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PubMed2002

N-Arylated pyrrolidin-2-ones and morpholin-3-ones as potassium channel openers.

Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-3-one (3-5), piperidin-2-one (6), and pyrrolidin-2-one (7-13) was synthesized and evaluated for potassium channel opening activity. In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-on (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demonstrated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder)=7.4 and 6.7 microM, respectively; IC50 ratio (portal vein/bladder)=41 and 51, respectively].

Amides↗
PubMed1998

Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors.

The synthesis of a series of 2,4-disubstituted morpholines is described and their affinities at human dopamine receptors reported. The orally bioavailable 7-azaindole compound 11 has nanomolar affinity at the hD4 receptor with > 1000-fold selectivity over the hD2 receptor.

Administration, Oral↗
PubMedDate not supplied

Design and synthesis of a diverse morpholine template library.

Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.

Aldehydes↗
PubMed1986

(S)-3-[(benzyloxy)methyl]morpholine hydrochloride: a nonstimulant appetite suppressant without conventional neurotransmitter releasing properties.

The synthesis and appetite-suppressant activity of (S)-3-[(benzyloxy)methyl]morpholine hydrochloride in dogs are reported. The oral ED50 for appetite suppression in dogs of 3 was 12 mg/kg, and it was tolerated up to 200 mg/kg. 3 had no inhibitory effect on the release or uptake of noradrenaline, dopamine, or serotonin at 10(-5) M. The (R) enantiomer of 3 was not anorexiant.

Animals↗
PubMed1979

Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adrenergic-stimulating activity and the potentiating effect on the responses to norepinephrine found in the open-chain compounds persist in their corresponding semirigid cyclic analogues. The results are discussed in the light of common knowledge of the structure-activity relationships of alpha-adrenergic drugs.

Adrenergic alpha-Antagonists↗
PubMed1998

(R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methanesulfonate: a new selective rat 5-hydroxytryptamine1B receptor antagonist.

In the search for new 5-hydroxytryptamine (5-HT) receptor antagonists it was found that the compound (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy] methyl] morpholine methanesulfonate, (R)-25, is a selective rat 5-hydroxytryptamine1B (r5-HT1B) receptor antagonist. The binding profile showed a 13-fold preference for r5-HT1B (Ki = 47 +/- 5 nM; n = 3) vs bovine 5-HT1B (Ki = 630 nM; n = 1) receptors. The compound had very low affinity for other monoaminergic receptors examined. The r5-HT1B receptor antagonism was demonstrated by the potentiation of the K+-stimulated release of [3H]-5-HT from superfused rat brain slices in vitro, an effect that was antagonized by addition of 5-HT to the superfusion fluid. (R)-25 at 20 mg/kg sc enhanced the 5-HT turnover in four rat brain regions (hypothalamus, hippocampus, striatum, and frontal cortex) with about 40% measured as the 5-HTP accumulation after decarboxylase inhibition with 3-hydroxybenzylhydrazine. At 3 mg/kg sc (R)-25 produced a significant increase in the number of wet dog shakes in rats, a 5-HT2A/5-HT2C response that was abolished by depletion of 5-HT after pretreatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine. These observations show that (R)-25, by inhibiting terminal r5-HT1B autoreceptors, increases the 5-HT turnover and the synaptic concentration of 5-HT.

Animals↗
PubMed2004

Synthesis and application of carbohydrate-derived morpholine amino acids.

The synthesis of series of diversely functionalized epsilon-morpholine amino acids (MAAs, 5a-h) starting from an epsilon-sugar amino acid and following a two-step oxidative glycol cleavage/reductive amination strategy, is described. In an alternative synthetic scheme, diastereoisomerically pure delta-MAAs (12a,b) were obtained. Oligopeptides containing MAAs were prepared either by direct incorporation of a MAA building block or by subjecting a fully assembled SAA-containing peptide to the two-step glycol cleavage/reductive amination procedure.

Amino Acids↗
PubMed2006

Asymmetric synthesis of 1-(2- and 3-haloalkyl)azetidin-2-ones as precursors for novel piperazine, morpholine, and 1,4-diazepane annulated beta-lactams.

A high-yielding, asymmetric synthesis of novel 4-formyl-1-(2- and 3-haloalkyl)azetidin-2-ones was developed as valuable starting materials for the synthesis of different enantiomerically enriched bicyclic azetidin-2-ones, such as piperazine, morpholine, and 1,4-diazepane annulated beta-lactam derivatives. Especially the hydride reduction of 4-imidoyl-1-(2- and 3-haloalkyl)azetidin-2-ones turned out to be an efficient and straightforward method for the preparation 2-substituted piperazines and 1,4-diazepanes.

Azetidines↗
PubMed2005

Hectochlorin and morpholine derivatives from the Thai sea hare, Bursatella leachii.

Investigation of the EtOAc extract from the Thai sea hare, Bursatella leachii, resulted in the isolation of a potent stimulator of actin assembly, hectochlorin (1), and its new derivative, deacetylhectochlorin (2). Compound 2 exhibited more potent cytotoxicity than 1 against different human carcinoma cell lines. In addition, a new morpholine-2,5-dione analogue, syn-3-isopropyl-6-(4-methoxybenzyl)-4-methylmorpholine-2,5-dione (3), was co-isolated.

Animals↗
PubMed2004

Efficient, stereoselective synthesis of trans-2,5-disubstituted morpholines.

[reaction: see text] Enantio- and diastereoselective syntheses of trans-2,5-disubstituted morpholine derivatives are described. The routes are initiated by the reaction of enantiopure epoxides (2) with amino alcohols (3) and address the problem of regioselective hydroxyl activation-ring closure of the resulting amino diol adducts for (amino alcohol-derived) alkyl substituents of different steric demands.

Amino Alcohols↗
PubMed1994

Differential-pulse polarographic determination of zinc and manganese in various pharmaceutical and biological samples after adsorption of their morpholine-4-carbodithioates on microcrystalline naphthalene.

A highly selective, sensitive, rapid and economical differential-pulse polarographic method was developed for the simultaneous determination of trace amounts of zinc and manganese in various standard alloys and pharmaceutical, biological and environmental samples after adsorption of their morpholine-4-carbodithioates on microcrystalline naphthalene in the pH range 4.1-9.0 for manganese and 6.5-10.2 for zinc. After filtration, the metal complexes are shaken with 10 ml of 1 mol l-1 HCl and determined simultaneously using a differential-pulse polarograph. There is no need to remove naphthalene from the solution. Dissolved oxygen is removed by adding a few millilitres of 4% NaBH4 solution. The detection limits are 0.06 ppm for Mn and 0.1 ppm for Zn (signal-to-noise ratio = 2). Linearity is maintained in the concentration ranges 0.06-10 ppm for Mn and 0.1-12 ppm for Zn with a correlation factor of 0.9997 and relative standard deviations of 0.95 and 0.81%, respectively. The characterization of the electroactive process included an examination of the degree of reversibility. Various parameters such as the effect of pH, volume of aqueous phase and interference of a number of metal ions on the determination of manganese and zinc were studied in detail to optimize the conditions for their simultaneous determination (based on the large difference in their Ep values) in various biological, pharmaceutical and environmental samples.

Humans↗
PubMed1987

13-week subchronic toxicity study with morpholine oleic acid salt administered to B6C3F1 mice.

The effect of subchronic administration of morpholine oleic acid salt (MOAS) was studied in B6C3F1 mice. The dose levels of MOAS used were 0%, 0.15%, 0.3%, 0.6%, 1.25%, and 2.5% in drinking water. Reduced weight gains were noted in both sexes in the 2.5% group as compared to controls, but reductions were not significant. Water consumption values showed a dose-related tendency for a decrease in both females and males. Urine analysis showed significant elevation of specific gravity in the males in the 0.6%, 1.25%, and 2.5% groups and the females in the 1.25% and 2.5% groups. Significant elevation of plasma urea nitrogen was observed in males of the 1.25% and 2.5% groups and in females of the 0.6%, 1.25%, and 2.5% groups. The relative weight of the kidneys showed a dose-dependent increase that was statistically significant for the 1.25% and 2.5% MOAS groups in both sexes. Except for cloudy swelling of the proximal tubules of the kidneys in mice on the 2.5% regimen, no treatment-related histopathological alterations were observed in organs of either sex.

Animals↗
PubMed1986

Inhibitory effect of alpha-tocopherol on the formation of nitrosomorpholine in mice treated with morpholine and exposed to nitrogen dioxide.

The possibility that alpha-tocopherol (vitamin E) inhibits the formation of nitrosomorpholine (NMOR) in vivo was investigated in mice orally pretreated with alpha-tocopherol (2.5-100 mg/kg body wt) once daily for 6 days. Twenty-four hours later, the animals were injected i.p. with 2 mg of morpholine (MOR) per animal followed by exposure to 47 p.p.m. of NO2 for 2 h. Under these conditions, low oral doses of alpha-tocopherol (2.5-5 mg/kg body wt) significantly decreased NMOR formation in vivo. As total body alpha-tocopherol levels increased, in vivo NMOR formation decreased, and a maximal 50-70% inhibition of NMOR formation occurred at alpha-tocopherol levels of 5 micrograms/g body wt. Additional results showed that NMOR was rapidly eliminated in mice, so that studies which measure the levels of NMOR found in animals treated with MOR and then exposed to NO2 may underestimate the amount of NMOR that is actually formed. Finally, oral pretreatment of up to 100 mg of alpha-tocopherol/kg body wt had no effect on NMOR elimination.

Animals↗
PubMed2006

Morpholine-2,5-dione.

In the title compound, C4H5NO3, the morpholine ring adopts a boat conformation that is distorted towards twist-boat, the boat ends being the two Csp3 atoms of the ring. The molecular packing is stabilized by the establishment of strong intermolecular NH...OC hydrogen bonds, which give rise to centrosymmetric dimers, and a network of weak CH2...OC hydrogen bonds, where each dimer interacts with eight neighbouring morpholinedione rings.

Crystallography, X-Ray↗
PubMed1997

Carcinogenicity of methylurea or morpholine in combination with sodium nitrite in rat multi-organ carcinogenesis bioassay.

For carcinogenic risk assessment of combinations of N-nitroso precursors in man, the effects of feeding methylurea (MU) or morpholine (Mor) plus sodium nitrite (NaNO2) were investigated using a multi-organ carcinogenesis model. In experiment 1, to initiate multiple organs, groups of 10 or 20 male F344 rats were treated with 6 carcinogens targeting different organs. Starting a week after completion of this initiation phase, animals were given 0.1% MU or 0.5% Mor in their food and/or 0.15% NaNO2 in their drinking water for 23 weeks. The induction of tumors and/or preneoplastic lesions in the forestomach and esophagus was significantly increased in the group receiving MU plus NaNO2. The numbers and areas of liver glutathione S-transferase placental form (GST-P)-positive foci were significantly elevated with MU or Mor plus NaNO2. Experiment 2 was conducted to assess formation of N-nitroso compounds in the stomach, and to detect DNA adduct generation in target organs by immunohistochemical staining. Groups of 5 or 14 animals were starved overnight, then given 0.4% MU or 2.0% Mor in the diet, or basal diet alone for 1 h. Then NaNO2 or distilled water was given intragastrically. The mean gastric N-methyl-N-nitrosourea yield in the MU plus NaNO2 group was 7700 micrograms at 2 h after combined administration. The mean N-nitrosomorpholine yield in the group given Mor plus NaNO2 was 6720 micrograms. Immunohistochemically, N7-methyldeoxyguanosine-positive nuclei were evident in the forestomach epithelium at 8 h after the combination treatment with MU plus NaNO2.

Administration, Oral↗
PubMed2004

Agar sublimation test for the in vitro determination of the antifungal activity of morpholine derivatives.

We studied the in vitro antifungal activities of a wide range of antimycotic agents, including amorolfine, terbinafine, naftifine, five morpholine derivatives, ciclopiroxolamine, bifonazole, clotrimazole, ketoconazole, itraconazole, fluconazole, voriconazole, flucytosine, amphotericin B, nystatin, and caspofungin, against Candida albicans and Trichophyton rubrum by conventional agar diffusion tests and by a novel sublimation method. For the sublimation method, 6 mm filter paper disks were soaked with defined amounts of antimycotic drugs, air dried, placed in the center of the lids of 9 cm Petri dishes, and incubated upside down with inoculated agar plates 10 mm above the disks. The conventional disk diffusion tests produced inhibition zones as previously described. The disk sublimation tests produced large inhibition zones with amorolfine, five amorolfine derivatives, and terbinafine, but with none of the other antifungal agents. Possible therapeutic advantages of agents, which are able to overcome air cavities in mycotic lesions, e.g. in onychomycosis, are discussed.

Agar↗
PubMed1988

Comparative studies of the sensitization potential of morpholine, 2-mercaptobenzothiazole and 2 of their derivatives in guinea pigs.

The aim of this study was to determine the sensitization potential of morpholine (M), 4,4'-dithiodimorpholine (DTDM), morpholinyl-mercaptobenzothiazole (MMBT) and 2-mercaptobenzothiazole (MBT) in guinea pigs. 5% and 10% DTDM, MMBT and MBT produced irritation reactions. M up to 10% failed to irritate. Sensitization tests showed that all the guinea pigs treated with DTDM and MMBT were sensitized. Cross-sensitization tests showed that 60% of the DTDM-sensitized animals reacted to challenge with MMBT; 30% of the animals sensitized to DTDM reacted to challenge with M; 80% of the MMBT-sensitized animals reacted to challenge with MBT and 10% to challenge with M; 42% of the MBT-sensitized animals reacted to MMBT. The rank order of sensitization potential in guinea pigs observed from this study is DTDM, MMBT and then MBT. It appears that the disulfide bond, sulfur linkage and the sulfhydryl group may each play a role in the sensitizing capacity of these compounds.

Allergens↗