László Hackler

Neighboring group participation ☆: Part 15. Stereoselective synthesis of some steroidal tetrahydrooxazin-2-ones, as novel presumed inhibitors of human 5α-reductase

During the alkaline methanolysis of 3beta-acetoxy-21-chloromethyl-pregn-5-ene-20beta-N-phenylurethane, and its p-substituted phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)tetrahydrooxazin-2-on-6-yl]androst-5-en-3beta-ol and its p-substituted phenyl derivatives are formed. The cyclization takes place with (N(-)-6) neighboring group participation. Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding delta4-3-ketosteroids. The structures of the new compounds were proved by IR, 1H and 13C NMR spectroscopy, using up-to-date measuring techniques such as 2D-COSY, HMQC, and HMBC. The inhibitory effects (CI50) of the delta4-3-ketosteroids on 5alpha-reductase were studied.

Stereochemical studies-XXXIII.1 Saturated heterocycles-IX2: Synthesis and conformations of stereoisomeric cis- and troans-tetramethylene- and pentamethylenedihydro-1,3-oxazines

Abstract By the reaction of cis- and trans-2-aminomethylcyclohexanol (1, 2), cis- and trans-2-hydroxymethyl-cyclohexylamine (3,4) and the homologous cycloheptane derivatives (5-8) with ethyl p-chlorobenzimidate (11), cis- and trans-5,6-tetramethylene- and pentamethylene-2,3,5,6-tetrahydro-4H-1,3-oxazines (12,13,16,17) and cis- and trans-4,5-tetramethylene- and pentaimethylene-4,5-dihydro-6H-1,3-oxazines (14, 15, 18, 19) were prepared. The amidine intermediate of the ring-closure reaction was isolated, and the mechanism of the acid-catalysed reaction is discussed. It follows from the 1H NMR data that in the preferred conformations of the cis-tetramethylene-tetrahydrooxazines the methylene group of the hetero ring is equatorial and the hetero atom (O or N) axial. In contrast, the conformation equilibria of the cis pentamethylene derivatives, in accordance with earlier X-ray analysis, are shifted towards the conformer containing the methylene group in isoclinal and the hetero atom in equatorial position. The preferred conformations 12a and 14a of the tetramethylene derivatives 12 and 14 were also determined by X-ray crystal analysis.

Steroids 54. Amino acylamidosteroids.

Aminosteroids were prepared and acylated with protected amino acids by means of the mixed anhydride or the active ester method. The tert-butyloxycarbonyl- (BOC) protecting group was eliminated by acidolysis, and the benzyloxycarbonyl- (Z) group by catalytic hydrogenation. 3 beta- and 6 beta-Glycylamidosteroids were prepared by indirect amination of chloroacetamido derivatives, formed by the Ritter reaction on the corresponding 3 alpha,5 alpha-cyclo and 5 alpha,6 alpha-epoxy steroids. Water-soluble double salts were produced from the compounds for pharmacological investigations.

N-arylurethane neighboring group participation during solvolysis of 3-methoxy-17-N-phenylcarbamoyloxy-16-p_tolylsulfonyloxymethylestra-1,3,5(10)-triene stereoisomers☆

Abstract During alkaline methanolysis of the four stereoisomers 1–4 of 3-methoxy-17-N-phenylcarbamoyloxy-16-p-tolylsulfonyloxymethylestra-1,3,5(10)-triene, a cyclization takes place, in the course of which the N-phenyl-tetrahydrooxazin-2-one derivatives 5–8 are formed. The cis isomers 5, 8 and 8a–e are thermodynamically stable endproducts, while the trans derivatives 6 and 7, formed in a kinetically controlled process, undergo ring cleavage on methanolysis to yield the 16-(N-phenyl, N-methoxycarbonylaminomethyl) derivatives 9 and 11. The cyclization takes place with (N−-6) neighboring group participation.

Steroids. Part 32. Configurational analysis of 16-methyltestosterone derivatives

The four possible isomers of 16-methylandrost-5-ene-3β,17-diol (1)–(4) have been converted into the corresponding 17-hydroxy-16-methylandrost-4-en-3-ones (5)–(8). The steric structures of the resulting epimers have been determined by 13C and 1H n.m.r. spectroscopy; thereby the exact configurational correlation of several 17-hydroxy-16-methylandrost-4-en-3-ones, reported in the literature, have been established.

Ring expansion of steroid oxethans into hihydrooxazines

Abstract In tha case of oxethans condensed in an appropriate steric position to the sterane skeleton, the formation of six-membered dihydrooxazines has been observed with aliphatic or aromatic acid nitriles in the presence of Lewis acids, involving thus ring expansion.

New synthesis of steroidal tetrahydrooxazin-2-ones

Abstract In the DMSO/NaHCO3 system, 16α-aminomethyl-, 16α-benzylaminomethyl- and substituted benzylaminomethyl-3-methoxy-17β-tosyloxyestra-1,3, 5(10)-triene ( 3 , 5a - k ) do not undergo oxidation, but form a tetrahydrooxa-zin-2-one ring ( 7 , 8a - k ) via neighboring group participation. Under similar conditions, 16β-aminomethyl-3-methoxy-17β-tosylestra-1,3,5(10)-triene ( 4 ) decomposes into 16-methylene-3-methoxyestra-l,3,5(10)-trien-17-one ( 12 ).

Configurational analysis of 16-methyl-androstene-5 derivatives

Abstract The four possible isomers of 16-hydroxymethyl-androst-5-ene-3β,17-diol were converted into the corresponding 16-methyl analogues characterized by 13C-NMR and 1H-NMR spectra. This made possible the configurational correlation of 16-methylandrost-5-ene derivatives described in the literature.

Steroids. Part 43. Thermal decomposition of steroidal azidoformates

Thermolysis of the four possible isomeric 3-methoxy-16-methylestra-1,3,5(10)-trien-17-yl azidoformates 1b, 6b, 10b and 14b, of 3-methoxyestra-1, 3, 5(10)-trien-17β-yl azidoformate 17b, and of 16β-azidoformyloxymethyl-3-methoxyestra-1,3,5(10)-triene 21b was realized at 100 °C. Thermolysis results in insertion of the nitrene intermediate into C–H bonds, the site of which depends on the steric position of the substituents in the D ring of the sterane skeleton.

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides

The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2‐b]pyrazole‐7‐carboxamides were investigated. Following a hit‐to‐lead optimization exploiting 2D and 3D cultures of MCF‐7 human breast, 4T1 mammary gland, and HL‐60 human promyelocytic leukemia cancer cell lines, a 67‐membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub‐micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL‐60 sensitivity (IC50u2009=u20090.183u2009μM).