Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-16
2001-12-18
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C540S456000
Reexamination Certificate
active
06331547
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to water soluble SDZ-RAD esters, methods for its preparation and methods for its use for inducing immunosuppression and in the treatment of transplantation rejection, autoimmune diseases, solid tumors. More particularly, this invention concerns pegylated esters of SDZ-RAD and methods for using them for inducing immunosuppression, and in the treatment of transplantation rejection, graft vs. host disease, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders.
SDZ-RAD is 40-O-(2-hydroxy)ethyl-rapamycin, the structure and synthesis of which is disclosed in WO 94/09010 (Cottens et al.).
Authors Crowe and Lemaire describe the in vitro and in situ absorption of SDZ-RAD, an analog of rapamycin having the structure:
in their article in Pharmaceutical Research, Vol. 15, No. 11, 1998
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. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); 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. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
The immunosuppressive effects of rapamycin have been disclosed in FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet 1183 (1978); and U.S. Pat. No. 5,100,899].
Rapamycin has also been shown to be useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [Fifth Int. Conf. Inflamm. Res. Assoc. 121 (Abstract), (1990)], smooth muscle cell proliferation and intimal thickening following vascular injury [Morris, R. J. Heart Lung Transplant 11 (pt. 2): 197 (1992)], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], and ocular inflammation [European Patent Application 532,862 A1].
Mono- and diacylated derivatives of rapamycin (esterified at the 28 and 43 positions) have been shown to be useful as antifungal agents (U.S. Pat. No. 4,316,885) and used to make water soluble aminoacyl prodrugs of rapamycin (U.S. Pat. No. 4,650,803). Recently, the numbering convention for rapamycin has been changed; therefore according to Chemical Abstracts nomenclature, the esters described above would be at the 31- and 42-positions. U.S. Pat. No. 5,023,263 describes the preparation and use of 42-oxorapamycin and U.S. Pat. No. 5,023,264 describes the preparation and use of 27-oximes of rapamycin.
Polyethylene glycol (PEG) is a linear or branched, neutral polymer available in a variety of molecular weights and is soluble in water and most organic solvents. At molecular weights less than 1000 PEGs are the viscous, colorless liquids; higher molecular weight PEGs are waxy, white solids. The melting point of the solid is proportional to the molecular weight, approaching a plateau at 67° C. Molecular weights range from a few hundred to approximately 20,000 are commonly used in biological and biotechnological applications. Of much interest in the biomedical areas is the fact that PEG is nontoxic and was approved by FDA for internal consumption.
SDZ-RAD is a rapamycin derivative which has immunosuppressive activity in animal model (U.S. Pat. No. 5,665,772). U.S. Pat. No. 5,665,772 (Cottens et al.) teaches O-alkylated rapamycin derivatives, particularly 9-deoxorapamycins, 26-dihydro-rapamycins, 40-O-substituted rapamycins and 28,40-O,O-disubstituted rapamycins. It is known that pegylated rapamycin is an ester derivative which shows immunosuppressive activity with improved aqueous solubility (U.S. Pat. No. 5,780,462). Using the similar synthetic method, water soluble derivatives of SDZ-RAD has been prepared.
DESCRIPTION OF THE INVENTION
This invention provides novel polyethylene glycol esters of SDZ-RAD, an analog of rapamycin, which are compounds of the formula:
wherein n is an integer from about 5 to about 450.
The compounds of this invention are water soluble analogs of SDZ-RAD and rapamycin which are useful as immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agents. Of the compounds of this invention, it is preferred that n=5-200; more preferred that n=8-135. Most preferred members are those in which n=8-20 and those in which n=90-120. The compounds of this invention may also be described and understood based upon the average molecular weight of the polyethylene glycol chains used to produce their ester chains. For instance, an SDZ-RAD-PEG-5000 conjugate ester refers to a compound of the general formula above in which the 42-O-(2-Hydroxy)-ethyl position ester is formed utilizing a polyethylene glycol derivative having an average molecular weight range at or near 5,000.
The esters of the present invention may be produced utilizing the polyethylene glycols known in the art, such as those described on pages 355 to 361 of the Handbook of Pharmaceutical Excipients, Second Edition, 1994 (Library of Congress Catalog Card No. 94-79492), which are incorporated herein by reference. The preferred compounds of this invention may also be described as those of the formula esterified using polyethylene glycols having an average molecular weight of from about 200 to about 200,000. A preferred range of the PEG esters of this invention includes those in which the molecular weight of the polyethylene glycol portion of the ester chain has a molecular weight in the range of from about 300 to about 20,000, more preferably between about 350 and about 6,000. Non-limiting specific examples of compounds of this invention include compounds of the formula above prepared using each of the PEGs listed in the Handbook of Pharmaceutical Excipients, Second Edition, 1994.
The compounds are useful in treating, preventing or inhibiting conditions for which rapamycin, its analogs and prodrugs may be used. These methods include the treatment or inhibition of transplantation rejection such as kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea, small bowel, and skin allografts, and heart valve xenografts; in the treatment or inhibition of graft vs. host disease; in the treatment or inhibition of autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and diseases of inflammation such as psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease, pulmonary inflammation (including asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis, and the like), and eye uveitis.
Because of the activity profile obtained, the compounds of this invention also are considered to have antitumor, antifungal activities, and antiproliferative activities. The compounds of this invention therefore also useful in treating solid tumors, including sarcomas and carcinomas, such as astrocytomas, prostate cancer, breast cancer, small cell lung cancer, and ovarian cancer; adult T-cell leukemia/lymphoma; fungal infections; and hyperproliferative vascular diseases such as restenosis and atherosclerosis. When used for restenosis, it is preferred that the compounds of this invention ar
Saunders Richard W.
Shah Syed M.
Zhu Tianmin
American Home Products Corporation
Kifle Bruck
Milowsky Arnold S.
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