CA1196924A - 2-methoxyphenyl esters of n-substituted amino acids, a process for their preparation and pharmaceutical compositions containing them - Google Patents
2-methoxyphenyl esters of n-substituted amino acids, a process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA1196924A CA1196924A CA000402568A CA402568A CA1196924A CA 1196924 A CA1196924 A CA 1196924A CA 000402568 A CA000402568 A CA 000402568A CA 402568 A CA402568 A CA 402568A CA 1196924 A CA1196924 A CA 1196924A
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- Prior art keywords
- methoxyphenyl
- aminoacetate
- compound
- thenoylthio
- formula
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract of the disclosure The invention provides 2-methoxyphenyl esters of N-substi-tuted amino acids, which have mucolytic, antitussive and antiinflammatory activity.
Description
2-METHOXYPHENYL ESTERS OF N-SUBSTITUTED AMINO ACI~S, A PROCESS FOR T~IEIR PREPARA~ION AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THEM
The present invention concerns a new class of guaiacyl (2-me-thoxyphenyl) esters with N-substituted amino acids, a process for their preparation, their use as therapeu-tic agents, and pharmaceutical compositions containing them.
More particularly, the invention concerns 2-methoxy-phenyl esters of the formula I:
R-CH-CO-O ~ (I) R'-CO-NH
in which:
R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or ~ CO-S-CH- .
More particularly, the invention concerns the 2-metho-xyphenyl esters of the following N-substituted amino acids: (1) N-acetylglycine; (2) N-/2-(2-thenoylthio)-propionyl/glycine; (3) N~acetylalanine; (4) N-/2-(2-thenoylthio)propionyl/alanine; (5) N-acetylcysteine;
(6) N,S-diacetylcysteine; (7) N-acetyl-S-carboxymethyl-cystei.ne; (8) N-/2-(2-thenoylthio)propionyl/cysteine;
(9) N-/2-(2-thenoylthio)propionyl/-S-acetylcysteine;
(10) N-/2-(2-thenoylthio)propionyl/-S-carboxymethylcy-steine.
~6~
2-Methoxyphenyl esters with amino acids are known, said components having mucolytic activity: Canadian Patent 1,137,993 issued ~ecember 21t 1982, claims guaiacyl esters of ~ and ~-mercaptopropionylalanine and a- and ~-mercaptopropionylglycine and the related pharmaceutical compositions containing these esters, which are endowed with high mucolytic properties (without increasing the bronchial secretion). However, some of the esters described in the mentioned Canadian Patent are not very stable; consequently, the pharma-ceutical formulations containing these compounds are subjected to an unpleasant smell after a relatively short-term storaye, particularly in tropical countries, with obvious negative effects on the patient and on the therapeutical effectiveness of the formulations.
Another drawback of the known 2-methoxyphenyl esters lies in their low melting point (some of them are liquid at room temperature); this fact involves obvious formulations difficulties.
It has now been found that the new 2~methoxyphenyl esters of ~ormula (I), endowed with a very good mucolytic antitussive and antiinflammatory activity, without increasing effects on the bronchial secretion~
show a much higher stability then the known guaiacyl esters, and are moveover crystalline compounds whose formulation does not involve any difficultyO
J.~
It has moreover been found that, ~Jhereas the free SH
group of known mercapto compounds (such as N-(2-mer~
captopropionyl)glycine) can be easily oxidized in the body before reaching the action place (for instance the respiratory apparatus mucose), this is not the ca-se of the compounds of formula I. Moreover, these com pounds are characterized by a slow hydrolysis; this fact allows the transport and the utilization of the still active SH groups.
The present invention concerns also a process for the preparation of the esters of formula I, characterized by the fact that:
a) a compound of formula II is reacted with 2-metho-xyphenol III, according to the scheme:
R-CH-COX
R'-CO-NH HO-Ar ~ ~ (I) (II) (III) wherein P~ and R' have the above mentioned meanings, Ar is 2-methoxyphenyl, and X represents Cl, a C1-C~
alkoxy group, or an -O-CO-OR" group, wherein R" is a C1-C4 alkyl group, or another activating group, such as the imidazolyl-carbonyloxy group; or b) a compound of formula IV is reacted with a compound of formula V, according to the scheme:
6~
R ' -COX + R-(~H-CO-O-Ar _ ~ t I ) (IV) (Vj wherein R , R ', Ar and X have the above mentioned 5meanings; or c) when R' is ~ CO-S-ICH- , a compound of formula VI is reacted with a compound of formula VII, accor-ding to the scheme:
R-C~-CO-O-Ar COX ~ HS-CH-CO-NH (I) (VI) (VII) wherein R, Ar and X are as above mentioned; or d) when P~' is ~ CO-S-CH- , a compound of formula IX is reacted with thiophene-2-thiocarboxylic acid VIII, according to the scheme:
R-CH-CO-O-Ar I~COSH + Hal-CH-CO-NH _ ( I ) ( VIII ) ( IX ) wherein R and Ar are as above mentioned, whereas Hal represents chlorine, bromine or iodine.
The above schematized reactions are preferably carried out in the presence of an inorganic or organic base (for instance an alkali metal alkoxyde or hydroxyde or carbo-nate or hydrogen carbonate; a tertiary amine, such as triethylamine or pyridine). Alternatively, 2-methoxyphe-nol (III) or thiophene-2-thiocarboxylic acid (VIII) may be used in the form of their alkali metal salts, prepa-red before the reaction.The reactions according to the schemes of the methods a), b) and c) are generally carried out in aprotic sol-velts, for instance CH2Cl2, tetrahydrofuran or dioxane, at temperatures ranging from about ~5C to about +20C
for the first 15-60 minutes, then at room temperatures for 2-24 hours.
When X represents an -O-CO-OR" group, the correspon-ding mixed anhydride is generally obtained starting from ethyl chlorocarbonate.
~0 When the reac~ion is carried out in a hydromiscible solvent (for instance in CH2Cl2), the solution is then washed with H20, diluted HCl and H20 until neu-trality, dried and vacuum evaporated. If other sol-vents (THF or dioxane) are used, the reaction product is recovered by filtration of the tertiary base hydro-chloride and concentration of the filtrate under vacuum.
If the amino acid used as a starting compound in the c~
schemes according to the above mentioned methods conta-ins free SH groups, these are preliminary protected as known per se, for instance by reaction with trityl chlo-ride or with a p-substituted ben~yl halide, the S-pro-tecting groups being later removed in conditions sui-ted to preserve the guaiacyl ester group. Such elimi-nation of the S-protecting group is carried out in acid medium, preferably in the presence of CF3-COOH.
The reaction of thiophene-2-thiocarboxylic acid (VIII) with the halo compounds (IX) is preferably carried out in water, the acid ~VIII) being employed in the form of sodium or potassium salt, obtained in situ by treat-ment of an aqueous solution of NaSH or KSH with 2-chlo-rocarbonyl-thiophene.
The process according to the invention is illustrated but not limited by the following examples.
~XAMPLE 1 To a solution of 26.9 g (0.1 moles) of 2 methoxyphenyl N-(2-thiopropionyl)aminoacetate in 120 ml of dioxane, 10.1 g (0.1 moles) of triethylamine are added. The tem-perature of the stirred solution is maintained between 10 and î5C; 14.6 g (0.1 moles) of 2-chlorocarbonyl-thiophene, dissolved in 30 ml of dioxane are added drop-wise. After half an hour stirring, about 100 ml of dio-xane are vacuum distilled and 150 ml of water are added.
The precipitatedoil is washed with three portions of 100 ml of H20, then cooled at 5-1 0C for some hours. The so-6~
lidified product is triturated, dried under vacuum andrecrystallized with diisopropyl ether: 23.9 g (63%) of 2-methoxyphenyl N-/2-(2-thenoylthio)propionyl/amino-acetate (2) are obtained, m.p. 90.5-92C.
5 Elemental analysis:
calc.% C=53.83; H=4.48; N=3.69; S=16.89 found% C=53.61; H=4.53; N-3.54; S=16.59 IR Spectrum (Nuio]~mull) :
3340 cm ; 1785 cm ; 1665 cm ; 1215 cm ; 1185 cm 830-750-720 cm NMR Spectrum (registered in DMSO; internal standard TMS;
the chemical shifts are reported in ~ ):
1.56 (d, 3H, CH3 CH); 3.83 (s, 3H, OCH3); 4.23 (d, 2H, NH-CH2); 4.53 (q, lH, CH-CH3); 6.9-8.3 (m, 7H, arom.);
8.93 (t, 1H, NH-CH2) TLC: Silica gel, toluene/diethylether 60:40; single spot.
HPLC: column: Lichrosorb RP 18 eluent: H20 65 UV rivelator ~ =254 m~
To a stirred aqueous solution of po-tassium thiophene-2-thiocarboxylate, prepared from 14.6 g (0.1 moles) of 2-chlorocarbonyl-thiophene and 7.92 g (0.1 moles) of KS~I in 50 ml of water, 31.6 g (0.1 moles) of 2-methoxy-phenyl (2-bromopropionyl)aminoacetate dissolved in 50 ml of ace~one are added; the pH is adjusted at about 7.5 by addition of a 2N KOH-solution, the temperature ranging from 25 to 30C. When the addition is comple-ted 7 stirring is continued for half an hour, the sol-vent is evaporated under vacuum, and the residue is dissolved in 70 ml of CH2Cl2. The organic solution is washed with water, dried on Na2S04, and evaporated.
The semisolid residue is dissolved in boiling diiso-lQ propyl ether; 26.9 g (71%) of the same compound as in Example 1 are obtained, by cooling.
The preparation is carried out as described in Exam-ple 2 but NaSH and NaOH are used instead of the cor-lS responding potassium compound. 2~Methoxyphenyl N-/2-(2-thenoylthio)propionyl/aminoacetate in a yield of 67% is obtained.
Operating as described in Example 2, but using 2-me-thoxyphenyl (2-chloropropionyl)aminoacetate, the same compound in a yield of 74% is obtained.
A solution of 21.6 g (0.1 moles) of 2-(2-thenoylthio)-propionic acid in 80 ml of CHC13 is treated with 14.3 g (0.12 moles) of SOC12, at room temperature. After 8 hours the solvent is removed under vacuum, and the raw acyl chloride is dissolved in 50 ml of benzene. ~his solution is added with 18.1 g (0.1 moles) of 2-metho-xyphenyl aminoacetate and 7.9 g of pyridine in 50 ml of benzene. The mixture is stirred for two hours at room temperature, and for two additional hours at 50 C. The solvent is vacuum distilled, the residue is tre-ated with water and extracted with CH2C12. The solu-tion is worked out as described in E~ample 2; the fi-nal product is recovered in a 5~% yield, m.p. 89-92C.
A solution of 21.6 g (0.1 moles) of 2-(2-thenoilthio~-propionic acid and 10.1 g (0.1 moles) of thriethylami-ne in 75 ml of CHCl3 is added with 10.8 g (0.1 moles) of ethyl chlorocarbonate 9 dissolved in 25 ml of CHCl3, ~he temperature ranging from -10 to 0C. The so~pre-pared solution of mixed anhydride is then reacted witha solution of 18.1 g (O.1 moles) of 2-methoxyphenyl aminoacetate in 50 ml of CHCl3. The mixture is kept at 0C for 1 hour, then at room temperature for 4 hours.
The solvent is evaporated under vacuum and the residue is worked out as described in Example 2. 29.6 Grams of 2-methoxyphenyl N-/2-(2-thenoylthio)propionyl/ami-noacetate are obtained, m.p. 90-92C.
A solution of 27.3 g (0.1 moles) of N~/2-(2-thenoyl-thio-propionyl/glycine in 250 ml of anhydrous te~rahy-drofuran is added with 16.2 g (0.1 moles) of carbonyl-diimidazole. The mixture is heated to 50C in a water bath- When the evolution of C02 is completed, 12.4 g ~0.1 moles) of guaiacol and about 100 mg of sodium methoxyde are added. The temperature is kept at 50C
for 2 hours, under stirring; the progress of the re-action is controlled by TLC. The solvent is then re-S moved under vacuum, the raw product is washed withwater and dissolved in CH2Cl2. The solution is worked out as in Example 2; 18.6 g of the same product are obtained, m.p. go-g20c.
5.4 Grams (0.02 moles) of N~/2-(2-thenoylthio)propionyl7- !
glycine and 2.0 g (0.02 moles) of triethylamine are ad-ded to 50 ml of anhydrous CH2Cl2. The mixture is cooled at 0C; then a solution of 2.2 g (0.02 moles) of ethyl chlorocarbonate in 10 ml of anhydrous CH2Cl2 is added.
The temperature of the mixture is then raised to 5C 9 and a solution of 2.5 g (0.02 moles) o~ guaiacol, 2.0 g (0.02 moles) of triethylamine and 20 ml of CH2Cl2 is added. Stirring is continued for 1 hour at 5C, then for 4 hours at room temperature. The solution is washed with H20, diluted HCl, H20, then is dried on Na2S04 and evaporated to dryness under vacuum. By crystallization from acetone~hexane, a very pure compound, identical to the product of Example 1, is obtained, m.p. 92-93 C.
The toxicological and pharmacological properties of ~he esters of formula I results from the below reported con-siderations.
ACUTE TOXICITY
L~50 of the compounds of formula (I), evaluated by the Weil method ("Tabl.es for convenient calculation of me-dian effective dose (LD50 or ED50) and instructions in their use", Biometrics, 249-253, 1952), by intraperito-neal administration in the mouse. The results are repor-ted in Table 1.
TA~LE 1 T.D50 and confidential limits, mg/kg i.p., of the compo-unds of formula I. Weil method, N = 4 K = 4 lO Compound LD50confidential limits (1) 1010 (960-1050) (2) 1240 (1180 - 1300)
COMPOSITIONS CONTAINING THEM
The present invention concerns a new class of guaiacyl (2-me-thoxyphenyl) esters with N-substituted amino acids, a process for their preparation, their use as therapeu-tic agents, and pharmaceutical compositions containing them.
More particularly, the invention concerns 2-methoxy-phenyl esters of the formula I:
R-CH-CO-O ~ (I) R'-CO-NH
in which:
R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or ~ CO-S-CH- .
More particularly, the invention concerns the 2-metho-xyphenyl esters of the following N-substituted amino acids: (1) N-acetylglycine; (2) N-/2-(2-thenoylthio)-propionyl/glycine; (3) N~acetylalanine; (4) N-/2-(2-thenoylthio)propionyl/alanine; (5) N-acetylcysteine;
(6) N,S-diacetylcysteine; (7) N-acetyl-S-carboxymethyl-cystei.ne; (8) N-/2-(2-thenoylthio)propionyl/cysteine;
(9) N-/2-(2-thenoylthio)propionyl/-S-acetylcysteine;
(10) N-/2-(2-thenoylthio)propionyl/-S-carboxymethylcy-steine.
~6~
2-Methoxyphenyl esters with amino acids are known, said components having mucolytic activity: Canadian Patent 1,137,993 issued ~ecember 21t 1982, claims guaiacyl esters of ~ and ~-mercaptopropionylalanine and a- and ~-mercaptopropionylglycine and the related pharmaceutical compositions containing these esters, which are endowed with high mucolytic properties (without increasing the bronchial secretion). However, some of the esters described in the mentioned Canadian Patent are not very stable; consequently, the pharma-ceutical formulations containing these compounds are subjected to an unpleasant smell after a relatively short-term storaye, particularly in tropical countries, with obvious negative effects on the patient and on the therapeutical effectiveness of the formulations.
Another drawback of the known 2-methoxyphenyl esters lies in their low melting point (some of them are liquid at room temperature); this fact involves obvious formulations difficulties.
It has now been found that the new 2~methoxyphenyl esters of ~ormula (I), endowed with a very good mucolytic antitussive and antiinflammatory activity, without increasing effects on the bronchial secretion~
show a much higher stability then the known guaiacyl esters, and are moveover crystalline compounds whose formulation does not involve any difficultyO
J.~
It has moreover been found that, ~Jhereas the free SH
group of known mercapto compounds (such as N-(2-mer~
captopropionyl)glycine) can be easily oxidized in the body before reaching the action place (for instance the respiratory apparatus mucose), this is not the ca-se of the compounds of formula I. Moreover, these com pounds are characterized by a slow hydrolysis; this fact allows the transport and the utilization of the still active SH groups.
The present invention concerns also a process for the preparation of the esters of formula I, characterized by the fact that:
a) a compound of formula II is reacted with 2-metho-xyphenol III, according to the scheme:
R-CH-COX
R'-CO-NH HO-Ar ~ ~ (I) (II) (III) wherein P~ and R' have the above mentioned meanings, Ar is 2-methoxyphenyl, and X represents Cl, a C1-C~
alkoxy group, or an -O-CO-OR" group, wherein R" is a C1-C4 alkyl group, or another activating group, such as the imidazolyl-carbonyloxy group; or b) a compound of formula IV is reacted with a compound of formula V, according to the scheme:
6~
R ' -COX + R-(~H-CO-O-Ar _ ~ t I ) (IV) (Vj wherein R , R ', Ar and X have the above mentioned 5meanings; or c) when R' is ~ CO-S-ICH- , a compound of formula VI is reacted with a compound of formula VII, accor-ding to the scheme:
R-C~-CO-O-Ar COX ~ HS-CH-CO-NH (I) (VI) (VII) wherein R, Ar and X are as above mentioned; or d) when P~' is ~ CO-S-CH- , a compound of formula IX is reacted with thiophene-2-thiocarboxylic acid VIII, according to the scheme:
R-CH-CO-O-Ar I~COSH + Hal-CH-CO-NH _ ( I ) ( VIII ) ( IX ) wherein R and Ar are as above mentioned, whereas Hal represents chlorine, bromine or iodine.
The above schematized reactions are preferably carried out in the presence of an inorganic or organic base (for instance an alkali metal alkoxyde or hydroxyde or carbo-nate or hydrogen carbonate; a tertiary amine, such as triethylamine or pyridine). Alternatively, 2-methoxyphe-nol (III) or thiophene-2-thiocarboxylic acid (VIII) may be used in the form of their alkali metal salts, prepa-red before the reaction.The reactions according to the schemes of the methods a), b) and c) are generally carried out in aprotic sol-velts, for instance CH2Cl2, tetrahydrofuran or dioxane, at temperatures ranging from about ~5C to about +20C
for the first 15-60 minutes, then at room temperatures for 2-24 hours.
When X represents an -O-CO-OR" group, the correspon-ding mixed anhydride is generally obtained starting from ethyl chlorocarbonate.
~0 When the reac~ion is carried out in a hydromiscible solvent (for instance in CH2Cl2), the solution is then washed with H20, diluted HCl and H20 until neu-trality, dried and vacuum evaporated. If other sol-vents (THF or dioxane) are used, the reaction product is recovered by filtration of the tertiary base hydro-chloride and concentration of the filtrate under vacuum.
If the amino acid used as a starting compound in the c~
schemes according to the above mentioned methods conta-ins free SH groups, these are preliminary protected as known per se, for instance by reaction with trityl chlo-ride or with a p-substituted ben~yl halide, the S-pro-tecting groups being later removed in conditions sui-ted to preserve the guaiacyl ester group. Such elimi-nation of the S-protecting group is carried out in acid medium, preferably in the presence of CF3-COOH.
The reaction of thiophene-2-thiocarboxylic acid (VIII) with the halo compounds (IX) is preferably carried out in water, the acid ~VIII) being employed in the form of sodium or potassium salt, obtained in situ by treat-ment of an aqueous solution of NaSH or KSH with 2-chlo-rocarbonyl-thiophene.
The process according to the invention is illustrated but not limited by the following examples.
~XAMPLE 1 To a solution of 26.9 g (0.1 moles) of 2 methoxyphenyl N-(2-thiopropionyl)aminoacetate in 120 ml of dioxane, 10.1 g (0.1 moles) of triethylamine are added. The tem-perature of the stirred solution is maintained between 10 and î5C; 14.6 g (0.1 moles) of 2-chlorocarbonyl-thiophene, dissolved in 30 ml of dioxane are added drop-wise. After half an hour stirring, about 100 ml of dio-xane are vacuum distilled and 150 ml of water are added.
The precipitatedoil is washed with three portions of 100 ml of H20, then cooled at 5-1 0C for some hours. The so-6~
lidified product is triturated, dried under vacuum andrecrystallized with diisopropyl ether: 23.9 g (63%) of 2-methoxyphenyl N-/2-(2-thenoylthio)propionyl/amino-acetate (2) are obtained, m.p. 90.5-92C.
5 Elemental analysis:
calc.% C=53.83; H=4.48; N=3.69; S=16.89 found% C=53.61; H=4.53; N-3.54; S=16.59 IR Spectrum (Nuio]~mull) :
3340 cm ; 1785 cm ; 1665 cm ; 1215 cm ; 1185 cm 830-750-720 cm NMR Spectrum (registered in DMSO; internal standard TMS;
the chemical shifts are reported in ~ ):
1.56 (d, 3H, CH3 CH); 3.83 (s, 3H, OCH3); 4.23 (d, 2H, NH-CH2); 4.53 (q, lH, CH-CH3); 6.9-8.3 (m, 7H, arom.);
8.93 (t, 1H, NH-CH2) TLC: Silica gel, toluene/diethylether 60:40; single spot.
HPLC: column: Lichrosorb RP 18 eluent: H20 65 UV rivelator ~ =254 m~
To a stirred aqueous solution of po-tassium thiophene-2-thiocarboxylate, prepared from 14.6 g (0.1 moles) of 2-chlorocarbonyl-thiophene and 7.92 g (0.1 moles) of KS~I in 50 ml of water, 31.6 g (0.1 moles) of 2-methoxy-phenyl (2-bromopropionyl)aminoacetate dissolved in 50 ml of ace~one are added; the pH is adjusted at about 7.5 by addition of a 2N KOH-solution, the temperature ranging from 25 to 30C. When the addition is comple-ted 7 stirring is continued for half an hour, the sol-vent is evaporated under vacuum, and the residue is dissolved in 70 ml of CH2Cl2. The organic solution is washed with water, dried on Na2S04, and evaporated.
The semisolid residue is dissolved in boiling diiso-lQ propyl ether; 26.9 g (71%) of the same compound as in Example 1 are obtained, by cooling.
The preparation is carried out as described in Exam-ple 2 but NaSH and NaOH are used instead of the cor-lS responding potassium compound. 2~Methoxyphenyl N-/2-(2-thenoylthio)propionyl/aminoacetate in a yield of 67% is obtained.
Operating as described in Example 2, but using 2-me-thoxyphenyl (2-chloropropionyl)aminoacetate, the same compound in a yield of 74% is obtained.
A solution of 21.6 g (0.1 moles) of 2-(2-thenoylthio)-propionic acid in 80 ml of CHC13 is treated with 14.3 g (0.12 moles) of SOC12, at room temperature. After 8 hours the solvent is removed under vacuum, and the raw acyl chloride is dissolved in 50 ml of benzene. ~his solution is added with 18.1 g (0.1 moles) of 2-metho-xyphenyl aminoacetate and 7.9 g of pyridine in 50 ml of benzene. The mixture is stirred for two hours at room temperature, and for two additional hours at 50 C. The solvent is vacuum distilled, the residue is tre-ated with water and extracted with CH2C12. The solu-tion is worked out as described in E~ample 2; the fi-nal product is recovered in a 5~% yield, m.p. 89-92C.
A solution of 21.6 g (0.1 moles) of 2-(2-thenoilthio~-propionic acid and 10.1 g (0.1 moles) of thriethylami-ne in 75 ml of CHCl3 is added with 10.8 g (0.1 moles) of ethyl chlorocarbonate 9 dissolved in 25 ml of CHCl3, ~he temperature ranging from -10 to 0C. The so~pre-pared solution of mixed anhydride is then reacted witha solution of 18.1 g (O.1 moles) of 2-methoxyphenyl aminoacetate in 50 ml of CHCl3. The mixture is kept at 0C for 1 hour, then at room temperature for 4 hours.
The solvent is evaporated under vacuum and the residue is worked out as described in Example 2. 29.6 Grams of 2-methoxyphenyl N-/2-(2-thenoylthio)propionyl/ami-noacetate are obtained, m.p. 90-92C.
A solution of 27.3 g (0.1 moles) of N~/2-(2-thenoyl-thio-propionyl/glycine in 250 ml of anhydrous te~rahy-drofuran is added with 16.2 g (0.1 moles) of carbonyl-diimidazole. The mixture is heated to 50C in a water bath- When the evolution of C02 is completed, 12.4 g ~0.1 moles) of guaiacol and about 100 mg of sodium methoxyde are added. The temperature is kept at 50C
for 2 hours, under stirring; the progress of the re-action is controlled by TLC. The solvent is then re-S moved under vacuum, the raw product is washed withwater and dissolved in CH2Cl2. The solution is worked out as in Example 2; 18.6 g of the same product are obtained, m.p. go-g20c.
5.4 Grams (0.02 moles) of N~/2-(2-thenoylthio)propionyl7- !
glycine and 2.0 g (0.02 moles) of triethylamine are ad-ded to 50 ml of anhydrous CH2Cl2. The mixture is cooled at 0C; then a solution of 2.2 g (0.02 moles) of ethyl chlorocarbonate in 10 ml of anhydrous CH2Cl2 is added.
The temperature of the mixture is then raised to 5C 9 and a solution of 2.5 g (0.02 moles) o~ guaiacol, 2.0 g (0.02 moles) of triethylamine and 20 ml of CH2Cl2 is added. Stirring is continued for 1 hour at 5C, then for 4 hours at room temperature. The solution is washed with H20, diluted HCl, H20, then is dried on Na2S04 and evaporated to dryness under vacuum. By crystallization from acetone~hexane, a very pure compound, identical to the product of Example 1, is obtained, m.p. 92-93 C.
The toxicological and pharmacological properties of ~he esters of formula I results from the below reported con-siderations.
ACUTE TOXICITY
L~50 of the compounds of formula (I), evaluated by the Weil method ("Tabl.es for convenient calculation of me-dian effective dose (LD50 or ED50) and instructions in their use", Biometrics, 249-253, 1952), by intraperito-neal administration in the mouse. The results are repor-ted in Table 1.
TA~LE 1 T.D50 and confidential limits, mg/kg i.p., of the compo-unds of formula I. Weil method, N = 4 K = 4 lO Compound LD50confidential limits (1) 1010 (960-1050) (2) 1240 (1180 - 1300)
(3) 1150 (1100-1200) t4) 960 (809~1140) (5) 1270 (1200-1340) ~6) 1580 ~1510-16503 (7) 1250 ( 1180-1320) (8) 980 ( 850-1110) (9) 1230 (1100-~3~0) (10) 1340 (1250 - 1430) EXP~CTORATIING ACTIVI~Y
The experimentation was carried out on male rabbits, weighting 2-3 kg, narcotized with ethyl urethane, ac-cording to the method described by Perry et al.(J.Pharm.
Exp. Ther. 73, 65 (1941)). ~ach compound of formula (I) was administered to 5 rabbits in doses ranging from 20 to 40 mg, 1 hour after the incannulation. The control group (8 rabbits) was given only water. The amount of secretion was de~ermined 1, 2 and 4 hours after the admini-stration. The results reported in Table 2 show that the compounds (I) do not possess expectorant activity.
Effects of compounds of formula (I) on the bronchial secre-tion Percentage variations (+standard error) of the bronchial secretion, in comparison with the ba-sic values, in the following times after the administration Compounds 1h 2h 4h _ _ Control (H2oj +1+0,03 +2+0,04 +3,5*0,06 ~1) +1,3+0,02 -1,4+0,03 +2,3+0,07 (2) +0,3+0,01 ~0,7+0,03 +1,4+0,G5 (3~ +0,8+0,04 +1,2+0,04 +2,7~0,08
The experimentation was carried out on male rabbits, weighting 2-3 kg, narcotized with ethyl urethane, ac-cording to the method described by Perry et al.(J.Pharm.
Exp. Ther. 73, 65 (1941)). ~ach compound of formula (I) was administered to 5 rabbits in doses ranging from 20 to 40 mg, 1 hour after the incannulation. The control group (8 rabbits) was given only water. The amount of secretion was de~ermined 1, 2 and 4 hours after the admini-stration. The results reported in Table 2 show that the compounds (I) do not possess expectorant activity.
Effects of compounds of formula (I) on the bronchial secre-tion Percentage variations (+standard error) of the bronchial secretion, in comparison with the ba-sic values, in the following times after the administration Compounds 1h 2h 4h _ _ Control (H2oj +1+0,03 +2+0,04 +3,5*0,06 ~1) +1,3+0,02 -1,4+0,03 +2,3+0,07 (2) +0,3+0,01 ~0,7+0,03 +1,4+0,G5 (3~ +0,8+0,04 +1,2+0,04 +2,7~0,08
(4) +1,5+0,05 +1,9~0,08 +2,5~0,~9
(5) +0,9+0,05 +2,1~0,01 +3,8~0,0g
(6) *0,4+0,05 +2,1+0,05 +1,9+0,04
(7) +0,5+0,03 +0,7+0,07 +1,9~0,09
(8) +1,8~0,04 +1,7~0,09 +2,7+0,05 (S) +1,9+0,03 ~1,5+0,04 ~2,4+0,04 (10) +0,8+0,02 +1,3+0,04 +2,1+0,03 , , . ~ _ _ _ _ MUCOLYTIC ACTIVITY
-The mucolytic activity was tested in vitro, using the method described by Morandini et al.(Lotta contro la 6~
tubercolosi 47, no.4 (1977)). The modifications induced by compounds of formula (I) and acetylcysteine on the rheological properties of the human secretion were fol-lowed using a thromboelastograph. The data reported in Table 3 show the bet~er activity of the compounds (I) in comparison with acetylcysteine, in terms of reduction of the density of human secretion.
Mucolytic activity in vitro of compounds (I) and acetyl-l~ cysteine: modifications of the density of human secretion.
Percentage decrease (+ standard error) of the curve versus the maximal amplitude (x) after addition of 1 ml of a 10% solution of the compounds, at the indicated dilutions.
Compounds 1/30 1/60 (l) 78 55 (2) 82 62 (3) 60 58 (4j 84 6G
(5) 32 57 (S) &2 5~
(7) ~6 S5 (~ 78 48 (S) 75 43 (lO~ 74 41 acetylcysteine 71 22 (x) Mucoly~ic activity index EFFECT ON THE CILIARY ACTIVITY
The effec~s of the compounds of formula (I) on the ci-liary motility were examined by microscopical observa-tion of the ciliary movement in tracheal rings of rats iramersed in solutions of the compounds. This method allows to control - against concentration and time -the block of the ciliary movement induced by the tes-ted compounds, said block being due to the removal of the mucus from the ciliate epithelium.
For compounds to be used in solution, said block must take place in a contact time at least of 15 minutes.
The compounds of formula (I), used as 2% aqueous solu-tions, induceà the block of the ciliary activity in ti-mes ranging from 18 to 20 minutes.
BRONCHOSECRETQGOGIC ACTIVITY OF COMPOUND (?) The bronchosecretogogic activity of compound (2), i.e.
2-methoxyphenyl N-/2-(2-thenoylthio1propionyl/aminoace-tate, was tested according to the method of the sodium fluoresceine in the rat, as described by Mawatari (Ex-perimental Studies on the expectorant action of severaldrugs, Kagoshima Daigaku Igaku Zasshi 27, 561 (1976)), in comparison with S-carboxymethyl-cysteine (CMC) and N-(2--mercaptopropionyl)glycine ~MPG).
The results are reported in Table 4.
3~
Removal of the sodium fluoresceine from the bronchial tree ~percentage increase versus the controls).
number of weight (g) compound mg/kg %increase animals + s.eO i.p.
226~2.9 CMC 500 33.4 206~7.1 t2) 500 123.5 216.6~4 MPG 500 21.9 As shown in Table 49 compound (2) is endowed with a bronchosecretogogic activity much higher than CMC and MPG, which are widely used as mucolytic agents.
ANTITUSSIVE ACTIVITY OF COMPOUND (2) This activity was tested on Guinea pigs, in which co-ugh was lnduced by citric acid aerosol, in comparison with codeine. Compound (2) was administered per os and intraPeritOneallY- The results are reported in Table 5.
Antitussive activity. Cough induced in Guinea pigs by citric acid aerosol.
dose %inhibition compound adminlstration mg/kg of the cough codeine 25 per os 75.6 5 codeine 12.5 i.p. 90.2 (2) 500 per os 82.3 (2) 100 i.p. 95.8 PHARMACOKTNETICS OF COMPOUND (2) ~In vitro" and "in vivo" tests were carried out. The "in vitro" tests showed that compound (2) is enzymeti-cally~hydrolized giving N-(2-mercaptopropionyl)glycine, thiophene-2-carboxylic acid and guaiacol. The highest esterase activity is showed by the lung.
~In vivo~ studies, carried out in the rat, showed that compound (2) is mostly absorbed as such after oral ad-ministration. After administration of equimolecular doses of N-~2-~2-thenoylthio)propionyl/glycine and of the corresponding 2-methoxyphenyl ester (compound ~2)), higher lung concentrations of N-(2-mercaptopropionyl)yly-cine and thiophene-2-car~oxylic acid are found in the ca~
se of compound (2) administration. In other words, com-pound (2) shows a high pulmonary tropism.
~6 This invention also concerns the therapeutic use of esters of ~ormula (I) in the treatment of bronchial diseases, and the oral and parentera] administration to patients of a therapeutically efficient amount of an ester of formula (I).
~his use comprises the administration of about 15~70 mg/kg of body weight of esters of f,ormula (I), altho-ugh lower or higher doses may by administered on the basis of age, weight, general conditions and patholo-gy of the patient.
The pharmaceutical ~ormulations of this invention may be in a solid or liquid form, for instance as tablets, solutions, syrups,phtials and so on. The following, non limitative examples 9 illustrate some formulations according to the invention.
Ph~ialsfor aerosol or intramuscular injection 2-Me~hoxyphenyl N-/2-(2-thenoylthio)-propionyl/amino~cetate mg 400 Sodium metabisulfite mg 10 Apyrogenic distilled water ml 3 -2-Methoxyphenyl N-/2-(2-thenoylthio)-propionyl/aminoacetate g 4 70% Sorbitol g 15 Saccharose g 50 Ethanol ml Methyl 4-hydroxybenzoate mg 0.2 Distilled water up to ml 100 6~æ~
Suppositories 2-Methoxyphenyl N-/2-(2-thenoylthio)-propionyl/aminoacetate mg 400 Sodium metabisulfite mg 20 Excipients sufficient to make up to
-The mucolytic activity was tested in vitro, using the method described by Morandini et al.(Lotta contro la 6~
tubercolosi 47, no.4 (1977)). The modifications induced by compounds of formula (I) and acetylcysteine on the rheological properties of the human secretion were fol-lowed using a thromboelastograph. The data reported in Table 3 show the bet~er activity of the compounds (I) in comparison with acetylcysteine, in terms of reduction of the density of human secretion.
Mucolytic activity in vitro of compounds (I) and acetyl-l~ cysteine: modifications of the density of human secretion.
Percentage decrease (+ standard error) of the curve versus the maximal amplitude (x) after addition of 1 ml of a 10% solution of the compounds, at the indicated dilutions.
Compounds 1/30 1/60 (l) 78 55 (2) 82 62 (3) 60 58 (4j 84 6G
(5) 32 57 (S) &2 5~
(7) ~6 S5 (~ 78 48 (S) 75 43 (lO~ 74 41 acetylcysteine 71 22 (x) Mucoly~ic activity index EFFECT ON THE CILIARY ACTIVITY
The effec~s of the compounds of formula (I) on the ci-liary motility were examined by microscopical observa-tion of the ciliary movement in tracheal rings of rats iramersed in solutions of the compounds. This method allows to control - against concentration and time -the block of the ciliary movement induced by the tes-ted compounds, said block being due to the removal of the mucus from the ciliate epithelium.
For compounds to be used in solution, said block must take place in a contact time at least of 15 minutes.
The compounds of formula (I), used as 2% aqueous solu-tions, induceà the block of the ciliary activity in ti-mes ranging from 18 to 20 minutes.
BRONCHOSECRETQGOGIC ACTIVITY OF COMPOUND (?) The bronchosecretogogic activity of compound (2), i.e.
2-methoxyphenyl N-/2-(2-thenoylthio1propionyl/aminoace-tate, was tested according to the method of the sodium fluoresceine in the rat, as described by Mawatari (Ex-perimental Studies on the expectorant action of severaldrugs, Kagoshima Daigaku Igaku Zasshi 27, 561 (1976)), in comparison with S-carboxymethyl-cysteine (CMC) and N-(2--mercaptopropionyl)glycine ~MPG).
The results are reported in Table 4.
3~
Removal of the sodium fluoresceine from the bronchial tree ~percentage increase versus the controls).
number of weight (g) compound mg/kg %increase animals + s.eO i.p.
226~2.9 CMC 500 33.4 206~7.1 t2) 500 123.5 216.6~4 MPG 500 21.9 As shown in Table 49 compound (2) is endowed with a bronchosecretogogic activity much higher than CMC and MPG, which are widely used as mucolytic agents.
ANTITUSSIVE ACTIVITY OF COMPOUND (2) This activity was tested on Guinea pigs, in which co-ugh was lnduced by citric acid aerosol, in comparison with codeine. Compound (2) was administered per os and intraPeritOneallY- The results are reported in Table 5.
Antitussive activity. Cough induced in Guinea pigs by citric acid aerosol.
dose %inhibition compound adminlstration mg/kg of the cough codeine 25 per os 75.6 5 codeine 12.5 i.p. 90.2 (2) 500 per os 82.3 (2) 100 i.p. 95.8 PHARMACOKTNETICS OF COMPOUND (2) ~In vitro" and "in vivo" tests were carried out. The "in vitro" tests showed that compound (2) is enzymeti-cally~hydrolized giving N-(2-mercaptopropionyl)glycine, thiophene-2-carboxylic acid and guaiacol. The highest esterase activity is showed by the lung.
~In vivo~ studies, carried out in the rat, showed that compound (2) is mostly absorbed as such after oral ad-ministration. After administration of equimolecular doses of N-~2-~2-thenoylthio)propionyl/glycine and of the corresponding 2-methoxyphenyl ester (compound ~2)), higher lung concentrations of N-(2-mercaptopropionyl)yly-cine and thiophene-2-car~oxylic acid are found in the ca~
se of compound (2) administration. In other words, com-pound (2) shows a high pulmonary tropism.
~6 This invention also concerns the therapeutic use of esters of ~ormula (I) in the treatment of bronchial diseases, and the oral and parentera] administration to patients of a therapeutically efficient amount of an ester of formula (I).
~his use comprises the administration of about 15~70 mg/kg of body weight of esters of f,ormula (I), altho-ugh lower or higher doses may by administered on the basis of age, weight, general conditions and patholo-gy of the patient.
The pharmaceutical ~ormulations of this invention may be in a solid or liquid form, for instance as tablets, solutions, syrups,phtials and so on. The following, non limitative examples 9 illustrate some formulations according to the invention.
Ph~ialsfor aerosol or intramuscular injection 2-Me~hoxyphenyl N-/2-(2-thenoylthio)-propionyl/amino~cetate mg 400 Sodium metabisulfite mg 10 Apyrogenic distilled water ml 3 -2-Methoxyphenyl N-/2-(2-thenoylthio)-propionyl/aminoacetate g 4 70% Sorbitol g 15 Saccharose g 50 Ethanol ml Methyl 4-hydroxybenzoate mg 0.2 Distilled water up to ml 100 6~æ~
Suppositories 2-Methoxyphenyl N-/2-(2-thenoylthio)-propionyl/aminoacetate mg 400 Sodium metabisulfite mg 20 Excipients sufficient to make up to
Claims (9)
1. Process for the preparation of 2-methoxyphenyl esters of formula (I) (I) in which:
R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or characterized by the fact that a) a compound of formula II is reacted with 2-methoxy-phenol III, according to the scheme:
+ (I) (II) (III) wherein R and R' have the above mentioned meanings, Ar is 2-methoxyphenyl, and X represents C1, a C1-C4 alkoxy group, or an -O-CO-OR" group, wherein R" is a C1-C4 alkyl group, or imidazolyl-carbonyloxy group; or b) a compound of formula IV is reacted with a compound of formula V, according to the scheme:
+ (I) (IV) (V) wherein R, R', Ar and X have the above mentioned meanings; or c) when R' is a compound of formula VI is reacted with a compound of formula VII, according to the scheme:
+ (I) (VI) (VII) wherein R, Ar and X are as above mentioned; or d) when R' is , a compound of formula IX is reacted with thiophene-2-thiocarboxylic acid VIII, according to the scheme:
+ (I) (VIII) (IX) wherein R and Ar are as above mentioned, whereas Hal represents chlorine, bromine or iodine.
R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or characterized by the fact that a) a compound of formula II is reacted with 2-methoxy-phenol III, according to the scheme:
+ (I) (II) (III) wherein R and R' have the above mentioned meanings, Ar is 2-methoxyphenyl, and X represents C1, a C1-C4 alkoxy group, or an -O-CO-OR" group, wherein R" is a C1-C4 alkyl group, or imidazolyl-carbonyloxy group; or b) a compound of formula IV is reacted with a compound of formula V, according to the scheme:
+ (I) (IV) (V) wherein R, R', Ar and X have the above mentioned meanings; or c) when R' is a compound of formula VI is reacted with a compound of formula VII, according to the scheme:
+ (I) (VI) (VII) wherein R, Ar and X are as above mentioned; or d) when R' is , a compound of formula IX is reacted with thiophene-2-thiocarboxylic acid VIII, according to the scheme:
+ (I) (VIII) (IX) wherein R and Ar are as above mentioned, whereas Hal represents chlorine, bromine or iodine.
2. 2-methoxyphenyl esters with N-substituted amino acids of formula I
(I) in which R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or whenever produced by the process according to claim 1 or an obvious chemical equivalent.
(I) in which R is hydrogen, -CH3 or -CH2SR", wherein R" represents hydrogen, -COCH3 or -CH2COOH;
R' is -CH3 or whenever produced by the process according to claim 1 or an obvious chemical equivalent.
3. A process for the preparation of 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate, which comprises reacting 2-methoxyphenyl N-(2-thiopropionyl) aminoacetate with 2-chlorocarbonyl-thiophene.
4. A process for the preparation of 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate, which comprises reacting potassium thiophene-2-thiocarboxylate with 2-methoxyphenyl(2-bromopropionyl)aminoacetate.
5. A process for the preparation of 2-methoxyphenyl N-[2 (2-thenoylthio) propionyl]aminoacetate, which comprises reacting potassium thiophene-2-thiocarboxylate with 2-methoxyphenyl(2-chloropropionyl)aminoacetate.
6. A process for the preparation of 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate, which comprises reacting 2-(2-thenoylthio)-propionic acid with 2-methoxy-phenyl aminoacetate.
7. A process for the preparation of 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate, which comprises reacting N-[2-(2-thenoylthio)propionyl] glycine with ethyl chlorocarbonate and then with 2-methoxyphenol.
8. The compound 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate whenever produced by the process according to claim 3, 4 or 5 or an obvious chemical equivalent.
9. The compound 2-methoxyphenyl N-[2-(2-thenoylthio) propionyl]aminoacetate whenever produced by the process according to claim 6 or 7 or an obvious chemical equivalent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21620A/81 | 1981-05-11 | ||
| IT21620/81A IT1137577B (en) | 1981-05-11 | 1981-05-11 | N-Acyl aminoacid 2-methoxy-phenyl ester(s) |
| IT48485/81A IT1170975B (en) | 1981-05-15 | 1981-05-15 | GUAIACLE ESTERS WITH N-SUBSTITUTED AMINO ACIDS PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| IT48485A/81 | 1981-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1196924A true CA1196924A (en) | 1985-11-19 |
Family
ID=26327948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000402568A Expired CA1196924A (en) | 1981-05-11 | 1982-05-10 | 2-methoxyphenyl esters of n-substituted amino acids, a process for their preparation and pharmaceutical compositions containing them |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4405638A (en) |
| KR (1) | KR890000486B1 (en) |
| AR (1) | AR231722A1 (en) |
| AT (1) | ATA183182A (en) |
| CA (1) | CA1196924A (en) |
| CH (1) | CH655095A5 (en) |
| DE (1) | DE3216986A1 (en) |
| DK (1) | DK154210C (en) |
| ES (1) | ES512769A0 (en) |
| FR (1) | FR2505329B1 (en) |
| GB (1) | GB2100723B (en) |
| IE (1) | IE52884B1 (en) |
| KE (1) | KE3521A (en) |
| LU (1) | LU84142A1 (en) |
| NL (1) | NL8201820A (en) |
| NO (1) | NO160779C (en) |
| SE (1) | SE453391B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1143209B (en) * | 1981-07-02 | 1986-10-22 | Sigma Tau Ind Farmaceuti | 2-TENOILMERCAPTOPROPIONYL GLYCIN ESTERS WITH HYDROXYBENZEN REPLACED PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4762849A (en) * | 1985-10-15 | 1988-08-09 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoylthiazolones |
| US4623651A (en) | 1985-10-15 | 1986-11-18 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic heterocyclocarbonyl- and acetyl-thiazolones |
| US4927939A (en) * | 1985-10-15 | 1990-05-22 | Merrell Dow Pharmaceuticals | Cardiotonic aroylthiazolones |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4108886A (en) * | 1977-03-11 | 1978-08-22 | E. R. Squibb & Sons, Inc. | Thiopropanoylamino acid derivatives |
| CA1121825A (en) * | 1978-04-11 | 1982-04-13 | Franco Bolasco | 2-(2-thenoylthio)-propionylglycine: method for its preparation and pharmaceutical formulations containing said compound |
| FR2430945A2 (en) * | 1978-07-12 | 1980-02-08 | Chauvin Blache Lab | Anti-bronchitic N-thenoyl derivs. of cysteine - for admin. orally or as aerosol sprays |
| IT1111384B (en) * | 1978-12-21 | 1986-01-13 | Sigma Tau Ind Farmaceuti | GUAIACYL ESTERS OF MERCAPTOPROPIONIC ACID DERIVATIVES PROCEDURE FOR THEIR PREPARATION AND THERAPEUTIC USE |
| US4279842A (en) * | 1979-07-26 | 1981-07-21 | Houston Systems Manufacturing Co., Inc. | Air diffuser assembly |
-
1982
- 1982-04-27 IE IE987/82A patent/IE52884B1/en unknown
- 1982-04-29 US US06/372,985 patent/US4405638A/en not_active Expired - Fee Related
- 1982-04-30 GB GB08212624A patent/GB2100723B/en not_active Expired
- 1982-04-30 CH CH2643/82A patent/CH655095A5/en not_active IP Right Cessation
- 1982-05-03 NL NL8201820A patent/NL8201820A/en not_active Application Discontinuation
- 1982-05-06 DE DE19823216986 patent/DE3216986A1/en not_active Ceased
- 1982-05-07 FR FR8207986A patent/FR2505329B1/en not_active Expired
- 1982-05-07 AR AR289337A patent/AR231722A1/en active
- 1982-05-10 CA CA000402568A patent/CA1196924A/en not_active Expired
- 1982-05-10 NO NO821545A patent/NO160779C/en unknown
- 1982-05-10 ES ES512769A patent/ES512769A0/en active Granted
- 1982-05-10 KR KR8202030A patent/KR890000486B1/en not_active Expired
- 1982-05-10 AT AT0183182A patent/ATA183182A/en not_active Application Discontinuation
- 1982-05-11 DK DK210882A patent/DK154210C/en not_active IP Right Cessation
- 1982-05-11 LU LU84142A patent/LU84142A1/en unknown
- 1982-05-11 SE SE8202962A patent/SE453391B/en not_active IP Right Cessation
-
1985
- 1985-04-04 KE KE3521A patent/KE3521A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3216986A1 (en) | 1982-11-25 |
| LU84142A1 (en) | 1982-09-13 |
| CH655095A5 (en) | 1986-03-27 |
| DK154210B (en) | 1988-10-24 |
| IE52884B1 (en) | 1988-03-30 |
| KR830010051A (en) | 1983-12-24 |
| GB2100723B (en) | 1985-01-09 |
| NO160779B (en) | 1989-02-20 |
| NO821545L (en) | 1982-11-12 |
| SE8202962L (en) | 1982-11-12 |
| FR2505329B1 (en) | 1986-04-25 |
| SE453391B (en) | 1988-02-01 |
| GB2100723A (en) | 1983-01-06 |
| KE3521A (en) | 1985-05-03 |
| DK154210C (en) | 1989-03-13 |
| ES8307717A1 (en) | 1983-08-01 |
| NO160779C (en) | 1989-05-31 |
| US4405638A (en) | 1983-09-20 |
| DK210882A (en) | 1982-11-12 |
| ATA183182A (en) | 1990-05-15 |
| KR890000486B1 (en) | 1989-03-18 |
| ES512769A0 (en) | 1983-08-01 |
| FR2505329A1 (en) | 1982-11-12 |
| SE8202962D0 (en) | 1982-05-11 |
| AR231722A1 (en) | 1985-02-28 |
| NL8201820A (en) | 1982-12-01 |
| IE820987L (en) | 1982-11-11 |
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