Isolation and identification of three urinary metabolites of retinoic acid in the rat.

After the intraperitoneal administration of high doses of ¹⁴C- and ³H-labelled retinoic acid ( 1 ) to rats three major urinary metabolites have been isolated in microgram amounts by use of column, thin-layer and high-pressure liquid chromatography. Their structures were elucidated by mass spectroscopy and Fourier transform ¹H-NMR. spectroscopy as 2 (5-methyl-5-[2-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-2-tetrahydrofuranone), 3 (5-[2-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone) and 4 (6-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)-4-methyl-4-hexenoic acid). In these metabolites the tetraene side chain of 1 is shortened and the cyclohexene ring oxidized. The radioactivity of 2 and 3 accounted for about 10% (0.9% of the dose) each, metabolite 4 for about 6% (0.5% of the dose) of the total urinary radioactivity.     

An unusual spatial structure of di-ortho-substituted hetaryl vinyl ethers according to1H and13C NMR data

According to¹H and¹³C NMR data, 2,6-dimethyl-3,5-dichloro-4-vinyloxy-pyridine and 2-methyl-4-methoxymethyl-5-hydroxymethyl-3-vinyloxypyridine exist predominantly as the sterically hindered s-cis conformation, with the angle between the hetaryl ring and the vinyloxypyridine plane about 60°.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2040–2044, September, 1991.     

Distribution coefficients of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane between aqueous and hydrocarbon liquid phases

Gas-liquid chromatography was used to study the distribution of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane between aqueous and organic liquid phases for seven binary solvents water-hydrocarbon (n-heptane, n-octane, n-decane, benzene, toluene, p-xylene). The distribution coefficients at low solute contents were measured in the temperature range 283–313 K. In all the systems, the ratio between the solute concentrations in the organic and aqueous phases is substantially smaller than unity and grows with increasing temperature. The ratios between the limiting activity coefficients of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane in the hydrocarbon and aqueous phases were estimated.     

A convenient method for 14C-labeling of 2-methylthio-1-[4-N-α-ethoxycarbonylbenzyl)-amino-benzyl]-5-hydroxymethyl-2-[14C]-1H-imidazole and 1-[4-N-α-ethoxy-carbonylbenzyl)-aminobenzyl]-5-hydroxymethyl-2-[14C]-1H-imidazole as potential antihypertensives

The key synthetic intermediate, (2-mercapto-1-(4-nitrobenzyl)-1H-imidazol-5-yl)methanol-[2-¹⁴C], has been synthesized by using one pot procedure from potassium[¹⁴C]-thiocyanate. It was converted to two nonpeptide angiotensin II receptor antagonists, 2-methylthio-1-[4-N-α-ethoxycarbonyl benzyl)-aminobenzyl]-5-hydroxymethyl-1H-imidazole-[2-¹⁴C] and 1-[4-N-α-ethoxy-carbonylbenzyl)-aminobenzyl]-5-hydroxymethyl-1H-imidazole-[2-¹⁴C] via a 3-step sequence synthetic pathway.     

New thiazinediones and other components from Xanthium strumarium

Two new thiazinediones along with five known compounds were isolated from the fruits of Xanthium strumarium L. The structures of the two new compounds were determined to be 7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzol[1,4]thiazine-3,5-dione-11-O-β-D-glucopyranoside (1) and 2-hydroxy-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzol[1,4]thiazine-3,5-dione-11-O-β-D-glucopyranoside (2). The five known compounds were identified as xanthiazone (3), chlorogenic acid (4), ferulic acid (5), formononetin (6), and ononin (7), respectively. Published in Khimiya Prirodnykh Soedinenii, No. 5, pp. 456–458, September–October, 2006.     

H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs

Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl₂ in CDCl₃/CD₃OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by ¹H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce Sn^IV to Sn^II, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.     

Apparent molar heat capacities and volumes,van der Waals volumes and accessible surface areas of alkylated derivatives of cytosine and uracil in aqueous solutions at 25°C.

Densities and specific heat capacities of aqueous solutions: 1,3,5,6-tetramethyluracil, 1,6-dimethyl-3-ethyluracil, 1,6-dimethyl-3-propyluracil, 1,6-dimethyl-3-butyluracil, 1,N⁴-trimethylcytosine, 1,N⁴-dimethyl-5-ethylcytosine, 1,N⁴ dimethyl-5-propylcytosine, 1,N⁴-dimethyl-5-butylcytosine were determined using flow calorimetry and flow densimetry at 25°C. Apparent molar volumes and heat capacities, van der Waals volumes and accessible surface areas were determined. It was stated that for alkylcytosines and alkyluracils partial molar volumes and heat capacities correlate linearly with the number of substituted methylene groups-CH₂-as well as with the van der Waals volumes and accessible surface areas of the compounds studied; for cyclooligouracils the cyclization effect was discussed.     

Synthesis of Urinary Metabolites of Retinoic Acid

Urinary metabolites 5-methyl-5-[2-(2,6,6-trimethyl -3-oxo-1-cyclohexen-1-yl)-vinyl]-2-tetrahydrofuranone (1) and 5-[2-(6-hydroxymethyl-2, 6-dimethyl-3-oxo-1- cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone (2) of retinoic acid have been synthesized from 4-[2,2,6-trimethyl-3-(tetrahydro-2 H -pyran-2-yl)oxy-1-cyclohexen-1-yl]-3-buten-2-one (4) and methyl 2-(3,3-ethylenedioxy-1-butenyl)-1, 3-dimethyl-4-oxo-2-cyclohexene-1-carboxylate (5) .     

THE PHOTOREACTIONS AND FREE RADICAL INDUCED REACTIONS OF 1,3-DIMETHYLURACIL IN METHANOL AND OTHER ALCOHOLS

Abstract— Photoexcited 1,3-dimethyluracil (DMU) reacts with methanol to give 1,3-dimethyl-6-hydroxymethyl-5-hydrouracil ( 1 a) in addition to cyclobutane type dimers and 1,3-dimethyl-6-methoxy-5-hydrouracil ( 2 a). Free radical induced reaction, initiated by photodecomposition of di- t -butyl peroxide with light of wavelength greater than 290nm, leads to 1 a, 5,6-dihydroxymethyl-5,6-dihydro-1,3-dimethyl-uracil ( 1 d) and 6-hydroxymethyl-1,3-dimethyluracil as the products.     

Oxidative Coupling in a Series of Derivatives of 4a,9-Diaza-1,2,4a,9a-tetrahydrofluorene. 6. Reactions with Substituted 2-Aminoethanols

Oxidative coupling of derivatives of 4a,9-diaza-1,2,4a,9a-tetrahydro-9H-fluorene with 2-ethyl-, 2,2-dimethyl-, and 2-hydroxymethyl-2-methylaminoethanol in the presence of MnO₂ led to the selective formation of the corresponding mono- and di(hydroxymethyl)quinonediimines, subsequent cyclization of which gave the products of 6,7-annelation. Coupling with 2,2-di(hydroxymethyl)aminoethanol gave the annelation products directly.     

Lithiation-methylation of thiasilinane 1-oxides

Lithiation-methylation of 3,3-dimethyl-1λ⁴,3-thiasilinane 1-oxide and 4,4-dimethyl-1λ⁴,4-thiasilinane 1-oxide under the action of butyllithium or lithium diisopropylamide and methyl iodide was studied. In both cases, monomethylation proceeds selectively α to the sulfoxide group to form 2,3,3-trimethyl-1λ⁴,3-thiasilinane 1-oxide and 2,4,4-trimethyl-1λ⁴,4-thiasilinane 1-oxide, respectively. Subsequently, 2,3,3-trimethyl-1λ⁴,3-thiasilinane 1-oxide undergoes monomethylation into the same α position to give 2,2,3,3-tetramethyl-1λ⁴,3-thiasilinane 1-oxide, while 4,4-dimethyl-1λ⁴,4-thiasilinane 1-oxide is dimethylated into the neighboring α’ position to form two stereoisomers of 2,4,4,6-tetramethyl-1λ⁴,4-thiasilinane 1-oxide with axial-equatorial or equatorial-equatorial methyl groups in the 2 and 6 positions.     

Conformation of 5,5-disubstituted 2,2-dimethyl-1,3-dioxanes

It was established by PMR spectral data that in solutions of derivatives of 5-acetoxymethyl-, 5-methyl-, and 5-hydroxymethyl-2,2-dimethyl-1,3-dioxanes with nitrogen-containing substituents (2,4-disubstituted 1,3,5-triazin-6-ylamino, benzamido, and nitro groups) with an N-C₍₅₎ bond the 1,3-dioxane ring exists in the chair conformation with primarily an axial orientation of the nitrogen-containing substituent. Depending on the nature of the substituents attached to the C₍₅₎ atom, the 1,3-dioxane ring may exist either in the stable chair conformation or may undergo rapid inversion of the chair-chair type at 20 °C.The author sincerely thanks A. I. Kol'tsov for his assistance in recording and interpreting the PMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 468–473, April, 1985.     

The Preparation of Dicompartmental Multifunctional Group Ligands

A convenient method for the preparation of the phenol-based ligands 1,6-bis(2-thiophenyl)-2,5-bis(2-hydroxy-3-hydroxymethyl-5-methylbenzyl)-2,5-diazahexane and 1,6-bis(5-methyl-2-thiophenyl)-2,5-bis(2-hydroxy-3-hydroxymethyl-5-methyl-benzyl)-2,5-diazahexane possessing two dissimilar compartments having multifunctional groups is reported. To synthesize these ligands, an equivalent of 1,6-bis(2-thiophene)-2,5-diazahexane or 1,6-bis(5-methyl-2-thiophene)-2,5-diazahexane and two equivalents of 2,2-dimethyl-6-methyl-8-(chloromethyl)benzo-1,3-dioxin were reacted in the presence of Na₂CO₃ in 1,4-dioxane, followed by acid hydrolysis of an acetonide-protecting group. Characterization data for the new compounds is reported.     

2-hydroxymethyl-2-propylpropane-1,3-diol in the synthesis of acetal-like and phosphacyclic lipids

New acetal-like and phosphacyclic lipids were synthesized on the basis of 2-hydroxymethyl-2-propylpropane-1,3-diol. The initial triol was initially treated with higher aldehydes to obtain the corresponding acetals, which were phosphorylated with chlorobis(diethylamino)phosphine. Intermediate phosphorodiamidites were oxidized (without isolation) with phenyliodane oxide or subjected to sulfurization or selenization. Bicyclic phosphite derived from 2-hydroxymethyl-2-propylpropane-1,3-diol was acylated with hexadecanoyl chloride to give 2-chloro-4-propyl-1,3,2-dioxaphosphinan-4-ylmethyl hexadecanoate, and methanolysis of the latter, followed by sulfurization, afforded 2-methoxy-5-propyl-2-thioxo-1,3,2λ⁵-dioxaphosphinan-5-ylmethyl hexadecanoate as a new phosphacyclic lipid.     

4,5-Dimethylimidazole: A correction and alternative synthesis

Fractional vacuum distillation of the product obtained from thermal condensation of acetoin with formamide is a formic acid complex of 4,5-dimethylimidazole, and not the expected free base. The ¹H and ¹³C nmr spectra suggest that the product may be closer to a 1:1 hydrogen-bonded adduct than to a true salt. Commercial 4-hydroxymethyl-5-methylimidazole is converted quantitatively to the 4-chloromethyl derivative with thionyl chloride; hydrogenolysis of the latter compound provides 4,5-dimethylimidazole in an overall 80–90% yield, doubling the yield obtained by the classical method.     

The structure of covalent hydrates of alloxazines. A reinvestigation

It is shown by ¹³C-NMR. and synthesis of 6,7-dimethyl-3-ethoxycarbonylamino-quinoxaline-2-carboxamide ( 5 ) and methyl 6,7-dimethyl-3-(N′-methylureido)-quinoxaline-2-carboxylate ( 6 ) that hydrolysis of lumichrome ( 1 , R = H) must yield 6,7-dimethyl-3-ureidoquinoxaline-2-carboxylic acid ( 2 , R = H) and not 6,7-dimethyl-2-oxo-1,2,9,9a-tetrahydrooxazolo[4,5-b]quinoxaline-9a-carboxamide ( 2a , R = H), as previously proposed.     

1,4,4a,10b-Tetrahydro-N,N-dimethyl-4-phenanthridinamines and 1,4,4a,5,6,10b-hexahydro-N,N-dimethyl-4-phenanthridinamines

Synthetic procedures to prepare the title compounds are described. Diels-Alder cycloaddition of β-nitrostyrene derivatives 5 to N,N-dimethyl-1,3-butadien-1-amine, 6 , gave 5-aryl-N,N-dimethyl-6-nitro-2-cyclohexen-1-amines 7. Reduction of 7 with zinc in acetic acid gave the diamino derivatives 8 . Schotten-Baumann acylation of 8 gave amides 9 . Treatment of 8 with alkyl isocyanates gave the aminourea derivatives 10 . Bischler-Napieralski cyclodehydration procudure of 9 and 10 gave 1,4,4a,10b-tetrahydrophenanthridinamines 3 and N⁶-alkyl-1,4,4a,10b-tetrahydro-N⁴,N⁴-dimethyl-4,6-phenanthridinediamines 11 , respectively. Condensation of diamines 8 with aryl aldehydes under azeotropic conditions gave imines 12 which on treatment with acids yielded 6-aryl-1,4,4a,5,6,10b-hexahydro-N,N-dimethyl-4-phenanthridinamines 4 . The stereochemistry of these materials is assigned from the proton magnetic resonance studies.     

Terpyridines as supramolecular initiators for living polymerization methods

Bis(5,5″-bis(bromomethyl)-2,2′:6′,2″-terpyridine), bis-4′-(4-bromomethylphenyl)-2,2′:6′,2″-terpyridine and 4-hydroxymethyl-5′,5″-dimethyl-2,2′:6′,2″-terpyridine metal complexes have been used as initiators for the living polymerization of 2-oxazolines and L-lactides. In both cases polymers with controlled molecular weights and narrow molecular weight distributions have been obtained. In-line diode array GPC measurements of iron(II) complexed poly(ethyloxazoline)s showed an unexpected absence of fragmentation. Viscosity experiments demonstrated the differences of the complexed and uncomplexed systems.     

Synthesis and characterization of novel dipeptide mimetics with hydantoin moiety

The synthesis of three novel 5,5-dimethylhydantoin derivatives 2-amino-N-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetamide, 2-amino-N-(4,4-dimethyl-2,5-dioxoimidazol idin-1-yl)-3-phenylpropanamide, and 2-amino-4-methyl-N-(4,4-dimethyl-2,5-dioxoimidazol idin-1-yl) pentanamide, is reported. The newly synthesized compounds have been characterized by infrared (IR), MS, and NMR (¹H and ¹³C) spectra.