4. Monofluoroisoquinolines. Part I

2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: A Potent, Selective, and Orally Bioavailable Dipeptide-Derived Inhibitor of Dipeptidyl Peptidase IV

“…Having arrived at the optimized structure in the β-alanine portion of the P2 site for good potency and selectivity, we went back to optimize the isoquinoline portion of the inhibitor. As expected, the gem-dimethyl series of derivatives with the introduction of 6-fluoro (21b) or 6,8difluoro (21c) substituents 20 in the phenyl ring of 21a, gave slight improvement in the inhibitory potency of DPP-IV, while both still maintained excellent selectivity for DPP-IV over DPP8 and DPP-II. Replacement of the isoquinoline ring of 21a with isoindoline gave a very potent DPP-IV inhibitor 21d, with an IC 50 value of 15 nM and >6700-fold selectivity over DPP8 and DPP-II.…”

“…Introduction of 3,4-dimethoxy substituents in 18b had a moderate decrease in DPP-IV potency by 4-fold of magnitude relative to 18a, but compound 18b was approximately equipotent to 18a as DPP8 inhibitor. On the other hand, introduction of an electron-withdrawing fluorine atom at the 6-position of the isoquinoline ring 20 in 18c led to some increase in potency (IC 50 ) 83 nM) with a slight drop in selectivity over DPP8 (20-fold).…”

“…2-[3-[2-[2-Cyano-( S )-pyrrolidin-1-yl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-6-fluoro-1,2,3, 4-tetrahydroisoquinoline (21b). The synthesis of 6-fluoro-1,2,3,4-tetrahydroisoquinoline was carried out as described in ref : 1 H NMR (CDCl 3 ) (4/1 mixture of trans/cis amide rotomers) δ 1.22 (s, 3H), 1.25 (s, 3H), 2.02−2.28 (m, 4H), 2.53 (s, 2H), 2.83 (t, 1H, J = 6.0 Hz), 2.89 (t, 1H, J = 6.0 Hz), 3.40−3.53 (m, 3H, overlapped doublet at 3.41, J = 5.4 Hz), 3.58−3.67 (m, 1H), 3.72 (t, 1H, J = 6.0 Hz), 3.80 (t, 1H, J = 6.0 Hz), 4.64−4.76 (m, 2.8H, two overlapped singlets at 4.64 and 4.68, 2H ArC H 2 N and 0.8H C H CN), 5.07 (d, 0.2H, J = 7.5 Hz, C H CN), 6.84−6.93 (m, 2H), 7.06−7.12 (m, 1H); HRMS (EI) m / z calcd for C 21 H 27 FN 4 O 2 386.2118, found 386.2116; HPLC (condition A) t R = 10.40 min, 100.0%, (condition B) t R = 6.97 min, 99.5%.…”

Mechanism of formation of doubly charged fragments from bis‐benzyltetrahydroisoquinolines under electron impact

“…The substituted l-benzyl-3,4-dihydroisoquinolines 6 were synthesized following the reported procedure. 16 They were reduced to the correspondíng l-benzyl-l,2,3,4-tetrahydroisoquinolines 7 with lithium aluminum hydride in ether, with the exception of 6a (X=NO,), which was treated instead with sodium cyanoborohydride: methanolic HCl was added to 1 -(4-nitrobenzy1)-3,4-dihydroisoquinoline (6a) (266 mg) and sodium cyanoborohydride (62 mg) in methanol (10 cm3) until bromocresol green turned blue. After stirring for 4 h the solvent was evaporated off, and 6 N NaOH was added until the residue dissolved.…”