Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the invention relates to quinic and shikimic acid derivatives. More specifically, the invention relates to amide derivatives of quinic acids and shikimic acids and to methods for their use as anti-inflammatory agents.
• Non-steroidal anti-inflammatory agents are prescribed to patients at a rate of approximately 70 to 100 million prescriptions a year. Approximately 30+ billion dollars are spent each year for the purchase of anti-inflammatory agents, and researchers are continually searching for new and better anti-inflammatory compositions.
• a significant percentage of human disease is considered to be "inflammatory disease” or is considered to have a significant inflammatory component as part of the causation or progression of the disease.
• Inflammatory diseases may affect any organ system, and although they may be more prevalent in older individuals, particular races, or may be more common in one gender, they can affect anyone.
• These diseases include neurodegenerative disorders, asthma, hepatitis, acute respiratory disorder (ARD), chronic obstructive pulmonary disease (COPD), hepatitis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, nephritis, glomerulonephritis, ischemia/reperfusion injury, septic shock, and sarcoidosis, just to name a few.
• ARD acute respiratory disorder
• COPD chronic obstructive pulmonary disease
• rhepatitis rheumatoid arthritis
• inflammatory bowel disease multiple sclerosis
• nephritis glomerulonephritis
• ischemia/reperfusion injury ischemia/reperfusion injury
• septic shock and sarcoidosis
• compositions which may be described as analogs of quinic acid, those analogs having a structure as in Formula I
• R 3 is absent and a double bond links carbons 1 and 6 of the ring.
• Fig. 1 is a scheme (Scheme 1) describing the synthesis of amides of the present invention. Amide groups for individual compounds are indicated by -NH-R 1 , and R 1 is shown for each corresponding compound synthesized.
• Fig. 2 is an alternate scheme (Scheme 2) for the synthesis of compound KZ-
• Fig. 3 is a scheme (Scheme 3) for the synthesis of compound KZ-09 and the heterocyclic amine-substituted KZ-45.
• Fig. 4 is a scheme (Scheme 4) for the synthesis of compounds of the present invention.
• Fig. 12 is a graph illustrating the levels of analog KZ-41 when provided orally (PO) or by intravenous administration (IV). Unlike native or synthetic quinic acid, which is degraded by enzymes produced by bacteria in the intestines, KZ-41 is not degraded and is available for absorption into the circulation.
• Quinic acid may be synthesized by methods previously described in the literature, or may be isolated from a variety of plant extracts, such as Cat's Claw extract. These extracts have previously been shown to have anti-inflammatory properties. Subsequent research demonstrated that a significant portion of this activity is attributable to the quinic acid portion of the plant extract. Extracts have been used therapeutically for a variety of diseases including allergy, arthritis, chemotherapy side effects, cancer, bacterial/fungal infections, gastrointestinal inflammation and gastric ulcers. Oral administration of a hot water Cat's Claw extract, C-Med-100 ® enhanced all leukocyte
• the compounds may be administered orally to provide levels of compound in the tissue similar to, or better than, that produced by intravenous (IV) administration. These properties make the compounds attractive options for therapeutic use as anti-inflammatory agents.
• IV intravenous
• the compounds are relatively easy to synthesize, and the inventors have found more than one approach for their synthesis, using combinations of steps for molecular rearrangements or the addition of functional groups generally known to those of skill in the art, as shown in the accompanying figures.
• synthesis of quinic acid analogs of the invention was performed by first forming the lactone. To the quinic acid starting material was added PTSA in refluxing benzene and DMF. To form the various individual analogs, the lactone was allowed to react with a variety of amines (see Fig. 1, R groups) in acetic acid at 85°C, as indicated in Fig. 1.
• Schemes for synthesis of additional compounds are described in Fig. 5 (Scheme 5). Briefly, compounds may be synthesized as shown, using chemistry previously described by Kaila, et al (Kaila, N., et al., (2005) J. Med. Chem. 48: 4346-4357), but with the addition of the indicated amines to improve the effects and the resistance to bacterial enzyme degradation.
• R 1 and R 2 are each independently hydrogen, straight or branched alkyl, cycloalkyl, aryl, benzyl, arylalkyl, heterocyclic amine, aminoalkyl, ketone, or
• R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or hydroxyl.
• R 1 and R 2 form a piperidine ring with N, and in another aspect of the invention is a compound such as compound KZ-41 wherein when R 1 or R 2 is hydrogen, the other of R 1 or R 2 is alkyl.
• the alkyl is -C 3 H 7 and each of R 3 -R 6 is hydroxyl.
• the ketone may be and each of R 3 -R 6 may be hydroxyl.
• Compounds of the invention may also comprise compounds of Formula I
• R 3 is substituted with as well as compounds of Formula where R 3 is absent and a double bond exists between carbons 1 and 6 of the ring.
• Compounds of the present invention may conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient.
• Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. Such methods and ingredients may be found in Remington's Pharmaceutical Sciences (Alfonso Gennaro et al., eds., Lippincott, Williams & W ⁇ lkins, Baltimore, Maryland, 20 th ed., 2000).
• the compounds and compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, or rectally.
• the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers, for example.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 100% of the weight of a given unit dosage form.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
• the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
• a liquid carrier such as a vegetable oil or a polyethylene glycol.
• Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the preparation of sterile injectable or infusible solutions or dispersions.
• the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
• Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients described above, followed by filter sterilization.
• the present compounds may be applied in pure form in liquid compositions or administered as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
• Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art (for example, see U.S. Pat. No. 4,938,949).
• Another aspect of the invention is a method for administering to a human or animal patient a compound of the invention to provide an anti-inflammatory effect.
• Compounds of the invention have demonstrated anti-inflammatory effects both in vivo and in vitro. Of the compounds tested, several demonstrated efficacy for inhibiting NF-kB activity, with the N-propyl amide substitution (designated KZ-41) being especially effective.
• Compounds of the invention also demonstrated efficacy in decreasing leukocyte adhesion, as well as decreasing the levels or activity of a variety of cytokines known to contribute to inflammatory disease or diseases having a significant inflammatory component.
• NF-kB The effects of the synthesized quinic acid analogs on NF-kB activity were assessed using a cell-based high-throughput screening system comprising A549 cells stably transfected with a plasmid containing a secreted alkaline phosphatase (SEAP) reporter gene driven by an NF-kB response element.
• SEAP secreted alkaline phosphatase
• NF-kB Upon TNF-alpha stimulation, NF-kB translocates to the nucleus and binds the kappaB response element, causing transcriptional activation. This activation drives production of the SEAP reporter, which can be measured in the cell culture supernatant as a surrogate marker for NF-kB.
• a circular section of the skin on one side of the skin fold, along with its cutaneous tissue and fascia was incised through the window of the assembly to expose the blood vessels and the striated muscle of the opposing skin of the dorsal skin fold.
• Antibiotic ointment containing bacitracin zinc, polymyxin B sulfate and neomycin sulfate was applied to the edges of the incised wound and a glass window fixed with a snap ring on top of the exposed area inside the dorsal skin fold assembly.
• Animals received buprenorphine (s.c. 0.1 mg/kg) immediately following surgery and every 12 hours for 48 hours for pain.
• a seed culture in 100 mL of medium was done overnight and transferred to 5 liters of fresh medium in a table top shaker incubator and cultivated for 12 hr under aeration.
• Harvested cells were suspended in medium (5 mM potassium phosphate and pH 6.5) and centrifuged to pellet cells. Cells were stored without freezing.
• Cell suspensions were prepared by homogenizing harvested cells at a ratio of 10 g of wet cells per 10 mL of 5 mM potassium phosphate, pH 6.5. Cell suspensions were passed twice through a French pressure cell press.
• Intact cells were removed by low speed centrifugation and the cell-free extract was further centrifuged (68,000 x g for 90 min) to separate the membrane and cytoplasmic soluble fraction. The membrane fraction was washed by homogenizing the precipitate in buffer and centrifugation repeated.
• a Waters Nova-Pak ® Ci 8 3 mm (2.1 x 50 mm) column protected by a 2-cm Cis guard column maintained at ambient temperature was used in the analysis.
• the mobile phase A consisted of 0.5% ammonia in water and mobile phase B consisted of 0.5% ammonia in acetonitrile.
• the flow rate was set at 0.3 mL/min with a gradient from 60% to 40% A in 4 min, isocratic for 3 min, then returned to 40% in 2 min.
• MS/MS analysis was performed using a Sciex ® API 3000 triple quadrupole mass spectrometer (Applied Biosystems, Foster City, CA).
• the mass spectrometry system was operated with turbo ionspray ionization source under negative ion mode.
• the spray needle voltage was set at 5,000 V, with the turbo gas temperature set at 400 ⁇ C, and the declustering potential set at 60 V.
• samples were analyzed using a Ql scan for product ion identification, a product ion scan for characterization of metabolites or enzymatic products and by using multiple-reaction monitoring (MRM) for quantitation of QA. Quantitation was performed using one set of MRM transitions: parent QA ions (MH " /191) ® selective daughter ions m/z 127.
• a switch valve was used before the mass spectrometer to remove buffer matrix in the sample. The peak areas, peak ratios, linear regression, assayed concentrations, and other quantitative analysis calculations were conducted Sciex Analyst 1.4 software.

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

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• 2008
  • 2008-11-10 AU AU2008323683A patent/AU2008323683B2/en not_active Ceased
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