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  • A61K31/47—Quinolines; Isoquinolines
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  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

• the invention relates generally to substituted tetracyclic benzamide derivatives and more particularly to indeno[1,2-c]isoquinoline.
• Inflammation disorders such as arthritis, colitis, and autoimmune diabetes
• inflammation and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis.
• pro-inflammatory cytokines can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO ⁇ ) (Szab ⁇ acute over (o ) ⁇ et al., Shock 6:79-88, 1996).
• the peroxynitrite-induced cell necrosis observed in inflammation and reperfusion injury involves, in significant part, the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS).
• PARS nuclear enzyme poly
• Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabó et al., Trends Pharmacol. Sci. 19: 287-98, 1998).
• indeno[1,2-c]isoquinoline derivatives are known in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al., J. Med. Chem., 43:3688-3698, 2000; Cushman et al., J. Med. Chem. 42:446-57, 1999; indeno[1,2-c]isoquinoline as antineoplastic agents are reported in Cushman et al., WO 99/23900; neoplasm inhibitors are disclosed in Hrbata et al., WO/9305023.
• the invention is based in part on the discovery of novel substituted tetracyclic benzamide derivatives and their unexpected effects in inhibiting inflammation, cell death and in treating shock and reperfusion injuries.
• the invention includes an indeno[1,2-c]isoquinoline derivative according to Formula I and Formula II, as set forth in the Detailed Description of the Invention, below.
• Also provided by the invention is a method of treating inflammatory and reperfusion conditions in mammals by administering to a mammal in need of such treatment an effective amount of a compound according to Formula I or Formula II.
• the invention also includes a method for the production of a compound according to Formula I or Formula II.
• the substituted indeno[1,2-c]isoquinoline compounds described in the current invention are potent compounds that can be used to treat a variety of conditions and diseases, typically those known to involve inflammatory mediator production and cell death.
• the present invention provides a novel class of substituted indeno[1,2-c]isoquinoline derivatives according to Formula I and Formula II, as set forth below:
• the present invention relates to a compound of Formula I, wherein:
• R 5 is O, N or S:
• R 6 is H or straight chain alkyl:
• X is CO, CH 2 , CH-Halo, CH(CH 2 ) n OH, aryl-C—OH, O, NH, S or CH—NR 11 R 12 ;
• n is zero or a positive integer
• R 11 and R 12 are, independently, H, C 1 -C 9 alkyl, or, taken together, N, R 11 , and R 12 form an optionally-substituted heterocycle including, but not limited to, piperidine, piperazine, and morpholine;
• R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are, independently, hydrogen, halo, alkylhalo, hydroxy, alkoxy, C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl group, C 3 -C 9 carbocyclic, aryl, alkylamino, amino, carboxy, ester, arylalkyl, nitro or A-B;
• A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, O, CO, OCO, CONH, NH, CH 2 , S or CS;
• B is C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl group, heterocycle, C 3 -C 8 carbocycle, aryl, amino, aminoalkyl, aminodialkyl, heterocyclic amine, alkylheterocycle, arylamido, carboxy, ester, or an arylalkyl group, any of which may be optionally substituted with one or more of alkoxy, halogen, alkylhalo, alkylhydroxy, alkylamino, hydroxy, nitro, amino, aminoalkyl, aminodialkyl, heterocyclic amine, C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl, C 2 -C 10 straight or branched chain alkynyl, aryl, benzyl, alkylamido, alkylcarboxy, alkylester, arylalkyl, or
• B is NZ 1 Z 2 , where Z 1 and Z 2 are, independently, H, or C1-5 alkyl, optionally-substituted with halo, OH or NZ 3 Z 4 , where Z 3 and Z 4 are independently, H or C1-C5 alkyl optionally-substituted with halo, OH or amino.
• NZ 1 Z 2 forms a heterocyclic amine.
• NZ 3 Z 4 forms an optionally-substituted heterocyclic amine.
• heterocyclic amines include, but are not limited to, piperidine, piperazine, morpholine, N-alkylated or alkylcarbonylated piperazines, pyrole, imidazole, benzimidazole, tetrazoles, indole, isoquinoline, quinoline, pyrrolidine and purine.
• heterocyclic amines formed by either NZ 1 Z 2 or NZ 3 Z 4 may be further substituted with one or more of alkoxy, halogen, alkylhalo, alkylhydroxy, alkylamino, hydroxy, nitro, amino, aminoalkyl, aminodialkyl, heterocyclic amine, C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl, C 2 -C 10 straight or branched chain alkynyl, aryl, benzyl, alkylamido, alkylcarboxy, alkylester, arylalkyl, or a heterocycle or C 3 -C 8 carbocycle optionally further substituted with alkyl, alkoxy, halogen, alkylhalo, alkylhydroxy, alkylamino, hydroxy, nitro or amino functionalities.
• the invention also relates to a compound of Formula II
• R 1 , R 4 , R 7 , and R 10 are hydrogen
• R 2 and R 3 are hydrogen, halo, alkylhalo, hydroxy, alkoxy, C1-C3 straight or branched chain alkyl, nitro, amino, amido, carboxy, or ester;
• R 8 and R 9 are either hydrogen or A-B; and A is —SO 2 —, —SO 2 NH—, or —NHCO, B is C 1 -C 3 straight or branched chain alkyl, heterocycle, amino, aminoalkyl, aminodialkyl, or heterocyclic amine, optionally substituted with one or more of alkylhydroxy, alkylamino, aminoalkyl, aminodialkyl, heterocyclic amine, or a heterocycle optionally further substituted with alkyl, or alkyl hydroxy.
• B is NZ 1 Z 2 , where Z 1 and Z 2 are, independently, H, or C1-3 alkyl optionally substituted with OH or NZ 3 Z 4 , where Z 3 and Z 4 are independently, H or C1-C3 alkyl optionally substituted with OH or amino.
• Z 1 and Z 2 are connected, NZ 1 Z 2 forms a heterocyclic amine.
• NZ 3 Z 4 forms an optionally substituted heterocyclic amine.
• Such a heterocyclic amine includes, but is not limited to, piperidine, piperazine, morpholine, N-alkylated or alkylcarbonylated piperazines, pyrrolidine, and imidazole.
• NZ 1 Z 2 or NZ 3 Z 4 is a heterocycle
• said heterocycle may be further substituted with alkyl, alkylhydroxy, or alkylamino.
• the invention also includes a pharmaceutical composition that includes a compound according to Formula I or Formula II and a pharmaceutically acceptable carrier.
• the invention includes a compound according to Formula I or Formula II when provided as a pharmaceutically acceptable prodrug, hydrated salt, such as a pharmaceutically acceptable salt, or mixtures thereof.
• Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid to produce “pharmaceutically-acceptable acid addition salts” of the compounds described herein. These compounds retain the biological effectiveness and properties of the free bases.
• Representative salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2′-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate
• the invention also includes a method of inhibiting poly(ADP-ribose) synthase activity (PARS) in a cell.
• This enzyme which is also known as poly(ADP-ribose)synthetase and PARP (poly(ADP-ribose) polymerase, EC 2.4.99), and ADP-ribosyltransferase (ADPRT, EC 2.4.2.30), is a nuclear enzyme that catalyzes a transfer of the ADP ribose moiety of NAD+ to an acceptor protein.
• the method includes contacting the cell with a compound of Formula I in an amount sufficient to inhibit poly (ADP)-ribose-synthase in the cell.
• a compound of Formula I in an amount sufficient to inhibit poly (ADP)-ribose-synthase in the cell.
• any cell having, or capable of having, PARS activity can be used.
• the cell can be provided in any form as long as it is accessible to the compound.
• the cell can be provided in vitro, ex vivo, or in vivo.
• PARS activity can be measured using any method known in the art, e.g., methods as described in Banasik et al., J. Biol. Chem. 267:1569-75 (1991).
• inflammation can be associated, e.g., with an inflammatory disease.
• Inflammatory diseases refer to diseases or conditions where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation.
• diseases and conditions include: transplant rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, including
• a systemic inflammation of the body exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
• shock can be induced, e.g., by a chemotherapeutic agent used cancer chemotherapy.
• the invention also includes a method of treating, preventing, or otherwise inhibiting reperfusion injury in a subject in need of treatment, prevention, or inhibition thereof.
• the method includes administering a compound of Formula I in an amount sufficient to inhibit reperfusion injury in the subject.
• Reperfusion refers to the process whereby blood flow in the blood vessels is resumed after blood flow has been interrupted, such as occurs following constriction or obstruction of the vessel.
• Reperfusion is typically associated with ischemia and may result following a naturally occurring episode, such as a myocardial infarction or stroke, or during a surgical procedure where blood flow in vessels is purposely or unintentionally blocked off.
• the subject treated by the compounds of the invention can be, e.g., a mammal, e.g., a human, mouse, rat, dog, cat, horse, cow, pig, or non-human primate.
• Administration can be systemic or topical, and can be prophylactic or therapeutic.
• the subject is treated with a pharmacologically effective amount of a compound of the invention.
• pharmacologically effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
• the invention also includes pharmaceutical compositions suitable for inhibiting or preventing inflammation or reperfusion injury, PARS activity, or more than one of these activities.
• compositions are preferably suitable for internal use and include an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
• the compounds are especially useful in that they have very low, if any toxicity.
• the compounds or their pharmaceutically acceptable salts are administered in amounts which will be sufficient to inhibit ischemic or inflammatory conditions or diseases and/or prevent the development of inflammation or inflammatory disease in animals or mammals, and are used in the pharmaceutical form most suitable for such purposes.
• Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, or topical administration modes.
• compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
• injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, preferably in unit dosages and consistent with conventional pharmaceutical practices.
• they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
• Preferred pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient, or the pharmaceutically acceptable salt thereof, together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,
• Liquid, particularly injectable compositions can, for example, be prepared by dissolving, dispersing, etc.
• the active compound is dissolved in or mixed with a pharmaceutically pure solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form the injectable isotonic solution or suspension.
• a pharmaceutically pure solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form the injectable isotonic solution or suspension.
• the active compound defined above may be also formulated as suppositories which are advantageously prepared from fatty emulsions or suspensions; using for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
• the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
• a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564.
• Active compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
• One approach for parenteral administration employs the implantation of a slow-release or sustained-released systems, which assures that a constant level of dosage is maintained, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.
• compositions may be sterilized and/or contain minor amounts of non-toxic adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances such as for example, sodium acetate, triethanolamine oleate, etc.
• non-toxic adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances such as for example, sodium acetate, triethanolamine oleate, etc.
• non-toxic adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances such as for example, sodium acetate, triethanolamine oleate, etc.
• they may also contain other therapeutically valuable substances.
• compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and of the above pharmaceutical compositions may contain 0.1 to 99%, preferably 1 to 70% of the active compounds, especially compounds of the Formula I as active ingredients.
• the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
• An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
• Oral dosages of the present invention when used for the indicated effects, will range between about 0.05 to 1000 mg/day orally.
• the compositions are preferably provided in the form of scored tablets containing 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 and 1000.0 mg of active ingredient.
• Effective plasma levels of the compounds of the present invention range from 0.002 mg to 50 mg per kg of body weight per day.
• Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Other preferred topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of active ingredient would range from 0.1% to 15%, w/w or w/v.
• 5,6-Dihydro-5-oxo-11H-indeno-[1,2-c]isoquinoline (6) is prepared by reduction of 5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline (2) or (1)11-hydroxy-5,6-dihydro-5-oxo-11H-indeno[1,2-c]isoquinoline (3a) using CF 3 COOH/triethylsilane.
• Method I To a stirred solution of the alcohol 3a (0.35 g, 1.4 mmol) in trifluoroacetic acid (10 mL), was added at room temperature triethylsilane (0.812 g, 7 mmol) and the reaction mixture was stirred for 24 h. Trifluoroacetic acid was evaporated under vacuo and EtOAc was added to the crude product. The resulting solid was filtered and washed with H 2 O and EtOAc to give the desired product 6 (0.285 g, 87%).
• Method II To a stirred suspension of 2 (40 g, 0.16 mol) in trifluoroacetic acid (2.5 L) was added triethylsilane (94 g, 0.8 mol) in small portions at room temperature and the reaction mixture was stirred for 96 h until the disappearance of the starting material (monitored by TLC, 5% MeOH/CH 2 Cl 2 ). The reaction mixture was slowly poured on ice and filtered and washed with copious amounts of H 2 O and MeOH and dried under vacuo to give the desired product 6 (33.1 g, 88%). The product gave identical spectral data with 6 obtained from Method I.
• Method I To a stirred suspension of 3-(4-morpholino)-1-propylamine (17.28, 0.12 mol) in EtOAc was added sat. aq. NaHCO 3 (300 mL) and stirred for 15 min, where 7 (4.0 gm, 0.012 mol) was introduced in small portions at room temperature. The reaction mixture was stirred for 24h, filtered and washed with H 2 O, EtOAc and MeOH. Then it was boiled in MeOH for 30 min. and was filtered while still warm and washed with MeOH to give the desired product 8l as a free base (2.330 gm, 44%).
• Free base 8l was added to methanesulphonic acid at 0° C. and the resulting mixture was allowed to come to room temperature, after which it was stirred for 2 h. The reaction mixture was then poured into cold MeOH (between ⁇ 10° C. and 0° C.) and the precipitated product was filtered, washed with MeOH (100 mL) and dried in vacuo. The dried solid was then dissolved in water ( ⁇ 200 mL) and lyophilized to give the desired methanesulphonate monohydrate salt 8l. (1.020 gm, 84%).
• Peroxynitrite was diluted in phosphate buffered saline (PBS) (pH 11.0) and added to the cells in a bolus of 50 ⁇ l. Cells were then incubated for 20 min. Peroxynitrite (decomposed by incubation for 30 min at pH 7.0) was used as a control, and failed to influence the parameter studied.
• PBS phosphate buffered saline
• the potency of inhibition on purified PARP enzyme was subsequently determined for selected compounds, and the potency was compared with that of 3-aminobenzamide, a prototypical benchmark PARP inhibitor.
• the assay was performed in 96 well ELISA plates according to instructions provided with a commercially available PARP inhibition assay kit (Trevigen, Gaithersburg, Md.). Briefly, wells were coated with 1 mg/ml histone (50 ⁇ l/well) at 4° C. overnight. Plates were then washed four times with PBS and then blocked by adding 50 ⁇ l Strep-Diluent (supplied with the kit). After incubation (1 h, room temperature), the plates were washed four times with PBS.
• This assay (the oxidant-stimulated thymocyte) represents an in vitro model of a situation where cells are dying because of exposure to pro-oxidant species, as it occurs in during the reperfusion of ischemic organs.
• TABLE 2 Reduction of peroxynitrite induced cytotoxicity by 30 nM-3 ⁇ M of the PARS inhibitor compound 81. +81 +81 +81 +81 +81 Control 30 nM 100 nM 300 nM 1 ⁇ M 3 ⁇ M Cyto-toxicity 98% 74% 39% 2% 0% 0%
• mice were pretreated with intraperitoneal injection of 0.1 and 1 mg/kg of compounds 8l, 8p and 8j, and LPS at 10 mg/kg was injected i.p., and TNF-alpha was measured in the plasma at 90 minutes. As shown in Table 3, all compounds substantially reduced TNF production, indicative of an anti-inflammatory activity.
• LPS causes multiple organ dysfunction resembling of septic shock, and ultimately death (in part because of the early release of TNF-alpha).
• CLP cecal ligation and puncture
• the live bacteria that derive from the intestinal flora induce systemic inflammation and shock.
• Agents that inhibit inflammatory mediator production, PARS activation, and cell death in this model will prevent mortality induced by LPS or CLP.
• injection of 100 mg/kg LPS intraperitoneally caused death in 50% of the animals over 24h, whereas treatment of the animals with 3 mg/kg/day of compound 8l reduced the endotoxin-induced mortality to 10% under the same experimental conditions.
• compound 8l In response to CLP induced shock, compound 8l (3 mg/kg/day) caused an improvement in the mortality from 100% death to 60% death over 24 hours.

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