Cycloadditions and other chemistry of 4-oxygenated pyrazoles

Fagan, Paul J.; Neidert, Eli; Nye, M. J.; O’Hare, Michael J.; Tang, Wah-Piu

doi:10.1139/v79-149

Cited by 32 publications

(8 citation statements)

References 9 publications

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“…The heterocycle 5 has been prepared and its UV spectrum in water recorded. 40 The reported absorption peak occurs at 4.36 eV. According to our calculations, which yield very low oscillator strengths for the lower energy transition to S 1 and S 2 , the observed peak probably corresponds to a transition to a singlet state higher than S 2 .…”

Section: ■ Discussionmentioning

confidence: 47%

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

2012

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Section: ■ Discussionmentioning

confidence: 47%

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

2012

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“…2-Aminobenzene-l,3-dicarboxamide (34). Hydrogenation of 32 in DMF over a palladium-charcoal catalyst gave the amine 34 (66%) as colorless crystals from water, mp 290-292 °C.…”

Section: Methodsmentioning

confidence: 99%

Antitumor Imidazotetrazines. 32.1 Synthesis of Novel Imidazotetrazinones and Related Bicyclic Heterocycles To Probe the Mode of Action of the Antitumor Drug Temozolomide

Clark¹,

Deans²,

Stevens³

et al. 1995

J. Med. Chem.

111

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A series of new imidazo[5,1-d]-1,2,3,5-tetrazinones with additional hydrogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs temozolomide (1) and mitozolomide (2) has been prepared. None of these compounds were significantly more cytotoxic in vitro against the mouse TLX5 lymphoma than the lead structures. Molecular modeling techniques have been used to design benzo- and pyrazolo[4,3-d]-1,2,3-triazinones bearing carboxamide groups in appropriate positions which are isosteric with temozolomide and mitozolamide but which cannot ring open to alkylating species. As predicted, these compounds have no inhibitory properties against human GM892A or Raji cell lines in vitro. Temozolomide and the spermidine-temozolomide conjugate 28 preferentially methylate guanines within guanine-rich sequences in DNA, but no experimental evidence has been found to support the hypothesis that such regions are involved in catalyzing the ring opening of the imidazotetrazinone prodrugs to their active forms.

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“…i) N ‐(3‐(3,5‐Dimethyl‐1 H ‐pyrazol‐4‐yloxy)propyl)phthalimide (46) : Prepared from N ‐(3‐bromopropyl)phthalimide and 3,5‐dimethyl‐1 H ‐pyrazol‐4‐ol, as per 32 , and purification by flash chromatography (90 % EtOAc/petroleum spirits) afforded the title compound (290 mg, 25 %). 1 H NMR (400 MHz, CDCl 3 ): δ =2.07 (2 H, dd, J =13.6, 6.4 Hz, CH 2 CH 2 N), 2.19 (6 H, s, 2×CH 3 ), 3.86 (4 H, td, J =6.6, 4.7 Hz, CH 2 N,CH 2 O), 7.67 (2 H, dd, J =5.4, 3.1, Ar), 7.81 ppm (2 H, dd, J =5.5, 3.1 Hz, Ar); 13 C NMR (100 MHz, CDCl 3 ): δ =9.8, 29.2, 35.4, 72.0, 123.2, 132.1, 140.0, 134.6, 138.9, 168.4 ppm; HRMS‐ESI m / z calcd for [C 16 H 17 N 3 O 3 +H] + : 300.1343, found: 300.1341.…”

Section: Methodsmentioning

confidence: 99%

Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel Na_V1.2‐Subtype‐Selective Inhibitors

et al. 2019

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We previously reported that a lipophilic N‐(4′‐hydroxy‐3′,5′‐di‐tert‐butylbenzyl) derivative (1) of the voltage‐gated sodium channel blocker mexiletine, was a more potent sodium channel blocker in vitro and in vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di‐tert‐butylphenol with an achiral 1,3‐propylene linker (to give (2)) maintains potency in vitro. We synthesized 25 analogues bearing the 1,3‐propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV1.2 and 1.6 channels by high‐throughput patch‐clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV1.2 inhibitors and >500 times less potent in inhibiting NaV1.6 channels. On the other hand, a derivative (compound 4) bearing 2,6‐dimethoxy groups in place of the 2,6‐dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective against both channels in the tonic, frequency‐dependent and inactivated states. In a kindled mouse model of refractory epilepsy, compound 2 inhibited seizures induced by 6 Hz 44 mA electrical stimulation with an IC50 value of 49.9±1.6 mg kg−1. As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco‐resistant epilepsy.

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Cycloadditions and other chemistry of 4-oxygenated pyrazoles

Cited by 32 publications

References 9 publications

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

Antitumor Imidazotetrazines. 32.1 Synthesis of Novel Imidazotetrazinones and Related Bicyclic Heterocycles To Probe the Mode of Action of the Antitumor Drug Temozolomide

Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel Na_V1.2‐Subtype‐Selective Inhibitors

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Cycloadditions and other chemistry of 4-oxygenated pyrazoles

Cited by 32 publications

References 9 publications

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

Search for a Small Chromophore with Efficient Singlet Fission: Biradicaloid Heterocycles

Antitumor Imidazotetrazines. 32.1 Synthesis of Novel Imidazotetrazinones and Related Bicyclic Heterocycles To Probe the Mode of Action of the Antitumor Drug Temozolomide

Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel NaV1.2‐Subtype‐Selective Inhibitors

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Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel Na_V1.2‐Subtype‐Selective Inhibitors