Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors

• US 5,639,782 A
• Filed: 01/03/1994
• Issued: 06/17/1997
• Est. Priority Date: 03/04/1992
• Status: Expired due to Fees

• Current Assignee: University of Virginia
• Original Assignee: The Center For Innovative Technology
• Inventors: Goldstein, David, Gingrich, Diane M., Shen, T. Y.
• Primary Examiner(s): Kumar, Shailendra
• Assistant Examiner(s): Cebulak, Mary C.
• Application Number:
  US08/117,024
• Time in Patent Office: 1,261 Days
• Field of Search: 514/440, 549/35, 549/39
• US Class Current: 514/440
• 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: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 317/28 Radicals substituted by nitrogen atoms nitro radicals C07D317/16
• CPC Class Codes: C07D 327/04 Five-membered rings
• CPC Class Codes: C07D 339/06 having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

Neolignan derivative compounds of the 2,4-diaryl-1,3-dithiolane and futoenone variety exhibit both PAF and 5-lipoxygenase antagonist activity.

Claims

1. A compound of the formula:

##STR4## wherein R¹ is selected from the group consisting of hydrogen, haloloweralkyl, loweralkenyl, loweralkynyl, --CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ Sr², and wherein Ar and Ar¹ are the same or different from each other and are substituted phenyl of the formula;

##STR5## where R⁴ -R⁸ independently are selected from the group consisting of --NO₂, --NR² R³, --NR² COR³, --N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R² N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³ independently represent C_1-10 alkyl, alkenyl, alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selected from the group consisting of haloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganic anion and X is halogen,

wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹ substituent is attached to the substituted phenyl, and wherein a N, O or S adjacent to R² or R⁹ indicates that the N, O, or S is bonded directly to the R² or R⁹ substituent.

2. The compound of claim 1 wherein R¹ is H.

3. The compound of claim 1 wherein R⁴ -R⁸ are selected from the group consisting of --CON(OH)R², --N(OH)COR², and --NR² CON(OH)R².

4. The compound of claim 1 wherein R⁴ -R⁸ are --R⁹ N (OH) CONR² R³.

5. The compound of claim 1 wherein R⁴ -R⁸ are --R⁹ NR² CON(OH)R².

6. The compound of claim 1 wherein R⁴ -R⁸ are --R² N(OH)CONR² R³.

7. The compound of claim 1 wherein R⁴ -R⁸ are selected from the group consisting of --OR⁹, --SR⁹, --OR², --SR², and --OR⁹ OR².

8. The compound of claim 1 wherein R⁴ -R⁸ are selected from the group consisting of hydrogen, --SO₂ R⁹, --NR² R³ and --R⁹ NR² R³.

9. The compound of claim 1 wherein R² and R³ are independently selected from the group consisting of hydrogen and C_1-10 alkyl.

10. The compound of claim 1 wherein R² and R³ are independently selected from the group consisting of C_1-10 alkenyl and alkynyl.

11. The compound of claim 1 wherein R⁹ is lower alkyl.

12. The compound of claim 1 wherein R⁹ is lower alkenyl or lower alkynyl.

13. The compound of claim 1 wherein R¹⁰ is an organic anion.

14. The compound of claim 1 wherein R¹⁰ is an inorganic anion.

15. A method of inhibiting PAF induced platelet aggregation in a patient wherein said method comprises administering to the patient an effective amount of a compound of the formula:

##STR6## wherein R¹ is selected from the group consisting of hydrogen, haloloweralkyl, loweralkenyl, loweralkynyl, --CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ SR², and wherein Ar and Ar¹ are the same or different from each other and are substituted phenyl of the formula;

##STR7## where R⁴ -R⁸ independently are selected from the group consisting of --NO₂, --NR² R³, --NR² COR³, --N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R² N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³ independently represent C_1-10 alkyl, alkenyl, alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selected from the group consisting of haloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganic anion and where X is halogen,

wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹ substituent is attached to the substituted phenyl, and wherein a N, O or S adjacent to R² or R⁹ indicates that the N, O, or S is bonded directly to the R² or R⁹ substituent.

18. The method of claims 15, 16, or 17, wherein R¹ is H.

19. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are selected from the group consisting of --CON(OH)R², --N(OH)COR², and --NR² CON(OH)R².

20. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are --R⁹ N(OH)CONR² R³.

21. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are --R⁹ NR² CON(OH)R².

22. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are --R² N(OH)CONR² R³.

23. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are selected from the group consisting of --OR⁹, --SR⁹, --OR², --SR², and --OR⁹ OR².

24. The method of claims 15, 16, or 17, wherein R⁴ -R⁸ are selected from the group consisting of hydrogen, --SO₂ R⁹, --NR² R³ and --R⁹ NR² R³.

25. The method of claims 15, 16, or 17, wherein R² and R³ are independently selected from the group consisting of hydrogen and C_1-10 alkyl.

26. The method of claims 15, 16, or 17, wherein R² and R³ are independently selected from the group consisting of C_1-10 alkenyl and alkynyl.

27. The method of claims 15, 16, or 17, wherein R⁹ is lower alkyl.

28. The method of claims 15, 16, or 17, wherein R⁹ is lower alkenyl or lower alkynyl.

29. The method of claims 15, 16, or 17, wherein R¹⁰ is an organic anion.

30. The method of claims 15, 16, or 17, wherein R¹⁰ is an inorganic anion.

16. A method of inhibiting the production of leukotrienes in a patient wherein said method comprises administering to the patient an effective amount of a compound of the formula:

##STR8## wherein R¹ is selected from the group consisting of hydrogen, haloloweralkyl, loweralkenyl, loweralkynyl, --CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ SR², and wherein Ar and Ar¹ are the same or different from each other and are substituted phenyl of the formula;

##STR9## where R⁴ -R⁸ independently are selected from the group consisting of --NO₂, --NR² R³, --NR² COR³, --N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R² N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³ independently represent C_1-10 alkyl, alkenyl, alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selected from the group consisting of haloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganic where X is halogen,

wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹ substituent is attached to the substituted phenyl, and wherein a N, O or S adjacent to R² or R⁹ indicates that the N, O, or S is bonded directly to the R² or R⁹ substituent.

17. A method of inhibiting the production of both PAF induced platelet aggregation and the production of leukotrienes in a patient wherein said method comprises administering to the patient an effective amount of a compound of the formula:

##STR10## wherein R¹ is selected from the group consisting of hydrogen haloloweralkyl, loweralkenyl, loweralkynyl, --CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ SR², and wherein Ar and Ar¹ are the same or different from each other and are substituted phenyl of the formula;

##STR11## where R⁴ -R⁸ independently are selected from the group consisting of --NO₂, --NR² R³, --NR² COR³, --N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R² N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³ independently represent C_1-10 alkyl, alkenyl, alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selected from the group consisting of haloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganic anion and where X is halogen,

wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹ substituent is attached to the substituted phenyl, and wherein a N, O or S adjacent to R² or R⁹ indicates that the N, O, or S is bonded directly to the R² or R⁹ substituent.