Derivatives of Imidazole. II. Synthesis and Reactions of Imidazo[1,2-α]pyrimidines and Other Bi- and Tricyclic Imidazo Derivatives with Analgesic, Antiinflammatory, Antipyretic, and Anticonvulsant Activity

Almirante, L; Polo, Luigi; Mugnaini, A; Provinciali, E; Rugarli, P. L.; Gamba, A; A, Olivi; Murmann, W

doi:10.1021/jm00319a007

Cited by 44 publications

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“…Earlier attempts to obtain representatives of IB and/or IIB include cyclization of 1,4-diphenacyl-1H-tetrazol-5(4H)-imine (5b: CH 2 COPh in place of Me) [3] as well as methylation of the imidazo[1,2-d]tetrazolide anion [4]; these efforts remained unrewarded, the latter since alkylation occurred exclusively at the imidazolic half-ring. A previously claimed N-unsubstituted derivative of IB [5] has been shown to be in fact the respective 1-phenacylated 5-aminotetrazole [3]. In this note we report on the first examples of the title classes IB and IIB.…”

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confidence: 81%

New Aromatic Azapentalenes: 3H- and 2H-Imidazo[1,2-d]tetrazoles

Moderhack¹,

Holtmann²

2000

J. prakt. Chem.

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591In contrast to imidazotetrazoles of type IA and IIA [1], the isomeric systems IB and IIB are still unknown; only a tricyclic congener of IIB, the tetrazolobenzimidazole III, has been described [2]. Earlier attempts to obtain representatives of IB and/or IIB include cyclization of 1,4-diphenacyl-1H-tetrazol-5(4H)-imine (5b: CH 2 COPh in place of Me) [3] as well as methylation of the imidazo[1,2-d]tetrazolide anion [4]; these efforts remained unrewarded, the latter since alkylation occurred exclusively at the imidazolic half-ring. A previously claimed N-unsubstituted derivative of IB [5] has been shown to be in fact the respective 1-phenacylated 5-aminotetrazole [3]. In this note we report on the first examples of the title classes IB and IIB.Abstract. A number of title compounds (3a,c, 4a -c) were prepared by cyclization of 5-aminotetrazolium salts having ketonic substituents (1, 2). The following procedures were applied: a) for 3a, 4a,b: heating of 1a, 2a,b with acetic anhydride/base; b) for 3c, 4c: heating of 1b, 2b in a buffer solution of pH 6.5 (Tschitschibabin reaction). The proclivity for ring desired product 3c, in agreement with the foregoing, was accompanied by substantial amounts of the tetrazolone 5c. Again, formation of the 2H-isomer was facilitated (see Table 2 for yield of 4c), evidently because the amino group of 2b is more nucleophilic (cf. [9]) and, second, because the competing hydrolysis to give the mesoionic analogue of 5c is a considerably slower process (cf. [10]). Attempts to cyclize 1a and 2a in like manner failed; additional efforts to cause ring closure of 5-aminotetrazolium salts having propargyl substituclosure was more pronounced with the salts 2. The 6-unsubstituted representatives 3c and 4c underwent S E -reactions, the 2H-isomer 4c being slightly more reactive; this was confirmed by AM1 calculations. The nitroso product 4g exists predominantly as the valence-isomeric nitrile oxide 6. Scheme 1When the tetrazolium salts 1a and 2a were treated with acetic anhydride in the presence of triethylamine, i.e. under the conditions formerly applied to 1-acetonyl-4,5-dimethyltetrazolium bromide [6a], the imidazotetrazoles 3a and 4a were formed in reasonable to excellent yield (Table 2). Extension of this experiment to the salts 1b and 2b only gave the derivative of the IIB series, viz. 4b (along with 4a; cf. our observations with pyrrolotetrazoles [6a,b]), whereas the reaction with 1b stopped at the open-chain stage 5a. Attempts to convert 5a into the target compound 3b resulted in deacetylation (→ 5b). This points to an enhanced proclivity for ring closure with the synthons of type 2. Regarding cyclization of 1 and 2 without an external reagent for C(5) (Tschitschibabin reaction), we found that 3c was formed on heating 1b in a buffer solution showing pH 6.5 [7]. However, the

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confidence: 81%

New Aromatic Azapentalenes: 3H- and 2H-Imidazo[1,2-d]tetrazoles

Moderhack¹,

Holtmann²

2000

J. prakt. Chem.

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“…Next, we proceeded to the nal step of the synthesis. The Hantzsch reaction of the bromoketones 10 and 2-aminopyrimidine (11) occurred in several polar solvents like methanol, acetonitrile, and ethanol; regarding heating, both conventional and microwave radiation afforded the cyclo-condensation.…”

Section: Chemistrymentioning

confidence: 99%

“…The imidazo [1,2-a]pyrimidine nucleus also exhibits antiarthritic properties, such as the pyridine-containing compound 3, which is capable of inhibit the mitogen-activated protein (MAP) kinase p38 [8]. Other works point out the antiviral [9], anthelmintic [10], and even antinociceptive [11] effects of the aforementioned heterocycle or related imidazopyridine.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxic/antimicrobial screening of 2-alkenylimidazo[1,2-a]pyrimidines

2022

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Polyaza-heterocycles show a plethora of biological properties and represent a signi cant percentage of clinically used drugs. However, the imizado[1,2-a]pyrimidine ring system needs more attention in terms of pharmaceutical applications. Herein, we report a sequence involving an aldolic condensation/bromination/Hantzsch reaction to construct a series of 3-alkenylimidazo[1,2-a]pyrimidines for exploring their cytotoxic and antimicrobial properties. After performing a preliminary screening, two compounds displayed good cytotoxicity against prostate, breast, and colon cancer types; bulky and an extra phenyl attached at the styryl moiety seem to be a requirement for good activity. With respect to the antimicrobial effect, some compounds showed considerable inhibition against multi-drug resistant K. pneumoniae, one of the most threating bacteria nowadays. Thus, the series may become the basis for the design of more active compounds.

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“…Among the series of aryl substi tuted acetic acids (185), nitriles (186), and ami des (187,188), analgesic and anti-inflammatory activities usually were greater among naphthyl than phenyl derivatives. Analgesic, anti-inflammatory, or both activities were ob served among new series of phenetidines (189), alkylpiperizine esters (190) , N-antipyryloxamides (191), arylacethydroxamic acids (192), 2,3-bis-(p-meth oxyphenyl) indoles (193), some aminoguanidine sympathetic blockers (194), and imidazoles (195), and pyridobenzimidazoles (196). Additional variations of pethidine have been studied which range from less than 0.1 to 28 times its potency (197).…”

Section: Oxotremorine Arecolinementioning

confidence: 99%

Some Relationships Between Chemical Structure and Pharmacological Activities

Cavallito¹

1968

Annu. Rev. Pharmacol.

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Earlier reviews in this series dealt with some relationships of chemical structure with biological activities (1-3) i the present assignment is restricted essentially to pharmacologically active compounds. As with the earlier re views, the published literature is not covered exhaustively, but some new re ports and observations are included which appeared from about September, 1964 [termination of coverage of last review (1)] to May, 1967. Where useful for purposes of relationship, selected older literature is cited.Over the years attempts have been made to devise general hypotheses pertaining to structure-activity relationships (SAR) and drug mechanisms of action. Recent efforts include variations of receptor occupancy hypotheses (Ariens, Stephenson), rate or kinetic hypotheses (Paton), and more chemi cally descriptive concepts (Belleau and others). In reviewing publications of the past two years that could be considered pertinent to SAR, one is im pressed by the gulf that exists between most synthesizers of new molecules and the developers of general hypotheses. For example, from 310 complete articles published in J. Med. Chern. (1965-66), only six made reference to these hypotheses either as stimuli for the project or as vehicles for cor relating SAR. This might indicate that the hypotheses are sterile or inade quate for either predictive or correlative purposes or that there is little in terest or inclination among most investigators in relating specific observa tions to general hypotheses. Most of these hypothes,t!s have indeed offered little that is of substantive value from a chemical perspective of devising novel molecules of biological interest. However, the efforts are commendable and some of these hypotheses may evolve and develop into theories with use ful correlative and predictive values. As hypotheses become more chemically descriptive, one can anticipate that there will be a greater consideration of such hypotheses by the designers of new, biologically interesting molecules.Their more recent concepts have been summarized by Ariens (4) and Paton (5). Shortcomings of the Ariens and Stephenson receptor occupancy and the Paton rate hypotheses have been analyzed by Belleau (6) as back ground for discussion of his "conformational perturbation" hypothesis.Bloom & Goldman (7) further consider these and modify and extend some of Belleau's views in proposing a "dynamic receptor hypothesis" relevant to catecholamine-adenine mononucleotide interactions in adrenergic mech anisms. These reviews are recommended to the cautious reader; space does 39 Annu. Rev. Pharmacol. 1968.8:39-66. Downloaded from www.annualreviews.org Access provided by New York University -Bobst Library on 05/14/15. For personal use only.Quick links to online content Further ANNUAL REVIEWS

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Derivatives of Imidazole. II. Synthesis and Reactions of Imidazo[1,2-α]pyrimidines and Other Bi- and Tricyclic Imidazo Derivatives with Analgesic, Antiinflammatory, Antipyretic, and Anticonvulsant Activity

Cited by 44 publications

References 0 publications

New Aromatic Azapentalenes: 3H- and 2H-Imidazo[1,2-d]tetrazoles

New Aromatic Azapentalenes: 3H- and 2H-Imidazo[1,2-d]tetrazoles

Synthesis and cytotoxic/antimicrobial screening of 2-alkenylimidazo[1,2-a]pyrimidines

Some Relationships Between Chemical Structure and Pharmacological Activities

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