CARBOLINE DERIVATIVES

Abstract: Carboline derivatives of formula (I), are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) and have utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.

Description: CARBOLINE DERIVATIVES. This invention relates to a series of carboline derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents In particular, the invention relates to carboline derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'- monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders Thus, according to a first aspect, the present invention provides compounds of formula (I) wherein R° represents -hydrogen or -halogen, R 1 is selected from the group consisting of -hydrogen, -NO 2) -tπfluoromethyl, -tπfluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)OR a or -Cι- 6 alkyl optionally substituted by -OR a , -Cι. 3 alkoxy -C(=0)R a , -O-C(=0)R a , -C(=0)OR a , -C^alkylene C(=0)OR a , -O-C^alkylene -C(=0)OR a , -Cι.4alkylene-0-Cι^alkylene-C(=0)OR a , -C(=0)NR a SO 2 R c , Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C^alkylene NR a R b , -C 2 ^alkenyleneNR a R b , -C(=0)NR a R b , -C(=0)NR a R c , -C(=0)NR a C^alkylene OR b -C(=0)NR a Cι-4alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -OR a -OC alkylene NR a R b , -OC 1 - 4 alkylene-CH(OR a )CH 2 NR a R b , Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-C 2 - 4 alkylene-OR a , -O-C 2-4 alkylene-NR a -C(=0)-OR b , -NR"R b , -NR a C^alkyleneNR a R b , -NR a C(=0)R b , -NR a C(=0)NR a R b , -N(SO 2 C^alkyl) 2 , -NR a (SO 2 Cι. 4 alkyl), -SO 2 NR a R b , and -O S0 2 trif I uoromethy I ; R 2 is selected from the group consisting of. -hydrogen, -halogen, -OR a , -Cι -6 alkyl, -NO 2l and -NR a R b , or R 1 and R 2 , together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom ; R 3 is selected from the group consisting of. -hydrogen, -halogen, -N0 2 , -trifluoromethoxy, -Ci-βalkyl, and -C(=0)OR a ; R 4 is hydrogen, or R 3 and R 4 together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom; R a and R b , which may be the same or different, are independently selected from hydrogen and Ci-ealkyl; R c represents phenyl or C 4 - 6 cycloalkyl, which phenyl or C 4 - 6 cycloalkyl can be optionally substituted by one or more halogen atoms, one or more -C(=0)OR a or one or more -OR 8 ; n is an integer selected from 1 , 2 and 3, m is an integer selected from 1 and 2; and pharmaceutically acceptable salts and solvates (e.g hydrates) thereof The terms alkyl or alkylene as used herein respectively contain the appropriate indicated number of carbon atoms and appropriately include straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups The term C 2-6 alkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenyiene groups, in particular ethenylene or the like The terms C 4 _ 6 cycloalkyl denotes cyclic groups containing 4 to 6 carbon atoms, namely cyclobutane, cyclopentane and cyclohexane The term halogen as used herein includes fluorine, chlorine, bromine and iodine. The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6- membered heterocycloalkyl and heteroaryl groups, e g tetrahydrofuranyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, imidazolyl, furyl, and tetrazolyl. Appropriately, R° represents hydrogen. Alternatively R° may represent halogen, in particular fluorine. R 1 may represent any of the substituents as hereinbefore described, or more particularly may represent any of -OR a , -O-C 2 -4alkyleneNR a R b , -O-Cv 4 alkyleneHet and -O-C 2-4 alkylene-OR a In particular, R 1 represents -0-C 2 . 4 alkylene NR a R b , wherein suitably C 2-4 alkylene may represent ethylene and aptly, R a and R b may independently represent methyl. Particularly suitably R 2 represents hydrogen Alternatively, in the case where R 1 and R 2 together form a 3- or 4- membered alkylene or alkenyiene chain optionally containing at least one heteratom as hereinbefore described, suitably R 1 and R 2 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NR a ethylene-O- Aptly, R 1 and R 2 together form methylenedioxy, propylene or -N(CH 3 )-(CH 2 ) 2 -O- Suitably R 3 and R 4 , together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom as hereinbefore described. Particularly suitably R 3 and R 4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NR a ethylene-O- Aptly R 3 and R 4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain or a propylene chain. In particular, R 3 and R 4 together form methylenedioxy or ethyleneoxy, most particularly ethyleneoxy. A particular subgroup of compounds according to the present invention can be represented by formula (la) wherein R 5 is selected from the group consisting of -OH, -OC 2-4 alkylene NR a R b and O-d. 4 alkylene Het, wherein Het is as hereinbefore described and R° represents wherein C represents a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by and pharmaceutically acceptable salts and solvates (e g hydrates thereof) Typically, R represents -OC^alkylene NR a R b in particular OCH 2 CH 2 N(CH 3 ) 2 Alternatively, R may represent -O-C^alkylene Het, where Het may suitable be piperidyl, pyrrolidinyl (optionally substituted by dialkyl, e g methyl) or morpholinyl Particularly aptly R 6 represents or especially The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as enantiomers or diastereoisomers It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I) The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids Examples include the hydrochloride, hydrobromide, sulphate or bisuiphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts Compounds of the formula (I) can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases Examples include the sodium and potassium salts Particular individual compounds of the invention include (E)-1 -(1-Phenyl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-phenylpropene-1-one (E)-1-(1-Phenyl-1 ,3 4,9-tetrahydro-β-carbolιn-2-yl)-3-(4-nιtrophenyl)propene-1 - one (E)-1-(1 -Phenyl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-(4-tπfluoromethylphenyl)- propene-1 -one (E)-1-(1-Phenyl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-(4-methoxy- phenyl)propene-1 -one (E)-1-[1-(4-Methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- trifluoromethylphenyl)propene-1-one (E)-N-[4-[3-Oxo-3-(1-phenyl-1 ,3,4,9-tetrahydro-β-carbohn-2-yl)propenyl]phenyl]- acetamide (E)-1-[1-(4-Methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-phenylpropene- 1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenyl-propene-1 -one (E)-1-(1-Phenyl-1 ,34,9-tetrahydro-β-carbolιn-2-yl)-3-(4-formylphenyl)propene-1- one (E)-N-[4-[3-Oxo-3-(1-(4-nιtrophenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]-phenyl]acetamιde (E)-1-[1-(4-Nιtrophenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-phenylpropene-1- one (E)-1 -[1 -(4-Tπfluoromethoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-phenyl- propene-1 -one (E)-1 -[1 -(4-Methylphenyl)-1 ,3,4,9-tetrahydro^-carbolin-2-yl]-3-phenylpropene-1 - one (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn- 2-yl)-propenyl]phenyl]acetamιde (E)-4-[3-Oxo-3-(1-phenyl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-propenyl]benzoιc acid, methyl ester (E)-1-[1-(2-Chlorophenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-ρhenylpropene-1- one (E)-1-(1-Phenyl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-(3,4- methylenedιoxyphenyl)-propene-1-one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- bromophenyl)propene-1 -one (E)-1 -[1 -(4-Chlorophenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-phenylpropene-1 - one (E)-1 -[1 -(3,4-Methylenedioxyρhenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- ethoxyphenyl)propene-1 -one (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]acetic acid, phenyl ester (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- hydroxyphenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- formylphenyl)propene-1-one (E)-1-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin- 2-yl)-propenyl]phenyl]-3-phenylurea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- aminophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedioxy-phenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- nitro-phenyl)-propene-1 -one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[(4- bis(methylsulfonyl)amιnophenyl]propene-1-one (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]-propenyl]benzoic acid, methyl ester (E)-N-[4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin- 2-yl]propenyl]phenyl]methanesulfonamide (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2- yl]propenyl]benzamide] (E)-4-[3-Oxo-3-[1 -(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]-propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4- cyanophenyl)propene-1 -one (E)-1-[1-(3,4-Methyienedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- trifluoromethylphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4- methylenedioxyphenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- chlorophenyl)propene-1 -one (E)-1-[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- trifluoromethoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbohπ-2-yl]-3-(4- methylphenyl)propene-1 -one (E)-[4-[3-Oxo-3-(1-(3,4-methylenedιoxyρhenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]phenyl]urea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- hydroxymethylphenyl)propene-1-one (E)-N-Benzyl-4-[3-oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolin-2-yl)propenyl]benzamide (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2,4- dιchlorophenyl)propene-1-one (E)-1 -[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- methoxy-4-hydroxyphenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carboiιn-2-yl]-3-(3- hydroxy-4-methoxyphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- f luorophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-ιndan- 5-yl-1 -propene-1 -one (E)-N-[4-[3-Oxo-3-(1 -(3,4-methytenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn- 2-yl)propenyl]benzoyl]benzenesu!fonamide (E)-1-[1-(3,4-Methylenedιoxyρhenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4- dιchtorophenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3,4- dιmethoxyphenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3,4- dιhydroxyphenyl)propene-1 -one (E)-N-Methyl-N-[4-(3-oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolιn-2-yl)propenyl]phenyl]acetamide (E)-2,2-Dimethyl-N-[4-[3-Oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 , 3,4,9- tetrahydro-β-carbolin-2-yl)propenyl]phenyl]propιonamιde (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3,5- dιmethoxyphenyl)propene-1 -one (E)-(N)-{4-[3-[1-(3,4-Methylenedιoxyphenyl)-6-fluoro-1 ,3 l 4,9-tetrahydro-β- carboiιn-2-yl]-3-oxopropenyl]phenyl}-acetamιde (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4,5- trimethoxyphenyl)propene-1 -one (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin- 2-yl )propenyl]phenyl]isobutyramide (E)-1-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]- 3-phenylpropene-1 -one (E)-N-(2-Methoxyethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1 , 3,4,9- tetrahydro-β-carbolin-2-yl)propenyl]benzamide (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- hydroxyphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- methoxyphenyi)propene-1 -one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- nitrophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(2- dimethylaminoethoxy)phenyl]propene-1-one (E)-N-(2-Morpholin-4-ylethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1 ,3,4,9- tetrahydro-β-carbolin-2-yl)propenyl]benzamide (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4- (1 H-tetrazol-5-yl)phenyl]propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- aminophenyl)propene-1 -one (E)-N-Cyclohexyl-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro- β-carbolin-2-yl)propenyl]benzamide (E)-N-(Tetrahydrofuran-2-ylmethylH-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)- 1 ,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- cyanophenyl)propene-1 -one (E)-N-(4-Piperidine-4-carboxylic acid, ethyl ester)-4-[3-oxo-3-(1-(3,4- methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide (E)-N-(4-Piperidine-4-carboxylic acid)-4-[3-oxo-3-(1-(3,4- methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]-propenyl]benzoic acid (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3-(4- methylpιperazιne-1-carbonyl)phenyl)propene-1-one (E)-N-(2-Pιperazιn-1 -ylethyl)-3-[3-oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 ,3,4,9- tetrahydro-β-carbolιn-2-yl)propenyl]benzamιde (E)-4-[3-Oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)-propenyl]acetιc acid ethyl ester (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-(3- tetrazolophenyl)propene-1 -one (E)-2-[3-Oxo-3-[1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]-propenyl]benzoιcacιd, methyl ester (E)-3-[3-Oxo-3-[1-(3,4-methylenedιoxyρhenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]-propenyl]benzoιc acid, methyl ester (E)-1-(4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn- 2-yl)-propenyl]phenyl)pιpeπdιne-4-carboxylιc acid, ethyl ester (E)-N-(1-Ethylpyrrolιdιn-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methyleπedιoxyphenyl)- 1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)propenyl]benzamιde (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3-(2- dιmethylamιnoethoxy)phenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3,5- dιterbutyl-4-hydroxyphenyl)propene-1 -one (E)-3-[3-Oxo-3-[1-(4-methoxycarbonylphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]propenyl]benzoιc acid, methyl ester (E)-2-[3-Oxo-3-[1-{3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]-propenyl]benzoιc acid (E)-(4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]phenoxy)acetιc acid, ethyl ester (EH4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)-propenyl]phenyl)acetιc acid (E)-(4-[3-Oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 ,3,4 9-tetrahydro-β-carbolιn-2- yl)propenyl]phenoxy)acetιc acid (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- nιtro-4-chlorophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl3-3-(5- nιtro-2-chlorophenyl)propene-1-one (E)-3-Chloro-4-[3-oxo-3-[1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolιn-2-yl]propenyl]benzoιc acid, methyl ester (E)-(4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]benzyloxy)acetιc acid (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(5- amιno-2-chlorophenyl)propene-1-one (E)-3-Chloro^-[3-oxo-3-[1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolιn-2-yl]propenyl]benzoιc acid (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbohn-2-yl3-3-(3,5- dιbromo-4-hydroxyphenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4-(2- dιmethylamιnopropoxy)phenyl)propene-1-one (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolιn-2-yl]propenyl]benzoιc acid, methyl ester (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4-(2- diιsopropylamιnoethoxy)phenyl)propene-1-one {E)-2-Chloro-5-[3-oxo-3-[1-{3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolιn-2-yl]propenyl]benzoιc acid (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- hydroxy-4-nιtrophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3,5- dιmethyl-4-hydroxyphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3-(2- dιmethylamιnoethoxy)-4-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3-(2- dιmethylamιnoethoxy)-4-amιnophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- nιtro-4-hydroxy-5-methoxyphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- chlorophenyl)propene-1-one (E)-1 -[1 -(4-Methoxy-phenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2-chloro-5- nιtrophenyl)propene-1 -one (E)-1 -[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2,6- dιchlorophenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- methylamιnomethylphenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- methylphenyl)-propene-1 -one (E)-N-Methyl-(4-[3-oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β- carbolin-2-yl)propenyl]benzenesulfonamide (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- hydroxy-4-acetylphenyl)propene-1-one (E)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3 1 4,9-tetrahydro-β-carbolιn-2-yl]-3-(2- chloro-5-nitrophenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2- hydroxyphenyl)propene-1 -one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- nitro-2-pιperidin-1 -ylphenyl)propene-1 -one (E)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenylpropene-1 -one (E)-1-[1-(4-lsopropylphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3- nitrophenyl)propene-1 -one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3 t 4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- nitrophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3- phenylpropene-1 -one (E)-(S)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenylpropene-1 -one (E)-1-[1-(4-Methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3(3- nitrophenyl)propene-1 -one (E)-1 -[1 -(4-Methylphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2-chloro-5- nιtrophenyl)propene-1 -one (E)-N-(Tetrahydrofuran-2-ylmethyl)-3-[3-oxo-3-(1-(3,4-methylenedιoxy)-1 , 3,4,9- tetrahydro-β-carbolin-2-yl)proρenyl]benzamide (E)-1 -[1 -(lndan-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-phenylpropene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(3- acetylphenyl)propene-1 -one (E)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4- (2-dιmethylamιnoethoxy)phenyl)propene-1 -one (E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]propenyl]-benzoιc acid, methyl ester (E)-1-[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- methyl-3,4-dihydro-2H-benzo[1 ,4]oxazιn-6-yl)propene-1 -one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2- hydroxy-5-nιtrophenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]propenyl]benzoιc acid, methyl ester (E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]propenyl]benzoιc acid (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]propenyl]benzoιc acid (E)-1 -[1 -(Benzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene- 1-one (E)-3-[3-Oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)-propenyl]phenyl)tπfluoromethanesulfonιc acid, phenyl ester (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-[4-(2- hydroxyethoxy)phenyl]propene-1-one (E)-1 -[1 -(Benzofuran-5-yl-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2- dιmethylamιπoethoxy)phenyl)propene-1 -one (E)-1 -[1 (3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2- dιmethylamιnophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(2- pιpeπdιn-1 -ylphenyl)propene-1 -one (E)-4-[3-Oxo-3-[1 -(benzofuran-5-yl-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-propenyl]- benzoic acid, methyl ester (E)-4-[3-(1-Benzofuran-5-yi-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-oxo-propenyl]- benzoic acid (E)-4-[3-Oxo-3-(1-(3,4-methylenedιoxyphenyl)-1,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]phenyl)trifluoromethanesulfonιc acιd, phenyl ester (E)-1-[1-(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbohn-2-yl]-3-(2-(2- dιmethylamιnoethoxy)phenyl)propene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenylpropene-1 -one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3- (4-(2-dιmethylaminoethoxy)phenyl)propene-1-one (E)-1 -(2,3-Dihydrobenzo[1 ,4]dioxιn-6-yl)-1 ,3,4,9-tetrahydro^-carbolin-2-yl]-3- phenylpropene-1 -one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3-(4- (2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-[4- pyrτolidin-1 -ylphenyi]propene-1 -one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (3-nitrophenyl )propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-[4- imidazol-1 -ylphenyl]propene-1 -one (EH-[3-[1-(2,3-Dihydrobenzo[1 ,4]dioxin-6-yl)-1,3,4,9-tetrahydro-β-carbolιn-2- yl]-3-oxopropenyl]benzoic acid, methyl ester (E)-1-[1-(2,3-Dihydrobenzo[1 ,4]dioxιn-6-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]- 3-(3-nιtrophenyl)propene-1 -one (E)-1-[1-(2,3-Dihydrobenzo[1 ,4]dιoxιn-6-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]- 3-(4-(2-dιmethylamιnoethoxy)phenyl)propene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3-(4-(2- dimethylamιnoethoxy)phenyl)propene-1 -one (E)-4-[3-[1 -(2,3-Dihydrobenzo[1 ,4]dιoxιn-6-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]-3-oxopropenyl]benzoic acid (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenylpropene-1 -one (E)-(S)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3- (4-(2-dιmethylamιnoethoxy)phenyl)propene-1-one (E)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4- aminophenyl)propene-1 -one (E)-(S)-1-[1-(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- phenylpropene-1 -one (E)-(S)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (3-nitrophenyl)propene-1 -one (E)-(R)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3- (4-(1 -(S)-methylpyrrolιdιn-2-yl-methoxy)phenyl)propene-1 -one (EHR)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3- (3-hydroxyphenyl)propene-1 -one (EHRJ-l-fl^.S-Dihydrobenzofuran-δ-yO-I .S^.Θ-tetrahydro-β-carbolin^-yl)]^- (4-(2-dimethylamino-1 -methylethoxy)phenyl)propene-1 -one (E)-1 -(1 -Phenyl-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-(4-methylpyperazin-1 - yl)-phenyl)propene-1 -one (E)-(RH -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one (E)-(R)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(2-dimethylamino-1 -methylethoxy)phenyl)propene-1 -one (E)-(R)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(3,4-fluorophenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]- propenyljbenzoic acid, methyl ester (E)-(RH"l-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4- (2-diethylaminoethoxy)phenyl)propene-1-one (E)-(R)1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]propenyl]-benzoic acid (E)-(RH -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro^-carbolin-2-yl]-3- (4-aminophenyl)propene-1 -one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2- yl]-3-(4-aminophenyl)propene-1-one (E)-(R)-1 -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(2-pyrrolidin-1 -ylethoxy)phenyl)propene-1 -one (E)-(RH -[1 -(3,4-Methylenedioxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3- (4-(2-diethylaminoethoxy)phenylpropene-1-one (E)-1 -[1 -(3-Fluoro-4-methoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(3- nitrophenyl)propene-1 -one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3- (4-trifluoromethylphenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolin-2-yl]-3- (3-trifluoromethylphenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(2-morpholιn-4-ylethoxy)phenyl)propene-1-one (EHR)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(2-(ethylmethylamιno)ethoxy)phenyl)propene-1-one (E)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3-(4-(3- (dιmethylamιno)propenyl)phenyl)propene-1-one (EHR)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(3-dιmethylamιno-2-hydroxypropoxy)phenyl)propene-1-one (E)-(R)-1 -(1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carboiιn-2-yl)-3- (4-formylphenyl)propene-1 -one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3 ,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-propylamιnomethyl)phenyl)propene-1-one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- [4-(2-dιmethylamιnoethylamιno)phenyipropene-1-one (E)-(R)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(2-amιnoethoxy)phenyl)propene-1-one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-hydroxyphenyl)propene-1 -one (E)-(RM -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(4-methylpιperazιn-1 -yl)phenylpropene-1 -one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-methylaminomethyl)phenyl)propene-1-one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-ιsopropylamιnomethyl)phenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-dιmethylamιnomethyl)phenyl)propene-1-one (E)-(R)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- [4-(3-dιmethylamιnopropoxy)phenyl]propene-1-one (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(2-pιpeπdιn-1 -ylethoxy)phenyl)propene-1 -one (E)-1 -[1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)-3-(4-(2- pιpeπdιn-1 -ylethoxy)phenyl]propene-1 -one (E)-(R)-[2-(4-{3-[1-(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl]-3-oxopropenyl}phenoxy)ethyl]methylcarbamιc acid, tertbutyl ester (E)-(R)-1 -[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- [4-(2-methylamιnoethoxy)phenyl]propene-1-one and pharmaceutically acceptable salts and solvates (e g hydrates) thereof A specific compound of the invention is (E)-(R)-1 -[1 -(2,3-Dihydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl)]-3- (4-(2-dιmethylamιnoethoxy)phenyl)propene-1-one and pharmaceutically acceptable salts and solvates (e g hydrates) thereof It has been shown that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE Thus, compounds of formula (I) are of interest for use in therapy, specifically for the treatment of a variety of conditions where inhibition of cGMP specific PDE is thought to be beneficial As a consequence of the selective PDE 5 inhibition exhibited by compounds of the present invention, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natnuretic and diuretic activities as well as potentiation of the effects of endothehum-deπved relaxing factor (EDRF), nitrovasodilators, atπal natnuretic factor (ANF), brain natnuretic peptide (BNP), C-type natnuretic peptide (CNP) and endothehum-dependent relaxing agents such as bradykinin, acetylchohne and 5-HT 1 The compounds of formula (I) therefore have utility in the treatment of a number of disorders, including stable, unstable and variant (Pπnzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e g. post- percutaneous translummal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction and diseases characterised by disorders of gut motility (e g irritable bowel syndrome) It will be appreciated that references herein to treatment extend to prophylaxis as well as treatment of established conditions It will also be appreciated that a compound of formula (I), or a physiologically acceptable salt or solvate thereof can be administered as the raw compound, or as a pharmaceutical composition containing either entity There is thus provided as a further aspect of the invention a compound of formula (I) for use in the treatment of stable, unstable and variant (Pπnzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g. IBS) According to another aspect of the invention, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of stable, unstable and variant (Pπnzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g IBS) In a further aspect, the invention provides a method of treating stable, unstable and variant (Pπnzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e g IBS) in a human or non-human animal body which comprises administering to said body a therapeutically effective amount of a compound with formula (I) Compounds of the invention may be administered by any suitable route, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal, topical or parenteral (including intravenous, intramuscular, subcutaneous and mtracoronary) administration. Oral administration is generally preferred For administration to man in the curative or prophylactic treatment of the disorders identified above, oral dosages of a compound of formula (I) will generally be in the range of from 0 5-800mg daily for an average adult patient (70kg). Thus for a typical adult patient, individual tablets or capsules contain from 0 2-400mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day Dosages for intravenous, buccal or subhngual administration will typically be within the range of from 0 1-400 mg per single dose as required In practice the physician will determine the actual dosing regimen which will be most suitable for an individual patient and it will vary with the age weight and response of the particular patient The above dosages are exemplary of the average case but there can be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention For human use a compound of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice For example, the compound may be administered orally, buccally or subhngually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents (e g methylcellulose, a semi-synthetic glycende such as witepsol or mixtures of glyceπdes such as a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glyceπdes) A compound may also be injected parenterally, for example intravenously, intramuscularly subcutaneously or mtracoronaπly For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example salts, or monosacchaπdes such as mannitol or glucose, to make the solution isotonic with blood Thus, the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier therefor There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a compound of formula (I), which process comprises mixing a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier therefor A compound of formula (I) may also be used in combination with other therapeutic agents which may be useful in the treatment of the above-mentioned disease states The invention thus provides in another aspect a combination of a compound of formula (I) together with another therapeutically active agent The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier comprise a further aspect of the invention The individual components of such a combination may also be administered either sequentially or simultaneously in separate pharmaceutical formulations Appropriate doses of known therapeutic agents for use in combination with a compound of formula (I) will be readily appreciated by those skilled in the art Compounds of formula (I) may be prepared by any suitable method known in the art or by the following processes which form part of the present invention In the methods below R°, R 1 ,R2. R3, and R 4 are are as defined in formula (I) above unless otherwise indicated There is a further provided by the present invention a process (A) of preparing a compound of formula (I), which process comprises reacting compounds of formula (II) and (III) where X represents a hydroxyl or halogen group Suitably the reaction is carried out in the presence of 1 ,3- dicyclohexylcarbodnmide (DCC) or 1 -(3-dιmethylamιnopropyl)-3- ethylcarbodiimide (EDCI) and 1 -hydroxybenzotriazole (HOBT) in a suitable organic solvent, such as dimethylformamide (DMF) or dichloromethane (DCM) for several hours, e g 8 hours to 2 days Compounds of formula (I) may be prepared as individual enantiomers from the appropriate enantiomer of formula (ll) or as a racemic mixture from the appropriate racemic compound of formula (II). Individual enantiomers of the compounds of the invention may be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constituent enantiomers, for example using HPLC on a chiral column such as Hypersil naphtyl urea or using separation of salts of diastereoisomers A compound of formula (II) may be prepared by Pictet-Spengler cyclization between a tryptamine derivative of formula (IV) and an aldehyde of formula (V) The reaction may conveniently be effected in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in the presence of an acid such as trifluoroacetic acid (TFA). The reaction may conveniently be carried out at a temperature of from 20 °C to reflux to provide a compound of formula (II) in one step The reaction may also be carried out in a solvent such as an aromatic hydrocarbon (e.g toluene) under reflux optionally using a Dean-stark apparatus to trap the water produced. The reaction provides racemic compounds of formula (II) Enantiomers may be obtained from a resolution with N-acetyl leucine using fractional crystallization in EtOAc:MeOH as solvent. (R) and (S) enantiomers may be isolated as salts depending upon whether N-acetyl-(D) and (L)-leucιne was used as the starting material Compounds of formulae (IV) and (V) are commercially available compounds or prepared by standard synthetic techniques as hereinafter described in the Examples A compound of formula (III) can be prepared from a corresponding aldehyde of formula (VI) ) suitably by employing a Wittig reaction followed by basic hydrolysis Alternatively a compound of formula (III) may be prepared from a compound of formula (VI) by a Knoevenhagel reaction employing malonic acid Compounds of formula (VI) can be prepared from known corresponding alcohol, nitrile, or halide derivatives, using techniques well known in the art of synthetic organic chemistry According to a further general process (B) compounds of formula (I) can be converted to alternative compounds of formula (I), employing suitable interconversion techniques such as hereinafter described in the Examples Compounds of this invention may be isolated in association with solvent molecules by crystallization from or evaporation of an appropriate solvent The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic centre may be prepared in a conventional manner For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base Both types of salt may be formed or interconverted using ion- exchange resin techniques Thus, according to a further aspect of the invention, we provide a process for preparing a compound of formula (I) or a salt or solvate (e g hydrate) thereof which comprises process (A) or (B) as hereinbefore described followed by i) salt formation, or u) solvate (e g hydrate) formation The following additional abbreviations are hereinafter used in the accompanying examples: rt (room temperature), DMSO (dimethylsulphoxide), NBS (N-bromosuccinimide), THF (tetrahydrofuran), TFA (trifluoroacetic acid), PTSA ( p_-toluene sulphonic acid), AIBN (2,2'-azobιs isobutyronitrile), and TBDMSCI (tert-butyldimethylsilyl chloride). Intermediate 1 1 -Phenyl-2.3.4.9-tetrahvdro-1 H-β-carboline A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10 9 g, 1 1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.) The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11 0 g, 47%) as white crystals MP: 175-177 °C Intermediate 2 1 -(4-Methoxyphenyl)-2,3.4,9-tetrahvdro-1 H-β-carbohne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mmol), 4-methoxybenzaldehyde (12 9 g, 1 1 equiv ) and TFA (14 6 mL, 2 equiv.) to give the title compound (20 9 g, 80%) as a brownish powder. MP. 131 °C Intermediate 3 1-(4-NitroDhenyl)-2.3.4.9-tetrahvdro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1 88 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (3 1 g, 86%) as a yellow powder MP. 190 °C. Intermediate 4 1 -(4-Trifiuoromethoxyphenyl)-2,3 4,9-tetrahydro-1 H-β-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2 0 g, 12 5 mmol), 4-trifluoromethoxybenzaldehyde (2 4 g, 1 equtv ) and TFA (1.9 mL, 2 equiv ) to give the title compound (1 6 g, 38%) as a white powder MP 68-69 °C Intermediate 5 1-(4-Chlorophenyl)-2 3 4 9-tetrahvdro-1 H-β-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5 0 g, 30 mmol), 4-chlorobenzaldehyde (4 6 g, 1 equiv ) and TFA (4.6 mL, 2 equiv ) to give the title compound (4 16 g, 49%) as a white powder MP 161 °C Intermediate 6 1-(4-Methylphenyl)-2 3 4 9-tetrahydro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1 0 g, 6.2 mmol), 4-methylbenzaldehyde (0 74 g, 1 equiv ) and TFA (1 mL, 2 equiv ) to give the title compound (1 6 g, 100%) as a white powder MP 207-209 °C Intermediate 7 1-(3 4-Methylenedιoxyphenyl)-2,3 4 9-tetrahydro-1 H-β-carbohne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (20 0 g, 120 mmol), 3,4-methylenedιoxybenzaldehyde (20 6 g, 1 1 equiv ) and TFA (18 mL, 2 equiv ) to give the title compound (22 g, 60%) as white crystals after recrystallization from ethanol MP 178 °C Intermediate 8 4-(2.3 4 9-Tetrahvdro-1 H-β-carbolιn-1 -yl)benzoιc acid, methyl ester This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2 8 g, 17 4 mmol), 4-formylbenzoιc acid, methyl ester (2 87 g, 1 1 equiv ) and TFA (2 7 mL, 2 equiv ) to give the title compound (0 5 g, 9%) as white crystals after recrystallization from isopropanol H 2 O MP 179 °C Intermediate 9 1-lndan-5-yl-2 3 4 9-tetrahvdro-1 H-β-carbohne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1 28 g, 8 0 mmol), ιndan-5-carboxaldehyde (1 3 g, 1 1 equiv ) and TFA (1 2 mL, 2 equiv ) to give the title compound (0 36 g, 14%) 1 H NMR (CDCI 3 ) δ 7 6 (s, 1 H), 7 4 (m, 1 H), 6 9-7 2 (m, 6H) 5 1 (s, 1 H), 3 3-3 4 (m, 1 H), 2 9-3 1 (m, 1 H), 2 7-2 9 (m, 6H), 1 9-2 2 (q, 2H) Intermediate 10 1 -(2 3-Dιhvdrobenzofuran-5-yl)-2 3 4 9-tetrahvdro-1 H-β-carbolιne This product was prepared using a two-step procedure A solution of tryptamine (32 4 g, 0 2 mol) and 2,3-dιhydrobenzofuran-5-carboxaldehyde (30 0 g, 1 equiv ) in toluene (1 L) was heated under reflux for 4 hours After removal of 4 mL of water and evaporation of toluene the residue was dissolved in DCM (1 L) in the presence of TFA (31 mL, 2 equiv ) The resulting mixture was stirred at rt for 16 hours Then 1 L of a saturated aqueous solution of NaHCO 3 was added After extraction with DCM and drying over MgSO 4 , the organic solution was evaporated in vacuo Recrystallization from DCM ιPr 2 O (2 30) gave the title compound as white crytals in a 80% yield 1 H NMR (CDCIs) δ 7 6 (s, 1 H), 7 5-7 6 (m, 1 H), 7-7 3 (m 5H), 6 7-6 75 (d, 1 H), 5 1 (s, 1 H), 4 5-4 6 (t, 2H), 3 3-3 45 (m, 1 H), 3 05-3 2 (t, 3H), 2 7-3 (m, 2H) Intermediate 11 1 -(4-lsopropylphenyl)-2,3 4.9-tetrahvdro-1 H-β-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5 0 g, 31 2 mmol), 4-ιsopropylbenzaldehyde (5 08 g, 1 1 equiv ) and TFA (4 8 mL, 2 equiv ) to give the title compound (5 9 g 67%) as white crystals after recrystallization from ιPr 2 O MP 146 °C Intermediate 12 1 -(2 3-Benzofuran-5-yl)-2 3 4 9-tetrahvdro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2 27 g, 14 1 mmol) 2,3-benzofuran-5-carboxaldehyde (2 1 g, 1 equiv , prepared according to the procedure of Dorn, C P et al EP 481671 A1 ) and TFA (2 2 mL, 2 equiv ) to give the title compound (3 0 g, 74%) as white crystals after recrystallization from cyclohexane MP 134-136 °C Intermediate 13 1-(2,3-Dιhvdrobenzoπ 41dιoxιn-6-yl)-2 3 4.9-tetrahvdro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4 92 g, 30 7 mmol), 2,3-dιhydrobenzo[1 ,4]dιoxιn-6-carboxaldehyde (5 05 g, 1 0 equiv ) and TFA (5 0 mL, 2 equiv ) to give the title compound (7 05 g, 75%) as white crystals after recrystallization from ιPr 2 O MP- 144 °C Intermediate 14 1 -(3-Fluoro-4-methoxyphenyl)-2,3,4 9-tetrahydro-1 H-β-carbohne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4 80 g, 30 0 mmol), 3-fluoro-4-methoxybenzaldehyde (4 86 g, 1 05 equiv ) and TFA (4 6 mL, 2 equiv ) to give the title compound (5 2 g, 59%) as white crystals MP 68 °C Intermediate 15 1 -(3.4-DιfluorophenvO-2 3.4.9-tetrahvdro-1 H-β-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5 4 g, 33 5 mmol), 3,4-dιfluorobeπzaldehyde (5 0 g, 1 05 equiv ) and TFA (5 2 mL, 2 equiv ) to give the title compound (7 8 g 82%) as white crystals MP 151 °C Intermediate 16 1 -.3 4-Methylenedιoχyphenvn-6-fluoro-2.3 4 9-tetrahvdro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamιne (1 59 g, 8 9 mmol), 3,4-methylenedιoxybenzaldehyde (1 47 g 1 1 equiv ) and TFA (1 4 mL , 2 equiv ) to give the title compound (2 34 g, 85%) as white crystals MP 172 °C Analysis for Cι 8 Hι 5 FN 2 O 2 Calculated C,69 67, H.4.87, N.6.12. Found C.69.47; H,4 85, N,6.23% Intermediate 17 1 -(2-Chlorophenyl)-2 3 4.9-tetrahvdro-1 H-β-carbolιne This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6 2 mmol), 2-chlorobenzaldehyde (0 7 mL, 1 0 equiv ) and TFA (1.0 mL, 2 equiv ) to give the title compound (1 2 g, 69%) 1 H NMR (CDCI 3 ) δ 7.6 (s, 1 H), 7.45 (d, 1 H), 7 40 (d, 1 H), 6 9-7 2 (m, 6H), 5 6 (s, 1 H), 3.2-3.0 (m, 2H), 2.9-2 7 (m, 2H), 2.4 (s, 1 H) Intermediate 18 (S)-1-(3.4-Methylenedιoxyphenvn-2.3.4.9-tetrahvdro-1 H-β-carbolιne (S)-1 -(3,4-Methyleπedιoxyphenyl)-2,3,4,9-tetrahydro-1 H-β-carbohne was obtained from the resolution of the corresponding racemic amine with N-acetyl- (L)-Leucιne (Sigma) in MeOH followed by a recrystallization from MeOH Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHCO 3 gave the enantiomeπcally pure (S)-1 - (3,4-methylenedιoxypheπyl)-2,3,4,9-tetrahydro-1 H-β-carbolιne as beige crystals in a 55% yield. MP- 173 °C. Analysis for C 18 Hi6N 2 O2 0 35H 2 O Calculated: C,72 39, H.5.64, N.9.38 Found: C,72 35, H.5 44, N,9.1 % [α]o 196 = -35 (c = 0.53, MeOH) Intermediate 19 (R)-1 -(3.4-Methylenedιoχyphenyl)-2.3.4,9-tetrahvdro-1 H-β-carbolιne Following the same protocol as for Intermediate 18 (R)-1 -(3,4- methylenedιoxyphenyl)-2,3,4,9-tetrahydro-1 H-β-carbolιne was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucιne (Sigma) in MeOH followed by a recrystallization from MeOH Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHCO 3 gave the enantiomeπcally pure (R)-1 -(3,4- methylenedιoxyphenyl)-2,3,4,9-tetrahydro-1 H-β-carbolιne as white crystals in a 59% yield MP 92-94 °C Analalysis for Cι 8 H 16 N 2 O 2 Calculated C,73 95, H,5 52, N,9 58 Found C,73 72, H.5 52, N,9 52% [ α ] D 21 = 34 (c = 0 50, MeOH) Intermediate 20 (R)-1-(2.3-Dιhvdrobenzofuran-5-yl)-2 3.4 9-tetrahvdro-1 H-β-carboline Following the same protocol as for Intermediate 18 (R)-1-(2,3- dιhydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-β-carbolιne was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucιne (Sigma) in MeOH EtOAc followed by a recrystallization from MeOH Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHCO 3 gave the enantiomeπcally pure (R)-1 -(2,3- dιhydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carbolιne as white crystals in a 55% yield MP 98-99 °C Analysis for C 19 H 18 N 2 O 0 15H 2 O Calculated C,77 87, H,6 29, N,9 56 Found C,77 83, H,6 33, N,9 44% [α]Q 21 = 42 (c = 0 50, MeOH) Intermediate 21 (S)-1-(4-(2 3-Dιhvdrobenzo(b)furanV2 3 4 9-tetrahvdro-1 H-β-carbolιne Following the same protocol as for Intermediate 18 (S)-1 -(2,3- dιhydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-β-carbolιne was obtained from the resolution of the corresponding racemic amine with N-acetyl-(L)-Leucιne (Sigma) in MeOH/EtOAc followed by a recrystallization from MeOH Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHCO 3 gave the enantiomeπcally pure (S)-1 -(2,3- dιhydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-β-carbolιne as a pale yellow powder in a 45% yield MP 175 °C Analalysιs for C 19 H 18 N 2 0 1 0H 2 O Calculated C,74 0, H,6 54, N,9 08 Found C,74 01 , H.5 88, N,8 92% [ α ] D 19 7 = -49 (c = 0 50, MeOH) Intermediate 22 (E)-3-(4-UreιdophenvPacrylιc acιd A stirred solution of (E)-3-(4-amιnophenyl)acrylιc acid (1 0 g, 5 0 mmol) and potassium isocyanate (2 0 g, 5 equiv ) in a mixture of water and acetic acid (50 mL) was heated at 100 °C for 12 hours After cooling, a white solid precipitated out Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0 82 g, 80%) as a white solid MP > 350 °C Intermediate 23 (E)-3-(4-Acetylmethylamιnophenyl)acrylιc acιd A stirred solution of N-(4-formylphenyl)-N-methylacetamιde (1 0 g, 5 64 mmol), malonic acid (1 06 g, 1 8 equiv ) and piperidine (0 1 g, catalytic amount) in pyridine (3 5 mL) was heated at 60 °C for 12 hours Pouring the resulting mixture into HCl (1 N) gave a precipitate Filtration gave the title compound (1 2 g, 98%) as a white solid MP 213-215 °C Analysis for C 12 H 13 NO 3 0 2H 2 O Calculated C,64 68, H,6 06, N,6 29, Found C,64 43, H,6 18, N,6 36% N-(4-Formylphenyl)-N-methylacetamιde (1 0 g, 46%) was obtained as an oil from N-(4-formylphenyl)acetamιde (2 0 g 12 2 mmol) in THF in the presence of lodomethane (1 2 mL, 1 5 equiv ) and NaH (0 73 g, 1 5 equiv , 60% in mineral 1 H NMR (CDCI 3 , 250 MHz) δ 2 0 (s, 3H), 34 (s, 3H), 7 4 (d, 2H), 8 0 (d, 2H) Intermediate 24 (E)-3-f4-(2-Methoxyethylcarbamoyl)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(2-methoxyethyl)benzamιde to give the title compound as a white powder in a 57% yield. MP: 205 °C. 4-Formyl-N-(2-methoxyethyl)benzamιde (158 mg, 48%) was obtained by oxidation of 4-hydroxymethyl-N-(2-methoxyethyl)benzamιde (330 mg, 1 6 mmol) in DCM in the presence of MnO 2 (3.0 g, 22 equiv.) 'H NMR (CDC.3, 250 MHz) δ 9.9 (s, 1 H), 7.8 (s, 4H), 6.8 (s, 1 H), 3 4-3 6 (m, 4H), 3.2 (s, 3H). 4-Hydroxymethyl-N-(2-methoxyethyl)benzamιde (330 mg, 14%) was obtained as an oil (Rf= 0.7, DCM:MeOH (9:1 )) by coupling 4-(hydroxymethyl)benzoιc acid (1.0 g, 6.5 mmol) with 2-methoxyethylamιne (0.6 mL, 6.5 mmol) in the presence of Et 3 N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1 0 equiv ) and HOBT (0 88 g, 1.0 equiv.) Intermediate 25 (EH4-(2-Dimethylamιnoethoxy)phenvnacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylamιnoethoxy)benzaldehyde to give the title compound as a white powder in a 100% yield. MP: 243 °C. 4-(2-Dιmethylamιnoethoxy)benzaldehyde (20.6 g, 65%) was obtained by alklylation of 4-hydroxybenzaldehyde (20 g, 164 mmol) in DMF with dimethylaminoethyl chloride (144 g, 8 equiv.) and K 2 CO 3 (24.9 g, 1 1 equiv.) for 16 hours at 80 °C. 1 H NMR (CDCI 3 , 250 MHz) δ 9 85 (s, 1 H), 7 9-7 8 (d, 2H), 7-6 9 (d, 2H), 4.2 (t, 2H), 2.7 (t, 2H), 2.3 (s, 6H) Intermediate 26 (E)-3-f4-(2-Morpholin-4-yl-ethylcarbamoyl)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(2-morpholιn-4-yl-ethyl)benzamιde to give the title compound as a gummy solid 4-Formyl-N-(2-morpholιn-4-yl-ethyl)benzamιde (0 14 g, 55%) was obtained by oxidation of 4-hydroxymethyl-N-(2-morphoiιn-4-yl-ethyl)benzamιde (0 24 g, 0 9 mmol) and MnO 2 (1 73 g, 20 mmol) 1 H NMR (CDC. 3 , 250 MHz) δ 10 (s, 1 H), 7 9 (s, 4H), 6 8 (s, 1 H), 3 5 (t, 5H), 2 6 (t, 2H), 2 3 (m, 5H) 4-Hydroxymethyl-N-(2-morpholιn-4-yl-ethyl)benzamιde (240 mg, 14%) was obtained as a colourless oil (Rf= 0 6, DCM MeOH (9 1 )) by coupling 4- (hydroxymethyl)benzoιc acid (1 0 g, 6 5 mmol) with 2-morpholιnethylamιne (0 85 g (1 0 equiv ) in the presence of Et 3 N (0 95 mL, 1 0 equiv ), EDCI (1 2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv ) Intermediate 27 (E)-3-(4-Cvclohexylcarbamoylphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from N-cyclohexyi-4-formylbenzamιde to give the title compound as a white powder in a 54% yield MP 214 °C N-Cyclohexyl-4-formylbenzamιde (0 6 g, 60%) was obtained by oxidation of N- cyclohexyl-4-(hydroxymethyl)benzamιde (1 0 g, 4 29 mol) with Mn0 2 (0 2 g, 22 equiv ), as a white powder MP 163 °C 1 H NMR (CDCI 3 , 250 MHz) δ 10 (s, 1 H), 7 95 (s, 4H), 6 6 (s 1 H), 4 1 (m, 1 H), 3 9-3 7 (m, 3H), 3 4-3 3 (m, 1 H), 2 1 -1 9 (m, 2H), 1 8-1 7 (m, 2H) N-Cyclohexyl-4-(hydroxymethyl)benzamιde(1 0 g, 66%) was obtained as white crystals by coupling 4-(hydroxymethyl)benzoιc acid with cyclohexylamine (0 75 mL, 1 equiv ) in the presence of Et 3 N (0 95 mL 1 0 equiv ) EDCI (1 2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv ) MP 185 °C 1 H NMR (CDCI 3 , 250 MHz) δ 7 8-7 7 (d, 2H), 7 5-7 4 (d, 2H) 6 8 (s 1 H), 4 8 (s, 2H), 4 2 (m, 1 H), 4 0-3 75 (m, 2H), 3 4-3 3 (m, 1 H) 2 7 (m 1 H) 2-1 9 (m, 2H), 1 6 (m, 1 H), 1 1 (m 1 H) Intermediate 28 (E)-3-f4-f (Tetrahydrof uran-2-ylmethyl)carbamovnphenyl}acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(tetrahydrofuran-2-ylmethyl)benzamιde to give the title compound as a white powder in a 49% yield MP 215 °C 4-Formyl-N-(tetrahydrofuran-2-ylmethyl)benzamιde (0 36 g, 50%) (Rf= 0 3, DCM MeOH) was obtained as an oil by oxidation of 4-hydroxymethyl-N- (tetrahydrofuran-2-ylmethyl)benzamιde (0 72 g, 3 0 mmol) with Mπ0 2 (0 36 g, 22 equiv ) 4-Hydroxymethyl-N-(tetrahydrofuran-2-ylmethyl)benzamιde (0 72 g 46%) was obtained as a colourless oil (Rf= 0 6, DCM MeOH (9 1 )) by coupling 4- (hydroxymethyl)benzoιc acid (1 0 g, 6 5 mmol) with tetrahydrofuran-2-yl- methylamine (0 67 mL, 1 0 equiv ) in the presence of Et 3 N (0 95 mL, 1 0 equiv ) EDCI (1 ,2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv ) Intermediate 29 (E)-1-f4-(2-Carboxyvιnyl)benzovπpιperιdιne-4-carboxylιc acid ethyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 1-(4-formylbenzoyl)pιperιdιne-4-carboxylιc acid, ethyl ester to give the title compound as a white powder in a 46% yield MP 165 °C 1-(4-Formylbenzoyl)pιperιdιne-4-carboxylιc acid, ethyl ester (960 mg, 49%) (Rf= 06, DCM MeOH(95 5)) was obtained as an oil by oxidation of 1-(4- hydroxymethylbenzoyl)pιperιdιne-4-carboxylιc acid, ethyl ester (2 0 g, 6 8 mmol) with MnO 2 (13 1 g, 22 equiv ) 1 H NMR (CDCI 3l 250 MHz) δ 10 0 (s, 1 H), 7 9 (d, 2H), 7 5 (d, 2H), 4 5 (d, 1 H) 4 1 (q, 2H), 3 6 (d, 1 H), 3 1 (br s, 2H), 2 5 (m, 1 H), 2 1 -1 6 (m, 4H), 1 2 (t, 3H) 1-(4-Hydroxymethylbenzoyl)pιperιdιne-4-carboxylιc acid, ethyl ester (1 9 g, 100%) was obtained as a colorless oil (Rf= 0 1 , DCM MeOH (95 5)) by coupling 4-(hydroxymethyi)benzoιc acid (1 0 g, 6 5 mmol) with 4-pιpeπdιne-4-carboxylιc acid, ethyl ester (1 mL, 6 5 mmol ) in the presence of Et 3 N (0 95 mL 1 0 equiv ), EDCI (1 2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv ) 1 H NMR (CDCI 3 , 250 MHz) δ 7 2 (s, 4H), 4 5 (s, 2H), 4 3 (br s, 1 H) 4 1 (q, 2H) 3 6 (br s, 1 H),3 (t, 2H), 2 5 (m, 1 H), 2 1-1 6 (m, 4H) 1 2 (t 3H) Intermediate 30 (E)-3-(4-Ethoxycarbonylmethylphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from (4-formylpheπyl)acetic acid, ethyl ester gave the title compound as a yellow gum in a 52% yield. 1 H NMR (CDCIs, 250 MHz) δ 7.8-7.6 (m, 3H), 7.4-7.3 (d, 2H), 6.9-6.8 (d, 1 H), 4.1-3.9 (q, 2H), 3.55 (s, 2H), 1.2 (t, 3H). 4-(4-Formylphenyl)acetic acid, ethyl ester was prepared according to the procedure of Biagi.G.; Livi.O.; Verugi,E. Farmaco-Ed. Sc. 1988, 43, 597-611 Intermediate 31 (E)-1-f4-(2-Carboxyvinyl)phenvnpιperidine-4-carboxylιc acid, ethyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 1-(4-formylphenyl)piperidιne-4-carboxylic acid, ethyl ester to give the title compound as a yellow powder in a 86% yield. MP. 212 °C Analysis for Cι 7 H 2 ιNO 4 . 0.15H 2 O Calculated. C.66.71 ; H.7.01 ; N.4.58; Found: C,66.77; H.7.01 ; N.479%. 1 -(4-Formylphenyl)pιperidine-4-carboxyiιc acid, ethyl ester was prepared according to the procedure of Duckworth, D.M. Hindley.R., Richard, M EP 68669A1 Intermediate 32 (E)-4-(2-Carboxyvinyl)-3-chlorobenzoic acid, methyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 3-chloro-4-formylbenzoιc acid, methyl ester to give the title compound as a white powder in a 58% yield MP. 221 °C. 3-Chloro-4-formylbenzoic acid, methyl ester (4 0 g, 81 %) was prepared by reaction of 4-bromomethyl-3-chlorobenzoιc acid, methyl ester (6.0 g, 26 mmol) with silver p-tolueπesulfonate (15.0 g, 2.0 equiv ) in 100 mL of DMSO in the presence of Et 3 N (100 mL, 7 equiv.) at rt for 1 hour. Quenching the resulting mixture with 100 mL of water, extraction with 2 x 100 mL of EtOAc, washing with 50 mL of water, drying over Na 2 SO 4 and flash chromatography with cyclohexane. EtOAc (95 5) as eluting solvent, gave the title compound (2 3 g 42%) as an oil 1 H NMR (CDCI 3 , 250 MHz) δ 10 5 (s, 1 H), 8 1 (s, 1 H), 7 8-7 7 (d, 1 H), 7 4-7 3 (d 1 H), 3 8 (s, 3H) 4-Bromomethyl-3-chlorobenzoιc acid, methyl ester (6 0 g, 87%) was obtained as an orange oil by refluxing for 12 hours 4-methyl-3-chlorobenzoιc acid, methyl ester (5 7 g, 31 mmol) with NBS (6 4 g, 1 2 equiv ) in the presence of a catalytic amount of AIBN in CCI 4 1 H NMR (CDC. 3 , 250 MHz) δ 8 0 (s, 1 H), 7.9-7 8 (d, 1 H), 7 45-7 35 (d, 1 H) 4 5 (s, 1 H), 3.9 (s, 3H) 4-Methyl-3-chlorobenzoιc acid, methyl ester (5 7 g, 53%) was obtained as an orange oil by refluxing overnight 4-methyl-3-chlorobenzoιc acid (9 9 g, 58 mmol) in MeOH in the presence of PTSA 1 H NMR (CDC.3, 250 MHz) δ 8 0 (d, 1 H), 7 85 (dd, 1 H), 7 3 (d, 1 H), 4 0 (s, 3H), 2 5 (s, 3H). Intermediate 33 (E)-5-(2-Carboxyvιnyl)-2-chlorobenzoιc acid methyl ester The same method was employed as in the preparation of Intermediate 32 but starting from 2-chloro-5-formylbenzoιc acid, methyl ester to give the title compound as a yellow powder in a 76% yield MP- 194 °C. 2-Chloro-5-formylbenzoιc acid, methyl ester (0 6 g, 25%) was obtained a gum by reaction of 5-bromomethyl-2-chlorobenzoιc acid, methyl ester (3 1 g, 11 7 mmol) with silver p-toluenesulfonate (6 4 g, 1 75 equiv ) in DMSO in the presence of Et 3 N (1 2 mL, 7 equiv ) at rt for 1 hour 1 H NMR (CDCIs, 250 MHz) δ 10 (s, 1 H), 8 4 (d, 1 H), 7 9 (dd, 1 H), 7 7-7 6 (d 1 H), 4.0 (s, 3H) 5-Bromomethyl-2-chlorobenzoιc acid, methyl ester (3 1 g, 11 7 mmol) was obtained as a gum in a 45% yield by refluxing for 12 hours 5-methyl-2- chlorobenzoic acid, methyl ester (4 78 g, 25 9 mmol) with NBS (5 56, 1 2 equiv ) in the presence of a catalytic amount of AIBN in CCI 4 1 H NMR (CDCI 3 . 250 MHz) δ 7 9 (s, 1 H), 7 4 (br s, 2H) 4 5 (s 2H), 3 9 (s, 3H) 5-Methyl-2-chlorobenzoιc acid, methyl ester (4 78 g, 90%) was obtained as a brown oil, by refluxing overnight 3-methyl-4-chlorobenzoιc acid (5 0 g, 29 mmol) in MeOH in the presence of a catalytic amount of PTSA 1 H NMR (CDCIs, 250 MHz) δ 7 6 (s, 1 H), 7 25-7 2 (d, 1 H) , 7 15-7 1 (d 1 H), 3 8 (s, 3H), 2 2 (s, 3H) Intermediate 34 (E)-(3-Hvdroxy-4-nιtrophenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 3-hydroxy-4-nιtrobenzaldehyde to give the title compound as a white powder in a 88% yield MP 237 °C Intermediate 35 (EH3,5-Dιmethyl-4-hvdroxyphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 3,5-dιmethyl-4-hydroxybenzaldehyde gave the title compound as a white powder in a 94% yield MP 190 °C Intermediate 36 (EH3-Nιtro-4-hvdroxy-5-tτιethoxphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 3-nιtro-4-hydroxy-5-methoxybenzaldehyde to give the title compound as a white powder in a 75% yield MP 248 °C Intermediate 37 (E)-3-(3-Nιtro-2-pιpeπdιn-1 -yl-phenvOacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-chloro-3-nιtrobenzaldehyde to give the title compound as a yellow powder in a 100% yield 1 H NMR (CDCI 3 , 250 MHz) δ 10 3 (br s, 1 H), 8 1 (d, 1 H) 7 65 (dd 1 H) 7 55 (dd 1 H), 7 05 (t, 41 H) 6 3 (d, 1 H), 2 9 (m, 2H), 1 6 (m, 6H) 2-Chloro-3-nιtrobenzaldehyde (150 mg, 20%) was prepared by reaction of 1 - bromomethyl-2-chloro-3-nιtrobenzene (1 0 g, 3 9 mmol) with silver p- toluenesulfonate (1 94 g, 1 75 equiv ) in DMSO in the presence of Et 3 N (4 mL, 7 equiv ) at rt for 1 hour 1 H NMR (CDCI 3l 250 MHz) δ 10 5 (s, 1 H), 8 1 (dd, 1 H), 8 0 (dd, 1 H), 7 5 (t, 1 H) 1-Bromomethyl-2-chloro-3-nιtrobenzene (13 3 g, 68%) was obtained as a yellow oil by refluxing for 2 hours a mixture of 2-chloro-3-nιtrotoluene (10 g, 58 mmol) with NBS (10 3 g, 1 equiv ) in the presence of a catalytic amount of AIBN in CCl 4 1 H NMR (CDCI 3 , 250 MHz) δ 7 75 (dd, 1 H), 7 65 (dd 1 H), 7 45 (m 1 H), 4 6 (s, 2H) Intermediate 38 (E)-3-(4-Methyl-3,4-dιhvdro-2H-benzof1 ,41oxazιn-6-yl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-methyl-3,4-dιhydro-2H-benzo[1 ,4]oxazιn-6-carboxaldehyde (prepared according to the procedure of Kotha.S , Bindra.V , Kuki.A Heterocyles 1994, 38, 5-8) to give the title compound as a yellow powder in a 61% yield MP 190 °C Analysis for Cι 2 Hι 3 NO 5 Calculated C.65 74, H,5 98, N,6 39, Found C,65 85, H,6 04, N,6 33% Intermediate 39 (E)-3-(2-Hydroxy-5-nιtrophenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-hydroxy-5-nιtro benzaldehyde to give the title compound as a yellow powder in a 11 % yield MP 265-267 °C Intermediate 40 (E)-3-f3-(Trifluoromethanesulfonyloxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from tπfluoromethanesulfonic acid, 3-formylphenyl ester (prepared according to the procedure of Kingsbury.W D , Pendrak I , Leber.J D Boehm, J C , Mallet.B , Sarau.H M , Foley, J J , Schmidt, D B , Dames, R A J Med Chem 1993, 36, 3308-3320) to give the title compound as pink crystals in a 36% yield MP 107 °C Intermediate 41 (E)-3-f4-(Trιfluoromethanesulfonyloxy)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from tπfluoromethanesulfonic acid, 4-formylphenyl ester (prepared according to the procedure of Creary.X , Benage.B , Hilton, K J Org Chem 1983, 48(17), 2887-2891 ) to give the title compound as white crystals in a 61 % yield MP 194 °C Intermediate 42 (E)-3-f4-(2-Pyrrolιdιn-1 -ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-pyrrolιdιn-1 -ylethoxy)benzaldehyde (prepared according to the procedure of Sakaguchi.J , Nishino, H , Ogawa.N , Iwanaga.Y , Yasuda.S , Kato,H , lto,Y Chem Pharm Bull 1992, 40, 202-211 ) to give the title compound as a yellow solid in a 60% yield MP 183 °C Intermediate 43 (E)-3-(4-Pyrrolιdιn-1-ylphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from (4-pyrrolιdιn-1-ylphenyl)benzaldehyde (prepared according to the procedure of Duckworth, D M Hindley.R , Richard, M EP 68669A1 ) to give the title compound as a yellow sohd in a 65% yield MP 265 °C Intermediate 44 (E)-3-(4-lmιdazol-1 -ylphenvQacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-ιmιdazol-1-ylbenzaldehyde (prepared according to the procedure of Sircar, I , Duell.B , Brιstol,J A , Weishaar.R E , Evans,D B J Med Chem 1987, 30, 1023-1029) to give the title compound as pink crystals in a 55% yield MP 326-327 °C Intermediate 45 (E)-(S)-3-f4-(1-Methylpyrrohdιn-2-ylmethoxy)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from (S)-4-(1-methylpyrrolιdιn-2-ylmethoxy)benzaldehyde to give the title compound as a beige powder in a 66% yield MP 251 °C MD 21 = -9 (c = 0 35, pyridine) (S)-4-(1 -Methylpyrrolιdιn-2-ylmethoxy)benzaldehyde (0 96 g, 44%) was obtained as an orange oil by refluxing for 12 hours at 80°C, 4-hydroxybenzaldehyde (1 22 g, 10 mmol) with (S)-2-chloromethyl-1 -methylpyrrolιdιne, hydrochloride (2 55 g, 1 5 equiv ) in DMF in the presence of K 2 CO 3 (3 82 g, 2 8 equiv) 1 H NMR (CDCI 3 , 250 MHz) δ 9 9 (s, 1 H), 7 85 (d, 2H), 7 0 (d, 2H), 4 1 (dd, 1 H) 4 0 (dd,1 H), 3 1 (d tr, 1 H), 2 7 (m, 1 H), 2 5 (s, 3H), 2 3 (m, 1 H), 2 (m, 1 H), 1 8 (m, 3H) (S)-2-Chloromethyl-1-methylpyrrolιdιne, hydrochloride was prepared according to the procedure of D'Ambra,T E , Bacon, E R , Edward, R , Bell.M R , Carabateas.P.M , Eιssenstat,M A , Kumar.V , Mallamo.J P , Ward.S J EP 444451 A2 Intermediate 46 (E)-3-[4-(2-Dιmethylamιno-1 -methylethoxy)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dιmethylamιno-1-methylethoxy)benzaldehyde to give the title compound as a white powder in a 86% yield MP 235 °C Analysis for Cι 4 H 19 NO 3 HCl Calculated C,58 84, H,7 05 N 4 9, Found C,58 49, H,7 08, N 5 05% 4-(2-Dιmethylamιno-1 -methylethoxy)benzaldehyde (2 1 g, 18%) was obtained as an orange oil by refluxing for 12 hours, 4-hydroxybenzaldehyde (7 g, 57 mmol) K 2 C0 3 (8 7 g, 1 1 equiv ) and 2-chloropropyldιmethylamιne, hydrochloride (13 6 g, 1 5 equiv ) in DMF 1 H NMR (CDCI 3 , 250 MHz) δ 9 7 (s, 1 H), 7 65 (d 2H), 6 85 (d, 2H), 4 5 (m, 1 H) 2.5 (m, 1 H), 2 3 (m, 1 H), 2 1 (m, 6H), 1 2 (d, 3H) Intermediate 47 (E)-3-f4-(4-Methylpιperazιn-1 -yl)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(4-methylpιperazιn-1-yl)benzaldehyde (prepared according to the procedure of Sakai.K , Suzuki, M , Nunami.K , Yoneda.N , Onoda,Y Iwasawa Y Chem Pharm Bull 1980, 28, 2384-2393) to give the title compound as a white powder in a 65% yield MP 223-226 °C Intermediate 48 (E)-3-,4-(2-Dtmethylamιnopropoxy)phenvπacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dιmethylamιnopropoxy)benzaldehyde (prepared according to the procedure of Mizzoπi.R H US 3483209) to give the title compound as a beige powder in a 100% yield MP 231 °C Intermediate 49 (E)-3-f4-(2-Morpholιn-4-ylethoxy)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-morpholιn-4-ylethoxy)benzaldehyde (prepared according to the procedure of Naruto.S , Mizuta.H , Sawayama.T , Yoshida.T , Uno.H Kawashima.K , Sohji.Y , Kadokawa.T , Nιshιmura,H J Med Chem 1982, 25, 1240-1245) to give the title compound as a white powder in a 96% yield MP 228 °C Intermediate 50 (E)-3-(4-f2-(Ethylmethylamιno)ethoxylphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(ethylmethylamιno)ethoxy]benzaldehyde to give the title compound as a beige powder in a 73% yield MP 206 °C Analysis for Cι 4 H 19 NO 3 HCl Calculated C,58 84, H,7 05, N,4 9, Found C,59 08, H,7 07, N,5 02% 4-[2-(Ethylmethylamιno)ethoxy]benzaldehyde(5 0 g, 59%) was obtained as a brown oil by refluxing for 12 hours 4-hydroxybenzaldehyde (5 g, 41 mmol) K 2 CO 3 (6 2 g, 1 1 equiv ) and (2-chloroethyl)ethylmethylamιne, hydrochloride (9 7 g , 1 5 equiv ) in DMF 1 H NMR (CDCI 3 , 250 MHz) δ 9 7 (s, 1 H), 7 7 (d 2H), 6 9 (d, 2H), 4 1 (t 2H), 2 6 (t, 2H), 2 (s, 6H) Intermediate 51 (E)-3-f4-(3-Dιmethylamιnopropenyl)phenvπacrylιc acid This product was prepared by refluxing for four hours, (E)-3-[4-(3- dιmethylamιnopropenyl)phenyl]acrylιc acid, methyl ester with NaOH (0 16 g, 2 equiv ) in 10 mL of MeOH After evaporation of the solvent in vacuo, treatment with 5 mL of HCl (1 N) gave the title compound (0 4 g 85%) as a gummy orange solid 1 H NMR (CDCI 3 , 250 MHz) δ 7 6 (d, 2H), 7 4 (d, 1 H) 7 2 (d, 2H), 6 6 (d, 1 H), 6 4 (d, 1 H), 5 8 (m, 1 H), 3 7 (d, 2H), 2 6 (s, 6H) (E)-3-[4-(3-Dιmethylamιnopropenyl)phenyl]acrylιc acid, methyl ester was prepared by the following way (2-dιmethylamιnoethyl)trιphenylphosphonιum bromide (7 2 g, 17 4 mmol) in 30 mL of DMF was treated with KHMDS (27 mL, 1 01 equiv , 0 5 M in toluene) at -78 °C for one hour At -40 °C, 3-(4- formylphenyl)acrylιc acid, methyl ester (2 54 g, 13 3 mmol, prepared according to the procedure of Syper.L , Miochowski.J Synthesis, 1984, 9, 747-752) was added dropwise The resulting mixture was stirred for 12 hours at rt and quenched with water Extraction with EtOAc, drying over MgS0 4 and evaporation in vacuo gave a residue that was purified via flash chromatography with DCM MeOH (90 10) as eluting solvent The title compound (1 1 g, 34%) was obtained as an orange oil 1 H NMR (CDCI 3 , 250 MHz) δ 7 6 (d, 1 H), 7 4 (d, 2H), 7 2 (d, 2H), 6 5 (d, 1 H) 6 4 (d, 1 H), 5 8 (m, 1 H), 3 2 (dd, 2H), 2 1 (s, 6H) Intermediate 52 (E)-3-f4-(2-(Tertbutyldιmethylsιlanyloxy)-3-dιmethylamιnopropenyl)phenyllacrylιc This product was prepared by refluxing for four hours (E)-3-[4-(2- (tertbutyldιmethylsιlanyloxy)-3-dιmethylamιnopropanyl]phenyl]acrylιc acid, methyl ester (0 8 g, 2 03 mmol) and NaOH (1 N) (4 mL, 2 equiv ) in 10 mL of MeOH Evaporation of the solvent in vacuo and treatment with 5 mL of HCl (1 N) gave the title compound (0 4 g, 60%) as a beige solid solid MP 207 °C (E)-3-[4-(2-(Tertbutyldιmethylsιlaπyloxy)-3-dιmethylamιnopropoxy)phenyl]acrylιc acid, methyl ester (0 8 g, 40%) was obtained as a yellow oil by reaction for 4 hours of (E)-3-[4-(3-dιmethylamιno-2-hydroxypropoxy)phenyl]acrylιc acid, methyl ester (1 35 g, 5 13 mmol) with TBDMSCI (0 93 g, 6 2 mmol) in 50 mL of DMF in the presence of imidazole (0 84 g, 2 4 equiv ) After evaporation in vacuo, the residue was taken up in DCM, washed with water, dried over MgSO 4 , evaporated in vacuo and purified via flash chromatography using DCM MeOH as eluting solvent 1 H NMR (CDCI 3 , 250 MHz) δ 7 5 (d, 1 H), 7 3 (d, 2H), 6 8 (d, 2H), 6 2 (d, 1 H), 4 0 (m, 2H), 3 8 (m, 1 H), 3 7 (s, 3H), 2 4-2 2 (m, 2H), 2 1 (s, 6H), 0 7 (s, 9H), 0 0 (d, 6H) (E)-3-[4-(3-Dιmethylamιno-2-hydroxypropoxy)phenyl]acrylιc acid, methyl ester (1 5 g, 60%) was obtained as an oil by reaction of 4-(3-dιmethylamιno-2- hydroxypropoxy)benzaldehyde (2 0 g, 8 96 mmol) in 80 mL of toluene with tπphenylphosphoraπylidene methyl acetate (3 6 g, 1 2 equiv ) at 100 °C for one day After concentration in vacuo, the residue was taken up in DCM, washed with water, dried over Na 2 SO 4 , evaporated in vacuo and purified via flash chromatography using DCM MeOH (95 5) as eluting solvent 1 H NMR (CDCI 3 , 250 MHz) δ 7 6 (d, 1 H), 7 5 (d, 2H), 7 3 (d, 2H), 6 3 (d, 1 H), 4 2 (m, 1 H), 4 1 (m, 1 H), 3 8 (m, 3H), 3 3 (s, 1 H), 2 8 (dd, 1 H), 2 6 (dd, 1 H), 2 4 (s, 6H) 4-(3-Dιmethylamιno-2-hydroxypropoxy)benzaldehyde (8 2 g, 61 %) was obtained as an a yellow oil by reaction of 4-oxιranylrηethoxybeπzaldehyde (6 g 33 6 mmol, prepared according to the procedure of Baldwin, J J , Hirchmann.R Lumma.W C , Ponticello.G S , Sweet, C. S , Scrιabιne,A J Med Chem 1977, 20, 1024-1029) in 100 mL of MeOH with dimethylamine (34 mL, 2 equiv ) The resulting mixture was stirred at reflux for 2 days Evaporation in vacuo gave a residue that was taken up in DCM, washed with brine and dried over MgS0 4 and evaporated in vacuo 1 H NMR (CDCI 3 , 250 MHz) δ 9 7 (s, 1 H), 7.6 (d, 2H), 7 0 (d, 2H), 4 (m, 3H), 3 6 (s, 1 H), 2.5 (dd, 1H), 2.3 (dd, 1 H), 2.25 (s, 6H) Intermediate 53 (E)-3-f4-(2-(Dιmethylamιnoethylamιno)phenvπacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(dιmethylamιnoethyl)amιno]benzaldehyde (prepared according to the procedure of Klaus, M , Mohr.P , Weiss, E EP 331983 A2) to give the title compound as an oil in a 100% yield 1 H NMR (CDCI 3 , 250 MHz) δ 7 5 (d, 1 H), 7 2 (d, 2H), 6 5 (d, 2H), 6 1 (d, 1 H), 4 6 (s, 1 H), 3 0 (m, 2H), 2 5 (t, 2H), 2 2 (s, 6H) Intermediate 54 (E)-3-(4-,2-(1 3-Dιoxo-l .3-dιhvdroιsomdol-2-v0ethoxylphenyl)acrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(1 ,3-dιoxo-1 ,3-dιhydroιsoιndol-2-yl)ethoxy]benzaldehyde (prepared from the procedure of Hιndley,R.M , Haιgh,D , Cottam.G P WO 9207839 A1) to give the title compound as an oil in a 99% yield 1 H NMR (CDC. 3 , 250 MHz) δ 12 3 (s, 1 H), 7 9 (m, 4H), 7 6 (d 2H), 7 5 (d, 1 H), 7 0 (d, 2H), 6 4 (d, 1 H), 4 4 (t, 2H), 4 0 (t, 2H) Intermediate 55 (E)-3-f4-(2-(Pιpeπdιn-1 -ylethoxy)phenyllacrylιc acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-pιpeπdιn-1-yl-ethoxy)benzaldehyde (which was prepared according to the procedure of Naruto.S , Mizuta.H , Sawayama,T Yoshida.T , Uno,H , Kawashιma,K Sohji.Y Kadokawa.T , Nishimura H J Med Chem 1982, 25, 1240-1245), to give the title compound as a white powder in a 60% yield MP: 231 °C Intermediate 56 (E)-3-f4-(2-(Tertbutoxycarbonylmethylamιno)ethoxy)phenvnacrylιc acid (E)-3-[4-(2-Methylamιnoethoxy)phenyl]acrylιc acid (0.8 g, 3 6 mmol) in dioxane (100 mL) was treated with NaOH (2N) (22 mL, 12 equiv.) After one hour of stirring at 70 °C, ditertbutyldicarbonate (1.6 g, 2 equiv ) was added slowly The reaction was judged to be complete after 3 hours of stirring at 70 °C After filtration of the white precipitate, the filtrate was acidified to pH=1 with HCl (1 N) A new white solid precipitated out . Filtration and drying in vacuo gave the title compound (0.6 g, 50%) as white crystals. 1 H NMR (CDCIa, 250 MHz) δ 7.8 (d, 1 H), 7.65 (d, 2H), 7 0 (d, 2H), 6 4 (d, 1 H), 4.25 (t, 2H), 3.7 (t. 2H), 3 1 (s, 3H), 1.5 (s, 9H). (E)-3-[4-(2-Methylamιnoethoxy)phenyl]acryiic acid (1 1 g, 41 %) was obtained as a white solid by hydrolysis of (E)-3-[4-(2-methylamιnoethoxy)phenyl]acrylιc acid, methyl ester (3.0 g, 12.0 mmol) with NaOH (6.0 g, 12 equiv ) in MeOH/THF at 40 °C. MP: 245 °C. (E)-3-[4-(2-Methylamιnoethoxy)phenyl]acrylic acid, methyl ester (3 0 g, 70%) was obtained as a yellow oil by reaction of tnmethylphosphonoacetate (4.2 g, 23.0 mmol) and n-butyl lithium (9.0 mL, 18.0 mmol, 2 0 M in cyclohexane) at -78 °C, followed by the addition of 4-(2-methylamιnoethoxy)benzaldehyde (3.2 g, 18.0 mmol) at - 40 °C The resulting mixture was stirred at rt for 16 hours, quenched with water, extracted with EtOAc, dried over MgSO 4 and concentrated in vacuo. 1 H NMR (CDCI3, 250 MHz) δ 7 65 (d, 1 H), 7 45 (d, 2H). 6 9 (d, 2H), 6.25 (d, 1 H), 4.10 (t, 2H), 3.75 (s, 3H), 2.95 (t, 2H), 2.5 (s, 3H) 4-(2-Methylaminoethoxy)benzaldehyde (3.2 g, 51 %) was obtained as a yellow oil by reaction of 4-(2-methylamιnoethoxy)benzonιtrile (7.0 g, 40.0 mmol) with diisobutylaluminum hydride (40 mL, 1.5 equiv., 1 5 M in toluene) in toluene (400 mL) at - 78°C. After 4 hours of stirring at - 78 °C the resulting mixture was treated with a mixture of water/MeOH (4 mL) At rt an additional 20 mL of water was added. The resulting suspension was filtered on a bed of celite The celite was washed with Et 2 O (3 x 200 mL) The filtrate was concentrated in vacuo and purified via flash chromatography of silica gel using MeOH DCM (1 9) as eluting solvent 1 H NMR (CDCIa, 250 MHz) δ 9 8 (s, 1 H), 7 8 (d 2H), 7 0 (d, 2H), 4 1 (t, 2H), 2 9 (t, 2H), 2 5 (s, 3H) 4-(2-Methylamιnoethoxy)benzonιtrιle (0 6 g, 15%) was obtained as a yellow oil by reaction of 4-(2-chloroethoxy)benzonιtrιle (2 0 g, 11 0 mmol, prepared according to the procedure of Mizuno.K , Kimura.Y Otsuji.Y Synthesis, 1979 9, 688) with methylamine (4 3 mL, 5 equiv , 40% in water) at 70 °C for 16 hours The resulting mixture was extracted with DCM, dried over MgSO 4 , concentrated in vacuo and purified via flash chromatography of silica gel using MeOH DCM (2 8) as eluting solvent, to give the title compound 1 H NMR (CDCIs, 250 MHz) δ 7 6 (d, 2H), 7 0 (d, 2H) 4 1 (t 2H), 3 0 (t, 2H), 2 5 (s, 3H) Example 1 (E)-1-(1-Phenyl-1 3,4 9-tetrahvdro-β-carboιιn-2-yl)-3-phenylpropene-1-one To a solution of Intermediate 1 (0 2 g, 0 81 mmol) and NaHCO 3 (0 08 g, 1 2 equiv ) in 10 mL of DCM was added (E)-cιnnamoyl chloride (0 2 g, 1 5 equiv ) After 4 hours of stirring at rt the reaction was judged to be completed by tic monitoring (SιO 2 , DCM MeOH 98 2) and was quenched with 5 mL of a saturated aqueous solution of NaHCO 3 The reaction mixture was extracted with DCM washed with brine (5 mL), dried over MgSO 4 and concentrated in vacuo Flash chromatography on a 2 x 20 cm 2 column using DCM MeOH (98 2) as eluting solvent and removal of the solvent in vacuo gave after recrystallization from 2- propanol, the title compound (0 1 g 33%) as white crystals MP 130-132 X Analysis for C 26 H 22 N 2 O Calculated C,82 51 , H,5 86, N,7 40, Found C,82 24, H,5 93, N,7 36% Example 2 (E)-1 -(1 -Phenyl-1 3,4 9-tetrahydro-β-carbolιn-2-yl)-3-(4-nιtrophenyl)propene-1 - one The same method as employed as in the preparation of Example 1 but starting from (E)-4-nιtrocιnnamoyl chloride gave after recrystallization from ιPr 2 O 2- propanol (3 1 ), the title compound as a yellow powder in a 47% yield MP 230-231 °C Analysis for C 26 H 2 ιN 3 O 3 Calculated C,73 74, H,5 00, N,9 92, Found C,73 89, H,5 12, N,9 86% Example 3 (E)-1-(1 -Phenyl-1.3.4.9-tetrahvdro-β-carbolιn-2-yl)-3-(4-trιfluoromethylphenyl)- propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-4-trifluoromethylcιnnamoyl chloride gave after recrystallization from pentane the title compound as a white powder in a 41 % yield MP 211 °C Analysis for C 27 H 21 F 3 N 2 O 0 4H 2 O Calculated C,71 48, H,4 84, N,6 17, Found C,71 84, H,4 81 , N,6 19% Example 4 (E)-1-(1 -Phenyl-1 ,3,4 9-tetrahvdro-β-carbolιn-2-yl)-3-(4-methoxy- phenyl )propene-1 -one The same method as employed in the preparation of Example 1 but starting from (E)-4-methoxycιnnamoyi chloride gave after recrystallization from 2-propanol, the title compound as white crystals in a 61 % yield MP 160-163 °C Analysis for C 27 H 24 N 2 O 2 0 5(2-propanol) Calculated C,78 06, H,6 44, N,6 39, Found C,78 04, H,6 02, N,5 97% Example 5 (E)-1 -π -(4-MethoxyphenylV1 3 4 9-tetrahvdro-β-carbolιn-2-vn-3-(4- tπfluoromethylphenvQpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 2 and (E)-4-trιfluoromethylcιnnamoyl chloride gave after recrystallization from pentane, the title compound as a white powder in a 61 % yield. MP- 130-135 °C. Analysis for C 28 H 23 N 2 O 2 F 3 0.3H 2 O: Calculated. C,69.79, H.4.94; N,5 81 ; Found C.69.9, H.4.84, N,5.73% Example 6 (E)-N-f4-r3-Oxo-3-(1-phenyl-1.3 4.9-tetrahydro-β-carbolιn-2-yl)propenyllphenvn- acetamide To a solution of Intermediate 1 (0.2 g, 0.81 mmol) in 40 mL of DCM were added Et 3 N (0 13 mL, 1 1 equiv.), DCC (0 18 g, 1.1 equiv ), HOBT (0 12 g, 1 1 equiv ) and (E)-3-(4-acetylamιnophenyl)acrylιc acid (0.18 g, 1 1 equiv ). After 24 hours of stirring at rt the reaction was judged to be completed by tic monitoring (SιO 2 , DCM:MeOH 95 5) and was quenched with 150 mL of water. A white solid precipitated out and was filtered off The filtrate was extracted with DCM, washed with brine (5 mL), dried over MgSO 4 and concentrated in vacuo Flash chromatography on a 2 5 x 25 cm 2 column of silica gel using DCM. MeOH (98.2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.18 g, 51 %) as yellow crystals after recrystallization from 2-propanol. pentane MP. 177-180 °C. Analysis for C 28 H 25 N 3 O 2 0 7H 2 O Calculated. C.75.05; H,5 94, N.9.38, Found: C.75.01 ; H.5.81 , N,9.22% Example 7 (E)-1-f1-(4-Methoχyphenyl)-1 ,3 4,9-tetrahydro-β-carbolιn-2-yl)-3-phenylpropene- 1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 2 gave the title compound as white crystals in a 56% yield MP: 127 °C Analysis for C 27 H 24 N 2 O 2 0 5H 2 O Calculated C,77 67, H,6 04, N,6 71 , Found C.77 91 , H.6.0, N.6 73% Example 8 (ΕVI -.1-.3 4-Methylenedιoxyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn-2-vπ-3- phenyl-propene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 gave after recrystallization from 2-propanol ιPr 2 O (2 8), the title compound as white crystals in a 38% yield MP 236-238 °C Analysis for C 27 H 24 N 2 O 2 0 5H 2 O Calculated C,76 76, H,5 25, N,6 63, Found C,76 87, H,5 35, N,6 54% Example 9 (E)-1 -(1 -Phenyl-1 3,4 9-tetrahydro-β-carbolιn-2-yl)-3-(4-formylphenyl)propene-1 - one The same method as employed in the preparation of Example 6 but starting from (E)-4-formylcιnnamιc acid gave after recrystallization from acetone MeOH (10 3), the title compound as yellow crystals in a 60% yield MP 146 °C Analysis for C 27 H 22 N 2 O 2 0 4H 2 O Calculated C,78 39, H,5 55, N,6 77, Found C,78 33, H,5 54, N,6 67% Example 10 (E)-N-f4-f3-Oxo-3-(1-(4-nιtrophenyl)-1 ,3,4,9-tetrahvdro-β-carbolιn-2- yDpropenyll-phenynacetamide The same method as employed in the preparation of Example 6 but starting from Intermediate 3 gave after recrystallization from 2-propanol the title compound as white crystals in a 51 % yield MP 185 °C Analysis for C 28 H 24 N 4 O 4 06H 2 O Calculated C,68 45 H 5 17, N, 11 4, Found C,68 37, H,5 06 N,1 1 26% Example 11 . EV-1 -f 1 -f 4-Nitrophenyl ) -1.3 4.9-tetrahydro-β-carbolιn-2-yll-3-phenylpropene-1 - one The same method as employed in the preparation of Example 1 but starting from Intermediate 3 gave after recrystallization from 2-propanol, the title compound as a yellow powder in a 15% yield. MP: 205-206 °C. Analysis for C 26 H 21 N 3 O3. 0.2H 2 O: Calculated: C.73.12, H.5.05; N,9.84; Found: C.72.95; H.5.15; N.9.81 %. Example 12 (E)-1-f1-(4-Trifluoromethoxyphenyl)-1 ,3 4,9-tetrahydro-β-carbolιn-2-yll-3-phenyl- propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 4 gave after recrystallization from pentane, the title compound as white crystals in a 44% yield. MP: 119 °C. Analysis for C 27 H 2 ιN 2 O 2 F 3 . Calculated: C.70.12; H.4.58; N.6.06, Found C,70.02, H.4.58; N,6.02%. Example 13 (E)-1-f1 -(4-Methylphenyl)-1 ,3.4.9-tetrahydro-β-carbolιn-2-vπ-3-phenylpropene-1 - one The same method as employed in the preparation of Example 1 but starting from Intermediate 6 gave after recrystallization from pentane, the title compound as white crystals in a 50% yield MP: 125-127 °C. Analysis for C 27 H 24 N 2 O. 0.6H 2 O Calculated C,80 41 ; H.6.3, N.6.95, Found C, 80.49 ; H.6.2 ; N,7.25% Example 14 (E)-N-f4-[3-Oxo-3-(1 -(3.4-methylenedιoxyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn- 2-yl)-propenvHphenvπacetamιde The same method as employed in the preparation of Example 6 but starting from Intermediate 7 and (E)-3-(4-acetylaminophenyl)acrylιc acid gave after recrystallization from 2-propanol:peπtane, the title compound as white crystals in a 85% yield. MP: 185 °C. Analysis for C 29 H 25 N 3 O 4 . 0.4H 2 O: Calculated: C.71.56; H.5.34; N.8.63; Found: C.71.59; H,5.32; 8.66%. Example 15 (E)-4-f3-Oxo-3-(1-phenyl-1 ,3.4.9-tetrahydro-β-carbolin-2-yl)-propenyllbenzoιc acid, methyl ester To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnO 2 (0.59 g, 14 equiv.), sodium cyanide (0 05 g, 2 equiv.) and acetic acid (0.05 g, 1 7 equiv.). The resulting mixture was stirred for 5 hours Tic monitoring showed a new compound (SiO 2 ,DCM:MeOH (95:5), Rf= 0.82). The mixture was filtered through a short column of celite using 150 mL of a mixture of MeOH:EtOAc CHCI 3 (1 :25:25) After evaporation in vacuo the residue was purified via flash chromatography on a 2 x 20 cm 2 column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals. MP: 222 °C. Analysis for C 28 H 24 N 2 O 3 . 0.03H 2 O Calculated: C.76.1 ; H.5.61 ; N.6.34, Found. C,76.05; H.5.68, N,6 15% Example 16 (E)-1 -f1-(2-Chlorophenyl)-1.3.4.9-tetrahydro-β-carbolin-2-vn-3-phenylpropene-1 - one The same method as employed in the preparation of Example 1 but starting from Intermediate 17 gave after recrystallization from EtOH, the title compound as white crystals in a 27% yield MP. 220-221 °C Analysis for C 26 H 2 ιN 2 OCI. Calculated C, 75.63, H,5 13, N,6 78, Found. C.75.4; H.5.21 ; N,6.79%. Example 17 (E)-1-(1-Phenyl-1 ,3.4.9-tetrahvdro-β-carbolιn-2-yl)-3-(3.4- methylenedιoxyphenyl)-propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-(3,4-methylenedioxy)cinnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 65% yield. MP: 221 °C. Analysis for C 27 H 22 N 2 O 3 . 0.3H 2 O: Calculated: C.75.79; H.5.32; N.6.55; Found: C,75.76; H,5.37; N,6.53%. Example 18 (E)-1 -f1-(3.4-Methylenedιoxyphenyl)-1.3.4 9-tetrahvdro-β-carbolιn-2-yn-3-(4- bromophenyl)propene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 and (E)-4-bromocιnnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 10% yield. MP: 188-190 °C. Analysis for C 27 H 21 N 2 O 3 Br. 0.3H 2 O. Calculated. C,63.99; H.4.3; N.5.53, Found: C.63.53; H.4.23; N,5.38% Example 19 (E)-1-f1-(4-Chlorophenyl)-1 ,3 4.9-tetrahvdro-β-carbolιn-2-yl]-3-phenylpropene-1- one The same method as employed in the preparation of Example 1 but starting from Intermediate 5 gave after recrystallization from EtOH, the title compound as white crystals in a 72% yield MP: 213-214 °C. Analysis for C 26 H 2 ιN 2 OCI Calculated. C.75.63, H,5 13; N,6 78, Found C,75 55, H,5 16, N,663% Example 20 (E)-1 -M-(3 4-Methylenedioχyphenyl)-1.3 4.9-tetrahydro-β-carbolιn-2-vπ-3-(4- ethoxyphenyl)proρene-1 -one To a solution of Intermediate 7 (0.2 g,0.68 mmol) in 40 mL of DCM were added Et 3 N (0.1 mL, 1.1 equiv ), EDCI (0.14 g, 1 1 equiv ), HOBT (0 12 g, 1 1 equiv ) and (E)-4-ethoxycinπamιc acid (0 14 g, 1.1 equiv ). After 48 hours of stirring at rt the reaction was judged to be completed by tic monitoring (SiO 2 , DCM MeOH (95:5)) and was quenched with 50 mL of water The reaction mixture was extracted with DCM, washed with brine (5 mL), dried over MgS0 4 and concentrated in vacuo. Flash chromatography on a 2.5 x 25 cm 2 column of silica gel using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.21 g, 67%) as white crystals after recrystallization from EtOH. MP: 199-200 °C. Analysis for C 29 H 26 N 2 O 4 0.3H 2 O Calculated: C.73.8, H,5.68; N,5.94, Found: C,73 72; H.5.68; N,5 97%. Example 21 (E)-4-,3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-β-carbolιn-2- vDpropenyllacetic acid, phenyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-acetoxycinnamic acid gave after recrystallization from MeOH, the title compound as white crystals in a 54% yield MP: 216 °C. Analysis for C 29 H 24 N 2 O 5 Calculated: C,72 49, H,5.03; N.5.83; Found. C72.3; H.5.11 ; N.5.84%. Example 22 (E)-1 -f 1 -(3 4-Methylenedioxyphenyl)-1.3 4.9-tetrahvdro-β-carbolιn-2-yll-3-(4- hydroxyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-hydroxycιnnamιc acid gave after recrystallization from EtOH pentane the title compound as white crystals in a 57% yield MP: 175 °C. Analysis for C 27 H 22 N 2 O 4 .0.3H 2 O: Calculated: C, 73.06; H.5.13; N.6.31 ; Found: C.73.14; H,5.36; N,6.44%. Example 23 (E.-1-f1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahvdro-β-carbolιn-2-yll-3-(4- formylphenvQpropene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-formyicιnnamic acid gave after recrystallization from MeOH the title compound as white crystals in a 100% yield MP: 208 °C. Analysis for C 28 H 22 N 2 O 4 . 0.3H 2 O: Calculated: C.73.77; H,5.00; N.6.15; Found: C.73.77; H.4.96; N.6.05%. Example 24 (E)-1-r4-r3-Oxo-3-(1-(3 4-methylenedιoxyphenyl)-1.3.4.9-tetrahvdro-β-carbolin- 2-yl)-propenvπphenvπ-3-phenylurea The same method as employed in the preparation of Example 20 but starting from (E)-3-[4-(3-(phenylureido)phenyl]acrylιc acid (which was prepared in situ by reaction of phenylisocyanate (1 equiv ), (E)-4-amιnocιnnamιc acid (1 equiv.) and Et 3 N (1 equiv.)), gave after recrystallization from EtOH the title compound as white crystals in a 61 % yield. MP: 192 °C. Analysis for C^H^C 0.22(EtOH:H 2 O) Calculated: C,72.48; H.5.26; N.9.82, Found. C,72 87; H.5.17; N.9.42%. Example 25 (EV-1 -f 1 -(3.4-Methylenedioxyphenvn-1.3 4.9-tetrahvdro-β-carbolιn-2-yll-3-(4- amιnophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-amιnocιnnamιc acid gave after recrystallization from EtOH. DCM.2- propanol (10.2:2) the title compound as white crystals in a 63% yield. MP 262-265 °C Analysis for C 27 H 23 N 3 O 3 0 3H 2 O Calculated C,73 22, H,5 37, N,9 49, Found C,72 9, H,5 47, 9 32% Example 26 (E)-1 -M-(3,4-Methylenedιoxyphenyl,-1 3 4 9-tetrahydro-β-carbolιn-2-vπ-3-(4- nιtrophenyl)-propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-nιtrocιnnamιc acid gave after recrystallization from EtOH, the title compound as yellow crystals in a 69% yield MP 158° C Analysis for C 27 H 21 N 3 O 5 Calculated C,69 37, H,4 53, N,8 99, Found C,69 57, H,4 61 , N,8 92% Example 27 (EV1-f1 -(3.4-Methylenedιoχyphenyl)-1.3,4,9-tetrahvdro-β-carbolιn-2-vn-3-f(4- bιs(methylsulfonyl)amιnophenvπpropene-1 -one This product was prepared by refluxing for two hours a solution of Example 25 (0 2 g, 0 6 mmol), mesyl chloride (0 1 mL, 5 equiv ), Et 3 N (0 4 mL, 5 equiv ) in 20 mL of THF The disappearance of the starting material and the formation of a new compound were confirmed by tic (SιO 2 , DCM MeOH (95 5), Rf= 0 84) After evaporation of THF the residue was dissolved in DCM (15 mL) and washed with H 2 O (10 mL) The organic solution was dried over MgSO 4 and concentrated in vacuo to give a residue which was purified via flash chromatography on a 2 5 x 25 cm 2 column using DCM MeOH (98 2) as eluting solvent Recrystallization from EtOH gave the title compound (0 09 g, 25%) as a white powder MP 276 °C Analysis for C 29 H 27 N 3 O 7 S 2 0 3H 2 O Calculated C,58 14, H,4 64, N,7 01 , Found C,57 76, H,4 69, N,6 81% Example 28 (E)-4-f3-Oxo-3-f1 -(3 4-methylenedιoxyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn-2- yll-propenyllbenzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-(2-carboxyvιnyl)benzoιc acid, methyl ester acid (prepared according to the procedure of Taylor.E C , Young, W.B , Chaudhan.R , Patel,H Heterocycles 1993, 36, 1897-1908), gave after recrystallization from MeOH H 2 0 (99 1 ), the title compound as yellow crystals in a 84% yield MP 211 °C Analysis for C 29 H 24 N 2 O 5 0 3H 2 O Calculated C.71.68, H,5 1 , N,5 76, Found C,71 76, H,5 02, N,5 68% Example 29 . E)-N-f4-f3-Oxo-3-M -f3.4-methylenedιoxyphenyl)-1.3.4 9-tetrahydro-β-carbolιn- 2-yllpropenyllphenyllmethanesulfonamιde The same method as employed in the preparation of Example 27 but using 1 equiv of mesyl chloride gave after recrystallization from EtOH the title compound as an off-white powder in a 10% yield MP 203 °C Analysis for C 28 H 25 N 3 O 5 S 02H 2 O Calculated C,64 78, H,4 93, N,8 09, Found C.64.66, H,5 15, N,7.73% Example 30 (E)-4-f3-Oxo-3-π-(3,4-methylenedιoxyphenyl)-1 ,3.4.9-tetrahvdro-β-carbolιn-2- yllpropenyllbenzamide Into a solution of Example 28 (0 2 g, 0 4 mmol) in 50 mL of MeOH was bubbled ammonia and the resulting mixture was stirred at 35°C for two days The mixture was concentrated in vacuo to give a residue which was washed with 2x30 mL of water Extraction, drying over MgSO 4 and concentration in vacuo gave a residue that was purified via radial chromatography using DCM MeOH (90 10) as eluting solvent and via preparative chromatography (20x20- cm plate, 0 5 mm , SιO 2 ) using the same eluant The title compound (0 025 g, 13%) was isolated as white crystals after recrystallization from MeOH H 2 O MP 183 °C Analysis for C 28 H 23 N 3 O 4 Calculated C,70 07, H,5 17, N,8 76, Found C,69 97, H,5 16, N,8 84% Example 31 (E)-4-f3-Oxo-3-π-(3 4-methylenedιoχyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn-2- vH-propenvnbenzoic acid This product was prepared by refluxing for four hours a stirred solution of Example 28 (0 5 g, 1 04 mmol) and NaOH (1 N) (5 2 mL, 5 equiv ) in 50 mL of MeOH After evaporation of the solvent in vacuo, the residue was treated with 10 mL of HCl (1 N) A solid precipitated out and was filtered off Recrystallization from MeOH gave the title compound (0 35 g, 72%) as white crystals MP 254-256 °C Analysis for C 28 H 22 N 2 O 5 0 2H 2 O Calculated C, 72 09, H, 4 75, N, 6 01 , Found C,71 60, H,4 84, N,5 88% Example 32 (E)-1-ri-(3 4-Methylenedιoχyphenyl)-1 3.4,9-tetrahydro-β-carbolιn-2-yll-3-(4- cvanophen yl )propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-cyanocιnnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 69% yield MP 167 °C Analysis for C 28 H 21 N 3 O 3 0 1 H 2 O Calculated C,74 85, H,4 76, N,9 35, Found C,74 72, H,4 81 , N,9 27% Example 33 (E)-1-f1-(3 4-Methylenedιoxyphenvn-1.3.4 9-tetrahydro-β-carbolιn-2-vn-3-(4- tnfluoromethylphenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-tπfluoromethylcιnnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 73% yield MP 233 °C Analysis for C 28 H 21 F 3 N 2 O 3 . 0.2H 2 O: Calculated: C, 68.07; H,4.37; N.5.67; Found. C.68.04; H.4.32; N.5.65%. Example 34 (E)-1-ri-(3,4-Methylenedιo χ yphenyl)-1.3.4.9-tetrahvdro-β-carbolin-2-vn-3-(3 4- methylenedιoχyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-methylenedioxycinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 73% yield. MP: 233 °C. Analysis for C 28 H 22 N 2 O 5 : Calculated: C.72.09; H,4.75; N.6.01 , Found. C.71 79; H.4.76; N,5.93% Example 35 (E)-1 -ri-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahvdro-β-carbolιn-2-yll-3-(4- chlorophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-chlorocinnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 55% yield. MP: 203 °C. Analysis for C 27 H 21 N 2 O 3 CI. Calculated: C,70.97; H.4.63; N.6.13; Found: C.71.04; H.4.76; N.6.04%. Example 36 (E)-1 -f 1 -(3.4-Methylenedιoχyphenyl)-1 ,3.4.9-tetrahvdro-β-carbolιn-2-yll-3-(4- trifluoromethoχyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-trifluoromethoxycinnamιc acid (prepared according to the procedure of Yagupol'skii, L.M , Troitskaya, V.I. Zhurnal Obshchei Khimn 1960, 30, 3102- 3104) gave after recrystallization from EtOH the title compound as yellow crystals in a 35% yield. MP. 203-205°C. Analysis for C 28 H 2 ιF 3 N 2 0 4 Calculated C,66 4, H,4 18, N,5 53, Found C,66 23, H,4 26, N,5 54 Example 37 (EV1-f1-(3 4-Methylenedιoχyphenyl)-1 3 4.9-tetrahvdro-β-carbolιn-2-vn-3-(4- methylphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-methylcιnnamιc acid gave after recrystallization from EtOH DCM (99 1 ) the title compound as white crystals in a 67% yield MP 240 °C Analysis for C 28 H 24 N 2 O 3 0 7H 2 O Calculated C,74 88, H,5 7, N,6 24, Found C,74 83, H,545, N,6 35 % Example 38 (EH4-f3-Oxo-3-(1-(3.4-methylenedιoxyphenyl)-1 ,3 4.9-tetrahvdro-β-carbolιn-2- vDpropenvnphenyllurea The same method as employed in the preparation of Example 20 but starting from Intermediate 22 gave after recrystallization from EtOH the title compound as white crystals in a 49% yield MP 208 °C Analysis for C 28 H 24 N 4 O 4 0 5H 2 O Calculated C,68 7, H,5 15, N,11 44, Found C.68.51; H,5 14, N,11 35% Example 39 (E)-1-f1-(3 4-Methylenedιoχyphenyl)-1 3,4 9-tetrahvdro-β-carbolιn-2-yll-3-(4- hvdroxymethylphenyl)propene-1-one This product was prepared by stirring a solution of Example 23 (0 3 g, 0 66 mmol) in 40 mL of MeOH with NaBH 4 (0 1 g, 4 equiv ) at rt for two hours Evaporation of the solvent gave a residue which was dissolved in DCM (100 mL) and washed twice with water (50 mL) Extraction with DCM, drying over MgSO 4 and evaporation in vacuo gave the title compound (0 2 g, 67%) as white crystals after recrystallization from EtOH MP 206 °C Analysis for C 28 H 24 N 2 O 4 0 3EtOH Calculated C,73 66, H,5 58, N,6 01 , Found C,73 69, H,5 5, N,6 06% Example 40 (E)-N-Benzyl-4-f3-oxo-3-(1-(3.4-methylenedιoxyphenyl)-1 3 4 9-tetrahvdro-β- carbolιn-2-yl)propenvnbenzamιde This product was prepared by stirring a solution of Example 31 (0 2 g, 0 43 mmol) in 50 mL of THF with benzylamine (0 5 mL, 9 equiv ), Et 3 N (1 mL) and diphenylphosphoryl azide (0 5 mL) After two days the reaction mixture was concentrated in vacuo The residue was taken up in 100 mL of DCM and washed with 3 x 50 mL of water Drying over Na 2 SO 4 and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and Et 2 O Evaporation in vacuo and recrystallization from EtOH gave the title compound (0 03 g, 13%) as white crystals MP 203 °C Analysis for C 35 H 29 N 3 O 4 Calculated C,75 66, H,5 26, N,7 56, Found C,75 5, H,5 22, N,7 55% Example 41 (E)-1 -f1-(3.4-MethylenedιoxyphenylV1 .3 4.9-tetrahvdro-β-carbolιn-2-vn-3-(2.4- dιchlorophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-2,4-dιchlorocιnnamιc acid gave after recrystallization from EtOH H 2 O the title compound as a white powder in a 66% yield MP 194 °C Analysis for C 27 H 20 N 2 O 3 CI 2 Calculated C,66 00, H,4 10, N,5 70, Found C,65 85, H 4 13, N,5 78% Example 42 (E)-1 -f1 -(3 4-Methylenedιoxyphenyl)-1 3 4 9-tetrahydro-β-carbolιn-2-yll-3-(3- methoxy-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxy-4-hydroxycιnnamιc acid gave after recrystallization from EtOH H 2 O (10 1 ) the title compound as an off-white powder in a 62% yield MP 155 °C Analysis for C 28 H 24 N 2 O 5 Calculated C.71 78, H,5 16, N,5 98, Found C-,71 44, H,5 16, N,5 76% Example 43 (E)-1-f1 -(3.4-Methylenedιoxyphenyl)-1 3 4 9-tetrahydro-β-carbolιn-2-yl1-3-(3- hydroxy-4-methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxy-4-methoxycιπnamιc acid gave after recrystallization from EtOH H 2 O the title compound as an off-white powder in a 47% yield MP 213 °C Analysis for C 28 H 24 N 2 O 5 0 3H 2 O Calculated C 70 96, H.5.23, N,5 91 , Found C.71 09, H,5 60, N,5 66% Example 44 (E.-1-f1-(3,4-Methylenedιoxyphenyl)-1.3 4 9-tetrahvdro-6-carbolιn-2-yl .-3-(4- fluorophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-4-fluorocιnnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 74% yield MP 138-139 °C Analysis for C 27 H 2 ιF 3 N 2 O 3 Calculated C 73 62, H,4 81 , N,6 36, Found C,73 78, H,4 81 , N,5 97% Example 45 (E)-1 -f1 -(3 4-MethylenedιoxyphenvP-1 3 4,9-tetrahydro-β-carbolιn-2-vn-3-ιndan- 5-yl-1 -propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3-ιndane-5-ylacryiιc acid gave after precipitation, the title compound as a yellow powder in a 22% yield MP 115 °C Analysis for C 20 H 26 N 2 O 3 06H 2 O Calculated C,76 12, H,5 79, N,5 92, Found C,76 13, H,5 79, N,5 72% Example 46 (E)-N-f4-f3-Oxo-3-(1-(3 4-methylenedιoxyphenyl)-1.3.4 9-tetrahydro-β-carbolιn- 2-vπpropenyllbenzovπbenzenesulfonamιde The same method as employed in the preparation of Example 20 but starting from Example 31 and benzenesulfonamide gave after recrystallization from EtOH H 2 O the title compound as white crytals in a 20% yield MP 134 °C Analysis for C 20 H 26 N 2 O 3 0 6H 2 O Calculated C,56 13, H,6 67 N.10 91 , Found C,55 97, H,6 75, N,10 82% Example 47 (EV1-f1 -(3.4-Methylenedιoxyphenyl)-1.3 4 9-tetrahvdro-β-carbolιn-2-vn-3-(3.4- dιchlorophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dιchlorocιnnamιc acid gave after recrystallization from EtOH H 2 O (99 1 ) the title compound as a white powder in a 45% yield MP 212 °C Analysis for C 27 H 20 CI 2 N 2 O 3 Calculated C 66 00, H,4 10, N,5 70, Found C,65 68, H,4 12, N, 5 68% Example 48 (E)-1 -f1-(3 4-Methvtenedιoxyphenyl)-1 3 4 9-tetrahydro-B-carbolιn-2-vn-3-(3.4- dιmethoxyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dιmethoxycιnnamιc acid gave after recrystallization from EtOH DCM the title compound as a white powder in a 61 % yield MP 233 °C Analysis for C 29 H 26 N 2 O 5 0 5 H 2 O Calculated C,70 86, H,5 54, N,5 70, Found C,70 66, H,5 44, N,5 70% Example 49 (EM -f 1 -(3,4-Methylenedιoχyphenyl)-1 ,3.4,9-tetrahydro-β-carbolιn-2-yll-3-(3 4- dιhydroxyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dιhydroxycιnnamιc acid gave after recrystallization from EtOH DMF the title compound as a white powder in a 41 % yield MP 163-165 °C Analysis for C 27 H 22 N 2 O 5 0 3DMF Calculated C,70 34, H,5 10, N,6 76, Found C,70 38, H,5 13, N,6 66% Example 50 (E)-N-Methyl-N-r4-(3-oxo-3-(1 -(3.4-methylenedιoχyphenyl)-1 ,3.4 9-tetrahvdro-β- carbolιn-2-yl)propenyllphenyllacetamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 23 gave after recrystallization from EtOH H 2 O (10 0 6) the title compound as an off-white powder in a 86% yield EtOH H 2 O MP 165 °C Analysis for C 30 H 27 N 3 O 4 04H 2 O Calculated C.71 96, H,5 6, N,8 39, Found C.71 8, H,5 57, N,8 28% Example 51 (E)-2 2-Dιmethyl-N-[4-r3-Oxo-3-(1-(3 4-methylenedιoxyphenyl)-1 3 4 9- tetrahydro-β-carbolιn-2-yl)propenvπphenyπpropιonamιde This product was prepared by condensation of Example 25 (0 2 g, 0 46 mmol) with 2,2-dιmethylpropιonyt chloride (0 09 mL, 1 5 equiv ) and NaOH (1 N) (0 7 mL, 1 5 equiv ) in a mixture of EtOAc DCM (6 1 ) When starting material had disappeared, 40 mL of a mixture of DCM H 2 O (2 1 ) was added Extraction with DCM, washing with a saturated aqueous solution of NH 4 CI and brine, drying over MgSO 4 and evaporation of the solvent in vacuo gave the title compound (0 2 g, 83%) after recrystallization from EtOH H 2 O (1 1 ) MP 172-174 °C Analysis for C 32 H 31 N 3 O 4 0 1 H 2 O Calculated C.71 23, H,6 16 N,7 79, Found C.70.99, H,6 02 , N 7 84% Example 52 (E)-1 -f1-(3.4-Methylenedιoxyphenyl)-1 3.4 9-tetrahvdro-β-carbolιn-2-vn-3-(3 5- dιmethoxyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dιmethoxycιnnamιc acid gave after recrystallization from EtOH the title compound as a white powder in a 61 % yield MP 178 °C Analysis for C 29 H 26 N 2 O 5 Calculated C,72 19, H,5 43, N,5 81 , Found C,72 3, H,5 48, N,5 63% Example 53 (EHNH4-f3-f 1 -(3.4-Methylenedιoχyphenvn-6-fluoro-1 ,3 4,9-tetrahydro-β- carbolιn-2-yll-3-oxopropenvnphenyl>-acetamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 16 and and (E)-3-(4-acetylamιnophenyl)acrylιc acid gave after recrystallization from MeOH the title compound as a white crystals in a 72% yield MP 179-181 °C Analysis for C 29 H 24 N 3 O 4 F 0 4H 2 O Calculated C,69 01 , H,4 95, N,8 33, Found C,68 97 H,4 91 , N 8 34% Example 54 (EM -H -.3 4-Methylenedιoxyρhenvn-1 3 4 9-tetrahydro-β-carbolιn-2-yll-3-(3 4 5- trιmethoxyphenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3,4,5-tπmethoxycιnnamιc acid gave after recrystallization from MeOH the title compound as a white powder in a 49% yield MP 211 °C Analysis for C 3 oH 2 sN 2 O e Calculated C,70 3 , H,5 51 , N,5 47, Found C,7049, H,5 59, N,5 34 % Example 55 (E)-N-.443-Oxo-3-(1 -(3 4-methylenedιoxyphenvn-1 ,3 4 9-tetrahydro-β-carbolιn- 2-vπpropenvnphenyπιsobutyramιde The same method as employed in the preparation of Example 51 but starting from isobutyryl chloride gave after recrystallization from EtOH the title compound as a white powder in a 85% yield MP 171 °C Analysis for C 31 H 29 N 3 O 4 04(H 2 O MeOH) Calculated C,72 61 , H,6 02, N,7 99, Found C,72 33, H,5 77, N,8 33% Example 56 (E)-1 -f 1 -(3.4-Methylenedιoχyphenvπ-6-fluoro-1 ,3,4 9-tetrahydro-β-carbolιn-2-vπ- 3-phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 16 gave after recrystallization from EtOH the title compound as white crystals in a 71% yield MP. 227-228 °C Analysis for C 27 H 2 ιN 2 O 3 F Calculated C,73 63, H,4 81 , N,6 36, Found C,73 72, H,4 77, N,643% Example 57 (E)-N-(2-Methoxyethyl)-4-f3-oxo-3-π -(3 4-methylenedιoxyphenyl)-1 3 4 9- tetrahydro-β-carbolιn-2-yl)propenyllbenzamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 24 gave after recrystallization from EtOH the title compound as white crystals in a 43% yield MP 170 °C Analysis for C 27 H 21 N 2 O 3 F 1 3H 2 O Calculated C,68 07, H,5 82, N,7 68, Found C,67 98, H,5 8, N,7 7% Example 58 (E)-1 -f 1 -(3,4-MethylenedιoxyphenylM .3 4.9-tetrahydro-β-carbolιn-2-yl1-3-(3- hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxycιnnamιc acid gave after recrystallization from EtOH H 2 O the title compound as white crystals in a 54% yield MP 248 °C Analysis for C 27 H 22 N 2 O 4 Calculated C,73 96, H,5 06, N,6 39, Found C,74 04, H,5 1 , N,6 37% Example 59 (E)-1-f1-(3 4-Methylenedιoχyphenyl)-1 ,3 4 9-tetrahydro-β-carbolιn-2-yl1-3-(3- methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxycιnnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 49% yield MP 218 °C Analysis for C 28 H 24 N 2 O 4 Calculated C,74 32, H,5 35, N,6 19, Found C,74 37, H 5 61 , N,6 32% Example 60 (E)-1 -f1 -(3 4-Methylenedιoxyphenvn-1 3 4 9-tetrahydro-β-carbolιn-2-vn-3-(3- nιtrophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3-nιtrocιnnamιc acid gave after recrystallization from EtOH H 2 0 (20 1 ) the title compound as white crystals in a 91% yield MP 156-158 °C Analysis for C 28 H 24 N 2 O 4 Calculated C,69 37, H,4 54, N,8 99, Found C,69 12, H,4 77, N,8 81% Example 61 (EM-f1-(3 4-Methylenedιoxyphenvn-1 ,3 4 9-tetrahydro-β-carbolιn-2-yl1-3-f4-(2- dιmethylamιnoethoxy)phenyllpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 25 gave after recrystallization from EtOH H 2 O the title compound as white crystals in a 45% yield MP 157 °C Analysis for C ST H^^O., Calculated C,73 07, H,6 13, N,8 25 Found C,72 7 H,6 17, N,8 12% Example 62 (E)-N-(2-Morpholtn-4-ylethyl)-4-[3-oxo-3-(1 -(3 4-methylenedιoxyphenyl)-1 3 4.9- tetrahydro-β-carbolιn-2-vπpropenyllbenzamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 26 gave after recrystallization from EtOH H 2 O the title compound as white crystals in a 13% yield MP 145 °C Analysis for C^HsJsL.Os 0 7H 2 O Calculated C,69 07, H,6 03, N948, Found C,69 08, H, 6 03, N,9 45% Example 63 (E)-1-f1-(3 4-Methylenedtoxyphenvn-1.3 4.9-tetrahydro-β-carbolιn-2-vn-3-f4- ( 1 H-tetrazol-5-vπphenyl1propene-1 -one To a solution of Example 32 (0 25 g 0 56 mmol) in 10 mL of toluene were added successively tnmethylsilylazide (0 30 mL, 4 equiv ) and dibutyltinoxide (0 06 g, 0 4 equiv ) The resulting mixture was stirred at reflux for two days Tic monitoring showed formation of a new compound (DCM MeOH (80 20), Rf=0 35) The reaction mixture was concentrated in vacuo The resulting yellow gum was dissolved in MeOH and concentrated in vacuo The residue was partitioned between EtOAc (25 mL) and an aqueous saturated solution of NaHCO 3 (25 mL) The organic phase was extracted with an additional portion of an aqueous saturated solution of NaHCO 3 (25 mL) The combined aqueous extracts were acidified to pH= 2 with HCl (1N) and then extracted with EtOAc (2x25 mL) The combined organic extracts were dried over MgSO 4 , filtered and concentrated to give a yellow powder that was purified via flash chromatography (SιO 2 , DCM MeOH (90 10)) Recrystallization from 2-propanol ιPr 2 O (1 1 ) gave the title compound (0 19 g, 70 %) as white crystals MP 232-233 °C Analysis for C 28 H 22 N 6 O 3 0 4H 2 O Calculated C,67 02, H,4 92, N 16 28, Found C,66 83, H,4 53, N,15 96% Example 64 (EM -f 1 -(3.4-Methylenedιoχyphenyl)-1 3,4,9-tetrahvdro-β-carbolιn-2-yll-3-(3- amιnophenyl)propene-1 -one A solution of Example 60 (1 36 g, 2 9 mmol), SnCI 2 H 2 O (2 8 g 5 equiv ) in EtOH was refluxed overnight After evaporation of the solvent, the residue was taken up in 50 mL of NaOH (1 N) The aqueous phase was extracted with 2 x 100 mL of DCM and 2 x 50 mL of EtOAc The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo Flash chromatography (SιO 2 DCM MeOH (95 5) and recrystallization from EtOH DCM gave the title compound (0 27 g 21 %) as a pale yellow powder MP 139-141 °C Analysis for C 27 H 23 N 3 O 3 Calculated C,74 13, H,5 30, N,9 60, Found C,73 93, H,5 35, N,9 43% Example 65 (E)-N-Cyclohexyl-4-[3-oxo-3-(1 -(3 4-methylenedιoxyphenyl)-1 3 4,9-tetrahydro- β-carbolιn-2-yl)propenvπbenzamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 27 gave after recrystallization from EtOH H 2 0 the title compound as white crystals in a 6% yield MP 214 °C Analysis for C 28 H 2 ιN 3 O 3 0 1 H 2 O Calculated C.72.19, H,6 24, N,7 43, Found C.72.28, H 6 19, N,6 93% Example 66 (E)-N-(Tetrahvdrofuran-2-ylmethyl)-4-f3-oxo-3-(1-(3,4-methylenedιoxyphenyl)- 1 ,3.4,9-tetrahvdro-β-carbolιn-2-yl)propenyllbenzamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 28 gave after recrystallization from EtOH H 2 0 (8 2) the title compound as white crystals in a 61% yield MP 168 °C Analysis for C 32 H 29 N 3 O 5 0 8H 2 O Calculated C,69 88, H,5 61 , N,7 64, Found C,69 74, H 5 78, N,7 22% Example 67 (EM -.1-(3.4-MethylenedιoχyphenylM .3.4 9-tetrahvdro-β-carbolιn-2-yl1-3-(3- cyanophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-cyanocιnnamιc acid gave after recrystallization from EtOH H 2 0 (8 2) the title compound as white crystals in a 46% yield MP 228-230 °C Analysis for C 28 H 2 ιN 3 O 3 0 8H 2 O Calculated C,72 81 , H,4 93, N,9 10, Found C,72 74, H,4 69, N,8 99% Example 68 (E)-N-(4-Pιperιdιne-4-carboxylιc acid, ethyl ester)-4-[3-oxo-3-(1 -(3.4- methylenedιoxyphenyl)-1 ,3 4 9-tetrahvdro-β-carbolιn-2-yi)propenvπbenzamιde The same method as employed in the preparation of Example 20 but starting from Intermediate 29 gave after recrystallization from ιPr 2 0 the title compound as white crystals in a 28% yield MP 144-145 °C Analysis for C 36 H 35 N 3 O 6 0 7H 2 O Calculated C, 69 93, H,5 93, N,6 8, Found C,69 84, H,5 83, N,6 81 % Example 69 (E)-N-(4-Piperιdιne-4-carboxylιc acιd)-4-f3-oxo-3-( 1 -(3.4- methylenedιoxyphenyl)-1 ,3 4 9-tetrahvdro-β-carbolιn-2-yl)propenyllbenzamιde This product was prepared by refluxing a solution of Example 68 (0 21 g, 0 36 mmol) with NaOH (1 N) (0 72 mL, 2 equiv ) in 20 mL of MeOH for 12 hours After cooling the mixture was poured into H 2 O (100 mL) and acidified with HCl (1 N) Extraction with 2 x 50 mL of DCM, drying over Na 2 SO 4 and concentration in vacuo gave a residue which was recrystallized from MeOH H 2 O to give the title compound (0 05 g, 24%) as white crystals MP 204-205 °C Analysis for C 34 H 31 N 3 O6 0 4H 2 O Calculated C,68 56, H,5 58, N,7 05, Found C,68 58, H,5 12, N 7 06% Example 70 (E)-3-.3-Oxo-3-f1-(3,4-methylenedιoxyphenvπ-1 3 4 9-tetrahvdro-β-carbolιn-2- vπ-propenyllbenzoic acid The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvιnyl)benzoιc acid gave after recrystallization from MeOH the title compound as a white powder in a 21 % yield MP 156-158 °C Analysis for C 28 H 22 N 2 O 5 0 8H 2 O Calculated C,69 93, H 4 95, N,5 83, Found C,69 94 H,4 62, N 5 65% Example 71 (EM-f1-(3.4-Methylenedioxyphenyl)-1.3 4.9-tetrahvdro-β-carbolιn-2-yll-3-(3-(4- methylpiperazine-1 -carbonyl)phenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Example 70 and 4-methylpiperazine gave after recrystallization from MeOH:H 2 O, the title compound as a white powder in a 30% yield MP: 151 °C. Analysis for C 33 H 32 N 4 0 4 . H 2 O: Calculated- C.69.95; H.6.05, N.9.89; Found: C, 69.63; H.5.93; N,9.99%. Example 72 (E)-N-(2-Piperazιn-1 -ylethyl)-3-r3-oxo-3-(1 -(3 4-methylenedιoxyphenyl)-1 .3.4.9- tetrahvdro-β-carbolιn-2-yl)propeπyllbenzamιde The same method as employed in the preparation of Example 20 but starting from Example 70 and 1-(2-aminoethyl)pιperazιne gave after recrystallization from iPr 2 O, the title compound as a white powder in a 23% yield MP- 138-140 °C. Analysis for C 34 H 35 NsO 4 . 3.1 H 2 O. Calculated. C.64.46; H.6.55; N, 1 1 .05; Found: C,64.46; H.6.25; N, 1 1.00%. Example 73 (E)-4-f3-Oxo-3-(1 -(3.4-methylenedιoxyphenvn-1 .3.4,9-tetrahvdro-β-carbolιn-2- yl)-propenvnacetιc acid ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 30 gave after recrystallization from DCM. pentane, the title compound as a white powder in a 17% yield. MP: 92-95 °C. Analysis for C 3 ιH 28 N 2 O 5 . 0.9H 2 O Calculated: C, 70.95, H.5.72; N.5.34; Found. C,71 32, H.6.0; N,4.93%. Example 74 (E)-1 -f1 -(3 4-Methylenedιoxyphenyl)-1 ,3,4 9-tetrahydro-β-carbolιn-2-yll-3-(3- tetrazolophenyl)propene-1 -one The same method as employed in the preparation of Example 63 but starting from Example 67 gave after recrystallization from MeOH H 2 0, the title compound as a white powder in a 5% yield MP: 260-264 °C. Analysis for C 28 H 22 N 6 O 3 . 2.2H 2 O: Calculated: C.63.43; H.5.02; N.15.85; Found: C.63.31; H.4.37; N, 15.47%. Example 75 (E)-2-f3-Oxo-3-f1 -(3.4-methylenedio χ yphenvn-1 ,3,4,9-tetrahvdro-β-carbolιn-2- vπ-propenvnbenzoιcacιd methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-2-(2-carboxyvιnyl)benzoic acid, methyl ester (prepared according to the procedure of Alabaster, R.J.; Cottrell, I F , Hands, D., Humphrey, G.R , Kennedy, D.J., Wright, S.H.B Synthesis 1989, 8, 598-603), gave after recrystallization from MeOH, the title compound as white crystals in a 46% yield MP 203-204 °C. Analysis for C 27 H 21 N 3 O 5 : Calculated: C.72.49, H.5.03, N.5.83; Found: C.72.59; H.5.1 , N.5.67%. Example 76 (E)-3-f3-Oxo-3-f1-(3.4-methylenedioxyphenvπ-1.3,4.9-tetrahydro-β-carbolιn-2- yll-propenvnbenzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvιnyl)benzoιcacid, methyl ester (prepared according to the procedure of Baker.S.R.; Jamieson.W.B, Todd.A EP 134111 A1 ), gave after recrystallization from MeOH, the title compound as yellow crystals in a 61 % yield. MP: 165-167 °C. Analysis for C 29 H 24 N 2 O 5 Calculated- C.72.49; H.5.03. N.5.83., Found: C,72.53, H.5.02, N,5.93% Example 77 (EM-(4-f3-Oxo-3-(1-(3 4-methylenedιoxyphenyl)-1 ,3 4 9-tetrahvdro-β-carbolιn- 2-yl)-propenyllphenvπpιperιdιne-4-carboxylιc acid ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 31 gave after recrystallization from MeOH, the title compound as yeliow crystals in a 45% yield MP 175 °C Analysis for C 3 5H35N 3 O 5 Calculated C,72 77, H,6 1 1 , N,7 27, Found C,72 99, H,6 16, N,7 03% Example 78 (EVN-(1 -Ethylpyrrolιdιn-2-yl-methyl)-3-r3-oxo-3-(1 -(3,4-methvienedιoχyphenyl)- 1 3,4 9-tetrahvdro-β-carbolιn-2-yl)propenvHbenzamιde The same method as employed in the preparation of Example 20 but starting from Example 70 and 2-pyrrolιdιn-1-ylethylamιne gave after recrystallization from ιPr 2 O, the title compound as a white powder in a 53% yield MP 128-130 °C Analysis for C 35 H 36 N 4 O 4 Calculated C,72 9 H.6 29, N,9 72, Found C,72 9, H,6 42, N,10 01 % Example 79 (E)-1-π-(3.4-Methylenedιoxyphenyl)-1 3,4.9-tetrahydro-β-carbolιn-2-vn-3-(3-(2- dιmethylamιnoethoxy)phenyl)propene-1 -one To a solution of Example 58 (0 25 g, 0 57 mmol) in 50 mL of DMF was added K 2 CO 3 (0 24 g, 3 equiv ) and an excess of dimethylaminodiethyl chloride (about 15 equiv ) The resulting mixture was heated at 60 °C for four hours until disappearance of the starting material (tic monitoring, DCM MeOH (90 10) A new compound was formed (Rf= 0 20) After evaporation of DMF the residue was taken up in 150 mL of DCM, washed with 2x50 mL of water, dried over Na 2 SO 4 and recrystallized from EtOH H 2 O to give the title compound (0 06 g 22%) as yellow crystals MP 76-78 °C Analysis for C 3 ιH 3 ιN 3 O 4 0 6H 2 O Calculated C,71 55, H,6 24, N,8 07 2 77 72 Found: C.71.34; H,6.45; N,7.8%. Example 80 (EM -f 1 -(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahvdro-β-carbolin-2-vn-3-(3 5- diterbutyl-4-hvdroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dιtertbutyl-4-hydroxycinnamιc acid gave after recrystallization from cyclohexane, the title compound as yellow crystals in a 45% yield MP: 137 °C. Example 81 (E)-3-r3-Oxo-3-f1 -(4-methoxycarbonylphenvπ-1.3.4.9-tetrahvdro-β-carbolιn-2- yllpropenvnbenzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 8 and (E)-3-(2-carboxy-vιnyl)benzoιc acid, methyl ester (prepared according to the procedure of Baker.S.R., Jamιeson,W.B, Todd,A EP 134111 A1), gave after recrystallization from 2-propanol, the title compound as white crystals in a 70% yield. MP: 182 °C. Analysis for C 30 H 26 N 2 O 5 : Calculated: C72.86, H.5.3; N,5.66; Found C.72 49 ; H.5.31 ; N,5.68%. Example 82 (E)-2-f3-Oxo-3-f 1 -(34-methylenedioxyphenyl)-1.3,4.9-tetrahvdro-β-carbolin-2- yll-propenvπbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 75 gave after recrystallization from MeOH the title compound as off-white crystals in a 78% yield. MP: 174 °C. Analysis for C 28 H 22 N 2 O 5 ' Calculated. C.72.09, H,4 75, N.6.01 , Found C.72.53, H.4.72, N,5.76%. Example 83 (EH4-f3-Qxo-3-(1 -(3 4-methylenedιoxyphenyl)-1 3 4 9-tetrahydro-β-carbolιn-2- yl)propenyllphenoxy)acetic acid ethyl ester The same method as employed in the preparation of Example 79 but starting from Example 22 and bromoacetic acid, ethyl ester, gave after recrystallization from EtOH 2-propanol the title compound as yellow crystals in a 28% yield MP 99-98 °C Analysis for C 31 H 28 N 2 O 6 2 4H 2 O Calculated C,65 57, H 5 82, N,4 93, Found C,65 34, H,5 4, N,5 09% Example 84 (EV(4-f3-Oxo-3-(1-(3,4-methylenedιoxyphenylM 3,4,9-tetrahydro-β-carbolιn-2- yl)-propenvπphenvπacetιc acid The same method as employed in the preparation of Example 31 but starting from a solution of Example 73 in EtOH gave after recrystallization from ιPr 2 0 2- propanol the title compound as white crystals in a 51 % yield MP 231 °C Analysis for C 29 H 24 N 2 O 5 0 25ιPrOH Calculated C, 72 11 , H, 5 29, N,5 64 Found C, 71 9, H 5 15, N, 5 74% Example 85 (E)-(4-r3-Oxo-3-(1-(3.4-methylenedιoxyphenyl)-1 ,3.4 9-tetrahvdro-β-carbolιn-2- yl)propenyllphenoxy)acetιc acid The same method as employed in the preparation of Example 31 but starting from Example 83 gave after recrystallization from ιPr 2 O 2-propanol the title compound as yellow crystals in a 45% yield MP 158-160 °C Analysis for C 29 H 24 N 2 O 6 0 9H 2 O Calculated C,67 93, H,5 07, N,5 46, Found C,68 0, H 4 86, N,5 21 % Example 86 (E)-1 -f1-(3.4-Methylenedιoxyphenyl)-1 3 4 9-tetrahydro-β-carbolιn-2-vn-3-(3- nιtro-4-chlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-nιtro-4-chlorocιnnamιc acid gave after recrystallization from EtOH the title compound as yellow crystals in a 56% yield MP 240 °C Analysis for C 27 H 20 N 3 O 5 CI Calculated C,64 61 , H,4 02, N,8 37, Found C,64 5, H,3 97, N,8 28% Example 87 (EM -π -(3,4-Mθthvtenedιo χ yphenylM .3 A9-tetrahvdro-β-carbolιn-2-yl 1-3-.5- nιtro-2-chlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-5-nιtro-2-chlorocιnnamιc acid gave after recrystallization from EtOH H 2 O the title compound as yellow crystals in a 44% yield MP 146 °C Analysis for C 27 H 20 N 3 O 5 CI 0 1 H 2 O Calculated C,64 38, H,4 04, N,8 34, Found C,64 12, H,3 81 , N,8 35% Example 88 (E)-3-Chloro-4-r3-oxo-3-[1 -(3.4-methylenedιoxyρhenyl)-1 3.4 9-tetrahydro-β- carbolιn-2-yllpropenvπbenzoιc acιd methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 32 gave after recrystallization from EtOH the title compound as a white powder in a 57% yield MP 166 °C Analysis for C 29 H 23 N 2 O 5 CI 0 15EtOH Calculated C,67 43, H,4 62, N,5 37, Found C,67 09, H,4 56, N,5 51 % Example 89 (E)-(4-.3-Oxo-3-(1 -(3 4-methylenedιoxyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn-2- yl)propenyllbenzyloxy)acetιc acid The same method as employed in the preparation of Example 79 but starting from a solution of (E)-(4-[3-oxo-3-(1-(3,4-methylenedιoxyphenyl)-1 3,4,9- tetrahydro-β-carbolιn-2-yl)propenyl]beπzyloxy)acetιc acid, ethyl ester in EtOH gave after recrystallization from MeOH H 2 O the title compound as an off-white solid in a 40% yield MP 162-163 °C Analysis for C 30 H 26 N 2 O6 0 1 H 2 O. Calculated C,68 17, H,5 13, N,5 49, Found C.68 16, H.5 46, N,5 51 % (E)-(4-[3-Oxo-3-(1 -(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn-2- yl)propenyl]benzyloxy)acetιc acid, ethyl ester To a solution of Example 39 (0 7 g, 1.5 mmol) in 50 mL of DMF was added K 2 CO 3 (0.25 g, 1 2 equiv ) and ethylbromoacetate (0 2 mL, 1 1 equiv ) The resulting mixture was heated at 60 °C for 16 hours until disappearance of the starting material (tic monitoring, DCM MeOH (95 5)) A new compound was formed (Rf= 0.8) After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2x50 mL of water, dried over Na 2 SO 4 and purified via radial chromatography with DCM to give the title compound (0 85 g 11 %) as a white powder 1 H NMR (CDCI3) δ 7 8-6 65 (m, 14H), 5 9 (s, 2H), 4 7 (s, 2H), 4 6-4 3 (q, 2H), 4 2-4 0 (m, 4H), 3 6-3 5 (m, 1 H), 3 2-2 9 (m, 2H), 1 3-1 2 (t, 3H) Example 90 (EM -f 1 -(3.4-MethylenedιoχyphenylM 3.4.9-tetrahvdro-β-carbolιn-2-yl1-3-(5- amιno-2-chlorophenyl)propene-1 -one The same method as employed in the preparation of Example 64 but starting from Example 87 gave after recrystallization from EtOH DCM, the title compound as a white powder in a 17% yield MP 251-252 °C Analysis for C 27 H 22 CIN 3 O 3 04H 2 O Calculated C,67 68, H,4 8, N,8 77, Found C,67 71 , H 4 73, N,8 65% Example 91 (E)-3-Chloro-4-,3-oxo-3-π -(3 4-methylenedιoxyphenyl)-1 3 4 9-tetrahydro-β- carbolιn-2-vnpropenyllbenzoιc acid The same method as employed in the preparation of Example 31 but starting from Example 88 gave after recrystallization from 2-propanol the title compound as a yellow powder in a 40% yield MP 169 °C Analysis for C 28 H 2 ιN 2 O 5 H 2 O Calculated C,64 8, H,4 47, N,5 40, Found C,64 47, H,4 13, N,5 60% Example 92 (E)-1 -f1 -(3 4-Methylenedιoxyphenyl)-1 3,4 9-tetrahydro-β-carbolιn-2-yl.-3-(3 5- dιbromo-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dιbromo-4-hydroxy cinnamic acid gave after recrystallization from EtOH H 2 O the title compound as white crystals in a 13% yield MP 148-150 °C Analysis for C 27 H 20 N 2 O 4 Br 2 1 6EtOH Calculated C,54 14, H,4 45, N,4 18, Found C,54 1 , H,4 15, N,3 77% Example 93 (E)-1-f1-(3.4-MethylenedιoχyphenylM 3.4 9-tetrahydro-β-carbolιn-2-vn-3-(4-(2- dιmethylamιnopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and dimethylammopropyl chloride gave after recrystallization from cyclohexane DCM pentane the title compound as white crystals in a 16% yield MP 106 °C Analysis for C 32 H 33 N 3 O 4 0 3H 2 O Calculated C,72 65, H,6 40, N,7 94, Found C,72 74 , H,6 56, N,7 63% Example 94 (EV2-Chloro-5-f3-oxo-3-[ 1 -(3,4-methylenedιoxyphenyl)-1 3 4,9-tetrahydro-β- carbolιn-2-vπpropenvπbenzoιc acid methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 33 gave after recrystallization from MeOH DCM the title compound as a white powder in a 59% yield MP 228 X Analysis for C 29 H 23 CIN 2 O 5 1 05H 2 O Calculated C,65 24, H,4 74, N,5 25, Found C.64 91 , H,4 27, N,5 13% Example 95 (E)-1 -f 1 -(3,4-Methylenedιoxyphenyl)-1 ,3,4,9-tetrahvdro-β-carbolιn-2-yll-3-(4-(2- dιιsopropylamιnoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and diisopropylaminodiethyl chloride gave after recrystallization from MeOH H 2 O the title compound as pale yellow crystals in a 12% yield MP 92-93 X Analysis for C 35 H 39 N 3 O 4 Calculated C,74 31 , H,6 95, N,7 43, Found C,74 34, H,7 16, N,7 10% Example 96 fE)-2-Chloro-5-,3-oxo-3-f1 -(3 4-methylenedιoxyphenvP-1.3 4 9-tetrahvdro-β- carbolιn-2-vHpropenvπbenzoιc acid The same method as employed in the preparation of Example 31 but starting from Example 94 gave after recrystallization from MeOH the title compound as white crystals in a 78% yield MP 178 X Analysis for C 28 H 21 N 2 O 5 0 7MeOH Calculated C,65 86, H,4 58, N,5 35, Found C, 65 73 , H, 4 44 , N, 5 51 % Example 97 (E)-1 -f1 -(3 4-MethylenedιoxyphenvP-1 3,4 9-tetrahydro-β-carbolιn-2-yl]-3-(3- hydroxy-4-nιtrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 34 gave after recrystallization from EtOH the title compound as yellow crystals in a 77% yield MP: 172 X. Example 98 (E)-1-f1-(3.4-MethylenedιoxyphenvP-1 ,3,4.9-tetrahvdro-β-carbolιn-2-yll-3-(3 5- dimethyl-4-hvdroxyphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 35 gave after recrystallization from MeOH H 2 O the title compound as a white powder in a 71 % yield MP: 151 -152 X Analysis for C 29 H 26 N 2 0 4 . 0 4H 2 O: Calculated. C,73.52, H.5.7, N.5.91 , Found: C,73 56, H.5.59; N 6.29%. Example 99 (EM -f 1 -(3 4-MethylenedιoxyphenylM 3 A9-tetrahvdro- β -carbolιn-2-yl 1-3-f 3-(2- dιmethylamιnoethoxy)-4-nιtrophenvPpropene-1-one The same method as employed in the preparation of Example 79 but starting from Example 97 and dimethylaminodiethyl chloride gave after recrystallization from MeOH the title compound as a pale yellow powder in a 18% yield MP: 189 X. Analysis for C 31 H 30 N 4 O 6 . 1.5H 2 O: Calculated: C,64.02; H.5.72, N.9.63, Found. C,64 18, H.5.41 , N,9.21 %. Example 100 (EM -fl -(3 4-Methylened.oxyphenylM ,3,4,9-tetrahydro-β-carbolιn-2-vn-3-(3-(2- dιmethylamιnoethoxy)-4-amιnophenyl)propene-1 -one The same method as employed in the preparation of Example 64 but starting from Example 99 gave after recrystallization from iPr 2 0 the title compound as a pale yellow powder in a 17% yield MP 143 X Analysis for C 3 ιH 32 N 4 O 4 0 5H 2 O Calculated: C,69.78 ;H,6.23; N.10.5, Found: C,69 87; H,5.98; N.10 42%. Example 101 (EM -H -(3 4-MethylenedioxyphenvP-1 3 4.9-tetrahydro-β-carbolιn-2-yll-3-(3- nitroA-hydroxy-5-methoxyphenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 36 gave after recrystallization from EtOH. DCM the title compound as pale yellow crystals in a 45% yield MP: 172 X. Analysis for C 28 H 23 N 3 O 7 0.8H 2 O. Calculated. C,63.7; H.4.7, N.7.96, Found: C.63.71; H.4.31 ; N,7.98%. Example 102 (EM-H-O 4-MethylenedιoxyphenvP-1 3.4 9-tetrahvdro-β-carbolιn-2-yl .-3-(3- chloro-phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-3-chlorocinnamιc acid, gave after recrystallization from EtOH the title compound as white crystals in a 48% yield MP: 212-213 X. Analysis for C 27 H 2 ιCIN 2 O: Calculated: C.70.97; H.4.63, N.6.13 Found: C.70.65; H.4.63; N,6 16%. Example 103 (EM 41 -(4-Methoxy-phenylM .3.4,9-tetrahvdro-β-carbolιn-2-yll-3-(2-chloro-5- nitrophenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-2-chloro-5-nιtrocιnnamιc acid gave after recrystallization from 2-propanol the title compound as a yellow powder white in a 18% yield. MP- 136-138 X Analysis for C 27 H 22 CIN 3 O 4 0.2H 2 O Calculated. C,65 98; H,4 59, N.8.55, Found C,65 91 , H,4 4, N,8 42% Example 104 (EM 41 -(3 4-Methylenedιo χ yphenylM .3.4,9-tetrahvdro-β-carbolιn-2-yll-3-(2 6- dιchlorophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-2,6-dιchlorocιnnamιc acid gave after recrystallization from cyclohexane the title compound as a white powder in a 41 % yield MP 118-120 X Analysis for C 27 H 20 CI 2 N 2 O 3 0 2H 2 O Calculated C,65 52, H,4 15, N,5 66, Found C,65 74, H,4 62, N,5 29% Example 105 (EM 41 -(3 4-MethylenedioxyphenylM .3 A9-tetrahvdro-β-carbolιn-2-yl .-344- methylamιnomethylphenyPpropene-1 -one A solution of (E)-1-[1 -(3,4-methylenedιoxyphenyl)-1 ,3,4,9-tetrahydro-β-carbolιn- 2-yl]-3-(4-methylιmιnomethylphenyl)propene-1-one (0 46 g, 1 1 mmol), NaBH 3 CN (0 14 g, 2 3 mmol) and acetic acid (0 11 mL) in 20 mL of MeOH was stirred at rt for one hour The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHCO 3 Extraction with 2x30 mL of DCM, washing with brine, drying over Na 2 SO 4 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM MeOH (97 3) as eluting solvent Recrystallization from DCM cyclohexane gave the title compound (0 05 g, 10%) as a white powder MP 201 X Analysis for C 29 H 27 CI 2 N 3 O 3 0 5H 2 O Calculated C,73 4, H,5 95, N,8 85, Found C 73 66, H.5 82, N,8 57% A stirred solution of Example 23 (0 5 g, 1 0 mmol) in MeOH was refluxed with methylamine (1 6 mL, 1 5 equiv , 33% in EtOH) for one hour Evaporation in vacuo gave (E)-1 -[1 -(3 4-methylenedιoxyphenyl)-1 3,4,9-tetrahydro-β-carbolιn- 2-yl]-3-(4-methylιmιnomethylphenyl)propene-1-one (0 46 g, 90%) 1 H NMR (CDCI 3 , 250 MHz) δ 8.2 (d, 1 H), 8.1 (s, 1 H), 7.8-7 65 (m, 3H), 7.55-7.5 (m, 3H), 7 4-7.1 (m, 3H), 7.0-6.85 (m, 2H), 6.8-6.6 (dd, 2H), 5 9 (s, 2H), 4.2A 1 (br d, 1 H), 3.5 (s+m, 4H), 3.05-2.85 (m, 2H). Example 106 (E)-14143.4-MethylenedioxyphenylM .3 4.9-tetrahvdro-β-carbolιn-2-vH-343- methylphenvP-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methyicinnamic acid gave after recrystallization from MeOH the title compound as a white powder in a 67% yield. MP: 196 X. Analysis for C 28 H 24 N 2 O 3 Calculated: C.77.04; H.5.54; N.6.62, Found. C.76.76; H.5.56; N,6.33%. Example 107 (E.-N-Methyl-(4-.3-oxo-3- ( 1- ( 3 4-methylenedιoxyphenylM .3 4.9-tetrahvdro-β- carbolin-2-vPpropenyllbenzenesulfonamide The same method as employed in the preparation of Example 20 but starting from (E)A-(N-methylsulfonamide)cιnnamιc acid gave after recrystallization from EtOH H 2 O the title compound as white crystals in a 79% yield MP: 162 X. Analysis for C 28 H 25 N 3 O 5 0.4EtOH: Calculated: C.64.78; H.5.17; N.7.87, Found: C,64.46; H,4.82; N,7.76% Example 108 (EM 4143.4-MethylenedioxyphenvP-1.3 4.9-tetrahvdro-β-carbolin-2-yll-3-(3- hvdroxyA-acetylphenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxyA-acetylcinnamιc acid gave after recrystallization from EtOH the title compound as yellow crystals in a 87% yield MP: 217-218 X. Analysis for C 29 H 24 N 2 O 5 Calculated C,72 49, H,5 03, N.5.83 Found C.72 24 H,5 25, N,5 53% Example 109 (EM 41 -(2 3-Dιhvdrobenzofuran-5-vP-1 3 4,9-tetrahvdro-β-carbolιn-2-yll-342- chloro-5-nιtrophenyppropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-2-chloro-5-nιtrocιnnamιc acid gave after recrystallization from EtOH H 2 O (95 5) the title compound as yellow crystals in a 62% yield MP 154 X Analysis for C 27 H 22 CIN 3 0 4 0 5(H 2 0 MeOH) Calculated C,66 08, H,4 55, N,8 36, Found C,66 3, H,4 52, N,7 94% Example 110 (EM 4143 4-MethylenedιoxyphenvP-1 3.4.9-tetrahydro-β-carbolιn-2-yll-342- hydroxyphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-2-hydroxy cinnamic acid gave after recrystallization from EtOH H 2 0, the title compound as white crystals in a 47% yield, MP 154 X Analysis for C 27 H 22 N 2 O 4 06H 2 O Calculated C,72 18, H,5 2, N,6 24, Found C,72 19, H,4 93, N,6 13% Example 111 (EM 41 -(3,4-MethylenedιoxyphenylM 3,4,9-tetrahvdro-β-carbolιn-2-yll-343- nιtro-2-piperιdιn-1 -ylphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 37 gave after recrystallization from MeOH the title compound as yellow crystals in a 31 % yield MP 162-163 X Analysis for C 32 H 30 N 4 O 5 0 2H 2 O Calculated C,65 52, H,5 84, N,9 55, Found C,65 9, H,5 49, N,9 59%. Example 112 (EM41-(2.3-Dihvdrobenzofuran-5-ylM .3.4.9-tetrahvdro-β-carbolιn-2-yll-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 10 gave after recrystallization from EtOH the title compound as white crystals in a 52% yield. MP: 190 X. Analysis for C 28 H 2-1 N 2 O 2 : Calculated: C.79.98, H.5.75; N.6.66; Found. C.79.94; H 5.86, N,6.62%. Example 113 (E)-14144-lsopropylphenvP-1.3,4.9-tetrahvdro-β-carbolιn-2-vn-343- nitrophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 11 and (E)-3-nιtrocιnnamιc acid gave after recrystallization from EtOH the title compound as yellow crystals in a 54% yield. MP- 195 X Analysis for C 29 H 27 N 3 0 3 Calculated: C,74 82, H.5.85; N.9.03, Found: C.74.43; H 5.84; N,9 17%. Example 114 (EM 4142,3-Dihvdrobenzofuran-5-ylM .3 A9-tetrahvdro-β-carbolιn-2-yl 1-343- nιtrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-3-πιtrocιnnamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 35% yield MP: 174-176 X. Analysis for C 28 H 23 N 3 O 4 . 0.1 H 2 O Calculated. C.71 97, H.5.0; N.8.99; Found: C.71.78, H 4 89, N,8 83% Example 1 15 (E)4R)-14143.4-MethylenedιoxyphenvP-1 3 4 9-tetrahvdro-β-carbolιn-2-yll-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 19 gave after recrystallization from EtOH the title compound as white crystals in a 60% yield MP: 232-233 X. Analysis for C 27 H 22 N 2 O 3 0.2H 2 O. Calculated: C.76.11 ; H.5.3; N.6.57; Found: C.76.2; H.5.27, N,6.77% [α] D 21 = -336 (c = 0.50, MeOH) Example 116 (E)4S)-14143.4-MethylenedioxyphenvP-1 3 4.9-tetrahvdro-β-carbolιn-2-vn-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 18 gave after recrystallization from iPrOH the title compound as white crystals in a 32% yield MP: 235-236 X. Analysis for C 27 H 22 N 2 O 3 0 1 H 2 O Calculated. C.76.43; H.5.27; N.6.6, Found: C, 76.26; H.5.21 ; N,6.61 %. [α]Q 21 = 378 (c = 0 5, MeOH) Example 117 (E)-14144-MethoxyphenvP-1.3 4,9-tetrahvdro-β-carbo1ιn-2-yl1-3(3- nitrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-3-nitrocιnnamιc acid gave after recrystallization from EtOH the title compound as yellow crystals in a 63% yield MP. 227 X Analysis for C 27 H 23 N 3 O 4 0 1 EtOH Calculated C.71.32, H,5 19, N,9 17, Found. C.70.96, H,5 14, N,9.23% Example 118 .ΕM-ri-f4-MethvlDheπvlM 3 4 9-tetr a hvdro-β-carbolin-2-vπ-3-r2-chloro-5- nitroDhenvnpropenβ-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 6 and (E)-2-chloro-5-nitrocinnamic acid gave after 5 recrystallization from EtOH the title compound as a yellow powder in a 57% yield. MP: 211 -213 X. Analysis for C 27 H 23 CIN 3 O 3 : Calculated: : C.68.72; H.4.7; N.8.9; 10 Found: C.68.42; H.4.73; N,8.91 %. Example 119 ■ E>-N-rTetrahydrofuran-2-ylmethyl.-3-[3-oxo-3-M-.3.4-methylenedioxyV1.3.4.9- tetrahydro-β-carbolin-2-yl)propenyl1benzamide 15 The same method as employed in the preparation of Example 20 but starting from Example 70 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as a white powder in a 30% yield. MP: 172-173 X. Analysis for C 33 H 31 N 3 0 5 . 0.4H 2 O: 20 Calculated: C.71.18; H.5.76; N.7.55; Found: C-,71.1 ; H.5.88; N,7.45%. Example 120 fEV1-ri-nndan-5-vh-1 .3.4.9-tetrahvdro-B-earbolln-2-vn-3-phenvlpropene-1-one 25 The same method as employed in the preparation of Example 1 but starting from Intermediate 9 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as white crystals in a 51% yield. MP: 223 X. Analysis for C 29 H 26 N 2 0. 0.4H 2 O: 30 Calculated: C,81.81 ; H.6.34; N.6.58; Found: C.81.87; H,6.34; N,6.5%. Example 121 (ΕV1 -f1-f3.4-MethvlenedioxvDhenvlV1.3.4.9-tetrahvdro-B-carbolln-2-vn.3-f3- •35 acetylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from 3-acetylcιπnamιc acid (prepared according to the procedure of Cleland.G H J Org Chem 1969, 34, 1AA-1Λ1) gave after recrystallization from EtOH the title compound as a yellow powder in a 42% yield MP 191 X Analysis for C 29 H 24 CIN 2 O 4 Calculated C,74 98, H,5 21 , N,6 03, Found C,74 85, H,5 28, N,6 1 % Example 122 (E)-14142 3-Dιhvdrobenzofuran-5-vP-1 3 4.9-tetrahvdro-β-carbolιn-2-vPl-3-(4- (2-dιmethylamιnoethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 25 gave after recrystallization from CH 3 CN the title compound as white crystals in a 37% yield MP 146 X Analysis for C 32 H 33 N 3 O 3 1 5H 2 O Calculated C,71 89, H,6 79, N,7 86, Found C,72 04, H,7 09, N,7 93% Example 123 (E)A43-Oxo-34144-methoχyphenvP-1 .3.4 9-tetrahvdro-β-carbolιn-2- yllpropenynbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)A-(2-carboxyvιnyl)benzoιc acid, methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 73% yield MP. 189 X Analysis for C 29 H 26 N 2 O 4 0 1 EtOH Calculated C,74 44, H,5 69, N,5 95, Found C,74 1 , H, 5 65, N,6 01 % Example 124 (EM 4143 4-MethylenedιoxyphenvP-1 3 4,9-tetrahydro-β-carbolιn-2-vn-3-(4- methyl-3 4-dιhvdro-2H-benzof1 ,4loxazιn-6-yppropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 38 gave after recrystallization from EtOH the title compound as yellow crystals in a 69% yield MP 231-232 X Analysis for C 29 H 26 N 2 O 4 0 1 EtOH Calculated C,73 01 , H,5 51 , N, 8 51 , Found C,72 54, H,5 58, N,8 44% Example 125 (EM 4143 4-MethylenedιoxyphenvP-1 3.4 9-tetrahvdro-β-carbolιn-2-yll-3-(2- hvdroxy-5-nιtrophenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 39 gave after recrystallization from EtOH the title compound as yellow crystals in a 30% yield MP 205 X Analysis for C 27 H 21 N 3 O 6 0 6EtOH Calculated C,65 78, H,5 14, N,7 94, Found C,65 52, H,4 98, N,8 04% Example 126 (E)A43-Oxo-34142.3-dιhvdrobenzofuran-5-vP-1 3.4 9-tetrahvdro-β-carbolιn-2- yllpropenyllbenzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)A-(2-carboxyvιnyl)benzoιc acid, methyl ester gave after recrystallization from EtOH the title compound as white needles in a 88% yield MP 186 X Analysis for C 30 H 26 N 2 O 4 0 2H 2 O Calculated C,74 73, H,5 52, N,5 81 , Found C,75 45, H, 5 38, N,6 07% Example 127 (E)A43-Oxo-34144-methoxyphenvP-1 3 4 9-tetrahvdro-β-carbolιn-2- yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 123 gave after recrystallization from MeOH H 2 0 the title compound as a grey powder in a 43% yield MP- 147-149 X Analysis for C 28 H 24 N 2 O 4 Calculated C.74.32, H.5.35, N,6 19, Found C,74 3, H.5.37, N,6.07% Example 128 . E)A43-Oxo-34142.3-dihvdrobenzofuran-5-vP-1.3.4 9-tetrahydro-β-carboiιn-2- yllpropenynbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 126 gave after recrystallization from MeOH the title compound as white crystals in a 53% yield MP. 222-224 X Analysis for C 29 H 24 N 2 O 4 Calculated. C, 74.98, H.5.21 , N,6 03, Found C.75 21 , H.5.3, N.6.21 % Example 129 (E)-1414Benzofuran-5-vP-1 3 4 9-tetrahvdro-β-carbolιn-2-yll-3-phenylpropene- 1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 12 gave after recrystallization from EtOH the title compound as white crystals in a 35% yield MP 241-242 X Analysis for C 28 H 22 N 2 O 2 Calculated C, 80.36, H,5 3, N,6 69, Found C,8044, H,5 3, IM.6 89% Example 130 (EV343-Oxo-34143,4-methylenedιoχyphenvP-1 3 4.9-tetrahydro-β-carbolιn-2- vP-propenyllphenvPtrifluoromethanesulfonic acid, phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 40 gave after recrystallization from EtOH the title compound as white crystals in a 38% yield MP 169 X Analysis for C 28 H 21 F 3 N 2 O 6 S 0 2H 2 O Calculated C,58 58, H,3 76, N,4 88, Found C,58 84, H,3 71 , N,4 3% Example 131 (E)-141 -(3.4-MethylenedιoχyphenvP-1 ,3.4 9-tetrahvdro-β-carbolιn-2-vn-34442- hvdroxyethoxy)phenvnpropene-1-one The same method as employed in the preparation of Example 20 but starting from (E)A-(2-hydroxyethoxy)phenyl (prepared according to the procedure of Oku,T , Kayakin.H , Satoh.S , Abe.Y , Sawada.Y , Inoue.T , Tanaka.H EP 622361) gave after recrystallization from EtOH the titie compound as white crystals in a 57% yield MP 136 X Analysis for C 29 H 26 N 2 O 5 1 2EtOH Calculated C 58 58 H,3 76, N,4 88, Found C,58 84, H.3 71 , N,4 3% Example 132 (E)-1414Benzofuran-5-yl-1 ,3.4,9-tetrahvdro-β-carbolιn-2-vP1-344-(2- dιmethylamιnoethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and Intermediate 25 gave after recrystallization from CH 3 CN the title compound as white crystals in a 23% yield MP 159 X Analysis for C 32 H 31 N 3 O 3 0 1 H 2 O Calculated C,75 75, H,6 2, N,8 28, Found C,75 58, H,5 97, N,8 35% Example 133 (E)-14143.4-Methylenedιoχyphenyl)-1 3 4 9-tetrahvdro-β-carbolιn-2-yll-342- dιmethylamιnophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2-dιmethylamιnocιnnamιc acid (prepared according to the procedure of Suschitzky.H., Hollywood, F. Synthesis 1982, 662-665) gave after recrystallization from MeOH H 2 O the title compound as a yellow powder in a 51 % yield. MP- 172 X Analysis for C 29 H 27 N 3 O 3 Calculated: C.74.82; H.5.85, N.9.03, Found. C.74.75, H,5 85, N,8 9%. Example 134 (EM 41 -(3.4-MethylenedιoxyphenvP-1 ,3 4.9-tetrahvdro-β-carbolιn-2-vn-342- pιperidιn-1 -ylphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from (E)-2-pιperιdιn-1 -ylcιnnamιc acid (prepared according to the procedure of Suschitzky.H , Hollywood, F Synthesis 1982, 662-665) gave after recrystallization from MeOH H 2 O the title compound as a yellow powder in a 37% yield. MP. 129 X. Analysis for C 32 H 31 N 3 O 3 Calculated C.76.02, H,6 18, IM.8.31 , Found- C-,75 66, H,6 18, N,8.29% Example 135 (E)A43-Oxo-341 -(benzofuran-5-yl-1 3 4 9-tetrahvdro-β-carbolιn-2-yll-propenvn- benzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and (E)A-(2-carboxyvιnyl)benzoιc acid methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 76% yield MP 221 X Analysis for C 30 H 24 N 2 O 4 Calculated C,75 62, H,5 08, N,5 88, Found C,75 75, H,5 31 , N,5 86% Example 136 (E)A43-(1-Benzofuran-5-yl-1 3 4 9-tetrahvdro-β-carbolιn-2-vP-3-oxo-propenyll- benzoic acid The same method as employed in the preparation of Example 31 but starting from Example 135 gave after recrystallization from CH 3 CN the title compound as yellow crystals in a 66% yield MP 283 X Analysis for C 29 H 22 N 2 O 4 0 6H 2 O Calculated C,73 59 H,4 94, N,5 92, Found C,73 48, H 4 78, N,5 93% Example 137 (E)A43-Oxo-34143 4-methylenedιoxyphenylM 3.4,9-tetrahydro-β-carbolιn-2- yPpropenyllphenyπtrifluoromethanesulfonic acid phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 41 gave after recrystallization from EtOH the title compound as white crystals in a 51 % yield MP 254 X Analysis for C 28 H 21 F 3 N 2 O 6 S Calculated C, 58 95 H, 3 71 , N,4 91 , Found C,58 79, H 3 8, N,4 77% Example 138 (E)-141-(3 4-MethylenedιoxyphenvP-1 ,3.4.9-tetrahvdro-β-carbolιn-2-yll-3-(2-(2- dιmethylamιnoethoxy)phenyl)propene-1 -one The same method as employed in the preparation of Example 79 but starting from Example 1 10 and dimethylammodiethyl chloride gave after recrystallization from CH 3 CN pentane the title compound as yellow crystals in a 70% yield MP 131 X Analysis for C 31 H 31 N 3 O 4 1 3H 2 O Calculated C,68 95 H 6 35, N,7 88 Found C,69 77 H 6 28, N,7 84% Example 139 (E)-14143-FluoroA-methoxyphenvP-1 3 4 9-tetrahvdro-β-carbolιn-2-yll-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 14 gave after recrystallization from DCM cyclohexane the title compound as white crystals in a 66% yield MP 122 X Analysis for C 27 H 23 FN 2 O 2 0 4CH 2 CI 2 Calculated C.71 47, H,5 21 , N,6 08, Found C,71 46, H,5 27, N,6 12% Example 140 (E)4R)-141 -(2 3-Dιhvdrobenzofuran-5-vP-1 3 4 9-tetrahvdro-β-carbolιn-2-vPl-3- (442-dιmethylamιnoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 25 gave after recrystallization from CH 3 CN the title compound as white crystals in a 85% yield MP 187-189 X Analysis for C 32 H 3 3N 3 O 3 Calculated C,75 71 , H,6 55, N 8 20, Found C,75 60, H,6 76, N,8 10% [α]D 2l = -310 (c = 0 40, CHCI 3 ) Example 141 (EM 42,3-DιhvdrobenzoH .4ldιoxιn-6-vP-1.3,4.9-tetrahvdro-β-carbolιn-2-yll-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after recrystallization from EtOH the title compound as white crystals in a 39% yield MP 216 X Analysis for C 28 H 24 N 2 O 3 06H 2 O Calculated C.75 18, H,5 68, N,6 26, Found C 75 17, H.5 41 , N,6 4%. Example 142 (EM 4142 3-Dιhvdrobenzofuran-5-vP-1 3 4 9-tetrahvdro-β-carbolιn-2-yl .1-344- (2-pyrrolιdιn-1 -ylethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 42 gave after recrystallization from 2- propanoi ιPr 2 O the title compound as white crystals in a 26% yield MP 152 X Analysis for C3 4 H 35 N 3 O3 0 5H 2 O Calculated C,75 25, H,6 69, N,7 74, Found C,75 31 , H,6 6, N,7 69%. Example 143 (EM 4143 4-MethylenedιoxyphenvP-1 3,4 9-tetrahvdro-β-carbolιn-2-yll-344- pyrrolιdιn-1 -ylphenyllpropene-l -one The same method as employed in the preparation of Example 20 but starting from Intermediate 43 gave after recrystallization from EtOH H 2 0 the title compound as white crystals in a 73% yield MP 154 X Analysis for C 3 iH 29 N 3 O 3 0 6H 2 O Calculated C,74 11 , H,6 06, N,8 36, Found C, 74.22, H,5 97, N,7 97%. Example 144 (E)4R)-14142.3-Dιhvdrobenzofuran-5-vP-1 ,3 4 9-tetrahvdro-β-carbolιn-2-vH-3- (3-nιtrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-nιtrocιnnamιc acid gave after recrystallization from EtOH the title compound as yellow crystals in a 51 % yield MP 155 X Analysis for C 28 H 23 N 3 O 4 Calculated C,72 25, H,4 98, N,9 03, Found C.72 2, H,5 0, N,9 01 %. [α]D 19 = -347 (c = 0 33, MeOH) Example 145 (E)-14143.4-MethylenedιoχyphenvP-1.3.4.9-tetrahvdro-β-carbolιn-2-vn-3-f4- imιdazol-1 -ylphenyllpropene-l -one The same method as employed in the preparation of Example 20 but starting from Intermediate 44 gave after recrystallization from EtOH the title compound as white crystals in a 69% yield. MP: 204 X. Analysis for C 3 oH 24 N 4 O 3 . 0.6H 2 O: Calculated: C, 72.68; H.5.04; N.1 1.3; Found: C,72.67; H.4.85; N, 11.34%. Example 146 (E)A434142.3-Dihvdrobenzof1.4ldioxin-6-ylM .3.4.9-tetrahvdro-β-carbolιn-2- vn-3-oxopropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)A-(2-carboxyvinyl)benzoιc acid, methyl ester gave after recrystallization from MeOH the title compound as a white powder in a 35% yield. MP: 136 X. Analysis for C 30 H 26 N 2 O5. 0.1 H 2 O. Calculated: C.72.6, H.5.32, N, 5.64; Found. C, 72.31 , H.5.26; N,5 74% Example 147 (EM 4142.3-Dihvdrobenzof 1 4ldioxιn-6-vP-1 ,3 ,4,9-tetrahvdro-β-carbolin-2-vn-3- (3-nitrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)-3-nιtrocinnamic acid gave after recrystallization from EtOH the title compound as a pale yellow powder in a 93% yield. MP: 154 X. Analysis for C 28 H 23 N 3 O 5 . 0.6H 2 O. Calculated. C,68 31 , H,4.95; N.8.54, Found. C.68.41 , H,4 87; N,8.61% Example 148 (EM41 -(2 3-DιhvdrobenzoH 4.dιoxιn-6-ylM 3 4 9-tetrahydro-β-carbolιn-2-yl)l- 344-(2-dιmethylamιnoethoxy)phenyPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and Intermediate 25 gave after recrystallization from CH 3 CN the title compound as a white powder in a 65% yield MP 145 X Example 149 (E)-141-(3-FluoroA-methoxyphenvP-1 3 4 9-tetrahvdro-β-carbolιn-2-vP]-34442- dιmethylamιnoethoxy)phenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and Intermediate 25 gave after recrystallization from ιPr 2 O the title compound as a white powder in a 60% yield MP 103 X Analysis for C 3 ιH 32 FN 3 θ 3 0 4H 2 O Calculated C.71 49, H,6 35, N,8 07, Found C.71 4, H,6 51 , N,8 04% Example 150 (EV44341-(2.3-Dιhvdrobenzoπ 41dιoxιn-6-yl)-1 3 4 9-tetrahydro-β-carbolιn-2- vn-3-oxopropenyllbenzoιc acid The same method as employed in the preparation of Example 31 but starting from Example 146 gave after recrystallization from MeOH the title compound as a white powder in a 93% yield MP 253 X Analysis for C 29 H 24 N 2 O 5 0 7H 2 O Calculated C.70 63, H,5 19, N,5 68, Found C,70 78, H,5 09, N,5 72% Example 151 (E)4R)-14142 3-Dιhvdrobenzofuran-5-vP-1.3 4 9-tetrahydro-β-carbolιn-2-vn-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 20 gave after recrystallization from MeOH the title compound as white crystals in a 100% yield MP 267 X Analysis for C 28 H 24 N 2 O 2 Calculated C,79 98, H,5 75, N,6 66, Found C,79 86, H,5 89, N,6 72% [α] D 22 = -362 (c = 0 35, CHCI 3 ) Example 152 (E)4S)-141 -(2 3-Dιhvdrobenzofuran-5-yl)-1 3.4.9-tetrahvdro-β-carbolιn-2-vPV3- (4-(2-dιmethylamιnoethoxy)phenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and Intermediate 25 gave after recrystallization from CH 3 CN the title compound as beige crystals in a 79% yield MP 153 X Analysis for C 32 H 33 N 3 O 3 0 5H 2 O Calculated C, ,74 39, H,6 63, N,8 13, Found C 74 36, H,6 69, N,8 44% [α} D 21 = 314 (c = 0 40, CHCI 3 ) Example 153 (EM 4142 3-Dιhvdrobenzofuran-5-vP-1.3 4.9-tetrahvdro-β-carbolιn-2-vn-344- amιnophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)A-amιnocιnnamιc acid gave after recrystallization from iPrOH the title compound as white crystals in a 43% yield MP 183 X Analysis for C 30 H 31 N 3 O 2 1 6H 2 O Calculated C,76 59, H,5 83, 9 57, Found C,76 62, H,5 82, N,9 59% Example 154 (E)-(SM 4142 3-Dιhydrobenzofuran-5-vP-1 ,3.4,9-tetrahvdro-β-carbolιn-2-vn-3- phenylpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 21 gave after recrystallization from EtOH the title compound as white crystals in a 98% yield MP. 266 X Analysis for C 28 H 24 N 2 O 2 0.2H 2 O. Calculated C.79.30, H,5.80; N.6 61 ; Found: C.79.24, H,5 92; N,6 48%. [α]D 20 = 356 (c = 0.35, CHCI 3 ) Example 155 (E)4S)-141-(2 3-Dihvdrobenzofuran-5-vP-1.3 4 9-tetrahvdro-β-carbolιn-2-yll-3- (3-nitrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and (E)-3-nιtrocιnnamιc acid gave after recrystallization from 2-propanol the title compound as yellow crystals in a 77% yield MP. 143 X. Analysis for C 28 H 23 N 3 0 4 0.3H 2 O Calculated- C.71 42, H,5 05; N.8.92, Found. C,71 51 , H.4.98, N,9.23% [α]o 19 = 294 (c = 0 30, CHCI 3 ) Example 156 (EHRM4142.3-Dihvdrobenzofuran-5-vP-1.3 4 9-tetrahvdro-β-carbolιn-2-vP1-3- (4-(14S)-methylpyrrolιdιn-2-yl-methoxy)phenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 45 gave after recrystallization from 2- propanol the title compound as white crystals in a 73% yield MP 167 X. Analysis for C H^^O;, Calculated. C.76.52, H,6 61 , N,7 87, Found. C,76 13, H, 6 71 , N,7.96% [α] D 20 = -344 (c = 0 30, CHCI 3 ) Example 157 (E)-(R)-14142.3-Dιhvdrobenzofuran-5-ylM 3 4 9-tetrahvdro-β-carbolιn-2-vn-3- (3-hydroxyphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-hydroxycιnπamιc acid gave after recrystallization from EtOH the title compound as white crystals in a 93% yield MP 251 X Analysis for C 28 H 24 N 2 O 3 0 8H 2 O Calculated C,74 58, H,5 72, N,6 21 , Found C,74 58, H,5 65, N,6 17% [α]o 21 = -342 (c = 0 53, CHCI 3 ) Example 158 (EHR)-14142 3-Dihydrobenzofuran-5-vP-1 34 9-tetrahydro-β-carbolιn-2-vP]-3- (442-dιmethylamιno-1 -methylethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 46 gave after recrystallization from CH 3 CN the title compound as white crystals in a 100% yield MP 193 X Analysis for C 3 3H 35 N 3 O 3 0 45H 2 O Calculated C,74 82, H,6 83, N,7 93, Found C,74 85, H, 6 76, N,8 21 % Example 159 (EM41-Phenyl-1.3 4,9-tetrahvdro-β-carbolιn-2-vP-344-(4-methylpyperazιn-1 - vP-phenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 1 and Intermediate 47 gave after recrystallization from EtOH the title compound as pale yellow crystals in a 26% yield MP 223-226 X Analysis for C 32 H 32 N 4 O 3 0 4H 2 O Calculated C.72 82, H.6 26, N.10 61 , Found C,72 77, H.6 31 , N,10 52% Example 160 (EHR)-141 -(3,4-MethylenedιoxyphenvP-1 3 4 9-tetrahydro-β-carbolιn-2-vP1-3- (4-(1 -(S)-methylpyrrolιdιn-2-yl-methoxy)phenyPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 45 gave after recrystallization from ιPr 2 0 the title compound as white crystals in a 83% yield MP 164 X Analysis for C 33 H 33 N 3 O 4 0 9H 2 O Calculated C.71 82, H,6 36, N,7 61 , Found C,72 05, H,6 57, N,7 24% [α] D 21 = -285 (c = 0 40, CHCI 3 ) Example 161 (EMRM-.143 4-Methv.enedιoxyphenylM 3.4 9-tetrahydro-β-carbolιn-2-vPl-3- (442-dιmethylamιno-1 -methylethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 46 gave after recrystallization from ιPr 2 0 the title compound as white crystals in a 56% yield MP 107 X Analysis for C 32 H 33 N 3 O 4 0 7H 2 O Calculated C.71 67, H,6 47, N,7 84, Found C,71 6, H 6 53, N,7 97 % Example 162 (EV(R)-14143.4-MethylenedιoxyphenvP-1 ,3 4 9-tetrahvdro-β-carbolιn-2-vPV3- (4-(2-dιmethylamιnopropoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 48 gave after recrystallization from ιPr 2 O the title compound as white crystals in a 78% yield MP 193 X Analysis for C 32 H 33 N 3 O 4 1 6H 2 O Calculated C,69 57, H,6 6, N,7 61 , Found C,6946, H 6 59, N,7 33% [α]D 21 = -266 (c = 0 40 CHCI 3 ) Example 163 (E)-443-Oxo-3-f143 4-fluorophenylM 3 4 9-tetrahvdro-β-carbolιn-2-vn- propenyllbenzoic acid methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 15 and (E)A-(2-carboxyvιnyl)benzoιc acid, methyl ester gave after recrystallization from EtOH H 2 0 the title compound as a yellow powder in a 100% yield MP. 200 X Analysis for C 2 8H 22 F 2 N 2 O 3 Calculated C,71 18, H,4 69, N,5 93, Found C,71 21 , H,4 77, N,6 03% Example 164 (E)4R)4142 3-Dihvdrobenzofuran-5-vP-1.3 4 9-tetrahydro-β-carbolιn-2-vP1-344- (2-dιethylamιnoethoxy)phenvDpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-(4-(2-dιethylamιnoethoxy)phenyl)acrylιc acid (prepared according to the procedure of Sharpe.C J , Shabolt.R S , Brown, G R , Ashford.A , Ross.J W J Med Chem 1971, 14, 836-842), gave after recrystallization from CH 3 CN the title compound as white crystals in a 80% yield MP 193 X Analysis for C Hs^sOs 0 6H 2 O Calculated. C, 74.73, H,7 05; N,7 69, Found C,74.53, H, 6 91 , N,7 68% [α]D 20 = -311 (c = 0.30, CHCI 3 ) Example 165 (E)4R)-14142 3-Dihvdrobenzofuran-5-vP-1 3.4 9-tetrahydro-β-carbolιn-2-vP1-3- (442-dιmethylamιnopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 48 gave after recrystallization from CH 3 CN the title compound as white crystals in a 79% yield MP 193 X Analysis for C 33 H 35 N 3 O 3 Calculated C,75 98, H,6 76, N,8 06, Found C.76 24, H 6 76, N, 8 21% [cx] D 20 = -293 (c = 0 40, CHCI 3 ) Example 166 (E)A43-Oxo-34143.4-difluorophenvP-1.3.4.9-tetrahvdro-β-carbolin-2- yllpropenvπbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 163 gave after recrystallization from MeOH:H 2 O the title compound as a white powder in a 100% yield. MP: 172 X. Analysis for C 27 H 20 F 2 N 2 O 3 : Calculated: C.68.06; H.4.65; N,5.88; Found: C.68.15; H.4.55; N.5.99%. Example 167 (EWRV14142.3-Dihvdrobenzofuran-5-vP-1 ,3.4.9-tetrahvdro-β-carbolin-2-vn-3- (4-aminophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)A-aminocinnamic acid gave after recrystallization from 2-propanol the title compound as white crystals in a 80% yield. MP: 176 X. Analysis for C 28 H 25 N 3 O 2 . 0.23H 2 O: Calculated: C.76.49; H,5.84; N.9.56; Found: C.76.21 ; H, 5.61; N,9.96%. [α]Q 21 = -375.3 (c = 0.0.35, CHCI 3 ). Example 168 (EHRM4143,4-MethylenedioxyphenvP-1 ,3,4.9-tetrahvdro-β-carbolin-2- vn-3-(4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and (E)A-aminocinnamic acid gave after recrystallization from 2-propanol: H 2 O the title compound as white crystals in a 63% yield. MP: 264 X. Analysis for C 27 H 23 N 3 O 3 . 0.6H 2 O: Calculated: C.72.34; H.5.44; N.9.37; Found: C.72.06; H,5.48; 9.55%. [α]o 21 = -266 (c = 0.3, MeOH). Example 169 (R.4EM41-(3.4-MethylenedιoxyphenvP-1 3.4 9-tetrahydro-β-carbolιn-2-vP]-3- (4-(2-pyrrolιdιn-1 -ylethoxy)phenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 42 gave after recrystallization from ιPr 2 0 the title compound as brown crystals in a 4% yield MP 116 X Analysis for C 33 H 33 N 3 O 4 1 7H 2 O Calculated C,69 99, H,6 48, N,7 42, Found C,70 02, H, 6 47, N,7 59% Example 170 (EHRV14143 4-MethylenedιoxyphenvP-1 ,3 4 9-tetrahvdro-β-carbolιn-2-vPl-3- (442-dιethylamιnoethoxy)phenylpropene-1 -one The same method as employed in the preparation of Example 20 but starting from 1 Intermediate 19 and (E)-3-(4-(2-dιethylamιnoethoxy)phenyl)acrylιc acid (prepared according to the procedure of Sharpe.C J , Shabolt.R S , Brown, G R , Ashford.A , Ross.J W J Med Chem 1971 , 14(9), 836-842) gave after recrystallization from ιPr 2 O the title compound as white crystals in a 67% yield MP 94 X Analysis for C 33 H 35 N 3 O 4 0 5H 2 O Calculated C,72 5, H,6 64, N.7.69, Found C,72 48, H,6 64, N,7 58% [α]o 21 = -287 (c = 0 3, CHCI 3 ) Example 171 (EM 4143-Fluoro-4-methoxyphenvP-1.3 4 9-tetrahvdro-β-carbolιn-2-vP1-3-(3- nιtrophenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and (E)-3-nιtrocιnnamιc acid gave after recrystallization from DCM 2-propanol the title compound as a yellow powder in a 90% yield MP 141 X Analysis for C 27 H 22 FN 3 O 4 0 9CH 2 CI 2 Calculated C,61 16, H,4 38, N,7 67, Found C,61 1 , H 4 39 N,7 56% Example 172 .EWRM4142.3-Dihvdrobenzofuran-5-ylM .3.4.9-tetrahvdro-β-carbolιn-2-vn-3- (4-trifluoromethylphenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)A-trifluoromethylcιπnamιc acid gave after recrystallization from 2-propanol the title compound as white crystals in a 91 % yield. MP: 141 X. Analysis for C 29 H 23 F 3 N 2 O 2 : Calculated: C.71.3; H.4.75; N.5.73; Found: C.71.37; H.4.79; N,5.86% [α] D 2 ° = -326 (c = 0.3, CHCI 3 ). Example 173 (E)-(RV14142.3-Dihvdrobenzofuran-5-vP-1 ,3,4 9-tetrahvdro-β-carbolin-2-vn-3- (3-trifluoromethylphenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-trifluoromethylcιnπamic acid gave after recrystallization from 2-propanol: H 2 O the title compound as white crystals in a 80% yield. MP: 223 X. Analysis for C 29 H 23 F 3 N 2 O 2 : Calculated: C.71.3; H.4.75; N,5.73; Found. C.71.44; H.4.73; N,5.85%. [α]o 20 = -326 (c = 0.3, CHCI 3 ) Example 174 (EWRM 4142,3-Dihvdrobenzofuran-5-ylM ,3,4.9-tetrahvdro-β-carbolin-2-yll-3- (4-(2-morpholinA-ylethoxy)phenvPpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 49 gave after recrystallization from 2- propanol H 2 O the title compound as white crystals in a 66% yield. MP: 148 X. Analysis for C 34 H 35 N 3 O 4 Calculated C.71 3, H,4 75, N.5 73, Found C.71 44, H,4 73, N,5 85% [α] D 19 = -288 (c = 0 3, CHCI 3 ) Example 175 (E)4RM4142.3-Dιhvdrobenzofuran-5-vP-1.3,4 9-tetrahvdro-β-carbolιn-2-yl.-3- (4-(2-(ethylmethylamιno)ethoxy)phenyl)propene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 50 gave after recrystallization from ιPr 2 O the title compound as a white powder in a 66% yield MP 107 X Analysis for C33H35N3O 3 0 8H 2 O Calculated C,73 94, H,6 88, N,7 84, Found C,74 09, H,7 15, N,7 48% [α] D 21 = -253 (c = 0 3, CHCI 3 ) Example 176 (E)-14142.3-Dιhvdrobenzofuran-5-vP-1 3,4 9-tetrahvdro-B-carbolιn-2-yl1-344-(3- (dιmethylamιno)propenvPphenvPpropene-l-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 51 gave after recrystallization from EtOH the title compound as a white powder in a 45% yield MP 216 X Analysis for C 33 H 33 N 3 O 2 02H 2 O Calculated C,78 14, H,6 88, N,7 84, Found C,78 03, H,6 74, N,8 21 % [α]o 198 = -312 (c = 0.29, CHCI 3 ) Example 177 (EHRM -M42 3-Dιhvdrobenzofuran-5-vP-1 ,3,4 9-tetrahvdro-β-carboiιn-2-vH-3- (4-(3-dιmethylamιno-2-hvdroxypropoxy)phenvPpropene-1 -one At 0 X to a solution (E)-(R)-1-[1-(2 3-dιhydrobenzofuran-5-yl)-1 , 3,4,9- tetrahydro-β-carbolιn-2-yl]-3-(4-(2-(tertbutyldιmethylsιlanyloxy)-3-dιmethyiamιno- 2-hydroxy-propoxy)phenyl)propene-1-one (0 4 g, 0 6 mmol) in 50 mL of anhydrous THF was added tetrabutyiammonium fluoride (0 6 mL, 1 equiv , 1 M in THF) The resulting mixture was stirred at rt for one day Quenching with water, extraction with DCM, washing with brine, drying over MgS0 4 and concentration in vacuo gave an oil Recrystallization from iPrOH H 2 0 gave the title compound (0 2 g, 62%) as an off-white powder MP 138 X Analysis for C 3 3H 3 5N 3 O 4 0 5H 2 O Calculated C,72 5, H,6 64, N,7 69, Found C,72 21 , H,6 75, N,7 48% [α] D 20 = -283 (c = 06, CHCI 3 ) (E)-(R)-1-[1-(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn-2-yl]-3- (4-(2-(tertbutyldιmethylsιlanyloxy)-3-dιmethylamιno-2-hydroxypropoxy)phenyl)- propene-1-one was obtained in a 89% yield as a yellow oil from the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 52 1 H NMR (CDCI 3 ,250 MHz) δ 8 1 (s, 1 H), 7 5-7 3 (m, 2H), 6 9-7 2 (m, 7H), 6 8-6 5 (m, 3H), 4 5 (t 2H), 4 2 (m, 1 H), 4 0 (m, 3H), 3 8 (m, 1 H), 3 3 (m, 1 H), 3 0 (t, 2H), 2 7-2 9 (m, 3H), 2 3-2 15 (m, 2H), 2 1 (s, 6H), 0 8 (s,9H), 0 05 (d, 6H) Example 178 (E)4RM-(1-(2,3-Dιhvdrobenzofuran-5-yl)-1 34 9-tetrahvdro-β-carbolιn-2-vP-3- (4-formylphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)A-formylcιnnamιc acid gave after recrystallization from EtOH the title compound as a white powder in a 53% yield MP 175 X Analysis for C 29 H 24 N 2 O 3 0 8H 2 O Calculated C.75 24, H,5 57, N,6 05, Found C.75 54, H.5 78, N,6 11% [α]o 20 = -340 (c = 0 33, CHCI 3 ) Example 179 (E)-(RM4142.3-Dιhvdrobenzofuran-5-vP-1 ,3,4 9-tetrahvdro-β-carbolιn-2-vn-3- (4-propylamιnomethvPphenvPpropene-1-one To a solution of a solution of Example 178 (0 5 g 1 1 mmol) in 50 mL of MeOH was added propylamine (14 mL, 1 5 equiv ) The resulting mixture was stirred at 50 X for 4 hours At rt polymer-supported borohydride (1 2 g 1 2 equiv , 2 5 mmol/g) was added and the resulting mixture was stirred at 50 X for 6 hours After evaporation in vacuo, the residue was washed with 2x50 mL of DCM After filtration, the filtrate was washed with 2x50 mL of water Drying over Na 2 SO 4 , evaporation in vacuo and recrystallization from MeOH gave the title compound (0 4 g, 81 %) as a pale yellow powder MP 170 X Analysis for C 32 H 33 N 3 O 2 0 4H 2 O Calculated C,77 05, H,6 83, N,8 42, Found C,77 04, H,6 78, N,8 29% [α]p 19 = -330 (c = 0 4, MeOH) Example 180 (E)4R)-14142 3-Dιhvdrobenzofuran-5-vP-1 ,3,4 9-tetrahvdro-β-carbotιn-2-yl]-3- f4-(2-dιmethylamιnoethylamιno)phenylpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 53 gave after recrystallization from EtOH the title compound as yellow crystals in a 12% yield MP 160 X Analysis for C 32 H 34 N 4 O 2 0 2H 2 O Calculated C,75 33, H,6 8, N.10.98, Found C.75 06, H,6 83, N,10 98% [α]D 20 = -214 (c = 0 1 , MeOH) Example 181 (E)-(R)-14142.3-Dιhvdrobenzofuran-5-ylM .3 A9-tetrahvdro-β-carbolιn-2-vn-3- (442-amιnoethoxy)phenyl)propene-1 -one To a solution of (E)-(R)-2-[2-(443-[1-(2,3-dιhydrobenzofuran-5-yl)-1 ,3,4,9- tetrahydro-β-carbolιn-2-yl]-3-oxo-propenyl}-phenoxy)ethyl]ιsoιndo!e-1 ,3-dιone (0 85 g, 1 4 mmol) in 50 mL of MeOH THF was added hydrazine (0 38 mL, 3 equiv , 35% in water) The resulting mixture was stirred at 45 X for 4 hours Evaporation in vacuo and flash chromatography with DCM MeOH (80 20) as eluting solvent gave the title compound (0 17 g, 26%) as yellow powder MP 186 X Analysis for C 3 oH 29 N 3 O 3 0 3CH 2 CI 2 Calculated C,72 06, H,5 91 , N,8 32, Found C,72 12, H,6 08, N,867% [α]o 20 = -285 (c = 0 29, MeOH) (E)-(R)-2-[2-(4-{3-[1 -(2,3-Dιhydrobenzofuran-5-yl)-1 ,3,4,9-tetrahydro-β-carbolιn- 2-yl]-3-oxo-propenyl}phenoxy)ethyl]tsoιndole-1 3-dιone was obtained after recrystallization from EtOH, as a gummy solid in a 90% yield using the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 54 1 H NMR (CDCI 3 250 MHz) δ 8 0-6 7 (m, 19H) 4 5 (t, 2H), 4 2A 0 (m, 5H), 3 4 (m, 1 H), 3 0 (t, 2H) 2 9 (m, 2H) Example 182 (E)4R)-14142 3-Dιhydrobenzofuran-5-vP-1.3,4 9-tetrahydro-β-carbolιn-2-yll-3- (4-hvdroxyphenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)A-hydroxycιnnamιc acid gave after recrystallization from DMF MeOH the title compound as a white powder in a 90% yield MP 189 X Analysis for C 28 H 24 N 2 O 3 0 5DMF Calculated C,75 51 H,5 77, N,7 12, Found C,75 31 , H 5 84, N,6 81 % [α]o 20 = -310 (c = 0 32, MeOH) Example 183 (EHRV14142 3-Dιhvdrobenzofuran-5-vP-1 ,3 4 9-tetrahydro-β-carbolιn-2-vn-3- (4-(4-methylpιperazιn-1 -ypphenylpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 47 gave after recrystallization from DMF EtOH the title compound as pale yellow crystals in a 48% yield MP 193 X Analysis for C 33 H 34 N 4 O 2 1 0DMF Calculated C,73 07 H,6 98, N 11 83, Found C,72 67, H 7 05 N.11 55% [α] D 20 = -330 (c = 0 3, CHCI 3 ) Example 184 (EHRM4142 3-Dιhvdrobenzofuran-5-vP-1 3 4 9-tetrahvdro-β-carbolιn-2-vH-3- (4-methylamιnomethyPphenvPpropene-1-one The same method as employed in the preparation of Example 179 but starting from methylamine gave after recrystallization from MeOH H 2 0 the title compound as a white powder in a 52% yield MP 129 X Analysis for C 30 H 29 N 3 O 2 1 1 H 2 O Calculated C,74 54, H.6.51 , N.8 69, Found C,74 68, H,6 57, N,8 59% [α] D 21 = -288 (c = 0 4, CHCI 3 ) Example 185 (EWR)-14142.3-Dιhvdrobenzofuran-5-vP-1.3.4.9-tetrahvdro-β-carbolιn-2-vn-3- (4-ιsopropylamιnomethyl)phenvPpropene-1-one The same method as employed in the preparation of Example 179 but starting from isopropylamme gave after recrystallization from MeOH H 2 0 the title compound as a white powder in a 47% yield MP 158 X Analysis for C 32 H 33 N 3 O 2 0 3H 2 O Calculated C,77 33, H,6 81 , N,8 45, Found C,77 42, H,6 74, N,8 26% [α]D 21 = -319 (c = 0 3, MeOH) Example 186 (E)4R)-14142.3-Dιhvdrobenzofuran-5-ylM 3 4 9-tetrahvdro-β-carbolιn-2-vn-3- (4-dιmethylamιnomethvPphenvPpropene-1 -one The same method as employed in the preparation of Example 179 but using dimethylamine gave after recrystallization from iPrOH H 2 O the title compound as a white powder in a 34% yield MP 153-154 X Analysis for C 3 ιH 3 ιN 3 0 2 0 2H 2 O Calculated C,77 38, H,6 58, N,8 73, Found C,77 4, H,6 49, N,8 61 % [α]o 21 = -336 (c = 0 3, MeOH) Example 187 ■ΕHRM4142 3-Dιhvdrobenzofuran-5-vP-1.3 4 9-tetrahvdro-β-carbolιn-2-yl.-3- f4-(3-dιmethylamιnopropoxy)phenvnpropene-1-one The same method as employed in the preparation of Example 79 but starting from Example 182 and dimethylammopropyl chloride gave after recrystallization from CH 3 CN the title compound as a white powder in a 53% yield MP 186 X Analysis for C 33 H 35 N 3 O 2 0 6H 2 O Calculated C,74 44, H,6 85, N,7 89, Found C,74 36, H,6 63, N,7 98% [α] D 20 = -326 (c = 0 3, MeOH) Example 188 (E )4R)-14142.3-Dιhvdrobenzofuran-5-vP-1.3 4.9-tetrahvdro-β-carbolιn-2-vn-3- (4-(2-pιpeπdιn-1 -ylethoxy)phenvPpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 55 gave after recrystallization from CH 3 CN the title compound as white crystals in a 50% yield MP 210 X Analysis for C 35 H 37 N 3 O 3 Calculated C,76 75, H,6 81 , N,7 67, Found C,76 68, H,7 11 , N,7 93% [α]D 189 = -290 (c = 0 4, CHCI 3 ) Example 189 (E)-14143 4-MethylenedιoxyphenvP-1.3.4 9-tetrahvdro-β-carbolιn-2-vP-3-(442- pιpeπdιn-1 -ylethoxy)phenvilpropene-1 -one The same method as employed in the preparation of Example 20 but starting from Intermediate 55 gave after recrystallization from MeOH H 2 O the title compound as a beige solid in a 32% yield MP 102 X Analysis for C 34 H 3 5N 3 O 4 0 6MeOH Calculated C,73 05, H,6 63, N,7 39, Found C,73 24, H,6 87, N,7 02% Example 190 (E)4RH244434142,3-Dihvdrobenzofuran-5-vP-1.3.4.9-tetrahvdro-β-carbolιn-2- yll-3-oxopropenyl)phenoxy)ethyl1methylcarbamic acid, tertbutyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 56 gave the title compound as a yellow powder in a 95% yield. MP: 110 X. Analysis for C 3 6H 39 N 3 O 5 . 0.3H 2 O. Calculated: C.72.17; H.6.66; N.7.01 , Found; C.71.9, H,6 86; N,7 17% Example 191 (EHRM 4142.3-Dihvdrobenzofuran-5-vP-1.3,4 9-tetrahvdro-β-carbolin-2-vn-3- f4-(2-methylamιnoethoxy)phenyl1propene-1 -one A solution of Example 190 (0.33 g, 0.55 mmol) in DCM (30 mL) was treated with zinc bromide (0.63 g, 5 equiv.) for 16 hours at 30 X A gummy solid was formed. Extraction with DCM:MeOH, washing with water, drying over Na 2 SO 4 and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield. MP: 145 X. Analysis for C 3 ιH 31 N 3 O 3 . 0.2H 2 O Calculated. C.74.89; H.6.37; N.8.45; Found: C.74.90; H.6.70; N,8 49%. ND 20 = -337 (c = 0 4, MeOH) Example 192 (E)-1-T1-(3.4-Methylenedioxyphenyl)-1 ,3.4,9-tetrahvdro-β-carbolin-2-yl>-3-f4-f2- piperidin-1 -ylethoxy.phenyllpropene-1 -one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after recrystallization from MeOH:H 2 0 the title compound as a beige solid in a 32% yield. MP: 102 °C. Analysis for C34H35N3O4. 0.6MeOH: Calculated: C.73.05; H.6.63; N.7.39; Found: C.73.24; H.6.87; N,7.02%. Inhibitory effect on cGMP-PDE cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells at al. (Wells, J. N., Baird, C. E., Wu, Y. J. and Hardman, J. G., Biochim. Biophys. Acta 384, 430 (1975)). The reaction medium contained 50mM Tris-HCl, pH 7.5, 5mM Mg-acetate, 250μg/ml 5'- Nucleotidase, 1mM EGTA and 0.15μM The enzyme used was a human recombinant PDE 5 (ICOS, Seattle USA). Compounds of the invention were dissolved in DMSO finally present at 2% in the assay. The incubation time was 30 minutes during which the total substrate conversion did not exceed 30%. The IC50 values for the compounds examined were determined from concentration-response curves using typically concentrations ranging from 10nM to 10μM. Tests against other PDE enzymes using standard methodology also showed that compounds of the invention are highly selective for the cGMP specific PDE enzyme. cGMP level measurements Rat aortic smooth muscle cells (RSMC) prepared according to Chamley et al. in Cell Tissue Res. 177, 503 - 522 (1977) were used between the 10th and 25th passage at confluence in 24-well culture dishes. Culture media was aspirated and replaced with PBS (0.5ml) containing the compound tested at the appropriate concentration After 30 minutes at 37 C C, particulates guanyiate cyclase was stimulated by addition of ANF (100πM) for 10 minutes. At the end of incubation, the medium was withdrawn and two extractions were performed by addition of 65% ethanol (0.25ml). The two ethanolic extracts were pooled and evaporated until dryness, using a Speed-vac system. cGMP was measured after acetylation by scintillation proximity immunoassay (AMERSHAM) The EC50 values are expressed as the dose giving half of the stimulation at saturating concentrations Biological data The compounds according to the present invention were typically found to exhibit an IC∞ value of less than 500 nM and an ECso value of less than 5 μM In vitro test data for representative compounds of the invention is given in the following table: Table 1. In vitro results Example No. IC» nM ECβo μM 14 5 0.45 25 72 0.3 28 55 0.3 31 4 1 55 40 0.4 61 20 1.8 140 2 0.1 142 18 1.5 156 15 < 1 164 11 1.5 165 9 < 1 177 12 < 1 184 44 3 180 25 3.5 181 9 2 183 24 2 182 2 < 1 188 24 < 1 191 8 < 1 The hypotensive effects of compounds according to the invention as identified in Table 2 were studied in conscious spontaneously hypertensive rats (SHR). The compounds were admnistered orally at a dose of 5 mg/kg in a mixture of 5% DMF and 95% olive oil. Blood pressure was measured from a catheter inserted in the carotid artery and recorded for 5 hours after administration. The results are expressed as Area Under the Curve (AUC from 0 to 5 hours, mmHg.hour) of the fall in blood pressure over time. Table 2. In vivo results Example No. AUC PO(mmHg.h) 14 128 25 72 26 102 28 114 31 86 55 97 61 95 112 71 122 76 140 105 142 74 156 57 175 52 177 100 181 77 188 86 191 84 The application of which this descπption and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any novel feature or combination of features described herein. They may take the form of product, composition, process or use claims and may include, by way of example and without limitation, the following claim:

Claims: CLAIM 1. A compound of formula (I) wherein R° represents -hydrogen or -halogen; R 1 is selected from the group consisting of: -hydrogen, -N0 2l -trifluoromethyl, -trifluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)OR" or C h alky!), -Ci-ealkyl optionally substituted by -OR", -Cι. 3 alkoxy, -C(=0)R a , -O-C(=0)R a , -C(=0)OR', -C 1-4 alkylene C(=0)OR a , -0-Ciw,alkylene -C(=0)OR", -C^alkylene O-C^alkylene-C(=0)OR a , -C(=0)NR a SO 2 R c , -C(=0)Cι- 4 alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C^alkylene NR"R b , -C 2 ^alkenyleneNR a R b , -C(=0)NR a R b , -C(=0)NR"R c , -C(=0)NR a C.- 4 alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -OR a -OC 2 ^alkylene NR a R b , -OCι. 4 alkylene-CH(OR a )CH 2 NR"R b , -0-Cι- 4 alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-C^alkylene-OR", -O-C 2 ...alkylene4\IR a -C(=0)-OR b , -NR a R b , -NR a C M alkyleneNR a R b , -NR a C(=0)R b , -NR"C(=0)NR a R b , -N(S0 2 C^alkyl) 2 , -NR a (S0 2 C,-,alkyl), -S0 2 NR β R b , and -OS0 2 trifluoromethyl; R 2 is selected from the group consisting of: -hydrogen, -halogen, -OR", -d-e alkyl, -N0 2 , and -NR a R\ or R 1 and R 2 , together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom ; R 3 is selected from the group consisting of: -hydrogen, -halogen, -NOa, 4rifluoromethoxy, -Ci-ealkyl, and -C(=0)OR"; R 4 is hydrogen, or R 3 and R 4 together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom; R a and R b , which may be the same or different, are independently selected from hydrogen and Ci-ealkyl; R c represents phenyl or C-v-scycloalkyl, which phenyl or C 4 ^cycloalkyl can be optionally substituted by one or more halogen atoms, one or more -C(=0)OR* or one or more -OR*; n is an integer selected from 1 , 2 and 3; m is an integer selected from 1 and 2; and pharmaceutically acceptable salts and solvates thereof. 2. A compound represented by formula (I) wherein R 1 is selected from the group consisting of -OH, -OC^alkylene NR a R b and -0- Het, wherein Het represents a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen, and sulphur, optionally substituted by R 2 represents wherein C represents a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C h alky!; R" and R b , which may be the same or different, are independently selected from hydrogen and d-ealkyl; and pharmaceutically acceptable salts and solvates thereof.

Inventors: BOMBRUN AGNES, BOMBRUN, AGNES
Applicants: BOMBRUN AGNES, ICOS CORP, BOMBRUN, AGNES, ICOS CORPORATION
Application year: 1997
Main classification: C07D471
IPC codes: A61K31, A61P9, A61P43, C07D209, C07D221, C07D265, C07D471