Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-25
2004-01-06
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S319000, C424S423000, C424S425000, C424S450000, C424S457000, C424S458000, C424S459000, C424S460000, C424S461000, C424S462000
Reexamination Certificate
active
06673814
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to delivery systems and methods useful for the treatment of neoplastic diseases, and to combinations of treatments useful for the treatment of neoplastic diseases.
2. Description of Related Art
Two important events in the cell division cycle are the duplication of the chromosomal DNA and the separation of the duplicated chromosomes. These events occur in two discrete phases: the synthetic phase (S-phase) and the mitotic phase (M-phase), which are separated from each other by distinct gaps in time, gap 1 (G1) and gap 2 (G2). The proper coordination of these events is achieved by checkpoint pathways that delay the progression of the cell cycle when proper completion of one phase is disrupted by physical damage or other means. Under normal circumstances, if the extent of damage is irreparable, most cells initiate a sequence of biochemical events leading to programmed cell death or apoptosis. Deregulation in any one or more of these checkpoint mechanisms sometimes leads to genetic instability which is a primary step for a tumor to evolve into invasive malignant state. The chemotherapeutic management of various cancers is achieved by drugs that block either the S-phase, the M-phase, or that block regulatory or metabolic pathways impinging upon the cell cycle machinery.
For example, some drugs affect the functions or structures of DNA or RNA, others interfere with enzymes involved in folate, purine, or pyrimidine metabolism, or the function of mitotic spindles. Anti-mitotic drugs such as vinica akaloids and taxoids can arrest cells in M-phase by interacting with mitotic spindle components, microtubules. Microtubules are one of the major filamentous components of the cytoskeleton, and, together with actin and intermediate filaments, they organize the cellular cytoplasm. In interphase cells, a dynamic radial array of microtubules emanates from the centrosome at the cell center. In this array, the fast growing and fast shrinking plus ends of microtubules project distally from the center.
During mitosis, the duplicated centrosomes nucleate assembly of much more dynamic and more numerous polymers as they move apart to form the opposite poles of the mitotic spindle. The increased dynamics and number of microtubules enhance the chance-encounter of growing microtubules with the primary construction of the duplicated chromatid pairs. Upon attaching to microtubules, chromosomes undergo a series of movements eventually leading to their conversion and final assembly at the mid-plate during metaphase. The onset of the next event in mitosis, the anaphase, is delayed until each of the chromatid pairs is assembled at the metaphase mid-plate and proper tension is generated on the attached sister chromatids.
Dynamic assembly or disassembly of microtubules is required for the morphogenesis of mitotic spindle. Accordingly, small organic molecules that modulate the dynamics of microtubules primarily because some of the microtubule interacting agents are useful for chemotherapeutic management of certain kinds of tumors. There are two classes of these anti-microtubule agents: those that prevent the assembly of tubulin, and those that promote the assembly of tubulin. A prototypic example of a potent assembly inhibitor is colchicine. Others are analogs of colchicine such as podophyllotoxin, MTC [(2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1one)], TCB (2,3,4-trimethoxy-4′-carbomethoxy-1, 1′-biphenyl) and TKB (
2,3,4-
trimethoxy-4′-acetyl-1,1′-biphenyl), and vinica akaloids. Taxol and its analogs represent a class of compounds that promote the assembly of microtubules. It is now clear that although all of these microtubule drugs prevent cell division, only a select few have been useful clinically. In addition, there are differences regarding the toxicity and the efficacy of these drugs for distinct classes of tumors.
SUMMARY
Applicants have discovered that the antitussive noscapine and its derivatives are useful in the treatment of neoplastic diseases. Noscapine is used as an antitussive drug and has low toxicity in humans. Noscapine arrests mammalian cells at mitosis, causes apoptosis in cycling cells, and has potent antitumor activity. Noscapine is an alkaloid from opium, and is readily available as a commercial byproduct in the commercial production of prescription opiates. Applicants have unexpectedly discovered that noscapine promotes assembly of tubulin subunits.
Applicants have synthesized derivatives of noscapine, a known antitussive having low toxicity in humans, and have shown they promote assembly of tubulin subunits, a characteristic suitable for the treatment of tumors and various neoplastic diseases.
In one embodiment of the invention, Applicants provide delivery systems and methods for the treatment of neoplastic diseases. For example, one delivery system according to an embodiment of this invention comprises a composition comprising noscapine or a noscapine derivative and a controlled-release mechanism to enhance delivery of the composition. In a further embodiment, Applicants provide a method for the treatment of neoplastic diseases wherein noscapine and its derivatives can be delivered in combination with another tumor therapy for the treatment or prevention of tumors.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF INVENTION
One embodiment of the present invention relates to systems and methods for the treatment of neoplastic diseases, comprising a composition comprising a compound of the formula
wherein:
1. A is
and W is C
1-6
alkyl;
and forms a six membered ring
with B, said ring containing one nitrogen;
Y is
(a) C
1-6
alkyl, or H;
(b) C(O)—C
1-6
alkyl;
wherein Z is C
1-6
alkyl or O-C
1-6
alkyl or O-C
1-6
alkyl;
(d) aryl; or
(e) heterocycle;
B is a single bond, OH or halo;
C is —OH, —CH
2
—, —O—, or forms a 5-membered lactone or lactam ring with D; and
D is:
(i) —OH, —CH
2
-halo, —CH(O)—, —COOH, —C(O)—O—C
1-6
alkyl, —(CH
2
)
n
—,—CHOH—, wherein n is an integer and is 1,2, or 3; or
(ii) forms a 5-membered lactone or lactam ring with C;
E is —H or —CH
3
; and
F is —OH or —OCH
3
,
or pharmaceutically acceptable salts thereof, and a controlled-release mechanism, whereby the delivery system enhances the delivery of the composition to a patient in need thereof.
Examples of controlled-release mechanisms suitable for use in the delivery system of the invention include, but are not limited to implantable devices, delivery pumps, wafers, gels, lotions, topical applications, and combinations thereof. Other examples of controlled-release mechanisms include but are not limited to controlled-release formulations comprising a modified compound. For the purposes of this document, “modified” means chemically changed, associated with, combined with, mixed with, delivered with, encapsulated by, caged, protected, lipidized, structurally modified to enhance stability, glycosylized, combined with nutrient transporters, used as a prodrug, incorporated with vector-based strategies, cationization, polymer conjugation, or combinations thereof, such that the compounds is at least partially altered from the above structure.
For example, controlled-release mechanisms may include but are not limited to the compound being caged, protected, or otherwise modified forms of the compound, such as modification to enhance its permeability through a patient's blood-brain barrier, modifications to the compound for tumor targeting purposes, and combinations thereof.
An example of a preferred compound that may be used in the delivery systems or methods of this invention is:
or pharmaceutically acceptable salt thereof.
Another embodiment of the present invention also relates to a method for the treatment of neoplastic diseases, comprising administering to a mammal in need of such treatment an effective amount of a composition comprising a compound of the formula
wherein:
A is
and W is C
1-6
alkyl;
and forms a six membered ring
with B, said ring containing one nitrogen;
Y is
(a)
Archer David
Armstrong Cheryl
Joshi Harish C.
Kapp Judith
Landen Jaren
Emory University
Gray Bruce D.
Jones Dwayne C.
Kilpatrick & Stockton LLP
LandOfFree
Delivery systems and methods for noscapine and noscapine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Delivery systems and methods for noscapine and noscapine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Delivery systems and methods for noscapine and noscapine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3246326