Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-05-23
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
06440990
ABSTRACT:
This invention comprises novel alkylated derivatives of rapamycin having pharmaceutical utility especially as immunosuppressants.
Rapamycin is a known macrolide antibiotic produced by
Streptomvces hyngroscopicus
having the structure depicted in Formula A:
See. e.g.. McAlpine. J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber. S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability as well as its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions.
It has now surprisingly been discovered that certain novel derivatives of rapamycin (the Novel Compounds) have an improved pharmacologic profile over rapamycin, exhibit greater stability and bioavailability, and allow for greater ease in producing galenic formulations. The Novel Compounds are alkylated derivatives of rapamycin having the structure of Formula I:
wherein
X is (H,H) or O;
Y is (H,OH) or O;
R
1
and R
2
are independent selected from
H, alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylaryalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, and (R
3
)
3
Si where each R
3
is independenty selected from H, methyl, ethyl, isopropyl, t-butyl, and phenyl; wherin “alkl-” or “alky-” refers to C
1-6
alkyl branched or linear preferably C
1-3
alkyl, in which the carbon chain may be optionally interrupted by an ether (-O-) linkage; and
R
4
is methyl or R
4
and R
1
together form C
2-5
alkylene;
provided that R
1
and R
2
are not both H; and
provided that where R
1
is (R
3
)
3
Si or carbalkoxyalkyl, X and Y are not both O.
Preferred Novel Compounds include the following:
1. 40-O-Benzyl-rapamycin
2. 40-O -(4′-Hydroxymethyl)benzyl-rapamycin
3. 40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin
4. 40-O-Allyl-rapamycin
5. 40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin
6. (2′E, 4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin
7. 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin
8. 40-O-(2-Hydroxy)ethyl-rapamycin
9. 40-O-(3-Hydroxy)propyl-rapamycin
10. 40-O-(6-Hydroxy)hexyl-rapamycin
11. 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin
12. 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin
13. 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin
14. 40-O-(2-Acetoxy)ethyl-rapamycin
15. 40-O-(2-Nicotinoyloxy)ethyl-rapamycin
16. 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin
17. 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin
18. 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin
19. 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin
20. (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin
21. 28-O-Methyl-rapamycin
22. 40-O-(2-Aminoethyl)-rapamycin
23. 40-O-(2-Acetaminoethyl)-rapamycin
24. 40-O-(2-Nicotinamidoethyl)-rapamycin
25. 40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin
26. 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin
27. 40-(2-Tolylsulfonamidoethyl)-rapamycin
28. 40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin
The Novel Compounds for immunosuppressive use are preferably the 40-O-substituted rapamycins where X and Y are both O, R
2
is H, R
4
is methyl, and R
1
is other than H; most preferably where R
1
is selected from hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl, and aminoalkyl; especially 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin. 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-(2-acetaminoethyl)-rapamycin).
Preferably, O-substitution at C40 or O,O-disubstitution at C28 and C40 is performed according to the following general process: Rapamycin (or dihydro or deoxorapamycin) is reacted with an organic radical attached to a leaving group (e.g., RX where R is the organic radical, e.g., an alkyl, allyl, or benzyl moiety, which is desired as the O-substituent, and X is the leaving group, e.g., CCl
3
C(NH)O or CF
3
SO
3
) under suitable reaction conditions, preferably acidic or neutral conditions, e.g., in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CCl
3
C(NH)O or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF
3
SO
3
. O-substitutions at C28 only are accomplished in the same manner but with prior protection at C40. Further modifications are possible. For example, where the substituent is allyl, the isolated monosubstituted double bond of the allyl moiety is highly amenable to further modification.
The 9-deoxorapamycin compounds are preferably produced by reducing a rapamycin using hydrogen sulfide, by reacting rapamycin with diphenyldiselenide and tributylphosphine or by other suitable reduction reaction.
The 26-dihydro-rapamycins are preferably produced by reducing rapamycins or 9-deoxorapamycins from keto to hydroxy at C26 by a mild reduction reaction, such as a borohydride reduction reaction.
The Novel Compounds are particularly useful for the following conditions:
a) Treatment and prevention of organ or tissue transplant rejection, e.g. for the treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants. They are also indicated for the prevention of graft-versus-host disease, such as following bone marrow transplantation.
b) Treatment and prevention of autoimmune disease and of inflammatory conditions in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific autoimmune diseases for which the compounds of the invention may be employed include, autoimmune hematological disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy) and juvenile dermatomyositis.
c) Treatment and prevention of asthma.
d) Treatment of multi-drug resistance (MDR). The Novel Compounds suppress P-glycoproteins (Pgp), which are the membrane transport molecules associated with MDR. MDR is particularly problematic in cancer patients and AIDS patients who will not respond to conventional chemotherapy because the medication is pumped out of the cells by Pgp. The Novel Compounds are therefore useful for enhancing the efficacy of other chemotherapeutic agents in the treatment and control of multidrug resistant conditions such as multidrug resistant cancer or multidrug resistant AIDS.
e) Treatment of proliferative disorders, e.g. rumors, hyperproliferative skin disorder and the like.
f) Treatment of fungal infections.
g) Treatment and prevention of inflammation, especially in potentiating the action of steroids.
h) Treatment and prevention of infection, especially infection by pathogens having Mip o
Cottens Sylvain
Sedrani Richard
Furman Diane E.
Kassenoff Melvyn M.
Kifle Bruck
Lopez Gabriel
Novartis AG
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