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Only two spinach herbicides are currently available to producers, and with limited choices in herbicide mode of action (MOA), overuse of the current herbicides can result in dominance of uncontrolled weeds. Therefore, spinach producers need more herbicide options. Trials were conducted in processing spinach to evaluate the crop safety of dimethenamid-p (0.56 kg ai/ha), EPTC (2.94 to 3.40 kg ai/ha), or ethofumesate (0.84, 1.12 or 2.24 kg ai/ha) applied pre-emergent (PRE), and ethofumesate (0.09 or 0.18 kg ai/ha) applied early postemergent (EPOST) for potential use as alternatives to s-metolachlor (0.73 kg ai/ha) and cycloate (2.52 kg ai/ha). The control of London rocket was excellent with s-metolachlor, dimethenamid-p, and ethofumesate. Weed control with cycloate and EPTC was fair, and generally inferior to all others. Cycloate and s-metolachlor were safe to spinach, and only minor crop injury was observed with all other herbicides, except the high rate of ethofumesate PRE, which resulted in high levels of...

A 4-amido-pyrrolidone library that was intentionally synthesized as pairs of diastereomers was produced by solution-phase parallel syntheses and purified by an automated high-throughput purification system. A total of 2592 4-amido-pyrrolidinones were ultimately isolated as single diastereomers from a matrix of 1920 syntheses. After the four-step synthesis and HPLC purification, the average yield of a single diastereomer was 36.6%. The average chemical purity was >90%, and the average diastereomeric purity was >87%. The choice of chiral amines used to make amides with heterocyclic acid chlorides had a dramatic effect on success. Analysis of the relationship between amines used for synthesis and the diastereomeric separation showed that amides made from chiral 1,2-amino alcohols gave superior separation to amides from chiral morpholines. The presence of a hydrogen bond donor on the amide side chain seems to be required for a better diastereomeric separation.

Base-promoted cyclization of tert-butyl [2-(benzylideneamino)phenyl]acetate (13a) and subsequent C3-alkylation with allyl bromide affords 3-allyl-2-phenyl-2,3-dihydro-1H-indole-3-carboxylic acid, tert-butyl ester (15b) in high yield as a single diastereomer. This result is contrary to prior publications that describe failed cyclization of an analogous ethyl ester (ethyl [2-(4-methoxybenzylideneamino)phenyl]acetate) under strongly basic conditions. N-Acylation, olefin dihydroxylation, and tert-butyl ester cleavage affords the spirocyclic lactone 18 as a pair of diastereomers. Isolation and characterization of individual diastereomers 18a and 18b are described.

The N-alkylation of primary nitrophenylsulfonamides followed by removal of the nitrophenylsulfonamide moiety under nucleophilic conditions to provide secondary amines has become an established literature procedure. Application of this methodology with less reactive alkylating agents can give rise to side products resulting from a nitrogen to carbon transfer of the nitrophenyl ring. This side product predominates when tetrabutylammonium hydroxide is used in place of metal carbonate bases in the N-alkylation step.

Two solid-supported synthesis strategies for the preparation of 3-thio-1,2,4-triazoles are described. In the first, Rink amide resin is combined with Fmoc-protected ω-amino acids, acid hydrazides, and alkyl halides to provide diverse sets of starting materials from which numerous triazoles may be prepared. The second employs t-alkylcarbamateresin (Boc resin) which permits the use of additional pools of starting materials, including isothiocyanates and α- and ω-amino esters, resulting in triazoles with patterns of functional groups that are not possible from the initial route. The combination of multiple resins and resin attachment sites allows the preparation of a diverse library based upon the3-thio-1,2,4-triazole scaffold and avoids the pitfallof having a single linker functionality present at the same position in all library members. General synthetic procedures and representative products from each route are presented. A similarity analysis of representative sublibraries from each synthesis strategy concludes that variation of the solid-phase linker chemistry and attachment site can enhance molecular diversity of the combined triazole library.

The preparation of polystyrene−divinylbenzene-supported derivatives of tris(2-aminoethyl)amine and methyl isocyanate are described. These polymeric reagents are used to quench excess reactants and remove known impurities from the crude reaction products obtained from the solution-phase, parallel syntheses of ureas, thioureas, sulfonamides, amides, and pyrazoles. In conjunction with the use of other polymeric reactants during the course of a reaction, the addition of polymer-supported quench reagent(s) at the conclusion of the reaction allows isolation of the desired product by a single filtration and evaporation of solvent. The mechanical simplicity and efficiency of this methodology make possible the rapid, parallel purification of crude reaction products obtained via solution-phase syntheses, regardless of whether the intended product is a single compound or a mixture of compounds, and hence offers an attractive alternative to solid-phase organic synthesis in the practice of combinatorial chemistry.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

New derivatives of the naturally occurring amino acid 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (spinacine) are reported. These include amide, ester, 5-alkyl and acyl, and regiospecific N im -alkyl and aralkyl derivatives. Synthesis via the Pictet-Spengler reaction of N im -substituted histidines is described. Cyclic hydantoin derivatives of spinacines are included

(C18H27NO)12n · (C10H10)n · (C8H8)87n) (Polymer-supported initiator of living free radical polymerization; core support for the preparation of Rasta resins.1-4) Alternate Name: TEMPO-methyl resin. Solubility: Insoluble in all solvents. Swells in aprotic solvents such as dichloromethane, chloroform, tetrahydrofuran, toluene, and N,N-dimethylformamide. Form Supplied in: Sand-colored, spherical polymer beads (75–192 μM, 1.0–1.86 mmol g−1). Analysis of Reagent Purity: Elemental analysis. Preparative Methods: Prepared by reaction of Merrifield's resin with the sodium salt of 1-hydroxy-2,2,6,6-tetramethylpiperidine in N,N-dimethylformamide (∼6 equiv) at room temperature.1 Purification: Wash repeatedly with a variety of solvents including water, methanol, N,N-dimethylformamide, dichloromethane, and hexanes; then dry at reduced pressure.1 Handling, Storage, and Precautions: Store at 0–20 °C. TEMPO-methyl-polystyrene resin does not require any special handling precautions other than avoiding conditions that crush the polymer beads.

The preparation and characterization of a homologous series of solid phase synthesis resins for anchoring amines via a Boc-like linker are described. The scope and limitations of these resins are explored with respect to procedures for attachment and cleavage of a variety of primary amines, secondary amines, and alpha-amino esters.

Angiotensin II (ANG II) produces its physiological effects via interaction with its specific receptors that are distributed among a number of different tissues.1–4 The wide variety of receptor locations as well as their varying affinity for angiotensin peptidic fragments5,6 in the presence or absence of dithiothreitol (DTT) allowed some authors to speculate about ANG II receptor subtypes.7 Indeed, some authors referred to different affinity states,8–10 the ability of ligands to bind competitively versus noncompetitively,11–13 and to different signal transduction pathways14–17 to validate their case. However, it was not until the recent discovery of selective ligands that this receptor heterogeneity was clearly established.18–28 Since the AT1 receptor subtype29 mediates a variety of therapeutically important events, in particular, vascular smooth muscle contraction, there has been little effort directed toward the design and synthesis of AT2-specific ligands. However, as losartan (DuP 753)30–33 and numerous other AT1-selective antagonists34–33 progress through the clinical departments44–46 of pharmaceutical companies, one is left to consider the clinical consequence of AT2 receptor activation. Although at present there have been very few functional correlates identified with the AT2 receptor, it would seem reasonable to expect the role of the AT2 receptor to be revealed during the long-term administration of AT1 antagonists, as a consequence of elevated ANG II levels.

Publisher Summary Traditional approaches to cancer management have involved cytotoxic intervention at the level of DNA replication. While cytotoxic anti-cancer drugs have shown limited efficacy against rapidly growing tumor cells, there remains a critical need for the development of agents targeted against more refractory, slow growing, and solid tumors. The 1990s have witnessed a revolution, in the understanding of signaling pathways, which are important to the growth of normal and neoplastic cells. Whether a cell divides or stops dividing depends, to a great extent, on its ability to respond to membrane localized growth stimuli. Among the numerous oncogene or protooncogene encoded proteins that serve as signal transducers in the pathway from the outer membrane to the nucleus, perhaps none are as central as the Ras protein. A distinguishing biochemical feature of the members of the Ras superfamily has their ability to bind guanine nucleotides, with high affinity, and their ability to hydrolyze bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and phosphate. Ras serves, as a molecular switch, for cellular growth and differentiation, by cycling, between an active, GTP-bound form, and an inactive, GDP-bound form. Selectivity for oncogenic Ras relative to normal Ras would be a desirable property of a pulmonary function testing (PFT) inhibitor, because Ras is expressed in virtually all tissues, and plays a critical role in normal cellular proliferation.

A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- 4 mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 less than 2 min). Fractional crystallization was employed to obtain the individual diastereomers in greater than 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

The mass spectral fragmentation of a series of 10 mitosene analogs is described. Major pathways arise through decomposition of the substituents in the 1 and 10 positions and are unaffected by the substituent in the 7 position. The base peak in the spectrum, in most cases, is represented by the basic mitosene ring. The patterns are general for this series of compounds and may have application in elucidating the structure of the DNA alkylation sites involved in reactions with mitosenes or natural mitomycins.

Oxindole is converted to its dianion by treatment with two equivalents each of n-BuLi and TMEDA. Alkylations with a number of common electrophiles define the scope of synthetically useful transformations leading to 3-monosubstituted and 3,3-disubstituted oxindoles.

Alkylation -deprotection de phenacyl-1 histidinates de methyle N-proteges; obtention d'alkyl-3 imidazolyl-5alanines

Alkylation -deprotection de phenacyl-1 histidinates de methyle N-proteges; obtention d'alkyl-3 imidazolyl-5alanines

A series of 1-substituted mitosene analogues of the mitomycin antitumor antibiotics was prepared by total synthesis and screened for activity against P388 leukemia in mice. In general, analogues with moderately good leaving groups (mostly esters) at the 1 position were active, whereas analogues without such substituents were inactive or barely active. These results lend support to the idea that mitosenes with leaving groups at position 1 are capable of bifunctional alkylation of DNA in a manner similar to that of mitomycin C. The most active mitosenes were equal in potency (minimum effective dose) to a corresponding aziridinomitosene, but they were less effective in prolonging life span.