Tetrahydro- and dihydroquinazolinones

Abstract

The present invention relates to the use of tetrahydro- and dihydroquinazolinones of formula (I) as protein kinase activators or inhibitors, a method for their manufacture, their use for the preparation of a medicament for the treatment of diseases, their use for the manufacture of a pharmaceutical composition and new tetrahydro- and dihydroquinazolinones.

1 . A method for the treatment and/or prevention of disorders, characterized in that the disorders are selected from the group consisting of hyperproliferative and non-hyperproliferative disorders, comprising administering to a subject in need thereof an effective amount of a compound of the formula I, 
       
         
           
           
               
               
           
         
         wherein 
            is a single or a double bond, 
         R 1  is Ar 1 , S-A or Het, 
         R 2  is H or A, 
         R 3  is H, A, CN, COOA, (CH) n NHA, (CH) n NA 2 , CONH 2 , CONHA, CONA 2 , (CH) n NHCONH 2 , (CH) n NHCONHA or (CH) n NHCONA 2 , 
         R 4  is H, SO 2 Ar 2 , A, CN, COOA, (CH) n NHA, (CH) n NA 2 , CONH 2 , CONHA, CONA 2 , (CH) n NHCONH 2 , (CH) n NHCONHA, or (CH) n NHCONA 2 , 
         R 5  is H or A, or is absent, if   is a double bond, 
         Ar 1  is phenyl, which optionally is substituted by one or more substituents, selected from the group consisting Hal, S-A, Ph, —O(CH 2 ) n -Ph, —N(CH 2 Ph) 2 , 
         Ar 2  is phenyl, which optionally is substituted by one or more substituents, selected from the group consisting of Hal. A, COOA, 
         A is alkyl or cycloalkyl with 1-12 C-atoms, wherein optionally 1-5H atoms are replaced by F and/or Cl, 
         Het is a mono- or bicyclic, saturated, unsaturated or aromatic heterocyclic residue which optionally is substituted by one or more substituents, selected from the group consisting of OOCA, Hal, A, (CH 2 ) n Ar 2 , (CH 2 ) n cycloalkyl, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHCONA 2 , NHSO 2 A, COA, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , SO 2 A, SOA 2 , CF 3 , OCF 3  and SCF 3 , with the provisio that said heterocyclic residue contains 1, 2, 3 or 4 N-, O- and/or S-atoms, at least comprising one N-atom and Het is linked via N to the pyrimidinone ring system, 
         Hal is F, Cl, Br or I, 
         n is 0, 1 or 2, 
         or the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         2 . A method according to  claim 1 , characterized in that the compound is selected from the group consisting of
 a) 6-Benzenesulfonyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   b) 6-Benzenesulfonyl-2-(p-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   c) 6-Benzenesulfonyl-2-(o-bromophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   d) 6-Benzenesulfonyl-2-(o-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   e) 6-Benzenesulfonyl-2-[(p-benzyloxy)phenyl]-5,6,7,8-tetrahydroquinazolin-4(3H)one   f) 6-Benzenesulfonyl-2-(o-biphenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   g) 6-Benzenesulfonyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   h) 2-Phenyl-7,8-dihydroquinazolin-4(3H)-one   i) 2-(p-Chlorophenyl)-7,8-dihydroquinazolin-4(3H)-one   j) 2-(o-Bromophenyl)-7,8-dihydroquinazolin-4(3H)-one   k) 2-(o-Fluorophenyl)-7,8-dihydroquinazolin-4(3H)-one   l) 2-(p-Benzoyloxyphenyl)-7,8-dihydroquinazolin-4(3H)-one   m) 2-(o-Biphenyl)-7,8-dihydroquinazolin-4(3H)-one   n) 2-Methylthio-7,8-dihydroquinazolin-4(3H)-one   o) 2-Phenyl-5,6,7,8-tetrahydroquinazolin-4(3)-one   p) 2-(p-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3)-one   q) 2-(o-Bromophenyl)-5,6,7,8-tetrahydroquinazolin-4(3)-one   r) 2-(o-Fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3)-one   s) 2-[(p-Benzoyloxy)phenyl]-5,6,7,8-tetrahydroquinazolin-4(3)-one   t) 2-(o-Biphenyl)-5,6,7,8-tetrahydroquinazolin-4(3)-one   u) 6-Benzenesulfonyl-6-methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   v) 6-Benzenesulfonyl-6-ethyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   w) 6-Methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   x) 6-Ethyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   y) 6-Methyl-2-phenyl-7,8-dihydroquinazolin-4(3H)-one   z) 6-Ethyl-2-phenyl-7,8-dihydroquinazolin-4(3H)-one   aa) 6-Benzenesulfonyl-7-methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)one   bb) 6-Benzenesulfonyl-2-(morpholine-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   cc) 2-(4-benzylpiperazin-1-yl)-6-Benzenesulfonyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   dd) 6-Benzenesulfonyl-2-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   ee) 2-(Morpholin-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   ff) 2-Piperazin-1yl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   gg) 2-(Morpholin-4-yl)-7,8-dihydroquinazolin-4(3H)-one   hh) 2-(4-Benzylpiperazin-1-yl)-7,8-dihydroquinazolin-4(3H)-one   ii) 2-(4-Methylpiperazin-1-yl)-7,8-dihydroquinazolin-4(3H)-one   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         3 . A method according to  claim 1 , characterized in that the disorder is non-cancerous. 
     
     
         4 . A method according to  claim 1 , characterised in that the disorders are selected from the group consisting of psoriasis, arthritis, rheumatoid arthritis, inflammation, endometriosis, scarring, infection or infectious diseases, e.g.  Helicobacter pylori  infection, Influenza A infection, begnin prostatic hyperplasia, immunodeficiency diseases, autoimmune disease, immunological diseases, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, fibrosis, atherosclerosis, restenosis, vascular disease, cardiovascular disease, renal disease and angiogenesis disorders, mesangial cell proliferative disorders, diabetic nephropathy, diabetic retinopathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders and neurodegenerative diseases. 
     
     
         5 . A method according to  claim 1 , characterized in that the disorder is cancer. 
     
     
         6 . A method according to  claim 1 , characterised in that the disorders are selected from the group consisting of melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia and acute leukaemia 
     
     
         7 . A method according to  claim 1 , further comprising administering to said subject a compound selected from the group consisting of estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, anti-proliferative agents, prenyl protein protease inhibitors, HMG CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, growth factor receptor inhibitors and angiogenesis inhibitors. 
     
     
         8 . A method according to  claim 1 , further comprising administering to said subject radio therapy and a compound selected from the group consisting of estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, anti-proliferative agents, prenyl protein protease inhibitors, HMG CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, growth factor receptor inhibitors and angiogenesis inhibitors. 
     
     
         9 . Method for the manufacture of a compound according to formula I of  claim 1 ,
 a. wherein   is a single bond, characterized in that a compound of the formula II,   
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  are as defined in  claim 1 , is reacted with a compound of the formula III, 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 , R 4  and R 5  are as defined in  claim 1 , or 
         
         b) wherein   is a double bond, characterized in that R 4 —H is eliminated from a compound formula I, wherein R 4  is SO 2 Ar 2  and   is a single bond, or 
         c) wherein   is a single bond, characterized in that in a compound of the i formula I, wherein   is a double bond, said double bond is transferred to a single bond by hydration, or 
         d) characterized in that a residue R 1 , R 2 , R 3 , R 4  and/or R 5 , as defined in  claim 1 , is converted in another residue R 1 , R 2 , R 3 , R 4  and/or R 5 , by e.g.
 i. introducing an alkyl group, 
 ii. converting a S-A residue in a Het residue, or 
 
         e) characterized in that a compound of formula I is isolated and/or treated with an acid or a base, to obtain the salt thereof. 
       
     
     
         10 . Compound of the formula IV, 
       
         
           
           
               
               
           
         
         wherein 
            is a single or a double bond, 
         R 1  is Ar 1 , S-A or Het, 
         R 2  is H or A, 
         R 3  is H, A, COOA′, (CH 2 ) n NHA, (CH 2 ) n NA 2 , CONH 2 , CONHA, CONA 2 , (CH 2 ) n NHCONH 2 , (CH 2 ) n NHCONHA or (CH 2 ) n NHCONA 2 . 
         R 4  is H, SO 2 Ar 2 , A, (CH 2 ) n NHA, (CH 2 ) n NA 2 , CONH 2 , CONHA, CONA 2 , (CH 2 ) n NHCONH 2 , (CH 2 ) n NHCONHA, or (CH 2 ) n NHCONA 2 , 
         A′ is alkyl or cycloalkyl with 2-12 C-atoms, wherein optionally 1-5H atoms are replaced by F and/or Cl, 
         R 5  is H or A, or is absent, if   is a double bond, 
         Ar 1  is phenyl, which is optionally substituted by one or more substituents selected from the group consisting of Hal, S-A, Ph, —O(CH 2 ) n -Ph and —N(CH 2 Ph) 2 , 
         Ar 2  is phenyl, which is optionally substituted by one or more substituents selected from the group consisting of Hal, A and COOA, 
         A is alkyl or cycloalkyl with 1-12 C-atoms, wherein optionally 1-5H atoms are replaced by F and/or Cl, 
         Het is a mono- or bicyclic, saturated, unsaturated or aromatic heterocyclic group which is optionally substituted by one or more substituents selected from the group consisting of OOCA, Hal, A, (CH 2 ) n Ar 2 , (CH 2 ) n cycloalkyl, OA, NH 2 , NHA, NA 2 , NO 2 , CN, COOH, COOA, CONH 2 , CONHA, CONA 2 , NHCOA, NHCONH 2 , NHCONA 2 , NHSO 2 A, COA, SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , SO 2 A, SOA 2 , CF 3 , OCF 3  and SCF 3 ,
 with the provisio that said heterocyclic group contains 1, 2, 3 or 4 N-, O- and/or S-atoms, at least comprising one N-atom and Het is linked via N to the pyrimidinone ring system, 
 
         Hal is F, Cl, Br or I, and 
         n is 0, 1 or 2, 
         with the provisio, that at least one of the residues R 3 , R 4  and R 5  must have a meaning other than H or   is a double bond, 
         and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         11 . Compound according to  claim 10 , wherein
    is a single bond,   R 1  is Ar 1 , S-A or Het,   R 2 , R 3 , R 5  are H,   R 4  is SO 2 Ar 2 ,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         12 . Compound according to  claim 10 , wherein
    is a double bond,   R 1  is Ar 1 , S-A or Het,   R 2 , R 3 , R 4  are H,   R 5  is absent,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         13 . Compound according to  claim 10 , wherein
    is a single bond,   R 1  is phenyl,   R 2 , R 3  are H,   R 4  is SO 2 Ar 2 ,   R 5  is A,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         14 . Compound according to  claim 10 , wherein
    is a single bond,   R 1  is phenyl,   R 2 , R 3   , R   4  are H,   R 5  is A,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         15 . Compound according to  claim 10 , wherein
    is a double bond,   R 1  is phenyl,   R 2 , R 3  are H,   R 4  is A   R 5  is absent,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         16 . Compound according to  claim 10 , wherein
    is a single bond,   R 1  is Het,   R 2 , R 3 , R 5  are H,   R 4  is SO 2 Ar 2 ,   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         17 . Compound according to  claim 10 , selected from the group consisting of
 a) 6-Benzenesulfonyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   b) 6-Benzenesulfonyl-2-(p-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   c) 6-Benzenesulfonyl-2-(o-bromophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   d) 6-Benzenesulfonyl-2-(o-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   e) 6-Benzenesulfonyl-2-[(p-benzyloxy)phenyl]-5,6,7,8-tetrahydroquinazolin-4(3H)one   f) 6-Benzenesulfonyl-2-(o-biphenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   g) 6-Benzenesulfonyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   h) 2-Phenyl-7,8-dihydroquinazolin-4(3H)-one   i) 2-(p-Chlorophenyl)-7,8-dihydroquinazolin-4(3H)-one   j) 2-(o-Bromophenyl)-7,8-dihydroquinazolin-4(3H)-one   k) 2-(o-Fluorophenyl)-7,8-dihydroquinazolin-4(3H)-one   l) 2-(p-Benzoyloxyphenyl)-7,8-dihydroquinazolin-4(3H)-one   m) 2-(o-Biphenyl)-7,8-dihydroquinazolin-4(3H)-one   n) 2-Methylthio-7,8-dihydroquinazolin-4(3H)-one   o) 6-Benzenesulfonyl-6-methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   p) 6-Benzenesulfonyl-6-ethyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   q) 6-Methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   r) 6-Ethyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   s) 6-Methyl-2-phenyl-7,8-dihydroquinazolin-4(3H)-one   t) 6-Ethyl-2-phenyl-7,8-dihydroquinazolin-4(3H)-one   u) 6-Benzenesulfonyl-7-methyl-2-phenyl-5,6,7,8-tetrahydroquinazolin-4(3H)one   v) 6-Benzenesulfonyl-2-(morpholine-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   w) 2-(4-benzylpiperazin-1-yl)-6-Benzenesulfonyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one   x) 6-Benzenesulfonyl-2-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one   y) 2-(Morpholin-4-yl)-7,8-dihydroquinazolin-4(3H)-one   z) 2-(4-Benzylpiperazin-1-yl)-7,8-dihydroquinazolin-4(3H)-one   aa) 2-(4-Methylpiperazin-1-yl)-7,8-dihydroquinazolin-4(3H)-one   and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         18 . A method for activating or inhibiting a protein kinase, comprising administering to a subject in need thereof an effective amount of a compound of  claim 10 . 
     
     
         19 . A method for the treatment and/or prevention of a disorder, comprising administering to a subject in need thereof an effective amount of a compound of  claim 10 . 
     
     
         20 . A method for the treatment and/or prevention of a disorder, which is caused, mediated and/or propagated by a protein kinase, comprising administering to a subject in need thereof an effective amount of a compound of  claim 10 . 
     
     
         21 . A pharmaceutical composition, comprising a compound according to  claim 10  and a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition according to  claim 21 , further comprising a pharmaceutically active agent other than a compound of formula IV. 
     
     
         23 . A kit comprising separate packets of
 a.a therapeutically effective amount of one or more compounds according to  claim 10  and   b.a therapeutically effective amount of one or more further pharmaceutically active agents other than a compound of formula IV.   
     
     
         24 . (canceled)