CARBOLINE DERIVATIVES

Title:

CARBOLINE DERIVATIVES

Document Type and Number:

WIPO Patent Application WO/1997/043287

Kind Code:

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.

Inventors:

BOMBRUN AGNES (FR)

Application Number:

PCT/EP1997/002277

Publication Date:

November 20, 1997

Filing Date:

May 05, 1997

Export Citation:

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Assignee:

ICOS CORP (US)
BOMBRUN AGNES (FR)

International Classes:

A61K31/435; A61K31/437; A61K31/44; A61K31/4545; A61K31/496; C07D471/04; A61K31/5377; A61P9/00; A61P43/00; C07D209/00; C07D221/00; C07D265/06; C07D; (IPC1-7): C07D471/04; A61K31/435

Domestic Patent References:

WO1995019978A1

1995-07-27

Foreign References:

EP0344577A2

1989-12-06

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Claims:

CLAIM

A compound of formula (I) wherein R° represents hydrogen or halogen; R¹ 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_halky!), Ciealkyl optionally substituted by OR", Cι.₃alkoxy, C(=0)R^a, OC(=0)R^a, C(=0)OR', C₁₄alkylene C(=0)OR^a, 0Ciw,alkylene C(=0)OR", C^alkylene OC^alkyleneC(=0)OR^a, C(=0)NR^aSO₂R^c, C(=0)Cι₄alkylene Het, wherein Het represents 5 or 6membered heterocyclic group as defined above, C^alkylene NR"R^b, C₂^alkenyleneNR^aR^b, C(=0)NR^aR^b, C(=0)NR"R^c, C(=0)NR^aC.₄alkylene Het, wherein Het represents a 5 or 6membered heterocyclic group as defined above, OR^a OC₂^alkylene NR^aR^b, OCι.₄alkyleneCH(OR^a)CH₂ NR"R^b, 0Cι₄alkylene Het, wherein Het represents a 5 or 6 membered heterocyclic group as defined above, OC^alkyleneOR", OC₂...alkylene4\IR^aC(=0)OR^b, NR^aR^b, NR^aC_MalkyleneNR^aR^b, NR^aC(=0)R^b, NR"C(=0)NR^aR^b, N(S0₂C^alkyl)₂, NR^a(S0₂C,,alkyl), S0₂NR^βR^b, and OS0₂trifluoromethyl; R² is selected from the group consisting of: hydrogen, halogen, OR", de alkyl, N0₂, and NR^aR\ or R¹ and R², together form a 3 or 4 membered alkylene or alkenyiene chain, optionally containing at least one heteratom ; R³ is selected from the group consisting of: hydrogen, halogen, NOa, 4rifluoromethoxy, Ciealkyl, and C(=0)OR"; R⁴ is hydrogen, or R³ and R⁴ 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 Ciealkyl; R^c represents phenyl or Cvscycloalkyl, which phenyl or C₄^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.

A compound represented by formula (I) wherein R¹ is selected from the group consisting of OH, OC^alkylene NR^aR^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 R² represents wherein C represents a 5 or 6membered 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_halky!; R" and R^b, which may be the same or different, are independently selected from hydrogen and dealkyl; and pharmaceutically acceptable salts and solvates thereof.

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- ₆alkyl optionally substituted by -OR ^a,

-Cι. ₃alkoxy

-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 ^aSO ₂R ^c, Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above,

-C^alkylene NR ^aR ^b,

-C ₂^alkenyleneNR ^aR ^b, -C(=0)NR ^aR ^b,

-C(=0)NR ^aR ^c,

-C(=0)NR ^aC^alkylene OR ^b

-C(=0)NR ^aCι-4alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -OR ^a

-OC alkylene NR ^aR ^b,

-OC ₁- ₄alkylene-CH(OR ^a)CH ₂ NR ^aR ^b, Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-C ₂- ₄alkylene-OR ^a,

-O-C _2-4alkylene-NR ^a-C(=0)-OR ^b,

-NR"R ^b,

-NR ^aC^alkyleneNR ^aR ^b,

-NR ^aC(=0)R ^b, -NR ^aC(=0)NR ^aR ^b,

-N(SO ₂C^alkyl) ₂,

-NR ^a(SO ₂Cι. ₄alkyl),

-SO ₂NR ^aR ^b, and

-O S0 ₂trif I uoromethy I ; R ² is selected from the group consisting of.

-hydrogen,

-halogen,

-OR ^a,

-Cι _-6 alkyl, -NO _2l and

-NR ^aR ^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- ₆cycloalkyl, which phenyl or C ₄- ₆cycloalkyl 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 _2-6alkenylene 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 ^aR ^b, -O-Cv ₄alkyleneHet and -O-C _2-4alkylene-OR ^a In particular, R ¹ represents -0-C ₂. ₄alkylene NR ^aR ^b, wherein suitably C _2-4alkylene 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 ^aethylene-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 ^aethylene-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 _2-4alkylene NR ^aR ^b and O-d. ₄alkylene 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 ^aR ^b in particular

OCH ₂CH ₂N(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-tπfluoromethylphe nyl)- 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)propen e-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-tetr ahydro-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 _l4,9-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-methylenedioxyp henyl)-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-methylen edioxyphenyl)-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-methylen edioxyphenyl)-

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-m ethyleπedιoxyphenyl)-

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 ₁4,9-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 _t4,9-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-met hylenedιoxy)-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-tet rahydro-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-tetrahyd ro-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-o ne

(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-tetrahy dro-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 ₂O 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 ₂O (2 30) gave the title compound as white crytals in a 80% yield

¹H 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 ₂O 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 ₂O 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 ₈Hι ₅FN ₂O 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%) ¹H 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 ₁₈Hi6N ₂O2 0 35H ₂O

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 ₈H ₁₆N ₂O 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 ₁₉H ₁₈N ₂O 0 15H ₂O

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 ₁₉H ₁₈N ₂0 1 0H ₂O 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 ₁₂H ₁₃NO ₃ 0 2H ₂O 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

¹H 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 ₃N (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 ₂CO ₃ (24.9 g, 1 1 equiv.) for 16 hours at 80 °C.

¹H 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)

¹H 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 ₃N (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

¹H 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 ₃N (0 95 mL 1 0 equiv ) EDCI (1 2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv )

MP 185 °C

¹H 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 ₃N (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-carboxy lιc 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 ) ¹H 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 ₃N (0 95 mL 1 0 equiv ),

EDCI (1 2 g, 1 0 equiv ) and HOBT (0 88 g, 1 0 equiv )

¹H 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. ¹H 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 ₇H ₂ιNO ₄. 0.15H ₂O

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 ₃N (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 ₂SO ₄ and flash chromatography with

cyclohexane. EtOAc (95 5) as eluting solvent, gave the title compound (2 3 g

42%) as an oil

¹H 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

¹H 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

¹H 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 ₃N (1 2 mL, 7 equiv ) at rt for 1 hour

¹H 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

¹H 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

¹H 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

¹H 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 ₃N (4 mL, 7 equiv ) at rt for 1 hour ¹H 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 ¹H 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 ₂Hι ₃NO 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)phenyllacryl ιc 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 ₂CO ₃ (3 82 g, 2 8 equiv) ¹H 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 ₄H ₁₉NO 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 ₂C0 ₃ (8 7 g, 1 1 equiv ) and 2-chloropropyldιmethylamιne, hydrochloride (13 6 g, 1 5 equiv ) in DMF ¹H 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 ₄H ₁₉NO 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 ₂CO ₃ (6 2 g, 1 1 equiv ) and (2-chloroethyl)ethylmethylamιne, hydrochloride

(9 7 g , 1 5 equiv ) in DMF

¹H 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

¹H 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

¹H 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-dιmethylamιn opropenyl)phenyllacrylιc

This product was prepared by refluxing for four hours (E)-3-[4-(2- (tertbutyldιmethylsιlanyloxy)-3-dιmethylamιnopropanyl]ph enyl]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-dιmethyla mιnopropoxy)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

¹H 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]acryl ιc 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 ₂SO ₄, evaporated in vacuo and purified via flash chromatography using DCM MeOH (95 5) as eluting solvent

¹H 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

¹H 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

¹H 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 ¹H 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)phenvn acrylιc 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.

¹H 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.

¹H 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 ₂O (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

¹H 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

¹H 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 ₂₆H ₂₂N ₂O 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 ₂O 2- propanol (3 1 ), the title compound as a yellow powder in a 47% yield MP 230-231 °C Analysis for C ₂₆H ₂ιN ₃O 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-trιfluor omethylphenyl)- 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 ₂₇H ₂₁F ₃N ₂O 0 4H ₂O

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 ₂₇H ₂₄N ₂O 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 ₂₈H ₂₃N ₂O ₂F ₃ 0.3H ₂O: 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 ₃N (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 ₂₈H ₂₅N ₃O ₂ 0 7H ₂O

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 ₂₇H ₂₄N ₂O ₂ 0 5H ₂O

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 ₂O (2 8), the title compound as white crystals in a 38% yield MP 236-238 °C

Analysis for C ₂₇H ₂₄N ₂O ₂ 0 5H ₂O 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 ₂₇H ₂₂N ₂O ₂ 0 4H ₂O 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 ₂₈H ₂₄N ₄O ₄ 06H ₂O

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 ₂₆H ₂₁N ₃O3. 0.2H ₂O:

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 ₂₇H ₂ιN ₂O ₂F 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 ₂₇H ₂₄N ₂O. 0.6H ₂O 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 ₂₉H ₂₅N ₃O ₄. 0.4H ₂O: 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 ₂₈H ₂₄N ₂O ₃. 0.03H ₂O 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-p henylpropene-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 ₂₆H ₂ιN ₂OCI. 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 ₂₇H ₂₂N ₂O ₃. 0.3H ₂O:

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 ₂₇H ₂₁N ₂O ₃Br. 0.3H ₂O.

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 ₂₆H ₂ιN ₂OCI

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 ₃N (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 ₂₉H ₂₆N ₂O ₄ 0.3H ₂O

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 ₂₉H ₂₄N ₂O 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 ₂₇H ₂₂N ₂O ₄ .0.3H ₂O:

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 ₂₈H ₂₂N ₂O ₄. 0.3H ₂O:

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 ₃N (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 ₂O)

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 ₂₇H ₂₃N ₃O ₃ 0 3H ₂O

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 ₂₇H ₂₁N ₃O 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-carbolι n-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 ₃N (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 ₂O (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 ₂₉H ₂₇N ₃O ₇S ₂ 0 3H ₂O

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 ₂0 (99 1 ), the title compound as yellow crystals in a 84% yield MP 211 °C

Analysis for C ₂₉H ₂₄N ₂O ₅ 0 3H ₂O 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 ₂₈H ₂₅N ₃O ₅S 02H ₂O

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 ₂O MP 183 °C

Analysis for C ₂₈H ₂₃N ₃O 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 ₂₈H ₂₂N ₂O ₅ 0 2H ₂O 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 ₂₈H ₂₁N ₃O ₃ 0 1 H ₂O

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 ₂₈H ₂₁F ₃N ₂O ₃. 0.2H ₂O: 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 ^χyphenyl)-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 ₂₈H ₂₂N ₂O 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-carbol� �n-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 ₂₇H ₂₁N ₂O ₃CI.

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 ₂₈H ₂ιF ₃N ₂0 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 ₂₈H ₂₄N ₂O ₃ 0 7H ₂O

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 ₂₈H ₂₄N ₄O ₄ 0 5H ₂O

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 ₂₈H ₂₄N ₂O 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 ₃N (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 ₂SO ₄ and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and Et ₂O Evaporation in vacuo and recrystallization from EtOH gave the title compound (0 03 g, 13%) as white crystals

MP 203 °C

Analysis for C ₃₅H ₂₉N ₃O 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 ₂O the title compound as a white powder in a 66% yield

MP 194 °C

Analysis for C ₂₇H ₂₀N ₂O ₃CI 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 ₂O (10 1 ) the title compound as an off-white powder in a 62% yield MP 155 °C Analysis for C ₂₈H ₂₄N ₂O 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 ₂O the title compound as an off-white powder in a 47% yield MP 213 °C

Analysis for C ₂₈H ₂₄N ₂O ₅ 0 3H ₂O

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 ₂₇H ₂ιF ₃N ₂O 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 ₂₀H ₂₆N ₂O ₃ 06H ₂O

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 ₂O the title compound as white crytals in a 20% yield MP 134 °C

Analysis for C ₂₀H ₂₆N ₂O ₃ 0 6H ₂O

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 ₂O (99 1 ) the title compound as a white powder in a 45% yield

MP 212 °C

Analysis for C ₂₇H ₂₀CI ₂N ₂O 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 ₂₉H ₂₆N ₂O ₅ 0 5 H ₂O

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 ₂₇H ₂₂N ₂O 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 ₂O (10 0 6) the title compound as an off-white powder in a 86% yield EtOH H ₂O

MP 165 °C

Analysis for C ₃₀H ₂₇N ₃O ₄ 04H ₂O

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 ₂O (2 1 ) was added Extraction with

DCM, washing with a saturated aqueous solution of NH ₄CI 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 ₂O (1 1 )

MP 172-174 °C

Analysis for C ₃₂H ₃₁N ₃O ₄ 0 1 H ₂O

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 ₂₉H ₂₆N ₂O 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 ₂₉H ₂₄N ₃O ₄F 0 4H ₂O

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 ₃oH ₂sN ₂O _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 ₃₁H ₂₉N ₃O ₄ 04(H ₂O 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 ₂₇H ₂ιN ₂O ₃F 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 ₂₇H ₂₁N ₂O ₃F 1 3H ₂O

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 ₂O the title compound as white crystals in a 54% yield MP 248 °C

Analysis for C ₂₇H ₂₂N ₂O 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 ₂₈H ₂₄N ₂O 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 ₂0 (20 1 ) the title compound as white crystals in a 91% yield MP 156-158 °C Analysis for C ₂₈H ₂₄N ₂O 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 ₂O the title compound as white crystals in a 45% yield MP 157 °C

Analysis for C _STH^^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 ₂O the title compound as white crystals in a 13% yield

MP 145 °C

Analysis for C^HsJsL.Os 0 7H ₂O

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 ₂O (1 1 ) gave the title compound (0 19 g, 70 %) as white crystals MP 232-233 °C Analysis for C ₂₈H ₂₂N ₆O ₃ 0 4H ₂O 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 ₂O (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 ₂SO 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 ₂₇H ₂₃N ₃O 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 ₂0 the title compound as white crystals in a 6% yield MP 214 °C Analysis for C ₂₈H ₂ιN ₃O ₃ 0 1 H ₂O

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-methyl enedιoxyphenyl)-

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 ₂0 (8 2) the title compound as white crystals in a 61% yield MP 168 °C

Analysis for C ₃₂H ₂₉N ₃O ₅ 0 8H ₂O

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 ₂0 (8 2) the title compound as white crystals in a 46% yield

MP 228-230 °C

Analysis for C ₂₈H ₂ιN ₃O ₃ 0 8H ₂O

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 ₂0 the title compound as white crystals in a 28% yield MP 144-145 °C Analysis for C ₃₆H ₃₅N ₃O ₆ 0 7H ₂O

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 ₂O (100 mL) and acidified with HCl (1 N) Extraction with 2 x 50 mL of DCM, drying over Na ₂SO ₄ and concentration in vacuo gave a residue which was recrystallized from MeOH H ₂O to give the title compound (0 05 g, 24%) as white crystals

MP 204-205 °C

Analysis for C ₃₄H ₃₁N ₃O6 0 4H ₂O 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 ₂₈H ₂₂N ₂O ₅ 0 8H ₂O

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 ₂O, the title compound as a white powder in a 30% yield

MP: 151 °C.

Analysis for C ₃₃H ₃₂N ₄0 ₄. H ₂O:

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 ₂O, the title compound as a white powder in a 23% yield

MP- 138-140 °C.

Analysis for C ₃₄H ₃₅NsO ₄. 3.1 H ₂O.

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 ₃ιH ₂₈N ₂O ₅. 0.9H ₂O 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 ₂0, the title compound as a white powder in a 5% yield MP: 260-264 °C. Analysis for C ₂₈H ₂₂N ₆O ₃. 2.2H ₂O:

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 ^χyphenvn-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 ₂₇H ₂₁N ₃O 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-tetr ahydro-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 ₂₉H ₂₄N ₂O 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 ₃5H35N ₃O 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 ₂O, the title compound as a white powder in a 53% yield

MP 128-130 °C

Analysis for C ₃₅H ₃₆N ₄O 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 ₂CO 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 ₂SO ₄ and recrystallized from EtOH H ₂O to give the title compound (0 06 g

22%) as yellow crystals

MP 76-78 °C

Analysis for C ₃ιH ₃ιN ₃O ₄ 0 6H ₂O Calculated C,71 55, H,6 24, N,8 07

2 77

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 ₃₀H ₂₆N ₂O 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 ₂₈H ₂₂N ₂O 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 ₃₁H ₂₈N ₂O ₆ 2 4H ₂O

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 ₂0 2- propanol the title compound as white crystals in a 51 % yield

MP 231 °C

Analysis for C ₂₉H ₂₄N ₂O 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 ₂O 2-propanol the title compound as yellow crystals in a 45% yield

MP 158-160 °C

Analysis for C ₂₉H ₂₄N ₂O ₆ 0 9H ₂O 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 ₂₇H ₂₀N ₃O ₅CI

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 ^χyphenylM .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 ₂O the title compound as yellow crystals in a 44% yield MP 146 °C

Analysis for C ₂₇H ₂₀N ₃O ₅CI 0 1 H ₂O

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 ₂₉H ₂₃N ₂O ₅CI 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 ₂O the title compound as an off-white solid in a 40% yield MP 162-163 °C Analysis for C ₃₀H ₂₆N ₂O6 0 1 H ₂O.

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 ₂CO 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 ₂SO 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 ₂₇H ₂₂CIN ₃O ₃ 04H ₂O 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 ₂₈H ₂ιN ₂O ₅ H ₂O

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 ₂O the title compound as white crystals in a 13% yield MP 148-150 °C

Analysis for C ₂₇H ₂₀N ₂O ₄Br 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 ₃₂H ₃₃N ₃O ₄ 0 3H ₂O

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 ₂₉H ₂₃CIN ₂O ₅ 1 05H ₂O

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 ₂O the title compound as pale yellow crystals in a 12% yield

MP 92-93 X

Analysis for C ₃₅H ₃₉N ₃O 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 ₂₈H ₂₁N ₂O 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 ₂O the title compound as a white powder in a 71 % yield

MP: 151 -152 X

Analysis for C ₂₉H ₂₆N ₂0 ₄. 0 4H ₂O:

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 ₃₁H ₃₀N ₄O ₆. 1.5H ₂O: 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 ₂0 the title compound as a pale yellow powder in a 17% yield

MP 143 X Analysis for C ₃ιH ₃₂N ₄O ₄ 0 5H ₂O

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 ₂₈H ₂₃N ₃O ₇ 0.8H ₂O. 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 ₂₇H ₂ιCIN ₂O:

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 ₂₇H ₂₂CIN ₃O ₄ 0.2H ₂O 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 ^χyphenylM .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 ₂₇H ₂₀CI ₂N ₂O ₃ 0 2H ₂O

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 ₃CN (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 ₂SO 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 ₂₉H ₂₇CI ₂N ₃O ₃ 0 5H ₂O 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%)

¹H 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 ₂₈H ₂₄N ₂O 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 ₂O the title compound as white crystals in a 79% yield

MP: 162 X.

Analysis for C ₂₈H ₂₅N ₃O 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 ₂₉H ₂₄N ₂O 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 ₂O (95 5) the title compound as yellow crystals in a 62% yield MP 154 X

Analysis for C ₂₇H ₂₂CIN ₃0 ₄ 0 5(H ₂0 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 ₂0, the title compound as white crystals in a 47% yield,

MP 154 X

Analysis for C ₂₇H ₂₂N ₂O ₄ 06H ₂O

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 ₃₂H ₃₀N ₄O ₅ 0 2H ₂O

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 ₂₈H _2-1N ₂O 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 ₂₉H ₂₇N ₃0 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 ₂₈H ₂₃N ₃O ₄. 0.1 H ₂O

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 ₂₇H ₂₂N ₂O ₃ 0.2H ₂O. 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 ₂₇H ₂₂N ₂O ₃ 0 1 H ₂O 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 ₂₇H ₂₃N ₃O 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 _ahvdro-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 ₂₇H ₂₃CIN ₃O 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-methy lenedioxyV1.3.4.9- 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 ₃₃H ₃₁N ₃0 ₅. 0.4H ₂O: 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 ₂₉H ₂₆N ₂0. 0.4H ₂O: 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 ₂₉H ₂₄CIN ₂O 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 ₃CN the title compound as white crystals in a 37% yield

MP 146 X

Analysis for C ₃₂H ₃₃N ₃O ₃ 1 5H ₂O

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 ₂₉H ₂₆N ₂O 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 ₂₉H ₂₆N ₂O 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 ₂₇H ₂₁N ₃O 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 ₃₀H ₂₆N ₂O ₄ 0 2H ₂O

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 ₂0 the title compound as a grey powder in a 43% yield MP- 147-149 X Analysis for C ₂₈H ₂₄N ₂O 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 ₂₉H ₂₄N ₂O 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 ₂₈H ₂₂N ₂O 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 ₂₈H ₂₁F ₃N ₂O ₆S 0 2H ₂O

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 ₂₉H ₂₆N ₂O 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 ₃CN the title compound as white crystals in a 23% yield

MP 159 X

Analysis for C ₃₂H ₃₁N ₃O ₃ 0 1 H ₂O 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 ₂O the title compound as a yellow powder in a

51 % yield.

MP- 172 X

Analysis for C ₂₉H ₂₇N ₃O 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 ₂O the title compound as a yellow powder in a

37% yield.

MP. 129 X. Analysis for C ₃₂H ₃₁N ₃O 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 ₃₀H ₂₄N ₂O 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 ₃CN the title compound as yellow crystals in a 66% yield MP 283 X

Analysis for C ₂₉H ₂₂N ₂O ₄ 0 6H ₂O 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 ₂₈H ₂₁F ₃N ₂O ₆S 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 ₃CN pentane the title compound as yellow crystals in a 70% yield

MP 131 X Analysis for C ₃₁H ₃₁N ₃O ₄ 1 3H ₂O

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 ₂₇H ₂₃FN ₂O ₂ 0 4CH ₂CI 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 ₃CN the title compound as white crystals in a 85% yield

MP 187-189 X

Analysis for C ₃₂H ₃3N ₃O 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 ₂₈H ₂₄N ₂O ₃ 06H ₂O

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 ₂O the title compound as white crystals in a 26% yield

MP 152 X

Analysis for C3 ₄H ₃₅N ₃O3 0 5H ₂O

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 ₂0 the title compound as white crystals in a 73% yield

MP 154 X

Analysis for C ₃iH ₂₉N ₃O ₃ 0 6H ₂O

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 ₂₈H ₂₃N ₃O 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-car bolιn-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 ₃oH ₂₄N ₄O ₃. 0.6H ₂O:

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 ₃₀H ₂₆N ₂O5. 0.1 H ₂O. 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 ₂₈H ₂₃N ₃O ₅. 0.6H ₂O.

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 ₃CN 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 ₂O the title compound as a white powder in a 60% yield

MP 103 X Analysis for C ₃ιH ₃₂FN ₃θ ₃ 0 4H ₂O

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 ₂₉H ₂₄N ₂O ₅ 0 7H ₂O

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 ₂₈H ₂₄N ₂O 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 ₃CN the title compound as beige crystals in a 79% yield

MP 153 X

Analysis for C ₃₂H ₃₃N ₃O ₃ 0 5H ₂O 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 ₃₀H ₃₁N ₃O ₂ 1 6H ₂O

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 ₂₈H ₂₄N ₂O ₂ 0.2H ₂O. 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 ₂₈H ₂₃N ₃0 ₄ 0.3H ₂O 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 ₂₈H ₂₄N ₂O ₃ 0 8H ₂O

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 ₃CN the title compound as white crystals in a 100% yield

MP 193 X

Analysis for C ₃3H ₃₅N ₃O ₃ 0 45H ₂O

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 ₃₂H ₃₂N ₄O ₃ 0 4H ₂O

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 ₂0 the title compound as white crystals in a 83% yield MP 164 X Analysis for C ₃₃H ₃₃N ₃O ₄ 0 9H ₂O

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 ₂0 the title compound as white crystals in a 56% yield

MP 107 X

Analysis for C ₃₂H ₃₃N ₃O ₄ 0 7H ₂O

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 ₂O the title compound as white crystals in a 78% yield

MP 193 X

Analysis for C ₃₂H ₃₃N ₃O ₄ 1 6H ₂O

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 ₂0 the title compound as a yellow powder in a 100% yield MP. 200 X

Analysis for C ₂8H ₂₂F ₂N ₂O 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 ₃CN the title compound as white crystals in a 80% yield

MP 193 X

Analysis for C Hs^sOs 0 6H ₂O 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 ₃CN the title compound as white crystals in a 79% yield MP 193 X

Analysis for C ₃₃H ₃₅N ₃O 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-c arbolin-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 ₂O the title compound as a white powder in a 100% yield. MP: 172 X.

Analysis for C ₂₇H ₂₀F ₂N ₂O 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 ₂₈H ₂₅N ₃O ₂. 0.23H ₂O: 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 ₂O the title compound as white crystals in a 63% yield. MP: 264 X.

Analysis for C ₂₇H ₂₃N ₃O ₃. 0.6H ₂O:

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 ₂0 the title compound as brown crystals in a 4% yield MP 116 X

Analysis for C ₃₃H ₃₃N ₃O ₄ 1 7H ₂O 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 ₂O the title compound as white crystals in a 67% yield MP 94 X

Analysis for C ₃₃H ₃₅N ₃O ₄ 0 5H ₂O

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 ₂₇H ₂₂FN ₃O ₄ 0 9CH ₂CI 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 ₂₉H ₂₃F ₃N ₂O 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 ₂O the title compound as white crystals in a

80% yield.

MP: 223 X.

Analysis for C ₂₉H ₂₃F ₃N ₂O 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 ₂O the title compound as white crystals in a 66% yield. MP: 148 X. Analysis for C ₃₄H ₃₅N ₃O 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 ₂O the title compound as a white powder in a 66% yield

MP 107 X

Analysis for C33H35N3O ₃ 0 8H ₂O

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 ₃₃H ₃₃N ₃O ₂ 02H ₂O 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-(tertbutyldιmethylsι lanyloxy)-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 ₂0 gave the title compound (0 2 g, 62%) as an off-white powder MP 138 X

Analysis for C ₃3H ₃5N ₃O ₄ 0 5H ₂O 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 ¹H 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 ₂₉H ₂₄N ₂O ₃ 0 8H ₂O

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 ₂SO 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 ₃₂H ₃₃N ₃O ₂ 0 4H ₂O 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 ₃₂H ₃₄N ₄O ₂ 0 2H ₂O

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 ₃oH ₂₉N ₃O ₃ 0 3CH ₂CI 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

¹H 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 ₂₈H ₂₄N ₂O 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 ₃₃H ₃₄N ₄O 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 ₂0 the title compound as a white powder in a 52% yield MP 129 X

Analysis for C ₃₀H ₂₉N ₃O ₂ 1 1 H ₂O 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 ₂0 the title compound as a white powder in a 47% yield

MP 158 X Analysis for C ₃₂H ₃₃N ₃O ₂ 0 3H ₂O

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 ₂O the title compound as a white powder in a 34% yield

MP 153-154 X

Analysis for C ₃ιH ₃ιN ₃0 ₂ 0 2H ₂O

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 ₃CN the title compound as a white powder in a 53% yield MP 186 X

Analysis for C ₃₃H ₃₅N ₃O ₂ 0 6H ₂O 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 ₃CN the title compound as white crystals in a 50% yield MP 210 X

Analysis for C ₃₅H ₃₇N ₃O 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 ₂O the title compound as a beige solid in a 32% yield

MP 102 X

Analysis for C ₃₄H ₃5N ₃O 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-tetrahvd ro-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 ₃6H ₃₉N ₃O ₅. 0.3H ₂O. 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 ₂SO ₄ and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield.

MP: 145 X.

Analysis for C ₃ιH ₃₁N ₃O ₃. 0.2H ₂O

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 ₂0 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 ^CC, 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:

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