CA2262788A1 - Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative - Google Patents
Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative Download PDFInfo
- Publication number
- CA2262788A1 CA2262788A1 CA002262788A CA2262788A CA2262788A1 CA 2262788 A1 CA2262788 A1 CA 2262788A1 CA 002262788 A CA002262788 A CA 002262788A CA 2262788 A CA2262788 A CA 2262788A CA 2262788 A1 CA2262788 A1 CA 2262788A1
- Authority
- CA
- Canada
- Prior art keywords
- clonixate
- analgesic
- nitroxybutyl
- compound
- formula
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
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]
Abstract
The clonixing derivative of formula (I), or 4-nitroxybutyl clonixate, is a novel non-steroidal analgesic-anti-inflammatory product that has an extraordinary good balance between high analgesic/anti-inflammatory activities and low ulcerogenic adverse effects, mainly as a consequence of a surprinsingly high anti-inflammatory activity (two times that of clonixic acid). Compound (I) is prepared by reaction of 4-chlorobutyl clonixate with silver nitrate in acetonitirle. 4-chlorobutyl clonixate is prepared by reaction of an alakaline clonixate with 1-bromo-4-chlorobutane in acetonitrile. 4-nitroxybutyl clonixate (I) is specially useful as an active principle for the treatment of pain and/or inflammation in mammals.
Description
W O 98/07701 PCTrEP96/03610 Non-ulcerogenic anal~esic/antiinflammatory clorliYi n derivative This invention refers to a novel product which is useful in human and animal therapeutics, particularly in the treatment of pain and/or inflammation with non-steroidal analgesic/antiinflammatory agents and with low ulcerogenic effect.
BACKGROUND ART
The treatment of pain and/or inflammation in mammals with concomitant absence of adverse side-effect has been a goal long sought. In general steroids having cortisone-like activity suffer from the drawback of the sideeffects induced by the corticoid, such as electrolyte imbalance, water retention, etc. Thus, the treatment with non-steroidal analgesic/antiinflammatory agents has emerged as a whole field in modern therapeutics.
Relatively active analgesic/antiinflammatory products are already known in the art, and many of them are on the market. However, virtually all of them present ulceration of the gastrointestinal track as an adverse side-effect.
Thus, the provision of new analgesic-antiinflammatory products that have a better balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects, is an important problem of modern therapeutics. This problem has not been solved satisfactorily yet, despite the existence of abundant research in the field.
From the chemical point of view, most commercial non-steroidal analgesic/antiinflammatory active principles 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, ketoprofen, naproxen, suprofen, tiaprofenic 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 ~efenamic and meclofenamic acids. Finally, 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.
O
~'N ~ N~
~ CH3 (IV) Most of the attempts to ameliorate the balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects of the above-mentioned carboxylic acids have involved the preparation of esters, such as those illustrated below.
US 5.508.301 discloses the 2-(1-pyrrolidinyl)ethyl ester of ketorolac. US 4.548.952 discloses the carboxymethyl ester of diclofenac, which is being used under the name aceclofenac. Nitroxy-(C1-C10)-alkyl esters of several CA 02262788 l999-02-09 W O 98/07701 PCT~EP96/03610 analgesic/antiinflammatory carboxylic acids, such as ketorolac, flurbiprofen, ketoprofen, naproxen, indomethacin and diclofenac, are claimed in WO 95/09831, WO 94/12463 or WO 94/04484.
In respect of 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. Thus, US
4.273.777 discloses pivaloyloxymethyl 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.
~ OCH2OCOC(CHJ)3 N NH
~CI
(III) The method of estimating the analgesic and antiinflammatory activities of these carboxylic acids and their esters, differ from one document to another;
therefore, significant comparisons between published activities are often difficult to make. In any case, it is generally observed that analgesic and antiinflammatory activities of esters are not substantially higher than those of the corresponding acids. Thus, for instance, US
W O 98/07701 PCT~EP96/0361 4.273.777 shows that pivaloyloxymethyl clonixate (III) and phthalidyl clonixate have analgesic and antiinflammatory activities similar to those of clonixic acid.
Methods of estimating ulcerogenicity also differ from one document to another. In any case, it is generally observed that ulcerogenic adver5e 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. In US
4.273.777 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.
Therefore, it is clear that, despite the numerous attempts to prepare esters of non-steroidal analgesic/antiinflammatory carboxylic acids with a better balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects, a completely satisfactory solution has not been reached yet. In particular, this is true for the case of esters of clonixic acid.
nF.S~pTIoN OF THE lwv~w lON
The present invention solves the above-mentioned problem W O 98/07701 PCT~EP96/03610 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).
,~ ~(~ H2)JCH20NO2 ~o~(CH2)3CH2X
~ 3 ~ CH
(I) (V) The subject matter of the present invention also includes the 4-halobutyl clonixates of formula (V), where X - Cl, Br, or I, which are novel intermediates for the preparation of (I). Specially preferred is 4-chlorobutyl clonixate, i.e. intermediate (V) where X = Cl.
The subject matter of the present invention includes pharmaceutical 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. In a particular embodiment, the 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. In other words, 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. Thus, for example, when the addition salt is the hydrochloride, the necessary reagent is HCl (g) or HCl (aq). ~n a preferred embodiment of the process, X is Cl, and the nitrate is silver nitrate.
In a particular embodiment of the process the 4-halobutyl clonixates of formula (V) are prepared by a reaction between an alkaline salt of clonixic acid, and the compound Y-(CH2) 4-X, where X is as defined above, and Y
is a leaving group better than X. Specially preferred is the process where the alkaline salt is the potassium one, X is Cl and Y is Br.
The 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. In a particular embodiment the solvent is acetonitrile.
W O 98/07701 PCT~EP96/03610 Compared with the non-steroidal analgesic-antiinflammatory products known in the art, the product of the present invention, 4-nitroxybutyl clonixate (I), unexpectedly presents an excellent balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects. This is so as a consequence of a surprisingly high antiinflammatory activity, simultaneous to an acceptable good analgesic activity and very low ulcerogenic adverse effects. Actually, the ulcerogenicity is so low that it appears as negligible (index = 0) in the comparative pharmacological tests of the accompanying examples.
In order to make significant comparison of analgesic activity, antiinflammatory activity and ulcerogenicity, products (I)-(IV) have been tested under comparable conditions in the accompanying Examples 3-5. The identity and origin of tested products (I)-(IV) in Table 1 is as follows:
(I): 4-Nitroxybutyl clonixate, subject matter of the present invention, prepared here for the first time (cf.
Example 1).
(II): Butyl clonixate, prepared here for the first time, for comparison (cf. Example 2).
(III): Pivaloyloxymethyl clonixate, proposed as analgesic-antiinflammatory product with low ulcerogenic adverse effects; disclosed in US 4.273.777.
(IV): Clonixic acid, commercially available analgesic-antiinflammatory agent, also known as clonixln.
_________________________ __ _ ____ __ _ ____________ Table 1: Comparative tests of analgesic activities, antiinflammatory activities, and ulcerogenic adverse effects of clonixic acid and some of their esters.
_________ Compound ANL,% ANT,% ULC
_________________________________ ____ _______________ tI) 4-nitroxybutyl clonixate - 27 58 0 (II) butyl clonixate 26 21 8 1~ (III) pivaloyloxymethyl clonixate 27 27 8 (IV) clonixic acid 25 28 333 ___________________________________ ___________________ ANL = analgesic activity as percentage of pain reduction in a writhing test (0 % = no activity)i ANT
antiinflammatory activity as percentage of edema inhibition (0 % = no activity); ULC = ulcerogenic index (0 = no adverse effects = none of the animals has any haemorrhage at all). 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.
Concerning the analgesic activities (ANL) in the table, tested clonixates (I)-(III) are roughly as active as W O 98/07701 PCT~EP96/03610 clonixic acid (IV).
Concerning the antiinflammatory activities (ANT) in the table, butyl clonixate (II) and pivaloyloxymethyl clonixate (III) are roughly as active as clonixic acid (IV), as it was expected. However, unexpectedly, 9-nitroxybutyl clonixate (IJ, the product of the present invention, has an antiinflammatory activity that is surprisingly high. Actually, this activity is two times the one of clonixic acid (IV).
The table also shows remarkable differences in ulcerogenicity. It is not surprising that all tested esters are less ulcerogenic than the corresponding acids.
However, nothing in the art allowed to predict that 4-nitroxybutyl clonixate (I) has such a low ulcerogenic adverse effect. Actually, it is so low that it appears as negligible ~value = 0) in the test, what means that none of the treated animals showed any haemorrhage at all.
The low ulcerogenicity, together with the acceptable good analgesic activity and the surprisingly high antiinflammatory activity, gives to product (I) an extraordinary good balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects. This unexpected technical feature of the product of the invention cannot be attributed to a mere esterification of clonixic acid. It can neither be attributed to the presence of the four carbon atoms of the butyl group. It can neither be attributed to the presence of the nitroxy substituent at the end of the butyl chain.
Thus, 4-nitroxybutyl clonixate (I) is a very useful analgesic-antiinflammatory active principle which W O 98/07701 PCT~EP96/03610 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.
EXAMPLES
Exam~le 1. Pre~aration of 4-nitroxybutyl clonixate (I).
(la) 4-Chlorobutvl clonixate. Clonixic acid (10 g, 83 mmol) was suspended in 300 mL acetonitrile. Potassium carbonate (10.5 g , 76 mmol) was added, and the mixture was stirred for 10 min under nitrogen. 1-Bromo-4-chlorobutane (8.8 mL , 76 mmol) was added dropwise and slowly, and the mixture was stirred at 80 ~C for 2 h.
Solids were filtered off. Solvent evaporation from filtrate, at 45 ~C under vacuum, yielded an oil residue.
Washing with ethanol:water 70:30, followed by solvent evaporation under vacuum, washing with hexane, and filtration, yielded 12.5 g of the title compound as a solid melting at 69-70 ~C, which was used in the following step without further purification.
(lb) 4-Nitroxybutvl clonixate (I~. A solution of silver nitrate (5.8 g, 34 mmol) in 10 mL acetonitrile was added dropwise onto a suspension of 4-chlorobutyl clonixate (6 g , 17 mmol) in 300 mL acetonitrile. The reaction mixture was refluxed for 90 h; then it was filtered. Solvent evaporation under vacuum from the filtrate yielded a solid residue that was dissolved with dichloromethane;
the obtained solution was washed with abundant water. The organic phase was separated from the aqueous one, it was dried with anhydrous magnesium sulfate, and the solvent was evaporated under vacuum. Column chromatography of the solid residue, in silicagel with isopropyl ether:hexane 1:1, allowed the collection of a fraction that, after solvent evaporation under vacuum, yielded the title compound (5.28 g , 82 %) as a solid melting at 55-7 ~C, wlth the following spectroscopic properties: IR (v, cm~1):
1700 (C=O); 1620 (asymmetrical NO2); 1280 (symmetrical NO~); 880 (NO stretching). NMR (~, ppm): 1.95 (m, 4H);
BACKGROUND ART
The treatment of pain and/or inflammation in mammals with concomitant absence of adverse side-effect has been a goal long sought. In general steroids having cortisone-like activity suffer from the drawback of the sideeffects induced by the corticoid, such as electrolyte imbalance, water retention, etc. Thus, the treatment with non-steroidal analgesic/antiinflammatory agents has emerged as a whole field in modern therapeutics.
Relatively active analgesic/antiinflammatory products are already known in the art, and many of them are on the market. However, virtually all of them present ulceration of the gastrointestinal track as an adverse side-effect.
Thus, the provision of new analgesic-antiinflammatory products that have a better balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects, is an important problem of modern therapeutics. This problem has not been solved satisfactorily yet, despite the existence of abundant research in the field.
From the chemical point of view, most commercial non-steroidal analgesic/antiinflammatory active principles 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, ketoprofen, naproxen, suprofen, tiaprofenic 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 ~efenamic and meclofenamic acids. Finally, 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.
O
~'N ~ N~
~ CH3 (IV) Most of the attempts to ameliorate the balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects of the above-mentioned carboxylic acids have involved the preparation of esters, such as those illustrated below.
US 5.508.301 discloses the 2-(1-pyrrolidinyl)ethyl ester of ketorolac. US 4.548.952 discloses the carboxymethyl ester of diclofenac, which is being used under the name aceclofenac. Nitroxy-(C1-C10)-alkyl esters of several CA 02262788 l999-02-09 W O 98/07701 PCT~EP96/03610 analgesic/antiinflammatory carboxylic acids, such as ketorolac, flurbiprofen, ketoprofen, naproxen, indomethacin and diclofenac, are claimed in WO 95/09831, WO 94/12463 or WO 94/04484.
In respect of 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. Thus, US
4.273.777 discloses pivaloyloxymethyl 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.
~ OCH2OCOC(CHJ)3 N NH
~CI
(III) The method of estimating the analgesic and antiinflammatory activities of these carboxylic acids and their esters, differ from one document to another;
therefore, significant comparisons between published activities are often difficult to make. In any case, it is generally observed that analgesic and antiinflammatory activities of esters are not substantially higher than those of the corresponding acids. Thus, for instance, US
W O 98/07701 PCT~EP96/0361 4.273.777 shows that pivaloyloxymethyl clonixate (III) and phthalidyl clonixate have analgesic and antiinflammatory activities similar to those of clonixic acid.
Methods of estimating ulcerogenicity also differ from one document to another. In any case, it is generally observed that ulcerogenic adver5e 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. In US
4.273.777 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.
Therefore, it is clear that, despite the numerous attempts to prepare esters of non-steroidal analgesic/antiinflammatory carboxylic acids with a better balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects, a completely satisfactory solution has not been reached yet. In particular, this is true for the case of esters of clonixic acid.
nF.S~pTIoN OF THE lwv~w lON
The present invention solves the above-mentioned problem W O 98/07701 PCT~EP96/03610 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).
,~ ~(~ H2)JCH20NO2 ~o~(CH2)3CH2X
~ 3 ~ CH
(I) (V) The subject matter of the present invention also includes the 4-halobutyl clonixates of formula (V), where X - Cl, Br, or I, which are novel intermediates for the preparation of (I). Specially preferred is 4-chlorobutyl clonixate, i.e. intermediate (V) where X = Cl.
The subject matter of the present invention includes pharmaceutical 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. In a particular embodiment, the 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. In other words, 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. Thus, for example, when the addition salt is the hydrochloride, the necessary reagent is HCl (g) or HCl (aq). ~n a preferred embodiment of the process, X is Cl, and the nitrate is silver nitrate.
In a particular embodiment of the process the 4-halobutyl clonixates of formula (V) are prepared by a reaction between an alkaline salt of clonixic acid, and the compound Y-(CH2) 4-X, where X is as defined above, and Y
is a leaving group better than X. Specially preferred is the process where the alkaline salt is the potassium one, X is Cl and Y is Br.
The 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. In a particular embodiment the solvent is acetonitrile.
W O 98/07701 PCT~EP96/03610 Compared with the non-steroidal analgesic-antiinflammatory products known in the art, the product of the present invention, 4-nitroxybutyl clonixate (I), unexpectedly presents an excellent balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects. This is so as a consequence of a surprisingly high antiinflammatory activity, simultaneous to an acceptable good analgesic activity and very low ulcerogenic adverse effects. Actually, the ulcerogenicity is so low that it appears as negligible (index = 0) in the comparative pharmacological tests of the accompanying examples.
In order to make significant comparison of analgesic activity, antiinflammatory activity and ulcerogenicity, products (I)-(IV) have been tested under comparable conditions in the accompanying Examples 3-5. The identity and origin of tested products (I)-(IV) in Table 1 is as follows:
(I): 4-Nitroxybutyl clonixate, subject matter of the present invention, prepared here for the first time (cf.
Example 1).
(II): Butyl clonixate, prepared here for the first time, for comparison (cf. Example 2).
(III): Pivaloyloxymethyl clonixate, proposed as analgesic-antiinflammatory product with low ulcerogenic adverse effects; disclosed in US 4.273.777.
(IV): Clonixic acid, commercially available analgesic-antiinflammatory agent, also known as clonixln.
_________________________ __ _ ____ __ _ ____________ Table 1: Comparative tests of analgesic activities, antiinflammatory activities, and ulcerogenic adverse effects of clonixic acid and some of their esters.
_________ Compound ANL,% ANT,% ULC
_________________________________ ____ _______________ tI) 4-nitroxybutyl clonixate - 27 58 0 (II) butyl clonixate 26 21 8 1~ (III) pivaloyloxymethyl clonixate 27 27 8 (IV) clonixic acid 25 28 333 ___________________________________ ___________________ ANL = analgesic activity as percentage of pain reduction in a writhing test (0 % = no activity)i ANT
antiinflammatory activity as percentage of edema inhibition (0 % = no activity); ULC = ulcerogenic index (0 = no adverse effects = none of the animals has any haemorrhage at all). 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.
Concerning the analgesic activities (ANL) in the table, tested clonixates (I)-(III) are roughly as active as W O 98/07701 PCT~EP96/03610 clonixic acid (IV).
Concerning the antiinflammatory activities (ANT) in the table, butyl clonixate (II) and pivaloyloxymethyl clonixate (III) are roughly as active as clonixic acid (IV), as it was expected. However, unexpectedly, 9-nitroxybutyl clonixate (IJ, the product of the present invention, has an antiinflammatory activity that is surprisingly high. Actually, this activity is two times the one of clonixic acid (IV).
The table also shows remarkable differences in ulcerogenicity. It is not surprising that all tested esters are less ulcerogenic than the corresponding acids.
However, nothing in the art allowed to predict that 4-nitroxybutyl clonixate (I) has such a low ulcerogenic adverse effect. Actually, it is so low that it appears as negligible ~value = 0) in the test, what means that none of the treated animals showed any haemorrhage at all.
The low ulcerogenicity, together with the acceptable good analgesic activity and the surprisingly high antiinflammatory activity, gives to product (I) an extraordinary good balance between high analgesic/antiinflammatory activities and low ulcerogenic adverse effects. This unexpected technical feature of the product of the invention cannot be attributed to a mere esterification of clonixic acid. It can neither be attributed to the presence of the four carbon atoms of the butyl group. It can neither be attributed to the presence of the nitroxy substituent at the end of the butyl chain.
Thus, 4-nitroxybutyl clonixate (I) is a very useful analgesic-antiinflammatory active principle which W O 98/07701 PCT~EP96/03610 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.
EXAMPLES
Exam~le 1. Pre~aration of 4-nitroxybutyl clonixate (I).
(la) 4-Chlorobutvl clonixate. Clonixic acid (10 g, 83 mmol) was suspended in 300 mL acetonitrile. Potassium carbonate (10.5 g , 76 mmol) was added, and the mixture was stirred for 10 min under nitrogen. 1-Bromo-4-chlorobutane (8.8 mL , 76 mmol) was added dropwise and slowly, and the mixture was stirred at 80 ~C for 2 h.
Solids were filtered off. Solvent evaporation from filtrate, at 45 ~C under vacuum, yielded an oil residue.
Washing with ethanol:water 70:30, followed by solvent evaporation under vacuum, washing with hexane, and filtration, yielded 12.5 g of the title compound as a solid melting at 69-70 ~C, which was used in the following step without further purification.
(lb) 4-Nitroxybutvl clonixate (I~. A solution of silver nitrate (5.8 g, 34 mmol) in 10 mL acetonitrile was added dropwise onto a suspension of 4-chlorobutyl clonixate (6 g , 17 mmol) in 300 mL acetonitrile. The reaction mixture was refluxed for 90 h; then it was filtered. Solvent evaporation under vacuum from the filtrate yielded a solid residue that was dissolved with dichloromethane;
the obtained solution was washed with abundant water. The organic phase was separated from the aqueous one, it was dried with anhydrous magnesium sulfate, and the solvent was evaporated under vacuum. Column chromatography of the solid residue, in silicagel with isopropyl ether:hexane 1:1, allowed the collection of a fraction that, after solvent evaporation under vacuum, yielded the title compound (5.28 g , 82 %) as a solid melting at 55-7 ~C, wlth the following spectroscopic properties: IR (v, cm~1):
1700 (C=O); 1620 (asymmetrical NO2); 1280 (symmetrical NO~); 880 (NO stretching). NMR (~, ppm): 1.95 (m, 4H);
2.40 (s, 3H); 4.4 (m, 2H); 4.54 (m, 2H); 6.7-8.5 (aromatic); 9.9 (s, lH). Mass spec~rum (m/z, 20 eV): 379 (M+).
Exam~le 2. Pre~aration of butYl clonixate (II).
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 min 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. Washing of the residue with ethanol:water 70:30, followed by solvent evaporation under vacuum, washing with hexane, solvent evaporation and recrystallization from acetonitrile, yielded 3.2 g (88 %) of the title compound as a solid melting at 65-8 ~C, with the following mass spectrum (m/z, 70 eV) : 318/20 (M+, 35 %); 303/5 (100 %); 261/63 (30 %); 89 (17 %).
Example 3: Com~arison of analgesic activities.
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 W O 98/07701 : PCTAEP96/03610 (but water ad libitum) for 12 h before treatment. Every mouse, 30 mln before receiving 0.25 mL of 3 % aqueous acetic acid i.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 (29.5 writhes), and the results -shown in Table 1 were obtained, expressed as percentages of reduction in the number of writhes. The higher the number in the ANL
column in Table 1, the better analgesic activity (0 % =
no activity).
Example 4. ComParison of antiinflammatory activities.
Antiinflammatory activities were assessed in Sprague Dawley rats, using a carrageenin induced paw edema test according to C.A. Winter et al. (Proc. Soc. Exp. Biol.
Med. 1962, vol. 111, pp. 544-7). Rats of both sexes, approximately weighing 150 g each, received 0.1 mL of 1 % carrageenin saline suspension by injection in the subplantar region of one paw. 30 min before the injection of carrageenin, the following doses of tested compound were administered p.o.: 22.5 mg/kg of clonixic acid (IV) or clonixates (I)-(III). Paw volumes were measured 3 h after the injection. The results shown in Table 1 were obtained, expressed as percentages of edema inhibition (volume reduction) of treated animals, compared with the untreated (control) set. The higher the number ir. the ANT
column of Table 1, the better antiinflammatory activity (0 % = no activity).
Example 5. ComParison of ulceroqenic adverse effects.
Ulcerogenic effects were evaluated by a macroscopic examination of the ulceration of gastric epithelium, according to M. Chaumontet et al. (Arzneim. Forsch. Dru~
Res. 1978, vol. 28 (II), pp. 2119-21). Sets of Sprague Dawley rats, approximately weighing 150 g each, received p.o. the following doses of the tested compounds: 125 mg/kg of clonixic acid (IV) or clonixates (I)-(III).
After 4 h of the administration, animals were sacrificed, the stomach was removed, open and examined for macroscopic damage. For every compound an ulcerogenic index was calculated according to the following evaluation: 0 = no haemorrhage; 1 = small haemorrhage; 2 = large haemorrhage; 3 = small ulcers (less than 2 mm diameter); 4 = large ulcers (more than 2 mm diameter); 5 = perforated ulcer. 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.
Exam~le 2. Pre~aration of butYl clonixate (II).
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 min 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. Washing of the residue with ethanol:water 70:30, followed by solvent evaporation under vacuum, washing with hexane, solvent evaporation and recrystallization from acetonitrile, yielded 3.2 g (88 %) of the title compound as a solid melting at 65-8 ~C, with the following mass spectrum (m/z, 70 eV) : 318/20 (M+, 35 %); 303/5 (100 %); 261/63 (30 %); 89 (17 %).
Example 3: Com~arison of analgesic activities.
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 W O 98/07701 : PCTAEP96/03610 (but water ad libitum) for 12 h before treatment. Every mouse, 30 mln before receiving 0.25 mL of 3 % aqueous acetic acid i.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 (29.5 writhes), and the results -shown in Table 1 were obtained, expressed as percentages of reduction in the number of writhes. The higher the number in the ANL
column in Table 1, the better analgesic activity (0 % =
no activity).
Example 4. ComParison of antiinflammatory activities.
Antiinflammatory activities were assessed in Sprague Dawley rats, using a carrageenin induced paw edema test according to C.A. Winter et al. (Proc. Soc. Exp. Biol.
Med. 1962, vol. 111, pp. 544-7). Rats of both sexes, approximately weighing 150 g each, received 0.1 mL of 1 % carrageenin saline suspension by injection in the subplantar region of one paw. 30 min before the injection of carrageenin, the following doses of tested compound were administered p.o.: 22.5 mg/kg of clonixic acid (IV) or clonixates (I)-(III). Paw volumes were measured 3 h after the injection. The results shown in Table 1 were obtained, expressed as percentages of edema inhibition (volume reduction) of treated animals, compared with the untreated (control) set. The higher the number ir. the ANT
column of Table 1, the better antiinflammatory activity (0 % = no activity).
Example 5. ComParison of ulceroqenic adverse effects.
Ulcerogenic effects were evaluated by a macroscopic examination of the ulceration of gastric epithelium, according to M. Chaumontet et al. (Arzneim. Forsch. Dru~
Res. 1978, vol. 28 (II), pp. 2119-21). Sets of Sprague Dawley rats, approximately weighing 150 g each, received p.o. the following doses of the tested compounds: 125 mg/kg of clonixic acid (IV) or clonixates (I)-(III).
After 4 h of the administration, animals were sacrificed, the stomach was removed, open and examined for macroscopic damage. For every compound an ulcerogenic index was calculated according to the following evaluation: 0 = no haemorrhage; 1 = small haemorrhage; 2 = large haemorrhage; 3 = small ulcers (less than 2 mm diameter); 4 = large ulcers (more than 2 mm diameter); 5 = perforated ulcer. 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.
Claims (12)
1. The compound 4-nitroxybutyl clonixate, of formula (I), and pharmaceutically acceptable solvates and addition salts thereof.
2. The compound 4-nitroxybutyl clonixate, of formula (I).
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 2, and appropriate amounts of pharmaceutically acceptable excipients or carriers.
4. A pharmaceutical composition for the treatment of pain and/or inflammation in mammals, comprising a compound according to claim 1 or 2 as active ingredient.
5. Use of a compound according to claim 1 or 2, for the preparation of an medicament for the treatment of pain and/or inflammation in mammals.
6. Method of treatment of a mammal suffering from pain and/or inflammation, comprising the administration to said mammal of a therapeutically effective amount of a compound according to claim 1 or 2, together with appropriate amounts of pharmaceutically acceptable excipients or carriers.
7. An intermediate compound of formula (V), where X is Cl, Br or I.
8. The intermediate compound according to claim 7, where X is Cl.
9. A preparation process of a compound according to claim 1 or 2, comprising the reaction, in an appropriate solvent, of an intermediate compound 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.
10. A process according to claim 9, where X is Cl and the nitrate is silver nitrate.
11. A process according to claim 9 or 10, where the intermediate compound of formula (V) is prepared by a reaction between an alkaline salt of clonixic acid and Y-(CH2) 4-X, where X is as defined above and Y is a leaving group better than X.
12. A process according to any of the claims 9 to 11, where the reactions are carried out in acetonitrile as solvent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP1996/003610 WO1998007701A1 (en) | 1996-08-16 | 1996-08-16 | Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2262788A1 true CA2262788A1 (en) | 1998-02-26 |
Family
ID=8166287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002262788A Abandoned CA2262788A1 (en) | 1996-08-16 | 1996-08-16 | Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JP2000516235A (en) |
| AU (1) | AU714258B2 (en) |
| BR (1) | BR9612730A (en) |
| CA (1) | CA2262788A1 (en) |
| CO (1) | CO4900065A1 (en) |
| PE (1) | PE99398A1 (en) |
| TW (1) | TW337521B (en) |
| UY (1) | UY24666A1 (en) |
| WO (1) | WO1998007701A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030042935A (en) * | 2001-11-26 | 2003-06-02 | 알앤피코리아 주식회사 | Clonixin lysinate formulation |
| ITMI20021861A1 (en) * | 2002-08-29 | 2004-02-29 | Nicox Sa | NITROXIALKYL ESTER SYNTHESIS PROCESS OF CARBOXYLIC ACIDS, INTERMEDIATES THAT CAN BE USED IN THAT PROCEDURE AND THEIR PREPARATION. |
Family Cites Families (2)
| 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 |
| IT1256345B (en) * | 1992-08-20 | 1995-12-01 | NITRIC ESTERS OF PHENYLACETIC 2- (2,6-DI-HALO-PHENYLAMIN) DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION |
-
1996
- 1996-08-16 AU AU69249/96A patent/AU714258B2/en not_active Ceased
- 1996-08-16 CA CA002262788A patent/CA2262788A1/en not_active Abandoned
- 1996-08-16 WO PCT/EP1996/003610 patent/WO1998007701A1/en not_active Application Discontinuation
- 1996-08-16 JP JP10510291A patent/JP2000516235A/en active Pending
- 1996-08-16 BR BR9612730A patent/BR9612730A/en not_active Application Discontinuation
- 1996-09-03 TW TW085110724A patent/TW337521B/en active
-
1997
- 1997-08-12 UY UY24666A patent/UY24666A1/en unknown
- 1997-08-14 PE PE1997000716A patent/PE99398A1/en not_active Application Discontinuation
- 1997-08-15 CO CO97046964A patent/CO4900065A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU6924996A (en) | 1998-03-06 |
| CO4900065A1 (en) | 2000-03-27 |
| BR9612730A (en) | 1999-08-24 |
| AU714258B2 (en) | 1999-12-23 |
| PE99398A1 (en) | 1999-01-25 |
| UY24666A1 (en) | 1998-02-03 |
| WO1998007701A1 (en) | 1998-02-26 |
| JP2000516235A (en) | 2000-12-05 |
| TW337521B (en) | 1998-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5621000A (en) | Nitric esters having a pharmacological activity and process for their preparation | |
| KR100343243B1 (en) | Nitric esters with anti-inflammatory and / or analgesic activity and methods for their preparation | |
| RU2109009C1 (en) | Derivatives of 2-(2,6-dihalophenylamino)-phenylacetic acid and a method of their synthesis | |
| EP0586490B1 (en) | Derivatives of perhydroisoindol, their preparation, and pharmaceutical compositions containing them | |
| EP0429366A1 (en) | Isoindolone derivatives, their preparation and pharmaceutical compositions containing them | |
| CH651561A5 (en) | DERIVATIVES OF NOR-TROPANE AND GRANATANE AND THEIR PREPARATION PROCESS. | |
| FR2466465A1 (en) | DERIVATIVES OF D-6-N-PROPYLERGOLINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME | |
| PL84190B1 (en) | 3-aroyl-alkenyleneimines[us3835149a] | |
| AU714258B2 (en) | Non-ulcerogenic analgesic/antiinflammatory clonixin derivative | |
| CA2089349C (en) | New pyrolidine derivatives, process for their preparation and pharmaceutical composition holding same | |
| CA2105683C (en) | N-¬¬4,5-dihydroxy-and 4,5,8-trihydroxy-9,10-dihydro-9, 10-dioxo-2-anthracene-yl|carbonyl|amino acids useful in the therapy of osteoarticular affections | |
| US5519043A (en) | Fluorenyl derivatives | |
| EP0922033A1 (en) | Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative | |
| US4116972A (en) | Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation | |
| US4168313A (en) | Phthalidyl 2-(3'-trifluoromethyl-anilino)-pyridine-3-carboxylate and its salts | |
| CS216206B2 (en) | Method of making the derivatives of the diphenylpyrazole | |
| MXPA99001358A (en) | Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative | |
| EP3390360A1 (en) | Process for the preparation of a pharmaceutical agent | |
| JPH0662547B2 (en) | Glycine derivative | |
| US4568690A (en) | 1-Methyl-5-p-methylbenzoylpyrrole-2-acetamidoacetanilides with antiinflammatory, analgesic, antipyretic and anti-platelet aggregant activity | |
| JPH04334358A (en) | Condensed benzeneoxy acetic acid derivative | |
| CA2111169C (en) | Phenylacetic acid derivatives, process for the preparation thereof and corresponding use | |
| EP0101633B1 (en) | Pyridinecarboxylic esters of dopamine and of its n-alkyl derivatives | |
| GB2027022A (en) | Pyridoxine derivatives and their use | |
| CN1226233A (en) | Non-ulcerogenic analgesic/anti-inflammatory clonixin derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |