Synthetic antispasmodics. II. Some acyclic analogues of papaverine

Cymerman‐Craig, J.; Martin, K. R.; Wailes, PC

doi:10.1071/ch9550385

Cited by 3 publications

(4 citation statements)

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“…5.6-Bis(4-(methylsulfinyl)phenyl)-2,3-dihydroimidazo-[2,1-5 jthiazole (35). Thione 58 (6.09 g, 0.016 mol) in DMF (30 mL) was added dropwise to a stirred suspension of KH (24% oil dispersion, 5.5 g, 0.032 mol) in DMF (30 mL) cooled to 0 °C.…”

Section: Methods Bmentioning

confidence: 99%

“…While changes in activity in the mouse contact sensitivity assay appear unrelated to structural variation, examination of the rat adjuvant arthritis data reveals a number of structural correlations. Maximum activity was achieved in symmetrically substituted 5,6-diaryl compounds having the following halogen or alkyl heteroatom functions at the para position of both phenyl rings: fluoro (19), chloro (7), bromo (30), methoxy (1), ethoxy (8), methylthio (22), methylsulfinyl (35), . A significant reduction in the activity of 1 was observed on substitution of both 4methoxy substituents with 2-methoxy (6); a 3-substituent such as 3-methoxy (4), 3-fluoro (27), or 3-methyl (25); multiple substituents such as 3,4-dimethoxy ( 13), 3,4methylenedioxy (17), or 3,4,5-trimethoxy ( 16); a 4-alkoxy substituent longer than a two-carbon atom chain such as 4-allyloxy ( 23) or 4-butoxy (9); a nonalkylated heteroatom substituent such as 4-hydroxy ( 14), 4-amino (31), 4-acylamino (20,32,34), or 4-acetoxy (15); or hydrogen (2).…”

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confidence: 99%

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5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents

Pe¹,

Dt²,

Ph³

et al. 1985

J. Med. Chem.

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A series of substituted 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles were synthesized and evaluated in the rat adjuvant-induced arthritis and mouse oxazolone-induced contact sensitivity assays to determine the potential of these compounds for use as immunoregulatory antiinflammatory agents. This class of compounds was derived by combining salient structural features of the antiinflammatory agent flumizole and the immunoregulatory drug levamisole. Unlike the latter two, a number of compounds in the target series were found to possess the desired combination of activities. Exploration of structure-activity relationships in the adjuvant-induced arthritic rat assay revealed that optimal potency was exhibited by symmetrically substituted 5,6-diaryl compounds having one of the following alkyl heteroatom or halogen functions at the para position: methoxy, ethoxy, methylthio, N-ethyl-N-methylamino, fluoro, or chloro. Scrambling of these two substituent classes to yield the asymmetrically substituted 5,6-diaryl compounds resulted in potent activity only with the 5-alkyl heteroatom, 6-halo-substituted regioisomers. However in the oxazolone-induced contact sensitivity assay, no consistent relationship of variation in activity with structural change was apparent. The initial target compound 5,6-bis(4-methoxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole (1) was compared with its progenitors in additional models of inflammation and immunoregulation.

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Section: Methods Bmentioning

confidence: 99%

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confidence: 99%

5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents

Pe¹,

Dt²,

Ph³

et al. 1985

J. Med. Chem.

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“…2-Bromo-l,2-bis(4-methoxyphenyl)ethanone ( 9). This compound was prepared according to the method of Cymerman-Craig and co-workers.10 Thioformamide (10). Following the work of Cerecedo and Tolpin,11 formamide (20.0 g, 0.444 mol) was covered with Et20 (200 mL) and freshly powdered (12.0 g, 0.054 mol) was added in several portions with ice-water bath cooling.…”

Section: Methodsmentioning

confidence: 99%

“…Compound 910 was converted into 11 by treatment of 9 with thioformamide (10).11 Compounds 13, 15, and 16 were respectively prepared by the reaction of trifluoro-methylthioacetamide12 with compounds 121314, and dose: mg/kg…”

mentioning

confidence: 99%

Synthesis and platelet aggregation inhibitory activity of 4,5-bis(aryl)-2-substituted-thiazoles

Rh¹,

Ee²,

Dp³

et al. 1981

J. Med. Chem.

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In our continuing effort to discover compound which inhibit collagen-induced platelet aggregation, we have screened compounds in a mouse pulmonary thromboembolism screen. Methyl 4,5-bis(4-methoxyphenyl)-2-thiazoleacetate (3) was very active in the above screen. However, 3 was active for less than 5 min when given orally to guinea pigs. As a result, our synthetic goal was to prepare 2-substituted thiazoles with a much longer duration of activity. This paper describes the preparation of a number 4,5-bis(aryl)-2-substituted-thiazoles and their in vitro and ex vivo activity against collagen-induced platelet aggregation. It was determined that 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl)thiazole (16) is the most promising compound.

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Synthesis of tritium and carbon‐14 labeled 4,5‐bis(4‐methoxyphenyl)‐ 2 ‐(trifluoromethyl)thiazole

Stolle

1986

Labelled Comp Radiopharmac

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Tritium labeled 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl)thiazole ( 1 ) wass nthesized with the tritium label located on the phenyl ring a t the C-4 position of tritium a t C-3 was used to prepare tritium la eled 1 with specific activity of 53 pCilmg in 53% overall radiochemical yield. The title compound I was also labeled with carbon-14 atthe C-4 position of the thiazole ring. [ W1Barium carbonate was used as the isotope source, and carbon-14 labeled compound 1 of 31.4 pCiimg was obtained in 54% overall radiochemical yield. Deuterium and carbon-1 3 labeled startin materials and intermediates were used as models for % t 1: e thiazole ring and meta to the methoxy roup. Anisole specifically labeled with preparing the tritium an B carbon-14 labelea compounds, respectively. Key Words. Synthesis, labeled 4,5-6is(4-methoxyphenyl)-2-(trifluoromethyl)thiazole, deuterium, tritium, carbon-13, carbon-14 1NTRODUCTlON A number of non-steroidal antiinflammatory drugs, e.g., aspirin (l), dipyridamole (2), flurbiprofen (3), and ibuprofen (4), are known to inhibit platelet aggregation. However the antiplatelet aggregation activity of these agents is low, and clinical demonstration of their antithrombotic utility has not been uniformly successful.A high-volume mouse pulmonary thromboembolism screen (5) was developed to identify compounds which inhibit collagen-induced platelet aggregation. One compound so identified was 4,5-bis(4-methoxyphenyl)-2-thiazoleacetic acid methyl ester (2). Its potency and unique structural features prompted an analog program which led to the synthesis of the trifluoromethylthiazole I (6), which possessed high potency against collagen-induced platelet aggregation, yet lacked effect on blood coagulation, and showed low toxicity and antiinflammatory activity. Compound 1 is currently under development as a potential antithrombotic agent with clinical utility. To provide tools 434 R. S. P. Hsi and W . T. Stolle for studying i t s absorption, metabolic transformations, and excretion in test animals and man, we embarked on the synthesis of tritium and carbon-14 labeled 1 . 1 DISCUSSION AND RESULTS The synthesis of tritium labeled 4,5-6is(4-methoxyphenyl)-2-(tri fluoromethyl)thiazole (16) is outlined in Scheme 1. Lithiation of 3-bromoanisole followed by quenching with tritiated water introduced tritium into a non-exchangeable position (meta to the methoxy group) in the phenyl ring. The meta position of the tritium label in [3-3H]anisole (36) in relation to the methoxy group was supported by the nuclear magnetic resonance (NMR) spectrum of the deuterated analog 3a prepared in the same manner from 3-bromoanisole and deuterium oxide. Friedel-Crafts acylation of 3a and 36 with 4-methoxyphenylacetyl chloride afforded deuterium and tritium labeled 1,2bis(4-methoxyphenyi)ethanone, 4a and 46 respectively. The assignment of the position of the deuterium label in 4a (and by analogy the tritium label in 46), in the phenyl ring adjacent to the carbonyl carbon and at the position ortho to the carbonyl group, wasbased on ...

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Synthetic antispasmodics. II. Some acyclic analogues of papaverine

Cited by 3 publications

References 0 publications

5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents

5,6-Diaryl-2,3-dihydroimidazo[2,1-b]thiazoles: a new class of immunoregulatory antiinflammatory agents

Synthesis and platelet aggregation inhibitory activity of 4,5-bis(aryl)-2-substituted-thiazoles

Synthesis of tritium and carbon‐14 labeled 4,5‐bis(4‐methoxyphenyl)‐ 2 ‐(trifluoromethyl)thiazole

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