Synthesis and Characterization of Two Danazol Derivatives

Two danazol derivatives were synthesized and characterized by spectral analyses. In order to characterize the structural and chemical requirements of danazol derivatives, several parameters such as logP, π, Rm and Vm were evaluated. The results showed an increase in the values of logP for the compound 6 in comparison with 3. The compound 3 showed an increase in the values of π, Rm and Vm with respect to 6. These data indicate a high degree of lipophilicity and a low steric impediment for compound 6 in comparison with 3.


Introduction
The studies for the establishment of parameters relationship between biological activity of steroids and its molecular structure (QSAR), plays an important role in the development of new steroid derivatives [1][2] .For example the QSAR analysis of a series of steroids binding to globulin was made using the electro topological state index for each atom in the molecule 3 ..The relationship of dihydrotestosteroneciprofloxacin conjugates with the descriptors such as logP, π, R m and V m . 6was evaluated recently.In this work our initial design included the synthesis of two danazol derivatives and its relationship with the logP, π, R m and V m .

QSAR
ACD Log P and KOWWIN programs 8,9 were used to estimate the parameters logP, π, R m , V m of the compounds studied.

Results and Discussion
It is important to mention that several steroid derivatives has been developed using the Mannich reaction.The structural chemistry of these compounds involves an activated methyl group in ring A and B 10 , or the aliphatic side chain attached to C 17 .Several androgen derivatives 11 , have been synthesized in this way.The reactivity of hydrogen atom involved in the ring A of compound 1 was studied in this work by means of Mannich reaction.The first step was achieved by reacting the compound 1 with ethylendiamine (2) and formaldehyde to form compound 3 (Figure 1). 1 H NMR spectrum of compound 3 showed signals at 0.84 and 0.96 ppm corresponding to methyl group presents in the steroid nucleus.Additionally, several signals at 2.67, 2.74 and 3.98 for methylenes bound to A-ring of compound 3; at 2.57 and 2.80 ppm for methylenes bound to carboxyl group were found.Finally, two signals at 2.96 ppm for the proton of alkyne group and at 8.03 ppm corresponding to the acidic hydrogen of C(=O)-OH were found. 13C NMR spectra display chemical shifts at 14.00 and 19.81 ppm for the carbons of methyl presents in the steroid nucleus.The chemical shift of the methylenes bound to carboxyl group is found at 29.45, 29.48 and 168.40 ppm.Other signals at 41.17-51.91ppm for the methylenes bound to amino group were found.There are several signals (20.83-162.02ppm) corresponding to carbons involved in the steroid nucleus; at 168.40 ppm for ester group and at 173.60 ppm for free carboxyl group.The presence of 3 was further confirmed from mass spectrum which showed a molecular ion at m/z 509.60.
The second step was achieved by the reaction of compound 4 with aminocaproic acid (5) in presence of formaldehyde to form compound 6 (Figure 2). 1 H NMR spectra of 6 showed chemical shifts at 0.78 and 1.01 ppm for methyl group present in the steroid nucleus.Additionally, several signals at 1.22, 240-2.43 and 3.76 ppm were found for methylenes involved in arm bound to steroid.Finally, other signals at 3.06 ppm for the proton of alkyne group at 5.60 ppm corresponding to the acidic hydrogen of C(=O)-OH were found. 13C NMR spectra displays chemical shifts at 14.04 and 19.10 ppm for the carbons of methyl group presents in the steroid nucleus of compound 6.Another chemical shifts at 25.30-28.95and 46.28-48.60ppm for carbons of methylenes involved in arm bound to the steroid nucleus were exhibited.In addition, two signals at 75.14 and 90.03 ppm for carbons corresponding to alkyne group were exhibited.Another chemical shifts at 175.30 for free carboxyl group.The presence of compound 6 was further confirmed from mass spectrum which showed a molecular ion at m/z 480.60.
In order to characterize the structural and chemical requirements of the compounds 3 and 6, the descriptors 12 such as logP and π were calculated.LogP describes the logarithmic octanol-water partition coefficient; therefore, it represents the lipophilic effects of a molecule that includes the sum of the lipophilic contributions of the parent molecule and its substituents 13 .The difference between the substituted and unsubstituted logP values is conditioned by the π value for a particular substituent 14 .In this work, the logP and π parameters were calculated by the method reported by Leo 15 .The results (Table 1 and 2, see) showed an increase in logP and a decrease in the π values of compound 6 with respect to 3.These results showed that aliphatic carbons (-CH 2 -) in compound 6 contribute to the high lipophilicity in comparison with 3.  On the other hand, other steric constants such as the molar volume (V m ) and molar refractivity (R m ) were calculated (Table 3).These options are a useful tool for the correlation of different properties that depend on characteristics of substituents attached to a constant reaction center.The results showed an increase in both R m and V m values for 3 in comparison with 6.These data indicate a high steric impediment and different conformational preferences and internal rotation of 3 in comparison with 6.These data are supported by studies of Bryantsev and coworkers 16 , who showed that conformational differences between several chemical functional groups have important consequences.

Conclusion
The results indicate a high degree of lipophilicity and a low steric impediment of compound 6 in comparison with 3.

Table 3 .
Physicochemical parameters R m and V m of compounds 3 and 6