Synthesis,SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity

We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF(3), 4-OCF(3), 4-SO(2)Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, (n)()Pr, (i)()Pr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.     

Determination of circular dichroism and ultraviolet spectral parameters of norgestimate- and other Delta(4)-3-ketosteroid oxime isomers via normal phase HPLC method

The oxime formation reaction of therapeutical progestogen (levonorgestrel, levonorgestrel acetate, norethisterone), androgen (methyltestosterone, testosterone phenylpropionate) and anabolic (nortestosterone phenylpropionate) Delta(4)-3-ketosteroids has been investigated. The ketosteroid-hydroxylamine reaction was monitored by reversed phase HPLC system. It was established, that under the experimental conditions applied the oxime formation was complete within 2 h. The reaction leads to the formation of Z and E oxime isomers. The isomers of norgestimate (levonorgestrel 17-acetate oxime) and other Delta(4)-3-ketosteroid oximes have been separated by a new normal phase HPLC method. The identification (elution order assignation) and determination of the formation ratio of the isomers have been performed by 1H NMR spectroscopy on the basis of the chemical shift differences of 4-H signals. The on-line CD and UV spectra of the pure oxime isomers were recorded and then molar ellipticities and absorbances of the isomers were calculated in the wavelength range of 200-300 nm via parameter estimation method.     

C(3)-cyclopropyl cephems and carbacephems

A series of C(3)-cyclopropyl cephems and carbacephems has been prepared by palladium catalyzed addition of diazomethane to the corresponding C(3)-vinyl derivatives. The phenylglycyl cyclopropyl cephem derivatives exhibit better Gram-positive activity than cephalexin or cefaclor, while the aminothiazole oxime cyclopropyl cephem derivatives were not as active as the corresponding C(3)-vinyl cephems.     

6-oxo-morphinane oximes: pharmacology, chemistry and analytical application

The permanent therapeutic importance of morphine derivatives in pain treatment has inspired continual synthetic efforts to modify the rigid pentacyclic systems in search for new selective analgesic agents. As a result, several morphinane oximes have been synthesized recently, which have the additional advantage of possessing an oxime group that can provide a method for selective determination of opiate alkaloids in biological matrices. The oximes of hydrocodone and oxycodone have stronger analgesic effect than the parent ketones and they also proved to be effective in preventing the respiratory depressant and hypotensive actions of fentanyl. In this work a review is given on the present status of oxime pharmacology, chemistry and analysis and also the oxime and O-methyl oxime formation of 6-oxo-morphinanes with therapeutic interest (codeinone, oxycodone, hydrocodone and 14-OH-codeinone). The oxime formation was monitored by reversed-phase HPLC and the chromatographic properties of oxime isomers have been characterized. The assignation of the individual isomers isolated by preparative HPLC was performed by (1)H NMR spectroscopy based on the chemical shift differences of the 5-H signals. In this way the isomeric ratio in the oxime products could also be determined. It was found that in the case of Delta(7)-6-oxo-morphinanes, depending on the substituents, the formation of the Z-isomer highly dominates (73-96%) over that of the E-isomer. However, for the saturated 7,8-(dihydro) derivatives the E-isomer is definitely preferred (>98%). In conclusion of a survey on the theoretical background of oxime isomerism, the conformational differences between the saturated and unsaturated morphinane systems were found responsible for the different E/Z ratios. On the basis of the isomeric ratio and the on-line CD and UV spectra of the pure isomers, the molar ellipticities and absorbancies of the isomers were calculated by a parameter estimation method.     

Synthesis of two and antibacterial activity of one novel oxime ether derivatives of erythromycin A

The synthesis of novel erythromycin A 9-O-(2-ethenesulfony-ethyl)-oxime and erythromycin A 9-O-(3-oxo-butyl)-oxime from erythromycin A (EA) by the Michael reaction is described and to describe the effects of transformation of ketone in position 9 of EA to an oxime ether. This transformation occurred in a single step without protecting of any functional moiety of erythromycin oxime and zero waste manner in good yield. The antibacterial screen of EA 9-O-(2-ethenesulfony-ethyl)-oxime is also reported.     

Percutaneous absorption of cis- and trans-permethrin in rhesus monkeys and rats: anatomic site and interspecies variation

Dermal absorption of cis- and trans-permethrin isomers was determined in rhesus monkeys and Sprague-Dawley rats. Four 14C radiolabels were used (cis alcohol, cis cyclopropyl, trans alcohol, and trans cyclopropyl). One microcurie of each radiolabel was applied to either the forehead or forearm of rhesus monkeys or to the midlumbosacral region of the rat. Urine was collected for 7 or 14 d. Correction factors for incomplete urine excretion were derived from measurements of radiolabel in the urine following im injection of an equivalent dose. It was noted that the total im dose recovered in the urine of both species was lower for the cis isomer than for the trans isomer. There was no significant difference between the dermal absorption of the cis isomer and that of the trans isomer in monkeys. The forehead, however, was more permeable for both isomers than the forearm (alcohol- and cyclopropyl-labeled cis and trans isomers, respectively, showed permeation in forehead, cis 28 +/- 6%, 24 +/- 6%, trans 21 +/- 3%, 14 +/- 4%, forearm, cis 9 +/- 3%, 9 +/- 3%, trans 12 +/- 3%, and 5 +/- 2%). There was no difference between absorption of the isomers (cis 46 +/- 4%, trans 43 +/- 5%) in rats, but absorption was significantly greater than in monkeys. The IM urinary t1/2 values in monkeys and rats were similar for both isomers (0.8-1.1 d).     

Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A

Structure-activity relationship analysis of synthetic analogues of curacin A revealed the lack of activity of traditional heterocyclic replacements of the thiazoline ring or cyclopropyl analogues of the core diene segment. The significance of the C(3)-C(4)-(Z)-alkene geometry was established, and a novel oxime analogue was designed that displays biological properties that are a close match of the natural product lead. The much less lipophilic, structurally simplified oxime 50 was only slightly weaker at inhibiting the growth of cultured human tumor cells than the natural product and was found to be more potent than curacin A at inhibiting the assembly of purified tubulin. Accordingly, the oxime moiety is likely to serve as a novel bioisostere of the (Z)-alkene group.     

Antifungal agents. 5. Chemical modification of antibiotics from Polyangium cellulosum var. fulvum. Alcohol, ketone, aldehyde, and oxime analogues of ambruticin.

Alcohol, ketone, aldehyde, and oxime analogues of ambruticin (1) were prepared. The analogues were tested against Histoplasma capsulatum, Microsporum fulvum, Candida albicans, and Streptococcus pyogenes. Structure-activity relationships are described. Increasing the bulk of substituent at C1 and C5 reduces antifungal activity.     

Synthesis of radio‐iodinated melatonergic agents

The synthesis of two ¹²⁵I‐labeled trisubstituted aromatic melatonergic agents is reported. N‐[[2‐[¹²⁵I]iodo‐5‐methoxyphenyl)‐1R, 2R‐cyclopropyl]methyl] butanamide was prepared from the corresponding thallium salt and Na ¹²⁵I in radiochemical yields of 13–45% (n = 3). High performance liquid chromatography separation of the two resulting radioiodinated isomers (8:2) from each other and the parent compound required the use of two different columns run in series. Synthesis of N‐[[2‐[¹²⁵I]iodo‐5‐fluorophenyl)‐1R, 2R‐cyclopropyl]methyl] butanamide was prepared from the corresponding trimethylstannane precursor in radiochemical yields consistently in the range of 60–65% (n = 6). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of Vinca Alkaloids and Related Compounds,XV1) A New Synthetic Route to (+)-Vincaminic and (+)-Apovincaminic Esters

Esters of types 7 and 8 , possessing excellent vasodilating effects, have been prepared. A method has been found for the resolution of methyl ester 7c. A new method is described for the preparation of the lactam (+)- 10 and its conversion to the oxime (+)- 11 , from which (+)-vincamine (1a) and the (+)-apovincaminic esters 2a,b were synthesized.     

Synthesis and antiviral evaluation of novel methyl branched cyclopropyl phosphonic acid nucleosides

A simple synthetic route for the synthesis of novel methyl branched cyclopropyl phosphonic acid nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed by employing Simmons-Smith reaction as a key step. The condensation of mesylate 11 with natural nucleosidic bases (A,C,T,U) under standard nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) and after subsequent hydrolysis resulted in the formation of target nucleosides, 16, 17, 18, and 19. In addition, the antiviral evaluations of the synthesized nucleotides against various viruses were also performed.     

Metabolic oxidation of aralkyl oximes to nitro compounds by fortified 9000g liver supernatants from various species

Incubation of ‘amphetamine oxime’ (IIa, anti-benzyl methyl ketoxime) with fortified rabbit liver 9000 g supernatants gave the nitro compound (Ie) and the β-hydroxylated oxime (IIc) in addition to the previously reported ketone (IIb) and alcohol (Ic) metabolites. Formation of the products was cofactor dependent. The nitro compound was also formed using mouse, hamster and guinea-pig 9000 g liver supernatants and to a minor extent by rat liver. The oximes of 2-phenethylamine (IIe) and norfenfluramine (IIg) were also metabolized to the corresponding nitro compounds, ketones and alcohols with rabbit 9000 g liver supernatants; however, no nitro compound (IIIb) was detected after the incubation of ‘mexiletine oxime’ (IVa). The metabolic products were identified and characterized by g.l.c., t.l.c. and g.l.c. linked mass spectrometry by comparison with synthetic materials.     

Synthesis and antihypertensive activity of 5-thio-2-pyridinecarboxylic acid derivatives.

Synthesis of various substituted 5-thio-2-pyridinecarboxylic acids and their derivatives is described by three methods, i.e., displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate (10) by a thiol anion, alkylation of methyl 5-thio-2-pyridinecarboxylate derived from reaction of the diazotized methyl-5-amino-2-pyridinecarboxylate (5) with thiocyanate followed by borohydride reduction of the product, and alkylation of 5-thio-2-pyridinecarbonitrile followed by hydrolysis. 5-Thio-2-pyridinecarbonitrile was obtained from butyl 6-methyl-3-pyridyl sulfoxide (2) by nitrosation and dehydration of the oxime. Many of these 5-thio-2-pyridinecarboxylic acid derivatives were orally active antihypertensive agents in the spontaneously hypertensive rat. Optimization of the structural parameters for this activity yiedled 5-[m-trifluorobenzyl) thio]-2-pyridinecarboxylic acid (41) and its sulfoxide, 42. Further biological studies with these compounds are described.     

Oxime silanes: structure/toxicity relationships

Acute and repeated oral and dermal rat toxicology studies of standard designs were conducted on four methyl ethyl ketoxime (MEKO) silanes and four methyl isobutyl ketoxime (MIBKO) silanes. Each compound contained either MEKO or MIBKO groups (but not both) and either a single methyl, vinyl, or phenyl group (trifunctional oxime silane), two methyl groups or a methyl and vinyl group (difunctional oxime silane), or no nonoxime group (tetrafunctional oxime silane) attached to the central silicon atom. All compounds caused transient narcosis and anemia, with oral exposure associated with the hydrolyzed oxime groups. Difunctional oxime silanes, containing both a methyl and a vinyl group, caused degeneration of the seminiferous tubules of the testes following oral administration. Serial testicular histopathology indicated the effect originated at the level of the spermatocyte, resulting in a wave of cellular depletion of later maturation stages of spermatogenesis. Spermatogenesis gradually recovered but function was not evaluated. Tetrafunctional oxime silanes, trifunctional oxime silanes, including those containing a single methyl or vinyl group, or difunctional oxime silane containing two methyl groups did not affect the testes, indicating that both a methyl and vinyl group needs to be present on the oxime silane molecule for testicular toxicity. The testicular toxicity appears to be associated with the methyl/vinyl silane portion and not the oxime portion of the oxime silane molecule. With the exception of the methyl/vinyl difunctional oxime silanes, the silane portion of oxime silanes does not appear to contribute any significant toxicity to these compounds.     

New series of N-substituted phenyl ketone oxime ethers: synthesis and bovine beta3-adrenergic agonistic activities

A series of ten novel phenyl ketone oxime ethers substituted on the terminal nitrogen by either 1,3 benzodioxole, alkyl, aralkyl or aryl moiety were synthesized and tested for their activity at bovine beta3-adrenoceptors. The best compound, which was the benzodioxole dicarboxylate derivative, showed potent beta3-adrenergic agonistic activities in Chinese hamster ovary cells expressing the bovine beta3-adrenoceptors with Kact and Ki values better than compound CL 316,243 used as reference (14 +/- 6 nM and 203 +/- 71 nM, respectively). In this series three compounds showed an antagonistic activity. Structure-activity relationships in these ketone oxime ethers are discussed.     

Oxime Silanes: Structure/Toxicity Relationships

Acute and repeated oral and dermal rat toxicology studies of standard designs were conducted on four methyl ethyl ketoxime (MEKO) silanes and four methyl isobutyl ketoxime (MIBKO) silanes. Each compound contained either MEKO or MIBKO groups (but not both) and either a single methyl, vinyl, or phenyl group (trifunctional oxime silane), two methyl groups or a methyl and vinyl group (difunctional oxime silane), or no nonoxime group (tetrafunctional oxime silane) attached to the central silicon atom. All compounds caused transient narcosis and anemia, with oral exposure associated with the hydrolyzed oxime groups. Difunctional oxime silanes, containing both a methyl and a vinyl group, caused degeneration of the seminiferous tubules of the testes following oral administration. Serial testicular histopathology indicated the effect originated at the level of the spermatocyte, resulting in a wave of cellular depletion of later maturation stages of spermatogenesis. Spermatogenesis gradually recovered but function was not evaluated. Tetrafunctional oxime silanes, trifunctional oxime silanes, including those containing a single methyl or vinyl group, or difunctional oxime silane containing two methyl groups did not affect the testes, indicating that both a methyl and vinyl group needs to be present on the oxime silane molecule for testicular toxicity. The testicular toxicity appears to be associated with the methyl/vinyl silane portion and not the oxime portion of the oxime silane molecule. With the exception of the methyl/vinyl difunctional oxime silanes, the silane portion of oxime silanes does not appear to contribute any significant toxicity to these compounds.     

Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities

In this study, oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone] were prepared as potential anticonvulsant and antimicrobial compounds. The oxime was synthesized by the reaction of ketone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock and subcutaneous metrazole tests in mice and rats according to procedures of the Anticonvulsant Screening Program of National Institutes of Health. Neurotoxicity was determined by the rotorod test in mice and the positional sense test, gait and stance test in rats. In addition to anticonvulsant tests, all compounds were also evaluated against the following microorganisms: S. aureus, E. coli, P. aeruginosa, E. faecalis, C. albicans, C. parapsilosis, and C. krusei using microdilution broth method for possible antibacterial and antifungal activities. Although most of the O-alkyl substituted oxime ethers exhibited both anticonvulsant and antimicrobial activities, the O-arylalkyl substituted compounds were found to be inactive in both screening paradigms.     

Basisch substituierte Styrylalkyloxime. Mitt. über ungesättigte Oxime

Basic Substituted Styrylalkyl-oximes 4-Phenyl-3-buten-2-one-oxime sodium reacted with dialkylaminoalkyl chlorides to the oximino ethers. These were also prepared from the ketone and O-alkylated hydroxylamines, which could be synthesised by hydrolysis of O-alkyl acetone oximes. All substances were examined by nmr-spectroscopy: the substituted acetone oximes showed two signals of the methyl groups contrary to acetone oxime itself; the O-alkylated oximes were almost pure E-isomers, and in the reaction between 4-phenyl-3-buten-2-one-oxime sodium and 2-chloro-1-dimethylamino-propane two products were found, separated, and identified.     

Synthesis and antiherpetic activity of (+/-)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine and related compounds

A series of analogues of acyclovir and ganciclovir were prepared in which conformational constraints were imposed by incorporation of a cyclopropane ring or unsaturation into the side chain. In addition, several related base-modified compounds were synthesized. These acyclonucleosides were evaluated for enzymatic phosphorylation and DNA polymerase inhibition in a staggered assay and for inhibitory activity against herpes simplex virus types 1 and 2 in vitro. Certain of the guanine or 8-azaguanine derivatives were good substrates for the viral thymidine kinase and were further converted to triphosphate, but none was a potent inhibitor of the viral DNA polymerase. Nevertheless, one member of this group, (+/-)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]methyl]guanine (3a), displayed significant antiherpetic activity in vitro, superior to that of the corresponding cis olefin 4a. Another group, typified by (+/-)-9-[[(E)-2-(hydroxymethyl)cyclopropyl]methyl]adenine (17b), possessed modest antiviral activity despite an apparent inability to be enzymatically phosphorylated. The relationship of side-chain conformation and flexibility to biological activity in this series is discussed.