The use of 2-oxazolidinones as latent aziridine equivalents. 2. Aminoethylation of aromatic amines, phenols, and thiophenols

Poindexter, Graham S.; Owens, D. Alfred; Dolan, Peter L.; Woo, E. P.

doi:10.1021/jo00049a037

Cited by 52 publications

(31 citation statements)

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“…These two cell lines have been reported to overexpress P-glycoprotein. 7) As shown in Table 4, VCR and ADM showed high cross resistance rates of 400 against PC-6/VCR and 22 against PC-6/ADM, respectively. Compounds 7a and 7e did not show cross-resistance as indicated by their equal rates of 0.9 against PC-6/VCR and 1.3 against PC-6/ADM.…”

Section: Biological Activity and Discussionmentioning

confidence: 93%

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Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. II. Optimization of the Phenylpiperazine Moiety of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.

Naito

Ohsuki

Sugimori

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the previous paper, 1) we reported the synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. These derivatives were found as new antiproliferative agents through random screening using our laboratory's chemical library. One of them, 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2), showed significant antitumor activity against several tumor models by both intraperitoneal injection and oral administration. Furthermore, 2 was free from the cross-resistance to some currently used antitumor agents such as vincristine (VCR) and adriamycin (ADM). These pyrazole derivatives, however, tended to cause undesirable effects, e.g., muscle relaxation and decrease of body temperature without body weight loss, because these compounds had previously been prepared as tranquilizers or antihypertensive agents. To overcome these problems, we have been seeking derivatives of 1 that might furthermore increase the antitumor activity while decreasing the side effects. As a first step in the structural modification of this scaffold, we focused on the phenylpiperazine moiety, namely, the introduction of some substituents on the phenyl ring and replacement of the phenylpiperazinyl group with some piperidinyl groups. We describe here the synthesis and structure-activity relationships (SARs) with regard to in vitro cytotoxic activity and in vivo antitumor activity of these pyrazole derivatives. ChemistryThe synthesis of the derivatives bearing a substituted phenylpiperazine moiety was carried out via the route shown in Chart 1. The new substituted piperazines 4a-d were prepared from aniline derivatives 3a-d and bis(2-chloroethyl)amine hydrochloride. Mannich reaction of 4-acetyl-5-methyl-1-pyrimidinylpyrazole (5) 1) with modified piperazines 4a-d or 4e-i 2) gave 6a-i, respectively. 1-Propanone derivatives 6j-l were prepared according to the reported procedure.3) Compounds 6a-l were reduced with sodium borohydride to give the corresponding alcohols, which were dehydrated by p-toluenesulfonic acid (p-TsOH) to afford 1-trans-propene derivatives 7a-l. Catalytic hydrogenation of 6i over Pd/C with acetic anhydride gave the 3-acetylaminophenyl derivative 8. Compound 9 was obtained from 8 by the same procedure as described for 7a-l from 6a-l. Carbamoylphenyl derivative 10 was prepared from 7c by hydrolysis of the cyano group with hydrochloride.We also developed a new, efficient synthetic method to construct this scaffold by employing reductive amination instead of Mannich reaction, because Mannich reaction of hydroxyphenylpiperazine 15 with 5 did not progress (Chart 2). Bromination of 5 with Br 2 and treatment with cesium acetate (CsOAc) gave 11. Compound 11 was hydrolyzed with aqueous NaOH to give the a-hydroxyketone, followed by reduction with sodium borohydride, and then oxidative cleavage of the 1,2-diol with sodium periodate to give the aldehyde 12. According to the Mukaiyama protocol, 4) the carbon-carbon bond formation of 12 with allyl bromide was performed using meta...

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Section: Biological Activity and Discussionmentioning

confidence: 93%

“…Aminoethylation of 22 with 2-oxazolidinone as an aziridine equivalent 7) afforded the desired N-phenylethylenediamine (23). 2-Piperazinone 24 was prepared from 23 in two steps (2-chloropropanoyl chloride, Et 3 N, CH 2 Cl 2 , then K 2 CO 3 , tert-BuOH), and the following reduction of the amide with LAH afforded 26a.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. II. Optimization of the Phenylpiperazine Moiety of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.

Naito

Ohsuki

Sugimori

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…• C. The lower temperature of decarboxylation [5,6] could be explained with the acidity of the reaction mixture. Under these conditions, the reaction mixture contained the monomethyl ester of phosphonic acid CH 3 OP(O)(H)OH (11) (m/z 97.0) and phosphonic acid 12 (H 3 PO 3 ) (m/z 83.0), which initiate the decarboxylation of 5-methyl-3-(2-hydroxyethyl)-2-oxazolidinone (4).…”

Section: Methodsmentioning

confidence: 99%

Novel routes to aminophosphonic acids: Interaction of dimethyl H‐phosphonate with hydroxyalkyl carbamates

Troev

Koseva

Hägele

2008

Heteroatom Chemistry

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“…Mitsunobu conditions with 3,4-dichlorophenol ( 35 ) and N -Bocethanolamine followed by TFA deprotection gave amine 37 55. The sulfur-containing fragment, 3,4-dichlorophenylthioethanamine ( 40 ), was generated by ring opening of 2-oxazolidinone ( 39 ) with 3,4-dichlorothiophenol ( 38 ) followed by decarboxylation 56. Lithium aluminum hydride reduction of propionamide 42 gave 3,4-dichlorophenylpropionamine ( 43 ).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-d-aspartate receptors☆

Mosley

Myers

Murray

et al. 2009

Bioorganic & Medicinal Chemistry

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The synthesis and structure–activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modu-lated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood–brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.

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The use of 2-oxazolidinones as latent aziridine equivalents. 2. Aminoethylation of aromatic amines, phenols, and thiophenols

Cited by 52 publications

References 0 publications

Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. II. Optimization of the Phenylpiperazine Moiety of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.

Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. II. Optimization of the Phenylpiperazine Moiety of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.

Novel routes to aminophosphonic acids: Interaction of dimethyl H‐phosphonate with hydroxyalkyl carbamates

Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-d-aspartate receptors☆

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