Diuretics. V. 3,4-Dihydro-1,2,4-benzothiadiazine 1,1-Dioxides

Whitehead, Calvert W.; Traverso, John J.; Sullivan, Hugh R.; Marshall, Frederick J.

doi:10.1021/jo01066a046

Cited by 25 publications

(20 citation statements)

References 1 publication

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“…of a mixture of 3 + 4. The relative area of the peak at 910 to that of the broad doublet at 718 (due to 3) and 666 (due to 4) determined for the 42 : 58 and 14: 85 mixtures is 16 and @%, , respectively. Therefore to deter- mine the percentage of 3 in a mixture of 3 + 4, the percent area of the 910 peak to the 718-666 doublet is multiplied by 2.6.…”

Section: Introductionmentioning

confidence: 84%

Solvolysis of Substituted Nortricyclanes and Norbornenes at 250°

Kadai¹

1972

Can. J. Chem.

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Solvolysis of nortricyclyl bromide ( l o ) , nortricyclyl chloride ( l b ) , nortricyclanol ( l c ) , and 5-and 7-norbornenols (26, 7 ) and e.~o-2,3-epoxybicyclo[2.2.I]heptane (11) in 10% v/v acetic acid-water at 250' yields 2-(cyclopentene)acetaldehyde ( 3 ) , 3-(cyclopentene)acetaldehyde (4), 3-(cyclohexene)carboxaldehyde ( 5 ) , norcamphor (6)-and norbornanediols. In each case the diol concentration builds up then decreases as the conversion to 3, 4, 5, and 6 occurs. When the substrates l a , b, and c, 26, 7, 10a, and 11 are solvolyzed in deuterated medium, deuterium other than cc to the carbornyl group is incorporated into the aldehydes and norcamphor.La solvolyse du bromure de nortricyclyle ( l o ) , chlorure de nortricyclyle ( I b ) nortricyclanol ( l c ) , norbornenols-5 et -7 (26, 7 ) , eso-epoxy-2,3 bicyclo[2.2.1] heptane ( I ] ) , dans un melange a 10% en volume d'acide acetique-eau a 250"; conduit au cyclopentene-2 acetaldehyde (3), cyclopentene-3 acetaldehyde (4). cyclohexene-3 carboxaldehyde (5). norcamphre (6), et norbonanediols. Dans tous les cas, la concentration en diol croit puis diminue au fur et a mesure que la conversion en 3, 4, 5, et 6 s'effectue. Quand les substrats lo, lb, et c, 2b,7, 100, et 1 1 sont solvolyses en milieu deuterie, un deuterium autre que celui en cc du groupe carbonyle est incorpori. dans les aldehydes et le norcamphre.

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Section: Introductionmentioning

confidence: 84%

Solvolysis of Substituted Nortricyclanes and Norbornenes at 250°

Kadai¹

1972

Can. J. Chem.

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“…In this reaction 5-norbornene-2-carboxaldehyde (1) is condensed with 6-amino-4-chloro-l,3-benzenedisulfonamide (2) in a mixture of hydrochloric acid and ethanol. Whitehead et al 13 did not mention any stereochemical aspects of cyclothiazide. Several patents based on aldehyde 1 or an imine derivative thereof have been issued for the synthesis of cy~lothiazide.…”

Section: Resultsmentioning

confidence: 99%

“…Cyclothiazide via reaction W: The reaction conditions given by Whitehead et al 13 were used, except that the precipitated product was not recrystallized. Cyclothiazide via reaction IPA: 6-amino-4-chloro-1,3-benzenedisulfonamide (29 mg), 5-norbornene-2-carboxaldehyde (12 mg), and isopropyl alcohol (400 pl) were placed in vial, and the vial was tightly capped and placed in a heating block.…”

Section: Synthesesmentioning

confidence: 99%

Excavations in drug chirality: 1. Cyclothiazide

1991

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There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.

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“…[33][34][35][36] It is no surprise then that this drug acts as a negative allosteric modulator of the GABA A receptor. [40][41][42][43][44] Information about the stereochemical consistency of this drug is very limited. 39 Cyclothiazide (12) was first synthesised in 1961 from the condensation of norbornenal (15) and 6-amino-4-chlorobenzenel,3-disulfonamide (16), which is obtained from m-chloroaniline (17), in 46% overall yield (Scheme 2).…”

Section: Cyclothiazidementioning

confidence: 99%

“…111,112 It is most popularly marketed as Suboxonet (Reckitt Benckskiser), a buprenorphine hydrochloride and naloxone hydrochloride mix, which is used as an opioid agonist/antagonist to treat opioid dependence. 114 Buprenorphine can actually be classified as a thevinol and an orvinol, as it can be derived from both thebaine and orvipavine (41). Further applications include intravenous, sublingual, implants and transdermal patches.…”

Section: Buprenorphinementioning

confidence: 99%

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

2015

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Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.

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Diuretics. V. 3,4-Dihydro-1,2,4-benzothiadiazine 1,1-Dioxides

Cited by 25 publications

References 1 publication

Solvolysis of Substituted Nortricyclanes and Norbornenes at 250°

Solvolysis of Substituted Nortricyclanes and Norbornenes at 250°

Excavations in drug chirality: 1. Cyclothiazide

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

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