WO2001093680A1 - Formes protegees d'une combinaison d'agents pharmacologiquement actifs et leurs utilisations - Google Patents

Formes protegees d'une combinaison d'agents pharmacologiquement actifs et leurs utilisations Download PDF

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Publication number
WO2001093680A1
WO2001093680A1 PCT/US2001/017480 US0117480W WO0193680A1 WO 2001093680 A1 WO2001093680 A1 WO 2001093680A1 US 0117480 W US0117480 W US 0117480W WO 0193680 A1 WO0193680 A1 WO 0193680A1
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Prior art keywords
inhibitor
nsaid
selective cox
subject
compound
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PCT/US2001/017480
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English (en)
Inventor
Ching-San Lai
Tingmin Wang
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Medinox, Inc.
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Priority claimed from US09/586,344 external-priority patent/US6306842B1/en
Application filed by Medinox, Inc. filed Critical Medinox, Inc.
Priority to AU2001275036A priority Critical patent/AU2001275036A1/en
Publication of WO2001093680A1 publication Critical patent/WO2001093680A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Definitions

  • the present invention relates to novel conjugated forms of pharmacologically active agents, and methods for the preparation and use thereof.
  • methods are provided for treating pathological conditions with a protected form of a combination of pharmacologically active agents, thereby reducing the occurrence of side-effects caused thereby.
  • NSAIDs non-steroid anti-inflammatory drugs
  • naproxen e.g., naproxen, aspirin, ibuprofen and ketoprofen
  • NSAIDs can cause gastrointestinal ulcers, a side-effect that remains the major limitation to the use of NSAIDs (see, for example, J. L. Wallace, in Gastroenterol. 112:1000-1016 (1997); A. H. Soil et al., in Ann Intern Med. 114:307-319 (1991); and J. Bjarnason et al., in Gastroenterol. 104:1832-1847 (1993)).
  • enteric coating or slow-release formulations designed to reduce the topical irritant properties of NSAIDs have been shown to be ineffective in terms of reducing the incidence of clinically significant side effects, including perforation and bleeding (see, for example, D. Y. Graham et al., in Clin. Pharmacol. Ther. 38:65-70 (1985); and J. L. Carson, et al., in Arch, ftitern. Med., 147:1054-1059 (1987)).
  • COX cyclooxygenase
  • the prostagladins derived from COX-1 are responsible for many of the physiological effects, including maintenance of gastric mucosal integrity.
  • conjugates of a combination of pharmacologically active agents e.g., NSAIDs and selective COX-2 inhibitors.
  • Invention conjugates e.g., NSAID-COX-2 1
  • provide a new class of pharmacologically active agents e.g., anti-inflamtiiatory agents
  • pharmacologically active agents e.g., anti-inflamtiiatory agents
  • conjugates according to the invention e.g., NSAID-COX-2 i ), including:
  • inventions comprising a conjugate wherein a NSAID is covalently attached to a selective COX-2 inhibitor.
  • invention compounds have the structure:
  • X a non-steroidal anti-inflammatory drug (NSAID)
  • L an optional linker/spacer
  • Y a selective COX-2 inhibitor
  • Invention compounds can be readily prepared in a variety of ways, e.g., by direct reaction of NSAIDs with COX-2 inhibitors, or by indirectly linking NSAIDs to COX-2 inhibitors employing a suitable linker/spacer.
  • linkages including an optional linker
  • linkages e.g., ester linkages, disulfide linkages, amide linkages, in-unine linkages, enamine linkages, ether linkages, thioether linkages, imide linkages, sulfate ester linkages, sulfonate ester linkages, sulfone linkages, sulfonamide linkages, phosphate ester linkages, carbonate linkages, O-glycosidic linkages, S-glycosidic linkages, and the like.
  • linkages can be accomplished using standard synthetic techniques as are well known by those of skill in the art, either by direct reaction of the starting materials, or by incorporating a suitable functional group on the starting material, followed by coupling of the reactants.
  • linker/spacer L has one of the following structures:
  • Z is alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, heterocyclic, substituted heterocyclic, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene or substituted aralkylene, and each W is independently ester, reverse ester, thioester, reverse thioester, amide, reverse amide, phosphate, phosphonate, sulfone, sulfonamide, immine, enamine, or the like.
  • alkylene refers to divalent hydrocarbyl radicals having 1 up to 20 carbon atoms, preferably 2-10 carbon atoms; and "substituted alkylene” comprises alkylene groups further bearing one or more substituents selected from hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano, nitro, nitrone, a ino, amido, -C(O)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and the like.
  • cycloalkylene refers to cyclic ring-containing groups containing in the range of about 3 up to 8 carbon atoms
  • substituted cycloalkylene refers to cycloalkylene groups further bearing one or more substituents as set forth above.
  • heterocyclic refers to cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above.
  • heteroatoms e.g., N, O, S, or the like
  • oxyalkylene refers to the moiety -O-alkylene-, wherein alkylene is as defined above, and "substituted oxyalkylene” refers to oxyalkylene groups further bearing one or more substituents as set forth above.
  • alkenylene refers to divalent, straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkenylene refers to alkenylene groups further bearing one or more substituents as set forth above.
  • alkynylene refers to divalent straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkynylene refers to alkynylene groups further bearing one or more substituents as set forth above.
  • arylene refers to divalent aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted arylene” refers to arylene groups further bearing one or more substituents as set forth above.
  • alkylarylene refers to alkyl-substituted arylene groups and "substituted alkylarylene” refers to alkylarylene groups further bearing one or more substituents as set forth above.
  • arylalkylene refers to aryl-substituted alkylene groups and "substituted arylalkylene” refers to arylalkylene groups further bearing one or more substituents as set forth above.
  • arylalkenylene refers to aryl-substituted alkenylene groups and "substituted arylalkenylene” refers to arylalkenylene groups further bearing one or more substituents as set forth above.
  • arylalkynylene refers to aryl-substituted alkynylene groups and "substituted arylalkynylene” refers to arylalkynylene groups further bearing one or more substituents as set forth above.
  • Diseases and conditions contemplated for treatment in accordance with the present invention include inflammatory and infectious diseases, such as, for example, septic shock, hemorrhagic shock, anaphylactic shock, toxic shock syndrome, ischemia, cerebral ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomeralonephritis, uveitis, ileitis, inflammation (e.g., liver inflammation, renal inflammation, and the like), burn, infection (including bacterial, viral, fungal and parasitic infections), hemodialysis, chronic fatigue syndrome, stroke, cancers (e.g., breast,
  • NSAIDs contemplated for modification in accordance with the present invention include acetaminophen (Tylenol, Datril, etc.), aspirin, ibuprofen (Motrin, Advil, Rufen, others), choline magnesium salicylate (Triasate), choline salicylate (Anthropan), diclofenac (voltaren, cataflam), diflunisal (dolobid), etodolac (Iodine), fenoprofen calcium (nalfon), flurbiprofen (ansaid), indomethacin (indocin, indometh, others), ketoprofen (orudis, oruvail), carprofen, indoprofen, ketorolac tromethamine (toradol), magnesium salicylate (Doan's, magan, mobidin, others), meclofenamate sodium (meclomen), mefenamic acid (relafan), ox
  • Selective COX-2 inhibitors contemplated for modification in accordance with the present invention include celecoxib, rofecoxib, valdecoxib, and the like, as well as analogs, homologs and derivatives thereof.
  • pharmacologically active agents comprising covalently attaching two defined pharmacologically active agents to one another.
  • the resulting conjugate provides a latent form of each of the pharmacologically active agents, releasing the biological activity thereof only when the conjugate is cleaved (e.g., by an esterase, amidase or other suitable enzyme).
  • invention conjugates can be prepared in a variety of ways. See, for example, Scheme 1, wherein a NSAID (1) bearing a carboxylic moiety can be reacted with a hydroxy substituted COX-2 inhibitor (2) under conditions suitable to produce invention conjugate (3).
  • invention conjugates can be prepared from a wide variety of pharmacologically active agents. See, for example, Examples 1- 13 provided herein.
  • NSAIDs for reducing the side effects induced by administration of NSAIDs to a subject, said method comprising covalently attaching a selective COX-2 inhibitor to said NSAID prior to administration to said subject.
  • methods for reducing the side effects induced by administration of selective COX-2 inhibitors to a subject comprising covalently attaching a NSAID to said selective COX-2 inhibitor prior to administration to said subject.
  • methods for enhancing the effectiveness of NSAIDs comprising covalently attaching a selective COX-2 inhibitor to said NS AID.
  • improved methods for the administration of NSAIDs and/or selective COX-2 inhibitors to a subject for the treatment of a pathological condition comprising covalently attaching said NSAID to said selective COX-2 inhibitor prior to administration thereof to said subject.
  • conjugates described herein can be delivered in a variety of ways, such as, for example, orally, intravenously, subcutaneously, parenterally, rectally, by inhalation, and the like.
  • the conjugates contemplated for use herein can be delivered in a variety of pharmaceutically acceptable forms.
  • the conjugate can be delivered in the form of a solid, solution, emulsion, dispersion, micelle, liposome, and the like.
  • physiologically active composition(s) comprising invention conjugates in a suitable vehicle rendering said conjugates amenable to oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, nasal delivery, and the like.
  • Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the conjugates of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • Invention conjugates may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • Invention conjugate is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing invention conjugate may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing inventon conjugate in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • formulations for oral use may be in the form of hard gelatin capsules wherein invention conjugate is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein invention conjugate is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • Conjugates contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the drag.
  • These compositions may be prepared by mixing invention conjugate with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drag.
  • the dosage of invention conjugate employed as described herein falls i the range of about 0.01 mmoles/kg body weight of the subject/hour up to about 0.5 mmoles/lcg/hr.
  • Typical daily doses lie within the range of from about 10 ⁇ g up to about 100 mg per kg body weight, and, preferably within the range of from 50 ⁇ g to 10 mg per kg body weight and can be administered up to four times daily.
  • the daily IV dose lies within the range of from about 1 ⁇ g to about 100 mg per kg body weight, and, preferably, within the range of from 10 ⁇ g to 10 mg per kg body weight.
  • improved methods for the treatment of a subject suffering from a pathological condition by administration thereto of a NSAID and/or a selective COX-2 inhibitor comprising covalently attaching said NSAID to said selective COX-2 inhibitor prior to administration thereof to said subj ect.
  • invention method for the treatment of a subject afflicted with a pathological condition comprises administering to a subject an effective amount of a modified pharmacologically active agent, wherein said pharmacologically active agent is a NSAID or a selective COX-2 inhibitor, and is effective for treatment of said condition, and wherein said pharmacologically active agent has been modified by the covalent attachment thereto of a NSAID or a selective COX-2 inhibitor.
  • Example 3 Compound 8 (Scheme 2).
  • Compound 8 is prepared as described in the general procedure above for compound 3 from naproxen (2.30g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 8 with a yield from 50% to 80%.
  • Compound 10 (Scheme 3).
  • Compound 10 is prepared as described in the general procedure above for compound 3 from ibuprofen (2.06g, 10 mmol), compound 5 (3.30g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol).
  • the compound is purified by column chromatography on a silica gel column to give compound 10 with a yield from 50% to 80%.
  • Compound 11 (Scheme 3). Compound 11 is prepared as described in the general procedure above for compound 3 from ibuprofen (2.06g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 11 with a yield from 50% to 80%.
  • Compound 14 (Scheme 4).
  • Compound 14 is prepared as described in the general procedure above for compound 3 from ketoprofen (2.54g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol).
  • the compound is purified by column chromatography on a silica gel column to give compound 14 with a yield from 50% to 80%.
  • Example 8 The synthesis described in this and the following example is illustrated in
  • Compound 16 (Scheme 5). Compound 16 is prepared as described in the general procedure above for compound 3 from diclofenac (2.96g, 10 mmol), compound 5 (3.30g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 16 with a yield from 50% to 80%.
  • Compound 17 (Scheme 5). Compound 17 is prepared as described in the general procedure above for compound 3 from diclofenac (2.96g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 17 with a yield from 50% to 80%.
  • Example 10 The synthesis described in this and the following example is illustrated in
  • Compound 19 (Scheme 6).
  • Compound 19 is prepared as described in the general procedure above for compound 3 from flurbiprofen (2.44g, 10 mmol), compound 5 (3.3g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 19 with a yield from 50% to 80%.
  • Example 11 Compound 20 (Scheme 6).
  • Compound 20 is prepared as described in the general procedure above for compound 3 from flurbiprofen (2.44g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol). The compound is purified by column chromatography on a silica gel column to give compound 20 with a yield from 50% to 80%.
  • Compound 22 (Scheme 7).
  • Compound 22 is prepared as described in the general procedure above for compound 3 from aspirin (1.80g, 10 mmol), compound 5 (3.30g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol).
  • the compound is purified by column chromatography on a silica gel column to give compound 22 with a yield from 50% to 80%.
  • Compound 23 (Scheme 7).
  • Compound 23 is prepared as described in the general procedure above for compound 3 from aspirin (1.80g, 10 mmol), compound 6 (3.29g, 10 mmol), DMAP (0.24g, 2 mmol) and DCC (2.06g, 10 mmol).
  • the compound is purified by column chromatography on a silica gel column to give compound 23 with a yield from 50% to 80%.
  • Wistar rats 200-250 grams, male are fasted overnight but allowed free access to water. Ten rats in each group are given naproxen, selective COX-2 inhibitor or an invention conjugate thereof orally at doses of 10, 20 or 50 mg/kg. The rats are sacrificed five hours later and the visible gastric damage is assessed by examining under microscope and by bistological evaluation.
  • invention conjugate produces the least visible gastric lesions, compared to the lesions induced by either naproxen or COX-2 inhibitor alone. This is attributed to the stability and inactivity of the invention conjugate in the stomach, thereby reducing local irritation and damage.
  • Wistar rats male, 200-250 grams are fasted overnight but allowed to free access to drinking water.
  • Naproxen, selective COX-2 inhibitor or an invention conjugate thereof is given orally at a dose of 1, 10 or 30 mg/kg (6 animals per group).
  • the rats are anesthetized and 0.1 ml of lambda carrageenan (0.1% solution) is injected into the right hind foot pad.
  • the volume of the pad is measured by hydroplethysmometry every hour for the next five hours.
  • the control group (given saline orally) shows a time-dependent increase in the volume of the footpad to near 0J- 1.0 ml at the five-hour time point.
  • all three treated groups reveal a dose-dependent reduction of the volume of the footpad.
  • Wistar rats male, 200-250 grams are fasted overnight but allowed free access to drinking water. The rats are anesthetized and their backs are shaved. After an incision to the back, a sponge (2.5 x 1 x 0.5 cm) soaked with 2 ml of 0.5% carrageenan is implanted. Five hours later, the rats (6 animals in each group) are given orally naproxen, selective COX-2 inhibitor or an invention conjugate thereof at a dose of 30 mg/kg or vehicle control. One hour later, the rats are sacrificed and the sponge is carefully removed. The exudate is recovered from the sponge and the prostaglandin E2 level in the exudate is measured by enzyme-linked immunosorbent assay.
  • the prostaglandin levels in the recovered exudates increase with time from 300 pg/ml to over 3000 pg/ml.
  • all three treated groups show substantial decreases in prostaglandin levels.
  • the increase in prostaglandin levels is indicative of inflammatory reaction.
  • the results suggest that the invention conjugate is cleaved in vivo, thereby releasing both naproxen and COX-2 inhibitor and exerting anti-inflammatory activities.
  • Example 17 The effects of the conjugate of naproxen and selective COX-2 inhibitor on chronic hindlimb inflammation in the rat adjuvant arthritis model
  • Lewis male rats (175 - 250 grams) are injected intradermally in the footpad with M. tuberculosis powder suspended in mineral oil at 5 mg/ml. Rats are dosed daily by oral gavage with 5 ml/kg of naproxen or selective COX-2 inhibitor at 1 and 10 mg/kg or equimolar doses of invention conjugate on days 5-8 and 11-14. Progressive swelling of the uninjected paw and ankle joint between days 11 and 15 are measured by plethysmometry.

Abstract

L'invention concerne des conjugués d'une combinaison d'agents pharmacologiquement actifs (des AINS et des inhibiteurs sélectifs de COX-2, par exemple). Les conjugués de l'invention donnent une nouvelle classe d'agents pharmacologiquement actifs (des agents anti-inflammatoires, par exemple) qui possèdent les avantages thérapeutiques offerts à la fois par AINS et par les inhibiteurs sélectifs de COX-2. Il est généralement observé que les effets secondaires découlant de l'usage de tels agents étaient considérablement inférieurs du fait de l'effet de protection apporté par la modification desdits agents.
PCT/US2001/017480 2000-06-02 2001-05-30 Formes protegees d'une combinaison d'agents pharmacologiquement actifs et leurs utilisations WO2001093680A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7163958B2 (en) 2002-07-03 2007-01-16 Nitromed Inc. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7244753B2 (en) 2002-07-29 2007-07-17 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2009037705A2 (fr) * 2007-09-20 2009-03-26 Ramot At Tel Aviv University Ltd. Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
EP2040699A2 (fr) * 2006-06-19 2009-04-01 Vanderbilt University Medical Center Méthodes et compositions de diagnostic et de ciblage thérapeutique de cox-2
CN101954084A (zh) * 2010-09-06 2011-01-26 北京大北农动物保健科技有限责任公司 一种治疗畜禽混合感染的药物组合物及其制备方法
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US9346803B2 (en) 2011-10-17 2016-05-24 Vanderbilt University Indomethacin analogs for the treatment of castrate-resistant prostate cancer
EP3693022A3 (fr) * 2015-01-09 2020-09-16 Reiley Pharmaceuticals, Inc. Conjugués contenant du platine et ciblant cox-2 et leur utilisation dans le traitement de tumeurs et de cancers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5603959A (en) * 1994-03-01 1997-02-18 Scotia Holdings Plc Fatty acid derivatives
US5607966A (en) * 1994-12-23 1997-03-04 Alcon Laboratories, Inc. Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory prodrugs
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5603959A (en) * 1994-03-01 1997-02-18 Scotia Holdings Plc Fatty acid derivatives
US5607966A (en) * 1994-12-23 1997-03-04 Alcon Laboratories, Inc. Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory prodrugs
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents

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US7244753B2 (en) 2002-07-29 2007-07-17 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
US8618169B2 (en) 2002-10-21 2013-12-31 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
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WO2009037705A3 (fr) * 2007-09-20 2009-07-09 Univ Ramot Méthodes et compositions utiles pour le traitement du cancer et de l'inflammation
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
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