Quinoline derivatives and quinazoline derivatives

Abstract

An object of the present invention is to provide compounds which have antitumor activity and do not change cytomorphosis. Disclosed are compounds represented by formula (I) and a pharmaceutically acceptable salts and solvates thereof and pharmaceutical compositions comprising said compounds: wherein X and Z each independently represent CH or N; R 1 to R 3 represent H, substituted alkoxy, unsubstituted alkoxy or the like; R 4 represents H; R 5 to R 8 represent H, halogen, alkyl, alkoxy, alkylthio, nitro, or amino, provided that R 5 to R 8 do not simultaneously represent H; R 9 and R 10 represent H, alkyl, or alkylcarbonyl; and R 11 represents alkyl, alkenyl, alkynyl, or aralkyl.

1 - 52 . (canceled)  
   
   
       53 . A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:  
     
       
         
         
             
             
         
       
     
     wherein 
 X and Z each represent CH or N;  
 R 1  represents a hydrogen atom, C 1-6  alkyl, C 1-6  alkoxy, C 2-6  alkenyl, C 2-6  alkynyl, nitro, or amino, which C 1-6  alkyl, C 1-6  alkoxy, C 2-6  alkenyl, and C 2-6  alkynyl are optionally substituted by a halogen atom; hydroxyl; C 1-4  alkoxy; C 1-4  alkoxycarbonyl; amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl or C 1-4  alkoxy; group R 12 R 13 N—C(═O)—O— wherein R 12  and R 13 , which may be the same or different, represent a hydrogen atom or C 1-4  alkyl which alkyl is optionally substituted by hydroxyl or C 1-4  alkoxy; or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C 1-4  alkyl and m is 0 or 1;  
 one of R 2 , and R 3 , represents an unsubstituted C 1-6  alkoxy, and the other represents C 1-6  alkoxy substituted by a halogen atom; hydroxyl; C 1-4  alkoxy; C 1-4  alkoxycarbonyl; amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl or C 1-4  alkoxy; group R 12 R 13 N—C(═O)—O— wherein R 12  and R 13 , which may be the same or different, represent a hydrogen atom or C 1-4  alkyl which alkyl is optionally substituted by hydroxyl or C 1-4  alkoxy; or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C 1-4  alkyl;  
 R 4  represents a hydrogen atom;  
 R 5 , R 6 , R 7 , and R 8 , which may be the same or different, represent a hydrogen atom, a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, nitro, or amino, provided that R 5 , R 6 , R 7 , and R 8  do not simultaneously represent a hydrogen atom;  
 R 9  and R 10 , which may be the same or different, represent a hydrogen atom, C 1-6  alkyl, or C 1-4  alkylcarbonyl, the alkyl portion of which C 1-6  alkyl or C 1-4  alkylcarbonyl is optionally substituted by a halogen atom; C 1-4  alkoxy; amino which is optionally substituted by C 1-4  alkyl optionally substituted by C 1-4  alkoxy; or a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group; and  
 R 11  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-6  alkoxy), or R 15 —(CH 2 )n- wherein n is an integer of 0 to 4 and R 15  represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by a halogen atom, C 1-6  alkyl, or C 1-6  alkoxy and is optionally condensed with other saturated or unsaturated three- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic ring.  
 
   
   
       54 . The compound according to  claim 53 , wherein R 1 , R 9 , and R 10  represent a hydrogen atom.  
   
   
       55 . The compound according to  claim 53 , wherein R 1  represents a hydrogen atom and one of or both R 9  and R 10  represent a group other than a hydrogen atom.  
   
   
       56 . The compound according to  claim 53 , wherein X represents N or CH and Z represents CH.  
   
   
       57 . A compound represented by formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:  
     
       
         
         
             
             
         
       
     
     wherein 
 X represents CH or N;  
 wherein one of R 21  and R 22 , represents unsubstituted C 1-6  alkoxy and the other represents a group R 31 —(CH 2 )p-O— wherein R 31  represents a halogen atom, hydroxyl, C 1-4  alkoxy, C 1-4  alkoxycarbonyl, amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl or C 1-4  alkoxy, group R 12 R 13 N—C(═O)—O— wherein R 12  and R 13 , which may be the same or different, represent a hydrogen atom or C 1-4  alkyl which alkyl is optionally substituted by hydroxyl or C 1-4  alkoxy, or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C 1-4  alkyl and m is 0 or 1; and p is an integer of 1 to 6;  
 R 23 , R 24 , R 21 , and R 26 , which may be the same or different, represent a hydrogen atom, a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, nitro, or amino, provided that R 23 , R 24 , R 25 , and R 26  do not simultaneously represent a hydrogen atom;  
 R 27  and R 28 , which may be the same or different, represent a hydrogen atom, C 1-6  alkyl, or C 1-4  alkylcarbonyl, the alkyl portion of which C 1-6  alkyl or C 1-4  alkylcarbonyl is optionally substituted by a halogen atom; C 1-4  alkoxy; amino which is optionally substituted by C 1-4  alkyl optionally substituted by C 1-4  alkoxy; or a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group; and  
 R 29  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-4  alkoxy), or R 32 —(CH 2 )q- wherein q is an integer of 0 to 4 and R 32  represents a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by a halogen atom, C 1-4  alkyl, or C 1-4  alkoxy and is optionally condensed with other saturated or unsaturated five- or six-membered carbocyclic ring or heterocyclic ring to form a bicyclic ring.  
 
   
   
       58 . The compound according to  claim 57 , wherein one of R 21  and R 21  represents unsubstituted C 1-4  alkoxy and the other represents group R 31 —(CH 2 )p-O—.  
   
   
       59 . The compound according to  claim 57 , wherein at least one of R 23 , R 24 , R 25 , and R 26  represents a halogen atom.  
   
   
       60 . The compound according to  claim 57 , wherein at least one of R 23 , R 24 , R 25 , and R 26  represents a chlorine atom or a fluorine atom.  
   
   
       61 . The compound according to  claim 57 , wherein at least one of R 23 , R 24 , R 25 , and R 26  represents C 1-4  alkyl.  
   
   
       62 . The compound according to  claim 57 , wherein two of R 23 , R 24 , R 25 , and R 26  represent methyl and the remaining two represent a hydrogen atom.  
   
   
       63 . The compound according to  claim 57 , wherein at least one of R 23 , R 24 , R 25 , and R 26  represents nitro, amino, C 1-4  alkoxy, or C 1-4  alkylthio.  
   
   
       64 . The compound according to  claim 57 , wherein R 23 , R 25 , and R 26  represent a hydrogen atom and R 24  represents a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, nitro, or amino.  
   
   
       65 . The compound according to  claim 57 , wherein both R 27  and R 28  represent a hydrogen atom.  
   
   
       66 . The compound according to  claim 57 , wherein any one of or both R 27  and R 28  represent a group other than a hydrogen atom.  
   
   
       67 . The compound according to  claim 57 , wherein 
 X represents CH or N;    one of R 21  and R 22  represents unsubstituted C 1-4  alkoxy and the other represents group R 31 —(CH 2 )p-O—;    R 23 , R 25 , and R 26  represent a hydrogen atom;    R 24  represents a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, or nitro;    R 27  and R 28  represent a hydrogen atom; and    R 29  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-4  alkoxy), or —(CH 2 )q-R 32  wherein q is an integer of 0 or 1 and R 32  represents phenyl, pyridyl, or naphthyl which phenyl, pyridyl, and naphthyl are optionally substituted by a halogen atom, C 1-4  alkyl, or C 1-4  alkoxy.    
   
   
       68 . The compound according to  claim 67 , wherein R 21  represents unsubstituted C 1-4  alkoxy and R 22  represents group R 31 —(CH 2 )p-O—.  
   
   
       69 . The compound according to  claim 67 , wherein R 31  represents hydroxyl, amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl, or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated five-membered heterocyclic group containing 1 to 4 nitrogen atoms and optionally substituted by C 1-4  alkyl, or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero); and p is an integer of 1 to 4.  
   
   
       70 . The compound according to  claim 67 , wherein p is 1.  
   
   
       71 . The compound according to  claim 67 , wherein R 31  represents group R 14 —(S)m- wherein R 14  represents an unsaturated six-membered heterocyclic group containing one or two nitrogen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero).  
   
   
       72 . The compound according to  claim 71 , wherein R 14  represents optionally substituted pyridyl.  
   
   
       73 . The compound according to  claim 57 , wherein 
 X represents CH or N;    one of R 21  and R 22  represents unsubstituted C 1-4  alkoxy and the other represents group R 31 —(CH 2 )p-O—;    R 23 , R 25 , and R 26  represent a hydrogen atom;    R 24  represents a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, or nitro;    any one of or both R 27  and R 28  represent a group other than a hydrogen atom; and    R 29  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-4  alkoxy), or —(CH 2 )q-R 32  wherein q is an integer of 0 or 1 and R 32  represents phenyl, pyridyl, or naphthyl which phenyl, pyridyl, and naphthyl are optionally substituted by a halogen atom, C 1-4  alkyl, or C 1-4  alkoxy.    
   
   
       74 . The compound according to  claim 73 , wherein R 21  represents unsubstituted C 1-4  alkoxy and R 22  represents group R 31 —(CH 2 )p-O—.  
   
   
       75 . The compound according to  claim 73 , wherein R 31  represents hydroxyl, amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl, or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated five-membered heterocyclic group containing 1 to 4 nitrogen atoms and optionally substituted by C 1-4  alkyl, or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero); and p is an integer of 1 to 4.  
   
   
       76 . The compound according to  claim 73 , wherein p is 1.  
   
   
       77 . The compound according to  claim 73 , wherein R 31  represents group R 14 —(S)m- wherein R 14  represents an unsaturated six-membered heterocyclic group containing one or two nitrogen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero).  
   
   
       78 . The compound according to  claim 77 , wherein R 14  represents optionally substituted pyridyl.  
   
   
       79 . The compound according to  claim 57 , wherein 
 X represents CH or N;    one of R 21  and R 22  represents unsubstituted C 1-4  alkoxy and the other represents group R 31 —(CH 2 )p-O—;    R 23 , R 25 , and R 26  represent a hydrogen atom;    R 24  represents a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, or nitro;    R 27  represents a hydrogen atom;    R 28  represents a group other than a hydrogen atom; and    R 29  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-4  alkoxy), or —(CH 2 )q-R 32  wherein q is an integer of 0 or 1 and R 32  represents phenyl, pyridyl, or naphthyl which phenyl, pyridyl, and naphthyl are optionally substituted by a halogen atom, C 1-4  alkyl, or C 1-4  alkoxy.    
   
   
       80 . The compound according to  claim 79 , wherein R 21  represents unsubstituted C 1-4  alkoxy and R 22  represents group R 31 —(CH 2 )p-O—.  
   
   
       81 . The compound according to  claim 79 , wherein R 31  represents hydroxyl, amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl, or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated five-membered heterocyclic group containing 1 to 4 nitrogen atoms and optionally substituted by C 1-4  alkyl, or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero); and p is an integer of 1 to 4.  
   
   
       82 . The compound according to  claim 79 , wherein p is 1.  
   
   
       83 . The compound according to  claim 79 , wherein R 31  represents group R 14 —(S)m- wherein R 14  represents an unsaturated six-membered heterocyclic group containing one or two nitrogen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero).  
   
   
       84 . The compound according to  claim 83 , wherein R 14  represents optionally substituted pyridyl.  
   
   
       85 . The compound according to  claim 57 , wherein 
 X represents CH or N;    one of R 21  and R 22  represents unsubstituted C 1-4  alkoxy and the other represents group R 31 —(CH 2 )p-O—;    R 23  and R 26  represent a hydrogen atom;    R 24  and R 25  represent a halogen atom, C 1-4  alkyl, C 1-4  alkoxy, or nitro;    R 27  and R 28  represent a hydrogen atom;    R 29  represents C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl (which C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl each are optionally substituted by a halogen atom or C 1-4  alkoxy), or —(CH 2 )q-R 32  wherein q is an integer of 0 or 1 and R 32  represents phenyl, pyridyl, or naphthyl which phenyl, pyridyl, and naphthyl are optionally substituted by a halogen atom, C 1-4  alkyl, or C 1-4  alkoxy.    
   
   
       86 . The compound according to  claim 85 , wherein R 21  represents unsubstituted C 1-4  alkoxy and R 22  represents group R 31 —(CH 2 )p-O—.  
   
   
       87 . The compound according to  claim 85 , wherein R 31  represents hydroxyl, amino on which one or two hydrogen atoms are optionally substituted by C 1-4  alkyl optionally substituted by hydroxyl, or group R 14 —(S)m- wherein R 14  represents a saturated or unsaturated five-membered heterocyclic group containing 1 to 4 nitrogen atoms and optionally substituted by C 1-4  alkyl, or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero); and p is an integer of 1 to 4.  
   
   
       88 . The compound according to  claim 85 , wherein p is 1.  
   
   
       89 . The compound according to  claim 85 , wherein R 31  represents group R 14 —(S)m- wherein R 14  represents an unsaturated six-membered heterocyclic group containing one or two nitrogen atoms and optionally substituted by C 1-4  alkyl and m is 0 (zero).  
   
   
       90 . The compound according to  claim 89 , wherein R 14  represents optionally substituted pyridyl.  
   
   
       91 . The compound according to  claim 57 , which is a compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: 
 (51) N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)-N′-(2,4-difluorophenyl)urea;    (119) N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phenyl)-N′-propylurea;    (135) N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phenyl)-N′-propylurea; (142) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N′-propylurea;    (143) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N′-propylurea;    (144) N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinolyl]oxy}phenyl)-N′-propylurea;    (145) N-[2-chloro-4-{(6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}oxy)phenyl]-N′-propylurea;    (146) N-[2-chloro-4-(7-{[2-(1H-1-imidazolyl)-ethoxy]-6-methoxy-4-quinolyl}oxy)phenyl]-N′-propylurea;    (148) N-[2-chloro-4-(6-methoxy-7-{[2-(4-methyl-piperazino)ethoxy]-4-quinolyl}oxy)phenyl]-N′-propylurea;    (149) N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-quinolyl]oxy}phenyl)-N′-propylurea;    (151) N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-N′-propylurea;    (152) N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinolyl}oxy)phenyl]-N′-propylurea;    (153) N-[2-chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazol-1-yl)propoxy]-4-quinolyl}oxy)phenyl]-N′-propylurea;    (157) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-quinolyl)oxy]-phenyl}-N′-propylurea;    (159) N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazol-1-yl)pentyl]oxy}-4-quinolyl)oxy]phenyl}-N′-propylurea;    (160) N-[2-chloro-4-(7-{[4-(1H-1-imidazolyl)-butoxy]-6-methoxy-4-quinolyl}oxy)phenyl]-N′-propylurea;    (162) N-(2-chloro-4-{[6-methoxy-7-(2-morpholino-ethoxy)-4-quinazolinyl]oxy}phenyl)-N′-(2,4-difluoro-phenyl)urea;    (163) N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinazolinyl]oxy}phenyl)-N′-(2,4-difluoro-phenyl)urea;    (164) N-[2-chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazino)propoxy]-4-quinazolinyl}oxy)phenyl]-N′-(2,4-difluorophenyl)urea;    (165) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-quinazolinyl)oxy]-phenyl}-N′-(2,4-difluorophenyl)urea;    (168) N-(2-chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-quinolyl]oxy}phenyl)-N′-(2,4-difluorophenyl)-urea;    (169) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N′-(2,4-difluorophenyl)-urea;    (170) N-[2-chloro-4-(6-methoxy-7-{[2-(1H-1,2,3-triazol-1-yl)ethoxy]-4-quinolyl}oxy)phenyl]-N′-(2,4-difluorophenyl)urea;    (184) N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phenyl)-N′-methylurea;    (185) N-(2-chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-quinazolinyl]oxy}phenyl)-N′-ethylurea; and    (186) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-quinolyl]oxy}phenyl)-N′-(2,4-difluorophenyl)-urea.    
   
   
       92 . A pharmaceutical composition comprising as active ingredient a compound according to  claim 53  or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       93 . A method for treating a disease selected from the group consisting of diabetic retinopathy, chronic rheumatism, psoriasis, and atherosclerosis, comprising: 
 administering, to a subject in need thereof, an effective amount of a compound according to  claim 53  or a pharmaceutically acceptable salt or solvate thereof.    
   
   
       94 . A method for treating human glioma, comprising: 
 administering, to a subject in need thereof, an effective amount of a compound according to  claim 53  or a pharmaceutically acceptable salt or solvate thereof.