SUBSTITUTED DIARYLUREAS AS STIMULATORS FOR FAS-MEDIATED APOPTOSIS

• US 20020188027A1
• Filed: 02/22/2002
• Published: 12/12/2002
• Est. Priority Date: 03/07/2001
• Status: Active Grant

• Current Assignee: Telik, Inc. (MabVax Therapeutics Holdings, Inc.)
• Original Assignee: Telik, Inc. (MabVax Therapeutics Holdings, Inc.)
• Inventors: Robinson, Louise, Villar, Hugo O.
• Granted Patent: US 6,525,091 B2
• Time in Patent Office: Days
• US Class Current: 514/597
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 317/42 Y being a hetero atom
• CPC Class Codes: G01N 2333/70578 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95 NGF-receptor G01N2333/71, TNF-receptor G01N2333/7151
• CPC Class Codes: G01N 2510/00 Detection of programmed cell death, i.e. apoptosis
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

Substituted diarylureas, pharmaceutical compositions containing them, and their use for stimulating Fas-mediated apoptosis. The compounds, as single stereoisomers or mixtures of stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them, are useful in methods of treating autoimmune diseases, infectious diseases, and malignancies.

Claims

1. A compound of the formula:

2. A compound of claim 1, where X¹ and X² are the same.

3. A compound of claim 1, where Y¹ and Y² are the same.

4. A compound of claim 1, where X¹ and X² are independently selected from —

F and —

Cl.

5. A compound of claim 1, where Y¹ and Y² are independently selected from —

CN, —

NO₂, and —

COR¹.

6. The compound of claim 1 which is 1,3-bis(4-chloro-3-nitrophenyl)urea.

7. A pharmaceutical composition comprising:

a compound of claim 1, and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising:

a compound of claim 2, and

a pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising:

a compound of claim 3, and

a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising:

a compound of claim 4, and

a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising:

a compound of claim 5, and

a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising:

a compound of claim 6, and

a pharmaceutically acceptable excipient.

13. A method of treating a disease in a mammal treatable by administration of a stimulator of Fas-mediated apoptosis, comprising:

administering to the mammal a therapeutically effective amount of a compound of claim 1.

14. The method of claim 13, where the disease is selected from the group consisting of autoimmune diseases, infectious diseases, and malignancies.

15. The method of claim 14, further comprising treating said mammal with a conventional form of therapy for the disease.

16. The method of claim 15, where the conventional form of therapy comprises administering a drug selected from the group consisting of immunosuppressants, antiinflammatory agents, antiviral agents, antibacterial agents, antifungal agents, and anticancer chemotherapeutic agents.

17. A method of stimulating Fas-mediated apoptosis in a cell with a Fas receptor, comprising contacting the cell with a compound of claim 1 in an amount sufficient to stimulate the Fas receptor.

18. A process for identifying a compound that has at least one function selected from the group of stimulating the Fas receptor and stimulating Fas-mediated apoptosis, the process comprising administering to an assay of Fas binding or of Fas-mediated apoptosis a compound of claim 1 and noting a first result, administering a test compound to the assay and noting a second result, and comparing the first and second results, whereby a test compound producing results similar to or better than the first result is identified as a compound having the desired function.

19. A process for identifying a target compound that mimics the function of a compound of claim 1 in an assay, the process comprising administering a compound of claim 1 to the assay and noting a first result, administering a test compound to the assay and noting a second result, and comparing the first and second results, whereby a test compound producing results similar to or better than the first result is identified as a target compound that mimics the function of a compound of claim 1.

20. A process for validating, optimizing, or standardizing a bioassay, the process comprising submitting a compound of claim 1 to the bioassay;

and validating, optimizing, or standardizing the bioassay by the activity of the compound in the bioassay.