WO1998007701A1 - Derive de clonixine anti-inflammatoire/analgesique non ulcerigene - Google Patents

Derive de clonixine anti-inflammatoire/analgesique non ulcerigene Download PDF

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Publication number
WO1998007701A1
WO1998007701A1 PCT/EP1996/003610 EP9603610W WO9807701A1 WO 1998007701 A1 WO1998007701 A1 WO 1998007701A1 EP 9603610 W EP9603610 W EP 9603610W WO 9807701 A1 WO9807701 A1 WO 9807701A1
Authority
WO
WIPO (PCT)
Prior art keywords
clonixate
analgesic
compound
nitroxybutyl
formula
Prior art date
Application number
PCT/EP1996/003610
Other languages
English (en)
Inventor
Gustavo Enrique Aldomá
Susana Élida PIATTI
Original Assignee
Handforth Investments 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 Handforth Investments Ltd. filed Critical Handforth Investments Ltd.
Priority to PCT/EP1996/003610 priority Critical patent/WO1998007701A1/fr
Priority to PL96331611A priority patent/PL331611A1/xx
Priority to EP96930045A priority patent/EP0922033A1/fr
Priority to BR9612730A priority patent/BR9612730A/pt
Priority to AU69249/96A priority patent/AU714258B2/en
Priority to JP10510291A priority patent/JP2000516235A/ja
Priority to CA002262788A priority patent/CA2262788A1/fr
Priority to TW085110724A priority patent/TW337521B/zh
Priority to UY24666A priority patent/UY24666A1/es
Priority to PE1997000716A priority patent/PE99398A1/es
Priority to CO97046964A priority patent/CO4900065A1/es
Publication of WO1998007701A1 publication Critical patent/WO1998007701A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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]

Definitions

  • This invention refers to a novel product which is useful in human and animal therapeutics, particularly m the treatment of pain and/or inflammation with non-steroidal analgesic/antiinflammatory agents and with low ulcerogenic effect.
  • carboxylic acids are carboxylic acids, often used in the form of salts.
  • One group of these products includes derivatives of salicylic acid, such as diflunisal.
  • Another group includes 2-aryl-substituted propionic acids, such as ibuprofen, etoprofen, naproxen, suprofen, tiaprofemc acid, flurbiprofen, and -in a broad sense- indobufen and ketorolac.
  • Another group includes aryl-substituted acetic acids, such as diclofenac, etodolac, fentiazac, sulindac and indomethacin.
  • Another group includes substituted 2- anilinobenzoic acids, such as mefenamic and meclofenamic acids.
  • Another group includes substituted 2- anilinonicotinic acids such as clonixin or clonixic acid (IV), the carboxylic acid which is structurally closest to the product of the present invention.
  • esters such as those illustrated below.
  • clonixic acid (IV) the carboxylic acid which is structurally closest to the product of the present invention, attempts have been made to ameliorate the balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects that have led to the preparation of several esters.
  • US 4.273.777 discloses pivaloyloxy ethyl clonixate (III) and ph ⁇ nalidyl clonixate, and provides some pharmacological comparative data.
  • US 3.689.653 discloses some lower-alkyl clonixates (methyl, ethyl, heptyl), but does not provide pharmacological data.
  • ulcerogenicity also differ from one document to another. In any case, it is generally observed that ulcerogenic adverse effects of esters, although smaller than those of the corresponding acids, still have a substantial value. Thus, for instance, in WO 95/09831 gastrointestinal damages of the 4-nitroxybutyl esters of ketorolac and indomethacin are estimated as 10- 15 % of those of the acids. In WO 94/12463 the relative ulcerogenicity of 4-nitroxybutyl esters of ketoprofen, flurbiprofen, suprofen, indobufen and etodolac are estimated as 20-35 % of those of the acids.
  • WO 94/04484 mention the low ulcerogenicity of the 4-nitroxybutyl ester of diclofenac, but it does not include data.
  • the ulcerogenic index of pivaloyloxymethyl and phthalidyl clonixate were evaluated as 3.0 and 3.6, values that are smaller than the one of clonixic acid (4.0), but that still are substantial.
  • the present invention solves the above-mentioned problem by providing 4-nitroxybutyl clonixate, a novel product of formula (I), and its pharmaceutically acceptable solvates (e.g. hydrates) and addition salts (e.g. hydrochloride) .
  • compositions comprising a therapeutically effective amount of 4-nitroxybutyl clonixate (I) or a pharmaceutically acceptable solvate or addition salt thereof, and appropriate amounts of pharmaceutically acceptable excipients or carriers, preferably for oral administration.
  • pharmaceutical compositions of the present invention are used for the treatment of pain and/or inflammation in mammals.
  • Another aspect of the present invention is the use of 4- nitroxybutyl clonixate (I) or a pharmaceutically acceptable solvate or addition salt thereof, for the preparation of a medicine for the treatment of pain and/or inflammation in mammals.
  • the present invention refers to a method of treatment of a mammal suffering from pain and/or inflammation, comprising the administration of a therapeutically effective amount of 4-nitroxybutyl clonixate (I) or a pharmaceutically acceptable solvate or addition salt thereof, together with appropriate amounts of pharmaceutically acceptable excipients or carriers.
  • Oral administration is the preferred way.
  • a further embodiment of the present invention is a preparation process of 4-nitroxybutyl clonixate (I) or a pharmaceutically acceptable solvate or addition salt thereof, that comprises the reaction, in an appropriate solvent, of a 4-halobutyl clonixate of formula (V) where X is Cl, Br or I, with a nitrate selected between silver nitrate and mercurous nitrate, optionally adding the necessary reagent to obtain the desired solvate or addition salt.
  • the addition salt is the hydrochloride
  • the necessary reagent is HCl (g) or HCl (aq) .
  • X is Cl
  • the nitrate is silver nitrate.
  • the 4-halobutyl clonixates of formula (V) are prepared by a reaction between an alkaline salt of clonixic acid, and the compound Y-(CH 2 ) -X, where X is as defined above, and Y is a leaving group better than X.
  • the alkaline salt is the potassium one
  • reaction steps of the processes of the present invention can be carried out in any appropriate solvent known in the art for reactions of the same type.
  • the solvent is acetonitrile .
  • the product of the present invention 4-nitroxybutyl clonixate (I)
  • Clonixic acid commercially available analgesic- antiinflammatory agent, also known as clonixm.
  • Table 1 Comparative tests of analgesic activities, antiinflammatory activities, and ulcerogenic adverse effects of clonixic acid and some of their esters.
  • ULC is the result of the sum of the ulceration scorer of each animal (with scorers above zero) multiplied by the percentage frequency of animals, divided by the total number of animals.
  • Table 1 summarizes the results of comparative tests of analgesic activities, antiinflammatory activities and ulcerogenic adverse effects of clonixic acid (IV) and clonixates (I)-(III).
  • Parameters ANL, ANT and ULC are defined in the footnote of the table, and they are fully explained in Examples 3, 4 and 5, respectively. For the desired purposes, the higher ANL value, the higher ANT value, and the lower ULC value, the better.
  • 4-nitroxybutyl clonixate (I) is a very useful analgesic-antiinflammatory active principle which represents a technical advantage in the treatment of pain and/or inflammation, over the non-steroidal analgesic- antiinflammatory products known in the art, and particularly over the known esters of clonixic acid.
  • Clonixic acid (3.0 g , 11.4 mmol) was suspended in 80 mL acetonitrile. Potassium carbonate (3.15 g , 22.8 mmol) was added, and the mixture was stirred for 10 mm under nitrogen. A solution of 1-bromobutane (2.5 mL , 22.8 mmol) in acetonitrile (5 mL) was added dropwise, and the mixture was stirred at 80 °C for 4 h. Solids were filtered off. From filtrate, solvent evaporation at 45 °C under vacuum yielded a solid residue.
  • mice Analgesic activities were assessed in mice using a writhing test according to R. Koster et al . (J . Fed . Proc. 1959, vol. 18, p. 412). Writhes were induced by acetic acid in sets of albino mice, of both sexes, from the CWF strain, each weighing 25-8 g. Mice had no food (but water ad libitum) for 12 h before treatment. Every mouse, 30 min before receiving 0.25 mL of 3 % aqueous acetic acid ⁇ .v., was treated p.o. with the following doses of the tested compounds: 8.5 mg/kg of clonixic acid (IV) or clonixates (I) -(III). Immediately after receiving the acetic acid, the number of writhes was counted for 20 min. The average values were compared with the control
  • the obtained ulcerogenic indexes are shown in the column ULC of Table 1.
  • a value ULC 0 means no adverse effects, i.e., that none of the animals had any haemorrhage at all.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le dérivé de la clonixine présentant la formule (I), ou le 4-nitroxybutyle clonixate est un nouveau produit anti-inflammatoire analgésique non stéroïde qui présente un équilibre extraordinaire entre de fortes activités analgésiques/anti-inflammatoires et de faibles effets défavorables ulcérigènes, grâce à une activité anti-inflammatoire très puissante (deux fois celle de l'acide clonixique). Le composé (I) est préparé en faisant réagir du 4-chlorobutyle clonixate avec du nitrate d'argent dans de l'acétonitrile. Le 4-chlorobutyle clonixate est préparé en faisant réagir un clonixate alcalin avec du 1-bromo-4-chlorobutane dans de l'acétonitrile. Le 4-nitroxybutyle cloxinate (I) est particulièrement utile comme principe actif dans le traitement des douleurs et/ou des inflammations chez le mammifère.
PCT/EP1996/003610 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene WO1998007701A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/EP1996/003610 WO1998007701A1 (fr) 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene
PL96331611A PL331611A1 (en) 1996-08-16 1996-08-16 Analgesic/anti-inflammatory derivative free of any ulcer formation causing side effects
EP96930045A EP0922033A1 (fr) 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene
BR9612730A BR9612730A (pt) 1996-08-16 1996-08-16 Derivado de clonixin analg-sico/antinflamatÄrio nÆo-ulcerog-nico
AU69249/96A AU714258B2 (en) 1996-08-16 1996-08-16 Non-ulcerogenic analgesic/antiinflammatory clonixin derivative
JP10510291A JP2000516235A (ja) 1996-08-16 1996-08-16 非潰瘍誘発性の鎮痛／抗炎症クロニキシン誘導体
CA002262788A CA2262788A1 (fr) 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene
TW085110724A TW337521B (en) 1996-08-16 1996-09-03 Non-ulcerogenic analgesic/anti-inflammatory cloixin derivative
UY24666A UY24666A1 (es) 1996-08-16 1997-08-12 Derivado analgesico/antiinflamatorio no ulcerogenico de clonixina
PE1997000716A PE99398A1 (es) 1996-08-16 1997-08-14 Derivado analgesico/antiinflamatorio no ulcerogenico de clonixina
CO97046964A CO4900065A1 (es) 1996-08-16 1997-08-15 Derivado analgesico/antiinflamatorio no ulcerogenico de clo- nixina

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1996/003610 WO1998007701A1 (fr) 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene

Publications (1)

Publication Number Publication Date
WO1998007701A1 true WO1998007701A1 (fr) 1998-02-26

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/003610 WO1998007701A1 (fr) 1996-08-16 1996-08-16 Derive de clonixine anti-inflammatoire/analgesique non ulcerigene

Country Status (9)

Country Link
JP (1) JP2000516235A (fr)
AU (1) AU714258B2 (fr)
BR (1) BR9612730A (fr)
CA (1) CA2262788A1 (fr)
CO (1) CO4900065A1 (fr)
PE (1) PE99398A1 (fr)
TW (1) TW337521B (fr)
UY (1) UY24666A1 (fr)
WO (1) WO1998007701A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030042935A (ko) * 2001-11-26 2003-06-02 알앤피코리아 주식회사 클로닉신리신 제제
WO2004020385A1 (fr) * 2002-08-29 2004-03-11 Nicox S.A. Procede de preparation d'esters d'acides carboxyliques a substitution nitrooxyalkyle, intermediaires utilises dans ledit procede et leur preparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273777A (en) * 1979-06-04 1981-06-16 Laboratorios Bago S.A. Methods of treating mammals suffering from inflammation and pain
WO1994004484A1 (fr) * 1992-08-20 1994-03-03 Corlay S.L. Esters nitriques des derives de l'acide phenylacetique 2-(2,6-di-halo-phenylamino) et procede pour leur preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273777A (en) * 1979-06-04 1981-06-16 Laboratorios Bago S.A. Methods of treating mammals suffering from inflammation and pain
WO1994004484A1 (fr) * 1992-08-20 1994-03-03 Corlay S.L. Esters nitriques des derives de l'acide phenylacetique 2-(2,6-di-halo-phenylamino) et procede pour leur preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. BUDAVARI ET AL.: "The Merck Index", 1996, MERCK RESEARCH LABORATORIES; MERCK & CO., INC., WHITEHOUSE STATION, N.J., XP002029466 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030042935A (ko) * 2001-11-26 2003-06-02 알앤피코리아 주식회사 클로닉신리신 제제
WO2004020385A1 (fr) * 2002-08-29 2004-03-11 Nicox S.A. Procede de preparation d'esters d'acides carboxyliques a substitution nitrooxyalkyle, intermediaires utilises dans ledit procede et leur preparation
US7723382B2 (en) 2002-08-29 2010-05-25 Nicox S.A. Process for preparing nitrooxyalkyl substituted esters of carboxylic acids, intermediates useful in said process and preparation thereof

Also Published As

Publication number Publication date
TW337521B (en) 1998-08-01
CA2262788A1 (fr) 1998-02-26
CO4900065A1 (es) 2000-03-27
AU714258B2 (en) 1999-12-23
JP2000516235A (ja) 2000-12-05
UY24666A1 (es) 1998-02-03
PE99398A1 (es) 1999-01-25
AU6924996A (en) 1998-03-06
BR9612730A (pt) 1999-08-24

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