DK159655B - ANALOGY PROCEDURE FOR PREPARING (SUBSTITUTED BENZEN) - OR 2-THIOPEN CARBOTHIOIC ACID AMINOAL COOLERS - Google Patents
ANALOGY PROCEDURE FOR PREPARING (SUBSTITUTED BENZEN) - OR 2-THIOPEN CARBOTHIOIC ACID AMINOAL COOLERS Download PDFInfo
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- DK159655B DK159655B DK333879A DK333879A DK159655B DK 159655 B DK159655 B DK 159655B DK 333879 A DK333879 A DK 333879A DK 333879 A DK333879 A DK 333879A DK 159655 B DK159655 B DK 159655B
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- 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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- 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
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- 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
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- 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
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Description
DK 159655 BDK 159655 B
iin
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte (substitueret benzen)- eller 2-thiophencarbothioinsyre-2-aminoalkylestere, der har mucolytisk virkning og kan anvendes til bekæmpelse 5 og regulering af mucus-dannelse hos et dyr med lungekonges-tion.The present invention relates to an analogous process for the preparation of novel (substituted benzene) or 2-thiophenecarbothioic acid 2-aminoalkyl esters which have mucolytic activity and can be used to control 5 and control mucus formation in an animal with lung congestion.
Fremgangsmåden er ejendommelig ved det i krav l's kendetegnende del omhandlede.The method is peculiar to the characterizing part of claim 1.
Syntese af benzencarbothioinsyre-2-aminoethyles-10 ter, hydrochlorid er kendt, jfr. W.O. Foye m.fl., J. Pharm.Synthesis of benzenecarbothioic acid-2-aminoethyl ester 10 hydrochloride is known, cf. W.O Foye et al., J. Pharm.
Sci. 51 (2), 168-171 (1962), men der er ikke omtalt nogen mucolytisk virkning. Substituering på phénylgruppen har ikke været omtalt. Der har tidligere været omtalt visse muco-lytiske midler såsom N-acetylcystein, der har en fri sulf-15 hydrylgruppe, som de forbindelser, der fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse, ikke har.Sci. 51 (2), 168-171 (1962), but no mucolytic effect is mentioned. Substitution on the phenyl group has not been discussed. Certain mucolytic agents, such as N-acetylcysteine, which have a free sulfhydryl group which have no compounds prepared by the process of the present invention have been disclosed previously.
A.L. Sheffner, Ann. N.Y. Acad. Sci 106, 298-310 (1963) fastslår anvendelse af gastrisk mucinmucoprotein som prøvemedie ved udviklingen af N-acetyl-L-cystein som mucolytisk middel 20 til behandling af lungesygdomme.EEL. Sheffner, Ann. NEW. Acad. Sci 106, 298-310 (1963) establish the use of gastric mucin mucoprotein as a test medium in the development of N-acetyl-L-cysteine as a mucolytic agent 20 for the treatment of lung diseases.
De forbindelser, der fremstilles ved fremgangsmåden ifølge opfindelsen, er (substitueret benzen)- og 2-thio-phencarbothioinsyre-2-aminoalkylestersyresalte, der kan gengives ved følgende formel 25 rThe compounds prepared by the process of the invention are (substituted benzene) and 2-thiophenecarbothioic acid-2-aminoalkyl ester acid salts which can be represented by the following formula
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R-C-S(CH2)n-NH3+ X~ IR-C-S (CH 2) n-NH 3 + X ~ I
30 hvor R betyder 2-thienyl eller betyder phenyl, som er monosubstitueret med halogen eller alkyl eller alkoxy med 1-4 carbonatomer, X betyder chlor eller brom, og n betyder 2 eller 3.Wherein R is 2-thienyl or phenyl which is monosubstituted with halogen or alkyl or alkoxy of 1-4 carbon atoms, X is chlorine or bromine and n is 2 or 3.
35 Forbindelserne har mucolytisk aktivitet og er an vendelige til at opløse eller fortynde mucus hos varmblode-The compounds have mucolytic activity and are useful for dissolving or diluting mucus in warm blood cells.
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de dyr, der frembyder symptomer på eller lider af lungekonge-stion.the animals that exhibit symptoms or suffer from pulmonary congestion.
Forbindelserne, der beskrives nedenfor, og som er gengivet ved formel I, er blevet påvist ved en modifikation 5 af den metode, der er angivet af S.J. Carne m.fl. i J. Phys.The compounds described below which are represented by Formula I have been demonstrated by a modification 5 of the method disclosed by S.J. Carne et al. in J. Phys.
242, 116 (1974), beskrevet nedenfor, at have mucolytisk virkning på dyr.242, 116 (1974), described below, to have mucolytic effect on animals.
De forbindelser, hvis mucolytiske virkning har vist sig at være af samme størrelsesorden som N-acetyl-L-cystein 10 på rottemavemucus, er de foretrukne forbindelser, og disse er som følger: 1) 4-Chlorbenzencarbothioinsyre-2-aminoethylester-monohydrochlorid (eksempel 1) 2) 4-Methylbenzencarbothioinsyre-2-aminoethyles-15 ter-monohydrochlorid (eksempel 2) 3) 4-Methoxybenzencarbothioinsyre-2-aminoethyles-ter-monohydrochlorid (eksempel 3) 4) 2-Thiophencarbothioinsyre-2-aminoethylester--monohydrochlorid (eksempel 4).The compounds whose mucolytic effect has been found to be of the same order of magnitude as N-acetyl-L-cysteine 10 on rat gastric mucus are the preferred compounds and are as follows: 1) 4-Chlorobenzene carbothioic acid 2-aminoethyl ester monohydrochloride (Example 1) 2) 4-Methylbenzenecarbothioic acid-2-aminoethyl-ter-monohydrochloride (Example 2) 3) 4-Methoxybenzenecarbothioic acid-2-aminoethyl-ter-monohydrochloride (Example 3) 4) 2-Thiophenecarbothioic acid-2-aminoethyl ester - monohydrochloride ( Example 4).
20 Den metode, der anvendes til at konstatere mucoly tisk virkning for forbindelserne, der fremstilles ved fremgangsmåden ifølge opfindelsen, er følgende:The method used to ascertain the mucolytic effect of the compounds prepared by the process of the invention is as follows:
Sprague-Dawley (Charles River Labs) hunrotter på 120-180 g fastes i 16 timer på ståltrådsnet, med to dyr i 25 hvert bur. For at bringe kdprophagi ned på et minimum la- 3 der man lyset være tændt under fasten. Der gives 2 cm vand oralt til hver rotte for at mindske indre efterladenskaber.Female Sprague-Dawley (Charles River Labs) 120-180 g rats are fasted for 16 hours on steel wire mesh, with two animals in each cage. In order to bring kdprophagi down to a minimum, the light is switched on during fasting. 2 cm of water is given orally to each rat to reduce internal residues.
30 minutter senere aflives rotterne ved cervikal dislokation. Maverne fjernes, befries for overflødigt væv, og epitheliet 30 kasseres. Kirteldelen skæres så meget langs den øvre og nedre rand, at mavens kan krænges ud, før den anbringes i præparatopløsningen. Maver med fækal lugt eller med synlige 3 fækalier kasseres. Maverne anbringes i 10 cm af en opløsning (vand eller 50% polyethylenglycol 300-H20 afhængigt af 35 opløselighed) indeholdende 2,5 mg prøveforbindelse/ml i 40 minutter. Efter behandling med præparatet anbringes maverne iThirty minutes later, the rats are sacrificed by cervical dislocation. The abdomen is removed, free of excess tissue, and the epithelium 30 discarded. The gland portion is cut so much along the upper and lower edges that the abdomen can be pulled out before being placed in the preparation solution. Stomachs with faecal odor or with visible 3 faeces are discarded. The stomachs are placed in 10 cm of a solution (water or 50% polyethylene glycol 300-H2 O depending on solubility) containing 2.5 mg of test compound / ml for 40 minutes. After treatment with the preparation, the stomachs are placed in
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10 cm "Alcian" blåt-opløsning (farvestof af phthalocyanin--typen) (opløsning 1), hvor farvestoffet danner kompleks med mavemucus. Efter to efter hinanden følgende 10-minutters 3 vaskningeri 10 cm af en 0,25 molær saccharoseopløsning (op- 3 5 løsning 2) anbringes maverne i 10 cm 0,5 MgCl2-opløsning (opløsning 3) i en time for at fjerne farvestofkomplekset. Det 3 ovenpå flydende MgCl0-lag rystes med 10 cm diethylether i en 3 Δ 60 cm skilletragt for at fjerne lipiderne. Den vandige fase aftappes i et "Spectronic" 20-glas, og den procentvise 10 transmission aflæses ved 605 mji i et "Spectronic" 20 spektro-fotometer. Den procentvise transmission omdannes til Jig/ml "Alcian"-blåt ud fra en standardkurve. (P. Whiteman, Biochem.10 cm "Alcian" blue solution (phthalocyanine type dye) (solution 1), where the dye complexes with the stomach mucus. After two consecutive 10-minute 3 washings in 10 cm of a 0.25 molar sucrose solution (solution 2), the stomachs are placed in 10 cm of 0.5 MgCl 2 solution (solution 3) for one hour to remove the dye complex. The 3 supernatant MgClO layer is shaken with 10 cm of diethyl ether in a 3 Δ 60 cm separatory funnel to remove the lipids. The aqueous phase is drained into a "Spectronic" 20 glass and the percent transmission is read at 605 microns in a "Spectronic" 20 spectrophotometer. The percentage transmission is converted to Jig / ml "Alcian" blue from a standard curve. (P. Whiteman, Biochem.
J. 131, 351-57 (1973)). Hver præparat eller præparatbærestof (kontrol) afprøves på tre maver. Gennemsnitsforskelle 15 mellem behandlede og kontrolværdier udtrykket som procentdele. Opløsning 1 - "Alcian"-blåt, 0,05¾ vægt/volumen (1 liter) 54,8 g saccharose (0,15 molær) 6,8 g natriumacetat 3 900 cm deioniseret vand.J. 131, 351-57 (1973)). Each preparation or preparation (control) is tested on three stomachs. Mean differences 15 between treated and control values expressed as percentages. Solution 1 - "Alcian" blue, 0.05¾ w / v (1 liter) 54.8 g sucrose (0.15 molar) 6.8 g sodium acetate 3 900 cm deionized water.
20 Bestanddelene opløses med en magnetisk omrører og indstilles til pH 5,8. Der tilsættes 500 mg "Alcian"-blåt GN (Matheson Coleman & Bell, nr. 8E13). Blandingen fyldes med en liter i en målekolbe og afkøles. Bør kun anvendes i 1 uge.The ingredients are dissolved with a magnetic stirrer and adjusted to pH 5.8. Add 500 mg of Alcian Blue GN (Matheson Coleman & Bell, No. 8E13). The mixture is filled with one liter in a volumetric flask and cooled. Should only be used for 1 week.
i 25 Opløsning 2 - saccharose, 0,25 molær (1 liter) Sæt 85,6 g saccharose til en enliters målekolbe, der fyldes med deioniseret vand. Bør kun anvendes i 1 uge. Opløsning 3 - Magnesiumchlorid (0,5 molær (1 liter)i 25 Solution 2 - sucrose, 0.25 molar (1 liter) Add 85.6 g of sucrose to a one liter volumetric flask filled with deionized water. Should only be used for 1 week. Solution 3 - Magnesium chloride (0.5 molar (1 liter)
Der sættes 101,7 g MgCl2.6H20 A.C.S. til en 1-li-30 ters målekolbe. Fyld op med deioniseret vand.101.7 g of MgCl2.6H2 O A.C.S. to a 1-liter 30-liter flask. Make up with deionized water.
Der opnås følgende resultater:The following results are obtained:
Forbindelse % Reduktion af mucusConnection% Reduction of mucus
Eksempel 1 70Example 1 70
Eksempel 2 89 35 Eksempel 3 48Example 2 89 35 Example 3 48
Eksempel 4 83Example 4 83
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4 (Substitueret benzen)- og thiophencarbothioinsyre--2-aminoalkylestersyresaltene fremstilles ved kendte metoder til fremstilling af benzenderivater som gengivet ved følgende skema.4 (Substituted benzene) and thiophene carbothioic acid - the 2-aminoalkyl ester acid salts are prepared by known methods for the preparation of benzene derivatives as represented by the following scheme.
5 0 .5 0.
R-C-X + HS(CH2)nNH2*HX -> HX I + 0R-C-X + HS (CH2) nNH2 * HX -> HX I + 0
R~C-S(CH0) -NH,+ x" i n JR ~ C-S (CHO) -NH, + x "i n J
10 hvor R, n og X har de ovenfor anførte betydninger.10 where R, n and X have the meanings set forth above.
I reglen blandes reaktanterne og opvarmes over en dampstråle, indtil der dannes en masse af krystaller. Denne 15 krystalmasse opbrydes derefter, tritureres med ligroin og omkrystalliseres ud fra vandfri ethanol.As a rule, the reactants are mixed and heated over a jet of steam until a mass of crystals is formed. This crystal mass is then broken up, triturated with ligroin and recrystallized from anhydrous ethanol.
De følgende eksempler tjener til yderligere at belyse opfindelsen.The following examples serve to further illustrate the invention.
20 Eksempel 1 4-Chlorbenzencarbothioinsyre-2-aminoethylester-monohydrochlo- ridExample 1 4-Chlorobenzenecarbothioic acid 2-aminoethyl ester monohydrochloride
En blanding af 60 ml frisk destilleret p-chlorben-zoylchlorid (0,47 mol) og 18,18 g (0,16 mol) 2-aminoethan- 25 thiol-hydrochlorid opvarmes (beskyttet mod fugt) over en dampstråle i 2 timer. Der dannes en fast krystallinsk masse, efterhånden som reaktionen løber til ende. Efter omhyggelig triturering med ligroin, der er 60-110°C varm, skilles krystallerne fra ved filtrering, idet der vaskes med ligroin.A mixture of 60 ml of freshly distilled p-chlorobenzoyl chloride (0.47 mol) and 18.18 g (0.16 mol) of 2-aminoethanethiol hydrochloride is heated (moisture protected) over a steam jet for 2 hours. A solid crystalline mass is formed as the reaction ends. After careful trituration with ligroin, which is 60-110 ° C warm, the crystals are separated by filtration, washing with ligroin.
30 Efter to omkrystallisationer ud fra vandfri ethanol, smelter produktet, der vejer 39,0 g (96,5%) ved 208-209,5°C. NMR, MS og IR viser alle strukturen af den i overskriften nævnte forbindelse ifølge formel I.After two recrystallizations from anhydrous ethanol, the product weighing 39.0 g (96.5%) melts at 208-209.5 ° C. NMR, MS and IR all show the structure of the title compound of formula I.
Analyse: Beregnet for CgH^^Cl2SNO: C 42,87, H 4,40, N 5,55.Analysis: Calculated for CgH ^^ ClCl₂SNO: C 42.87, H 4.40, N 5.55.
35 Fundet: C 42,79, H 4,43, N 5,59.Found: C 42.79, H 4.43, N 5.59.
DK 159655BDK 159655B
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Eksempel 2 4-Methylbenzencarbothioinsyre~2-aminoethylester-monohydro- chloridExample 2 4-Methylbenzenecarbothioic acid ~ 2-aminoethyl ester monohydrochloride
En blanding af 30 ml (ca. 0,18 mol) frisk destille-5 ret p-toluoylchlorid, kogepunkt 122°C/32 mm Hg, og 9,68 g (0,085 mol) 2-aminoethanthiol-hydrochlorid opvarmes (beskyttet mod fugt) over en dampstråle i 2,25 timer. Der dannes en fast krystallinsk masse, når reaktionen er afsluttet. Massen knuses og tritureres omhyggeligt med ligroin, der er 60-10 110°C varm, og krystallerne skilles fra ved filtrering og va skes med varm ligroin. Efter to omkrystallisationer ud fra vandfri ethanol smelter produktet, der vejer 19,07 g (97%) ved 206,5-208°C. NMR, MS og IR viser alle strukturen af den i overskriften nævnte forbindelse ifølge formel I.A mixture of 30 ml (about 0.18 mol) of freshly distilled p-toluoyl chloride, boiling point 122 ° C / 32 mm Hg, and 9.68 g (0.085 mol) of 2-aminoethanthiol hydrochloride are heated (protected from moisture ) over a steam jet for 2.25 hours. A solid crystalline mass is formed when the reaction is complete. The mass is crushed and triturated carefully with ligroin that is 60-10 110 ° C hot, and the crystals are separated by filtration and washed with hot ligroin. After two recrystallizations from anhydrous ethanol, the product weighing 19.07 g (97%) melts at 206.5-208 ° C. NMR, MS and IR all show the structure of the title compound of formula I.
15 Analyse: Beregnet for C^qH^NOCIS: C 51,83, H 6,09, N 6,04.Analysis: Calculated for C ^HH ^NOCIS: C 51.83, H 6.09, N 6.04.
Fundet: C 51,57, H 6,06, N 6,11.Found: C, 51.57; H, 6.06; N, 6.11.
Eksempel 3 4-Methoxybenzencarbothioin5yre-2-aminoethylester-monohydro- chloridExample 3 4-Methoxybenzenecarbothioic acid 2-aminoethyl ester monohydrochloride
En blanding af 23 ml (ca. 0,135 mol) p-anisoylchlo-rid og 7,4 g 2-aminoethanthiol-hydrochlorid (0,065 mol) opvarmes (beskyttet mod fugt) over en dampstråle i ca. 2 timer.A mixture of 23 ml (about 0.135 mole) of p-anisoyl chloride and 7.4 g of 2-aminoethanethiol hydrochloride (0.065 mole) is heated (protected against moisture) over a steam jet for approx. 2 hours.
Den fremkomne krystallinske masse knuses og tritureres om- 25 o hyggeligt med ligroin, der er 60-110 C varm, og krystallser- ne skilles fra ved filtrering og vaskes med varm ligroin.The resulting crystalline mass is crushed and triturated comfortably with ligroin which is 60-110 ° C warm, and the crystals are separated by filtration and washed with hot ligroin.
Efter to omkrystallisationer ud fra vandfri ethanol smelter produktet, der vejer 14,6 g (90,6%), ved 191,5-193°C. NMR, MS og IR viser alle strukturen af den i overskriften nævnte 30 forbindelse ifølge formel I.After two recrystallizations from anhydrous ethanol, the product weighing 14.6 g (90.6%) melts at 191.5-193 ° C. NMR, MS and IR all show the structure of the title compound of formula I.
Analyse: Beregnet for c10H14C1NO2S: C 48,48, H 5,69, N 5,65.Analysis: Calculated for C 10 H 14 ClNO 2 S: C 48.48, H 5.69, N 5.65.
Fundet: C 48,42, H 5,73, N 5,66.Found: C, 48.42; H, 5.73; N, 5.66.
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Eksempel 4 2-Thiophencarbothioinsyre-2-aminoethylester-hydrochloridExample 4 2-Thiophenecarbothioic acid 2-aminoethyl ester hydrochloride
En blanding af 15,8 g (QflQ8 mol) frisk destilleret 2-thiophencarbonylchlorid og 11,3 g (0,1 mol) 2-aminoethan-5 thiol -hydrochlorid opvarmes (beskyttet mod fugt) over en dampstråle i 6 timer. Den fremkomne faste krystallinske masse knuses og tritureres med ligroin, der er 60-110°C varm, og filtreres for at opsamle krystallerne. Efter to omkrystallisationer ud fra vandig ethanol smelter produktet, der 10 vejer 8,41 g (75,5%) ved 195-196,5°C. NMR, MS og IR viser alle strukturen af den i overskriften nævnte forbindelse i-følge formel I.A mixture of 15.8 g (QflQ8 mol) of freshly distilled 2-thiophenecarbonyl chloride and 11.3 g (0.1 mol) of 2-aminoethanethiol-hydrochloride is heated (moisture protected) over a steam jet for 6 hours. The resulting solid crystalline mass is crushed and triturated with ligroin, 60-110 ° C hot, and filtered to collect the crystals. After two recrystallizations from aqueous ethanol, the product weighing 8.41 g (75.5%) melts at 195-196.5 ° C. NMR, MS and IR all show the structure of the title compound according to Formula I.
Analyse: Beregnet for C^H^qC1N0S2: C 37,58, H 4,51, N 6,26.Analysis: Calculated for C ^H ^ qClCNO₂: C 37.58, H 4.51, N 6.26.
Fundet: C 37,68, H 4,50, N 6,30.Found: C, 37.68; H, 4.50; N, 6.30.
1515
Forbindelserne med formlen I kan indgå i farmaceutiske præparater i en mængde, der er tilstrækkelig til at give en effektiv virkning mod lungekongestion hos varmblodede dyr, når det anvendes topisk eller som inhaleringsmiddel.The compounds of formula I may be included in pharmaceutical compositions in an amount sufficient to provide an effective effect against pulmonary congestion in warm-blooded animals when used topically or as an inhalant.
2Q Forbindelserne med formlen I indgives i en mængde, der er tilstrækkelig til at bevirke, at mucus i åndedrætsvejene hos varmblodede dyr bliver flydende, når dette er påkrævet. Intratracheal indgivelse af forbindelserne med formlen I sker ved hjælp af forskellige inhalerings- eller inddryp-ningsmidler såsom næsedråber, sprays, aerosoler og lignende.2Q The compounds of formula I are administered in an amount sufficient to cause the mucus of the respiratory tract of warm-blooded animals to become fluid when required. Intratracheal administration of the compounds of formula I is by various inhalation or instillation agents such as nasal drops, sprays, aerosols and the like.
Andre egnede midler til indgivelse er ved indsnusning af mikroniserede partikler eller ultra-fint pulver, idet der udelukkende anvendes indåndingens virkning^ eller ved anvendelse af aerosoldrivmidler. Opløsninger eller suspensioner 30 med ca. 0,5 til 5 vægtprocent af det mucolytiske middel med formlen I er egnet til anvendelse ved sprøjtning med forstøver, aerosol og lignende.Other suitable agents for administration are by crushing of micronized particles or ultra-fine powder, using only the effect of inhalation ^ or using aerosol propellants. Solutions or suspensions 30 with approx. 0.5 to 5% by weight of the mucolytic agent of formula I is suitable for use in spraying with atomizer, aerosol and the like.
Den korrekte dosering af en forbindelse, der skal anvendes til et bestemt pattedyr, bestemmes af hvor alvorlig 35 den tilstand er, der kræver mucolytisk terapi, samt af patientens alder, køn, vægt og almene fysiske tilstand. Individuelle doser på fra 5 til 100 mg til inhalering af mennesker er passende og kan være nødvendige for opnåelse af en mucolytisk virkning.The correct dosage of a compound to be used for a particular mammal is determined by the severity of the condition requiring mucolytic therapy, as well as by the patient's age, gender, weight and general physical condition. Individual doses of 5 to 100 mg for inhalation of humans are appropriate and may be necessary to achieve a mucolytic effect.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93274778A | 1978-08-10 | 1978-08-10 | |
| US93274778 | 1978-08-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK333879A DK333879A (en) | 1980-02-11 |
| DK159655B true DK159655B (en) | 1990-11-12 |
| DK159655C DK159655C (en) | 1991-04-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK333879A DK159655C (en) | 1978-08-10 | 1979-08-09 | ANALOGY PROCEDURE FOR PREPARING (SUBSTITUTED BENZEN) - OR 2-THIOPEN CARBOTHIOIC ACID AMINOAL COOLERS |
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| 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 |
| 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 |
| IE48794B1 (en) | 1985-05-15 |
| 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 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |