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Last Updated: March 29, 2024

Details for Patent: 6,440,990


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Title: O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
Abstract:Novel derivatives of rapamycin, particularly 9-deoxo-rapamycins, 26-dihydro-rapamycins, and 40-O-substituted and 28,40-O,O-disubstituted rapamycins. are found to have pharmaceutical utility, particularly as immunosuppressants.
Inventor(s): Cottens; Sylvain (Witterswil, CH), Sedrani; Richard (Basel, CH)
Assignee: Novartis AG (Basel, CH)
Filing Date:May 23, 1997
Application Number:08/862,911
Claims:1. A method for treating or preventing graft versus host disease or for treating an autoimmune disease selected from the group consisting of arthritis, rheumatic diseases, autoimmune hematological disorders, systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes, anterior uveitis, posterior uveitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome), and juvenile dermatomyostis comprising administering to a person in need thereof an effective amount of a compound of the formula ##STR3##

wherein R.sup.1 is hydroxy(C.sub.1-6)alkyl or hydroxy(C.sub.1-3)alkoxy(C.sub.1-3)alkyl.

2. A method of claim 1 wherein R.sup.1 is hydroxy(C.sub.1-3)alkyl or hydroxy(C.sub.1-3)alkoxy(C.sub.1-3)alkyl.

3. A method of claim 1 wherein R.sup.1 is hydroxy(C.sub.1-3)alkyl.

4. A method of claim 1 wherein R.sup.1 is hydroxy(C.sub.1-3)alkoxy(C.sub.1-3)alkyl.

5. A method of claim 1 wherein the compound is 40-O-(3-hydroxypropyl)-rapamycin.

6. A method of claim 1 wherein the compound is 40-O-[2-(2-hydroxyethoxy)ethyl]-rapamycin.

7. A method of claim 1 wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, arthritis chronica progrediente, arthritis deformans, hemolytic anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, ulcerative colitis, Crohn's disease, idiopathic nephrotic syndrome, and minimal change nephropathy.

8. A method for treating or preventing graft versus host disease or for treating an autoimmune disease selected from the group consisting of arthritis, rheumatic diseases, autoimmune hematological disorders, systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes, anterior uveitis, posterior uveitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome), and juvenile dermatomyostis comprising administering to a person in need thereof an effective amount of 40-O-(2-hydroxyethyl)-rapamycin.

9. A method of claim 8 wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, arthritis chronica progrediente, arthritis deformans, hemolytic anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, ulcerative colitis, Crohn's disease, idiopathic nephrotic syndrome, and minimal change nephropathy.

10. A method for treating or preventing the rejection of a transplanted organ or graft versus host disease or for treating an autoimmune disease selected from the group consisting of arthritis, rheumatic diseases, autoimmune hematological disorders, systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine ophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes, anterior uveitis, posterior uveitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome), and juvenile dermatomyostis comprising administering to a host in need thereof an effective amount of a first compound of the formula ##STR4##

wherein R.sup.1 is hydroxy(C.sub.1-6)alkyl or hydroxy(C.sub.1-3)alkoxy(C.sub.1-3)alkyl

and a second compound which is Ciclosporin, FK-506, an immunosuppressive derivative of Ciclosporin or FK-506, a corticosteroid, azathioprene, an immunosuppressive monoclonal antibody, an antiviral, or an antibiotic.

11. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is Ciclosporin.

12. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is FK-506.

13. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an immunosuppressive derivative of Ciclosporin or FK-506.

14. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is a corticosteroid.

15. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is azathioprene.

16. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an immunosuppressive monoclonal antibody.

17. A method of claim 16 wherein the second compound is an antibody to CD25.

18. A method of claim 16 wherein the second compound is an antibody to CD3.

19. A method of claim 16 wherein the second compound is an antibody to CD45.

20. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an antiviral.

21. A method of claim 10 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an antibiotic.

22. A method of claim 10 wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, arthritis chronica progrediente, arthritis deformans, hemolytic anaemia, aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, ulcerative colitis, Crohn's disease, idiopathic nephrotic syndrome, and minimal change nephropathy.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula ##STR5##

wherein R.sup.1 is hydroxy(C.sub.1-3)alkyl

and a pharmaceutically acceptable carrier therefor.

24. A composition of claim 23 wherein the compound is 40-O-(3-hydroxypropyl)-rapamycin.

25. A pharmaceutical composition comprising a therapeutically effective amount of 40-O-(2-hydroxyethyl)-rapamycin and a pharmaceutically acceptable carrier therefor.

26. A pharmaceutical composition comprising a therapeutically effective amount of a first compound which is of the formula ##STR6##

wherein R.sup.1 is hydroxy(C.sub.1-6)alkyl or hydroxy(C.sub.1-3)alkoxy(C.sub.1-3)alkyl

and a second compound which is Ciclosporin, FK-506, an immunosuppressive derivative of Ciclosporin or FK-506, a corticosteroid, azathioprene, an immunosuppressive monoclonal antibody, an antiviral, or an antibiotic, and a pharmaceutically acceptable carrier therefor.

27. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is Ciclosporin.

28. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is FK-506.

29. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an immunosuppressive derivative of Ciclosporin or FK-506.

30. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is a corticosteroid.

31. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is azathioprene.

32. A composition of claim 26 wherein the first compound is 40-O-(2-hydroxyethyl)-rapamycin and the second compound is an immunosuppressive monoclonal antibody.

33. A composition of claim 32 wherein the second compound is an antibody to CD25.

34. A composition of claim 32 wherein the second compound is an antibody to CD3.

35. A composition of claim 32 wherein the second compound is an antibody to CD45.

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