Novel unsaturated tetracyclic tetrahydrofuran derivatives

Abstract

This invention concerns novel substituted unsaturated tetracyclic tetrahydrofuran derivatives with binding affinities towards serotonine receptors, in particular 5-HT 2A and 5-HT 2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production. The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein: 
         n is an integer, equal to zero, 1, 2, 3, 4, 5 or 6; 
         i, j are integers, independently from each other, equal to zero, 1, 2, 3 or 4; 
         r is an integer, equal to zero, 1, 2 or 3; 
         R 1  and R 2  are, each independently from each other, selected from the group of hydrogen; alkyl; alkenyl; aryl; arylalkyl; arylalkenyl; alkyloxyalkyl; arylcarbonylalkyl; alkylcarbonyloxyalkyl; alkyloxycarbonylalkyl; alkylcarbonyl; arylcarbonyl; arylalkylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl; alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)aminocarbonyl; mono- or di(aryl)aminocarbonyl; mono- or di(arylalkyl)aminocarbonyl; aminocarbonylalkyl; mono- or di(alkyloxycarbonylalkyl)aminocarbonyl; mono- or di(alkyl)aminocarbonylalkyl; mono- or di(aryl)aminocarbonylalkyl; mono- or di(alkyl)aminocarbonylalkenyl; mono- or di(alkylsulphonyl)-aminocarbonylalkyl; mono- or di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; arylsulphonyl; arylalkylsulphonyl; mono- or di(alkyl)aminothiocarbonyl; mono- or di(aryl)aminothiocarbonyl; mono- or di(arylalkyl)aminothiocarbonyl; mono-, di- or tri(alkyl)amidino; mono-, di- or tri(alkyl)amidinoalkyl; mono-, di- or tri(aryl)amidino and mono-, di- or tri(arylalkyl)amidino; pyrrolidinyl, optionally substituted with one or more oxo moieties; tetrazolylalkyl; or 
         R 1  and R 2  taken together with the nitrogen atom to which they are attached may form a radical of Formula (a-1) to (a-7): 
       
       
         
           
           
               
               
           
         
         wherein: 
         P is an integer, equal to zero, 1, 2, 3 or 4; 
         q is an integer, equal to 1 or 2; 
         m is an integer, equal to zero, 1, 2 or 3; 
         each R 3  is, independently from each other, selected from the group of halo; hydroxy; alkyloxy; aryloxy; alkyl; aryl; alkylcarbonyl; alkyloxycarbonyl; arylcarbonyl; aryloxycarbonyl and mono- or di(alkyl)amino; or 
         two R 3 -radicals may form together a bivalent radical of Formula
   —CR 5 R 5 —CR 5 R 5 —O—  (b-1);
 
   —O—CR 5 R 5 —CR 5 R 5 —  (b-2);
 
   —O—CR 5 R 5 —CR 5 R 5 —O—  (b-3);
 
   —O—CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —  (b-4);
 
   —CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —O—  (b-5);
 
   —O—CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —O—  (b-6);
 
   —O—CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —  (b-7);
 
   —CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —O—  (b-8); and
 
   —O—CR 5 R 5 —CR 5 R 5 —CR 5 R 5 —O—  (b-9);
 
 
         wherein R 5  is selected from the group of hydrogen; halo; hydroxy; alkyloxy and alkyl; 
         R 4  is selected from the group of hydrogen; alkyl; alkylcarbonyl; arylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl; arylalkylcarbonyl; alkyloxycarbonylalkylcarbonyl; arylalkyl; alkyloxyalkyl; alkylcarbonyloxyalkyl; alkyloxycarbonylalkyl; mono- or di(alkyl)aminocarbonyl; mono- or di(aryl)aminocarbonyl; mono- or di(arylalkyl)aminocarbonyl; mono- or di(alkyloxycarbonylalkyl)aminocarbonyl; alkylsulphonyl; arylsulphonyl; arylalkylsulphonyl; mono- or di(alkyl)aminothiocarbonyl; mono- or di(aryl)aminothiocarbonyl; mono- or di(arylalkyl)aminothiocarbonyl; mono-, di- or tri(alkyl)amidino; mono-, di- or tri(aryl)amidino and mono-, di- or tri(arylalkyl)amidino; 
         A and B are, each independently from each other, aryl or an heteroaryl radical selected from the group of furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; imidazolyl; isoxazolyl; isothiazolyl; oxadiazolyl; triazolyl; pyridinyl; pyridazinyl; pyrimidinyl; pyrazinyl; indolyl; indolizinyl; isoindolyl; benzofuryl; isobenzofuryl; benzothienyl; indazolyl; benzimidazolyl; benzthiazolyl; quinolizinyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; chromenyl; naphthyridinyl and naphthalenyl; 
         each R 9  is, independently from each other, selected from the group of hydrogen; halo; cyano; hydroxy; carboxyl; nitro; amino; mono- or di(alkyl)amino; alkylcarbonylamino; aminosulfonyl; mono- or di(alkyl)aminosulfonyl; alkyl; alkenyl; alkyloxy; alkylcarbonyl and alkyloxycarbonyl; 
         R 10  is selected from the group of hydrogen; alkyl; halo and cyano; 
         Y is O; 
         X is O or S; wherein
 R 6  and R 7  each independently from each other, are selected from the group of hydrogen; hydroxy; alkyl and alkyloxy; or 
 R 6  and R 7  taken together may form a radical selected from the group of methylene (═CH 2 ); mono- or di(cyano)methylene; a bivalent radical of Formula —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —O—(CH 2 ) 2 —O—, —O—(CH 2 ) 3 O—; or, together with the carbon atom to which they are attached, a carbonyl; 
 R 8  is selected from the group of hydrogen; alkyl; alkylcarbonyl; arylcarbonyl; arylalkyl; arylalkylcarbonyl; alkylsulfonyl; arylsulfonyl and arylalkylsulfonyl; 
 
         aryl is phenyl, optionally substituted with 1, 2 or 3 substituents independently from each other, selected from the group of halo, hydroxy, alkyloxy and alkyl; 
         alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted with one or more radicals selected from the group of halo, cyano, oxo, hydroxy, formyl, carboxyl and amino; 
         alkenyl is a straight or branched unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic unsaturated hydrocarbon radical having from 3 to 6 carbon atoms; each radical optionally substituted with one or more radicals selected from the group of halo, cyano, oxo, hydroxy, formyl, carboxyl or amino radicals; and 
         halo is fluoro, chloro, bromo or iodo. 
       
     
     
         2 . A compound according to  claim 1 , characterized in that
 n is equal to 1 or 2;   i, j are, independently from each other, equal to zero or 1;   r is equal to 0 or 1;   R 1  and R 2  are, each independently from each other, hydrogen; alkyl; alkenyl; aryl; arylalkenyl; arylcarbonylalkyl; alkyloxycarbonylalkyl; aryloxycarbonyl; alkyloxycarbonylalkylcarbonyl; aminocarbonylalkyl; mono- or di(alkyl)aminocarbonylalkyl; mono- or di(aryl)aminocarbonylalkyl; mono- or di(alkyl)aminocarbonylalkenyl; mono- or di(alkylsulphonyl)-aminocarbonylalkyl; mono- or di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; mono-, di- or tri(alkyl)amidinoalkyl; pyrrolidinyl, optionally substituted with one or more oxo moieties; tetrazolylalkyl; or   R 1  and R 2  taken together with the nitrogen atom to which they are attached may form a radical of Formula (a-1), (a-3), (a-5), (a-6) or (a-7) wherein:
 p is equal to zero, 1 or 2; 
 q is equal to 1; 
 m is equal to 1 or 2; 
 each R 3  is, independently from each other, selected from the group of hydroxy; alkyloxy; alkyl; and mono- or di(alkyl)amino; or
 two R 3 -radicals may form together a bivalent radical of Formula (b-3) wherein R 5  is hydrogen; 
 
 R 4  is selected from the group of alkyl; alkylcarbonyl; arylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl; arylalkylcarbonyl; alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)aminocarbonyl; mono- or di(aryl)aminocarbonyl; mono- or di(arylalkyl)aminocarbonyl; mono- or di(alkyloxycarbonylalkyl)aminocarbonyl; alkylsulphonyl; arylsulphonyl and arylalkylsulphonyl; 
   A and B are, each independently from each other, aryl or an heteroaryl radical selected from the group of thienyl; pyridinyl and indolyl;   each R 9  is, independently from each other, selected from the group of hydrogen; halo; cyano; alkyl and alkenyl;   R 10  is hydrogen;   Y is O;   X is O or S; wherein
 R 6  and R 7  each independently from each other are selected from the group of hydrogen and alkyl; or 
 R 6  and R 7  taken together may form the radical methylene (═CH 2 ); or, together with the carbon atom to which they are attached, a carbonyl; 
 R 8  is selected from the group of alkyl and arylalkyl; 
   aryl is phenyl, optionally substituted with 1 substituent selected from the group of halo, hydroxy, alkyloxy and alkyl;   alkyl is a straight saturated hydrocarbon radical having from 1 to 6 carbon atoms, optionally substituted with one or more hydroxy, cyano or carboxyl radicals;   alkenyl is a straight unsaturated hydrocarbon radical having from 1 to 6 carbon atoms; and   halo is fluoro, chloro or bromo.   
     
     
         3 - 4 . (canceled) 
     
     
         5 . A method for the treatment of conditions, either prophylactic or therapeutic or both, mediated through the 5-HT 2 , and D2 receptor, as well as the through norepinephrine reuptake inhibition, wherein said method comprises the step of administering a therapeutic amount of a compound of  claim 1 . 
     
     
         6 . A method for the treatment and/or prevention of central nervous system disorders like anxiety, depression and mild depression, bipolar disorders, sleep- and sexual disorders, psychosis, borderline psychosis, schizophrenia, migraine, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, organic mental disorders, mental disorders in children, aggression, memory disorders and attitude disorders in older people, addiction, obesity, bulimia and similar disorders, wherein said method comprises the step of administering a therapeutic amount of a compound of  claim 1 . 
     
     
         7 . A method for the treatment and/or prevention of anxiety, depression, psychosis, schizophrenia, migraine and addictive properties of drugs of abuse, wherein said method comprises the step of administering a therapeutic amount of a compound of  claim 1 . 
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound  claim 1 . 
     
     
         9 . A process for the preparation of a composition as claimed in  claim 8 , characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of  claim 1 . 
     
     
         10 - 13 . (canceled)