Piperazine amides

Abbott has also demonstrated in vivo efficacy with two piperazine amides, A-304121 (26) and A-317920 (27). Both (26) and (27) bind to the rat H3 receptor with high affinity (pA) = 9.15 and 8.6, respectively) [92] and are active in several in vivo models, including the acute dipsogenia model and models of cognitive performance and inhibitory avoidance [93]. Unfortunately, these compounds showed markedly reduced affinity for the human H3 receptor, reinforcing the need to screen against the human receptor. 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

A few synthetic approaches were reported to obtain sets of new 1,2,4-triazine derivatives. A well-known synthetic protocol was used to prepare a series of the 1,2,4-triazine derivatives 14 bearing a piperazine amide moiety. The synthetic route included the condensation of S-methyl thiosemicarba-zide 15 and benzil derivatives 16 followed by nucleophilic substitution of the methylthio group with piperazine resulting in 1,2,4-triazines 17 and further functionalization of the piperazine moiety. In vitro antitumor activity against breast cancer cells of the 1,2,4-triazines 14 was evaluated using the XTT method, BrdU method, and flow cytometric analysis. A few of the compounds demonstrated antiproliferative effect comparable with an effective anticancer drug, cisplatin (14BMC6313). 

Shin Y, Chen W, Habel J, Duckett D, Ling YY, Koenig M, He Y, Vojkovsky T, LoGrasso P, Kamenecka TM (2009) Synthesis and SAR of piperazine amides as novel c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett 19 3344-3347... 

Triazole-substituted piperazine amides mimicking )8-tum stractures were reported by the Burgess group. Fifteen piperazine amides were prepared and isolated in high yields (23, 71-96%, Scheme 10.7) and used in couplings with dichlorotriazine derivatives (tagged with fluorescein or an alkyne) to afford combinatorial libraries 24, which were... 

Scheme 10.7 ji-turn mimics produced from piperazine amides and dichlorotriazines... 

FIGURE 4.2 Membrane surface atomic force microscopy images (a) PES pure membrane and (b) poly(piperazine-amide) composite membrane. (Reprinted with permission from Jahanshahi, M. et al, Desalination 257, 129-136, 2010.)... 

Jahanshahi, M., A. Rahimpour, and M. Peyravi. 2010. Developing thin film composite poly (piperazine-amide) and poly( vinyl-alcohol) nanofiltration membranes. Desalination 257 129-136. 

Significant quantities of amine and amide esters are formed by side reactions (9). In addition, with dialkanolamines, amide diesters, morpholines, and piperazines can be obtained, depending on the starting material. Reaction of dialkanolamines with fatty acids in a 2 1 ratio, at 140—160°C, produces a second major type of alkanolamide. These products, in contrast to the 1 1 alkanolamides, are water soluble they are complex mixtures of AJ-alkanolamides, amine esters, and diesters, and still contain a considerable amount of unreacted dialkanolamine, accounting for the water solubiUty of the product. Both the 1 1 and the 2 1 alkanolamides are of commercial importance in detergents. 

Amines or amides Alkyl amines (iindecyloctyl and diamyl methyl amine) polyamides (acyl derivatives of piperazine) Boiler foam sewage foam fermentation dye baths... 

Acylation of the monosubstituted piperazine, 99 (obtainable by the protection-deprotection scheme outlined above), with cinnamoyl chloride gives the corresponding amide (100). Reduction of the carbonyl by means of lithium aluminum hydride affords cinnarizine (101). ... 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

Alfuzosin (91) is a prazosin-like hypotensive adrenergic a-1 receptor blocker with the special structural feature that two carbons have been excised conceptually from the piperazine ring normally present in this series. Following the usual sequence for this series, reaction of 4-amino-2-chloro-7-dimethoxyquinazoline (89) with the tetrahydro-2-furyl amide of 3-methylaminopropyla-mine (90) gives alfuzosin (91) [25], Alfuzosin is claimed to cause less orthostatic hypotention (dizziness or fainting upon sudden rising) than prazosin. 

Ethy I mercapto-phenothiazine 1 -Methyl-4-(3 -chloropropyl-1 )-piperazine Sodium amide... 

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

Alkylation of piperazine with the amide formed by reaction of chloroacetyl chloride with pyrrolidine gives amide 133. Acylation with 3,4,5-trimethoxy-... 

Monaca et al. (2003) examined the effect of the SSRI citalopram on REMS in 5-HTia and 5-HTib knockout mice. Citalopram suppressed REMS in wild-type and 5-HTib mice but not in 5-HT,A I mutants. The 5-HTja receptor antagonist WAY 100635 prevented the citalopram-induced inhibition of REMS in wild-type and 5-HTib knockout mice. However, pretreatment with the 5-HTib receptor antagonist GR 127935 [2 -methyl-4 -(5-methyl-(l,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid ((4-methoxy-piperazine-l-yl)-phenyl)amide] was ineffective in this respect. It was concluded that the action of citalopram on REMS in the mouse depends exclusively on the activation of 5-HT,A receptors. Notwithstanding this, there is unequivocal evidence showing that administration of selective 5-HTib receptor agonists suppresses REMS in the rat. 

In a similar fashion, Li and co-workers have described the synthesis of bis-amides 145 by the reaction of 1,4-dibromobutane with the piperazine counterparts 144 (Equation 33) <2003BML1729>. The compounds were tested as analgesics yields were not reported. 

The synthesis of azoniaspirocycles can also be carried out on solid support (Scheme 17) <2005JOC9622>. In the following example the resin-bound piperazine-tethered secondary amine 149 underwent an acylation to give amide 150. This was followed by a spontaneous intramolecular displacement of the bromide to yield the trisubstituted azoniaspiroundecane 151. 

---