[go: up one dir, main page]

WO2005030224A1 - Nitrosylated analgesic and/or anti-inflammatory drugs having antiviral activity - Google Patents

Nitrosylated analgesic and/or anti-inflammatory drugs having antiviral activity Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
group
integer
equal
acid
branched
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2004/051551
Other languages
French (fr)
Inventor
Manlio Bolla
Giancarlo Santus
Piero Del Soldato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nicox SA
Original Assignee
Nicox SA
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 SA filed Critical Nicox SA
Publication of WO2005030224A1 publication Critical patent/WO2005030224A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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

Landscapes

  • 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

Use for the prevention and/or treatment of viral diseases and/or their complications, of nitroderivatives of general formula (I) or salts or stereoisomers thereof: A-T-Y-ONO2 (I).

Description

TITLE OF THE INVENTION
NITROSYLATED ANALGESIC AND/OR ANTI-INFLAMMATORY DRUGS HAVING ANTIVIRAL ACTIVITY
5 ****** 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. However, 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. In addition, the virus rapidly develops resistance to them (The Merck Manual of Medical Information, Second Home Edition, Chapter 198, Viral Infections) . Other used compounds are paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) . It has been reported that paracetamol causes damages at hepatic level (hepatic toxicity) and it has been known that the use of NSAIDs is often accompanied by several side effects, mainly at the charge of the gastrointestinal tract. For the cold treatment there are generally no effective antiviral drugs and an effective vaccine has not yet been developed (The Merck Manual of Medical Information, Second Home Edition, Chapter 198, Viral Infections) . The viral infections affecting the heart muscle (myocarditis) 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 . Object of the present invention is the use, for the prevention and/or treatment of viral diseases and/or their complications, of nitroderivatives of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof: A-T-Y-ON02 (I) wherein A is the residue of a drug (A -OH or A-H) selected from the group consisting of non-steroidal anti- inflammatory, analgesic and antipyretic drugs and COX-2 inhibitors, in which T = -0-, -NH-, -S-, -CO- or - (CH2)niOCO- wherein nl is an integer from 1 to 20; A is selected from the group consisting of: Ha)
Figure imgf000004_0001
where c and d are independently 0 or 1;
RD is selected from the group consisting of H, a linear or branched C1-C12 alkyl, C-Cι2 alkenyl; when c is equal to 0 , d is 1, RA is selected from the group consisting of:
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000005_0001
wherein: Rc is selected from the group consisting of H, halogen, amino, RECONH- and -OCOR; RD is H, OH, halogen, a linear or branched C1-C4 alkyl, a linear or branched C1-C4 alkoxyl, trifluoromethyl, amino, mono- or di-(Cι~C4) alkylamino; RF' is H and a linear or branched C1-C5 alkyl; e is 0 or 1; M is carbon or nitrogen atom; when c is equal to 1, d is equal to 1, RB is hydrogen, RA is selected from the group consisting of:
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
wherein R is H or CH3 and Εr is Cl or F; when c is equal to 1, d is equal to 1 and RB is CH3, RA is selected from the group consisting of:
Figure imgf000006_0002
Figure imgf000007_0001
when c is equal to 0, d is equal to 0, RA is selected from the group consisting of:
Figure imgf000007_0002
Figure imgf000008_0001
lib)
Figure imgf000008_0002
wherein :
RD is as above defined;
RG is selected from the group consisting of:
Figure imgf000008_0003
lie)
Figure imgf000009_0001
wherein RH is phenyl or cyclohexyl; lid)
Figure imgf000009_0002
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 R1, wherein R1 is linear or branched alkyl with from 1 to 10 carbon atoms, preferably CH3; b)
Figure imgf000009_0003
c)
Figure imgf000009_0004
wherein n is an integer from 0 to 20, and nl is an integer from 1 to 20 as above defined; d)
Figure imgf000010_0001
wherein : nl is as defined above and n2 is an integer from 0 to 2;
X! -OCO- or -COO- and R is H or CH3;
Figure imgf000010_0002
wherein: nl, n2,R? and Xi are as above defined; Y1 is -CH2-CH2- or -CH=CH- (CH2)n2-; f)
Figure imgf000010_0003
wherein: nl and R? are as above defined, R3 is H or COCH3; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ONO2 group is linked to a -CH2 group; g) R2 R2 —(CH-CH^X^CH-CHj- —(CH2-CH-X2)n—CH2-CH- R2 R2 wherein X2 is -0- or -S-, n3 is an integer from 1 to preferably from 1 to 4, R? is as above defined; h)
Figure imgf000011_0001
wherein : n4 is an integer from 0 to 10; n5 is an integer from 1 to 10;
R4, R 5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R4, R5, R6, R7 are H; and wherein the -ON02 group is bound to
-[C]„5
n5 being as defined above;
Y2 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
Figure imgf000011_0002
Figure imgf000012_0001
(Y10) (Yll) (Y12) (Y13)
Non limiting examples of non-steroidal anti- inflammatory, analgesic and antipyretic drugs (A-OH or A-H) used in the present invention are:
Aspirin, Salicylic acid, Mesalamine, Acetylsalicylsalicylic acid, 5-amino-acetylsalicylic acid, Flunixin, Ketorolac, Tolfenamic acid, Niflumic acid, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Enfenamic acid, Etodolac, Pirazolac, Tolmetin, Bromefenac, Fenbufen, Mofezolac, Diclofenac, Pemedolac, Sulindac, Indomethacin, Suprofen, Ketoprofen, Tiaprofenic acid, Fenoprofen, Indoprofen, Carprofen, Naproxen, Loxoprofen, Ibuprofen, Pranoprofen, Bermoprofen, CS-670, Zaltoprofen, Flurbiprofen, Tenoxicam, Piroxicam, Meloxicam, Lornoxicam, Paracetamol and Salacetamide. Preferably, 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. Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acid. Examples of 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. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) . The preferred compounds according to the present invention are those wherein: T = -0-, -NH-, -S- or -CO-;
A is selected from the group consisting of: Ha)
Figure imgf000013_0001
where c and d are independently 0 or 1;
RB is selected from the group consisting of H, a linear or branched C1-C12 alkyl; when c is equal to 0 , d is 1, RA is selected from the group consisting of:
Figure imgf000013_0002
wherein: Rc is -OCOCH3 in ortho-position with respect to -CO- and RD is H; when c is equal to 1, d is equal to 1 and RB is CH3, RA is selected from the group consisting of:
Figure imgf000014_0001
when c is equal to 0, d is equal to 0, RA is:
Figure imgf000014_0002
Y is a bivalent radical having the following meaning: a) linear Ci-Cδ alkylene, preferably having from 3 to 5 carbon atoms; b)
Figure imgf000014_0003
Figure imgf000014_0004
wherein n is an integer from 0 to 5, and nl is an integer from 1 to 5; d)
Figure imgf000014_0005
wherein : nl is as defined above and n2 is an integer from 0 to 2; Xi = -OCO- or -COO- and R2 is H or CH3; e)
Figure imgf000015_0001
wherein: nl, n2,R and Xi are as above defined; Y1 is -CH=CH-; f)
Figure imgf000015_0002
wherein : nl and R2 are as above defined, R3 is H or COCH3; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ON02 group is linked to a -CH2 group; g)
Figure imgf000015_0003
wherein X2 is -0- or -S-, n3 is an integer from 1 to 4 , preferably 1 , R7 is as above defined; h)
Figure imgf000015_0004
wherein : n4 is an integer from 0 to 3; n5 is an integer from 1 to 3;
R4, R5, R6, R7 are the same and are H; and wherein the -ONO2 group is bound to ■ [C]π3
Y is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or more atoms of nitrogen and selected for example from
Figure imgf000016_0001
(Y13! The preferred compounds of formula (I) for the use according to the present invention are the following:
Figure imgf000016_0002
(1) (2)
Figure imgf000016_0003
(3)
Figure imgf000017_0001
(7) (CH2)3-ON02 o O H.C N 3 H (8)
Figure imgf000017_0002
(9)
Figure imgf000018_0001
(10)
Figure imgf000018_0002
(11)
Figure imgf000018_0003
(15)
Figure imgf000018_0004
The preparation of the compounds of formula (I) with the linking group Y of formula h) is described in published PCT application WO 00/51988, pages 28-31, in the name of the Applicant, herein incorporated by reference. When Y is selected from bivalent radicals mentioned under a)-c) and g) , the compounds of formula (I) can be obtained according to U.S. Pat. No. 5,861,426, pages 15-16, in the name of the Applicant, herein incorporated by reference. The preparation of the compounds of formula (I) with the linking group Y selected from bivalent radicals mentioned under d) -f) is described in published PCT application WO 00/61537, pages 49-59, in the name of the Applicant, herein incorporated by reference. The preparation of the compounds of formula (I) wherein A is selected from the groups lib) -lid) is described in not published application PCT/EP03/06502 pages 12-19, in the name of the Applicant, herein incorporated by reference. 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 15th Ed.". 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.
Example 1 Subconfluent monolayers of MDCK cells are grown Petri dishes (60 mm diameter) . Cells are infected with influenza virus A/NWS/33 (MOI=l, multiplicity of infection) , and three different concentrations of 4- (acetylamino)phenyl 4- (nitrooxy) butanoate (corresponding to compound (8)) (1 to 100 μM) were tested. Assays were performed in double for each concentration and compared to control non infected dishes . The viral replication after 24 hours infective cycle (preliminary results at 10 hours are available) was titrated by the plaque infectivity assay, using supernatant dilutions from 10_1 a 10"8 plus the undiluted supernatant. Results allowed to assess the antiviral activity of compound (8) in influenza virus A/NWS/33 -infected MDCK cells at 24 hours (and one evidence at 10 hours) post infection. Virus replication is assessed by infectivity plaque assay expressed as UFP/ml (UFP: unity forming plaque) and the obtained results, reported in Table 1, are expressed as % infectivity vs control.
Table 1
Figure imgf000021_0001
Furthermore, the effect of compound (8) on viral nucleoprotein (NP) expression and distribution in influenza virus A/NWS/33 -infected MDCK after a replication cycle of 10 hours is determined by immunoflurescence assay using a monoclonal antibody specific for NP. The obtained results, reported in Table 2, are expressed as % of the total. Table 2
Figure imgf000021_0002
ECP- = no cytopathic effect induced by the virus
4- (acetylamino)phenyl 4- (nitrooxy)butanoate (compound
(8) ) showed antiviral effect against human influenza virus (A/NWS/33 type) , reducing the viral production with a infective title ratio ranging from 3.5 (Exp 1) to 1.98 (Exp
2), with a mean of 2.74. Furthermore the anti-viral effect was reduced in a concentration dependent manner, suggesting specificity for the antiviral activity of compound (8) . The treatment with 100 μM of compound (8) for 10 hours after viral infection reduced the viral nucleoprotein expression by 20% of monolayer cells when compared to the control infection plates.

Claims

1. Use for the preparation of a medicament for preventing and/or treating viral diseases and/or their complications of compounds, or pharmaceutically acceptable salts or stereoisomers thereof, having the general formula (I) :
A-T-Y-0N02 (I) wherein A is the residue of a drug (A-OH or A-H) selected from the group consisting of non-steroidal anti- inflammatory, analgesic and antipyretic drugs and COX -2 inhibitors, in which T = -0-, -NH-, -S-, -CO- or - (CH2)niOCO- wherein nl is an integer from 1 to 20; A is selected from the group consisting of: Ha)
Figure imgf000023_0001
where c and d are independently 0 or 1;
RB is selected from the group consisting of H, a linear or branched Cχ-Ci2 alkyl, C2-C12 alkenyl; when c is equal to 0 , d is 1, RA is selected from the group consisting of:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
wherein : Rc is selected from the group consisting of H, halogen, amino, RECONH- and -OCORR; RD is H, OH, halogen, a linear or branched Cι~C4 alkyl, a linear or branched C1-C4 alkoxyl, trifluoromethyl, amino, mono- or di-(Cτ-C4) alkylamino; RE is H and a linear or branched Ci-Cs alkyl; e is 0 or 1; M is carbon or nitrogen atom; when c is equal to 1, d is equal to 1, RB is hydrogen, RA is selected from the group consisting of:
Figure imgf000024_0003
Figure imgf000025_0001
wherein RFΛ is H or CH3 and RC1 is Cl or F; when c is equal to 1, d is equal to 1 and RB is CH3, RA is selected from the group consisting of:
Figure imgf000025_0002
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
when c is equal to 0, d is equal to 0, RA is selected from the group consisting of:
Figure imgf000026_0004
Figure imgf000027_0001
lib)
Figure imgf000027_0002
wherein:
RD is as above defined;
RG is selected from the group consisting of:
Figure imgf000027_0003
lie)
Figure imgf000028_0001
wherein R11 is phenyl or cyclohexyl;
l id)
Figure imgf000028_0002
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 R1, wherein R1 is linear or branched alkyl with from 1 to 10 carbon atoms, preferably CH3; b)
Figure imgf000028_0003
c )
Figure imgf000029_0001
wherein n is an integer from 0 to 20 , and nl i s an integer from 1 to 20 as above defined; d)
Figure imgf000029_0002
wherein : nl is as defined above and n2 is an integer from 0 to 2;
Xi = -OCO- or -COO- and R2 is H or CH3; e)
Figure imgf000029_0003
wherein : nl, n2,R2 and Xi are as above defined; Y1 is -CH2-CH2- or -CH=CH- (CH2) nz~ i f)
Figure imgf000029_0004
wherein : nl and R2 are as above defined, R3 is H or C0CH3; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ONO2 group is linked to a -CH2 group; g)
Figure imgf000030_0001
wherein X2 is -0- or -S- , n3 is an integer from 1 to 6 , preferably from 1 to 4 , R2 is as above defined; h)
Figure imgf000030_0002
wherein : n4 is an integer from 0 to 10; n5 is an integer from 1 to 10;
R4, R5, R6, R7 ar e the same or different, and are H or straight or branched Cι-C4 alkyl, preferably R4, R5, R6, R7 are H; and wherein the -0N02 group is bound to I -[C]»5
n5 being as defined above;
Y2 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
Figure imgf000030_0003
Figure imgf000031_0001
(Y10 ) (γιι : ( Y12 ) ( Y13 )
2. Use according to claim 1, wherein the drug (A-OH or A-H) is selected from the group consisting of: Aspirin, Salicylic acid, Mesalamine, Acetylsalicylsalicylic acid, 5- amino-acetylsalicylic acid, Flunixin, Ketorolac, Tolfenamic acid, Niflumic acid, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Enfenamic acid, Etodolac, Pirazolac, Tolmetin, Bromefenac, Fenbufen, Mofezolac, Diclofenac, Pemedolac, Sulindac, Indomethacin, Suprofen, Ketoprofen, Tiaprofenic acid, Fenoprofen, Indoprofen, Carprofen, Naproxen, Loxoprofen, Ibuprofen, Pranoprofen, Bermoprofen,
CS-670, Zaltoprofen, Flurbiprofen, Tenoxicam, Piroxicam,
Meloxicam, Lornoxicam, Paracetamol and Salacetamide,
Celecoxib, Valdecoxib, JTE-522 (Tilmacoxib) , COX-189
(Lumiracoxib) , Nimesulide, N- (4-nitro-2-cycloexyloxy- ρhenyl)methanesulfonanilide (NS-398) and N-[6-[(2,4- difluorophenyl) thio] -2, 3-dihydro-l-oxo-lH-inden-5-yl] - methanesulfonamide (L-745337).
3. Use according to claims 1-2, wherein Y is a bivalent radical having the following meaning: a) linear Ci-Cβ alkylene, preferably having from 3 to 5 carbon atoms; b)
Figure imgf000032_0001
c)
Figure imgf000032_0002
wherein n is an integer from 0 to 5, and nl is an integer from 1 to 5 ; d)
Figure imgf000032_0003
wherein : nl is as defined above and n2 is an integer from 0 to 2;
XT = -OCO- or -COO- and R2 is H or CH3; e)
Figure imgf000032_0004
wherein : nl, n2,R2 and XT are as above defined;
Y1 is -CH=CH-; f)
Figure imgf000032_0005
wherein : nl and R2 are as above defined, R3 is H or COCH3; with the proviso that when Y is selected from bivalent radicals mentioned under b) -f) , the -ON02 group is linked to a -CH2 group; g) R2 R2 —(CH-CH2-X2)^CH-CH2— 1 1 R2 R2 —(CH2-CH-X2)^-CH2-CH—
wherein X2 is -0- or -S-, n3 is an integer from 1 to 4, preferably 1, R2 is as above defined; h)
Figure imgf000033_0001
wherein : n4 is an integer from 0 to 3; n5 is an integer from 1 to 3;
R4, R5, R6, R7 are the same and are H; and wherein the -ONO2 group is bound to I -[C]n5 r
Y2 is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or more atoms of nitrogen and selected for example from
Figure imgf000033_0002
Figure imgf000034_0001
(Y5) (Y13)
4. Use according to claims 1-3, wherein T = -0-, -NH-, -S- or -CO-;
A is selected from the group consisting of: Ha)
Figure imgf000034_0002
where c and d are independently 0 or 1; RB is selected from the group consisting of H, a linear or branched C1-C12 alkyl; when c is equal to 0 , d is 1, RA is selected from the group consisting of:
Figure imgf000034_0003
wherein :
Rc is -OCOCH3 in ortho-position with respect to -CO- and RD is H; when c is equal to 1, d is equal to 1 and RB is CH3, RA is selected from the group consisting of:
Figure imgf000034_0004
when c is equal to 0, d is equal to 0, RA is
Figure imgf000035_0001
5. Use according to claims 1-4, wherein the non-steroidal anti-inflammatory, analgesic and antipyretic drugs are selected from the group consisting of: Aspirin, Naproxen, Ibuprofen and Paracetamol .
6. Use according to claims 1-5, wherein the preferred compounds of formula (I) are the following:
Figure imgf000035_0002
(1) (2)
Figure imgf000035_0003
(3)
Figure imgf000036_0001
(5)
Figure imgf000036_0002
(6)
Figure imgf000036_0003
(7)
Figure imgf000036_0004
(8)
Figure imgf000037_0001
(9)
Figure imgf000037_0002
(10)
Figure imgf000037_0003
(11)
Figure imgf000037_0004
(12)
Figure imgf000037_0005
(13) ■ 31 ■
Figure imgf000038_0001
Figure imgf000038_0002
(15)
Figure imgf000038_0003
(16)
7. Use of compounds or salts or stereoisomers thereof according to claims 1-6, for the preparation of a medicament for preventing and/or treating of influenza, cold and viral infections affecting the cardiovascular system and/or their complications.
8. Use according to claims 1-7, wherein the compounds or salts or stereoisomers thereof are used in the corresponding pharmaceutical formulations for parenteral, oral and topical use.
PCT/EP2004/051551 2003-09-26 2004-07-20 Nitrosylated analgesic and/or anti-inflammatory drugs having antiviral activity Ceased WO2005030224A1 (en)

Applications Claiming Priority (2)

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

Publications (1)

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

Family

ID=34384697

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/051551 Ceased WO2005030224A1 (en) 2003-09-26 2004-07-20 Nitrosylated analgesic and/or anti-inflammatory drugs having antiviral activity

Country Status (1)

Country Link
WO (1) WO2005030224A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070006A3 (en) * 2004-01-22 2005-11-03 Nitromed Inc Nitrosated and/or nitrosylated compounds, compositions and methods of use
US7087630B2 (en) 2002-06-27 2006-08-08 Nitromed, Inc. Cyclooxygenase 2 selective inhibitors, compositions and methods of use
WO2007060112A1 (en) 2005-11-23 2007-05-31 Nicox S.A. Salicylic acid derivatives
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
FR2974299A1 (en) * 2011-04-21 2012-10-26 Agronomique Inst Nat Rech ANTIVIRAL COMPOSITIONS DIRECTED AGAINST NUCLEOPROTEIN INFLUENZA VIRUSES
WO2014111957A1 (en) 2013-01-21 2014-07-24 Apparao Satyam Nitric oxide releasing prodrugs of therapeutic agents
WO2017153950A1 (en) * 2016-03-10 2017-09-14 Biotech Innovations Spółka Z Ograniczoną Odpowiedzialnością Inhibitors of influenza virus nuclease (polymerase complex)

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 (en) * 1999-12-23 2001-06-28 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
EP1219306A1 (en) * 2000-12-29 2002-07-03 Nicox S.A. Compositions comprising cyclodextrins and NO- releasing drugs
WO2003013432A2 (en) * 2001-08-10 2003-02-20 Nitromed, Inc. Methods of use for novel sulfur containing organic nitrate compounds

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 (en) * 1999-12-23 2001-06-28 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
EP1219306A1 (en) * 2000-12-29 2002-07-03 Nicox S.A. Compositions comprising cyclodextrins and NO- releasing drugs
WO2003013432A2 (en) * 2001-08-10 2003-02-20 Nitromed, Inc. Methods of use for novel sulfur containing organic nitrate compounds

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 (en) * 2004-01-22 2005-11-03 Nitromed Inc Nitrosated and/or nitrosylated compounds, compositions and methods of use
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 (en) 2005-11-23 2007-05-31 Nicox S.A. Salicylic acid derivatives
FR2974299A1 (en) * 2011-04-21 2012-10-26 Agronomique Inst Nat Rech ANTIVIRAL COMPOSITIONS DIRECTED AGAINST NUCLEOPROTEIN INFLUENZA VIRUSES
WO2012143141A2 (en) 2011-04-21 2012-10-26 Institut National De La Recherche Agronomique Antiviral compositions directed against the influenza virus nucleoprotein
WO2012143141A3 (en) * 2011-04-21 2012-12-13 Institut National De La Recherche Agronomique Antiviral compositions directed against the influenza virus nucleoprotein
US9783482B2 (en) 2011-04-21 2017-10-10 Institut National De La Recherche Agronomique Antiviral compositions directed against the influenza virus nucleoprotein
WO2014111957A1 (en) 2013-01-21 2014-07-24 Apparao Satyam Nitric oxide releasing prodrugs of therapeutic agents
US9844599B2 (en) 2013-01-21 2017-12-19 Apparao Satyam Nitric oxide releasing produgs of therapeutic agents
WO2017153950A1 (en) * 2016-03-10 2017-09-14 Biotech Innovations Spółka Z Ograniczoną Odpowiedzialnością Inhibitors of influenza virus nuclease (polymerase complex)

Similar Documents

Publication Publication Date Title
EA201500266A1 (en) ANTI-FLY VIRUS REPLICATION INHIBITORS
JP2011051993A5 (en)
CN104136023A (en) Ways to reduce the risk of cardiovascular disease
RU2342398C2 (en) New non-steroidal anti-inflammatory substances, compositions and methods of their administration
CN101506161A (en) Positively charged water-soluble aryl and heteroaryl propionate prodrugs with fast skin penetration
JP2004510705A5 (en)
CA2415577A1 (en) Use of cox-2 inhibitors for preventing immunodeficiency
WO2005030224A1 (en) Nitrosylated analgesic and/or anti-inflammatory drugs having antiviral activity
RU2002101622A (en) Naphthoquinone derivatives and their use for the treatment and control of tuberculosis
Botting Antipyretic therapy
EA200900868A1 (en) COMBINED THERAPY OF DISEASES OF THE LOWER URINARY CARE WITH THE USE OF α2δ LIGANDS AND NONSTEROID ANTI-INFLAMMATORY DRUGS (NSAIDs)
JPH09511755A (en) New treatment method
JP5053665B2 (en) Hypnotic pharmaceutical composition
ES2270634T3 (en) CONVERSION OF COX-INHIBITION COMPOUNDS THAT ARE NOT SELECTIVE COH-2 INHIBITORS IN DERIVATIVES THAT ARE SELECTED COX-2 INHIBITORS.
TW200301100A (en) Treatment of neurodegenerative and cardiovascular disorders
WO2021217053A1 (en) Plasma kallikrein inhibitors for the treatment of ards and related conditions
CA2380381A1 (en) Combination treatment of multiple sclerosis (ms) other demyelinating conditions and peripheral neuropathy, especially painful neuropathies and diabetic neuropathy
EA200500942A1 (en) MEANS FOR TREATING JOINT DISEASES
WO2007075102A1 (en) Medicinal agent for treating viral infections
EA200800071A1 (en) DERIVATIVES OF BENZOFURANILA AS AN INHIBITORS OF 5-НТ6-RECEPTOR
JP2008115168A (en) Anti-adenovirus agent
RU2015112586A (en) PHARMACEUTICAL COMPOSITIONS CONTAINING FLURBIPROFEN
AU2013250891B2 (en) Materials and methods for prevention and treatment of viral infections
CN102470122A (en) Medications for long-term use of NSAIDs
AR038198A1 (en) PHARMACEUTICAL USES OF A COX-2 INHIBITOR

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application