AP410A - Diamines in the treatment of arrhythmia. - Google Patents

Abstract

A method for the treatment

Description

NOVEL TREATMENT

Iff

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.

Antiarrhytlimic drugs have been grouped according to<he pattern of⁵ electrophysiological effects they produce $nd/or their presurfcd mechanism of action. *A classification in /our groups has been originally proposed hy Vaughan Williams in 1970. At the molecular level, class 1 compounds act on Na*^ currents; class II compounds possess b-adrenoceptor blocking activity; class 111 drugs block K⁺ . channels; and class IV drugs target C8++ 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.

Ir has now surprisingly heen discovered that certain compounds ol lormuia U) of EPO233762 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 (1) surprisingly evidenced a prolongation of the cardiac action potential and are therefore considered to show particular promise as class ΙΠ antiarrhythmic agents, ₅

Most surprisingly however, certain of the compounds ot formula (1) ot EP0233762 demonstrated both class ill and class IV activity, the class IV 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 Ill agents, having less proanrhythmic 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 or tr-A-»0UJ/b3 named as (N-l3,4-dimethoxy-phenyijN-3-[N!-2-(3,4-dimethoxyphenyl)-ethyl-N^,-fnethylamino]propyl)-N'-4nitrobenzamide, (also referred to herein as’Compound Γ).

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 (1): ‘

R,-N—A~*N—B—R₄

I J

R₂ Rj

0)

A

-4.

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P30384

or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein · Rj and R4 are independently phenyl optionally substituted by one, two or three of halogen, C1-4 alkoxy, C4-4 alkyl, cyano, hydroxy, nitro, NR5R6 or O2SNR5R6 . wherein R5 and R$ are independently hydrogen or Cj-g all^yl or together are ' polymethylene, or disubstituted at adjacent carbon atoms by Cj-2 alkylenedioxy and optionally further substituted by one of the above groups; ¹

Rj is selected from (CH2)_Z CN where £ is O or an integer from 1 to 4, C|-j2 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alky), phenyl Ci-4 alkyl, pyridyl, pyridyl Ci-4 alkyl, COR7, COCH2COR7, SO2R7, CO2R7, CONHR7 and CSNHR71 where R7 is selected from Cpi2 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 Rj and R4 and any cycloalkyl moiety in R2 optionally substituted.by one or two Cj-4 alkyl groups; _s ,

R3 is hydrogen, C2-6 alkyl, C2-6 alkene or, C3-g cycloalkyi; ·

A represents C2-5 alkylene; and ' ' f *

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 pharmaceuticajly acceptable salt there. .- nd/or a pharmaceutically acceptable solvate thereof and a pharmaceutically acc. .-.ble carrier therefore.

Arrhythmia pa, - ularly includes cardiac arrhythmia and ischxmic rhythm disorders, especially . :iac arryhthmia.

Suitable value? Rj and R4 include phenyl, phenyl di-substituted by methylenedioxy and c nally further substituted by chlord* or phenyl substituted by one of fluoro, chloro . uromo or by one, two or three of methoxy, ethoxy, 11-421»

J *· iso-propoxv. methyl, ethyl, n - or iso-propyl, cyano, hydroxy or amino optionally substituted by one or two methyl groups.

.<·

Rl and R4 are preferably the saftne group, most preferably 3,4-dimethoxypher.yl. ^Λ

Particular values for R^and R^ are halophenyl, especially 4-halophenyl, l· '

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AP 0 0 0 4 1 β

-S'

P30384 ·· : G «Μ*

A ·.. ·’.*

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

Examples of R¹ and R^ include 4-fluorophenyl, 3,4-dichlorophenyl, 3,4dimethoxyphenyl, (3-methoxy, 4-hydroxy)phenyI and 3,4,$.-trimethoxyphenyL

Phenyl moieties in R2 include phenyl, 2-, 3- and 4-nitrophenyl, . / 3,5-dinitrophenyl, 3-methoxyphenyl, 3-methoxy-6-methylp|tenyl,

Λ .

2,4,6-trimethylphenyl, 4-cyanophenyl, 4-chlorophenyl and 4-methylphepyL :

/γ

..f

A . ' · 3 ’ ¹ • Suitable values for alkylene moieties in R2 include rCH2-, -CH(CH3>- χ. y

-CH2CH2CH2- and -CH2CH2-. Suitable values for R2 when alkyl include n-jrentyk £' Suitable values for alky) R7 in R2 includes Cj.g alkyl, such as methyl, ethyl, n-and iso-C3H7, n-C4H9, η-<?5Ηιμ nC6Hj3, nC7Hj5, nCgHi7 and nCnH23·

Suitable values for pyridyl moieties in R2 ihclude2-; 4 - pr'dyI * _: -• _ __ r ν' * , ',.· '

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

Suitable values for z in R2 include 0 of 1. ‘ .

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

Suitable values for R3 include hydrogen, methyl, ethyl, fl- and iso-propyl, and <

· n. iso -. sec - and t-butyl.

Preferably R3 is methyl. ί

Suitable values for A and B include.-(CH2)2* and -(CH^-.

Preferably, A is -(012)3-. . *

Preferably, B is -(CH2)2There is a group of compounds within formula (I) of formula (IA):

AVetfilui·· *·

R,—N—(CFUa —N—(CH^—R,

F ·>·.

- .- 'ί (IA) wherein R2* is CONHR7 or CSNHR7 where R7 is as defirtqd ifi formula (I), and the remaining variables are as defined in formula (I). ♦ :·* » .., ' / J

There is another group of compounds within formula (I) of formula (IB):

R,-N—(CKa)₃— N—(ChU_f—R. * » ' (IB) wherein R2^ is COR7 where R7 is as defined in formula (I), and the remaining variables are as defined in formula (I).

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J

CORP PATG CTDURCII

TCL tiay 93 15:35

P30384

-4^0.010 ' ΧίΪΕ'Χ* wB • v L .

. ' - Z ;,T ' 5+ Suitable and preferred variables of fromulae (1A) and as described for the corresponding variables under formula (II).

There ib m preferred group uf compounds within furmula (IB) which are characterised in that R7 is C|.i2 ^Q'kyl- /,

The compounds of formula (IB) wherein R7 is Cj.i2 ,®ikyl, or pharmaceutically acceptable salts thereof and/or a pharmaceutically «acceptable

Eolvata thereof, are elacc III antiarrhythmio agofttc, and honoo oan bo uaod aaeuoh, for.;' /¾¼ example they are effective against ventricular fibrillation.

Ϊ1Β) are

There is a particularly preferred group of compounds within formuIa*(lB) fitn which ore characterised in that R7 is optionally substituted phenyl, optional , ,. . substituents bgng selected from one halogen atom, especially a chlorine atom, and one, two or three of cyano, hydroxy, nitro and NRsRg wherein R5 and Rg arc ’⁴ independently hydrogen (espectaily)or Cj-g alkyl; a prclcrred substituent is a nitro group, especially a 4-nitro group.

The compounds of formula (IB) 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 NRgRg wherein Rj and Rg are independently hydrogen (especially)or Cj-g alkyl, or pharmaceutically acceptable / salts thereof and/or a pharmaceutically acceptable solvates thereof, are combine^ class 111 and class IV aniiarripdhmie agents and hence can be used as such, for · < example tncy arc particularly effective against ventricular fibrillation, they wv also considered to be effective against atrial fibrillation and flutter..

In its most preferred aspect, the compound of formula (I) is that compound wherein Ri represents 3,4-dimethoxyphenyl, Rj represents a 4-nkrobenzoyl group,

R3 represents methyl, R4 represents 3,4-dimethoxyphenyl, A represents (CH2)3 and B represents (CH2)2· i.e.the compound of example 50 of Eh 0233762. , /

Where the compounds of formula (I) possess chiral carbon atoms (for example when A and/or 8 are branched alkylene) they may oniot in mjro than ono ,, stereoisomeric form, the invention extends to ail such stcreoisometric forms, including enantiomers of the compounds of formula (1) and to’mixtures thereof, • ί * including racemates.

The different stereoisomeric forms tnay bjp separated or resolved one from the other by the usual methods or any given isomer may be obtained by stercospeciftc or asynunetric syntheses.

When used herein alkyl, alkene and alkylene includes Straight-and branchcd-chain alkyl, alkene and alkylene groups, each with yp to 12, suitably up to 6 carbon atoms, unless staled to the contrar/.

Pharmaceutically acceptable salts include acid addition salts with conventional acide tuch ac hydroohlorio, hydrobromio, boric, phosphoric, sulphuric and 1 pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, <·

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-5methanesulphonic, a-keto-glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids. Preferably the acid addition salt is a hydrochloride.

Pharmaceutically acceptable salts also include quaternary salts. Examples of quaternary salts include such compounds quatemised by compounds such as Rg-T wherein Rg is (4-(5 alkyl, phenyl-Cp^ 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 fl- and iso- 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):

F^-N—A—Ν—B—Ft,

I I

K₃ (IC) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein

Rj, R₂, A, B and R4 are as defined in relation to formula (I), and R'3 represents C₂-6 alkene or C3_g 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

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-χ . ' -6- .

have not beenMisclosed in EP-A-0233762 and which ate considered to be novel and

Λ form part of the present invention. 2-(3,4-dimethoxyphenyl)ethyl -N- 3 . ,. , . . 2-(3,4-dimethoxyphenyl)ethyl methyl

Accordingly, there is provided: _{amino prO}pyl.-4-nitrobenzamide

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

N-(3,4-dichlorophenyl)-N-[3-[f2-(3,4-dimeth0xyiftienyl)ethyl] methylaminojpropyl] -4-nitrobenzamide,

N-(3,4,5-trimethoxyphenyl)-N-(3-[[2-(3,4-dimethoxyphenyl)ethyl] .,/ i methylaminojpropyl] -4-nitrobenzamide,

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-2propenylamino]propyl]-4-nitrobenzamide, · 4‘-amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- . _f dimethoxyphenyl)ethyl]methyl-amino] propyljbenzamide,

N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylaminoJpropyl]-N-(3,4-bis(l15 methylethoxy) phenyl]-4-nitrobenzamide,

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxypheriyl)ethyl](l-methylethyl)amino]propyl]-4-nitrobenzamide, *

N-(3,4-diethQxyphenyl)-N-[3-[[2-(3,4-Diethoxyphehyl)ethyl]methyl- * amino]propyl]-4-nitrobenzenecarboxamide, * *

N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimetl|oxyphenyl)ethylJcyclopropylamino]propyl]-4-nitrobenzamide, * *

N-(4-hydroxy-3-methoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]- . methylamino]propylJ-4-nitrobenzamide, and

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- \ dimethoxyphenyl)ethyl]methylamino]propyl]-4-pyridinecarboxamide, (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 35 disclosed in EP-A-0233762, but in particular the hydrochloride.

Pharmaceutically acceptable so^ates include hydrates.

The compounds of-formula (I), pharmaceutically ? ί ^;

4ccriptabl« salts.-thereof-ahd/or pharmaceutically ·, *·.

accotable solvates . *

BAD ORIGINAL A

1)

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AP Ο Ο Ο 4 1 Ο

-7disclosed in EP-A-0233762. In particular, the compound wherein Rj represents 3,4dimethoxyphenyl, 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 (H):

Rj - NH - A - NR3 - B - R4 (Π) 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 (Π) show potential as an antiarrhythmic agents.

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

The invention also provides a compound of formula (Π) 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 (Π) 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 (Π) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

The invention also provides the use of a compound of formula (Π) 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 preferred values for the variables Rj, A, R3, B and R4 in the compound of foimula (Π) are as defined herein in regard to the compounds of formula (I)

A compound of formula (Π) 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.

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-8Active 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 5 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 a70 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 administrable 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.

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AP 0 0 0 4 1 0

-9These 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 p-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 Oennatological 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

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-10administered in the above mentioned dosage ranges.

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

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AP 0 0 0 4 1 0

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

Description 1

ch₃

Et

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 pooling to room 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.

iH NMR (CDC1₃) δ = 1.25 (t,3H,J=7Hz,CH₃); 2.32 (s,3H^JCH₃); 2.40-2.85

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

Description 2

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

H

CHCH

A mixture of 1.5 g (5 mmol) of ethyl [3-(2-(2-(3,4dimethoxyphenyl)ethyl]methylamino]-propionate (DI) and 0.9 g (5 mmol) of (3,4dimethoxy)-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 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

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- 12600 mg (30%) of a yellow amorphous solid.

*H NMR (CDCI3) δ = 2.20 (s,3H,NCH₃); 2.25-2.95 (m,10H,CH₂x5); 3.35

Description 3

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

H

Cl

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-Fluorophenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methyIamino]propanamide

CH

H

OCH

OCH

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.

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AP 0 0 0 4 1 0

150 ml of ethyl acetate were added and the solution was washed with 100 ml water. The organic phase was separated, dried over MgSC>4 and 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-Fluorophenyl)-N'-[2-(3,4-dimethoxyphenyl)ethyl]-N’-methyl-13propanediamine

H

OCH

To a stirred solution of 1.0 g (2.7 mmol) of N-(4-fluorophenyl)-3-[[2-(3,4dimethoxyphenyl) ethyl]methylamino]-propanamide (D4) in 20 ml of tetrahydrofuran, 0.15 g of L1AIH4 (4.1 mmol) was added cautiously and the reaction mixture was refluxed for 4 hours.

A further 0.15 g of L1AIH4 (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-dichIorophenyl)propanamide.

Cl

Cl

Cl

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 neutral.The organic phase was separated,

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-14dried 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-DichlorophenyI)-3-[[2-(3,4-dimethoxyphenyl)]ethyl]methylamino]propanamide.

Cl

H

Cl

OCH

OCH

To a stirred solution of 5.2 g (20 mmol) of 3-chloro-N-(3,4dichlorophenyl)propanamide (D6) 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 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-Dichlorophenyl)-N'-[2-(3,4-dimethoxyphenyl)ethyl]-N'-methyl-13propanediamine

Cl

Cl

OCH

OCH

To a stirred solution of 4.32 g (11 mmol) of N-(3,4-dichlorophenyl)-3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]-propanamide (D7) in 40 ml of tetrahydrofuran,0.59 g (16 mmol) of L1AIH4 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 filtration.The organic phase was separated,

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P30384

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- 15dried over MgSO₄ and 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-Chloro-N-(3,4,5-trimethoxyphenyl)propananiide.

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 HQ, 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-(3,43-Trimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propanamide

ch₃o

To a stirred solution of 6.70 g (20 mmol) of 3-chloro-N-(3,4,5trimethoxyphenyl)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

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P30384 ·« c - ⁿ A

- 16organic 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-iS^^-TrimethoxyphenyO-N'-Il-lS^-dimethoxyphenyOethyll-N'-methyl-l^ propanediamine

ch₃o

To a stirred solution of 7.4 g (17 mmol) of N-(3,4,5-trimethoxyphenyl)-3-[[2-(3,4dimethoxyphenlyl)ethyl]methylamino]-propanamide (DIO) in 50 ml of tetrahydrofuran, 0.97 g of LiAUfy (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-propenyl)-benzeneethanamine

H

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

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AP Ο Ο Ο 4 1 Ο

-17times with 100 ml water, dried over MgSC>4 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-dimethoxyphenyl)ethyl]-N'-2-propenyI-13propanediamine

To a stirred solution of 1.0 g (2.4 mmol) of N-(3,4-dimethoxyphenyl)-3-[[2-(3,4dimethoxyphenyl)ethyl]2-propenylamino]-propanamide (D13) in 15 ml of tetrahydrofuran, 0.133 g (3.5 mmol) of L1AIH4 were added cautiously and the

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P30384

-18reaction 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)phenyI-propanamide iPri iPri

Cl

H

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 0.1 N aqueous hydrochloric acid, water, a saturated aqueous NaHCO3 solution, again with water and then dried over MgSC>4 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 !h NMR(CDCl3) 5 = 1.31 (d,6HJ=6.4Hz,CH₃x2); 1.34 (d,6H,J=6.4Hz,CH₃x2);

2.79 (t,2H,J=6.4Hz,CH₂-CO); 3.88 (t,2H,J=6.4Hz,CH₂Cl); 4.36-4.46 (m,2H,CH(CH3)₂); 6.80-6.95 (broad band,2H,Ar); 7.21 (broad band,lH,exchD₂O,NH); 7.31 (s,lH,Ar) ppm.

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P30384

AP 0<0 0 4/1 0,/ ;

•25

Description 16

-19' ^s, ;^: ι · ‘‘^z ’ > .· ; ♦ · · A AAA * . . *V

N-[3,4-bis(l-methylethoxy)phenyl]-3-[[2-(3,4-dimethoxypheny))ethyl]methylaminojpropanamide

CH₃ .- - .’V* - s *<. -Ό

iP // ° . ^Ax

OCH,

A solution of 1.95 g (10 mmol) of N- ethyl-3,4-dimethoXybenzenethanamine, 3 g (10 mmol) of 3-chloro-N-3,4-bis (1 -methylethoxy)phenyl-j>ropanafnide 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 SO ml methylene chloride. The organic solution was washed with water, dried over MgSO^ and the solvent was evaporated jn vacuo. The resulting brown oil was purified by

A · chromatography on silica gel using 99:1 methylene chloride:methanol to afford 3.74 g (81.5%) of a light brown oil. , lH NMR (CDC1₃) δ - 1.30 (d,6H,J==6.1Hz,CH₃x2); 1.33 (<f₅6H,J=6.1Hz,CH₃x2); A 2.42 (s,3H,NCH₃); 3.8 land 3.84 (2s,6H,2CH3,O); 4.37 and 4.50 (2 < ’ hept,2HJ=6.1Hz,2CH); 6.56(άά,2Η>2.5Ηζ,Γ=8.5Ηζ,Ατ$; (5.7O-^.73(m,3H„Ar)t 6.81(d,lHJ4=8.5Hz,Ar); 7.40(d,lHJ=2.-5Hz,Ar); 10.53(s,lH,exch.D20,NH)ppm. J %

Description 17 _?

N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-N'-[3,4-bis(l-methylethoxy)phenyl} 1,3-propanediamine « v V

Jit < ·ϊ^ι0¾ \ ’ ^f A

A' ‘

0.139g (3,6 mmol) of lithium_al^iminium hydride were added by small fractions, under stirring, to 10 πύ dry_ATHF 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]prcflanamide (DI 6) 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 foflowed by 0.14 m^of 15% aqueous NaOH and again 0.14 ml of water. The precipitate was filtered off, washed * twice with 5 ml pf ethyl acetate and the organic solutions were concentrated in vacuo ’ ^V BAD ORIGINAL Ώ

Ρ30384

ι.

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

IH NMR (CDG3) δ = 1.27 and 1.32 (2d,12HJ=6.1Hz,(CH3)_x4); 1.82 (q,2HJ=6.6HzCH2);2.36(s,3H,NCH3);2.53-2.84(m,6H,3CH2);3.13 >

. (t,2HJ=6.6Hz,CH2); 3.85 and 3.87 (2s,6H^CH3O); 4.24 and 4.48 (2 hept,2HJ=6.1Hz^CH(CH3)2); 6.13₍(dd,(HJ=2.7HzJ’=8.5Hz,Ar); 6.22 (d,lHJ=2.7Hz,Ar); 6.70-6.82 (m,4H,Ar) ρρπί. λ ' . .

. '· ' ' * Description 18 *

N-(3,4-DimethoxyphenyI)-3-[[2-(3,4-dimdthoxyphenyl)ethyl](l-methylethyI)amino] propanamide >

H 0' CHaCT^ ,	Y^xOCHa '.	*
II 1	V
Starting from 2.0 g (8.9 mmol) of N-(l-methylethyl)-3,4-dimethoxy		4

benzeneethanamine and 2.18 g (8.9 riiniol) of 3-chloro-N-3,4-dimethoxyphen/l propanamide and following the method described in description^l6, 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.

IH NMR (CDCI3) δ = 1.11 (d,6H,J=6.6Hz,(CH₃)₂-CH); 2.45-2.60 (m,2H,CH2CO); 2J5-2.90 (m,6H,3CH2); 3.26<hept,lH,J=6.64,NCH(CH3)2); 3.79, 3.83,3.85land

3.87 (4s,12H,4CH3O); 6.57-6.81 (m,5H,Ar); 7.44 (s,lH,Ar); 10.65 (s,lH,exch D₂O,NH)ppm. '

Description 19

N-(3,4-Dimethoxyphenyl)-N'-[2-(3,4-dimethoxyphenyl)ethyl]-N'-(l-methyIethyl)1,3-propanediamine

f I ' ^Λ,

Starting from 580 mg (1.3 mmol) of N-(3,4-dimethoxyphehyl)-3-[[2-(3,4- * ^r , . / dimethoxyphenyl) ethyl] (l-methylethyl)amino]propanamide (DIB) and following the ί. ^r »< ’ ·' ; '

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P30384

AP 9 Ο Ο 4 1 Ο

- 21 method described in description 16 yielded 180 mg (33.3 %) of the title compound as yellow oil. The compound was purified by chromatography on Silica gel usirig 98:2 methylene chloride:methanol.

lH NMR (CDC1₃) δ - 1.11 (d,6HJ=5.7Hz,(CH₃)₂-CH); 1.78-2.00 (m^KCH^; 2.67-2.92 (m,6H,3CH2); 3.16 (t,2HJ=6.2Hz,CH2); 3.00-3.-20 (m,lH,CH£CH₃)2); 3.80, 3.84, 3.85 and 3.86 (4s,12H,4CH₃)2); 6.12 (dd,lHJ=2.6HzJ'=8.5HzAr); 6.23 (d,lHJ=2.6Hz,Ar); 6.70-6.82 (m,4H,Ar)ppm. ’

Description 20 . s t \ «

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

Cl

3.7 g (29 mmol) of 3-chloropron|onyl chloride were added dropwise to an ice cooled stirred solution of 5.0 g (27.6 jnmol) of 3,4-diethoxybenzei^unine and 3.07 g (30 mmol) of triethylamine in 40 ml methylene chloride. The-mixture was stirred for 15 a

hours at room temperature, then washed with water, with 0.1N aqueous HQ, with a * > saturated aqueous solution of NaHCO₃ and again with water. The organic solqtion - was dried over MgSO4. Some ^lica gel was added, stiiTed some minutes, and filtered off to remove polar impurities. The solvent was concentrated to dryness in vacuo and the residue was triturated in diisopropyl etfier to afford 4.8 g (63.7%) of crystals. m,p = 118°C * *H NMR (CDC1₃) δ = 1.36-1.51 (m,6H,2CH₃); 2.79 (t,2H,J=6.4Hz,CH₂CO); 3.88 (t,2H,J=6.4Hz,CH₂Cl); 4.00-4.17 (m,4H,2CH₂); 6.77-6.92 (m,2H,Ar);7.32 * (s,lH,Ar); 7.28-7.40 (s, 1H,exch D₂0,NH)ppm. _Λ

Description 21

N-(3,4-Diethoxyphenyl)-3-[[2-(3,4-diethoxyphenyl)ethyl]methylaminolpropanamide

OEt ,OEt

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

1.8 g (6.6 mmol) of 3-chloro-N-3,4-diethoxyphenyl)-propanamide (D20) and following the method described in description 1$ yielded 1.65 g (54.5 %) of the title

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**s

P30384 , -22compound as brown oil. The compound was purified by chromatography on silica gel using 95:5 methylene chloride:tnethanol. _rt · lH NMR (DMSO-d^) δ = 1.23-1.37 (m,12H,4CH₃); 2.24 (s,3H,CH₃n); 2.40' (t,2HJ=6.6Hz,CH2); 2.50-2.77 (m,6H,3CH2); 3.39-4.03 (m,8H,4GH₂O); 6.69 (dd,lH, J=1.5HzJ’=8.1HMr); 6.73-6.89 (m,3H,Ar); 6.99 , (dd,lHJ=2.2HzJ=8.7HzAr); 7.29 (d,lHJ=2.2Hz,Ar); 9.8^ (s.lH.exch D₂O,NH)ppm.

> *'

Description 22

N-(3,4-DiethoxyphenyI)-N'-[2-(3,4-diethoxyphenyl)ethyl]-N'-inethyI-13propanediamine ' ^ΕΎγ

Etcr^

Starting from 1.65 (3.6 mmol) of N-(3,4-Diethoxyphenyl)-3-[[2-(3,4diethoxyphenyl)ethyl] methylamino]propanamide (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.

lH NMR (DMSO-d^) δ = 1.17-1.36 (m,12H,4CH₃); 1.65 (q,2H,J=6.7Hz,CH2); 2.22 (s,5H,CH₃N); 2.38-2.68 (m,6H,3CH2); 2.93 (t,2H,J=6.7Hz,CH2); 3.77-4.03 (m,8H,4CH₂9); 5.15 (s,lH,exch D2O.NH); 5.99 (dd₁lHJ=2.2HzAr); 6.53-6,74 (m,4H,Ar) ppm.

Description 23

N-Cydopropyl-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 € i · triethylamine in 200 ml methylene chloride. The reaction mixture was stirred for 15b. at room temperature then washed twice with water, dried oyer’MgSCfy and

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APO 00 4 1.0

P30384 ί

-23t -·'.·· ''sFi • r> · :

^: FF concentrated in vacuo to dryness affording 25.2 g (89.4%) of yellow crystals.

!h NMR (DMSO-d^) δ = 0.32-0.42 (πΟΗΧ^-Οφ; 0.5?-0.64,(m^H,CH₂-£H2); 2.59 (mJi.CH); 3.25 (s,2H,CH₂CO); 3.71 an^3.72 (2s,6h4cH3O); 6.73 ’ (dd,lHJ= 1.9Hz, Γ=8.1 Hz,Ar); 6.84 (s,lH,Ar); 6.86 (d,lHJ*=8.1HzAr); 8.05 (s,lH,exch D₂0,NH) ppm. · \

Description 24 , z

N-Cyclopropyl 3,4-dimethoxybenzeneethanamine

CH

A solution of 12 ml of acetic acid in 15 ml of dioxane was added dropwise to a stired 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 jethylacetate, basified with 35% aqueous NaOH and extracted three time with 150 ml of methylene chloride. The organic solution was dried over MgS04 and concentrated (λ vacuo to dryness^ affording 5.5 g (59%) of a yellow oil. . ¹ iH NMR (DMSO-dg) δ = 0.12-0.23 (m,2H,CH₂-CH₂); 0.33-0.40 (m,2H,CH₂-CH₂); 1.98-2.14 (m,2H,CH and NH); 2.63 (t^HJ=6.7Hz,CH₂ Ar); 2.78 . ?

(t,2H,J=6.7Hz,CH₂N); 3.70 and 3.73 (2s,6H;2CH₃O); 6.15-6.87 (m,3H,Ar) ppm.

A

Description 25 ♦ ,, f · ·

N-(3,4-Dimethoxyphenyl)-3-n2-(3,4-dimethoxyphenyI)ethyl]cydopropyk aminojpropanamide z ’

Fi

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

FF *.&

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P30384 (D23), 5.5 g (22.5 mmol) 3-chloro-N-3,4-dimpthoxyphenyl.propanamide and <L4 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 z · g (29.6%) of the title compound as'brown oil.

lH NMR (DMSO-d₆) δ = 0.24-0.53 (m,4H,(CH2)2); 1.80-L93 (m,lH,CH) ;2.57• 2.88 (m,4H,2CH₂); 2.88-3.03 (m,2H,CH₂); 3.63-3.76 (m,14H,4CH₃O and CH^;

6.71 (dd,lHJ=1.6HzJ-8.2Hz,Ar); 6.76-6.90 (m,3HXr); 7.06 (dd,lHJ=2.2HzJ'=8.2HzAr); 7.28 (d,lHJ=2.2Hz,Ar); 9.80 (s,lH,exch D₂O,NH) ppm ·

Description 26 « * / • ί t '· '· , ♦ ,

N-(3,4-Dimethoxyphenyl)-N'-[2-(3;4-dimethoxyphenyl)ethyl]-N'-cyclopropyl-13-

dimethoxyphenyl) ethyl]cyclopropylamino]prOpynamide (D2^) and following the 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. . * *H NMR (DMSO-d^) δ = 0.23-0.53 (m^H/CH^; 1.53-1.88 (m,3H,CH₂ and CH) * ; 2.60-2.83 Οη,όΗ^ΟΗ^; 2.87-3.00 (m,2H,CH₂); 3.61*3.68,3.70 and 3.72 (4s,12H,4CH₃O); 5.09-5.23 (broad band,lH.exch D₂O,NH); 6.01 « (dd,lHJ=2.3HzJ'=8.6Hz,Ar); 6.24 (d,lHJ=£’3Hz,Ar); 6.65-6.87 (m,4H,Ar) ppm x

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AP Ο Ο Ο 4 1 ο

P30384

Description 27 . * , \

Λ

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

Starting from 3.3 g (0.014 mole) [3-methoxy-4-(phenyfcnethoxy)}benzenamine 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 ₄ . ' ·

NMR (CDCI3) 5 = 2.78(t,2HJ=6.4Hz,CH₂CO); 3.87 (t,2HJ=6.4Hz,CH₂a); 3.88 (s,3H,CH₃O); 5.12 (s,2H,OCH₂Ar); 6.75-6.84 (m,2H,Ar); 7.27-7.48 (m,6H,Ar) ppm

Description 28 ' * . 3-[[2-(3,4-DimethoxyphenyI)ethyl]methyIamino]-N-[3-methoxy-4 (phenylmethoxy)phenylj-propanamide *

A

(phenylmethoxy)phenyl]propanamide (D27), 1.83 g (9.4 mmol) N-methyl-3,4* ¹ dimethoxybehzeneethanamine and 1.04 g (10.3 mmol) triethylamine in 50 ml 25 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 30 crystals. . . ··

m.p = 121°C » iH NMR (DMSO-dg) δ = 2.25 (s,3H,NCH₃); 2.36-2.78 (rn.8H.4CH2); 3.68,3.70 and 3.73 (3s,9H,3CH₃O); 5.02 (s^H.CH^; 6.67-7.04 (m,5H,Ar); 7.28-7.47.

(m,6H,Ar);9.90(s,lH,exchD₂O,NH)ppm ' · '

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Ρ30384

- ·»

Description 29

N-[(3-Methoxy-4-(phenylmethoxy)phenyl]-N'-[2-(3,4-dimethoxyphenyl)ethyl]N’-methyl-13-propanediamine.

ΟΗ-,

OCH,

Λ

PhCH,

0^/^ * ^^OCHj ,

Starting from 3 g (6.3 mmol) 3-[[2-(3,4-dimethoxyphenyl)ethyl]-mcthylamino]-N-[310 methoxy-4-(phenylmethaxy)pUenyl]propanamide (D2Q and following the method described in Description 17, yielded 669 tag (22.9%) of the_atitl6 compound as'brown oil. The compound was purified by chromatography on silica gel using 98/2 methylene chloride/methanol. . „ *H NMR (DMSO-d^) 5 = 1.66 (q,2H J=6.7Hz,CH₂); 2.23 (s,3H,CH₃NH); 2.,45-2.74 (m,6H,3CH₂); 2.95 (t3HJ=6.7Hz,CH₂); 3.69,3.71 and 3.72 (3s,9H,3CH₃O); 4.89 (s,2H,OCH₂Ar); 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)ethyl]-N'-methyl1,3-propanediamine

H CH

O'

OCHj

OCHj

1.06 g (2.3 mmol) N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-N^,-[(3-methoxy-4phenylmethoxy)phenyl]-1,3--propanediamine (D21) 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.

IH NMR (DMSO-d^) δ = 1.66 (q,2HJ=6.8Hz,CH₂); 2.23 (s,3H,NCH₃); 2.37-2.72 (m,6H,3CH2); 2.93 (t3HJ=6.6Hz,CH₂); 3.68, 3.70 and 3.72 (3s,9H,3CH₃O); 4.35 ^A (broad band, 1 H.exch D₂O,ArOH) 5.94 (dd, 1 HJ=2.3HzJ'=8.3Hz,Ar); 6,20

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P30384

AP Ο Ο Ο 4 1 Ο

-27(d,lHJ=2.3Hz,Ar); 6.52 (d,lH,J=8.3Hz,Ar); 6.65-6.86 (m,3H,Ar); 7.85 (s,lH, exch D2O.NH) ppm

BAD ORIGINAL fi

P30384

-28Example 1

N-[2-(3,4-Dimethoxyphenyl)ethyl]-N’-[3-[[2-(3,4-dimethoxyphenyI)ethyl]methylaminojpropyl} -4-nitrobenzamide hydrochloride

A solution of 6.4 g, (15 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-[2-(3,4dimethoxyphenyl)ethyl]methylamino]-propanamide in 100 ml of THF was added dropwise under argon to a suspension of 1.13 g (30 mmol) L1ALH4 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 with brine, dried over MgSC^ 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 MgSC>4 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 HCI 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.

iH NMR (DMSO-d(;): presence of syn and anti forms (ratio = 75/25) δ = 1.85-2.25 (m,2H,CH₂); 2.50-3.50 (m,13H,(CH₂)x5,NCH₃); 3.50-3.85 (m,14H, (OCH₃)x4,CH₂); 6.40-7.00 (m,6H,Ar); 7.30-7.65 (m^H.Ar); 8.10-8.35 (m,2H,Ar); 10.45-10.75 (m,lH,exch.D2O,NH) ppm.

BAD ORIGINAL ft

Η

P30384

AP Ο Ο Ο 4 1 Ο

-29Example 2

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

A solution of 0.7 g (2.0 mmol) of N’-(4-fluorophenyl)-N-[-2-(3,4dimethoxyphenyl)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.

f *H NMR(DMSO-d6) δ =1.97 (t,2HJ=6.9Hz,CH₂); 2.78 (s,3H,NCH₃); 2.94 (t,2H,J=7.9Hz, CH₂); 3.24 (m,4H,CH₂x2); 3.72 (s,3Hx2,OCH₃x2); 3.92 (m,2H,CH₂NCO); 6.78 (d,lH,J=8.4Hz,Ar); 6.89-7.41 (m,6H,Ar); 7.54 (d^HJ=8.4Hz,Ar)8.09 (d,2H,J=8.4Hz,AR); 10.40 (s,lH,exchD₂O,NH).

BAD ORIGINAL &

P30384

-30Example 3

N-(3,4-dichlorophenyl)-N-[3-[[2-(3,4-dimethoxyphenyI)ethyI] methylamino]propyl] -4-nitrobenzamide hydrochloride.

O,F

0CH₃

OCH

HCl

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-1,3 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^oC.

^JH NMR(DMSO-d6) δ =1.96 (m,2H,CH2); 2.78 (s,3H,NCH3); 2.93 (m,2H,CH2);

BAD ORIGINAL

P30384

AP Ο Ο Ο 4 1 Ο

-31Example 4

N-(3,43-Trimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)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-1,3 propanediamine (Dll) 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 with 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.

!h NMR(DMSO-d6) δ = 2.02 (m,2H,CH₂); 2.79 (s,3H,CH₃N); 2.96 (t,2H,CH₂);

3.25 (m,4H,CH₂x2); 3.56-3.74 (m,15H,OCH₃x5); 3.96 (m,2H,CH₂) 6.65 (s,2H,AR);

6.77 (d,lHJ=8.2Hz,Ar); 6.89 (m,2H,Ar); 7.61 (d,2H,J=8.4Hz,Ar); 8.10 (d,2H3=8.4Hz,Ar); 10.70 (s,lH,exch.D2O,NH)ppm.

BAD ORIGINAL &

£ \3

P30384 <· h

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-2propenylamino]propyI]-4-nitrobenzamide, hydrochloride.

-32Example 5

To a stirred solution of 0.25 g (0.6 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4dimethoxyphenyl)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 4nitrobenzoyl 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 MgSC>4 and 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 *H NMR(DMSO-D6) δ = 2.02 (m,2H,CH₂); 2.93 (m,2H,CH₂); 3.21 (s,4H,CH₂x2); 3.66-3.74 (m,12H,OCH₃x4); 3.89 (m,4H,CH₂x2); 5.56 (m,2H,CH₂); 6.05 (m,lH,CH=CH₂); 6.76-6.96 (m,6H,Ar); 7.56 (d,2H,J=8.6Hz,Ar); 8.09 (d,2HJ+8.6Hz,Ar); 10.67 (s,lH,exchD2O,NH)ppm.

Example 6

4-Amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyI)ethyl]methylamino] propyljbenzamide, dihydrochloride.

BAD ORIGINAL fi

APO 00 4 1 Ο

Ρ30384

-3310

A mixture of 1.12 g (2.0 mmol) of N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4dimethoxyphenyl) ethyl] methylamino] propyl]-4-nitrobenzamide hydrochloride (described in, EP 233 762) and 2.25 g (10 mmol) of stannous chloride dihydrate in 15 ml ethanol were refluxed under stiiring 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 Mg£P4 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 ethef was added. The main part of the solvent was removed under reduced pressure and anhydrous dieth'yl ether was added to precipitate the desired dihydrochloride : 0.89 g (77%). m.p = 135-40°C ^JH NMR(DMSO-d6) δ = 1.82-2.04 (m,2H,CH₂); 2.78 (d;3HJ=4.3Hz,CH3NH); 2.86-2.99 (m,2H,CH₂); 3.04-3.37 (m,4H,2CH₂); 3.66, 3.69, 3.72 and 3.75 (4s,12H,4CH3O); 3.78-3.94 (m,2H,CH₂); 6.60-6.93(m,8H,Ar); 7.16 (d,2HJ=8.4Hz,Ar); 10.36 (s,lH,exchD₂O,NH+) ppm .

Example 7 f * r ^Λ

N-[3-[[2-(3,4-DimethoxyphenyI)ethyI]methylamino]pfop9U*N’[3,4-bis(lmethylethoxy) phenyl]-4-nitrobenzamide,hydrochloride

OCH,

HCl

Starting from 800 mg (1.8 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-N’- t

Λ « [3,4-bis(l-methylethoxy)phenyl)l,3-propanediamine (Dll) and 400 mg (2.16 mmol) ' of 4-nitrobenzoyl chloride and following the method described in example f, 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 ysing 99:1 methylene chloride:methanol, and as hydrochloride by trituration first in diethylether then in diisopropyl ether. ’ ' ’

m.p = 78°C ft ‘ · ^b -/ , /' V :

lH NMR (DMSO-d^) δ = 1.00-1.18 (m,12H,2x(£H3)₂CH)i; 1.87-2.08 (m^H.CH^/_;

BAD ORIGINAL ft $

P30384 γ“’ Λ

-342.81 (d,3H,CH₃NH+); 2.85-3.02 (m,4H,CH₂); 3.08-3.40 (m,4H,2CH2); 3.83-3.98 (m,2H,CH₂); 4.26-4.50 (m,2H,2xCH(CH₃)₂); 6.72-6.94 (m;6H,Ar); 7.55 (d^HJ=8.5Hz,Ar); 8.08 (d,2H,J=8.5Hz,Ar); 10.12 (s,lH,exch D₂O,NH+) ppm.

BAD ORIGINAL &

P30384

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyI)ethyI](l-methyl-₄ ethyl)amino]propyl]-4*nitrobenzamide, hydrochloride ' .

AP 0 00 4 1 0

-35Example 8

Starting from 540 mg (1.3 mmol) of N-(3,4-dimethoxyphenyl)-N'-(2-(3,4dimethoxyphenyl) ethyl]-N’-(l-methylethyl)-l,3-propanediamine (DIS) and 2^70 mg (1.4 mmol) of 4-nitrobenzoyl chloride and following th^ method described in ’ i * * · 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 ’ * !h NMR (DMSO-d^) δ = 1.18-1.35 (broad band^H/CH^CH); 1.95-2.20 * (m^H,CH2); 2.85-3.05 (m,2H,CH₂); 3.05-3.32 (m,4H,2CH2);3t28-3.43(m; 1H.CH); 3.66 (s,6H,2CH₃O); 3.72 and 3.75 (2s,6H,2CH₃O); 3.85-4.02 (m^H.CH^; 6.756.98 (m;6H,Ar); 7.57 (d,2HJ=8.4Hz,Ar); 8.08 (d^HJ=8.4Hz,Ar); 10.19 (s,lH,exch D₂O,NH⁺)ppin. _{t t} ·

Example 9 a t

»

N-(3,4-Diethoxyphenyl)-N-[3-[[2-(3,4-Diethoxyphenyl)ethyljmethylamino]propyl]-4-nitrobenzenecarboxamide, hydrodiloride

Starting from 1.04 g (2.3 mmol) ofN-(3y4-DiethoxyphenyI)-N'-[2-(3,4diethoxyphenyl)ethyl]-N’-methyl-l,3-pr0panadiamine (1522) and 480 rag (2.6 mmol) ” i it 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

J * - ‘ «

BAD ORIGINAL fl t ’ ?

P30384 free base by chromatography on silica gel using 95:5 methylene chloride:methanol. ’ NMR (DMSO-cQj) δ = 1.12-1.35 (m, 12H,4CH₃CH₂O); 1.87-2.05 (nUH.CH^;

2.78 (s,3H,CH₃); 2.82-3.00 (m,2H,CH2); 3.08-3.38 (ni,4H,2CH2); 3.85-4.05 (m, 10H,4CH₂O and CH₂N); 6.70-6.95 (rti,6H,Ar); 7.56 (d,2HJ=8.5Hz,Ar); &08 ' (d^HJ=8.5Hz,Ar); 10.42 (s,lH,exch D₂O,NH+) ppm.

t * t

Example 10 , « .

N-(3^-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphen^l)ethyl]methyl10 amino]propyl]-N«(4-nitrophenyl)urea, hydrochloride

,HC1

A solution of 1 g (2.6 mmol) of N-(3,4-dimethoxyphenyl)-N’-[2-(3,415 dimethoxyphenyl)ethyl]-N’-methyl-l,3-propanedia- /nine 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 5f5N anhydrous HCl in diethyl ether. The crude salt was triturated in diethyl ether to afford 0.8 g (55.7%) « of a yellow solid. m.p around 115°C ^? .

NMR (DMSO-d₆) δ = 1 ^0-1.98.(m,2H,CH₂); 2.78 (d,3HJ=4.5Hz,CH₃NH⁺); ¹

2.86-3.02 (m,2H,CH₂); 3.08-3.43 (m,4H,2CH₂); 3.68-3.87 (m^H.CH^; 3.7/, 3.74,, 3.77 and 3.79 (4s,12H,4CH₃O); 6.72-7.07 (m,6H,Ar); 7.76 (d,2H,J=9.3Hz,Ar); 8.12 (d^HJ=9.3Hz,Ar); 8.48(s,lH,exch.p₂O,NH); 10.27(broad s,lH,exch.D₂O,NH+)ppm. ,

BAD ORIGINAL &

P30384

AP O Ο Ο 4 1 O' >37Example 11

N-(3,4-DimethoxyphenyI)-N-[3[[2-(3,4-dime(hoxyphenyl)ethyl]methylamino] propyljbenzamide, hydrochloride ^f ·

³ \hci , • Starting from 800 mg (1.6 mmol) N-(3,4-dimethoxyphenyl)-N-[3i[2-(3,4;

dimethoxyphenyl)ethyl]methylaminolpropyl]benzamide and following the method of

Ί0 salification described in example 4, yielded 534 mg (63%) of-the title compound as

A grey crystals, m.p = 75°C ί » lH NMR (DMSO-dg) δ = 1.83-2.05 (m,2H,CH2); 2.80 (d,3H,J=4Hz,CH₃NH⁺); 2.88-3.00 (m,2H,CH2); 3.05-337 (m,4H,2CH₂); 3.63,3.73 and 3.75 (4s,12H,4CH₃O); 3.82-3.96 (m,2H,CH₂NCO); 6.62-6.93 (m,6H,Ar); 7.17-7.33 (m;5H,Ar); 10.25 (broad band,IH,exch D₂O,NH⁺) ppm. ,

Example 12

4-Cyano-N-(3,4-Dimethoxyphenyl)_:N-[3[[2-(3,420 dimethoxyphenyl)ethyl]methylamino]propyl] benzaihide, hydrochloride

HCl

Starting from 1.26 mg (2.43 mmol) 4-Cyano-N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,425 dimethoxyphenyl)ethyl]methylamino]propyl-benzamide and following the method of salification described in example 4, yielded 844 mg (62.7%) ofthe title compound as grey crystals, m.p = 90°C * *H NMR (DMSO-dg) 5 = 1.83-2.10 (m,2H,CH2); 2.79 (d,3H,J=4. 1Hz£H₃NH⁺); 2.85-3.05 (m,2H,CH2); 3.00-3.40 (m,4lf,2CH₂N); 3.66,3.67,3.73 and 3.75 ’ (4s,12H,4CH₃O); 3.82-4.00 (m,2H,CH₂CO); 6.65-7.00 (m,6H,Ar); 7.48

A .

badpriginal m

Ρ30384

- 38 (d^HJ=8.1Hz,Ar); 7.73 (d,2H,J=8.1Hz,Ar); 10.51 (broad band.lH.exch D2Q,NH⁺) ppm. /

Example 13 * * A

N-(3,4-Dimethoxyphenyl)-N-[3([2-(3,4-dimethoxyphenyl)ethyl]methyl- * amino]propyl]3,5-dinitrobenzamide, hydrochloride

t , HCI

Starting from 1.5 g (2.6 mmol) N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4dimethoxyphenyl)ethyl]methylamino]propyl]-3,5-dinitrobenzamide and following the

Λ .

method of salification described in example 4 , yielded 1.53 g (95%) of the title compound as yellow solid. * ' » *H NMR (DMSO-d^) δ = 1.90-2.10 (m,2H,CH₂); 2.81 (d,3H,J=4.2Hz£H₃NH+);

. 2.98-3.07 (m,2H,CH₂); 3.02-3.40 (n?,4H,2CH₂N); 3.66,3.67,3.73 and 3.75 , _? (4s,12H,4CH₃O); 3.88-4.02 (m,2H,CH2NCO); 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 D2O,NH⁺) ppm.

Example 14 : ,

N-(3,4-Dimethoxyphenyl)-N-J3[[2-(3,4-dimethoxyphenyl)ethyl]cycIopropylamino]propyl}-4-nitrobenzamide* hydrochloride \

·,' λ *

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

AP rf 0 0 4 1 0

X

P30384 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.

ΪΗ NMR (DMSO-dg) 5 = 0.74-1.00 and 1.00-1.27 (2m,4H;(CH₂)₂); 1 -97-2.12 (m,2H,CH2); 2.78-3.14 (m,3H12i2^r and NCJKCH^; 3.25-3.44 (m,4H,2CH₂N); 3.65 (s,6H,2CH₃O); 3.73 and 3.75 (2s,6H,2CH₃O); 3.90-4.04 (m,2H,CH₂NCO); . 6.68-7.03 (m,6H,Ar); 7.57 (d,2HJ=8.4Hz,Ar); 8.08 (d,2l£j=8.4Hz,Ar); 10.50 (broad band, 1 H,exch D₂O,NH⁺) ppm. * io .

\ ii

Example 15 , · *

N-(4-Hydroxy-3_:methoxyphenyl)-N-[3-[{2-(3,4-dimethoxyphenyl)ethyl]jnethyIamino]propyl]-4-ntfrobenzamide, hydrochloride

Starting from 500 mg (1.2 mmol) N-(4-hydroxy-3-methoxyphenyl)-N'-[2-(3,4dimethoxyphenyl)ethyl]-N'-methyl-l,β-propanediamine (D3Q) and 226 mg (1.2 mmol) 4-nitrobenzoyl chloride and following the method described in example 4,

A 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 *

Ή NMR (DMSO-dg) δ = 1,86-2.10 (m,2H,CH2); 2.81 (d,3HJ=4.3Hz,CH₃NH+) 2.86-3.00 (rn,2H,CH₂); 3.08-3.43 (m,4H,2CH₂N); 3.65, 3.?3 ahd 3.75 ' (3s,9H,3CH₃O); 3.84-3.98 (m,2H,CH₂NCO); 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 D₂O,NH+) ppns

BAD .ORIGINAL' ft

Λ

Ρ30384 , ·.

* - 40 Example 16 _fr

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4- „ dimethoxyphenyl)ethyl]methyIamino]propyI]-4-pyridinecarboxamide, dihydrochloride ·*

Starting from 1 g of (2.6 mmol) N-(3',4-dimethoxyphenyl)-N’-[2-(3,4- · _f dimethoxyphenyl)echyl]-N’-methyI-l,3-propanediamine and 0.50 g (2.8 mmol) of 4pyridine carbonyl chloride, hydrochloride and following the method described in example^, (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 = 13040°C *H NMR(DMSO-d6) δ = |.86-2.10 (m,2H,CH2); 2.79 (d,3HJ=3.5Hz,CH₃N); 2.863.04 (m,2H,CH2); 3.07-3.42 (m,4H,2CH2); 3.67 (s,6H,2CH₃O); 3.72 and 3.75 (2s,6H,2CH₃O); 3.84-4.00 (m,2H,CH2); 6.70-7.05 (m,6H,Ar); 7.41 *' (d^HJ=5.7HzAr); 8.53 (d,2H,J=5.7Hz,Ar); 10.57 (s,lH,exchD2O,NH⁺) ppm i

Example 17 < * .

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(i,4dimethoxyphenyl)ethyl]methy|amino]propyl]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]30 Ν’-methyl-1,3-propanediamine and 0. ΐ 98 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 wfes washed with a saturated aqueous solution of NaHCOj again vyith 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

i·

BAD ORIGINAL $

P30384

APO 00 4 1 Ο

-41a light beige solid, mp. around 85°C.

*H NMR(DMSO-d6)6 = 1.75(s,3H,CH₃); 1.76-1.93(m,2H,CH₂); 2;76(d,3H,J=3.7Hz,CH₃); 2.85-3.00(m,2H,CH₂); 3.05-3.48(m,4H,CH₂x2); 3.603.80(m,2H,CH₂); 3.72,3.75,3.76,3.77(s,12H,CH₃); 6.70-7,03(m,6H,Ar); 10.49(Broad s, lH.exch. D₂O,NH) ppm.

BAD ORIGINAL ft

*

Λ

P30384

-42PHARMACOLOGICAL METHODS , ' λ „

I

EFFECTS IN THE POG .,

5. .' · '

Surgical preparation. Dogs were anesthetized using 30 mg/kg tv. sodium pentobarbital. A tracheal cannula was placed for artificial respirationwith room air (Harvard 613 pump). A catheter wasinserted 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 the 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 Π ECG. For determination of the Q-T • * interval of ECG a CV5RL precordial lead of ECG was measured as previously Jcrrdiovasculai? Pharmacol vol p3i>3 '393 described (Koerner et al.,J990). After a left thoracotomy through the fifth intercostal space, the heart was suspended in a pericardial cradle. TJa£ 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 the 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 the drug was performed in 10 minutes. After the drug administration, hemodynamic and ECG variables were again measured and the LCX was occluded for 45 minutes by placing a microclamp. Reperfusion performed by removing the clamp was continued for 5 hours.

4./

Measurements. Vent; . alar arrhythmias were analyzed during the preischemic period, during ischerrii.i and dujing the first hour of reperfusion. Ventricular * , · < Λ ‘ premature beats (λ js) were defined as identifiable premature QRS complexes and salvos as more th.. . consecutive VPBs. Ventricular tachycardia was defined as 4 or i

more consecutive V PBs. Ventricular fibrillation (VF) was diagnosed when tolal irregularity of rhythrn 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 convertor and analysed on an IBM s

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P30384 ftp ο Ο Ο 4 1 ο

-43computer 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)’A

ELECTROPHYSIOLOCAL STUDIES

Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy the heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to the 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 the following (mM): NaCl 125, KC14.0, MgCl₂ 0.5, CaCl₂ 1.8, NaHCO₃ 24, NaH₂PC>4 0.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% O₂ - 5% CO₂.

After a stabilisation period (at least 1 h), transmembrane action potentials were recorded with conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to the preparation with bipolar platinum electrodes placed at one end of the muscle. The pulse duration was 1 ms and the 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 (APD₃q, APD50 and APD9Q respectively). Recordings were made after 30 min of equilibration for each concentration. Only recordings in which the same impalement was maintained throughout the 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

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Ρ30384

- 44 - λ , and the number of VPBs which were not found Gaussian-distributed, medians were 7 compared using the Mann-Withney test. Binomially distributed variables such as incidence of VT and VF and mortality were compared using X² 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 (BBN Software Product Corporation, Cambridge, MA) on the VAX 4000-200 computer. A p value less than 0.05 was considered statistically significant.

RESULTS >

¹⁰ .

EFFECTS - < IN ANESTHETIZED DOGS.

• · A ' *

Hemodynamic and electrocardiographic parameters. * ' • A

The effects of Compound I (0.3 and 1.0 mg/kg) in anesthetized dogs were compared ¹ # ' to those of d-sotalol (3.0 and 10.0 mg/kg). At the end of the stabilisation period, before drug .administration, there was no difference between the groups in the hemodynamic parameters. During the preischemic period, both compound reduced >

. heart rate in a dose-dependent manner. With only minimal changes in mean arterial 20 and left ventricular pressure, Compound I and d-sptalol both reduced the pressure rate product. This effect was associated for both compounds with a reduction in the left ventricular dP/dtmax. Similar changes in hemodynamic parameters were also observed both during the ischemic period and after 60 mip of reperfusion.

’’ ‘ \

During the preischemic period both Compound I and d-Sotalol prolonged QT and QTc intervals (table 1) but did not change the PR interval. Although a similar prolongation of QT interval was also observed during ischemia, a lesser effect was noted during the reperfusion period. During ischemia the high doses of Compound I and d-sotalol both increased QTc interval and this action was abolished during the t

reperfusion. Except for the lower dose of Compound I during the ischemic period, there was no marked change in the PR interval duration.

\ /

Ischemia and reperfusioh-induced arrhythmias.

· *

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

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-45these 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 μΜ) 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 the concentration. An action potential prolongation was observed with Compound I at low concentrations (0.3 and 1 μΜ). However, when the concentration was further increased (3 μΜ) there was no further increase in APD. At a higher concentration (10 μΜ) Compound I reduced action potential duration.

The results summarized in table 2 show that both Compound I and d-Sotalol did not change the resting membrane potential, the action potential amplitude, and the Vmax, even at the highest concentrations.

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Table 1: Effect of Compound I and d-Sotalol on electrocardiographic parameters measured in anesthetized dog.

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Claims;

1 » '

20 represents a 4-nitrobenzoyl group, R3 represents methyl, R4 represents 3,4dimethoxyphenyl, A represents (CH2)3 and B represents (CH

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11. A compound of formula (I), being selected from the list ebnsisting of:

» Λ

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

N-(3,4-dichlorophenyl)-N-[3-[[2-(3,4-dimethoxypbenyl)ethyl] * methylamino]propyl] -4-nitrobenzamide , · *

BAD ORIGINAL ft

P30384

AP Ο Ο Ο 4 1 Ο

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

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-2propeny lamino] propyl] -4-nitrobenzamide,

5 4-amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4dimethoxyphenyl)ethyl]tnethyl-amino] propyl]benzamide,

N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-N-[3,4-bis(lmethylethoxy) phenyl]-4-nitrobenzamide,

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl](l-methyl10 ethyl)amino]propyl]-4-nitrobenzamide,

N-(3,4-diethoxyphenyl)-N-[3-[[2-(3,4-Diethoxyphenyl)ethyl]methylamino]propyl]-4-nitrobenzenecarboxamide,

N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl)ethyl]cyclopropylamino]propyl]-4-nitrobenzamide,

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

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]propyl]-4-pyridinecarboxainide; or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate

20 thereof.

12. A pharmaceutical composition comprising a compound of formula (Π):

25 Ri - NH - A - NR₃ - B - R₄ (Π) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof wherein, Rj, A, R3, B and R4 are as defined in relation to formula (I) in claim 1.

13. A method according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, is in unit dosage form.

35 14. A method according to claim 13, wherein the unit dose comprises 0.1 to 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

BAD ORIGINAL

P30384 s' - r? λ ’

-415. A method according to claim 13 or claim 14, wherein the unit dose comprises 2 to 50 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

1. 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

5 compound of formula (I):

R,-N—A—Ν—B—R₄

I I

Rj Rj (I)

10 or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein

Rj and R4 are independently phenyl optionally substituted by one, two or three of halogen, C1-4 alkoxy, C4-4 alkyl, cyano, hydroxy, nitro, NRgRg or O₂SNR5Rg

15 wherein R5 and Rg are independently hydrogen or Cj-g alkyl or together are C3-g polymethylene, or disubstituted at adjacent carbon atoms by Cp₂ 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, C4-12 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl (4-4 alkyl, phenyl C1-4 alkyl, pyridyl, pyridyl

20 Cp4 alkyl, COR7, COCH2COR7, SO₂R7, CO2R7, CONHR7 and CSNHR7, where R7 is selected from Cj-i₂ alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Cp4 alkyl, phenyl and phenyl (4-4 alkyl, any alkyl moiety in R7 optionally substituted by hydroxy or C}~4 alkanoyloxy, any pyridyl or phenyl moiety in R₂ optionally substituted as defined for Rj and R4 and any cycloalkyl moiety in R₂ optionally substituted by one

25 or two C j-4 alkyl groups;

^r3 is hydrogen, C₂-g alkyl, C₂-g alkene or C3-8 cycloalkyl;

A represents C₂-5 alkylene; and

B represents ¢4-4 alkylene; compounds and pharmaceutical compositions for use in such method.

2. A method according to claim 1, for the treatment of cardiac arrhythmia and ischemic rhythm disorders.

3. A method according to any one of claims 1 to 2, wherein R1 and R4 each 35 represent 3,4-dimethoxyphenyl.

4.

P30384

-25. A method according to any one of claims 1 to 4, wherein A is -(CH₂)3- and B is -(CH₂)₂-.

5

6. A method according to claim 1, wherein the compound of formula (I) is a compound of formula (IB): *

5 »

R ,-N— (CH₂), — N—(CH₂)i—R« i^{2 1} ’ n₂

R₃· (IB)

10 wherein R₂^ is COR

7 where R7 is as defined in formula (I), and the remaining • variables are as defined in formula (I). ·

Γ ,7. A method according to c.laim 6, wherein R7 is Ci_i₂ alkyl.

ι A '

15

8. A method according to claim 6, wherein'R? is optionally substitute ptenej, opboro.1 selec tea from 0¾. halogen atom and ' · subsbluents - one, two or three of cyano, hydroxy, nitrq.or NR5R5 wherein

R5 and are independently hydrogen or alkyl. * • r. »

9. A method according to claiJn 1, wherein Rj represents 3,4^dimethoxyphenyi, R₂

4. A method according to any one of claims 1 to 3, wherein R3 is methyl.

BAD ORIGINAL A

5 16. A method according to any one of claims 1 to 6, wherein the medicament is adapted for oral or parenteral administration.