2-'4-(hydroxymethyl-phenylamino) -piperidine-1-yl!-n- (9h-carbazol-3yl) - acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity

Abstract

The present invention relates to 1,4-disubstituted piperidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals. The substituents are as defined in the present claim 1.

1 : A compound or its salt of the formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         a is 0, 1, 2, 3 or 4, 
         b is 0, 1, 2 or 3, 
         c is 0, 1, 2, 3 or 4, 
         R 1 , R 2 , R 3 , R 4  each independently is hydrogen; a halogen; —CN; —NO 2 ; —OR 8 ; a linear or branched, saturated or unsaturated, which may be optionally at least mono-substituted; a saturated or unsaturated cycloaliphatic radical, which optionally may be at least mono-substituted, and optionally comprises at least one heteroatom as a ring member containing cycloaliphatic radical, and which optionally may be bonded via an alkylen group; or an optionally at least mono-substituted aryl- or heteroaryl radical, which optionally may be at least mono-substituted, which optionally may be bonded via an alkylen group and/or which optionally may be condensed with an optionally at least mono-substituted, saturated or unsaturated mono- or bicyclic ring system, 
         R 5  is hydrogen, a linear or branched, saturated or unsaturated, aliphatic radical which, optionally, may be at least mono-substituted, or a saturated or unsaturated cycloaliphatic radical, which optionally may be at least mono-substituted, 
         R 6 , R 7  and R 8 , identical or different, each independently is hydrogen or a linear or branched C1-3 alkyl, and 
         A represents a —CH 2 — or —CH 2 —CH 2 — group, optionally in form of one of its stereoisomers, its racemate or in form of a mixture of at least two of its stereoisomers, in any mixing ratio. 
       
     
     
         2 : The compound or its salt of  claim 1 , wherein R 1 , R 2 , R 3 , R 4  each independently is H; F; Cl; Br; —CN; —NO 2 ; —OR 8 ; a linear or branched, saturated or unsaturated C 1-6 -aliphatic radical, which may be optionally at least mono-substituted; a saturated or unsaturated C 3-8 -cycloaliphatic radical, which optionally may be at least mono-substituted, which optionally comprises at least one heteroatom as ring member, and which optionally may be bonded via a C 1-3 -alkylene group; or an aryl- or heteroaryl radical, which optionally may be at least mono-substituted, and which optionally may be bonded via a C 1-3 -alkylene group and/or which optionally may be condensed with an optionally at least mono-substituted, saturated or unsaturated mono- or bicyclic ring system,
 R 5  is hydrogen, a linear or branched, saturated or unsaturated, C 1-6 -aliphatic radical, which optionally may be at least mono-substituted, or a saturated or unsaturated C 3-8 -cycloaliphatic radical, which optionally may be at least mono-substituted,   R 6 , R 7  and R 8 , identical or different, each independently is hydrogen or a linear or branched C1-3 alkyl, and   A represents a —CH 2 — or —CH 2 —CH 2 — group.   
     
     
         3 : The compound or its salt of  claim 1 , wherein R 1 , R 2 , R 3 , R 4  each independently is H; F; Cl; Br; —CN; —NO 2 ; —OR 8 ; a linear or branched C 1-4 -alkyl radical, which optionally may be at least mono-substituted, or a saturated C 5 - or C 6 -cycloaliphatic radical, which optionally may be at least mono-substituted, which optionally may comprise at least one heteroatom as a ring member containing C 5 - or C 6 -cycloaliphatic radical, and which optionally may be bonded via an optionally at least mono-substituted C 1 - or C 2 -alkylene group. 
     
     
         4 : The compound or its salt of  claim 1 , wherein R 5  is H or a linear or branched C 1-6  alkyl radical. 
     
     
         5 : The compound or its salt of  claim 1 , wherein R 6 , R 7  and R 8 , are identical or different, and each independently is H or a linear or branched C 1-3 -alkyl. 
     
     
         6 : The compound or its salt of  claim 5 , wherein R 6 , R 7  and R 8 , are identical or different, and each independently is H or a linear or branched alkyl selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl. 
     
     
         7 : The compound or its salt of  claim 1  wherein R 6 , R 7  and R 8  each independently is hydrogen. 
     
     
         8 : The compound or its salt of  claim 1 , wherein A is a —CH 2 -group. 
     
     
         9 : The compound or its salt of  claim 1 , wherein a is 1, 2 or 3. 
     
     
         10 : The compound or its salt of  claim 1 , wherein b is 0, 1 or 2. 
     
     
         11 : The compound or its salt of  claim 1  wherein c is 0, 1 or 2. 
     
     
         12 : The compound or its salt of  claim 1 , wherein at least one of the substituents R 1 , R 2 , R 3  and R 4  is —OR 8 . 
     
     
         13 : The compound or its salt of  claim 1 , wherein one or two of the substituents R 1 , R 2 , R 3  and R 4  are —OR 8 . 
     
     
         14 : The compound or its salt of  claim 1 , wherein one or two of the substituents R 1 , R 2 , R 3  and R 4  are —OR 8 , and wherein b and c are each 0. 
     
     
         15 : The compound or its salt of  claim 1 , selected from the group consisting of:
 [1] 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,   [2] 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,   [3] 2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,   [4] 2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,   [5] 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,   [6] 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,   [7] 2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide, and   [8] 2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide.   
     
     
         16 : A process for the preparation of a 1,4-disubstituted piperidine or its salt, comprising reacting at least one compound of the formula (II), 
       
         
           
           
               
               
           
         
         with at least one compound of the formula (III), 
       
       
         
           
           
               
               
           
         
         wherein F is a halogen, hydroxy or an O-acyl group and G is a halogen, in a suitable reaction medium, to obtain a compound of the formula (IV) 
       
       
         
           
           
               
               
           
         
         and reacting the compound of the formula (IV) with at least one piperidine compound of the formula (V) or its salt, 
       
       
         
           
           
               
               
           
         
         wherein R 1  to R 4 , R 5 , R 6  and R 7 , a, b, c and A are as defined in  claim 1 , in a suitable reaction medium, to form the 1,4-disubstituted piperidine or its salt. 
       
     
     
         17 : A process for the preparation of a physiologically acceptable salt of the compound of  claim 1 , comprising reacting at least one compound of the formula (I) with at least one acid, thereby forming the physiologically acceptable salt of the compound. 
     
     
         18 : A process for the preparation of a physiologically acceptable salt of the compound of  claim 1 , comprising reacting at least one compound of the formula (I) comprising at least one acidic group with at least one base, thereby forming the physiologically acceptable salt of the compound. 
     
     
         19 : A pharmaceutical composition comprising at least one compound or its salt of  claim 1  and one or more pharmaceutically acceptable adjuvants. 
     
     
         20 : A method of treating at least on disease in a patient in need thereof, comprising administering the compound or its salt of  claim 1  to the patient in an amount sufficient to treat the at least one disease, wherein the at least one disease is selected from the group consisting of obesity, anorexia, cachexia, bulimia, diabetes, and combinations thereof. 
     
     
         21 : A method of treatment of at least one disease in a patient in need thereof, comprising administering a compound or its salt of  claim 1  to the patient in an amount sufficient to treat or prevent the at least one disease, wherein the at least one disease is selected from the group consisting of disorders of the peripheral nervous system; disorders of the central nervous system; arthritis; epilepsy; anxiety; depression; memory disorders; cardiovascular diseases; pain; hypertensive syndrome; inflammatory diseases; immune diseases; panic attacks; bipolar disorders; and combinations thereof.