Carboxamide derivatives

The PBRis distinct from the central BZ receptor although both can be present in the same tissues in differing ratios. PBRs are predominately localized on the outer mitochondrial membrane and are thus intracellular BZ recognition sites. The PBR is composed of three subunits an 18,000 mol wt subunit that binds isoquinoline carboxamide derivatives a 30,000 mol wt subunit that binds BZs and a 32,000 mol wt voltage-dependent anion channel subunit. The porphyrins may be endogenous ligands for the PBR. PBRs are involved in the control of cell proliferation and differentiation and steroidogenesis. 

Further SAR studies on the cyclopentane scaffold have included variation of the hydrophobic side-chain to incorporate a carboxamide substituent (Chand et al. 2004), equivalent to the C6-carboxamide derivatives of zanamivir, and extension of the length of the hydrophobic side-chains (Chand et al. 2005a). Analogues that incorporate a longer 4-heptyl side-chain showed comparable efficacy to 34 upon oral and intranasal administration in mice, and comparable or better efficacy than oseltamivir and zanamivir (Chand et al. 2005a). 

An intramolecular ring expansion of aziridine esters can be accomplished by installing an appropriate nucleophilic entity in these substrates. Conversion of the ester moiety into carboxamides derived from aminomalonate ester gives compounds 44 containing the requisite nucleophilic site in the malonate moiety (Scheme 35). 

This reaction to bicyclic compounds containing the aziridine group was also observed for other amides, viz., 44c-f, when treated with a catalytic amount of f-BuOK in THF or MeONa in methanol. LDA treatment of the tosyl-activated substrate 44 a gave the five-membered ring product albeit in a low yield (31 %). Remarkably, the carboxamide derived from the cz5-aziridine failed to react with base, probably due to steric hindrance. 

Synthesis of the ortho- and peri-fused pyrido[3,2,l- 1[l,3,2]benzodiazaphosphorine ring system was accomplished from the quinoline carboxamide derivative 197 by treatment with phosphoryl chloride <1978JHC1169, 1979JHC897>. The iV-chloropropyl derivative 198b could be transformed to the tetracycle 199 (Scheme 27) <1979JHC897>. 

In a correction to previous work, the cyclization of 4-ureidobutyric acids with thionyl chloride has been shown (by NMR spectroscopy) to result in pyrrolidinone carboxamide derivatives and not aryl perhydro-l,3-diazepine-2,4-diones <00JHC111>. Optimization of the geometry of l-(o-nitrophenyl)-2-phenyl-l//-4,5,6,7-tetrahydro-l,3-diazepine has been undertaken using computer-based molecular modelling, and correlations made with theoretical and experimental UV spectra . 

Aminoacridine carboxamide derivatives binding with DNA, 194, 195 Anomeric amides, 37, see also A-acyloxy-A-alkoxyamides... 

A-acetoxy-lV-/e//-butoxybenzamide, 55 /V-acyloxy- /V-alkoxyalky lam ides, 55 /V- acy I o x y- /V-a I k o x y u re as, 56 /V-chlorohydroxamic esters, 56 N, /V-dialkoxyamidcs, 56 Intercalative guest molecules, binding dynamics of DNA with, 186-201 acridine derivatives, 190-194 9-aminoacridine carboxamide derivatives, 194, 195... 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

A series of 3-(lH-indol-l-yl)-3-arylpropan-l-amines was recently reported as a new class of SNRIs [69]. Compound 22 exhibited potent inhibition of SERT and NET (IC50 = 9 and 12nM, respectively). A number of N-(pyrrolidin-3-yl) carboxamide derivatives were reported as SNRIs in a recent patent application [70]. Compound 23 showed potent inhibition of 5-HT and NE reuptake (IC50 = 12 and 23 nM, respectively). 

Two series of aminopyridine carboxamide derivatives have been reported to be potent, selective and ATP-competitive pan-JNK inhibitors [42—45]. Compound 9 containing a 6-aminophenylacetamide group inhibits JNK1 and JNK2 with IC50... 

FIGURE 6.16 Protecting groups for carboxamides. Derivatives are obtained by reaction of the carboxamide with an alcohol or the acid with an amine. Mbh = 4,4 -dimethoxybenzhydryl64 Trt = trityl [Sieber Iselin, 1991] Xan = 9-xanthenyl63 Dmb = 2,4-dimethoxybenzyl66 Tmb = 2,4,6-trimethoxybenzyl65 BHR = benzhydryl-resin.68... 

Scheme 7 Alternative four-component synthesis of carboxamide derivatives of azoloazines...

This procedure can be used for the MCRs based on other 1,3-binucleophiles. For example, the same authors applied it to form pyrido[2,3-d]pyrimidine-6-carboxamide derivatives from 6-aminouracile [40]. 

Scheme 49 Four-component synthesis of 4,5-dthydro-l//-pyrrol-3-carboxamide derivatives...

Alizadeh A, Rezvanian A, Zhu LG (2008) One-pot synthesis of 4,5-dihydro-lH-pyrrol-3-carboxamide derivatives via a four-component reaction. Tetrahedron 64 351-355... 

The chiral enolate-imine addition methodology was examined in detail (Thiruvengadam et al., 1999). Enolate formation proceeds to completion within an hour at temperatures from — 30 to 0°C with either 1 equiv. TiCl4 or TiClaO-iPr (preformed or prepared in the presence of substrate by addition of TiCl4 and followed by a third of an equivalent Ti(0-iPr)4 and two equivalents of a tertiary amine base). Unlike the aldol process with the same titanium enolate, the nature of the tertiary amine base had no effect on the diaster-eoselectivity. The diastereoselectivity is maximized by careful control of the internal temperature to below — 20°C during the imine addition (2 equiv.) as well as during the acetic acid quench. The purity of the crude 2-amino carboxamide derivatives (17a or... 

Ohuchida et al. have studied to synthesize a series of sulfonamide and carboxamide derivatives having an affinity with EP1 receptor. They have discovered that ONO-8713 having 2-sulfonylamino-5-trifluoromethylphenol as a core... 

The question then arises if a regioselective opening of a 2,3-rraMS-epoxy carboxamide derived from aldonic acids would occur. The 2,5-di-O-tosyl-D-ribono-1,4-lactone (62) (Scheme 13) was used to find an answer to this question. If treated with ammonia, the 2,5-diamino-2,5-dideoxy-D-ribono-1,5-lactam (63) was obtained as the only product [79]. The NMR spectra of the reaction mixture showed the formation of the diepoxy amide A which was opened at C-5 by ammonia. In this case no internal lactamization could occur, due to the trans 2,3-epoxy group in B (Scheme 13). Thus, a regioselective opening of an acyclic 2,3-epoxy carboxamide took place at C-2. The reaction was complete within 6 days. 

Alkaline hydrolysis of the carboxamide derivatives 142 upon heating in 1M KOH at reflux afforded the N-3-unsubstituted bicycle 143 (Equation 8) <1992FA1021>. Methanolic ammonia has also been used to remove the N-3-substituent from 144 giving 145 (Equation 9) <1996USP5508154>. 

The reaction of /V-pentenyl-2-iodoindole in the presence of a palladium-triphenylphosphine catalyst led to the formation of a mixture of isomeric products in good yield (4.8.), Addition of thallium(I) acetate favoured the formation of an exocyclic double bond, while in its absence the product containing the endocyclic olefin moiety is formed preferentially. The shortening of the A-alkenyl chain by one carbon leads to the selective formation of a five membered ring.9 Starting from indole-carboxamide derivatives both /3-. and carbolinones are available in intramolecular Heck coupling. 

Diazotization followed by cyclization has been used to prepare fused thiophene derivatives. Thus diazotization of 3-aminothiophene-2-carboxamides in cone. HC1 leads to thieno-1,2,3-triazines (Scheme 122) (75CRV241). A similar reaction was also observed with the 4-carboxamide derivatives. With 2,4-dicarboxamides as substrates the 3-diazo group preferred to cyclize with the 2-carboxamide group. 

Another method, which generated in most cases good yields of N-protected gem-diaminoalkyl compounds, involves N-protected peptidyl or aminoacyl carboxamide derivatives. These are subjected to a Hofmann-type rearrangement with the mild oxidizing reagent iodobenzene bis(trifluoroacetate) (IBTFA). 83 IBTFA is also known as phenyl iodosyl... 

The directed sorting method will first be illustrated by the preparation of libraries of piperazine-2-carboxamide derivatives.18 The piperazine-2-carboxylic acid scaffold is a pharmacologically important19 center core... 

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