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At least 487 records · Page 27Linked to original sources
PubMed1993

Conformationally restricted analogues of remoxipride as potential antipsychotic agents.

Several conformationally restricted derivatives of (S)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide (remoxipride) were synthesized and evaluated in vitro for their ability to inhibit [3H]raclopride binding at the dopamine D-2 receptor. The cyclic benzamides designed to mimic the intramolecular hydrogen bonding of desmethylremoxipride (4, FLA-797) included 2,3-dihydro-4H-1,3-benzoxazin-4-ones, 2,3-dihydro-4H-1,3-benzthiazin-4-ones, phthalimides, 1-isoindolinones, 1,2-benzisothiazol-3(2H)-ones, and 1,2-benzisothiazol-3(2H)-one 1,1-dioxides. In this series, enhanced affinities to the dopamine D-2 receptor were not observed. The phthalimidine analogue 24b ((S)-6-chloro-2-(1-ethylpyrrolidinyl)-1-isoindolinone) exhibited the highest affinity to the dopamine D-2 receptor with an IC50 of 1.3 microM, which was equipotent to remoxipride.

Animals↗
PubMed1992

Synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine.

A series of novel 6-fluoro-7-diazabicycloalkylquinolonecarboxylic acids substituted with various C8 (H, F, Cl, N) and N1 (ethyl, cyclopropyl, vinyl, 2-fluoroethyl, 4-fluorophenyl, 2,4-difluorophenyl) substituents, as well as, 9-fluoro-10-diazabicycloalkylpyridobenzoxazinecarboxylic acids, were prepared and evaluated for antibacterial activity against a range of important veterinary pathogenic bacteria. The diazabicycloalkyl side chains investigated at the 7-position (benzoxazine 10-position) include (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (2), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (3), (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (4), 8-methyl-3,8-diazabicyclo[3.2.1]octane (5), 9-methyl-3,9-diazabicyclo[4.2.1]nonane (6), 1,4-diazabicyclo[3.2.2]nonane (7), 1,4-diazabicyclo[3.3.1]nonane (8), and 9-methyl-3,9-diazabicyclo[3.3.1]nonane (9). Among these side chains, in vitro potency was not highly variable; other properties therefore proved more critical to the selection of possible development candidates. However, the relative potencies observed for several of these compounds in mouse, swine, and cattle infection models correlated well with those seen in vitro. A combination of the N1 cyclopropyl group and the C7 (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl appendage conferred the best overall antibacterial, physiochemical, and pharmacodynamic properties. Hence, danofloxacin (Advocin, 2c) (originally CP-76,136, 1-cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1] hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) was selected as a candidate for development as a therapeutic antibacterial agent for veterinary medicine.

Actinobacillus Infections↗
PubMed1988

New "ofloxacin" type antibacterial agents. Incorporation of the spiro cyclopropyl group at N-1.

The first example incorporating a spiro cyclopropyl group into an "ofloxacin" type of quinolone antibacterial agent has been prepared by potassium fluoride mediated ring closure of the hydroxymethyl cyclopropyl intermediate to give 9'-fluoro-7'-oxo-10'-(1-piperazinyl)spiro[cyclopropane-1,3'(2'H)-[7H] pyrido[1,2,3-de][1,4]benzoxazine]-6'-carboxylic acid. Analogues were made by substitution at C-7 by various complex amines. Evaluation of these compounds for antibacterial activity was carried out. All examples prepared and examined showed in vitro minimum inhibitory values and in vivo mouse protection results to be diminished as compared to the parent, ofloxacin.

Animals↗
PubMed1986

New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamindes.

N-(omega-Aminoalkyl)-2,2,5,5-tetramethyl-3-pyrroline- or -pyrrolidine-3-carboxamides were acylated on the primary amino group of the side chain by means of reactive acid derivatives (acid chlorides, activated esters, phthalic anhydrides, phthalimide, 2-alkyl-4H-3,1-benzoxazin-4-ones) or they were alkylated by forming the Schiff bases and subsequent sodium borohydride reduction. Other tetramethyl-3-pyrrolinecarboxamide compounds were synthesized by acylating the aminoalkyl compounds with 2,2,6,6-tetramethyl-3,5-dibromo-4-piperidinone in a reaction involving Favorskii rearrangement. Saturation of the double bond of some pyrroline derivatives furnished the pyrrolidinecarboxamides. The new compounds of each type were active against aconitine-induced arrhythmia and several of them had higher activity and better chemotherapeutic index than quinidine. A few selected examples from each type of the active new compounds showed strong activity against ouabain-induced arrhythmia; for comparison known drugs such as lidocaine, mexiletine, and tocainide were selected. The most potent compounds were oxidized to the paramagnetic nitroxides and the latter were reduced to the N-hydroxy derivatives; these products had no or only decreased antiarrhythmic effect.

Animals↗
PubMed1983

2-(Aminomethyl)phenols, a new class of saluretic agents. 6. Effects of N,O-spiroannulation and subsequent quaternization.

The synthesis of a number of 3,4-dihydrospiro-2H-1,3-benzoxazines and their corresponding benzoxazinium salts are reported. The saluretic effects displayed by these N,O-spiroannulated 2-(aminomethyl)phenols appear to be, in part, inversely related to their respective in vivo rates of hydrolysis. Good antihypertensive effects are found only in spirobenzoxazinium 22. Thus, a combination of spiroannulation and quaternization on 2 to produce 22 leads to a loss of saluretic effects with maintenance of antihypertensive effects and, thereby, serves to separate these pharmacological properties.

Amines↗
PubMed2002

Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor.

N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) is a potent and selective antagonist for the CB1 cannabinoid receptor. Using the AM1 molecular orbital method, conformational analysis of 1 around the pyrazole C3 substituent identified four distinct conformations designated Tg, Ts, Cg, and Cs. The energetic stability of these conformers followed the order Tg > Cg > Ts > Cs for the neutral (unprotonated) form of 1 and Ts > Tg > Cs > Cg for its piperidine N-protonated form. Unified pharmacophore models for the CB1 receptor ligands were developed by incorporating the protonated form of 1 into the superimposition model for the cannabinoid agonists 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]perhydro-2alpha,6beta-dihydroxynaphthalene (CP55244; 2) and the protonated form of (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55212-2; 3) reported previously (Shim et al. In Rational Drug Design Symposium Series; Parrill, A. L., Reddy, M. R., Eds.; American Chemical Society: Washington, DC, 1999; pp 165-184). Values of K(i) for 1 and a series of 31 structural analogues were determined from radioligand binding analyses by competitive displacement of [3H]CP55940 from cannabinoid receptors in a rat brain membrane preparation. Comparative molecular field analysis (CoMFA) was employed to construct three-dimensional (3D)-quantitative structure-activity relationship (QSAR) models for this data set as unprotonated species assuming the Tg, Cg, and Ts conformers and for the protonated species assuming the Ts, Tg, and Cs conformers. Values of the conventional r2 and cross-validated r2 (r(cv)2) associated with these CoMFA models exceeded the threshold for statistical robustness (r2 > or = 0.90) and internal predictive ability (r(cv)2 > or = 0.50) in each of these six cases except for the protonated species assuming the Tg conformer (i.e., r2 = 0.97; r(cv)2 = 0.36). Results from conformational analyses, superimposition models, and 3D-QSAR models suggest that the N1 aromatic ring moiety of 1 dominates the steric binding interaction with the receptor in much the same way as does the C3 alkyl side chain of cannabinoid agonists and the C3 aroyl ring of the aminoalkylindole agonists. We also determined that several of the conformers considered in this study possess the proper spatial orientation and distinct electrostatic character to bind to the CB1 receptor. We propose that the unique region in space occupied by the C5 aromatic ring of 1 might contribute to conferring antagonist activity. We further propose that the pyrazole C3 substituent of 1 might contribute to conferring either neutral antagonist or inverse agonist activity, depending upon the interaction with the receptor.

Algorithms↗
PubMed1998

Novel thieno[2,3-d][1,3]oxazin-4-ones as inhibitors of human leukocyte elastase.

A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with Ki values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.

Enzyme Inhibitors↗
PubMed1999

2-(diethylamino)thieno1,3ŏxazin-4-ones as stable inhibitors of human leukocyte elastase.

A series of 2-(diethylamino)thieno1,3ŏxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase (HLE). The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates. These precursors were subjected to a five-step route to obtain thieno2,3-d1,3ŏxazin-4-ones bearing various substituents at positions 5 and 6. Both thieno2,3-d and thieno3,2-d fused oxazin-4-ones possess extraordinary chemical stability, which was expressed as rate constants of the alkaline hydrolysis. The kinetic parameters of the HLE inhibition were determined. The most potent compound, 2-(diethylamino)-4H-1benzothieno2,3-d1,3ŏxazin-4-one, exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno1, 3ŏxazin-4-ones act as acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. The isosteric benzene-thiophene replacement accounts for an enhanced stability of the acyl-enzyme intermediates.

Enzyme Inhibitors↗
PubMed2001

A novel straightforward synthesis of enantiopure tetrahydroisoquinoline alkaloids.

A novel, direct,and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.

Indicators and Reagents↗
PubMed2001

Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C.

Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized as a key intermediate and dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The natural products were attained via rearrangements to an amidine intermediate, deprotection with 45% HBr in acetic acid, and cyclization on silica gel.

Alkaloids↗
PubMed2002

Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines.

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.

Journal Article↗
PubMed2002

Ring[bond]chain tautomerism of 2-Aryl-substituted cis- and trans-decahydroquinazolines.

In CDCl(3) at 300 K, 2-aryl-substituted cis- and trans-3-isopropyldecahydroquinazolines and trans-3-phenyldecahydroquinazolines proved to be three-component (r(1)[bond]o[bond]r(2)) ring[bond]chain tautomeric mixtures, whereas only ring-closed tautomers could be detected for the 3-methyl-substituted analogues. The proportions of the ring-chain tautomeric forms at equilibrium were strongly influenced by the N-substitutents and the cis-trans ring junction and could be described by the equation log K(X) = rho sigma(+) + log K(X=H). These are the first examples among 2-aryl-1,3-N,N-heterocycles of a three-component ring-chain tautomeric equilibrium characterized by a Hammett-type equation. The stabilities of the ring-closed forms of cis- and trans-2-aryldecahydroquinazolines and the corresponding 3,1-benzoxazines were found to increase in the following sequence of the heteroatom at position 3: NPh < N-i-Pr < O < NMe.

Journal Article↗
PubMed2003

Cascade cyclizations via N,4-didehydro-2-(phenylamino)pyridine biradicals/zwitterions generated from enyne-carbodiimides.

Thermolysis of the enyne-carbodiimides 7 having the central carbon-carbon double bond incorporated as part of the cyclopentene ring favors the formation of the corresponding N,4-didehydro-2-(phenylamino)pyridine intermediates, either as the sigma,pi-biradicals 8 or as the zwitterions 8', for subsequent synthetic elaborations. By placing appropriate substituents at the acetylenic terminus, a variety of the intramolecular decay routes are available for the initially formed sigma,pi-biradicals/zwitterions, leading to the 5,6-dihydrobenzo[c][1,8]naphthyridine 21, the 1,2,3,4-tetrahydro[1,8]naphthyridine 24 and related compounds 25 and 26, the 5,6-dihydrobenz[f]isoquinoline 28, and the benzofuro[3,2-c]pyridine 30. Surprisingly, the use of the dimethylamino group of the 2-(dimethylamino)phenyl substituent to capture the carbocationic center in the zwitterion 8e' furnished the 5H-pyrido[4,3-b]indole 32 in only 14% yield. The majority of the products were the 1H-pyrrolo[2,3-b]quinolines 34 and 35, isolated in 48 and 7% yields, respectively. However, it was possible to redirect the reaction toward 32 by conducting thermolysis of the enyne-carbodiimide 7e in the presence of 5 equiv of dimethylphenylsilyl chloride. Under this reaction condition, the 2-pyridone imine 37 was isolated in 86% yield, which on exposure to silica gel was converted to 32 in essentially quantitative yield. Thermolysis of the enyne-carbodiimide 42 having a methoxymethyl substituent at the acetylenic terminus led to the formation of 46' as a pyridine analogue of ortho-quinone methide imine. An intramolecular hetero-Diels-Alder reaction of 46' then furnished the tetrahydro[1,8]naphthyridino[2,1-c][1,4]benzoxazine 47.

Journal Article↗
PubMed2003

An efficient route to 3-aryl-substituted quinolin-2-one and 1,8-naphthyridin-2-one derivatives of pharmaceutical interest.

Reaction of arylacetic ester enolates with 2-alkoxy-4H-3,1-benzoxazin-4-ones offers a short and versatile synthetic route to 3-aryl-4-hydroxyquinolin-2(1H)-ones, through the cyclization of the beta-ketoesters produced. Similar reactions of 4H-pyrido[2,3-d][1,3]oxazin-4-ones with ester enolates afford 1-acyl-4-hydroxy-1,8-naphthyridin-2(1H)-ones in a convenient two-step, one-pot procedure.

Catalysis↗
PubMed2005

Diastereoselective yang photocyclization reactions in solution. synthesis of enantiopure azetidin-3-ol derivatives.

[reaction: see text] Chiral 2-acyl-3-allyl- or 2-acyl-3-benzyl-substituted perhydro-1,3-benzoxazines readily cyclized under irradiation to azetidin-3-ol derivatives. The diastereoselectivity of the cyclization is dependent on the nature of the substituents at the nitrogen atom. N-allyl-substituted derivatives yielded only two of the four possible diastereomers in moderate to good diastereomeric excess. The cyclization of N-benzyl derivatives was totally diastereoselective leading to a single diastereomer. The elimination of the menthol appendage lead to enantiopure 2,3-disubstituted azetidin-3-ol derivatives.

Journal Article↗
PubMed2005

Chiral template mediated diastereoselective intramolecular Diels-Alder reaction using furan as a diene. Toward the synthesis of enantiopure trisubstituted tetrahydroepoxyisoindolones.

[reaction: see text] Chiral precursors to the intramolecular Diels-Alder reaction using furan as a diene (IMDAF) have been prepared by diastereoselective addition of furyllithium to imines attached to perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol. The acylation of the furylamines with alpha,beta-unsaturated acyl chlorides and subsequent IMDAF reaction under thermal conditions provided the corresponding cycloadducts as single diastereoisomers. The hydrolytic elimination of the chiral template yielded enantiopure perhydroepoxyisoindolones with up to five stereocenters.

Journal Article↗
PubMed1999

A formylating agent by dehydration of the natural product DIMBOA

The natural aglucone 2,4-dihydroxy-7-methoxy-2H-1, 4-benzoxazin-3(4H)-one (DIMBOA, 1) of maize underwent spontaneous dehydration and rearrangement to form 3-formyl-6-methoxybenzoxazolin-2(3H)-one (FMBOA, 2) on reaction with N-ethoxycarbonyl-trichloroacetaldimine. Compound 2 was proven to be a reactive formyl donor toward N-, O-, and S-nucleophiles, which may be important in case 2 is formed under biological conditions.

Journal Article↗
PubMed2002

New synthetic catecholate-type siderophores with triamine backbone.

New analogues of triscatecholate siderophores based on linear or tripodal triamines with or without spacer groups or lipophilic and hydrophilic substituents were synthesized. The catecholate moieties were prepared in OH-forms, as acetylated compounds or masked as 8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine derivatives. Some of the new compounds were active as siderophores tested by growth promotion assays using various gram-negative bacteria and mycobacteria under iron limitation and by CAS-assay. Structure-activity-correlations have been studied.

Amines↗