Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-10-28
2002-04-09
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S120000, C514S253030, C514S258100, C514S418000, C514S570000, C560S116000, C560S194000
Reexamination Certificate
active
06369109
ABSTRACT:
I. FIELD OF INVENTION
The present invention relates to the field of cancer treatment and is based on the discovery that betulinic acid and its derivatives are potent anti-neuroectodermal agents. As disclosed herein, betulinic acid and its derivatives are useful for the treatment of neurodectodermal tumors, due to its distinct mechanism of action, including neuroectodermal tumors that are resistant to conventional chemotherapeutical agents. In addition to the new use of known compounds, the invention discloses novel compounds and pharmaceutical compositions for the treatment of neuroectodermal tumors.
II. BACKGROUND OF INVENTION
Neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. Chemotherapy is the primary treatment for many types of neuroectodermal tumors. Two thirds of the neuroblastoma cases occur in children of 5 years of age or younger. The early onset of neuroblastoma is illustrated by prenatal neuroblastoma detectable by fetal ultrasonography. Jennings et al 1993
, J. Ped. Surg.
28:1168-1174. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. Neuroblastoma presents serious clinical consequences including symptoms associated with tumor mass or bone pain from metastases. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord, causing paralysis. Azizkhan and Haase, 1993
, Sem. Surg. Oncol.
9: 493-501. Approximately 70% of all patients with neuroblastoma have metastatic disease at diagnosis. See, e.g., Brodeur et al., 1993
, J. Clin. Oncol.
11: 1466-1477; Adams et al., 1993
, J. Ped. Surg.
28:372-378; Evans et al., 1976
, Cancer
38:661-666.
Chemotherapy remains to be one of the most effective treatments for neuroblastoma tumors. Neuroblastoma patients are generally treated with chemotherapy with cyclophosphamide and doxorubicin, cisplatin with teniposide or etoposide or vincristine with cisplatin and teniposide or etoposide for more resistant tumors. For patients younger than one year, aggressive chemotherapy using combinations of cyclophosphamide, doxorubicin, cisplatin, and teniposide or etoposide is generally used. Castleberry et al., 1991
, J. Clin. Oncol.
9:789-795; Bowman et al., 1997
, J. Natl. Cancer Inst.
89:373-380; Castleberry et al., 1992
, J. Clin. Oncol.
10:1299-1304.
Aggressive multiagent chemotherapy has resulted in a 2-year survival rate of approximately 20% in older children with stage IV neuroblastoma. Bowman et al., 1991
, J. Clin. Oncol.
9:1599-1608; Williams et al., 1995
, Med. Ped. Oncol.
24:176-180. Neuroblastoma in the adolescent or adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course. Franks et al., 1997
, Cancer
79: 2028-2035.
Ewing's sarcoma (EWS) usually occurs in bone and is diagnosed most frequently in the second decade of life. The most common sites for the primary lesion are the pelvic bones, femur, humerus, and ribs. Ewing's sarcoma occurs less commonly at non-bone primary sites, a presentation that has historically been termed extraosseous Ewing's sarcoma. However, the morphological and biological characteristics of Ewing's tumors developing in soft tissues appear to be indistinguishable from those of tumors developing at bone sites. Delattre et al., 1994
, New Engl. J. Med.
331:294-299; Llombart-Bosch et al., 1990
, Cancer
66:2589-2601.
Primitive neuroectodermal tumors (PNETs) have been referred to by different terms depending on their location and extent of neural differentiation: peripheral neuroepithelioma, Askin tumor, adult neuroblastoma, peripheral neuroblastoma, and primitive neuroectodermal tumors. The collective term is primitive neuroectodermal tumors. Ewing's sarcoma and PNET represent a biological spectrum of the same tumor. Greater than 90% of these tumors are characterized by chromosome 11/22 translocation. Since these tumors exhibit only neuroectodermal markers of differentiation, it has been suggested that they arise from neural crest cells. Because treatment is the same for these tumors, they are often referred to as Ewing's sarcoma.
Studies suggest that more than 50% of patients without metastatic disease may have a long-term disease-free survival, compared to only 20-30% for patients who present with metastatic disease. See, e.g., Burgert et al., 1990
, J. Clin. Oncol.
8:1514-1524; Grier et al., 1994
, Proc. Am. Soc. Clin. Oncol.
13: A-1443; Rosen et al., 1981
, Cancer
47:2204-2213; Dunst et al., 1995
, Int. J. Rad. Oncol. Biol. Phy.
32:919-930; Arai et al., 1991
, Int. J. Rad. Oncol. Biol. Phy.
21:1501-1508.
Surgery of Ewing's sarcoma is usually limited to the initial diagnostic biopsy of the primary tumor. Patients usually underwent induction chemotherapy followed by radiation therapy for local control. The successful treatment of patients with Ewing's sarcoma requires the use of multidrug chemotherapy. Combination chemotherapy for Ewing's sarcoma has traditionally included vincristine, doxorubicin, cyclophosphamide, and dactinomycin (VAdriaC or VAC). The importance of doxorubicin has been demonstrated in randomized comparative trials with increased doxorubicin dose intensity during the early months of therapy resulting in improved event-free survival. See, e.g., Nesbit et al., 1990
, J. Clin. Oncol.
8:1664-1674; Kinsella et al., 1991
, Int. J. Radiat. Oncol. Biol. Phy.
20:389-395; Smith et al., 1991
, J. Natl. Cancer Inst.
83:1460-1470.
Although many neuroectodermal tumors initially respond to chemotherapy, the prognosis of children who relapse or present with disseminated disease remain poor, because of the development of drug resistance. Some chemotherapeutical agents, such as doxorubicin, rely upon the presence of functioning CD95 system in the target tumor cells to exert their anti-tumor activities. Cells lacking functional CD95 are resistant to doxorubicin. Some other chemotherapeutical agents relay upon the presence of a functional p53 system to exert their anti-tumor activities. Such chemotherapeutical agents are ineffective against cells lacking functional p53 protein.
Therefore, there is a great need to develop chemotherapeutical drugs that target neuroectodermal tumors and particularly drug resistant neuroectodermal tumors. Accordingly, this invention provides chemical compositions and the use thereof for the treatment of neuroectodermal tumors. Those compositions do not relay upon the CD95 or p53 systems to exert their anti-tumor activities.
II. SUMMARY OF THE INVENTION
The present invention provides novel compounds, useful for treatment of neuroectodermal tumors, having the general formula (I):
wherein
R
1
is selected from the group consisting of hydrogen, —SO
3
H, —PO
3
H
2
, —C
1
-C
20
straight or branched chain alkenyl, —C
2
-C
20
straight or branched chain alkenyl, —C
2
-C
20
straight or branched chain alkynyl, —(CH
2
CH
2
O)
n
H, —(CH
2
CH
2
O)
n
CH
3
, —(CH
2
CH
2
O)
n
CH
2
CH
3
, —C(O)C
6
H
5
, —C(O)C
1
-C
20
straight or branched chain alkyl, —C(O)C
2
-C
20
straight or branched chain alkenyl, —C(O)C
2
-C
20
straight or branched chain alkynyl, myo-inosityl, scyllo-inosityl, a cyclitol, conduritol A, quebrachitol, a monosaccharide, a disaccharide and an oligosaccharide; the —(CH
2
CH
2
O)
n
H, myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide and oligosaccharide being optionally substituted with one or more —C(O)C
1
-C
20
straight or branched chain alkyl, —C(O)C
2
-C
20
straight or branched chain alkenyl, —C(O)C
2
-C
20
straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R
2
is selected from the group consisting of —CO
2
H, —CO
2
(C
6
H
5
), —CO
2
(C
1
-C
20
straight or branched chain alkyl), —CO
2
(C
2
-C
20
straight or branched chain alkenyl), —CO
2
(C
2
-C
20
straight or branched chain alkynyl), —CO
2
(myo-inosityl), —CO
2
(scyllo-inosityl), —CO
2
(c
Debatin Klaus Michael
Fulda Simone
Los Marek
Mier Walter
Wiessler Manfred
Deutsches Krebsforschungszentrum Stiftung des Offentlichen Recht
Geist Gary
Owens Howard V.
Pennie & Edmonds LLP
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