6‐(substituted phenyl)‐5‐methyl‐4,5‐dihydro‐pyridazin‐3(2<i>H</i>)‐ones of medicinal interest. The synthesis of SK&amp;F 94836 and SK&amp;F 95654

Burpitt, B. E.; Crawford, L. P.; Davies, Brian; Mistry, J.; Mitchell, Mark B.; Pancholi, K. D.; Coates, W. J.

doi:10.1002/jhet.5570250615

Cited by 15 publications

(8 citation statements)

References 20 publications

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“…Removal of the CBZ (carbobenzyloxy) protecting group from 4 was readily achieved under catalytic hydrogenation conditions. Treatment of the resulting diamine intermediate 5 with dimethyl N -cyanodithioiminocarbonate provided the seven-membered cyclic cyanoguanidines 6 in 61% yield …”

Section: Synthesis Of Cyanoguanidinesmentioning

confidence: 99%

Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies

et al. 1998

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Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information.

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Section: Synthesis Of Cyanoguanidinesmentioning

confidence: 99%

Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies

et al. 1998

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“…The selected acid chloride (maximum of 2.5 mmol) was diluted with dichloromethane (10 mL) and added to a solution of aniline 1 , 2 , or 20 (2.5 mmol) in pyridine (75 mL) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP).…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis of γ-keto acids 5 − 8 has already been described in previous articles. ,, Aniline 1 was prepared from 6-(4-nitrophenyl)-2 H -pyridazin-3-one, which was obtained according to literature procedures by reduction of the nitro group with Fe in a mixture of butanol, water, and HCl. The synthesis of aniline 2 has also been described in the literature …”

Section: Chemistrymentioning

confidence: 99%

“…Hybrids 29, 30, 32, 34, and 36 were synthesized as depicted in Scheme 1. In this approach, 6-(4-aminophenyl)-2H-pyridazin-3-one (1, R 3 ) A) and 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone 30 (2, R 3 ) B) were converted into the corresponding arylhydrazines 3 and 4 by treatment with nitrous acid, which was generated in situ from sodium nitrite, and by subsequent reduction of the resulting aryldiazonium ions with tin(II) chloride according to literature procedures. 31 Condensation of arylhydrazine 3 with 6-(3,4dimethoxybenzoyl)cyclohex-3-enecarboxylic acid (5) in pyridine at reflux temperature provided hybrid 29 in good yield.…”

Section: Chemistrymentioning

confidence: 99%

“…The synthesis of aniline 2 has also been described in the literature. 30 Scheme 2 shows the general synthetic procedure for analogues 37-41 containing an amide linker. Phthalazinone 9 26 was treated with sodium hydride and ethyl bromoacetate to afford ester 10, which was hydrolyzed without further purification in a mixture of 2 N KOH, THF, and MeOH, yielding the acetic acid derivative 11.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Structure−Activity Relationships ofcis-Tetrahydrophthalazinone/Pyridazinone Hybrids: A Novel Series of Potent Dual PDE3/PDE4 Inhibitory Agents

Mey¹,

Bommele²,

Boss³

et al. 2003

J. Med. Chem.

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In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC(50) = 7.0-8.7), whereas the pIC(50) values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30 micromol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.

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2000

Chemistry of Heterocyclic Compounds: A Series of Monographs

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6‐(substituted phenyl)‐5‐methyl‐4,5‐dihydro‐pyridazin‐3(2H)‐ones of medicinal interest. The synthesis of SK&F 94836 and SK&F 95654

Cited by 15 publications

References 20 publications

Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies

Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies

Synthesis and Structure−Activity Relationships ofcis-Tetrahydrophthalazinone/Pyridazinone Hybrids: A Novel Series of Potent Dual PDE3/PDE4 Inhibitory Agents

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