2-piperidinecarboxylic Acid Research Articles

Regio- and stereo-selective introduction of a bis(methoxycarbonyl)methyl group into the γ-position of the piperidine sketeton

A new method for a regioselective introduction of a bis(methoxycarbonyl)-methyl group into the 4-position of the piperidine skeleton was explored, and this method was applied to the preparation of cis- and trans-2,4-disubstituted piperidines starting from 2-piperidinecarboxylic acid. The key steps in the method involved electrochemical oxidation of carbamates.

Metabolism of the antihypertensive drug methiapril

Considerable recent attention has been focused on the creation of drugs inhibiting the renin-angiotensin system (RAS) of an organism which are advantageous for treating various forms of arterial hypertension. In screening a broad range of derivatives of piperidinecarboxylic acids, cis-l-(3-acetylthiopropionyl)-6-methylpipecolinic acid was found to be the most efficient inhibitor of the RAS and was named METHIAPRIL (I) [ l ]. In the efficacy and duration of action on various models of arterial hypertension, it is close or superior to the foreign antihypertensive drug CAPTOPRIL (II).

Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1 R-(1 α( Z),2 β,3 β,5 α))-7-(5-((1,1′-biphenyl)-4-ylmethoxy)-3-hydrpxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A 2 receptor antagonist); argatroban ((2R,4R)-4- methyl-1-[N 2-(3- methyl-1,2,3,4- tetrahydro-8- quinolinyl)sulfonyl]- L-arginyl )]-2- piperidine-carboxylic acid , a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t -butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time ( T 1) for reopening of the vessel and the frequency of reocclusion ( F ro) 24 h after thrombolysis were monitored. With rt-PA alone, T 1 was 28 ± 7 min ( n=10) and F ro was 70%. T 1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. F ro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A 2, thrombin and leucocytes are involved in reocclusion after thrombolysis.

Competitive NMDA receptor antagonists: synthesis of β-ketophosphonate-substituted piperidine carboxylic acid derivatives

A series of substituted 3(S)-phosphonoacetyl-2(R)-piperidinecarboxylic acids has been synthesized. Substitution with a methyl group in the 4 position, trans to the phosphonoacetyl group has been found to substantially increase binding affinity (IC 50=15 nM vs [ 3H] CPP) at the NMDA receptor complex over that of the parent compound (IC 50=40 nM).

Asymmetric Transformations of Proline and 2-Piperidinecarboxylic Acid via Formation of Salts with Optically Active Tartaric Acid

Abstract The rates of racemization of optically active proline [Pro] and 2-piperidinecarboxylic acid [Pia] by using aldehydes as a catalyst tended to increase with a decrease in the acidity of the carboxylic acid used as solvent. Based on these results, the asymmetric transformations of Dl-Pro and (RS)-Pia were carried out via formation of salts with (2R, 3R)-tartaric acid to give optically pure l-Pro in over 80% yield and (R)-Pia in 70% yield. The asymmetric transformation of l-Pro was more successfully achieved by using (2S, 3S)-tartaric acid to give optically pure d-Pro in 85% yield based on the starting l-Pro.

Synthesis of Proline and 2-Piperidinecarboxylic Acid via Cobalt-Catalyzed Isomerization–Carbonylation of N-Acyl Unsaturated Cyclic Amines

Abstract N-Acyl derivatives of proline and 2-piperidinecarboxylic acid (pipecolic acid) were synthesized in moderate yield from N-acyl unsaturated cyclic amines through cobalt-catalyzed isomerization–carboxylation under hydroformylation conditions in the presence of H2O. A possible mechanism for the process is discussed which is related to that of the amidocarbonylation (cobalt-catalyzed formation of N-acyl α-amino acid from aldehyde, amide and carbon monoxide).

Synthesis of 3( [formula omitted])-phosphonoacetyl-2( [formula omitted])-piperidinecarboxylic acid, a conformationally-restricted glutamate antagonist

The synthesis of the conformationally-restricted β-ketophosphonic acid, 3( S )-phosphonoacetyl-2( R )-piperidinecarboxylic acid ( 4 ) is described. This compound is a competitive, glutamate antagonist (IC 50 = 40 nM vs [ 3H]CPP) of the NMDA receptor complex.

ChemInform Abstract: Synthesis of 3,5‐Disubstituted 1‐Azabicyclic Systems: Intermediates for Novel Muscarinic Ligands.

AbstractStarting with the pyridinedicarboxylic acid monoester hydrochloride (I), the piperidinecarboxylic acid ester hydrobromide (VI) is synthesized which is transformed into a mixture of the stereoisomeric azabicyclooctanonecarboxylic acid esters (VII) and (VIII) with predominance of (VII).

Substitution of proline with pipecolic acid at the scissile bond converts a peptide substrate of HIV proteinase into a selective inhibitor

The nonapeptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-NH 2 containing the retroviral Tyr-Pro cleavage site is a good substrate for the proteinase of human immunodeficiency viruses but it is not readily hydrolyzed by other nonviral proteinases including the structurally related pepsin-like aspartic proteinases. Replacing the Pro by L-pipecolic acid (2-piperidinecarboxylic acid) converted the substrate into an effective inhibitor of HIV-1 and HIV-2 proteinases with IC 50 of ∼ 1 μM. This compound showed a high degree of selectivity in that it did not inhibit cathepsin D and renin.

ChemInform Abstract: Synthesis and Pharmacology of a Series of 3‐ and 4‐(Phosphonoalkyl)pyridine(piperidine)‐2‐carboxylic Acids. Potent N‐Methyl‐D‐aspartate Receptor Antagonists.

AbstractThe hydroxyalkylpyridines (I) are transformed into the phosphonoalkyl‐substituted piperidinecarboxylic acids (IX) as shown in the reaction scheme.

ChemInform Abstract: Stereoselective Synthesis of Substituted Pipecolic Acids.

AbstractThe key steps in the formation of the piperidinecarboxylic acid (IX) are the acid‐induced ring closure of the N‐(2‐hydroxyalkyl)glycinate (IV) to give the lactone (V) and the thermal rearrangement of the semicyclic ketene acetal (VII), yielding the tetrahydropyridinecarboxylate (VIII).

ChemInform Abstract: Mass Spectra of Piperidinecarboxylic Acids and Their Esters.

ChemInform Abstract: Mass Spectra of Piperidinecarboxylic Acids and Their Esters.

ChemInform Abstract: Chemical Conversion of Cyclic α‐Amino Acids to α‐Aminodicarboxylic Acids by Improved Ruthenium Tetroxide Oxidation.

AbstractDie aus den cyclischen Aminosäuren (I) erhaltenen Derivate (II) werden mit RuO4 zu den Lactamen (III) oxidiert, die weiter zu den Amino‐dicarbonsäuren (IV) hydrolysiert werden.

Orally active and potent inhibitors of gamma-aminobutyric acid uptake.

3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].

Chemical conversion of cyclic .ALPHA.-amino acids to .ALPHA.-aminodicarboxylic acids by improved ruthenium tetroxide oxidation.

The ruthenium tetroxide (RuO4) oxidation of N-acylated L-proline esters, prepared from L-proline, was carried out under two-phase conditions to afford good yields of the corresponding lactams with no appreciable racemization, and the products were hydrolyzed in aqueous hydrochloric acid to L-glutamic acid. Similar transformation starting with recemic 2-piperidinecarboxylic acid and 2-azetidinecarboxylic acid gave 2-aminoadipic acid and aspartic acid, respectively. A novel chemical conversion of cyclic α-amino acids into α-aminodicarboxylic acids has been accomplished. A new solvent system, ethyl acetate-water, was developed for this two-phase oxidation. It was found to be very useful in reducing the necessary reaction time.

Hydroxy- and amino-substituted piperidinecarboxylic acids as gamma-aminobutyric acid agonists and uptake inhibitors.

The syntheses of (3RS,4RS)-4-hydroxypiperidine-3-carboxylic acid (4), (3RS,5SR)-5-hydroxypiperidine-3-carboxylic acid (20), (3RS,4SR)-4-acetamidopiperidine-3-carboxylic acid (10), and (3RS,5SR)-5-acetamidopiperidine-3-carboxylic acid (18), related to the specific gamma-aminobutyric acid (GABA) uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21), are described. Furthermore, (3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), has been synthesized. The structures of 4, 10, 14, 18, and 20 have been established by 270-MHz 1H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the neuronal (synaptosomal) GABA uptake system in vitro has been measured. Compound 14 interacts selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer 22. Compounds 4, 18, and 20 are inhibitors of the GABA uptake system, although much weaker than nipecotic acid and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21). Compound 10 is inactive in both test systems.

Synthesis of 1, 2-diazabicyclo [2.2.2] octane, 1, 2-diazabicyclo [3.2.1]-octane, and their derivatives

1, 2-Diazabicyclo [2.2.2] octane, its 6-methyl homolog, and 1, 2-diazabicyclo [3.2.1] octane are synthesized by a general method involving nitrosation of piperidine carboxylic acids, subsequent reduction to 1-aminopiperidine carboxylic acids, cyclization to 3-keto-1, 2-diazabicycloalkanes, reduction of the latter to 1, 2-diazabicycloalkanes. A number of 2-substituted 1, 2-diazabicyclo [2.2.2] octanes are synthesized.

Hypotensive Agents. II. Aminoalkyl Esters of Piperidinecarboxylic Acids and Their “Reversed” Ester Derivatives

Hypotensive Agents. II. Aminoalkyl Esters of Piperidinecarboxylic Acids and Their “Reversed” Ester Derivatives

Local Anesthetics I. N-Alkyl Pyrrolidine and N-Alkyl Piperidine Carboxylic Acid Amides.

Local Anesthetics I. N-Alkyl Pyrrolidine and N-Alkyl Piperidine Carboxylic Acid Amides.

The Paper-Chromatography of the Pyridine- and Piperidine-Carboxylic Acids

SUMMARY The Rp values in three conditions, and measured under carefully controlled conditions, are given in these solvent systems for pyridine 2-, 3-, and 4-carboxylic acids and for piperidine 2-, 3-, and 4-carboxylic acids. Certain anomalies in these Rp values are discussed. in work leading to tne identincation ot the amino-acids responsible tor two ninhydrin-reacting spots on two-dimensional paper chromatograms of apple fruit extracts (Hulme and Arthington, 1952) a study was made of the behaviour of the cyclic pyridine- and piperidine-carboxylic acids. The results obtained are described below, since it appears possible that all these acids may be present in biological material. EXPERIMENTAL Chromatographic technique. Chromatograms were run by downward flow in