The Selective Reduction of α,β-Unstaurated Nitriles with Sodium Borohydride in Methanolic Pyridine

Rhodes, R. A.; Boykin, David W.

doi:10.1080/00397918808077356

Cited by 18 publications

(9 citation statements)

References 10 publications

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“…Selective double-bond reduction of 21a was effectively accomplished with NaBH 4 in pyridine/methanol to give 23 , which was then converted to tetrazole 24 . Exhaustive reduction of 21 with LiAlH 4 provided amine 25 which was converted to trifluoromethylsulfonamide 26 on treatment with triflic anhydride in CH 2 Cl 2 .…”

Section: Chemistrymentioning

confidence: 99%

Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

et al. 1996

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The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

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Section: Chemistrymentioning

confidence: 99%

Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

et al. 1996

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“…Compounds 6a and b were synthesized from 1-benzyl-4-piperidone (14) using the Horner-Wadsworth-Emmons reaction to give olefin 15. Reduction of 15 using NaBH 4 , 17) followed by reduction of the nitrile and N,N-dimethylation, afforded tertiary amine 18. After debenzylation, acylation of the secondary amine gave the target compounds 6a and b.…”

Section: Synthesismentioning

confidence: 99%

“…11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.…”

mentioning

confidence: 99%

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

et al. 2016

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The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3-and 4-substituents influenced the effect mediated through the KOR.Key words antinociception; kappa opioid receptor (KOR); matrine; piperidone; acetic acid-induced abdominal contraction test; mouse Narcotic analgesics such as morphine are administered for pain relief to cancer patients. Most narcotic analgesics are µ-opioid receptor (MOR) agonists and have adverse effects such as addiction, 1) respiratory depression, 2) and constipation.3,4) Although stimulation of the κ-opioid receptor (KOR) results in significant analgesia, KOR agonists do not suffer from the same adverse effects as MOR agonists. Many KOR agonists, including ethylketocyclazocine, U-50,488H, and nalfurafine (TRK-820), have been developed and investigated for their analgesic, anti-inflammatory and antipruritic activity 5,6) ( Fig. 1). However, these agonists suffer from dose-limiting dysphoria, sedation, and psychotomimetic effects. 7,8) Consequently, the development of a KOR agonist that does not cause adverse effects is important.We previously reported that (+)-matrine (1) and (+)-allomatrine (2), typical matrine-type lupine alkaloids produced by Sophora Leguminosae, have antinociceptive properties identical to those of pentazocine.9) The effects of 1 were mediated mainly through activation of the KOR and partially through the MOR, and those of 2 were mediated only through the KOR.10) Furthermore, we found that neither 1 nor 2 provided the activation in the guanosine-5′-O-(3-[ 11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1-17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.Because the pharmacological mechanism of action and chemical structures of 1 and 2 differ from conventional KOR agonists, we performed structure-activity relationship (SAR) studies for 1 and 2 and their antinociceptive activity using modifications of the A-D ring systems. The SAR studies showed that the amide group, tertiary amine group, and Cring of 1 and 2 were important in determining their activity. 4-Dimethylamino-1-pentanoylpiperidine (3) was identified as a lead compound through the antinociceptive eff...

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“…Compound 7 was then reduced with NaBH4 in a mixture of pyridine and methanol, to give 8 by in 82% yield. 9 After the ring closure reaction, 2 was obtained as a colourless powder. The highlight of this method lies on the condensation between acetonitrile and aldehyde 4, and on its reduction by NaBH4 in the system of pyridine and methanol.…”

mentioning

confidence: 99%

A practical synthesis of 1-cyano-4,5-dimethoxybenzocyclobutene

Zhao

Liang

Shao

et al. 2009

Journal of Chemical Research

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A practical synthesis of 1-cyano-4,5-dimethoxybenzocyclobutene, the key intermediate of Ivabradine, was developed in four or five steps using two different routes. 2-Bromo-4,5-dimethoxyhydrocinnamonitrile was produced via the condensation of 2-bromo-4,5-dimethoxybenzaldehyde with acetonitrile or cyanoacetic acid and reduction by NaBH4. Cyclisation gave 1-cyano-4,5-dimethoxybenzocyclobutene. Overall yields of the routes A and B were 30% and 37% respectively. Route B is a short and simple route, permitting the synthesis of 1-cyano-4,5-dimethoxybenzocyclobutene on a large scale.

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The Selective Reduction of α,β-Unstaurated Nitriles with Sodium Borohydride in Methanolic Pyridine

Cited by 18 publications

References 10 publications

Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

A practical synthesis of 1-cyano-4,5-dimethoxybenzocyclobutene

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The Selective Reduction of α,β-Unstaurated Nitriles with Sodium Borohydride in Methanolic Pyridine

Cited by 18 publications

References 10 publications

Diphenylpropionic Acids as New AT1 Selective Angiotensin II Antagonists

Diphenylpropionic Acids as New AT1 Selective Angiotensin II Antagonists

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

A practical synthesis of 1-cyano-4,5-dimethoxybenzocyclobutene

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Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists