Antalarmin

In the molecule of the title compund [systematic name: N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine], C24H34N4, the pyrrolopyrimidine ring system is nearly planar, its five- and six-membered rings forming a dihedral angle of 5.3 (2)°. The benzene ring is nearly orthogonal to the central ring system. The N atom carrying the ethyl and n-butyl groups is flattened pyramidal.


Comment
Corticotropin releasing factor (CRF) is a 41 amino acid hormone that has been implicated in the stress response cascade (Vale et al.,1981). This action is achieved by the release of adrenocorticotropic hormone (ACTH) by stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (Rivier & Vale, 1983). CRF creates this release by binding to G-protein coupled receptors designated as CRF1 and CRF2 (Steckler & Holsboer, 1999). The CRF1 receptor has been designated as the subtype responsible for the physiological reaction to stress (Dieterich et al., 1997). Both subtypes are found widely distributed in the central nervous system and have been correlated to numerous other responses (Hsin et al., 2002).
In the search for non-peptide, selective antagonists for CRF1, antalarmin (1) has emerged as a lead candidate. Analogs have been developed to increase activity and decrease LogP, yet none have been reported as superior in overall performance (Gross et al., 2005;Hsin et al., 2002;Chorvat et al., 1999). Antalarmin has shown anxiolytic activity in primates, as well as a reduction of self-administration of ethanol in addiction models (Habib et al., 2000;Chu et al., 2007). Recently, detailed toxicology has been reported indicating a favorable safety profile and suggesting that clinical trials may begin soon (Horn et al., 2008).
Data collection was initially attempted at 90 K, but an apparent phase change destroyed the crystal at that temperature.
Thus, data were collected at 150 K, and the structure based upon those data is presented in Fig. 1. The pyrimidine and pyrrole rings are slightly nonplanar, exhibiting maximum deviations 0.036 (1) Å (for C2) and 0.016 (1) Å (for C6), respectively.
No other pyrrolopyrimidines having substituents at N4 are found in the Cambridge Structural Database (version 5.29, Nov. 2007;Allen, 2002). The structure of a similar molecule, ICAKOM, having a cyclopentyl group at N3 and a 4-phenoxyphenyl group at C4, has been reported Banić Tomišić et al. (2001).

Experimental
Synthesis of antalarmin has been reported (Greiner et al., 2002). It was crystallized from acetonitrile:water to afford trans-  N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.