Quinoline-3-carboxamide

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>. 

Scheme 41 Synthesis of spiro-P-lactams via cyclization of lithiated pyridine and quinoline carboxamides...

Clay den et al. [115] have reported the synthesis of spirocyclic p-lactams 176 (Scheme 41) by exo-cyclization of lithiated pyridine and quinoline carboxamides. The reaction of isonicotinamide or chlorinated isonicotinamide 175 with LDA at -40°C with addition of methyl chloroformate led to the formation of spirocyclic p-lactams 176 in good yields. Benzyl chloroformate, benzoyl chloride, methyl triflate can also be used as the effective acylating agents. In these type of reactions, lithiation of /V-benzyl pyridine and quinoline carboxamides to nitrogen provided... 

LhbucameJ (quinoline carboxamide tertiary amine) Synthetic V-Na+ CH blocker (inhibits AP) (23) [allergic contact dermatitogenic, local anaesthetic, antiarrhythmic]... 

Dibucaine-HCl 2-Butoxy-N-(2- (diethylamino)ethyl)-4-quinoline-carboxamide hydrochloride Cinchocaine... 

Bennacef I, Tymdu S, DhiUy M, Lasne M, Debrayne D, Perrio C, Barre L (2004) Synthesis and biological evaluation of novel fluoro and iodo quinoline carboxamides as potential ligands of NK-3 receptors for in vivo imaging studies. Biootg Med Chem 12 4533 541... 

The thermal ring closure of /V-(3-chlorophenyl)aminomethylenemalo-namate (781, R = Cl) to quinoline-3-carboxamide (782, R = Cl) in 50-59% yields was carried out in boiling diphenyl ether (46JA1251, 46JA1253) in a higher dilution than for its diester derivative (250) (46JA1204). A similar reaction took place with phenylaminomethylenemalonate (781, R = H) (50JCS607). 

Further extensions of the slilbene photocydizatinn are seen in analogous reactions of compounds containing the imine chro-mophore (e.g. 3,71 or an amide group (3.72). The amide reaction can be considered formally as giving a zwitterion intermediate, which undergoes proton shifts and oxidation to form the observed product. Non-oxidative cyclizations that start with either JV-vinyl aromatic carboxamides (C=C—N—CO—Ar) or N-aryl a. -unsaturated carboxamides (Ar—N—CO—C—C) have been extensively used to make quinoline or isoquinoline alkaloids and their derivatives a fairly simple example is given in (3.73). 

Treatment of ethyl l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylates with ammonia in methanol and hydrazine hydrate in ethanol at ambient temperature afforded 2-carboxamides and 2-carbohydrazides, respectively (74MIP1 79MIP2). Reaction of l-oxo-l//-pyrimido[l,2,-a]quinoline-2-carboxylic acids (169) with A-. /V-carbonyldiimidazole in dimethyl-formamide, then with 5-aminotetrazole gave 7V-(5-tetrazolyl)-1 -oxo-1H-pyrimido[l,2-a]quinoline-2-carboxamides (170) (77GEP2630469 77USP 4017625). 

Methoxy-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxamide (228) was prepared by cyclization of A -(4-methoxy-2-quinolyl)aminomethylene-malononitrile (227) in polyphosphoric acid at 110-130°C for 4.5 h (79MIP2). 

N-(3-chloro-5-methoxycarbonylphenyl)-5-bromo-l,2,3,4-tetrahydro-quinoline-8-carboxamide was obtained from 8-bromo-6,7-dihydro-lH,3H,5H-pyrido[3,2,l-z/][3,l]benzoxazine-l,3-dione with methyl 3-amino-5-chlorobenzoate in NMP at 170 °C for 16 h (07WOP2007/028789). 

N-Methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide was prepared using synthetic methodology reported by Thiesen et al (J. Org. 

To a solution of the N-methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide amide (10 g, 28.4 mmol) in anhydrous ether (100 ml) was added a solution of 2-pyridyl lithium (Pinder et al (J. Med. Chem. 1968, 11, 267)) [formed by addition of 2-bromopyridine (3.3 ml, 34.6 mmol) to a solution of butyl lithium (29.7 ml of a commercial 1.6 M solution, diluted with an equal quantity of ether) at -78°C] at -78°C. Analysis of the reaction by TLC after 10 min showed that no starting material remained. The reaction was allowed to warm to room temperature, then poured into aqueous ammonium acetate, and extracted with ether, the combined organic layers washed with brine and dried (MgS04). Filtration through a pad of silica gel using ethyl acetate-hexane (1 1) afforded 9.0 g (84%) of the crude 2,8-bis(trifluoromethyl)-4-quinolinyl-2-pyridinylmethanone. This was recrystallised from isopropyl alcohol to give the product as colourless needles, identical to that described in the literature (Hickmann et al. Pinder et al. Ohnmacht et al. and Adam et al. (Tetrahedron 1991, 36, 7609)). 

Similarly, the fluorine salts of 2-quinoline and 1-isoquinoline can also be harnessed to generate carboxamides 27 and 28 albeit in moderate yields (Equations 9 and 10) <2005TL2279>. 

Fig. 4 Molecular structure of tasquinimod, a second-generation orally active quinoline-3-carboxamide analog [36]...

Tasquinimod (structure shown in Fig. 4) is a second-generation orally active quinoline-3-carboxamide analog with enhanced potency against prostate cancer via its antiangiogenic activity. It is presently undergoing clinical trials [35]. Androgen ablation and taxanes are standard therapies for metastatic prostate cancer [36]. 

Isaacs JT, et al. (2006) Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer. Prostate 66(16) 1768-1778... 

Dalrymple SL, Becker RE, Isaacs JT (2007) The quinoline-3-carboxamide antiangiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts. Prostate 67(7) 790-797... 

Irradiation of 3-chloro-A-phenylbenzo[Z ]thiophene-2-carboxamide and triethylamine in benzene/methanol (4/1) yielded [l]benzothieno[2,3-c]quinolin-6(5//)-one (92%)597. 

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