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

Abstract

The invention 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 Cl 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.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein Ring A is a 6-membered aromatic ring optionally comprising one or two nitrogen atoms and 
         wherein R is Cl and is located in the para-, meta-, or ortho-position of Ring A, 
         wherein S* is a sulphur atom that represents a chiral center, 
         or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
       
     
     
         2 . The compound of formula I according to  claim 1 , wherein R is in the para-position of Ring A, or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
     
     
         3 . The compound of formula I according to  claim 1 , wherein Ring A is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
     
     
         4 . The compound of formula I according to  claim 2 , wherein Ring A is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
     
     
         5 . The compound according to  claim 1 , which is a compound of formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
     
     
         6 . The compound according to  claim 1 , which is a compound of formula III 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or an enantiomer or racemate thereof. 
     
     
         7 . The compound according to  claim 1 , wherein S* is in the R-configuration. 
     
     
         8 . The compound according to  claim 1 , wherein S* is in the S-configuration. 
     
     
         9 . A crystalline anhydrous compound of formula III according to  claim 6 , which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.62 Å. 
     
     
         10 . A crystalline anhydrous compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Å, 6.82 Å, and 10.09 Å. 
     
     
         11 . A crystalline anhydrous compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Å, 4.17 Å, and 3.66 Å. 
     
     
         12 . A crystalline anhydrous compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Å, 6.82 Å, 10.09 Å, 3.93 Å, and 4.94 Å. 
     
     
         13 . A crystalline anhydrous compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Å, 4.17 Å, 3.66 Å, 3.73 Å, and 18.47 Å. 
     
     
         14 . A crystalline dihydrate compound of formula III according to  claim 6 , which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.12 Å. 
     
     
         15 . A crystalline dihydrate compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Å, 4.29 Å, and 5.15 Å. 
     
     
         16 . A crystalline dihydrate compound of formula III according to  claim 6 , which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Å, 4.29 Å, 5.15 Å, 3.95 Å, and 3.36 Å. 
     
     
         17 . A method of treating a disease which can be treated by the inhibition of the PDE4-enzyme comprising the step of administering an effective amount of the compound according to  claim 1  to a patient in need thereof. 
     
     
         18 . The method of  claim 17 , wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, the skin or the eyes, cancer, and a disease of the peripheral or central nervous system. 
     
     
         19 . The method of  claim 18 , wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from a respiratory or pulmonary disease which is accompanied by increased mucus production, inflammations and/or obstructive diseases of the respiratory tract. 
     
     
         20 . The method of  claim 19 , wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from COPD, chronic sinusitis, asthma, and chronic bronchitis. 
     
     
         21 . The method of  claim 17 , wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from Crohn's disease or ulcerative colitis. 
     
     
         22 . The method of  claim 17 , wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from 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 pain and brain damage caused by stroke, hypoxia or cranio-cerebral trauma, dry eyes syndrome, and glaucoma. 
     
     
         23 . A pharmaceutical composition comprising a compound of formula I according to  claim 1  and an active substance selected from the group consisting of betamimetics, corticosteroids, anticholinergics, other PDE4 inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, MRP4-inhibitors, and SYK inhibitors. 
     
     
         24 . A method of manufacturing a compound A 
       
         
           
           
               
               
           
         
         wherein HX is a pharmaceutically acceptable acid, 
         comprising the steps a) and b), wherein in 
         step a) compound B 
       
       
         
           
           
               
               
           
         
         wherein HY is a pharmaceutically acceptable acid, is reduced by borane and wherein in 
         step b) a pharmaceutically acceptable acid HX is added to obtain compound A. 
       
     
     
         25 . The method of  claim 24 , wherein the borane for the reduction in step a) is added directly. 
     
     
         26 . The method of  claim 24 , wherein the borane for the reduction in step a) is generated in situ. 
     
     
         27 . The method of  claim 26 , wherein the borane for the reduction in step a) is generated either from the combination of NaBH 4  and I 2  or from the combination of NaBH 4  and BF 3 —OEt 2 . 
     
     
         28 . The method of  claim 24 , wherein HX is tosylic acid or hydrochloric acid. 
     
     
         29 . The method of  claim 24 , wherein the pharmaceutically acceptable acid HY in compound B is HCl. 
     
     
         30 . A method of manufacturing compound C 
       
         
           
           
               
               
           
         
         wherein HX is tosylic acid, hydrochloric acid, or sulphuric acid, 
         comprising the steps A), B), and C), 
         wherein in step A) 4-cyanopiperidine is contacted first with an acid and is then reacted with ammonia in order to obtain intermediate E 
       
       
         
           
           
               
               
           
         
         and wherein in step B) intermediate E is reacted with compound D in the presence of a base 
       
       
         
           
           
               
               
           
         
         and wherein in step C) the acid HX is added. 
       
     
     
         31 . The method of  claim 30 , wherein in step A) 4-cyano-piperidine is contacted with hydrochloric acid and is then reacted with ammonia in order to obtain intermediate E. 
     
     
         32 . The method of  claim 30 , wherein in step B) intermediate E is reacted with compound D in the presence of sodium methanolate. 
     
     
         33 . The intermediate of formula VIII 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         34 . The intermediate of formula IX 
       
         
           
           
               
               
           
         
         wherein S* stand for a sulphur atom that represents a chiral center, 
         or a salt thereof.