Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-19
2002-08-27
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
06440991
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to ethers of 7-desmethyirapamycin, which are useful in inducing immunosuppression and in the treatment of transplantation rejection, autoimmune diseases, solid tumors, fungal infections, and vascular disease or disorders.
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]. 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. Calne 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].
Ethers-of rapamycin are disclosed in U.S. Pat. No. 5,665,772. In particular, 42-O-(2-hydroxy)ethyl rapamycin, also known as SDZ-RAD, has been reported to be useful in treating or inhibiting transplant rejection.
The preparation and use of 7-desmethylrapamycin and certain derivatives thereof are disclosed in U.S. Pat. No. 5,728,710.
DESCRIPTION OF THE INVENTION
This invention provides ethers of 7-desmethylrapamycin having the structure
wherein
R
1
and R
2
are each, independently, hydrogen, thioalkyl of 1-6 carbonlatoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12 carbon atoms, aminoalkyl, of 1-6 carbon atoms, alkylaminoalkyl of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms, acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms, arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group, hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbon atoms, or dioxolanylallyl;
with the proviso that R
1
and R
2
are both not hydrogen, 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.
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.
The term alkyl includes both branched and straight chain moieties. It is preferred that aryl groups are phenyl or naphthyl. This invention covers compounds in which the stereochemistry of the 7-position is racemic (R,S) as well as the individual R and S stereoisomers at the 7-position.
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 compounds of this invention, it is preferred that R
2
is hydrogen, and more prefered that R
2
is hydrogen and R
1
is hydroxyalkyl. 42-O-(2-Hydroxy)ethyl 7-desmethylrapamycin acid is particularly preferred.
The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
The preparation of the ethers of rapamycin, from which the 7-desmethylrapamycin ethers are made from, are described in U.S. Pat. No. 5,665,772, which is hereby incorporated by reference. The conversion of the 7-(S)-methoxy group of the rapamycin hydroxyester to the 7-(R,S)-hydroxy group can be accomplished by nucleophilic substitution in the mixture of water and aprotic organic solvent such as acetonitrile in acidic condition. The ratio of aqueous to organic solvent is preferred between 1:9 and 9:1, more preferred is between 1:2 and 2:1. Most preferred ratio of aqueous to organic solvent is 1:1. Resolution of the 7-isomers can be accomplished by standard methodology, such as preparative HPLC.
The antifungal activity for the ethers of 7-desmethylrapamycin of this invention was confirmed in a standard pharmacological test procedure which measured the ability of the compound being evaluated to inhibit fungal growth. 42-O-(2-Hydroxy)ethyl 7-desmethylrapamycin acid (Compound I) was evaluated as a representative compound of this invention. The procedure used and results obtained are briefly described below. A 96 U-bottom microtiter plate was filled (50 &mgr;l/well) with RPMI 1640. The compounds to be evaluated were placed in appropriate wells, and serial diluted in successive wells to provide 11 dilutions. The concentrations ranged from 64 through 0.06 &mgr;ug/ml. An adjusted inoculum of fungi (50 &mgr;l) was added to each well and the plates were incubated at 35° C. for 24-48 hours. The MIC is the lowest concentration of compound which completely inhibited growth of organism in the wells. The following table shows the results obtained in this standard pharmacological test procedure. Where the same fungi is listed more than once, it indicates that more than one strain was evaluated. Nystatin and amphotericin B were used for the purpose of comparison.
TABLE 1
ANTIFUNGAL ACTIVITY (MIC in &mgr;g/mL)
Com-
Ny-
Amphoteri-
Yeast/Fungi
ID
pound I
statin
cin B
Candida albicans
1063
1
1
≦0.06
Candida albicans
1117
2
1
0.12
Candida albicans
ATCC 90028
2
1
0.12
Candida parapsilosis
94-9
2
1
0.12
Candida parapsilosis
94-8
2
2
≦0.06
Candida parapsilosis
ATCC 90018
2
2
≦0.06
Candida pseudotropicalis
ATCC 28838
2
1
≦0.06
Candida tropicalis
94-14
0.5
1
≦0.06
Candida tropicalis
94-13
0.5
1
≦0.06
Candida krussii
94-2
0.5
1
0.12
Candida lusitaniae
94-3
1
1
≦0.06
Candida rugosa
94-10
1
1
0.25
Aspergillus fumigatus
ATCC 26933
64
2
0.25
Aspergillus niger
S430
64
1
0.25
Aspergillus niger
S399
64
2
0.50
The results obtained in this standar
Enever Robin
Zhu Tianmin
Kifle Bruck
Milowsky Arnold S.
Wyeth
LandOfFree
Ethers of 7-desmethlrapamycin does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Ethers of 7-desmethlrapamycin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ethers of 7-desmethlrapamycin will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2935028