I suggested and supplied a patent reference for the 2-chloro-5-methoxy homologue of K. It's interesting to note that the two substituents are para to each other. I guess CMXE would be the appropriate acronym,
What makes it all the more interesting is that the Parke-Davis (a US company) issued about 150 patents concerning K and it's homologues. BUT for CMXE they chose to obtain a British patent. My GUESS is that it was to prevent others from finding it. What heaps on the suspicion is that most patents cover many, many compounds but in the case of this patent, it was for a very small number of compounds.
It looks like on one hand they wanted to ensure they held the patent in a hurry but conversely didn't want others to know of the work.
GB1202834A 'Novel Cyclohexanone Compounds and Process Means for the Production Thereof'
Compound 1 - back in the day, patents would generally list examples from best to worst.
Before you ask, addition of a
meta methoxy to isophenidine didn't appear to increase activity but the addition of an
ortho chloro DID. The problem turned out to be that scaling the synthesis of the o-Cl derivative was difficult. But we did get samples and it was notably better. Other halogens and pseudohalogens are less successful. The complex metal hydrides used to reduce the imine to the amine also removed the -Cl meaning that it was much more work.
When people produce the -Br and -F homologues of ketamine, I always point out that it's Parke-Davis obtained all of those patents but not in a single case was any other halogen covered by said patents - and I PRESUME they tested such compounds and noted some sort of issue with them. They DID cover examples with an
ortho methoxy so I wouldn't be surprised if the 2,5-dimethoxy homologue was quite active.
But TBH, none of them would be as cheap as isophenidine. It has that NMDA/DRI balance that produces the very specific effects that make K so special.
BTW why the N-isopropyl? Because of the N-monosubstituted amine homologues of PCP, it's the N-isopropyl that is the most active by far. An N-isopropyl also makes the compound a reasonably potent DRI but less so than an N-methyl or N-ethyl. Balance, you see.