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  • The synthesis of tricyclic analogs is described in

    2019-07-30

    The synthesis of tricyclic analogs 28–33 is described in Scheme 3. Oxidative C–C bond cleavage of the terminal olefin of 39i afforded a tricyclic product 52 without isolation of an aldehyde expected as an intermediate. Aminolysis of the chloride 52 with optionally substituted anilines afforded 28–30 and 32. Replacement of the chlorine of 52 with 4-ethyl-2-methoxyphenol in the presence of a Protease Inhibitor Cocktail (EDTA-Free, 100X in DMSO) resulted in the corresponding ether analog 33 (Table 3: X=O). The substitution reaction of 52 with 2,4,6-trimethylbenzyl zinc bromide afforded the corresponding methylene analog 31 (Table 3: X=CH2).
    Results and discussion The compounds listed in Table 1, Table 2, Table 3 were tested for their binding affinity to the human CRF1 receptor and antagonist activity in a CRF-stimulated adenylate cyclase assay. One of the leading compounds with higher receptor binding and antagonist activity was then evaluated in a cAMP assay and pharmacokinetic study in rats. Anxiolytic efficacy was also assessed in the Elevated Plus Maze model for rats.16, 17, 18 The human CRF1 receptor binding and antagonist activity data for pyrazolo[1,5-a]-1,5-pyrimidines 2–19 are summarized in Table 1. Pyrazolo[1,5-a]pyrimidin-5-amine core analog 2 and its corresponding tertiary amine analog 4 showed moderate antagonist activity and binding affinity. Introduction of a methyl group into position 6 of the pyrazolo[1,5-a]pyrimidin-5-amine core of 2 and 4 afforded 3 and 5, respectively. Analogs 3 and 5 resulted in an improvement in their binding affinity and antagonist activity relative to 2 and 4, respectively. Introduction of bulkier groups such as ethyl, n-propyl, i-propyl, n-butyl, cyclopentyl and methoxy groups instead of the methyl group of 5 afforded 6–11, respectively. The most potent analog 6 had an ethyl group at position 6. The n-propyl analog 7 exhibited moderate binding affinity and antagonist activity. The methoxy analog 11 showed quite good improvement in its binding affinity but showed unexpectedly weak antagonist activity for its strong binding affinity. The corresponding i-propyl, n-butyl and c-pentyl analogs 8–10 resulted in a significant reduction of binding affinity. Replacement of the NH moiety at position 5 of the pyrazolopyrimidine core of 4 with N-methyl, N-ethyl, N-propyl, N-methallyl, N-allyl, N-cyclopropylmethyl, N-methoxyethyl and N-methoxymethyl groups afforded analogs 12–19, respectively. Among them, the most potent binding affinity was obtained in the N-allyl analog 16 whereas the most potent antagonist activity was obtained in the N-methoxymethyl analog 19. Analogs 12–15 showed moderate binding affinity and antagonist activity, respectively. Analogs 17 and 18 exhibited moderate binding affinity. Remarkably weaker potency of 18 relative to 19 was ascribed to the relatively more Lewis basic and more hydrophilic methoxy moiety of 18, which is more exposed outside of the molecule relative to that of 19. As a result, small substituents such as methyl and ethyl groups were found as a favored R1, where R2 is hydrogen. N-Allyl and N-methoxymethyl groups were found as a favored R2, where R1 is hydrogen. Miscellaneous bicyclic core structures were also synthesized and evaluated for their CRF1 binding affinity and antagonist activity. The human CRF1 receptor binding and antagonist activity data for triazolopyrimidines 20–23, imidazolopyrimidines 24–26 and pyrazolotriazine 27 are summarized in Table 2. Triazolopyrimidine analogs 20–23 exhibited moderate-to-strong binding affinity. Among them, the NH analogs 20 and 22 exhibited relatively more potency than the corresponding N-methyl analogs 21 and 23, respectively. In a series of imidazolopyrimidine analogs 24–26, the tertiary amine analog 27 showed quite potent activity in both evaluations. The N-Methyl analog 25 and the corresponding N-ethyl analog 26 showed moderate potency in their binding affinity and/or antagonist activity. Thus, N-methyl analogs 23 and 25 tended to show less potent in vitro activities relative to the corresponding NH analogs 22 and 24, respectively. The same structure–activity relationship was observed between N-methyl analog 12 and NH analog 5 (Table 1). The pyrazolotriazine analog 27 showed quite potent activities in receptor affinity and antagonist activity. Hence, introduction of an additional nitrogen atom into the bicyclic core moiety of 3 afforded 20 with a reduction of in vitro activity. Introduction of another nitrogen atom into the core structures of 5 and 12 afforded 22 and 23, respectively also with a tendency of reduction of in vitro activities. The pyrazolotriazine analog 27 also with an additional nitrogen atom showed close receptor affinity to that of 12. Imidazopyrimidine analogs 24–25 showed relatively weaker in vitro activities than the corresponding triazolopyrimidine analogs 20, 22 and 23, respectively.