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  • It is well known that corticotropin releasing factor CRF exe

    2019-07-16

    It is well-known that corticotropin-releasing factor (CRF) exerts its biological functions through binding to type-1 (CRF1) and/or type-2 (CRF2) receptors. Several clinical evidences suggest the association of a high level of CRF and the onset of anxiety and depressive disorders.2, 3, 4, 5, 6, 7 Significant contributions have been made in the past two decades by several pharmaceutical research groups to discover non-peptide CRF1 AZD5363 antagonists as a potential treatment for stress-related illnesses (including depression). 7H-Pyrrolo[2,3-d]pyrimidine (CP-154,526) as well as pyrazolo[1,5-a]pyrimidine (R121919) and pyrazolo[1,5-a][1,3,5]triazine (DMP-696) are among the first and most representative compounds identified. In an effort to discover structurally novel CRF1 receptor antagonists exhibiting improved in vivo profiles, many scaffolds have been designed and synthesized. In this report, we describe novel bicyclic core CRF1 antagonists 2–3 (Fig. 1). These are designed based on the tricyclic core CRF1 antagonist 1 reported in our previous study. Cleavage of the C-ring of the tricyclic core structure consisting of A-, B- and C-rings resulted in a novel bicyclic core structure consisting of A- and B-rings (Fig. 1). Bicyclic core structures consisting of B- and C-rings were previously reported with dihydroimidazoles, dihydropyrrolopyrimidines,11, 12 tetrahydroimidazopyrimidines and imidazoimidazoles while the bicyclic core structures in this report consist of A- and B-rings.
    Chemistry Test compounds listed in Table 1, Table 2, Table 3 were synthesized as shown in Scheme 1, Scheme 2, Scheme 3. The synthesis of analogs 2–19 is described in Scheme 1a. The cyclization reaction of 5-aminopyrazole 34 with optional alkyl diethyl malonates 37a–i followed by chlorination with phosphorous oxychloride afforded dichlorides 38a–i, respectively. Aminolysis of 38a–b and 38i with 1-ethylpropylamine resulted in aminochlorides 39a–b and 39i, respectively. Aminolysis of 39a and 39b with 2-chloro-4-methoxyaniline afforded 2 and 3, respectively. Chemoselective aminolysis of 38a–i with dipropylamine afforded 40a–h, respectively. Aminolysis of 40a–h with 2-chloro-4-methoxyaniline afforded 4–11, 5-N-alkylation of which with optional alkyl halides in the presence of sodium hydride produced 12–19, respectively. The synthesis of 20–23 is outlined in Scheme 1b. The cyclization reaction of 3-amino-1,2,4-triazole 35 with optional diethyl alkyl malonates 37a–b resulted in dichlorides 41a–b. Monoamination of 41a and 41b with 1-ethylpropylamine afforded 42a and 42b, respectively. Aminolysis of 42a–b with 2-chloro-4-methoxyaniline and N-methyl-2-chloro-4-methoxyaniline afforded 20 and 21, respectively. Chemoselective monoaminolysis of 41a with dipropylamine afforded 43a, further aminolysis of which with 2-chloro-4-methoxyaniline afforded 22. N-Alkylation of 22 with methyl iodide in the presence of sodium hydride resulted in 23. The synthesis of analogs 24–26 is described in Scheme 1c. The cyclization reaction of 2-aminoimidazole 36 with 37a–b followed by chlorination with phosphorous oxychloride afforded 44a–b. Chemoselective monoamination of 44a–b with dipropylamine afforded 45a–b, respectively. Aminolysis of 45b with 2-chloro-4-methoxyaniline afforded 24. Aminolysis of 45a with 2-chloro-4-methoxyaniline followed by N-alkylation with methyl iodide and ethyl iodide afforded N-methyl analog 25 and N-ethyl analog 26, respectively. Pyrazolotriazine analog 27 was prepared from 3-aminopyrazole 34 as shown in Scheme 2. Reaction of 34 with ethoxycarbonyl isothiocyanate afforded a thiourea 46, treatment of which under alkaline condition provided a cyclized compound 47. S-Methylation of 47 with methyl iodide afforded 48, chlorination of which with phosphorous oxychloride in N,N-dimethylformamide provided 48. Aminolysis of the chloride 49 with dipropylamine afforded 50, oxidation of which with m-CPBA provided a methylsulfonyl compound 51. Aminolysis of the methylsulfone 51 with 2-chloro-4-methoxyaniline resulted in a pyrazolotriazine analog 27.