Chemical modification of fumagillin. II. 6-Amino-6-deoxyfumagillol and its derivatives.

6-Amino-6-deoxyfumagillol (5) was synthesized by reductive amination of 6-oxo-6-deoxyfumagillol (4), which was obtained by oxidation of fumagillol (2). The reduction proceeded stereoselectively by the equatorial attack of hydride and 5 was found to have the same stereochemistry as that of 2. Several derivatives of 5 were prepared and most of them showed anti-angiogenic activity comparable to that of fumagillol derivatives.     

2-Polyfluoroalkylchromones. 5. Nitration and chlorination of 2-trifluoromethylchromones

Electrophilic nitration of 2-trifluoromethylchromone and its 6- and 7-methoxy derivatives affords 6-, 5-, and 8-nitro derivatives, respectively, while 5,7-dimethyl-2-trifluoromethylchromone yields a 6,8-dinitro derivative. Radical chlorination results in 3-chloro derivatives.     

Antiandrogen. I. 2-azapregnane and 2-oxapregnane steroids.

2-Azachlormadinone acetate (5a, 17-acetoxy-6-chloro-2-azapregna-4,6-diene- 3,20-dione), 2-oxachlormadinone acetate (6, 17-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione) and the derivatives were prepared as potential antiandrogenic agents. Biological evaluation showed that 5a and 6 had a potent antiandrogenic activity when tested in the castrated male rat.     

Furopyridines. IX. Syntheses and properties of 3-ethoxy derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

Reaction of ethyl 3-ethoxycarbonylmethoxyfuropyridine-2-carboxylates 2a-2d with sodium ethoxide afforded 3-ethoxy derivatives 3a-3d which converted to 3-ethoxyfuropyridines 5a-5d by hydrolysis and decarboxylation of the ester group. Vilsmeier reaction of 5a and 5b gave 2-formyl-3-ethoxy derivatives 6a and 6b and 2-formyl-3-chloro derivatives 7a and 7b , while 5c and 5d did not give any formyl compound. Bromination of 3-ethoxyfuropyridines with 1 equivalent mole of bromine gave 2-bromo-3-ethoxyfuropyridines 9a-9d , whereas reaction with 3 equivalents of bromine yielded 2,2-dibromo-3,3-diethoxy-2,3-dihydrofuropyridines ( 10a and 10b ) and/or 2-bromo-3,3-diethoxy-2,3-dihydrofuropyridines 11b , 11c and 11d . Treatment of compounds 5a-5d with n-butyllithium in hexane-tetrahydrofuran at ?70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 6a-6d .     

6(5H)-phenanthridinones. III. halo-6(5H)phenanthridinones

Halogenation of 6(5H)-phenanthridinone or its 3,8-dihalo derivatives with N-bromo or N-chlorosuccinimide in dimethylformamide gives the corresponding 2-halophenanthridinones (I,V,XI-XIV). Further halogenation of 2-halo-6(5H)-phenanthridinone with the appropriate N-halosuccinimide, in the same medium, gives the corresponding 2,4-dihalo derivatives (II,VI). NXS/DMF is found to be a very convenient halogenating system in these preparations. 1,3,8-Trihalo-6(5H)-phenanthridinones (XIX,XX) are prepared from the 1-nitro derivatives which are obtained by a Schmidt rearrangement of 2,7-dihalo-4-nitro-9-oxofluorenes. Similarly, rearrangement and further reaction of 2-nitro-5-chloro-9-oxofluorene (XXI) leads to 3,10-dichloro-6(5H)-phenanthridinone (XXIV). UV absorptions as well as selected IR absorptions of these 6(5H)-phenanthridinones are described.     

Steroid compounds of marine sponges. VII. Preparation of derivatives of sokotrasterol and halistanol sulfates and structure-activity interrelationships among these compounds

Five new sulfated derivatives of sokotrasterol and halistanol have been obtained: 24-nor-5α-cholane-2β,3α,6α,23-tetraol 2β,3α,6α-tri(sodium sulfate); 24-nor-5α-cholane-2β,3α,6α,23-tetraol 2β,3α,6α-tri(sodium sulfate) 23-palmitate; 24ε,25-dimethyl-5α-cholestane-2β,3α,6α-triol 3α-(sodium sulfate); 24ε,25-dimethyl-5α-cholestane-2β,3α,6α-triol 6α-(sodium sulfate); and 24ε,25-dimethyl-5α-cholestane-2β,3α,6α-triol 2β,6α-di(sodium sulfate). The inhibiting and membranolytic properties of the polysulfated steroids from sponges and their derivatives have been studied. It has been shown that physiological activity in this series of compounds depends on biphilicity.     

Research on the synthesis of 5, 6-benzoquinoline derivatives. Infrared spectra of 2-phenyl-5, 6-benzoquinoline derivatives

The infrared spectra of a number of 2-phenyl-5, 6-benzoquinoline derivatives are measured. It is found that in the 690–900 cm^–1 range, correlations found for benzene homologs and applicable to pyridine and quinoline derivatives also apply to these 2-phenyl-5, 6-benzoquinoline derivatives.     

2-Imidazolines. III (1). 1-Aryl- and 1-acyl-2-amino-(ormethoxy)-4,5-diamino-4,5-dihydroimidazoles. Synthesis and properties

Diimmonium salt (5) reacts with guanidines (6) and o-methylisoureas (7) affording 2-amino-4,5-dimorpholinoimidazolines (9) . 1-Aryl-2-amino-4,5-dimorpholinoimidazolines lose the amino functionality under mild acidic conditions with formation of 2-amino-5-morpholinoimidazole derivatives (10) whereas 1-acyl derivatives undergo under the same conditions a ring expansion process leading to pyrimidine derivatives (13) .     

Studies on cytotoxic constituents in pericarps of Mallotus japonicus. IV

Two new phloroglucinol derivatives, isomallotolerin (1) and isomallotochromanol (2), were isolated from the cytotoxic fraction of the pericarps of Mallotus japonicus. The new derivatives were identified as 3-(3-methyl-2-hydroxybut-3-enyl)-5-(3-acetyl-2,4-dihydroxy-5-methy l-6- methoxybenzyl)-phlorisobutyrophenone (1) and 6-acetyl-5,7-dihydroxy-8-(3-acetyl-2,4-dihydroxy-5-methyl-6-methoxybenzy l)-2,2- dimethyl-3-hydroxychroman (2) from chemical and spectral data. Isomallotolerin and its acetate were found to be cytotoxic to KB cell line.     

Reactions with 2-mercaptopyrimidines. Synthesis of some new thiazolo[3,2-a]- and triazolo[4,3-a]pyrimidines

Alkylation of 5-cyano-4-oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine I with methyl iodide, chloroacetic acid or 3-chloro-2,4-pentanedione, afforded the S-alkyl derivatives IIa-c. 2-Carboxymethylthio and 2-(2′,4′-dioxopentan-3-ylthio) derivatives IIb and IIc could be cyclised by acetic anhydride or polyphosphoric acid to give 6-cyano-3,5-dioxo-5H-7-phenylthiazolo[3,2-a]pyrimidine III and 2-acetyl-6-carboxamido-5H-3-methyl-7-phenylthiazolo[3,2-a]pyrimidine-5-one IX , respectively. Benzoylation of 2-hydrazinopyrimidine derivative XII , in anhydrous dioxan, afforded the N-benzoyl derivative XIII , which could be cyclised by heating in dimethylformamide to give 5-amino-6-cyano-3,7-diphenyl-s-triazolo[4,3-a]pyrimidine ( XIV ). The 2-hydrazinopyrimidine derivatives XII and XV reacted with benzoyl isothiocyanate in dioxane to yield 4-benzoylthiosemicarbazide derivatives XVI and XVII , which were converted into the 2-s-trizolopyrimidine derivatives XVIII and XIX , respectively. Also, XVI and XVII reacted with 2,4-pentanedione and 3-chloro-2,4-pentanedione to yield 2-pyrazolopyrimidine derivatives XX and XXI , respectively.     

Fused s-triazino heterocycles. X. Displacement reactions of 7,9-dibromo-2-tribromomethyl-5-trichloromethyl-1,3,4,6,9b-pentaazaphenalene and 7,9-dibromo-2,5-bis(tribromomethyl)- 1,3,4,6,9b-pentaazaphenalene

The preparation of 7, 9-dibromo-2-tribromomethyl-5-trichloromethyl-1, 3, 4, 6, 9b-pentaazaphenalene ( 1c ) and 7, 9-dibromo-2, 5-bis(tribromomethyl)-1, 3, 4, 6, 9b-pentaazaphenalene ( 1d ) is described. Reaction of 1c with various nucleophiles converted it to the corresponding 7, 9-dibromo-2, 5-bis-substituted derivatives, the tri-halomethyl groups serving as leaving groups. Displacement, first of one tribromomethyl group on 1d by pyrrolidine, and then by various nucleophiles on the remaining tribromomethyl group led to several mixed 2, 5-disubstituted derivatives.     

Microbiological transformation of bicyclic monoterpenes by Absidia orchidis (Vuill.) Hagem. 2. Hydroxylation of fenchone and isofenchone. 18. Section on reactions with microorganisms

(+)-Fenchone ( 3a ) was transformed to 6-exo-hydroxy-fenchone (6β-hydroxy-1, 3, 3-trimethyl-nor-bornan-2-one) ( 1a ) and to 5-exo-hydroxy-fenchone 5β-hydroxy-1, 3, 3-trimethyl-nor-bornan-2-one ( 4a ) by the mycelium of Absidia orchidis (Vuill.) Hagem. The structure of the two products was proven by a detailed analysis of the NMR. spectra of the corresponding acetyl derivatives 2a and 5a respectively, and by CrO₃-oxidation. 1a yielded the β-diketone 6a , and 4a the diketone 8a. Whereas 8a was stable to alkali 6a was cleaved to the cyclopentane carboxylic acids 7 and 9 . — Incubation of (—)-fenchone ( 3b ) yielded the enantiomeric hydroxylation products 1b and 4b in the same ratio. - (—)-Isofenchone ( 11a ) was transformed by Absidia orchidis into the two epimers 6-endo-hydroxy-isofenchone (6β-hydroxy-1, 5, 5-trimethyl-nor-bornan-2-one) ( 12a ) and 6-exo-hydroxy-isofenchone (6β-hydroxy-1, 5, 5-trimethyl-nor-bornan-2-one) ( 10a. ) CrO₃-oxidation of both 10a and 12a gave the same β-diketone 6a. - (+)-Isofenchone gave the corresponding enantiomeric hydroxy derivatives 10b and 12b on incubation with Absidia orchidis.     

Neuraminic acid and related compounds. V. Syntheses of biologically active sialosyl-glycerol derivatives and galactosyl-glycerol derivative

New 1-acyl-sialosyl-glycerol derivatives (1a--d alpha, 1a--d beta, 2 alpha, 2 beta, which mimic the structure of the capsular polysaccharide of group C meningococcal were synthesized by the use of a chiral glycerol derivative, and were found to have phospholipases A2 and C inhibitory activities. Furthermore, synthesis of 2-palmitoyl-sialosyl-glycerol derivative (4 alpha, 4 beta, 5 alpha, 5 beta), galactosyl-glycerol derivative (6), and sialosyl-galactosyl-glycerol derivative (7) were carried out to examine the difference between these activities. Among these sialosyl derivatives, 3-palmitoyl-sialosyl-glycerol derivatives (1--3 alpha, 1--3 beta) demonstrated the most potent inhibitory activities.     

Thiazolo[4,5-d]pyrimidines. Part I. synthesis and anti-human cytomegalovirus (HCMV) activity in vitro of certain alkyl derivatives

Alkyl derivatives of the thiazolo[4,5-d]pyrimidine congeners of guanine and uracil were prepared and assessed for in vitro activity against human cytomegalovirus (HCMV). The finding that the 3-pentyl 1b and 3-hexyl 1c derivatives of 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1e) had potent in vitro anti-HCMV activity prompted a broader study of alkyl derivatives in this ring system. A series of 3-alkyl derivatives of 1e , viz. 1f-w , were prepared by direct alkylation of the sodium salt of 1e and by subsequent modifications, 2a-d. For comparison with 1c , 5-amino-2-hexylaminothiazolo[4,5-d]pyrimidin-7(6H)-one (4) was prepared and studied. The 3-(2-alkenyl) derivatives of 1e were found to be the more active antiviral agents with the Z isomer of 5-amino-3-(2-penten-1-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1f) having the better therapeutic index. Analogous 4-(2-alkenyl) derivatives of 2-aminothiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 6a and 6b were also prepared but were found to have poor therapeutic indices. Single crystal X-ray diffraction analysis was used to unequivocally establish the structure of 1f.     

Thiazolidinone arylhydrazones. Ring cleavage and alkylation of the 5-arylhydrazone derivatives of rhodanine and isorhodanine

The 5-aryihydrazone derivatives of rhodanine and isorhodanine were subjected to the action of hydrazine hydrate to afford the arylhydrazonomercaptomethyltriazolinthione and -triazolinone derivatives 3 and 4 , respectively. Treatment of 1 with benzylamine afforded thioxalic acid dibenzylamide 5 . On the other hand, treatment of 2 with the same reagent afforded the corresponding benzylamino derivatives 6 . Alkylation of 1 and 2 with ethyl bromoacetate and chloroacetamide yielded the corresponding S-alkyl derivatives 7 and 8 , respectively.     

α-Pyrones. II . Synthesis of tetrahydroquinoline derivatives of 4-aminobutanoic and 2-amino-2-pentenedioic acids

Ethyl 3-benzoylamino-2-oxo-6-triphenylphosphoranylidenemethyl-2H-pyran-5-carboxylate ( 1 ) reacts with 2- nitrobenzaldehydes ( 2 ) to give 6-(2-nitrostyryl)-2H-pyran-2-ones ( 3 ), as the E stereoisomers, in good yields. The reduction of compounds 3 , performed with hydrogen over Pd/C at room temperature and 1 atmosphere, leads to a mixture of 2-amino-4-tetrahydroquinolinylidene-2-pentenedioic acid derivatives 5a-d as the main products, the corresponding 3-butenoic acid derivatives 6 and a minor amount of pyrano[2,3-c]benzazocines 9a-c. At 40 atmospheres and 90°, the reduction gives 4-amino-2-tetrahydroquinolinylbutanoic acid derivatives 8a-d as the main products and their precursors 7a,b,d as the minor ones. Amines 4c,d are isolated by stopping the reduction after the uptake of 3 equivalents of hydrogen.     

Studies on the chemistry of pharmacologically active heterocycles. Part I. Acid hydrolysis of hydrazino-1,2,4-triazine derivatives

The acid hydrolysis of 3-hydrazino-5,6-disubstituted-1,2,4-triazine, 3,5-dihydrazino-6-substituted-1,2,4-triazine, and 2-hydrazinopyrimidine derivatives was studied. It was found that the reaction proceeded through the formation of 3-keto and 3,5-diketo derivatives of the related 2,3-dihydro, 2,3,4,5-tetrahydro-1,2,4-triazines, and 2-keto derivatives of 1,2-dihydropyrimidines. It was concluded from these reactions that in 1,2,4-triazine derivatives the C-5 carbon is more reactive than the C-3 carbon toward nucleophiles. The reaction mechanism is discussed.     

4- And 5-hydroxylaminothiazolidine-2-thiones. Acylation,synthesis, and structural investigation of new 6-thioxo(oxo) derivatives of 4,5-dihydro-6H-1,2,5-thiadiazine

The treatment of 4- and 5-hydroxylaminothiazolidine-2-thiones as well as 5-hydroxylaminothiazolidin-2-one with acetic anhydride or benzoyl chloride is accompanied, as a rule, by the formation of O-acyl derivatives. The 4-(O-acyl) derivatives are thereby either stable to thermal or alkaline treatment, or are converted to 4-iminothiazolidine-2-thione; the 5-(O-acetyl)-hydroxylamines rearrange to 6-thioxo(oxo) derivatives of 4,5-dihydro-6H-1,2,5-thiadiazine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1280–1284, September, 1987.     

Potentiometric differentiated titration of the components of nucleic acids and their derivatives. VII. Acidimetric determination of some N-acyl-2′-deoxyribonucleosides and their 5′-tritylated derivatives

The conditions have been investigated for the potentiometric titration of N-acyl-2′-deoxyribonucleotides and of trityl carbinol derivatives and their two-component mixtures with a nitromethane solution of perchloric acid. The influence of water, acetone, chloroform, and acetic acid on the conditions for the acidimetric analysis of tri-p-methyltrityl carbinol, p-monomethoxytrityl carbinol, and di-p-methoxy trityl carbinol in nitromethane have been shown. Procedures have been developed for the quantitative determination of N⁶-benzoyl-5′-di-p-methoxytrityl-2′-deoxyriboadenosine, the 5′-tri-p-methyltrityl and 5′-p-monomethoxytrityl derivatives of N⁴-benzoyl-2′-deoxyribocytidine, of N⁶-benzoyl-2′-deoxyriboadenosine, and of N²-isobutyryl-2′-deoxyriboguanosine by differentiated potentiometric titration. For the determination of the 5′-di-p-methoxy derivatives of N⁴-benzoyl-2′-deoxyribocytidine and of N⁶-benozyl-2′-deoxyriboadenosine a procedure is proposed which includes the use of two parallel titrations. Methods have been developed for the use of milligram amounts of substance.     

Saturated heterocycles. Part 216 . Synthesis,structure and ring opening of trans-perhydro-1,4-benzoxazepin-3-one derivatives

trans-Perhydro-1,4-benzoxazepin-3-ones 2a-c were synthesized and transformed to condensed-skeleton perhydro-trans-1,4-benzoxazepines 3a,b , the thiones 4a,b , the urea derivatives 5a,b , and N-acylated compounds 6a-e . Compounds 6b,d were ring-opened by hydrochloric acid in ethanol to yield trans-2-(1-carbethoxyethoxy)-1-acylaminomethylcyclohexane derivatives 7b,d . The ¹H- and ¹³C-nmr investigation and X-ray analysis of 5b and 6c,d proved that the expected N-acylated derivatives were formed and that both rings of the trans anellated compounds have a chair conformation.