WO2005030224A1 - Analgesiques et/ou anti-inflammatoires nitrosyles a activite antivirale - Google Patents

Analgesiques et/ou anti-inflammatoires nitrosyles a activite antivirale Download PDF

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Publication number
WO2005030224A1
WO2005030224A1 PCT/EP2004/051551 EP2004051551W WO2005030224A1 WO 2005030224 A1 WO2005030224 A1 WO 2005030224A1 EP 2004051551 W EP2004051551 W EP 2004051551W WO 2005030224 A1 WO2005030224 A1 WO 2005030224A1
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WIPO (PCT)
Prior art keywords
group
integer
equal
acid
branched
Prior art date
Application number
PCT/EP2004/051551
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English (en)
Inventor
Manlio Bolla
Giancarlo Santus
Piero Del Soldato
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 WO2005030224A1 publication Critical patent/WO2005030224A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to the use of drugs for treating viral diseases and/or their complications. More specifically, the present invention relates to the use of nitroderivatives for treatment of influenza, cold and viral 10 infections affecting the cardiovascular system, in particular the heart muscle.
  • the viral infections are very diffused.
  • the cold and influenza are the common infectious diseases of the respiratory tract caused by different viruses (rhinovirus, 15 influenza viruses) .
  • the influenza produces symptoms that are more severe, such as a fever, runny nose, sore throat, cough, headache and muscle aches. Complications may prolong the illness, some people develop secondary bacterial infections such as otitis 20 media, sinuses, bronchitis and pneumonia.
  • Vaccination is the best way to avoid contracting influenza and several antiviral drugs can be used to prevent infection and are also helpful in treating people who have influenza. 25
  • the drawback of vaccines is that the virus can change each year.
  • Amantadine and rimantadine are older antiviral drugs that offer protection against influenza type A but not influenza type B. These drugs can cause side effects such 30 as stomach upset, nervousness and sleeplessness.
  • New analogs, oseltamivir and zanamivirm can prevent infection with either influenza virus types.
  • the use of antiviral drugs does not eliminate the risk of complications and these drugs work only if taken in the first day or two of illness.
  • the viral infections affecting the heart muscle are caused by different viruses such as coxsackie, adenovirus, and echovirus.
  • the therapeutic treatment is generally unsatisfactory for the viral myocarditis .
  • the need was felt to have available compounds active in viral infections, specifically those affecting the cardiovascular system, in particular the heart muscle, and for the prevention and/or treatment of influenza and cold. It has been surprisingly and unexpectedly found by the Applicant that it is possible to solve the above technical problem with specific nitroderivatives as described hereunder .
  • c and d are independently 0 or 1;
  • R D is selected from the group consisting of H, a linear or branched C1-C12 alkyl, C-C ⁇ 2 alkenyl; when c is equal to 0 , d is 1, R A is selected from the group consisting of:
  • R c is selected from the group consisting of H, halogen, amino, R E CONH- and -OCOR;
  • R D is H, OH, halogen, a linear or branched C1-C4 alkyl, a linear or branched C1-C4 alkoxyl, trifluoromethyl, amino, mono- or di-(C ⁇ C 4 ) alkylamino;
  • R F ' is H and a linear or branched C1-C 5 alkyl; e is 0 or 1; M is carbon or nitrogen atom; when c is equal to 1, d is equal to 1, R B is hydrogen, R A is selected from the group consisting of:
  • R is H or CH 3 and ⁇ r is Cl or F; when c is equal to 1, d is equal to 1 and R B is CH 3 , R A is selected from the group consisting of:
  • R A is selected from the group consisting of:
  • R D is as above defined
  • R G is selected from the group consisting of:
  • R H is phenyl or cyclohexyl
  • Y is a bivalent radical having the following meaning: a) - linear or branched C1-C20 alkylene, preferably having from 2 to 5 carbon atoms; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains R 1 , wherein R 1 is linear or branched alkyl with from 1 to 10 carbon atoms, preferably CH 3 ; b)
  • n is an integer from 0 to 20, and nl is an integer from 1 to 20 as above defined;
  • nl is as defined above and n2 is an integer from 0 to 2;
  • nl and R ? are as above defined, R 3 is H or COCH 3 ; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ONO2 group is linked to a -CH 2 group; g) R 2 R 2 —(CH-CH ⁇ X ⁇ CH-CHj- —(CH 2 -CH-X 2 ) n —CH 2 -CH- R 2 R 2 wherein X 2 is -0- or -S-, n3 is an integer from 1 to preferably from 1 to 4, R ? is as above defined; h)
  • n4 is an integer from 0 to 10
  • n5 is an integer from 1 to 10
  • R 4 , R 5 , R 6 , R 7 are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R 4 , R 5 , R 6 , R 7 are H; and wherein the -ON0 2 group is bound to
  • n5 being as defined above;
  • Y 2 is a 5 or 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and selected for example from
  • Non limiting examples of non-steroidal anti- inflammatory, analgesic and antipyretic drugs (A-OH or A-H) used in the present invention are:
  • the COX-2 inhibitors used in the present invention are selected from the group consisting of: Celecoxib, Valdecoxib, JTE-522 (Tilmacoxib) , COX-189 (Lumiracoxib) , Nimesulide, N- (4-nitro-2-cycloexyloxy- phenyl)methanesulfonanilide (NS-398) and N-[6-[(2,4- difluorophenyl) thio] -2, 3-dihydro-l-oxo-lH-inden-5-yl] - methanesulfonamide (L-745337) .
  • the compounds of formula (I), according to the present invention when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acid.
  • organic acids are: oxalic, tartaric, maleic, succinic, citric acid.
  • inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acid. Salts with nitric or hydrochloric acid are preferred.
  • the compounds of the invention which have one or more asymmetric carbon atoms can exist as the optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures.
  • A is selected from the group consisting of: Ha
  • c and d are independently 0 or 1;
  • R B is selected from the group consisting of H, a linear or branched C1-C12 alkyl; when c is equal to 0 , d is 1, R A is selected from the group consisting of:
  • R c is -OCOCH 3 in ortho-position with respect to -CO- and R D is H; when c is equal to 1, d is equal to 1 and R B is CH 3 , R A is selected from the group consisting of:
  • R A is:
  • Y is a bivalent radical having the following meaning: a) linear Ci-C ⁇ alkylene, preferably having from 3 to 5 carbon atoms; b)
  • n is an integer from 0 to 5
  • nl is an integer from 1 to 5
  • nl is as defined above and n2 is an integer from 0 to 2;
  • Xi -OCO- or -COO- and R 2 is H or CH 3 ;
  • nl and R 2 are as above defined, R 3 is H or COCH 3 ; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ON0 2 group is linked to a -CH2 group; g )
  • X 2 is -0- or -S-, n3 is an integer from 1 to 4 , preferably 1 , R 7 is as above defined; h)
  • n4 is an integer from 0 to 3
  • n5 is an integer from 1 to 3
  • R 4 , R 5 , R 6 , R 7 are the same and are H; and wherein the -ONO2 group is bound to ⁇ [C] ⁇ 3
  • Y is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or more atoms of nitrogen and selected for example from
  • the amount on a molar basis of the active principle in said formulations is the same, or lower, with respect to that used as anti-inflammatory, analgesic and antipyretic drug of the corresponding precursor drug.
  • the daily administrable doses are those of the precursor drugs, or optionally lower.
  • the daily doses can be found in the publications of the field, such as for example in "Physician's Desk reference". The following examples are to further illustrate the invention without limiting it.
  • ECP- no cytopathic effect induced by the virus

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation, à des fins de prévention et/ou de traitement de maladies virales et/ou de leurs complications, de nitrodérivés de formule générale (I) ou de sels ou de stéréo-isomères de ceux-ci.
PCT/EP2004/051551 2003-09-26 2004-07-20 Analgesiques et/ou anti-inflammatoires nitrosyles a activite antivirale WO2005030224A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03292378.1 2003-09-26
EP03292378 2003-09-26

Publications (1)

Publication Number Publication Date
WO2005030224A1 true WO2005030224A1 (fr) 2005-04-07

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070006A3 (fr) * 2004-01-22 2005-11-03 Nitromed Inc Composes nitroses et/ou nitrosyles, compositions et procede pour les utiliser
US7087630B2 (en) 2002-06-27 2006-08-08 Nitromed, Inc. Cyclooxygenase 2 selective inhibitors, compositions and methods of use
WO2007060112A1 (fr) 2005-11-23 2007-05-31 Nicox S.A. Derives d’acide salicylique
US7521435B2 (en) 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
WO2012143141A2 (fr) 2011-04-21 2012-10-26 Institut National De La Recherche Agronomique Compositions antivirales dirigees contre la nucleoproteine des virus influenza
WO2014111957A1 (fr) 2013-01-21 2014-07-24 Apparao Satyam Promédicaments d'agents thérapeutiques libérant de l'oxyde nitrique
WO2017153950A1 (fr) * 2016-03-10 2017-09-14 Biotech Innovations Spółka Z Ograniczoną Odpowiedzialnością Inhibiteurs de nucléase du virus de la grippe (complexe de polymérases)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861426A (en) * 1994-05-10 1999-01-19 Nicox S.A. Nitro compounds of the formula A-Xi -NO2 and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities
WO2001045703A1 (fr) * 1999-12-23 2001-06-28 Nitromed, Inc. Inhibiteurs de cyclooxygenase-2 nitroses et nitrosyles, compositions et procedes d'utilisation
EP1219306A1 (fr) * 2000-12-29 2002-07-03 Nicox S.A. Compositions contenant des cyclodextrines et des médicaments libérant le NO
WO2003013432A2 (fr) * 2001-08-10 2003-02-20 Nitromed, Inc. Procedes d'utilisation de nouveaux composes de nitrate organique contenant du soufre

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861426A (en) * 1994-05-10 1999-01-19 Nicox S.A. Nitro compounds of the formula A-Xi -NO2 and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities
WO2001045703A1 (fr) * 1999-12-23 2001-06-28 Nitromed, Inc. Inhibiteurs de cyclooxygenase-2 nitroses et nitrosyles, compositions et procedes d'utilisation
EP1219306A1 (fr) * 2000-12-29 2002-07-03 Nicox S.A. Compositions contenant des cyclodextrines et des médicaments libérant le NO
WO2003013432A2 (fr) * 2001-08-10 2003-02-20 Nitromed, Inc. Procedes d'utilisation de nouveaux composes de nitrate organique contenant du soufre

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DE CLERCQ E ET AL: "5-Nitro-2'-deoxyuridine and 5-nitro-2'-deoxyuridine 5'-monophosphate: Antiviral activity and inhibition of thymidylate synthetase in vivo", MOLECULAR PHARMACOLOGY 1978 UNITED STATES, vol. 14, no. 3, 1978, pages 422 - 430, XP008036061 *
FIORUCCI S ET AL: "A NO-releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway", BRITISH JOURNAL OF PHARMACOLOGY 2002 UNITED KINGDOM, vol. 135, no. 3, 2002, pages 589 - 599, XP008036060, ISSN: 0007-1188 *
KHALILI P ET AL: "Biochemical and pharmacokinetic evaluation of a novel pyrimidine nucleoside nitric oxide donor as a potential anticancer/antiviral agent", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 2003 NETHERLANDS, vol. 19, no. 4, 2003, pages 305 - 313, XP008036045, ISSN: 0928-0987 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087630B2 (en) 2002-06-27 2006-08-08 Nitromed, Inc. Cyclooxygenase 2 selective inhibitors, compositions and methods of use
US7442802B2 (en) 2002-06-27 2008-10-28 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2005070006A3 (fr) * 2004-01-22 2005-11-03 Nitromed Inc Composes nitroses et/ou nitrosyles, compositions et procede pour les utiliser
US7521435B2 (en) 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
WO2007060112A1 (fr) 2005-11-23 2007-05-31 Nicox S.A. Derives d’acide salicylique
WO2012143141A2 (fr) 2011-04-21 2012-10-26 Institut National De La Recherche Agronomique Compositions antivirales dirigees contre la nucleoproteine des virus influenza
FR2974299A1 (fr) * 2011-04-21 2012-10-26 Agronomique Inst Nat Rech Compositions antivirales dirigees contre la nucleoproteine des virus influenza
WO2012143141A3 (fr) * 2011-04-21 2012-12-13 Institut National De La Recherche Agronomique Compositions antivirales dirigees contre la nucleoproteine des virus influenza
US9783482B2 (en) 2011-04-21 2017-10-10 Institut National De La Recherche Agronomique Antiviral compositions directed against the influenza virus nucleoprotein
WO2014111957A1 (fr) 2013-01-21 2014-07-24 Apparao Satyam Promédicaments d'agents thérapeutiques libérant de l'oxyde nitrique
US9844599B2 (en) 2013-01-21 2017-12-19 Apparao Satyam Nitric oxide releasing produgs of therapeutic agents
WO2017153950A1 (fr) * 2016-03-10 2017-09-14 Biotech Innovations Spółka Z Ograniczoną Odpowiedzialnością Inhibiteurs de nucléase du virus de la grippe (complexe de polymérases)

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