WO2009051504A1 - Benzo- et pyridopyridazinones présentant une activité analgésique et anti-inflammatoire - Google Patents

Benzo- et pyridopyridazinones présentant une activité analgésique et anti-inflammatoire Download PDF

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Publication number
WO2009051504A1
WO2009051504A1 PCT/PL2008/000070 PL2008000070W WO2009051504A1 WO 2009051504 A1 WO2009051504 A1 WO 2009051504A1 PL 2008000070 W PL2008000070 W PL 2008000070W WO 2009051504 A1 WO2009051504 A1 WO 2009051504A1
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WO
WIPO (PCT)
Prior art keywords
straight
branched alkyl
compounds
alkenyl
phenyl
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/PL2008/000070
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English (en)
Inventor
Jan Epsztajn
Elzbieta Czarnecka
Aleksandra Szczesniak
Wanda Pakulska
Zbigniew Malinowski
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.)
UNIWERSYTET LODSKI
Original Assignee
UNIWERSYTET LODSKI
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Application filed by UNIWERSYTET LODSKI filed Critical UNIWERSYTET LODSKI
Publication of WO2009051504A1 publication Critical patent/WO2009051504A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to novel derivatives of benzo- and pyridopyridazinones likewise to pharmaceuticals containing benzo- and pyridopyridazinones.
  • the new compounds stimulates central nervous system exhibiting analgesic and anti-inflammatory activity.
  • phoshodiesterase PDE the enzyme that acts in the transformation of cyclic nucleotides, which affect hormone functioning, cellular transport and vision.
  • the invention relates to novel phthalazinone and pyridopyridazinone derivatives of formulas I and II and their pharmaceutically tolerable salts.
  • n is an integer from 1 to 8 for straight or branched alkyl or alkenyl
  • Rl is -NR7R8, where R7, R8 are
  • aryl or heteroaryl e.g. phenyl, pyridyl
  • aryl [phenyl, monosubstitued (2 or 3 or 4 position) or disubstituted (2,3 or 3,4 positions) benzene ring (straight or branched alkyl (Cl - C6), RlOO-, where RlO is straight or branched alkyl (C1-C4), halogen (F, Cl, Br, I); -COZ, where Z is
  • aryl e.g. phenyl, monosubstituted (2 or 3 or 4 position) benzene ring: straight or branched alkyl (C1-C4), RlOO- (straight or branched alkyl or alkenyl (C1-C6), halogen (F, Cl, Br, I)
  • R12 is straight or branched alkyl (C1-C6), aryl (substituted in 2 or/and 3 or/and 4 or/and 5 or/and ⁇ position, or halogen (F, Cl, Br, I) poli-substituted benzene ring)
  • R2 is:
  • RlOO- (RlO is straight or branched alkyl (C 1 -C6)
  • the compounds according to the invention containing acidic or basic functional groups can be transformed into water-soluble salts, which are physiologically more useful than starting derivatives.
  • lithium, sodium, potassium, calcium magnesium, aluminium and etc. salts of mentioned derivatives are the examples of pharmaceutically tolerable compounds, but not exclusively.
  • the conversion of compounds I and II into related salts is carried out with one or several equivalents of base or using ion- exchange resins.
  • Non-toxic addition salts of the compounds according to the invention with inorganic and organic bases e.g. ammonium salts, quaternary ammonium salts and other salts of base containing nitrogen are also acceptable.
  • Basic group or groups present in the compounds according to the invention can react with non-toxic inorganic acids such as hydrochloric acid, nitric acid, orthophosphoric acid, sulphuric acid, hydrobromic acid, phosphorous acid as well as with non-toxic organic acids such as mono- and dicarboxylic aliphatic acids, phenyl substituted alkanocarboxylic acids, alkanocarboxylic hydroxyacids, alkanodicarboxylic acids, aromatic acids, aliphatic and aromatic sulphonic acids, forming salts, but not exclusively, such as bicarbonates, bisulphates, bitartrates, borates, bromides, iodides, carbonates, chlorides, fluorides, nitrates, phosphates, sulphates, acetates, benzenesulphonates, benzoates, citrates, fumarates, gluconates.,, glutamates, glucoarsanilates, hexylresor
  • some of the compounds can contain one or more chiral centres, so they can exist in optically active form. If the compounds contain alkenyl or alkynyl groups isomers E/Z (cis/trans) are possible.
  • the invention relates to isomers of absolute configuration R and S, including racemic mixtures, as well as isomers cis and trans and their mixtures. Additional asymmetric carbon atoms in substituents e.g. alkyl are possible. All this isomers and their mixtures are granted protection.
  • the invention relates also to pharmaceuticals containing as active component novel phthalazinone and pyridopyridazinone derivatives as well as pharmaceuticals with additives and/or media or solvents that are pharmaceutically tolerable according to the invention.
  • the invention relates also to the application of the newly synthesised benzo- and pyridopyridazinones, described in the invention as analgesic and anti-inflammatory drugs.
  • Compounds of formula I or II are the active components of pharmaceutic composition, while typical solids like lactose, calcium sulphate, saccharose, talc, gelatine, agar, pectin, magnesium stearate, cellulose derivatives can be used as useful carriers. Water, syrup, fatty acids and olive oil can serve as solvents.
  • compositions comprise the compounds according to the invention are obtained using typical techniques described in Remington's Pharmaceutical Sciences.
  • hydrogen atom of the NH- group present in starting phthalazinone or pyridopyridazinone is removed by a base such as potassium carbonate, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide in a suitable solvents such as dimethylsulphoxide, dimethylformamide, tetrahydrofuran.
  • a base such as potassium carbonate, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide in a suitable solvents such as dimethylsulphoxide, dimethylformamide, tetrahydrofuran.
  • one or more functional groups present in compounds I, II, III, IV, V or VI may be transformed into another functional group, using known methods.
  • the conversions of compounds according to the invention are carried out analogous to known methods described in the literature, for example in the manner, which is described in the following examples.
  • the substances (products and substrates) according to the invention are isolated and purified in manners known per se, e. g. subjecting to column chromatography on a suitable support material, recrystallizing from a suitable solvent as well as vacuum distillation.
  • the salts of corresponding compounds are obtained by dissolving the free compound in a low molecular weight aliphatic alcohol, e.g. methanol, which contains the desired acid or base, or to which the desired acid or base is then added. Evaporating the solvent, precipitating with a non-solvent for the additional salt, reprecipitating or filtering, allow to isolate the salts.
  • the salts obtained can be transformed by basification or by acidifying into the free compounds, in turn, can be converted into salts pharmacologically tolerable.
  • the investigating of anti-inflammatory activity consists in estimation of decreasing in inflammatory state, caused by pro-inflammatory agent.
  • Karagenine is quite often used agent causing paw inflammatory oedema.
  • Analgesic activity of the investigated compounds was tested on Balb/c male mice and was compared with the strong analgesic, which is metamizole.
  • the compounds according to the invention have useful pharmacological properties, which make them industrially utilizable.
  • the acute toxicity is the strong toxic effect, which occurs in a short time after giving the tested compound in a single dose or during 24 hours after giving the multiple dose.
  • This kind of tests, performed on animals, should give the answers to several basic questions: (a) What dose of the compound is needed to cause death of an animal? (b) What organs are damaged in strong intoxication? (c) Has the tested compound allergenic or irritating activity?
  • the acute toxicity is usually tested on mice and rats. The experiments on male and female animals are recommended in the first evaluation. The acute toxicity is determined quantitatively as the medial lethal dose DL 50 , i.e. dose causing dead of 50% of the animals subjected to the experiments.
  • the acute toxicity of the tested compounds was evaluated according to the classification obligatory in the countries of The European Union and recommended by OECD.
  • the acute toxicity of the compounds was compared with the toxicity of metamizole, which is the active component of commonly used analgetic medicament.
  • the LD 50 values for tested compounds were given in Table 2.
  • mice The LD 50 (mg/kg) of the compounds (p.o. administration) for mice.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de phtalazinone et de pyridopyridazonone de formule (I) et (II) ayant des applications pratiques en tant qu'analgésiques et médicaments anti-inflammatoires. Dans ces formules, n représente un nombre entier de 1 à 8 pour un groupe alkyle ou alcényle linéaire ou ramifié et R1 représente -NR7R8; -COZ; M représente azote (N) et G = Y = X = carbone (C); R3 = pas de substituant; G représente azote (N) et M = Y = X = carbone (C); R4 = pas de substituant; Y représente azote (N) et M = G = X = carbone (C); R5 = pas de substituant; X représente azote (N) et M = G = Y = carbone (C); R6 = pas de substituant et les sels de ces composés.
PCT/PL2008/000070 2007-10-15 2008-09-26 Benzo- et pyridopyridazinones présentant une activité analgésique et anti-inflammatoire Ceased WO2009051504A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL383550A PL383550A1 (pl) 2007-10-15 2007-10-15 Nowe pochodne benzeno- i pirydopirydazynonów
PLP383550 2007-10-15

Publications (1)

Publication Number Publication Date
WO2009051504A1 true WO2009051504A1 (fr) 2009-04-23

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PCT/PL2008/000070 Ceased WO2009051504A1 (fr) 2007-10-15 2008-09-26 Benzo- et pyridopyridazinones présentant une activité analgésique et anti-inflammatoire

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PL (1) PL383550A1 (fr)
WO (1) WO2009051504A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022509534A (ja) * 2018-10-30 2022-01-20 ニューベイション・バイオ・インコーポレイテッド Ｂｅｔ阻害剤としてのヘテロ環式化合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB808636A (en) * 1955-08-02 1959-02-11 Cassella Farbwerke Mainkur Ag Basically substituted heterocyclic compounds
EP0242173A1 (fr) * 1986-04-16 1987-10-21 Pfizer Limited Agents antiarhytmiques
EP0309765A2 (fr) * 1987-09-30 1989-04-05 Fisons Corporation 1(2H)-Phtalazinones comme médicaments cytoprotectifs
WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB808636A (en) * 1955-08-02 1959-02-11 Cassella Farbwerke Mainkur Ag Basically substituted heterocyclic compounds
EP0242173A1 (fr) * 1986-04-16 1987-10-21 Pfizer Limited Agents antiarhytmiques
EP0309765A2 (fr) * 1987-09-30 1989-04-05 Fisons Corporation 1(2H)-Phtalazinones comme médicaments cytoprotectifs
WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DENIZ S. DOGRUERA, ESRA KUPELIB, ERDEM YESILADAB, M. FETHI SAHINA: "Synthesis of New 2-[1(2H)-Phthalazinon-2-yl]-acetamide and 3-[1(2H)-Phthalazinon-2-yl]-propanamide Derivatives as Antinociceptive and Anti-inflammatory Agents", ARCH. PHARM. PHARM. MED. CHEM., vol. 337, no. 6, 2 June 2004 (2004-06-02), pages 303 - 310, XP002516615 *
GALVEZ J ET AL: "TOPOLOGICAL APPROACH TO ANALGESIA", JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, AMERICAN CHEMICAL SOCIETY, COLOMBUS,OHIO, US, vol. 34, no. 5, 1 January 1994 (1994-01-01), pages 1198 - 1203, XP000907050, ISSN: 0095-2338 *
NICOLETTA CESARI, CLAUDIO BIANCALANI, CLAUDIA VERGELLI, VITTORIO DAL PIAZ, ALESSIA GRAZIANO,: "Arylpiperazinylalkylpyridazinones and Analogues as Potent and Orally Active Antinociceptive Agents: Synthesis and Studies on Mechanism of Action", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 26, 6 December 2006 (2006-12-06), pages 7826 - 7835, XP002516616 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022509534A (ja) * 2018-10-30 2022-01-20 ニューベイション・バイオ・インコーポレイテッド Ｂｅｔ阻害剤としてのヘテロ環式化合物

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