Photochemical Rearrangement of a Steroidal α, β-Epoxylactam. Photochemical reactions,XII [1]

The UV. irradiation of 17β-hydroxy-4α, 5α-epoxy-2-azaandrostan-3-one ( 1 ) yields 17β-hydroxy-2-aza-10 (5 → 4-abeo)-4ζ (H)-androsta-3,5-dione ( 3 ).     

A Norrish Type I cleavage in the photolysis of a steroidal α,β-unsaturated δ-lactone. Photochemical Reactions. XIV [1]

The UV. irradiation of 17 β-acetoxy-4-oxa-5 α-androst-1-en-3-one (1) yields A,B-diseco-steroids originating from a Norrish I process of the lactone function.     

Photochemical reactions VII [1]. A ‘type A rearrangement’ in the photolysis of a steroidal α, β-unsaturated lactone

The irradiation of 17 β-hydroxy-2-oxa-androst-4-en-3-one ( 1 ) yield a cyclopropane derivative 2 , which is the result of a rearrangement, formally analogous to the ‘type A rearrangement’ of the enones. Two other products, the dihydroxy compound 5 and the dimer 6 , have also been isolated (Scheme 1).     

Synthesis of 17β-hydroxy-1′-H-5α-androst-2-eno[3,2-b]pyrrole and 17β-hydroxy-1′-H-5α-androst-3-eno[3,4-b]pyrrole from O-(2-hydroxyethyl)ketoxime precursors

Pyrrolosteroids such as 17β-hydroxy-1′-H-5α-androst-2-eno[3,2-b]pyrrole ( 1 ) and the novel 17β-hydroxy-1′-H-5α-androst-3-eno[3,4-b]pyrrole ( 12 ) can be synthesized from the corresponding O-(2-hydroxyethyl)ketoxime precursors. In the case of 1 , yields compare favourably with previously reported literature methods.     

Synthesis of D-seco-13α-Androst-5-ene Derivatives

Summary. 3β-Hydroxy-16,17-seco-13α-androsta-5,16-dien-17-al was obtained from 3β-acetoxyandrost-5-en-17-one in six steps with a Grob fragmentation as the key step. This seco-steroid, containing a formyl group and an unsaturated side-chain in a sterically favourable cis position, is a useful synthon for the synthesis of novel heterocycles condensed to the 3β-hydroxy-13α-androst-5-en-17-one skeleton.     

Synthesis of D-seco-13α-Androst-5-ene Derivatives

3β-Hydroxy-16,17-seco-13α-androsta-5,16-dien-17-al was obtained from 3β-acetoxyandrost-5-en-17-one in six steps with a Grob fragmentation as the key step. This seco-steroid, containing a formyl group and an unsaturated side-chain in a sterically favourable cis position, is a useful synthon for the synthesis of novel heterocycles condensed to the 3β-hydroxy-13α-androst-5-en-17-one skeleton.     

On the formation of homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid isomers and their antitumor activity

The N, N-bis(2-chloroethyl)aminobenzoate isomers and the 4-methyl-3-N, N-bis(2-chloro-ethyl)aminobenzoate of 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5-androsten-17-oic-13,17-lactam and 17β-hydroxy-3-aza-A-homo-4α-androsten-4-one, have been prepared and their biological activity evaluated against P388 leukemia in vivo and Ehrlich Ascites tumor (EAT), P388 and L1210 leukemias and Baby Hamster cells (BHK) in vitro. The esters in which the alkylating congener is linked to the lactam alcohol in the axial position are inactive in vivo in P388 leukemia, while compounds 1, 4, 6, 13, 14 and the alkylating congeners 17, 18 and 20 are active. The effect of the homo-azasteroidal of N, N-bis(2-chloroethyl)aminobenzoic acid isomers and of 4-methyl-3-N, N-bis(2-chloroethyl)aminobenzoic acid on the incorporation of the radioactive precursor into the DNA of L1210, P388 leukemias, Ehrlich ascites tumor and, baby Hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursor was obtained with the ortho derivatives, yielding <70% inhibition of thymidine incorporation in all tumor lines tested.     

Synthesis and Evaluation of 2-{[(2-Oxo-1H-quinolin-8-yl)oxy]methyl}-Substituted α-Methylidene-γ-butyrolactones

O-Alkylation of 8-hydroxy-1H-quinolin-2-one ( 1 ) afforded 8-(2-oxopropoxy)-1H-quinolin-2-one ( 2 ) which was immediately cyclized to form the tricyclic 2,3-dihydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]benzoxazine,-5-one ( 3). The Reformatsky-type condensation of 3 furnished antiplatelet 8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)melhoxy]-1H-quinolin-2-one ( 4 ). Its counterparts 7a – f , Ph-substituted at C(2) of the furan ring, were obtained from 1 via alkylation and the Reformatsky-type condensation. Although compound 4 was less active against platelet aggregation than 7a – f , it was the only compound which exhibited significant inhibitory activity on high-K⁺ medium, Ca²⁺-induced vasoconstriction and was more active than most of its Ph-substituted counterparts against norepinephrine-induced vasoconstrictions.     

A novel fragmentation of trimethylsilyl ethers of 3β-hydroxy-Δ5-steroids

An ion formed by loss of 56 mass units from the molecular ion is often seen in mass spectra of trimethylsilyl ethers of C₁₉ and C₂₁ steroids having a 3β-hydroxy-Δ⁵ structure and an oxo group at C-17 or C-20. The nature of this fragment was investigated by the use of perdeuteriotrimethylsilyl ether derivatives and of [4-¹⁴C], [3-¹⁸O], [4,4-²H₂] and [2,2,4,4-²H] labelled derivatives of 3β-hydroxy-5-androsten-17-one and 3β-hydroxy-5-pregnen-20-one. Evidence is presented to show that the neutral fragment of mass 56 is composed of carbon atoms 1, 2 and 3, the oxygen at C-3 and four hydrogen atoms. During the fragmentation process, the trimethylsilyl group and one of the hydrogens at C-2 are transferred to the fragment that carries the charge.     

Synthese von 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-on (Hothesimogenin). Partialsynthetische Versuche in der Reihe der Herzgifte, 11. Mitteilung

Synthesis of 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-one (hothesimogenin) We describe the synthesis of 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-one (24-aza-24-desoxa-digitoxigenin) (7) , starting from 3-O-acetyl-digitoxigenin (1) .     

20, 21-Azirdin-Steroide: Reaktion von Derivaten der Oxime von 5-Pregnen-20-on,9β,10α-5-Pregnen-20-on und 9β,10α-5,7-Pregnadien-20-on mit Lithiumaluminiumhydrid und von 3β-Hydroxy-5-pregnen-20-on-oxim mit Grignard-Verbindungen

20, 21-Aziridine Steroids: Reaction of Derivatives of the Oximes of 5-Pregnen-20-one, 9β, 10α-5-Pregnen-20-one and 9β, 10α-5,7-Pregnadiene-20-one with Lithium Aluminium Hydride, and of 3β-Hydroxy-5-pregnen-20-one Oxime with Grignard Reagents. Reduction of 3β-hydroxy-5-pregnen-20-one oxime ( 2 ) with LiAlH₄ in tetrahydrofuran yielded 20α-amino-5-pregnen-3β-ol ( 1 ), 20β-amino-5-pregnen-3β-ol ( 3 ), 20β, 21-imino-5-pregnen-3β-ol ( 6 ) and 20β, 21-imino-5-pregnen-3β-ol ( 9 ). The aziridines 6 and 9 were separated via the acetyl derivatives 7 and 10 . The reaction of 6 and 9 with CS₂ gave 5-(3β-hydroxy-5-androsten-17β-yl)-thiazolidine-2-thione ( 8 ). Treatment of the 20-oximes 12 and 15 of the corresponding 9β,10α(retro)-pregnane derivatives with LiAlH₄ gave the aziridines 13 and 16 , respectively. Their deamination led to the diene 14 and triene 17 , respectively. Reduction of isobutyl methyl ketone-oxime with LiAlH₄ in tetrahydrofuran yielded 2-amino-4-methyl-pentane ( 19 ) as main product, 1, 2-imino-4-methyl-pentane ( 22 ) as second product and the epimeric 2,3-imino-4-methyl-pentanes 20 and 21 as minor products. – 3β-Hydroxy-5-pregnen-20-one oxime ( 2 ) was transformed by methylmagnesium iodide in toluene to 20α, 21-imino-20-methyl-5-pregnen-3β-ol ( 23 ) and 20β, 21-imino-20-methyl-5-pregnen-3β-ol ( 26 ). Acetylation of these aziridines was accompanied by elimination reactions leading to 3β-acetoxy-20-methylidene-21-N-acetylamino-5-pregnene ( 30 ) and 3β-acetoxy-20-methyl-21-N-acetylamino-5,17-pregnadiene ( 32 ). The reaction of oxime 2 with ethylmagnesium bromide in toluene gave 20α, 21-imino-20-ethyl-5-pregnen-3β-ol ( 24 ) and 20α,21-imino-20-ethyl-5-pregnen-3β-ol ( 27 ). Acetylation of 24 and 27 led to 3β-acetoxy-20-ethylidene-21-N-acetylamino-5-pregnene ( 31 ), 3β-acetoxy-20-ethyl-21-N-acetylamino-5,17-pregnadiene 33 and 3β, 20-diacetoxy-20-ethyl-21-N-acetylamino-5-pregnene ( 37 ). With phenylmagnesium bromide in toluene the oxime 2 was transformed to 20β, 21-imino-20-phenyl-5-pregnen-3β-ol ( 25 ) and 20β,21-imino-20-phenyl-5-pregnen-3β-ol ( 28 ). Acetylation of 25 and 28 yielded 3β-acetoxy-20-phenyl-21-N-acetylamino-5, 17-pregnadiene ( 34 ) and 3β,20-diacetoxy-20-phenyl-21-N-acetylamino-5-pregnene ( 39 ). LiAlH₄-reduction of 39 gave 3β, 20-dihydroxy-20-phenyl-21-N-ethylamino-5-pregnene ( 41 ). – The 20, 21-aziridines are stable to LiAlH₄. Consequently they are no intermediates in the formation of the 20-amino derivatives obtained from the oxime 2 .     

Metabolic studies of methenolone acetate in horses

Methenolone acetate (17β-acetoxy-1-methyl-5α-androst-1-en-3-one), a synthetic anabolic steroid, is frequently abused in human sports. It is preferred for its therapeutic efficiency and lower hepatic toxicity compared with its 17α-alkylated analogs. As with other anabolic steroids, methenolone acetate may be used to enhance performance in racehorses. Metabolic studies on methenolone acetate have been reported for humans, whereas little is known about its metabolic fate in horses. This paper describes the investigation of in vitro and in vivo metabolism of methenolone acetate in racehorses.Studies on the in vitro biotransformation of methenolone acetate with horse liver microsomes were carried out. Methenolone (M1, 1-methyl-5α-androst-1-en-17β-ol-3-one) and seven other metabolites (M2-M8) were detected in vitro. They were 1-methyl-5α-androst-1-ene-3,17-dione (M2), 1-methyl-5α-androst-1-en-6-ol-3,17-dione (M3) and two stereoisomers of 1-methylen-5α-androstan-2-ol-3,17-dione (M4 and M5), 1-methyl-5α-androst-1-en-16-ol-3,17-dione (M6) and monohydroxylated 1-methyl-5α-androst-1-en-17-ol-3-one (M7 and M8). After oral administration of Primobolan^® (80 tablets × 5 mg of methenolone acetate each) to two thoroughbred geldings, the parent steroid ester was not detected in the post-administration urine samples. However, seven metabolites, namely M1, M6-M8, two stereoisomers of M7 (M9 and M10) and 1-methyl-5α-androst-1-en-17α-ol-3-one (M11), could be detected. The metabolic pathway for methenolone acetate is postulated. This study has shown that metabolite M1 could be targeted for controlling the abuse of methenolone acetate in horses.     

β-Ribo- and α-arabinonucleosides containing the 1,2-benzisoxazole and 1,2-benzisothiazole rings

The reaction of the silylated base of 1,2-benzisoxazol-3(2H)-one ( 1 ) and its 7-methyl derivative 5 and 5-methyl-1,2-benzisothiazol-3(2H)-one ( 9 ), respectively, with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose followed by basic deprotection gave the corresponding β-D-ribonucleosides, and the silylated base of 1 , when treated with 1-O-acetyl-2,3,5-tri-O-benzoyl-α-D-arabinofuranose in the presence of stannic chloride, afforded the corresponding α-arabinonucleoside. Structural proofs of these nucleosides are provided from elemental analyses and ¹H and ¹³C nmr spectra.     

Totalsynthese von Steroiden. 1. Mitteilung. rac-17β-Hydroxydes-A-androst-9-en-5-on

In connection with earlier work on the synthesis of 9β, 10α-steroids, a new and practical synthesis of rac-17α-hydroxy-des-A-androst-9-en-5-one ( 19 ) has been developed, based on a novel stereoselective condensation of 7-hydroxy-1-nonen-3-one ( 3 ) with 2-methyl-cyclopentane-1, 3-dione ( 9 ) and subsequent transformations of the resulting tricyclic diene ether 12 .     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

8-Aza-7-deaza-2′,3′-dideoxyguanosine: Deoxygenation of its 2′deoxy-β-D-ribofuranoside

The synthesis of 6-amino-1-(2′,3′-dideoxy-β-D -glycero-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( =8-aza-7-deaza-2′,3′-dideoxyguanosine; 1 ) from its 2′-deoxyribofuranoside 5a by a five-step deoxygenation route is described. The precursor of 5a, 3a , was prepared by solid-liquid phase-transfer glyscosylation which gave higher yields (57%) than the liquid-liquid method. Ammonoloysis of 3b furnished the diamino nucleoside 3c . Compound 1 was less acid sensitive at the N-glycosydic bond than 2′,3′-dideoxyguanosine ( 2 ).     

Zur Reaktionsweise von Enaminen mit Cyclopropenonen V. Einsatz von β-Carbonyl-enaminen

Diphenylcyclopropenone ( 10 ) was heated with five different β-carbonyl-enamines, namely 4-pyrrolidino-pent-3 E-en-2-one ( 12 ), 4-dimethylamino-pent-3E-en-2-one ( 13 ), 4-dimethylamino-but-E-en-2-one ( 14 ), 3-dimethylamino-1-phenyl-prop-E-en-1-one ( 15 ) and ethyl 3-pyrrolidino-isocrotonate ( 16 ). The resulting reactions were more sluggish than those of 10 with ordinary enamines. The main reaction (between 10 and 69% yield) was in all cases a ‘C, N-insertion’. The major products were: from 12 : an inseparable mixture of 4-methyl-6-oxo-2,3-diphenyl-hepta-2E, 4E-dienoic acid pyrrolidide ( 17 ) and its 2Z, 4E-stereomer ( 18 ); from 13 : 4-methyl-6-oxo-2, 3-diphenyl-hepta-2E-dienoic acid dimethylamide ( 19 ) and its 2Z, 4E-stereomer ( 20 ); from 14 : 6-oxo-2, 3-diphenyl-hepta-2E, 4E-dienoic acid dimethylamide ( 21 ); from 15 : 6-oxo-2,3,6-triphenyl-hexa-2E, 4E-dienoic acid dimethylamide ( 22 ); and from 16 : 5-ethoxycarbonyl-4-methyl-2, 3-diphenyl-penta-2E, 4E-dienoic acid pyrrolidide ( 23 ) and its 2Z, 4E-stereomer ( 24 ). The constitutions of 17 to 24 were derived mainly from spectral properties. For these products the E-configuration at the 4,5-double bond was assigned on the assumption that the insertion of the side-chain (cyclopropenone carbons) between the enamine carbon and nitrogen atoms occurred with retention of configuration, as had been concluded earlier. This was confirmed in the cases of 21 and 22 by the trans-coupling between H? C(4) and H? C(5) in the ¹H? NMR. spectrum, the educts ( 14 and 15 ) having the E-configuration. The configurational difference between the stereomeric products 17 / 18 , 19 / 20 and 23 / 24 was, therefore attributed to the 2,3-double bond. This was confirmed by aqueous acid treatment in the case of the pair 19 / 20 : The 2E-configuration for 19 followed from its conversion to 4-acetonyl-4-methyl- 2,3-diphenyl-isocrotonolactone ( 25 ) and the 2Z-configuration of 20 by its conversion first to a mixture ol two diastereomers of (presumably) 1-acetyl-4-dimethylaminocarbonyl-2-methyl-3- phenyl-l,4-dihydronaphthalene ( 27a ) and then, under more drastic conditions, to 6-methyl-11H-benzo[a]fluorene ( 26 ).The structures of 25 and of 26 were derived from their spectral properties, and that of the 27a -mixture was made probable by the plausibility of its intermediacy on the way to 26 . A pathway for the conversion of 20 to 27a (scheme 3) and of the latter to 26 (scheme 4)is proposed. In the case of the reaction of 10 with 12 , two stereomeric basic by-products were isolated (combined yield 150/,). Their structures as traw- and cis-4-acetonyl-4,5-diphenyl-3-pyrrolidinocyclopent-2-en-ones ( 30 and 31 ) were deduced from their spectral properties and from those of their hydrochlorides 32 and 33 . The enamino-ketone function was found to be resistant to a number of reagents, among which were excess sodium borohydride, which converted 30 to the secondary alcohol 34 , and excess methyllithium, which converted 31 to the tertiary alcohol 35 . A mechanism (called ‘rearrangement’) is proposed (scheme 5) for the formation of the enaminoketones (such as 30 and 31 ), which proceeds via the same ammonio-enolate intermediate ( 36 ) which plays a role in the formation of the major products, the amides (such as 17 to 24 ). It is suggested (scheme 6) that the 3-membered ring of the ammonio-enolate 40 may open in three ways, one of which leads to the amides and another to the enamino-ketones.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Transformations of isomeric naphthopyranones. The synthesis of substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives

The opening of the pyranone ring in 2H-naphtho[1,2-b]pyran-2-one derivative (1) and 3H-naphtho[2,1-b]-pyran-3-one derivatives 8 and 20 with nucleophiles afforded 3-(naphthyl-1)- and 3-(naphthyl-2)propenoates (substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives) 7, 13, 14, 15, 24 , and 35 .     

Synthesis and thermolysis of N-heteroarylacetylazides and α-oximino-α-(N-heteroaryl)acetylazides

Treatment of N-heteroarylacethydrazides with an equimolar amount of nitrous acid afforded N-heteroaryacetylazides and subsequent thermolysis of these azides gave the analogues of 2,3-dihydroimidazo[1,5-a]pyridin-3-one. When some of these cyclized compounds were treated with nitrous acid, the ring opening reaction occurred and recyclized 3-(N-heteroaryl)-1,2,4-oxadiazolin-5-ones were obtained. Treatment of N-heteroarylacethydrazides with two equivalent moles of nitrous acid afforded α-oximino-α-(N-heteroaryl)acetylazides. Thermolysis of these azides gave mixtures of 3-(N-heteroaryl)-1,2,4-oxadiazolin-5-one and 3-hydroxy-4-(N-heteroaryl)furazan. On the basis of the effects of heterocyclic rings and solvents upon the relative yield of two types of the products, one plausible mechanistic explanation for the decomposition of such azides was proposed. α-Oximino-α-(H-heteroaryl)acetylazides were converted into cyano N-heterocycles by the action of alkali in good yields.