CH660480A5 - D-2- (6-METHOXY-2-NAFTIL) PROPIONIC DERIVATIVES WITH THERAPEUTIC ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

D-2- (6-METHOXY-2-NAFTIL) PROPIONIC DERIVATIVES WITH THERAPEUTIC ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. Download PDF

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Publication number
CH660480A5
CH660480A5 CH1411/83A CH141183A CH660480A5 CH 660480 A5 CH660480 A5 CH 660480A5 CH 1411/83 A CH1411/83 A CH 1411/83A CH 141183 A CH141183 A CH 141183A CH 660480 A5 CH660480 A5 CH 660480A5
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methoxy
preparation
process according
reaction
derivatives
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CH1411/83A
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Italian (it)
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Osvaldo Ponchiroli
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Isnardi Pietro & C Spa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

La presente invenzione riguarda derivati dell'acido d-2(6--metossi-2-naftil)-propionico, noto anche con il nome di Naproxen, e più precisamente i derivati con acido p-amino-benzoico, aventi formula generale: The present invention relates to derivatives of d-2 (6 - methoxy-2-naphthyl) -propionic acid, also known by the name of Naproxen, and more precisely the derivatives with p-amino-benzoic acid, having general formula:

dove X rappresenta idrogeno, un radicale di una base organica od inorganica non tossica e farmaceuticamente accettabile, un gruppo aminico oppure il radicale di un aminoacido basico. where X represents hydrogen, a radical of a non-toxic and pharmaceutically acceptable organic or inorganic base, an amine group or the radical of a basic amino acid.

Sono note le proprietà anti-infiammatorie del Naproxen. Tuttavia, al pari di altri farmaci ad attività anti-infiammatoria, esso presenta alcuni effetti collaterali sfavorevoli, come ad esempio una bassa tollerabilità a livello gastrico nonché una tossicità non trascurabile. È evidente che questi effetti assumano importanza nel caso terapie prolungate. The anti-inflammatory properties of Naproxen are known. However, like other drugs with anti-inflammatory activity, it has some unfavorable side effects, such as low gastric tolerability and non-negligible toxicity. It is evident that these effects assume importance in the case of prolonged therapies.

I derivati della presente invenzione, invece, mantenendo inalterate le proprietà anti-infiammatorie del Naproxen, hanno dimostrato di possedere una minore tossicità ed una migliore attività, specialmente sotto il profilo della durata nel tempo dell'effetto terapeutico. The derivatives of the present invention, on the other hand, maintaining the anti-inflammatory properties of Naproxen unaltered, have been shown to have less toxicity and better activity, especially in terms of the duration of the therapeutic effect over time.

Come sopra menzionato, oltre al derivato amidico, (in cui X = H nella formula precedente), la presente invenzione prevede anche i sali non tossici e farmacologicamente accettabili del-l'amide stessa, in conformità ai significati di X sopra indicati. As mentioned above, in addition to the starch derivative, (wherein X = H in the previous formula), the present invention also provides the non-toxic and pharmacologically acceptable salts of the same amide, in accordance with the meanings of X indicated above.

Un altro aspetto della presente invenzione riguarda il procedimento per la preparazione dei derivati suddetti, procedimento che si caratterizza per gli stadi seguenti: Another aspect of the present invention relates to the process for the preparation of the aforementioned derivatives, a process which is characterized by the following stages:

a) preparazione di un derivato funzionale reattivo dell'acido d-2(6-metossi-2-naftil)-propionico ; a) preparation of a reactive functional derivative of d-2 (6-methoxy-2-naphthyl) -propionic acid;

b) reazione di detto derivato reattivo con acido p-amino-benzoico e c) eventuale salificazione con un'opportuna base organica od inorganica, un'amica organica oppure un aminoacido basico, a seconda del derivato desiderato. b) reaction of said reactive derivative with p-amino-benzoic acid and c) possible salification with a suitable organic or inorganic base, an organic friend or a basic amino acid, according to the desired derivative.

Per quanto riguarda lo stadio a) precedente detto derivato reattivo dell'acido d-2(6-metossi-2-naftil)-propionico è preferibilmente scelto tra il cloruro, preparato per reazione con un appropriato agente clorurante (cloruro di tionile, pentacloruro di fosforo, fosgene e simili) e l'anidride mista con cloroformiato di etile, od appropriati carbonati alchilici reattivi. As regards the step a) above, said reactive derivative of d-2 (6-methoxy-2-naphthyl) -propionic acid is preferably selected from the chloride, prepared by reaction with an appropriate chlorinating agent (thionyl chloride, pentachloride of phosphorus, phosgene and the like) and mixed anhydride with ethyl chloroformate, or appropriate reactive alkyl carbonates.

A sua volta lo stadio b) prevede di preferenza che la reazione venga effettuata in una miscela binaria di solventi, come ad esempio acqua e cloroformio; inoltre il mezzo di reazione deve essere reso alcalino oppure si preferisce usare un sale con un metallo alcalino dell'acido p-amino benzoico. In turn, step b) preferably provides that the reaction is carried out in a binary mixture of solvents, such as for example water and chloroform; furthermore, the reaction medium must be made alkaline or it is preferred to use a salt with an alkaline metal of p-amino benzoic acid.

L'esempio che segue illustra senza alcun intendimento limitativo il procedimento secondo l'invenzione. The following example illustrates the method according to the invention without any limiting intent.

Esempio a) Preparazione del cloruro dell'acido d-2(6-metossi-2-naf-til)-propionico Example a) Preparation of the chloride of d-2 (6-methoxy-2-naf-tyl) -propionic acid

In un pallone da 1 litro, munito di agitatore, refrigerante e trappola per gas, si caricano in sequenza 117,4 g (0,51 moli) di acido d-2-(6-metossi-2-naftil)-propionico, 150 mi di cloroformio e 150 mi di cloruro di tionile. 117.4 g (0.51 moles) of d-2- (6-methoxy-2-naphthyl) -propionic acid are loaded in a 1 liter flask, equipped with a stirrer, coolant and gas trap. ml of chloroform and 150 ml of thionyl chloride.

Si riscalda la miscela di reazione a bagno maria fino alla temperatura di riflusso e si mantiene a tale temperatura fino a quando cessa lo sviluppo di gas. The reaction mixture is heated in a bain-marie to the reflux temperature and is maintained at this temperature until the gas development ceases.

Si concentra la miscela di reazione a pressione ridotta, ottenendo un prodotto solido, di colore marrone ed odore pungente, con resa pari al 98% del teorico. The reaction mixture is concentrated under reduced pressure, obtaining a solid product, brown in color and pungent odor, with a yield equal to 98% of the theoretical.

b) Preparazione dell'anide con acido p-amino benzoico dell'acido d-2-(6-metossi-2-naftil)-propionico b) Preparation of the anide with p-amino benzoic acid of d-2- (6-methoxy-2-naphthyl) -propionic acid

Ad una soluzione di 97 g (0,61 moli) di p-amino benzoato solido in 500 mi di acqua si aggiunge sotto forte agitazione, ad una temperatura di 10°C una soluzione di 126 g (0,51 moli) del cloruro di acido d-2-(6-metossi-2-naftil)-propionico preparato nello stadio precedente in 700 mi di cloroformio. To a solution of 97 g (0.61 moles) of solid p-amino benzoate in 500 ml of water, under a stirring, at a temperature of 10 ° C, a solution of 126 g (0.51 moles) of the chloride of d-2- (6-methoxy-2-naphthyl) -propionic acid prepared in the previous stage in 700 ml of chloroform.

Si forma un precipitato molto fine di colore crema, che viene lasciato a sè stesso per 4 ore, dopo di che si acidifica con 10 mi di acido cloridrico al 37% e si mantiene sotto agitazione per 30 minuti. A very fine cream-colored precipitate is formed, which is left to itself for 4 hours, after which it is acidified with 10 ml of 37% hydrochloric acid and is kept under stirring for 30 minutes.

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Si filtra sotto pressione ridotta e, dopo essiccamento, si ricuperano 150 g di prodotto che all'esame cromatografico risulta quasi puro. It is filtered under reduced pressure and, after drying, 150 g of product are recovered, which on the chromatographic examination is almost pure.

Si ricristallizza il prodotto da una miscela di diossano ed acqua, ottenendo 85 g di prodotto secco cromatograficamente puro, ossia 4' -carbossi, 6-metossi, metil-2-naftalenacetanilide, avente punto di fusione di 228-230°C, con resa del 47%. The product is recrystallized from a mixture of dioxane and water, obtaining 85 g of chromatographically pure dry product, i.e. 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide, having a melting point of 228-230 ° C, with yield 47%.

Il prodotto si presenta sotto forma di polvere microcristallina, bianca, insolubile in acqua e solubile a caldo in alcool, diossano ed acetone. Su questo prodotto sono state effettuate indagini spettografiche, ottenendo gli spettri IR, UV ed NMR riportati rispettivamente nelle figure 1, 2 e 3 allegate. The product comes in the form of a microcrystalline, white powder, insoluble in water and hot soluble in alcohol, dioxane and acetone. Spectographic surveys were carried out on this product, obtaining the IR, UV and NMR spectra shown respectively in figures 1, 2 and 3 attached.

I composti della presente invenzione sono stati oggetto di indagini tossicologiche e farmacologiche. The compounds of the present invention have been subject to toxicological and pharmacological investigations.

Nel seguito si riportano i risultati relativi all'amide con acido p-aminobenzoico dell'acido d-2-(6-metossi-2-naftil)-propio-nico (A), in confronto con quest'ultimo (B) (i simboli A e B essendo usati per semplicità). Below are the results relating to the amide with p-aminobenzoic acid of d-2- (6-methoxy-2-naphthyl) -propionic (A) acid, in comparison with the latter (B) (i symbols A and B being used for simplicity).

Dati tossicologici e farmacologici preliminari Preliminary toxicological and pharmacological data

Le ricerche su A sono state effettuate in comparazione con dosi equimolari di B e le dosi nel seguito riportate sono espresse in mg di questo ultimo composto. Researches on A have been carried out in comparison with equimolar doses of B and the following doses are expressed in mg of this last compound.

1) Tossicità acuta 1) Acute toxicity

II composto A è risultato meno tossico del composto B nel topo e nel ratto sia per via orale che per via parenterale Compound A was less toxic than compound B in the mouse and rat both orally and parenterally

Composto Composed

Specie Species

Via di somm. Via di somm.

DL50 (mg/kg) LD50 (mg / kg)

A TO

topo orale oral mouse

3050 3050

B B

topo orale oral mouse

700 700

A TO

topo intraperitoneale intraperitoneal mouse

720 720

B B

topo intraperitoneale intraperitoneal mouse

440 440

A TO

ratto orale oral rat

1600 1600

B B

ratto orale oral rat

440 440

A TO

ratto intraperitoneale intraperitoneal rat

450 450

B B

ratto intraperitoneale intraperitoneal rat

310 310

2) Attività ulcerogena 2) Ulcerogenic activity

È stata valutata nel ratto dopo somministrazione orale per 5 giorni consecutivi di A e B a 4 diversi livelli di dose. Entrambi i composti hanno manifestato un'azione gastrolesiva di intensità dose-dipendente ma significamente minore per A alla dose di 30 mg/kg. It was evaluated in the rat after oral administration of A and B for 5 consecutive days at 4 different dose levels. Both compounds exhibited a dose-dependent but significantly lower gastrolesive action for A at a dose of 30 mg / kg.

660 480 660 480

Composto Media dei punteggi per lesioni gastriche a: Compound Average of scores for gastric lesions at:

1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg 1 mg / kg 3 mg / kg 10 mg / kg 30 mg / kg

1,88 2,88 2,88 5,50 1,50 3,00 3,50 7,75 1.88 2.88 2.88 5.50 1.50 3.00 3.50 7.75

3) Tossicità subacuta 3) Subacute toxicity

È stata studiata nel ratto somministrando A per via orale per 30 giorni consecutivi a dosi di 5 e 15 mg/kg. Queste dosi sono apparse entrambe ben tollerate in base allo stato generale e all'incremento ponderale degli animali ed ai risultati dei diversi esami ematologici, ematochimici, urinari, autoptici ed istologici. It was studied in the rat by administering A by mouth for 30 consecutive days at doses of 5 and 15 mg / kg. These doses both appeared well tolerated based on the general state and weight gain of the animals and the results of the various hematological, blood chemistry, urinary, autopsy and histological tests.

4) Attività antiinflammatoria 4) Anti-inflammatory activity

Con il test dell'edema da carragenina nel ratto l'attività antiinflammatoria di A è risultata analoga per intensità e durata a quella del composto B. With the test of carrageenan edema in the rat, the anti-inflammatory activity of A was similar in intensity and duration to that of compound B.

Composto Composed

Dosi (mg/kg) Doses (mg / kg)

Via di somm. Via di somm.

DE50 (mg/kg) DE50 (mg / kg)

alla 3a ora at the 3rd hour

A TO

1,5-3-6 1,5-3-6

orale oral

2,60 2.60

B B

1,5-3-6 1,5-3-6

orale oral

2,45 2.45

5) Attività antipiretica 5) Antipyretic activity

Con il test dell'ipertermia da lievito di birra nel ratto l'attività antipiretica di A è risultata analoga per intensità e durata a quella del composto B. With the test of beer yeast hyperthermia in the rat, the antipyretic activity of A was similar in intensity and duration to that of compound B.

Composto Composed

Dose Dose

Via Street

Decremento termico Thermal decrease

(mg/kg) (Mg / kg)

di somm. of somm.

medio (°C) in 4 ore medium (° C) in 4 hours

A TO

5 5

orale oral

-1,23 -1.23

B B

5 5

orale oral

-1,14 -1.14

Con i derivati secondo l'invenzione si possono preparare le composizioni farmaceutiche già note ed in uso per l'acido d-2-(6-metossi-2-naftil)-propionico e con dosaggi equivalenti. With the derivatives according to the invention, the pharmaceutical compositions already known and in use for the d-2- (6-methoxy-2-naphthyl) -propionic acid and with equivalent dosages can be prepared.

Anche per le modalità di somministrazione valgono quelle già note per il Naproxen. The methods already known for Naproxen also apply to the methods of administration.

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3 fogli disegni 3 drawings sheets

Claims (12)

660 480 660 480 2. 4' -carbossi, 6-metossi, metil-2-naftalenacetanilide secondo la rivendicazione 1. 2. 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide according to claim 1. 2 2 RIVENDICAZIONI 1. Derivati dell'aciso d-2-6 (6-metossi-2-naftil)-propionico con acido p-amino benzoico avente formula: CLAIMS 1. Derivatives of the acid d-2-6 (6-methoxy-2-naphthyl) -propionic with p-amino benzoic acid having formula: ch3° ch3 ° in cui X rappresenta idrogeno, un radicale di una base organica od inorganica, non tossica e farmaceuticamente accettabile, un residuo di un'amina organica od un radicale di un aminoacido basico. wherein X represents hydrogen, a radical of an organic or inorganic base, non-toxic and pharmaceutically acceptable, a residue of an organic amine or a radical of a basic amino acid. 3. Procedimento per la preparazione dei derivati della rivendicazione 1, caratterizzato dagli stadi di: 3. Process for the preparation of the derivatives of claim 1, characterized by the steps of: a) preparazione di un derivato funzionale reattivo dell'acido d-2-(6-metossi-2-naftil)-propionico; a) preparation of a reactive functional derivative of d-2- (6-methoxy-2-naphthyl) -propionic acid; b) reazione di detto derivato reattivo con acido p-amino benzoico; b) reaction of said reactive derivative with p-amino benzoic acid; c) eventuale reazione con una base organica od inorganica, non tossica e farmaceuticamente accettabile. c) possible reaction with an organic or inorganic base, non-toxic and pharmaceutically acceptable. 4. Procedimento secondo la rivendicazione 3, caratterizzato dal fatto che detto derivato reattivo è il cloruro o l'anidride mista con cloroformiato di etile. 4. Process according to claim 3, characterized in that said reactive derivative is chloride or anhydride mixed with ethyl chloroformate. 5. Procedimento secondo la rivendicazione 4, caratterizzato dal fatto che detto cloruro viene preparato per reazione con cloruro di tionile. 5. Process according to claim 4, characterized in that said chloride is prepared by reaction with thionyl chloride. 6. Procedimento secondo la rivendicazione 3, caratterizzato dal fatto che detto stadio b) viene realizzato in una miscela solvente binaria. 6. Process according to claim 3, characterized in that said step b) is carried out in a binary solvent mixture. 7. Procedimento secondo la rivendicazione 6, caratterizzato dal fatto che detta miscela solvente è costituita da acqua e cloroformio. 7. Process according to claim 6, characterized in that said solvent mixture consists of water and chloroform. 8. Procedimento secondo la rivendicazione 3, caratterizzato dal fatto che detto derivato dell'acido p-amino benzoico è un suo sale con un metallo alcalino. 8. Process according to claim 3, characterized in that said derivative of p-amino benzoic acid is a salt thereof with an alkaline metal. 9. Procedimento secondo la rivendicazione 3, caratterizzato dal fatto che detto stadio b) viene effettuato addizionando inizialmente alla miscela di reazione un idrato di metallo alcalino. 9. Process according to claim 3, characterized in that said step b) is carried out by initially adding an alkali metal hydrate to the reaction mixture. 10. Procedimento per la preparazione dei derivati della rivendicazione 1 in cui X rappresenta un radicale di un'amina organica o di un'aminoacido, caratterizzato dagli stadi a) - b) secondo la rivendicazione 3 e dallo stadio di e) reazione con un'amina organica od un aminoacido basico. 10. Process for the preparation of the derivatives of claim 1 wherein X represents a radical of an organic amine or an amino acid, characterized by the steps a) - b) according to claim 3 and by the step of e) reaction with a organic amine or a basic amino acid. 11. Composizione farmaceutica ed attività anti-infiamma-toria, caratterizzata dal comprendere, quale ingrediente attivo, un derivato secondo la rivendicazione 1, unitamente agli eccipienti e veicoli. 11. Pharmaceutical composition and anti-inflammatory activity, characterized by comprising, as an active ingredient, a derivative according to claim 1, together with the excipients and vehicles. 12. Composizione farmaceutica secondo la rivendicazione 11, caratterizzata dal fatto che detto ingrediente attivo 4' -carbossi, 6-metossi, metil-2-naftalenacetanilide. 12. Pharmaceutical composition according to claim 11, characterized in that said active ingredient 4 '-carboxy, 6-methoxy, methyl-2-naphthalenacetanilide.
CH1411/83A 1982-03-16 1983-03-15 D-2- (6-METHOXY-2-NAFTIL) PROPIONIC DERIVATIVES WITH THERAPEUTIC ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. CH660480A5 (en)

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IT20190/82A IT1150687B (en) 1982-03-16 1982-03-16 D-2- (6-METHOXY-2-NAFTYL) ACID DERIVATIVES THERAPEUTIC PROPIONIC, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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KR (1) KR840003812A (en)
CH (1) CH660480A5 (en)
DE (1) DE3309258A1 (en)
ES (1) ES8403860A1 (en)
FR (1) FR2523577B1 (en)
IT (1) IT1150687B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2505411A1 (en) * 1981-05-08 1982-11-12 Binder Adam DEVICE FOR RECOVERING WIND ENERGY
EP0195582B1 (en) * 1985-03-14 1990-01-24 SMITH KLINE DAUELSBERG GmbH 5-aminosalicylic acid derivatives of non-steroidal antiinflammatory acids

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* Cited by examiner, † Cited by third party
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US3978116A (en) * 1971-11-04 1976-08-31 Syntex Corporation 2-naphthyl acetic acid derivatives and compositions and methods thereof
IT1064700B (en) * 1976-07-28 1985-02-25 Pessina Raffaele PROCEDURE FOR THE PREPARATION OF THE ACID D.2.6 METHOXY 2 PROFIONIC NAFTYL
FR2388789A1 (en) * 1977-04-27 1978-11-24 Seuref Ag BENZOIC ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
FR2416214A1 (en) * 1978-02-02 1979-08-31 Inst Rech Scient Irs DERIVATIVES OF NAPHTHYL-1 ACETIC ACID, THEIR METHOD OF PREPARATION AND THEIR THERAPEUTIC APPLICATION

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DE3309258C2 (en) 1990-10-04
KR840003812A (en) 1984-10-04
DE3309258A1 (en) 1983-09-22
FR2523577A1 (en) 1983-09-23
IT1150687B (en) 1986-12-17
ES520623A0 (en) 1984-04-01
ES8403860A1 (en) 1984-04-01
IT8220190A0 (en) 1982-03-16
FR2523577B1 (en) 1986-10-31

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