4-(4-pyridinyl)-benzamides and their use as rock activity modulators

Abstract

The present invention relates to novel 4-(4-pyridyl)-benzamides of the formula (I). The compounds I possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of Rho kinases (ROCKs). R 1 and R 2 are, independently of each other, hydrogen, hydroxy, cyano, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy or C 1 -C 8 -haloalkoxy; R 3 , R 4 , R 5 and R 6 are, independently of each other, hydrogen, hydroxy, halogen, cyano, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkoxy, amino, C 1 -C 8 -alkylamino or di-(C 1 -C 8 -alkyl)-amino; R 7 is hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, aryl or aryl-C 1 -C 8 -alkyl; R 8 is a group of the formula —X—W, where X is a single bond, C 1 -C 4 -alkylene or C 1 -C 4 -alkylene-O—, where the alkylene group in the three last-mentioned radicals may be linear or branched and may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or may be interrupted by an oxygen atom; and W is a cyclic radical selected from phenyl and a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected O, S, and N and optionally 1 or 2 carbonyl groups; R 9 is a group of the formula —Y—Z, where Z is hydrogen, halogen, OR 11 , NR 12 R 13 , S(O) m —R 14 , phenyl which may carry 1, 2, 3 or 4 substituents R 15 or a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring; and Y is linear or branched C 1 C 4 -alkylene which may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or a phenyl ring; or, in case Z is phenyl or the 5- or 6-membered heterocyclic ring as defined above, Y can also be a single bond.

1 . A compound of the formula I 
       
         
           
           
               
               
           
         
         or a physiologically tolerated acid addition salt thereof, wherein
 R 1  and R 2  are, independently of each other, hydrogen, halogen, hydroxy, cyano, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy or C 1 -C 8 -haloalkoxy; 
 R 3 , R 4 , R 5  and R 6  are, independently of each other, hydrogen, hydroxy, halogen, cyano, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkoxy, amino, C 1 -C 8 -alkylamino or di-(C 1 -C 8 -alkyl)-amino; 
 R 7  is hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 6 -C 14 -aryl or C 6 -C 14 -aryl-C 1 -C 4 -alkyl; 
 R 8  is a group of the formula X—W, where 
 X is a single bond, linear or branched C 1 -C 4 -alkylene or C 1 -C 4 -alkylene-O—, where the alkylene group in the three last-mentioned radicals may be linear or branched and may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or may be interrupted by an oxygen atom; and 
 W is a cyclic radical selected from phenyl and a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups, where phenyl and the heterocyclic ring may be fused to phenyl, to a 5-, 6- or 7-membered saturated or partly unsaturated carbocyclic ring, which may contain as ring members 1 or 2 carbonyl groups, or to a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups, where the fused phenyl ring, the fused carbocyclic ring and the fused heterocyclic ring may for their part be fused to a phenyl ring; and where the cyclic radical W may carry 1, 2, 3, 4 or 5 substituents R 10 ; 
 R 9  is a group of the formula Y—Z, where 
 Z is hydrogen, halogen, OR 11 , NR 12 R 13 , S(O) m —R 14 , phenyl which may carry 1, 2, 3 or 4 substituents R 15  or a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups and which may carry 1, 2, 3 or 4 substituents R 15 ; and 
 Y is linear or branched C 1 -C 4 -alkylene which may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or a phenyl ring; or, in case Z is phenyl or the 5- or 6-membered heterocyclic ring as defined above, Y can also be a single bond; 
 or R 8  and R 9 , together with the CH group to which they are bonded, form a CH-bound saturated or partly unsaturated 5- or 6-membered carbocyclic ring which may contain 1 or 2 carbonyl groups as ring members or a saturated or partly unsaturated 5- or 6-membered heterocyclic ring, where the heterocyclic ring contains 1 or 2 heteroatoms selected from O, S and N and optionally 1 carbonyl group as ring members, where the carbocyclic ring and the heterocyclic ring are fused to a phenyl ring or to a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups, where the carbocyclic ring and the heterocyclic ring and/or the ring fused thereto may carry 1, 2 or 3 substituents R 15 , with the proviso that in case the carbocyclic ring is fused to a phenyl ring, the points of fusion are not in the 3,4-position, relative to the 1-position of the bond to the group NR 7 ; 
 each R 10  is independently selected from halogen, hydroxyl, SH, CN, nitro, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, aryl, heterocyclyl, aryl-C 1 -C 4 -alkyl, aryl-C 2 -C 4 -alkenyl, aryl-C 2 -C 4 -alkynyl, heterocyclyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyloxy, C 2 -C 6 -alkynyloxy, C 3 -C 6 -cycloalkoxy, aryloxy, heterocyclyloxy, aryl-C 1 -C 4 -alkoxy, aryloxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkylthio, C 2 -C 6 -alkenylthio, C 2 -C 6 -alkynylthio, arylthio, heterocyclylthio, aryl-C 1 -C 4 -alkylthio, arylthio-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfinyl, C 2 -C 6 -alkenylsulfinyl, C 2 -C 6 -alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 2 -C 6 -alkenylsulfonyl, C 2 -C 6 -alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 2 -C 6 -alkenylcarbonyl, C 2 -C 6 -alkynylcarbonyl, arylcarbonyl, aryl-C 1 -C 4 -alkylcarbonyl, heterocyclylcarbonyl, carboxyl, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxycarbonyl, C 2 -C 6 -alkynyloxycarbonyl, aryloxycarbonyl, aryl-C 1 -C 4 -alkoxycarbonyl, heterocyclyloxycarbonyl, C 1 -C 6 -alkylcarbonyloxy, C 2 -C 6 -alkenylcarbonyloxy, C 2 -C 6 -alkynylcarbonyloxy, arylcarbonyloxy, aryl-C 1 -C 4 -alkylcarbonyloxy, heterocyclylcarbonyloxy and NR a R b , where R a  and R b  are independently selected from H, C 1 -C 6 -alkyl, aryl, formyl, C 1 -C 6 -alkylcarbonyl, arylcarbonyl and C 1 -C 6 -alkylsulfonyl or, together with the nitrogen atom to which they are bound, form a 4-, 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which may contain as ring members 1 or 2 further heteroatoms selected from O, S and N and/or 1 or 2 carbonyl groups, and where the heterocyclic ring may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
 where aryl in R 10  is selected from phenyl and naphthyl, 
 where heterocyclyl is a saturated, partly unsaturated or aromatic 5 or 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups as ring members, 
 where the aliphatic and cycloaliphatic moieties in the radicals R 10  may be partly or fully halogenated and/or may carry 1, 2 or 3 substituents selected from OH, CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio and C 1 -C 4 -haloalkylthio, where the cycloaliphatic moieties may also carry 1, 2 or 3 C 1 -C 6 -alkyl substituents, 
 where the aromatic and heterocyclic moieties in the radicals R 10  may be partly or fully halogenated and/or may carry 1, 2, 3, 4 or 5 substituents selected from OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -haloalkylsulfonyl; 
 R 11  is hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, phenyl or benzyl, where the phenyl moiety in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
 R 12  and R 13 , independently of each other, are hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -hydroxyalkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -haloalkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -haloalkoxycarbonyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -haloalkylsulfinyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -haloalkylsulfonyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl, benzyl, phenylcarbonyl, benzylcarbonyl, phenylsulfonyl or benzylsulfonyl, where the phenyl moiety in the six last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
 or R 12  and R 13 , together with the nitrogen atom to which they are bound, form a 4-, 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which may contain as ring members 1 or 2 further heteroatoms selected from O, S and N and/or 1 or 2 carbonyl groups, and where the heterocyclic ring may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
 R 14  is hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, phenyl or benzyl, where the phenyl moiety in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; 
 each R 15  is independently halogen, hydroxyl, CN, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 4 -alkyl, aryloxy, aryl-C 1 -C 4 -alkoxy, heterocyclyl or NR c R d , where R c  and R d , independently of each other, are selected from H, C 1 -C 6 -alkyl and aryl; 
 where aryl is selected from phenyl and naphthyl, 
 where heterocyclyl is a saturated, partly unsaturated or aromatic 5 or 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups as ring members, 
 where the aromatic and heterocyclic moieties in the radicals R 15  may be partly or fully halogenated and/or may carry 1, 2, 3, 4 or 5 substituents selected from OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkylsulfonyl and C 1 -C 4 -haloalkylsulfonyl; and 
 m is 0, 1 or 2; 
 except for N-[1-(3-chlorophenyl)-2-hydroxyethyl]-4-(2-fluoro-5-methyl-pyridin-4-yl)-benzamide. 
 
       
     
     
         2 . The compound or salt as claimed in  claim 1 , wherein R 1  and R 2  are, independently of each other, hydrogen, hydroxy, cyano, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy or C 1 -C 8 -haloalkoxy. 
     
     
         3 . The compound or salt as claimed in  claim 1 , wherein R 1  and R 2  are hydrogen, C 1 -C 4 -alkyl, fluorine or chlorine. 
     
     
         4 . The compound or salt as claimed in  claim 1 , wherein R 3  and R 4  are independently selected from hydrogen, halogen, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl. 
     
     
         5 . The compound or salt as claimed in  claim 4 , wherein one of R 3  and R 4  is hydrogen and the other is hydrogen, halogen or C 1 -C 4 -alkyl. 
     
     
         6 . The compound or salt as claimed in  claim 1 , wherein R 5  and R 6  are independently selected from hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkoxy. 
     
     
         7 . The compound or salt as claimed in  claim 6 , wherein one of R 5  and R 6  is hydrogen and the other is hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy. 
     
     
         8 . The compound or salt as claimed in  claim 1 , wherein R 7  is hydrogen. 
     
     
         9 . The compound or salt as claimed in  claim 1 , wherein X is a single bond, CH 2 , CH(OH) or CH 2 CH 2 . 
     
     
         10 . The compound or salt as claimed in  claim 1 , wherein W is selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, indanyl, dihydronaphthyl, tetralinyl, indolyl, 2,3-dihydroindolyl, indoxylyl, oxindolyl, indazolyl, 2,3-dihydroindazolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, cumaronyl (benzo[b]furanyl), 2,3-dihydrobenzofuranyl, benzo-1,3-dioxyl, benzo-1,4-dioxanyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[b]thienyl, 2,3-dihydrobenzothienyl, benzothiazolyl, 2,3-dihydrobenzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromenyl, chromenonyl, isochromenyl, chromanyl, chromanonyl, isochromanyl, acenaphthenyl, dihydroacenaphthenyl, fluorenyl, carbazolyl, dibenzofuranyl, dibenzothienyl, acridinyl, carbazinyl (acridanyl), phenazinyl, 9,10-dihydrophenazinyl, dibenzomorpholinyl (phenoxazinyl), dibenzothiomorpholinyl (phenothiazinyl), where the 42 last-mentioned radicals are bonded via the phenyl moiety of the fused system to the group X, a saturated, partly unsaturated or aromatic 5- or 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups as ring members and a saturated, partly unsaturated or aromatic 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups as ring members which is fused to a phenyl ring and which is bonded via the heterocyclyl moiety of the fused system to the group X, where the above radicals may carry 1, 2, 3, 4 or 5 substituents R 10  as defined in  claim 1 . 
     
     
         11 . The compound or salt as claimed in  claim 10 , wherein W is selected from phenyl, naphthyl, a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from O, S and N as ring members and a saturated, partly unsaturated or aromatic 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups as ring members which is fused to a phenyl ring and which is bonded via the heterocyclyl moiety of the fused system to the group X, where the above radicals may carry 1, 2, 3, 4 or 5 substituents R 10  as defined in  claim 1 . 
     
     
         12 . The compound or salt as claimed in  claim 11 , wherein W is selected from phenyl, naphthyl, pyridyl, indolyl, benzo-1,4-dioxanyl and pyrrolidinyl, where the above radicals may carry 1, 2, 3, 4 or 5 substituents R 10  as defined in  claim 1 . 
     
     
         13 . The compound or salt as claimed in  claim 1 , wherein R 10  is selected from halogen, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, phenyl, benzyl, phenoxy and benzoxy. 
     
     
         14 . The compound or salt as claimed in  claim 1 , wherein Y is CH 2 , CH(OH), CH(phenyl) or CH 2 CH 2 . 
     
     
         15 . The compound or salt as claimed in  claim 1 , wherein Z is hydrogen, halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenyl or a group NR 12 R 13 , where R 12  and R 13  are as defined in  claim 1 . 
     
     
         16 . The compound or salt as claimed in  claim 1 , wherein R 12  and R 13 , independently of each other, are hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkylsulfonyl, phenyl, benzyl, phenylcarbonyl, benzylcarbonyl, phenylsulfonyl or benzylsulfonyl, where the phenyl moiety in the six last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
 or R 12  and R 13 , together with the nitrogen atom to which they are bound, form a 4-, 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which may contain as ring members 1 or 2 further heteroatoms selected from O, S and N and/or 1 or 2 carbonyl groups, and where the heterocyclic ring may carry 1, 2 or 3 substituents selected from halogen, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy.   
     
     
         17 . The compound or salt as claimed in  claim 1 , wherein R 8  and R 9 , together with the CH group to which they are bonded, form a CH-bound saturated or partly unsaturated 5- or 6-membered carbocyclic ring which may contain 1 or 2 carbonyl groups as ring members or a saturated or partly unsaturated 5- or 6-membered heterocyclic ring, where the heterocyclic ring contains 1 or 2 heteroatoms selected from O, S and N and optionally 1 carbonyl group as ring members, where the carbocyclic ring and the heterocyclic ring are fused to a phenyl ring where the carbocyclic ring and the heterocyclic ring and/or the phenyl ring fused thereto may carry 1, 2 or 3, preferably 1, substituents R 15 , with the proviso that in case it is the carbocyclic ring which is fused to a phenyl ring, the points of fusion are not in the 3,4-position, relative to the 1-position of the bond to the group NR 7 . 
     
     
         18 . A pharmaceutical composition containing at least one compound of  claim 1 , or a physiologically tolerated acid addition salt thereof, and at least one physiologically acceptable carrier or auxiliary substance. 
     
     
         19 - 22 . (canceled) 
     
     
         23 . A method for treating a medical disorder comprising administering an effective amount of a compound or salt as claimed in  claim 1  to a subject in need thereof, wherein the medical disorder is selected from the group consisting of hypertension, chronic and congestive heart failure, cardiac hypertrophy, chronic renal failure, cerebral vasospasm, pulmonary hypertension, ocular hypertension, cancer, tumor metastasis, asthma, male erectile dysfunctions, female sexual dysfunctions, over-active bladder syndrome, preterm labor, restenosis, atherosclerosis, neuronal injury, in particular spinal cord injury, traumatic brain injury and stroke, Parkinson's disease, Alzheimer disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, encephalomyelitis, pain, rheumatoid arthritis, osteoarthritis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, HIV-1 encephalitis, diabetes, insulin resistance, ischemic CNS disorders, vascular or AD type dementia, glaucoma, psoriasis, retinopathy, benign prostatic hypertrophy, psychiatric disorders, in particular depression, schizophrenia, obsessive compulsive disorder and bipolar disorder, epilepsy and seizure disorders, for decreasing ischemia-reperfusion injury, myocardial infarct size and myocardial fibrosis, for the prevention of graft failure and for treating diseases caused by viral and bacterial infections. 
     
     
         24 . A method for treating a medical disorder comprising administering an effective amount of a compound or salt as claimed in  claim 1  to a subject in need thereof, wherein the medical disorder is selected from the group consisting of pain, asthma, cognitive dysfunctions, multiple sclerosis, cancer, rheumatoid arthritis and injuries of the spinal cord.