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

• US 6,159,969 A
• Filed: 01/12/1998
• Issued: 12/12/2000
• 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:
  US09/006,009
• Time in Patent Office: 1,065 Days
• Field of Search: 514/235.8, 544/123, 544/310, 544/311, 544/313, 540/598
• US Class Current: 514/235.8
• 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'"'"'):

##STR171## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and

R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyan group;

a (lower alkyl) amidino group;

a group --CH₂ N(R^a)R^b in which R^a and R^b may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^a and R^b may form a pyrrolidine ring together with the nitrogen atom to which R^a and R^b are bonded;

a group --NH--(CH₂)_m --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3;

a group NR^c (CH₂)_n --OH in which R^c represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4;

a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups;

or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group, with the proviso that R¹ and R² are not a bromine atom and an amino group, respectively, at the same time;

or a salt thereof.

2. The uracil derivative or salt thereof according to claim 1, wherein in the formula (1'"'"'), the group represented by R² is an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group;

or a (lower alkyl)amidino group.

3. The uracil derivative or salt thereof according to claim 1, wherein in the formula 1'"'"', the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethylamidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3-dimethylguanidino and an acetoamidino group.

4. The uracil derivative or salt thereof according to claim 2, wherein in the formula 1'"'"', the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethylamidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3-dimethylguanidino and an acetoamidino group.

5. The uracil derivative or salt thereof according to claim 1, wherein in the formula 1'"'"', the group represented by R¹ is selected from the group consisting of chlorine, bromine, and cyano, and the group represented by R² is an amidinothio or 1-guanidino group.

6. The uracil derivative or salt thereof according to claim 1, which is selected from the group consisting of 2-(5-chlorouracil-6-ylmethyl)-isothiourea hydrochloride, 2-(5-cyanouracil-6-ylmethyl)isothiourea hydrochloride and 5-chloro-6-(1-guanidino)methyluracil hydrochloride.

7. A pharmaceutical composition comprising:

a uracil derivative represented by the following formula (1);

##STR172## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and

R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group;

a (lower alkyl)amidino group;

a group --CH₂ N(R^a)R^b in which R^a and R^b may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^a and R^b may form a pyrrolidine ring together with the nitrogen atom to which R^a and R^b are bonded;

a group --NH--(CH₂)_m --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3;

a group NR^c (CH₂)_n --OH in which R^c represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4;

a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups;

or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

or a salt thereof; and

a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R² is an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each by substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each by substituted by a lower alkyl or cyano group;

or a (lower alkyl)amidino group.

9. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethyl-amidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3,-dimethylguanidino and an acetoamidino group.

10. The pharmaceutical composition according to claim 8, wherein in the formula (1), the group represented by R² is selected from the group consisting of an amidinothio, N¹ -methylamidinothio, N¹,N² -dimethyl-amidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2,3,-dimethylguanidino and an acetoamidino group.

11. The pharmaceutical composition according to claim 7, wherein in the formula (1), the group represented by R¹ is selected from the group consisting of chlorine, bromine, and cyano, and the group represented by R² is an amidinothio or 1-guanidino group.

12. The pharmaceutical composition according to claim 7, wherein the compound represented by the formula (1) is selected from the group consisting of 2-(5-chlorouracil-6-ylmethyl)isothiourea hydrochloride, 2-(5-cyanouracil-6-ylmethyl)isothiourea hydrochloride and 5-chloro-6-(1-guanidino)methyluracil hydrochloride.

13. A method for potentiating an antitumor 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):

##STR173## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group; and

R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group;

a (lower alkyl)amidino group;

a group --CH₂ N(R^a)R^b in which R^a and R^b may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^a and R^b may form a pyrrolidine ring together with the nitrogen atom to which R^a and R^b are bonded;

a group --NH--(CH₂)_m --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group, or a cyano group, and m stands for an integer of from 0 to 3;

a group NR^c (CH₂)_n --OH in which R^c represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4;

a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups;

or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

or a salt thereof.

14. A therapeutic method for treating cancer, which comprises administering to a patient in need of treatment an effective amount of a uracil derivative represented by the following formula ##STR174## wherein R¹ is selected from the group consisting of chlorine, bromine, iodine, cyano and a lower alkyl group;

and R² represents an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group;

a (lower alkyl)amidino group;

a group --CH₂ N(R^a)R^b in which R^a and R^b may be the same or different and each represents a hydrogen atom or a lower alkyl group or R^a and R^b may form a pyrrolidine ring together with the nitrogen atom to which R^a and R^b are bonded;

a group --NH--(CH₂)_m --Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group or a cyano group, and m stands for an integer of from 0 to 3;

a group NR^c (CH₂)_n --OH in which R^c represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4;

a group --X--Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups;

or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group;

or a salt thereof; and

a 2'"'"'-deoxypyrimidine nucleoside.