Cell differentiation inducer

• US 6,174,905 B1
• Filed: 09/26/1997
• Issued: 01/16/2001
• Est. Priority Date: 09/30/1996
• Status: Expired due to Term

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Mitsui Chemicals Incorporated (Mitsui Chemicals)
• Inventors: Ando, Tomoyuki, Saito, Akiko, Yamashita, Takashi, Suzuki, Tsuneji, Shiraishi, Yoshinori, Tanaka, Eishi, Tsuchiya, Katsutoshi, Nakanishi, Osamu
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): DESAI, RITA J
• Application Number:
  US08/935,087
• Time in Patent Office: 1,208 Days
• Field of Search: 546/290, 546/314, 546/340, 546/341, 546/342, 514/346, 514/351, 514/352
• US Class Current: 514/346
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07C 233/80 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07C 271/20 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 335/16 having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 335/20 being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 215/54 : attached in position 3
• 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 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 261/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 275/03 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/40 : Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 307/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/16 : by oxygen atoms
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

The novel benzamide derivative represented by formula (1) and the novel anilide derivative represented by formula (13) of this invention has differentiation-inducing effect, and are, therefore, useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma.

Claims

1. A compound represented by formula (1):

wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group wherein the substituent(s) for the phenyl group or the heterocyclic group is (are) 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a phenyl group and a heterocyclic group;

X is a bond or a moiety having a structure selected from those illustrated in formula (2);

 

wherein e is an integer of 1 to 4;

g and m are independently an integer of 0 to 4;

R⁴ is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3)

 

wherein R⁶ is an optionally substituted alkyl group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group or a heterocyclic group;

R⁵ is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons;

n is an integer of 0 to 4, provided that when X is a bond, n is not zero;

Q is a moiety having a structure selected from those illustrated in formula (4)

 

wherein R⁷ and R⁸ are independently a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons;

R¹ and R² are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbons;

R³ is a hydroxyl or amino group or a pharmaceutically acceptable salt thereof.

2. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein n is an integer of 1 to 4.

3. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein Q is selected from the structures illustrated in formula (5):

wherein R⁷ and R⁸ are as defined above.

4. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein A is an optionally substituted hetero ring.

5. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein A is an optionally substituted pyridyl group.

6. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein X is a direct bond.

7. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R¹ and R² are a hydrogen atom.

8. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 7, wherein R³ is an amino group.

9. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is the structure represented by formula (6):

10. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 9, wherein n is 1;

and R¹ and R² are a hydrogen atom.

11. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 10, wherein R³ is an amino group.

12. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structures illustrated in formula (7):

wherein e, g and R⁴ are as defined above.

13. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 12, wherein n is 1;

and R¹ and R² are a hydrogen atom.

14. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 13, wherein R³ is an amino group.

15. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structures illustrated in formula (8):

wherein g, m and R⁵ are as defined above.

16. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 15, wherein n is 1;

and R¹ and R² are a hydrogen atom.

17. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 16, wherein R³ is an amino group.

18. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein n is zero.

19. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 18, wherein Q is selected from the structures illustrated in formula (5).

20. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 19, wherein A is an optionally substituted hetero ring.

21. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein A is an optionally substituted pyridyl group.

22. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 21, wherein R¹ and R² are a hydrogen atom.

23. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 22, wherein R³ is an amino group.

24. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (9)

25. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (10)

26. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (11)

27. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (12)

28. A composition suitable for the treatment of cancer which comprises a therapeutic effectively amount of a compound as set forth in claim 1, and a pharmaceutically acceptable carrier or excipient.

29. The composition of claim 28, wherein said carrier or excipient is selected from the group consisting of lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quarternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol.

30. The composition of claim 28, which is in the form of a dosage formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository.

31. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound according to claim 1.

32. The composition of claim 31, which is a pharmaceutically acceptable formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository.