[Synthesis of 1-butyl-3,5-bis-(pyridinemethyl)-piperidone-4 and 1-butyl-3,5-bis-(4-pyridinemethyl)-piperidone-4].
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Piperidines↗
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New nonsteroidal steroid 5 alpha-reductase inhibitors. Syntheses and structure-activity studies on carboxamide phenylalkyl-substituted pyridones and piperidones.
In the search for nonsteroidal inhibitors of 5 alpha-reductase for the treatment of benign prostatic hyperplasia (BPH), we synthesized diisopropyl (1a-8a) and tert-butyl (1b-8b) benzamides, as well as ethyl benzoates (1c, 3c), which were substituted in 4 position via variable alkyl spacer (n = 0: 1-4, n = 1: 5, 7 and n = 3: 6, 8) with a 1-methyl-2-pyridone (1, 2, 5, 6) or a 1-methyl-2-piperidone (3, 4, 7, 8) moiety mimicking steroidal ring A. The directly connected benzamides (1a-4a, 1b-4b) and benzoates (1c, 3c) were obtained by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-borane with 4-bromobenzoic acid derivatives, followed by alpha-oxidation of the 1-methyl-pyridinium salt and subsequent separation of the regioisomers. Catalytic hydrogenation of the pyridones (1, 2) led to the piperidones (3, 4). The preparation of the benzamides with a methylene (5, 7) and a propylene spacer (6, 8), respectively, started with the reduction of the keto group of 5-benzoyl-1,2-dihydro-1-methyl-2(1H)-pyridone and catalytic hydrogenation of the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-methyl-2(1H)-pyridone with (2-phenylethyl)triphenylphosphonium bromide, respectively. The phenyl ring was functionalized by Friedel-Crafts reaction, haloform cleavage to give the acid, formation of the acid chloride, and subsequent treatment with the appropriate amines. Again, catalytic hydrogenation of the pyridones (5, 6) led to the piperidones (7, 8). The 5 alpha-reductase inhibitory properties were determined using rat ventral prostate, as well as human BPH tissue as enzyme source, 1 beta-2 beta-[3H]testosterone as substrate and a HPLC procedure for the separation of dihydrotestosterone (DHT). Tested at a concentration of 100 microM, the inhibition values of 1-8 ranged from 0-79%. Significant differences were observed between rat and human enzyme. The most active compound was ethyl 4-(1-methyl-2-oxopiperid-5-yl)benzoate 3c (68%) for the human enzyme and N,N-bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl) propyl] benzamide 6a (79%) for the rat enzyme.
5-alpha Reductase Inhibitors↗
Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds.
A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC(50) values of 54% of the enones were less than 10 microM when all four screens were considered and less than 1 microM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett sigma, Hansch pi and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.
Animals↗
Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors.
The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)- (cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleuci namide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)- [(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5- methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.
Benzazepines↗
Synthesis and biological activities of 2,6-diaryl-3-methyl-4-piperidone derivatives.
In the present study, a new series of 2,6-diaryl-3-methyl-4-piperidones was synthesized by Mannich reaction (condensation) of ethyl-methyl ketone, substituted aromatic aldehydes and ammonium acetate. Oximes and thiosemicarbazone derivatives of 2,6-diaryl-3-methyl-4-piperidones were synthesized by reaction with hydroxylamine hydrochloride and thiosemicarbazide respectively. The chemical structures were confirmed by means of IR, 1H-, 13C-NMR and mass spectral data. The compounds were screened for acute toxicity, analgesic, local anaesthetic and antifungal activity. 2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-one 2 exhibited the highest analgesic and local anaesthetic activity. The oximes and thiosemicarbazones were completely devoid of analgesic and local anaesthetic activity. 2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime 21 and 2-(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 17 exhibited potent antifungal activity against Aspergillus niger. Antifungal activity against Candida albicans was observed only with 2-(4-dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 20. 2,6-Diaryl-3-methyl-4-piperidones did not exhibit antifungal property.
Analgesics↗
Synthesis and lateral root-inducing activity of novel N-substituted-2-piperidones with a 1,4-benzodioxan ring.
Novel N-substituted-2-piperidones with a 1,4-benzodioxan ring were prepared and evaluated for their activity to induce lateral roots in lettuce seedlings. Compounds were obtained by aldol condensation of the lithium enolate of N-substituted-2-piperidones with 1,4-benzodioxan-6-carbaldehyde. Of the series compounds tested, N-cinnamyl-3-[1-(1,4-benzodioxan-6-yl)-1-hydroxymethyl]-2-piperidone (2e) had the highest activity. In seedlings treated with 10 ppm of 2e, all of the primary roots formed lateral roots. Only erythro-2e showed lateral root-inducing activity, while threo-2e was inactive.
Dioxanes↗
Cytotoxic evaluation of some 3,5-diarylidene-4-piperidones and various related quaternary ammonium compounds and analogs.
A number of 3,5-diarylidene-4-piperidones (1) and some related quaternary ammonium salts (5) as well as closely related analogs were prepared principally as candidate cytotoxic agents in two screens. The first test system used an average of 54 human tumor cell lines from eight neoplastic diseases, namely leukemia, melanoma, colon, non-small-cell lung, small-cell lung, central nervous system, ovarian, and renal cancers. Selective toxicity was demonstrated by some of the compounds, especially toward leukemia. The second screen used L1210 lymphoid leukemia cells. In general, the compounds were less cytotoxic than the reference drug melphalan in both screens. Linear plots were made between the Hammett (sigma), fragment (f), and molar refractivity (MR) constants of the nuclear substituents in series 1 and 5 with the IC50 figures of both the human tumor cell lines and L1210 cells. Evaluation against the human tumor cell lines revealed that increases in the f values were correlated with elevation of cytotoxicity in both series 1 and 5; MR constants were also important in series 5. In the L1210 screen, sigma and MR constants were positively correlated with cytotoxicity. X-ray crystallography was undertaken on 3,5-bis-[[4'-(methylthio)phenyl]methylene]-1-methyl-4-piperidone methiodide (5d), which had significant cytotoxicity, and 3,5-bis(4-pyridylmethylene)-1-methyl-4-piperidone methiodide (6), which was virtually inactive in both screens.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)- 5-[2-[(3-substituted)-1-azetidinyl]ethyl]-2-piperidones. 1. Selective antagonists of the neurokinin-2 receptor.
The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-[2-[(3-substituted)-1-azetidinyl]ethyl]-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2 (T1/2(HLM) of 30 min vs <10 min for 2). This series was further optimized by replacing the 4,4-disubstituted piperidine functionality found in 4 with simple 3-substituted azetidines. This series, exemplified by 1-benzyl-5-(3,4-dichlorophenyl)-5-[2-[3-(4-morpholinyl)-1-azetidinyl]ethyl]-2-piperidone 5, was found to possess excellent functional potency for the NK2 receptor in the Rabbit pulmonary artery (RPA) assay (pA2 = 9.3) and increased in vitro metabolic stability (T1/2(HLM) = 70 min) relative to 4. Metabolic route identification studies revealed that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the molecule gave a balance of good potency and high metabolic stability. For example, the significantly less lipophilic analogue 29 (log D = 2.3) possessed both good functional potency (RPA, pA2 = 8.1) and high in vitro metabolic stability (T1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-substituent as a strategy to further increase potency and moderate log D led to the identification of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T1/2(HLM) >120 min) and high potency in both RPA (pA2 = 8.9) and human bladder smooth muscle (pK(b) = 8.9) functional assays. In addition, NK2 antagonist 33 (IC50 = 4 nM) showed excellent selectivity over both the related human neurokinin receptors h-NK1 (IC50 = 7.9 microM) and h-NK3 (IC50 = 1.8 microM) in radioligand binding studies.
Animals↗
Green chemistry approach to the synthesis of N-substituted piperidones.
An efficient green chemistry approach to the synthesis of N-substituted piperidones and piperidines was developed and applied to the synthesis of 1-(2-pyridinylmethyl)-piperidin-4-one, 1, a key starting material for the synthesis of LY317615, an antiangiogenic agent currently under development at Eli Lilly and Company (Chart 1).(1) The general utility of this methodology, which presents significant advantages over the classical Dieckman approach to this class of compounds, was also demonstrated by the direct synthesis of a series of substituted piperidones and piperidines, including potential dopamine D4 receptor antagonists 2 and 3, that have been evaluated in the clinic as antipsychotic agents (Chart 2).(2)
Environmental Pollution↗
Biosynthesis of 5-aminopentanoic acid and 2-piperidone from cadaverine and 1-piperideine in mouse.
1-Piperideine, 5-aminopentanoic acid, and its lactam, 2-piperidone, were identified as metabolites of cadaverine in 10,000 g mouse liver supernatants to which diamine oxidase had been added. Both metabolites were also found when the cadaverine metabolite 1-piperideine was incubated with the preparation which suggested that 1-piperideine is an intermediate in the formation of 5-aminopentanoic acid and 2-piperidone. Identification of the metabolites was based on gas chromatography-mass spectrometric analysis in comparison to authentic standards. Mouse brain homogenates converted 1-piperideine to 5-aminopentanoic acid. The results suggest that the metabolic fate of cadaverine may provide precursors of pharmacologically active analogues of GABA.
Amine Oxidase (Copper-Containing)↗
Addition-Rearrangement of Aryl- and Alkoxysulfonyl Isocyanates with 5-Methyl-Substituted 3,4-Dihydro-2-methoxy-2H-pyrans. Selective Synthesis of Functionalized 2-Piperidones(1).
3,4-Dihydro-2-methoxy-5-methyl-2H-pyran and 3,4-dihydro-2-methoxy-5,6-dimethyl-2H-pyran undergo addition-rearrangement reactions with arylsulfonyl isocyanates to generate the corresponding 3-formyl- and 3-acetyl-6-methoxy-3-methyl-1-(arylsulfonyl)-2-piperidones. For example, 3,4-dihydro-2-methoxy-5-methyl-2H-pyran and phenylsulfonyl isocyanate afforded 3-formyl-6-methoxy-3-methyl-1-(phenylsulfonyl)-2-piperidone as a separable trans/cis mixture in high yield. The more reactive phenoxysulfonyl and alkoxysulfonyl isocyanates provided analogous results.
Journal Article↗
2-Piperidone Type of Chiral Building Block for 3-Piperidinol Alkaloid Synthesis.
An enantiomeric pair of a new 2-piperidone type of chiral building block (1) has been prepared by bakers' yeast reduction of beta-keto ester (2) or lipase-mediated transesterification of hydroxy ester (+/-)-(1), derived from NaBH(4) reduction of 2, in enantiopure form. The absolute stereochemistry of (-)-1 was verified by its conversion to known piperidine (-)-3, an intermediate for the synthesis of (-)-spectaline. The 2-piperidone (-)-1 was converted to all four diastereomers of 2,6-disubstituted 3-piperidinol chiral building blocks on the basis of homologation of (-)-1 at the lactam carbonyl using the Eschenmoser method via corresponding thiolactams (-)-9, (-)-20, (-)-25, (-)-27, and (-)-34, followed by stereocontrolled reduction of the resulting vinylogous urethanes (+)-10, (+)-15, (+)-23, (+)-28, and (+)-32, respectively, and epimerization of the hydroxyls at the 3-position [(-)-16 via (+)-17 to (-)-18 and (+)-29 via (+)-30 to (+)-31]. The versatility of these chiral buliding blocks has been demonstrated by the chiral synthesis of the 3-piperidinol alkaloids (+)-prosafrinine, (-)-iso-6-cassine, (-)-prosophylline, and (-)-prosopinine from (-)-37, (-)-14, (+)-36, and (-)-26, respectively.
Journal Article↗
Enhancing effect of piperidone derivatives on the percutaneous absorption of indomethacin.
Following our previous demonstration that Azone and 2-n-alkylcyclohexanones enhanced the percutaneous absorption of indomethacin, six 1-n-alkylpiperidones were prepared and examined as potential transdermal absorption enhancers. In vitro skin experiments showed that indomethacin absorption enhancement was related to the lipophilicity of the enhancer, and that 1-n-dodecyl piperidone caused the greatest enhancement. The structure of this piperidone is similar to that of Azone, and both compounds had similar lipophilicity and drug absorption enhancement activity. We suggest that they act in the same way by decreasing diffusional resistance in the stratum corneum, and so modifying the hard barrier of the stratum corneum.
Animals↗
[Pyrrolidone and piperidone derivatives with antihistaminic and antianaphylactic activities. Synthesis and pharmacological study].
The preparation of several derivatives to oxatomide (A), with the benzimidazolinone moiety replaced by another heterocyclic residue is described. In some cases changes to the basic chain of (A) were also considered. All the new compounds were evaluated as antihistaminics (H1) and antianaphylactics. The derivatives where the heterocyclic moiety was an unsubstituted or phenylsubstituted 2-pyrrolidone or 2-piperidone residue showed antihistaminic and antianaphylactic activities similar to those of oxatomide while modification of the basic side chain with elimination of the benzhydryl group, gave a complete loss of activity. The pharmacological screening was completed by the evaluation of the barbiturate induced sleep prolongation and of acute toxicity.
Anaphylaxis↗
3-Amino-2-piperidone in the urine of patients with hyperornithinemia.
3-Amino-2-piperidone, a delta-lactam of ornithine, has been detected in the urine of a number of patients with hyperornithinemia. The distinctive yellow colour formed with a ninhydrin-cadmium reagent should help in the detection of hyperornithinemia by urinary chromatography.
Adolescent↗
Imidazole derivatives of pyrrolidonic and piperidonic as potential inhibitors of human placental aromatase in vitro.
Inhibitory activities towards human Placental aromatase of novel pyrrolidinone and piperidinone drugs were investigated and compared with those of aminoglutethimide (AG) in vitro. All compounds showing a stronger inhibitory effect than this of AG had the following common structural feature: an imidazole side-chain in C-3 position, with a substituted or non-substituted aromatic ring in the C-2 position and an aliphatic chain (n-butyl or n-octyl) or a phenyl moiety on the nitrogen of the pyrrolidone or piperidone ring. When the C-3 side-chain did not bear any imidazole ring, no activity was observed. Respective Ki values for the competitive inhibition exerted by the more potent inhibitors 10, 11, 13 and 21 with androstenedione as substrate were 19.2, 20.3, 16.8 and 15.4 microM, respectively (Ki AG= 77.0 microM).
Aminoglutethimide↗
Gramicidin S synthetase. Stability of reactive thioester intermediates and formation of 3-amino-2-piperidone.
The reactive thioester complexes of gramicidin S synthetase with substrate amino acids and intermediate peptides are slowly hydrolyzed in neutral buffer solutions under mild conditions. Fully active enzyme is recovered. These processes are strongly accelerated by certain thiol protective agents. In the presence of 1 mM dithioerythritol the half-life times of these hydrolysis reactions are in the range of 1-90 h at 3 degrees C. The thioester complex of gramicidin S synthetase 2 (GS2, the heavy enzyme) with the tripeptide DPhe-Pro-Val is distinguished by the highest stability of all these intermediates. A different decomposition pattern is observed for the thioester complex of GS2 with LOrn. Here 3-amino-2-piperidone (cyclo-LOrn) is formed in a rapid cyclization reaction. This product specifically blocks the activation center of GS2 for LOrn at the thioester binding site. All other activation reactions of gramicidin S synthetase are unaffected. A procedure for a specific labelling of the reaction centers of the multienzyme is outlined.
Amino Acid Isomerases↗
A study of baker's yeast reduction of piperidone-carboxylates.
The stereoselective baker's yeast reduction of various N-protected piperidone-carboxylic acids have been studied, and the enantioselectivity was found to be widely dependent on whether fermenting or non-fermenting conditions were employed. Thus reaction of N-tert-butoxycarbonyl-4-oxopiperidine-3-carboxylic acid ethyl ester (6) with fermenting baker's yeast gave almost racemic N-tert-butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid ethyl ester (7), however, with complete diastereoselectivity. Reduction of 6 with non-fermenting yeast gave 7 with a 24-41% enantiomeric excess. Similarly, reduction of N-tert-butoxycarbonyl-3-oxopiperidine-4-carboxylic acid ethyl ester (17) with fermenting baker's yeast gave racemic N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic acid ethyl ester [(+/-)-18] diastereoselectively. A convenient method for determining the enantiomeric excess of the hydroxypiperidine carboxylic acids derivatives was found in the reaction with Sanger's reagent followed by HPLC on a chiral column.
Carboxylic Acids↗