In brief: Pyrimido[2,1-b]benzothiazol-4-one, thiazolo[3,2-a]pyrimidin-5-one, pyrimido[2,1-b]benzoxazol-4-one, and pyrimido[1,2-a]benzimidazole were all reported in one 1951 paper by H. Antaki and V. Petrow (J. Chem. Soc., 551–555; DOI). See the separate history of pyrido[1,2-a]pyrimidin-4-one, including its 1951 structural correction and later medicinal chemistry, for the fifth ring system from the same paper. Each ring system on this page acquired a different later history in pharmaceutical or academic research.
At a glance
| Source paper | Antaki & Petrow, J. Chem. Soc. 1951, 551–555 (DOI) |
| Thesis reference | Ph.D. Thesis, University of London, 1950, Part I — Sections B, C, D, E |
| Thiazolo[3,2-a]pyrimidin-5-one | Reported new in 1951; re-entered the patent record in 1980 (Mead Johnson) |
| Pyrimido[2,1-b]benzothiazol-4-one | Reported new in 1951; four independent academic groups, several patent programmes, and later research literature |
| Pyrimido[2,1-b]benzoxazol-4-one | Reported new in 1951; two patents, 1970 and 1984 |
| Pyrimido[1,2-a]benzimidazole | Previously known; Antaki extended its substitution and fusion chemistry; independently selected as best-performing scaffold by Takeda Pharmaceutical, 2018 |
Historical summary
| 1950 | All four ring systems documented in Antaki's doctoral thesis, Part I, Sections B–E |
| 1951 | Published by Antaki & Petrow, J. Chem. Soc., 551–555 |
| 1962–1973 | Pyrimido[2,1-b]benzothiazol-4-one independently developed by academic groups: Gompper, Galasko, Dunwell, Alaimo |
| 1970 onward | Pharmaceutical patent development begins: Ciba (1970), Pfizer (1977), Mead Johnson (1980), Riker (1984), Roussel-Uclaf (1988) |
| 2010–2020 | Pyrimido[2,1-b]benzothiazol-4-one derivatives continue to appear in academic literature, including antimicrobial, antitumour, and synthetic-methodology studies |
| 2018 | Takeda Pharmaceutical selects tetrahydropyrimido[1,2-a]benzimidazole as the best-performing ring system in a CRF-1 receptor antagonist programme |
| 2021 | Computational follow-up study models the structure-activity relationships of the Takeda series |
In November 1950, H. Antaki and V. Petrow submitted a paper to the Journal of the Chemical Society reporting that ethyl β-aminocrotonate was "markedly superior" to ethyl acetoacetate for a class of ring-closing condensations. Having used the reagent to correct the structure of pyrido[1,2-a]pyrimidin-4-one — see the separate history of that ring, including its 1951 structural correction and later medicinal chemistry — they extended the same reaction across a series of different cyclic amidines. Four further fused ring systems resulted, each built by reacting the same reagent with a different 2-aminoheterocycle. This page documents those four ring systems: what Antaki reported, and what happened to each of them in the decades that followed.
Thiazolo[3,2-a]pyrimidin-5-one was reported as a previously unknown fused ring system in Antaki's 1950 doctoral thesis and the subsequent 1951 Antaki–Petrow paper. The ring later entered pharmaceutical patent research as a tetrazole-substituted antiallergic series.
Names used in the literature: thiazolo[3,2-a]pyrimidin-5-one; older literature: 4-keto-7:9-diazathianaphthen; 7:9-diazathianaphthene.
Antaki's thesis records the ring as previously unknown: "A 7:9-diazathianaphthen has not therefore been described in the literature, and previous attempts to obtain compounds of this type have been only partially successful." Reacting ethyl β-aminocrotonate directly with 2-aminothiazole gave "the hitherto unknown 4-keto-6-methyl-7:9-diazathianaphthen (XI)" in good yield, where prior attempts using ethyl acetoacetate had failed to close the ring at all (Ph.D. Thesis, University of London, 1950, Part I, Section B).
Thiazolo[3,2-a]pyrimidin-5-one reappears in the patent record in 1980, in Mead Johnson's US 4,223,031, which covers 6-(1H-tetrazol-5-yl)thiazolo[3,2-a]pyrimidin-5-ones as antiallergic agents alongside the related benzothiazole ring (Section C, below). The patent's background section cites Antaki's 1951 paper directly, among six sources describing the two ring systems: "Thiazolo[3,2-a]pyrimidinones and pyrimido[2,1-b]benzothiazolones have been previously described by Ogura, et al. … Antaki, et al., J. Chem. Soc., 551 (1951), Baetz, U.S. Pat. No. 3,888,983 … Dunwell, et al. … Gompper, et al. … and Galasko, et al. … but none of those references discloses a 1H-tetrazol-5-yl substituted compound."
No further academic literature focused specifically on this ring has been identified in the sources examined to date.
The broader thiazolo[3,2-a]pyrimidine family to which this ring belongs remains an active synthetic and medicinal-chemistry scaffold. The following studies document that continuing activity:
Cai et al. — Molecules 2015, 20, 16419–16434. DOI: 10.3390/molecules200916419
5H-Thiazolo[3,2-a]pyrimidin-5-ones synthesized and evaluated for in vitro antibacterial activity against Gram-positive and Gram-negative bacteria and antitubercular activity against Mycobacterium tuberculosis by broth dilution assay.
Mahgoub et al. — Molecules 2019, 24, 2306. DOI: 10.3390/molecules24122306
Fused thiazolo[3,2-a]pyrimidines evaluated as human acetylcholinesterase inhibitors (IC50 values in the 1 µM range), confirmed by X-ray crystallography and molecular docking; investigated as potential leads relevant to Alzheimer's disease.
Abdel-Megid et al. — Results in Chemistry 2024, 11, 101807. DOI: 10.1016/j.rechem.2024.101807
A dedicated review of nitrogen-bridgehead thiazolo[3,2-a]pyrimidines covering synthetic strategies and reported biological activities including antitumour (Topo II inhibition), antimicrobial, antipsychotic, anti-inflammatory, anti-Parkinson, analgesic, antidepressant and anti-HIV. The review notes that specific derivatives in the surveyed literature reached antitumour activity comparable to doxorubicin.
Khator & Monga — Archiv der Pharmazie 2025, 358, e2400870. DOI: 10.1002/ardp.202400870
Review describing the thiazolopyrimidine scaffold as a "privileged scaffold" in medicinal chemistry, with anticancer, antimicrobial, analgesic, antioxidant and anti-inflammatory applications; the scaffold also functions as a key intermediate for fused heterocycles of medicinal importance.
Pyrimido[2,1-b]benzothiazol-4-one was reported as a novel ring system by H. Antaki and V. Petrow in 1951. Antaki's 1950 doctoral thesis records the same chemistry, and the scaffold was subsequently developed by academic groups and pharmaceutical companies for several biological applications.
Names used in the literature: pyrimido[2,1-b]benzothiazol-4-one; 4H-pyrimido[2,1-b]benzothiazol-4-one; older literature: 1:11-diaza-9-thiafluorene.
Antaki's paper describes the ring explicitly as new: "condensation of 2-aminobenzthiazole with (IV) led to 4:11-dihydro-4-keto-2-methyl-1:11-diaza-9-thiafluorene (VII; R = H). The 6-chloro-, 6-amino-, 6-carbethoxy-, and 6-ethoxy-derivatives of this novel ring system were obtained in the same way" (J. Chem. Soc., 1951, 551–555).
Independent research groups took up pyrimido[2,1-b]benzothiazol-4-one across the following two decades: Gompper et al. (Chem. Ber., 1962, 95, 2871–2880), Galasko et al. (J. S. Afr. Chem. Inst., 1969, 22, 121–127), Dunwell et al. (J. Chem. Soc. (C), 1971, 2094–2097), and Alaimo (J. Heterocyclic Chem., 1973, 10, 769).
The ring's pharmaceutical record subsequently spans four companies and several therapeutic programmes over nearly two decades:
"Antaki, et al., J.C.S. 1951:551-5 (1951)."
Ciba Ltd. cited the 1951 paper in US 3,538,086 (1970), covering pharmacologically active pyrimido[2,1-b]benzothiazole/benzoxazole derivatives reported to have antiviral — particularly anti-influenza — and antifungal activity. The patent identifies specific benzothiazole compounds as having "outstanding antiviral, particularly anti-influenza properties," with dosing and activity data from animal studies. The patent contains specific compounds, animal-activity data, dosage information, and proposed antiviral and antifungal uses; it therefore represents an active development programme rather than a passing mention of the ring.
"The pyrimido[2,1-b]benzothiazole ring system was first reported by Antaki, et al., J. Chem. Soc., 551 (1951)." — Pfizer Inc., US 4,041,163 (1977), antiallergy agents.
Mead Johnson (US 4,223,031, 1980) and Roussel-Uclaf (US 4,762,840, 1988) followed with further pyrimido[2,1-b]benzothiazol-4-one antiallergic compounds, both citing the 1951 paper directly.
Pyrimido[2,1-b]benzothiazol-4-one remains present in the modern research literature. Academic papers from 2010 to 2020 report its derivatives with antimicrobial, antitumour, and enzyme-catalysed synthetic applications, including use as a subcellular imaging scaffold. The following primary studies document that continuing activity:
Gabr, El-Gohary, El-Bendary & El-Kerdawy — Eur. J. Med. Chem. 2014. DOI: 10.1016/j.ejmech.2014.07.097
Nineteen pyrimido[2,1-b]benzothiazole derivatives screened by the National Cancer Institute (NCI), USA, against a panel of 60 cancer cell lines. Most active: compound 17 (GI₅₀ = 0.44 µM, TGI = 1.2 µM) and compound 4 (GI₅₀ = 0.77 µM, TGI = 2.08 µM). Pharmacophoric mapping carried out for both.
Keihanfar, Mirjalili & Bamoniri — Scientific Reports 2025, 15, 6328. DOI: 10.1038/s41598-024-80092-z
One-pot three-component solvent-free synthesis of pyrimido[2,1-b]benzothiazole derivatives using a bentonite/Ti(IV) nanocatalyst. The paper reviews reported activities of the scaffold in the prior literature: anti-allergic, antitumour, antiviral and antituberculosis.
Bhoi et al. — Phosphorus, Sulfur, and Silicon and the Related Elements 2023, 198, 822–835. DOI: 10.1080/10426507.2023.2199994
Enantioselective one-pot three-component synthesis of fourteen 4H-pyrimido[2,1-b]benzothiazole single-isomer derivatives using a chiral camphorsulphonic acid catalyst (20 mol%), achieving 84–99% ee; antibacterial evaluation of all products.
Pyrimido[2,1-b]benzoxazol-4-one was first prepared in Antaki's doctoral work by extending the same cyclisation used for the related pyrido and thiazole systems. It later appeared in Ciba and Riker pharmaceutical patents.
Names used in the literature: pyrimido[2,1-b]benzoxazol-4-one; 4H-pyrimido[2,1-b]benzoxazol-4-one; older literature: 1:11-diaza-9-oxafluorene.
Antaki's thesis records the same deliberate extension of method used for Section B: "The 1:11-diaza-9-oxafluorene ring system has not hitherto been reported in the literature, but has now been successfully prepared by the application of the reaction outlined in sections A and B to 2-aminobenzoxazole" (Ph.D. Thesis, University of London, 1950, Part I, Section D, p. 39).
Ciba Ltd.'s US 3,538,086 (1970) — discussed above in connection with Section C — is broader than its benzothiazole examples alone: its general formula explicitly allows the ring's bridgehead heteroatom to be oxygen or sulfur, and Example 16 of the patent prepares 3-cyano-4-imino-4H-pyrimido[2,1-b]benzoxazole directly from 2-aminobenzoxazole, citing Antaki's 1951 paper in its references. This is the earliest appearance in the patent record confirmed in the sources examined for this page.
A second, later patent addresses the ring specifically: Riker Laboratories, Inc. (a 3M subsidiary), US 4,476,130 (filed 1982, granted 1984, shown in the consulted patent record as lapsed in 1988), covering 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzoxazol-4-one as an antiallergic compound. Its background section cites three earlier patents on the related pyrido and benzothiazole rings — US 4,122,274, US 4,209,620, and US 4,223,031 — without citing Antaki's 1951 paper directly. By this point in the record, the patents built on Antaki's chemistry had themselves become the cited prior art.
No later activity specific to this ring has yet been identified in the sources examined after the Riker patent's 1988 lapse.
Pyrimido[1,2-a]benzimidazole was already known before Antaki's work. His contribution was to extend the chemistry to new substitution patterns and fused derivatives using the same synthetic programme developed in his thesis.
Names used in the literature: pyrimido[1,2-a]benzimidazole; older literature: 1:11-diazacarbazole.
Unlike the three ring systems above, this one was not new when Antaki worked on it. His thesis records five earlier routes to the same ring system: Crippa and Perroncito (Gazzetta, 1935, 65, 38), Morgan and Stewart (J. Chem. Soc., 1938, 1292), Petrow and Saper (J. Chem. Soc., 1946, 588), Ochiai and Yanai (J. Pharm. Soc. Japan, 1940, 60, 493), and Henecka (German Patent 641,598, 1937).
Antaki's own account of his contribution, in his words: "It has now been found that 2-substituted ethyl acetoacetates react with 2-aminobenzimidazole to give the corresponding 2-methyl-3-alkyl-4-keto-1:11-diazacarazoles" — new alkyl substituents at the 3-position, not reported in the earlier syntheses. He further recorded the first fused-ring variants of the class: reacting 2-aminobenzimidazole with ethyl cyclohexanone-2-carboxylate gave "2:3-cyclotetramethylene-4-keto-1:11-diazacarbazole (XVI), the first representative of this type of compound to be prepared"; the corresponding cyclopentanone reagent gave the cyclopentane-fused analogue in good yield. Finally, he reported a route to a class of compounds not previously accessible by the standard method: "2-aminocrotononitrile and 2-phenyl-2-aminoacrylonitrile may be used in the above transformations of 2-aminobenzimidazole into the corresponding 1:11-diazacarbazoles," giving the 4-imino derivatives (XVII, XVIII) in place of the 4-keto compounds obtained by every earlier route (Ph.D. Thesis, 1950, Part I, Section E).
Nearly seventy years later, researchers at Takeda Pharmaceutical reported 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as a new class of CRF-1 receptor antagonists (Kojima et al., Bioorg. Med. Chem. 2018, 26, 2229–2250; DOI: 10.1016/j.bmc.2018.01.020). Their programme began from Takeda's own 2-anilinobenzimidazole series and used scaffold hopping to design several conformationally constrained tricyclic systems. Among those tested, the tetrahydropyrimido[1,2-a]benzimidazole series was selected as the best-performing ring system.
A 2021 computational follow-up study modeled the structure-activity relationships of the same compound series using QSAR, molecular docking, and molecular dynamics simulation (Kumar et al., Iran. J. Pharm. Res. 2021, 20(2), 22–34; DOI: 10.22037/ijpr.2020.113746.14464).
One 1951 paper, arising from Antaki's doctoral research, reported four fused ring systems beyond the pyrido[1,2-a]pyrimidin-4-one treated elsewhere on this site. Three were explicitly described as new. Their subsequent histories differed markedly: some were taken up directly by later academic chemists; some entered pharmaceutical patent lineages in which the 1951 paper continued to be cited; others resurfaced decades later without a demonstrated documentary connection to Antaki's work. Across those different paths, the chemistry remained useful for more than seventy years. This page documents where each ring entered the record and what became of it, without attributing later inventions to the original authors.
Antaki, H.; Petrow, V. J. Chem. Soc. 1951, 551–555. DOI
Antaki, H. Ph.D. Thesis, University of London, 1950, Part I, Sections B–E.
Gompper, R. et al. Chemische Berichte 1962, 95, 2871–2880.
Galasko, G. et al. Journal of the South African Chemical Institute 1969, 22, 121–127.
Dunwell, D. W. et al. Journal of the Chemical Society C 1971, 2094–2097.
Alaimo, R. J. Journal of Heterocyclic Chemistry 1973, 10, 769.
Ciba Ltd., US 3,538,086 (1970)
Pfizer Inc., US 4,041,163 (1977)
Mead Johnson & Company, US 4,223,031 (1980)
Riker Laboratories, Inc., US 4,476,130 (1984)
Roussel-Uclaf, US 4,762,840 (1988)
Kojima, T. et al. Bioorg. Med. Chem. 2018, 26, 2229–2250. DOI
Kumar, S. et al. Iran. J. Pharm. Res. 2021, 20(2), 22–34. DOI
Cai, D. et al. Molecules 2015, 20, 16419–16434. DOI
Mahgoub, M. Y. et al. Molecules 2019, 24, 2306. DOI
Gabr, M. T. et al. Eur. J. Med. Chem. 2014. DOI
Abdel-Megid, M. et al. Results in Chemistry 2024, 11, 101807. DOI
Khator, R.; Monga, V. Arch. Pharm. 2025, 358, e2400870. DOI
Keihanfar, M. et al. Sci. Rep. 2025, 15, 6328. DOI
Bhoi, M. N. et al. Phosphorus Sulfur Silicon Relat. Elem. 2023, 198, 822–835. DOI
See the separate history of pyrido[1,2-a]pyrimidin-4-one, including its 1951 structural correction and later medicinal chemistry — the fifth ring system reported in the same 1951 paper.