Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-02
2001-12-11
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06329386
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel chemical compounds having immunomodulatory activity and synthetic intermediates useful for the preparation of the novel compounds, and in particular to macrolide immunomodulators. More particularly, the invention relates to semisynthetic analogs of rapamycin, means for their preparation, pharmaceutical compositions containing such compounds, and methods of treatment employing the same.
BACKGROUND OF THE INVENTION
The compound cyclosporine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. Recently, several classes of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara et al., in European Patent Application No. 184,162, published Jun. 11, 1986, disclose a number of macrocyclic compounds isolated from the genus Streptomyces, including the immunosuppressant FK-506, a 23-membered macrocyclic lactone, which was isolated from a strain of
S. tsukubaensis.
Other related natural products, such as FR-900520 and FR-900523, which differ from FK-506 in their alkyl substituent at C-21, have been isolated from
S. hygroscopicus yakushimnaensis
. Another analog, FR-900525, produced by
S. tsukubaensis
, differs from FK-506 in the replacement of a pipecolic acid moiety with a proline group. Unsatisfactory side-effects associated with cyclosporine and FK-506 such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety, including an immunosupressive agent which is effective topically, but ineffective systemically (U.S. Pat. No. 5,457,111).
Rapamycin is a macrocyclic triene antibiotic produced by
Streptomyces hygroscopicus
, which was found to have antifungal activity, particularly against
Candida albicans
, both in vitro and in vivo (C. Vezina et al.,
J. Antibiot
. 1975, 28, 721; S. N. Sehgal et al.,
J. Antibiot
. 1975,28, 727; H. A. Baker et al.,
J. Antibiot
. 1978, 31, 539; U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749).
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity. In 1977, rapamycin was also shown to be effective as an immunosuppressant in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and was shown to effectively inhibit the formation of IgE-like antibodies (R. Martel et al.,
Can. J. Physiol. Pharmacol
., 1977, 55, 48).
The immunosuppressive effects of rapamycin have also been disclosed in
FASEB
, 1989, 3, 3411 as has its ability to prolong survival time of organ grafts in histoincompatible rodents (R. Morris,
Med. Sci. Res
., 1989, 17, 877). The ability of rapamycin to inhibit T-cell activation was disclosed by M. Strauch (
FASEB
, 1989, 3, 3411). These and other biological effects of rapamycin are reviewed in
Transplantation Reviews
, 1992, 6, 39-87.
Mono-ester and di-ester derivatives of rapamycin (esterification at positions 31 and 42) have been shown to be useful as antifungal agents (U.S. Pat. No. 4,316,885) and as water soluble prodrugs of rapamycin (U.S. Pat. No. 4,650,803).
Fermentation and purification of rapamycin and 30-demethoxy rapamycin have been described in the literature (C. Vezina et al.
J. Antibiot
. (Tokyo), 1975, 28 (10), 721; S. N. Sehgal et al.,
J. Antibiot
. (Tokyo), 1975, 28(10), 727; 1983, 36(4), 351; N. L. Pavia et al.,
J. Natural Products
, 1991, 54(1), 167-177).
Numerous chemical modifications of rapamycin have been attempted. These include the preparation of mono- and di-ester derivatives of rapamycin (WO 92/05179), 27-oximes of rapamycin (EPO 467606); 42-oxo analog of rapamycin (U.S. Pat. No. 5,023,262); bicyclic rapamycins (U.S. Pat. No. 5,120,725); rapamycin dimers (U.S. Pat. No. 5,120,727); silyl ethers of rapamycin (U.S. Pat. No. 5,120,842); and arylsulfonates and sulfamates (U.S. Pat. No. 5,177,203). Rapamycin was recently synthesized in its naturally occuring enantiomeric form (K. C. Nicolaou et al.,
J. Am. Chem. Soc
., 1993, 115, 4419-4420; S. L. Schreiber,
J. Am. Chem. Soc
., 1993, 115, 7906-7907; S. J. Danishefsky,
J. Am. Chem. Soc
., 1993, 115, 9345-9346.
It has been known that rapamycin, like FK-506, binds to FKBP-12 (Siekierka, J. J.; Hung, S. H. Y.; Poe, M.; Lin, C. S.; Sigal, N. H.
Nature
, 1989,341, 755-757; Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L.
Nature
1989, 341, 758-760; Dumont, F. J.; Melino, M. R.; Staruch, M. J.; Koprak, S. L.; Fischer, P. A.; Sigal, N. H. J.
Immunol
. 1990, 144, 1418-1424; Bierer, B. E.; Schreiber, S. L.; Burakoff, S. J.
Eur. J. Immunol
. 1991, 21, 439-445; Fretz, H.; Albers, M. W.; Galat, A.; Standaert, R. F.; Lane, W. S.; Burakoff, S. J.; Bierer, B. E.; Schreiber, S. L.
J. Am. Chem. Soc
. 1991, 113, 1409-1411). Recently it has been discovered that the rapamycin/FKBP-12 complex binds to yet another protein, which is distinct from calcineurin, the protein that the FK-506/FKBP-12 complex inhibits (Brown, E. J.; Albers, M. W.; Shin, T. B.; Ichikawa, K.; Keith, C. T.; Lane, W. S.; Schreiber, S. L.
Nature
1994,369, 756-758; Sabatini, D. M.; Erdjument-Bromage, H.; Lui, M.; Tempest, P.; Snyder, S. H.
Cell
, 1994, 78, 35-43).
Although some of these modified compounds exhibit immunosuppressive activity, the need remains for macrocyclic immunosuppressants which do not have the serious side effects frequently associated with immunosuppressant therapy due, in part, to the extended half lives of the immunosupressants. Accordingly, one object of this invention is to provide novel semisynthetic macrolides which possess the desired immunomodulatory activity but which may be found to minimize unwanted side effects due to their shortened half-life.
REFERENCES:
patent: 3929992 (1975-12-01), Sehgal et al.
patent: 3993749 (1976-11-01), Sehgal et al.
patent: 4316885 (1982-02-01), Rakhit
patent: 4401653 (1983-08-01), Eng
patent: 4650803 (1987-03-01), Stella et al.
patent: 4885171 (1989-12-01), Surendra et al.
patent: 5023262 (1991-06-01), Caufield et al.
patent: 5120725 (1992-06-01), Kao et al.
patent: 5120727 (1992-06-01), Kao et al.
patent: 5120842 (1992-06-01), Failli et al.
patent: 5177203 (1993-01-01), Failli et al.
patent: 5457111 (1995-10-01), Luly et al.
patent: 5527907 (1996-06-01), Or et al.
patent: 0184162 (1986-06-01), None
patent: 0467606 (1992-01-01), None
patent: 9205179 (1992-04-01), None
patent: 9514023 (1995-05-01), None
patent: 9809970 (1998-03-01), None
patent: 9809972 (1998-03-01), None
Prescott, ed., Methods in Cell Biology, vol. XIV, Academic Press, New York, NY (1976), p. 33-71.
C. Vezina et al., “Rapamycin (AY-22, 989), A New Antifungal Antibiotic I”, Journal of Antibiotics, vol. 28, (1975), pp. 721-726.
S. N. Sehgal et al., “Rapamycin (AY-22, 989), A New Antifungal Antibiotic II”, Journal of Antibiotics, vol. 28, (1975), pp. 727-732.
N. L. Pavia et al., “Incorporation into Rapamycin”, Journal of Natural Products-Lloydia, vol. 54, No. 1, (1991), pp. 167-177.
E. J. Brown et al., “A Mammalian Protein Targeted by G1-arresting Rapamycin-Receptor Complex”, Nature, vol. 369, (1994), pp. 756-758.
C. Hayward et al., “Total Synthesis of Rapamycin vis a Novel Titanium-Mediated Aldol Macrocyclization Reaction”, Journal of the American Chemical Society, vol. 115 (1993), pp. 9345-9346.
Romo “Total Synthesis of (—) —Rapamycin Using an Evans-Tishchenko Fragment Coupling”, Journal of the American Chemical Society, vol. 115, (1993), pp. 7906-7907.
K. C. Nicolau et al., “Total Synthesis of Rapamycin”, Journal of the American Chemical Society, vol. 115, (1993), pp. 4419-4420.
H. Fretz et al., “Rapamycin and FK506 Binding Proteins (Immunophilins)”, Journal of the American Chemical Society, vol. 113 (1991), pp. 1409-1411.
F.J. Dumont et al., “The Immunosuppressive Macrolides FK-506 and Rapamycin Act as Reciprocal Antagonists in Murine T Cells”, Journal of Immunology, vo
Abbott Laboratories
Cook Rebecca
Miller Robert A.
Sickert Dugal S.
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