WO2006015930A1 - Derives de phenol - Google Patents

Derives de phenol Download PDF

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Publication number
WO2006015930A1
WO2006015930A1 PCT/EP2005/053500 EP2005053500W WO2006015930A1 WO 2006015930 A1 WO2006015930 A1 WO 2006015930A1 EP 2005053500 W EP2005053500 W EP 2005053500W WO 2006015930 A1 WO2006015930 A1 WO 2006015930A1
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WO
WIPO (PCT)
Prior art keywords
inflammatory
compound
diseases
disease
cardiovascular
Prior art date
Application number
PCT/EP2005/053500
Other languages
English (en)
Inventor
Ennio Ongini
Francesco Impagnatiello
Original Assignee
Nicox S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nicox S.A. filed Critical Nicox S.A.
Publication of WO2006015930A1 publication Critical patent/WO2006015930A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the use of nitroxyalkylderivatives of phenol for treating inflammatory disease states or disorders, cardiovascular and/or peripheral vascular disorders.
  • NCX 4016 which is a nitric oxide-releasing non steroidal anti-inflammatory drug (NSAID) and consists of the parent molecule (aspirin) linked to the nitric-oxide moiety (NO) through a "spacer”; according to the authors the benzenemethanol, 3-hydroxy- ⁇ -nitrate is one of the metabolites arising from the molecule of NCX 4016 and is a "bioactive storage form" of the nitric-oxide moiety, but they do not mention any specific pharmacological activity of the molecule.
  • NSAID non steroidal anti-inflammatory drug
  • NCX 4016 A study by Corazzi T. et al (unpublished results) on the evaluation of the cyclooxygenase (COX-I and COX-2) inhibiting activity of NCX 4016 demonstrated that its metabolites comprising the benzenemethanol, 3-hydroxy- ⁇ nitrate are ineffective on both enzymes .
  • WO 95/30641 and WO 97/16405 describe the synthesis of 3-nitrooxymethyl-phenol which is used as intermediate in the preparation of a new class of NO-NSAID.
  • the present invention is based on the unexpected discovery that the nitroxyalkylderivatives of phenol possess potent anti-inflammatory properties, anti ⁇ platelets and anti-thrombotic activities and a good bioavailability.
  • the benzenemethanol, 3- hydroxy- ⁇ -nitrate possess potent anti-inflammatory properties .
  • Object of the present invention is the use for treating inflammatory diseases or disorders and cardiovascular and/or peripheral vascular diseases of a phenol nitroxyalkylderivative of general formula (I) or a pharmaceutically acceptable salt thereof:
  • n ranges from 1 to 20;
  • R is H, an halogen atom, a linear or branched (Ci-Ci 0 ) - alkoxy group, an hydroxy group, -CF 3 , -NHR' wherein R' is H or a linear or branched (Ci-Ci 0 ) -alkyl;
  • n is an integer from 1 to 4 and R is H.
  • a particularly preferred compound according to the present invention is benzenemethanol, 3-hydroxy- ⁇ -nitrate (NCX 4015) of formula (II) :
  • the compound of formula (I) can be used for treating numerous inflammatory disease states and disorders.
  • inflammatory disease states or disorders are reperfusion to an ischemic organ, a myocardial infarction, inflammatory bowel disease, rheumathoid arthritis, osteoarthritis, hypertension, psoriasis, an organ trasplant rejection, organ preservation, impotence, a radiation-induced injury, asthma, atherosclerosis, thrombosis, vasculites, disseminated intravascular coagulation, platelet aggregation, metastasis, influenza, a stroke, a burn, a trauma, acute pancreatitis, pyelonephritis, hepatitis, an autoimmune disease, insulin dependent diabete mellitus, disseminated intravascular coagulation, a fatty embolism, adult respiratory disease, adult respiratory distress, infantile respiratory distress, carcinogenesis, or a hemorrhage in neonates, inflammatory ocular disorders,post-trauma inflammation such as head and spinal cord injury.
  • cardiovascular or central nervous systems such as atherosclerosis, myocardial infarction, coronary artery- diseases, vascular complication associated with diabetes, peripheral vascular diseases, Alzheimer disease, Parkinson disease, neuropathic and inflammatory pain.
  • the compounds of the present invention have anti ⁇ platelet activity and anti-thrombotic activity and they can be used to treat cardiovascular diseases and/or peripheral vascular disorders.
  • Cardiovascular diseases include coronary artery- disease, myocardial infarction, stroke.
  • Peripheral vascular disorders include peripheral arterial occlusion, peripheral arterial obstructive disease (PAOD) , thromboangitis obliterans, venous thrombosis and varicose veins .
  • PAOD peripheral arterial obstructive disease
  • thromboangitis obliterans thromboangitis obliterans
  • venous thrombosis varicose veins .
  • Another object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for reducing the toxicity of drugs not containing a -ONO2 group to the gastrointestinal and or renal and/or cardiovascular and/or respiratory apparatus.
  • the drug not containing a -ONO 2 group may belong to one of the following groups : non steroidal anti- inflammatory drugs, anti-thrombotic drugs, steroidal anti ⁇ inflammatory drugs, ACE inhibitors, Angiotensin II receptor antagonist, ⁇ -adrenergic receptor blockers, ⁇ -adrenergic receptor agonists, statins, prostaglandins for the treatment of glaucoma, drugs for treatment of chronic pain.
  • the non steroidal anti-inflammatory drug may be a COXl or a COX2 inhibitor.
  • non steroidal anti-inflammatory drug examples include: Paracetamol, Etodolac, Pirazolac, Tolmetin, Bromefenac, Fenbufen, Mofezolac, Diclofenac, Pemedolac, Sulindac, Ketorolac, Indomethacin, Suprofen, Ketoprofen, Tiaprofenic acid, Fenoprofen, Indoprofen, Carprofen, Naproxen, Loxoprofen, Ibuprofen, Pranoprofen, Bermoprofen, CS-670, Zaltoprofen, Tenoxicam, Piroxicam, Meloxicam, Tenidap, Aceclofenac, Acemetacin, 5-amino-acetylsalicylic acid, Alclofenac, Alminoprofen, Amfenac, Bendazac, ⁇ -bisabolol, Bromosaligenin, Bucloxic acid, Butibufen, Cinmetacin, C
  • Another object of the present invention is the use of the compounds of formula (I) in association with compounds used to treat inflammatory diseases, cardiovascular diseases and/or peripheral vascular disorders, glaucoma and inflammatory and chronic pain.
  • association means that the compounds can be administered separately or in form of a composition.
  • the treatment is a long-term therapy, and preferably patients suffering from cardiovascular disease and/or peripheral vascular disorders or inflammatory diseases are diabetics and/or older than forty years old. "Long term treatment” ranges from about one month to over two years of chronic/maintenance administration.
  • Compounds used to treat inflammatory diseases refers to non steroidal anti-inflammatory drugs as above defined, or steroidal anti-inflammatory drugs .
  • Compounds used to treat cardiovascular diseases refers to any therapeutic compound, or a pharmaceutically acceptable salt thereof, used to treat any cardiovascular disease.
  • Suitable compounds include, but are not limited to aspirn and derivatives thereof, angiotensin-converting enzyme (ACE) inhibitors; beta-adrenergic blockers, cholesterol reducers (such as, for example,HMG-CoA reductase inhibitors, including, but not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin) , calcium channel blockers angiotensin II receptor antagonists; endothelin antagonists, renin inhibitors .
  • ACE angiotensin-converting enzyme
  • beta-adrenergic blockers such as, for example,HMG-CoA reductase inhibitors, including, but not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin
  • Compounds used to treat glaucoma refers for example to prostaglandins such as latanaprost.
  • Compounds used to treat inflammatory and chronic pain refers to typical anti-convulsing drugs such as gabapentin, tiogabine, pregabalin, carbamazepin, topiramate, lamotrigine.
  • the present invention also refers to a kit comprising a compound of formula (I) and a compound used to treat inflammatory diseases, cardiovascular diseases, peripheral vascular disorders, glaucoma and/or inflammatory and chronic pain for simultaneous, separated or sequential use for the treatment of inflammatory diseases, cardiovascular diseases, peripheral vascular disorders, glaucoma and/or inflammatory and chronic pain.
  • the compounds object of the present invention are formulated in the corresponding pharmaceutical compositions for parenteral, oral and topical use according to the techniques well known in the art, together with the usual excipients; see for example the volume “Remington's Pharmaceutical Sciences 15 th Ed.”.
  • the usually daily doses of the compounds in the pharmaceutical composition can be in amounts of about 0.1 to about 500 mg/kg of body weight, preferably about 1 to about 50 mg/kg of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems .
  • the compounds of formula (I) can be prepared by employing method well known in literature using starting materials that are readily available.
  • the benzenemethanol, 3-hydroxy- ⁇ -nitrate is prepared from commercially available 3- [ (hydroxyl)methyl]phenol using a two-step process described in the reaction scheme (Scheme 1) reported below: Scheme 1 Step 1
  • NCX 4016 and NCX 4015 alone or in combination with ASA (Acetyl Salicilic Acid) on inflammatory markers.
  • ASA Aceyl Salicilic Acid
  • the monocyte-macrophage cell line, RAW264.7, activated with a combination of the bacterial endotoxin lipopolysaccharide (LPS) and interferon- ⁇ (IFN ⁇ ) was used to establish the anti-inflammatory activity of the association of NCX 4016, ASA and NCX 4015 and NCX 4015 alone.
  • LPS bacterial endotoxin lipopolysaccharide
  • IFN ⁇ interferon- ⁇
  • RAW 264.7 was obtained from Sigma and cultured in T-75 Flasks with DMEM containing 10% FBS and gentamicin (50 ⁇ g/ml) .
  • Cells were routinely detached with standard trypsin procedures and subcultured in 6 or 96 multiwell plates, for 3-4 days prior to the experiments. After reaching subconfluence, cells were incubated for 24 h in the presence of DMEM containing 0.4% FBS and gentamicin. Cells were preincubated for 30 min in the presence of NCX 4016 or
  • NCX 4015 or vehicle (0.1% DMSO) then subjected to LPS
  • NCX 4016 and NCX 4015 were carried out in order to establish the effects of NCX 4016 and NCX 4015 on LPS/INF ⁇ -induced TNF ⁇ accumulation.
  • the stimulation of RAW 264.7 macrophages resulted in a time- dependent increase in TNF ⁇ following the application of the toxin.
  • the effects of the test drugs on this parameters were determined at 16h post-exposure.
  • NCX 4016 inhibited LPS/INF ⁇ -induced TNF ⁇ accumulation in a concentration-dependent manner and with an estimated potency similar to that observed on iNOS activity.
  • NCX 4015 alone or in combination with ASA elicited virtually identical responses to that of NCX 4016 (Table 3) .
  • Example 3 Measurements of cGMP in rat PC12 cell line.
  • the neurosecretory/neuronal PC12 is a clonal cell line derived from a pheochromocytoma of rat adrenal medulla. Cells were maintained at 37 0 C in DMEM medium enriched with 10% horse serum and 5% FBS under a 5% CO 2 atmosphere. The cultured undifferentiated cells were routinely detached

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'un composé de formule générale (I) dans laquelle n représente un nombre entier compris entre 1 et 20, R représente H, un atome d'halogène, un groupe (C1-C10)-alkoxy linéaire ou ramifié, un groupe hydroxy, -CF3, -NHR', où R' représente H ou (C1-C10)-alkyl linéaire ou ramifié ou un sel correspondant, dans le traitement de troubles ou de problèmes inflammatoires, de maladies cardio-vasculaires et/ou vasculaires périphériques.
PCT/EP2005/053500 2004-08-10 2005-07-20 Derives de phenol WO2006015930A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59985704P 2004-08-10 2004-08-10
US60/599,857 2004-08-10

Publications (1)

Publication Number Publication Date
WO2006015930A1 true WO2006015930A1 (fr) 2006-02-16

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007230A1 (fr) 2007-07-09 2009-01-15 Nicox S.A. Utilisation de composés libérant de l'oxyde nitrique dans le traitement de la douleur chronique
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
CN103739499A (zh) * 2011-10-24 2014-04-23 尼科斯股份有限公司 醌基一氧化氮供体化合物
US8722669B2 (en) 2009-12-08 2014-05-13 Case Western Reserve University Compounds and methods of treating ocular disorders
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CARINI, MARINA ET AL: "Chemiluminescence and LC-MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 35, no. 2, 16 April 2004 (2004-04-16), pages 277 - 287, XP002356417 *
CARINI, MARINA ET AL: "Nitric oxide release and distribution following oral and intraperitoneal administration of nitroaspirin (NCX 4016) in the rat", LIFE SCIENCES, vol. 74, no. 26, 14 May 2004 (2004-05-14), pages 3291 - 3305, XP002356416 *
J. L. WALLACE, P. DEL SOLDATO: "The therapeutic potential of NO-NSAIDs", FUNDAMENTAL & CLINICAL PHARMACOLOGY, vol. 17, 2003, pages 11 - 20, XP002356418 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007230A1 (fr) 2007-07-09 2009-01-15 Nicox S.A. Utilisation de composés libérant de l'oxyde nitrique dans le traitement de la douleur chronique
US8722669B2 (en) 2009-12-08 2014-05-13 Case Western Reserve University Compounds and methods of treating ocular disorders
US10208049B2 (en) 2009-12-08 2019-02-19 Case Western Reserve University Compounds and methods of treating ocular disorders
CN103739499A (zh) * 2011-10-24 2014-04-23 尼科斯股份有限公司 醌基一氧化氮供体化合物
CN103739499B (zh) * 2011-10-24 2016-09-07 尼科斯科学爱尔兰公司 醌基一氧化氮供体化合物
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules

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