Dehalogeno compounds

Abstract

3-(1-Aminocycloalkyl)pyrrolidinyl-substituted-6-dehalodeno(hydrogen-substituted)quinolon carboxylic acid derivatives having specific substitunets as represented by the following formula (I), its salts, and hydrates thereof exhibit a broad and potent antibacterial activity on gram-negative and gram-positive bacteria, in particular, resistant bacteria typified by gram-positive cocci, including MRSA, PRSP and VRE. Thus these compounds are usable as drugs.

1 . A compound represented by the following general formula (I), its salts, and hydrates thereof:  
       
         
           
           
               
               
           
         
       
       [wherein R 1  represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms; 
 R 2  represents an alkylthio group having 1 to 6 carbon atoms or a hydrogen atom, 
 wherein R 2  and the abovementioned R 1  may be integrated to form a ring structure by incorporating a part of the mother skeleton, the thus formed ring may contain a sulfur atom as a ring-constituent atom, and the ring may be substituted by an alkyl group having 1 to 6 carbon atoms, which may have a substituent;  
 
 R 3  represents a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl group, or a 3-acetoxy-2-oxobutyl group;  
 R 4  represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a hydroxyl group, a thiol group, or a halogenomethyl group, and 
 among the above, the amino group may have one or more substituents selected from among the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group;  
 
 A represents a nitrogen atom or a partial structure represented by formula (II):  
                     
  (wherein X represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, or a halogenomethoxy group, 
 among the above, the amino group may have one ore more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and a formyl group,  
 wherein X 1  and the aforementioned R 1  may be integrated to form a ring structure by incorporating a part of the mother skeleton, the thus formed ring may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom, and this ring may be substituted by an alkyl group having 1 to 6 carbon atoms, which may have a substituent);  
 
 each of R 5  and R 6  independently represents an alkyl group having 1 to 6 carbon atoms, a hydrogen atom, or a substituted carboxyl group derived from an amino acid, dipeptide, or tripeptide, 
 wherein the alkyl group may have one ore more substituents selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, and a halogen atom; and  
 
 n represents an integer 1 or 2].  
 
     
     
         2 . The compound according to  claim 1 , its salts or hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound.  
     
     
         3 . The compound according to  claim 1  or  2 , its salts or hydrates thereof, wherein n in the formula (I) is 1.  
     
     
         4 . The compound according to any one of  claims 1  to  3 , its salts or hydrates thereof, wherein R 3  in the formula (I) is a hydrogen atom.  
     
     
         5 . The compound according to any one of  claims 1  to  4 , its salts or hydrates thereof, wherein R 2  in the formula (I) is a hydrogen atom.  
     
     
         6 . The compound according to any one of  claims 1  to  5 , its salts or hydrates thereof, wherein R 4  in the formula (I) is a hydrogen atom.  
     
     
         7 . The compound according to any one of  claims 1  to  6 , its salts or hydrates thereof, wherein A in the formula (I) is a partial structure represented by the formula (II).  
     
     
         8 . The compound according to  claim 7 , its salts or hydrates thereof, wherein X 1  in the formula (II) is a methoxy group, a methyl group, a difluoromethoxy group, a fluorine atom, or a chlorine atom.  
     
     
         9 . The compound according to  claim 7 , its salts or hydrates thereof, wherein X 1  in the formula (II) is a methoxy group or a methyl group.  
     
     
         10 . The compound according to any one of  claims 1  to  9 , its salts or hydrates thereof, wherein each of R 5  and R 6  in the formula (I) is a hydrogen atom.  
     
     
         11 . The compound according to any one of  claims 1  to  9 , its salts or hydrates thereof, wherein one of either R 5  or R 6  in the formula (I) is a hydrogen atom and the other is a methyl group.  
     
     
         12 . The compound according to any one of claims  1  to  9 , its salts or hydrates thereof, wherein one of either R 5  or R 6  in formula (I) is a hydrogen atom and the other is a substituted carboxyl group derived from an amino acid, a dipeptide, or a tripeptide.  
     
     
         13 . The compound according to any one of  claims 1  to  12 , its salts or hydrates thereof, wherein the cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, in R 1  is a halogenocyclopropyl group.  
     
     
         14 . The compound according to  claim 13 , its salts or hydrates thereof, wherein the halogenocyclopropyl group is a 1,2-cis-2-halogenocyclopropyl group.  
     
     
         15 . The compound according to  claim 14 , its salts or hydrates thereof, wherein the halogenocyclopropyl group is a stereochemically pure substituent.  
     
     
         16 . The compound according to  claim 15 , its salts or hydrates thereof, wherein the halogenocyclopropyl group is a (1R, 2S)-2-halogenocyclopropyl group.  
     
     
         17 . The compound according to any one of  claims 13  to  16 , its salts or hydrates thereof, wherein the halogen atom of the halogenocyclopropyl group is a fluorine atom.  
     
     
         18 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         19 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         20 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         21 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         22 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         23 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         24 . 7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         25 . 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         26 . 7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         27 . 7-[3-(R)-[1-(ethylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         28 . 5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-fluoro-4-oxoquinoline-3-carboxy lic acid, its salts or hydrates thereof.  
     
     
         29 . 5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         30 . 5-amino-7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         31 . 5-amino-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         32 . 10-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, its salts or hydrates thereof.  
     
     
         33 . 1-(cyclopropyl)-8-methyl-7-[3-(R)-[1-(methylamino)cyclopropyl]pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salts or hydrates thereof.  
     
     
         34 . A medicament, which comprises the compound described in any one of  claims 1  to  33 , its salts or hydrates thereof as an active ingredient.  
     
     
         35 . An antibacterial agent, which comprises the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         36 . A therapeutic agent for an infectious disease, which comprises the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         37 . A method for treating a disease, which comprises administrating the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         38 . A method for treating an infectious disease, which comprises administrating the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         39 . A method for producing a medicament, which comprises formulating the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         40 . A method for producing an antibacterial agent, which comprises formulating the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         41 . A method for producing an infectious disease treating agent, which comprises formulating the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, as an active ingredient.  
     
     
         42 . Use of the compound described in any of  claims 1  to  33 , its salts or hydrates thereof, for the production of a medicament.  
     
     
         43 . Use of the compound described in any of  claims 1  to  33 , its salts or hydrates thereof for the production of an antibacterial agent.  
     
     
         44 . Use of the compound described in any of  claims 1  to  33 , its salts or hydrates thereof for the production of an infectious disease treating agent.