DE3023206A1 - Antiinflammatory indomethacin di:alkylamino-ethyl ester derivs. - prepd. by heating indomethacin with an O-di:alkyl:aminoethyl-N,N'-di:isopropyl isourea in benzene - Google Patents

Antiinflammatory indomethacin di:alkylamino-ethyl ester derivs. - prepd. by heating indomethacin with an O-di:alkyl:aminoethyl-N,N'-di:isopropyl isourea in benzene

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Publication number
DE3023206A1
DE3023206A1 DE19803023206 DE3023206A DE3023206A1 DE 3023206 A1 DE3023206 A1 DE 3023206A1 DE 19803023206 DE19803023206 DE 19803023206 DE 3023206 A DE3023206 A DE 3023206A DE 3023206 A1 DE3023206 A1 DE 3023206A1
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Prior art keywords
indomethacin
benzene
isourea
heating
ethyl
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Ceased
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DE19803023206
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German (de)
Inventor
Thomas Prof. Graz Kappe
Joachim Dr. 3300 Braunschweig Wagner
Heinz-Martin 3004 Isernhagen Weidemann
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Efeka Friedrich & Kaufmann Gmb
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Efeka Friedrich & Kaufmann Gmb
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Priority claimed from DE19792944347 external-priority patent/DE2944347A1/en
Application filed by Efeka Friedrich & Kaufmann Gmb filed Critical Efeka Friedrich & Kaufmann Gmb
Priority to DE19803023206 priority Critical patent/DE3023206A1/en
Publication of DE3023206A1 publication Critical patent/DE3023206A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

Indomethacin dialkylaminoethyl esters (I) and their hydrochlorides are new. In (I), R is methyl, ethyl or a higher homologue. (I) have antiinflammatory properties and can be used for the treatment of inflammatory (esp. rheumatic) diseases. Dimethylaminoethanol (18 g), diisopropyl-carbodiimide (26 g) and CuCl (0.1 g) are stirred 2 days at room temp., initial exothermic reaction causes the temp. to rise to 60 deg. Distn. of the reaction mixt. under reduced pressure gives N,N'-diisopropyl- 0-(2-dimethyl aminoethyl) isourea (IIIa) (32.0 g), b.pt. 92 deg/6 mm. (IIIa) (4.4 g) and indomethacin (7.2 g) in benzene (100 ml) are refluxed 22 hrs., cooled to room temp., filtered from pptd. diisopropylurea (2.4 g), washed with ice-cold IN NaOH and evaporated. The residual oil is digested with petroleum ether to give crystalline (I; R:CH3) (8.0 g) as colourless crystals, m.pt. 84 deg.

Description

Die Erfindung betrifft Indometacin-Ester der Formel The invention relates to indomethacin esters of the formula

worin R Methyl oder Äthyl oder ein höheres Homologes bedeuten, und Verfahren zu ihrer Herstellung.wherein R is methyl or ethyl or a higher homologue, and Process for their manufacture.

Es ist bekannt, daß Ester des Indometacins der Formel mit Aminoalkoholen nicht nach den üblichen Verfahren der Veresterung und auch nicht nach der Carbodiimid-Methode herstellbar sind.It is known that esters of indomethacin of the formula cannot be prepared with amino alcohols by the usual esterification process and also not by the carbodiimide method.

Überraschenderweise wurde gefunden, daß die Veresterung des Indometacins mit Isoharnstoff-Derivaten der entsprechenden Aminoalkohole glatt und in guten Ausbeuten verläuft, wenn man erfindungsgemäß Indometacin der Formel mit Isoharnstoff-Derivaten der Aminoalkohole der Formel worin R Methyl oder Äthyl bedeuten, durch Erhitzen in Benzol umsetzt. Besonders vorteilhaft haben sich hierbei als Isoharnstoff-Derivat die N,N'-Diisopropylisoharnstoffe wegen der niedrigeren Siedepunkte und der damit verbundenen erleichterten Reinigung erwiesen; jedoch auch mit höheren Homologen, z.B. Cyclohexyl,läßt sich die Veresterung durchführen. Die Darstellung von N,N'-Diisopropyl-O-2-(dimethylamino)-äthyl-isoharnstoff erfolgt dabei nach bekannten Verfahren durch Umsetzung von Diäthylaminoäthanol mit Diisopropylcarbodiimid und CuCl als Katalysator (Schmidt,Mossmüller, Liebigs Anm. Chem. 597, 235 (1958); Däbritz, Angew.Chem.It has surprisingly been found that the esterification of indomethacin with isourea derivatives of the corresponding amino alcohols proceeds smoothly and in good yields when indomethacin of the formula is used according to the invention with isourea derivatives of the amino alcohols of the formula where R is methyl or ethyl, converted into benzene by heating. The N, N'-diisopropylisoureas have proven to be particularly advantageous as isourea derivatives because of their lower boiling points and the associated ease of cleaning; however, the esterification can also be carried out with higher homologues, for example cyclohexyl. N, N'-diisopropyl-O-2- (dimethylamino) -ethyl-isourea is prepared according to known processes by reacting diethylaminoethanol with diisopropylcarbodiimide and CuCl as a catalyst (Schmidt, Mossmüller, Liebigs Anm. Chem. 597, 235 ( 1958); Däbritz, Angew. Chem.

78,483 (1966).78,483 (1966).

Außerdem wurde aufgefunden, daß die neuen Ester entzündungshemmende Eigenschaften besitzen und zur erfolgreichen Behandlung entzündlicher, vorwiegend rheumatischer Erkrankungen geeignet sind.The new esters have also been found to be anti-inflammatory Possess properties and to successfully treat inflammatory, predominantly rheumatic diseases are suitable.

Die Erfindung umfaßt somit auch pharmazeutige Zubereitungen, die neben nichttoxischen, inerten pharmazeutisch geeigneten festen oder flüssigen Trägerstoffen einen oder mehrere erfindungsgemäße Wirkstoffe enthalten oder die aus einem erfindungsgemäßen Wirkstoff bestehen. Die Verabreichung der Wirkstoffe erfolgt durch innerliche Einnahme oder durch Injektion.The invention thus also includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable solid or liquid carriers contain one or more active ingredients according to the invention or from one according to the invention Active ingredient. The active ingredients are administered internally or by injection.

Die folgenden Beispiele zeigen die Herstellung der Ester: Beispiel 1 N,N'-Diisopropyl-0-2-(dimethylamino)-äthyl-isoharnstoff der Formel 18 g(0,2 Mol) Dimethylaminoäthanol, 26g (0,2 Mol) Diisopropylcarbodiimid und 0,1 g CuCl werden miteinander vermischt und bei Raumtemperatur zwei Tage lang gerührt, wobei zu Beginn der Reaktion eine Erwärmung auf 60 0C eintritt. Danach erfolgt eine Destillation unter verindertem Druck; ° Kp 92 C/6mm, Ausbeute 32,0 g (74,4% d.Th.).The following examples show the preparation of the esters: Example 1 N, N'-Diisopropyl-0-2- (dimethylamino) -ethyl-isourea of the formula 18 g (0.2 mol) of dimethylaminoethanol, 26 g (0.2 mol) of diisopropylcarbodiimide and 0.1 g of CuCl are mixed with one another and stirred at room temperature for two days, heating to 60 ° C. at the beginning of the reaction. This is followed by distillation under reduced pressure; ° Bp 92 ° C./6 mm, yield 32.0 g (74.4% of theory).

NMR (CC1 ): = 0.9-1.2 ppm (m,i-Prop.); 2.2 (s, 2CH3); 4 3' 2,45 (t, J= 6 Hz, N-CH2); 4.0 (t, J=6 Hz, OCH 2 C11H25N3O (215.1) Ber. N 19.53 Gef. N 19.45 Beispiel 2 l-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessiqsäure-dimethylamino-äthylester der Formel 4,4g ( 2q mmol) nach Beispiel 1 hergestellter N,N'-Diisopropyl-0-2-(dimethylamino)-äthyl-isoharnstoff und 7,2 g (20 mmol) Indometacin werden in 100 ml Benzol gelöst und 22 Stunden unter Rückfluß erhitzt. Während der Reaktion fällt ein farbloser Niederschlag von Diisopropylharnstoff aus. Nach Abkühlen auf Raumtemperatur filtriert man den Harnstoff (2,4 g) ab. Die benzolische Lösung wird zur Entfernung von nicht umgesetzter Säure mit eiskalter 1 n NaOH ausgeschüttelt. Nach Entfernung des Lösungsmittels bleibt ein öliges Produkt zurück, das durch Digerieren mit Petroläther kristallin wird.NMR (CC1): = 0.9-1.2 ppm (m, i-prop.); 2.2 (s, 2CH3); 4 3 '2.45 (t, J = 6 Hz, N-CH2); 4.0 (t, J = 6 Hz, OCH 2 C11H25N3O (215.1) Calc. N 19.53 Found. N 19.45 Example 2 lp-Chlorobenzoyl-5-methoxy-2-methyl-3-indolessiq acid dimethylaminoethyl ester of the formula 4.4 g (2q mmol) of N, N'-diisopropyl-0-2- (dimethylamino) ethyl isourea prepared according to Example 1 and 7.2 g (20 mmol) of indomethacin are dissolved in 100 ml of benzene and refluxed for 22 hours heated. A colorless precipitate of diisopropylurea separates out during the reaction. After cooling to room temperature, the urea (2.4 g) is filtered off. The benzene solution is shaken out with ice-cold 1N NaOH to remove any unreacted acid. After the solvent has been removed, an oily product remains which becomes crystalline on digestion with petroleum ether.

° Ausbeute 8,0 g (93% d.Th.); farbl.Prismen vom Schmp. 84 C. ° Yield 8.0 g (93% of theory); colored prisms of m.p. 84 C.

IR (KBr): 2940-2520 (CH), 1740 s (CO-Ester), 1680 s (C0),1580/cm.IR (KBr): 2940-2520 (CH), 1740 s (CO ester), 1680 s (C0), 1580 / cm.

¹H-NMR (CDCl3):# = 2.2 ppm (s, 2CH3-N); 2.35 (s,CH ) 2.5(t, J=6 Hz, N-CH2) 3.65 (s,CH2); 3.8 (s, 0-CH3); 4.15 (t, J=6 Hz, 2' 2' O-CH2); 6.45-6.9 (m, 3 aromat.H); 7.25-7.7 (m, 4 aromat.H).1 H-NMR (CDCl3): # = 2.2 ppm (s, 2CH3-N); 2.35 (s, CH) 2.5 (t, J = 6 Hz, N-CH2) 3.65 (s, CH2); 3.8 (s, O-CH3); 4.15 (t, J = 6 Hz, 2 '2' O-CH2); 6.45-6.9 (m, 3 aromatic H); 7.25-7.7 (m, 4 aromatic H).

c23H25cl N204 Ber. N. 6.53 C1 8.27 (428,7) Gef. N. 6.61 C1 8.36 Beispiel 3 l-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessiqSäuredimethlamino-äthylester-Hydrochlorid 2,1 g ( 5 mmol)l-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessigsäure-dimethylamino-äthylester werden in 20 ml Essigester gelöst und mit ätherischer HCl-Lösung versetzt, bis das Ausfallen eines farblosen Niederschlages beendet ist. Dieser wird mit Essigester gewaschen. Ausbeute 1.5 g (65%);farbl.Prismen, Schmp. 1770C.c23H25cl N204 Ber. N. 6.53 C1 8.27 (428.7) Found N. 6.61 C1 8.36 Example 3 l-p-chlorobenzoyl-5-methoxy-2-methyl-3-indolessiq dimethylamino-ethyl ester hydrochloride 2.1 g (5 mmol) of l-p-chlorobenzoyl-5-methoxy-2-methyl-3-indole acetic acid dimethylaminoethyl ester are dissolved in 20 ml of ethyl acetate and mixed with ethereal HCl solution until the A colorless precipitate has ended. This is made with ethyl acetate washed. Yield 1.5 g (65%); colored prisms, m.p. 1770C.

C23H26C1 2N204 Ber. N 6.02 C1 15.24 (465.1) Gef. N 6.01 C1 15.36 Beipsiel 4 1-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessigsäure-diäthylamino-äthylester der Formel 2,5 g (10 mmol)N,N'.Diisopropyl-0-2(diäthylamino)-äthylisoharnstoff, hergestellt nach Schmidt,Mossmüller/Däbritz, und 3,6 g (10 mmol) Indometacin werden in 50 ml Benzol gelöst und 20 Stunden unter Rückfluß erhitzt. Nach dem Abkühlen auf Raumtemperatur wird der entstandene Harnstoff abfiltriert und die benzolische Lösung mit eiskalter 1 n NaOH ausgeschüttelt.C23H26C1 2N204 calc. N 6.02 C1 15.24 (465.1) Found N 6.01 C1 15.36 Example 4 1-p-chlorobenzoyl-5-methoxy-2-methyl-3-indole acetic acid diethylamino-ethyl ester of the formula 2.5 g (10 mmol) of N, N'.Diisopropyl-0-2 (diethylamino) ethylisourea, prepared according to Schmidt, Mossmüller / Däbritz, and 3.6 g (10 mmol) of indomethacin are dissolved in 50 ml of benzene and 20 Heated under reflux for hours. After cooling to room temperature, the urea formed is filtered off and the benzene solution is shaken out with ice-cold 1N NaOH.

Nach Entfernen des Lösungsmittels bleibt ein gelbes Öl zurück, das nicht in den kristallinen Zustand übergeführt werden kann.After removing the solvent, a yellow oil remains which cannot be converted into the crystalline state.

Ausbeute 3,2 g (70 d.Th.). Zur Charakterisierung wird die Verbindung, wie nachstehend beschrieben, in das Hydrochlorid überführt.Yield 3.2 g (70 of theory). The connection is used for characterization as described below, converted into the hydrochloride.

Beispiel 5 1-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessigsäure-diäthylamino-äthylester-Hydrochlorid 2,3 g (5 mmol) 1-p-Chlorbenzoyl-5-methoxy-2-methyl-3-indolessigsäure-diäthylamino-thylester werden in 10 ml Essigester gelöst und nach Zugabe der berechneten Menge ätherischer HC1 wird das Hydrochlorid mit Petroläther ausgefällt.Example 5 1-p-Chlorobenzoyl-5-methoxy-2-methyl-3-indole acetic acid diethylaminoethyl ester hydrochloride 2.3 g (5 mmol) of 1-p-chlorobenzoyl-5-methoxy-2-methyl-3-indole acetic acid diethylamino-ethyl ester are dissolved in 10 ml of ethyl acetate and, after adding the calculated amount, more ethereal HC1 the hydrochloride is precipitated with petroleum ether.

Ausbeute 2,2 g (89%), farbl. Prismen vom Schmp. 142 C.Yield 2.2 g (89%), colored prisms with a melting point of 142 C.

IR (KBr): 3600-2800, 2600-2400, 1750 s (CO-Ester), 1680 s (CO-Amid), 1595 (Aromat).IR (KBr): 3600-2800, 2600-2400, 1750 s (CO ester), 1680 s (CO amide), 1595 (aromatic).

¹H-NMR (DMSO-d6): # =1,2 ppm (t, J= 7 Hz, 2CH3-Et);2,35 (s, CH3); 2.7-3.35 (m, N-CH2 + 2 CH2-Et); 3.75 (s, CH2); 3. 8(s.0-CH 3' 2 2' 3 4.55 (t, J= 6 Hz, O-CH2); 6.45-7.0 (m, 3 aromat.H); 7.2-7.7 (m, 4 aromat.H); 12.15 (s, H-N+).1 H-NMR (DMSO-d6): # = 1.2 ppm (t, J = 7 Hz, 2CH3-Et); 2.35 (s, CH3); 2.7-3.35 (m, N-CH2 + 2 CH2-Et); 3.75 (s, CH2); 3. 8 (s.0-CH 3 '2 2' 3 4.55 (t, J = 6 Hz, O-CH2); 6.45-7.0 (m, 3 aromatic H); 7.2-7.7 (m, 4 aromatic H); 12.15 (s, H-N +).

C25H30C12N204 Ber. N 5.68 C1 14.38 (493.1) Gef. N 5.32 C1 14.02C25H30C12N204 Calc. N 5.68 C1 14.38 (493.1) found N 5.32 C1 14.02

Claims (4)

T 1 t e 1: "Indometacin-Ester, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel" Patentansprüche 1. Indometacin-Ester der Formel worin R Methyl oder Äthyl oder ein höheres Homologes bedeuten, und deren Hydrocloride.T 1 part 1: "Indomethacin esters, process for their preparation and their use as medicaments" Patent claims 1. Indomethacin esters of the formula where R is methyl or ethyl or a higher homologue, and their hydrochloride. 2. Verfahren zur Herstellung von Indometacin-Estern gemäß Anspruch 1, dadurch gekennzeichnet, daß man Indometacin der Formel durch Erhitzen in Benzol mit Isoharnstoff-Derivaten der Aminoalkohole der Formel worin R Methyl oder Äthyl oder ein höheres Homologes bedeuten, verestert und gegebenenfalls den erhaltenen Indometacin-Ester in sein Hydrochlorid überführt.2. Process for the preparation of indomethacin esters according to claim 1, characterized in that indomethacin of the formula by heating in benzene with isourea derivatives of the amino alcohols of the formula where R denotes methyl or ethyl or a higher homologue, esterified and optionally converted the indomethacin ester obtained into its hydrochloride. 3. Antirheumatisch wirksame pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an einer der Verbindungen nach Anspruch 1.3. Antirheumatically effective pharmaceutical preparation, characterized by a content of one of the compounds according to claim 1. 4. Antirheumatisch wirksame pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an einer der Verbindungen nach Anspruch 1 mit festen oder flüssigen Träger- und Hilfsstoffen.4. Antirheumatically effective pharmaceutical preparation, characterized by a content of one of the compounds according to claim 1 with solid or liquid Carriers and auxiliary materials.
DE19803023206 1979-11-02 1980-06-21 Antiinflammatory indomethacin di:alkylamino-ethyl ester derivs. - prepd. by heating indomethacin with an O-di:alkyl:aminoethyl-N,N'-di:isopropyl isourea in benzene Ceased DE3023206A1 (en)

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DE19803023206 DE3023206A1 (en) 1979-11-02 1980-06-21 Antiinflammatory indomethacin di:alkylamino-ethyl ester derivs. - prepd. by heating indomethacin with an O-di:alkyl:aminoethyl-N,N'-di:isopropyl isourea in benzene

Applications Claiming Priority (2)

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DE19792944347 DE2944347A1 (en) 1979-11-02 1979-11-02 Di:alkyl-aminoethyl ester(s) of indomethacin - obtd. by esterification of indomethacin with an isourea deriv. of an aminoalcohol
DE19803023206 DE3023206A1 (en) 1979-11-02 1980-06-21 Antiinflammatory indomethacin di:alkylamino-ethyl ester derivs. - prepd. by heating indomethacin with an O-di:alkyl:aminoethyl-N,N'-di:isopropyl isourea in benzene

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0237495A2 (en) * 1986-03-04 1987-09-16 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Halogenides of the ester of 2,N,N,N-dimethyl-alkyl-amino-ethanol with substituted acetic acid and pharmaceutical compositions having antiinflammatory and antiseptic activities containing same
EP0647133A1 (en) * 1992-06-12 1995-04-12 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
JP2010529101A (en) * 2007-06-04 2010-08-26 テックフィールズ インコーポレイテッド NSAIA prodrug with very fast skin and membrane permeation rate and novel pharmaceutical use thereof
JP2013147515A (en) * 2013-05-08 2013-08-01 Techfields Inc Nsaia prodrug having very fast skin- and film-infiltration rate, and new use thereof as medicine
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US11813256B2 (en) 2012-05-16 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0237495A2 (en) * 1986-03-04 1987-09-16 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Halogenides of the ester of 2,N,N,N-dimethyl-alkyl-amino-ethanol with substituted acetic acid and pharmaceutical compositions having antiinflammatory and antiseptic activities containing same
EP0237495A3 (en) * 1986-03-04 1988-06-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Halogenides of the ester of 2,n,n,n-dimethyl-alkyl-amino-ethanol with substituted acetic acid and pharmaceutical compositions having antiinflammatory and antiseptic activities containing same
EP0647133A1 (en) * 1992-06-12 1995-04-12 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
EP0647133A4 (en) * 1992-06-12 1997-10-29 Affymax Tech Nv Compositions and methods for enhanced drug delivery.
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US10233198B2 (en) 2007-06-04 2019-03-19 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses
JP2010529101A (en) * 2007-06-04 2010-08-26 テックフィールズ インコーポレイテッド NSAIA prodrug with very fast skin and membrane permeation rate and novel pharmaceutical use thereof
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US11813256B2 (en) 2012-05-16 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions
US11857545B2 (en) 2012-05-16 2024-01-02 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
JP2013147515A (en) * 2013-05-08 2013-08-01 Techfields Inc Nsaia prodrug having very fast skin- and film-infiltration rate, and new use thereof as medicine

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