WO1989001478A1 - IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO - Google Patents

IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO Download PDF

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Publication number
WO1989001478A1
WO1989001478A1 PCT/AU1988/000291 AU8800291W WO8901478A1 WO 1989001478 A1 WO1989001478 A1 WO 1989001478A1 AU 8800291 W AU8800291 W AU 8800291W WO 8901478 A1 WO8901478 A1 WO 8901478A1
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WIPO (PCT)
Prior art keywords
compound
substituted
methoxy
mixture
formula
Prior art date
Application number
PCT/AU1988/000291
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English (en)
Inventor
Gordon Bruce Barlin
Leslie Philip Davies
Stephen James Ireland
Maria Mee Leng Ngu
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The Australian National University
University Of Sydney
Australasian Drug Development Limited
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
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Application filed by The Australian National University, University Of Sydney, Australasian Drug Development Limited filed Critical The Australian National University
Priority to PCT/AU1988/000291 priority Critical patent/WO1989001478A1/fr
Publication of WO1989001478A1 publication Critical patent/WO1989001478A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms

Definitions

  • This invention relates to imidazo[1,2-b]- pyridazine compounds, and in particular it relates to a group of imidazo[1,2-b]pyridazines bearing substituents in the 2-, 3- and 6- positions which have been found to interact with the receptors in the central nervous system which mediate the anxiolytic, anticonvulsant, muscle-relaxant, hypnotic and other activities of the benzodiazepine class of drugs.
  • X is a group of the formula -OAr or-SCH 2 Ar, where Ar is aryl or substituted aryl (including phenyl or substituted phenyl);
  • Y is a group of the formula OR, where R is alkyl
  • aryl groups represented by X and Z are phenyl and ⁇ - and ⁇ -naphthyl groups, however other aryl groups are encompassed within the scope of this invention.
  • Preferred heteroaryl groups represented by Z are ⁇ -, ⁇ - and ⁇ -pyridyl and ⁇ - and ⁇ -thienyl groups, however other heteroaryl groups are also encompassed within the scope of this invention.
  • Preferred optional substituents on the groups represented by X and Z include one or more alkyl (particularly methyl), alkoxy (particularly methoxy), alkylthio (particularly methylthio), halo (particularly fluoro, chloro or bromo), trifluoromethyl, dialkylamino (particularly dimethylamino), nitro or amino groups.
  • Particularly preferred compounds of the general formula IV are compounds wherein:
  • X is phenoxy or substituted phenoxy, or benzylthio or substituted benzylthio;
  • Y is selected from methoxy or ethoxy; and Z is selected from phenyl or substituted-phenyl, or pyridyl.
  • the present invention provides a pharmaceutical composition for use in treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises a compound of the general formula IV as broadly described above, in association with a pharmaceutically acceptable carrier or diluent.
  • this invention comprises a method for the treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises administration of an effective amount of a compound of the general formula IV as broadly described above.
  • the starting materials for the reaction schemes set out above may be prepared from 3,6-dichloropyridazine as follows :
  • Specific tests performed to investigate this biological activity include a test for displacement of 3 H-diazepam from rat brain membranes.
  • 6-Phenoxypyridazin-3-amine 6-Chloropyridazin-3-amine (1.0g; Steck, Brundage and Fletcher, J. Am. Chem. Soc. 1954, 76, 3225) and aqueous sodium phenoxide (prepared from 0.6 g sodium hydroxide in 15 ml water with 2.0 g phenol) were heated in a screw-top bomb at 170° for 16 h. After cooling, the solid was filtered off, washed with 1M sodium hydroxide and water, dried and recrystallised from benzene to give 6-Phenoxypridazin-3-amine (0.5 g), m.p.
  • 6-Chloropyridazin-3-amine (1 g) and aqueous sodium 2- chlorophenoxide (prepared from 0.8 g sodium hydroxide in 15 ml water with 2.57 g of 2-chlorophenol) were heated in a screw top bomb at 160° for 14 h. After cooling the product was extracted into chloroform, extract washed with M sodium hydroxide and water and dried (Na 2 SO 4 ). The solvent was evaporated and the product (1.0 g) recrystallised from toluene to give 6-(2'- chlorophenoxy)pyridazin-3-amine, m.p.
  • 6-(3'-Nitrophenoxy)pyridazin-3-amine 6-Chloropyridazin-3-amine (1.0 g) and aqueous sodium 3- nitrophenoxide (prepared from 0.6 g sodium hydroxide and 12 ml water with 2.2 g 3-nitrophenol) were heated in a screw top bomb at 160° for 16 h. After cooling and adjusting to pH 12-13 the reaction mixture was extracted with chloroform, the extract washed with M sodium hydroxide and water and dried (Na 2 SO 4 ). The solvent was evaporated and the product recrystallised from toluene to give 6-(3'-nitrophenoxy)pyridazin-3-amine (0.52 g), m.p.
  • 6-Chloropyridazin-3-amine 2-oxide (1.0 g; Itai and Nakashima Chem. Pharm. Bull., 1962, 10. 936) and aqueous sodium 3- nitrophenoxide (prepared from 0.56 g sodium hydroxide, 1.82 g 3- nitrophenol and 10 ml water) were heated in a screw top reaction vessel at 155° for 16 h. After cooling the mixture was adjusted to pH 12-13, chilled, and the solid (0.6 g) was filtered off and washed with water and ether. The product was recrystallised from a mixture of methanol and ethanol to give 6-(3'- nitrophenoxy)pyridazin-3-amine 2-oxide, m.p.
  • 6-Aminopyridazine-3-thiol 6-Aminopyridazine-3-thiol was prepared from 6- chloropyridazin-3-amine through 3-acetamido-6-chloropyridazine and 6-acetamidopyridazine-3-thiol as described by Kumagai and
  • 6-Aminopyridazine-3-thiol (0.15 g) was dissolved in a solution of 0.25 M sodium hydroxide (6.0 ml) and stirred with 2- methylbenzyl chloride (0.18 g) at 20° for 3 h. The precipitate was collected and recrystallised from toluene to give 6-(2'- methylbenzylthio)pyridazin-3-amine (0.160 g), m.p. 93-94° (Found, for a sample dried at 60° and 0.1 mm Hg for 8 h: C, 62.1; H, 6.0;
  • 6-Aminopyridazin-3-thiol (0.35 g) in a solution of sodium hydroxide (0.15 g) and water (15 ml) was shaken with 3- chloromethylbenzotrifluoride (0.57 g) for 4 h.
  • [1.2-b]pyridazine as an oil (0.040 g) (Found, for a sample dried at 40° and 0.1 mmHg for 5 h: C, 66.9; H, 5.2. C 21 H 19 N 3 O 2 S requires C, 66.8; H, 5.1%).
  • 1 H n.m.r. (CDCl 3 ): 8 3.82, s, 3'-OMe 4.12, s, 3-OMe; 4.48, s, CH 2 ; 6.80, d, J 7,8 9 Hz, H7; 7.66, d, J 7,8 9 Hz, H8; 7.07-8.16, complex, H2',4',5',6' and Ph.
  • 6-Chloropyridazin-3-amine 2-oxide 3 (1.0 g) with crude 3- methoxybenzylthiol (1.3 g) and 0.5M sodium hydroxide (20 ml) were heated in a sealed reaction vessel at 115° for 16 h. The product was extracted into chloroform, washed with M sodium hydroxide and water and dried (Na 2 SO 4 ) sulphate. After evaporation of the solvent the solid was recrystallised from benzene to give 6-(3'- methoxybenzylthio)pyridazin-3-amine 2-oxide (1.16 g), m.p. 127- 128° (Found: C, 55.0; H, 5.0; N, 15.9.
  • aliquots of the membrane suspension (approx.0.6-0.8mg protein) were incubated with tritiated diazepam (86.6 Ci/mmol, 0.70 + - 0.05 nM final concentration) and 3 to 5 separate concentrations of the test compounds, in a final volume of 2 ml of 50 mM Tris-HCl buffer. Assays were conducted on ice for an incubation period of 35 min. Unless otherwise stated, assays also contained 100 ⁇ M GABA to stimulate the binding of the ligand to the benzodiazepine receptors in the plasma membranes. Nonspecific binding was determined in separate tubes by the addition of a large excess (10 ⁇ M) of unlabelled diazepam.
  • Membranes were collected by filtration under vacuum on glass-fibre filters (Whatman GF/B, 2.4 cm) and washed with 12 ml of ice-cold buffer. Filters were placed in scintillation vials with 1 ml of water and 8 ml of toluene/triton X-100 scintillation fluid; bound radioactivity was determined using conventional techniques. Test compounds (imidazo[1,2-b]pyridazines) were routinely tested at 4 separate concentrations; within each experiment all assays were performed in triplicate.

Abstract

Les composés d'imidazo[1,2-b]pyridazine décrits, ayant un substituant aryloxy ou aralkylthio en position 6 et également substitués aux positions 2 et 3, sont utiles dans le traitement des syndromes d'angoisse, de l'épilepsie, de l'insomnie ou des tensions musculaires transosseuses ou pour inverser les effets sédatifs de médicaments appartenant à la classe des benzodiazépines.
PCT/AU1988/000291 1987-08-07 1988-08-05 IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO WO1989001478A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/AU1988/000291 WO1989001478A1 (fr) 1987-08-07 1988-08-05 IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AU361787 1987-08-07
AUPI3617 1987-08-07
PCT/AU1988/000291 WO1989001478A1 (fr) 1987-08-07 1988-08-05 IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202324A (en) * 1989-01-31 1993-04-13 Takeda Chemical Industries, Ltd. Imidazopyridazines
EP0305093B1 (fr) * 1987-08-15 1994-04-06 The Wellcome Foundation Limited Dérivés de l'imidazo[1,2-b]pyridazine
WO1995010521A1 (fr) * 1993-10-13 1995-04-20 Knoll Ag Agents therapeutiques
WO1996032393A1 (fr) * 1995-04-08 1996-10-17 Knoll Aktiengesellschaft Derives de 1,2,4-triazolo[4,3-b]pyridazine et leur utilisation
US7868001B2 (en) * 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
US8034812B2 (en) 2006-08-04 2011-10-11 Takeda Pharmaceutical Company Limited Imidazopyridazine derivative having kinase inhibitory activity and pharmaceutical agent thereof
CN103261198A (zh) * 2010-12-22 2013-08-21 江苏恒瑞医药股份有限公司 2-芳基咪唑并[1, 2-b]哒嗪、2-苯基咪唑并[1, 2-a]吡啶、和2-苯基咪唑并[1, 2-a]吡嗪衍生物
JP2018509416A (ja) * 2015-03-12 2018-04-05 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ 複素環置換二環式アゾール殺有害生物剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464372A (en) * 1982-08-16 1984-08-07 Schering Corporation Imidazo[1,2-b]pyridazines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464372A (en) * 1982-08-16 1984-08-07 Schering Corporation Imidazo[1,2-b]pyridazines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AUSTRALIAN JOURNAL OF CHEMISTRY, Volume 36, No. 6, issued June 1983, GORDON B. BARLIN et al., "Imidazo-(1,2-b) pyridazines and an Imidazo (1,2-a) pyrizine from Pyridazin- and Pyrazin-amines" see pages 1215 to 1220. *
AUSTRALIAN JOURNAL OF CHEMISTRY, Volume 39, No. 11, issued November 1986, GORDON B. BARLIN, "Imidazo (1,2-b) pyridazines I. Some 3-Alkoxy-6-halogeno-2-phenyl- (and 4'-substituted phenyl) imidazo (1,2-b)-pyridazines and 3-Methoxy-2,6-diphenylimidazo (1,2-b) pyridazine", see pages 1803 to 1809. *
AUSTRALIAN JOURNAL OF CHEMISTRY, Volume 40, No. 8, issued August 1987, GORDON B. BARLIN and STEPHEN J. IRELAND, "Imidazo (1,2-b) pyridazines. II 6-Alkylthio- and 6-Arylthio-3-methoxy-2-phenylimidazo (1,2-b) pyridazines", see pages 1491 to 1497. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305093B1 (fr) * 1987-08-15 1994-04-06 The Wellcome Foundation Limited Dérivés de l'imidazo[1,2-b]pyridazine
US5202324A (en) * 1989-01-31 1993-04-13 Takeda Chemical Industries, Ltd. Imidazopyridazines
CN1040537C (zh) * 1993-10-13 1998-11-04 克诺尔有限公司 取代的1,2.4－三唑并[1,5－a]嘧啶类其制备方法以及含有它的药物组合物
WO1995010521A1 (fr) * 1993-10-13 1995-04-20 Knoll Ag Agents therapeutiques
AU679573B2 (en) * 1993-10-13 1997-07-03 Knoll Aktiengesellschaft Therapeutic agents
US5753665A (en) * 1993-10-13 1998-05-19 Knoll Aktiengesellschaft Therapeutic agents
WO1996032393A1 (fr) * 1995-04-08 1996-10-17 Knoll Aktiengesellschaft Derives de 1,2,4-triazolo[4,3-b]pyridazine et leur utilisation
US5905079A (en) * 1995-04-08 1999-05-18 Knoll Aktiengesellschaft 1,2,4-triazolo 4,3-b!pyridazine derivatives and their use
US8034812B2 (en) 2006-08-04 2011-10-11 Takeda Pharmaceutical Company Limited Imidazopyridazine derivative having kinase inhibitory activity and pharmaceutical agent thereof
US8044049B2 (en) 2006-08-04 2011-10-25 Takeda Pharmaceutical Company Limited Fused heterocyclic derivative and use thereof
US8273741B2 (en) 2006-08-04 2012-09-25 Takeda Pharmaceutical Company Limited Imidazo-pyridazinyl compounds and uses thereof
US7868001B2 (en) * 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
CN103261198A (zh) * 2010-12-22 2013-08-21 江苏恒瑞医药股份有限公司 2-芳基咪唑并[1, 2-b]哒嗪、2-苯基咪唑并[1, 2-a]吡啶、和2-苯基咪唑并[1, 2-a]吡嗪衍生物
JP2018509416A (ja) * 2015-03-12 2018-04-05 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ 複素環置換二環式アゾール殺有害生物剤

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