Pyrazoloquinoline derivatives

Abstract

A compound and/or pharmacologically acceptable salt thereof represented by the formula (I) has PDE9 inhibitory action, so that the intracerebral cGMP concentration is anticipated to be elevated. The PDE9 inhibitory action and the increase in cGMP lead to the improvement of learning and memory behaviors, and the compound (I) has applicability as a therapeutic agent for cognitive dysfunctions in Alzheimer's disease. wherein R 1 is a hydrogen atom; R 2 is an aromatic ring group, etc.; R 3 is a hydrogen atom, etc; R 4 is a hydrogen atom; R 5 is an oxepanyl group, etc.; R 6 is a hydrogen atom.

1 - 20 . (canceled) 
     
     
         21 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof a compound represented by the formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a hydrogen atom; 
 R 2  is an aromatic ring group selected from the group consisting of a phenyl group, a pyridinyl group, and a pyrimidinyl group, where the two atoms on the aromatic ring which are adjacent to the carbon atom attached to the pyrazolo[4,3-c]quinoline ring each independently has a substituent selected from Group A1, and the other atoms on the aromatic ring independently optionally have a substituent selected from Group B 1; 
 R 3  is a hydrogen atom, or a fluorine atom; 
 R 4  is a hydrogen atom; 
 R 5  is an oxepanyl group, a dioxepanyl group, a tetrahydropyranyl group, or a tetrahydrofuranyl group optionally substituted with a methoxy group; 
 R 6  is a hydrogen atom; 
 Group A1 consists of a halogen atom, a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and a C1-6 alkoxy group; and 
 Group B1 consists of a halogen atom, a cyano group, a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and a tetrahydropyranyl group, 
 with the proviso that when R 2  is a 3-pyridinyl group, the substituent at the 4-position is a halogen atom, or a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms. 
 
     
     
         22 . The method of  claim 21 , wherein
 R 2  is an aromatic ring group selected from the group consisting of a phenyl group, a 3-pyridinyl group, a 4-pyridinyl group, and a 5-pyrimidinyl group, where the two atoms on the aromatic ring which are adjacent to the carbon atom attached to the pyrazolo[4,3-c]quinoline ring each independently has a substituent selected from Group A2, and the other atoms on the aromatic ring independently optionally have a substituent selected from Group B2;   R 5  is a 4-oxepanyl group, a 1,4-dioxepan-6-yl group, a 3,4,5,6-tetrahydro-2H-3-pyranyl group, a 3,4,5,6-tetrahydro-2H-4-pyranyl group, or a 3-tetrahydrofuranyl group;   Group A2 consists of a chlorine atom, a methyl group optionally substituted with 1 to 2 fluorine atoms, an ethyl group, a methoxy group, and an ethoxy group; and   Group B2 consists of a fluorine atom, a chlorine atom, a cyano group, a methyl group optionally substituted with 1 to 3 fluorine atoms, an ethyl group, a methoxymethyl group, a methoxy group optionally substituted with 1 to 3 fluorine atoms, an ethoxy group, an isopropyloxy group, and a 3,4,5,6-tetrahydro-2H-4-pyranyl group.   
     
     
         23 . The method of  claim 22 , wherein R 3  is a fluorine atom. 
     
     
         24 . The method of  claim 21 , wherein
 R 3  is a hydrogen atom; and   R 5  is a tetrahydropyranyl group, or a tetrahydrofuranyl group optionally substituted with a methoxy group.   
     
     
         25 . The method of  claim 22 , wherein
 R 3  is a hydrogen atom; and   R 5  is a 3,4,5,6-tetrahydro-2H-3-pyranyl group, a 3,4,5,6-tetrahydro-2H-4-pyranyl group, or a 3-tetrahydrofuranyl group.   
     
     
         26 . The method of  claim 21 , wherein
 R 2  is an aromatic ring group selected from the group consisting of a phenyl group, a 3-pyridinyl group, and a 4-pyridinyl group, where the two atoms on the aromatic ring which are adjacent to the carbon atom attached to the pyrazolo[4,3-c]quinoline ring each independently has a substituent selected from Group A3, and the other atoms on the aromatic ring independently optionally have a substituent selected from Group B3;   R 3  is a hydrogen atom;   R 4  is a hydrogen atom;   R 5  is a 3,4,5,6-tetrahydro-2H-4-pyranyl group, or a 3-tetrahydrofuranyl group;   Group A3 consists of a methyl group, and a methoxy group; and   Group B3 consists of a methyl group, a methoxy group, and a methoxymethyl group.   
     
     
         27 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof a compound selected from the group consisting of:
 1) 7-(6-methoxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   2) 7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   3) (S)-7-(6-isopropyloxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   4) 8-fluoro-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   5) 1-(1,4-dioxepan-6-yl)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   6) 1-(1,4-dioxepan-6-yl)-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   7) (S)-8-fluoro-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   8) 7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   9) (−)-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   10) (−)-7-(6-methoxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   11) (S)-8-fluoro-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   12) (S)-7-(6-ethoxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   13) (S)-8-fluoro-7-(6-methoxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one, and   14) (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one,   
       or a pharmacologically acceptable salt of any of the aforementioned. 
     
     
         28 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof 7-(6-isopropyloxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof. 
     
     
         29 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof (S)-7-(6-isopropyloxy-2,4-dimethylpyridin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         30 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof 8-fluoro-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof. 
     
     
         31 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof (S)-8-fluoro-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof 7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4 (5H)-one or a pharmacologically acceptable salt thereof. 
     
     
         33 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof (S)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         34 . A method for improving cognitive impairment in Alzheimer's disease, comprising administering to a patient in need thereof 1-(1,4-dioxepan-6-yl)-7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method for increasing intracerebral cGMP concentration, comprising administering to a patient in need thereof a compound represented by the formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a hydrogen atom; 
 R 2  is an aromatic ring group selected from the group consisting of a phenyl group, a pyridinyl group, and a pyrimidinyl group, where the two atoms on the aromatic ring which are adjacent to the carbon atom attached to the pyrazolo[4,3-c]quinoline ring each independently has a substituent selected from Group A1, and the other atoms on the aromatic ring independently optionally have a substituent selected from Group B 1; 
 R 3  is a hydrogen atom, or a fluorine atom; 
 R 4  is a hydrogen atom; 
 R 5  is an oxepanyl group, a dioxepanyl group, a tetrahydropyranyl group, or a tetrahydrofuranyl group optionally substituted with a methoxy group; 
 R 6  is a hydrogen atom; 
 Group A1 consists of a halogen atom, a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and a C1-6 alkoxy group; and 
 Group B 1 consists of a halogen atom, a cyano group, a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C1-6 alkoxy-C1-6 alkyl group, a C1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and a tetrahydropyranyl group, 
 with the proviso that when R 2  is a 3-pyridinyl group, the substituent at the 4-position is a halogen atom, or a C1-6 alkyl group optionally substituted with 1 to 3 halogen atoms.