New pyridone derivates with mch antagonistic activity and medicaments comprising these compounds

Abstract

The present invention relates to compounds of general formula I wherein the groups and radicals B, k, L, U, V, W, X, Y, Z, R 1 , R 2 , have the meanings given in claim 1 . Moreover the invention relates to pharmaceutical compositions containing at least one compound according to the invention. By virtue of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2  independently of one another denote H, C 1-8 -alkyl or C 3-7 -cycloalkyl, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R 11 , and a —CH 2 — group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by —O—, —S— or —NR 13 —; or
 R 2  denotes a C 1-3 -alkylene bridge which is linked to the group Y, wherein the alkylene bridge may be substituted with one or more C 1-3 -alkyl-groups, and R 1  is defined as hereinbefore or denotes a group selected from C 1-4 -alkyl-CO—, C 1-4 -alkyl-O—CO—, (C 1-4 -alkyl)NH—CO— or (C 1-4 -alkyl) 2 N—CO— wherein alkyl-groups may be mono- or polyfluorinated; or 
 R 1  and R 2  form a C 3-8 -alkylene bridge, wherein a —CH 2 — group not adjacent to the N atom of the R 1 R 2 N— group may be replaced by —CH═N—, —CH═CH—, —O—, —S—, —SO—, —(SO 2 )—, —CO—, —C(═CH 2 )—, —C(═N—OH)—, —C(═N—(C 1-4 -alkyl))— or —NR 13 —, 
 while in the case when R 1  and R 2  form an alkylene bridge in the alkylene bridge one or more H atoms may be replaced by identical or different groups R 14 , and 
 the alkylene bridge defined hereinbefore may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is made
 via a single or double bond, 
 via a common C atom forming a spirocyclic ring system, 
 via two common adjacent C and/or N atoms forming a fused bicyclic ring system or 
 via three or more C and/or N atoms forming a bridged ring system; 
 
 
 X denotes a C 1-3 -alkylene bridge, which may comprise one, two or three identical or different C 1-4 -alkyl substituents, while two alkyl groups may be joined together forming a 3 to 7-membered cyclic group, and while in a C 2-3 -alkylene bridge one or two C atoms may be monosubstituted by R 10 ; and 
 R 10  is selected from the group consisting of hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy or C 1-4 -alkoxy-C 1-3 -alkyl; and 
 Y denotes a 5- to 6-membered aromatic carbocyclic group, which may contain 1, 2 or 3 heteroatoms independently selected from N, O and/or S; which cyclic group may be mono- or polysubstituted by identical or different substituents R 20 ; 
 Z denotes —CH 2 —CH 2 —, —C(═O)—CH 2 —, —C(═CH 2 )—CH 2 — or —C(OH)H—CH 2 — all of which may be mono- or polysubstituted with substituents independently from each other selected from C 1-3 -alkyl; 
 U, V both denote CH or one of the groups U, V denotes N and the other of U, V denotes CH, wherein CH may be substituted with L; and 
 L independently of each other denotes halogen, cyano or C 1-3 -alkyl; and 
 k denotes 0, 1 or 2; 
 W is selected from the group consisting of —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH═CH—, —CH 2 —NR N —, —NR N —CH 2 —, —CH 2 —, —O—, —S— and —NR N —; 
 R N  denotes H, C 1-4 -alkyl, formyl, C 1-3 -alkylcarbonyl or C 1-3 -alkylsulfonyl; and
 in case the group W denotes —NR N —CH 2 — the group R N  may denote a —CH 2 — or —CH 2 —CH 2 — bridge being linked to the cylic group B; and 
 
 B is a 5- or 6-membered unsaturated or aromatic carbocyclic group which may contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and/or S; which cyclic group may be mono- or polysubstituted by identical or different substituents R 20 ; and 
 Cy denotes a carbo- or heterocyclic group selected from one of the following meanings
 a saturated 3- to 7-membered carbocyclic group, 
 an unsaturated 4- to 7-membered carbocyclic group, 
 a phenyl group, 
 a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as heteroatom, 
 a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, 
 an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, 
 
  while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C 1-4 -alkyl)-imino, methylene, ethylene, (C 1-4 -alkyl)-methylene or di-(C 1-4 -alkyl)-methylene bridge, and 
  while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R 20 , or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 ; and 
  while in the above-mentioned saturated or unsaturated carbo- or heterocyclic groups a —CH 2 — group may be replaced by a —C(═O)— group; 
 R 11  denotes halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—, R 15 —O—CO—, R 15 —CO—O—, cyano, R 16 R 17 N—, R 18 R 19 N—CO— or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF 3 , C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-3 -alkyl; 
 R 13  has one of the meanings given for R 17  or denotes formyl; 
 R 14  denotes halogen, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—, R 15 —O—CO—, R 15 —CO—, R 15 —CO—O—, R 16 R 17 N—, HCO—NR 15 —, R 18 R 19 N—CO—, R 18 R 19 N—CO—NH—, R 15 —O—C 1-3 -alkyl, R 15 —O—CO—C 1-3 -alkyl-, R 15 —SO 2 —NH—, R 15 —SO 2 —N(C 1-3 -alkyl), R 15 —O—CO—NH—C 1-3 -alkyl-, R 15 —SO 2 —NH—C 1-3 -alkyl-, R 15 —CO—C 1-3 -alkyl-, R 15 —CO—O—C 1-3 -alkyl-, R 16 R 17 N—C 1-3 -alkyl-, R 18 R 19 N—CO—C 1-3 -alkyl- or Cy—C 1-3 -alkyl-, 
 R 15  denotes H, C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, pyridinyl or pyridinyl-C 1-3 -alkyl, 
 R 16  denotes H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 4-7 -cycloalkenyl, C 4-7 -cycloalkenyl-C 1-3 -alkyl, ω-hydroxy-C 2-3 -alkyl, ω-(C 1-4 -alkoxy)-C 2-3 -alkyl, amino-C 2-6 -alkyl, C 1-4 -alkyl-amino-C 2-6 -alkyl, di-(C 1-4 -alkyl)amino-C 2-6 -alkyl or cyclo-C 3-6 -alkyleneimino-C 2-6 -alkyl, 
 R 17  has one of the meanings given for R 16  or denotes phenyl, phenyl-C 1-3 -alkyl, pyridinyl, C 1-4 -alkylcarbonyl, C 3-7 -cycloalkylcarbonyl, hydroxycarbonyl-C 1-3 -alkyl, C 1-4 -alkoxycarbonyl, C 1-4 -alkoxycarbonyl-C 1-3 -alkyl, C 1-4 -alkylcarbonylamino-C 2-3 -alkyl, N—(C 1-4 -alkylcarbonyl)-N—(C 1-4 -alkyl)amino-C 2-3 -alkyl, C 1-4 -alkylamino-carbonyl, C 1-4 -alkylsulphonyl, C 1-4 -alkylsulphonylamino-C 2-3 -alkyl or N—(C 1-4 -alkylsulphonyl)-N(—C 1-4 -alkyl)amino-C 2-3 -alkyl; 
 R 18 , R 19  independently of one another denote H or C 1-6 -alkyl wherein R 18 , R 19  may be linked to form a C 3-6 -alkylene bridge, wherein a —CH 2 — group not adjacent to an N atom may be replaced by —O—, —S—, —SO—, —(SO 2 )—, —CO—, —C(═CH 2 )— or —NR 13 —; 
 R 20  denotes halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, R 22 —C 1-3 -alkyl or has one of the meanings given for R 22 ; and 
 R 21  denotes C 1-4 -alkyl, ω-hydroxy-C 2-6 -alkyl, ω-C 1-4 -alkoxy-C 2-6 -alkyl, ω-C 1-4 -alkyl-amino-C 2-6 -alkyl, ω-di-(C 1-4 -alkyl)amino-C 2-6 -alkyl, ω-cyclo-C 3-6 -alkyleneimino-C 2-6 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-4 -alkyl-carbonyl, C 1-4 -alkoxy-carbonyl, C 1-4 -alkylsulphonyl, aminosulphonyl, C 1-4 -alkylaminosulphonyl, di-C 1-4 -alkylaminosulphonyl or cyclo-C 3-6 -alkylene-imino-sulphonyl, 
 R 22  denotes pyridinyl, phenyl, phenyl-C 1-3 -alkoxy, cyclo-C 3-6 -alkyleneimino-C 2-4 -alkoxy, OHC—, HO—N═HC—, C 1-4 -alkoxy-N═HC—, C 1-4 -alkoxy, C 1-4 -alkylthio, carboxy, C 1-4 -alkylcarbonyl, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di-(C 1-4 -alkyl)-aminocarbonyl, cyclo-C 3-6 -alkyl-amino-carbonyl, cyclo-C 3-6 -alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C 3-6 -alkyleneimino-C 2-4 -alkyl-aminocarbonyl, C 1-4 -alkyl-sulphonyl, C 1-4 -alkyl-sulphinyl, C 1-4 -alkyl-sulphonylamino, C 1-4 -alkyl-sulphonyl-N—(C 1-4 -alkyl)amino, amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonyl-amino, C 1-4 -alkyl-carbonyl-N—(C 1-4 -alkyl)-amino, cyclo-C 3-6 -alkyleneimino, phenyl-C 1-3 -alkylamino, N—(C 1-4 -alkyl)-phenyl-C 1-3 -alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C 2-3 -alkyl-aminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidin-yl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, aminocarbonylamino or C 1-4 -alkylaminocarbonylamino, 
 
       while in the above-mentioned groups and radicals, particularly in L, W, X, Z, R N , R 10 , R 11 , R 13  to R 22 , in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br and/or in each case one or more phenyl rings may additionally comprise independently of one another one, two or three substituents selected from the group F, Cl, Br, I, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl- and di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl and/or may be monosubstituted by nitro, and
 the H atom of any carboxy group present or an H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo, 
 
       a tautomer thereof, a diastereomer thereof, an enantiomer thereof, a mixture of any such forms or a salt thereof. 
     
     
         2 . The compound according to  claim 1 , characterised in that the groups R 1 , R 2  are selected independently of one another from the group comprising H, C 1-6 -alkyl, C 3-5 -alkenyl, C 3-5 -alkynyl, C 3-7 -cycloalkyl, hydroxy-C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, (hydroxy-C 3-7 -cycloalkyl)-C 1-3 -alkyl, hydroxy-C 2-4 -alkyl, ω-NC—C 2-3 -alkyl, C 1-4 -alkoxy, C 2-4 -alkyl, hydroxy-C 1-4 -alkoxy-C 2-4 -alkyl, C 1-4 -alkoxy-carbonyl-C 1-4 -alkyl, carboxyl-C 1-4 -alkyl, amino-C 2-4 -alkyl, C 1-4 -alkyl-amino-C 2-4 -alkyl, di-(C 1-4 -alkyl)amino-C 2-4 -alkyl, cyclo-C 3-6 -alkyleneimino-C 2-4 -alkyl, pyrrolidin-3-yl, N—(C 1-4 -alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C 1-3 -alkyl, N—(C 1-4 -alkyl)-pyrrolidinyl-C 1-3 -alkyl, piperidin-3-yl, piperidin-4-yl, N—(C 1-4 -alkyl)-piperidin-3-yl, N—(C 1-4 -alkyl) -piperidin-4-yl, piperidinyl-C 1-3 -alkyl, N—(C 1-4 -alkyl)-piperidinyl-C 1-3 -alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, phenyl-C 1-3 -alkyl or pyridyl-C 1-3 -alkyl, while in the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F, C 1-3 -alkyl or hydroxy-C 1-3 -alkyl, and/or one or two C atoms independently of one another may be monosubstituted by Cl, Br, OH, CF 3  or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R 20 , in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 , wherein R 20  and R 21  are defined as in  claim 1 . 
     
     
         3 . The compound according to  claim 1 , characterised in that R 1  and R 2  together with the N atom to which they are bound form a heterocyclic group which is selected from the meanings azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine in which the free imine function is substituted by R 13 , piperidin-4-one, morpholine, thiomorpholine, 1-oxo-thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl;
 while one or more H atoms may be replaced by identical or different groups R 14 , and/or   the heterocyclic groups specified may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is made
 via a single or double bond, 
 via a common C atom forming a spirocyclic ring system, 
 via two common adjacent C and/or N atoms forming a fused bicyclic ring system or 
 via three or more C and/or N atoms forming a bridged ring system; 
   and the groups R 13 , R 14  and the group Cy are defined as in  claim 1 .   
     
     
         4 . The compound according to  claim 1 , characterised in that R 2  denotes a C 1-3 -alkylene bridge which is linked to the group Y, wherein the alkylene bridge may be substituted with one or more C 1-3 -alkyl-groups, and R 1  is defined as in  claim 2  or denotes a group selected from C 1-4 -alkyl-CO—, C 1-4 -alkyl-O—CO—, (C 1-4 -alkyl)NH—CO— or (C 1-4 -alkyl) 2 N—CO— wherein alkyl-groups may be mono- or polyfluorinated. 
     
     
         5 . The compound according to  claim 1 , characterised in that X denotes a —CH 2 —, —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 — bridging group, wherein one or two hydrogen atoms may be replaced by identical or different C 1-3 -alkyl-groups, while two alkyl-groups may linked together to form a 3 to 6-membered cycloalkyl group. 
     
     
         6 . The compound according to  claim 1 , characterised in that the group Y denotes phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thiophenyl and thiazolyl all of which may be mono- or polysubstituted by identical or different substituents R 20 , while R 20 . 
     
     
         7 . The compound according to  claim 1 , characterised in that the group Z denotes a group selected from —CH 2 —CH 2 —, —C(═O)—CH 2 —, —C(═CH 2 )—CH 2 —, —C(OH)H—CH 2 — and —CFH—CH 2 —. 
     
     
         8 . The Compound according to  claim 1 , characterised in that the group W denotes —CH 2 —O—, —O—CH 2 — or —NR N —CH 2 —. 
     
     
         9 . The compound according to  claim 1 , characterised in that the group B is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl, wherein said group B may be mono- or polysubstituted by identical or different substituents R 20 . 
     
     
         10 . The physiologically acceptable salt of the compound according to  claim 1 . 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  or its salt, together with one or more inert carriers or diluents. 
     
     
         12 . A method for influencing the eating behaviour of a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         13 . A method for reducing the body weight of a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         14 . A method for preventing and/or treating symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         15 . A method for preventing and/or treating metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         16 . A method for preventing and/or treating diseases and/or disorders associated with obesity, particularly diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         17 . A method for preventing and/or treating hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         18 . A method for preventing and/or treating micturition disorders, such as for example urinary incontinence, hyperactive urinary bladder, urgency, nycturia and enuresis in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         19 . A method for preventing and/or treating dependencies and/or withdrawal symptoms in a mammal which comprises administering to the mammal at least one compound according to  claim 1  or its salt. 
     
     
         20 . A pharmaceutical composition comprising
 a first active substance which is a compound according to  claim 1 ,   a second active substance which is a compound selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression,   and one or more inert carriers or diluents.