Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. II. Optimization of the Phenylpiperazine Moiety of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.

Abstract

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...

Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole Derivatives. III. Synthesis and Antitumor Activity of 3-Phenylpiperazinyl-1-trans-propenes

“…These compounds also did not cause a decrease of body temperature as the side effect at the level of each MTD. Furthermore, muscle relaxation and crouching posture were not observed for these compounds at the MTD in mice, although the lead compound (2) in this scaffold caused these visible symptoms. The tumor growth inhibition curves of 29b and 5-FU are shown in Fig.…”

“…12) Compound (12) was treated with sulfuric acid and then oxidized with manganese (IV) oxide to afford 5-demethylpyrazole (15a). Migration of the pyrimidinyl group of 13 1,2) to the 2-position from the 1-position on the pyrazole ring was carried out by using diethyl carbonate and sodium hydride to produce 3-methylpyrazole (15b). Dimethylpyrazole (15c) was prepared following the reported procedure.…”

“…Water solubility of both monohalogenated and dihalogenated compounds (2-4) were low at pHϭ6.8, whereas the appropriate amount could be dissolved at pHϭ1.1 because of the existence of piperazine. Especially, the dihalogenated compounds (3, 4) showed poor water solubility compared with the monohalogenated compound (2). The logarithm of the distribution coefficient (LogD) of compound (29b) in n-octanol/water system was 2.9 while those of the mono and dihalogenated compounds (2-4) were more than 3.5 at pHϭ6.8.…”

The Chemistry of Acetylpyrazoles and Its Utility in Heterocyclic Synthesis

“…4‐Acetyl‐5‐methyl‐1‐(pyrimidin‐2‐yl)‐1 H ‐pyrazole derivatives 137a,b were prepared by reaction of N ‐(2‐pyrimidinyl) hydrazine 136 with 3‐ethoxymethylene 2,4‐pentanedione 135 in acetic anhydride under reflux (Scheme ) .…”

Synthesis and Screening of Benzofuran Fused C-2,4,6-Substituted Pyrimidine Derivatives as a New Antibacterial and Antifungal Agent

“…Synthesis of six-membered heterocyclic compounds such as pyrimidine ring is very important because of the synthetic condition and pharmacological properties [6][7][8][9][10]. It is noteworthy that fused heterocyclic structures containing pyrimidine ring exhibited diverse biological activities such as antimicrobial [11,12], DNA cleavage [13], anti-inflammatory [14], antiviral [15], anti-HIV [16] and antitumor [17]. Benzofuran nucleus directly linked at C-2 to various substituted heterocyclic ring systems exhibited promising biological activity [18].…”