(1, 1yl)-1,6-naphthyridinyl]-1, 3-propanediamine; N-[7-(6-methoxynaphthalenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1, 6-naphthyridinamine; 6-naphthyridinyl]methylamino]-propanenitrile; 3-[[7-[4-(dimethylamino)phenyl]-1, 7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)piperidinyl]-1, 6-naphthyridinamine; 2013/026797 T/EP2012/066104 WO PC 2S)-N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 2-cyclo hexanediamine, (1R.
N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 2-benzenedimethanamine; N-[7-[4-(diethylamino)phenyl]-1, 6-naphthyridinyl]-1, 4-butanediamine; N-[7-[3'.5'-bis(trifluoromethyl) 1'-biphenyl]yl]-1, 6-naphthyridinyl]. 3-propanediamine; N-[7-(3'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(3'-fluoro 1'-biphenyl]yl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]oxy]butano N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridinyl]- 4-cyclohexanediamine; 7-[4-(dimethylamino)phenyl]-N-(2. 2.6.6-tetramethy1piperidinyl)-1, 6-naphthyridin amine; N-[7-[3-bromo(dimethylamino)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(1-methyl-1H-indo 1yl)-1,6-naphthyridinyl]-1, 3-propanediamine; N-[7-[3-(trifluoromethyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-[4-(trifluoromethyl)phenyl]-1, 6-naphthyridinyl]-1, 3-propanediamine; N-[7-(3-bromomethoxyphenyl)-1, 6-naphthyridinyl]-1, 3-propanediamine; 6-naphthyridinyl]-1, N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1, cyclohexanediamine; N-[7-[4-[[2-(dimethylamino) ethyl]methylamino]phenyl]-1, 6-naphthyridinyl]-1, cyclohexanediamine; 6-naphthyridinyl]-1, 4-cyclo hexanediamine; N-[7-[4-(dimethylamino)methoxyphenyl]-1, N-[7-[4-(4-morpho 6-naphthyridinyl]-1, 4-cyclo hexanediamine; linyl)phenyl]-1, N-[7-[3-bromo(4-morpho 6-naphthyridinyl]-1, 4-cyclo hexanediamine; linyl)phenyl]-1, 4-[[7-[4-[[2-(dimethylamino) ethyl]methylamino]phenyl]-1, 6-naphthyridinyl]oxy]- cyclohexanol; 2013/026797 T/EP2012/066104 WO PC N-[7-[3-bromo(4-morpho 6-naphthyridinyl]-1, 3-propanediamine; linyl)phenyl]-1, N-dimethyl[5-(4-methylpiperazinyl)-1, 6-naphthyridinyl]-benzenamine; 4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1, 6-naphthyridinyl]oxy]- cyclohexanol; 6-naphthyridinyl]-1, N-[7-[4-[[2-(dimethylamino) ethyl]methylamino]phenyl]-1, butane diamine; 1-dimethylethyl 6-naphthyridin 1, [3-[[5-[(3-aminopropyl)amino](4-methoxyphenyl)-1, amino]propyl]-carbamate.
The invention further relates to pharmaceutical preparations which contain a triple combination a of formula II or III and two further active both comprising compound I, agents, independently from one another selected from the above-mentioned of active agents groups such as another PDE4B-inhibitor, an anticholinergic, a betamimetic, a corticosteroid, an PAF- EGFR-inhibitor, a MRP4-inhibitor, an LTD4-antagonist, an iNOS-inhibitor, a a H l-antihistamine, SYK inhibitor. The invention further refers antagonist, dopamin agonist, to the of such a double or combination and the use thereof for treating preparation triple respiratory complaints. 8. Formulations Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective in each case should in the from 1 to wt. to compound(s) be range 0. 90 %, preferably 0.5 50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage range hereinaAer. specified The administered in the form of a as a as a preparations may be orally tablet, powder, powder in a a hard gelatine as a solution or suspension. When administered capsule (e.g. capsule), by inhalation the active substance combination be given as a as an aqueous or may powder, aqueous-ethanolic solution or a formulation. using propellant gas 2013/026797 T/EP2012/066104 WO PC therefore, pharmaceutical formulations are characterised the content of one or Preferably, more compounds of formula according to the preferred embodiments above.
It is if the of formula are administered and it is particularly preferable compounds orally, also if are administered once or twice a Suitable tablets particularly preferable they day. may be obtained, for mixing the active with known for example, substance(s) excipients, example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as stearate or talc and/or for such as magnesium agents delaying release, carboxymethyl cellulose, cellulose acetate or acetate. The tablets also comprise phthalate, polyvinyl may several layers.
Coated tablets may be prepared accordingly coating cores produced analogously to the tablets with substances normally used for tablet for example collidone or shellac, coatings, arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. containing the active substances or combinations thereof according to the invention Syrups may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e. a flavouring such as vanillin or orange extract. They may also contain or thickeners such as sodium suspension adjuvants carboxymethyl cellulose, wetting agents such for condensation of alcohols with ethylene oxide, or as, example, products fatty preservatives such as p-hydroxybenzoates. 2013/026797 T/EP2012/066104 WO PC one or more active substances or combinations of active substances Capsules containing may for example be mixing the active substances with inert carriers such as lactose or prepared sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example mixing with carriers provided for this such as neutral fats or or the derivatives thereof. purpose, polyethyleneglycol Excipients which be used include, for water, pharmaceutically acceptable may example, organic solvents such as paraffins petroleum fractions), vegetable oils groundnut or (e.g. (e.g. mono- sesame oil), or polyfunctional alcohols (e. ethanol or glycerol), carriers such as e. g. g. natural mineral mineral powders (e. kaolins, clays, talc, chalk), synthetic powders (e. g. g. dispersed silicic acid and cane lactose and highly silicates), sugars (e. sugar, glucose), emulsifiers lignin, spent sulphite liquors, methylcellulose, starch and (e.g. polyvinylpyrrolidone) and lubricants Magnesium stearate, talc, stearic acid and sodium (e.g. lauryl sulphate).
For oral administration the tablets of course, contain, apart from the abovementioned may, carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. lubricants such as sodium and talc Moreover, magnesium stearate, lauryl sulphate may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances be combined with various flavour enhancers or colourings in addition to the mentioned above. excipients It is also if the of formula are administered inhalation, preferred compounds particularly if are administered once or twice a For this the compounds of preferably they day. purpose, formula have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable metered-dose aerosols or powders, propellant-containing propellant-free inhalable which are in admixture with conventional solutions, optionally present acceptable excipients. physiologically 2013/026797 T/EP2012/066104 WO PC Within the of the the term inhalable solutions also scope present invention, propellant-free includes concentrates or sterile ready-to-use inhalable solutions. The which preparations may be used according to the invention are described in more detail in the next part of the specification.
Inhalable powders If the active substances of formula are in admixture with present physiologically acceptable the following acceptable excipients be used to the excipients, physiologically may prepare inhalable powders according to the invention: monosaccharides glucose or arabinose), (e.g. disaccharides lactose, saccharose, maltose), oligo- and polysaccharides dextran), (e.g. (e.g. salts sodium calcium polyalcohols (e. sorbitol, mannitol, xylitol), (e. chloride, carbonate) g. g. or mixtures of these with one another. mono- or disaccharides are excipients Preferably, used, while the use of lactose or is but not in the form glucose preferred, particularly, exclusively, of their hydrates. For the purposes of the invention, lactose is the particularly preferred while lactose is most Methods of the excipient, monohydrate particularly preferred. preparing inhalable to the invention and and powders according grinding micronising finally by by mixing the components together are known from the prior art.
Propellant-containing inhalable aerosols The propellant-containing inhalable aerosols which be used according to the invention may contain the compounds of formula dissolved in the propellant or in dispersed form.
The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the art. Suitable are selected from prior propellant gases among hydrocarbons such as n-butane or isobutane and halohydrocarbons such as n-propane, preferably fluorinated derivatives of methane, ethane, butane, cyclopropane or propane, cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. are fluorinated alkane derivatives selected Particularly preferred propellant gases from TG134a 2-tetrafluoroethane), TG227 and 1,1, 1,1,2,3,3,3-heptafluoropropane) (1, (1, mixtures thereof. The propellant-driven inhalation aerosols used within the of the use scope according to the invention may also contain other ingredients such as co-solvents, stabilisers, 2013/026797 T/EP2012/066104 WO PC antioxidants, lubricants and All these are known in the surfactants, adjusters. ingredients Propellant-free inhalable solutions The compounds of formula according to the invention are used to preferably prepare propellant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and ethanol. The solutions or are to a of 2 suspensions adjusted to 2 to suitable acids. The be acids selected from 7, preferably 5, using pH may adjusted using inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric maleic succinic fumaric acetic formic acid and/or acid, acid, acid, acid, acid, propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which 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 mixtures of the above acids also in the case of acids which desired, may be used, particularly have other properties in addition to their acidifying qualities, e. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the Co-solvents and/or other added to the inhalable solutions excipients may be propellant-free used for the according to the invention. Preferred co-solvents are those which contain purpose or other polar e. alcohols particularly alcohol, glycols- hydroxyl groups groups, g. isopropyl particularly glycolether, propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote acceptable substance which is not an any pharmacologically active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired no or at least no undesirable therapy, appreciable pharmacological effect. The excipients and additives include, for example, surfactants such as lecithin, soya 2013/026797 T/EP2012/066104 WO PC oleic sorbitan such as other acid, esters, polysorbates, polyvinylpyrrolidone, stabilisers, antioxidants and/or preservatives which guarantee or the shelf life complexing agents, prolong of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic The include antioxidants such as agents. preferred excipients ascorbic for that it has not been to the acid, example, provided already used adjust vitamin vitamin tocopherols and similar vitamins or provitamins occurring in the human A, E, body. Preservatives may be used to protect the formulation from contamination with Suitable are those which are known in the pathogens. preservatives art, particularly cetyl benzalkonium chloride or benzoic acid or benzoates such as sodium pyridinium chloride, benzoate in the concentration known from the art. prior For the treatment forms described above, ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for the words COPD or with example respiratory disease, asthma, together dihydrothienopyrimidine and one or more combination partners selected from those described above. 2013/026797 T/EP2012/066104 WO PC PATENT

Claims (4)

1. Compound of formula I HN OH wherein Ring A is a 6-membered aromatic ring which optionally comprise one or two atoms and nitrogen wherein R is Cl and meta- wherein R be located either in the para-, or ortho-position of Ring may A, wherein is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.
2. The of formula I to claim wherein R is Cl and wherein R is compound according 1, located in the para-position of and all pharmaceutically acceptable salts thereof, Ring A, enantiomers and racemates thereof.
3. The compound of formula I according to one of claims 1 or 2, wherein Ring A is selected from the consisting of and and all pharmaceutically group phenyl, pyridinyl pyrimidinyl, acceptable salts thereof, enantiomers and racemates thereof.
4. The to one of claims 1 to which is a of formula II compound according 3, compound
NZ620199A 2011-08-24 2012-08-17 Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating copd and asthma NZ620199B2 (en)

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