FI69060C - PROCEDURE FOR THE FRAMSTATION OF AN ETH PHARMACEUTICAL ACTIVATED 2-MINOETHYL ESTERSYRASAL AV EN SUBSTITUTES BENSEN- ELLER OS UBTITUERAD TIOFENKARBOTIOINSYRA - Google Patents

Description

phrase ΓΜ mix ADVERTISEMENT 69060

UTLÄGGN, NGSSKRIFT

C (45) Γ. · Ti ay · -. _. : y .1. 1Z 1955 (51) Kv.lk. * / Lnt.CI. 'C 07 C 153 / Π, C 07 D 333/38 FINLAND —FINLAND (21) Patent application - Patentansöknlng 792 ** 7 ** (22) Filing date— Ansöknlngsdag 09.08 79 (Fl) (23) Start date - Giltighetsdag 09.08.79 (41) Become public - Blivit offentlig 1 j 02 80

Patent · and the National Board of Registration Date of display and publication— «o gr

Patents and Registration Cases '' Ansökan utlagd och utl.skriften publlcerad ju.uo.05 (32) (33) (31) Claim Requested — Begärd Priority 10.08.78 USA (US) 9327 ^ 7 (71) AH Robins Company, Incorporated , 1407 Cummings Drive, Richmond, Virginia 23220, USA (72) Harry Randall Munson, Jr., Richmond, Virginia, USA (7 * 0 Berggren Oy Ab (54) Method of pharmaceutically active substituted benzene or subs The present invention relates to a process for the preparation of is a formula

~ O

r-c-sch2ch2nh3 + X "I

wherein R is a 2-thiophene group or a benzene group substituted by halogen, lower alkyl or lower alkoxy and X is a chlorine or bromine radical. The compounds of formula I have mucolytic activity and are useful in controlling and controlling the accumulation of mucus in an animal suffering from pulmonary congestion.

Examples of the benzene ring substituent include methyl, ethyl, propyl, butyl, fluoro, bromo, chloro, iodo, methoxy, ethoxy and butoxy groups.

The synthesis of benzenecarbothioic acid 2-aminoethyl ester hydrochloride has been previously described in the art, W.O. Foye et al. J. Pharm. Sci 51 (2), 168-71 (1962), but there is no mention of 2,69060 mucolytic activity. Substitution of the benzene ring is not shown. Certain mucolytic agents have been previously described in the art, such as N-acetylcysteine having a free sulfhydryl group which is not present in the compounds of this invention. A. L. Sheffner, Ann. N.Y. Acad. 106, 298-310 (1963) established the use of abdominal mucin mucoprotein as a test medium in the development of N-acetyl-L-cysteine as a mucolytic agent in the treatment of lung diseases.

The compounds of formula I are prepared as a compound of formula

O

II

R-C-X

wherein R and X are as defined above, is reacted with an aminoethanethiol hydrohalide of formula

hsch2ch2nh2 <HX

where X is as defined above.

Preferably, the starting materials are mixed and heated with a steam jet until a crystalline mass is formed, which is then crushed, triturated in naphtha and recrystallized from anhydrous ethanol.

The compounds of formula I are shown by a modification of the method described below by S.J. Carne et al., J. Phys. 242, 16 (1974), to have cloth activity in animals.

The compounds of formula I in which the mucolytic activity was found to be of the same order of magnitude as N-acetyl-L-cysteine in rat gastric mucus were as follows: 1 2 3

II

4-chlorobenzenecarbothioic acid 2-aminoethyl ester monohydrochloride, 2,4-methylbenzenecarbothioic acid 2-aminoethyl ester monohydrochloride, 3,4-methoxybenzenecarbothioic acid 2-aminoethyl ester monohydrochloride, and 3,69060 4)

The method used to detect mucolytic activity in the compounds of this invention is as follows.

Female Sprague-Dawley rats (Charles River Labs) weighing 120-180 g are fasted for 16 hours on wire, keeping two animals in each cage. To reduce stool eating, the lights are left on during fasting. Two cm of water is given orally to each rat to reduce internal cracking. Thirty minutes later, the rats are killed by folding the neck. The stomachs are removed, smoothed out of excess tissue, and the epithelial portion is discarded. The glandular portion is cut along a sufficiently larger and smaller curvature to cause the stomach to invert before being placed in the drug solution. Stomachs that smell feces or contain visible feces are discarded. The stomachs are placed in 10 enamel solution (water or 50% PEG 300-H 2 O depending on solubility) containing 2.5 mg of test compound / ml for 40 minutes. After drug treatment, the stomachs are placed in 10 cm 2 of Alcian Blue solution for 90 minutes. (Solution 1), in which the dye forms a complex with gastric mucus. After two successive 10-minute washes in 10 cm of 0.25 M sucrose solution 3 (Solution 2), the stomachs are placed in 10 cm of 0.5 M MgCl 2 solution (Solution 3) for one hour to remove the complexed dye. The supernatant MgCl 2 solution is shaken with 10 cm 2 of diethyl ether in a 60 cm 2 separatory funnel to remove lipids. The aqueous phase is drained into a Spectronic 20 tube and the percentage transmittance is read at 605 on a Spectronic 20 spectrophotometer. The permeation percentage is changed to μg / ml Alcian Blue from the standard curve. £ P. Whiteman, Biochem. J. 131, 351-57 (1973). Each drug or drug inversion (check) is tested on three stomachs. Mean differences between treated and control values are expressed as percentages.

4,69060

Solution 1 - Alcian Blue, 0.05% w / v. (1 liter) 54.8 g of sucrose (0.15 M) 6.8 g of sodium acetate 3,900 cm of deionized water

Dissolve with a magnetic stirrer and adjust to pH 5.8. Add 500 mg of Alcian Blue 8 GN (Matheson, Coleman &

Bell No. 8 E 13). Make up to 1 liter in a graduated flask. Deep-cooled. Used for one week only.

Solution 2 - Sucrose, 0.25-M (1 liter)

Add 85.6 g of sucrose to a 1 liter volumetric flask. Make up to volume with deionized water. Used for one week only.

Solution 3 - Magnesium chloride, 0.5 M (1 liter)

101.7 g of MgCl 2 are added. to a one liter volumetric flask. Make up to volume with deionized water.

The following examples illustrate this invention.

Example 1 4-Chloro-benzenecarbothioic acid 2-amino-ethyl ester monohydrochloride____

A mixture of 60 ml (0.47 mol) of freshly distilled p-chlorobenzoyl

II

69060 5 chloride and 18.18 g (0.16 mol) of 2-aminoethanethiol hydrochloride were heated (protected from moisture) with a steam jet for 2 hours. A solid crystalline mass formed when the reaction was complete. After thorough trituration with warm 60-110 ° C naphtha, the crystals were separated by filtration, washing with the same naphtha. After two recrystallizations from anhydrous ethanol, the product, 39.0 g (96.5%), melted at 208-209.5 ° C. NMR, MS and IR analyzes all supported the structure of the title compound of formula I.

Analysis: Calculated from C 9 H 11 Cl 2 SNO: C 42.87, H 4.40, N 5.55 Experimental: C 42.79, H 4.43, N 5.59

Example 2 Monohydrochloride of 2-aminoethyl ester of 4-methylbenzenecarbothioic acid

A mixture of 30 ml (ca. 0.18 mol) of freshly distilled p-toluoyl chloride, b.p. 122 ° C / 32 mmHg and 9.68 g (0.085 mol) of 2-aminoethanethiol hydrochloride were heated (protected from moisture) with a steam jet for 2.25 hours. A solid crystalline mass formed at the end of the reaction. The mass was crushed and triturated thoroughly in warm 60-110 ° C naphtha and the crystals were separated by filtration and washed with warm naphtha. After two recrystallizations from anhydrous ethanol, the product, 19.07 g (97%), melted at 206.5-208 ° C. NMR, MS and IR analyzes all supported the structure of the title compound of formula I.

Analysis: Calculated from the formula C 18 H 19 N 2 O 2: C 51.83, H 6.09, N 6.04 Experimental: C 51.57, H 6.06, N 6.11

Example 3 Monohydrochloride of 2-aminoethyl ester of 4-methoxybenzenecarbothioic acid

A mixture of 23 ml (ca. 0.135 mol) of p-anisoyl chloride and 7.4 g (0.065 mol) of 2-aminoethanethiol hydrochloride was heated (protected from moisture) with a steam jet for about 2 hours. The resulting crystalline mass was crushed and carefully triturated with 60-110 ° C naphtha, and the crystals were separated by filtration and washed with warm naphtha. After two recrystallizations from anhydrous ethanol, the product, 14.6 g (90.6%), melted at 191.5-193 ° C. NMR, MS and IR analyzes all supported the structure of the title compound of formula I.

69060

Analysis: Calculated from the formula gH ^ ^ ClNC ^ S: C 48.48, H 5.69, N 5.65

Experimentally C 48.42, H 5.73, N 5.66.

6

Example 4 2-Thiophenecarbothioic acid 2-aminoethyl ester hydrochloride A mixture of 15.8 g (0.108 mol) of freshly distilled 2-thiophenecarbonyl chloride and 11.3 g (0.1 mol) of 2-aminoethanethiol hydrochloride was heated (protected from moisture). ) with a steam jet for 6 hours. The resulting solid crystalline mass was crushed and triturated in warm 60-110 ° C in naphtha and filtered to collect crystals. After two recrystallizations from anhydrous ethanol, the product, 8.4 g (75.5%), melted at 195-196.5 ° C. NMR, MS and IR all supported the structure of the title compound of formula I.

Analysis: Calculating from the formula QCINOS2: C 37.58, H 4.51, N 6.26

Experimental: C 37.68, H 4.50, N 6.30 li