Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: VII. Synthesis and Properties 1-[(Adamantan-1-yl)methyl]-3-(fluoro, chlorophenyl) Ureas

A series of 1,3-disubstituted ureas containing a lipophilic adamantane moiety tethered to the ureido group by a methylene bridge were synthesized by the reaction of 1-(isocyanatomethyl)adamantane with monohalo- and dihaloanilines in yields of up to 92%. The synthesized ureas are target oriented inhibitors of human soluble epoxide hydrolase (sEH).

Proceeding with the research on the synthesis of soluble epoxide hydrolase (sEH, E.C. 3.3.2.10), an enzyme of the arachidonic cascade enzyme [4][5][6][7], involved in the metabolic transformation of epoxy fatty acids to vicinal diols, we performed targeted modifi cation of the lipophilic part of inhibitor molecules. It was found that the separation of the adamantyl from ureido/ thioureido group with a methylene bridge enhances the inhibitory activity against sEH by a factor of 2-4, and also has a positive effect on water solubility [8][9][10].
The choice of the structure of the starting compounds is explained by that they contain both an aromatic fragment, which can enter hydrophobic interactions with the target, and fl uorine and chlorine atoms, which are H-bond acceptors. The presence of such groups can ensure additional bonding in the enzyme active site and thus enhance inhibitory activity and affect the water solubility and melting point of the synthesized compounds.

RESULTS AND DISCUSSION
The well-known Curtius synthesis of 1-(isocyanatomethyl)adamantane (3) from (adamantan-1-yl)acetic acid involves the intermediate synthesis of (adamantan-1-yl)acetyl chloride, followed by the reaction of the latter with sodium azide [11]. A signifi cant disadvantage of this method is that it makes use of a toxic thionyl chloroide and an explosive sodium azide. Therefore, in this work, isocyanate 3 was synthesized by a one-step procedure using diphenylphosphoryl azide (DPPA) as a source of the acylazido group (Scheme 1).
The synthesis was performed in dry DMF for 12 h at room temperature. The yields were 10-92%.
The structure of the synthesized compounds was conformed by NMR spectroscopy and mass spectrometry. The 1 H NMR spectra contain two characteristic urea NH proton signals. The signal at 5.68-6.81 ppm corresponds to the proton of the NH group proximate to the adamantyl fragment, whereas the signal at 7.75-8.64 ppm, to the proton of the NH group linked to the aromatic ring.
Analysis of the 19 F NMR signals showed the dependence of the shifts of the signals of the F atom on their position in the aromatic ring. Thus, the signals of the F atoms in the R 1 positions of the aromatic rings appear at -119.08 to -133.10 ppm (5c, 5d, 5f, 5k, 5m, and 5n); the signals of F atoms in the R 2 and R 4 are at -110.01 to -137.77 ppm (5a, 5e-5g, and 5l); and the signals of the F atoms in the R 3 and R 5 positions, at -120.52 to 148.57 ppm (5b, 5c, 5e, 5i, and 5j) and -116.70 to -119.08 ppm (5d), respectively. In the 19 F NMR spectrum of compound 5o, the trifl uoromethyl fl uorine atoms give one signal at -61.33 ppm. The chemical shifts of the fl uorine atoms are also dependent on whether there are other F and Cl substituents in the aromatic ring.
The yields of ureas were directly related to the substrate structure. The highest yields (92%) were characteristic of the ureas containing one F atom in the aromatic ring. With the substrates containing two F atoms, the yields decreased to 10-82%. The lowest yield was obtained with urea 5d (10%), in while the F atoms are ortho to each other. The properties of the synthesized 1,3-disubstituted ureas 5a-5o are listed in the Table 1.
The calculated lipophilicity coeffi cients log P of the synthesized compounds span the range 4.52-5.25, which is higher, on average, by 0.09 compared to those of the related compounds derived from unsubstituted 1-(isocyanato)adamantane [1] and lower by 0.17 compared to those of the related compounds derived from 1-(isocyanatoethyl)adamantane [12]. The log P values of ureas 5a-5g, which contain no other substituents in the aromatic ring but fl uorines, vary between 4.52 and 4.64, and, therefore, comply with the Lipinskiʼs rule [13]. The replacement of the fl uorine substituent in the aromatic ring by chlorine increases the lipophilicity coeffi cient to 5.04-5.25. This change Scheme 1.
is likely to be associated with the lower electrophilicity of Cl composed to F. The C-F bond conjugated with a double bond acquires a double-bond character, as a resul of which the radius of the covalent bond becomes even smaller, and, as a result, spatially the fl uorine atom becomes almost indistinguishable from the hydrogen atom [14].
The melting points of the synthesized ureas, which contain a methylene bridge between the adamantane and urea fragments are lower by 49-122°C compared to those of the related compounds derived from unsubstituted 1-(isocyanato)adamantane. Lower melting points are a positive property of inhibitors, because this facilitates the manufacturing of dosage forms.    The structure of the synthesized compounds was confi rmed by 1 H, 13 C, and 19 F NMR spectroscopy, gas chromatography-mass spectrometry, and elemental analysis. The mass spectra were run on an Agilent GC 7820/MSD 5975 system and an Advion Expression compact mass spectrometer in the full scan mode (ESI). The 1 H, 13 C, and 19 F NMR spectra were measured on a Bruker Avance 600 spectrometer in DMSO-d 6 ; internal reference SiMe 4 . The elemental analyses were obtained on a Perkin-Elmer Series II 2400 CHNS/O analyzer.
(Adamantan-1-yl)acetic acid (2). A three-necked reactor placed in an ice bath and equipped with a thermometer, a dropping funnel, and an overhead stirrer was charged, with stirring, with 540 mL of 98% H 2 SO 4 and 12.5 mL of 65% HNO 3 . The mixture was cooled to 0-2°C, after which 100 g (0.475 mol) of 1-bromoadamantane was added and then 271 mL (3.487 mol) of vinylidene chloride was added dropwise over the course of 1.5 h, maintaining the temperature at 0-2°C. The mixture was stirred at the same temperature for another 1 h and poured onto ice. After the ice had melted, the product was fi ltered off, washed with distilled water, and purifi ed by reprecipitation. Yield