WO2007110876A2 - Dérives innovants du sulfonanilide, compositions pharmaceutiques qui les contiennent et procédés qui les concernent - Google Patents

Dérives innovants du sulfonanilide, compositions pharmaceutiques qui les contiennent et procédés qui les concernent Download PDF

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WO2007110876A2
WO2007110876A2 PCT/IN2007/000098 IN2007000098W WO2007110876A2 WO 2007110876 A2 WO2007110876 A2 WO 2007110876A2 IN 2007000098 W IN2007000098 W IN 2007000098W WO 2007110876 A2 WO2007110876 A2 WO 2007110876A2
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group
formula
derivatives
compound
novel
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WO2007110876A3 (fr
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Rajesh Jain
Kour Chand Jindal
Jaspal Singh
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Panacea Biotec Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to novel sulfonanilide derivatives and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof.
  • novel derivatives having the general formula as shown in Formula- II, which are the derivatives of N-(4-Nitro-2-phenoxy-phenyl)methane-sulfonamide (also known as nimesulide) having the formula as shown in Formula-I, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof.
  • novel derivatives have improved solubility, preferably aqueous solubility, and/or improved bioavailability with reduced adverse effects associated with the therapy. Further, this invention relates to process of preparation of such novel derivatives, pharmaceutical composition comprising the same and method of using such compositions for the prophylaxis, amelioration and/or treatment of inflammation and/or pain, and other associated disorders which comprises administering to a subject in need thereof an effective amount of such composition.
  • Ri an alkyl group 1-3 carbon atomic number, cycloalkyl group 3-6 atomic number, a phenyl group, or a substituted phenyl group, more particularly acetylaminophenyl group, or an aromatic heterocyclic group preferably having a 5-membered or 6- membered ring comprising a N and/or S and/or O
  • R 2 a phenyl group, a halophenyl group, an amino group, a lower alkyl amino group, an allyl group, a vinyl group, an amino acid group, a lower N-substituted carboxy alkyl, or a lower N,N-disubstituted carboxy alkyl group, or an aromatic heterocyclic group preferably having a 5-membered or 6-membered ring comprising a N and/or S and/or O 5
  • R 3 -H
  • n 1-4 or their physiologically acceptable organic or inorganic base addition salts
  • X is alkyl, a substituted alkyl, an aryl, a substituted aryl, a heterocyclic compound, or a physiologically acceptable organic or inorganic acid salt), or
  • R 4 hydrogen, halogen, lower alkyl, an aryl or a substituted aryl, or a heterocyclic group.
  • R 5 hydroxyl or an alkoxy group.
  • novel derivatives of the present invention possess improved solubility, preferably aqueous solubility, and/or improved bioavailability with reduced adverse effects associated with the therapy and can be easily be formulated into desired pharmaceutical compositions which can be administered orally, parenterally, or by any route of administration.
  • Non-steroidal anti-inflammatory drugs which suppress inflammation and/or pain in a manner similar to steroids, but without the side effects of steroids, and commonly referred to by acronym NSAIDs, have been extensively used clinically in treatment of various inflammations (such as osteoarthritis, inflammation of respiratory tract), back pain, sciatica, sprains, strains, dental pain, migraine, rheumatism, post-operative pain, period pain (dysmenorrhoea) and heavy periods (monorrhagia), pain from kidney stones (renal colic), particularly useful in the inflammatory forms of arthritis (e.g. rheumatoid arthritis) and, sometimes, in more severe, forms of osteoarthritis, besides its use also as an antipyretic.
  • various inflammations such as osteoarthritis, inflammation of respiratory tract
  • sciatica such as rheumatism, post-operative pain, period pain (dysmenorrhoea) and heavy periods (monorrhagia)
  • renal colic particularly useful in
  • Prostaglandins are neutral chemicals which are involved in body inflammation by inhibiting the body's production of certain chemical messengers.
  • certain prostaglandins are also important in protecting the stomach lining from the corrosive effects of stomach acid as well as playing a role in maintaining the natural healthy conditions of the stomach lining.
  • These prostaglandins are produced by an enzyme called COX-I.
  • the cyclooxygenase exists in two-isoforms viz. cyclooxygenase- 1 (COX-I) and cyclooxygenase-2 (COX-2).
  • NSAIDs which belong to COX-2 inhibitors, are commonly used in clinical context. Among them, sulfonanilide such as nimesulide, would inhibit preferentially COX-2 more than COX-I and is better tolerated by the gastrointestinal tract compared to other conventional NSAIDs.
  • sulfonanilide such as nimesulide
  • Another negative property of nimesulide from its formulation perspective is its poor solubility in water (approximately 0.01 mg/ml).
  • nimesulide Due to the poor solubility of nimesulide, it becomes very difficult to manufacture some galenic compositions such as drinkable and injectable solution and some oral preparations. Further, the poor solubility leads to poor bioavailability of nimesulide in vivo. Furthermore, since nimesulide has an acidic proton in its chemical structure, it can form a salt with alkali metals or organic bases. The water soluble form in particular the sodium salt, impose a relatively alkaline pH or is far from the physiological values, so it is poorly tolerated.
  • PCT Publication Nos. WO 91/17774 and WO94/02177 disclose nimesulide complex with cyclodextrins that improve the aqueous solubility of nimesulide upto 5 times the solubility of nimesulide.
  • PCT Publication No. WO94/15932 describes thiophene and furan derivatives which selectively inhibit COX-2.
  • PCT Publication No. WO 95/15316 describes pyrazolyl sulfonamide derivative which selectively inhibit COX-2.
  • prodrugs of anti-inflammatory compounds are advantageous, especially where the prodrug have increased water solubility or delayed onset of action. Compounds which selectively inhibit COX-2 have been described.
  • Nimesulide having the Formula-I as herein described, is known from US Patent Nos. 3840597 and European Patent No. 1604976.
  • US Patent No. 4866091 relates to alkali sulfonamide derivative and acceptable salts thereof which have antiinflammatory and analgesic activities and their pharmaceutical compositions.
  • US Patent No. 5344991 describes cyclopentenes which selectively inhibit COX-2.
  • US Patent No. 5393790 describes spiro compounds which selectively inhibit COX-2.
  • compositions comprising such novel derivatives having the general Formula-II as stated herein and process of preparation of such compositions.
  • novel derivatives are preferably capable of being administered for showing activity for longer periods of time, and are highly effective especially for the treatment of
  • novel derivatives or pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, of the present invention can easily be formulated into desired pharmaceutical compositions 20. which can be administered orally, parenterally, or by any route of administration.
  • the present invention provides novel sulfonanilide derivatives and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates,
  • the present invention provides novel derivatives having the general Formula-II as stated herein, of N-(4-Nitro-2-phenoxy-phenyl) methane-sulfonamide having the Formula-I as stated herein and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric
  • R 1 an alkyl group 1-3 carbon atomic number, cycloalkyl group 3-6 atomic number, a phenyl group, or a substituted phenyl group, more particularly acetylaminophenyl group, or an aromatic heterocyclic group preferably having a 5-membered or 6- membered ring comprising a N and/or S and/or O,
  • n 1-4 or their physiologically acceptable organic or inorganic base addition salts, -CO-CHX-NH 2 (X is alkyl, a substituted alkyl, an aryl, a substituted aryl, a heterocyclic compound, or a physiologically acceptable organic or inorganic acid salt), or
  • novel derivatives have improved anti-inflammatory and/or analgesic and/or antipyretic and/or antiallergic activity and are highly useful for the management such as prophylaxis, amelioration and/or treatment of inflammatory diseases or pain or other associated disorders with reduced side effects associated with such active agents such as gastro-intestinal disorders and the like. Furthermore, the novel derivatives of the present invention are capable of being administered for longer time periods, have excellent safety profile and improved water solubility.
  • the inventors of the present invention using intellectual expertise and careful experimentation have designed and synthesized novel sulfonanilide derivatives particularly derivatives of nimesulide or salts thereof which have a substantially improved aqueous solubility and/or bioavailability, and which can easily be formulated into desired safe and effective compositions.
  • the present invention provides novel derivatives of nimesulide represented by Formulas III, IV, V, VI and VII respectively.
  • R 6 is H or a physiologically acceptable, organic or inorganic cation.
  • R 7 is alkyl, substituted alkyl, aryl, or substituted aryl.
  • the method of preparation of a product of Formula-Ill comprises the following steps: i) A compound of the Formula- VIII, namely 4-hydroxyacetanilide, when reacted with 2-halonitrobenzene ('halo' being selected from the group consisting of fluoro, bromo, choloro and iodo), in the presence of a base, selected from the group comprising of alkali metal hydroxides and/or mild bases, for example, alkali metal carbonates and/or sodium and/or potassium methoxide, sodium and/or potassium ethoxide, sodium and/or potassium hydride, sodium and/or potassium t- butoxide and the like in the absence or presence of the solvent such as dipolar aprotic solvents, for example dimethylformamide and the like, and/or selected from the group consisting of aliphatic cyclic ethereal solvents, for instance dioxane and the like, and/or from the group consisting of non polar water imm
  • a suitable sulphonating agent selected from but not limited to a group comprising CH 3 SO 2 Z and/or (CH 3 SOi) 2 O 5 wherein Z is selected from the group comprising of halogen atom, preferably chloro, in the presence of a pharmaceutically acceptable organic solvent, preferably selected from aprotic solvents having low polarity, ethereal solvents and/or dipolar aprotic solvents, advantageously a halogenated solvent e.g. dichloromethane, and in the presence or absence of pharmaceutically acceptable organic or inorganic base or by means of a suitable acid acceptor.
  • the acid acceptor is triethylamine.
  • the compound of Formula-IV is prepared in the following manner: reacting N-(4-Nitro-2-phenoxy phenyl) methane sulfonamide, i.e. nimesulide, of Formula-I as herein described as starting material with Q-alkyl-COORs, wherein Q belongs to the class of halo atoms, more specifically, bromo, and alkyl refers to lower alkyl, more preferably from C-I to C-6 atomic number, typically methylene, and R 5 is H and/or lower alkyl selected from but not limited to a group comprising methyl, ethyl, propyl, t-butyl, lower aromatic and the like, in the presence or absence of a suitable physiologically acceptable organic base, for instance, as described herein above and in a suitable organic solvent, for instance dipolar aprotic solvent and also as described herein above so as to furnish the desired compound of Formula-IV.
  • Q belongs to the class of halo atoms, more
  • the compound of Formula-V is prepared in the following manner: reacting N-(4-Nitro-2-phenoxy phenyl) methane sulfonamide of Formula-I or its alkali metal salt, more preferably sodium or potassium, as starting material with Z-OC-CHX-NH 2 (with protected NH 2 group), wherein X is defined above and Z belongs to the class of halo atoms, more preferably chlorine atom, in the absence or presence of an organic aniinic base, more preferably for instance, triethylamine, in a suitable organic solvent, for instance halogenated solvents preferably dichloromethane, and also as described herein above so as to furnish the desired compound represented by Formula-V.
  • Formula- VI is prepared in the following manner: i) reacting 2-phenoxy aniline, an easily available intermediate of nimesulide, with suitable sulphonating agent, for instance, ArSO 2 Z, wherein Ar is selected from but not limited to the group comprising aryl or substituted aryl preferably acetyl amino phenyl, and Z belongs to the class of halogen atoms preferably chlorine atom, in the presence of an organic aminic base for instance triethylamine and the like in a suitable organic solvent for instance aprotic polar solvent, preferably tetrahydrofuran to give sulfonanilide.
  • suitable sulphonating agent for instance, ArSO 2 Z
  • Ar is selected from but not limited to the group comprising aryl or substituted aryl preferably acetyl amino phenyl
  • Z belongs to the class of halogen atoms preferably chlorine atom, in the presence of an organic aminic base for instance triethylamine and the
  • nitration methods known in the art, selected from a group comprising chloroform/nitric acid or in acetic acid/nitric acid or sulphuric acid/nitric acid and the like, so as to get the compound represented by Formula- VI.
  • the compound of Formula- VII is prepared in the following manner: i) A compound of the Formula-X, namely 4-allyl-2-methoxyphenol, when reacted with 2-halonitrobenzene ('halo' being selected from the group consisting of fluoro, bromo, choloro and iodo), in the presence of a base, selected from the group comprising of alkali metal hydroxides and/or mild bases, for example, alkali metal carbonates and/or sodium and/or potassium methoxide, sodium and/of potassium ethoxide, sodium and/or potassium hydride, sodium and/or potassium t- butoxide and the like in the absence or presence of the solvent such as dipolar aprotic solvents, for example dimethylformamide and the like, and/or selected from the group consisting of aliphatic cyclic ethereal solvents, for instance dioxane and the like, and/or from the group consisting of non polar water immisc
  • a suitable sulphonating agent selected from but not limited to a group comprising CH 3 SO 2 Z and/or (CH 3 SO 2 ) 2 O, wherein Z is selected from the group comprising of halogen atom, preferably chloro, in the presence of a pharmaceutically acceptable organic solvent, preferably selected from aprotic solvents having low polarity, ethereal solvents and/or dipolar aprotic solvents, advantageously a halogenated solvent e.g. dichloromethane, and in the presence or absence of pharmaceutically acceptable organic or inorganic base or by means of a suitable acid acceptor.
  • the acid acceptor is triethylamine.
  • the mixture of novel derivatives of the present invention can be in the form of an associate or a complex or inclusion compounds with the pharmaceutically acceptable excipients.
  • a mixture of the novel derivatives and povidone can be in the form of an associate of the novel derivatives with povidone
  • a mixture of novel derivatives and phospholipid can be in the form of a complex
  • a mixture of the derivatives with cyclodextrin can be in the form of an inclusion of the novel derivatives in cyclodextrin.
  • NIM nimesulide
  • NMS chemically known as N-(4-Nitro-2-phenoxyphenyl) methanesulfonyl aniline acetic acid (Formula IV); Acetyl-NMS chemically known as N-(4-Nitro-2- phenoxyphenyl) acetylsulfanilyl aniline (Formula VI) and EUG-NMS chemically known as N-(4-Nitro-2-(4-allyl-2-methoxyphenoxy) phenyl)-methanesulfonamide (Formula VII).
  • a pharmacokinetic study has been carried out to study the analgesic effect of nimesulide derivatives, namely compounds of Formula- III and Formula-IV (wherein R 5 is H) as stated herein against acetic acid-induced writhing in mice.
  • Swiss albino mice (18-22 g) of either sex were selected for the study comprising 5 to 6 animals in each group for the period of 6 hours with sampling intervals of 1, 3 and 6 hours.
  • a dose of 2.5 mg/kg, p.o. of nimesulide and molar equivalent dose of nimesulide derivative was administered through oral route.
  • Acetic acid-induced writhing assay was conducted by carrying out abdominal constriction test in mice. Abdominal constrictions (development of tension in abdominal muscles, elongation of the body and hind limb, arching of back) after 3 minutes of injection of acetic acid (1% v/v, 10 mL kg "1 , i.p.) were recorded in mice as a response to nociceptive stimuli for 20 minutes.
  • Nimesulide (2.5 mg/kg p.o.) or its derivatives described herein as compounds of Formula-Ill also referred to herein as PAR-NMS and Formula-IV (wherein R 5 is H) also referred to herein as ACT-NMS (dose equivalent to nimesulide) were administered Ih, 3h and 6h before acetic acid-challenge in mice.
  • the number of writhes was expressed as mean ⁇ S.E.M. and analyzed by one-way ANOVA followed by Student-Newman-Keuls multiple-range test. PO.05 was considered statistically significant.
  • ACT-NMS & PAR-NMS doses are molar equivalents to nimesulide 2.5 mg/kg. * P ⁇ 0.05 as compared to control group. a PO.05 as compared to nimesulide-treated group.
  • nimesulide derivatives namely compounds of Formula- VI and Formula- VII as stated herein against acetic acid-induced writhing in mice.
  • Swiss albino mice (20-22 g) of either sex were selected for the study comprising 5 to 6 animals in each group.
  • a dose of 4.0 mg/kg, p.o. of nimesulide and molar equivalent dose of nimesulide derivative was administered through oral route, before acetic acid-challenge in mice.
  • mice All the drugs were suspended in 1% v/v Tween80-water and administered in a dose volume of 10ml/kg control animals received 1% v/v Tween80-water in a dose volume of 10nil/kg body weight.
  • Acetic acid-induced writhing assay was conducted by carrying out abdominal constriction test in mice. Abdominal constrictions (development of tension in abdominal muscles, elongation of the body and hind limb, arching of back) after 3 minutes of injection of acetic acid (1% v/v, 10 ml kg "1 , i.p.) were recorded in mice as a response to nociceptive stimuli for 15 minutes, 3 minutes after the administration of acetic acid.
  • Nimesulide (4.0 mg/kg p.o.) or its derivatives described herein as compounds of Formula- VI also referred to herein as Acetyl-NMS and Formula-VII also referred to herein as EUG-NMS (dose equivalent to nimesulide) were administered 0.5h before acetic acid-challenge in mice.
  • the number of writhes was expressed as mean ⁇ S.E.M. and analyzed by one-way ANOVA followed by Student-Newman- Keuls multiple-range test. P ⁇ 0.05 was considered statistically significant.
  • EUG-NMS (4.90) 29.16 ⁇ 1.76 b Acetyl-NMS and EUG-NMS doses are molar equivalents to nimesulide 4.0 mg/kg. * P ⁇ 0.05 as compared to control group. a PO.05, b P ⁇ 0.05 as compared to nimesulide-treated group.
  • nimesulide derivatives namely compounds of Formula- III and Formula- VI as stated herein against lipopolysaccharide (LPS)-induced febrile response in rats.
  • Wistar rats 180-220 g of either sex were selected for the study comprising 3 animals in each group.
  • a dose of 5 mg/kg, p.o. of nimesulide and molar equivalent dose of nimesulide derivative was administered through peroral route.
  • the basal rectal temperature was measured by inserting the rectal probe, a plastic coated thermocouple attached to a thermometer up to 2.2 cm in the rectum of the rat (Tele-thermometer, dual channel, Electronic manufacturing corporation, India).
  • LPS dissolved in saline was injected intraperitoneally in a dose of 100 ⁇ g/rat (Paul et al., 1999) and the rectal temperature was recorded at 1, 2, 3, and 4h. All other drugs were suspended in 0.5% w/v CMC containing Tween 80 (0.1%v/v) and administered per orally in a constant volume of 10 ml/kg body weight, 30 minutes before administration of LPS. Rats injected with LPS displayed a biphasic response.
  • nimesulide derivatives namely compounds of Formula- VI and Formula- VII as stated herein against nimesulide in rats.
  • Wistar rats 140-170 g of either sex were selected for the study comprising 5 animals in each group.
  • a dose of 50 mg/kg (ulcerogenic dose), p.o. of nimesulide and molar equivalent dose of nimesulide derivative was administered through per oral route.
  • the animals are randomly divided into different groups and receive one of the following treatments for 15 days: Nimesulide (50mg/kg), Acetyl-NMS (69.0 mg/kg), EUG-NMS (61.0 mg/kg) and vehicle (10 mg/kg, p.o.).
  • the drugs were suspended in [0.5% CMC containing Tween ⁇ O (1% w/v)] and administered in a constant dose volume of 10ml/kg body weight.
  • the overnight fasted animals were euthanized.
  • the abdomen was cut open to isolate stomach.
  • the stomach was excised from greater curvature and rinsed with saline.
  • the ulceration in the antral region was quantified as per the method of Singh et al., 2005 (Singh VP et al., 2005, Effect of licofelone against NSAID s-induced gastrointestinal ulceration and inflammation, 43:247- 253). Spot ulcers were assigned a score of 1, and lesions were scored according to their length (a score of 5 for lesions with length between 1 and 3 mm; a score of 10 for lesions greater than 3 mm). The sum of total scores was used for comparison. The rats treated with vehicle did not show any inflammation or ulceration of the stomach. Three rats out of five (One each on day 4, 5, and 7) died during treatment with Nimesulide (50.0 mg/kg, po X 15d).
  • nimesulide derivatives namely compounds of Formula-Ill and Formula-IV as stated herein against nimesulide in rats.
  • Wistar rats 140-170 g of either sex were selected for the study comprising 5 animals in each group.
  • a dose of 50 mg/kg p.o. of nimesulide and molar equivalent dose of nimesulide derivative was administered through per oral route.
  • the animals are randomly divided into different groups and receive one of the following treatments for 15 days: Nimesulide (50mg/kg), ACT-NMS (59.35 mg/kg), PAR-NMS (59.19 mg/kg) and vehicle (10 mg/kg).
  • the drugs were suspended in Tween ⁇ O-water (1% w/v) and administered in a constant dose volume of 10ml/kg body weight. On day 16, the overnight fasted animals were euthanized. The abdomen was cut open to isolate stomach. The stomach was excised from greater curvature and rinsed with saline. The ulceration in the antral region was quantified as per the method of Singh et al, 2005 (Singh VP et al., 2005. Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation. 43:247-253).
  • EUG-NMS is a safer and a gastrotolerable compound as it does not cause any ulceration in the stomach as compared to Nimesulide.
  • the present invention provides pharmaceutically acceptable water soluble salt of novel sulfonanilide derivative.
  • a pharmaceutically acceptable salt of compound according to Formula-II refers to a salt formed with a pharmaceutically acceptable organic or inorganic cation and/or base, for example, a salt with alkali metal or an alkaline earth metal, selected from but not limited to a group comprising sodium, potassium, calcium and magnesium and for example a salt with primary, secondary, tertiary and quaternary amines, selected form but not limited to a group comprising mono-, di- and tri-methylamine, propylamine 2-hydroxypropylamide, diethylamine, lysine, arginine, ornithine, N-methylglucamine, triethanolamine, cetylpyridinium, benzalkonium, choline and the like or mixtures thereof.
  • a pharmaceutically acceptable organic or inorganic cation and/or base for example, a salt with alkali metal or an alkaline earth metal, selected from but not limited to a group comprising sodium, potassium, calcium and magnesium and for example a
  • the present invention provides pharmaceutical compositions comprising such novel derivatives having the general Formula-II as stated herein and process of preparation of such compositions.
  • the novel derivatives of the present invention can be easily be formulated into desired pharmaceutical compositions which can be administered orally, parenterally, topically, transdermally, rectally or by any route of administration.
  • the novel derivatives of the present invention possess improved solubility, preferably aqueous solubility, and/or improved bioavailability with reduced adverse effects associated with therapy.
  • the novel derivatives are preferably capable of being administered for longer periods of time, and are highly effective especially for the treatment of inflammation and/or pain or other associated disorders.
  • the dosage form also contains pharmaceutically acceptable excipients known to the art such as but not limited to diluents, disintegrants, binders, preservatives, stabilizers, solubilizers, surfactants, buffers, salts for regulating the osmotic pressure, emulsifiers sweeteners, dyes, flavourings and the like when required for peculiar treatments.
  • pharmaceutically acceptable excipients known to the art such as but not limited to diluents, disintegrants, binders, preservatives, stabilizers, solubilizers, surfactants, buffers, salts for regulating the osmotic pressure, emulsifiers sweeteners, dyes, flavourings and the like when required for peculiar treatments.
  • the novel derivatives represented by compound corresponding to Formula-II can be administered alone or in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention can be administered orally, parenterally or topically and the dosage form can be tablet, capsule, drops, injection, suppository, patch, ointment and the other formulations for oral administration, injection or topical application.
  • the pharmaceutical composition may additionally contain other pharmacologically active ingredient(s) whose concurrent administration may be useful.
  • the pharmaceutical composition can be prepared by well known methods in the art, e.g. by mixing the compound of Formula-II with one or more pharmaceutically acceptable excipient(s) optionally with other active ingredient(s).
  • the solid dosage forms can be produced by known methods such as direct compression, granulation, compaction, extrusion, molding, or the like using conventional excipients such as fillers, binders, disintegrants, glidants, lubricants, or the like, or mixtures thereof.
  • liquid and/or semi-solid excipients known to the art are used.
  • an injectable composition such as an intra- venous or intra-muscular injection
  • the novel derivatives are treated with pharmaceutical excipients such as solvents, buffers, and the like, known to a person skilled in art.
  • the amount of the novel derivatives of the present invention to be incorporated into the pharmaceutical composition of the present invention can vary over a wide range depending on known factors such as, for example, the disorder to be treated, the severity of the disorder, the patient's body weight, the dosage form, the chosen route of administration and the number of administration per day. However, selection of optimum amount is simple and routine for a person skilled in the art. Typically, the amount of product of Formula-II in the pharmaceutical composition of the present invention will range from approximately 5 mg to about 800 mg.
  • the daily posology comprises the administration of an effective amount of derivative represented by the Formula-II preferably at a dose and/or frequency lesser or at least comparative to the dose of nimesulide.
  • the present invention provides a method of using such novel derivatives or pharmaceutical compositions comprising such novel derivatives which comprise administering to a patient in need thereof an effective amount of such novel derivatives or composition thereof.
  • the novel derivatives and the compositions comprising the novel derivatives of the present invention are useful in the treatment of inflammation and/or pain associated with, for example, osteoarthritis, respiratory tract inflammation, postoperative pain, inflammation of the ear, nose and throat, headache, toothache, post-traumatic pain, fever and the like, or other associated disorders.
  • Example 1 Preparation of 4-Nitro-2-[(4"-Acetyl amino)-phenoxy]-methanesulfonyl aniline [Formula-Ill] i) Preparation of 2-(4-Acetylamino-phenoxy)-nitrobenzene (A): I g of p- acetylaminophenol was added to 30 ml of dioxane suspension containing 0.36g of
  • Example 2 Preparation of N-(4-Nitro-2-phenoxy-phenyl) methanesulfonyl aniline acetic acid [Formula-IV]: i) Preparation of N-(4-Nitro-2-phenoxy-phenyl)methanesulfonyl aniline acetic acid t-butyl ester (D): (10 mmol) of Nimesulide was charged into 10 ml of dimethyl acetamide and stirred for 10 minutes at room temperature. (12 mmol) of sodium hydride was charged into the above solution and the solution was agitated for further 20 minutes at room temperature.
  • Example 3 Preparation of N-(4-Nitro-2-phenoxyphenyl) acetylsulfanilyl aniline [Formula- VI]: i) Preparation of N-(2-phenoxyphenyl) acetylsulfanilyl aniline (E): 7 g of 2-phenoxy aniline, 5.67 g of triethylamine and tetrahydrofuron were charged together in a 250 ml assembly.
  • Example 4 Preparation of N-(4-Nitro-2-[(4-allyl-2-methoxyphenoxy) phenyl)- methanesulfonamide [Formula- VII] i) Preparation of 2-(4-allyl-2-methoxyphenoxy)-nitrobenzene (F): 1 g of 4-allyl-2- methoxyphenol was added to 100 ml of dioxane suspension containing 1.8g of 60% sodium hydride at room temperature for about 1 hour. The mixture was heated to
  • step (i) Croscarmellose sodium were sifted through #40 sieve and were mixed together, ii) The blend of step (i) was granulated by using Isopropyl alcohol. iii) The wet mass of step (ii) was sifted through #24 sieve and granules obtained were dried, iv) Hydrogenated castor oil, Purified talc and Colloidal silicon dioxide were sifted through #40 sieve and were mixed together. v) Granules of step (iii) were mixed with the mixture of step (iv). vi) The material of step (v) was compressed into tablets by using a tablet compression machine.
  • step (ii) Crospovidone, and Magnesium stearate were sifted through #40 sieve and were mixed together. ii) The blend of step (i) was compacted and the compacts were passed through #30 sieve, iii) The granules of step (ii) were lubricated with #60 sieve passed Magnesium stearate. iv) The material of step (iii) was filled into hard gelatin capsule.
  • step (v) Specified quantity (10.0 ml) of Sodium hydroxide (NaOH) 4.0% w/v solution was added to the step (iv) with continuous stirring to form a homogeneous solution.
  • step (v) The solution of step (v) was mixed for about 30 minutes by continuous stirring, vii) Remaining quantity of Glycine Buffer pH 11.3 was added to make up volume to
  • step (viii) The solution of step (vii) was mixed for about 10 minutes by continuous stirring, ix) Final pH was adjusted to 10.0 by adding Sodium hydroxide (NaOH) 4.0% w/v solution.
  • step (ix) The solution of step (ix) was mixed for about 10 minutes by continuous stirring.
  • step (v) The material of step (v) was mixed with the material of step (iv) and compressed into tablets.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des dérivés innovants du sulfonanilide, de préférence des dérivés du N-(4-nitro-2-phénoxy-phényl)méthane-sulfonamide, et leurs sels, esters, amides, polymorphes, solvates, hydrates, analogues, énantiomères, formes tautomères ou mélanges pharmaceutiquement acceptables. L'invention concerne également un procédé de préparation de tels dérivés innovants, une composition pharmaceutique qui les comprend et un procédé d'utilisation de telles compositions pour la prophylaxie, l'amélioration et/ou le traitement d'une inflammation et/ou de la douleur et d'autres troubles associés, ledit procédé comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'une telle composition. Les dérivés innovants présentent des caractéristiques améliorées de solubilité, de préférence la solubilité aqueuse, et/ou de biodisponibilité et/ou une réduction des effets secondaires associés au traitement.
PCT/IN2007/000098 2006-03-24 2007-03-09 Dérives innovants du sulfonanilide, compositions pharmaceutiques qui les contiennent et procédés qui les concernent WO2007110876A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102557994A (zh) * 2011-12-15 2012-07-11 天津药物研究院药业有限责任公司 2-苯氧甲烷磺酰苯胺的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3840597A (en) * 1971-02-24 1974-10-08 Riker Laboratories Inc Substituted 2-phenoxy alkane-sulfonanilides
EP1336602A1 (fr) * 2002-02-13 2003-08-20 Giovanni Scaramuzzino Prodrogues nitrées capable de libérer du monoxyde d'azote de manière controlée et sélective ainsi que leur utilisation pour la prévention et le traitement de maladies inflammatoires, ischémiques et proliferatives
WO2004058164A2 (fr) * 2002-12-20 2004-07-15 Tularik, Inc. Modulateurs de l'asthme et de l'inflammation allergique
EP1586557A1 (fr) * 2002-12-31 2005-10-19 Institute of Radiation Medicine, Academy of Military Medical Sciences Pla Derives de 4-nitro-2- (4'-methoxy)-phenoxy]-methanesulfonanilide et leur utilisation a des fins pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3840597A (en) * 1971-02-24 1974-10-08 Riker Laboratories Inc Substituted 2-phenoxy alkane-sulfonanilides
EP1336602A1 (fr) * 2002-02-13 2003-08-20 Giovanni Scaramuzzino Prodrogues nitrées capable de libérer du monoxyde d'azote de manière controlée et sélective ainsi que leur utilisation pour la prévention et le traitement de maladies inflammatoires, ischémiques et proliferatives
WO2004058164A2 (fr) * 2002-12-20 2004-07-15 Tularik, Inc. Modulateurs de l'asthme et de l'inflammation allergique
EP1586557A1 (fr) * 2002-12-31 2005-10-19 Institute of Radiation Medicine, Academy of Military Medical Sciences Pla Derives de 4-nitro-2- (4'-methoxy)-phenoxy]-methanesulfonanilide et leur utilisation a des fins pharmaceutiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102557994A (zh) * 2011-12-15 2012-07-11 天津药物研究院药业有限责任公司 2-苯氧甲烷磺酰苯胺的合成方法

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