Brefeldin A derivatives

Details Brefeldin A derivatives Brefeldin A derivatives

2000-06-16

2002-03-26

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S270000, C549S271000

Reexamination Certificate

active

06362218

ABSTRACT:

FIELD OF INVENTION
This invention relates to novel cytotoxic macrolide compounds. More particularly, this invention is directed to derivatives of brefeldin A, pharmaceutical formulations comprising said derivatives, and a method of using certain of those derivatives as brefeldin A prodrugs.
BACKGROUND AND SUMMARY OF THE INVENTION
Brefeldin A is a macrolide antibiotic first isolated from the fungus
Penicillium decumbers.
The bicyclic ring structure was subsequently established by X-ray crystallography. Brefeldin A possesses a number of biological properties of potential therapeutic interest, including antitumor, antiviral, antifungal, nematocidal, and antimitotic effects. Mode of action studies have revealed that brefeldin A inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus, causes reversible disassembly of the Golgi complex, and blocks protein transport beyond the Golgi complex. Recently, it has been shown that brefeldin A induces DNA fragmentation that is associated with apoptosis in cancer cells. This recent discovery has stimulated a great deal of interest in the preclinical development of brefeldin A as an anticancer agent.
Clinical use of brefeldin A is severely limited by certain of its pharmacokinetic properties; negligible bioavailability after oral administration, and rapid clearance from the blood plasma after intravenous administration. Studies in Chinese hamster ovary cells have indicated that brefeldin A is secreted as glutathione and cysteine conjugates. Studies have also revealed that glutathione-S-transferase system may be responsible for the inactivation of brefeldin A in mammalian cells.
Formulation of brefeldin A is also complicated by its low solubility in aqueous solutions. Despite the existence of the lactone system and two hydroxyl groups on its bicyclic ring system, brefeldin A is only marginally soluble in aqueous medium. This severely limits the formulation of brefeldin A in solution for intravenous or intramuscular injection.
In accordance with this invention cytotoxic derivatives of brefeldin A having increased solubility and apparent prodrug activity have been prepared. Thus in accordance with one embodiment of this invention there is provided a compound of formula
wherein R
1
and R
1
′ are independently hydrogen or carboxy substituted C
1
-C
5
, alkanoyl, Y is H or OH, and Z is OH or —S(O)
n
R wherein n is 0, 1 or 2 and wherein R is C
1
-C
6
alkyl, phenyl, or C
1
-C
6
alkyl or phenyl substituted with one or more groups selected from the group consisting of OH, C
1
-C
4
alkoxy, halo, carboxy, carbo(C
1
-C
4
alkoxy), amino, —SO
3
H, and mono or di (C
1
-C
4
alkyl)amino, provided that when n is 0, R is not a 2-amino-2-carboxy alkyl group or an acylated derivative thereof, and provided that when Y is OH, Z is OH. The compounds of formula I wherein n is 0, 1, or 2 represent the corresponding sulfides, sulfoxide and sulfones, respectively.
This invention also directed to a method for preparing compounds of formula I by reacting brefeldin A, or a derivative thereof, with a thiol of the formula RSH to produce a compound of formula I wherein n is 0. The corresponding compounds wherein n is 1 or 2 are prepared by oxidizing the sulfide intermediates (n=O). In addition, brefeldin A and its derivatives can be optionally reacted with a C
1
-C
6
cyclic anhydride to form a compounds of formula I wherein at least one of R
1
and R
1
′ is carboxy substituted C
1
-C
5
alkanoyl.
In yet another embodiment of this invention there is provided a method for providing therapeutically effective serum levels of brefeldin A in a patient in need of the therapeutic benefit of brefeldin A by administering an effective amount of a compound of formula 1 wherein n is 0 or 1 in a pharmaceutically acceptable carrier.
The present invention further provides pharmaceutical formulations comprising an effective amount of the brefeldin A derivatives for treating a patient having a tumor or other neoplastic disease. As used herein, an effective amount of the brefeldin A derivative defined as the amount of the compound which, upon administration to a patient, inhibits growth of tumor cells, kills malignant cells, reduces the volume or size of the tumors or eliminates the tumor entirely in the treated patient.
The effective amount to be administered to a patient is typically based on body surface area, patient weight, and patient condition. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich, E. J., et al.,
Cancer Chemother. Rep.,
50 (4): 219 (1966). Body surface area may be approximately determined from patient height and weight (see e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, pages 537-538 (1970)). An effective amount of the brefeldin A derivative in the present invention can range from about 5 mg/kg to about 100 mg/kg, more preferably from about 0.25 mg/kg to about 50 mg/kg, and most preferably about 0.1 to about 10 mg/kg.
Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage and the possibility of co-usage with other therapeutic treatments including other anti-tumor agents, and radiation therapy.
The pharmaceutical formulation may be administered via the parenteral route, including subcutaneously, intraperitoneally, intramuscularly and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active agent, in a isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier. In one preferred aspect of the present embodiment, the brefeldin A derivative is dissolved in a saline solution containing 5% of dinmethyl sulfoxide and 10% Cremphor EL (Sigma Chemical Company). Additional solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the present compounds, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the present compounds.
The present compound can also be formulated into dosage forms for other routes of administration utilizing well-known methods. The pharmaceutical compositions can be formulated, for example, in dosage forms for oral administration in a capsule, a gel seal or a tablet. Capsules may comprise any well-known pharmaceutically acceptable material such as gelatin or cellulose derivatives. Tablets may be formulated in accordance with conventional procedure by compressing mixtures of the active brefeldin A derivatives and solid carriers, and lubricants well-known to those familiar with the art. Examples of solid carriers include starch, sugar, bentonite. The compounds of the present invention can also be administered in a form of a hard shell tablet or capsule containing, for example, lactose or mannitol as a binder and conventional fillers and tableting agents.
The following description is provided to illustrate various embodiments of Applicants' invention, and are not intended to in any way limit the scope of the invention as set forth in this specification and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
Brefeldin A is a macrolide antibiotic first isolated from the fungus
Penicillium decumbens.
The structure 1 was subsequently established by X-ray crystallography. It has been known for a long time that brefeldin A possesses a number of interesting biological properties of potential therapeutic interest, including antitumor, antiviral, antifungal, nematocidal, and antimitotic effects. Studies of the mode of action of brefeldin A have revealed that it inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus, causes reversible disassembly of the Golgi complex, and blocks protein transport beyond the Golgi complex. In addition, the ability of brefeldin A to induce DNA fragmentation associated with apoptosis in cancer cells has stimulated a great deal of recent interest in its preclinical development as an anticancer agent. Ho

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