In the previous paper, 1) we reported the synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. These derivatives were found as new antiproliferative agents through random screening using our laboratory's chemical library. One of them, 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2), showed significant antitumor activity against several tumor models by both intraperitoneal injection and oral administration. Furthermore, 2 was free from the cross-resistance to some currently used antitumor agents such as vincristine (VCR) and adriamycin (ADM). These pyrazole derivatives, however, tended to cause undesirable effects, e.g., muscle relaxation and decrease of body temperature without body weight loss, because these compounds had previously been prepared as tranquilizers or antihypertensive agents. To overcome these problems, we have been seeking derivatives of 1 that might furthermore increase the antitumor activity while decreasing the side effects. As a first step in the structural modification of this scaffold, we focused on the phenylpiperazine moiety, namely, the introduction of some substituents on the phenyl ring and replacement of the phenylpiperazinyl group with some piperidinyl groups. We describe here the synthesis and structure-activity relationships (SARs) with regard to in vitro cytotoxic activity and in vivo antitumor activity of these pyrazole derivatives.
ChemistryThe synthesis of the derivatives bearing a substituted phenylpiperazine moiety was carried out via the route shown in Chart 1. The new substituted piperazines 4a-d were prepared from aniline derivatives 3a-d and bis(2-chloroethyl)amine hydrochloride. Mannich reaction of 4-acetyl-5-methyl-1-pyrimidinylpyrazole (5) 1) with modified piperazines 4a-d or 4e-i 2) gave 6a-i, respectively. 1-Propanone derivatives 6j-l were prepared according to the reported procedure.3) Compounds 6a-l were reduced with sodium borohydride to give the corresponding alcohols, which were dehydrated by p-toluenesulfonic acid (p-TsOH) to afford 1-trans-propene derivatives 7a-l. Catalytic hydrogenation of 6i over Pd/C with acetic anhydride gave the 3-acetylaminophenyl derivative 8. Compound 9 was obtained from 8 by the same procedure as described for 7a-l from 6a-l. Carbamoylphenyl derivative 10 was prepared from 7c by hydrolysis of the cyano group with hydrochloride.We also developed a new, efficient synthetic method to construct this scaffold by employing reductive amination instead of Mannich reaction, because Mannich reaction of hydroxyphenylpiperazine 15 with 5 did not progress (Chart 2). Bromination of 5 with Br 2 and treatment with cesium acetate (CsOAc) gave 11. Compound 11 was hydrolyzed with aqueous NaOH to give the a-hydroxyketone, followed by reduction with sodium borohydride, and then oxidative cleavage of the 1,2-diol with sodium periodate to give the aldehyde 12. According to the Mukaiyama protocol, 4) the carbon-carbon bond formation of 12 with allyl bromide was performed using meta...