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Last Updated: March 28, 2024

Claims for Patent: 6,444,671


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Summary for Patent: 6,444,671
Title: Cyclic AMP-specific phosphodiesterase inhibitors
Abstract:Novel compounds that are potent and selective inhibitors of PDE4, as well as methods of making the same, are disclosed. Use of the compounds in the treatment of inflammatory diseases and other diseases involving elevated levels of cytokines, as well as central nervous system (CNS) disorders, also is disclosed.
Inventor(s): Gaudino; John J. (Boulder, CO)
Assignee: ICOS Corporation (Bothell, WA)
Application Number:10/002,867
Patent Claims:1. A compound having the formula ##STR16## wherein R.sup.1 is hydrogen, lower alkyl, bridged alkyl, aryl, heteroaryl, cycloalkyl, a 5- or 6-membered saturated heterocyclic, C.sub.1-3 alkylenecycloalkyl, aryl- or heteroaryl-substituted propargyl, aryl- or heteroaryl-substituted allyl, or halocycloalkyl; R.sup.2 is hydrogen, lower alkyl, bridged alkyl, cycloalkyl, haloalkyl, halocycloalkyl, C.sub.1-3 alkylenecycloalkyl, a 5- or 6-membered saturated heterocycle, aryl, heteroaryl, aralkyl, alkaryl, heteroaralkyl, or heteroalkaryl; R.sup.3 is morpholinyl or piperizinyl; R.sup.4 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, or aryl; R.sup.5 is lower alkyl, alkynyl, haloalkyl, cycloalkyl, or aryl; R.sup.6 is hydrogen, lower alkyl, or C(.dbd.O)R.sup.7 ; R.sup.7 is lower alkyl, branched or unbranched, or aryl, either optionally substituted with one or more of RO.sup.8, NR.sup.8 R.sup.9, or SR.sup.8 ; and R.sup.8 and R.sup.9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, heteroalkaryl, and aralkyl, or R.sup.8 and R.sup.9 together form a 4-membered to 7-membered ring; R.sup.10 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, C(.dbd.O)alkyl, C(.dbd.O)cycloalkyl, C(.dbd.O)aryl, C(.dbd.O)Oalkyl, C(.dbd.O)Ocycloalkyl, C(.dbd.O)aryl, CH.sub.2 OH, CH.sub.2 Oalkyl, CHO, CN, NO.sub.2, or SO.sub.2 R.sup.11 ; and R.sup.11 is alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, or NR.sup.8 R.sup.9.

2. The compound of claim 1 having the structure: ##STR17##

3. The compound of claim 1 wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, C.sub.1-3 alkylenecycloalkyl, halocycloalkyl, aryl, and heteroaryl.

4. The compound of claim 1 wherein R.sup.2 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl.

5. The compound of claim 1 wherein R.sup.5 is hydrogen or methyl.

6. The compound of claim 1 wherein R.sup.6 is selected from the group consisting of hydrogen, acetyl, and benzoyl.

7. The compound of claim 1 wherein R.sup.7 is methyl.

8. The compound of claim 1 wherein R.sup.1 is selected from the group consisting of cyclopentyl, tetrahydrofuryl, indanyl, norbornyl, phenthyl, and phenylbuty; R.sup.2 is selected from the group consisting of hydrogen, ethyl, methyl, and difluoromethyl; R.sup.4 is hydrogen; R.sup.5 is hydrogen or methyl; R.sup.6 is hydrogen; R.sup.7 is methyl; and R.sup.10 is hydrogen.

9. The compound of claim 1 having an IC.sub.50 vs. human recombinant PDE4 of about 0.001 .mu.M to about 0.3 .mu.M.

10. The compound of claim 1 having an IC.sub.50 vs. human recombinant PDE4 of about 100.times.10.sup.-9 M or less.

11. The compound of claim 1 having an IC.sub.50 vs. human recombinant PDE4 of about 50.times.10.sup.-9 M or less.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

13. The composition of claim 12 further comprising an antiinflammatory therapeutic agent selected from the group consisting of etanercept and infliximab.

14. A method of treating a mammal having a condition where inhibition of a cAMP-specific PDE is of therapeutic benefit, said method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

15. A method of increasing cAMP levels in a mammal comprising administering to said mammal an effective amount of a compound of claim 1.

16. A method of treating a mammal having a condition where inhibition of a cAMP-specific PDE is of a therapeutic benefit comprising administering to said mammal an effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

17. The method of claim 16 wherein the condition is dermititis.

18. The method of claim 16 wherein the condition is rheumatoid arthritis, osteoarthritis, gouty arthritis, or spondylitis.

19. The method of claim 16 wherein the condition is thyroid-associated ophthalmopathy, Behcet disease, sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shock syndrome, allergic conjunctivitis, vernal conjunctivitis, or eosinophilic granuloma.

20. The method of claim 16 wherein the condition is asthma, chronic bronchitis, allergic rhinitis, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, or pulmonary sarcoidosis.

21. The method of claim 16 wherein the condition is reperfusion injury of the myocardium, brain or extremities as a brain or spinal cord injury due to trauma.

22. The method of claim 16 wherein the condition is a fibrosis, keloid formation, or scar tissue formation.

23. The method of claim 16 wherein the condition is systemic lupus erythematosus, a transplant rejection disorder, a graft vs. host reaction, or an allograft rejection.

24. The method of claim 16 wherein the condition is chronic glomerulonephritis, an inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

25. The method of claim 16 wherein the condition is proliferative lymphocytic disease or a leukemia.

26. The method of claim 16 wherein the condition is an inflammatory dermatosis, atopic dermatitis, psoriasis, or urticaria.

27. The method of claim 16 wherein the condition is a cardiomyopathy, congestive heart failure, atherosclerosis, pyrexia, cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome, ARC, cerebral malaria, osteoporosis, a bone resorption disease, fever and myalgias due to infection, diabetes insipidus, a central nervous system disorder, depression, multi-infarct dementia, an anxiety or stress response, cerebral ischemia, tardive dyskinesia, Parkinson's disease, and premenstrual syndrome.

28. The method of claim 16 wherein the mammal exhibits an emetic response less severe than an emetic response exhibited by the mammal after administration of a therapeutically equivalent amount of rolipram.

29. The method of claim 16 wherein the mammal is free of an emetic response.

30. The method of claim 16 wherein the mammal exhibits adverse central nervous system side effects less severe than adverse central nervous system side effects exhibited by the mammal after administration of a therapeutically equivalent amount of rolipram, said adverse central nervous system side effects selected from the group consisting of retching, vomiting, and sedation.

31. The method of claim 16 wherein the mammal is free of adverse central nervous system side effects selected from the group consisting of retching, vomiting, and sedation.

32. A method of reducing TNF.alpha. levels in a mammal comprising administering to said mammal therapeutically effective amount of a compound of claim 1.

33. A method of suppressing inflammatory cell activation in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

34. A method of inhibiting PDE4 function in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

Details for Patent 6,444,671

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Janssen Biotech, Inc. REMICADE infliximab For Injection 103772 08/24/1998 ⤷  Try a Trial 2019-12-23
Immunex Corporation ENBREL etanercept For Injection 103795 11/02/1998 ⤷  Try a Trial 2019-12-23
Immunex Corporation ENBREL etanercept For Injection 103795 05/27/1999 ⤷  Try a Trial 2019-12-23
Immunex Corporation ENBREL etanercept Injection 103795 09/27/2004 ⤷  Try a Trial 2019-12-23
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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