JPS6341899B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to certain carbothioic acid-2-aminoalkyl esters having mucolytic activity;
It relates to substituted benzene and 2-thiophene-carbothioic acid-2-aminoalkyl ester salts for combating and inhibiting mucus accumulation, especially in animals exhibiting pulmonary congestion.

The prior art discloses benzenecarbothioic acid-2-aminoethyl ester hydrochloride [WD
Foge et al, J.Pharm.Sci51(2), 168-71 (1962)]
However, there is no disclosure of mucolytic activity. Although the prior art discloses certain mucolytics, such as N-acetyl-cysteine, which has a free sulfhydryl group, the compounds of the present invention do not have that group. ALScheffner, Ann.NYAcad.Sci.106,
298-310 (1963), in the development of N-acetyl-L-cysteine as a mucolytic agent in the treatment of lung diseases, established the use of gastric mucus mucoproteins as a test vehicle.

The compounds of the present invention are substituted benzene and 2-thiophenecarbothioic acid-2-aminoalkyl ester salts generally represented by the following formula: Here, R is a 2-thienyl group or a phenyl group substituted with the same or different 1 to 3 groups selected from halogen, lower alkyl, lower alkoxy, carboxy or trifluoromethyl, and X ^- is chlorine or bromine. and n
is 2 or 3. The compound has mucolytic activity and is useful for dissolving and diluting mucus in warm-blooded animals exhibiting or suffering from pulmonary congestion.

The compounds described hereinafter and represented by the above formula are:
As described below, SJCarne et al.
A modification of the method of Phys. 242, 116 (1974) was shown to have mucolytic activity in animals.

Compounds whose mucolytic activity was found to be of the same order of magnitude as N-acetyl-L-cysteine for rat heteromucus are preferred compounds, and they are as follows.

(1) 4-chlorobenzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride, (2) 4-methylbenzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride, (3) 4-methoxybenzenecarbothioic acid acid, 2-aminoethyl ester, monohydrochloride, (4) 4-thiophenecarbothioic acid, 2-aminoethyl ester, monohydrochloride.

The method used to establish the mucolytic activity of compounds of the invention is as follows.

Female Spraque
(Charles River Labo) Rats weighing 120-180 g are housed at a ratio of 2 animals per cage and fasted for 16 hours on wire. Lights are left on during the fast to minimize coprophagia. Administer 2 c.c. of water orally to each rat to minimize internal waste. After 30 minutes, rats are killed by cervical dislocation. Remove the stomach, cut away excess tissue,
Discard the epithelial portion. Before placing the stomach in the drug solution, cut the glandular section well along the major and minor curvature to evert the stomach. Discard stomachs that smell of feces or contain visible fecal material. The stomach is placed in 10 c.c. of a solution (water or 50% polyethylene glycol 300- _H2O depending on solubility) containing 2.5 mg/ml of the test compound for 40 minutes. After drug treatment, the stomach is placed in 10 c.c. of Alcian Blue solution (Solution 1) for 90 minutes, where the dye complexes with the gastric mucus. 10c.c.
After two consecutive 10 minute washes in a 0.25 molar sucrose solution (solution 2), the stomach was washed with 10 c.c.
Place in MgCl ₂ solution (solution 3) for 1 hour to remove complexed dye. Remove lipids by shaking the upper layer of MgCl ₂ in a 60 c.c. separatory funnel with 10 c.c. diethyl ether. The aqueous phase was drained into a Spectronic 20 tube and the transmittance (%) was measured on a Spectronic 20 spectrophotometer at 605 mμ.
Read in. Convert transmittance from standard curve to Alcian blue in μg/ml [P. Whiteman,
Biochem, J. 131, 351-57 (1973)]. Each drug or drug excipient (control) is tested on three stomachs. The mean difference between treated and control values is expressed as a percentage.

Solution 1 - Alcian Blue, 0.05%
W/V (1) 54.8g Sucrose (0.15mol) 6.8g Sodium acetate 900c.c. Deionized water Dissolve with a magnetic stirrer and adjust to PH5.8.
500mg Alcian Blue 8GN (Matheson
Coleman & Bell #8E13). Fill volumetric flask with 1. Refrigerate. Use for only one week.

Solution 2 - Sucrose, 0.25 moles (1) Add 85.6 g of sucrose to volumetric flask 1. Fill the volume with deionized water. Use for only one week.

Solution 3 - Magnesium Chloride, 0.5 mol (1) Add 101.7 g of MgCl ₂ .6H ₂ O ACS to 1 volumetric flask. Fill the volume with deionized water.

It is therefore an object of the present invention to provide certain novel carbothionic acid, 2-aminoalkyl ester salts, which have mucolytic activity in warm-blooded animals.

Other objects and advantages of the invention will become apparent from the following description of the best mode of carrying out the invention, and from the claims.

In the definitions of symbols and the above formulas, and when appearing elsewhere in the claims and specification, the terms have the following meanings:

As used herein, "benzene substituted with 1 to 3 groups" refers to a phenyl group substituted with 1 to 3 groups selected from the group defined above under the definition of R. and these substituents can be present on various effective parts of the phenyl nucleus, and when more than one substituent is present, they may be the same or different, They can be in various positions with respect to each other. Each of the lower alkyl and lower alkoxy substituents preferably has 1 to 4 carbon atoms and they can be arranged as straight or branched chains. Examples of preferred substituents are methyl, ethyl, propyl,
butyl, fluoro, bromo, chloro, iodo, methoxy, ethoxy, butoxy, carboxy and trifluoromethyl.

Substituted benzene and thiophenecarbothioic acid, 2-aminoalkyl ester salts are prepared by known methods for preparing benzene derivatives as shown in the following reaction scheme: Here, R, n and X ^- are as defined above.

Generally, the reactants are mixed and heated over a jet of steam until crystals form. The crystals are then crushed, triturated with ligroin, and recrystallized from absolute ethanol.

The following examples of the preparation of compounds are intended only to illustrate the invention and are not to be considered as limiting the invention in any way.

Reference Example Synthesis of benzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride A mixture of 15 ml (approximately 0.13 mol) of benzoyl chloride and 4.54 g (0.04 mol) of 2-aminoethanethiol hydrochloride was heated by steam injection. (protected from moisture) for 2 hours. Crystals formed upon slight cooling. After grinding, filtering and drying with ligroin at 60~110℃, the crystals are 177~
Melted at 180℃. Several recrystallizations from absolute ethanol gave a colorless solid, melting point 178.5-179.5°C. Nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared analysis (IR) all confirmed the structure of benzenecarbothioic acid, 2-aminoethyl ester, monohydrochloride. The yield is 5.1g (59.1
%).

Analysis: _Calculated value for _C9H12ClNOS : C, 49.65; H, 5.55; N, 6.43 Actual value: C, 49.58; H, 5.59; N, 6.49 Example 1 4-chlorobenzenecarbothioic acid, 2-aminoethyl Ester, monohydrochloride 60 ml (0.47 mol) of freshly distilled p-chloride
A mixture of chlorobenzoyl and 2-aminoethanethiol hydrochloride was heated over a steam jet for 2 hours. As the reaction approached completion, solid crystals formed. After careful trituration with warm 60-110°C ligroin, the crystals were separated by filtration while washing with ligroin. After recrystallization twice from absolute ethanol, the product, 39.0 g (96.5
%), melted at 208-209.5℃. All NMR, MS and IR analyzes confirmed the structure of the title compound according to the formula.

Analysis: _Calculated value for _C9H11Cl2SNO : C, 42.87; H, 4.40; N, 5.55 Actual value: C, 42.79; H, 4.43; N, 5.59 Example 2 4 _- Methylbenzenecarbothionic acid, 2-Aminoethyl ester, monohydrochloride 30 ml (approximately 0.18 mol) of freshly distilled p chloride
-Toru oil, boiling point 122°C/32mmHg and 9.68g
A mixture of (0.085 mol) of 2-aminoethanethiol hydrochloride was heated over a steam jet (protected from moisture) for 2.25 hours. Solid crystals formed when the reaction was complete. Crush this and warm it to 60-110℃.
of ligroin and the crystals were separated by filtration and washed with warm ligroin. After recrystallizing twice from absolute ethanol, the product,
19.07g (97%) melted at 206.5-208°C. With all NMR, MS and IR analyses,
The structure of the title compound according to the formula was confirmed.

Analysis: _Calculated value for _C10H14NOClS : C, 51.83; H, 6.09; N, 6.04 Actual value: C, 51.57; H, 6.06; N, 6.11 Example 3 4-methoxybenzenecarbothionic acid, 2-amino Ethyl ester, monohydrochloride A mixture of 23 ml (about 0.135 mol) of p-anisoyl chloride and 7.4 g (0.065 mol) of 2-aminoethanethiol hydrochloride was heated over a steam jet for about 2 hours (protected from moisture). did). Crush the resulting crystals and carefully grind with warm 60-110°C ligroin, separate the crystals by filtration,
Then I washed it with warm ligroin. After two crystallizations from absolute ethanol, the product, 14.6 g (90.6%),
melted at 19.15-193℃. NMR, MS and
All IR analyzes confirmed the structure of the title compound according to the formula.

Analysis: Calculated value for C ₁₀ H ₁₄ ClNO ₄ S: C, 48.48; H, 5.69; N, 5.65 Actual value: C, 48.42; H, 5.73; N, 5.66 Example 4 In the procedure of the reference example, benzoyl chloride If, instead of, equimolar amounts of 3,4,5-trimethoxybenzoyl chloride, 4-trifluorobenzoyl chloride, 3-triflumethylbenzoyl chloride, 3,4-dimethylbenzoyl chloride, 4-carboxybenzoyl chloride are used , 3,4,5-trimethoxybenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride, 4-fluorobenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride, 3-trifluoromethylbenzenecarbothioic acid, 2-aminoethyl ester, hydrochloride, 3,4-dimethylbenzenecarbothioic acid, 2-
Aminoethyl ester, hydrochloride, 4-carboxybenzenethioic acid, 2-aminoethyl ester, hydrochloride are obtained.

Example 5 If an equimolar amount of 3-aminopropanethiol hydrochloride is used in place of 2-aminoethanethiol hydrochloride in the procedure of the reference example, benzenecarbothioic acid-3-aminopropyl ester hydrochloride is obtained.

Example 6 In the procedure of the reference example, instead of 2-aminoethanethiol hydrochloride, an equimolar amount of 3-aminopropanethiol hydrochloride is used, and instead of benzoyl chloride, p-chlorobenzoyl chloride, p-chloride When using toluoyl, or p-anisoyl chloride, 4-chlorobenzenecarbothioic acid, 3-aminopropyl ester hydrochloride, 4-methylbenzenecarbothioic acid, 3-aminopropyl ester hydrochloride, and 4-methoxybenzenecarbothioic acid , 3-aminopropyl ester hydrochloride, is obtained.

Example 7 2-Thiophenecarbothioic acid, 2-aminoethyl ester, hydrochloride 15.8 g (0.108 mol) freshly distilled 2-thiophenecarbonyl chloride and 11.3 g (0.1 mol) 2-aminoethanethiol hydrochloride The salt mixture was heated over a steam jet for 6 hours (protected from moisture). Crush the resulting crystals and warm 60
Crystals were collected by trituration and straining with ligroin at ~110°C. After recrystallization twice from absolute ethanol, the product, 8.41 g (75.5%), is 195~
It melted at 196.5°C. NMR, MS and IR analyzes all confirmed the structure of the title compound according to the formula.

Analysis: _Calculated value _{for C7H10ClNOS2} : C, 37.58; H, 4.51; N, 6.26 Actual value: C, 37.68; H, 4.50; N, 6.30 Example 8 In the procedure of Example 7, 2- When an equimolar amount of 3-aminopropanethiol hydrochloride is used in place of aminoethanethiol hydrochloride, thiophenecarbothioic acid, 3-aminopropyl ester hydrochloride is obtained.

The compounds of the invention can be formulated into pharmaceutical compositions to provide effective mucolytic action against pulmonary retention in mammalian subjects when applied topically as an inhalant.

A compound of formula is administered in an amount sufficient to induce liquefaction of mucus in the respiratory tract of a warm-blooded animal in need of treatment. Intra-respiratory administration of compounds of formula can be accomplished by various means of inhalation or instillation, such as nasal instillation,
Perform by spraying, fumes, etc. Other suitable means of administration are by injection of fine particles or very fine powders, using the energy of respiration alone or by the use of aerosol propellants. Approximately 0.5
Solutions or suspensions containing ~5% by weight of mucolytic agents of the formula are suitable for application by spray using nebulizers, fumes, aerosols, and the like.

As is clear to those skilled in the medical field,
The correct dosage of the compound to be used for a particular mammalian subject will be determined by the severity of the condition requiring mucolytic treatment, as well as the age, sex, weight and general physiological condition of the subject. For inhalation by humans, individual doses in the range 5-100 mg will be appropriate and required for mucolysis.

Pharmaceutical compositions can take the form of dilutions of the particulate compound in powders or solutions and suspensions in liquids suitably dispensed for inhalation.

A 4-chlorobenzenecarbothioic acid of powder example 1 for administration using an inhalation device;
2-Aminoethyl ester monohydrochloride, finely ground 2.5 g Lactose powder 2.5 g The powders are blended aseptically and filled into hard gelatin capsules. Each capsule contains 50mg of the mixture. It is suitable for dispersion into the inspiratory breath by means of a breath-actuated inhalation device having means for tearing the capsule wall apart before administration.

B Sterile solution for administration using an inhalation device 1 100 mg of active ingredient 2 Amount to make 1.0 cc of 95% alcohol Ingredients 1 and 2 are dissolved by heating and administered via a breath-actuated inhalation device.

C Aqueous solution 1 Active ingredient, Example 1, 3 or 5 10 g 2 Distilled water 90 g Total 100 g Components 1 and 2 are diluted into a dosage form and administered by inhalation device or aerosol.

Claims (1)

[Claims] 1. General formula: (R is the same or different group selected from 2-thienyl group, halogen, lower alkyl, lower alkoxy, carboxy or trifluoromethyl)
A phenyl group substituted with ~3 groups, X ^-
is a chlorine or bromine ion, and n is 2
or 3). 2. The compound according to claim 1, which is 4-chlorobenzenecarbothioic acid 2-aminoethyl ester monohydrochloride. 3. The compound according to claim 1, which is 4-methylbenzenecarbothioic acid 2-aminoethyl ester monohydrochloride. 4. The compound according to claim 1, which is 4-methoxybenzenecarbothioic acid 2-aminoethyl ester monohydrochloride. 5. The compound according to claim 1, which is 2-thiophenecarbothioic acid 2-aminoethyl ester monohydrochloride.