Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-03-27
2003-12-09
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06660861
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of dihalomethanes as reagents for the preparation of Topotecan{4-(S)-10(dimethylamino)-methyl-4-ethyl 4,9 dihydroxyl-H-pyrano[3′4′:6,7]indolizino-[1,2-b]quinoline-3,14(4H,12H)dione} of formula I from hydroxycamptothecin. The invention discloses the rationale use of dichloromethane under solid-liquid phase transfer catalysis, which can behave both as solvent and a reactant when it serves as a source for C-1 unit for amino-alkylation of 10-hydroxy-4-(S)camptothecin.
BACKGROUND OF THE INVENTION
Topotecan (TPT)[9-(dimethylamino)-methyl]-10-hydroxy-(4S)-camptothecin) which is of the chemical structure of Formula I, is under clinical trials and its chemotherapeutic efficacy appears to be very promising. (Slichenmyer, W. J., Rowinsky, E. K., Donehower, R. C., J. Natl. Cancer Inst., 85:271 1993) Topotecan is one of he new class agents those targets topoisomerase I (Topo I) and stabilize the DNA-Topo-I complex, ultimately resulting in the cell death. The rationale for the use of Topotecan in chronic lymphocytic leukemia (CLL) is based on the finding of Top-I being elevated in the lymphocytes of patients with this disease (O'Brien, S., Kantajian, H., Ellis, A., Zweling, L., Estey, E., Keating, M., Cancer, 75 (5) 104-1995).
Camptothecin and congeners represent a clinically very useful class of anticancer agents. The discovery that the (S) enantiomer of camptothecin (CPT), a compound isolated from the bark, leaves and fruit of
Camptotheca acuminata
, can kill cell through selective poisoning of the human enzyme topoisomerase-I bound to its substrate DNA, was important breakthrough for its development as an anticancer agent, The intact 20-(S)-lactone form of CPT first isolated over 30 years ago, (Wall, M. E., Wani, M. C., Cooke, C. E., Palmer, K. H., McPhail, A. T., J. Am. Chem. Soc. 88 3888 1966) can bind non-covalently to the complex formed by topoisomerase-I and DNA thus inhibiting the resealing of broken DNA backbone. The intrinsic ability of CPT to trap this complex has been clearly linked to antitumor activity especially for tumors over-expressing topoisomerase-I such as colorectal and cervical cancer (Tahimoto, C. H., Wright, H. J., Arbuck, S. G., Biochim. Biophys. Acta 1400 107 1998 and Iyer, L., Ratain, M. J., Cancer Chemotherapy Pharamcol 42 31 1998). Nanomolar concentrations of the drug are in fact sufficient to cause DNA damage in vivo, which becomes irreversible following its collision with DNA processing machineries. This collision event produces irreparable damage to the DNA (Hsiang, Y. H., Lihou, M. G., Liu, L. F., Cancer Res. 49 5077 1989) and finally results in cell death (Tsao, Y. P., Arpa, D., Liu, L. F., Cancer Res. 52 1823 1992 and Holm, C., Covey, J. M., Kerrigan, D., Pommier, Y., Cancer Res. 49 6365 1989). CPT is not an optimal drug as it exhibits very limited water solubility in addition to severe toxicity and erratic absorption. Despite its serious side effect, it has become such a promising antitumor agent that extensive research, considering both pharmokinetics and pharmacodynamic has led to the successful development of new closely related compounds. 10-Hydroxy-(20S)camptothecin (HCPT) was shown to possess therapeutic effect on liver carcinoma, leukemia, cancers associated with head and neck. 10-Hydroxy-(20S)-camptothecin was reported to show improved antitumor activity and was found to be ten times more potent against P-388 and 1210 mouse leukemia than the parent camptothecin and was found also to be less toxic. The hydrophobicity of CPT precluded its development as a clinical agent and necessitated the use of the hydrophilic synthetic congeners in various phases of clinical trails, 10-Hydroxycamptothecin has been isolated as a minor compound (0.002%) from the extra of stem wood of
C. acuminata
by Wall, M. E., & Wani, M. C., (J. Org. Chem. 34.1364 1969) and
Ophirrhiza mungos
Linn Tafur, S., Nelson, J. D., Delong, D. C. and Svobodo, G. H., Lloydia 39 261 1976). Wani, M. C., (J. Med. Chem. 23(5) 554 1980) reported the total synthesis of (dl)-9-[(dimethylamino)-methyl]-10-hydroxycamptothecin with the ring E intact involving a number of steps. However, the method gives a low yield and therefore is only of academic value.
Kingbury, W. D., (J. Med. Chem. 31 98 1991) converted CPT to HCPT by reduction-oxidation sequence using platinum catalyst to afford mixture of compounds including 10-acetoxycamptothecin and unreacted CPT. This method of preparation is not economically viable. Among HCPT congeners Camptosar (Irinotecan HCl CPT-11 by Pharmacia & Upjohn) and Hycamtin (Topotecan HCl TPT SmithKline Beecham Pharmaceutical) have been approved for the treatment of metastatic colorectal carcinoma and small cell lung cancer along with refractory ovarian cancer.
New potent and water soluble derivatives have been synthesized and are now in clinical studies while other potent drugs are in pre-clinical stage as second generation camptothecin. Functionalization at 7,9,10, positions is compatible with increase in activity as shown by the 9-amino-20-(S)-camptothecin, Lurtotecan (G-I147211) (Takimoto, C. H., Wright, J. S., Arbuck, G., Chemother. Pharmacol. 42 1400 1998) and Exetecan (Dx-8951) (Mitsui, I., Kumazawa, E., Hirota, Y., Aonuma, M., Sugumori, M., Ohsuki, S., Uoto, K., Ejima, A., Tersawa, H., Sato, K., Jpn, J Cancer Res. 88 760 1995).
OBJECTS OF THE INVENTION
The main object of the present invention is to present an improved process for the preparation of Topotecan-HCl from 10-Hydroxycamptothecin by aminoalkylation, using dihalomethane, viz. dichloromethane, dibromomethane, or diidomethane as a reagent, by unconventional Mannich reaction.
Another object of the invention is to obtain better yield than by classical methods of inducting C-1 unit using low boiling, low density and less toxic reagent, dichloromethane in place of formaldehyde.
Another object of the invention is to carry out reaction under mild conditions at low pressure and at room temperature with high reactivity and to prevent at the same time polyalkylation, which is a problem for electron-rich phenolic substrate.
Another object is to obtain Eschenmoser's salts (N-methyl-N-methylenmethaniminium salts) which follow the reaction pathway in which soluble and reactive “ion pair” formed after gegenion exchange from potassium ortho phenolate and Escheumoser's salts which eventually collapses to give ortho-attacked products.
Another object of the invention is to compare the behavior of protic/aprotic solvents for ortho-regiospecific monoalkylated products.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a process for preparing 9-[(dimethylamino)-methyl]-10-hydroxycamptothecin(topotecan) of the formula I below
from 10-hydroxy-20-(S)-camptothecin (HCPF) dissolved in an organic solvent, the process comprising ortho-regioselective aminomethylation of HCPT with dimethylamine, using a dihalomethane which behaves both as solvent and a reactant, under solid-liquid phase transfer catalysis along with a solid base catalyst in suspension form, and under stirring and at room temperature, filtering the solid product obtained and washing the obtained solid product, evaporating the solvent and purifying the residue to obtain the desired product.
In one embodiment of the invention, the dihalomethane is selected from he group consisting of dichloromethane, dibromomethane and diidomethane.
In another embodiment of the invention, the solvent medium is selected from the group consisting of methylene halides, toluene, acetonitrile, dimethylformamide and any mixture thereof.
In yet another embodiment of the invention, the solid base catalyst is selected from the group consisting of potassium carbonate, sodium carbonate, ammonium carbonate, lithium carbonate and hydrated potassium carbonate.
In a further embodiment of the invention, the stirring is done at a pressure in the range of 10-18 psi. for a period of 4-8 hours.
In a further embodiment of the invention, t
Dhar Kanaya Lal
Handa Geeta
Puri Satish Chander
Qazi Ghulam Nabi
Suri Om Parkash
Council of Scientific and Industrial Research
Morris Patricia L.
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