Macrocyclic Lactams and Pharmaceutical Use Thereof

Abstract

The present invention relates to novel macrocyclic compounds of the formula wherein R 1 , R 2 , R 3 , U, V, W, X, Y, Z and n are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as pharmaceuticals and to pharmaceutical compositions comprising them.

1 . A compound of the formula 
     
       
         
         
             
             
         
       
     
     in which
 R 1  is CH(R e )C(═O)N(R a )R b  or (CH 2 ) k N(R c )R d , wherein
 k is 0, 1 or 2; 
 R a  and R b , independently, are hydrogen or an optionally substituted (C 1-8 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl or heteroaryl(C 1-4 )alkyl group, 
 R c  and R d , independently, are hydrogen or an optionally substituted (C 1-8 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, hetero-aryl(C 1-4 )alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*6*-isothiochroman-4-yl, 1,2,3,4-tetrahydro-quinolin-4-yl, 1,2,3,4-tetrahydro-isoquinolin-4-yl, 1,2,3,4-tetrahydro-naphthalen-1-yl, 1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[e][1,2]thiazin-4-yl, 2,2-dioxo-1,2,3,4-tetrahydro-2lambda*6*-benzo[c][1,2]thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1 lambda*6*-benzo[c][1,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, or 
 R a  and R b , or R c  and R d , together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or piperazinyl group; and 
 R e  is optionally substituted (C 1-8 )alkyl, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 3-7 )cycloalkyl or (C 3-7 )cycloalkyl(C 1-4 )alkyl; 
 
 R 2  is hydrogen or (C 1-4 )alkyl; 
 R 3  is hydrogen, (C 1-6 )alkyl or an optionally substituted (C 1-6 )alkylOC(═O)NH, (C 3-7 )cyclo-alkylOC(═O)NH, (C 3-7 )cycloalkyl(C 1-4 )alkylOC(═O)NH, aryl(C 1-4 )alkylOC(═O)NH, heteroaryl(C 1-4 )alkylOC(═O)NH, (C 1-4 )alkylC(═O)NH, (C 3-7 )cycloalkylC(═O)NH, arylC(═O)NH, aryl(C 1-4 )alkylC(═O)NH, heteroarylC(═O)NH or heteroaryl(C 1-4 )alkylC(═O)NH group; 
 U is a bond, CF 2 , CF 2 CF 2 , CHF, CHFCHF, cycloprop-1,2-ylene, (C 1-3 )alkylenoxy, (C 1-8 )alkylene, NR g  or an aromatic or heteroaromatic ring, which ring is optionally substituted with halogen, (C 1-4 )alkoxy, hydroxy or (C 1-4 )alkyl, whereby Z and V are in ortho- or meta-position to each other, wherein
 R g  is hydrogen, (C 1-8 )alkyl or (C 3-7 )cycloalkyl; 
 
 V is CH═CH, cycloprop-1,2-ylene, CH 2 CH(OH), CH(OH)CH 2  or CR h R h CR h R h , wherein each R h , independently, is hydrogen, fluorine or (C 1-4 )alkyl; 
 W is (C 1-6 )alkylene, O, S, S(═O) 2 , C(═O), C(═O)O, OC(═O), N(R f )C(═O), C(═O)NR f  or NR f , wherein
 R f  is hydrogen or (C 1-4 )alkyl; 
 
 X is an optionally substituted (C 1-4 )alkanylylidene, (C 1-4 )alkylene, (C 3-7 )cycloalkylene, piperidin-diyl, pyrrolidin-diyl, benzothiazole-4,6-diyl, benzoxazole-4,6-diyl, 1H-benzotriazole-4,6-diyl, imidazo[1,2-a]pyridine-6,8-diyl, benzo[1,2,5]oxadiazole-4,6-diyl, benzo[1,2,5]thiadiazole-4,6-diyl, 1H-indole-5,7-diyl, 1H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl or 1H-indazole-1,6-diyl group or an optionally substituted aromatic or heteroaromatic ring, whereby Y and C(═O)NR 2  are in meta-position to each other; 
 Y is a bond, O, S(═O) 2 , S(═O) 2 NR g , N(R g )S(═O) 2 , NR g , C(R g )OH, C(═O)NR g , N(R g )C(═O), C(═O)N(R g )O or ON(R g )C(═O), wherein 
 R g  is hydrogen, (C 1-8 )alkyl or (C 3-7 )cycloalkyl; 
 Z is O, CH 2 , CF 2 , CHF, cycloprop-1,2-ylene or a bond; and 
 n is 0 to 5, 
 
     the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form. 
   
   
       2 . A process for the preparation of a compound as defined in  claim 1  of the formula I, in free base form or in acid addition salt form, comprising the steps of cyclisation by metathesis of a compound of the formula 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 3 , U, W, X, Y, Z and n are as defined for the formula I, in the presence of a catalyst, for instance a ruthenium, tungsten or molybdenum complex, optionally followed by reduction, oxidation or functionalisation of the resulting carbon-carbon-double bond, and of recovering the so obtainable compound of the formula I in free base form or in acid addition salt form. 
   
   
       3 . A compound according to  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical. 
   
   
       4 . A compound according to  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, for use in the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation. 
   
   
       5 . A pharmaceutical composition comprising a compound as claimed in  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, as active ingredient and a pharmaceutical carrier or diluent. 
   
   
       6 . The use of a compound as claimed in  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation. 
   
   
       7 . The use of a compound as claimed in  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, for the manufacture of a medicament for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation. 
   
   
       8 . A method for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound as claimed in  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form. 
   
   
       9 . A combination comprising a therapeutically effective amount of a compound as claimed in  claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, and a second drug substance, for simultaneous or sequential administration.