Water soluble rapamycin esters

Details Water soluble rapamycin esters Water soluble rapamycin esters

2001-09-18

2002-08-13

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

06432973

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to water soluble rapamycin esters which are useful in inducing immunosuppression and in the treatment of transplantation rejection, autoimmune diseases, solid tumors, fungal infections, and vascular disease. More particularly, this invention concerns methoxypoly(ethylene glycol) esters of hydroxyesters of rapamycin 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, cardiovascular disease, cerebral vascular disease, peripheral vascular disease or hyperproliferative vascular disorders.
Rapamycin is a macrocyclic triene antibiotic produced by
Streptomyces hygproscopicus
, 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]. Additionally, 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.
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. Caine et al., Lancet 1183 (1978); and U.S. Pat. No. 5,100,899]. 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.
Rapamycin is also 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 [U.S. Pat. No. 5,321,009], skin disorders, such as psoriasis [U.S. Pat. No. 5,286,730], bowel disorders [U.S. Pat. No. 5,286,731], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], ocular inflammation [U.S. Pat. No. 5,387,589], malignant carcinomas [U.S. Pat. No. 5,206,018], cardiac inflammatory disease [U.S. Pat. No. 5,496,832], and anemia [U.S. Pat. No. 5,561,138].
A rapamycin ester, rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid [disclosed in U.S. Pat. No. 5,362,718], also known as CCl-779, has been shown to have antitumor activity against a variety of tumor cell lines, in in vivo animal tumor models, and in Phase I clinical trials. [Gibbons, J., Proc. Am. Assoc. Can. Res. 40: 301 (1999); Geoerger, B., Proc. Am. Assoc. Can. Res. 40: 603 (1999); Alexandre, J., Proc. Am. Assoc. Can. Res. 40: 613 (1999); and Alexandre, J., Clin. Cancer. Res. 5 (November Supp.): Abstr. 7 (1999)].
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 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 weight 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. Peglyated rapamycin is disclosed in US Pat. No. 5,780,462.
DESCRIPTION OF THE INVENTION
This invention provides methoxypoly(ethylene glycol) esters of hydroxyesters of rapamycin having the structure
wherein
R
1
and R
2
are each, independently, hydrogen or —CO(CR
3
R
4
)
b
(CR
5
R
6
)
d
CR
7
R
8
R
9
;
R
3
and R
4
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
R
5
and R
6
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR
3
R
4
)
f
OR
10
, —CF
3
, —F, or —CO
2
R
11
;
R
7
is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR
3
R
4
)
f
OR
10
, —CF
3
, —F, or —CO
2
R
11
;
R
8
and R
9
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR
3
R
4
)
f
OR
10
, —CF
3
, —F, or —CO
2
R
11
;
R
10
is hydrogen or —COCH
2
—S—CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OCH
3
;
R
11
is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
b=0-6;
d=0-6;
f=0-6;
n=5-450;
with the proviso that R
1
and R
2
are both not hydrogen and further provided that either R
1
or R
2
contains at least one —(CR
3
R
4
)
f
OR
10
group in which R
10
is —COCH
2
—S—CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OCH
3
, or a pharmaceutically acceptable salt thereof which are useful 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, cardiovascular disease, cerebral vascular disease, peripheral vascular disease or hyperproliferative vascular disorders. The compounds of this invention can also be referred to as pegylated hydroxyesters of rapamycin.
When applicable, pharmaceutically acceptable salts can be formed from organic and inorganic bases (i.e., when a compound contains a free hydroxyl group), such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when the rapamycin or antiestrogen contains a suitable acidic moiety.
As used in accordance with this invention, the term “providing,” with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analog which will form the equivalent amount of the compound or substance within the body.
Of the pegylated hydroxyesters of rapamycin covered by this invention, it is preferred that the hydroxyester of rapamycin is CCl-779, in which one or both of the hydroxyl groups of the 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid moiety are pegylated. 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 values of n refer to the range of repeating ethoxy units in the PEG side chain. For example, when a compound is described as having n=5-200, it means that such compound consists of a mixture of compounds having a normal distribution between n=5 and n=200, with approximately n=100 having the greatest frequency. With compounds III and IV, the average n was 108, and 99% of n being between 65 and 155. 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 CCl-779-PEG 5000 ester refers to a compound of the general formula above in which one side chain PEG ester is formed utilizing a p

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