Piperidine amides

Researchers at GlaxoSmithKline have numerous recent patent applications describing several series of H3 antagonists including the benzazapines (41) [115] and (42) [116], quinolizidines (43) [117], isoindolines (44) [118], and the piperidine amides (45) [119] and (46) [120]. All of these structures were disclosed as functional H3 antagonists. 

Though the destabilisation is much less severe than with a nitrogen lone pair, an amide-stabilised organolithium prefers to minimise the interaction (shown below) between the C-Li bond and the 7i-system of the amide. Hindered amides of piperidines such as 37 are therefore deprotonated to give an equatorial organolithium such as 38.5 4 The equatorially substituted piperidine amide products 39 and 40 are less stable than their axially substituted products owing to the interaction between the new substituent and the pseudoequatorial amide group. Oxidation and equilibration leads to the axial substituted ketone 41.4... 

The fruit of the plant Piper nigrum is the common black pepper of the household. This fruit yields an alkaloid known as pipeline present to about 4 to 9 per cent in commercial pepper. On hydrolysis the alkaloid yields piperidine or hexa-hydro pyridine and an acid known as piperic acid. Piperine is thus considered as a piperidine amide of piperic acid. Physiologically this alkaloid acts like quinine but is less active and is uncertain. It is only rarely used in medicine. 

Metalated piperidine amides and formamidines may be converted to a-alkylated piperidines, as illustrated in Scheme 9. Again, the two examples illustrate the superiority of the formamidine moiety in both yield and ease of removal. 

Further exploitation of these leads led to the discovery that the shortened piperidino-piperidine amide analog (55) also shows significant inhibition of CCR5 (CCR5 = 66 nAf,... 

In a nutshell if you want to make a bond to a nitrogen atom, use the anion. The simplest examples are tetrazoles. The anti-inflammatory broperamole is the piperidine amide of the acid 124 that has a 1,3-relationship that can be disconnected first to reveal a simple tetrazole 125 available by 1,3-dipolar cycloaddition. 

A new piperidine amide (150) was isolated from Achillea lingustica. Its structure was determined using UV, MS and NMR [417],... 

Seven new piperidine amides were isolated from Achillea species [418], Amides 143-147, and 149 were obtained from A. lycaonica, and 148, from A. chamaemelifolia. The structures of these compounds were determined using UV, IR, FDMS, EIMS, and H NMR [418]. 

New piperidine amide 154 was isolated from Achillea falcata, along with several known amides. Its structure was established using MS, UV, IR and and 13C NMR [419]. 13C NMR spectra were obtained, and H NMR-lanthanide induced shifts were determined for the amides [419],... 

A new piperideide (155) was isolated from Achillea millefolium, and its structure was determined using MS, UV, and H NMR [420]. Several previously known piperidine amides were also isolated from this plant, including the dominant 156. The stereochemistry of amides 157 and 158 was determined using the lanthanide induced shift method [420],... 

Five piperidine amides produced by Achillea (151-153,156,159) were tested as inhibitors of cyclooxygenase and 5-lipoxygenase, key enzymes in arachidonic acid metabolism. Each of the amides inhibited cyclooxygenase. Amides 152 and 153 inhibited 5-lipoxygenase, 156 and 159 were weak inhibitors of this enzyme, and 151 showed no inhibition. [421]. 

HPLC was used to separate and analyze amides in the Achillea millefolium group [423], and a number of known piperidine amides were isolated from Achillea ptarmica [424,425]. 

Under mild conditions, DEPC promotes the coupling of TV-protected amino acid (115) with TV-substituted amino piperidine 116 to afford substituted piperidine amide 117.48 Amide 117 shows TV-type calcium channel antagonism and it is endowed with potent action on pain and neuropathic pain. 

After the structure of piperidine had been established (30), it was possible to confirm the early assumption that pipeline is the piperidine amide of piperic acid (29). Piperine resulted when the acid chloride of II (PCI5) was treated with piperidine (37). Hence, piperine must be represented by III. Methyl, ethyl and phenyl analogs of piperine have been prepared by similar syntheses (39). 

Palani, A., et al. Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-FIIV activity. J. Med. Chem. 2002, 45, 3143-3160. 

Fig. 11.11 Piperidine amides isolated from Piper longum [11]...

Spirocyclic piperidine amides as potent, nonpeptide inhibitors of human mast cell tryptase... 

The serine protease tryptase is released from mast cells at sites of inflammation. Thus, tryptase inhibitors have potential for treating inflammatory disorders, such as asthma, allergic rhinitis, and inflammatory bowel disease. We explored a series of spirocyclic piperidine amide derivatives (1) as tryptase inhibitors and identified 2 (JNJ-27390467) as a potent, selective inhibitor of human p-tryptase (Ki = 3.7 nM). This compound has -700-fold selectivity vs. inhibition of trypsin, and greater selectivity vs. inhibition of 12 other serine proteases. In pharmacokinetics studies in dogs and rats, 2 showed... 

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