WO1994004484A1 - Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation - Google Patents

Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation Download PDF

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Publication number
WO1994004484A1
WO1994004484A1 PCT/EP1993/001906 EP9301906W WO9404484A1 WO 1994004484 A1 WO1994004484 A1 WO 1994004484A1 EP 9301906 W EP9301906 W EP 9301906W WO 9404484 A1 WO9404484 A1 WO 9404484A1
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WO
WIPO (PCT)
Prior art keywords
halo
phenylamino
phenylacetic acid
derivatives
linear
Prior art date
Application number
PCT/EP1993/001906
Other languages
French (fr)
Inventor
José Antonio MATJI
Antonio Alcaide
Original Assignee
Corlay S.L.
Metgrove Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Corlay S.L., Metgrove Ltd. filed Critical Corlay S.L.
Priority to KR1019940701286A priority Critical patent/KR100269727B1/en
Priority to EP93917596A priority patent/EP0609415B1/en
Priority to RU94046148A priority patent/RU2109009C1/en
Priority to CA002120942A priority patent/CA2120942C/en
Priority to US08/211,447 priority patent/US5597847A/en
Priority to DE69305322T priority patent/DE69305322T2/en
Priority to UA94005348A priority patent/UA39172C2/en
Priority to JP50582694A priority patent/JP3231042B2/en
Publication of WO1994004484A1 publication Critical patent/WO1994004484A1/en
Priority to GR960402711T priority patent/GR3021404T3/en
Priority to HK98106190A priority patent/HK1006967A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • Object of the present invention are nitric esters of derivatives of 2-(2, 6-di-halo-phenylamino)phenylacetic acid, their pharmaceutical utilization and process for their preparation.
  • Such protective barrier and therefore the integrity of tha vasal endothelium, is ensured, on the physiological plane, by the presence of nitric oxide and prostacy- clin.
  • the treatment with drugs having an anti-inflammatory activity causes the inhibition of the cyclo-oxygenase, an enzyme which governs the synthesis of the prostacyclin precursor.
  • drugs having an anti-inflammatory activity such as, for instance, the sodium salt of the 2-(2, 6-di-chloro-phenylamino)phenylacetic acid
  • drugs having an anti-inflammatory activity causes the inhibition of the cyclo-oxygenase, an enzyme which governs the synthesis of the prostacyclin precursor.
  • the production of prostacyclin being in this way inhibited, the tissular reserve of same is markedly depauperated, with ensuing compromisesion of the vasal endothelium.
  • Object of the present invention is to provide a pro ⁇ duct which, while ensuring the maintenance of the pharmacological activity characteristic of the known anti-inflammatory preparations, can also eliminate the adverse reactions caused by the treatment with said drugs.
  • Another object of the present invention is the realiza ⁇ tion of a process for the preparation of derivatives of the 2-(2 , 6-di-halo-phenylamino)phenylacetic acid having an anti-inflammatory activity and that are exempt from those adverse reactions that are typical of the anti-inflammatory drugs.
  • a and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is a halogen selected among chloride and bromine, Y is selected among oxygen, NH, NR lf wherein R ⁇ is a linear or bran ⁇ ched alkyl group and n is comprised between 1 and 10.
  • R ⁇ is a linear or bran ⁇ ched alkyl group and n is comprised between 1 and 10.
  • the derivatives (I) are useful for the treatment of different unhealthy condi ⁇ tions, such as for instance rheumatic diseases in general, immunologic disorders, and that they can also alleviate painful conditions of low-middle severity of any kind.
  • the derivatives (I) subject matter of the present invention are useful in the treatment of the illnesses of the cardiovascular apparatus and in parti ⁇ cular in the treatment of myocardial and brain ische- miae, as well as in cases of arterial thrombosis.
  • a nitric ester of a derivative of the 2-(2, 6-di-halo-phenylami- no)phenylacetic acid (I) proved to be especially advan ⁇ tageous, wherein: A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal to four, according to the following formula:
  • nitric ester of a derivative of the 2- (2, 6-di-halo-phenylamino)phenylacetic acid (I) , wherein: A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal to two, according to the following formula:
  • a first process proved to be particularly advantageous which, according to the present invention, comprises the following phases: - Reaction between the sodium salt of the 2-(2,6-di- halo-phenylamino)phenylacetic acid or of the 2-(2,6-di- halo-phenylamino)phenylacetic acid functionalized to the carboxylic group, and a compound having the follo ⁇ wing general formula:
  • n is comprised bet ⁇ ween 1 and 10, the carboxylic group of the 2-(2,6-di- halo-phenyla ino)phenylacetic acid being functionalized as acylic chloride, anhydride or the like, obtaining in this way the corresponding monomer ester or the corre ⁇ sponding amide;
  • a second process proved also particularly advantageous which, always according to the present invention, comprises the following phases:
  • R 4 is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chains, A and B are selected among hydrogen, Tinear or branched, substi ⁇ tuted or non substituted alkyl chains, and n is compri ⁇ sed between 1 and 10, the carboxylic group of the 2- (2,6-di-halo-phenylamino)phenilacetic acid being func ⁇ tionalized as acylic chloride, anhydride or the like, obtaining in this way either the corresponding monomer ester or the corresponding amide; - Reaction of said monomer ester or said corresponding amide with an halogenating compound such as PBr 3 or the like, ⁇ btaing in this way said monomer ester or said amide, characterized by the presence of a terminal halogen group;
  • nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid (I) are preferably selected among chloroform, methylene chloride, acetonitrile, dimethylforma ide, tetrahydrofuran, dioxan and the like.
  • Such processes for the preparation of derivatives of the 2-(2 , 6-di-halo-phenylamino)phenylacetic acid (I), subject matter of the present invention consist of a limited number of phases, allowing to obtain the pro ⁇ ducts deriving from such processes rapidly, with sati ⁇ sfactory yields and to high amounts, even on an indu ⁇ strial basis.
  • the preparation of nitric esters of deriva ⁇ tives of the 2-(2 , 6-di-chloro-phenylamino)phenylacetic acid proved particularly advantageous, having the following formulae:
  • EXAMPLE 1 a) 6 g of l-Br-4-Cl-butane diluted in 250 ml of dimet- hylformamide were dripped to a solution of 10 g of sodium salt of the 2-(2, 6-di-chloro-phenylamino)pheny ⁇ lacetic acid in 100 ml of dimethylformamide. The reac ⁇ tion mix was stirred for 12 hours at room tempera ⁇ ture, then diluted with water and extracted with methy- lene chloride. The so extracted organic phase was anhydried on sodium sulfate and the solvent was low- pressure evaporated until 14 g of dry residual were obtained.
  • the solvent was low-pressure evaporated and 2.8 g of dry residual were obtained, which were purified thereafter by chro- matography on silica gel, utilizing an eluant mix constituted by hexane/ether 7/3 (v/v) .
  • the fractions containing the product were collected, the solvent was low-pressure evaporated and 2.5 g of nitric ester of 2- (2, 6-di-chloro-penylamino) phenylacetate of 4-hydr ⁇ xibu- tyl (II) were obtained.
  • Mass ⁇ pectrometry PM 366 b) 1,14 g of PBr 3 were added to a solution of 0,19 g of 2-(2, 6-di-chloro-phenylamino) -4-hydroxybutyl-phenyla- cetamide (XII) in 10 ml of chloroform; the mix so obtained was stirred for 30 minutes and then diluted with 10 ml of water. The organic phase was separated and anhydried on sodium sulfate, and then the solvent was low-pressure evaporated, obtaining in this way a raw residual which was purified by chromatography, utilizing an eluant mix constituted by methylene chlo ⁇ ride/ethyl acetate 10/0,1 (v/v) .
  • the anti-inflammatory activity of said derivatives of the 2-(2,6-di-chloro-phenylamino)phenylacetic acid has been determined in istar rats, by utilizing the method of the carrageenan edema, as reported in C.A.WINTER, E.RISLEY, G.W.NUSS, Proc. Soc. Exp.Biol.Med. Ill, 544- 547 (1962) , while the analgesic activity of said deri ⁇ vatives has been determined in Swiss mice, as reported by L.C.HENDERSHOT, J.FORSAITH, J.Pharmacol.Exp.Ter. 125, 237-249 (1959) .
  • the anti-inflammatory and analgesic activity of said derivatives is given on Table 1, and is expressed as a power ratio relative to 2-(2, 6-di-chloro- phenyla ino)phenylacetic acid taken as a reference. Each value represents a mean of the values obtained by the treatment of 10 animals.
  • RAT CARRAGEENAN PAW EDEMA the values of ED 30 (mg/kg p.o.) obtained are respectively equal to 4,88 for the compound (II) and to 4,21 for the 2-(2 , 6-di-chloro- phenylamino)phenylacetic acid, showing a comparable effectiveness between the two compounds.
  • MOUSE PHENYLQUINONE WRITHING at doses ranging between 3 and 10 mg/kg p.o. , the derivative (II) has shown a full effectiveness and its potency resulted almost comparable to that of the 2-(2 , 6-di-chloro- phenylamino)phenylacetic acid and of indomethacin. Subacute models
  • RAT ADJUVANT ARTHRITIS the animals treated for 19 consecutive days (from the 3rd to the 21th day after the adjuvant injection) with 3,0 mg/kg p.o. of 2-(2,6- di-chloro-phenylamino)phenylacetic acid or with 1,5 or 3,0 mg/kg p.o. of the compound (III), have shown a significant reduction of the arthritic symptomatology.
  • Rat gastrointestinal tolerability the animals treated for 19 consecutive days (from the 3rd to the 21th day after the adjuvant injection) with 3,0 mg/kg p.o. of 2-(2,6- di-chloro-phenylamino)phenylacetic acid or with 1,5 or 3,0 mg/kg p.o. of the compound (III), have shown a significant reduction of the arthritic symptomatology.
  • Rat gastrointestinal tolerability the animals treated for 19 consecutive days (from the 3rd to the 21th day after the adjuvant injection) with 3,0 mg/kg p.o
  • the average dose of ulcerogenicity for the 2-(2,6-di- chloro-phenylamino)phenylacetic acid has been calcula- ted as beeing equal to 6,1 mg/kg p.o.
  • the compound (II) showed to be very well tolerated even at much higher doses compared to the above mentio ⁇ ned ones; small ulcers have been noticed only in 2 animals out of 10, treated with 100 mg/kg. Therefore i was impossible to determine the average ulcerogeni ⁇ city dose for the compound (II) .
  • General pharmacology Secondary pharmacological evaluations of the compound (II) have been carried out by comparison with the 2- (2 , 6-di-chloro-phenylamino)phenylacetic acid; no addi ⁇ tional effects have been observed besides the primary pharmacological activity on the central nervous system, the autonomic system, the cardiovascular, respiratory and gastrointestinal systems. B.
  • the compound (II) was very well tolerated in this animal species which, as known, is particularly sensi- tive to this class of compounds.
  • the animals have been treated with doses increasing from 250 to 1000 mg/kg of compound (II) : the lowest dose caused no symptomatology, the intermediate dose caused only a reversible diarrhea, while the highest dose caused a severe but reversible diarrhea.
  • the administration in the same conditions of 10 mg/kg of 2-(2 , 6-di-chloro-phenylamino) phenylacetic acid caused the death of the animals.
  • the animals have been treated with 5, 15 and 30 mg/kg of compound (II) for 4 weeks.
  • the general conditions and clinical behaviour, body weight gain, water and food consumption, hematology and clinical chemistry have shown that the two lowest doses have been well tolerated.
  • Subacute toxicity in the dog The animals have been treated with 5, 15 and 30 mg/kg of compound (II) for 4 weeks.
  • the general conditions and clinical behaviour, body weight gain, water and food consumption, hematology and clinical chemistry have shown that the two lowest doses have been well tolerated.

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Abstract

Object of this invention are nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid, having general formula (I), as well as their pharmaceutical utilization and process for their preparation.

Description

NITRIC ESTERS OF DERIVATIVES OF THE 2-(2,6-DI- HALO-
PHENYLAMINO) PHENYLACETIC ACID AND PROCESS FOR THEIR
PREPARATION
TECHNICAL FIELD
Object of the present invention are nitric esters of derivatives of 2-(2, 6-di-halo-phenylamino)phenylacetic acid, their pharmaceutical utilization and process for their preparation.
PRIOR ART The sodium salt of the 2-(2,6-di-chloro- phenylamino)phenylacetic acid has been used for a long time in the pharmaceutical field for its anti- inflammatory activity and has been sold throughout the world for many years. The process for its preparation has been described in the Dutch Patent application No. 6.604.752 and in the US Patent No. 3.558690. The pharmacological profile, and the effectiveness of the sodium salt of the 2-(2, 6-di-chloro- phenylamino)phenylacetic acid are described in Am.J.Med.80, Suppl. 4B, 1-87 (1986), while other data concerning its pharmacological activity as anti-inflam¬ matory agent are reported, for instance, in C.A.74, 86215 (1971); Krupp et al. Experimentia 29,450 (1973) .
The utilization of the 2-(2 , 6-di-chloro- phenyla ino)phenylacetic acid as an anti-inflammatory preparation causes, as known, very severe adverse reactions, for instance in the gastro-intestinal appa¬ ratus, as well as damages to the liver and the kidneys. There exist numerous experimental evidences [S.MONCADA, R.M.J.PALMER, E.A.HIGGS, Pharmacological Reviews, 43(2), 109-142 (1991); T.F.LUSHER, CM.BOULANGER, Y.DOHI, Z.YANG, Hypertension, 19, 117-130 (1992)], on whose basis the integrity of the vasal endothelium is assumed to act as a basically important protective barrier to prevent the onset of pathologic reactions in various organs and apparatuses.
Such protective barrier, and therefore the integrity of tha vasal endothelium, is ensured, on the physiological plane, by the presence of nitric oxide and prostacy- clin.
The treatment with drugs having an anti-inflammatory activity, such as, for instance, the sodium salt of the 2-(2, 6-di-chloro-phenylamino)phenylacetic acid, causes the inhibition of the cyclo-oxygenase, an enzyme which governs the synthesis of the prostacyclin precursor. As a consequence, the production of prostacyclin being in this way inhibited, the tissular reserve of same is markedly depauperated, with ensuing compromission of the vasal endothelium.
As said, because of this endothelial damage due to the reduction of prostacyclin, diffuse pathologic reactions break out which affect the gastrointestinal apparatus, the kidneys and the liver. OBJECTS OF THE INVENTION
Object of the present invention is to provide a pro¬ duct which, while ensuring the maintenance of the pharmacological activity characteristic of the known anti-inflammatory preparations, can also eliminate the adverse reactions caused by the treatment with said drugs.
Another object of the present invention is the realiza¬ tion of a process for the preparation of derivatives of the 2-(2 , 6-di-halo-phenylamino)phenylacetic acid having an anti-inflammatory activity and that are exempt from those adverse reactions that are typical of the anti-inflammatory drugs.
DESCRIPTION OF THE INVENTION These and still other objects and advantages which shall appear from the following description are obtai¬ ned by derivatives of the 2-(2,6-di-halo- phenylamino)phenylacetic acid, which derivatives, according to the present invention, have the following general formula:
Figure imgf000005_0001
wherein:
A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is a halogen selected among chloride and bromine, Y is selected among oxygen, NH, NRlf wherein R^ is a linear or bran¬ ched alkyl group and n is comprised between 1 and 10. In fact, it has been observed that the introduction of a group such as a terminal nitric ester in the deriva¬ tives of the 2-(2, 6-di-halo-phenylamino)phenylacetic acid as in (I) permits to preserve the pharmacological activity of anti-inflammatory drugs, while eliminating the adverse reactions caused by the treatment with said drugs.
It has also been noticed that the derivatives (I) are useful for the treatment of different unhealthy condi¬ tions, such as for instance rheumatic diseases in general, immunologic disorders, and that they can also alleviate painful conditions of low-middle severity of any kind.
Besides, the derivatives (I) subject matter of the present invention are useful in the treatment of the illnesses of the cardiovascular apparatus and in parti¬ cular in the treatment of myocardial and brain ische- miae, as well as in cases of arterial thrombosis. Always according to the present invention, a nitric ester of a derivative of the 2-(2, 6-di-halo-phenylami- no)phenylacetic acid (I) proved to be especially advan¬ tageous, wherein: A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal to four, according to the following formula:
Figure imgf000007_0001
Also particularly advantageous according to this inven¬ tion is a nitric ester of a derivative of the 2- (2, 6-di-halo-phenylamino)phenylacetic acid (I) , wherein: A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal to two, according to the following formula:
Figure imgf000007_0002
For the preparation of the derivatives (I) of the 2- (2 , 6-di-halo-phenylamino)phenylacetic acid subject matter of this invention, a first process proved to be particularly advantageous which, according to the present invention, comprises the following phases: - Reaction between the sodium salt of the 2-(2,6-di- halo-phenylamino)phenylacetic acid or of the 2-(2,6-di- halo-phenylamino)phenylacetic acid functionalized to the carboxylic group, and a compound having the follo¬ wing general formula:
A I
(i )
Figure imgf000008_0001
wherein: 4 is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chain, A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, R3 is selected among chlorine, bromine and iodine; and n is comprised bet¬ ween 1 and 10, the carboxylic group of the 2-(2,6-di- halo-phenyla ino)phenylacetic acid being functionalized as acylic chloride, anhydride or the like, obtaining in this way the corresponding monomer ester or the corre¬ sponding amide;
- Reaction of said monomer ester or of said correspon¬ ding amide with a nitrating agent such as AgNO-- or the like, obtaining in this way nitric esters of derivati¬ ves of the 2-(2,6-di-halo-phenylamino)phanylacetic acid (I). A second process proved also particularly advantageous which, always according to the present invention, comprises the following phases:
- Reaction between the sodium salt of the 2-(2,6-di- halo-phenylamino)phenylacetic acid or of the 2-(2,6-di- halo-phenylamino)phenylacetic acid functionalized to the carboxylic group, with a compound having the following general formula:
Figure imgf000009_0001
wherein: R4 is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chains, A and B are selected among hydrogen, Tinear or branched, substi¬ tuted or non substituted alkyl chains, and n is compri¬ sed between 1 and 10, the carboxylic group of the 2- (2,6-di-halo-phenylamino)phenilacetic acid being func¬ tionalized as acylic chloride, anhydride or the like, obtaining in this way either the corresponding monomer ester or the corresponding amide; - Reaction of said monomer ester or said corresponding amide with an halogenating compound such as PBr3 or the like, σbtaing in this way said monomer ester or said amide, characterized by the presence of a terminal halogen group;
- Reaction of said monomer ester or said amide, charac¬ terized by the presence of a terminal halogen group with a nitrating agent such as AgN03 or the like, obtaining in this way nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid (I) . The solvents which are utilized in the processes sub¬ ject matter of this invention are preferably selected among chloroform, methylene chloride, acetonitrile, dimethylforma ide, tetrahydrofuran, dioxan and the like.
Such processes for the preparation of derivatives of the 2-(2 , 6-di-halo-phenylamino)phenylacetic acid (I), subject matter of the present invention, consist of a limited number of phases, allowing to obtain the pro¬ ducts deriving from such processes rapidly, with sati¬ sfactory yields and to high amounts, even on an indu¬ strial basis. According to the processes subject matter of this invention, the preparation of nitric esters of deriva¬ tives of the 2-(2 , 6-di-chloro-phenylamino)phenylacetic acid proved particularly advantageous, having the following formulae:
Figure imgf000011_0001
and
Figure imgf000011_0002
which are prepared as described in the following exam¬ ples, which are given as mere indications that do no limit in any way the protection scope of this inven¬ tion. EXAMPLE 1 a) 6 g of l-Br-4-Cl-butane diluted in 250 ml of dimet- hylformamide were dripped to a solution of 10 g of sodium salt of the 2-(2, 6-di-chloro-phenylamino)pheny¬ lacetic acid in 100 ml of dimethylformamide. The reac¬ tion mix was stirred for 12 hours at room tempera¬ ture, then diluted with water and extracted with methy- lene chloride. The so extracted organic phase was anhydried on sodium sulfate and the solvent was low- pressure evaporated until 14 g of dry residual were obtained.
The residual was purified by chromatography on silica gel, utilizing chloroform as eluant system. The head fractions were then collected, and by low- pressure evaporation of the solvent 11 g of dry resi¬ dual were obtained and then chromatographed anew on silica gel, utilizing an eluant mix constituted by hexane/ether 7/3 (v/v) . The head fractions were collected, the solvent was low- pressure evaporated, and 3 g of 2-(2, 6-di-chlσro-pheny- lamino)phenylacetate of 4-chlorobutyl (VIII) were obtained. IR (cm-1): C=0, 1741; NH, 3340. 1H-NMR(300MHz) (CDC13): 1.9 ppm(m, 4H) ; 3.6 ppm(m, 2H);
3.85 ppm(s,2H); 4.2 ppm(m, 2H) ; 6.5-7.45 ppm(m, aroma- tics) .
Mass spectrometry (i.e) : M+' 385 b) 1.2 g of AgN03 diluted in 11 ml of acetonitrile were dripped to 2 g of (VIII) obtained as described in a) , diluited in 7 ml of acetonitrile. The reaction mix was stirred for 12 hours at the temperature of 85°C and then filtered. The solvent was low-pressure evaporated from the resul¬ ting solution, and a residual was obtained to which 30 ml of ethylene chloride were added. The mix so obtai- ned was filtered anew, the organic phase was water- washed and then anydried on sodium sulfate. The solvent was low-pressure evaporated and 2.8 g of dry residual were obtained, which were purified thereafter by chro- matography on silica gel, utilizing an eluant mix constituted by hexane/ether 7/3 (v/v) . The fractions containing the product were collected, the solvent was low-pressure evaporated and 2.5 g of nitric ester of 2- (2, 6-di-chloro-penylamino) phenylacetate of 4-hydrσxibu- tyl (II) were obtained.
IR (cm-1) : C=0, 1729; NH, 3322; ON02 , 1637. 1H-NMR(80 MHz) (CDCI3) : 1.75 ppm (m, 4H) ; 3.8 ppm (s, 2H) ; 4.2 ppm (m, 2H) ; 4.4 ppm (m, 2H) ; 6.45-7.4 ppm (m, aromatics) . Mass spectrometry (i.e.) M+'412 EXAMPLE 2 a) 0,5 g of ethylester of the 2-(2,6-di- chlorophenylamino)phenylacetic acid were added to 0,5 ml of 4-aminobutanol and the mix so obtained was stir- red at the temperature of 100°C for 12 hours. The mix was then brought again to room temperature, diluted with 5 ml of water and extracted with 5 ml of methylen chloride. The organic phase so extracted was anydried on sodium sulfate and the solvent was low-pressure evaporated until 0,19 g of 2-(2,6-di-chloro-phenylami- no)-4-hydroxibutyl-phenylacetamide (XII) were obtained. IR (cm-1) (nujol) : C=0, 1648; NH and OH, 3413. 1H-NMR(80 MHz) (CDC13) : 1.65 ppm (m, 4H) ; 3.3 ppm (m, 2H) ; 3.6 ppm ( , 2H) ; 6.08 ppm (m, 1H) ; 6.5 ppm (dd, 1H) ; 6.85-7.5 ppm ( , 6H) . Mass εpectrometry: PM 366 b) 1,14 g of PBr3 were added to a solution of 0,19 g of 2-(2, 6-di-chloro-phenylamino) -4-hydroxybutyl-phenyla- cetamide (XII) in 10 ml of chloroform; the mix so obtained was stirred for 30 minutes and then diluted with 10 ml of water. The organic phase was separated and anhydried on sodium sulfate, and then the solvent was low-pressure evaporated, obtaining in this way a raw residual which was purified by chromatography, utilizing an eluant mix constituted by methylene chlo¬ ride/ethyl acetate 10/0,1 (v/v) . The intermediate fractions were recovered, the solvent was low-pressure evaporated and 50 mg of 2-(2,6-di- chloro-phenylamino) -4-bromobutyl-phenylacetamide (XIII) were obtained. 1H-NMR(80 MHz) (CDC13): 1.73 ppm (m, 4H) ; 3.3 ppm (m, 8H) ; 3.67 ppm (s, 2H) ; 5.91 ppm (broad s, 1H) ; 6.5 ppm (dd, 1H) ; 6.92-7.29 ppm (m, 5H) ; 7.4 ppm (d, 1H) . c) 1.5 g of AgN03 diluted in 10,7 ml of acetonitrile were added to a solution constituted by 2,8 g of 2-(2, 6-di-chloro-phenylamino) -4-bromobutyl-phenylacetamide (XIII) diluted in 9 ml of acetonitrile. The reaction mix was stirred at the temperature of 25°C for 3 days and then filtered. The solvent was low-pressure evapo- rated from the resulting solution, obtaining in this way a residual which was purified by chromatography, utilizing methylene chloride as eluant. The fractions containing the product were collected, the solvent was low-pressure evaporated, and 0,5 g of nitric ester of 2-(2,6-di-chloro-phenylamino) -4-hydroxibutylphenylacetamide (XI) were obtained.
IR(cm-1) (nujol) : C=0, 1650; NH, 3290; ON02 , 1630. 1H-NMR (80 MHz) (CDCl3) : 1.62 ppm (m, 4H) ; 3.28 ppm (m, 2H) ; 4.4 ppm (t, 2H) ; 5.3 ppm (broad s, 1H) ; 6.49 ppm (dd, 1H) ; 6.85-7.36 ppm (m, 5H) ; 7.4 ppm (d, 1H) . Mass spectrometry: PM 411.
There has been determined by means of biologic tests, the anti-inflammatory and analgesic activity for instance of derivatives of the 2-(2, 6-di-halo-phenylamino)pheny¬ lacetic acid (I) having the following formulae:
Figure imgf000015_0001
PCI7EP93/01906 84
14
Figure imgf000016_0001
The anti-inflammatory activity of said derivatives of the 2-(2,6-di-chloro-phenylamino)phenylacetic acid has been determined in istar rats, by utilizing the method of the carrageenan edema, as reported in C.A.WINTER, E.RISLEY, G.W.NUSS, Proc. Soc. Exp.Biol.Med. Ill, 544- 547 (1962) , while the analgesic activity of said deri¬ vatives has been determined in Swiss mice, as reported by L.C.HENDERSHOT, J.FORSAITH, J.Pharmacol.Exp.Ter. 125, 237-249 (1959) .
The anti-inflammatory and analgesic activity of said derivatives is given on Table 1, and is expressed as a power ratio relative to 2-(2, 6-di-chloro- phenyla ino)phenylacetic acid taken as a reference. Each value represents a mean of the values obtained by the treatment of 10 animals.
The compounds (II) and (XI) utilized for said biolo¬ gical tests were suspended in 0.5% carboxymethylcellu- lose before the administration.
TABLE 1 COMPOUND ANTI-INFLAMM. ACTIVITY ANALGESIC ACTIVITY XI 1.25 1.40
II 1.30 1.50
2-(2, 6-di-chloro- phenylamino)phenyl¬ acetic acid 1 1 Then, the acute toxicity of said derivatives (II) and (XI) was evaluated by oral administration of a single dose of each compound (II) and (XI) , utilizing for each derivative groups of 10 Swiss mice. The lethality incidence and the onset of toxic symptoms were asses¬ sed within a period of observation of 14 days. Even upon administration of 250 mg/kg of the compound (II) or the compound (XI) no apparent toxicity symptoms have been observed in the studied animals. Further biological experiments, suitable to determine the pharmacotoxicologic profile of the derivative (II) have been carried out by examining said derivative (II) in comparison with the 2-(2, 6-di-chloro- phenylamino)phenylacetic acid taken as a reference. A. PHARMACODYNAMIC ACTIVITY Acute models
RAT CARRAGEENAN PAW EDEMA: the values of ED 30 (mg/kg p.o.) obtained are respectively equal to 4,88 for the compound (II) and to 4,21 for the 2-(2 , 6-di-chloro- phenylamino)phenylacetic acid, showing a comparable effectiveness between the two compounds. MOUSE PHENYLQUINONE WRITHING: at doses ranging between 3 and 10 mg/kg p.o. , the derivative (II) has shown a full effectiveness and its potency resulted almost comparable to that of the 2-(2 , 6-di-chloro- phenylamino)phenylacetic acid and of indomethacin. Subacute models
RAT ADJUVANT ARTHRITIS: the animals treated for 19 consecutive days (from the 3rd to the 21th day after the adjuvant injection) with 3,0 mg/kg p.o. of 2-(2,6- di-chloro-phenylamino)phenylacetic acid or with 1,5 or 3,0 mg/kg p.o. of the compound (III), have shown a significant reduction of the arthritic symptomatology. Rat gastrointestinal tolerability
In all the animals treated with 15 mg/kg p.o. of 2-(2,6-di-chloro-phenilamino)phenylacetic acid, severe diffuse ulcerations have been observed; small ulcers have been observed also in animals treated with 3,5 and 7,0 mg/kg p.o.
The average dose of ulcerogenicity for the 2-(2,6-di- chloro-phenylamino)phenylacetic acid has been calcula- ted as beeing equal to 6,1 mg/kg p.o.
The compound (II) showed to be very well tolerated even at much higher doses compared to the above mentio¬ ned ones; small ulcers have been noticed only in 2 animals out of 10, treated with 100 mg/kg. Therefore i was impossible to determine the average ulcerogeni¬ city dose for the compound (II) . General pharmacology Secondary pharmacological evaluations of the compound (II) have been carried out by comparison with the 2- (2 , 6-di-chloro-phenylamino)phenylacetic acid; no addi¬ tional effects have been observed besides the primary pharmacological activity on the central nervous system, the autonomic system, the cardiovascular, respiratory and gastrointestinal systems. B. TOXICOLOGY Acute toxicity in rodents Studies have been carried out in two animal species and following two different administration routes. The following values of LD50 (mg/kg) and of the 95% fiducial limits have been obtained: rat, oral route: 511 (356-732) ; mause, oral route: 497 (323-762); rat, intraperitoneal route: 237 (156-359) ; mouse, intraperitoneal route: 253 (171-374) . Maximum tolerated dose in non-rodents
The compound (II) was very well tolerated in this animal species which, as known, is particularly sensi- tive to this class of compounds.
The animals have been treated with doses increasing from 250 to 1000 mg/kg of compound (II) : the lowest dose caused no symptomatology, the intermediate dose caused only a reversible diarrhea, while the highest dose caused a severe but reversible diarrhea. On the contrary, the administration in the same conditions of 10 mg/kg of 2-(2 , 6-di-chloro-phenylamino) phenylacetic acid caused the death of the animals.
Subacute toxicity in rodents
The animals have been treated with 5, 15 and 30 mg/kg of compound (II) for 4 weeks. The general conditions and clinical behaviour, body weight gain, water and food consumption, hematology and clinical chemistry have shown that the two lowest doses have been well tolerated. Subacute toxicity in the dog The animals have been treated with 5, 15 and 30 mg/kg of compound (II) for 4 weeks. The general conditions and clinical behaviour, body weight gain, water and food consumption, hematology and clinical chemistry have shown that the two lowest doses have been well tolerated.

Claims

CLAIMS 1. Derivatives of the 2-(2 , 6-di-halo-phenylamino)pheny¬ lacetic acid, characterized in that they have the following general formula:
Figure imgf000021_0001
wherein:
A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is an halogen selected among chorine and bromine, Y is selected among oxygen, NH, NR-^, wherein R-^ is a linear or bran¬ ched alkyl group, and n is comprised between 1 and 10.
2. A derivative of the 2-(2 ,6-di-halo- phenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydro¬ gen, Y is oxygen and n is equal to 4.
3. A derivative of the 2-(2 , 6-di-halo- phenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydro¬ gen, Y is oxygen and n is equal to 2.
4. A derivative of the 2-(2 , 6-di-halo- phenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydro¬ gen, Y is NH and n is equal to 4.
5. Derivatives of the 2-(2 , 6-di-halo-phenylamino)pheny¬ lacetic acid according to claim 1, characterized in that they are utilizable in the pharmaceutical field as anti-inflammatory drugs.
6. Derivatives of the 2-(2, 6-di-halo-phenylamino)pheny¬ lacetic acid according to claim 1, characterized in that they are utilizable in the treatment of rheumatic diseases, in the treatment of immunological disorders and of middle severity painful conditions.
7. Derivatives of the 2-(2, 6-di-halo-phenylamino)pheny¬ lacetic acid according to claim 1, characterized in that they are utilizable in the treatment of illnesses of the cardiovascular apparatus, of miocardial an brain ischemiae and in the arterial thrombosis.
8. A process for the preparation of derivatives of the 2-(2, 6-di-halo-phenylamino)phenylacetic acid, having the following general formula:
Figure imgf000022_0001
wherein: A and B are selected among hydrogen, linear and branched, substituted and non substituted alkyl chains, X is an halogen selected among chlorine and bromine, Y is selected among oxygen, NH, NR, , wherein R-, is a linear or bran- ched alkyl group and n is comprised between 1 and 10, characterized in that it comprises the following pha¬ ses:
- Reaction between the sodium salt of the 2-(2,6-di- halo-phenylamino) phenylacetic acid or of the 2-(2,6-di- halo-phenyla ino) phenylacetic acid funtionalized to the carboxylic group, with a compound having the following general formula:
Figure imgf000023_0001
wherein:
R4 is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chain, A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, R3 is selected among chlorine, bromine and iodine, and n is comprised bet¬ ween 1 and 10, the carboxylic group of the 2-(2,6-di- halo-phenylamino)phenylacetic acid being functionalized as acilic chloride, anhydride or the like, obtaining in this way the corresponding monomer ester or the corre- sponding amide;
- Reaction of said monomer ester or said amide with a nitrating agent such as AgN03 or the like, obtaining in this way nitric esters of derivatives of the 2-(2,6-di- halo-phenylamino)phenylacetic acid (I) .
9. Process for the preparation of derivatives of the 2- (2, 6-di-halo-phenylamino)phenylacetic acid, having the following general formula:
Figure imgf000024_0001
wherein:
A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is an halogen selected among chlorine and bromine, Y is selected among oxygen, NH, NR-^, wherein R-^ is a linear or bran¬ ched alkyl group and n is comprised between 1 and 10, characterized in that it comprises the following pha¬ ses:
- Reaction between the sodium salt of the 2-(2,6-di- halo-phenylamino)phenylacetic acid or of the 2-(2,6-di- halo-phenyla ino)phenylacetic acid functionalized to the carboxylic group, with a compound having the following general formula:
Λ π. ■( 9 )n~OH (V)
B
wherein:
R4 is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chain, A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, and n is comprised between 1 and 10, the carboxylic group of the 2-(2, 6-di-halo-phenylamino)phenylacetic acid being functionalized as acilic chloride, anydride or the like, obtaining in this way the corresponding monomer ester or the corresponding amide;
- Reaction of said monomer ester or said amide with an halogenating compound such as PBr3 or the like, obtaining in this way said monomer ester or said amide, characterized by the presence of a terminal halogen group;
- Reaction of said monomer ester or said amide, charac¬ terized by the presence of a terminal halogen group with a nitrating agent such as AgN03 or the like, obtaining in this way nitric esters of derivatives of the 2- (2 , 6-di-halo-phenylamine)phenylacetic acid (I) . NITRIC ESTERS OF DERIVATIVES OF THE 2-(2,6-DI- HALO- PHENYLAMINO)PHENYLACETIC ACID AND PROCESS FOR THEIR PREPARATION
ABSTRACT Object of this invention are nitric esters of derivati¬ ves of the 2-(2, 6-di-halophenylamino)phenylacetic acid, having the following general formula:
Figure imgf000026_0001
as well as their pharmaceutical utilization and process for their preparation.
PCT/EP1993/001906 1992-08-20 1993-07-20 Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation WO1994004484A1 (en)

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KR1019940701286A KR100269727B1 (en) 1992-08-20 1993-07-20 Nitric esters of derivatives of the 2-(2,6-do-halophenylamino) phenylacetic acid and process for their preparation
EP93917596A EP0609415B1 (en) 1992-08-20 1993-07-20 Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation
RU94046148A RU2109009C1 (en) 1992-08-20 1993-07-20 Derivatives of 2-(2,6-dihalophenylamino)-phenylacetic acid and a method of their synthesis
CA002120942A CA2120942C (en) 1992-08-20 1993-07-20 Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)phenyl-acetic acid and process for their preparation
US08/211,447 US5597847A (en) 1992-08-20 1993-07-20 Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino) phenylacetic acid and process for their preparation
DE69305322T DE69305322T2 (en) 1992-08-20 1993-07-20 NETOLIC ACID ESTERS OF 2- (2,6-DIHALOPHENYLAMINO) PHENYL ACETIC DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
UA94005348A UA39172C2 (en) 1992-08-20 1993-07-20 derivatives of 2-(2,6-digalophenylamino) phenylacetic acid and method for the preparation thereof
JP50582694A JP3231042B2 (en) 1992-08-20 1993-07-20 Nitrate ester of 2- (2,6-di-halo-phenylamino) phenylacetic acid derivative and method for producing the same
GR960402711T GR3021404T3 (en) 1992-08-20 1996-10-21 Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation.
HK98106190A HK1006967A1 (en) 1992-08-20 1998-06-23 Nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid and process for their preparation

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WO1995009831A1 (en) * 1993-10-06 1995-04-13 Nicox S.A. Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation
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WO2003013499A2 (en) * 2001-08-09 2003-02-20 Nicox S.A. Drugs for vasculopaties
US6525098B1 (en) 1999-10-27 2003-02-25 Nobex Corporation 6-methoxy-2-naphthylacetic acid prodrugs
US6552078B2 (en) 1999-10-27 2003-04-22 Nobex Corp 6-methoxy-2-naphthylacetic acid prodrugs
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US7087588B2 (en) 1996-02-26 2006-08-08 Nicox S.A. Nitric oxide donors capable of reducing toxicity from drugs
US7202364B2 (en) 2002-11-26 2007-04-10 Novartis, Ag Certain phenylacetic acids and derivatives
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US7465803B2 (en) 2000-10-12 2008-12-16 Nicox S.A. Nitroderivatives as drugs for diseases having an inflammatory basis
US7736666B2 (en) 2000-03-08 2010-06-15 Nicox S.A. Self emulsifying drug delivery system
US7815933B2 (en) 2001-09-07 2010-10-19 Nicox S.A. Self emulsifying drug delivery system
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8362294B2 (en) 2006-06-26 2013-01-29 Novartis Ag Phenylacetic acid derivatives

Families Citing this family (8)

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Publication number Priority date Publication date Assignee Title
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IT1311924B1 (en) * 1999-04-13 2002-03-20 Nicox Sa PHARMACEUTICAL COMPOUNDS.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558690A (en) * 1965-04-08 1971-01-26 Gelgy Chemical Corp Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
DE3407507A1 (en) * 1984-03-01 1985-09-05 A. Nattermann & Cie GmbH, 5000 Köln Novel o-(2,6-dichloroanilino)phenylacetic acid esters, process for their preparation, and pharmaceutical preparations containing them
WO1991006539A1 (en) * 1989-10-27 1991-05-16 American Home Products Corporation 2-anilino phenylacetic acid derivatives as inhibitors of pla2 and lipoxygenase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3558690A (en) * 1965-04-08 1971-01-26 Gelgy Chemical Corp Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
DE3407507A1 (en) * 1984-03-01 1985-09-05 A. Nattermann & Cie GmbH, 5000 Köln Novel o-(2,6-dichloroanilino)phenylacetic acid esters, process for their preparation, and pharmaceutical preparations containing them
WO1991006539A1 (en) * 1989-10-27 1991-05-16 American Home Products Corporation 2-anilino phenylacetic acid derivatives as inhibitors of pla2 and lipoxygenase

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US6043232A (en) * 1997-07-23 2000-03-28 Nitromed, Inc. Nitroso esters of beta-oxo-amides and aryl propionic acid derivatives of non-steroidal antiinflammatory drugs
US6727281B2 (en) 1997-08-28 2004-04-27 Novartis Ag Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
US7115662B2 (en) 1997-08-28 2006-10-03 Novartis Ag Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
US6451858B2 (en) 1997-08-28 2002-09-17 Novartis Ag Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
US6291523B1 (en) 1997-08-28 2001-09-18 Novartis Ag Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
US6310099B1 (en) 1997-08-28 2001-10-30 Novartis Ag Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
US6593347B2 (en) 1998-10-30 2003-07-15 Nitromed, Inc. Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use
US6297260B1 (en) 1998-10-30 2001-10-02 Nitromed, Inc. Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use
US6613784B1 (en) 1999-03-02 2003-09-02 Nicox S.A. Nitroxyderivatives having antinflammatory, analgesic and antithrombotic activity
JP2002538142A (en) * 1999-03-02 2002-11-12 ニコックス エス エイ Nitroxy derivatives having anti-inflammatory, analgesic and antithrombotic activity
AU780678B2 (en) * 1999-06-01 2005-04-07 Astrazeneca Ab New use of compounds as antibacterial agents
US6593339B1 (en) 1999-06-01 2003-07-15 Astrazeneca Ab Use of compounds as antibacterial agents
WO2000072838A1 (en) * 1999-06-01 2000-12-07 Astrazeneca Ab New use of compounds as antibacterial agents
US6713454B1 (en) 1999-09-13 2004-03-30 Nobex Corporation Prodrugs of etoposide and etoposide analogs
US7119074B2 (en) 1999-09-13 2006-10-10 Nobex Corporation Treatment of cancers, tumors and malignancies using amphiphilic prodrugs
US6552078B2 (en) 1999-10-27 2003-04-22 Nobex Corp 6-methoxy-2-naphthylacetic acid prodrugs
US6610739B2 (en) 1999-10-27 2003-08-26 Nobex Corporation 6-methoxy-2-naphthylacetic acid prodrugs
US6713510B2 (en) 1999-10-27 2004-03-30 Nobex Corporation 6-Methoxy-2-naphthylacetic acid prodrugs
US6653348B2 (en) 1999-10-27 2003-11-25 Nobex Corporation 6-methoxy-2-naphthylacetic acid prodrugs
US6525098B1 (en) 1999-10-27 2003-02-25 Nobex Corporation 6-methoxy-2-naphthylacetic acid prodrugs
US6436990B1 (en) 1999-10-27 2002-08-20 Nobex Corporation 6-methoxy-2-naphthylacetic acid prodrugs
US6649629B2 (en) 1999-12-23 2003-11-18 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7166618B2 (en) 1999-12-23 2007-01-23 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7432285B2 (en) 1999-12-23 2008-10-07 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7736666B2 (en) 2000-03-08 2010-06-15 Nicox S.A. Self emulsifying drug delivery system
US7629368B2 (en) 2000-10-12 2009-12-08 Nicox S.A. Nitroderivatives as drugs for diseases having an inflammatory basis
US7465803B2 (en) 2000-10-12 2008-12-16 Nicox S.A. Nitroderivatives as drugs for diseases having an inflammatory basis
US6706724B2 (en) 2000-12-21 2004-03-16 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2003013499A2 (en) * 2001-08-09 2003-02-20 Nicox S.A. Drugs for vasculopaties
WO2003013499A3 (en) * 2001-08-09 2003-12-31 Nicox Sa Drugs for vasculopaties
US7815933B2 (en) 2001-09-07 2010-10-19 Nicox S.A. Self emulsifying drug delivery system
US7589124B2 (en) 2002-06-11 2009-09-15 Nicox, S.A. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7211598B2 (en) 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7163958B2 (en) 2002-07-03 2007-01-16 Nitromed Inc. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8222277B2 (en) 2002-07-03 2012-07-17 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8304409B2 (en) 2002-07-03 2012-11-06 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
EP1539729A2 (en) * 2002-07-03 2005-06-15 Nitromed, Inc. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US7754772B2 (en) 2002-07-03 2010-07-13 Nicox, S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
EP1539729A4 (en) * 2002-07-03 2008-02-20 Nitromed Inc Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US7883714B2 (en) 2002-07-03 2011-02-08 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8088762B2 (en) 2002-07-03 2012-01-03 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US7244753B2 (en) 2002-07-29 2007-07-17 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2004035042A1 (en) * 2002-10-18 2004-04-29 Astrazeneca Uk Limited New use of no donating nsaids
US7202364B2 (en) 2002-11-26 2007-04-10 Novartis, Ag Certain phenylacetic acids and derivatives
US8067464B2 (en) 2004-10-04 2011-11-29 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US8362294B2 (en) 2006-06-26 2013-01-29 Novartis Ag Phenylacetic acid derivatives
US8586782B2 (en) 2006-06-26 2013-11-19 Novartis Ag Phenylacetic acid derivatives

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US5597847A (en) 1997-01-28
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CA2120942A1 (en) 1994-03-03
GR3021404T3 (en) 1997-01-31
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