IE48794B1 - Benzene and thiophene-carbothioic acid 2 aminoalkyl ester acid salts - Google Patents
Benzene and thiophene-carbothioic acid 2 aminoalkyl ester acid saltsInfo
- Publication number
- IE48794B1 IE48794B1 IE1520/79A IE152079A IE48794B1 IE 48794 B1 IE48794 B1 IE 48794B1 IE 1520/79 A IE1520/79 A IE 1520/79A IE 152079 A IE152079 A IE 152079A IE 48794 B1 IE48794 B1 IE 48794B1
- Authority
- IE
- Ireland
- Prior art keywords
- acid
- compound
- radicals
- radical
- substituted
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention comprises benzene and 2 - thiophene carbothioic acid 2- aminoalkyl ester acid salts having the formula: wherein R is 2-thiophene, benzene or substituted benzene; n is 2 or 3 and X<-> is a chlorine or bromine radical and methods of using the compounds and compositions.
Description
The present invention is concerned with certain carbothioic acid aminoalkytesters possessing mucolytic activity and is particularly concerned with the use of substituted benzene and 2-thiophene-carbothioic acid aminoalkylester acid salts in combating and controlling mucus build-up in an animal exhibiting lung congestion and compositions containing these compounds for use as mucolytic agents.
The prior art discloses synthesis of benzene carbothioic acid-2-aminoethytester hydrochloride, W.O. Foye et al, J· Pharm. Sci. 51 (2), 168-71 (1962) but there is no disclosure of mucolytic activity. Substitution on the benzene ring has not been disclosed. The prior art discloses certain mucolytic agents such as N-acetyl-cysteine having a free sulphhydryl group, which group compounds of the present invention do not have. A.L. Sheffner, Ann. N.Y. Acad. Sci.106,.
298-310 (1963) established the use of gastric mucin mucioprotein as a test media in development of N-acetyl-L-cysteine as a mucolytic agents in the treatment of lung disease.
The compounds of the present invention are substituted benzene and 2-thiophenecarbothioic acid aminoalkylester acid salts illustrated generally by the following formula:
Formula 1 wherein;
R represents 2-thiophene, or benzene substituted by one to three radicals which may be halogenatoms, or loweralkyl, lower-alkoxy, carboxy or trifluoromethyl groups and may (3) be the same or different and in various positions relative to one another in the ring,
X is a chlorine or bromine radical and n is 2 or 3.
The terms lower-alkyl and lower-alkoxy denote groups having from one to four carbon atoms.
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. Came et al, J. Phys. 242, 116 (1974) as described herein-below to have mucolytic activity in animals.
Compounds for which mucolytic activity was found to be of the same order of magnitude as N-acetyl-L-cysteine on rat stomach mucus are the preferred compounds which are as follows:
(1) 4-Chlorobenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride, (2) 3-Methylbenzenecarbothioic acid, 2-aminoethyl ester monohydrocholride, (3) 4-Methoxybenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride, (4) 2-Thiophenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
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 (4) weighing 12O-18Og are fasted for 16 hours on wire, housed two animals per cage. To minimize coprophogia, 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 cervalcal 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 matter are discarded.
Stomachs are placed in 10 cc of an aqueous solution containing 2.5mg of the test compound/ml for 40 minutes, the aqueous solution being made up from water or a 50% aqueous solution of polyethylene glycol of MW 300 (PEG300) depending on the solubility of the test compound. After this drug exposure 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 10-minute washes in 10 cc of 0.25 M sucrose solution (Solution 2 prepared as described below), the stomachs are placed in 10 cc of 0.5 M aqueous magnesium chloride solution (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 diethyl in a 60 cc separatory funnel to remove lipids. The aqueous (5) phase is drained into a Spectronic 20 tube and the percent transmission is read at 6O5mp in a Spectronic (Trade Mark) 20 spectrophotometer. The percent transmission is converted to ug/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 Alcian Blue dye. It is made up by dissolving 54.8g of sucrose (0.15 M) and 6.8g of sodium acetate with stirring in 900 cc of deionized water using a magnetic stirrer. The pH is adjusted to pH 5.8. 500 mg Alcian Blue 8 GN (supplied by Matheson Coleman & Bell as # 8E13) is then added and the mixture topped up to 1 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 85.6g of sucrose in deionized water in a one litre volumetric flask and then making up with deionized water to one litre. The solution should only be used for one week after making up.
The aqueous magnesium chloride solution referred to as Solution 3 herein is made up by dissolving 101.7g of Mg 01^-6^0 (A.C.S.) in deionized water in one litre volumetric flask and than making up to 1 litre (6) deionized water.
It is an object of the present invention to provide certain novel carbothioic acid, aminoalkyl-ester acid salts having mucolytic activity in a warm-blooded animal.
A further object is to provide a method of using substituted benzene and 2-thiophene carbothioic acid aminoalkylester acid salts as mucolytic agents to combat mucus build-up in a warm-blooded animal suffering from lung congestion.
A further object is to provide pharmaceutical compositions containing the compounds useful for controlling congestion due to mucus in a warm-blooded animal body.
In the definition of the symbols and in Formula 1 given above, and where they appear elsewhere throughout the claims and specification hereof, the following terms have the following significance.
Benzene substituted by one to 3 radicals as used herein shall mean a phenyl radical which is substituted by one to 3 radicals selected fron the groups as hereinabove defined under the definition of R and these substituents can be in various available positions in 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 lower-alkyl and lower-alkoxy substituents having from one to four carbon atoms can be arranged as straight or branched chains. Examples of the preferred substituents are methyl, ethyl, propyl, butyl, fluoro, bromo, chloro, iodo,methoxy, ethoxy, butoxy, carboxy, (7) and trifluoromethyl radicals.
The substituted benzene and thiophene-carbothioic acid, aminoalkylester acid salts are prepared by procedures represented by the following equation:
R—C~X-*-HS(CH2) IW2 KX
R-C-S (θφ3+
X- wherein R, n and X are as defined hereinabove.
Generally, the reactants are mixed and heated over a steam jet until a mass of crystals are formed. The mass of crystals is then broken up, triturated with ligroine and recyrstallized from anhydrous ethanol.
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, Examples 1 to 8 describe the preparation of compounds of the present invention and Examples 9 to 11 describe pharmaceutical compositions in accordance with the invention.
Example 1
4-Chlorobenzenecarbothioic Acid, 2-Aminoethyl Ester
Monohydrochloride
A mixture of freshly distilled p-chlorobenzoyl chloride, 60 ml (0.47 mole) and 2-aminoethanethiol hydrochloride, 18.18 g (0.16 mole) was heated (protected (8) from moisture) over a steam jet for 2 hours. A solid crystalline mass formed as the reaction went to completion. After careful trituration with warm ligroine at a temperature of 60-110°C crystals were separated by filtration while washing with ligroine. After two recrystallizations from anhydrous ethanol, the product, 39.Og (yield 96.5%), melted at 208-209.5°C. NMR, MS and IR analyses all corroborated that the product was the compound given in the title of this example and had the structure of Formula 1.
Analysis: Calculated for CgH-^C^SNO:C,42.87; H,4.4O;
N,5.55
Found: C,42.79; H,4.43; N,5.59
Example 2
4-Methylbenzenecarbothioic Acid, 2-Aminoethyl Ester Monohydrocnloride.
A mixture of freshly distilled p-toluoyl chloride,
b.p. 122°C (at 32mm of mercury pressure) 30ml (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 and had the structure of Formula 1.
(9)
Analysis: Calculated for C^QH^^NOCIS: C,51.83; H,6.O9;
N,6.O4
Found: C,5.57;H,6.O6;N6.11
Exainple 3
4-Methoxybenzencarbothoic Acid, 2-Aminoethyl Ester Monohydrochloride.
A mixture of p-anisoyl chloride, 23ml (about 0.135 mole) and 2-aminoethanethiol hydrochloride, 7.4 g (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 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 analysis all corroborated that the product was the compound given in the title of this example and has the structure of Formula 1. Analysis: Calculated for CjpH^ClNOjS: C,48.48; H,5.69;
N,5.65
Found: C,48.42;H,5.73; N,5.66
Examples 4A to. 4_F
When in the procedure of Example 1, p-chloro benzoyl chloride is replaced by equal molar amounts of
3,4,5-trimethoxybenzoyl chloride,
4-fluorobenzoyl chloride, (10)
3- trifluoromethylbenzoyl chloride,
3.4- dichlorobenzoyl chloride,
3.4- dimethylbenzoyl chloride, and
4- carboxybenzoyl chloride there are obtained
3,4,5-trimethoxybenzenecarbothioic acid, 2-aminoethyl ester hydrochloride (Example 4A),
4-fluorobenzencarbothioic acid, 2-aminoethyl ester hydrochloride (Example 4B),
3-trifluoromethylbenzenecarbothioic acid, 2-aminoethyl ester hydrochloride (Example 4C),
3.4- dichlorobenzenecarbothioic acid, 2-aminoethyl ester hydrochloride (Example 4D),
3.4- dimethylbenzenecarbothioic acid, 2-aminoethyl 15 ester hydrochloride (Example 4E) and
4-carboxybenzenecarbothioic acid, 2-aminoethyl ester hydrochloride (Example 4F).
Examples 5A to 5C
When in the procedure of Example 1, 2-aminoethanethiol 20 hydrochloride is replaced by equal molar amounts of 3aminopropanethiol hydrochloride and, where appropriate, pchloro benzoyl chloride is replaced by p-chlorobenzoyl chloride, p-toluoyl chloride, or p-anisoyl chloride there are obtained
4-chlorobenzenecarbothioic acid, 3-aminopropyl
8 7 9 4 (11) ester hydrochloride (Example 5A),
4-methylbenzenecarbothioic acid, 3-aminopropyl ester hydrochloride (Example 5B) and
4-methoxybenzenecarbothioic acid,
3-aminopropyl ester hydrocholoride (Example 5C).
Example 6
2-Thiophenecarbothioic Acid, 2-Aminoethyl Ester Hydrochloride
A mixture of freshly distilled 2-thiophenecarbonyl chloride, 15.8g (0.108 mole) and 2-aminoethanethiol hydrochloride, 11.3g (0.1 mole) was heated (protected from moisture) over a steam jet for 6 hours. The resulting solid crystalline mass was crushed and triturated with warm ligroine at a temperature of 60-110°C and filtered to collect the crystals. After two recrystallizations from anhydrous ethanol, the product, 8.41 g (yield 75.5%) melted at 195-196.5°C. NMR, MS and IR all corroborated that the product was the compound given in the title of this example and had the structure of Formula 1.
Analysis: Calculated for C^H-^ClNOSg: C,37.58; H,4.51;
N,6.26
Found: C,37.68;H4.5O;N,6.30
Example 7
When in the procedure of Example 6, 2-aminoethanthiol hydrochloride is replaced by equal molar amounts of 3aminopropanethiol hydrochloride, there is obtained thiophenecarbothioic acid, 3-aminopropyl ester hydrochloride.
(12)
The pharmaceutical compositions of this invention comprise compounds of Formula 1 above in an amount sufficient to provide effective action against lung congestion in warm-blooded animal subjects when applied topically as an inhalant.
The compounds of Formula 1 are adminstered 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 installation means such as nose drops,sprays, or aerosol. Examples of pharmaceutically acceptable liquid carriers are water and polyethylene glycol-300 (MW 300). Another suitable means of administration is by insufflation of micronized particles or ultra-fine powders 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 50 or 75 weight %. Solutions or suspensions having about 0.5 to 20% by weight preferably 5% to 10% or 0.5% to 5% by weight of the mucolytic agent of
Formula 1 are suitable for application by spraying with for example an atomizer, nebulizer, or aersol.
Dusts containing about 25-75% or more active agent in micronized form are also suitable, about 50% being preferred. 25 It will be readily apparent to those skilled in the (13) 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 as illustrated by the following Examples 8 to 10.
Example 8
Powder for Administration via an Inhaler Device.
4-Chlorobenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride of Example 1, 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.
Example 9
Sterile Solution for Administration via an Inhaler
Device.
1. Active Ingredients (any one or more of the products of Examples 1 to 7 100 mg
2. Alcohol 95%, q.s. l.Occ (14)
Constituents 1 and 2 are dis^m^d by warming and the mixture administered by means of a breath-operated inhaler device.
Example 10
Aqueous Solution.
1. Active Ingredient (the compounds of Example 2 or A to 4F)
2. Distilled water
Constituent 1 is dissolved mixture diluted to dosage form and of an inhaler device or aerosol.
g 90 g
Total 100 g in the water and the administered by means
Claims (21)
1. A compound having the formula: R—1-S(CH 2 )-NH 3 X' wherein; R represents a 2-thiophene, or a substituted benzene radical, the substituted benzene radical being substituted by one to 3 radicals which may be the same or different, and which are halogen, lower-alkyl, loweralkoxy, carboxy, or triflouromethyl radicals; X is a chlorine or bromine radical, and n is 2 or 3, for use in combating mucus build-up in an animal body for the purpose of alleviating lung congestion in an animal suffering therefrom.
2. 4-Chlorobenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride as claimed in Claim 1.
3. 4-Methylbenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride as claimed in Claim 1.
4. 4-Methoxybenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride as claimed in Claim 1.
5. 2-Thiophenecarbothioic acid, 2-aminoethyl ester monohydrochloride as claimed in Claim 1.
6. A compound as claimed in Claim 1 prepared substantially as specifically desribed in any one of Examples 1 to 7. (16)
7. A pharmaceutical composition adapted for use by inhalation, instillation or insufflation as a mucolytic agent in an animal body suffering from lung congestion comprising 5 a) a compound of the formula R-C-S(CH 2 )4 R represents a 2-thiophene, of a substituted benzene radical, the substituted benzene radical being substituted by one to 3 radicals, which may be the same or different and which are halogen, lower alkyl, lower alkoxy, carboxy or trifluoromethyl radicals, X - is a chlorine or bromine radical, and n is 2 or 3, and b) a pharmaceutically acceptable carrier therefor.
8. A pharmaceutical composition in inhalable liquid form adapted for use as a mucolytic agent in an animal body suffering from lung congestion comprising a) 0.5 to 20% by weight of a compound of the formula Wherein; (17) R represents a 2-thiophene, or a substituted benzene radical, the substituted benzene radical being substituted by one to 3 radicals, which may be the same or different and which are halogen, lower alkyl, lower alkoxy, carboxy or trifluoromethyl radicals, X is a chlorine or bromine radical, and n is 2 or 3 and b) a pharmaceutical acceptable carrier therefor.
9. A pharmaceutical composition in insufflatable powder form adapted for use as a mucolytic agent in an animal body suffering from lung congestion comprising a) 25 to 75% of a micronized compound of the formula X' represents a 2-thiophene, or a substituted benzene radical, the substituted benzene radical being substituted by one to 3 radicals, which may be the same or different and which are halogen, lower alkyl, lower alkoxy, carboxy trifluoromethyl radicals, X _ is a chlorine or bromine radical, and n is 2 or 3, and b) A pharmaceutically acceptable powder carrier therefor. (18)
10. A composition as claimed in Claim 7,8, or 9 in which the compound is 4-chlorobenzenecarbothioic acid, 2aminoethyl ester monohydrochloride.
11. A composition as claimed in Claim 7,8, or 9 in 5 which the compound is 4-methyIbenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
12. A composition as claimed in Claim 7,8, or 9 in which the compound is 4-methoxybenzenecarbothioic acid, 2-aminoethyl ester 10 monohydrochloride.
13. A composition as claimed in Claim 7,8, or 9 in which the compound is 2-thiophenecarbothioic acid, 2aminoethyl ester monohydrochloride.
14. A composition as claimed in Claim 7 substan15 tially as specifically described herein with reference to Example 8,9, of 10.
15. A substituted benzene or thiophenecarbothioic acid, aminoalkyl ester acid salt having the formula: wherein; R represents a 2-thiophene, or a benzene radical 25 substituted by one to three radicals, which may be the same or different, which are halogen, lower alkyl, lower alkoxy, (19) carboxy or trifluoromethyl radicals, X is a chlorine or bromine radical, and n is 2 or 3.
16. 4-chlorobenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
17. 4-methylbenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
18. 4-methoxybenzenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
19. 2-thiophenecarbothioic acid, 2-aminoethyl ester monohydrochloride.
20. A compound as claimed in Claim 15 substantially as specifically described herein with reference to any one of Examples 1 to 7.
21. A pharmaceutical composition according to claim 7, substantially as herein described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US93274778A | 1978-08-10 | 1978-08-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE791520L IE791520L (en) | 1980-02-10 |
IE48794B1 true IE48794B1 (en) | 1985-05-15 |
Family
ID=25462846
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE1520/79A IE48794B1 (en) | 1978-08-10 | 1979-08-08 | Benzene and thiophene-carbothioic acid 2 aminoalkyl ester acid salts |
Country Status (17)
Country | Link |
---|---|
JP (2) | JPS5536486A (en) |
AU (1) | AU520791B2 (en) |
BE (1) | BE878169A (en) |
CA (1) | CA1125297A (en) |
CH (1) | CH642062A5 (en) |
DE (1) | DE2932402A1 (en) |
DK (1) | DK159655C (en) |
EG (1) | EG14416A (en) |
ES (1) | ES483269A1 (en) |
FI (1) | FI69060C (en) |
FR (2) | FR2433016A1 (en) |
GB (1) | GB2028325B (en) |
IE (1) | IE48794B1 (en) |
IL (1) | IL57859A (en) |
IT (1) | IT1118828B (en) |
PH (1) | PH16277A (en) |
ZA (1) | ZA794171B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1170862B (en) * | 1981-03-31 | 1987-06-03 | Sigma Tau Ind Farmaceuti | MERCAPTOACIL-CARNITINE PROCEDURE FOR THEIR PREPARATION AND THERAPEUTIC USE |
JP3635780B2 (en) * | 1996-04-08 | 2005-04-06 | 株式会社デンソー | Honeycomb structure forming apparatus and forming method |
CN110597249B (en) * | 2019-08-23 | 2022-08-05 | 深圳市优必选科技股份有限公司 | Robot and recharging positioning method and device thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2342142A (en) * | 1937-09-09 | 1944-02-22 | Squibb & Sons Inc | Esters of sulphur-containing benzoic acids and process of preparing them |
US3328442A (en) * | 1963-12-18 | 1967-06-27 | Massachusetts College Of Pharm | Anti-radiation compounds and their preparation |
DE2335079C3 (en) * | 1973-02-21 | 1979-02-15 | Laboratories Made S.A., Madrid | Aminoalkyl derivatives of 3,5-dimethylbenzoic acid and their salts and processes for their preparation |
US4210666A (en) * | 1978-08-10 | 1980-07-01 | A. H. Robins Company, Inc. | Mucolytic thiophenecarboxamido alkyl mercaptans |
IL57881A (en) * | 1978-08-10 | 1982-12-31 | Robins Co Inc A H | Pharmaceutical compositions containing benzamidoalkyl merccaptans |
-
1979
- 1979-07-20 IL IL57859A patent/IL57859A/en unknown
- 1979-08-03 CH CH716879A patent/CH642062A5/en not_active IP Right Cessation
- 1979-08-03 PH PH22851A patent/PH16277A/en unknown
- 1979-08-08 EG EG487/79A patent/EG14416A/en active
- 1979-08-08 IE IE1520/79A patent/IE48794B1/en unknown
- 1979-08-08 GB GB7927694A patent/GB2028325B/en not_active Expired
- 1979-08-09 DK DK333879A patent/DK159655C/en not_active IP Right Cessation
- 1979-08-09 FI FI792474A patent/FI69060C/en not_active IP Right Cessation
- 1979-08-09 IT IT68643/79A patent/IT1118828B/en active
- 1979-08-09 CA CA333,424A patent/CA1125297A/en not_active Expired
- 1979-08-09 BE BE0/196671A patent/BE878169A/en not_active IP Right Cessation
- 1979-08-09 AU AU49756/79A patent/AU520791B2/en not_active Ceased
- 1979-08-09 ES ES483269A patent/ES483269A1/en not_active Expired
- 1979-08-09 FR FR7920412A patent/FR2433016A1/en active Granted
- 1979-08-09 DE DE19792932402 patent/DE2932402A1/en active Granted
- 1979-08-10 ZA ZA00794171A patent/ZA794171B/en unknown
- 1979-08-10 JP JP10212879A patent/JPS5536486A/en active Granted
-
1980
- 1980-02-14 FR FR8003290A patent/FR2453150A1/en active Granted
-
1987
- 1987-10-27 JP JP62271595A patent/JPS63119423A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
GB2028325B (en) | 1982-11-17 |
BE878169A (en) | 1979-12-03 |
AU520791B2 (en) | 1982-02-25 |
ZA794171B (en) | 1980-08-27 |
JPH0262530B2 (en) | 1990-12-26 |
FR2453150B1 (en) | 1983-05-20 |
DK159655C (en) | 1991-04-08 |
IL57859A (en) | 1983-02-23 |
EG14416A (en) | 1984-06-30 |
DK159655B (en) | 1990-11-12 |
DE2932402C2 (en) | 1988-12-22 |
IT1118828B (en) | 1986-03-03 |
DE2932402A1 (en) | 1980-02-21 |
AU4975679A (en) | 1980-02-14 |
JPS5536486A (en) | 1980-03-14 |
FI69060C (en) | 1985-12-10 |
FR2453150A1 (en) | 1980-10-31 |
FR2433016B1 (en) | 1983-05-13 |
ES483269A1 (en) | 1980-04-16 |
JPS63119423A (en) | 1988-05-24 |
JPS6341899B2 (en) | 1988-08-19 |
FI792474A (en) | 1980-02-11 |
CH642062A5 (en) | 1984-03-30 |
DK333879A (en) | 1980-02-11 |
GB2028325A (en) | 1980-03-05 |
IL57859A0 (en) | 1979-11-30 |
PH16277A (en) | 1983-08-26 |
CA1125297A (en) | 1982-06-08 |
IE791520L (en) | 1980-02-10 |
IT7968643A0 (en) | 1979-08-09 |
FI69060B (en) | 1985-08-30 |
FR2433016A1 (en) | 1980-03-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0232328A1 (en) | Zwitterionic bicyclic compounds and their salts, solvates, hydrates and esters. | |
IE48794B1 (en) | Benzene and thiophene-carbothioic acid 2 aminoalkyl ester acid salts | |
JPS6058954A (en) | Dihydroxybenzamide derivative | |
US4210666A (en) | Mucolytic thiophenecarboxamido alkyl mercaptans | |
JPS6072843A (en) | Novel derivatives of 4-phenyl-4-oxo-2-butenoic acid, manufacture, use as drug and composition | |
CA1134273A (en) | Benzene and thiophene-carbothioic acid 2-aminoalkyl ester acid salts | |
US4296092A (en) | Mucolytic benzene and thiophene-carbothioic acid 2-aminoalkyl ester acid salts | |
EP0037187B1 (en) | Salts and aqueous solutions of 6-methylamino-4-oxo-10-propyl-4h-pyrano(3,2-g)-quinoline-2,8-di-carboxylic acid and pharmaceutical compositions containing such salts and solutions | |
JPH0365338B2 (en) | ||
JPS60158149A (en) | Antiinflammatory 1,4-naphthoquinone derivative | |
EP1963270B1 (en) | Quaternary 3 -amido, n-methylpyridinium salts as anti -inflammatory agents | |
GB2028656A (en) | Benzamidoalkyl mercaptans | |
CA1133913A (en) | N-(1-methyl-2-pyrrolidinyl-methyl)-2,3- dimethoxy-5-methylsulphamoyl benzamide and its derivatives, their preparation processes and their use in the treatment of disorders of the lower urinary apparatus | |
US4472424A (en) | Esters of 2-thenoylmercaptopropionylglycine with substituted hydroxybenzenes, process for their preparation and pharmaceutical compositions containing same | |
JPS6350355B2 (en) | ||
JPH02250896A (en) | 3-pyrroglutamyl-thiazolidine-4-carboxylic acid derivative | |
US4148912A (en) | Pharmaceutical compositions and methods of using the same | |
JPS6361311B2 (en) | ||
US4156009A (en) | Diazepine derivatives | |
JPS6152822B2 (en) | ||
JP2988637B2 (en) | Glutathione derivative | |
JPS60346B2 (en) | S-(3-methyl-2-butenyl)cysteine and its production method | |
JPH0725771B2 (en) | 2-Aminoethanesulfonic acid zinc complex compound | |
JPS61204127A (en) | Antiviral compound | |
JPS61200916A (en) | Remedy for hepatopathy |