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-NR1R2 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 R3 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 NOIR2 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 compounds 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) : ArOANRtR2 (I) wherein- Ar is a bicyclic or tricyclic aromatic group including at least one benzene ring andbearing- 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 Rl 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.

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) :

wherein Hal is a halogen substituent and A, R1 and R2 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, Rl 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, R1 and R2 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- (CH2) n, wherein- X is O, S, SO, S02, 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, S02, 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 R'and W are each independently hydrogen, a straight or branched alkyl or alkenyl group of 1 to 4 carbon atoms, benzyl or cyclopropylmethyl are preferred. Preferably Rl and R2 are each independently hydrogen or methyl, especially a compound in which Rl 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, p-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 (1) 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- X is 0, S, SO, S02, NR4, CH (OH) or CO, wherein R 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.

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) : ArOANRIR2 (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 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-,-S02-, NR4-,-CH (OH)- or-CO-, wherein R4 is hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms; and Rl 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.

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 HNRlR2, wherein Rl 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-Al-CO-NR1R2 (NID 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) :<BR> <BR> Ar-O-Al-CHa-NR1R2 (IE) The amide starting material may be obtained by reacting an activated derivative of the corresponding carboxylic acid with an amine of the formula HNRIR2 wherein Rl 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 Example No Experiment No. Structure Example1Tt0 (CH. NHCH. HC1 Br Example2 srJXo (cH2) 8NHcu3 HCI Brocs Example34. 0 (CH,), NH,. HCl Br Example 4 IS O (CHZ) ioNHCH2CH3. HCl Bu Example510 O (CH2) gNHCH,. HCI Bu Example6'20. 0 (CH. N (CH, CH,),. HC1 Bu Example710 (CH,),. NHCH,. HCt I S Br Example819 O (CH 2) ON (CH3) 2. HCI Br'iocr Example9'39. 0 (CH,) NHCH,. HC ! F Example 10 17 BrJXO (CI12XH-HCI I Sr ExampleIt8 O (CH 2) 6 NHCH3. HCI Example12"290 (CH,) NHCH,. HC1 Br Br Example13 66 O (CHz) IONHCH3. HC1 Ber F Br Example No Experiment No. Structure Example14 71 O (CH2), ONHCH 3. HCI o Example15'31. 0 (CH,), NHCH,. HCI Example 16 76 0 O (CI12), ONHCH3. HCI Example17 24 j- ber Br Example18 63 O (CH2), ONHCH3' HC' 0 Example19 79 gCH2) 10NHCH3. HCI I S Example 20 18 O (CH) NU. HCI 2 10 Example 21 51 O (CH2) 6SO (CH2) 6NHCH3. HCI Br Example22 36 O (CH) NHCH3. HCI I w w I Example 23 58 O (CH 2) 6SO (CH2) NHCH3. HCI Br Example 24 44 i i (C2) 6NH (c) 4 2HCI sr Example 25 12 OI (CH2) 12 NHCH3. HCI Bu Example 26 54 O (CH2) 6SO2 (CH2) 6NHCH3. HC' Br Example No Experiment No. Structure Example 27 46 O (CH) 2NH (CIi), NH2. 2HCI Br Example 28 16 O (CH2), ONH. RCI Br I Example 29 43 . O (CHZ) oNHCH3. HCI cl i Example 30 45 O (Cl2) 4NH (Cli) 6NH. 2HCI Br

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 a,-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 MgS04, filtered, and concentrated in vacuo. Excess a, co-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 Na2S04, 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 a, co-dibromoalkane by the General method A.

6-Bromo-2- (2-bromoethvloxy) naphthalene (1).

% Yield: 74.

M. p. : 130-132 °C.

8H : 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, OCH2CH2Br), 3.67 (1H, t, OCH2CH2Br).

8C : 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-bromobutyloxv) naphthalene (2).

% Yield: 68.

M. p. : 51-54 °C.

8H : 7.89 (1H, d, ArH), 7.64-7.46 (3H, m, ArH), 7.13 (1H, dd, ArH), 7.07 (1H, d, ArH), 4.08 (2H, t, OCH2 (CH2) 3Br), 3.50 (2H, t, O(CH2)3CH2Br), 2.10 (2H, m, OCH2CH2 (CH2) 2Br), 2.02 (2H, m, O (CH2) 2CH2CH2Br).

8C : 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.

8H : 7.89 (1H, d, ArH), 7.64-7.46 (3H, m, ArH), 7.15 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.04 (2H, t, OCH2(CH2)5Br), 3.42 (2H, t, O (CH2) 5CH2Br), 1.92-1.82 (4H, m, OCH2CH2 (CH2) 2CH2CH2Br), 1.55-1.49 (4H, m, O (CH2) 2 (CH2)2 (CH2)2Br).

8C : 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-bromooctyloxv) naphthalene (4).

% Yield: 78.

M. p.: 59-60 °C.

8H : 7.89 (1H, d, ArH), 7.63-7.45 (3H, m, ArH), 7.16 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.03 (2H, t, OCH2(CH2)7Br), 3.40 (2H, t, O (CH2) 7CH2Br), 1.88-1.80 (4H, m, OCH2CH2 (CH2) 4CH2CH2Br), 1.49-1. 36 (8H, m, O (CH2) 2(CH2)4(CH2)2Br),@ 8C : 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.

8H : 7.91 (1H, d, ArH), 7.64-7.55 (2H, m, ArH), 7.49 (1H, dd, ArH), 7.13 (1H, dd, ArH), 7.04 (1H, d, ArH), 4.03 (2H, t, OCH2 (CH2) 8Br), 3.41 (2H, t, O (CH2) 8CH2Br), 1.88-1.82 (4H, m, OCH2CH2 (CH2) 5CH2(CH2Br), 1.55-1.30 (10H, m, O (CH2) 2(CH2)5 (CH2) 2Br).

8C : 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 % Yield: 76.

M. p.: 70-72 °C.

8H : 7.90 (1H, d, ArH), 7.64-7.46 (3H, m, ArH), 7.17 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 9Br), 3.41 (2H, t, O(CH2)9CH2Br), 1.88-1.81 (4H, OCH2CH2 (CH2) 6CH2CH2Br), 1.55-1.33 (12H, m, O (CH2) 2(CH2)6(CH2)2Br).

8C : 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.

8H : 7.90 (1H, d, ArH), 7.64-7.46 (3H, m, ArH), 7.16 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.05 (2H, t, OCHz (CH2) llBr), 3.40 (2H, t, O (CH2) 11CH2Br), 1.88-1.81 (4H, m, O-CH2CH2 (CH2) BCH2CH2Br), 1.56-1.29 (16H, m,-O (CH2) 2(CH2)8(CH2)2Br).

8C : 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-(n-methylaminoaLkyloxy) naphthalene hydrochlorides.

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

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

% Yield : 85.

M. p.: 179-180 °C.

Found: C, 54.85; H, 6.46 ; N, 3.60. C17H23BrClNO requires: C, 54.78; H, 6.22; N, 3.76 %.

8H : 7.88 (1H, d, ArH), 7.62-7.54 (2H, m, ArH), 7.48 (1H, dd, ArH), 7.13 (1H, dd, ArH), 7.04 (1H, d, ArH), 4.00 (2H, t, OCH2 (CH2) 5NHCH3), 2.94 (2H, t,

O (CH2) 5CH2NHCH3), 2.67 (3H, s,-O (CH2) 6NHCH3), 1.90-1.80 (4H, m, OCH2CH2 (CH2) 2CH2CH2NHCH3), 1.51 (4H, m,-O (CH2) 2 (CH2) 2 (CH2) 2NHCH3).

8C : 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 HCl. (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 %.

8H : 7.88 (1H, d, ArH), 7.62-7.55 (2H, m, ArH), 7.49 (1H, dd, ArH), 7.15 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.02 (2H, t, OCH2 (CH2) 6CH2NHCH3-), 2.91 (2H, t, O (CH2) 7CH2NHCH3), 2.66 (3H, s, O (CH2) gNHCH3), 1.83-1.81 (4H, m, OCH2CH2 (CH2) 4CH2CH2NHCH3), 1. 37 (8H, m, O (CH2) 2 (CH2)4 (CH2)2NHCH3).

8C : 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 HCl. (10).

% Yield : 76.

M. p.: 160-161 OC.

Found: C, 58. 02; H, 7.16; N, 3.08. C20H29BrClNO requires: C, 57.91; H, 7.05; N, 3.38 %.

8H : 7.87 (1H, d, ArH), 7.62-7.58 (2H, m, ArH), 7.48 (1H, dd, ArH), 7.16 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.01 (2H, t, OCH2(CH2)8NHCH3), 2.91 (2H, t, O (CH2) 8CH2NHCH3), 2.66 (3H, s, O (CH2) 9 NHCH3), 1.84-1.81 (4H, m, OCH2CH2 (CH2) 5CH2CH2NHCH3), 1.34 (10H, m, O (CH2) 2(CH2)5(CH2) 2NHCH3).

8C : 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-methylaminodecyloxy)naphthalene HCl. (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%.

8H : 7.89 (1H, d, ArH), 7.64-7.59 (2H, m, ArH), 7.49 (1H, dd, ArH), 7.16 (1H, dd, ArH), 7.07 (1H, d, ArH), 4.03 (2H, t, OCH2 (CH2) 9NHCH3), 2.87 (2H, t, O (CH2) 9CH2NHCH3), 2.66 (3H, s, O (CH2) 10NHCH3), 1.85-1.80 (4H, m, OCH2CH2 (CH2) 6CH2CH2NHCH3), 1.31 (12H, m, O (CH2) 2(CH2)6(CH2)2NHCH3).

8C : 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 HCl. (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%.

8H : 7.90 (1H, d, ArH), 7.65-7.89 (2H, m, ArH), 7.50 (1H, dd, ArH), 7.17 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.04 (2H, t, OCH2 (CH2) 11NHCH3), 2.91 (2H, t, O (CH2) 11CH2NHCH3), 2.67 (3H, s, O(CH2)12NHCH3), 1.86-1.81 (4H, m, OCH2CH2 (CH2) 8CH2CH2NHCH3), 1.27 (16H, m, O (CH2) 2 (CH2)8(CH2)2NHCH3).

8C : 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- nNRIR2 where Ar is 6-bromo-2-naphthyl.

Primary amine Preparation of 6-bromo-2-(8-aminootyloxy)naphthalene HCl (14). a) Preparation of N1-[8-(6-bromo-2-naphthyloxy) octyl]-2,2,2-trifluoroacetamide (13).

To a suspension of NaH (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 nunol) 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 MgS04, 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.

8H : 7.89 (1H, d, ArH), 7.65-7.56 (2H, m, ArH), 7.49 (1H, dd, ArH), 7.16 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.04 (2H, t, OCH2(CH2)7NHCOCF3), 3.37 (2H, q, O (CH2) 7CH2NHCOCF3), 1.85-1.80 (2H, m, O (CH2) 6CH2CH2NHCOCF3), 1.61-1.47 (4H, m, OCH2CH2 (CH2) 3CH2CH2CH2NHCOCF3), 1.40-1.36 (6H, m, O (CH2) 2 (CHi3 (CH2) 3NHCOCF3).

8C : 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 Na2S04, 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. C18H25BrCINO requires: C, 55.90; H, 6.52; N, 3. 62 %.

8H : 8.10 (1H, d, ArH), 7.84-7.77 (2H, m, ArH), 7.58 (1H, dd, ArH), 7.35 (1H, d, ArH), 7.23 (1H, dd, ArH), 4.06 (2H, t, OCH2(CH2)7NH2), 2.76 (2H, t, O (CH2) 7CH2NH2), 1.77 (2H, m, OCH2 CH2 (CH2) 6NH2), 1.58 (2H, m, O (CH2) 6CH2CH2NH2), 1.44 (2H, m, O (CH2) 2CH2 (CH2) 3NH2), 1.31 (6H, m, O (CH2) 3 (CH2) 3 (CH2) 2NH2).

8C : 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 HCl (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 %.

8H : 8.10 (1H, d, ArH), 7.84-7.76 (2H, m, ArH), 7.57 (1H, dd, ArH), 7.35 (1H, d, ArH), 7.22 (1H, dd, ArH), 4.07 (2H, t, OCH2 (CH2) 9NHCH2CH3), 2.91-2.82 (4H, m, O (CH2) 9CH2NHCH2CH3), 1.77 (2H, m, OCH2CH2 (CH2) 8NHCH2CH3), 1.58 (2H, m, O (CH2) 8CH2CH2NHCH2CH3), 1.45 (2H, m, OCH2CH2CH2 (CH2) 7NHCH2CH3), 1.29 (10H, m, O (CH2) 3(CH2)5(CH2)2NHCH2CH3).

8C : 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 HCl (16).

% Yield: 69.

M. p.: 173-175 °C.

Found: C, 56.05; H, 6.46; N, 3. 71. C27H33BrClNO 1/4 H20 requires: C, 55.90; H, 6.52; N, 3.62 %.

8H : 8.10 (1H, d, Arnap) 7.83-7.76 (2H, m, Arnap), 7.57-7.53 (3H, m, Arbzx2, Arnapx1), 7.44-7.41 (3H, m, Arbz), 7.35 (1H, d, Arnap), 7.22 (1H, dd, Arnap), 4.11 (4H, m, OCH2 (CH2) 9NHCH2Ph), 2.85 (2H, t, O (CH2) 9CH2NHCH2Ph), 1.80 (2H, m, OCH2CH2 (CH2) 8NHCH2Ph), 1.77 (2H, m, O (CH2) 8CH2CH2 NHCH2Ph), 1.45 (2H, m, OCH2CH2CH2 (CH2) 7NHCH2Ph), 1.27 (10H, m, O (CH2) 3(CH2)5(CH2) 2 NHCH2Ph).

8C : 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 HCl (17).

% Yield : 74.

M. p.: 147-149°C.

Found: C, 58.83; H, 7.21; N, 3.02. C2lH3oBrClNO requires: C, 58.96; H, 7.07; N, 3.27 %.

8H : 8.10 (1H, d, ArH), 7.84-7.76 (2H, m, ArH), 7.58 (1H, dd, ArH), 7. 36 (1H, d, ArH), 7.20 (1H, dd, ArH), 4.08 (2H, t, OCH2 (CH2) 7NHCH (CH3) 2), 3.22 (1H, m, O (CH2) 8NHCH (CH3) 2), 2.82 (2H, t, O (CH2) 7CH2NHCH (CH3) 2), 1.78 (2H, m, OCH2CH2 (CH2) 6NHCH (CH3) 2), 1.63 (2H, m, O (CH2) 6 CH2CH2NHCH (CH3) 2), 1.46- 1. 33 (8H, m, O (CH2) 2 (CH2) 4 (CH2) 2NHCH (CH3) 2), 1.25-1.22 (6H, d, O (CH2) 8NHCH(CH3)2). bC : 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-cyclopropylmethylaminodecyloxy)naphthalene HCl (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 %.

8H : 7.89 (1H, d, ArH), 7.63-7.58 (2H, m, ArH), 7.54 (1H, dd, ArH), 7.15 (1H, dd, ArH), 7.06 (1H, 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) 10NHCH2CH (CH2) 2), 1.85- 1.79 (4H, m, OCH2CH2 (CH2) 6CH2CH2NHCH2 CH (CH2) 2), 1.48 (2H, m,

O (CH2) 2CH2 (CH2) 7NHCH2CH (CH2) 2), 1.31 (11H, m, O (CH2) 3 (CH2) 5 (CH2) 2NHCH2CH (CH2) 2), 0.71 (2H, d, O (CH2) IoNHCH2CH (CH2) 2), 0.46 (2H, d, O(CH2)10NHCH2CH(CH2)2).

8C : 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 HCl (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 %.

5H : 7.90 (1H, d, ArH), 7.65-7.57 (2H, m, ArH), 7.49 (1H, d, ArH), 7.17 (1H, dd, ArH), 7.09 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 9N (CH3) 2), 2.96 (2H, t, O (CH2) gCH2N (CH3) 2), 2.80 (6H, d, O (CH2) 10N(CH3)2), 1.86-1.81 (4H, m, OCH2CH2 (CH2) 6CH2CH2N (CH3) 2), 1.49 (2H, m, O (CH2) 2 CH2 (CH2) 7N(CH3) 2), 1.33 (10H, m, O (CH2) 3(CH2)5(CH2)2N(CH3)2).

8C : 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 HCl (20).

% Yield: 64.

M. p.: 112-114°C.

Found: C, 60.51; H, 7.99; N, 2.71. C24H37BrClNO 1/4H20 requires: C, 60.63; H, 7.95; N, 2.95 %.

8H : 8.10 (1H, d, ArH), 7.84-7.76 (2H, m, ArH), 7.58 (1H, dd, ArH), 7.35 (1H, d, ArH), 7.19 (1H, dd, ArH), 4.07 (2H, t, OCH2 (CH2) 9N (CH2CH3) 2), 3.04 (4H, m, O (CH2) ioN (CH2CH3) 2), 2.94 (2H, t, O (CH2) 9CH2N (CH2CH3) 2), 1.78 (2H, t,

OCH2CH2 (CH2) 8N (CH2CH3) 2), 1.75 (2H, m, O (CH2) $ CH2CH2(CH2CH3)2), 1. 45 (2H, m, OCH2CH2CH2 (CH2) s (CH2) 2N (CH2CH3) 2), 1.29 (10H, m, O (CH2) 3 (CH) s (CH2) 2N (CH2CH3) 2), 1.20 (6H, t, O (CH2) 10N (CH2CH3) 2).

8C : 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-1-naphthyloxy and 5-bromo-1-naphthyloxy derivatives.

Preparation of 4-bromo-1- (10-methylaminodecvloxy) naphthalene HC1 (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 dichloromcthane (50 ml) and partitioned with H2O (2 x 20 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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. (l)] 8H : 8.19 (2H, dd, ArH), 7.59-7.56 (3H, m, ArH), 6.71 (1H, d, ArH), 5.38 (1H, br. s., disappeared on D20 shake, ArOW).

8C : 151.25,132.68,129.38,127.87,126.04,125.59,122.15,113.42,109. 16. b) Preparation of 4-bromo-1- (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.

8H : 8.28 (1H, d, ArH), 8. 14 (1H, d, ArH), 7.65-7.51 (3H, m, ArH), 6.68 (1H, d, ArH), 4.10 (2H, t, OCH2 (CH2) 9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.94-1.82 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.55 (2H, m, O (CH2) 2CH2 (CH2) 7Br), 1.39-1.32 (10H, m, O (CH2) 3(CH2)5(CH2)2Br).

8C : 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-1-(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. C2lH3lBrClNO requires: C, 58.82; H, 7.29; N, 3.27%.

8H : 8.23 (1H, d, ArH), 8.13 (1H, d, ArH), 7.64-7.50 (3H, m, ArH), 6.66 (1H, d, ArH), 4.09 (2H, t, OCH2 (CH2) 9NHCH3), 2.87 (2H, t, O (CH2) gCH2NHCH3), 2.66 (3H, s, O (CH2) 10NHCH3), 1.91-1.87 (4H, m, OCH2CH2 (CH2) 6CH2CH2NHCH3), 1.53 (2H, m, O (CH2) 2CH2 (CH2) 7NHCH3), 1. 38-1. 33 (10H, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

8C : 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-1-(10-methylaminodecyloxy)naphthalene HCl (29), a) Preparation of 5-bromo-1-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. Na2S2O5 (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 NaC03 (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] AH : 10.37 (1H, s, ArCHO), 9.22 (1H, d, ArH), 8.55 (1H, d, ArH), 7.99 (1H, d, ArH), 7.85 (1H, d, ArH), 7.73-7.67 (1H, m, ArH), 7.52-7.46 (1H, m, ArH).

8C : 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-1-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 MgS04, 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 HC1 (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 MgS04, 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)]

5H : 8.20 (1H, d, ArH), 7.84-7.77 (2H, m, ArH), 7.40 (1H, m, ArH), 7.29 (1H, m, ArH), 6.86 (1H, d, ArH), 5.37 (1H, br. s., disappeared on D20 shake, ArOR).

8C : 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-1-(10-bromodecyloxy) naphthalene (28).

The title compound was prepared from 5-bromo-1-naphthol (27) and 1,10-dibromodecane by the General method A.

% Yield: 77.

M. p.: 61-63 °C.

8H : 8.26 (1H, d, ArH), 7.80-7.49 (2H, m, ArH), 7.46-7.43 (1H, m, ArH), 7.31-7.25 (1H, m, ArH), 6.86 (1H, d, ArH), 4.12 (2H, t, OCH2 (CH2) gBr), 3.40 (2H, t, O (CH2) 9CH2Br), 1.94-1.81 (4H, m, OCH2 CH2 (CH2) 6CH2CH2Br), 1.55 (2H, m, OCH2CH2CH2 (CH2) 7Br), 1.42-1.31 (1OH, m, O (CH2) 3 (CH2) 5 (CH2) 2Br).

8C : 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-1-(10-methylaminodecycloxy) naphthalene HC1 (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. C2lH3iBrCINO requires: C, 58.82; H, 7.29; N, 3.27 %.

8H : 8.29 (1H, d, ArH), 7.80-7.76 (2H, m, ArH), 7.46 (1H, t, ArH), 7.26 (1H, m, ArH), 6.85 (1H, d, ArH), 4.11 (2H, t, OCH2(CH2)9NHCH3), 2.88 (2H, t, O (CH2) 9CH2NHCH3), 2.65 (3H, s, O (CH2) io NHCH3), 1.93-1.85 (4H, m, OCH2CH2 (CH2) 6CH2CH2NHCH3), 1.54 (2H, m, OCH2CH2CH2 (CH2) 7NHCH3), 1.33 (10H, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

8C : 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 HCl (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.

8H : 7.77-7.70 (3H, m, ArH), 7.45-7.39 (1H, t, ArH), 7.35-7.31 (1H, t, ArH), 7.16- 7.12 (2H, d, ArH), 4.07 (2H, t, OCH2(CH2)7Br), 3.41 (2H, t, O (CH2) 7CH2Br), 1.89- 1.81 (4H, m, OCH2CH2 (CH2) 4CHzCH2Br), 1.54-1.38 (8H, m, O (CH2) 2 (CHz) 4 (CH2) 2Br).

8C : 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 HC1 (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 1/4H20 requires: C, 69.92; H, 8.80; N, 4.29 %.

8H : 7.76-7.70 (3H, m, ArH), 7.45-7. 39 (1H, m, ArH), 7.34-7.26 (1H, m, ArH), 7.14 (2H, d, ArH), 4.04 (2H, t, OCH2 (CH2) 7NHCH3), 2.89 (2H, t, O (CH2) 7CH2NHCH3), 2.64 (3H, s, O (CH2) 8NHCH3), 1.85-1.79 (4H, m, OCH2CH2 (CH2) 4CH2CH2NHCH3), 1.48-1. 38 (8H, m, O (CH2) 2(CH2)4(CH2)2NHCH3).

5C : 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 HCl (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% Na2S205 (20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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)] 8H : 7.89 (1H, d, ArH), 7.59-7.56 (2H, m, ArH), 7.49 (1H, dd, ArH), 7.15 (1H, dd, ArH), 7.06 (1H, d, ArH), 3.89 (3H, s, ArOCH3).

6C : 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 tetrahydrofuran (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 tetrahydrofuran (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% Na2S205 (20 ml), 2M HC1 (20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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)]

8H : 8.12 (1H, d, ArH), 7.67-7.62 (2H, m, ArH), 7.48 (1H, dd, ArH), 7.14 (1H, dd, ArH), 7.07 (1H, d, ArH), 3.90 (3H, s, ArOCH3).

6C : 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 HC1 (15 ml) and stirred for 30 min. The mixture was extracted with dichloromethane (35 ml), separated, and the organic fraction was partitioned with Ha0 (20 ml) and sat. NaCl (15 ml), dried over MgS04, 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)] 8H : 8. 13 (1H, d, ArH), 7.65-7.60 (2H, m, ArH), 7.42 (1H, d, ArH), 7.10-7.07 (2H, m, ArH), 5.10 (1H, s, disappeared on D20 shake, ArOW).

8C : 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.

8H : 8.12 (1H, d, ArH), 7.63-7.59 (2H, m, ArH), 7.47 (1H, d, ArH), 7.16-7.11 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 9Br), 3.41 (2H, t, O (CH2) 9CH2Br), 1.87-1.80 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.55-1.33 (12H, m, O (CH2) 2(CH2)6(CH2)2Br).

8C : 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). oH : 8.12 (1H, d, ArH), 7.66-7. 58 (2H, m, ArH), 7.46 (1H, d, ArH), 7.15-7.12 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.04 (2H, t, OCH2(CH2)9NHCH3), 2.55 (2H, t, O (CH2) gCH2NHCH3), 2.42 (3H, s, O (CH2) 10NHCH3), 1.83 (2H, m, OCH2CH2 (CH2) 8NHCH3), 1.47-1.30 (14H, m, O (CH2) 2 (CH) 7CH2NHCH3).

8C : 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 HCl (39). a) Preparation of 6-fluoro-2-naphthol (37) I/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 tetrahydrofuran (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 tetrahydrofuran (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 HC1 (20 ml) and sat. NaCl (15 ml).

The organic fraction was dried over MgS04, 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, 9.0mmol). 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 HC1 (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 MgS04, 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)].

5H : 7.70-7.64 (2H, m, ArH), 7.41-7. 37 (1H, d, ArH), 7.25-7.11 (3H, m, ArH), 4.97 (1H, br. s., disappeared on D20 shake, ArOH).

8C : 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- (10-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.

8H : 7.71-7.65 (2H, m, ArH), 7. 39 (1H, dd, ArH), 7.21-7.18 (3H, m, ArH), 4.05 (2H, t, OCH2 (CH2) 9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.88-1.80 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.49-1. 33 (12H, m, O (CH2) 2 (CH2) 6 (CH2) 2Br).

8C : 161.02,157.45,156.83,131.44,129.23,128.75,128.53,128. 41,126.66,120.09, 116.60,116.22,110.94,110.64,106.67,68.01,34.07,32.81,29.45,2 9.34,29.22, 28.73,28.16,26.07. c) Preparation of 6-fluoro-2- (10-methylaminodecyloxy) naphthalene HC1 (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.

EIMS (relative abundance %): MH+ 332.4 (100), 333.3 (22).

8H : 7.71-7.66 (2H, m, ArH), 7.39 (1H, 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) 10NHCH3), 1.86-1.81 (2H, m, OCH2CH2 (CH2) gNHCH3), 1.49-1.31 (14H, m, O (CH2) 2 (CH) 7CH2NHCH3). bC : 161.02,157.46,156.58,131.46,129.23,128.75,128.53,128.46,126. 27,120.11, 116.60,116.22,110.94,110.64,106.67,68.05,52.24,36.57,29.96,2 9.58,29.54, 29.40,29.24,27.35,26.11.

Preparation of6-chloro-2- (10-methvlaminodecvloxv) naphthalene HC1 (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 HC1 (20 ml). The mixture was diluted with H20 (30 ml) and extracted with ethyl acetate (3 x 20 ml).

The combined organics were partitioned with H20 (2 x 15 ml) and sat. NaCl (15 ml), dried over MgS04, 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.

8H : 7.73 (1H, d, ArH), 7.67-7.62 (2H, m, ArH), 7.39-7.35 (1H, dd, ArH), 7.18-7.14 (1H, dd, ArH), 7.08 (1H, d, ArH), 3.90 (3H, s, ArOCH3).

8C : 157.77,132.81,129.45,129.05,128.52,128.21,127.15,126.38,119. 80,105.69, 55.31.

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 HC1 (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 Ha0 (20 ml) and sat. NaCl (15 ml), dried over MgS04, 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 (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- (10-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.

8H : 7.73 (1H, d, ArH), 7.67-7.63 (2H, m, ArH), 7.38-7.34 (1H, dd, ArH), 7.18-7.14 (1H, dd, ArH), 7.09 (1H, d, ArH), 4.05 (2H, t, OCH2(CH2)9Br), 3.41 (2H, t, O (CH2) 9CH2Br), 1.88-1.80 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.52-1.33 (12H, m, O (CH2) 2(CH2)6(CH2)2Br).

8C : 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 HCl (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.

EIMS (relative abundance %): MH+ 348. 4 (100), 350.3 (33).

8H : 7.99 (1H, d, ArH), 7.85-7.79 (2H, m, ArH), 7.47-7.43 (1H, dd, ArH), 7.35 (1H, d, ArH), 7.23-7.19 (1H, dd, ArH), 4.06 (2H, t, OCH2 (CH2) 9NHCH3), 2.40 (2H, t,

O (CH2) 9CH2NHCH3), 2.23 (3H, s, O (CH2) oNHCH3), 1. 81-1. 71 (2H, m, OCH2CH2 (CH2) gNHCH3), 1.43-1.25 (14H, m, O (CH2) 2(CH2)7CH2NHCH3).

8C : 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)hexyl]-1,4-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; N, 5.68. C2oH3iBrCl2N20 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-[2-(6-bromo-2-naphthyloxy) ethyl]-1, 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; N, 5.71. C2oH3o. 5BrCli. 5N20 requires: C, 53.61; H, 6.86; N, 6.25 %.

Preparation of compounds with the general formula Ar-0- (CH2) mS (0) n (CH2) p NHCH3 HC1 where Ar is 6-bromo-2-naphthol.

Preparation of N1-methyl-6-[6-(6-bromo-2-naphtyloxy)hexylsulfinyl]-1-hexana mine Cl 51. a) Preparation of 6-mercapto-1-(t-butyldiphenylsilyloxy) hexane (47).

To a mixture of 6-mercapto-1-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 (11.3ml, 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 H20 (30 ml), 0. 1M HC1 (15ml), and sat. NaCl (15ml). 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%).

8H : 7.68-7.65 (4H, dd, ArH), 7. 39 (6H, m, ArH), 3.66 (2H, t, HS (CH2) sCH2OSi (Ph) 2C (CH3) 3), 2.47 (2H, m, HSCH2 (CH2) 50Si (Ph) 2C (CH3) 3), 1.58-1.53 (4H, m, HSCH2CH2 (CH2) 2CH2CH2 OSi (Ph) 2C (CH3) 3), 1.38-1.27 (5H, m, HS (CH2) 2(CH2)2(CH2)2OSi (Ph) 2C (CH3) 3, lxH exchanged on D20 shake).

8C : 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-1- (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 nitrogen, 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 Ha0 (30 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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%).

8H : 7.88 (1H, d, ArH), 7.68-7.65 (4H, dd, ArH), 7.62-7.54 (2H, m, ArH), 7.48-7.41 (1H, dd, ArH), 7.40-7.36 (6H, m, ArH), 7.16-7.12 (1H, dd, ArH), 7.06 (1H, d, ArH), 4.03 (2H, t, ArOCH2 (CH2) sS (CH2) 60Si (Ph) 2C (CH3) 3), 3.65 (2H, t, O (CH2) 6S (CH2) 5CH2OSi (Ph) 2C (CH3) 3), 2.52 (4H, m, O (CH2) 5CH2SCH2 (CH2) 5OSi (Ph) 2C (CH3) 3), 1.84 (2H, t, OCH2CH2 (CH2) 4S (CH2) 60Si (Ph) 2C (CH3) 3), 1.63-1.47 (10H, m, O (CH2) 2CH2CH2CH2CH2SCH2CH2CH2(CH2)2CH2OSi (Ph) 2C (CH3) 3,1.38-1.33 (4H, m, O (CH2) 3CH2 (CH2) 2S (CH2) 2CH2 (CH2) 30Si (Ph) 2C (CH3) 3), 1.05 (9H, s, O (CH2) 6S (CH2) 60Si (Ph) 2C (CH3) 3). bC : 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]-1-hexanol (49).

To a mixture of (48) (0.35 g, 0.50 mmol) and 4A molecular sieves (1. OOg) in dichloromethane (10 ml) at room temperature under an atmosphere of nitrogen, was added 1M tetrabutylammonium 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 H20 (2 x 20 ml), and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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. C22H3lBrO2S requires: C, 60.13; H, 7.11 %.

8H : 7.90 (1H, d, ArH), 7.65-7.60 (2H, m, ArH), 7.56-7.50 (1H, dd, ArH), 7.17-7. 13 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 5S (CH2) 60H), 3.64 (2H, t, O (CH2) 6S (CH2) 5CH2OH), 2.55-2.49 (4H, m, O (CH2) 5CH2SCH2 (CH2) 50H), 1.85 (2H, m, OCH2CH2 (CH2) 4S (CH2) 60H), 1.65-1.48 (10H, m, O (CH2) 2CH2CH2CH2CH2SCH2CH2CH2(CH2)2CH2OH), 1.42-1.36 (5H, m, O (CH2) 3 CH2 (CH2) 2S (CH2) 2CH2 (CH2) 3OH, 1xH exchanged on D20 shake).

8C : 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]-1-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 H20 (20 ml) and sat. NaCl (15 ml), dried over MgS04, 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. C22H3iBr03S requires: C, 58.02; H, 6.86 %.

8H : 7.90 (1H, d, ArH), 7.65-7.56 (2H, m, ArH), 7.17-7.12 (1H, dd, ArH), 7.08 (1H, 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, OCH2(CH2)2(CH2)3SO(CH2)4CH2CH2OH, 1#H exchanged on D20 shake), 1.58-1.50 (6H, m, O (CH2) 4CH2CH2SOCH2CH2CH2CH2 (CH2) 20H), 1.47-1. 38 (4H, m, O (CH2) 3CH2 (CH2) 2SO (CH2) 2CH2 (CH2) 30H).

8C : 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 Nl-methyl-6-[6-(6-bromo-2-naphthyloxy) hexylsulfinyl]-l-hexan- amine HC1 (51). i/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 NH3, 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 (40ml) and partitioned with 2M NaOH (20ml) and sat. NaCl (15 ml), dried over Na2S04, 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. C23H3sBrClN02S requires: C, 54.71; H, 6.99; N, 2.77%.

8H : 7.90 (1H, d, ArH), 7.65-7.57 (2H, m, ArH), 7.51-7.47 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.06 (2H, t, OCH2 (CH2) 5SO (CH2) 6NHCH3), 2.71- 2.62 (4H, m, O (CH2) 5 CH2SOCH2 (CH2) 5NHCH3), 2.56 (2H, t, O (CH2) 6SO (CH2) 5CH2NHCH3), 2.43 (3H, s, O (CH2) 6 SO (CH2) 6NHCH3), 1.83-1.75 (4H, m, OCH2CH2 (CH2) 4SO (CH2) 4CH2CH2NHCH3), 1.57-1.42 (12H, m, O (CH2) 2(CH2)3CH2SOCH2(CH2)3(CH2)2NHCH3).

8C : 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 Nl-methyl-6-E6-(6-bromo-2-naphthyloxythexYlsulfonyl]-l-hexan amine HC1 (54). a) Preparation of 6-[6-(6-bromo-2-naphthyloxy) hexylsulfonyl]-1-(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. NaHCO3 (15 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgS04, 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%).

8H : 7.89 (1H, 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 (1H, dd, ArH), 7.07 (1H, d, ArH), 4.04 (2H, t, OCH2 (CH2) 5 SO2 (CH2) 6OSi (Ph) 2C (CH3) 3), 3.65 (2H, t, O (CH2) 6SO2 (CH2) 5CH20Si (Ph) 2C (CH3) 3), 2.95-2.87 (4H, m, O (CH2) 5CH2SO2CH2 (CH2) 5OSi (Ph) 2C (CH3) 3), 1.86-1.83 (6H, m, OCH2 (CH2) 2 (CH2) 3 SO2 (CH2) 4CH2CH2OSi (Ph) 2C (CH3) 3), 1.56-1.54 (6H, m, O (CH2) 4CH2CH2SO2CH2CH2CH2CH2 (CH2) 20Si (Ph) 2C (CH3) 3), 1.40 (4H, m, O (CH2) 3CH2 (CH2) 2SO2 (CH2) 2CH2 (CH2) 30Si (Ph) 2C (CH3) 3), 1.05 (9H, s, O(CH2)6SO2(CH2)6OSi(Ph)2C(CH3)3).

8C : 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]-1-hexanol (53).

To a mixture of (52) (1.05 g, 1.50 mmol) and 4A molecular sieves (1. Og) in dichloromethane (15 ml) at room temperature under an atmosphere of nitrogen, was added 1M tetrabutylammonium 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 MgS04, 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.

8H : 7.91 (1H, d, ArH), 7.66-7.57 (2H, m, ArH), 7.50 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 7.07 (1H, d, ArH), 4.06 (2H, t, OCH2 (CH2) 5SO2 (CH2) 60H), 3.65 (2H, t, O (CH2) 6SO2 (CH2) 5CH20H), 3.00-2.92 (SH, m, O (CH2) 5CH2SO2CH2 (CH2) soH7 1#H disappeared on D20 shake), 1.91-1.83 (6H, m, OCH2fCH2) 2 (CH2) 3SO2 (CH2) 4CH2CH2OH), 1.61-1.42 (10H, m, O (CH2) 3 (CHi2CH2SO2CH2 (CHi3 (CH2) 20H).

8C : 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 Nl-methyl-6-[6-(6-bromo-2-naphthyloxy) hexylsulfonyl]-l-hexan- amine HCl (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 Na2S04, 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. C23H35BrClN02Sl/4H20 requires: C, 52.57; H, 6.81; N, 2.67 %.

8H : 7.90 (1H, d, ArH), 7.66-7.50 (2H, m, ArH), 7.47 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 4.06 (2H, t, OCH2 (CH2) 5SO2 (CH2) 6NHCH3), 2.97 (4H, m, O (CH2) 5CH2SO2CH2 (CH2) 5NHCH3), 2.56 (2H, t, O (CH2) 6SO2 (CH2) 5CH2NHCH3), 2.43 (3H, s, O (CH2) 6SO2 (CH2) 6NHCH3), 1.89-1.82 (6H, m, OCH2CH2 (CH2) 2CH2CH2SO2CH2CH2 (CH2) 4NHCH3), 1.58-1.35 (10H, m, O (CH2) 2(CH2)2(CH2) 2 SO2 (CH2) 2 (CH2) 3CH2NHCH3).

8C : 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-naphthyloxy)hexylsulfinyl]-1-propa n- amine HC1 (58). 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 H20 (25 ml) and sat. NaCl (15 ml).

The organic fraction was dried over MgS04, 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.: 45-46 °C.

8H : 7.90 (1H, d, ArH), 7.65-7.57 (2H, m, ArH), 7.50-7.46 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.19-4.12 (2H, q, O (CH2) 6S (CH2) 2C02CH2CH3), 4.05 (2H, t, OCH2 (CH2) 5 S (CH2) 2CO2CH2CH3), 2.82-2.76 (2H, t, O (CH2) 6SCH2CH2CO2CH2CH3), 2.62-2.53 (4H, m, O (CH2) 5CH2SCH2CH2CO2CH2CH3), 1.87-1.82 (2H, m, OCH2CH2 (CH2) 4S (CH2) 2C02CH2CH3), 1.67-1.59 (2H, m, O (CH2) 4CH2CH2S (CH2) 2CO2CH2CH3), 1.53-1.47 (4H, m, O (CH2) 2 (CH2) 2 (CH2) 2 S (CH2) 2CO2CH2CH3), 1.26 (3H, t, O (CH2) 6S (CH2) 2CO2CH2CH3).

5C : 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 HC1 (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 Ha0 (20 ml) and sat. NaCl (15 ml), dried over MgSO4, 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.

8H : 7.90 (1H, d, ArH), 7.65-7.49 (2H, m, ArH), 7.46 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 5S (CH2) 30H), 3.76 (2H, t, O (CH2) 6S (CH2) 2CH2OH), 2.67-2.53 (4H, m, O (CH2) 5CH2SCH2 (CH2) 2OH), 1.90- 1.80 (4H, m, OCH2CH2 (CH2) 4SCH2CH2CH2OH), 1.70-1.62 (3H, m, O (CH2) 4CH2CH2 S (CH2) 30H, 1xH disappeared on D20 shake), 1.55-1.46 (4H), m, O (CH2) 2(CH2)2(CH2) 2S (CH2) 30H).

8C : 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]-1-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 MgS04, filtered, and concentrated in vacuo to give an amorphous solid upon exposure to high vacuum, 0.74 g (95%).

M. p.: 110-112 °C.

8H : 7.90 (1H, d, ArH), 7.65-7.56 (2H, m, ArH), 7.50-7.46 (1H, dd, ArH), 7.17-7.12 (1H, dd, ArH), 7.07 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 5SO (CH2) 30H), 3.75 (2H, t, O (CH2) 6SO (CH2) 2CH20H), 3.26 (1H, br. s, disappeared on D20 shake, O (CH2) 6SO (CH2) 30H), 2.88-2.66 (4H, m, O (CH2) 5CH2SOCH2 (CH2) 20H), 2.11- 2.05 (2H, m, O (CH2) 6SOCH2CH2CH2OH), 1.86-1.82 (4H, m, OCH2CH2 (CH2) 2CH2CH2SO (CH2) 30H), 1.57 (4H, m, O (CH2) 2(CH2)2(CH2)2SO (CH2) 30H).

#C : 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 Nl-methyl-3-[6-(6-bromo-2-naphthyloxy) hexylsulfinyl]-l-propan- amine HCl (58). i/Preparation 3-[6-(6-bromo-2-naphthyloxy) hexylsulfinyl] 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 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. 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. C2oH29BrClNO2S requires: C, 51.90; H, 6.31; N, 3.03%.

8H : 7.90 (1H, d, ArH), 7.65-7.57 (2H, m, ArH), 7.50 (1H, dd, ArH), 7.17-7.13 (1H, dd, ArH), 7.08 (1H, d, ArH), 4.05 (2H, t, OCH2 (CH2) 5SO (CH2) 3NHCH3), 2.78-2.72 (6H, m, O (CH2) 5CH2SO CH2CH2CH2NHCH3), 2.45 (3H, s, O (CH2) 6SO (CH2) 3NHCH3), 1.99-1.96 (2H, m, O (CH2) 6SO CH2CH2CH2NHCH3),

1.86-1.80 (4H, m, OCH2CH2 (CH2) 2CH2CH2SO (CH2) 3NHCH3), 1.57 (4H, m, O (CH2) 2 (CHi2 (CH2) 2SO (CH2) 3NHCH3).

5C : 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.

BENZOLIOXOLE DERIVATIVES.

Preparation ofNl-methyl-10-benzo [b oxol-4-vloxy-l-decanamine HC1 (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 H20), 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 conc. HC1. 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)].

8H : 13. 26 (1H, br. s., disappeared on D20 shake, C02H), 8.07 (1H, s, OCH=CH2), 3.01 (2H, t, CHa), 2.71 (2H, t, CH2), 2.31 (2H, m, CH2).

8C : 199.49,170.78,161.42,150.19,117.95,117.23,36.51,23.23,22. 39. b) Preparation of 4-hydroxybenzo [boxole-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)].

8H : 8. 66 (1H, s, ArH), 7.30 (1H, t, ArH), 7.18 (1H, d, ArH), 6.74 (1H, d, ArH), 4.23 (1H, br. s., ArOH, disappeared on D2O shake).

8C : 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 HCl (2x80 ml) and sat. NaCl (2 x 30 ml), dried over MgS04, filtered, and concentrated 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)].

8H : 7. 51 (1H, d, ArH), 7.12 (2H, d, ArH), 6.86 (1H, d, ArH), 6.63 (1H, m, ArH), 6.23 (1H, br. s., disappeared on D2O shake, ArOH).

8C : 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.

8H : 7.52 (1H, d, ArH), 7.22-7.10 (2H, m, ArH), 6.87 (1H, d, ArH), 6.66 (1H, d, ArH), 4.09 (2H, t, OCH2 (CH2) 9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.90-1.80 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.47-1.31 (12H, m, O (CH2) 2 (CH) 6 (CH2) 2Br).

6C : 156.26,153.15,143.34,124.89,117.84,104.37,104.10,103.97,68.3 0,34.07, 32.81,29.45,29.36,29.24,28.75,28.16,26.07. e) Preparation of Nl-methyl-10-benzotb] 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. Ci9H3oClN021/4H20 requires: C, 66.26; H, 8.93; N, 4.07 %.

8H : 7.92 (1H, d, ArH), 7.25-7.21 (2H, m, ArH), 6.92 (1H, d, ArH), 6.81 (1H, d, ArH), 4.13 (2H, t, OCH2 (CH2) 9NHCH3), 2.83 (2H, t, O (CH2) 9CH2NHCH3), 2.52 (3H, s, O (CH2) 10NHCH3), 1.80 (2H, m, OCH2CH2(CH2)8NHCH3), 1.61 (2H, m, O (CH2) 8CH2CH2NHCH3), 1.48 (2H, m, OCH2CH2CH2 (CH2) 7NHCH3), 1.30 (1OH, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

8C : 155.58,152.58,144.49,125.23,117.18,104.53,104.19,103.90,67.8 7,48.11, 32.24,28.90,28.77,28.67,28.52,25.92,25.54,25.32.

Preparation of Nl-methyl-10 (7-bromobenzorblfuran-4-vloxv ! l-decanamine HC1 (66). 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, (petroleum 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 H20 (2xi5 ml) and sat. NaCl (15 ml). The organic fraction was dried over MgS04, filtered, and concentrated in vacuo to give a pale brown solid. The solid was purified by flash column chromatography eluting with (petroleum 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.

8H : 7.54 (1H, d, ArH), 7.35 (1H, d, ArH), 7.04 (1H, d, ArH), 6.89 (1H, d, ArH), 5.79 (1H, br. s., disappeared on Da0 shake, ArOH).

8C : 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.

8H : 7.55 (1H, d, ArH), 7.44-7.41 (1H, d, ArH), 7.14-7.10 (1H, d, ArH), 6.86 (1H, d, ArH), 4.22 (2H, t, OCH2 (CH2) 9Br), 3.41 (2H, t, O(CH2)9CH2Br), 1.85 (4H, m, CH2CH2 (CH2) 6CH2CH2Br), 1.57 (2H, m, OCH2CH2CH2 (CH2) 7Br), 1.33 (10H, m, O (CH2) 3(CH2)(CH2)2Br).

8C : 155.70,149.43,144.74,128.44,121.13,108.12,107.64,104.53,73.6 2,34.09, 32.81,30.15,29.43,29.34,28.73,28.16,25.95. c) Preparation of Nl-methyl-10-(7-bromobenzo [b3furan-4-yloxy) l-decanamine HC1 (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 %.

8H : 8.05 (1H, d, ArH), 7.52-7.45 (1H, d, ArH), 7.33-7.30 (1H, d, ArH), 7.19 (1H, d, ArH), 4.30 (2H, t, OCH2 (CH2) gNHCH3), 2.83 (2H, t, O (CH2) 9CH2NHCH3), 2.52 (3H, s, O (CH2) ioNHCH3), 1.78 (2H, m, OCH2CH2(CH2)8NHCH3), 1.62 (2H, m, O (CH2) 8CH2CH2NHCH3), 1.52 (2H, m, OCH2CH2CH2 (CH2) 7NHCH3), 1.30 (10H, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

8C : 155.26,148.79,146.15,128.16,120.11,107.51,106.78,104.87,72.7 6,48.11, 32.24,29.55,28.88,28.75,28.70,28.52,25.93,25.39,25.32.

Preparation ofNl-methyl-10-benzo [blfuran-5-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. NaCl (50 ml), dried over MgS04, filtered, and concentrated in vacuo to give the crude decarboxylated product as an oil (1.30 g). The aqueous phase was acidified with cone. HCl to precipitate the crude acid. Recrystallisation 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 HC1 (200 ml), and filtered. The filtrate was extracted with chloroform (3x100 ml) and the combined organics were partitioned with Ha0 (80 ml) and sat. NaCl (50 ml). The residue was purified by flash column chromatography eluting with (petroleum 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)].

8H : 7.57 (1H, d, ArH), 7.40-7. 37 (lH, d, ArH), 7.04 (1H, d, ArH), 6.92-6.87 (1H, d, ArH), 6.69 (1H, s, ArH), 3.82 (3H, s, ArOCH3).

8C : 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 conc. HC1. The aqueous mixture was extracted with ethyl acetate (2x100 ml) and the combined organics were partitioned with 2M HGl (2x50 ml) and sat. NaCl (50 ml). The organic fraction was dried over MgS04, 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)].

8H : 7.58 (1H, d, ArH), 7.36-7.33 (1H, d, ArH), 7.00 (1H, d, ArH), 6.83-6.79 (1H, d, ArH), 6.65 (1H, s, ArH), 5.30 (1H, br. s., disappeared on D20 shake, ArOW).

8C : 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.

8H : 7.57 (1H, s, ArH), 7.36 (1H, d, ArH), 7.04 (1H, d, ArH), 6.92-6.87 (1H, d, ArH), 6.69 (1H, d, ArH), 3.97 (2H, t, OCH2 (CH2) 9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.90-1.74 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.47-1.32 (12H, m, O (CH2) 2 (CH2) 6 (CH2) 2Br).

8C : 155.40,149.86,145.62,127.90,113.62,111.71,106.67,104.38,68.7 9,34.07, 32.81,29.45,29.36,28.73,28.16,26.07. e) Preparation of Nl-methyl-10-benzo [b] furan-5-yloxy-l-decanamine HC1 (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.

8H : 7.90 (1H, d, ArH), 7.47-7.43 (1H, d, ArH), 7.14 (1H, d, ArH), 6.90-6.87 (1H, d, ArH), 6.85 (1H, s, ArH), 3.97 (2H, t, OCH2(CH2)9NHCH3), 2.81 (2H, t, O (CH2) 9CH2NHCH3), 2.49 (3H, s, O (CH2) 10NHCH3), 1.72 (2H, m, OCH2CH2 (CH2) 8NHCH3), 1.61 (2H, m, O (CH2) 8CH2CH2NHCH3), 1.28 (12H, m, O (CH2) 2 (CHi6 (CH2) 2NHCH3).

8C : 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[b]furan-7-yloxy-1-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)].

8H : 13.31 (1H, br. s., disappeared onD20 shake, CO2g), 7.38 (1H, s, ArH), 7.08-6.96 (2H, m, ArH), 6.84-6.80 (1H, d, ArH), 3.69 (3H, s, ArOCH3).

8C : 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.

8H : 7.60 (1H, d, ArH), 7.19-7.10 (2H, m, ArH), 6.78-6.75 (1H, d, ArH), 6.73 (1H, d, ArH), 3.97 (3H, s, ArOCH3).

8C : 145.53,144.92,144.29,129.09,123.43,113.48,106.86,106.25,55.9 6. 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.

5H : 7.58 (1H, d, ArH), 7.17-7.05 (2H, m, ArH), 6.86-6.82 (1H, d, ArH), 6.75 (1H, d, ArH), 6.02 (1H, br. s., disappeared on D20 on shake, ArOI).

8C : 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.

8H : 7.61 (1H, d, ArH), 7.19-7.09 (2H, m, ArH), 6.80-6.77 (1H, d, ArH), 6.74 (1H, d, ArH), 4.16 (2H, t, OCH2 (CH2) 9Br), 3.39 (2H, t, O (CH2) 9CH2Br), 1.90-1.78 (4H, m, OCH2CH2 (CH2) 6 CH2CH2Br), 1.52-1.28 (12H, m, O (CH2) 2 (CH2) 6 (CH2) 2Br).

8C : 145.01,144.80,144.44,129.13,123.38,113.24,107.37,106.83,68.8 9,34.00, 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-1-decanamine HCl (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; N, 4.26. C19H30ClNO2 1/4H20 requires: C, 66.26; H, 8.93 ; N, 4.07 %.

8H : 7.94 (1H, 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) 9CH2NHCH3), 2.52 (3H, s, O (CH2) ioNHCH3), 1.81 (2H, m, OCH2CH2 (CH2) 8NHCH3), 1.62 (2H, m, O (CH2) gCH2CH2NHCH3), 1.49 (2H, m, O (CH2) 2CH2 (CH2) 7NHCH3), 1.31 (IOH, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

6C : 145.45,145.20,144.84,129.43,123.36,113.08,107.73,106.74,68.3 0,48.00, 32.08,28.63,28.58,28.50,28.27,25.68,25.29,25.07.

BENZOrb] THIOPHENE DERIVATIVES Preparation of N1-methyl-10-benzo[b]thiol-4-yloxy-1-decanamine HCl (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 sulfur (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 conc. HC1 and extracted with dichloromethane (3x30 ml). The organics were combined and partitioned with sat. NaCl (20 ml), dried over MgS04, 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. (")].

8H : 7.48-7.45 (2H, m, ArH), 7. 36 (1H, d, ArH), 7.24-7.16 (1H, m, ArH), 6.72-6.69 (1H, d, ArH), 5.29 (1H, br. s., disappeared on D20 shake, ArOH).

8C : 150.69,141.83,129.18,125.25,125.04,119.64,115.22,108.75. b) Preparation of 4- (10-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.

8H : 7.52-7.49 (1H, d, ArH), 7.45-7.43 (1H, d, ArH), 7.32-7.22 (2H, m, ArH), 6.74- 6.71 (1H, d, ArH), 4.10 (2H, t, OCH2(CH2)9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.90- 1.79 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.54-1.49 (2H, m, O (CH2) 2CH2 (CH2) 7Br), 1.32-1.29 (10H, m, O (CH2) 3 (CH2) s (CH2) 2Br).

8C : 154.55,141.24,130.65,125.25,124.33,120.66,114.57,104.58,68.0 7,34.05, 32.79,29.43,29.34,29.24,28.81,28.73,28.14,26.11. c) Preparation of Nl-methyl-10-benzo [b] thiol-4-yloxy-l-decanamine HC1 (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; N, 3.70. ClsH30ClNOS requires: C, 64.11; H, 8.49; N, 3.93 %.

8H : 7.52-7.50 (1H, d, ArH), 7.46-7.43 (1H, d, ArH), 7.32-7.22 (2H, m, ArH), 6.75- 6.72 (1H, d, ArH), 4.10 (2H, t, OCH2(CH2)NHCH3), 2.55 (2H, t, O (CH2) 9CH2NHCH3), 2.42 (3H, s, O (CH2) 10NHCH3), 1.87 (2H, m, OCH2CH2 (CH2) 8NHCH3), 1.50 (2H, m, O (CH2) gCH2CH2NHCH3), 1.39-1.30 (12H, m, O (CH2) 2 (CH2) 6 (CH2) 2NHCH3)- #C : 154.57,141.24,130.65,125.25,124.31,120.70,114.55,104.60,68.1 0,52.22, 36.57,29.94,29.52,29.38,29.25,27.35,26.15.

Preparation of Nl-methyl-10- (7-bromobenzofblthiol-4-yloxy) 1-decanamine HC1 (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 H20 (2x20 ml) and sat. NaCl (15ml). The organic fraction was dried over MgS04, filtered, and concentrated in vacuo to give a black oil. The oil was purified by flash column chromatography eluting with (petroleum ether: ethyl acetate, 50: 1). Fractions containing the product were combined and concentrated in vacuo to give compound (80) as a colourless oil, 0.53 g (87%).

8H : 7.58 (1H, d, ArH), 7.39-7. 34 (2H, m, ArH), 6.65-6.61 (1H, d, ArH), 4.07 (2H, t, OCH2 (CH2) 9Br), 3.40 (2H, t, O (CH2) 9CH2Br), 1.90-1.79 (4H, m, OCH2CH2 (CH2) 6CH2CH2Br), 1.50-1.29 (12H, m, O (CH2) 2(CH2)6(CH2)2Br).

5C : 153.91,142.62,131.37,127.67,125.32,121.83,106.49,105.98,34.0 3,32.79, 29.42,29.33,29.29,29.13,28.72,28.14,26.06. b) Preparation of Nl-methyl-10- (7-bromobenzo [b] thiol-4-yloxy) 1-decanamine HC1 (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 %.

8H : 7.60-7.58 (1H, d, ArH), 7.38-7. 35 (2H, m, ArH), 6.65-6.62 (1H, d, ArH), 4.07 (2H, t, OCH2 (CH2) 9NHCH3), 2.55 (2H, t, O (CH2) 9CH2NHCH3), 2.42, (3H, s, O (CH2) 10NHCH3), 1.90-1.80 (2H, m, OCH2CH2 (CH2) sNHCH3), 1.49-1.44 (4H, m, O (CH2) 2CH2 (CH2) 5CH2CH2NHCH3), 1.30 (10H, m, O (CH2) 3(CH2)5(CH2)2NHCH3).

8C : 153.92,142.62,131.39,127.67,125.30,121.85,106.50,105.98,68.4 4,52.22, 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. glabrata, C. krusei, C. tropicalis, Cryptococcus neoformans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton quinckeanufn.

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 [A1 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 Zg/ml and diluted to four times the top test concentration in RPMI.

The Test Method The test is carried out in microtitre plates. 100 u, l of broth is added to all the wells and 100 al 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 IC50 values for various species of Candida, as well as for Cryptococcus neoformans, Saccharomyces cerevisiae, Aspergillus fumigatus and Trichophyton quinkeanum. The known anti- fungal agents amphoteracin and fluconazole are included for comparison.

Table 2: Pathogen MIC & IC50 (µg/ml) Candida Candida Candida Candida Candida Candida Candida Crytococcus Sacch. Aspergillus Trichophyton albicans albicans albicans parapsilosis glabrata krusei tropicalis neoformans cerevisiae fumigatus quinkeanum 128101 128181 131001 173003 133001 128107 138001 132002 136001 127001 184002 Example MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 Ampho- 0.06 0.06 1 0.5 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.13 0.06 0.06 0.06 teracin Fluconazole 128 8 128 128 128 32 1 0.06 128 16 128 32 128 0.13 16 1 128 2 128 128 32 2 Example 1 0.13 0.13 0.25 0.13 0.25 0.13 128 0.25 0.06 0.06 0.06 0.06 0.50 0.50 0.13 0.13 0.06 0.06 0.25 0.25 0.25 0.13 Example 2 0.50 0.25 0.06 0.06 0.5 0.25 0.50 0.25 0.25 0.25 0.06 0.06 1 1 0.13 0.13 0.13 0.13 0.25 0.13 0.13 0.06 Example 3 0.50 0.25 1 1 0.50 0.25 1 0.25 0.25 0.13 0.25 0.06 0.50 0.50 0.25 0.13 0.25 0.13 1 0.25 0.50 0.25 Example 4 1 0.5 1 0.25 1 0.5 128 0.5 0.13 0.13 0.25 0.06 2 2 0.25 0.25 0.5 0.25 0.13 0.13 0.25 0.25 Example 5 1 1 1 0.5 1 0.5 2 1 0.25 0.25 0.25 0.08 1 1 0.5 0.5 0.5 0.5 1 0.5 0.5 0.25 Example 6 1 1 1 0.25 2 1 4 0.5 0.5 0.5 0.5 0.25 1 1 0.25 0.25 0.5 0.5 1 1 0.5 0.5 Example 7 1 1 1 1 2 2 2 0.13 0.6 0.5 0.5 0.25 2 2 0.5 0.25 1 1 1 0.26 2 1 Example 8 1 1 1 0.5 2 1 2 1 0.6 0.5 0.5 0.5 1 1 0.5 0.5 1 0.5 1 1 0.5 0.5 Example 9 4 2 4 2 4 4 8 2 0.5 0.5 0.5 0.25 2 0.5 0.5 0.25 1 1 1 1 0.125 0.06 Example 10 8 4 4 1 4 4 8 2 1 1 0.50 0.25 4 2 0.50 0.13 0.50 0.50 4 1 1 0.25 Example 11 4 2 2 0.60 4 2 4 1 2 1 1 0.5 4 4 2 1 2 1 2 1 1 0.5 Example 12 4 4 8 2 4 2 128 4 2 0.5 1 0.5 64 4 1 0.25 2 1 1 1 1 0.5 Example 13 4 4 4 4 8 8 8 4 2 2 1 0.5 4 4 1 0.5 2 1 2 0.25 2 1 Example 14 8 2 8 2 16 8 16 4 4 1 2 0.25 16 4 4 1 4 2 2 1 2 1 Candida Candida Candida Candida Candida Candida Candida Cryptococcus Sacch. Aspergillus Trichophyton albicans albicans albicans parapsilosis glabrata krusel tropicalis neoformans cerevisiae fumigatus quinkeanum 128101 128181 131001 173003 133001 128107 138001 132002 136001 127001 184002 Example MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 MIC IC50 Example 15 16 4 4 1 8 8 16 4 4 2 2 0.50 16 4 0.25 0.25 4 4 4 1 2 1 Example 16 16 4 8 1 8 4 8 4 4 4 1 0.5 8 4 2 1 2 2 4 0.5 4 1 Example 17 8 8 8 4 8 4 128 4 8 2 1 0.25 128 128 1 1 4 1 8 0.6 2 0.25 Example 18 8 4 8 4 8 8 16 4 4 2 2 0.5 8 4 0.5 0.5 4 4 2 0.25 4 2 Example 19 8 4 8 4 8 8 8 2 4 4 2 0.25 8 8 1 1 2 2 4 1 4 2 Example 20 128 64 32 1 128 64 128 64 0.5 0.25 0.25 128 128 64 0.25 0.13 0.5 0.25 0.5 0.13 0.06 0.06 Example 21 8 4 4 4 8 8 16 4 4 2 2 1 8 8 1 1 4 4 4 2 4 4 Example 22 128 16 128 8 128 64 128 128 4 2 2 0.5 128 128 1 1 2 1 128 16 0.5 0.25 Example 23 16 8 8 8 16 16 16 4 8 8 4 2 8 8 4 2 8 8 16 4 8 8 Example 24 32 16 16 4 32 32 16 8 8 8 8 2 8 8 4 1 16 16 128 16 8 4 Example 25 128 32 128 8 128 64 128 128 16 4 16 1 128 128 1 0.50 32 8 64 2 4 1 Example 26 128 16 128 4 128 128 128 16 8 4 2 2 128 32 2 2 128 4 128 32 8 8 Example 27 128 16 16 4 128 128 32 8 8 8 8 2 128 8 2 1 16 16 128 128 32 16 Example 28 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 0.5 128 128 128 128 128 128

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