This invention relates to a novel treatment and in particular to a novel treatment for arrhythmia and to certain novel compounds and compositions used in such treatment .

Antiarrhythmic drugs have been grouped according to the pattern of electrophysiological effects they produce and/or their presumed mechanism of action. A classification in four groups has been originally proposed by Naughan Williams in 1970. At the molecular level, class I compounds act on Νa ⁺ currents; class II compounds possess b-adrenoceptor blocking activity; class III drugs block K ⁺ channels; and class IN drugs target Ca ⁺⁺ channels.

European Patent Application, Publication Number 0233762 discloses compounds of formula (I) therein which are stated to have cardiovascular activity, including use in the treatment of angina. It has now surprisingly been discovered that certain compounds of formula (I) of EP0233762 show potential as antiarrhythmic agents: This antiarrhythmic activity is considered to be associated with an increase in the QT interval.

Certain of the compounds of formula (I) surprisingly evidenced a prolongation of the cardiac action potential and are therefore considered to show particular promise as class HI antiarrhythmic agents.

Most surprisingly however, certain of the compounds of formula (I) of EP0233762 demonstrated both class III and class IV activity, the class IN activity providing the compounds with a self limiting increase of the cardiac cell action potential duration. These compounds therefore show an improved profile over pure class HI agents, having less proarrhythmic potential, and also a lack of cardiodepressive activity in ischaemic myocardium. These compounds are also considered to be effective against atrial fibrillation and flutter.

One compound in particular demonstrates such dual activity, this is the compound of Example 50 of EP-A-8603765 named as (Ν-[3,4-dimethoxy-phenyl]- N-S-pST'^- S^-dimethoxypheny^-ethyl-N'-methylaminolpropy -N'-^ nitrobenzamide, (also referred to herein as 'Compound I').

Accordingly, the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (I):

R,-N— A— N— B— R ₄

(I)

or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein Ri and R are independently phenyl optionally substituted by one, two or three of halogen, C1-4 alkoxy, C1-4 alkyl, cyano, hydroxy, nitro, NR5R or O2SNR5R5 wherein R5 and Rg are independently hydrogen or C - ^~ alkyl or together are C3-6 polymethylene, or disubstituted at adjacent carbon atoms by Cj-2 alkylenedioxy and optionally further substituted by one of the above groups; R2 is selected from (CH2) _Z CN where z is O or an integer from 1 to 4, Cχ-i2 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, phenyl C1-4 alkyl, pyridyl, pyridyl C1-4 alkyl, COR7, COCH2COR7, SO2 7, CO2 7, CONHR7 and CSNHR7, where R7 is selected from Cι-12 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, phenyl and phenyl C1-4 alkyl, any alkyl moiety in R7 optionally substituted by hydroxy or Cj-4 alkanoyloxy, any pyridyl or phenyl moiety in R2 optionally substituted as defined for R and R4 and any cycloalkyl moiety in R2 optionally substituted by one or two Cι~ alkyl groups;

R3 is hydrogen, C2-6 alkyl, C2-6 alkene or C3-8 cycloalkyl;

A represents C2-5 alkylene; and B represents C1-4 alkylene.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia. The invention further provides a pharmaceutical composition for the treatment of arrhythmia, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefore.

Arryhthmia particularly includes cardiac arrhythmia and ischaemic rhythm disorders, especially cardiac arrhythmia.

Suitable values for Rj and R4 include phenyl, phenyl di-substituted by methylenedioxy and optionally further substituted by chloro, or phenyl substituted by one of fluoro, chloro or bromo or by one, two or three of methoxy, ethoxy, n- oχ iso-propoxy. methyl, ethyl, n - or iso-propyl. cyano, hydroxy or amino optionally substituted by one or two methyl groups.

Rl and R4 are preferably the same group, most preferably 3,4-dimethoxyphenyl.

Particular values for * and R^ are halophenyl, especially 4-halophenyl,

dihalophenyl, especially 3,4-dihalophenyl, dialkylphenyl, especially 3,4- dialkoxyphenyl, (hydroxy, alkoxy )phenyl such as (3-alkoxy,4-hydroxy)phenyl and trialkoxyphenyl such as 3,4,5-trialkoxyphenyl.

Examples of R* and R^ include 4-fluorophenyl, 3,4-dichlorophenyl, 3,4- dimethoxyphenyl, (3-methoxy, 4-hydroxy)phenyl and 3,4,5-trimethoxyphenyl.

Phenyl moieties in R2 include phenyl, 2-, 3- and 4-nitrophenyl, 3,5-dinitrophenyl, 3-methoxyphenyl, 3-methoxy-6-methylphenyl, 2,4,6-trimethylphenyl, 4-cyanophenyl, 4-chlorophenyl and 4-methylphenyl.

Suitable values for alkylene moieties in R2 include -CH2-, -CH(CH3)- -CH2CH2CH2- and -CH2CH2-. Suitable values for R2 when alkyl include n-pentyl.

Suitable values for alkyl R7 in R2 includes C\_( ^~ alkyl, such as methyl, ethyl, n- and iso- C3H7, n^Ho,, n-C5H.11, nC^H^, nθ7Hi5, nCgH^ and nCj 1H23.

Suitable values for pyridyl moieties in R2 include 2-and 4 - pyridyl.

Suitable values for optional substituents on alkyl moieties in R7 include acetoxy.

Suitable values for z in R2 include 0 or 1.

Suitable values for C1-4 alkyl groups in R2 include methyl and ethyl.

Suitable values for R3 include hydrogen, methyl, ethyl, n- and iso-propyl. and R, 252 -, -SS£ - and i-butyl. Preferably R3 is methyl.

Suitable values for A and B include -(CH2..2- and -(CH2..3-.

Preferably, A is -(CH2>3-.

Preferably, B is -(CH2>2-.

There is a group of compounds within formula (I) of formula (IA):

R,- (CH ₂ ) ₂ — R<

(IA) wherein R2* is CONHR7 or CSNHR7 where R7 is as defined in formula (I), and the remaining variables are as defined in formula (I). There is another group of compounds within formula (I) of formula (IB):

R,- (CH ₂ ) ₂ — R ₄

(IB) wherein R2^ is COR7 where R7 is as defined in formula (I), and the remaining variables are as defined in formula (I).

Suitable and preferred values for the variables of formulae (IA), and (IB) are

as described for the corresponding variables under formula (II).

There is a preferred group of compounds within formula (IB) which are characterised in that R7 is Cι_ 2 alkyl.

The compounds of formula (IB) wherein R7 is Cι_i2 alkyl, or pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvate thereof, are class HI antiarrhythmic agents, and hence can be used as such, for example they are effective against ventricular fibrillation.

There is a particularly preferred group of compounds within formula (IB) which are characterised in that R7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and N 5R6 wherein R5 and R6 are independently hydrogen (especially)or C - alkyl; a preferred substituent is a nitro group, especially a 4-nitro group.

The compounds of formula tJB) wherein R7 is optionally substituted phenyl, optional substituents being selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NR5R5 wherein R5 and R are independently hydrogen (especially)or C - _β alkyl, or pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof, are combined class HI and class IN antiarrhythmic agents and hence can be used as such, for example they are particularly effective against ventricular fibrillation, they are also considered to be effective against atrial fibrillation and flutter.

In its most preferred aspect, the compound of formula (I) is that compound wherein R represents 3,4-dimethoxyphenyl, R2 represents a 4-nitrobenzoyl group, R3 represents methyl, R4 represents 3,4-dimethoxyphenyl, A represents CH2)3 and B represents (CH^l- i.e.the compound of example 50 of EP 0233762.

Where the compounds of formula (I) possess chiral carbon atoms (for example when A and or B are branched alkylene) they may exist in more than one stereoisomeric form, the invention extends to all such stereoisometric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates.

The different stereoisomeric forms may be separated or resolved one from the other by the usual methods or any given isomer may be obtained by stereospecific or asymmetric syntheses.

When used herein alkyl, alkene and alkylene includes straight- and branched-chain alkyl, alkene and alkylene groups, each with up to 12, suitably up to 6 carbon atoms, unless stated to the contrary.

Pharmaceutically acceptable salts include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and

pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto-glutaric, a-glycerophosphoric, and glucose- 1 -phosphoric acids. Preferably the acid addition salt is a hydrochloride; this is conveniently prepared by treating the relevant compound with HCl in a solvent such as diethylether.

Pharmaceutically acceptable salts also include quaternary salts. Examples of quaternary salts include such compounds quaternised by compounds such as Rg-T wherein Rg is C - _. alkyl, phenyl-Ci-g alkyl or C5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rg include methyl, ethyl and n- and is2- propyl; and benzyl and phenethyl. Suitable T include halide such as chloride, bromide and iodide.

Pharmaceutically acceptable salts also include pharmaceutically acceptable N-oxides, and the invention extends to these.

The compounds of the formula (I) and their pharmaceutically acceptable salts may also form solvates with pharmaceutically acceptable solvates and the invention extends to these.

It will also be realised that salts of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of the formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.

Certain of the compounds of formula are considered to be novel. Such compounds therefore form a further part of the present invention.

Accordingly, there is provided a compounds of formula (IC):

R,-N— A— N— B— R ₄

I I R2 R's

(IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein

Rl, R2, A, B and R4 are as defined in relation to formula (I), and R ^* 3 represents C2-6 alkene or C3_ cycloalkyl.

The invention also provides a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier. The invention also provides a compound of formula (IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance, in particular for use in the

treatment of arrhythmia.

There are also certain compounds of formula (I) and the pharmaceutically acceptable salts thereof and/or the pharmaceutically acceptable solvates thereof which have not been disclosed in EP-A-0233762 and which are considered to be novel and form part of the present invention.

Accordingly, there is provided:

N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[3-[[2-(3,4- dimethoxyphenyl)ethyl]methyl-amino]propyl] -4-nitrobenzamide,

N-(4-fluorophenyl)-N'-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-4-nitrobenzamide,

N-(3,4-dichIorophenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethy l] methylamino]propyI] -4-nitrobenzamide ,

N-(3,4,5-trimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl) ethyI] methylamino]propyl] -4-nitrobenzamide, N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyI)ethyl] -2- propenylaπdno]propyl]-4-mtrobenzamide,

4-amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimemoxyphenyl)ethyl]meΛyl-aπ-dno] propyl]ben-jamide,

N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]p--opyl]- N-[3,4-bis(l- methylethoxy) phenyl]-4-nitrobenzamide,

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)eth yl](l-methyl- ethyl)amino]propyl]-4-nitrobenzamide,

N-(3,4-diethoxyphenyl)-N-[3-[[2-(3,4-Diethoxyphenyl)ethyl ]methyl- aιmno]propyl]-4-nitrobenzenecarboxamide, N-(3,4-d-.methoxvphenyl)-N-[3[[2-(3,4-dimethoxyphenyl)ethyl] cyclopropyl- amino]propyl]-4-nitrobenzamide,

N-(4-hydroxy-3-methoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphen yl)ethyl]- methylamino]propyl]-4-nitrobenzamide, and

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- d.-memoxyphenyl)ethyl]memyIamino]propylI-4-pyriά^ecarboxami de, (each of which which may be referred to hereinafter as a 'Novel Compound'); or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

The invention also provides a pharmaceutical composition comprising a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

The invention also provides a Novel Compound or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance, in particular for use in the treatment of arrhythmia.

Pharmaceutically acceptable salts include conventional salts such as those disclosed in EP-A-0233762, but in particular the hydrochloride:

Pharmaceutically acceptable solvates include hydrates.

The compounds of formula (I), pharmaceutically acceptable salts thereof and/or a pharmaceutically acceptable solvates thereof may be prepared according to known methods including those methods disclosed in EP-A-0233762. In particular, the compound wherein Ri represents 3,4-dimethoxyphenyl, R2 represents a 4- nitrobenzoyl group, R3 represents methyl, R4 represents 3,4-dimethoxyphenyl, A represents (CH2)3 and B represents (CH2)2 may be prepared according to methods disclosed in Example 50 of EP-A-0233762.

EP-A-0233762 also discloses certain intermediates for preparing the compounds of formula (I) which intermediates have the formula (II):

Rl - NH - A - NR3 - B - R ₄ (ID

wherein Rj, A, R3, B and R4 are as defined in relation to formula (I).

Surprisingly, it has been discovered that the compounds of formula (II) show potential as an antiarrhythmic agents.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the above defined formula (II) and a pharmaceutically acceptable carrier therefor.

The invention also provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as a therapeutically active compound. In particular , the invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of arrhythmia.

In a further aspect, the present invention provides a method for the treatment of arrhythmia in human or non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

The invention also provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia.

Particular, suitable and prefeπred values for the variables R , A, R3, B and R4 in the compound of formula (II) are as defined herein in regard to the compounds of formula (I)

A compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be prepared according to known methods including those methods disclosed in EP-A-0233762.

As indicated above compounds of formula (I) and (II) and the pharmaceutically acceptable salts thereof and/or the pharmaceutically acceptable solvates thereof (the active compounds) are of use in medicine.

Active compounds or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form. An amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of the active compounds , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 50 to 2000 mg, for example 10 to 75mg, that is in the range of approximately 0.002 to 35 mg kg day, more usually 1 to 30 mg/kg/day, for example 0.15 to 1 mg kg day.

At the above described dosage range, no toxicological effects are indicated for the compounds of the invention.

In such treatment, the active compound may be administered by any suitable route, e.g. by the oral, parenteral or topical routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.

Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally ad inistrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting

agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl β-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound. For topical administration, the composition may be in the form of a transdermal ointment or patch for systemic delivery of the active compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as 'Dermatological Formulations' - B.W. Barry (Drugs and the

Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).

In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

No toxicological effects are indicated when an active compound is administered in the above mentioned dosage ranges.

The following, descriptions, examples and pharmacological methods illustrate the invention but do not limit it in any way.

Description 1

Ethyl [3-[2-[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-propionate

A solution of 7.8 g, (40 mmol) of 3,4-dimethoxy-N-methylbenzeneethanamine ,5.5 g,

(40 mmol) of ethyl 3-chloropropionate , and 4.3 g, (42 mmol) of triethylamine in

150 ml of acetonitrile was refluxed for two and half hours. After cooling to room 0 temperature, the reaction mixture was concentrated in vacuo. The resulting crude product was dissolved in ethyl acetate and washed successively with water and brine.

The organic layer was dried over MgSO4 and concentrated in vacuo to dryness, affording 10.7 g (90%) of a pure yellow oil.

1H NMR (CDC1 ₃ ) δ = 1.25 (t,3H,J=7Hz,CH ₃ ); 2.32 (s,3H,NCH ₃ ); 2.40-2.85 5 (m,8H,(CH2)x4); 3.85 (s,3H,OCH ₃ ); 3.88 (s,3H,OCH ₃ ); 4.13

6.65-6.85 (m,3H,Ar) ppm.

Description 2

0 N-[2-(3,4-Dimethoxyphenyl)ethyI]-3-[2-(3,4-dimethoxyphenyl)e thyl]methyl- aminojpropanamide

5 A mixture of 1.5 g (5 mmol) of ethyl [3-[2-[2-(3,4- dimethoxyphenyl)ethyl]methylamino]-propionate (Dl) and 0.9 g (5 mmol) of (3,4- dimethoxy)-benzeneethanamine was warmed up to 150°C under argon for 18 hours, in the presence of a catalytic amount of trimethylaluminium. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate and washed 0 with water and treated with a 5% aqueous HCl. The aqueous layer was separated and successively washed with ethyl acetate, basified with 5N aqueous NaOH, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel using 97:3 methylene chloride:methanol afforded

600 mg (30%) of a yellow amorphous solid.

^X H NMR (CDCI3) δ = 2.20 (s,3H,NCH ₃ ); 2.25-2.95 (m,10H,CH ₂ x5); 3.35

(m^H,CH ₂ ); 3.81 (s,3H,OCH ₃ ); 3.82 (s,3H,OCH ₃ ); 3.87 (s,3H,OCH3); 3.88

(s,3H,OCH ₃ ); 6.60-6.85 (m,6H,Ar); 8.12 (m,lH,exch.D ₂ O,NH) ppm.

Description 3

3-Chloro-N-(4-fluorophenyl)-propanamide

To a solution of 5.00 g (45 mmol) of 4-fluorobenzeneamine and 4.88 g (56 mmol) of triethylamine in 30 ml of methylene chloride at 0°C,was added dropwise 5.72 g (45 mmol) of 3-chloropropionyl chloride neat or dissolved in 5 ml methylene chloride and the reaction mixture was allowed to stir at room temperature for 1 hr.The reaction mixture was then washed with 100 ml water, 100 ml of 0.5N HCl, and then with water until neutral.

The organic phase was separated, dried over MgSO4 and concentrated to afford 5.51 g (60%) of a pale pink product which was purified by trituration with diisopropyl ether. m.p. 106-107°C.

Description 4

N-(4-Fluoropheπyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]meth ylamino]- propanamide

To a stirred solution of 4.22 g (20 mmol) of 3-chloro-N-(4-fluorophenyl)- propanamide (D3) and 2.1 g (26 mmol) of triethylamine in 50 ml of acetonitrile, 4.08 g (21 mmol) of 3,4-dimethoxy-N-methylbenzeneethanamine were added and the reaction mixture was refluxed for 24 hours. After cooling the reaction mixture was concentrated to dryness.

150 ml of ethyl acetate were added and the solution was washed with 100 ml water.

The organic phase was separated, dried over MgSO4 ^anα ^ concentrated in vacuo affording 1.09g (14%) of an orange oil. This was purified by flash chromatography on silica gel using 95:5 ethyl acetate : methanol.

Description 5

N-(4-Fluorophen l)-N'-[2-(3,4-dimethoxyphen l)ethyI]-N'-methyl-1 - propanediamine

To a stirred solution of 1.0 g (2.7 mmol) of N-(4-fluorophenyl)-3-[[2-(3,4- dimethoxyphenyl) ethyl]methylamino]-propanamide (D4) in 20 ml of tetrahydrofuran, 0.15 g of LiAlHLt (4.1 mmol) was added cautiously and the reaction mixture was refluxed for 4 hours.

A further 0.15 g of IJAIH4 (4.1 mmol) was added and the mixture was refluxed for 2 hours.

The mixture was then cooled to room temperature and quenched with 0.30 ml water, then washed with 0.30 ml of 15% aqeous NaOH and 0.60 ml water, then diluted with

15 ml of diethyl ether.The precipitate was removed by filtration.The organic phase was separated, dried over MgSO4 and concentrated to give 0.7g (73%) of a yellow oil.

Description 6

3-Chloro-N-(3,4-dichlorophenyl)propanamide.

To a solution of 5.00 g (30 mmol) of 3,4-dichlorobenzeneamine and 3.30 g (38 mmol) of triethylamine in 30 ml of methylene chloride cooled to 0°C 3.81 (30 mmol) of 3-chloropropionyl chloride neat or dissolved in 5 ml methylene chloride were added dropwise and the reaction mixture was allowed to stir for 1 hour. The reaction mixture was then washed with 100 ml water and 100 ml of 0.5N aqueous HCl, then again with water until neutraLThe organic phase was separated,

dried over Na2SO4, concentrated and triturated with diisopropyl ether to afford 5.21 g (67%) of an off-white product, mp = 126-127°C.

Description 7

N-(3,4-Dichlorophenyl)-3-[[2-(3,4-dimethoxyphenyl)]ethyl] methylamino]- propanamide.

To a stirred solution of 5.2 g (20 mmol) of 3-chloro-N-(3,4- dichlorophenyl)propanamide (D6) and 1.74 g ( 20 mmol) of triethylamine in 50 ml of acetonitrile, 3.90 g ( 20 mmol) of 3,4-dimemoxy-N-memylben-reneethanamine were added and the reaction mixture was refluxed for 24 hours.

On cooling, the reaction mixture was concentrated to dryness. 200 ml of ethyl acetate were added and the solution was washed with 100 ml water.

The organic phase was separated, dried over Na2SO4 and concentrated, to afford 4.32 g (90%) of a pale yellow oil which was used directly in a subsequent reaction.

Description 8

N 3,4-DichIorophenyl)-N42-(3AdimethoxyphenyI)ethyl]-N^methyl-l ,3- propanediamine

To a stirred solution of 4.32 g (11 mmol) of N-(3,4-dϊchlorophenyl)-3-[[2-(3,4- dimethoxyphenyl)ethyl]methylamino]-propanamide (D7) in 40 ml of tetrahydrofuran,0.59 g (16 mmol) of LiAlH4 were added cautiously, and the reaction mixture was refluxed for 4 hours.The mixture was then cooled to room temperature and quenched with 0.56 ml water, then washed with 0.56 ml of 15% aqueous NaOH, then with 1.03 ml of water The organic phase was diluted with 15 ml diethyl ether.The precipitate was removed by fiItration.The organic phase was separated,

dried over MgSO4 ^an ^ concentrated in vacuo to give a yellow oil. This was purified by flash chromatography on silica gel using 3:1 methylene chloride : ethyl acetate and then 9:1 methylene chloride : methanol to afford 2.6 g (62%) of a pale yellow oil.

Description 9

3-Ch-oro-N-(3,4-5-trimethoxyphenyl)propanamide.

To an ice cooled stirred solution of 5.50 g (30 mmol) of 3,4,5 trimethoxybenzeneamine and 3.30 g (38 mmol) of triethylamine in 30 ml of methylene chloride, 3.81 g (30 mmol) of 3-chloropropionyl chloride neat or dissolved in 5 ml methylene chloride were added dropwise and the reaction mixture was allowed to stir for 1 hour.The reaction mixture was then washed with 100 ml of water, 100 ml of 0.5N aqueous HCl, and again with water until neutral.

The organic phase was separated, dried over Na2SO4 concentrated and triturated with diisopropyl ether to afford 6.70 g (82%) of an off-white solid. mp = 99-100°C.

Description 10

N-(3,4^-TrimethoxyphenyI)-3-[[2-(3,4-dimethoxyphenyI)ethy l]methylamino]- propanamide

To a stirred solution of 6.70 g (20 mmol) of 3-chloro-N-(3,4,5- trimethoxyphenyl)propanamide (D9) and 1.74 g (20 mmol) of triethylamine in 50 ml of acetonitrile, 3.90 g (20 mmol) of 3,4-dimethoxy-N-methylbenzeneethanamine were added and the reaction mixture was refluxed for 24 hours.

On cooling, the reaction mixture was concentrated in vacuo to dryness, 200 ml of ethyl acetate were added and the solution was washed with 100 ml of water. The

organic phase was separated, dried over Na2SO4 and concentrated affording 7.4 g

(70%) of a pale yellow oil which was used directly in a subsequent reaction.

Description 11

N-O^^-TrimethoxyphenyD-N'-P-CS^-dimethoxypheny ethyπ-N'-inethyl-l^- propanediamine

To a stirred solution of 7.4 g (17 mmol) of N-(3,4,5-trimethoxyphenyl)-3-[[2-(3,4- dimethoxyphenlyl)ethyl]methylamino]-propanamide (D10) in 50 ml of tetrahydrofuran, 0.97 g of LiAlH-4 (26 mmol) were added cautiously and the reaction mixture was refluxed for 4 hours. The mixture was then cooled to room temperature and quenched with 1.03 ml water, then washed with 1.03 ml of 15% aqueous NaOH then with 2.6 ml of water. The organic phase was diluted with 15 ml of diethyl ether and the precipitate was removed by filtration.The organic phase was then separated, dried over MgSO4 and concentrated in vacuo to give a pale pink oil. This was purified by flash chromatography on silica gel using 9:1 methylene chloride : methanol to afford 1.14 g (16%) of a pale pink oil.

Description 12

3,4-Dimethoxy-N-(2-propenyI)-benzeneethanamine

To a stirred solution of 5.43 g (30 mmol) of 3,4-dimethoxybenzeneethanamine in 60 ml acetonitrile, 5.14 g (30 mmol) of K2CO3 were added.Then 3.63 g (30 mmol) of allyl bromide in 20 ml acetonitrile were added dropwise over a period of 30 minutes. Agitation was maintained at room temperature overnight The mixture was then concentrated in vacuo to dryness, dissolved in 100 ml of diethyl ether washed three

times with 100 ml water, dried over MgSO4 and concentrated in vacuo.

Purification by flash chromatography on silica gel using 95:5 methylene chloride : methanol afforded 1.70 g (25%) of an oil.

Description 13

N-(3,4-DimethoxyphenyI)-3-[[2-(3,4-dimethoxyphenyl)ethyl] 2-propenylamino]- propanamide

To a stirred solution of 1.62 g (7.3 mmol) of 3,4-dimethoxy-N-(2-propenyl)- benzeneethanamine (D12) and 0.73 g (7.3 mmol) of triethylamine in 20 ml of acetonitrile 1.80 g (7.3 mmol) of 3-chloro-N-(3,4-dimethoxyphenyl)-propanamide were added and the mixture was refluxed for 20 hours.

On cooling the mixture was concentrated to dryness in vacuo, the residue dissolved in 100 ml ethyl acetate, washed with 100 ml water and extracted with 100 ml of IN aqueous HCl. The aqueous phase was separated, basified with IN aqueous NaOH and the product was extracted twice with 50 ml ethyl acetate, washed twice with 50 ml of water, dried over MgSO4 and concentrated in vacuo.

Purification by flash chromatography on silica gel using 95:5 ethyl acetate : ethanol followed by concentration to dryness yielded 1 g (32%) of an oil.

Description 14

N-(3,4-DimethoxyphenyI)-N ^, -[2-(3,4-dimethoxyphenyI)ethyl]-N'-2 _T propenyl-1 - propanediamine

To a stirred solution of 1.0 g (2.4 mmol) of N-(3,4-dimethoxyphenyl)-3-[[2-(3,4- dimethoxyphenyl)ethyl]2-propenylamino]-propanamide (D13) in 15 ml of tetrahydrofuran, 0.133 g (3.5 mmol) of iAlH4 were added cautiously and the

reaction mixture was then refluxed for 3 hours. After cooling to room temperature it was quenched with 0.15 ml water, then washed with 0.15 ml of 15% aqueous NaOH and 0.45 ml water.The organic phase was diluted with 15 ml of diethyl ether and the precipitate removed by filtration. The organic phase was then separated, washed twice with 20 ml water, dried over MgSO4 and concentrated in vacuo.

Purification by flash chromatography on silica gel using 97:3 methylene chloride : ethanol afforded 0.25 g (25%) of an oil.

Description 15

3-Chloro-N-3,4-bis(l-methylethoxy)phenyl-propanamide

2.0 g (16 mmol) of 3-chloropropionyl chloride were added dropwise to an ice cooled stired solution of 3 g (14 mmol) of 3,4-bis(l-methylethoxy)benzamine and 1.59 g (16 mmol) of triethylamine in 30 ml methylene chloride. The mixture was stirred for 1 hour at room temperature and 20 ml water were added. The organic phase was washed sucessively with 20 ml 0.1N aqueous hydrochloric acid, water, a saturated aqueous NaHCO3 solution, again with water and then dried over MgSO4 and concentrated in vacuo to dryness. The residue was triturated in 75 ml of diisopropyl ether to yield 2.5 g (59.6%) of the desired compound as white crystals.m.p = 106°C ¹ HNMR(CDC1 ₃ ) δ = 1.31 (d,6H,J=6.4Hz,CH ₃ x2); 1.34 (d,6H,J=6.4Hz,CH ₃ x2); 2.79 (t,2H,J=6.4Hz,CH ₂ -CO); 3.88 (t,2H,J=6.4Hz,CH ₂ Cl); 4.36-4.46 (m,2H,CH(CH3)2); 6.80-6.95 (broad band,2H,Ar); 7.21 (broad band,lH,exchD2θ,NH); 7.31 (s,lH,Ar) ppm.

Description 16

N-[3,4-bis(l-methyIethoxy)phenyl]-3-[[2-(3,4-dimethoxyphe nyI)ethyl]methyl- aminojpropanamide

A solution of 1.95 g (10 mmol) of N-Methyl-3,4-dimethoxybenzenethanamine, 3 g (10 mmol) of 3-chloro-N-3,4-bis (l-methylethoxy)phenyl-propanamide and 1.52 ml (11 mmol) of triethylamine in 50 ml acetonitrile was refluxed for 18 hours under stirring. The solvent was concentrated to dryness and the residue taken up in 50 ml methylene chloride. The organic solution was washed with water, dried over MgSO4 and the solvent was evaporated in vacuo. The resulting brown oil was purified by chromatography on silica gel using 99:1 methylene chloride:methanol to afford 3.74 g (81.5%) of a light brown oil.

*H NMR (CDCI3) δ = 1.30 (d,6H,J=6.1Hz,CH ₃ x2); 1.33 (d,6H,J=6.1Hz,CH ₃ x2); 2.42 (s,3H,NCH ₃ ); 3.81 and 3.84 (2s,6H,2CH ₃ O); 4.37 and 4.50 (2 hept,2H,J=6. lHz,2CH); 6.56(dd,2H, J=2.5Hz, J'=8.5Hz,Ar); 6.70-6.73(m,3H„ Ar); 6.81(d,lH,J4=8.5Hz,Ar); 7.40(d,lHJ=2.5Hz,Ar); lO.53(s,lH,exch.D2O,NH)ppm.

Description 17

N-[2-(3,4-dimethoxyphenyI)ethyl]-N-methyl-N'-[3,4-bis(l-m ethylethoxy)phenyI]- 1,3-propanediamine

0.139g (3,6 mmol) of lithium aluminium hydride were added by small fractions, under stirring, to 10 ml dry tetrahydofuran (THF) cooled at 0°C. Then a solution of 1 g of (2.2 mmol) of N-[3,4-bis(l-methylethoxy) phenyl]-3-[[2-(3,4- dimethoxyphenyl)ethyl]methylamino]propanamide (D 16) in 5 ml dry THF was added dropwise. The mixture was stirred some minutes at room temperature then refluxed for 3 hours. Then 0.14 ml of water were added dropwise followed by 0.14 ml of 15% aqueous NaOH and again 0.14 ml of water. The precipitate was filtered off, washed twice with 5 ml of ethyl acetate and the organic solutions were concentrated in vacuo

to dryness. The residue was purified by chromatography on silica gel using first 98:2 then 95:5 methylene chIoride:methanol to afford 817 mg (84.5%) of a brown oil.

^J H NMR (CDC1 ) δ = 1.27 and 1.32 (2d,12H,J=6.IHz,(CH ₃ ) _x4 ); 1.82

(q,2H,J=6.6HzCH ₂ ); 2.36 (s,3H,NCH ₃ ); 2.53-2.84 (m,6H,3CH ₂ ); 3.13 (t,2H,J=6.6Hz,CH ₂ ); 3.85 and 3.87 (2s,6H,2CH ₃ O); 4.24 and 4.48 (2 6.13 (dd,lH,J=2.7Hz,J ^, =8.5Hz,Ar); 6.22

(d,lHJ=2.7Hz,Ar); 6.70-6.82 (m,4H,Ar) ppm.

Description 18

N-(3,4-DimethoxyphenyI)-3-[[2-(3,4-dimethoxyphenyI)ethyI] (l-methylethyl)- amino] propanamide

Starting from 2.0 g (8.9 mmol) of N-(l-methylethyl)-3,4-dimethoxy benzeneethanamine and 2.18 g (8.9 mmol) of 3-chloro-N-3,4-dimethoxyphenyl propanamide and following the method described in description 16, yielded 580 mg (15%) of the title compound as purple oil. The compound was purified by chromatography on silica gel using 95:5 methylene chloride: methanol. iHNMR (CDCI3) δ = 1.11 (d,6H,J=6.6Hz,(CH ₃ ) ₂ -CH); 2.45-2.60 (m,2H,CH ₂ CO); 2.75-2.90 (m,6H,3CH2); 3.26 (hept,lH,J=6.64,NCH(CH3) ₂ ); 3.79, 3.83,3.85 and 3.87 (4s,12H,4CH ₃ O); 6.57-6.81 (m,5H,Ar); 7.44 (s,lH,Ar); 10.65 (s,lH,exch D2θ,NH)ppm.

Description 19

N-O^-Dimethoxypheny -N'-P^S^-dimethoxyphenyDethyπ-N'^l-methylethyl)- 1,3-propanediamine

Starting from 580 mg (1.3 mmol) of N-(3,4-dimethoxyphenyI)-3-[[2-(3,4- dimethoxyphenyl) ethyl](l-methylethyl)amino]propanamide (D18) and following the

method described in description 17, yielded 180 mg (33.3 %) of the title compound as yellow oil. The compound was purified by chromatography on silica gel using 98:2 methylene chloride:methanol.

!H NMR (CDCI3) δ = 1.11 (d,6H,J=5.7Hz,(CH ₃ ) ₂ -CH); 1.78-2.00 (m,2H,CH ₂ ); 2.67-2.92 (m,6H,3CH ₂ ); 3.16 (t,2H,J=6.2Hz,CH ₂ ); 3.00-3.20 (m,lH,CH{CH3)2);

3.80, 3.84, 3.85 and 3.86 (4s,12H,4CH ₃ ) ₂ ); 6.12 (dd,lH,J=2.6Hz,J'=8.5Hz,Ar); 6.23

(d,lHJ=2.6Hz,Ar); 6.70-6.82 (m,4H,Ar)ppm.

Description 20

3-Chloro-N-(3,4-diethoxyphenyl)-propanamide

3.7 g (29 mmol) of 3-chloropropionyl chloride were added dropwise to an ice cooled stirred solution of 5.0 g (27.6 mmol) of 3,4-diethoxybenzeneamine and 3.07 g (30 mmol) of triethylamine in 40 ml methylene chloride. The mixture was stirred for 15 hours at room temperature, then washed with water, with 0.1N aqueous HCl, with a saturated aqueous solution of NaHCO3 and again with water. The organic solution was dried over MgSO4. Some silica gel was added, stirred some minutes, and filtered off to remove polar impurities. The solvent was concentrated to dryness in vacuo and the residue was triturated in diisopropyl ether to afford 4.8 g (63.7%) of crystals. m.p = 118°C

*H NMR (CDCI3) δ = 1.36-1.51 (m,6H,2CH ₃ ); 2.79 (t,2H,J=6.4Hz,CH ₂ CO); 3.88 (t,2H,J=6.4Hz,CH ₂ Cl); 4.00-4.17 (m,4H,2CH ₂ ); 6.77-6.92 (m,2H,Ar); 7.32 (s, 1H,AΓ); 7.28-7.40 (s,lH,exch D ₂ O,NH)ppm.

Description 21

N-(3,4-Diethoxyphenvl)-3-[[2-(3,4-diethoxyphenyl)ethvl]me thyl- amino] propanamide

Starting from 1.47 g (6.6 mmol) of N-methyl-3,4-diethoxybenzeneethanamine and

1.8 g (6.6 mmol) of 3-chloro-N-3,4-diethoxyphenyl)-propanamide (D20) and following the method described in description 16, yielded 1.65 g (54.5 %) of the title

compound as brown oil. The compound was purified by chromatography on silica gel using 95:5 methylene chloride:methanol.

^J HNMR (DMSO-d ₆ ) δ = 1.23-1.37 (m,12H,4CH ₃ ); 2.24 (s,3H,CH ₃ n); 2.40

(t,2H,J=6.6Hz,CH ₂ ); 2.50-2.77 (m,6H,3CH ₂ ); 3.39-4.03 (m,8H,4CH ₂ O); 6.69 (dd,lH, J=1.5Hz,J'=8.1Hz,Ar); 6.73-6.89 (m,3H,Ar); 6.99

(dd,lH,J=2.2Hz,J'=8.7Hz,Ar); 7.29 (d,lH _r T=2.2Hz,Ar); 9.85 (s,lH,exch

D2θ,NH)ppm.

Description 22

^(S^-DiethoxyphenyD-N'-P^S^-diethoxyphenyDethyll-N'-methy l-l^- propanediamine

Starting from 1.65 (3.6 mmol) of N-(3,4-Diethoxyphenyl)-3-[[2-(3,4- diethoxyphenyl)ethyl] methylaminojpropanamide (D21) and following the method described in description 17, yielded 1.1 g (68.7 g) of the title compound as brown oil. The compound was purified twice by chromatography on silica gel using first 92.5:7.5 methylene:methanol then 90:10 ethylacetate:methanol. iHNMR (DMSO-d6) δ = 1.17-1.36 (m,12H,4CH ₃ ); 1.65 (q,2H,J=6.7Hz,CH ₂ ); 2.22 (s,3H,CH N); 2.38-2.68 (m,6H,3CH ₂ ); 2.93 (t,2H,J=6.7Hz,CH ₂ ); 3.77-4.03 (m,8H,4CH ₂ O); 5.15 (s,lH,exchD2O,NH); 5.99 (dd,lH,J=2.2Hz,Ar); 6.53-6.74 (m,4H,Ar) ppm.

Description 23

N-Cyclopropyl-3,4-dimethoxybenzeneacetamide

26.4 g (0.123 mol) of 3,4-dimethoxybenzeneacetyl chloride were added dropwise to a stirred solution of 6.7 g (0.12 mol) of cyclopropanamine and 13.35 g (0.132 mol) of triethylamine in 200 ml methylene chloride. The reaction mixture was stirred for 15h at room temperature then washed twice with water, dried over MgSO4 and

concentrated in vacuo to dryness affording 25.2 g (89.4%) of yellow crystals. ^l H NMR (DMSO-d<5) ^δ = 0.32-0.42 (m,2H£H - H ₂ ); 0.53-0.64 (m,2H,CH ₂ -CU2);

2.59 (m,H,CH); 3.25 (s,2H,CH ₂ CO); 3.71 and3.72 (2s,6H,2CH ₃ O); 6.73

(dd,lH,J=1.9Hz, J'=8.1Hz,Ar); 6.84 (s,lH,Ar); 6.86 (d,lH ^* =8.1Hz,Ar); 8.05 (s, 1 H,exch D2θ,NH) ppm.

Description 24

N-Cyclopropyl 3,4-dimethoxybenzeneethanamine

A solution of 12 ml of acetic acid in 15 ml of dioxane was added dropwise to a stirred solution of 10 g (42 mmol) of N-cyclopropyl-3,4-dimethoxybenzeneacetamide (D23) and 8.04 g (210 mmol) of sodium borohydride in 50 ml of dioxane, at room temperature. The reaction mixture was refluxed for 3 hours under stirring then poured onto 500 g of crushed ice. The aqueous phase was extracted four times with 150 ml of methylene chloride and the organic solution was extracted three times with 2N aqueous HCl. The acidic phases were washed with 100 ml ethylacetate, basified with 35% aqueous NaOH and extracted three time with 150 ml of methylene chloride. The organic solution was dried over MgSO4 ^anc ^ concentrated in vacuo to dryness affording 5.5 g (59%) of a yellow oil.

!H NMR (DMSO-c ) δ = 0.12-0.23 (m,2H,CH ₂ -CH ₂ ); 0.33-0.40 (m,2H,CH ₂ -CH ₂ ); 1.98-2.14 (m,2H,CH and NH); 2.63 (t,2H,J=6.7Hz,CH ₂ Ar); 2.78 (t,2H,J=6.7Hz,CH N) ; 3.70 and 3.73 (2s,6H,2CH ₃ O); 6.15-6.87 (m,3H,Ar) ppm.

Description 25

N-(3,4-Dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] cyclopropyI- aminojpropanamide

H

A solution of 2.5 g (11.2 mmol) of N-cyclopropyl 3,4-dimethoxybenzeneethanamine

(D23), 5.5 g (22.5 mmol) 3-chloro-N-3,4-dimethoxyphenyl propanamide and 3.4 ml

(22.5 mmol) triethylamine in 50 ml acetonitrile were refluxed for 15 hours under stirring. The reaction mixture was poured on water and extracted with methylene chloride. The methylene chlordie solution was washed with water, dried over MgSO4 and concentrated to dryness. The residue was chromatographed on silica gel using ethyl acetate then 95/5 ethyl acetate/methanol. The compound was then taken up in methylene chloride and extracted with 2N aqueous HCl. The acid aqueous phase was basified with 30% aqueous NaOH and extracted with ethyl acetate. The organic solution was dried over MgSO4 and concentrated in vacuo to dryness affording 1.42 g (29.6%) of the title compound as brown oil. ^r H NMR (DMSO-d ₆ ) δ = 0.24-0.53 (m,4H,(CH2)2). 1.80-1.93 (m,lH,CH) ; 2.57- 2.88 (m,4H,2CH ₂ ); 2.88-3.03 (m,2H,CH ₂ ); 3.63-3.76 (m,14H,4CH ₃ O and CH2); 6.71 (dd,lHJ=1.6HzJ'=8.2Hz,Ar); 6.76-6.90 (m,3H,Ar); 7.06 (dd,lHJ=2.2HzJ'=8.2Hz,Ar); 7.28 (d,lH,J=2.2Hz,Ar) 9.80 (s,lH,exch D ₂ O,NH) ppm

Description 26

N-(3,4-DimethoxyphenyI)-N'-[2-(3,4-dimethoxyphenyl)ethyI] -N'-cyclopropyl-l,3- propanediamine

Starting from 1.37 g (3.2 mmol) N-(3,4-Dimethoxyphenyl)-N-3-[[2-(3,4- dimethoxyphenyl) ethyl]cyclopropylamino]propynamide (D25) and following d e method described in Description 17, yielded 0.78 g (58.7%) of the title compound as brown oil. The compound was purified by chromatography on silica gel using 95/5 methylene chloride/methanol.

^X H NMR (DMSO-dg) δ = 0.23-0.53 (m,4H,(CH2)2); 1-53-1.88 (m,3H,CH ₂ and CH) ; 2.60-2.83 (m,6H,3CH2); 2.87-3.00 (m,2H,CH ₂ ); 3.61, 3.68, 3.70 and 3.72

(4s,12H,4CH ₃ O); 5.09-5.23 (broad band, lH,exch D ₂ O,NH); 6.01

(dd,lHJ=2.3Hz '=8.6Hz,Ar); 6.24 (d,lH,J=2.3Hz,Ar); 6.65-6.87 (m,4H,Ar) ppm

Description 27

3-Chloro-N-[3-methoxy-4-(phenylmethoxy)phenyl]propanamide

Starting from 3.3 g (0.014 mole) [3-methoxy-4-(phenylmethoxy)]benzeneamine and following the method described in Description 15, yielded 3.19 g (69.3%) of the title compound as pink crystals. The compound was purified by chromatography on silica gel using 98/2 methylene chloride/methanol. m.p = 121 °C

NMR (CDC1 ₃ ) δ = 2.78(t,2H,J=6.4Hz,CH ₂ CO); 3.87 (t,2HJ=6.4Hz,CH ₂ Cl); 3.88 (s,3H,CH ₃ O); 5.12 (s,2H,OCH ₂ Ar); 6.75-6.84 (m,2H,Ar); 7.27-7.48 (m,6H,Ar) ppm

Description 28

3-[[2-(3,4-DimethoxyphenyI)ethyl]methylamino]-N-[3-methox y-4- (phenylmethoxy)phenyl]-propanamide

A soluton of 3 g (9.4 mmol) of 3-chloro-N-[3-methoxy-4- (phenylmethoxy)phenyl]propanamide (D27), 1.83 g (9.4 mmol) N-methyl-3,4- dimethoxybenzeneethanamine and 1.04 g (10.3 mmol) triethylamine in 50 ml acetonitrile were refluxed for 4 hours. The solvent was concentrated to dryness and the residue taken up in 50 ml methylene chloride. The organic solution was washed with water, dried over MgSO4 and the solvent was evaporated in vacuo. The resulting pink oil was chromatographed on silica gel using 98.5/1.5 methylene chloride/methanol affording 3.47 g (77.4%) of the title compound as light pink crystals. m.p = 121°C

!H NMR (DMSO-d ₆ ) δ = 2.25 (s,3H,NCH ₃ ); 2.36-2.78 (m,8H,4CH2); 3.68, 3.70 and 3.73 (3s,9H,3CH ₃ O); 5.02 (s,2H,CH ₂ ); 6.67-7.04 (m,5H,Ar); 7.28-7.47 (m,6H,Ar) ; 9.90 (s,lH,exch D2O.NH) ppm

Description 29

N-[(3-Methoxy-4-(phenylmethoxy)phenyI]-N'-[2-(3,4-dimetho xyphenyI)ethyl]- N'-methyl-l^-propanediamine.

Starting from 3 g (6.3 mmol) 3-[[2-(3,4-dimethoxyphenyl)ethyl]-methylamino]-N-[3- methoxy-4-(phenylmethoxy)phenyl]propanamide (D28) and following the method described in Description 17, yielded 669 mg (22.9%) of the title compound as brown oil. The compound was purified by chromatography on silica gel using 98/2 methylene chloride/methanol. iHNMR (DMSO-d^) ^δ = ⁶⁶ (q,2HJ=6.7Hz,CH2); 2.23 (s,3H,CH ₃ NH); 2.45-2.74 (m,6H,3CH2); 2.95 3.69, 3.71 and 3.72 (3s,9H,3CH ₃ O); 4.89

(s^H,OCH ₂ Aτ) ; 5.97 (dd,lHJ=2.3HzJ'=8.5Hz,Ar); 6.25 (d,lHJ=2.3Hz,Ar); 6.65-

6.85 (m,4H„Ar); 7.38-7.46 (m,5H,Ar) ppm

Description 30

N-(4-Hydroxy-3-methoxyphenyl)-N'-[2-(3,4-dimethoxyphenyl) ethyI]-N ^, -methyl- 1,3-propanediamine

1.06 g (2.3 mmol) N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-N'-[(3-methoxy-4- phenylmethoxy)phenyl]-l,3—propanediamine (D20) and 0.12 g 10% Pd/C were hydrogenated in 50 ml methanol at 15°C under 5 to 10 bars for 4 hours. The catalyst was filtered off and the solvent concentrated to dryness. The resulting brown oil was chromatographed on silica gel using 98/2 methylene chloride/methane affording 510 mg (54%) of the title compound as brown oil.

^X HNMR (DMSO-d6) δ = 1.66 (q,2HJ=6.8Hz,CH ₂ ); 2.23 (s,3H,NCH ₃ ); 2.37-2.72 (m,6H,3CH2); 2.93 (t,2HJ=6.6Hz,CH ₂ ); 3.68, 3.70 and 3.72 (3s,9H,3CH ₃ O); 4.35 (broad band,lH,exch D ₂ O,ArOH) 5.94 (dd,lHJ=2.3Hz,J'=8.3Hz,Ar); 6.20

(d,lH,J=2.3Hz,Ar); 6.52 (d,lH,J=8.3Hz,Ar); 6.65-6.86 (m,3H,Ar); 7.85 (s,lH, exch

D ₂ O,NH) ppm

Example 1

N-[2-(3,4-Dimethoxyphenyl)ethyl]-N'-[3-[[2-(3,4-dimethoxy phenyI)ethyl]methyl- amino]propyI] -4-nitrobenzamide hydrochloride

A solution of 6.4 g, (15 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-[2-(3,4- dimethoxyphenyl)ethyl]methylamino]-propanamide in 100 ml of THF was added dropwise under argon to a suspension of 1.13 g (30 mmol) LiALH4 in 100 ml of

THF. The reaction mixture was then refluxed for two and half hours. After cooling to room temperature, the reaction was quenched by 1 ml of water, then washed by 1 ml of 15% aqueous NaOH, and 3 ml of water. The inorganic solid was removed by filtration and washed with THF. The filtrate was concentrated in vacuo. The resulting crude product was dissolved in diethyl ether, washed witii brine, dried over MgSO4 and concentrated in vacuo to dryness, affording 5 g of a yellow oil. A mixture containing 5 g, (12 mmol) of the isolated oil, 2.5 g (13 mmol) of 4-nitrobenzoyl chloride , and 1.4 g (14 mmol) of triethylamine in 150 ml of chloroform was refluxed under argon for 9 hours. After cooling down to room temperature, the reaction mixture was washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to dryness. The resulting crude product was purified by flash chromatography on silica gel using 95:5 methylene chloride:methanol, affording 1 g (12%) of an amorphous solid.The product was then disolved in 5 ml of ethyl acetate and 5.5N anhydrous HCl in diethyl ether was added dropwise. The resulting amorphous solid was triturated in anhydrous diethyl ether and afforded 0.9 g (85%) of the title compound as yellow cristals. m.p = decomp. ^l H NMR (DMSO-d^) : presence of syn and anti forms (ratio = 75/25) δ = 1.85-2.25 (m,2H,CH ₂ ); 2.50-3.50 (m,13H,(CH ₂ )x5,NCH ₃ ); 3.50-3.85 (m,I4H, (OCH )x4,CH2); 6.40-7.00 (m,6H,Ar); 7.30-7.65 (m,2H,Ar); 8.10-8.35 (m,2H,Ar); 10.45-10.75 (m,lH,exch.D2θ,NH) ppm.

Example 2

N-(4-Fluorophenyl)-N'-[3-[[2-(3,4-dimethoxyphenyI)ethyI] methyiamino]propyI]-4-nitrobenzamide

A solution of 0.7 g (2.0 mmol) of N'-(4-fluorophenyl)-N-[-2-(3,4- dimethoxyphenyl)ethyl]-N-methyl-l,3-propanediamine (D5), and 0.41 g (4.0 mmol) of triethylamine in 30 ml of chloroform was stirred in an ice bath.Then 0.45 g (2.4 mmol) of 4 nitrobenzoyl chloride dissolved in 10 ml chloroform were added dropwise.Agitation was maintained for 1 hour.

100 ml ethyl acetate were added and the mixture was washed twice with 100 ml of water, then with 50 ml of IN aqueous HCl. The aqueous phase was basified with NaOH and the product was extracted with ethyl acetate.The organic phase was then separated, dried over MgSO4 and concentrated in vacuo resulting in an orange oil.This last was purified by flash chromatography on silical gel using 9:1 methylene chloride : methanol. The product was then dissolved in diethyl ether and 0.1 ml of 5.5N anhydrous HCl in ether was added. The mixture was concentrated and dried in vacuo to afford 0.4 g (69%) of a yellow mousse. m.p = 80° C.

!HNMR(DMSO-d6) δ =1.97 (t,2H,J=6.9Hz,CH ₂ ); 2.78 (s,3H,NCH ₃ ); 2.94 (t,2H,J=7.9Hz, CH ₂ ); 3.24 (m,4H,CH ₂ x2); 3.72 (s,3Hx2,OCH ₃ x2); 3.92 (m,2H,CH ₂ NCO); 6.78 (d,lH,J=8.4Hz,Ar); 6.89-7.41 (m,6H,Ar); 7.54 (d,2H,J=8.4Hz,Ar)8.09 (d,2H,J=8.4Hz,AR); 10.40 (s,lH,exchD O,NH).

Example 3

N-(3,4-dichlorophenyI)-N-[3-[[2-(3,4-dimethoxyphenyl)ethy I] methylamino]propyI] -4-nitrobenzamide hydrochloride.

To an ice cooled stirred solution of 1 g (2.5 mmol) of N-(3,4-dichlorophenyl)-N'-[2- (3,4-dimethoxyphenyl)ethyl]-N'-methyl-l,3 propanediamine (D8) and 0.51 g (5 mmol) of triethylamine in 50 ml of chloroform, 0.56 g (3.0 mmol) of 4-nitrobenzoyl chloride dissolved in 10 ml of chloroform, were added dropwise. Agitation was maintained for 1 hour.

100 ml of ethyl acetate were added and the mixture was washed twice with 100 ml water, then with 50 ml of IN aqueous HCl. The aqueous phase was then separated and basified with aqueous NaOH.50 ml of ethyl acetate were added and the product was extracted. The organic phase was then separated, washed with water until neutral, dried over MgSO4 and concentrated, resulting in a yellow oil. This was purified by flash chromatography on silica gel using 98:2 ethyl acetate : methanol. The product was then dissolved in 10 ml diethyl ether and 0.1 ml of 5.5M anhydrous HCl in ether were added. The mixture was concentrated and dried in vacuo at 60°C and 0.1 mmHg affording 1.2Og (87%) of a pale yellow mousse, mp = 101°C.

!HNMR(DMSO-d6) δ =1.96 (m,2H,CH2); 2.78 (s,3H,NCH3); 2.93 (m,2H,CH2); 3.23 (m, 4H, CH2x2); 3.72 (s,3H,OCH3); 3.75 (s,3H,OCH3); 3.95 (m,2H,CH2NCO); 6.77 (d,lH,J=8.3Hz,Ar); 6.90 (m,2H,Ar); 7.32 (m,lH,Ar); 7.58 (m, 3H,Ar); 7.79 (d,lHj=2Hz,Ar); 8.15 (d,2H,J=8.3Hz,Ar); 10.37 (s,lH,exch.D ₂ O,NH)ppm.

Example 4

N-(3,4,5-Triιnethoxyphenyl)-N-[3-[[2-(3,4-diπιethoxyph enyl)ethyl] methylaminojpropyl] -4-nitrobenzamide hydrochloride.

To an ice cooled stirred solution of 1 g (2.4 mmol) of N-(3,4,5-trimethoxyphenyl)-N'- [2-(3,4-dimethoxyphenyl)ethyl]-N'-methyl-l,3 propanediamine (Dl 1) and 0.48 g (4.8 mmol) of triethylamine in 50 ml of chloroform, 0.53 g (2.9 mmol) of 4-nitrobenzoyl chloride dissolved in 10 ml chloroform were added dropwise. Agitation was maintained for 1 hour.Then 100 ml of ethyl acetate were added and the mixture was washed twice with 100 ml water, then extracted with 50 ml of IN aqueous HCl. The aqueous phase was then separated and basified witii NaOH. Then 50 ml of ethyl acetate were added and the product extracted. The organic phase was then separated, whashed with water until neutral, dried over MgSO4 and concentrated. This was purified by flash chromatography on silica gel using 9:1 ethyl acetate : methanol. The product was then dissolved in 10 ml diethyl ether and 0.1 ml of 5.5M anhydrous HCl in ether were added. The mixture was concentrated and dried in vacuo at 60°C under 0.1 mm Hg to afford O.91g (63%) of a pale yellow foam, mp = 94°C.

^l NMR(DMSO-d6) δ = 2.02 (m,2H,CH ₂ ); 2.79 (s,3H,CH N); 2.96 (t,2H,CH ₂ ); 3.25 (m,4H,CH ₂ x2); 3.56-3.74 (m,15H,OCH ₃ x5); 3.96 (m,2H,CH ₂ ) 6.65 (s,2H,AR); 6.77 (d,lH,J=8.2Hz,Ar); 6.89 (m,2H,Ar); 7.61 (d,2H,J=8.4Hz,Ar); 8.10 (d,2H,J=8.4Hz,Ar); 10.70 (s,lH,exch.D2O,NH)ppm.

Example 5

N-(3,4-dimethoxyphenyI)-N-[3-[[2-(3,4-dimethoxyphenyI)eth yl]-2- propenylamino] propyI]-4-ni trobenzamide, hydrochloride.

To a stirred solution of 0.25 g (0.6 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl)ethyl]-N'-propenyl-l,3-propanediamine (D14) and 0.06 g (0.6 mmol) of triethylamine in 20 ml of methylene chloride 0.11 g (0.6 mmol) of 4- nitrobenzoyl chloride were added over a period of 10 minutes at room temperature. Agitation was maintained for 1 hour. Additional 20 ml of methylene chloride were added and the organic phase was washed three times with 30 ml water, dried over MgSO4 ^an< i concentrated. Purification by flash chromatography on silica gel using ethyl acetate yielded 0.2 g (59%) of product

This product was dissolved in 10 ml ethyl acetate and 0.1 ml of 5.5M anhydrous HCl in diethyl ether was added. The mixture was concentrated and dried in vacuo at 60°C under 0.1 mmHg to yield 0.2g (54%) of the title compound as yellow solid. m.p. around 120°C

iHNMRφMSO-Dό) δ = 2.02(m,2H,CH2); 2.93 (m,2H,CH ₂ ); 3.21 (s,4H,CH ₂ x2); 3.66-3.74 (m,12H,OCH ₃ x4); 3.89 (m,4H,CH ₂ x2); 5.56 (m,2H,CH ₂ ); 6.05 (m,lH,CH=CH ₂ ); 6.76-6.96 (m,6H,Ar); 7.56 (d,2H,J=8.6Hz,Ar); 8.09 (d,2H,J+8.6Hz,Ar); 10.67 (s,lH,exchD2O,NH)ppm.

Example 6

4-Amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyph enyI)ethyl]methyI- amino] propyl] benzamide, di hydrochloride.

,2HC1

A mixture of 1.12 g (2.0 mmol) of N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl) ethyl]methylamino]propyl]-4-nitrobenzamide hydrochloride (described in, EP 233762) and 2.25 g (10 mmol) of stannous chloride dihydrate in 15 ml ethanol were refluxed under stirring for 30 minutes. The solvent was concentrated to dryness and the residue taken up in water. The aqueous mixture was basified with an aqueous solution of NaHCO3 and extracted three times with ethyl acetate. The organic solution was separated, dried over MgSO4 and concentrated in vacuo to dryness. The crude base (0.88 g) was taken up in methanol and a solution of 5.5N anhydrous HCl in diethyl ether was added. The main part of the solvent was removed under reduced pressure and anhydrous diethyl ether was added to precipitate the desired dihydrochloride : 0.89 g (77%). m.p = 135-40°C 1H NMR(DMSO-d ₆ ) δ = 1.82-2.04 (m,2H,CH ₂ ); 2.78 (d,3H,J=4.3Hz,CH ₃ NH); 2.86-2.99 (m,2H,CH ₂ ); 3.04-3.37 (m,4H,2CH ₂ ); 3.66, 3.69, 3.72 and 3.75 (4s,12H,4CH O); 3.78-3.94 (m,2H,CH ₂ ); 6.60-6.93(m,8H,Ar); 7.16 (d,2H,J=8.4Hz,Ar); 10.36 (s,lH,exchD ₂ O,NH+) ppm

Example 7

N-[3-[[2-(3,4-DimethoxyphenyI)ethyl]methylamino]propyI]-N -[3,4-bis(l- methylethoxy) phenyl]-4-nitrobeπzamide,hydrochloride

Starting from 800 mg (1.8 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-N'- [3,4-bis(l-methylethoxy)phenyl]l,3-propanediamine (D17) and 400 mg (2.16 mmol) of 4-nitrobenzoyl chloride and following the method described in example 4, 668 mg (58.9%) of the title compound were obtained as yellow crystals. The compound was purified as free base by chromatography on silica gel using 99: 1 methylene chloride:methanol, and as hydrochloride by trituration first in diethylether then in diisopropyl ether. m.p = 78°C

*H NMR (DMSO-d ₆ ) δ = 1.00-1.18 (m,12H,2x(Cϋ^) ₂ CH); 1.87-2.08 (m,2H,CH ₂ );

2.81 (d,3H,CH ₃ NH+); 2.85-3.02 (m,4H,CH ₂ ); 3.08-3.40 (m,4H,2CH ₂ ); 3.83-3.98

(m,2H,CH ₂ ); 4.26-4.50 (m,2H,2xCH.(CH ₃ ) ₂ ); 6.72-6.94 (m;6H,Ar); 7.55

(d,2HJ=8.5Hz,Ar); 8.08 (d,2H,J=8.5Hz,Ar); 10.12 (s,lH,exch D ₂ O,NH+) ppm.

Example 8

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyI)eth yl](l-ιnethyI- ethyI)amino]propyI]-4-nitrobenzamide, hydrochloride

Starting from 540 mg (1.3 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl) ethyl]-N'-(l-methylethyl)-l,3-propanediamine (D19) and 270 mg (1.4 mmol) of 4-nitrobenzoyl chloride and following the method described in example 4, yielded 420 mg (53.7%) of the title compound as a yellow solid. The compound was purified as free base by chromatography on silica gel using 95:5 methylene chloride:methanol and as hydrochloride by trituration in diethylether. m.p = 105°C iH NMR (DMSO-d6) ^δ = 1-18-1.35 (broad band,6H,(CH ₃ ) ₂ CH); 1.95-2.20

(m,2H,CH ₂ ); 2.85-3.05 (m,2H,CH ₂ ); 3.05-3.32 (m,4H,2CH ₂ );3.28-3.43(m,lH,CH); 3.66 (s,6H,2CH O); 3.72 and 3.75 (2s,6H,2CH ₃ O); 3.85-4.02 (m,2H,CH ₂ ); 6.75- 6.98 (m;6H,Ar); 7.57 (d,2HJ=8.4Hz,Ar); 8.08 (d,2H,J=8.4Hz,Ar); 10.19 (s,lH,exch D2θ,NH ⁺ ) ppm.

Example 9

N-(3,4-Diethoxyphenyl)-N-[3-[[2-(3,4-Diethoxyphenyl)ethyI ]methyI- amino]propyI]-4-nitrobenzenecarboxamide, hydrochloride

Starting from 1.04 g (2.3 mmol) of N-(3,4-Diethoxyphenyl)-N'-[2-(3,4- diethoxyphenyl)ethyl]-N'-methyl-l,3-propanadiamine (D22) and 480 mg (2.6 mmol) of 4-nitrobenzoylchloride and following the method described in example 4, yielded 1.05 g (72.5%) of the title compound as yellow solid. The compound was purified as

free base by chromatography on silica gel using 95:5 methylene chloride:methanol. iHNMR (DMSO-d ₆ ) δ = 1.12-1.35 (m,12H,4CH ₃ CH ₂ O); 1.87-2.05 (m,2H,CH ₂ );

2.78 (s,3H,CH ₃ ); 2.82-3.00 (m,2H,CH ₂ ); 3.08-3.38 (m,4H,2CH ₂ ); 3.85-4.05

(m,10H,4CH ₂ O and CH ₂ N); 6.70-6.95 (m,6H,Ar); 7.56 (d,2H,J=8.5Hz,Ar); 8.08 (d,2HJ=8.5Hz,Ar); 10.42 (s,lH,exch D ₂ O,NH+) ppm.

Example 10

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)eth yl]methyl- amino]propyI]-N-(4-nitrophenyI)urea, hydrochloride

A solution of 1 g (2.6 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl)ethyl]-N'-methyl-l,3-propanediamine (Int 1 prepared according to methods in EP 0233762) and 0.48 g (3 mmol) of 4-nitrobenzeneisocyanate in 25 ml dry methylene chloride was stirred at room temperature for 15 hours. The precipitate was filtered and purified by chromatography on silica gel using 95:5 methylene chloride:methanol yielding 0.83 g of a yellow solid which was salified in methanol by addition of 5.5N anhydrous HCl in diethyl eti er. The crude salt was triturated in diethyl ether to afford 0.8 g (55.7%) of a yellow solid. m.p around 115°C iHNMR (DMSO-dg) δ = 1.80-1.98 (m,2H,CH ₂ ); 2.78 (d,3H,J=4.5Hz,CH NH ⁺ ); 2.86-3.02 (m,2H,CH ₂ ); 3.08-3.43 (m,4H,2CH ₂ ); 3.68-3.87 (m,2H,CH ₂ ); 3.72, 3.74, 3.77 and 3.79 (4s,12H,4CH ₃ O); 6.72-7.07 (m,6H,Ar); 7.76 (d,2H,J=9.3Hz,Ar); 8.12 (d,2HJ=9.3Hz,Ar); 8.48(s,lH,exch.D ₂ O,NH); 10.27(broad s, lH,exch.D2θ,NH+)ppm.

Example 11

N-(3,4-Dimethoxypheπyl)-N-[3[[2-(3,4-dimethoxyphenyl)eth yl]methylamino] propyl] benzamide, hydrochloride

Starting from 800 mg (1.6 mmol) N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4- dimethoxyphenyl)ethyl]methylamino]propyl]benzamide and following the method of salification described in example 4, yielded 5.34 mg (63%) of the title compound as grey crystals. m.p = 75°C

1H NMR (DMSO-d ₆ ) δ = 1.83-2.05 (m,2H,CH ₂ ); 2.80 (d,3H,J=4Hz,CH ₃ NH+); 2.88-3.00 (m,2H,CH ₂ ); 3.05-3.37 (m,4H,2CH ₂ ); 3.63, 3.73 and 3.75 (4s,12H,4CH ₃ O); 3.82-3.96 (m,2H,CH ₂ NCO); 6.62-6.93 (m,6H,Ar); 7.17-7.33 (m;5H,Ar); 10.25 (broad band, lH,exch D ₂ O,NH+) ppm.

Example 12

4-Cyano-N-(3,4-Dimethoxyphenyl)-N-[3[[2-(3,4- dimethoxyphenyl)ethyI]methylamino]propyl] benzamide, hydrochloride

Starting from 1.26 mg (2.43 mmol) 4-Cyano-N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4- dimethoxyphenyl)ethyl]methylamino]propyl-benzamide and following the method of salification described in example 4, yielded 844 mg (62.7%) of the title compound as grey crystals, m.p = 90°C iH NMR (DMSO-d ₆ ) δ = 1.83-2.10 (m,2H,CH ₂ ); 2.79 (d,3H,J=4.1Hz,CU3NH ⁺ );

2.85-3.05 (m,2H,CH ₂ ); 3.00-3.40 (m,4H,2CH ₂ N); 3.66, 3.67, 3.73 and 3.75 (4s,12H,4CH ₃ O); 3.82-4.00 (m,2H,CH ₂ CO); 6.65-7.00 (m,6H,Ar); 7.48

(d,2HJ=8.1Hz,Ar); 7.73 (d,2H,J=8.1Hz,Ar); 10.51 (broad band,lH,exch D ₂ O,NH+) ppm.

Example 13

N-(3,4-Dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyI)ethy I]methyl- amino]propyl]3-5-dinitrobenzamide, hydrochloride

Starting from 1.5 g (2.6 mmol) N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4- dimed oxyphenyl)ethyl]methylamino]propyl]-3,5-dinitrobenzamide and following the method of salification described in example 4, yielded 1.53 g (95%) of the title compound as yellow solid. !H NMR (DMSO-ctø δ = 1.90-2.10 (m,2H,CH ₂ ); 2.81 (d,3H,J=4.2Hz£H3NH ⁺ ); 2.98-3.07 (m,2H,CH ₂ ); 3.02-3.40 (m,4H,2CH ₂ N); 3.66, 3.67, 3.73 and 3.75 (4s,12H,4CH ₃ O); 3.88-4.02 (m,2H,CH ₂ NCO); 6.72-7.00 (m,5H,Ar); 7.16 (s,lH,Ar); 8.57 (s,2H,Ar); 8.70 (s,lH,Ar); 10.50 (broad band,lH,exch D ₂ O,NH+) ppm.

Example 14

N-(3,4-DimethoxyphenyI)-N-[3[[2-(3,4-dimethoxyphenyl)ethy l]cyclopropyI- amino]propyl]-4-nitrobenzamide, hydrochloride

Starting from 0.7 g (1.7 mmol) N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl)ethyl]-N'-cyclopropyl-l,3-propanediamine (D26) and 0.34 g (1.85 mmol) 4-nitrobenzoyl chloride and following the method described in example 4,

yielded 0.555 g (54%) of the title compound as yellow solid.

The compound was purified as free base twice by chromatography on silica gel using first 97/3, then 98/2 methylene chloride/methanol, and as hydrochloride by trituration in diethyl ether. !H NMR (DMSO-d6) δ = 0.74-1.00 and 1.00-1.27 (2m,4H,(CH ₂ ) ₂ ); 1-97-2.12

(m,2H,CH ₂ ); 2.78-3.14 (m,3H,£H ₂ Ar an ^d NCH(CH ₂ ) ₂ ); 3.25-3.44 (m,4H,2CH ₂ N);

3.65 (s,6H,2CH3O); 3.73 and 3.75 (2s,6H,2CH ₃ O); 3.90-4.04 (m,2H,CH ₂ NCO);

6.68-7.03 (m,6H,Ar); 7.57 (d,2H,J=8.4Hz,Ar); 8.08 (d,2H,J=8.4Hz,Ar); 10.50 (broad band,lH,exch D ₂ O,NH+) ppm.

Example 15

N-(4-Hydroxy-3-methoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphen yl)ethyl]- methyIamino]propyI]-4-nitrobenzamide, hydrochloride

Starting from 500 mg (1.2 mmol) N-(4-hydroxy-3-methoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl)ethyl]-N'-methyl-l,3-propanediamine (D30) and 226 mg (1.2 mmol) 4-nitrobenzoyl chloride and following the method described in example 4, yielded 285 mg (42.4%) of the title compound as yellow crystals. The compound was purified as free base by chromatography on silica using methylene chloride/methanol : 98/2 eluent and as hydrochloride by trituration in diethyl ether. m.p = 109°C !H NMR (DMSO-dg) δ = 1.86-2.10 (m,2H,CH ₂ ); 2.81 (d,3H,J=4.3Hz,CH ₃ NH+) 2.86-3.00 (m,2H,CH ₂ ); 3.08-3.43 (m,4H,2CH ₂ N) ; 3.65, 3.73 and 3.75 (3s,9H,3CH ₃ O); 3.84-3.98 (m,2H,CH ₂ NCO) ; 6.54-6.95 (m,6H,Ar) ; 7.55 (d-2HJ=8.6Hz,Ar); 8.08 (d,2H,J=8.6Hz,Ar); 9.22 (s,lH,exch D2O,ArOH); 10.03 (broad band,lH,exch D ₂ O,NH+) ppm

Example 16

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyI)ethyl]methylamino]propyI]-4-pyridinecarboxam ide, dihydrochloride

Starting from 1 g of (2.6 mmol) N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimemoxyphenyl)ethyl]-N'-methyI-l,3-propanediamine and 0.50 g (2.8 mmol) of 4- pyridine carbonyl chloride, hydrochloride and following the method described in example 4, (except using 2 equivalents of triethylamine), yielded 0.77 g (52.3%) of the title compound as an off yellow solid. The compound was purified as free base by chromatography on silica gel using 95:5 methylene chloride:methanol. m.p = 130- 40°C iH MRφMSO-c ) δ = 1.86-2.10 (m,2H,CH ₂ ); 2.79 (d,3HJ=3.5Hz,CH ₃ N); 2.86- 3.04 (m,2H,CH2); 3.07-3.42 (m,4H,2CH ₂ )i 3-67 (s,6H,2CH ₃ O); 3.72 and 3.75 (2s,6H,2CH ₃ O); 3.84-4.00 (m,2H,CH2); 6.70-7.05 (m,6H,Ar); 7.41 (d,2H,J=5.7Hz,Ar); 8.53 (d,2H,J=5.7Hz,Ar); 10.57 (s,lH,exchD ₂ O,NH+) ppm

Example 17

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]methyIamino]propyI]acetamide, hydrochloride

0.13 ml (1.8 mmol) of acetyl chloride were added to an ice cooled stirred solution of 504 mg (1.3 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4-dimethoxyphenyl)ethyl]- N'-methyl-l,3-propanediamine and 0.198 ml (1.43 mmol) of triethylamine in 20 ml dry methylene chloride. The mixture was stirred for 1 additional hour and poured in water. Methylene chloride was added, the organic phase was washed with a saturated aqueous solution of NaHCO3, again with water and dried over MgSO4. The solvent was concentrated in vacuo and the residue was purified by chromatography on silica gel using 93:7 methylene chloride:methanol to give 350 mg of a yellow oil. The compound was salified in methanol by additon of 5.5N anhydrous HCl in diethyl ether and triturated in diethyl ether to afford 290 mg (47.8%) of the title compound as

a light beige solid, mp. around 85°C.

!H NMR(DMSO-d6)δ = 1.75(s,3H,CH ₃ ); 1.76-1.93(m,2H,CH ₂ ); 2;76(d,3H,J=3.7Hz,CH ₃ ); 2.85-3.00(m,2H,CH ₂ ); 3.05-3.48(m,4H,CH ₂ x2); 3.60- 3.80(m,2H,CH ₂ ); 3.72,3.75,3.76,3.77(s,12H,CH ₃ ); 6.70-7.03(m,6H,Ar); 10.49(Broad s, lH,exch. D ₂ O,NH) ppm.

PHARMACOLOGICAL METHODS

EFFECTS IN THE DOG

Surgical preparation. Dogs were anesthetized using 30 mg/kg i.v. sodium pentobarbital. A tracheal cannula was placed for artificial respiration with room air (Harvard 613 pump). A catheter was inserted into the right femoral artery to measure the systemic arterial pressure (Statham P23 ID, GOULD). A 5F Millar microtip catheter pressure transducer was inserted into die left carotid artery and advanced into the left ventricular lumen to measure the left ventricular pressure (LVP) and its first positive derivative dP/dt. Peripheral venous and arterial catheters were placed for drug administration and blood samples collection, respectively. Electrocardiographic variables were measured via a standard lead II ECG. For determination of the Q-T interval of ECG a CV5RL precordial lead of ECG was measured as previously described (Koerner et al. J.,Cardiovascular Pharmacol. Vol. 16, p.383-393, 1990). After a left thoracotomy through the fifth intercostal space, the heart was suspended in a pericardial cradle. The left circumflex coronary artery (LCX) was isolated close to its origin and a silk suture was placed around it for later occlusion.

Experimental time course. After placement of the silk strand die animal was allowed to stabilize for at least 10 minutes. Arterial blood gases were determined (ABL500, Radiometer), and ventilation was adjusted to maintain these parameters within the normal range. Then, intravenous administration of die drag was performed in 10 minutes. After the drag administration, hemodynamic and ECG variables were again measured and the LCX was occluded for 45 minutes by placing a microclamp. Reperfusion performed by removing d e clamp was continued for 5 hours.

Measurements. Ventricular arrhythmias were analyzed during die preischemic period, during ischemia and during die first hour of reperfusion. Ventricular premature beats (VPBs) were defined as identifiable premature QRS complexes and salvos as more than 2 consecutive VPBs. Ventricular tachycardia was defined as 4 or more consecutive VPBs. Ventricular fibrillation (VF) was diagnosed when total irregularity of rhythm occurred and when a rate could no longer be measured. If defibrillation was required a DC shock was given.

Arterial blood pressure and ECG were recorded continuously on a Gould polyrecorder. Signals were digitised by an A/D convenor and analysed on an IBM

computer using an interactive software (Clodia, Clod sari) and then transfered to a

VAX 4000-200 computer (Digital Equipment Corporation, Maynard, MA) for further analysis. Heart rate was calculated from the ECG. A corrected QT interval was calculated according to the formula of Bazett (Heart 1920; 7: 353-370): QTc = (QT interval in msec) / (R-R interval in sec)

ELECTROPHYSIOLOCAL STUDIES

Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy die heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to die silastic base of a 5 ml organ bath and superfused with oxygenated Tyrode solution maintained at 37 ± 1 °C.

The modified Tyrode solution (pH 7.35) contained die following (mM): NaCl 125, KCl 4.0, MgCl ₂ 0.5, CaCl ₂ 1.8, NaHCO ₃ 24, NaH ₂ PO40.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% O ₂ - 5% CO ₂ .

After a stabilisation period (at least 1 h), transmembrane action potentials were recorded witii conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to d e preparation with bipolar platinum electrodes placed at one end of die muscle. The pulse duration was 1 ms and die amplitude was twice threshold. The basic cycle length was 1000 ms (PULSAR 6i stimulator). The signals were monitored on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis.

Measurements were made of resting membrane potential (RMP), action potential amplitude (APA) and action potential durations at 30, 50 and 90% repolarization (APD30, APD50 and APD90 respectively). Recordings were made after 30 min of equilibration for each concentration. Only recordings in which die same impalement was maintained throughout die entire experiment were used for analysis.

STATISTICAL ANALYSIS

Values were expressed as mean ± SEM and were compared using analysis of variance followed by Duncan's new multiple range test or Student's t-test as appropriate when the variables where found to be Gaussian distributed. For the duration of VT and VF

and the number of VPBs which were not found Gaussian-distributed, medians were compared using die Mann-Withney test. Binomially distributed variables such as incidence of NT and VF and mortality were compared using X ² for a 2 x n table, followed by Fisher exact tests to compare individual groups. All statistical comparisons were performed using RS/1 release 4 software (BBΝ Software Product

Corporation, Cambridge, MA) on die VAX 4000-200 computer. A p value less man

0.05 was considered statistically significant

RESULTS

EFFECTS IN ANESTHETIZED DOGS.

Hemodynamic and electrocardiographic parameters.

The effects of Compound I (0.3 and 1.0 mg/kg) in anesthetized dogs were compared to tiiose of d-sotalol (3.0 and 10.0 mg/kg). At the end of die stabilisation period, before drag administration, there was no difference between die groups in the hemodynamic parameters. During die preischemic period, both compound reduced heart rate in a dose-dependent manner. With only minimal changes in mean arterial and left ventricular pressure, Compound I and d-sotalol both reduced die pressure rate product This effect was associated for both compounds widi a reduction in die left ventricular dP/dtmax. Similar changes in hemodynamic parameters were also observed both during die ϊschemic period and after 60 min of reperfusion.

During the preischemic period botii Compound I and d-Sotalol prolonged QT and QTc intervals (table 1) but did not change die PR interval. Although a similar prolongation of QT interval was also observed during ischemia, a lesser effect was noted during die reperfusion period. During ischemia the high doses of Compound I and d-sotalol both increased QTc interval and this action was abolished during die reperfusion. Except for the lower dose of Compound I during d e ischemic period, tiiere was no marked change in the PR interval duration.

Ischemia and reperfusion-induced arrhythmias.

The effects of Compound I (0.3 and 1 mgKg) were compared to tiiose of D-sotalol (3 and 10 mg/kg). Ventricular arrhythmias were analyzed during ischemia, maintained for 45 min, and again during die first 60 min of die reperfusion period. The effects of Compound I and D-sotalol on the incidence of ventricular fibrillation observed during

these period were summarized in figure 1. The results show that 66.7 % of the control dogs (8 out of 12 dogs) exhibited ventricular fibrillation during either ischemia (2 dogs) or reperfusion (4 dogs). The incidence of ventricular fibrillation was reduced to 33.3 % and 14.3 % (p <0.05) in presence of Compound I (0.3 or 1.0 mg/kg, respectively), and none of the dogs treated with Compound I experienced ventricular fibrillation during ischemia. In comparison, only the high dose of D-sotalol (10.0 mg/kg) reduced the incidence of ventricular fibrillation (figure 2), and one dog treated with 3.0 mg/kg showed ventricular fibrillation during the ischemic period.

EFFECTS OF COMPOUND I ON ACTION POTENTIAL CHARACTERISTICS OF GUINEA PIG MUSCLE.

The most prominent effect of sotalol (3 to 100 μM) was a dose-dependent increase in action potential duration. The results summarized in table 2 show that Compound I induced a biphasic effect on action potential duration, depending on die concentration. An action potential prolongation was observed with Compound I at low concentrations (0.3 and 1 μM). However, when the concentration was further increased (3 μM) tiiere was no further increase in APD. At a higher concentration (10 μM) Compound I reduced action potential duration.

The results summarized in table 2 show that both Compound I and d-Sotalol did not change d e resting membrane potential, the action potential amplitude, and the Vmax, even at die highest concentrations. Table 3 summarises the results obtained from these experiments when repeated using the test compounds indicated therein.

Table 1; Effect of Compound I and d-Sotafo! on electrocardlographlc parameters measured In anesthetized dog.

Values represent mean ± SEM of n experiments. Analysis of variance followed by Duncan's new multflpJe range test or

Student's t test for paired values were used as appropriate. * < p 0.05, ** p < 0.01, * * * p < 0.001 vs before drug values, § p < 0,05 vs vehicle group.

Table 2 Effects of (Compound I and d-Sotalol on action potential parameters of guinea pig papillary muscles.

RMP; resting membrane potential, APA; action potential amplitude, APD30, APD50 and APD90; action potential durations at 30, 50 a d 90 % of the repofarizatfon respectively.

TABLE 3 (Continued)