GB2098596A - Benzamidoalkyl mercaptans - Google Patents

Abstract

Benzamidoalkyl mercaptans having the formula: <IMAGE> in which -alk- represents a C2-4 alkylene radical, R represents a hydrogen or halogen atom or a lower-alkyl, lower-alkoxy, amino, carboxyl or trifluoromethyl radical, n is one to three, and when n is more than one, R may be the same or different in various positions relative to one another in the ring, are useful as mucolytic agents.

Description

1 GB 2 098 596 A 1

SPECIFICATION Benzamidoalkyl mercaptans

The present invention is concerned with certain mercaptans possessing mucolytic activity and is particularly concerned with certain benzamidoalkyl mercaptans, compositions containing those compounds and methods for employing the mercaptans as mucolytic agents in controlling and 5 combating mucus build-up in an animal exhibiting or suffering from lung congestion.

A. L. Sheffner, Ann. N. Y. Acad. Sci. 106, 298-310 (1963) discloses sulphhydryl-containing compounds having mucolytic activity and established the use of mucin mucoprotein as a test media.

None of the compounds disclosed by Sheffner were of the benzamidoalkyl mercaptan type. T. A. Martin etaL, in U.S. Patent 4,005,222 disclose mucolytic anilido alkyl mercaptans distinguishable in part from 10 compounds of the instant invention in having the nitrogen interposed between the carbonyl and phenyl groups rather than between the carbonyl and alkyl groups.

Benzamido-ethyimercaptan is a compound known from the disclosure of A. A. Goldberg et al., J. Chem. Soc. 1948, 1919-26, but there has been no disclosure that it has mucoyitic activity.

The compounds of the present invention are benzamidoalkyl mercaptans having the formula: 15 0 in which when -alk- represents an ethylene radical D11 -C-NH-alk-SH Formula 1 R represents a halogen, lower-alkyl, lower-alkoxy, amino, carbonyl or trifluoromethyl radical; n is one to three, and when n is more than one, R may be the!game or different in various positions relative to one another in the ring; and when R represents hydrogen, -alk- represents a straight or branched divalent alkylene radical of 3 or 4 carbon atoms. The compounds have mucolytic activity and are useful in dissolving and diluting mucus in warm- blooded animals exhibiting or suffereing from lung congestions.

The compounds described hereinafter and represented by the foregoing Formula 1 have been 25 shown by a modification of the method of S. J. Come et al., J. Phys. 242, 116 (1974) as described hereinbelow to have mucolytic activity in animals.

Compounds for which mucolytic activity was found to be of the same order of magnitude as N acety]-L-cysteine on rat stomach mucus are the preferred compounds which are as follows:

(1) 4-chlorobenzamido-ethyimercaptan (2) 4-methylbenzamido-ethyimercaptan (3) 4-methoxybenzamido-ethyimercaptan The method used to demonstrate the mucolytic activity of the compounds of the present invention is as follows: Female Sprague-Dawley (Charles Riber Labs) rats weighing 120-180 g are fasted for 16 hours on wire, housed two animals per cage. To minimize coprophagia, the lights are left 35 on during the fast. Two cc of water are given orally to each rat to minimize interal debris. Thirty minutes later the rats are sacrificed by cervical dislocation. The stomachs are removed, trimmed of excess tissue and the epithelia] portion discarded. The glandular portion is cut sufficiently along the greater and lesser curvature to cause eversion of the stomach before placing it in the drug solution. Stomachs with a fecal odour or containing visible fecal meatter are discarded. Stomachs are placed in 10 cc of an 40 aqueous solution of polyethylene glycol of MW 300 (50% PEG-300-1-1,0) containing 2.5 mg of the test compound/mi for 40 minutes. After this exposure to the drug the stomachs are placed in 10 cc of Alcian Blue aqueous dye solution (Solution 1 -prepared as described below) for 90 minutes and the dye complexes with the stomach mucus. After two successive 1 0-minute washes in 10 cc of 0.25 M aqueous sucrose (Solution 2-prepared as described below), the stomachs are placed in 10 cc of 0.5 45 M aqueous magnesium chloride (Solution 3-prepared as described below) for one hour to remove the complexed dye. The supernatant magnesium chloride solution is shaken with 10 cc of dietliyi ether in a cc separatory funnel to remove lipids. The aqueous phase is drained into a Spectronic 20 Tube and the percent transmission is read at 605 miu in a Spectronic 20 Spectrophoto meter. The percent transmission is converted to pg/mi of Alcian Blue from a standard curve (P. Whiteman, Blochem. J. 50 131, 351-57 (1973)). Each drug or drug vehicle (control) is tested on three stomachs. Mean differences between treated and control values are expressed as percentages.

The aqueous Alcian Blue solution referred to as Solution 1 herein contains 0.05% w/v of Alcian Blue dye. It is made up by dissolving 54.8 g of sucrose (0.15 M) and 6.8 g of sodium acetate with stirring in 900 cc of deionized water using a magnetic stirrer. The pH is adjusted to 5.8. 500 mg of Alcian Blue 8GN (supplied by Matheson, Coleman & Bell as #8E1 3) is then added and the mixture topped up to one litre in a volumetric flask with deionized water and the solution stored in a refrigerator. The solution should only be used for 1 week after being made up.

The aqueous sucrose solution referred to as Solution 2 herein is made up by dissolving 85.6 g of GB 2 098 596 A 2 sucrose in deionized water in a 1 litre volumetric flask and then making up with delonized water to 1 litre. The solution should only be used for 1 week after being made up.

The aqueous 0.5 M magnesium chloride solution referred to as Solution 3 herein is made up by dissolving 101.7 9 Of M9C12.6H20 (A. C. S.) in deionized water in a one litre volumetric flask and then 5 making up to 1 litre with deionized water.

It is an object of the present invention to provide certain novel benzamidoalkyl mercaptans having mucolytic activity in a warm-blooded animal.

Pharmaceutical compositions in inhalable liquid form adapted for use as a mucolytic agent in an animal body comprising:

a) 0.5 to 20 weight % as active agent of a compound of the formula:

C-NH-alk-SH wherein; radical, R represents a hydrogen, halogen, lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl -alkrepresents a straight or branched divalent alkalene radical of from 2 to 4 carbon atoms, 15 n is one to three, and when in inhalable liquid form b) a pharmaceutically acceptable carrier therefore, and pharmaceutical compositions in insuffiatable powder form adapted for use as a mucolytic agent in an animal body, comprise:

a) 25-75 weight % of the said active agent in micronized form, and b) a pharmaceutically acceptable powder carrier therefor are described and claimed in our copending British patent specification No.

The compounds of the present invention are useful for the same purposes.

In the definition of the symbols and in Formula 1 given above and where they appear elsewhere throughout the claims and the specification hereof, the following terms have the following significance. 25

The 1ower-alkyl" and---lower-alkoxy" substituents each have from one to four carbons atoms which can be arranged as straight or branched chains. Examples are methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy.

-(R)n refers to 1 to 3 substituents of R in various available positions on the phenyl nucleus and when more than one substituent is present, may be the same or different and may be in various 30 position combinations relative to each other.

The term---alk- refers to as examples ethylene (-CH2CH2-), propylene (CH2CH2CH2-), 1,2 propylene and 2,3-butylene (-CHCH27-L 1 L^ (-CH-CH-). 1 1 CH, CH3 The mercaptans of the present invention are prepared by one of three known methods as represented by the following equations.

Method (1) 40 Via carbothioic acid ester acid salts 0 11 - & 11 KOH C-Cl. + HS-A-NH2. HQ. C-S-alk-NH2'HCI QC-NH-alk-SH Method (2) Via isothiouronium salts 0 0 0 11 11 C-R + NH2-a[k-cl- a-, C-NH-alk-C[ (R) C (R)n 0 (R)n C 1 3 GB 2 098 596 A 3 0 S 11 11 C-NH-a[k-Cl + H2-C-NH2 (R)n Method (3) 0 NH KOH M-C-NM-aLK--C-NH2.HC[ H20 (R) n 0 C NH-alk-SH (R)n 0 COOH + HS-a[k-U2 ' HQ PC13 I (R) Pyridine C-NH-atk-SH (R)n The invention may be put into practice in various ways and certain specific embodiments will be 5 described by way of example to illustrate the invention with reference to Examples 1 to 6 which describe the preparations of intermediates and Examples 7 to 15 which describe the preparation of compounds in accordance with the invention and Example 16 which describes a pharmaceutical composition in accordance with the invention. We will now describe the preparation of intermediates for use in Method (1).

Example 1

Benzenecarbothioic acid 2-aminoethyl ester monohydrochloride A mixture of benzoylchloride, 15 m] (about 0.13 mole) and 2- aminoethanethiol hydrochloride, 4.54 g (0.04 mole) was heated (protected from moisture) over a steam jet for 2 hours. Slight cooling produced a mass of crystals. After trituration with ligroine at a temperature of 60-11 OOC, filtration 15 and drying, the crystals melted at 177-1 801C. Several recrystallizations from anhydrous ethanol produced a colourless solid which metied at 178.5-179.51C. Nuclear Magnetic Resonance (NMR), Mass Spectrophotometer (MS), and Infra Red (IR) analyses all corroborated that the product was the compound given in the title of this Example. The yield was 5.1 9 (59.1 M.

Analysis:

Calculated for C91-112CINOS:

C,49.65; H,5.55; N,6.43 Found:

C49.58; K5.59; K6.49 Example 2

4-M ethyl benzeneca rbothioic acid 2-aminoethyl ester monohydrochloride A mixture of freshly distilled p-toluoyl chloride, b.p. 1220C at 32 mm of mercury, 30 mi (about 0. 18 moles) and 2-aminoethanethiol hydrochloride, 9.68 g (0.085 moles) was heated (protected from moisture) over a steam jet for 2.25 hours. A solid crystalline mass formed on completion of the reaction. The mass was crushed and carefully triturated with warm ligroine at a temperature of 60- 30 11 OIC, and crystals were separated by filtration and washed with warm ligroine. After two recrystallizations from anyydrous ethanol, the product, 19.07 g (yield 97%), melted at 206.5-2080C.

NMR, MS and IR analyses all corroborated that the product was the compound given in the title of this example.

Analysis: Calculated for C1,1-114NOCIS; Found:

Q51.83; 1-1,6.09;K6.04 C,51.57; 1-1,6.06;N,6A 1 Example 3 4-Methoxybenzenecarbothioic acid 2-aminoethyl ester monohydrochloride A mixture of p-anisoyl chloride, 23 m] (about 0. 135 mole) and 2aminoethanethiol hydrochloride, 7.4 9 (0.065 mole) was heated (protected from moisture) over a steam jet for about 2 hours. The resultant crystalline mass was crushed and carefully triturated with warm ligroine at a temperature of 45 60-11 OOC and crystals were separated by filtration and washed with warm ligroine. After two recrystallizations from anhydrous ethanol, the product, 14.6 g (yield 90.6%) melted at 191.5- 1931C. NMR, MS and IR analyses all corroborated that the product was the compound given in the title of this Example.

4 GB 2 098 596 A 4 Found:

Analysis: Calculated for C,,H14CINOA:

CA8.48; H,5.69; N,5.65; CA8.42; H,5.73; N,5.66 5 Examples 4A to 4D When in the procedure of Example 1, benzoyl chloride is replaced by equal molar amounts of 3,4,5-trimethoxybenzoyl chloride, 3- trifluoromethyibenzoyl chloride, 10 3,4-dimethy[benzoyl chloride, 4- carboxybenzoyi chloride, there are obtained 3,4,5-trimethoxybenzenecarbothioic acid, 2-amino-ethyl ester hydrochloride, (Example 4A) e-trifluoromethyibenzenecarbothioic acid, 2- amino-ethyl ester hydrochloride, (Example 4B) 3,4-di methyl benzenecarbothloic acid, 2-aminoethyl ester hydrochloride, (Example 4C) and 15 4-carboxybenzenecarbothioic acid, 2-aminoethyl ester hydrochloride, (Example 4D).

Example 5

When in the procedure of Example 1, 2-aminoethanethiol hydrochloride is replaced by equal molar amounts of 3-aminopropanethiol hydrochloride, there is obtained Benzenecarbothiolc acid-3-aminopropylester hydrochloride.

Examples 6A and 6B When in the procedure of Example 1, 2-aminoethanethlol hydrochloride is replaced by equal molar amounts of 3-aminopropanethiol hydrochloride and benzoyl chloride is replaced by p-toluoyl chloride, or p-anisoyl chloride there are obtained 4-methyibenzenearbothioic acid, 3-aminopropyl ester hydrochloride, (Example 6A) and 4-methoxybenzenecarbothioic acid, 3- aminopropyl ester hydrochloride (Example 6B). We will. now describe the preparation of compounds in accordance with the invention.

Example 7

4-Chlorobenzamido-ethyimercaptan To a solution of 2-aminoethanethlol hydrochloride 22.7 g (0.02 mole) in 300 mi of dry pyridine was added, with stirring, phosphorus trichloride, 13.7 g (0.1 mole) in 50 m] of dry pyridine. Slight exothermic reaction was noted. After stirring for an additional 30 minutes, p-chlorobenzoic acid, 31.2 g (0.2 mole) in 100 mi of dry pyridine was added. The reaction mixture was heated to reflux for 4 hours, cooled and poured onto 400 g of ice. The reaction mixture was extracted 4 times with 100 ml portions 35 of methylene chloride. The combined extract was washed twice with 200 mi ice water, 4 times with m[ of 5% sodium carbonate and twice more with 200 mi of ice water. After drying over magnesium sulphate, the washed extract was concentrated by evaporation to cream coloured oil which solidified on standing. The solid was stirred in warm water, filtered and the residue washed twice with 200 mi water and air dried to give 29 g of crude material. The crude product was dissolved in 400 mI of methanol and 200 mi of 10% aqueous sodium carbonate solution added. The solution was filtered and cooled overnight in a refrigerator. Tan coloured amorphous material was filtered off and discarded. The volume of the filtered solution was adjusted to 1 litre. The solution was allowed to stand at OIC for 96 hours and the precipitate was collected by filtration and dried. The yield of the off white product, which melted at 73-781C, was 5 g (15%) Analysis: Calculated for C^OCINOS:

C,50.12; H,4.67 N, 6.49 Found:

Q50.00 H,4.63 K6.53 50 Examples 8A to 8D When in the procedure of Example 7, 4-chlorobenzoic acid is replaced by equal molar amounts of the following:

4-fluorobenzoic acid, 4-bromobenzoic acid, 55 2-chlorobenzoic acid, and 3,4,5-trichlorobenzoic acid, there are obtained 4-fluorobenzamido-ethyimercaptan (Example 8M q GB 2 098 596 A 5 4-bromobenzamido-ethyimercaptan (Example 8B) 2-chlorobenzamidoethyimercaptan (Example 8C) and 3,4,5-trichlorobenzamido-ethyimereaptan (Example 8D).

Example 9.

4-Chlorobenzamido-propyimercaptan 5 When in the procedure of Example 7, 2aminopropanethiol hydrochloride is substituted for 2 aminoethanethiol hydrochloride is equal molar amounts, the compound given in the title of this

Examples is obtained.

Examples 1 OA to 1 OD When in the procedure of Example 8, 2-aminopropanethiol hydrochloride is substituted for 2aminoethanethioi hydrochloride in equal molar amount, there are obtained:

4-fluorobenzamido-propyimercaptan (Example 'I OA) 4-bromobenzamido-propyimereaptan (Example 1 OB) 2-chlorobenzamido-propylmercaptan (Example 1 OC) and 3,4,5-tridhiorobenzamido-propylmercaptan (Example 1 OD). 15 Example 11

4-Methylbenzamido-ethyimercaptan To a solution of potassium hydroxide, 6.2 g (0.11 mole) in 200 mi of oxygen-free water was added in one portion 4-methylbenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride (see Example 2), 12.0 g (0.052 mole). Nitrogen was bubbled through the suspension which was maintained 20 at reflux temperature for 1.5 hours. A small amount of insoluble material was filtered off and discarded.

The alkaline filtrate was extracted.with chloroform. The aqueous alkaline solution was then acidified with concentrated hydrochloric acid and again extracted with chloroform. The chloroform extracts were combined and dried and concentrated to a thin syrup. Addition of ligroine at a temperature of 60 11 OIC caused precipitation of a crystalline solid, 9.31 g, melting at 110-11 30C. The yield of the 25 product after a single recrystallization from benzene-ligroine (1:5) was 7.41 g (yield 76.3%), melting at 112.5-1140 C.

Analysis:

Calculated for C1,1-113SNO:

C,61.50; Irl,6.7 1; N,7A 7 Found:

C,61.34; H,6.65; N,7A 6 Example 12

4-Methoxybenzamido-ethyl mercaptan To a solution of potassium hydroxide, 5.6 9 (0.10 mole) in 170 m[ of oxygen-free water under a 35 nitrogen atmosphere was added 4-methoxybenzenecarbothioic acid, 2- aminoethyl ester monohydrochloride (see Example 3), 7.01 g (0.0283 mole). The temperature was raised to and held at reflux for 1.5 hours. Tetra hyd rofu ran, 30 mi, was added during the last 30 minutes to effect full solution. After cooling, the-solution was extracted while alkaline with chloroform, then acidified and extracted again. The extracts were combined, dried, concentrated and then diluted with ligroine. The 40 solid obtained was recrystallized from benzene ligroine (11:5) at a temperature of 60-11 OIC. The yield was 3.97 9 (57.7% based 2-aminoethanethiol hydrochloride), and the product melted at 107108.50C.

Found:

Analysis Calculated for C1.H13NO2S:

C,56.85; H,620; N,6.63 C,56.90; 1-1,6.16;N,6.64 Examples 13Ato 13D 50 When in the procedure of Example 12, 4- methoxybenzenecarbothioic acid, 2-aminoethyl ester, 50 monohydrochloride is replaced by equal molar quantities by the following: 3,4,5- trimethoxybenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4A), 3-trifl uoro methyl be nzeneca rbothioi c acid, 2aminoethyl ester, hydrochloride (see Example 4B), 3,4-dimethyibenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4Q or 4- carboxybenzoylcarbothioic acid, 2-aminoethyl ester hydrochloride (see Example 413), there are obtained 3,4,5-trimethoxybenzamido-ethyimercaptan (Example 14A), 3-trifluoromethylbenzamido-ethyimercaptan (Example 14B), 6 GB 2 098 596 A 6 3,4-dimethylbenzamido-ethyimercaptan (Example 14C) and 4-carboxybenzamido- ethyimereaptan (Example 14D).

Examples 14A to 14C When in the procedure of Example 12, 4-methoxybenzenecarbothioic acid, 2- aminoethyl ester monohydrochloride is replaced by equal molar amounts of benzenecarbothioic acid-3-aminopropyl 5 eAter hydrochloride (see Example 5) 4-methylbenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride (see Example 6A) or 4-methoxybenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride (see Example 613) there are obtained benzamido-propyl mercaptan (Example 15A) 4-m ethyl benza m ido-propyl mercaptan (Example 1513) and 4-methoxybenzamido-propyl mercaptan (Example 1 5C).

Examples 1 5A and 1 5B (a) lsothiouronium salt of N-(2-mercaptoethyl)-4aminobenzamide When in the procedure of Example 11 A N-(2-chloroethyl)-4-aminobenzamide is substituted in 15 equal molar amount for N-(2-chloroethyl)benzamide, the compound given in the title above is obtained.

(b) 4-Aminobenzamide-ethyimercaptan When in the procedure of Example 11 B the isothiouronium salt of W(2- mercaptoethyl)-4aminobenzamide is substituted for the isothiouronium salt of N-(2-mercpatoethyl)benzamide in equal molar amount, 4-aminobenzamide-ethyimercaptan is obtained.

Halobenzamidoethyl (and propyl) mercaptans, of this invention may used in pharmaceutical compositions (as claimed in U.K. Specification No.) in an amount sufficient to provide effective action against lung congestion in mammalian subjects when applied topically as an inhalant together with an acceptable carrier therefor.

26 The compounds of Formula 1 may be administered in an amount sufficient to induce liquiefaction 25 of mucus in the respiratory tract of warm-blooded animals in need thereof. Intratracheal administration of the compounds of Formula 1 may be effected by various inhalation or instillation means such as nose drops, sprays, or aerosols. Examples of pharmaceutically acceptable liquid carriers are water and polyethylenegiycol-300 (MW 300). Another suitable means of administration is by insufflation of micronized particles or ultra-fine powder utilizing only the energy of the inspiratory action or by use of 30 aerosol propellants. Generally, the amount of the compound in the inhalant composition will vary from about 0.5 to 75 weight % depending on the type of carrier, i.e. liquid or solid. Solutions or suspensions having about 0.5to 20% by weight, preferably 5-10 wt.%, of the mucolytic agent of Formula 1 are suitable for application by spraying with for example an atomizer, nebulizer, or aerosol. Dusts containing-about 25-75% or more active agent in micronized form are also suitable, about 50% being 35 preferable. An example of a pharmaceutically acceptable solid diluent and carrier for the micronized powder is lactic acid or lactose.

It will be readily apparent to those skilled in the medical arts that the correct dosage of a compound to be employed with any particular mammalian subject is determined by the severity of the condition requiring mucolytic therapy, as well as the age, sex, weight and general physical condition of 40 the subject. Individual doses ranging from 5-100 mg inhalation by man are suitable and may be required for the mucolytic effect.

The pharmaceutical compositions may take the form of dilutions of the micronized compounds in dusts or solutions and suspensions in liquids suitably dispersed for inhalation.

Example 16 Powder for administration via inhaler device 4-chlorobenzamido ethyl mercaptan of Example 7, micronized Lactose powder 2.5 g. 2.5 g.

The powders are blended aseptically and filled into hard gelatin capsules each containing 50 mg 50 of the mixture. This is suitable for dispersion into the inspired breath by means of a breath-operated inhaler device containing means for rupture of the capsule wall prior to dosing.

Claims (22)

Claims

1. A benzamido alkylmercaptan having the formula:

0 C_ ,ll NH-alk-SH 55 (R) n - - in which when -alk- represents an ethylene radical -i 7 GB 2 098 596 A 7 is R represents a halogen, lower-alkyl, iower-alkoxy, amino, carboxy or trifluoromethyl radical, n is one to three, and when n is more than one, R may be the same or different in various positions relative to one another in the ring, and when R represents hydrogen, -alk- represents a straight or branched divalent alkylene radical of 3 or 4 carbon atoms.

2. 4-Chlorobenzamido-ethyimercaptan.

3. 4-Methyibenzamido-ethyimereaptan.

4. 4-Methoxybenzamido-ethyimercaptan.

5. 4-FI uo robe nza mido-ethyl me rcapta n.

6. 4-Bromobenzamido-ethyimercaptan.

7. 2-Chlorobenzamido-ethyimercaptan.

8. 3,4,5-Trichlorobenzamido-ethyimercaptan.

9. 4-Chlorobenzamido-ethyimercaptan.

10. 4-Fluorobenzamido-propyimercaptan.

11. 4-Bromobenzamido-propyimereaptan.

12. 2-Chlorobenzamido-propyimercaptan.

13. 3,4,5-Trichlorobenzamido-propyimercaptan.

14. 3,4,5-TrLmethoxybenzamido-ethyimercaptan.

15. 3-Trifi uoro methyl benza mido-ethyl merca pta n.

16. 3,4-Di methyl benza mido-ethyl mercaptan.

17. 4-Carboxybenzamido-ethyimercaptan.

18. Benzamido-propyimercaptan.

19. 4-M ethyl benza m ido-propyl m ercapta n.

20. 4-Methoxybenzamido-propyimercaptan.

21. Isothiouronium salt of N-(2-mercaptoethyi)-4-aminobenzamide.

22. A compound as claimed in Claim 1 whenever made by a method as described in any one of EXamples 6 to 14B.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1982. Published by the Patent Office, 25 Southampton Buildings, London. WC2A 1 AY, from which copies may be obtained.

1

22. 4-Aminobenzamide-ethyimercaptan.

23. A compound as claimed in Claim 1 whenever made by a method as described in any one of Examples 7 to 1513.

New Claims or Amendments to Claims filed on 11-6-82 Superseded Claims 1 to 23 New or Amended Claims:- 1. A benzamido alkylmercaptan having the formula:

0 11 C-NH-alk-SH in which -alk- represents a straight or branched divalent alkylene radical of from 2 to 4 carbon atoms; n is one to three and R represents a hydrogen or a halogen atom, or a lower-alky], lower-alkoxy, amino, carboxy or trifluoromethyl radical and when R represents other than a hydrogen atom and n is more than one, R may be the same or different in various positions relative to one another in the ring, provided that, when R' represents a hydrogen atom, -alk- represents a straight or branched divalent radical40 of 3 or 4 carbon atoms and provided that, when -alkrepresents an ethylene radical, R represents other than a hydrogen atom.

2. 4-Chlorobenzamido-ethyimercaptan.

3. 4-Methyibenzamido-ethyimercaptan.

4. 4-Methoxybenzamido-ethyimercaptan.

5. 4-FI uo robe nza m Wo-ethyl merca pta n.

6. 4-Bromobenzamido-ethyimercaptan.

7. 2-Chl o robe nza m ido-ethyl m erca ptan.

8. 3,4,5-T.richlorobenzamido-ethyimercaptan.

9. 4-Fluorobenzamido-propyimercaptan.

10. 4-Bromobenzamido-propyimereaptan.

11. 2-Chlorobenzamido-propyimercaptan.

12. 3,4,5-Trichlorobenzamido-propyimercaptan.

13. 3,4,5-Trimethoxybenzamkd6-ethyimercaptan.

14. 3-Trifluoromethyibenzamido-ethyimercaptan.

15. 3,4-Di methyl benza m ido-ethyl m ercapta n.

16. 4-Carboxybenzamidoethyimercaptan.

8 GB 2 098 596 A. 8 17. Benzamido-propyimercaptan.

18. 4-Methy[benzamido-propyimereaptan.

19. 4-Methoxybenzamido-propyimercaptan.

20. Isothiouronium salt of N-(2-mercaptoethyi)-4-aminobenzamide.

21. 4-Aminobenzamide-ethyimercaptan.