70. Synthetic antimalarials. Part III. Some derivatives of mono- and di-alkylpyrimidines

Hull, Roy; Lovell, B. J.; Openshaw, Harry; Payman, L. C.; Todd, A. R.

doi:10.1039/jr9460000357

Cited by 26 publications

(11 citation statements)

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“…On the other hand the alternative hypothesis that an interference with an adenosine-containing enzyme system might result in antimalarial activity has led to the preparation of successful antimalarial compounds (Hull et al, 1946(Hull et al, , 1947. A biochemical relationship between adenosine derivatives and antimalarials may be found in the observation (Hellerman, Bovarnick, and Potter, 1946) that adenylic acid and adenosine triphosphate prevent the inhibition which mepacrine causes in the recovery of oxygen uptake by washed Plasmodium lophurae in the presence of glucose.…”

Section: Discussionmentioning

confidence: 93%

“…Others were obtained from Professor A. R. Todd (Hull, Lovell, Openshaw, Payman, and Todd, 1946;Hull, Lovell, Openshaw, and Todd, 1947). Quinidine and hydroquinidine were a gift of Messrs. Amsterdamshe Chininefabriek, Amsterdam.…”

Section: Methodsmentioning

confidence: 99%

“…Alkylpyrimidines (Hull, Lovell, Openshaw, Payman, and Todd, 1946;Hull, Lovell, Openshaw, and Todd, 1947) Because only small samples of these compounds were available, they were not tested in a full range of doses. For this reason it was neither possible to study the relative order of the intensities of their antagonisms nor to compare these with their antimalarial activities.…”

Section: Antimalarials -As Adenosine Antagonistsmentioning

confidence: 99%

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Antimalarial Compounds as Antagonists of Adenosine

Madinaveitia

Raventós

1949

British Journal of Pharmacology and Chemotherapy

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The possible antagonism of the action of adenosine on some tissues by antimalarial drugs has been studied with the object of obtaining some information on the mode of action of this type of drug. METHODS Antagonism of adenosineThe following techniques were used in these experiments:(1) The isolated hen's caecum.-The action of adenosine on this tissue (Barsoum and Gaddurn, 1935) was studied before and after the addition to the bath -of known concentrations of antimalarials. Although it was possible to demonstrate an antagonism between these compounds and adenosine by this method, satisfactory results were not obtained because ofthe intense relaxation of the caecum produced by the antimalarial substances themselves.(2) The measurement of the duration of the auriculoventricular (a.v.) block produced by intravenous administration of adenosine in the anaesthetized guinea-pig (Drury and Szent-Gybrgyi, 1929 In each experiment a series of doses of adenosine from 0.1 to 0.3 mg./kg. was first administered in order to produce varying degrees of a.v. block. The cannula was then washed with the solution of antimalarial and the drug slowly infused by means of a motor-driven syringe which delivered the solution at the rate of 0.02 ml./min. This infusion was maintained for 30 min. after which the cannula was washed with adenosine solution and a second series of adenosine injections was administered in doses large enough to produce measurable heart blocks.The dose of antimalarial was calculated in mg./kg./min. and adjusted by varying the concentration according to the body-weight of each animal. At least 3 guinea-pigs were used for each dose level of antimalarial.This series was used mainly for the selection ofchemical types able to antagonize the action of adenosine.(b) In the second series the compounds were administered orally in a dosage regime similar to that used by Davey (1946) for the assessment of antimalarial activity against P. gallinaceum in chicks.Batches, usually of 6 guinea-pigs each, were used for each dose level of every compound tested. The animals received two doses daily for -31 days, a total of 7 doses. The drugs were administered in solution in water, or in fine suspensions when insoluble, by means of a stomach tube. After the 7th dose, the guinea-pigs were anaesthetized with pentobarbitone and a series of adenosine injections-was administered as described above.These experiments will be referred to as " chronic" later on.(c) Some experiments were carried out with heart-lung preparations of guinea-pigs. The method was essentially that described by Cruickshank (1945) for the rat; 25 ml. of heparinized guinea-pig's blood were used in the apparatus. The elastic peripheral resistance was adjusted to give a pressure of 80-100 mm. Hg in the aortic cannula; e.c.g. records were taken with leads placed in the superior vena cava and in the apex of the heart. Adenosine was injected into the venous cannula of the preparation.

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Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Antimalarials -As Adenosine Antagonistsmentioning

confidence: 99%

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Antimalarial Compounds as Antagonists of Adenosine

Madinaveitia

Raventós

1949

British Journal of Pharmacology and Chemotherapy

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“…We therefore decided to investigate alternative ways of synthesizing the thiomethylcyclopropyl moiety, and we were interested in building the pyrimidine ring via classical condensation chemistry. A literature investigation identified the work of Kanel and Dingwall,5 which demonstrated the ring opening of 3chloro-2-methoxytetrahydrofuran (14) with thionyl chloride and pyridine to give 2,4-dichlorobutanal, which was isolated as sodium bisulfite adduct 15 (Scheme 2). This was then reacted with sodium thiomethoxide followed by sodium hydroxide to give aldehyde 16 in 80% yield.…”

Section: ■ Introductionmentioning

confidence: 99%

Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

Graham

Askey

Campbell

et al. 2020

Org. Process Res. Dev.

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Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An S N Ar reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer−Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

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“…The three dimethylpyrazines and 4,6-dimethylpyrimidine were commercially available. 2,4-and 2,5-Dimethylpyrimidine, 24 4,5-dimethylpyrimidine, 25 4,6-dimethylpyrimidine, 26,27 3,6-dimethylpyridazine 28 were synthesized according to literature procedures. Irradiation procedure.…”

Section: Methodsmentioning

confidence: 99%

Vapor phase phototransposition chemistry of dimethylpyrazines and dimethylpyrimidines

Pavlik¹,

Vongakorn²,

Kebede³

2017

Arkivoc

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Based on their phototransposition chemistry, the three dimethylpyrazines and four dimethylpyrimidines can be arranged into two groups. 2,5-Dimethylpyrazine, 2,5-dimethylpyrimidine, and 4,6-dimethylpyrimidine constitute a photochemical triad. Irradiation of any one member of the triad in the vapor phase results in the formation of the other two members. The other four isomers, 2,6-dimethylpyrazine, 2,3-dimethylpyrazine, 2,4-dimethylpyrimidine, and 4,5-dimethylpyrimidine constitute a photochemical tetrad. Irradiation of any one member results in the formation of the other three. In addition, 2,4-dimethylpyrimidine and 2,6-dimethylpyrazine also photoisomerize to 3,6-dimethylpyridazine. Irradiation of the last in the vapor state resulted in the four members of the tetrad.

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70. Synthetic antimalarials. Part III. Some derivatives of mono- and di-alkylpyrimidines

Cited by 26 publications

References 0 publications

Antimalarial Compounds as Antagonists of Adenosine

Antimalarial Compounds as Antagonists of Adenosine

Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

Vapor phase phototransposition chemistry of dimethylpyrazines and dimethylpyrimidines

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