IE48793B1 - Benzamidoalkyl mercaptans - Google Patents

Abstract

Benzamidoalkyl mercaptans having the formula: 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

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

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 et al., in U. S. Patent Specification No. 4,005,222 disclose mucolytic anilido alkyl mercaptans distinguishable in part from compounds of the instant invention in having the nitrogen interposed between the carbonyl anc phenyl groups rather than between the carbonyl and alkyl groups.

Benzamido-ethylmercaptan 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 mucolytic activity.

The compounds of the present invention are benzamidoalkyl mercaptans illustrated generally by the following formula: C-NH-alk-SH Formula I -3wherein: R represents a hydrogen, or a halogen atom, or a lower-alkyl, lower alkoxy, amino, carboxy or trifluoromethyl group; -alk- represents a straight or branched divalent alkylene radical of 2 to 4 carbon atoms; and n is from 1 to 3, and when n is more than 1, R may be the same or different in various positions relative to one another in the ring; for use in combating mucus build-up in a living warmblooded animal suffering from lung congestion.

The compounds have mucolytic activity and are useful in dissolving and diluting mucus in warm-blooded animals exhibiting or suffering from lung congestion.

The compounds described hereinafter and represented by the foregoing Formula 1 have been shown by a modification of the method of S. J. Corne 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-acetyl-Lcysteine on rat stomach mucus are the preferred compounds which are as follows: (1) 4-chlorobenzamido-ethylmercaptan (2) benzamido-ethylmercaptan (3) 4-methylbenzamido-ethylmercaptan (4) 4-methoxybenzamido-ethylmercaptan 8 7 9 3 - 4 The method used to demonstrate the mucolytic activity of the compounds of the present invention is as follows: Female Sprague-Dawley (Charles River 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 on during the fast. Two cc of water are given orally to each rat to minimize internal debris. Thirty minutes later the rats are sacrificed by cervical dislocation. The stomachs are removed, trimmed of excess tissue and the epithelial 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 matters are discarded. Stomachs are placed in 10 cc of an aqueous solution of polyethylene glycol of MW 300 (50% PEG-300-H20) containing 2.5 mg of the test compound/ml for 40 minutes. After this exposure to the drug the stomachs are placed in 10 cc of Alcian (Trade Mark) Blue aqueous dye solution (Solution 1 - prepared as described below) for 90 minutes and the dye complexes with the stomach mucus. After two successive 10-minute washes in 10 cc of 0.25 M aqueous sucrose (Solution 2 - prepared as described below), the stomachs are placed in lOcc of 0.5M aqueous magnesium chloride (Solution 3 - prepared as - 5 described below) for one hour to remove the complexed dye. The supernatant magnesium chloride solution is shaken with 10 cc of diethyl ether in a 60 cc separatory funnel to remove lipids. The aqueous phase is drained into a Spectronic (Trade Mark) 20 Tube and the percent transmission is read at 605mp in a Spectronic 20 Spectrophotometer. The percent transmission is converted to pg/ml of Alcian Blue from a standard curve (P.

Whiteman, Biochem. J. 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 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 #8E13) 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 8 7 9 3 - 6 Solution 2 herein is made up by dissolving 85.6 g of sucrose in deionized water in a 1 litre volumetric flask and then making up with deionized 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 101.7g of MgCl 6H 0 (A.C.S.) in deionized water in a one litre volumetric flask and then making up to 1 litre with deionized water.

It is an object of the present invention to provide benzamidoalkyl mercaptans for use in combating mucus build-up in a living warm-blooded animal suffering from or exhibiting lung congestion.

A further object is to provide novel pharmaceutical compositions for combating mucus in warm-blooded animals.

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.

The lower-alkyl and lower-alkoxy substituents each have from one to four carbon atoms which can be arranged as straight or branched chains. Examples are methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy. 8 7 9 3 - 7 ~(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 position combinations relative to each other.

The term alk refers to as examples ethylene (-CH2CH2-), propylene (-CH2cii2Cli2~^' 1,2-propylene (-CHCH2-), and 2,3-butylene (-CH- CH-), CH3 ch3 ch3 The compounds of the present invention are prepared by one of three known methods as represented by the following equations. 8 7 9 3 METHOD (1) Via carbothioic acid ester acid salts C-Cl + HS-alk-Nffe HCl . R)n (R)n C-S-alk-NHa-HCl KOH.

C-NH-alk-SH (R)n METHOD (2) Via isothiouronium salts 0 C-Cl + NHg-alk-cl -» ^^—C-NH-alk-Cl Wn (R)n ι R)n (RV METHOD (3) S « C-NH-alk-Cl + NHg-C-NHg -» NH II II C-NH-alk-S-C-NHgHCl KOH HaO (R)nC-NH-a lk-SH ( R)n pels COOH + HS—alk—NHg”HCl pyridine C-NH-alk-SH (R)n - 9 The invention may be put into practice in various ways and certain specific embodiments will be described by way of example to illustrate the invention with reference to Examples 1 to 6 which describe the preparation of intermediates and Examples 7 to 16B which describe the preparation of compounds in accordance with the invention and Example 17 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 ml (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 60-110°C, filtration and drying, the crystals melted at 177-180°C. Several recrystallizations from anhydrous ethanol produced a colourless solid which melted at 178.5-179.5°C. 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 g (59.1%). Analysis: Calculated for CgH^ClNOS: C,49.65; H,5.55; N,6.43 Found: C,49.58; H,5.59; N,6.49 8 7 9 3 - 10 Example 2 4-Methylbenzenecarbothioic Acid, 2-Aminoethyl Ester Monohydrochloride.

A mixture of freshly distilled p-toluoyl chloride, b.p. 122°C at 32 mm of mercury, 30 ml (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 60-110°C, and crystals were separated by filtration and washed with warm ligroine. After two recrystallizations from anhydrous ethanol, the product, 19.07 g (yield 97%), melted at 206,5-208°C. NMR,MS and IR analyses all corroborated that the product was the compound given in the title of this Example.

Analysis: Calculated for C10H14NOC1S!C'51.83;H,6.09;N,6.04 Found :C,51.57,-H, 6.06,-N, 6.11 Example 3 4-Methoxybenzenecarbothioic Acid, 2-Aminoethyl Ester Monohydrochloride.

A mixture of p-anisoyl chloride, 23 ml (about 0.135 mole) and 2-aminoethanethiol hydrochloride, 7.4g (0.065 mole) - 11 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 60-110°C 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 191.5-193°C.NMR,MS and IR analyses all corroborated that the product was the compound given in the title of this Example.

Analysis: Calculated for CjqH|^C1NO^S: C,48.48;H,5.69;N,5.65 Found : C,48.42;H,5.73?N,5.66 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- trifluoromethylbenzoyl chloride, 3,4-dimethylbenzoy1 chloride, 4- carboxybenzoyl chloride, there are obtained 3.4.5- trimethoxybenzenecarbothioic acid, 2-aminoethyl ester hydrochloride, (Example 4A) 3-trifluoromethylbenzenecarbothioic acid, 2-aminoethyl ester hydrochloride, (Example 4B) 8 7 9 3 - 12 3,4-dimethylbenzenecarbothioic acid, 2-aminoethyl ester hydrochloride, (Example 4C) and 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 3aminopropanethiol hydrochloride, there is obtained Benzenecarbothioic acid-3-aminopropylester hydrochloride.

Examples 6A and 6B When in the procedure of Example 1, 2-aminoethanethiol 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-methylbenzenecarbothioic 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. - 13 Example 7 4-Chlorobenzamido-ethylmercaptan To a solution of 2-aminoethanethiol hydrochloride 22.7 g (0.02 mole) in 300 ml of dry pyridine was added, with stirring, phosphorus trichloride, 13.7 g(0.1 mole) in 50 ml 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 ml 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 of methylene chloride. The combined extract was washed twice with 200 ml ice water, 4 times with 100 ml of 5% sodium carbonate and twice more with 200 ml of ice water. After drying over magnesium sulphate, the washed extract was concentrated by evaporation to a cream coloured oil which solidified on standing. The solid was stirred in warm water, filtered and the residue washed twice with 200 ml water and air dried to give 29 g of crude material. The crude product was dissolved in 400 ml of methanol and 200 ml 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 0°C for 96 hours and the - 14 precipitate was collected by filtration and dried. The yield of the off-white product, which melted at 73-78°C, was 5 g (15%) Analysis: Calculated for CgH^ClNOS: C,50.12;H, 4.67;N, 6.49 Found : C,50.00;H,4.63;N,6.53 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, 2-chlorobenzoic acid, and 3.4.5- trichlorobenzoic acid, there are obtained 4-fluorobenzamido-ethylmercaptan (Example 8A) 4-bromobenzamido-ethylmercaptan (Example 8B) 2-chloroben2amido-ethylmercaptan (Example 80 3.4.5- trichlorobenzamido-ethylmercaptan (Example 8D) Example 9 4-Chlorobenzamido-propylmercaptan.

When in the procedure of Example 7, 2-aminopropanethiol hydrochloride is substituted for 2-aminoethanethiol hydrochloride in equal molar amounts, the compound given in the title of this Example is obtained. - 15 Examples 10A to 10D When in the procedure of Examples 8A to 8D, 2-aminopropanethiol hydrochloride is substituted for 2-aminoethanethiol hydrochloride in equal molar amounts, there are obtained: 4-fluorobenzamido-propylmercaptan (Example 10A) 4-bromobenzamido-propylmercaptan (Example 10B) 2-chlorobenzamido-propylmercaptan (Example IOC) and 3,4,5-trichlorobenzamido-propylmercaptan (Example 10D) Examples 11A and 11B (a) Isothiouronium Salt of N-(2-mercaptoethyl)-benzamide.

A mixture of N-(2-chloroethyl)benzamide, 18.3 g (0.10 mole) and thiourea, 9.1 g (0.12 mole) in 120 ml of anhydrous ethanol were refluxed under nitrogen (protected from moisture) overnight. The solvent was removed by distillation and the resulting isothiouronium hydrochloride salt of N-(2-mercaptoethyl) benzamide, 25.2g (yield 94.7%), melted at 169-173°C. (b) Benzamido-ethylmercaptan.

The product of Example 11A was added to 300 ml of an aqueous solution of potassium hydroxide (2 moles) and warmed to about 90°C for 2-3 hours. The solution was cooled, washed with ether and acidified to pH 3. The - 16 resultant turbid solution was extracted with several portions of chloroform and the combined extracts dried over magnesium sulphate. The solution was evaporated under reduced pressure to give a light syrup which was then diluted while warmed with ligroine at a temperature of 60-110°C. The solid obtained was recrystallized from benzene-ligroine (1:5) to yield 13.1 g (42.3%) of a colourless, crystalline solid melting at 62.5-65.5°C. Analysis: Calculated for CgH^NOS: C,59.62;H,6.11;N,7.72 Found : C,59.50;H,5.98;N,7.59 Example 12 4-Methylbenzamido-ethylmercaptan.

To a solution of potassium hydroxide, 6.2 g (0.11 mole) in 200 ml 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 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 60-110°C caused - 17 precipitation of a crystalline solid, 9.31 g, melting at 110-113°C. The yield of the product after a single recrystallization from benzene-ligroine (1:5) was 7.41 g (yield 76.3%), melting at 112.5-114°C.

Analysis: Calculated for C1QH13SNO: C,61.50?H,6.71;N,7.17 : C,61.34;H,6.65;N,7.16 Example 13 4-Methoxybenzamido-ethyl Mercaptan.

To a solution of potassium hydroxide, 5.6 g (0.10 mole) in 170 ml of oxygen-free water under a 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. Tetrahydrofuran, 30 ml, 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 solid obtained was recrystallized from benzene-ligroine (1:5) at a temperature of 60-110°C. The yield was 3.97 g (57.7% based 2-aminoethanethiol hydrochloride), and the product melted at 107-108.5°C.

Analysis: Calculated for C|qH|jNO2S:C,56.85;H,6.20;N,6.63 Found :C,56.90;H,6.16;N,6.64 - 18 Examples 14A to 14D When in the procedure of Example 12, 4-methoxybenzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride is replaced by equal molar quantities of the following; 3,4,5-trimethoxybenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4A), 3- trifluoromethylbenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4B), 3,4-dimethylbenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4C), or 4- carboxybenzoylcarbothioic acid, 2-aminoethyl ester, hydrochloride (see Example 4D), there are obtained 3,4,5-trimethoxybenzamido-ethylmercaptan (Example 14A), 3- trifluoromethylbenzamido-ethylmercaptan (Example 14B), 3,4-dimethylbenzamido-ethylmercaptan (Example 14C) and 4- carboxybenzamido-ethylmercaptan (Example 14D).

Examples 15A to 15C 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 ester hydrochloride (see Example 5) 4-methylbenzenecarbothioic acid, 3-aminopropyl ester, 8 7 9 3 - 19 hydrochloride (see Example 6A) or 4-methoxybenzenecarbothioic acid, 3-aminopropyl ester, hydrochloride (see Example 6B) there are obtained benzamido-propyl mercaptan (Example 15A) 4-methylbenzamido-propyl mercaptan (Example 15B) and 4-methoxybenzamido-propyl mercaptan (Example 15C).

Examples 16A and 16B (a)Isothiouronium Salt of N-(2-mercaptoethyl)-4-aminobenzamide.

When in the procedure of Example 11A, N-(2-chloroethyl)4-aminobenzamide is substituted in equal molar amounts for N-(2-chloroethyl) benzamide, the compound given in the title above is obtained. (b) 4-Aminobenzamide-ethylmercaptan.

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

The pharmaceutical compositions of this invention comprise benzamidoalkyl mercaptans in an amount sufficient to provide effective action against lung congestion in mammalian subjects when applied topically as an inhalant - 20 together with an acceptable carrier therefor.

The compounds of Formula 1 are administered in an amount sufficient to induce liquefaction 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 polyethyleneglycol-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 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 0.5 to 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 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 - 21 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 the subject. Individual doses ranging from 5-100 mg for 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 17 Powder for Administration via Inhaler Device. 4-chlorobenzamido ethyl mercaptan of Example 7, micronized 2.5 g Lactose powder 2,5 g The powders are blended aseptically and filled into hard gelatin capsules each containing 50 mg 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 (23)

1. A compound having the formula: wherein : R represents a hydrogen or a halogen atom, or a lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl radical, -alk- represents a straight or branched divalent alkylene radical of from 2 to 4 carbon atoms and 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.

2. A compound as claimed in Claim 1 in which the compound is 4-chlorobenzamido-ethylmercaptan

3. A compound as claimed in Claim 1 in which the compound is benzamido-ethylmercaptan.

4. A compound as claimed in Claim 1 in which the compound is 4-methylbenzamido-ethylroercaptan.

5. A compound as claimed in Claim 1 in which the compound is 4-methoxybenzamido-ethylmercaptan.

6. A pharmaceutical composition in inhalable liquid form comprising - 23 a) 0.5 to 20 weight % of a compound of the formula: wherein; R represents a hydrogen, halogen,lower alkyl, loweralkoxy, amino, carboxy or trifluoromethyl radical, -alk- represents a straight or branched divalent alkylene radical of from 2 to 4 carbon atoms, n is one to three, and b) a pharmaceutically acceptable carrier therefor.

7. A pharmaceutical composition in insufflatable powder form comprising a) 25-75 weight % of a micronized compound of the formula wherein; R represents a hydrogen, halogen, lower-alkyl, lower-alkoxy, amino, carboxy or trifluoromethyl radical, -alk- represents a straight or branched divalent alkylene radical of from 2 to 4 carbon atoms, n is one to three, and b) a pharmaceutically acceptable powder carrier therefor. - 24

8. A composition as claimed in Claim 6 or Claim 7 in which the compound is 4-chlorobenzamido-ethylmercaptan.

9. A composition as claimed in Claim 6 or 7 in which the compound is benzamido-ethylmercaptan. 5 10. A composition as claimed in Claim 6 or 7 in which the compound is 4-methylbenzamidp+ethylmercaptan. 11. A composition as claimed in Claim 6 or Claim 7 in which the compound is 4-methoxybenzamido-ethylmercaptan. 12. 4-Fluorobenzamido-ethylmercaptan.

10. 13. 4-Bromobenzamido-ethylmercaptan.

11. 14. 2-Chlorobenzamido-ethylmercaptan.

12. 15. 3,4,5-Trichlorobenzamido-ethylmercaptan.

13. 16. 4-Fluorobenzamido-propylmercaptan.

14. 17. 4-Bromobenzamido-propylmercaptan. 15

15. 18. 2-Chlorobenzamido-propylmercaptan.

16. 19. 3,4,5-Trichlorobenzamido-propylmercaptan.

17. 20. 3,4,5-Trimethoxybenzamido-ethylmercaptan.

18. 21. 3-Trifluoromethylbenzamido-ethylmercaptan.

19. 22. 3,4-Dimethylbenzamido-ethylmercaptan. 20

20. 23. 4-Carboxybenzamido-ethylmercaptan.

21. 24. Benzamido-propylmercaptan.

22. 25 4-Methylbenzamido-propylmercaptan.

23. 26. 4-Methoxybenzamido-propylmercaptan.