Claims for Patent: 5,744,475

Summary for Patent: 5,744,475

Title:	Uracil derivatives, and antitumor effect potentiator and antitumor agent containing the same
Abstract:	PCT No. PCT/JP96/00828 Sec. 371 Date Nov. 21, 1996 Sec. 102(e) Date Nov. 21, 1996 PCT Filed Mar. 28, 1996 PCT Pub. No. WO96/30346 PCT Pub. Date Oct. 3, 1996The invention relates to novel uracil derivatives having excellent inhibiting effects of human derived thymidine phosphorylase and anti-tumor activity. The pharmaceutical compositions, anti-tumor potentiators, antitumor agents containing such novel compounds, and a process for their preparation and use is described. The novel compounds satisfy the general formula (1): (1)
Inventor(s):	Shingo Yano, Yukio Tada, Hideki Kazuno, Tsutomu Sato, Junichi Yamashita, Norihiko Suzuki, Tomohiro Emura, Masakazu Fukushima, Tetsuji Asao
Assignee:	Taiho Pharmaceutical Co Ltd
Application Number:	US08/737,677
Patent Claims:	1. A uracil derivative represented by the following formula (1): ##STR170## wherein R1 represents a chlorine, bromide or iodine atom or a cyano or lower alkyl group; and R2 is selected from the group consisting of a 4-5 membered heterocyclic group having 1-3 nitrogen atoms, piperidine and piperazine, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; or a salt thereof. 2. The uracil derivative or salt thereof according to claim 1, wherein in formula (1), the 4-5 membered heterocyclic group represented by R2 is selected from the group consisting of 1-3 nitrogen atoms, piperidine and piperazine, or R2 is a 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 1-pyrrolyl, 1-pyrazolidinyl, 2-pyrazolin-1-yl, 3-pyrazolin-1-yl, 4-pyrazolin-1-yl, 1-pyrazolyl, 1-imidazolidinyl, 2-imidazolin-1-yl, 3-imidazolin-1-yl, 4-imidazolin-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, piperidino, or 1-piperazyl group. 3. The uracil derivative or salt thereof according to claim 1, wherein in formula (1), R2 may be substituted by one or more lower alkyl, imino, hydroxy, hydroxymethyl, methanesulfonyloxy, amino or nitro groups, and is a 1-azetidinyl, 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-iminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, 3-methanesulfonyloxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 1-pyrrolyl, 2-pyrazolin-1-yl, 1-pyrazolyl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino- 3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, 1-imidazolyl, 2-methylimidazol-1-yl, 2-nitroimidazol-1-yl, 4-nitroimidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 3-nitro-1,2,4-triazol-1-yl, piperidino or 4-methylpiperazin-1-yl group. 4. The uracil derivative or salt thereof according to claim 1, wherein in the formula (1'), the group represented by R2 is a 1-azetidinyl, 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, or 1-imidazolyl group. 5. The uracil derivative or salt thereof according to claim 1, wherein in the formula (1'), the group represented by R1 is a chlorine or bromine atom or a cyano group, and the group represented by R2 is a 1-pyrrolidinyl, 1-azetidinyl, 2-iminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl, or 1-imidazolyl group. 6. The uracil derivative or salt thereof according to claim 1, which is selected from 5-chloro-6-(1-pyrrolidinylmethyl)uracil, 5-bromo-6-(1-pyrrolidinyl-methyl)uracil, 5-chloro-6-(1-azetidinylmethyl)uracil, 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride, 5-bromo-6-(1-(2-iminopyrrolidinyl)methyl)-uracil hydrochloride, 5-cyano-6-(1-(2-iminopyrrolidinyl)methyl)uracil, 5-chloro-6-(1-(2-iminoimidazolidinyl)methyl)uracil, 5-bromo-6-(1-(2-iminoimidazolidinyl)methyl)uracil, or 5-chloro-6-(1-imidazolylmethyl)-uracil hydrochloride. 7. A pharmaceutical composition comprising:a uracil derivative represented by the following formula (1): ##STR171## wherein R1 represents a chlorine, bromide or iodine atom or a cyano or lower alkyl group; and R2 is selected from the group consisting of a 4-5 membered heterocyclic group having 1-3 nitrogen atoms, piperidine and piperazine, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; or a salt thereof; and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition according to claim 7, wherein in formula (1), R2 is a 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 1-pyrrolyl, 1-pyrazolidinyl, 2-pyrazolin-1-yl, 3-pyrazolin-1-yl, 4-pyrazolin-1-yl, 1-pyrazolyl, 1-imidazolidinyl, 2-imidazolin-1-yl, 3-imidazolin-1-yl, 4-imidazolin-1-yl, 1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, piperidino or 1-piperazyl group. 9. The pharmaceutical composition according to claim 7, wherein in formula (1), R2 is a 1-azetidinyl, 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-iminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, 3-methanesulfonyloxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 1-pyrrolyl, 2-pyrazolin-1-yl, 1-pyrazolyl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, 1-imidazolyl, 2-methylimidazol-1-yl, 2-nitroimidazol-1-yl, 4-nitroimidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 3-nitro-1,2,4-triazol-1-yl, piperidino or 4-methylpiperazin-1-yl group. 10. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R2 is a 1-azetidinyl, 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino-3-ethyl-imidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, or 1-imidazolyl group. 11. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R1 is a chlorine or bromine atom or a cyano group, and the group represented by R2 is a 1-pyrrolidinyl, 1-azetidinyl, 2-iminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl, or 1-imidazolyl group. 12. The pharmaceutical composition according to claim 7, wherein the compound represented by the formula (1) is selected from 5-chloro-6-(1-pyrrolidinyl-methyl)uracil, 5-bromo-6-(1-pyrrolidinylmethyl)uracil, 5-chloro-6-(1-azetidinylmethyl)uracil, 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride, 5-bromo-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride, 5-cyano-6-(1-(2-iminopyrrolidinyl)-methyl)uracil, 5-chloro-6-(1-(2-iminoimidazolidinyl)-methyl)uracil, 5-bromo-6-(1-(2-iminoimidazolidinyl)-methyl)uracil, or 5-chloro-6-(1-imidazolylmethyl)uracil hydrochloride. 13. A method for inducing the effect of an antitumor agent containing a 2'-deoxypyrimidine nucleoside, which comprises administering to a patient an effective amount of a uracil derivative represented by the following formula (1): ##STR172## wherein R1 represents a chlorine, bromide or iodine atom or a cyano or lower alkyl group; and R2 is selected from the group consisting of a 4-5 membered heterocyclic group having 1-3 nitrogen atoms, piperidine and piperazine, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; or a salt thereof. 14. A therapeutic method for treating cancer, which comprises administering to a patient an effective amount of a uracil derivative represented by the following formula (1): ##STR173## wherein R1 represents a chlorine, bromide or iodine atom or a cyano or lower alkyl group; and R2 is selected from the group consisting of a 4-5 membered heterocyclic group having 1-3 nitrogen atoms, piperidine and piperazine, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; or a salt thereof; and a 2'-deoxypyrimidine nucleoside.