IE890140L

IE890140L - Process for preparing 1,5-benzothiazepine derivatives

Info

Publication number: IE890140L
Application number: IE890140A
Authority: IE
Inventors: Hirozumi Inoue; Tsunehiro Harada; Masaaki Nagasawa
Original assignee: Therma Tru Corp
Priority date: 1988-01-19
Filing date: 1989-01-18
Publication date: 1989-07-19
Also published as: DK732088D0; IT8919080A0; JPH01186875A; FR2626000A1; KR890011867A; FI93010C; KR940011461B1; IE61200B1; IT1227852B; FI93010B; IL88849A0; DK732088A; FI885985A; FR2626000B1

Abstract

The invention relates to a process for preparing 1,5-benzothiazepine derivatives of formula: <IMAGE> in which R<1> to R<6> are defined, or one of their addition salts with pharmaceutically suitable acids, which have hypotensive, cerebral coronary vasodilatory and/or platelet aggregation inhibitory activities, which consist in subjecting a propionamide derivative of formula: <IMAGE> in which X is a bromine or iodine atom, to an intramolecular cyclisation. [FR2626000A1]

Description

612 00 FP-1717 Process for preparing 1,5-benzothiazepinie derivatives This invention relates to a process for preparing 1,5-5 benzothiazepine derivatives. More particularly, it relates to a process for preparing 1,5-benzothiazepine derivatives of the formula: wherein is a lower alkyl or lower alkoxy group; R2 is hydrogen atom or a lower alkanovl group; one of and R4 is halogen atom or a lower 15 alkyl group and the other is hydrogen atom; and each of R® and R® is a lower aikvl group, and pharmaceutically acceptable acid addition salts thereof.

The 1,5-benzothiazepine derivatives (I) and pharmaceutically acceptable acid addition salts thereof are useful pharmaceutical 20 compounds having an excellent hypotensive activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among these compounds, the compound (I) in which R2 is hydrogen atom is also useful as an intermediate for synthesis of other pharmaceutical compounds.

It is hitherto known that the above-mentioned 1,5-benzothiazepine derivatives can be prepared by reacting the corresponding N-unsubstituted-1 .S-benzothiazepine derivatives with a di(lower 1 a alkyDaminoethyl halide [Japanese Patent Publication (unexamined) No. 225174/1984 and 20871/1985].

As a result of various investigation, we have now found a novel and industrial process for preparing the 1,5-benzothiazepine derivative 5 (I). Namely, according to the present invention, the 1,5-benzothiazepine derivatives (I) or pharmaceutically acceptable acid addition salts thereof can be prepared by condensing a propionic acid derivative of the formula: wherein X is bromine atom or iodine atom, R1 - R4 are the same as defined above, or a reactive derivative thereof and N,N-di(lower alkyl)ethylenediamine to give a propionarnide derivative of the formula: wherein ~ R§ and X are the same as defined above, and subjecting 2 5 the propionarnide derivative to intramolecular cyclization.

The condensation reaction of the propionic acid derivative (II) or a reactive derivative thereof and N,N-di(lower alkyl)ethylenediamine can be carried out according to a conventional manner of peptide synthesis. For example, when a reactive derivative of the compound (II) is used as 30 a starting compound, the condensation reaction may be carried out in the presence of a conventional acid acceptor (e.g., di or tri(lower alkyl)amine, N-(lower alkyl)morpholine, di(lower alkyl)aminopyridine, alkali metal bicarbonate or alkali metal carbonate). Suitable examples of the reactive derivative of the compound (II) include a corresponding 2 acid halide (e.g., chloride, bromide), mixed anhydride (e.g., a mixed anhydride of the compound (II) with ethoxycarboxvlic, t-butoxvcarboxvlic and benzyloxycarboxylic acid) or active ester (e.g., p-nitrophenvl, 2,4-dinitrophenyl, N-hydroxy~benzotriazole, phthalimide, 5 succimide, piperidine, 2-pyridine, 2-pyrrolidon-1-yl and diethvlchlorophosphinate ester). On the other hand, when a free propionic acid derivative (II) is used as a starting compound, the condensation reaction may be carried out in the presence of a conventional condensing agent (e.g., dicvclohexylcarbodiimide, 10 diethvlchlorophosphate, ethoxyacetylene, l-methyl-2-halopyridinium halide, carbonvldiimidasiole). It is preferred to carry out the above-mentioned reactions in an inert solvent (e.g., dichloromethane, dioxane, toluene, tetrahydrofuran, dimethylformamide and so forth) between a cooling temperature and a heating temperature, especially at a 15 temperature of -20 to 100 "G.

The intramolecular cvclization of the thus-obtained propionarnide derivative (III) can be carried out in the presence of a catalyst and a base. Suitable examples of the catalyst include transition metal catalysts such as copper powder, copper compounds (e.g., cuprous 20 oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, cuprous iodide, cupric iodide, copper carbonate and the like), palladium compounds (e.g., palladium acetate, tetrakis(triphenvlphosphine) palladium complex and the like), nickel compounds (e.g., nickel chloride, nickel bromide, tetrakis(triphenyl-25 phosphine) nickel complex and the like), rhodium compounds (e.g., rhodium chloride, rhodium acetate and the like) and platinum compounds (e.g., platinum (IV) chloride, platinum (IV) bromide and the like). Inorganic bases (e.g., an alkali metal bicarbonate, an alkali metal carbonate and the like), and organic bases (e.g., a tri(lower 30 alkyl)amine, a di(lower alkyl)arylamine, an N-(lower alkyl)rnorpholine and the like) may be preferably used in the reaction. It is preferred to carry out the reaction in an inert solvent (e.g., chlorobenzene, toluene, dimethyl sulfoxide and the like) under heating, especially at a temperature of 50 to 200"C. 3 The thus-obtained 1,5-benzothiazepine derivative (I) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt thereof, for example, by treating the compound with an acid. Examples of the pharmaceutically acceptable acid addition 5 salts include inorganic acid addition salts (e.g., hydrochloride, hvdrobromide, hvdroiodide, perchlorate, sulfate, phosphate), organic acid addition salts (e.g., oxalate, maleate, tartrate, methanesulfonate), and so forth.

Since the above-mentioned reaction of the present invention 10 proceeds without racernization, the compound (I) can be obtained in an optical form by the use of an optically active propionic acid derivative (H).

According to the present invention as mentioned above, the preferred examples of the 1,5-benzothiazepine derivative obtained in 15 the present invention include the compounds of the formula (I) in which r1 is an alkyl or alkoxy group of one to 6 carbon atoms; R2 is hydrogen atom or an alkanoyl group of 2 to B carbon atoms; one of R3 and R4 is a halogen atom or an alkyl group of one to 6 carbon atoms and the other is hydrogen atom; and each of R^ and r6 is an alkyl group of one to 6 20 carbon atoms.

More preferred examples include those of the formula (l) in which R1 is an alkyl or alkoxy group of one to 4 carbon atoms; R2 is hydrogen atom or an alkanoyl group of 2 to 4 carbon atoms; one of R^ and R4 is chlorine atom or an alkyl group of one to 4 carbon atoms and the other 25 is hydrogen atom; and each of R^ and R® is an alkyl group of one to 4 carbon atoms.

While the compound (I) can exist in the form of cis or trans isomer or optical isomer [e.g., (+)-cis, (-)-cis, (+)~trans and (-)-trans) due to the two asymmetric carbon atoms involved therein, all of these isomers and 30 a mixture thereof are included within the scope of the invention. Among these isomers, however, the cis isomer of the compound (I) is preferred for the medicinal use.

The starting compound (II) of the present invention is prepared, for example, by reacting a thiophenol derivative of the formula: 4 SH X (IV) wherein the R3, r4 and X are the same as defined above, with glycidate compound of the formula: wherein R® is an lower alkyl group and R^ is the same as defined above, hydrolyzing the product, and if required, acvlating the hydroxy group of the resulting product in a conventional manner.

Further, when the starting compound (II) is a racemic mixture, 15 optically active substance thereof can be obtained, for example, by the steps of (A) reacting the compound (II) in which is hydrogen atom, with a reactive derivative of an optically active acid, (e.g., 1-(2-naphthyl-sulfonyl)pyrrolidin-2-carbonyl chloride) or making diastereoisomeric salts of the compound (II) with an optically active base (e.g., (p-hydroxyphenyl)glycine methyl ester, cinchonidine, ephedrine, a-methylbenzylamine, various amino acids or esters thereof and the like) (B) separating two kinds of diastereomers of the product according to a conventional manner (e.g., column chromatography, fractional crystallization), or two kinds of diastereoisomeric salts by fractional crystallization (C) hydrolyzing the diastereomer or recovering the optically active compond (II) from diastereoisomeric salts, and (D) if required, acvlating hydroxy group at 2-position thereof.

Example i (1) A mixture of 10g of sodium S-chloro-2-iodobenzenesulfonate, 10g of phosphorus pentachloride and 5ml of phosphorus oxychloride is stirred at room temperature for one hour and refluxed for one hour. r (V) After the reaction, the mixture is condensed under reduced pressure, and the residue is recrystallized from n-hexane to give 8.66g of 5-chloro-2-iodobenzenesulfonyl chloride.

M.p. 66 to 68°G 8.56g of the product obtained above are added to a mixture of ice and 9.47ml of conc. sulfuric acid, and 8.45g of zinc powder are added thereto under ice-cooling. The mixture is stirred for one hour and heated gradually for 2 hours and refluxed. Three g of zinc powder is further added thereto, and the mixture is allowed to stand at room 10 temperature for cool down. The mixture is extracted with toluene, and the extract is washed, dried and condensed under reduced pressure to give 3.4g of 5-chloro-2-iodothiophenol as colorless oil. (2) A toluene solution containing 1.7g of the product obtained above, 1.5g of methyl trans-3~(4-rnethoxy-phenyl)glycidate and 2 drops 15 of tin (II) 2-ethylhexanoate is stirred. After the reaction, the mixture is condensed under reduced pressure. The residue is purified by silica gel column chromatography [solvent; toluene : ethyl acetate = 20 : 1] and recrystallized from diethyl ether and n-hexane to give 1.8g of methyl (±)-threo-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-20 hy dr oxypropi on ate.

M.p. 66 to 68"C Nujol IR v (cm"1): 3480, 1740, 1605 Max 1.8g of the product obtained above are added to a mixture of 30ml of methanol and 15ml of 10% aqueous sodium hydroxide, and the mixture is stirred at room temperature for 3 hours. The mixture is acidified and extracted with ether. The extract is washed with water, dried and evaporated to remove the solvent, and the residue is 30 recrystallized from ethyl acetate and isopropyl ether to give 1.07g of (±)~ threo-3-(4-methoxyphenv|)-3-(2~iodo~5-chlorophenyl)thio-2-hydroxypropionic acid.

M.p. 168 to 169"C 6 Nujol IR v (cm-1): 3470, 3200 to 2100, 1700, 1600 Max (3) A mixture of 2.0g of the product obtained above and 10ml of acetic anhydride is stirred at 60"C for 2 hours. After the reaction, 200ml of water and 100ml of tetrahydrofran are added to the mixture and further stirred at room temperature for one hour. The reaction mixture is alkalized with potassium carbonate to decompose acetic anhydride completely, acidified with hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and condensed under reduced pressure to give 2.18g of (+)-threo-3-(4-methoxyphenyl)-3-(2=iodo-5-chlorophenyl)thio-2-acetoxypropionic acid as oil in quantitative yield.

Liq.

IR v (cm-1): 3600 to 2200, 1750, 1605, 1580 Max The product obtained above is dissolved in 10ml of dichloromethane, 4ml of thionvl chloride is added thereto, and then the mixture is refluxed for 2 hours. The reaction mixture is condensed under reduced pressure to give 2.27g of (±)-threo-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-acetoxypropionyl chloride in quantitative yield.

Liq.

IR v (cetH) : 1795, 1760, 1610 Max (4) A solution of 2.27g of the product obtained above in 100 ml of dichloromethane is added to a solution of 480mg of N,N-dimethylethylenediamine and 570mg of triethylamine in 70 ml of dichloromethane at room temperature. The mixture is stirred at the same temperature for one hour. After the reaction, the mixture is diluted with ethyl acetate, washed with 5% sodium bicarbonate and water, dried and condensed under reduced pressure to give 2.48g of (iHhreo-N-[2-(dimethylamino)ethyl]-3-(4-methoxyphenyl)-3~(2--iodo-5~ ehlorophenvl)thio-2-acetoxypropianamide as oil in quantitative yield. 7 Liq.

IR v (cm-1): 3330, 3070, 2820, 2770, 1750, 1670, Max 1610, 1530, 1515 (5) A mixture of 2.3g of the product obtained above, 50mg of cuprous iodide and 1.21 q of potassium carbonate in 20ml of chlorobenzene is refluxed for 2 hours. After the reaction, the mixture is diluted with ethyl acetate. Insoluble inorganic materials are filtered off and washed with ethyl acetate and the filtrate and the washings are combined and condensed under reduced pressure. The residual oil is purified by silica gel column chromatography [solvent; chloroform : ethanol = 20 : 1], and the product is converted into its hydrochloride, then, recrystallized from ethanol - diethylether to give 1.53g of (±) cis-2-(4-methoxyphenyl)~3-acetoxy-5-[2-(dimethylamino)ethyl]~8~chloro-2,3-dihydro-1,5~benzothiazepin-4(5H)-one hydrochloride in 79.4% Yield.

M.p. 159 to 161"C Example 2 25mg of cuprous iodide and 520mg of potassium carbonate are added to a solution of 1.0g of (±)-threo-N-[2-(dimethylamino)ethyl}-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-acetoxypropionamide in 10ml of dimethylsulfoxide and 10ml of toluene, and the mixture is stirred at 110"C for 2 hours. After the reaction, the mixture is diluted with ethyl acetate. Insoluble inorganic materials are filtered off, and the filtrate is washed with water, dried and condensed under reduced pressure. The residual oil is purified by silica gel column chromatography [solvent; chloroform : ethanol = 20 : 1], and the product is converted into its hydrochloride, then, recrystallized from chloroform -ethanol - diethylether to give 410mg of (±)-cis-2~(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]~8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one hydrochloride in 48.7% Yield.

The physico-chemical properties of the product are indentical with those of the product obtained in Example 1-(5). 8 Example 3 (1) 6.7g of (+) threo-3-(4-methoxyphenyl)-3-(2-iodo-5-chloro- phenyl)thio-2-hydroxypropionic acid are dissolved in 30 ml of pyridine. 4.95g of (S)-1~(2-naphthylsulfonyl)pyrrolidine-2~carbonyl chloride are 5 added to the solution of under ice-cooling, and the mixture is stirred at room temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, and the mixture is acidified with diluted hydrochloric acid. The organic layer is separated and washed with 10% hydrochloric acid and water, dried and evaporated to remove the solvent. The residue is separated by silica gel column chromatography {solvent; chloroform : ethyl acetate : acetic acid : water: ethanol = 1430 : 1170 : 12 : 8 : 120] to give 4.45g of (2S, 3S)-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-[(S)-1"(2"naphthylsulfonvl)pyrrolidin-2-carbonvl]oxypropionic acid. (2) 4.45g of the product obtained above is added to a solution of S.Sg of potassium carbonate in 36ml of water and 66ml of methanol, and the mixture is stirred at room temperature overnight. The reaction mixture is acidified and extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent, and the residue is purified by silica gel column chromatography [solvent; chloroform : ethanol : acetic acid = 600 : 48 : 5] to give 2.32g of (+)-threo-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-hydroxy-propionic acid as oil in 84.4% yield. 24 [a] +94.5" (C=0.40, tetrahydrofuran) D Nujol IR v (cm-1): 3300(broad), 1710, 1610, 1580 Max (3) A mixture of 1.9g of the product obtained above and 10ml of acetic anhydride is stirred at 60"C for 2 hours. The reaction mixture is treated in the same manner as described in Example 1-(3) to give 2.07g of (H-)-threo-3-(4-rnethoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-acetoxypropionic acid. 9 23 [a ] +69.7 " (C=0.83, chloroform) D Chloroform IR v (cm"1): 1750, 1715, 1340. 1600 Max The product obtained above is dissolved in 10ml of dichloromethane, and 4ml of thionyl chloride are added thereto, and the mixture is refluxed for 2 hours. The reaction mixture is condensed under reduced pressure to give 2.log of (+)-threo-3-(4-methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-acetoxypropionyl chloride as oil in quantitative yield. (4) A solution of the product obtained above in 100 ml of dichloromethane are added to a solution of 480rng of N,N~ dimethylethylenediamine and 570rng of triethylamine in 60 ml of dichloromethane, and the mixture is treated in the same manner as described in Example 1-(4) to give 2.35g of (+)-threo-N-[2-(dimethylarnino)ethyl3-3-(2~iodo-5-chlorophenyl)thio-3-(4-methoxy" phenyl)-2-acetoxypropionamide as oil in quantitative yield. 21 [a) +80.2 * (C=0.41, chloroform) D Liq.

IR v (cm"1): 3320, 3070, 2930, 2850, 2830, 2760, 1740, Max. 1660, 1600, 1575, 1505 (5) A mixture of 4.1g of the product obtained above, 100mg of cuprous iodide, 2.6g of potassium carbonate and 50ml of chlorobenzene is refluxed for 3 hours. The reaction mixture is treated in the same manner as described in Example 1-(5), and the product is converted into maleate and then recrystallized from ethanol to give 3.35g of (+)~cis-2~(4-rnethoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8~chloro-2,3~dihydro~1,5-benzothiazepin-4(5H)~ one maleate in 83.4% Yield.

M.p. 158 to 160"C Examples 4 to 10 The corresponding starting compounds are treated in the same manner as described in either one of Examples 1 to 3 to give the following compounds. [4] (+)-cis-2-(4-methoxvph0nyl)-3-hydroxy-5-[2-(dimethylamino>-ethyl]-8-chloro-2,3-dihvdrQ-1,5-benzothiszepin~4(5H)-one.

M.p. 123 to 125°C [5] (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)-ethyl]-9-chloro-2,3~dihydro-1,5-benzothiazepin-4(5H)-one perchlorate 1/4hvdrate.

M.p. 190 to 192*C [8] (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-9-chloro-2,3-dihydro-1,5-ben20thiazepin-4(5M)-0ne hydrochloride monohvdrate.

M.p. 140 to 143"C [7] (±)-ciS"2-(4-methylphenyl)-3-hydroxy-5-t2-(dimethylamino)ethvlJ-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H )-one.

M.p. 142 to 143"C (recrystallized from eihvl acetate) [8] (+)-cis-2-(4-methylphenyl)-3-acetoxy~5-[2-(dimethylamino)ethyl]-8- methyl-2,3-dihydro-1,5-benzoihiazepin-4(5H)-one hydrochloride. M.p. 190 to 192*C (recrystallized from acetone and isopropvl ether) M.p. 184 to 186"C (recrystallized from isopropyl alcohol and ether) Fumarate: M.p. 198.5 to 198.5°C (decomp., recrystallized from propanol) Maleate: M.p. 172.5 to 174"C (recrystallized from methanol) M.p. 191.9*0 (recrystallized from water) Methanesulfonate: M.p. 124 to 128*0 (recrystallized from propanol) [9] (+)-cis-2-(4-methylphenyl)-3~acetoxy-5-[2-(dimethylamino)ethyI]-8-methyI-2,3-dihydro-1,5-benzoihiazepin~4(5H)-one maleate.

M.p. 194 to 197"C (decornp., recrystallized from ethanol) [a ] +83.7 " (0=0.382, methanol) D Oxalate: M.p. 179 to 180"C (recrystallized from ethanol) [a ] +88.2 " (0=0.288, methanol) D

[10] (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8~ methyl-2,3-dihydrO"1,5-benzothiazepin-4(5H)-one maleate.

M.p. 195 to 197.5*C (decornp., recrystallized from ethanol) [a ] -83.6 " (0=0.50, methanol) D Oxalate: M.p. 179.5 to 181"C (decomp., recrystallized from ethanol) [a ] -83.8 * (0=0.333, methanol) D 12 Fumarate: M.p. 210.5 to 212.5*C (decomp., recrystallized from ethanol) fa ] -91.3 * (C=0.323, methanol) D L-N-^tartrate: M.p. 140 to 143"C (recrystallized from ethanol and diethyl ether)

Claims

What we claim is:

1. A process for preparing a 1,5-benzothiazepine derivative of the formula: - r* r;VoR* (I) H -<\ | 0 Is CH»CHaN< XSa 10 wherein R1 is a lower alkyl or lower alkoxy group; is a hydrogen atom or a lower alkanoyl group; one of and R4 is halogen atom or a lower alkvl aroup and the other is hvdrogen atom; and each of and r6 is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, which comprises subjecting a propionarnide 15 derivative of the formula: R3 r 9n 0 NHCH«CHaN^ XR4 wherein X is bromine or iodine atom, and R1 " R® are the same as defined above, to intramolecular cyclization, and, if required, further converting the product into a pharmaceutically acceptable acid addition 25 salt thereof.

2. A process for preparing a 1,5-benzothiazepine derivative of the formula: i?3 r (I) I 0 Rs CHgGHgMcf 14 wherein R1 is a lower alkyl or lower alkoxy group; r2 is a hydrogen atom or a lower alkanoyl group; one of R^ and R4 is halogen atom or a lower alkyl group and the other is hydrogen atom; and each of and r6 is a lower alkyl group, or a pharmaceutically acceptable acid 5 addition salt thereof, which comprises condensing a propionic acid derivative of the formula: wherein X is bromine or iodine atom, and R1 " R4 are the same as defined above, or a reactive derivative thereof and N,N~di(lower 15 alkyl)ethylenediamine to give a propionarnide derivative of the formula: 3 r 4 r 1 R //\ /8s 0 NHCHsCHgMC 20 wherein R1" R® and X are the same as defined above, subjecting the propionarnide derivative to intramolecular cyclization, and, if required, further converting the product into a pharmaceutically acceptable acid 25 addition salt thereof.

3. The process according to claim 1 or 2, wherein the intramolecular cyclization is carried out in the presence of a catalyst and a base.

4. The process according to claim 3, wherein the intramolecular 30 cyclization is carried out in the presence of a transition metal catalyst and an inorganic or organic base at a temperature of 50 to 200 "C. 5. The process according to claims 1 to 4, wherein the 1,5-benzothiasepine derivative is 2-(4-methoxyphenyl)-3-acetoxy-5- [2- 15 (dimethylamino)ethyl]-8-chloro-2,3~dihydro-1,5-benzothiazepin-4(5H)- one. 6. The process according to claims 1 to 4, wherein the 1,5-benzothiazepine derivative is 2-(4~methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. 7. A process for preparing a 1s5-benzothiazepine derivative of the formula (1) as'defined'in claim 15 substantially as hereinbefore described by way of Example. 8. A 195-ben2:othiazepine derivative of the formula (1) as defined in claim ls whenever prepared by a process as claimed in any of the preceding claims. Dated this the 18th day of January, 1989. BY: TOMKINS & CO., Applicants' Agents, (Signed)

5. Dartmouth Road, DUBLIN

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