KinasePro

Kinase Chemistry – Just a year and a half behind the times.

Oximes from J&J

Posted by kinasepro on July 22, 2007

So J&J has a BMCL describing the amino-pyrimidine-oxime moiety as quinazoline isostere, and a there’s a handful of other applications describing the motif.   Here’s a Lapatinib-esque example where they describe the EGF activity: WO/2007/081630

NC1=C(/C=N/OCCN2CCOCC2)C(NC3=CC(Cl)=C(OCC4=CC=CC=C4)C=C3)=NC=N1

< 2g/d plz

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6 Responses to “Oximes from J&J”

  1. They don’t seem to have a structure. What do you think binds to the backbone residue? (There seem to be a couple of candidates; morpholine oxygen, oxime, and the regular ortho-NH2)

  2. A reactive metabolite problem in the making? Electrophilic carbon attatched to heteroaromatic ring with conveniently positioned hydrogen bond donors to assist attacking nucleophile. Presume they’ve checked otherwise somebody is going on a long job rotation in the Siberian office.

  3. sks said

    I am wondering if the oxime N be protonated at physiological pH?

  4. Protonation of that oxime is highly unlikely under physiological conditions. The oxygen is electron withdrawing, the pyrimidine is likely to be electron withdrawing. Furthermore the lone pair is likely to be having a deep & meaningful relationship with one of the NH hydrogen bond donors. You might compare with isoxazole which is one of the least basic heteroaromatics. I think the pKa for isoxazole is around 0.

  5. sks said

    GMC,
    i would guess that you would need to protonate or quaternerize the oxime N to aid the attack of a nucleophile on the adjacent imine carbon. just wondering about comment # 2.

  6. kinasepro said

    They aint no dummies. I’d wager its solid as a rock.

    But if you can’t figger what goes where, just click the lapatinib link above. The two compounds are drawn roughly the same way. In fact you may have noticed I’ve been trying to standardize over the last few months and draw the 2D representations to match the 3D structures I generate – Hinge:Upper left / H1:Upper right H2:Lower left.

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