Uracil derivatives, and antitumor effect potentiator and antitumor agent containing the same

• US 5,744,475 A
• Filed: 11/21/1996
• Issued: 04/28/1998
• Est. Priority Date: 03/29/1995
• Status: Expired due to Term

• Current Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: Sato, Tsutomu, Asao, Tetsuji, Yamashita, Junichi, Suzuki, Norihiko, Fukushima, Masakazu, Yano, Shingo, Tada, Yukio, Emura, Tomohiro, Kazuno, Hideki
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US08/737,677
• Time in Patent Office: 523 Days
• Field of Search: 544/255, 544/309, 514/274, 514/359
• US Class Current: 514/274
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 239/553 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

The 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): ##STR1##

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.