Non-basic melanin concentrating hormone receptor-1 antagonists and methods

Abstract

The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I wherein R 1 , R 2 , R 3 , R 8 , and R 9 are defined herein. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       is a phenylene ring or a heteroaryl ring which contains one or two nitrogen atoms or one oxygen atom;
 R 1  is Z-Y—X—, wherein 
 
       
         
           
           
               
               
           
         
         
           Y is a bond, a 3- to 6-membered cycloalkyl, an alkyl chain; and 
           Z is aryl or heteroaryl; 
         
         R 2  is -E-G-(J) m , with m being an integer from 1 to 3; 
         E is O, S or a bond; 
         G is lower alkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, cycloalkoxy, alkylcycloalkoxy, or cycloalkoxyalkyl, and 
         each J is independently hydrogen, hydroxyl, CN, —SO 2 R 7 , —SR 7 , —SOR 7 , lower alkyl, lower alkoxy, CF 3 , CF 3 O—, —COOR 5 , or —CO—NR 5a R 6 , wherein R 5a  and R 6  are each independently selected from the group consisting of H, C 1-3  alkyl, and cycloalkyl, or R 5a  and R 6  taken together can be propanediyl, butanediyl or pentanediyl with the N atom to which they are attached to form a 4-, 5- or 6-membered cyclic amine which may be optionally substituted; 
         R 5  is H, C 1-6  alkyl, or cycloalkyl; 
         R 7  is lower alkyl; and 
         R 3  is C 1-6  alkyl, cycloalkyl, C 1-6  alkoxy, halogen, hydrogen, —S—C 1-6  alkyl, CN, CF 3 O, or CF 3 ; 
         and wherein R 2  and R 3  can be taken together to form a 5- to 7-membered ring which is saturated or partially unsaturated and may optionally include an E heteroatom which is O or 0, 1 or 2 N atoms, which ring is substituted with one or two —O-G-(J) m  groups wherein at least one J is OH, and which may optionally be substituted with other substituents as set out for “alkyl” or “heteroaryl”; 
         with the proviso that where 
       
       
         
           
           
               
               
           
         
       
       is a phenylene group, E-G and R 3  are not identical unsubstituted lower alkoxy groups, and when G is lower alkyl and J is H, R 3  is not hydrogen; and
 R 8  and R 9  are each independently hydrogen, halogen, or lower alkyl; 
 including esters thereof, prodrugs thereof, solvates thereof, and all stereoisomers thereof. 
 
     
     
         2 . The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is a phenylene or wherein 
       
         
           
           
               
               
           
         
       
       is a monocyclic or bicyclic heteroaryl ring. 
     
     
         3 . The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound as defined in  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound as defined in  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or prodrug of any of the above. 
     
     
         6 . The compound as defined in  claim 4  wherein
 X is O or S; and/or   R 1  is Z-Y—X,   wherein Y is a bond or an alkylene chain of 1 to 3 atoms; and/or   wherein Z is phenyl or aryl;   wherein Z is heteroaryl; and/or   wherein R 2  is -E-G-J; and/or   wherein E is O or S; and/or   wherein G is an alkylene chain or alkylcycloalkyl; and/or   wherein J is H, OH, SO 2 R 7 , lower alkyl, lower alkoxy, or CF 3 ; and/or   R 3  is C 1-6  alkyl, C 1-6  alkoxy, H, or halo; and or   R 8  is H or alkyl; and/or   R 9  is H; and or   R 2  and R 3  may optionally be taken together to form a 5- to 7-membered ring which is saturated, unsaturated or partially unsaturated, and may include an O atom or 1 or 2 N atoms, which ring is substituted with one or two —O-G-(J) m  groups wherein at least one J is OH, and which may be optionally substituted with other substituents as set out for “alkyl” or “heteroaryl”.   
     
     
         7 . The compound as defined in  claim 1  or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound as defined in  claim 7  wherein
 R 1  is Z-Y—X;   X is S; and/or   Y is a bond or alkylene chain; and/or   Z is phenyl or pyridyl; and/or   E is O; and/or   G is an alkylene chain or alkylcycloalkyl; and/or   J is H or OH; and/or   R 3  is H, alkoxy, alkyl, or halo; and/or   R 8  is H or CH 3 ; and/or   R 9  is H;   wherein R 2  and R 3  may be taken together to form a 5- to 7-membered ring which is saturated, unsaturated or partially unsaturated, and may include an O atom or 1 or 2 N atoms, which ring is substituted with 1 or 2 —O-G-(J) m  groups wherein at least one J is OH, and which may be further optionally substituted with alkyl and/or OH.   
     
     
         9 . The compound as defined in  claim 1  wherein
 Z is aryl or heteroaryl, with any of the foregoing Z moieties either unsubstituted or substituted with 1, 2 or 3 of amino, halo, C 1-6  alkyl, C 1-3  alkylamino, di-C 1-3  alkylamino, C 1-3  alkoxy, C 1-3  thioalkyl, C 1-3  trifluoroalkoxy, trifluoromethyl, cycloalkyl, cycloalkoxy, or heteroaryl; and or   J is hydrogen, hydroxyl, CN, —SO 2 R 7 , —SR 7 , —SOR 7 , lower alkyl, lower alkoxy, CF 3 , CF 3 O—, —COOR 5 , or —CO—NR 5a R 6 , wherein R 5a  and R 6  are each independently selected from the group consisting of H, C 1-3  alkyl, and cycloalkyl, or R 5a  and R 6  taken together can be propanediyl, butanediyl or pentanediyl with the N atom to which they are attached to form a 4-, 5- or 6-membered cyclic amine optionally substituted with lower alkyl, lower alkoxy, hydroxyl, CF 3 , or CF 3 O.   
     
     
         10 . The compound of  claim 1  wherein:
 Z is
 (1) aryl, which is optionally substituted with:
 a) halogen, 
 b) alkyl, 
 c) alkoxy, 
 d) polyhaloalkyl, 
 e) polyhaloalkoxy, 
 f) amino, alkylamino or dialkylamino, 
 g) alkylthio, 
 h) OH, 
 i) an ester, or 
 j) aryl, 
 
 (2) heteroaryl which is:
 a) pyridinyl, 
 b) pyrazinyl, or 
 c) pyrimidinyl, 
 
 each of a), b) or c) being optionally substituted with alkyl, polyhaloalkyl, alkoxy, or halogen, 
 (3) benzothiazole optionally substituted with halo or alkoxy, 
 (4) benzoxazole optionally substituted with halo, 
 (5) benzimidazole, 
 (6) thiazole optionally substituted with aryl or alkyl, 
 (7) indanyl, 
 (8) quinolinyl optionally substituted with CF 3 , or 
 (9) imidazolidinyl; and/or 
   Y is a bond or alkylene; and/or   X is S, O, SO, or SO 2 ; and/or   J is
 (1) H, 
 (2) —CO—NR 5a R 6  wherein R 5a  and R 6  together with the N to which they are attached form a pyrrolidinyl ring, 
 (3) OH, 
 (4) COOH, 
 (5) COOalkyl, 
 (6) SO 2 R 7 , or 
 (7) prodrug esters which are selected from glycine 
   
       
         
           
           
               
               
           
         
       
       valine 
       
         
           
           
               
               
           
         
       
       and phosphate 
       
         
           
           
               
               
           
         
       
       and/or
 m is 1 or 2; and/or 
 G is a bond or CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       , cycloalkyl which is 
       
         
           
           
               
               
           
         
       
       or cycloalkoxy which is 
       
         
           
           
               
               
           
         
         E is O; and/or 
         wherein R 2  and R 3  can be optionally taken together to form a 5- or 6-membered unsaturated or aromatic ring containing one or two N atoms, which ring is optionally substituted with hydroxyalkyl which is 
       
       
         
           
           
               
               
           
         
       
       and is 
       
         
           
           
               
               
           
         
         and wherein R 2  and R 3  can optionally be taken together to form a 6-membered saturated or partially unsaturated O-containing ring, which ring is optionally substituted with hydroxyalkyl, alkyl, and/or OH; and/or 
         R 3  is H, alkoxy, hydroxyalkyl, alkyl, halo, or hydroxyalkoxy; and/or 
         R 8  is H, halo or alkyl; and/or 
         R 9  is H. 
       
     
     
         11 . The compound of  claim 7 , wherein Z is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, and benzoxazolyl. 
     
     
         12 . The compound of  claim 7 , wherein R 3  is C 1 -C 6  alkoxy or C 1-6  alkyl. 
     
     
         13 . The compound of  claim 7 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 7  wherein 
       
         
           
           
               
               
           
         
       
       is a phenylene; and/or 
       
         
           
           
               
               
           
         
       
       and/or
 R 3  is methoxy or methyl; 
 R 1  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound as defined in  claim 7  wherein
 X is S;   Y is a bond or (CH 2 ) 2 ;   
       
         
           
           
               
               
           
         
         R 3  is CH 3 O or CH 3 ; 
         R 8  is H; and 
         R 9  is H. 
       
     
     
         16 . The compound as defined in  claim 1  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1  in a prodrug ester form, wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound of Formula IB or a pharmaceutically acceptable salt thereof having the structure 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound as defined in  claim 18  wherein
 R 1  is Z-Y—X— wherein
 X is S, 
 Y is an alkyl chain of 1 to 3 carbons or a bond, 
 Z is heteroaryl or phenyl, 
 each of which Z is optionally substituted with CF 3 , CF 3 O, or halo; 
   R 2  is -E-G-J wherein
 E is O, 
 G is lower alkyl or alkylcycloalkyl, and 
 J is OH; 
   R 3  is alkoxy, alkyl or halo;   R 8  is H or alkyl; and   R 9  is H.   
     
     
         20 . The compound as defined in  claim 18  wherein
 X is S;   Y is a bond or (CH 2 ) 2 ;   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 3  is H, Cl, CH 3 , or CH 3 O; and 
         R 8  and R 9  are each H. 
       
     
     
         21 . The compound of  claim 1  wherein 
       
         
           
           
               
               
           
         
       
       is a heteroaryl ring; 
       
         
           
           
               
               
           
         
         R 3  is methoxy, Cl, H, or methyl; and 
         R 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in  claim 1 , alone or in combination with at least one additional therapeutic agent, in association with a pharmaceutically acceptable carrier or diluent. 
     
     
         23 . A pharmaceutical combination comprising:
 at least one compound according to  claim 1 , and   at least one additional therapeutic agent.   
     
     
         24 . The combination as defined in  claim 23  wherein the additional therapeutic agent is an acetyl-cholinesterase inhibitor, a muscarinic receptor-1 agonist, a nicotinic agonist, a glutamic acid receptor (AMPA and NMDA) modulator, a nootropic agent, an agent for Alzheimer's disease, an agent for treatment of Parkinson's disease, anti-hyperlipidemia agent, an anti-obesity agent; anti-diabetic agent, appetite suppressant; cholesterol/lipid-lowering agent, HDL-raising agent, cognition enhancing agent, an agent used to treat neurodegeneration, an agent used to treat respiratory conditions, an agent used to treat bowel disorders, an anti-inflammatory agent; anti-anxiety agent; an anti-depressant; an anti-hypertensive agent; an anti-sleep disorder agent; a cardiac glycoside; or an anti-tumor agent. 
     
     
         25 . The combination as defined in  claim 24  wherein the anti-obesity agent is a melanocortin receptor (MC4R) agonist, a cannabinoid receptor modulator, a growth hormone secretagogue receptor (GHSR) antagonist, a galanin receptor modulator, an orexin antagonist, a CCK agonist, a GLP-1 agonist, a Pre-proglucagon-derived peptides; an NPY1 or NPY5 antagonist, an NPY2 or NPY4 modulator, a corticotropin releasing factor agonist, a histamine receptor-3 (H3) modulator, an aP2 inhibitor, a PPAR gamma modulator, a PPAR delta modulator, an acetyl-CoA carboxylase (ACC) inhibitor, an 11-β-HSD-1 inhibitor, an adinopectin receptor modulator; a beta 3 adrenergic agonist, a thyroid receptor beta modulator, a lipase inhibitor, a serotonin receptor agonist, a monoamine reuptake inhibitor or releasing agent, an anorectic agent, a CNTF (ciliary neurotrophic factor), a BDNF (brain-derived neurotrophic factor), a leptin and leptin receptor modulator, or a cannabinoid-1 receptor antagonist, and the antidiabetic agent is an insulin secretagogue or insulin sensitizer, which is a biguanide, a sulfonyl urea, a glucosidase inhibitor, an aldose reductase inhibitor, a PPAR γ agonist, a PPAR α agonist, a PPAR δ antagonist or agonist, a PPAR α/γ dual agonist, anl 1-β-HSD-1 inhibitor, a dipeptidyl peptidase IV (DP4) inhibitor, a SGLT2 inhibitor, a glycogen phosphorylase inhibitor, a meglitinide, a glucagon-like peptide-1 (GLP-1), a GLP-1 agonist, and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor), and wherein the additional therapeutic agent is an anti-hyperlipidemia agent, or agent used to treat arteriosclerosis, which is an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, aspirin, a bile acid sequestrant, an ACAT inhibitor, an upregulator of LDL receptor activity, a cholesterol absorption inhibitor, a cholesteryl transfer protein (CETP) inhibitor, an ileal Na+/bile acid cotransporter inhibitor, a phytoestrogen, a beta-lactam cholesterol absorption inhibitor, an HDL upregulator, a PPAR α-agonist and/or an FXR agonist; an LDL catabolism promoter such, a sodium-proton exchange inhibitor, an LDL-receptor inducer or a steroidal glycoside, an anti-oxidant, or an antihomocysteine agent, isoniazid, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor, a PPAR δ agonist, or a sterol regulating element binding protein-I (SREBP-1), and the anti-hypertensive agent, which is a beta adrenergic blocker, a calcium channel blocker (L-type and/or T-type), a diuretic, a renin inhibitor, an ACE inhibitor, an AT-1 receptor antagonist, an ET receptor antagonist, a Dual ET/AII antagonist, a neutral endopeptidase (NEP) inhibitor, a vasopeptidase inhibitor (dual NEP-ACE inhibitor) or a nitrate; the sleep disorder agent is a melatonin analog, a melatonin receptor antagonist, an ML 1 B agonist, a GABA receptor modulator, an NMDA receptor modulator, a histamine-3 (H3) receptor modulator, a dopamine agonist or an orexin receptor modulator; an agent for treating substance abuse or, addictive disorders which is a cannabinoid receptor modulator, a selective serotonin reuptake inhibitor (SSRI), methadone, buprenorphine, nicotine or bupropion; the anti-anxiety agents or antidepressants, which is a benzodiazepine, a 5HT1A receptor agonist, or a corticotropin releasing factor (CRF) antagonist; or a norepinephrine reuptake inhibitor (tertiary and secondary amine tricyclics), a selective serotonin reuptake inhibitor (SSRI), a monoamine oxidase inhibitor (MAOI), a reversible inhibitor of monoamine oxidase (RIMA), a serotonin and norepinephrine reuptake inhibitor (SNRI), a corticotropin releasing factor (CRF) receptor antagonist, an alpha-adrenoreceptor antagonist, or an atypical antidepressant. 
     
     
         26 . A method for treating obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin resistance, hypercholesterolemia, hypertriglyceridemia, choletithiasis, dyslipidemia, bulimia nervosa and compulsive eating disorders; sleep disorders; and psychiatric disorders, depression, anxiety, schizophrenia, substance abuse, cognition-enhancement or Parkinson's disease, which comprises administering to a patient in need of treatment, a compound as defined in  claim 1 . 
     
     
         27 . The method as defined in  claim 26  for treating obesity or Type II diabetes. 
     
     
         28 . A method of treating Type II diabetes, which comprises administering to a patient in need of treatment a compound as defined in  claim 1 . 
     
     
         29 . Use of a compound as defined in  claim 1  in the manufacture of a medicament for the treatment of diabetes. 
     
     
         30 . Use of a compound as defined in  claim 1  in the manufacture of a medicament for treatment of diabetes, in which such treatment comprises a combination with another therapeutic agent, for concurrent or sequential use, in any order. 
     
     
         31 . Combination of a compound as defined in  claim 1  and another therapeutic agent as a medicament for the treatment of diabetes.