WO2002024619A1

WO2002024619A1 - Amine compounds

Info

Publication number: WO2002024619A1
Application number: PCT/GB2001/004264
Authority: WO
Inventors: Ian George Cormack Coutts; Robert William Allcock
Original assignee: BTG International Ltd
Current assignee: BTG International Ltd
Priority date: 2000-09-25
Filing date: 2001-09-25
Publication date: 2002-03-28
Anticipated expiration: 2003-03-25
Also published as: GB0023467D0; AU2001287933A1

Abstract

Ar is a bicyclic or tricyclic aromatic group including at least one benzene ring, the oxygen group of the side chain being attached to the benzene ring of Ar; A is a straight or branched alkylene group of 6 to 16 carbon atoms which may be interrupted by -O-, -S-, -SO-, -SO2-, -NR4-, -CH(OH)- or -CO-, wherein R4 is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and R?1 and R2¿ are each independently hydrogen or a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, optionally substituted by phenyl or a cycloalkyl group of 3 to 7 carbon atoms; are useful for the treatment of fungal infection.

Description

Amine compounds

This invention is in the field of amine compounds and in particular it relates to aryloxy-substituted amines which possess antifungal properties.

Aryloxy-substituted amines are already known, and various activities have been reported. Thus the simple unsubstituted amine:

is known from EP 0082005-A and EP 0188333-A (both Syntex (U.S.A.) Inc.), as is the N,N-dimethyl derivative:

The pharmacological activity stated for these compounds is as anti-inflammatory agents. In the later Syntex application, they are used as intermediates only. The possibility of a halogen substituent is allowed for on the ring remote from the aminoalkoxy substituent, but there is no exemplification of this; the general teaching of the document is that this ring should be unsubstituted.

WO 94/07875-A (British Technology Group Limited) discloses a pharmaceutical composition which comprises as an active ingredient a heterocyclic amine of the formula:

Ar— X— A— R^!R² wherein — Ar is an optionally substituted bicyclic or tricyclic aromatic group;

X is a direct link or is -O-, -S-, -SO- or -SO₂- or has the formula -C(R³)=CH- wherein R is hydrogen or alkyl of up to 4 carbon atoms;

A is straight or branched alkylene or alkenylene of 3 to 8 carbon atoms which may be interrupted by -O-, -S- or -NH-; and

NR^!R² is a cyclic amino group.

The compounds are said to have calmodulin antagonist properties and also to be of interest for the treatment of fungal infections. The compounds are all cyclic amines and typical compoimds include the following naphthyloxy-substituted piperidine derivative:

and a corresponding compound with a 6-bromo substituent in the aromatic ring system:

The disclosure of WO 94/07875- A focuses on the calmodulin antagonist properties of the compounds, saying that they find particular use for the treatment of myocardial ischaemia or hypertension. Little data are given on their possible antifungal applications, other than a statement that compounds containing a bromo-substituted benzo[b]thienyl group Ar have been found to be of particular interest in this context. We have now surprisingly found that replacement of the cyclic amine by an acyclic amine gives compounds with useful antifungal properties. Thus according to the present invention there is provided a compound of formula (I):

Ar— O— A— NR^JR² (I)

wherein —

Ar is a bicyclic or tricyclic aromatic group including at least one benzene ring and bearing —

• one or more halogen substituents, and/or

• one or more ring heteroatoms,

the oxygen group of the side chain being attached to the benzene ring of Ar;

A is a straight or branched alkylene group of 6 to 16 carbon atoms which may be interrupted by — O— , — S— , —SO—, — SO₂— , — NR⁴— , — CH(OH)— or — CO — , wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and

R and R are each independently hydrogen or a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, optionally substituted by phenyl or a cycloalkyl group of 3 to 7 carbon atoms;

or a pharmaceutically acceptable acid derivative thereof.

Ar may be any bicyclic or tricyclic aromatic group including at least one benzene ring, but is preferably selected from —

• naphthalene bearing one or more halogen substituents; and

• benzothiophene and benzofuran, optionally bearing one or more halogen substituents on the benzene ring. When Ar represents a benzothiophene and benzofuran ring, any pattern of substitution is possible and the heteroatom may be in the position either adjacent to the benzene ring or remote from it. However, the compound preferably comprises a compound of formula (IA) or (IB):

(IB)

wherein Hal is a halogen substituent and A, R 1 a „„ndJ τR2 are as defined for formula I

When Ar represents naphthalene, any number of halogen substituents may be present, but preferred is a compound of formula (IC):

wherein Hal is a halogen substituent and A, R¹ and R² are as defined for formula I. A preferred substitution pattern has been found to be a compound of formula (ID):

wherein Hal is a halogen substituent and A, R 1 a „_ndJ τ R»2 are as defined for formula I

Although which may be interrupted by various groups, particularly good antifungal activity is obtained when A is a straight or branched alkylene group of 6 to 16 carbon atoms. High potency is shown for compounds having an alkylene group of 6 to 11 carbon atoms, especially when A is a straight or branched alkylene group of 8 to 10 carbon atoms.

Alternatively, A may represent a group (CH₂)_m — X — (CH )_n, wherein —

X is O, S, SO, SO₂, NR⁴, CH(OH) or CO, wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and

m and n are integers each greater than 1 such that the sum (m + n) is between 8 and 16.

Preferably X is O, S, SO₂, NR⁴, CH(OH) or CO, wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, and the sum (m + n) is between 9 and 11. More preferably X is SO and the sum (m + n) is between 12 and 14.

In all cases, compounds in which R¹ and R² are each independently hydrogen, a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, benzyl or cyclopropylmethyl are preferred. Preferably R¹ and R² are each independently hydrogen or methyl, especially a compound in which R¹ is methyl and R² hydrogen.

Substitution may be by any number of halogen groups, but preferably the halogen substituent is a single fluoro, chloro, bromo or iodo group, more preferably fluoro, chloro or bromo, especially bromo. In many cases, introduction of bromine has resulted in a significant increase in antifungal activity.

The invention includes compounds which are significantly more active than those referred to in passing in WO 94/07875-A. Unlike their predecessors they have broad spectrum antifungal activity.

It will be appreciated that the majority of the compounds of the invention are basic in nature, Thus the most suitable pharmaceutically acceptable derivative comprises an acid addition salt, though other derivatives are possible. A suitable pharmaceutically acceptable acid addition salt is, for example, a salt derived from an inorganic acid, for example a hydrochloride, hydrobromide, phosphate or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, succinate, tartrate, acetate, salicylate, citrate, benzoate, β-naphthoate or adipate.

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in association with a pharmaceutically acceptable diluent or carrier.

The exact chemical nature of the best compound can depend on the mode of administration. For administration by the topical route, a lipophilic side-chain is preferred. Thus one preferred pharmaceutical composition is adapted for topical administration and the ingredient comprises a compound of formula (I) wherein A is a straight or branched alkylene group of 6 to 16 carbon atoms, or a pharmaceutically acceptable derivative thereof.

On the other hand, when systemic administration is desired, a modified side-chain with a lower partition coefficient is more appropriate. For the drug to reach the site of action, it must be able to interact with two different environments, lipophilic, such as cellular membranes, and aqueous, the exobiophase. As a suitable measure of lipophilicity, the partition coefficient, P, between an organic phase, 1-octanol, and aqueous phase can be useful. This is often expressed as its logarithm, log P.

Thus another preferred pharmaceutical composition is adapted for systemic administration and the active ingredient comprises a compound of formula (I), wherein A is a group (CH₂)_m — X — (CH₂)_n, wherein —

m and n are integers each greater than 1 such that the sum (m + n) is between

8 and 16,

or a pharmaceutically acceptable derivative thereof. The invention includes the compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use as a pharmaceutical.

The compounds of the invention may be used in the treatment of fungal infections. We have found that this useful property is not merely restricted to the compounds defined above. Thus, in a further aspect of the invention there is provided the use of a compound of formula (I):

Ar— O— A— NR R² (I)

wherein —

Ar is a bicyclic or tricyclic aromatic group including at least one benzene ring optionally bearing one or more halogen substituents, the oxygen group of the side chain being attached to the benzene ring of Ar;

A is a straight or branched alkylene group of 6 to 16 carbon atoms which may be interrupted by — O— , — S— , —SO— — SO₂— , — NR⁴— , — CH(OH)— or — CO — , wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and

R¹ and R² are each independently hydrogen or a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, optionally substituted by phenyl or a cycloalkyl group of 3 to 7 carbon atoms;

or a pharmaceutically acceptable acid derivative thereof;

in the manufacture of a medicament for use in the treatment of a fungal infection.

There is also provided a method for the treatment of a fungal infection in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of foπnula (I): Ar— O— A— NR^!R² (I)

wherein-

1 9 R and R are each independently hydrogen or a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, optionally substituted by phenyl or a cycloalkyl group of 3 to 7 carbon atoms;

or a pharmaceutically acceptable acid derivative thereof.

When used for the treatment of fungal infections in man, it is expected that the pharmaceutical composition of the invention would be administered such that the amine compound would be given to man at a total oral dose of between 20 mg and 600 mg daily or an intravenous dose of between 1 mg and 20 mg. However, therapeutically effective doses outside the ranges may be used where appropriate.

Preferred oral dosage forms are tablets or capsules containing between 10 and 100 mg, and preferably 10 mg or 50 mg, of active ingredient. Preferred topical dosage forms are compositions containing similar amounts to the oral dosage forms within a volume of 1 to 10 ml. Preferred intravenous dosage forms are sterile solutions of the basic ether or of a non-toxic acid addition salt thereof, containing between 0.05% and 1% w/v of active ingredient, and more particularly containing 0.1% w/v of active ingredient. The novel compounds of the invention may be prepared by any process known for the preparation of chemically-related compounds. Accordingly, certain such processes form a further feature of the invention.

According to a further feature of the invention there is provided a process for the manufacture of a compound as defined above which comprises the reaction of a compound of formula (II):

Ar— O— A— Z (II)

wherein Ar and A are as defined above and wherein Z is a displaceable group, for example a halo or sulfonyloxy group such as the bromo or tosyl group, with an amine of the formula H OR^R², wherein R¹ and R² are as defined above.

According to a further feature of the invention there is provided a process for the manufacture of a compound as defined above which comprises the reduction of an amide of formula (III):

Ar— O— A¹— CO— NR R² (III)

wherein Ar, R¹ and R² are as defined above and wherein A¹ is such that A¹ — CH₂ has the same meaning as defined above for A, thereby producing a compound of formula (IE):

Ar— O— A¹— CH₂— NR R² (IE)

The amide starting material may be obtained by reacting an activated derivative of the corresponding carboxylic acid with an amine of the formula HNR^² wherein R¹ and R² have the meanings stated above.

The invention will now be illustrated by way of example only.

Table 1 show compounds of the invention that have been synthesized: Table 1

EXPERIMENTAL

General Methods

A. Williamson Ether Synthesis

To the appropriate phenol (1 equivalent) and powdered potassium carbonate (3 equivalents) suspended in 2-butanone (0.3M) at room temperature under an atmosphere of nitrogen was added the appropriate cc,ω-dibromoalkane (5 equivalents). The heterogeneous mixture was stirred vigorously and gently refluxed until the reaction was judged complete by t.l.c, allowed to cool, and the solvent was removed in vacuo. The residue was suspended in dichloromethane, filtered, and sequentially partitioned with 2M NaOH and sat. NaCl. The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo. Excess α,ω-dibromoalkane was removed by Kugelrohr distillation at reduced pressure and the residue was triturated with 1 to 5 % ethanolic petroleum ether to give a precipitate that was recrystallised from an appropriate solvent.

B. Alkylation of Amines.

To the appropriate alkyl halide (1 equivalent) and triethylamine (2 equivalents) dissolved in dimethylformamide (0.1M), at room temperature under an atmosphere of nitrogen, was added the appropriate amine (10 equivalents)*. The mixture was stirred at room temperature for 18 h. and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and sequentially partitioned, twice with water, and sat. NaCl. The organic fraction was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with (ethyl acetate : methanol : 880 NH₃, 90:(10 to 15): 3). Fractions containing the product were combined and concentrated in vacuo to give the desired amine as the free base.

* Methylamine was used as a 33% solution in ethanol; ethylamine was used as a 2M solution in methanol; dimethylamine was used as a 2M solution in methanol.

C. Preparation of Hydrochloride Salts.

To the appropriate amine dissolved in the minimum amount of dichloromethane at room temperature was slowly added an excess of ethereal hydrogen chloride. The mixture was cooled to 0 °C, filtered, and the hydrochloride salt was purified by recrystallisation from an appropriate solvent.

NAPHTHALENE DERIVATIVES.

Preparation of 6-bromo-2-(n-bromoalkyloxy)naphthalenes.

The ethers were prepared from commercially available 6-bromo-2-naphthol and the appropriate α,ω-dibromoalkane by the General method A.

6-Bromo-2-(2-bromoethyloxy naphthalene (1 ) . % Yield : 74. M.p. : 130-132 °C. δH : 7.88 (1H, d, ArH), 7.64-7.46 (3H, m, ArH), 7.15 (1H, dd, ArH), 7.04 (1H, d, ArH), 4.34 (2H, t, OCi^C^Br), 3.67 (1H, t, OC^Ci^Br). δC : 156.24, 132.79, 130.20, 129.72, 129.63, 128.71, 128.37, 119.71, 117.39, 106.93, 67.78, 28.93.

6-Bromo-2-(4-bromobutyloxy nat)hthalene (2y % Yield : 68. M.p. : 51-54°C. δH : 7.89 (IH, d, ArH), 7.64-7.46 (3H, m, ArH), 7.13 (IH, dd, ArH), 7.07 (IH, d, ArH), 4.08 (2H, t, OCff^" ₂(CH₂)₃Br), 3.50 (2H, t, O(CH₂)₃Cfi₂Br), 2.10 (2H, m, OCH₂CH^" ₂(CH₂)₂Br), 2.02 (2H, m,

δC : 157.07, 132.99, 129.97, 129.61, 129.52, 128.50, 128.34, 119.91, 117.03, 106.47, 66.86, 33.44, 29.45, 27.80.

6-Bromo-2-(6-bromohexyloxy naphthalene (3).

% Yield : 71.

M.p. : 55-56 °C. δH : 7.89 (IH, d, ArH), 7.64-7.46 (3H, m, ArH), 7.15 (IH, dd, ArH), 7.06 (IH, d,

ArH), 4.04 (2H, t, OCff₂(CH₂)₅Br), 3.42 (2H, t, 0(CΗ,₂)_sCH₂ τ), 1.92-1.82 (4H, m,

OCH.₂CH₂(CH.₂)₂C I₂CH₂ T), 1.55-1.49 (4H, m, O(CH₂)₂(CH^₂(CH₂)₂Br). δC : 157.28, 133.04, 129.92, 129.61, 129.54, 128.43, 128.32, 119.99, 116.91, 106.45,

67.76, 33.82, 32.65, 29.13, 27.92, 25.34.

6-Bromo-2-(8-bromooctyloxy naphthalene (4 .

% Yield : 78.

M.p. : 59-60 °C. δH : 7.89 (IH, d, ArH), 7.63-7.45 (3H, m, ArH), 7.16 (IH, dd, ArH), 7.06 (IH, d, ArH), 4.03 (2H, t, OC0₂(CH₂)₇Br), 3.40 (2H, t, O(CH₂)₇Cff₂Br), 1.88-1.80 (4H, m,

OCH₂Cff₂(CH₂)₄CH₂CH₂Br), 1.49-1.36 (8H, m, O(CH₂)₂fC!^ CH₂)₂Br),. δC : 157.34, 133.06, 129.90, 129.61, 129.50, 128.41, 128.32, 120.03, 116.87, 106.45,

67.96, 34.02, 32.76, 29.31, 29.13, 28.68, 28.09, 25.98.

6-Bromo-2-(9-bromononyloxy)naphthalene (5).

% Yield : 69.

M.p. : 62-63 °C. δH : 7.91 (IH, d, ArH), 7.64-7.55 (2H, m, ArH), 7.49 (IH, dd, ArH), 7.13 (IH, dd,

ArH), 7.04 (IH, d, ArH), 4.03 (2H, t, OCff-₂(CH₂)₈Br), 3.41 (2H, t, O(CH₂)₈CH2Br), 1.88-1.82 (4H, m, OCH₂Ci7₂ (CH₂)₅CH₂CH₂Br), 1.55-1.30 (10H, m,

O(CH₂)₂fC#₂)₅(CH₂)₂Br). δC : 157.35, 133.06, 129.88, 129.59, 129.50, 128.39, 128.30, 120.03, 116.85, 106.45,

67.99, 34.03, 32.78, 29.45, 29.25, 28.68, 28.12, 26.12, 26.04, 24.74. 6-Bromo-2-( 10-bromodecyloxy)naphthalene (6) .

% Yield : 76.

M.p. : 70-72 °C. δH : 7.90 (IH, d, ArH), 7.64-7.46 (3H, m, ArH), 7.17 (IH, dd, ArH), 7.08 (IH, d,

ArH), 4.05 (2H, t, OCH^" ₂(CH₂)₉Br), 3.41 (2H, t, O(CH₂)₉CH2Br), 1.88-1.81 (4H,

OCH₂C#₂(CH₂)₆C_H^" ₂CH₂Br), 1.55-1.33 (12H, m, O(CH₂)₂rC_fir >_tf(CH₂)₂Br). δC : 157.37, 133.08, 129.90, 129.61, 129.52, 128.41, 128.32, 120.05, 116.85, 106.47,

68.03, 34.03, 32.79, 29.43, 29.33, 29.16, 28.73, 28.14, 26.06.

6-Bromo-2-(12-bromododecyloxy naphthalene (7 . % Yield : 82. M.p. : 69-71 °C. δH : 7.90 (IH, d, ArH), 7.64-7.46 (3H, m, ArH), 7.16 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.05 (2H, t, OCH₂(CΗ.₂)ιιBv), 3.40 (2H, t, 0(CH₂)iiC ₂Bv), 1.88-1.81 (4H, m, O-CH₂Cff₂(CH₂)₈CΗ₂CH₂Br), 1.56-1.29 (16H, m, -O(CH₂)₂fCΗ2 ₅(CH₂)₂Br). δC : 157.39, 133.08, 129.90, 129.61, 129.52, 128.39, 128.32, 120.07, 116.85, 106.47, 68.07, 34.09, 32.83, 29.52, 29.42, 29.38, 29.18, 28.75, 28.16, 26.07.

Preparation of 6-bromo-2-(«-methylaminoalkyloxy)naphthalene hydrochlorides.

The amine hydrochloride derivatives were prepared from the appropriate ω-bromoalkyl-6-bromo-2-naphthyl ether and excess methylamine by the General methods B and C respectively.

6-Bromo-2-(6-methylaminohexyloxy naphthalene HCI. (8).

% Yield : 85.

M.p. : 179-180 °C.

Found : C, 54.85; H, 6.46; N, 3.60. Cι₇H₂₃BrClNO requires : C, 54.78; H, 6.22; N, 3.76 %. δH : 7.88 (IH, d, ArH), 7.62-7.54 (2H, m, ArH), 7.48 (IH, dd, ArH), 7.13 (IH, dd,

ArH), 7.04 (IH, d, ArH), 4.00 (2H, t, OCffXCB^NHCHs), 2.94 (2H, t, O(CH₂)₅CH₂NHCH₃), 2.67 (3H, s, -O(CH₂)₆NHCHj), 1.90-1.80 (4H, m,

δC : 157.18, 133.01, 129.90, 129.59, 129.54, 128.43, 128.35, 119.94, 116.93, 106.47,

67.58, 49.33, 32.88, 28.89, 26.42, 25.84, 25.61.

6-Bromo-2-(8-methylaminooctyloxy naphthalene HCI. (9).

% Yield : 72.

M.p. : 163-165 °C.

Found : C, 57.14; H, 6.75; N 3.30. C₁₉H₂₇BrClNO requires : C, 56.94; H, 6.79; N, 3.49 %. δH : 7.88 (IH, d, ArH), 7.62-7.55 (2H, m, ArH), 7.49 (IH, dd, ArH), 7.15 (IH, dd,

ArH), 7.06 (IH, d, ArH), 4.02 (2H, t, OCH₂(CH₂)₆CH₂NHCH₃-), 2.91 (2H, t,

O(CH₂)₇C#₂NHCH₃), 2.66 (3H, s, O(CH₂)₈NHCff₅), 1.83-1.81 (4H, m,

OCH₂C_H₂(CH₂)₄CH₂CH₂NHCH₃), 1.37 (8H, m, O(CH₂)₂ <r#aMCH₂)₂NHCH₃). δC : 157.32, 133.04, 129.88, 129.59, 129.50, 128.41, 128.34, 120.02, 116.87, 106.47,

67.89, 49.40, 32.83, 29.29, 29.09, 28.95, 26.59, 25.95, 25.86.

6-Bromo-2-(9-methylaminononyloxy)naphthalene HCI. (10).

% Yield : 76. M.p. : 160-16 re

Found : C, 58.02; H, 7.16; N, 3.08. C₂₀H₂₉BrClNO requires : C, 57.91; H, 7.05; N,

3.38 %. δH : 7.87 (IH, d, ArH), 7.62-7.58 (2H, m, ArH), 7.48 (IH, dd, ArH), 7.16 (IH, dd,

ArH), 7.06 (IH, d, ArH), 4.01 (2H, t, OCH₂(CH₂)₈NHCH₃), 2.91 (2H, t, O(CH₂)₈CfiT₂NHCH₃), 2.66 (3H, s, O(CH₂)₉ NHCH₅), 1.84-1.81 (4H, m,

OCH₂Cir₂(CH₂)₅C#₂CH₂NHCH₃), 1.34 (10H, m, O(CH₂)₂fC#; CH₂)₂NHCH₃). δC : 157.36, 133.08, 129.90, 129.60, 129.52, 128.41, 128.35, 120.05, 116.87, 106.47,

67.96, 49.40, 32.79, 29.31, 29.24, 29.15, 28.97, 26.65, 26.02, 25.88.

6-Bromo-2-(10-methylaminodecyloxymaphthalene HCI. (11). % Yield : 73. M.p. : 154-156 °C. Found : C, 58.75; H, 7.22; N, 3.17. C₂₁H₃₁BrClNO requires : C, 58.82; H, 7.29; N, 3.27 %. δH : 7.89 (IH, d, ArH), 7.64-7.59 (2H, m, ArH), 7.49 (IH, dd, ArH), 7.16 (IH, dd, ArH), 7.07 (IH, d, ArH), 4.03 (2H, t, OC#₂(CH₂)₉NHCH₃), 2.87 (2H, t,

2.66 (3H, s, O(CH₂)₁₀NHCH^"i , 1.85-1.80 (4H, m, OCH₂Cff₂(CH₂)₆C#₂CH₂NHCH₃), 1.31 (12H, m, O(CH₂)₂ CO^CH^ HCHs). δC : 157.37, 133.08, 129.90, 129.61, 129.52, 128.41, 128.34, 120.07, 116.87, 106.47, 68.01, 49.42, 32.78, 29.43, 29.31, 29.18, 29.02, 26.67, 26.07, 25.89.

6-Bromo-2-(12-methylaminododecyloxy)naphthalene HCI. (12).

% Yield : 68.

M.p. : 152-155 °C.

Found : C, 60.52; H, 7.90; N, 3.10. C₂₃H₃₅BrClNO requires : C, 60.46; H, 7.72; N,

3.07 %. δH : 7.90 (IH, d, ArH), 7.65-7.89 (2H, m, ArH), 7.50 (IH, dd, ArH), 7.17 (IH, dd,

ArH), 7.08 (IH, d, ArH), 4.04 (2H, t, OC^CH^πNHCHs), 2.91 (2H, t,

O(CH₂)_πC#₂NHCH₃), 2.61 (3H, s, O(CH₂)₁₂NHCff5), 1.86-1.81 (4H, m,

OCH₂CH₂(CH₂)₈CH₂CH₂NHCH₃), 1.27 (16H, m, O(CH₂)₂ fCff> CH₂)₂NHCH₃). δC : 157.54, 133.21, 130.04, 129.65, 129.56, 128.41, 128.32, 120.07, 116.93, 106.85, 68.23, 49.33, 29.53, 29.47, 29.36, 29.24, 29.02, 26.70, 26.09, 25.81.

Preparation of compounds with the general structure Ar-O-(CH₂)nNR₁R₂ where Ar is 6-bromo-2-naphthyl.

Primary amine

Preparation of 6-bromo-2-(8-aminooctyloxy naphthalene HCI (14).

a) Preparation of N¹-[8-(6-bromo-2-naphthyloxy) octyl]-2,2,2-trifluoroacetamide (13).

To a suspension of ΝaH (60% in oil, 0.21 g, 5.3 mmol), in dry dimethylformamide (25 ml) at room temperature under an atmosphere of nitrogen, was added a solution of trifluoroacetamide (0.59 g, 5.2 mmol) in dimethylformamide (5 ml) over a period of 5 min. The mixture was stirred for 1 h. A solution of intermediate (4) (1.2 g, 2.9 mmol) in dimethylformamide (5 ml) was added and the mixture was gently refluxed for 3 h. T.l.c, (petroleum ether : ethyl acetate, 7 : 3), indicated disappearance of starting material, Rf 0.49, and formation of a new compound, Rf 0.23. The mixture was allowed to cool and was quenched by the dropwise addition of methanol (2 ml). The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml) and partitioned with H₂O (2 x 20 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo. The crude solid was purified by flash column chromatography, gradient elution with (petroleum ether : ethyl acetate, 20:1 to 4:1). Fractions containing the product were combined and concentrated in vacuo to give compound (13) as a white solid, 0.66 g, 51 %. M.p. : 84 - 86 °C. δH : 7.89 (IH, d, ArH), 7.65-7.56 (2H, m, ArH), 7.49 (IH, dd, ArH), 7.16 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.04 (2H, t, OCH₂(CH₂)₇NHCOCF₃), 3.37 (2H, q, O(CH₂)₇αT₂NHCOCF₃), 1.85-1.80 (2H, m, O(CH₂)₆CH₂CH₂NHCOCF₃), 1.61-1.47 (4H, m, OCH₂Ciy₂(CH₂)₃CiΪ2CH2CH2NHCOCF₃), 1.40-1.36 (6H, m, O(CH₂)₂fCH2 CH₂)₃NHCOCF₃). δC : 157.45, 157.34, 156.91, 133.08, 129.90, 129.61, 129.52, 128.41, 128.34, 120.03, 117.99, 116.89, 113.75, 106.47, 67.94, 29.18, 29.13, 29.06, 28.91, 26.58, 25.98.

b) Preparation of compound (14).

Intermediate (13) (0.34 g, 0.8 mmol) was suspended in a mixture of 20% NaOH (10 ml) and methanol (4 ml) at room temperature and stirred vigorously for 6 h. T.l.c, (petroleum ether : ethyl acetate, 4:1), indicated disappearance of starting material, Rf 0.27, and formation of baseline material. The mixture was extracted with dichloromethane (2 x 20 ml) and the combined organics were partitioned with sat. NaCl (15 ml). The organic fraction was dried over Na2SO₄, filtered, and concentrated in vacuo to give a white solid. The hydrochloride salt was prepared by the General method C to give compound (14) as a white crystalline solid, 0.21 g, 71%. M.p. : 179-182 °C.

Found : C, 56.05; H, 6.46; N, 3.71. C₁₈H₂₅BrClNO requires : C, 55.90; H, 6.52; N, 3.62 %. δH : 8.10 (IH, d, ArH), 7.84-7.77 (2H, m, ArH), 7.58 (IH, dd, ArH), 7.35 (IH, d,

ArH), 7.23 (IH, dd, ArH), 4.06 (2H, t, OCfl^r ₂(CH₂)₇NH₂), 2.76 (2H, t,

O(CH₂)₇Cfl^r ₂NH₂), 1.77 (2H, m, OCH₂ Cff₂(CH₂)₆NH₂), 1.58 (2H, m,

O(CH₂)₆C^βiCH₂ H2), 1.44 (2H, m, 0(CR₂)₂CH₂(CH₂)₃Wi2), 1.31 (6H, m,

O(CH₂)3fCΗ₃MCH₂)2NH₂). δC : 157.07, 133.03, 129.65, 129.40, 129.26, 128.99, 128.66, 120.02, 116.23, 106.72,

67.69, 38.58, 28.68, 28.59, 27.01, 25.92, 25.56.

Secondary Amines.

The following secondary amine hydrochlorides were prepared from intermediates (6) or (4) and the appropriate primary amine by the General methods B and C respectively.

6-Bromo-2-(10-ethylaminodecyloxy naphthalene HCI (15).

% Yield : 62.

M.p. : 155-157 °C.

Found : C, 59.72; H, 7.53; N, 3.14. C₂₂H₃₃BrClNO requires : C, 59.67; H, 7.51; N,

3.16 %. δH : 8.10 (IH, d, ArH), 7.84-7.76 (2H, m, ArH), 7.57 (IH, dd, ArH), 7.35 (IH, d,

ArH), 7.22 (IH, dd, ArH), 4.07 (2H, t, OCff₂(CH₂)₉NHCH₂CH₃), 2.91-2.82 (4H, m,

O(CH₂)₉CH₂NHCH₂CH₃), 1.77 (2H, m, OCH₂C#₂(CH₂)₈NHCH₂CH₃), 1.58 (2H, m,

O(CH₂)₈Ci7₂CH₂NHCH₂CH₃),1.45 (2H, m, OCH₂CH₂C02(CH₂)₇NHCH₂CH₃), 1.29

(10H, m, O(CH₂)₃rCH_z)₅(CH₂)₂NHCH₂CH₃). δC : 157.37, 133.08, 129.90, 129.59, 129.50, 128.41, 128.34, 120.05, 116.85, 106.47,

68.03, 50.46, 45.84, 28.88, 28.79, 28.72, 28.58, 28.54, 26.10, 25.54, 22.90, 8.38.

6-Bromo-2-(10-benzylaminodecyloxy)naphthalene HCI (16). % Yield : 69. M.p. : 173-175 °C.

Found : C, 56.05; H, 6.46; N, 3.71. C₂₇H₃₃BrClNO 1/4 H₂O requires : C, 55.90; H, 6.52; N, 3.62 %. δH : 8.10 (IH, d, Ar_nap), 7.83-7.76 (2H, m, Ar_nap), 7.57-7.53 (3H, m, Ar_bzx2, Ar_napxl), 7.44-7.41 (3H, m, Ar_bz), 7.35 (IH, d, Ar_nap), 7.22(1H, dd, Ar_nap), 4.11 (4H, m, OCH₂(CH₂)₉NHCfl^r ₂Ph), 2.85 (2H, t, O(CH₂)₉Cff₂NHCH₂Ph), 1.80 (2H, m, OCH₂Cff-₂(CH₂)₈NHCH₂Ph), 1.77 (2H, m, O(CH₂)₈C7ϊ₂CH₂ NHCH₂Ph), 1.45 (2H, m, OCH₂CH₂C_H2(CH₂)₇NHCH₂Ph), 1.27 (10H, m, O(CH₂)₃(rø;_{5 5}(CH₂)₂ NHCH₂Ph). δC : 158.49, 139.23, 134.57, 129.94, 129.59, 129.50, 128.81, 128.26, 127.93, 127.87, 126.80, 121.93, 117.00, 106.90, 67.85, 52.77, 50.99, 30.02, 29.79, 29.68, 29.22, 29.06, 28.70, 27.28, 25.66.

6-Bromo-2-(8-isopropylaminooctyloxy)naphthalene HCI (17).

% Yield : 74.

M.p. : 147-149 °C.

Found : C, 58.83; H, 7.21; N, 3.02. C₂₁H₃₀BrClNO requires : C, 58.96; H, 7.07; N, 3.27 %. δH :8.10 (IH, d, ArH), 7.84-7.76 (2H, m, ArH), 7.58 (IH, dd, ArH), 7.36 (IH, d, ArH), 7.20 (IH, dd, ArH), 4.08 (2H, t, OCff₂(CH₂)₇NHCH(CH₃)₂), 3.22 (IH, m, O(CH₂)₈NHCH(CH₃)₂), 2.82 (2H, t, O(CH₂)₇Cff₂NHCH(CH₃)₂), 1.78 (2H, m, OCH₂Cff₂(CH₂)₆NHCH(CH₃)₂), 1.63 (2H, m, O(CH₂)₆ CH₂CH₂NHCH(CH₃)₂), 1.46- 1.33 (8H, m, O(CH₂)₂rGH_{2 4}(CH2)₂NHCH(CH₃)2), 1.25-1.22 (6H, d, O(CH₂)₈NHCHfCff₃)₂). δC : 157.00, 132.94, 129.90, 129.35, 129.18, 128.88, 128.57, 119.93, 116.23, 106.69, 67.60, 49.24, 43.74, 28.88, 28.58, 28.50, 26.04, 25.66, 25.47, 18.57.

6-Bromo-2-( 10-cycloprop ylmethylaminodecylox y)naphthalene HCI (18).

% Yield : 55.

M.p. : 173-175 °C.

Found : C, 61.31; H, 7.56; N, 3.19. C₂₄H₃₅BrClNO requires : C, 61.48; H, 7.52; N,

2.99 %. δH : 7.89 (IH, d, ArH), 7.63-7.58 (2H, m, ArH), 7.54 (IH, dd, ArH), 7.15 (IH, dd,

ArH), 7.06 (IH, d, ArH), 4.02 (2H, t, OCH₂(CH₂)₉NHCH2CH(CH₂)2), 2.99 (2H, t,

O(CH₂)₉CH2NHCH₂CH(CH₂)2), 2.83 (2H, m, O(CH₂)₁₀NHC2Ϊ₂CH(CH₂)₂), 1.85-

1.79 (4H, m, OCH₂C#₂(CH₂)₆C#₂CH₂NHCH₂ CH(CH₂)₂), 1.48 (2H, m, O(CH₂)2C#₂(CH₂)₇NHCH₂CH(CH2)2), 1.31 (11H, m, O(CH₂)₃ (CH s (CH₂)₂NHCH₂CEr(CH₂)2), 0.71 (2H, d, O(CH2)ι₀NHCH₂CHfCH2)₂), 0.46 (2H, d, O(CH₂)ιoNHCH₂ CH(CH2)₂). δC : 157.37, 133.08, 129.90, 129.59, 129.50, 128.41, 128.34, 120.05, 116.85, 106.47, 68.01, 52.04, 46.99, 29.45, 29.38, 29.33, 29.18, 29.09, 26.92, 26.07, 25.97, 6.90, 4.73.

Tertiary amines

The following tertiary amine hydrochlorides were prepared from 6-bromo-2-(10-bromodecyloxy)naphthalene (6) and the appropriate secondary amine by the General methods B and C respectively.

6-Bromo-2-(10-dimethylaminodecyloxy)naphthalene HCI (19).

% Yield : 76. M.p. : 138-140 °C.

^• Found : C, 59.57; H, 7.54; N, 3.18. C₂₂H₃₃BrClNO requires : C, 59.67; H, 7.51; N,

3.16 %. δH : 7.90 (IH, d, ArH), 7.65-7.57 (2H, m, ArH), 7.49 (IH, d, ArH), 7.17 (IH, dd,

ArH), 7.09 (IH, d, ArH), 4.05 (2H, t, OC_fiT₂(CH₂)₉N(CH₃)₂), 2.96 (2H, t, O(CH₂)₉CH-₂N(CH₃)2), 2.80 (6H, d, O(CH₂)₁₀NrClΪ5. 2), 1.86-1.81 (4H, m,

OCH₂CH₂(CH₂)₆C_eiCH₂N(CH₃)2), 1.49 (2H, m, O(CH₂)₂ Cff₂(CH₂)₇N(CH₃)₂), 1.33

(10H, m, O(CH₂)₃rCHa)5(CH₂)₂N(CH₃)₂). δC : 157.39, 133.08, 129.90, 129.61, 129.52, 128.41, 128.35, 120.07, 116.87, 106.50,

68.01, 58.06, 42.80, 29.36, 29.24, 29.15, 28.98, 26.63, 26.02, 24.22.

6-Bromo-2-(10-diethylaminodecyloxy)naphthalene HCI (20).

% Yield : 64.

M.p. : 112-114 °C.

Found : C, 60.51; H, 7.99; N, 2.71. C₂ H₃₇BrClNO l/4H₂O requires : C, 60.63; H, 7.95; N, 2.95 %. δH : 8.10 (IH, d, ArH), 7.84-7.76 (2H, m, ArH), 7.58 (IH, dd, ArH), 7.35 (IH, d,

ArH), 7.19 (IH, dd, ArH), 4.07 (2H, t, OCiy₂(CH₂)₉N(CH₂CH₃)₂), 3.04 (4H, m,

O(CH₂)₁₀N(CH₂CH₃)₂), 2.94 (2H, t, O(CH₂)₉Cfl^" ₂N(CH₂CH₃)₂), 1.78 (2H, t, OCH₂CH₂(CH₂)₈N(CH₂CH₃)₂), 1.75 (2H, m, O(CH₂)₈ CH2CH₂N(CH₂CH₃)₂), 1.45 (2H, m, OCH₂CH₂CH^" ₂(CH₂)₅(CH₂)₂N(CH₂CH₃)₂), 1.29 (10H, m, O(CH₂)₃CCHa>5(CH₂)₂N(CH₂CH₃)₂), 1.20 (6H, t, O(CR₂)_l0N(CR₂CH₃)2). δC : 157.41, 133.10, 129.91, 129.62, 129.56, 128.86, 128.37, 119.91, 116.85, 106.51, 68.01, 50.46, 45.84, 28.88, 28.79, 28.72, 28.58, 28.54, 26.10, 25.54, 22.90, 8.38.

Preparation of 4-bromo-l-naphthyloxy and 5-bromo-l-naphthyloxy derivatives.

Preparation of 4-bromo-l-(10-methylaminodecyloxy naphthalene HCI (24).

a) Preparation of 4-bromo- 1-naphthol (22).

To a solution of 1-naphthol (0.72 g, 5.0 mmol) in dry acetonitrile (20 ml) at room temperature under an atmosphere of nitrogen was added N-bromosuccinimide (0.89 g, 5.0 mmol) in one portion to give a deep red homogenous mixture which was stirred for 30 min. T.l.c, (petroleum ether : ethyl acetate, 4:1), indicated the presence of a new compound with an Rf value similar to that of 1-naphthol, Rf 0.23. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (50 ml) and partitioned with H₂O (2 x 20 ml) and sat. aCl (15 ml). The organic fraction was dried over MgSO_4, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 5 : 1). Fractions containing the product, Rf 0.22, were combined and concentrated in vacuo to give compound (22) as a crimson solid, 0.71 g (63%). M.p. : 116-118 °C, [lit. m.p. : 121 °C.⁽¹⁾] δH : 8.19 (2H, dd, ArH), 7.59-7.56 (3H, m, ArH), 6.71 (IH, d, ArH), 5.38 (IH, br.s., disappeared on D₂O shake, ArQfl). δC : 151.25, 132.68, 129.38, 127.87, 126.04, 125.59, 122.15, 113.42, 109.16.

b) Preparation of 4-bromo-l-(10-bromodecyloxy)naphthalene (23).

The title compound was prepared from 4-bromo- 1-naphthol (22) and 1,10-dibromodecane by the General method A. % Yield : 78 M.p. : 53-55 °C. δH : 8.28 (IH, d, ArH), 8.14 (IH, d₅ ArH), 7.65-7.51 (3H, m, ArH), 6.68 (IH, d, ArH), 4.10 (2H, t, OCH₂(CH₂)₉Br), 3.40 (2H, t, O(CH₂)₉Ciy₂Br), 1.94-1.82 (4H, m, OCH₂CH₂(CH₂)₆CH₂CH₂Br), 1.55 (2H, m, O(CH₂)₂Cff₂(CH₂)₇Br), 1.39-1.32 (10H, m, O(CH₂)₃rCHa)5(CH₂)₂Br). δC : 154.68, 132.43, 129.50, 127.67, 126.95, 126.83, 125.82, 122.50, 112.88, 105.23, 68.34, 34.07, 32.79, 29.45, 29.36, 29.33, 29.16, 28.73, 28.16, 26.20.

c) Preparation of 4-bromo- l-(10-methylaminodecyloxy)naphthalene_HCl (24).

The title compound was prepared from intermediate (23) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

% Yield : 52.

M.p. : 107-109 °C.

Found : C, 58.98; H, 7.12; N, 2.86. C₂₁H₃₁BrClNO requires : C, 58.82; H, 7.29; N,

3.27 %. δH : 8.23 (IH, d, ArH), 8.13 (IH, d, ArH), 7.64-7.50 (3H, m, ArH), 6.66 (IH, d,

ArH), 4.09 (2H, t, OCH₂(CH₂)₉NHCH₃), 2.87 (2H, t, O(CH₂)₉Ci_f₂NHCH₃), 2.66

(3H, s, O(CH₂)ιo HC0₅), 1.91-1.87 (4H, m, OCH₂Cff₂(CH₂)₆CH₂CH₂NHCH₃),

1.53 (2H, m, O(CH₂)₂Cff₂(CH₂)₇NHCH₃), 1.38-1.33 (10H, m,

O(CH₂)₃rCffa>₅(CH₂)₂NHCH₃). δC : 154.77, 132.56, 129.56, 127.69, 127.10, 126.86, 125.86, 122.55, 112.99, 105.43,

68.48, 49.58, 33.14, 29.45, 29.33, 29.22, 29.06, 26.77, 26.24, 26.00.

Preparation of 5-bromo-l-(10-methylaminodecyloxy)naphthalene HCI (29),

a) Preparation of 5-bromo-l-naphthaldehyde (25).

To a solution of 1-naphthaldehyde (10.0 g, 64 mmol) in chloroform (20 ml) at room temperature was added bromine (3.30 ml, 64 mmol) and the mixture was refluxed until the evolution of HBr had ceased. The mixture was allowed to cool and the solvent was removed in vacuo to give an orange residue. The residue was extracted with boiling toluene (50 ml) and filtered. The filtrate was allowed to cool, stirred vigorously with sat. Na₂S₂θ₅ (70 ml) for 1 h, and allowed to stand at room temperature for 18 h. The pale yellow heterogeneous mixture was filtered and the solid bisulfite complex was suspended in a 10% solution of NaCO₃ (45 ml), stirred vigorously for 3 h and filtered. The pale yellow solid was recrystallised from ethanol to give compound (25) as a white solid, 6.90 g (69%). M.p. : 98-100 °C, [lit. m.p. : 105 °C.⁽²⁾] δH : 10.37 (IH, s, ArCHO), 9.22 (IH, d, ArH), 8.55 (IH, d, ArH), 7.99 (IH, d, ArH), 7.85 (IH, d, ArH), 7.73-7.67 (IH, m, ArH), 7.52-7.46 (IH, m, ArH). δC : 192.92, 137.94, 134.14, 131.46, 131.18, 129.29, 128.44, 126.20, 124.85, 124.65, 123.34.

b) Preparation of 5-bromo- 1-naphthol (27). i/ Preparation of 5-bromo- 1-naphthyl formate (26).

To a solution of 5-bromo-l-naphthaldehyde (25) (3.0 g, 12.8 mmol) in chloroform (80 ml) at room temperature was added a solution of m-chloroperoxybenzoic acid (50%, 8.8 g, 25.5 mmol) over a period of 5 min. The mixture was stirred at room temperature for 48 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1), indicated disappearance of starting material, Rf 0.41, and formation of a new compound , Rf 0.35. The mixture was partitioned with sat. NaHCO₃ (2 x 25 ml) and sat. NaCl (25 ml) and the organic phase was dried over MgSO₄, filtered, and concentrated in vacuo to give the crude formate as a grey solid, 2.27 g (71%), which was used without further purification. M.p. : 73-75 °C.

ii/ Preparation of 5-bromo- 1-naphthol (27).

To a solution of the naphthyl formate (26) (1.98 g, 7.9 mmol) suspended in methanol

(40 ml) at room temperature was added 2M HCI (5 ml) and the heterogeneous mixture was stirred for 3 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1), indicated disappearance of the formate, Rf 0.35, and formation of a new compound , Rf 0.24.

The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml), and partitioned with sat. NaCl (20 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid which was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 4 : 1). Fractions containing the product were combined and concentrated in vacuo to give compound

(27) as a buff coloured solid, 1.30 g (74%).

M.p. : 134-136 °C, [lit. m.p. : 138 °C. ⁽³⁾] δH : 8.20 (IH, d, ArH), 7.84-7.77 (2H, m, ArH), 7.40 (IH, m, ArH), 7.29 (IH, m,

ArH), 6.86 (IH, d, ArH), 5.37 (IH, br.s., disappeared on D₂O shake, AxOH). δC : 151.41, 133.24, 130.64, 127.67, 127.13, 125.26, 122.60, 121.67, 119.93, 109.38.

c) Preparation of 5-bromo-l-(10-bromodecyloxy)naphthalene (28).

The title compound was prepared from 5-bromo-l-naphthol (27) and

1,10-dibromodecane by the General method A.

% Yield : 77.

M.p. : 61-63 °C. δH : 8.26 (IH, d, ArH), 7.80-7.49 (2H, m, ArH), 7.46-7.43 (IH, m, ArH), 7.31-7.25

(IH, m, ArH), 6.86 (IH, d, ArH), 4.12 (2H, t, OCff₂(CH₂)₉Br), 3.40 (2H, t,

O(CH₂)₉C_ff₂Br), 1.94-1.81 (4H, m, OCH₂ CH₂(CΕ₂)₆CH₂ Α₂ τ), 1.55 (2H, m,

OCH₂CH₂CH2(CH₂)₇Br), 1.42-1.31 (10H, m, O(CH₂)₃ eH^"aJ5 (CH₂)₂Br). δC : 154.80, 132.97, 130.46, 127.38, 126.99, 125.21, 122.41, 122.05, 118.96, 105.25, 68.37, 34.05, 32.79, 29.43, 29.36, 29.33, 29.20, 28.73, 28.14, 26.20.

d) Preparation of 5-bromo-l-(10-methylaminodecyloxy)naphthalene HCI (29),

The title compound was prepared from (28) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. % Yield : 63.

M.p. : 157-159 °C.

Found : C, 58.81; H, 7.38; N, 3.13. C₂₁H₃₁BrClNO requires : C, 58.82; H, 7.29; N,

3.27 %. δH : 8.29 (IH, d, ArH), 7.80-7.76 (2H, m, ArH), 7.46 (IH, t, ArH), 7.26 (IH, m, ArH), 6.85 (IH, d, ArH), 4.11 (2H, t, OC#₂(CH₂)₉NHCH₃), 2.88 (2H, t,

O(CH₂)₉ay₂NHCH₃), 2.65 (3H, s, O(CH₂)₁₀ NHCfls), 1.93-1.85 (4H, m,

OCH₂Cfl^r ₂(CH₂)₆CH₂CH₂NHCH₃), 1.54 (2H, m, OCH₂CH₂Cfl₂(CH₂)₇ HCH₃), 1.33

δC : 154.89, 132.90, 130.47, 127.33, 127.06, 125.25, 122.42, 122.08, 119.01, 105.34, 68.43, 49.40, 32.74, 29.43, 29.31, 29.24, 29.02, 26.68, 26.24, 25.88.

Preparation of 2-naphthol, 6-iodo-2-naphthol, 6-fluoro-2-naphthol, and 6-chloro- -2-naphthol derivatives. Preparation of 2-(8-methylaminooctyloxy naphthalene HCI (31)

a) Preparation of 8-bromooctyl-2-naphthyl ether (30). The title compound was prepared from 2-naphthol and 1,8-dibromooctane by the

General method A.

% Yield : 78.

M.p. : 128-129 °C. δH : 7.77-7.70 (3H, m, ArH), 7.45-7.39 (IH, t, ArH), 7.35-7.31 (IH, t, ArH), 7.16- 7.12 (2H, d, ArH), 4.07 (2H, t, OCff₂(CH₂)₇Br), 3.41 (2H, t, O(CH₂)₇Cff₂Br), 1.89-

1.81 (4H, m, OCH₂Cff2 (CH₂)₄Ci__T₂CH₂Br), 1.54-1.38 (8H, m,

δC : 157.05, 134.59, 129.31, 128.86, 127.62, 126.66, 126.29, 123.47, 118.99, 106.50,

67.91, 34.02, 32.78, 29.20, 28.70, 28.10, 26.02.

b) Preparation of 2-(8-methylaminooctyloxy)naphthalene HCI (31)

The title compound was prepared from (30) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

% Yield : 76.. M.p. : 162-163 °C.

Found : C, 70.28; H, 8.68; N, 4.23. C₁₉H₂₈BrClNO l/4H₂O requires : C, 69.92; H,

8.80; N, 4.29 %. δH : 7.76-7.70 (3H, m, ArH), 7.45-7.39 (IH, m, ArH), 7.34-7.26 (IH, m, ArH), 7.14

(2H, d, ArH), 4.04 (2H, t, OCH₂(CH₂)₇NHCH₃), 2.89 (2H, t, O(CH₂)₇CΗ^" ₂NHCH₃), 2.64 (3H, s, O(CH₂)₈ NHCH^), 1.85-1.79 (4H, m, OCH₂Cff₂(CH₂)₄Cff₂CH₂NHCH₃),

δC : 157.01, 134.57, 129.29, 128.84, 127.60, 126.68, 126.27, 123.45, 118.99, 106.50,

67.80, 49.36, 32.76, 29.11, 28.95, 28.72, 26.58, 25.97, 25.84.

Preparation of 6-iodo-2-(10-methylaminodecyloxy)naphthalene HCI (36).

a) Preparation of 6-bromo-2-methoxynaphthalene (32). To a suspension of 6-bromo-2-naphthol (5.00 g, 22.4 mmol) and powdered potassium carbonate (7.74 g, 56.0 mmol) in 2-butanone (100 ml) at room temperature under an atmosphere of nitrogen, was added methyl iodide (2.80 ml, 44.8 mmol). The heterogeneous mixture was stirred at room temperature for 24 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1), indicated disappearance of starting material, Rf 0.26, and formation of a new compound, Rf 0.54. The solvent was removed in vacuo and the residue suspended in ethyl acetate (75 ml), filtered, and partitioned with 2M NaOH (2 x 20 ml), 10% Na₂S₂O₅ (20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a white solid. The solid was recrystallised from ethanol to give compound (32) as a white solid, 4.40 g (83%). M.p. : 109-110 °C, [lit. m.p. : 108-111 °C. ⁽⁴⁾] δH : 7.89 (IH, d, ArH), 7.59-7.56 (2H, m, ArH), 7.49 (IH, dd, ArH), 7.15 (IH, dd, ArH), 7.06 (IH, d, ArH), 3.89 (3H, s, A1OCH3). δC : 157.86, 133.04, 129.99, 129.65, 129.61, 128.48, 128.37, 119.76, 117.02, 105.73, 55.33.

b) Preparation of 6-iodo-2-methoxynaphthalene (33).

To a suspension of magnesium (0.45 g, 18.6 mmol) in dry tefrahydrofuran (4 ml) at room temperature under an atmosphere of nitrogen, was added 1 ml of intermediate (32) (4.00 g, 16.9 mmol) dissolved in tefrahydrofuran (12.0 ml). The reaction was initiated by the addition of a crystal of iodine, with gentle heating, and once initiated the remaining solution of (32) was added at such a rate to maintain reflux. Upon complete addition, 15 min., the mixture was maintained at gentle reflux for 30 min. to give a pale yellow homogenous mixture. The mixture was cooled to 0 °C and iodine (4.28 g, 33.7 mmol) was added in one portion. The mixture was allowed to attain room temperature and stirred for 1 h, quenched by the addition of methanol (1 ml), and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 ml) and partitioned with 10% Na₂S₂O₅ (20 ml), 2M HCI (20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a pale yellow solid. The solid was recrystallised from ethanol to give compound (33), 2.70 g (56%). M.p. : 143-145 °C, [lit. m.p. 141-142 °C. :⁽⁵⁾] δH : 8.12 (IH, d, ArH), 7.67-7.62 (2H, m, ArH), 7.48 (IH, dd, ArH), 7.14 (IH, dd, ArH), 7.07 (IH, d, ArH), 3.90 (3H, s, A1OCH3). δC : 157.99, 136.24, 134.73, 133.33, 130.60, 128.39, 128.34, 119.55, 105.68, 88.07, 55.33.

c) Preparation of 6-iodo-2-naphthol (34).

To a solution of intermediate (33) (1.20 g, 4.20 mmol), in dichloromethane (22 ml) at -78 °C (acetone / dry ice bath) under an atmosphere of nitrogen, was added a solution of 1M boron tribromide in dichloromethane (4.30 ml, 4.30 mmol). The mixture was allowed to attain room temperature and stirred for 3 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1), indicated disappearance of starting material, Rf 0.53, and formation of a new compound, Rf 0.23. The mixture was slowly added to a slurry of ice (20 ml) and 2M HCI (15 ml) and stirred for 30 min. The mixture was extracted with dichloromethane (35 ml), separated, and the organic fraction was partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 4 : 1) to give compound (34) as a pale yellow crystalline solid, 0.65 g (57%). M.p. : 136-138 °C, [lit. m.p. : 135-136 °C. ⁽⁵⁾] δH : 8.13 (IH, d, ArH), 7.65-7.60 (2H, m, ArH), 7.42 (IH, d, ArH), 7.10-7.07 (2H, m, ArH), 5.10 (IH, s, disappeared on D₂O shake, ArQff). δC : 153.73, 136.39, 134.93, 133.30, 130.60, 128.88, 128.03, 118.54, 109.56, 88.23.

d) Preparation of 6-iodo-2-(10-bromodecyloxy)naphthalene (35). The title compound was prepared from 6-iodo-2-naphthol (34) and

1,10-dibromodecane by the General method A.

% Yield : 74

M.p. : 76-77 °C. δH : 8.12 (IH, d, ArH), 7.63-7.59 (2H, m, ArH), 7.47 (IH, d, ArH), 7.16-7.11 (IH, dd, ArH), 7.06 (IH, d, ArH), 4.05 (2H, t, OCff₂(CH₂)₉Br), 3.41 (2H, t,

O(CH₂)₉Cff₂Br), 1.87-1.80 (4H, m, O Α₂CH₂(CΑ₂)₆CH₂ Α₂ r), 1.55-1.33 (12H, m, O(CH₂)₂ CH₂)_(J(CH₂)₂Br). δC : 157.52, 136.24, 134.66, 133.40, 130.53, 128.35, 128.26, 119.85, 106.41, 87.91, 68.03, 34.07, 32.79, 29.43, 29.33, 29.16, 28.73, 28.14, 26.06.

e) Preparation of 6-iodo-2-(10-methylaminodecyloxy)naphthalene_HCl (36). The title compound was prepared from intermediate (35) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

% Yield : 85.

M.p. : 191-193 °C.

EIMS (relative abundance %) : MH^ 440.3 (100), 441.2 (22). δH : 8.12 (IH, d, ArH), 7.66-7.58 (2H; m, ArH), 7.46 (IH, d, ArH), 7.15-7.12 (IH, dd, ArH), 7.06 (IH, d, ArH), 4.04 (2H, t, OC#₂(CH₂)₉NHCH₃), 2.55 (2H, t,

O(CH₂)₉C#₂NHCH₃), 2.42 (3H, s, O(CH₂)₁₀NHCH5), 1-83 (2H, m,

OCH₂C#₂(CH₂)₈NHCH₃), 1.47-1.30 (14H, m, O(CH₂)₂fC#^₇CH₂NHCH₃). δC : 157.52, 136.22, 134.64, 133.40, 130.53, 128.35, 128.25, 119.85, 106.41, 87.89, 68.05, 52.22, 36.57, 29.94, 29.56, 29.51, 29.38, 29.16, 27.33, 26.07.

Preparation of 6-fluoro-2-(10-methylaminodecyloxy)naphthalene HCI (39).

a) Preparation of 6-fluoro-2-naphthol (37) 1 A 1.06M solution of 2-methoxy-6-naphthyl magnesium bromide in tetrahydrofuran was prepared as described for the synthesis of intermediate (33).

ii/ To a stirred solution of N-fluorobenzenesulfonimide (5.85 g, 18.6 mmol) in tefrahydrofuran (10 ml) at -35 °C (acetonitrile / dry ice bath) under an atmosphere of nitrogen, was added a solution of 2-methoxy-6-naphthylmagnesium bromide in tefrahydrofuran (8.0 ml, 8.4 mmol) over a period of 15 min. The mixture was stirred at -35 °C for 30 min., allowed to attain room temperature, quenched by the addition of methanol (5 ml), and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (50 ml) and partitioned with 2M HCI (20 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was recrystallised from ethanol and used without further purification. M.p. : 51-53 °C, [lit. m.p. : 59-60 °C. ⁽⁶⁾] iii/ To a solution of 6-fluoro-2-naphthyl methyl ether (1.56 g, 8.9 mmol) in dry dichloromethane (40 ml) at -78 °C (acetone / dry ice bath) under an atmosphere of nitrogen, was added 1M boron tribromide (9.0 ml, 9.0 mmol). The mixture was allowed to attain room temperature and stirred for 18 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1), indicated disappearance of starting material, Rf 0.57, and formation of a new compound, Rf 0.28. The mixture was slowly added to a slurry of ice (20 ml) and 2M HCI (15 ml), and stirred for 30 min. Dichloromethane was removed in vacuo and the aqueous was extracted with ethyl acetate (2 x 25 ml). The combined organics were partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 4 : 1) to give compound (37) as a white solid, 0.72 g (50%). M.p. : 111-113 °C, [lit. m.p. : 116-117.5 °C. ⁽⁶ ]. δH : 7.70-7.64 (2H, m, ArH), 7.41-7.37 (IH, d, ArH), 7.25-7.11 (3H, m, ArH), 4.97 (IH, br.s., disappeared on D₂O shake, AxOH). δC : 161.02, 157.45, 156.83, 131.46, 129.07, 129.00, 128.50, 128.37, 126.54, 118.79, 117.03, 116.66, 111.00, 110.69, 109.67.

b) Preparation of 6-Fluoro-2-(l 0-bromodecyloxy)naphthalene (38),

Compound (38) was prepared from 6-fluoro-2-naphthol (37) and 1,10-dibromodecane by the General method A. % Yield : 82. M.p. : 65-66 °C. δH : 7.71-7.65 (2H, m, ArH), 7.39 (IH, dd, ArH), 7.21-7.18 (3H, m, ArH), 4.05 (2H, t, OCff^CH^Br), 3.40 (2H, t, O(CH₂)₉Cff₂Br), 1.88-1.80 (4H, m, OCH₂Cfl₂(CH₂)₆CH₂CH₂Br), 1.49-1.33 (12H, m, O(CH₂)₂fCHaMCH₂)₂Br). δC : 161.02, 157.45, 156.83, 131.44, 129.23, 128.75, 128.53, 128.41, 126.66, 120.09, 116.60, 116.22, 110.94, 110.64, 106.67, 68.01, 34.07, 32.81, 29.45, 29.34, 29.22, 28.73, 28.16, 26.07.

c) Preparation of 6-fluoro-2-(10-methylaminodecyloxy)naphthalene HCI (39). The title compound was prepared from intermediate (38) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. % Yield : 88. M.p. : 140-143 °C. EMS (relative abundance %) : MH ^" 332.4 (100), 333.3 (22). δH : 7.71-7.66 (2H, m, ArH), 7.39 (IH, dd, ArH), 7.21-7.11 (3H, m, ArH), 4.04 (2H, t, OCH₂(CH₂)₉NHCH₃), 2.55 (2H, t, O(CH₂)₉CH₂NHCH₃), 2.43 (3H, s, O(CH₂)₁oNHCfl^r ₃), 1.86-1.81 (2H, m, OCH₂Cff₂(CH₂)₈NHCH₃), 1.49-1.31 (14H, m,

δC : 161.02, 157.46, 156.58, 131.46, 129.23, 128.75, 128.53, 128.46, 126.27, 120.11, 116.60, 116.22, 110.94, 110.64, 106.67, 68.05, 52.24, 36.57, 29.96, 29.58, 29.54, 29.40, 29.24, 27.35, 26.11.

Preparation of 6-chloro-2-(10-methylaminodecyloxy)naphthalene HCI (43).

a) Preparation of 6-chloro-2-methoxynaphthalene (40).

To a solution of intermediate (32) (2.0 g, 8.44 mmol) in tetrahydrofuran (40 ml) at -70 °C (acetone / dry ice) under an atmosphere of nitrogen was added butyllithium (2.5M in hexane, 3.5 ml, 8.8 mmol) over a period of 10 min. The pale yellow mixture was stirred for a further 30 min. and a solution of hexachloroethane (3.99 g, 16.9 mmol) in tetrahydrofuran (5 ml) was added dropwise over a period of 10 min. The mixture was stirred at -70 °C for lh., allowed to attain room temperature, and quenched by the slow addition to a mixture of ice (20 ml) and 2M HCI (20 ml). The mixture was diluted with H₂O (30 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organics were partitioned with H₂O (2 x 15 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a pale brown solid. The crude solid was purified by recrystallisation from ethanol to give compound (40) as a white solid, 1.60 g (98%). M.p. : 64-65 °C. δH : 7.73 (IH, d, ArH), 7.67-7.62 (2H, m, ArH), 7.39-7.35 (IH, dd, ArH), 7.18-7.14 (IH, dd, ArH), 7.08 (IH, d, ArH), 3.90 (3H, s, ArOCff,). δC : 157.77, 132.81, 129.45, 129.05, 128.52, 128.21, 127.15, 126.38, 119.80, 105.69, b) Preparation of 6-chloro-2-naphthol (41).

To a solution of intermediate (40) (1.30 g, 6.8 mmol) in dry dichloromethane (27 ml) at -78 °C (acetone / dry ice bath) under an atmosphere of nitrogen, was added 1M boron tribromide (7.1 ml, 7.1 mmol). The mixture was allowed to attain room temperature and stirred for 18 h. The mixture was slowly added to a slurry of ice (20 ml) and 2M HCI (15 ml), and stirred for 30 min. Dichloromethane was removed in vacuo and the aqueous was extracted with ethyl acetate (2 x 25 ml). The combined organics were partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (pefroleum ether : ethyl acetate, 4 : 1) to give compound (41) as a white solid, 1.04 g (86%). M.p. : 118-120 °C, [lit. m.p. : 115 °C. ⁽⁷⁾].

c) Preparation of 6-chloro-2-(l 0-bromodecyloxy)naphthalene (42).

Compound (42) was prepared from 6-chloro-2-naphthol (41) and

1,10-dibromodecane by the General method A.

M.p. : 123-124 °C. δH : 7.73 (IH, d, ArH), 7.67-7.63 (2H, m, ArH), 7.38-7.34 (IH, dd, ArH), 7.18-7.14 (IH, dd, ArH), 7.09 (IH, d, ArH), 4.05 (2H, t, OCi__r₂(CH₂)₉Br), 3.41 (2H, t,

O(CH₂)₉CH₂Br), 1.88-1.80 (4H, m, OCH₂CH^r ₂(CH₂)₆CH₂CH₂Br), 1.52-1.33(12H, m,

O(CH₂)₂(C#a CH₂)₂Br). δC : 157.67, 132.81, 129.42, 129.05, 128.44, 128.17, 127.08, 126.36, 120.11, 106.47,

68.05, 34.07, 32.81, 29.45, 29.36, 29.18, 28.75, 28.16, 26.07.

d) Preparation of 6-chloro-2-(10-methylaminodecyloxy)naphthalene HCI (43).

The title compound was prepared from intermediate (42) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

M.p. : 141-143 °C. EMS (relative abundance %) : MH⁺ 348.4 (100), 350.3 (33). δH : 7.99 (IH, d, ArH), 7.85-7.79 (2H, m, ArH), 7.47-7.43 (IH, dd, ArH), 7.35 (IH, d, ArH), 7.23-7.19 (IH, dd, ArH), 4.06 (2H, t, OCH^" ₂(CH₂)₉NHCH₃), 2.40 (2H, t, O(CH₂)₉C#₂_NHCH₃), 2.23 (3H, s, O(CΑ₂)_l0NHCH₃), 1.81-1.71 (2H, m, OCH₂CH₂(CH₂)₈NHCH₃), 1.43-1.25 (14H, m, O(CH₂)₂

δC : 156.95, 132.78, 129.00, 128.74, 128.57, 127.75, 126.70, 126.11, 119.98, 106.63, 67.59, 51.67, 36.27, 29.31, 29.01, 28.79, 28.61, 26.89, 25.56.

Preparation of compounds with the general formula Ar-O-(CH₂)_mNH(CH₂)_nNH₂ xHCl where Ar is 6-bromo-2-naphthol.

Preparation of N¹-[6-(6-bromo-2-naphthyloxy)hexyll-l,4-butanediamine xHCl (44).

The title compound was prepared from intermediate (3) and 1,6-diaminohexane by the General methods B and C respectively.

% Yield : 55.

M.p. : >200°C. Found : C, 51.92; H, 6.65; Ν, 5.68. C₂₀H₃₁BrCl₂Ν₂O requires : C, 51.52; H, 6.70; N,

6.01 %.

Preparation of N¹-[4-(6-bromo-2-naphthyloxy) butyl! -1,6-hexanediamine xHCl (45).

The title compound was prepared from intermediate (2) and 1,4-diaminobutane by the general methods B and C respectively. % Yield : 64. M.p. : >200°C.

Preparation of N¹-r2-(6-bromo-2-naphthyloxy) ethyll-l,8-octanediamine xHCl (46).

The title compound was prepared from intermediate (1) and 1,8-diaminooctane by the general methods B and C respectively. % Yield : 81. M.p. : >200°C.

Found : C, 53.14; H, 7.23; Ν, 5.71.

requires : C, 53.61; H, 6.86; Ν, 6.25 %. Preparation of compounds with the general formula Ar-O-(CH₂)_mS(O)_n(CH₂)_p NHCH₃ HCI where Ar is 6-bromo-2-naphthol.

Preparation of N¹-methyl-6-[6-(6-bromo-2-naphthyloxy)hexylsulfinyll-l-hexanamine HCI (51).

a) Preparation of 6-mercapto-l-(t-butyldiρhenylsilyloxy)hexane (47).

To a mixture of 6-mercapto-l-hexanol (5.0 ml, 36.7 mmol) and imidazole (3.00 g, 44.0 mmol) in dimethylformamide (88 ml) at room temperature, under an atmosphere of nitrogen, was added t-butyldiphenylsilyl chloride (11.3 ml, 44.0 mmol). The homogeneous mixture was stirred at room temperature for 24 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1) indicated disappearance of t-butyldiphenylsilyl chloride, Rf 0.53, and formation of a new compound , Rf 0.39. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml) and partitioned with H₂O (30 ml), O.lM HCI (15 ml), and sat. ΝaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude oil. The oil was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 4 : 1). Fractions containing the product were combined and concentrated in vacuo to give compound (47) as a viscous oil, 8.40 g (61%). δH : 7.68-7.65 (4H, dd, ArH), 7.39 (6H, m, ArH), 3.66 (2H, t, HS(CH₂)₅CH^" ₂OSi(Ph)₂C(CH₃)₃), 2.47 (2H, m, HSCH₂(CH₂)₅OSi(Ph)₂C(CH₃)₃), 1.58-1.53 (4H, m, Η&C i₂CH₂( R₂)₂CH₂ai₂ OSi(Ph)₂C(CH₃)₃), 1.38-1.27 (5H, m, _JfirS(CH₂)₂rCH_{2 2}(CH₂)₂OSi(Ph)₂C(CH₃)₃, lxH exchanged on D₂O shake). δC : 135.52, 134.03, 129.49, 127.69, 63.74, 33.46, 32.34, 28.21, 26.85, 25.21, 24.53, 19.17.

b) Preparation of 6-[6-(6-bromonaphthyloxy)hexylsulfanyl]-l-(t-butyldiphenyl- silyloxy)hexane (48). 6-Mercapto-l-(t-butyldiphenylsilyloxy)hexane (47) (2.90 g, 7.80 mmol), intermediate (3) (3.00 g, 7.70 mmol), powdered potassium carbonate (3.76 g, 27.2 mmol), and sodium metabisulfite (0.02 g) were suspended in degassed 2-butanone (50 ml) at room temperature under an atmosphere of nifrogen, and heated at reflux for 7 h. T.l.c, (petroleum ether : ethyl acetate, 40 : 1) indicated disappearance of intermediate (47), Rf 0.46, and formation of a new compound, Rf 0.29. The solvent was removed in vacuo and the residue dissolved in dichloromethane (50 ml), filtered, and the filtrate was sequentially partitioned with H₂O (30 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude oil. The oil was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 40 : 1). Fractions containing the product were combined and concentrated in vacuo to give compound (48) as a viscous oil, 4.10 g (78%). . δH : 7.88 (IH, d, ArH), 7.68-7.65 (4H, dd, ArH), 7.62-7.54 (2H, m, ArH), 7.48-7.41 (IH, dd, ArH), 7.40-7.36 (6H, m, ArH), 7.16-7.12 (IH, dd, ArH), 7.06 (IH, d, ArH), 4.03 (2H, t, AιOCH₂ (CH₂)₅S(CH₂)₆OSi(Ph)₂C(CH₃)₃), 3.65 (2H, t, O(CH₂)₆S(CH₂)₅CH₂OSi(Ph)₂C(CH₃)₃), 2.52 (4H, m,

O(CH₂)₅CH₂SC_H₂(CH₂)₅OSi(Ph)₂C(CH₃)₃), 1.84 (2H, t,

OCH₂Cff₂(CH₂)₄S(CH₂)₆OSi(Ph)₂C (CH₃)₃), 1.63-1.47 (10H, m, 0(CE₂)2CH₂CB₂CH₂CH₂SCH₂CH₂CR₂(CH₂)₂CΕL₂OSi (Ph)₂C(CH₃)₃, 1.38-1.33 (4H, m, O(CH₂)₃CH₂(CH₂)₂S(CH₂)₂CH₂(CH₂)₃OSi(Ph)₂C(CH₃)₃), 1.05 (9H, s,

O(CH₂)₆S (CH₂)₆osi(Ph)₂c cfir₃ 3). δC : 157.32, 135.54, 134.07, 133.04, 129.88, 129.59, 129.49, 128.39, 128.30, 127.87, 127.56, 120.02, 116.85, 106.45, 67.87, 63.81, 32.42, 32.11, 32.08, 29.67, 29.60, 29.40, 29.07, 28.64, 26.86, 25.77, 25.41, 19.19.

c) Preparation of 6-[6-(6-bromo-2-naphthyloxy)hexylsulfanyl]-l-hexanol (49).

To a mixture of (48) (0.35 g, 0.50 mmol) and 4A molecular sieves (1.00 g) in dichloromethane (10 ml) at room temperature under an atmosphere of nitrogen, was added IM tefrabutylammonium fluoride, in tetrahydrofuran (10 ml, 10.0 mmol). The heterogeneous mixture was stirred at room temperature for 60 h. T.l.c, (petroleum ether : ethyl acetate, 1 : 1) indicated disappearance of starting material, Rf 0.81, and formation of a new compound, Rf 0.33. The mixture was diluted with dichloromethane (40 ml), filtered, and the filtrate was partitioned with H₂O (2 x 20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgSO , filtered, and concentrated in vacuo to give a crude oil. The oil was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 3 : 2). Fractions containing the product were combined and concentrated in vacuo to give compound (49) as a white solid, 0.26 g (94%). M.p. : 60-62 °C.

Found : C, 60.35; H, 7.26. C₂₂H₃₁BrO₂S requires : C, 60.13; H, 7.11 %. δH : 7.90 (IH, d, ArH), 7.65-7.60 (2H, m, ArH), 7.56-7.50 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.05 (2H, t, OCff₂(CH₂)₅S(CH₂)₆OH), 3.64 (2H, t, 0(CΑ₂)₆S(CΗ.₂)₅CH₂OR), 2.55-2.49 (4H, m, O(CH₂)₅Cff₂SCff₂(CH₂)₅OH), 1.85 (2H, m, OCH₂CH₂(CH₂)₄S(CH₂)₆OH), 1.65-1.48 (10H, m,

O(CH₂)₂CH₂CH₂CH₂CH₂SCH₂Cff₂CH₂rCfl_{2 2}CH₂OH), 1.42-1.36 (5H, m, O(CH₂)₃ CH₂(CH₂)₂S(CH₂)₂CEr₂(CH₂)₃Ofi^r, lxH exchanged on D₂O shake). δC : 157.34, 133.06, 129.92, 129.61, 129.54, 128.43, 128.32, 120.03, 116.89, 106.49, 67.91, 62.87, 32.61, 32.09, 29.60, 29.07, 28.64, 25.77, 25.37.

d) Preparation of 6-[6-(6-bromonaphthyloxy)hexylsulfinyl]-l-hexanol (50). To a solution of (49) (0.63 g, 1.40 mmol) in dichloromethane (25 ml) at -10 °C (salt / ice bath) under an atmosphere of nitrogen, was added a solution of m-chloroperoxybenzoic acid (50%, 0.50 g, 1.50 mmol) in dichloromethane (15 ml) over a period of 15 min. The mixture was stirred for 2 h. T.l.c, (ethyl acetate : methanol, 10 : 0.2) indicated disappearance of starting material, Rf 0.65, and formation of a new compound, Rf 0.13. The mixture was partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give compound (50) as a white solid, 0.64 g (98%). M.p. : 82-83 °C. Found : C, 57.78; H, 6.95. C₂₂H₃₁BrO₃S requires : C, 58.02; H, 6.86 %. δH : 7.90 (IH, d, ArH), 7.65-7.56 (2H, m, ArH), 7.17-7.12 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.06 (2H, t, OCH₂(CH2)₅SO(CH₂)₆OH), 3.63 (2H, t, O(CH₂)₆SO(CH₂)₅CH₂OH), 2.72-2.59 (4H, m, O(CH₂)₅CH₂SOCH₂(CH₂)₅OH), 1.84-1.71 (7H, m, C ₂(CH₂)₂(C ₂)₃ O(C ₂)^CH₂CB.₂OH, lxH exchanged on D₂O shake), 1.58-1.50 (6H, m, O(CH₂)₄Cff₂CH₂SOCH₂CΗ₂CH₂CH₂(CH₂)₂θH), 1.47-1.38 (4H, m, O(CH₂)₃CH^r ₂(CH₂)₂SO(CH2)2 Η₂(CH₂)₃OH). δC : 157.28, 133.06, 129.95, 129.63, 129.58, 128.46, 128.35, 120.00, 116.94, 106.50, 67.73, 62.60, 52.33, 32.38, 28.93, 28.59, 25.80, 25.37, 22.64, 22.61. e) Preparation of N¹-methyl-6-[6-(6-bromo-2-naphthyloxy)hexylsulfinyl]-l-hexan- amine HCI (51).

ϊl Preparation of 6-[6-(6-bromonaphthyloxy)hexylsulfanyl)hexyl methanesulfonate. To a solution of (50) (0.60 g, 1.30 mmol) and triethylamine (0.30 ml, 2.20 mmol) in dichloromethane (7.0 ml) at -25 °C (acetonitrile / dry ice) under an atmosphere of nitrogen, was added methanesulfonyl chloride (0.10 ml, 1.50 mmol) over a period of 5 min. The mixture was stirred for 10 min. T.l.c, (ethyl acetate : methanol, 10 : 0.2) indicated disappearance of starting material, Rf 0.19, and formation of a new compound, Rf 0.26.

ii/ Preparation of compound (51).

To the mesylate solution at -25 °C was added a solution of triethylamine (0.30 ml,

2.20 mmol) and 33% methylamine in ethanol (15 ml) over a period of 5 min. The mixture was allowed to attain room temperature and stirred for 18 h. T.l.c, (ethyl acetate : methanol : 880 ΝH₃, 9 : 1 : 0.2) indicated disappearance of mesylate, Rf 0.59, and formation of a new compound, Rf 0.11. The mixture was diluted with dichloromethane (40 ml) and partitioned with 2M NaOH (20 ml) and sat. NaCl (15 ml), dried over Na₂SO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (ethyl acetate : methanol : 880NH₃, 9 : 1.5 : 0.2). Fractions containing the product were combined and concentrated in vacuo to give the free base as a white solid, 0.36 g (58%). iii/ The hydrochloride salt was prepared by the General method C. M.p. : 87-89 °C dec. Found : C, 54.72; H, 6.80; N, 2.75. C₂₃H₃₅BrClNO₂S requires : C, 54.71; H, 6.99; N, 2.77 %. δH : 7.90 (IH, d, ArH), 7.65-7.57 (2H, m, ArH), 7.51-7.47 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.06 (2H, t, OCH₂(CH₂)₅SO(CH₂)₆NHCH₃), 2.71- 2.62 (4H, m, O(CH₂)₅ C_H₂SOCH₂(CH₂)5NHCH₃), 2.56 (2H, t, O(CH₂)₆SO(CH₂)₅Cff₂NHCH₃), 2.43 (3H, s, O(CH₂)₆

1.83-1.75 (4H, m, OCH₂CH₂(CH₂)₄SO(CH₂)₄CH_2CH₂NHCH₃), 1.57-1.42 (12H, m, O(CH₂)₂ ϊ_a)₅CH₂SOCH₂rCΗ_{2 5}(CH₂)₂NHCH₃). δC : 157.27, 133.06, 129.94, 129.63, 129.58, 128.46, 128.34, 120.00, 116.94, 106.49, 67.71, 67.62, 52.42, 52.33, 51.93, 36.51, 29.61, 28.93, 28.81, 28.63, 26.94, 25.80, 22.61.

Preparation of N¹-methyl-6-[6-(6-bromo-2-naphthyloxy)hexylsulfonyl]-l-hexanamine HCI (54).

a) Preparation of 6-[6-(6-bromo-2-naphthyloxy)hexylsulfonyl]-l-(t-butyldiphenyl- silyloxy)hexane (52). To a solution of (48) (2.50 g, 3.70 mmol) in dichloromethane (20 ml) at room temperature under an atmosphere of nitrogen, was added a solution of m-chloroperoxybenzoic acid (50%, 2.56 g, 7.40 mmol) in dichloromethane (10 ml). The mixture was gently refluxed for 3 h. T.l.c, (petroleum ether : ethyl acetate, 40 : 1) indicated disappearance of intermediate (48), Rf 0.48, and formation of a new compound, Rf 0.28. The mixture was allowed to cool, diluted with dichloromethane (20 ml) and partitioned with sat. ΝaHCO₃ (15 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude oil. The oil was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 40 : 1). Fractions containing the product were combined and concentrated in vacuo to give compound (52) as viscous oil, 1.45 g (55%). δH : 7.89 (IH, d, ArH), 7.68-7.66 (4H, m, ArH), 7.65-7.55 (2H, m, ArH), 7.49-7.41 (2H, m, ArH), 7.40-7.37 (5H, m, ArH), 7.15 (IH, dd, ArH), 7.07 (IH, d, ArH), 4.04 (2H, t, OCH₂(CΕL₂)₅ SO₂(CH2)₆OSi(Ph)₂C(CH₃)₃), 3.65 (2H, t, O(CH₂)₆Sθ₂(CH₂)₅α_f₂OSi(Ph)₂C(CH₃)₃), 2.95-2.87 (4H, m, O(CH₂)₅CH2SO₂Cff₂(CH₂)₅OSi(Ph)₂C(CH₃)3), 1.86-1.83 (6H, m,

OCΑ₂(CH₂)₂(CΕ₂) S0₂(CR₂)₄CH₂CΗ.₂OSi(Vh)₂C(CJΪ3)3), 1.56-1.54 (6H, m, O(CH2)₄CH₂CH₂SO₂CH₂CH₂CH₂Cff₂ (CH₂)₂OSi(Ph)₂C(CH₃)₃), 1.40 (4H, m, O(CH₂)₃CH₂(CH2)₂SO₂(CH₂)2CH₂(CH₂)₃OSi(Ph)₂C (CH₃)₃), 1.05 (9H, s, O(CH2)₆SO₂(CH₂)₆OSi(Ph)₂CrCH3 5). δC : 157.21, 135.54, 133.94, 133.03, 129.94, 129.61, 129.56, 128.46, 128.34, 127.62, 119.96, 116.94, 106.45, 67.60, 63.54, 52.74, 52.52, 32.11, 28.82, 28.27, 26.86, 25.70, 25.34, 21.92, 21.85, 21.06, 19.21, 14.20. b) Preparation of 6-[6-(6-bromo-2-naphthyloxy)hexylsulfonyl]-l-hexanol (53).

To a mixture of (52) (1.05 g, 1.50 mmol) and 4A molecular sieves (1.0 g) in dichloromethane (15 ml) at room temperature under an atmosphere of nitrogen, was added 1M tefrabutylammonium fluoride in tetrahydrofuran (3.0 ml, 3.0 mmol). The mixture was stirred at room temperature for 60 h. T.l.c, (petroleum ether : ethyl acetate, 7 : 3) indicated disappearance of starting material, Rf 0.73, and formation of a new compound, Rf 0.16. The mixture was diluted with dichloromethane (40 ml) and partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 4 : 1). Fractions containing the product, Rf 0.28, were combined and concentrated in vacuo to give compound (53) as a white solid, 0.63 g (90%). M.p. : 106-108 °C.

δH : 7.91 (IH, d, ArH), 7.66-7.57 (2H, m, ArH), 7.50 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.07 (IH, d, ArH), 4.06 (2H, t, OCH₂(CΕL₂)₅ θ₂(CΑ₂)₆OΗ), 3.65 (2H, t, O(CH₂)₆SO₂(CH₂)₅Cff₂OH), 3.00-2.92 (5H, m, O(CH₂)₅CH₂SO₂CH₂(CH₂)₅OH, lxH disappeared on D₂O shake), 1.91-1.83 (6H, m,

0CΕL₂(CH₂)₂(CR₂)₃S0₂(CH₂)₄CH₂CH₂0}1), 1.61-1.42 (10H, m,

δC : 157.23, 133.53, 129.95, 129.63, 129.61, 128.50, 128.35, 119.96, 116.98, 106.50, 67.62, 62.62, 52.65, 32.26, 28.82, 28.27, 25.71, 25.27, 21.89.

c) Preparation of N¹-methyl-6-[6-(6-bromo-2-naphthyloxy)hexylsulfonyl]-l-hexan- amine HCI (54).

i Preparation of 6-[6-(6-bromonaphthyloxy)hexylsulfanyl)hexyl methanesulfonate. To a solution of (53) (0.51 g, 1.10 mmol) and triethylamine (0.23 ml, 1.60 mmol) in dichloromethane (7.0 ml) at -25 °C (acetonitrile / dry ice) under an atmosphere of nitrogen, was added methanesulfonyl chloride (0.09 ml, 1.20 mmol) over a period of 5 min. The mixture was stirred for 15 min. T.l.c, (ethyl acetate : petroleum ether, 7 : 3) indicated disappearance of starting material, Rf 0.20, and formation of a new compound, Rf 0.35. ii/ Preparation of compound (54).

To the mesylate solution at -25 °C was added 33% methylamine in ethanol (15 ml) over a period of 5 min. The mixture was allowed to attain room temperature and stirred for 18 h. T.l.c, (ethyl acetate : methanol : 880NH₃, 9 : 1 : 0.2) indicated disappearance of mesylate, Rf 0.88, and formation of a new compound, Rf 0.17. The mixture was diluted with dichloromethane (40 ml) and was partitioned with 2M NaOH (20 ml) and sat. NaCl (15 ml), dried over Na₂SO₄, filtered, and concentrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (ethyl acetate : methanol : 880 NH₃, 9 : 1 : 0.2). Fractions containing the product were combined and concentrated in vacuo to give the free base as a white solid, 0.35 g (63%).

iii/ The hydrochloride salt was prepared by the General method C. M.p. : 156-158 °C.

Found : C, 52.65; H, 6.73; N, 2.91. C₂₃H₃₅BrClNO₂Sl/4H₂O requires : C, 52.57; H,

6.81; N, 2.67%. δH : 7.90 (IH, d, ArH), 7.66-7.50 (2H, m, ArH), 7.47 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 4.06 (2H, t, OCi7₂(CH₂)₅SO₂(CH₂)₆NHCH₃), 2.97 (4H, m, O(CH₂)₅C_H^r ₂SO2CH₂(CH₂)5NHCH₃), 2.56 (2H, t, 0(CH₂)₆S0₂(CR₂)₅CH₂imCH₃),

2.43 (3H, s, O(CH₂)₆SO₂(CH₂)₆NHCi?5), 1.89-1.82 (6H, m,

OCH₂C_H₂(CH₂)₂Cfi₂CH₂SO2CH₂CH^r ₂(CH₂)₄NHCH₃), 1.58-1.35 (10H, m,

O(CH₂)₂fO?^ (CH₂)₂ SO₂(CH₂)₂(Oy^CH₂NHCH₃). δC : 157.23, 133.04, 129.95, 129.63, 129.59, 128.48, 128.35, 119.98, 116.98, 106.49, 67.62, 52.72, 52.60, 51.86, 36.51, 29.52, 28.82, 28.45, 28.28, 26.81, 25.71, 21.90,

21.87.

Preparation of N¹-methyl-3-[6-(6-bromo-2-naphτhyloxy hexylsulfinyl]-l-ρropan- amine HCI (58V

a) Preparation of ethyl 3-[6-(6-bromo-2-naphthyloxy)hexylsulfanyl]propanoate (55). Intermediate (3) (3.08 g, 7.77 mmol), powdered potassium carbonate (2.68 g, 19.4 mmol), and ethyl 3-mercaptopropionate (2.68 g, 20.0 mmol) were suspended in degassed 2-butanone (50 ml) at room temperature under an atmosphere of nitrogen. The heterogeneous mixture was gently refluxed for 3.5 h. T.l.c, (petroleum ether : ethyl acetate, 4 : 1) indicated disappearance of starting material, Rf 0.46, and formation of a new compound, Rf 0.34. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was suspended in dichloromethane (50 ml), filtered, and the filtrate partitioned with H₂O (25 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a crude oil. The oil was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 10 : 1). Fractions containing the product, Rf 0.20, were combined and concentrated in vacuo to give compound (55) as a white solid, 1.80 g (54%). M.p. : 45^16 °C. δH : 7.90 (IH, d, ArH), 7.65-7.57 (2H, m, ArH), 7.50-7.46 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.19-4.12 (2H, q, O(CH₂)₆S(CH₂)₂CO₂C_H₂CH₃), 4.05 (2H, t, OC_fir₂(CH₂)₅ S(CH₂)2CO₂CH₂CH₃), 2.82-2.76 (2H, t, O(CH₂)₆SCH₂CH^" ₂CO₂CH₂CH₃), 2.62-2.53 (4H, m,

O(CH₂)₅CH₂SCH₂CH₂CO₂CH₂CH₃), 1.87-1.82 (2H, m,

OCH₂C#₂(CH₂)₄S(CH₂)₂CO₂CH₂CH₃), 1.67-1.59 (2H, m,

O(CH₂)₄CH₂CH₂S(CH₂)₂CO₂CH₂CH₃), 1.53-1.47 (4H, m, 0(CU₂)₂(CH₂)₂(CH₂)₂ S(CH₂)₂CO₂CH₂CH₃), 1.26 (3H, t, O(CH₂)₆S(CH₂)₂CO₂CH₂Cff . δC : 172.02, 157.32, 133.06, 129.92, 129.81, 129.52, 128.43, 128.32, 120.03, 116.89, 106.47, 67.85, 60.66, 34.93, 32.06, 29.45, 29.07, 28.57, 27.01, 25.75, 14.21.

b) Preparation 3-[6-(6-bromo-2-naphthyloxy)hexylsulfanyl]-l- propanol (56). To a solution of intermediate (55) (1.50 g, 3.41 mmol) and methanol (0.21 ml, 5.12 mmol) in dry tetrahydrofuran (17 ml), at room temperature under an atmosphere of nitrogen, was added lithium borohydride (0.11 g, 5.12 mmol) over a period of 5 min. The mixture was heated to 50 °C and stirred for 1 h. T.l.c, (petroleum ether : ethyl acetate, 3 : 2) indicated disappearance of starting material, Rf 0.46, and formation of a new compound, Rf 0.23. The mixture was allowed to cool and slowly added to a mixture of ice (30 ml) and 2M HCI (10 ml) over a period of 10 min. and stirred for a further 30 min. The volume of the solvent was reduced by 30% in vacuo and extracted with dichloromethane (2 x 25 ml). The organic fractions were combined and partitioned with H₂O (20 ml) and sat. NaCl (15 ml), dried over MgSO , filtered, and concentrated in vacuo to give a crude solid. The solid was recrystallised from ethanol to give compound (56) as a white solid, 1.13 g (83%). M.p. : 52-53 °C. δH : 7.90 (IH, d, ArH), 7.65-7.49 (2H, m, ArH), 7.46 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.05 (2H, t, OCH₂(CR₂)₅S(CR₂)₃θR), 3.76 (2H, t, O(CH₂)₆S(CH₂)₂CH₂OH), 2.67-2.53 (4H, m, 0(CR₂)₅CH₂SCH₂(CR₂)₂OR), 1.90- 1.80 (4H, m, OCH₂Ci7₂(CH₂)₄SCH₂C#₂CH₂OH), 1.70-1.62 (3H, m, O(CH₂)₄CH^r ₂CH₂ S(CR₂)₃OH, lxH disappeared on D₂O shake), 1.55-1.46 (4H), m, O(CH₂)₂rCH₂)₂(CH₂)2S(CH₂)₃OH). δC : 157.32, 133.06, 129.92, 129.61, 129.54, 128.43, 128.32, 120.03, 116.89, 106.47, 67.87, 61.98, 32.02, 31.86, 29.45, 29.07, 28.89, 28.63, 25.75.

c) Preparation 3-[6-(6-bromo-2-naphthyloxy)hexylsulfinyl]-l- propanol (57). To a solution of intermediate (56) (0.75 g, 1.89 mmol) in dichloromethane (20 ml) at -10 °C (salt / ice bath), under an atmosphere of nitrogen, was added a solution m-chloroperoxybenzoic acid (50%, 0.66 g, 1.91 mmol) in dichloromethane (10 ml) over a period of 10 min. The mixture was stirred for 2 h. T.l.c, (ethyl acetate : methanol, 10 : 0.2) indicated disappearance of starting material, Rf 0.60, and formation of a new compound, Rf 0.13. The mixture was allowed to attain room temperature and partitioned with sat. NaHCO₃ (15 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give an amorphous solid upon exposure to high vacuum, 0.74 g (95%). M.p. : 110-112 °C.

δH : 7.90 (IH, d, ArH), 7.65-7.56 (2H, m, ArH), 7.50-7.46 (IH, dd, ArH), 7.17-7.12 (IH, dd, ArH), 7.07 (IH, d, ArH), 4.05 (2H, t, OCH₂(CH₂)₅SO(CH₂)₃OH), 3.75 (2H, t, O(CH₂)₆SO(CH₂)2CH₂OH), 3.26 (IH, br.s, disappeared on D₂O shake, O(CH₂)₆SO(CH₂)₃Ofl), 2.88-2.66 (4H, m, 0(CR₂)₅CH₂$>OCH₂(CR₂)₂OR), 2.11- 2.05 (2H, m, O^H^SOCHzCH^CHsOH), 1.86-1.82 (4H, m, OCH₂CH₂(CH₂)₂Cfl^r ₂CH₂SO(CH₂)₃OH), 1.57 (4H, m,

O(CH₂)₂CCH₂j₂(CH₂)₂SO(CH2)₃OH). δC : 157.25, 133.04, 129.92, 129.61, 129.56, 128.46, 128.34, 119.98, 116.93, 106.47, 67.67, 61.01, 51.81, 49.70, 28.89, 28.55, 26.65, 25.79, 22.70.

d) Preparation of N¹-methyl-3-[6-(6-bromo-2-naphthyloxy)hexylsulfinyl]-l-propan- amine HCI (58).

i/ Preparation 3-[6-(6-bromo-2-naphthyloxy)hexylsulfmyl] propyl methanesulfonate. To a solution of intermediate (57) (0.60 g, 1.45 mmol) and triethylamine (0.30 ml, 2.18 mmol) in dichloromethane (7.0 ml) at -25 °C (acetonitrile / dry ice), under an atmosphere of nitrogen, was added methanesulfonyl chloride (0.12 ml, 1.60 mmol) over a period of 5 min. The mixture was stirred for a further 15 min. T.l.c, (ethyl acetate : methanol, 10 : 0.2) indicated disappearance of starting material, Rf 0.13, and formation of a new compound, Rf 0.21.

ii/ Preparation of compound (58).

To the mesylate solution at -25 °C was added 33% methylamine in ethanol (15 ml) over a period of 5 min. The mixture was allowed to attain room temperature and stirred for 18 h. The mixture was diluted with dichloromethane (40 ml) and partitioned with 2M ΝaOH (20 ml) and sat. ΝaCl (15 ml) dried over Νa₂SO , filtered, and concenfrated in vacuo to give a crude solid. The solid was purified by flash column chromatography eluting with (ethyl acetate : methanol : 880NH₃, 9 : 1.5 : 0.3). Fractions containing the product were combined and concentrated in vacuo to give the free base as a white solid, 0.51 g (82%).

iii/ The hydrochloride salt was prepared by the General method C.

M.p. : 130-132 °C.

Found : C, 51.71; H, 6.51; N, 3.06. C₂₀H₂₉BrClNO₂S requires : C, 51.90; H, 6.31; N,

3.03 %. δH : 7.90 (IH, d, ArH), 7.65-7.57 (2H, m, ArH), 7.50 (IH, dd, ArH), 7.17-7.13 (IH, dd, ArH), 7.08 (IH, d, ArH), 4.05 (2H, t, OC27₂(CH₂)₅SO(CH₂)₃NHCH₃), 2.78-2.72

(6H, m, O(CH₂)₅Ciϊ₂SO C ^CHzCH^NHCH^, 2.45 (3H, s,

O(CH₂)₆SO(CH₂)₃NHCH₃), 1.99-1.96 (2H, m, O(CH₂)₆SO CH₂Cff₂CH₂NHCH₃), 1.86-1.80 (4H, m, OCH₂C_fir₂(CH₂)₂CJy₂CH₂SO(CH₂)₃NHCH₃), 1.57 (4H, m,

O(CH₂)₂fCH₂)₂(CH₂)₂SO(CH₂)₃NHCH₃). δC : 157.27, 133.06, 129.94, 129.63, 129.56, 128.46, 128.35, 120.00, 116.93, 106.49,

67.71, 52.38, 50.48, 50.15, 36.12, 28.91, 28.59, 25.80, 22.82, 22.62.

BENZOrblOXOLE DERIVATIVES.

Preparation of N¹-methyl-10-benzorb]oxol-4-yloxy-l-decanamine HCI (63).

a) Preparation of 4-oxo-4,5,6,7-tetrahydrobenzo[b]oxole-3-carboxylic acid (59).

To a solution of 1,3-cyclohexanedione (6.71 g, 59.9 mmol) in aqueous potassium hydroxide (3.40 g, 61.1 mmol, in 12 ml H₂O), cooled in an ice bath, was added a freshly prepared solution of bromopyruvic acid (10.0 g, 59.9 mmol) in methanol (30 ml) over a period of 5 min. The red mixture was stirred at 5 °C for 2 h. and then allowed to attain room temperature. The methanol was removed in vacuo and the resulting slurry was diluted with water (60 ml) and acidified to pH 1 by the dropwise addition of con HCI. The acidic mixture was stirred and heated to 100 °C for 2 h, a precipitate having formed after 30 min. The mixture was cooled in an ice bath, filtered, and the pale brown solid was recrystallised from ethanol with charcoaling to give compound (59) as a buff coloured solid, 8.42 g (78%). M.p : 142-144 °C [lit. m.p. : 141-143 °C. ⁽⁸⁾]. δH : 13.26 (IH, br.s., disappeared on D₂O shake, CO₂H), 8.07 (IH, s, OCH=CH₂), 3.01 (2H, t, CH₂), 2.71 (2H, t, CH₂), 2.31 (2H, m, CH₂). δC : 199.49, 170.78, 161.42, 150.19, 117.95, 117.23, 36.51, 23.23, 22.39.

b) Preparation of 4-hydroxybenzo[b]oxole-3 -carboxylic acid (60). Intermediate (59) (6.80 g, 37.8 mmol), dodecene (10 ml, 45.0 mmol), and palladium (10% on carbon, 3.40 g) were suspended in Decalin (80 ml) at room temperature under an atmosphere of nitrogen. The black heterogeneous mixture was stirred vigorously and heated to reflux for 20 h. (Caution : excessive bumping was observed). The mixture was allowed to cool and slowly diluted with ethanol (130 ml), filtered through Arbosil, washing with ethanol (2 x 30 ml). The ethanol was removed in vacuo and the resulting slurry was cooled to 5°C. The white precipitate was collected by filtration and dried in vacuo to give compound (60) as a white solid, 5.42 g (81%).

M.p : 210-213°C [lit. m.p. : 209-212°C. ⁽⁸⁾]. δH : 8.66 (IH, s, ArH), 7.30 (IH, t, ArH), 7.18 (IH, d, ArH), 6.74 (IH, d, ArH), 4.23 (IH, br.s., ArOH, disappeared on D₂O shake). δC : 168.30, 156.48, 151.34, 151.21, 127.41, 114.50, 112.42, 109.29, 102.95.

c) Preparation of 4-hydroxybenzo[b]furan (61). 3-Carboxy-4-hydroxybenzo[b]furan (60) (5.40 g, 30.3 mmol) and copper powder (5.40 g, 85.0 mmol) were suspended in quinoline (40 ml) at room temperature under an atmosphere of nitrogen. The heterogeneous mixture was stirred vigorously and heated to 220°C for 3.5h. T.l.c, (diethyl ether : methanol, 10:1) confirmed disappearance of (56), Rf 0.13, and formation of a new compound Rf 0.74. The black mixture was allowed to cool to 100°C and poured onto crushed ice (300 ml). The mixture was diluted with diethyl ether (200 ml), filtered, and the two layers of the filtrate were separated. The organic fraction was partitioned with 2M HCI (2x80 ml) and sat. NaCl (2 x 30 ml), dried over MgSO₄, filtered, and concenfrated in vacuo to give a black viscous oil. The crude oil was purified by reduced pressure Kugelrohr distillation (b.p. 130°C / 0.5 mm Hg) to give compound (61) as a pale yellow solid on cooling, 3.40 g (84%).

M.p : 51-53°C [lit. m.p. : 55-56°C. ⁽⁸⁾]. δH : 7.51 (IH, d, ArH), 7.12 (2H, d, ArH), 6.86 (IH, d, ArH), 6.63 (IH, m, ArH),

6.23 (IH, br.s., disappeared on D₂O shake, ArOH). δC :156.64, 149.32, 143.72, 124.98, 116.71, 107.83, 104.49, 103.38.

d) Preparation of 4-(10-bromodecyloxy) benzo[b]furan (62).

Compound (58) was prepared from intermediate (61) and 1,10-dibromodecane by the General method A. %yield : 78. M.p : 38-39 °C. δH : 7.52 (IH, d, ArH), 7.22-7.10 (2H, m, ArH), 6.87 (IH, d, ArH), 6.66 (IH, d, ArH), 4.09 (2H, t, OCHXCH^Br), 3.40 (2H, t, O(CH₂)₉CH₂Br), 1.90-1.80 (4H, m,

OCH₂Cfl₂(CH₂)₆CH₂CH₂Br), 1.47-1.31 (12H, m,

δC : 156.26, 153.15, 143.34, 124.89, 117.84, 104.37, 104.10, 103.97, 68.30, 34.07, 32.81, 29.45, 29.36, 29.24, 28.75, 28.16, 26.07.

e) Preparation of N¹-methyl-10-benzo[b]furan-4-yloxy-l-decanamine.HCl (63). Compound (63) was prepared from intermediate (62) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

M.p : 107-108 °C.

Found : C, 66.37; H, 9.15; N, 4.09. C₁₉H₃₀C1NO₂ l/4H₂O requires : C, 66.26; H, 8.93;

N, 4.07 %. δH : 7.92 (IH, d, ArH), 7.25-7.21 (2H, m, ArH), 6.92 (IH, d, ArH), 6.81 (IH, d,

ArH), 4.13 (2H, t, OCH₂(CH₂)₉NHCH₃), 2.83 (2H, t, O(CH₂)₉CH₂NHCH₃), 2.52

(3H, s, O(CH₂)₁₀NHCHj), 1.80 (2H, m, OCH₂Cfl₂(CH₂)₈NHCH₃), 1.61 (2H, m,

O(CH₂)₈C_H₂CH₂NHCH₃), 1.48 (2H, m, OCR₂CR₂CH₂ (CH₂)₇NHCH₃), 1.30 (10H, m, 0(CR₂)₃(CH₂)₅(CR₂)₂NRCR₃). δC : 155.58, 152.58, 144.49, 125.23, 117.18, 104.53, 104.19, 103.90, 67.87, 48.11,

32.24, 28.90, 28.77, 28.67, 28.52, 25.92, 25.54, 25.32.

a) Preparation of 7-bromo-4-hydroxybenzo[b]furan (64).

4-Hydroxybenzo[b]furan (61), (1.00 g, 7.45 mmol) was dissolved in dry acetonitrile (30 ml) at room temperature under an atmosphere of nitrogen and N-bromosuccinimide (1.33 g, 7.45 mmol) was added in one portion to give a dark red homogeneous mixture. The mixture was stirred at room temperature for 3.5h. to give a pale yellow mixture. T.l.c, (pefroleum ether : ethyl acetate, 4:1) indicated presence of compound (61), Rf 0.20, and formation of two new compounds, Rf 0.27, and Rf 0.19. The solvent was removed in vacuo to give a yellow viscous oil. The crude oil was dissolved in dichloromethane (50 ml) and partitioned with H₂O (2x15 ml) and sat. ΝaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a pale brown solid. The solid was purified by flash column chromatography eluting with (pefroleum ether : ethyl acetate, 5 : 1). Fractions containing the product, Rf 0.27, were combined and concentrated in vacuo to give compound (64) as a pale yellow solid, 0.38 g (24%). Fractions containing second compound, Rf 0.17, were combined and concentrated in vacuo to give a waxy solid, 0.43 g, confirmed to be a complex mixture by NMR analysis. M p : 62-64 °C. δH : 7.54 (IH, d, ArH), 7.35 (IH, d, ArH), 7.04 (IH, d, ArH), 6.89 (IH, d, ArH), 5.79 (IH, br.s., disappeared on D₂O shake, AiOH). δC : 155.72, 145.82, 144.67, 126.93, 117.20, 105.53, 104.15, 102.05.

b) Preparation of 7-bromo-4-(10-bromodecyloxyl) benzo[b]furan (65). Compound (65) was prepared from intermediate (64) and 1,10-dibromodecane by the

General method A.

%Yield: 83, as a colourless oil. δH : 7.55 (IH, d, ArH), 7.44-7.41 (IH, d, ArH), 7.14-7.10 (IH, d, ArH), 6.86 (IH, d,

ArH), 4.22 (2H, t, OCH CH^Br), 3.41 (2H, t, O(CH₂)₉C_H₂Br), 1.85 (4H, m, CH₂C_H₂(CH₂)₆CH₂CH₂Br), 1.57 (2H, m, OCHaCHsCH CHz^Br), 1.33 (10H, m,

0(CR₂)₃(CH₂)s(CR₂)₂Bτ). δC : 155.70, 149.43, 144.74, 128.44, 121.13, 108.12, 107.64, 104.53, 73.62, 34.09,

32.81, 30.15, 29.43, 29.34, 28.73, 28.16, 25.95.

c) Preparation of N¹-methyl-10-(7-bromobenzo[b]furan-4-yloxy)l-decanamine HCI

(66).

Compound (66) was prepared from intermediate (65) and an excess of 33% methylamine in ethanol by the General methods B and C respectively.

% Yield : 72. M p : 104-106 °C.

Found : C, 54.19; H, 6.94; N, 3.22. C₁₉H₂₉ClBrNO₂ requires : C, 54.49; H, 6.98; N,

3.34 %.

δH : 8.05 (IH, d, ArH), 7.52-7.45 (IH, d, ArH), 7.33-7.30 (IH, d, ArH), 7.19 (IH, d, ArH), 4.30 (2H, t, OCff₂(CH₂)₉NHCH₃), 2.83 (2H, t, O(CH₂)₉CH₂NHCH₃), 2.52 (3H, s, O(CH₂)₁₀NHCH₅), 1.78 (2H, m, OCH₂CH₂(CH₂)₈NHCH₃), 1.62 (2H, m, O(CH₂)₈CH₂CH₂NHCH₃), 1.52 (2H, m, OCHsCHzCHXO^NHCHs), 1.30 (10H, m, O(CH₂)₃rCHa)₅(CH₂)₂NHCH₃). δC : 155.26, 148.79, 146.15, 128.16, 120.11, 107.51, 106.78, 104.87, 72.76, 48.11, 32.24, 29.55, 28.88, 28.75, 28.70, 28.52, 25.93, 25.39, 25.32.

Preparation of N^methyl-lO-benzorb furan-S-yloxy-l-decanamine (71).

a) Preparation of 2-carboxy-5-methoxybenzo[b]furan (67).

2-Hydroxy-5-methoxybenzaldehyde (5.0 g, 32.8 mmol), ethyl chloroacetate (4.82 g, 39.4 mmol), and freshly ground potassium carbonate (9.00 g, 65.0 mmol) were suspended in anhydrous dimethylformamide (75 ml) at room temperature under an atmosphere of nitrogen. The heterogeneous mixture was stirred vigorously and heated to reflux for 8h., allowed to cool, and poured onto crushed ice (200 g). The resulting slurry was extracted with toluene (2x60 ml), separated, and the organic fraction was partitioned with sat. ΝaCl (50 ml), dried over MgSO₄, filtered, and concenfrated in vacuo to give the crude decarboxylated product as an oil (1.30 g). The aqueous phase was acidified with cone HCI to precipitate the crude acid. Recrystalhsation form a toluene / ethanol mixture gave compound (67) as a colourless crystalline solid, 2.70 g (43%). M.p : 58-59°C [lit. m.p. : 58°C.⁽⁹⁾].

b) Preparation of 5-methoxybenzo[b]furan (68).

2-Carboxy-5-methoxybenzo[b]furan (67) (2.65 g, 13.8 mmol) and copper powder (0.90 g, 13.8 mmol) were suspended in quinoline (20 ml) at room temperature under an atmosphere of nitrogen. The heterogeneous mixture was stirred vigorously and heated to reflux for 1.5h. The mixture was cooled, poured into 2M HCI (200 ml), and filtered. The filfrate was extracted with chloroform (3x100 ml) and the combined organics were partitioned with H₂O (80 ml) and sat. ΝaCl (50 ml). The residue was purified by flash column chromatography eluting with (pefroleum ether : ethyl acetate, 10:1), to give compound (68) as a colourless solid, 1.80 g (90%). M p : 56-57°C [lit. m.p. : 58-59°C. ⁽⁹⁾]. δH : 7.57 (IH, d, ArH), 7.40-7.37 (lH,d, ArH), 7.04 (IH, d, ArH), 6.92-6.87 (IH, d, ArH), 6.69 (IH, s, ArH), 3.82 (3H, s, ArOCH ). δC : 155.90, 149.92, 145.71, 127.94, 113.04, 111.79, 106.68, 103.45, 55.85. c) Preparation of 5-hydroxybenzo[b]furan (69).

5- Methoxybenzo[b]furan (68) (8.38 g, 56.6 mmol) and pyridine hydrochloride (20 g) were combined at room temperature under an atmosphere of nitrogen and heated to 180°C for 2.5h. The mixture was allowed to cool, poured onto ice water (250 ml), and acidified to pH 1 by the addition of cone HCI. The aqueous mixture was extracted with ethyl acetate (2x100 ml) and the combined organics were partitioned with 2M HCI (2x50 ml) and sat. NaCl (50 ml). The organic fraction was dried over MgSO₄, filtered, and concentrated in vacuo to give a yellow oil. The residue was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate, 8 : 1) to give compound (69) as a colourless solid, 7.30 g (96%). M.p : 77-78°C [lit. m.p. : 79°C. ⁽⁹⁾]. δH : 7.58 (IH, d, ArH), 7.36-7.33 (IH, d, ArH), 7.00 (IH, d, ArH), 6.83-6.79 (IH, d, ArH), 6.65 (IH, s, ArH), 5.30 (IH, br.s., disappeared on D₂O shake, ArOiϊ). δC : 151.32, 150.04, 145.78, 128.28, 112.94, 111.80, 106.45, 106.14.

d) Preparation of 5-(10-bromodecyloxy) benzo[b]furan (70).

Compound (70) was prepared from intermediate (69) and 1,10-dibromodecane by the

General method A.

%Yield : 78. M.p : 50-51 °C. δH : 7.57 (IH, s, ArH), 7.36 (IH, d, ArH), 7.04 (IH, d, ArH), 6.92-6.87 (IH, d,

ArH), 6.69 (IH, d, ArH), 3.97 (2H, t, OCff₂(CH₂)₉Br), 3.40 (2H, t, 0(CR₂)₉CH₂Bτ),

1.90-1.74 (4H, m, OCR₂CH₂ (CH₂)₆C_H₂CH₂Br), 1.47-1.32 (12H, m,

O(CH₂)₂fC#₂ (CH₂)₂Br). δC : 155.40, 149.86, 145.62, 127.90, 113.62, 111.71, 106.67, 104.38, 68.79, 34.07,

32.81, 29.45, 29.36, 28.73, 28.16, 26.07.

e) Preparation of N'-methyl-lO-benzotbjfuran-S-yloxy-l-decanamine HCI (71). Compound (71) was prepared from intermediate (70) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. %Yield : 71. M.p : 130-131 °C. δH : 7.90 (IH, d, ArH), 7.47-7.43 (IH, d, ArH), 7.14 (IH, d, ArH), 6.90-6.87 (IH, d, ArH), 6.85 (IH, s, ArH), 3.97 (2H, t, OCH^" ₂(CH₂)₉NHCH₃), 2.81 (2H, t, O(CH₂)₉CH₂NHCH₃), 2.49 (3H, s, O(CH₂)₁oNHCff₅), 1.72 (2H, m, OCH₂CH^" ₂(CH₂)₈NHCH₃), 1.61 (2H, m, O(CH₂)₈Cfl₂CH₂NHCH₃), 1.28 (12H, m, O(CH₂)₂(Cff^(CH₂)₂NHCH₃). δC : 154.93, 149.13, 146.48, 127.80, 113.31, 111.53, 106.77, 104.53, 68.10, 48.09, 32.15, 28.80, 28.72, 28.66, 28.43, 25.86, 25.48, 25.19.

Preparation of N¹-methyl-10-benzo[blfuran-7-yloxy-l-decanamine (76).

a) Preparation of 2-carboxy-7-methoxybenzo[b]furan (72).

Compound (72) was prepared from 2-hydroxy-7-methoxybenzaldehyde in an analogous manner to that described for intermediate (67).

%Yield : 41. M.p : 224-226°C [lit. m.p. : >200°C. ⁽¹⁰⁾]. δH : 13.31 (IH, br.s., disappeared onD₂O shake, C0₂H), 7.38 (IH, s, ArH), 7.08-6.96

(2H, m, ArH), 6.84-6.80 (IH, d, ArH), 3.69 (3H, s, ArOCHi). δC : 160.02, 146.20, 145.39, 144.48, 128.39, 124.62, 114.68, 113.75, 109.13, 55.87.

b) Preparation of 7-methoxybenzo[b]furan (73).

Compound (73) was prepared from intermediate (72) in an analogous manner to that described for intermediate (68).

% Yield : 50, as a colourless oil. δH : 7.60 (IH, d, ArH), 7.19-7.10 (2H, m, ArH), 6.78-6.75 (IH, d, ArH), 6.73 (IH, d, ArH), 3.97 (3H, s, AxOCH₃). δC : 145.53, 144.92, 144.29, 129.09, 123.43, 113.48, 106.86, 106.25, 55.96.

c) Preparation of 7-hydroxybenzo[b]furan (74).

Compound (74) was prepared from intermediate (73) in an analogous manner to that described for intermediate (69). %Yield : 58, as a colourless oil. δH : 7.58 (IH, d, ArH), 7.17-7.05 (2H, m, ArH), 6.86-6.82 (IH, d, ArH), 6.75 (IH, d, ArH), 6.02 (IH, br.s., disappeared on D₂O on shake, ArOH). δC : 144.85, 143.39, 141.11, 129.13, 123.72, 113.33, 110.51, 107.26.

d) Preparation of 7-(10-bromodecyloxy) benzo[b]furan (75).

Compound (75) was prepared from intermediate (74) by the General method A. %Yield : 75, as a pale brown oil. δH : 7.61 (IH, d, ArH), 7.19-7.09 (2H, m, ArH), 6.80-6.77 (IH, d, ArH), 6.74 (IH, d, ArH), 4.16 (2H, t, OCH^CH^Br), 3.39 (2H, t, 0(CR₂)₉C ₂Bτ), 1.90-1.78 (4H, m, OCH₂C#₂(CH₂)₆ C27₂CH₂Br), 1.52-1.28 (12H, m, 0(CR₂)₂(CH₂)₆(CR₂)₂Bτ). δC : 145.01, 144.80, 144.44, 129.13, 123.38, 113.24, 107.37, 106.83, 68.89, 34.00, 32.78, 29.56, 29.40, 29.27, 28.68, 28.10, 25.98.

e) Preparation of N¹-methyl-10-benzo[b]furan-7-yloxy-l-decanamine HCI (76). Compound (76) was prepared from intermediate (75) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. % Yield : 74.

M.p : 145-148 °C.

Found : C, 66.56; H, 9.16; Ν, 4.26. C₁₉H₃₀C1ΝO₂ l/4H₂O requires : C, 66.26; H, 8.93;

N, 4.07 %. δH : 7.94 (IH, d, ArH), 7.24-7.13 (2H, m, ArH), 6.95-6.91 (2H, m, ArH), 4.18 (2H, t, OCH₂(CH₂)₉NHCH₃), 2.85 (2H, t, O(CH₂)₉CH^" ₂NHCH₃), 2.52 (3H, s,

O(CH₂)₁₀NHCH₃), 1.81 (2H, m, OCH₂CET₂(CH₂)₈]NHCH₃), 1.62 (2H, m,

O(CH₂)₈αy₂CH₂NHCH₃), 1.49 (2H, m, O(CH₂)₂Cff₂ (CH₂)₇NHCH₃), 1.31 (10H, m,

O(CH₂)₃rCfla ₅(CH₂)₂NHCH₃). δC : 145.45, 145.20, 144.84, 129.43, 123.36, 113.08, 107.73, 106.74, 68.30, 48.00, 32.08, 28.63, 28.58, 28.50, 28.27, 25.68, 25.29, 25.07.

BENZOrblTHIOPHENE DERIVATIVES

Preparation of N¹-methyl-10-benzo[blthiol-4-yloxy-l-decanamine HCI (79).

a) Preparation of benzo[b]thiol-4-ol (77).

4,5,6,7-Tetrahydrobenzo[b]thiol-4-one (3.25 g, 21.35 mmol) and sulήir (0.89 g,

27.76 mmol) were suspended in diphenyl ether (30 ml) at room temperature under an atmosphere of nitrogen and heated to 240°C for 4.5h. to give a deep red homogenous mixture. The mixture was allowed to cool, diluted with diethyl ether (80 ml), and extracted with 2M NaOH (3x50 ml). The basic aqueous layer was acidified to pH 3 with cone HCI and extracted with dichloromethane (3x30 ml). The organics were combined and partitioned with sat. NaCl (20 ml), dried over MgSO₄, filtered, and concentrated in vacuo to give a red oil that solidified on standing. The crude solid was purified by flash column chromatography eluting with (petroleum ether : ethyl acetate : methanol, 80 : 20 : 2.5). Fractions containing the product, Rf 0.30, were combined and concentrated in vacuo to give compound (77) as a yellow solid, 1.84 g (57%). M.p : 78-82 °C [lit. m.p. : 80-82°C. ⁽¹¹⁾]. δH : 7.48-7.45 (2H, m, ArH), 7.36 (IH, d, ArH), 7.24-7.16 (IH, m, ArH), 6.72-6.69 (IH, d, ArH), 5.29 (IH, br.s., disappeared on D₂O shake, AiOH). δC :150.69, 141.83, 129.18, 125.25, 125.04, 119.64, 115.22, 108.75.

b) Preparation of 4-(l 0-bromodecyloxy) benzo[b]thiole (78)

Compound (78) was prepared from intermediate (77) and 1,10-dibromodecane by the

General method A.

%Yield : 81.

M.p : 52-54 °C. δH : 7.52-7.49 (IH, d, ArH), 7.45-7.43 (IH, d, ArH), 7.32-7.22 (2H, m, ArH), 6.74-

6.71 (IH, d, ArH), 4.10 (2H, t, OCH₂(CR₂)₉Bτ), 3.40 (2H, t, 0(CR₂)₉CH₂Bτ), 1.90-

1.79 (4H, m, OCR₂CH (CH₂)₆CH₂CH₂Br), 1.54-1.49 (2H, m,

O(CH₂)₂Cff₂(CH₂)₇Br), 1.32-1.29 (10H, m,

δC : 154.55, 141.24, 130.65, 125.25, 124.33, 120.66, 114.57, 104.58, 68.07, 34.05, 32.79, 29.43, 29.34, 29.24, 28.81, 28.73, 28.14, 26.11.

c) Preparation of N¹-methyl-10-benzo[b]thiol-4-yloxy-l-decanamine HCI (79). Compound (79) was prepared from intermediate (78) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. %Yield : 67.

M.p : 117-120 °C.

Found : C, 64.04; H, 8.85; Ν, 3.70. C₁₉H₃₀C1ΝOS requires : C, 64.11; H, 8.49; N,

3.93 %. δH : 7.52-7.50 (IH, d, ArH), 7.46-7.43 (IH, d, ArH), 7.32-7.22 (2H, m, ArH), 6.75- 6.72 (IH, d, ArH), 4.10 (2H, t, OC#₂(CH₂)₉NHCH₃), 2.55 (2H, t, O(CH₂)₉Cff₂NHCH₃), 2.42 (3H, s, O(CH₂)₁₀NHC_tf₅), 1.87 (2H, m, OCH₂CH₂(CH₂)₈NHCH₃), 1.50 (2H, m, O(CH₂)₈Ciϊ₂CH2NHCH₃), 1.39-1.30 (12H, m, O(CH₂)₂rCH_{2 6}(CH₂)₂NHCH₃). δC : 154.57, 141.24, 130.65, 125.25, 124.31, 120.70, 114.55, 104.60, 68.10, 52.22, 36.57, 29.94, 29.52, 29.38, 29.25, 27.35, 26.15.

Preparation of N¹-methyl-10-(7-bromobenzo[b1thiol-4-yloxy 1-decanamine HCI (81).

a) Preparation of 7-bromo-4-(10-bromodecyloxy) benzo[b]thiole (80). Intermediate (78) (0.50 g, 1.35 mmol) was dissolved in a mixture of acetonitrile (7.0 ml) and chloroform (0.5 ml) at room temperature under an atmosphere of nitrogen. N-bromosuccinimide (0.24 g, 1.35 mmol) was added in one portion to give a pale yellow homogeneous mixture. The mixture was stirred at room temperature for 24h. T.l.c, (petroleum ether : ethyl acetate, 40:1) indicated disappearance of compound (78) Rf 0.57 and formation of a new compound Rf 0.43. The solvent was removed in vacuo to give a pale brown oil. The crude oil was dissolved in ethyl acetate (50 ml) and partitioned with H₂O (2x20 ml) and sat. ΝaCl (15 ml). The organic fraction was dried over MgSO₄, filtered, and concenfrated in vacuo to give a black oil. The oil was purified by flash column chromatography eluting with (pefroleum ether : ethyl acetate, 50:1). Fractions containing the product were combined and concenfrated in vacuo to give compound (80) as a colourless oil, 0.53 g (87%). δH : 7.58 (IH, d, ArH), 7.39-7.34 (2H, m, ArH), 6.65-6.61 (IH, d, ArH), 4.07 (2H, t, OCff^" ₂(CH₂)₉Br), 3.40 (2H, t,

1.90-1.79 (4H, m, OCH₂CH₂(CH₂)₆Cff₂CH₂Br), 1.50-1.29 (12H, m, O(CH₂)₂fC_e₂)₆(CH₂)₂Br). δC : 153.91, 142.62, 131.37, 127.67, 125.32, 121.83, 106.49, 105.98, 34.03, 32.79, 29.42, 29.33, 29.29, 29.13, 28.72, 28.14, 26.06.

b) Preparation of N¹-methyl-10-(7-bromobenzo[b]thiol-4-yloxy) 1-decanamine HCI (81). Compound (81) was prepared from intermediate (80) and an excess of 33% methylamine in ethanol by the General methods B and C respectively. %Yield : 82. M.p : 98-101 °C Found : C, 50.43; H, 6.69; N, 3.49. C₁₉H₂₉ClBrNOSO H₂O requires : C, 50.39; H, 6.90; N, 3.09 %. δH : 7.60-7.58 (IH, d, ArH), 7.38-7.35 (2H, m, ArH), 6.65-6.62 (IH, d, ArH), 4.07 (2H, t, OCH₂(CH₂)₉NHCH₃), 2.55 (2H, t, O(CH₂)₉CH₂NHCH₃), 2.42, (3H, s, O(CH₂)₁₀NHCΪ_ , 1.90-1.80 (2H, m, OCH₂Cff₂(CH₂)₈NHCH₃), 1.49-1.44 (4H, m, O(CH₂)₂C__e₂(CH₂)₅CH₂CH₂NHCH₃), 1.30 (10H, m, O(CH₂)₃fCHa CH₂)₂NHCH₃). δC : 153.92, 142.62, 131.39, 127.67, 125.30, 121.85, 106.50, 105.98, 68.44, 52.22, 36.57, 30.10, 29.94, 29.56, 29.51, 29.34, 29.15, 27.33, 26.07.

Evaluation for antifungal activity

Testing for antifungal activity was carried out as follows.

Each compound is titrated in a synthetic medium RPMI-1640 (RPMI) against nine fungal species: Candida albicans (three strains), C. parapsilosis, C. glάbrata, C. krusei, C. tropicalis, Cryptococcus neoformans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton quinckeanum.

Fungal Isolates

Candida albicans B2630 [A 1 128 101], Candida albicans AD (azole resistant) [A 1 128 107], Candida albicans 6-4 (Amphoteracin B resistant) [A 1 128 181], Candida parapsilosis [Al 138 001], C. glabrata [Al 132 002], Candida krusei [Al 136 001] Candida tropicalis [Al 127 001] and Saccharomyces cerevisiae [Al 131 001] are grown 24 h at 37 °C. Cryptococcus neoformans 251 [A 1 184 002] for 48 h and Aspergillus fumigatus 110.1 [A 1 173 003] and Trichophyton quinckeanum [Al 133 001] for about 7 days at 30 °C on Sabouraud Dextrose slopes. The isolates are harvested in physiological saline and diluted to give a concentration of 5 x 10³ cells/ml in RPMI [5 x 10⁵ for S. cerevisiae and 1 x 10⁵ for T. quinckeanum]. Antifungal Agents

Amphoteracin B, fluconazole and the compounds to be evaluated are formulated in dimethyl sulfoxide (DMSO) at 2560 μg/ml and diluted to four times the top test concentration in RPMI.

The Test Method

The test is carried out in microtifre plates. 100 μl of broth is added to all the wells and 100 μl of compound [at 4 times final top concentration] is added to first well of appropriate row and titrated out using a Biomek 2000 Automation Workstation (doubling dilutions). The plates are incubated at 30°C. The plates are read by eye [MIC] and by the multiscan (540 nm) [IC₅₀] at 48 h.

Table 2 shows the minimum inhibitory concentrations and ICso values for various species of Candida, as well as for Cryptococcus neoformans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton quinkeanum. The known antifungal agents amphoteracin and fluconazole are included for comparison.

REFERENCES

1) Fieser and Desreux, J. Am. Chem. Soc, 1938, 60, 2255. Militzer, J. Am. Chem. Soc, 1938, 60, 256.

2) P. Ruggli and R. Preuss, Helv. Chim. Acta, 1941, 24, 1345.

3) L. Syper, Synthesis, 1989, 3, 167-172.

4) Beil., 6, 651.

5) W. B. Smith, J. Org. Chem., 1985, 50, 3649-3651.

6) W. Adcock and M. J. S. Dewar, J. Am. Chem. Soc, 1967, 89, 386-390.

7) James and Woodcock, J. Am. Chem. Soc, 1953, 2089.

8) G. Knee and P. J. Maddocks, Synth. Commun., 1986, 16, 1641.

9) L. Rene and R. Royer, Bull. Soc. Chim. Fr., 1973, 7, 2355.

10) A. G. Brewster, P. W. R. Caulkett, and R. Jessup, J. Med. Chem., 1987, 30, 67-70.

11) N. Garcia-Domingeuz, E. Ravina, L. Santana, C. Teran, and G. Garcia-Mera, Ace. Pharm., 1988, 321, 735.

Claims

1. A compound of formula (I) :

Ar— O— A— NR R² (I)

wherein —

• one or more halogen substituents, and/or

• one or more ring heteroatoms,

the oxygen group of the side chain being attached to the benzene ring of Ar;

A is a straight or branched alkylene group of 6 to 16 carbon atoms which may be interrupted by — O— , — S— , —SO—, — SO₂— , — NR — , — CH(OH)— or — CO — , wherein R⁴ is hydrogen or a sfraight or branched alkyl group of 1 to 4 carbon atoms; and

or a pharmaceutically acceptable acid derivative thereof.

2. A compound as claimed in claim 1, wherein Ar is a bicyclic aromatic group selected from —

• naphthalene bearing one or more halogen substituents; and

• benzothiophene and benzofuran, optionally bearing one or more halogen substituents on the benzene ring.

3. A compound as claimed in claim 2, wherein the compound comprises a compound of formula (IA) or (IB):

(IB)

wherein Hal is a halogen substituent and A, R¹ and R² are as defined for formula I in claim 1;

or a pharmaceutically acceptable acid derivative thereof.

4. A compound as claimed in claim 2, wherein the compound comprises a compound of formula (IC):

wherein Hal is a halogen substituent and A, R »ι and τ R>2 are as defined for formula I in claim 1;

or a pharmaceutically acceptable acid derivative thereof.

5. A compound as claimed in claim 4, wherein the compound comprises a compound of formula (ID):

or a pharmaceutically acceptable acid derivative thereof.

6. A compound as claimed in any preceding claim, wherein A is a straight or branched alkylene group of 6 to 16 carbon atoms.

7. A compound as claimed in claim 6, wherein A is a straight or branched alkylene group of 6 to 11 carbon atoms

8. A compound as claimed in claim 7, wherein A is a straight or branched alkylene group of 8 to 10 carbon atoms.

9. A compound as claimed in any one of claims 1 to 5, wherein A is a group (CH₂)_m— X— (CH₂)_n, wherein—

X is O, S, SO, SO₂, NR⁴, CH(OH) or CO, wherein R⁴ is hydrogen or a sfraight or branched alkyl group of 1 to 4 carbon atoms; and

10. A compound as claimed in claim 9, wherein X is O, S, SO₂, NR⁴, CH(OH) or CO, wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, and the sum (m + n) is between 9 and 11.

11. A compound as claimed in claim 9, wherein X is SO and the sum (m + n) is between 12 and 14.

12. A compound as claimed in any preceding claim, wherein R and R are each independently hydrogen, a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, benzyl or cyclopropylmethyl.

13. A compound as claimed in claim 12, wherein R and R are each independently hydrogen or methyl.

1 9

14. A compound as claimed in claim 13, wherem R is methyl and R hydrogen.

15. A compound as claimed in any preceding claim, wherein the halogen substituent is a single fluoro, chloro, bromo or iodo group.

16. A compound as claimed in claim 15, wherein the halogen substituent is a fluoro, chloro or bromo group.

17. A compound as claimed in claim 16, wherein the halogen substituent is a bromo group.

18. A compound as claimed in any preceding claim, wherein the pharmaceutically acceptable derivative comprises an acid addition salt.

19. A pharmaceutical composition which comprises as an active ingredient a compound of formula (I), as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable derivative thereof, in association with a pharmaceutically acceptable diluent or carrier.

20. A pharmaceutical composition as claimed in claim 19 adapted for topical administration, wherein the active ingredient comprises a compound of formula (I) wherein A is a straight or branched alkylene group of 6 to 16 carbon atoms, or a pharmaceutically acceptable derivative thereof.

21. A pharmaceutical composition as claimed in claim 19 adapted for systemic administration, wherein the active ingredient comprises a compound of formula (I), wherein A is a group (CH₂)_m — X — (CH₂)_n, wherein — X is O, S, SO, SO₂, NR⁴, CH(OH) or CO, wherein R⁴ is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and

m and n are integers each greater than 1 such that the sum (m + n) is between

8 and 16,

or a pharmaceutically acceptable derivative thereof.

22. A compound of formula (I), as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable derivative thereof, for use as a pharmaceutical.

23. Use of a compound of formula (I) :

Ar— O— A— NR^:R² (I)

wherein —

or a pharmaceutically acceptable acid derivative thereof;

in the manufacture of a medicament for use in the freatment of a fungal infection.

24. A method for the treatment of a fungal infection in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I):

Ar— O— A— NR R² (I)

wherein-

or a pharmaceutically acceptable acid derivative thereof.

25. A process for the manufacture of a compound as claimed in any one of claims 1 to 18 which comprises the reaction of a compound of formula (II):

Ar— O— A— Z (II)

wherein Ar and A are as defined in claim 1 and wherein Z is a displaceable group,

with an amine of the formula H ^R², wherein R¹ and R² are as defined in claim 1.

26. A process for the manufacture of a compound as claimed in any one of claims 1 to 18 which comprises the reduction of an amide of formula (III):

Ar— O— A¹— CO— NR*R² (III)

1 9 1 1 wherein Ar, R and R are as defined in claim 1 and wherein A is such that A — CH has the same meaning as defined in claim 1 for A, thereby producing a compound of formula (IE):

Ar— O— A¹— CH₂— NR R² (IE)