Enantiomers of 8-hydroxyquinoline derivatives and the synthesis thereof

Abstract

Enantiomer derivatives of 8-hydroxyquinoline derivatives with general formula (I) and (II) and the synthesis thereof and pharmaceutically acceptable salts and metal complexes thereof, and the medicinal and/or pharmaceutical compositions comprise these compounds: The compounds according to the invention can be used preferably as cytoprotective, neuroprotective, cardioprotective, anxiolytic and antidepressant agent for treatment of neuropsychiatric and neurologic diseases and diseases in connections with transplantations and with ischemia and reperfusion injuries thereof, and inhibition of organ, advantageously skin graft rejection.

1 . Novel R-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (I) and novel S-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (II), and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, 
       
         
           
           
               
               
           
         
         wherein 
         in general formulas (I) and (II) 
         R 1  is a lower alkyl group, lower cycloalkyl group, aryl group, aralkyl group or six membered heteroaryl or heteroaralkyl group wherein said cyclic groups are optionally substituted at the ortho, meta or para positions with one, two, three or four electron withdrawing groups or electron donating groups or optionally substituted five membered heteroaryl or heteroaralkyl group wherein the five or six membered heteroaryl or heteroaralkyl groups comprising one, two or three nitrogen; oxygen or sulfur atoms or combinations thereof; 
         R 2  is a hydrogen atom; aryl group; or six membered heteroaryl group wherein said cyclic groups are optionally substituted at the ortho; meta or para positions with one, two, three or four electron withdrawing groups or electron donating groups or optionally substituted five membered heteroaryl group wherein the five or six membered heteroaryl groups comprising one, two or three nitrogen; oxygen or sulfur atoms or combinations thereof; 
         R 3  represents a hydrogen atom; lower alkyl group; —CH 2 F; 
         CHF 2 ; —CF 3 ; —CH 2 CH 2 F; —CH 2 CHF 2 ; —CH 2 CF 3 ; —CH 2 OR 5 ; —CH 2 CH 2 OR 6 ; or —CH 2 —NR 7 R 8  group; 
         R 4  represents a hydrogen atom; halogen atom; methylthio group; methylsulfinyl group; methylsulfonyl group; or azido group; 
         R 5  represents a hydrogen atom; or lower alkyl group; 
         R 6  represents a hydrogen atom; or lower alkyl group; 
         R 7  represents a hydrogen atom; or lower alkyl group; 
         R 8  represents a hydrogen atom; or lower alkyl group; 
         R 7  and R 8  represents jointly —(CH 2 ) n — group; or —CH 2 CH 2 OCH 2 CH 2 — group or —CH 2 CH 2 SCH 2 CH 2 — group or —CH 2 CH 2 NR 9 CH 2 CH 2 — group,
 wherein 
 n is 4, 5 or 6; 
 
         R 9  represents a lower alkyl group; or —COR 10  group, 
         R 10  represents a hydrogen atom; lower alkyl group; methoxy group; or ethoxy group; 
         in the general formula (I) 
         X represents a hydrogen substituted C atom with “R” configuration; 
         in the general formula (II) 
         Y represents a hydrogen substituted C atom with “S” configuration; 
         with the proviso that 
         R 1  cannot represent non-substituted phenyl group, in case 
         R 2  represents a non-substituted phenyl group; or non-substituted 2-pyridyl group; or 4-carboxyphenyl group; or 2-carboxyphenyl group; 
         R 3  represents a hydrogen atom or methyl group; 
         R 4  represents hydrogen atom or chlorine substituent; 
         and 
         R 1  cannot represent 3,4-dimethylphenyl group, in case 
         R 2  represents a non-substituted 2-pyridyl group; 
         R 3  represents methyl group and 
         R 4  a hydrogen atom; 
         and 
         R 1  cannot represent 2-furyl group, in case 
         R 2  represents a non-substituted 2-pyridyl group; 
         R 3  represents a hydrogen atom and 
         R 4  represents a chlorine substituent, 
         and 
         R 1  cannot represent a non-substituted 2-pyridyl group, in case 
         R 2  represents 5-methylisoxazol-3-yl group; 
         R 3  represents a hydrogen atom; 
         R4 represents a hydrogen atom. 
       
     
     
         2 . Novel R-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (I′) according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, 
       
         
           
           
               
               
           
         
         wherein 
         in general formula (I′) 
         R 1′  represents an aryl group substituted with an electron withdrawing group in meta or para position, or an aryl group substituted with an electron donating group in ortho, meta or para position; or a double-substituted aryl group with electron withdrawing groups in meta and para positions; or an aryl group double-substituted with electron withdrawing groups in ortho and para positions; or a substituted or unsubstituted heteroaryl group; 
         R 2′  represents an aryl group substituted with an electron withdrawing group in para position, or an aryl group substituted with an electron donating group in ortho, meta or para position; or an unsubstituted heteroaromatic group or a heteroaromatic or aryl group substituted with alkyl group and/or with electron withdrawing groups in ortho, meta or para positions; 
         R 3′  represents a hydrogen atom 
         R 4′  represents a hydrogen atom and 
         in general formula (I′) 
         X represents a hydrogen substituted C atom with “R” configuration. 
       
     
     
         3 . Novel S-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (II′) according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, 
       
         
           
           
               
               
           
         
         wherein 
         in general formula (II′) 
         R 1′  represents an aryl group substituted with an electron withdrawing group in meta or para position, or an aryl group substituted with an electron donating group in ortho, meta or para position; or a double-substituted aryl group with electron withdrawing groups in meta and para positions; or an aryl group double-substituted with electron withdrawing groups in ortho and para positions; or a substituted or unsubstituted heteroaryl group; 
         R 2′  represents an aryl group substituted with an electron withdrawing group in para position, or an aryl group substituted with an electron donating group in ortho, meta or para position; or an unsubstituted heteroaromatic group or a heteroaromatic or aryl group substituted with alkyl group and/or with electron withdrawing groups in ortho, meta or para positions; 
         R 3′  represents a hydrogen atom; 
         R 4′  represents a hydrogen atom and 
         in general formula (I′) 
         Y represents a hydrogen substituted C atom with “S” configuration. 
       
     
     
         4 . Novel R-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (I″) according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, 
       
         
           
           
               
               
           
         
         wherein 
         in general formula (I″) 
       
       R 1″  represents a phenyl or pyridyl group optionally single or double substituted with a trifluoromethyl group, hydroxy group, fluorine atom or isopropoxy group; 
       R 2″  represents a phenyl group optionally single or double substituted with a trifluoromethyl group or methoxy-carbonyl group; or a pyridyl, pyrimidyl, pyrrolidinyl, oxazolidinyl group optionally single or double substituted with a methyl group or fluorine atom; 
       R 3″  represents hydrogen atom; 
       R 4″  represents hydrogen atom; and 
       in general formula (I″) 
       X represents a hydrogen substituted C atom with “R” configuration; 
     
     
         5 . Novel S-enantiomeric derivatives of 8-hydroxyquinoline derivatives of general formula (II″) according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, 
       
         
           
           
               
               
           
         
         wherein 
         in general formula (II″) 
         R 1″  represents a phenyl or pyridyl group optionally single or double substituted with a trifluoromethyl group, hydroxy group, fluorine atom or isopropoxy group; 
         R 2″  represents a phenyl group optionally single or double with a trifluoromethyl group or methoxy-carbonyl group; or a pyridyl, pyrimidyl, pyrrolidinyl, oxazolidinyl group optionally single or double substituted with a methyl group or fluorine atom; 
         R 3″  represents hydrogen atom; 
         R 4″  represents hydrogen atom and 
         in general formula (II″) 
         Y represents a hydrogen substituted C atom with “S” configuration. 
       
     
     
         6 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof characterized in listed as follows:
 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol), 
 7-[(S)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol, 
 Potassium 7-[(R)-[(4-methylpirimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-olate, 
 Potassium 7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-olate, 
 Natrium 7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinolin-8-olate, 
 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-ol fumarate, 
 7-[(S)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-ol fumarate, 
 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol zinc complex, 
 7-[(R)-[(6-Methylpyridin-2-yl)amino]4-nitrophenyl)methyl]-quinolin-8-ol, 
 7-[(S)-[(6-Methylpyridin-2-yl)amino]4-nitrophenyl)methyl]-quinoline-8-ol, 
 7-[(R)-[(6-Methylpyridin-2-yl)amino]3-hydroxyphenyl)methyl]-quinoline-8-ol, 
 7-[(S)-[(6-Methylpyridin-2-yl)amino]3-hydroxyphenyl)methyl]-quinoline-8-ol, 
 7-[(R)-[(6-Methylpyridin-2-yl)amino](4-hydroxy-3-methoxiphenyl)methyl]-quinoline-8-ol, 
 7-[(S)-[(6-Methylpyridin-2-yl)amino](4-hydroxy-3-methoxiphenyl)methyl]-quinoline-8-ol, 
 7-[(R)-[(6-Methylpyridin-2-yl)amino](5-bromopyridin-2-yl)methyl]-quinoline-8-ol, 
 7-[(S)-[(6-Methylpyridin-2-yl)amino](5-bromopyridin-2-yl)methyl]-quinoline-8-ol, 
 7-[(R)-[(6-Methylpyridin-2-yl)amino]2-hydroxyphenylmethyl]-quinoline-8-ol, 
 7-[(S)-[(6-Methylpyridin-2-yl)amino]2-hydroxyphenylmethyl]-quinoline-8-ol, 
 5-Chloro-7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinolin-8-ol, 
 5-Chloro-7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 5-Chloro-7-[(R)-[(6-methylpyridin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-Methyl-7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-Methyl-7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-[(Dimethylamino)methyl]-7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-[(Dimethylamino)methyl]-7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-[(Dimethylamino)methyl]-7-[(R)-[(4-methylpyridin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-[(Dimethylamino)methyl]-7-[(S)-[(4-methylpyridin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 5-Nitro-7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 5-Nitro-7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 7-[(R)-[(Pyridin-2-yl)[4-(trifluoromethyl)phenylamino]methyl]quinoline-8-ol, 
 7-[(S)-[(Pyridin-2-yl)[4-(trifluoromethyl)phenylamino]methyl]quinoline-8-ol 
 2-(Hydroxymethyl)-7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol, 
 2-(Hydroxymethyl)-7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinoline-8-ol. 
 
     
     
         7 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof wherein the metal complexes are iron, zinc or copper complexes. 
     
     
         8 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 1  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof wherein the metal complex is zinc complex. 
     
     
         9 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 6  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, wherein the enantiomeric derivative is 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol. 
     
     
         10 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 6  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, wherein the enantiomeric derivative is 7-[(S)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol. 
     
     
         11 . Novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 6  and pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof, wherein the salts and the complex are listed as follows:
 Potassium 7-[(R)-[(4-methylpirimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-olate, 
 Potassium 7-[(S)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-olate, 
 Natrium 7-[(R)-[(4-methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]methyl]quinolin-8-olate, 
 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-ol fumarate, 
 7-[(S)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)-phenyl]methyl]quinolin-8-ol fumarate, 
 7-[(R)-[(4-Methylpyrimidin-2-yl)amino][4-(trifluoromethyl)phenyl]-methyl]quinolin-8-ol zinc complex. 
 
     
     
         12 . Medicinal and/or pharmaceutical compositions comprising the novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 1  and/or pharmaceutically acceptable salts and complexes with divalent or polyvalent metals thereof. 
     
     
         13 . Medicinal and/or pharmaceutical compositions according to  claim 12 , further comprising the novel enantiomeric derivatives of 8-hydroxyquinoline derivatives according to  claim 1  and/or pharmaceutically acceptable salts and metal complexes thereof and inert, pharmaceutically acceptable, solid or liquid carrier and/or excipient. 
     
     
         14 . Medicinal and/or pharmaceutical compositions according to  claim 12 , further comprising medicinal acceptable carriers and/or excipients as following listed: starch, gelatinized starch, cellulose, microcrystalline cellulose or cellulose-derivatives, lactose, lactose monohydrate, talcum, mannitol, sodium chloride, sodium carbonate, saccharose, maltose, calcium carbonate, colloidal anhydrous silicon dioxide, stearic acid, magnesium stearate and/or isomalt. 
     
     
         15 . Medicinal and/or pharmaceutical compositions according to  claim 12 , wherein the composition is solid, semi-solid or liquid. 
     
     
         16 . Medicinal and/or pharmaceutical compositions according to  claim 12 , wherein the composition is tablet, inhalation powder, capsule, suppository or solution for injection. 
     
     
         17 . Medicinal and/or pharmaceutical compositions according to  claim 12 , wherein the composition is tablet.