AU639758B2 - Branched alkyl esters of 4-bis (chloroethyl) aminophenyl-alkyl carboxylic acids for treatment of primary and metastatic tumors of the lymphatic system, and of cancers of the breast and ovaries - Google Patents

Description

WO 91/11998 PCT/US91/00763 -1- BRANCHED ALKYL ESTERS OF 4-BIS (CHLOROETHYL) AMINOPHENYL-ALKYL CARBOXYLIC ACIDS FOR TREATMENT OF PRIMARY AND METASTATIC TUMORS OF THE LYMPHATIC SYSTEM, AND OF CANCERS OF THE BREAST AND OVARIES The tertiary butyl esters of anticancer drugs are provided which have the formula as thought herein.

Compounds of the invention can be used in treatment of cancers that originate or disseminate to the lymph nodes and lymphatics, breast, and ovaries.

BACKGROUND OF THE INVENTION Chlorambucil-tertiary butyl ester was developed by Greig and Rapoport as a lipophilic anticancer alkylating agent for the chemotherapeutic treatment of tumors that develop or metastasize into tissue that comprise of a high lipid content. Extensive previous studies have demonstrated that the agent appreciably enters and maintains high and therapeutic concentrations within the brain. As a consequence, the agent was patented for the treatment of brain tumors Patent No. 4,835,182 European Patent No.

88307767.9).

U.S. Patent No. 4,835,182 describes compounds of the formula: R3 R C H icHcl

(I)

I4-C-O-C-C-(CH 2

N

I I R2 CHzCZClI in which Ri is H, F, Cl, Br, or I; R 2 is H, F, Cl, Br, I or NH 2

R

3

R

4 and Rs, which are the same or different, are H, F, Cl, Br, I, or C 1

-C

3 alkyl; and n is 0 to 4 and the use of these compounds for the treatment or tumors of the brain. Significantly high levels of WO 91/11998 PCT/US91/00763 2 these compounds and active metabolites thereof accumulate in the brain.

Several other important organs comprise of a high lipid content and frequently develop life-threatening tumors. These include primary (Hodgkins and Nonhodgkins lymphomas) and metastatic tumors of the lymphatic system, and cancers of the breast and ovaries. Recent studies, included in this report, indicate that chlorambucil-tertiary butyl ester will be of clinical value in the chemotherapeutic treatment of these diseases.

SUMMARY OF THE INVENTION Methods for treating malignancies that originate or disseminate to the lymph nodes and lymphatics, breasts, and ovaries by administering compounds of formula (I) are provided. In preferred embodiments, compounds of formula in which R 3

R

4 and R 5

C

1

-C

3 alkyl and n is 0 to 4 are administered.

Hodgkin's disease Hodgkin's disease is a malignancy of the lymphatic system which occurs in approximately 7,000 patients in the United States annually It usually develops in a single lymph node, spreads to contiguous lymph nodes and, during the final stages of the disease, disseminates to extralymphatic organs (primarily to bone marrow, bone, liver and lung). Diagnosis is established by lymph node biopsy, and the disease then is categorized on the basis of pathology into lymphocyte predominant, mixed cellularity, nodular sclerosis and lymphocyte-depleted subtypes. Although pathological categorization is useful for predicting sites of involvement and prognosis, it seldom affects WO 91/11998 PCT/US91/00763 3 the choice of therapy. Treatment, primarily radiation therapy and/or combination chemotherapy, depends on the staging of a patients disease (ie, the involvement of a single or more than one lymph node, and the presence of local or distant spread of the disease).

Radiation therapy is the standard treatment for patients with limited stage (localized) disease, and is associated with a high success rate. Therefore, in limited stage disease, it is seldom combined with chemotherapy, unless there is massive mediastinal disease. Combination chemotherapy is the usual treatment for patients with advanced stages of Hodgkin's disease (stages IIIB, IVA and IVB as defined by the Ann Arbor Conference in 1971) [10,28]. Standard chemotherapy remains the MOPP regimen (Nitrogen mustard (mechlorethamine), vincristine, procarbazine and prednisolone on a 28 day cycle for 6 cycles), developed at the National Cancer Institute (Bethesda, MD) Several modified MOPP regimens have been developed which, in general, have substituted another anticancer alkylating agent for mechlorethamine (such as cyclophosphamide). Mechlorethamine is highly reactive and unstable when dissolved in aqueous solution for its required i.v. administration. It therefore must be administered immediately, through a running i.v.

infusion to reduce local host tissue damage, and it is rapidly hydrolyzed with 90% being cleared from blood within one minute Additionally, it can cause severe lesions at the injection side. The anticancer agent chlorambucil was developed by Ross [23] to overcome these problems; it is widely used and is among the best tolerated of anticancer agents [28].

WO 91/11998 PCT/US9/00763 4 Substitution of the plant alkaloid vincristine by vinblastine has also been undertaken in MOPP regimens.

MOPP and modified regimens achieve complete, long-term remission in a high percent of patients.

Non-Hodgkin's lymphovas Non-Hodgkin's lymphomas are lymphoid malignancies that differ dramatically from Hodgkin's disease, and occur in approximately 26,500 patients in the United States annually Non-Hodgkin's lymphomas are a group of tumors arising from various differentiation stages of B and T cells, and can develop in any lymphatic organ. The biological behavior of most of the forms of Non-Hodgkin's lymphomas can be separated into two broad groups. The first, indolent or favorable lymphomas include diffuse well-differentiated lymphocytic, nodular poorly-differentiated lymphocytic, and nodular mixed lymphomas. These are not usually curable with current therapies and have a long natural history. Therefore patients often live with slow growing disease for many years. The second group, aggressive or unfavorable lymphomas include nodular histiocytic, diffuse poorly-differentiated lymphocytic, diffuse mixed, diffuse histiocytic and diffuse undifferentiated lymphomas. These grow rapidly and, if untreated or fail treatment, are fatal in a short time [10,28). In addition, there is a subset, lymphoblastic lymphoma, that disseminates systemically early, and metastasizes to the central nervous system very commonly. Non-Hodgkin's lymphomas are staged in a manner similar to Hodgkin's lymphomas.

Over 90% of patients with indolent lymphomas are of stages III and IV, involving more than one lymph node, WO 91/11998 PCT/US91/00763 local extralymphatic spread and/or dissemination to more distant extralymphatic sites. Chemotherapy is the prime mode of treatment; primarily involving the use of alkylating agents. Chlorambucil frequently is administered daily, between 0.1 and 0.2 mg/kg orally, cyclophosphamide is sometimes used, at a daily dose of between 1.5 and 2.5 mg/kg. Additionally, alkylating agents are sometimes combined with other agents, such as with vincristine and prednisone in a CVP regimen, or with vincristine, procarbazine and prednisone in a C- MOPP regimen [7,28].

All these treatments are approximately equivalent.

None are curative, but result in long-term remissions in a high proportion of patients. All patients invariably relapse, and can be retreated with the same therapy, however, the response rate and duration are reduced. Eventually, patients become refractory to treatment [10,28].

Aggressive lymphomas of stage II and above, are treated with combination chemotherapy. Several regimens have been developed, all include an anticancer alkylating agents (often mechlorethamine and/or cyclophosphamide). Complete remissions have been reported to occur in 40% to 60% of patients, and for some intensive regimens involving the use of 6 or 7 drugs complete remissions can occur in up to 75% of patients. In most, however, relapses often occur during the initial 2 years of treatment. Relapsed patients can rarely be cured with further conventional chemotherapy, and have a short survival [10,28].

WO 91/11998 PCT/US91/00763 6 Ovarian Cancer Ovarian canc.er is the most common cause of death from a gynecological malignancy. It occurs in 1 of women in the United States, approximately 19,000 cases per year and causes some 12,000 deaths annually.

Once ovarian cancer develops it spreads by direct extension, into the lymphatic system as well as into the peritoneum. The majority of patients with ovarian cancer are first diagnosed afcer the disease has already spread into the lymphatic system and, often, intraperitoneally Usually, localized ovarian cancer is asymptomatic. Staging of the disease has been under taken by the International Federation of Gynecology and Obstetrics (FIGO), and broadly relates to the extension of the disease. Ovarian cancers can be divided into two groups; FIGO stages I and II, in which the disease is localized in the pelvic region (approximately 15% of total patients in each stage), and FIGO stages III and IV, involving intra-abdominal of systemic spread of the disease (approximately and 10% of total patients, respectively).

Additionally, the disease can be separated, on the basis of pathology, into epithelial tumors (approximately 85% of all tumors), stromal and germ cell tumors.

Treatment of early ovarian cancer, FIGO stages I and II, generally involves surgery and radiation therapy. As some 20% of these patients relapse and die, more aggressive adjuvant approaches, including chemotherapy, are sometimes applied. Approximately of patients present with advanced ovarian cancer at diagnosis (FIGO stages III and IV). Treatment includes WO 91/11998 PC/US91/00763 7 surgery for cytoreduction, abdominal radiation therapy and extensive postoperative chemotherapy [7,10,28].

Single, anticancer alkylating agents, primarily chlorambucil and melphalan, and sometimes cyclophosphamide, have most frequently been used in the treatment of ovarian cancer, and have achieved objective responses in between 35% and 65% of cases.

Following treatment, median survival time is 10 to 14 months duration. In more recent studies, the addition of several other classes of anticancer drugs to the core anticancer alkylating drug has led to higher overall response rates, numbers of complete remissions and to a longer median survival time (up to 29 months).

Insufficient data exists to assess whether long-term survival has been dramatically altered; 5-year survival rates of between 5% and 13% and of between 3% and 4% have been reported for patients with Stage III and IV disease, respectively (10,28].

Breast Cancer Breast cancer is the most common malignancy in women, with approximately 119,000 cases occurring in the United States annually Its treatment depends on the extent of disease, on patient age, menopausal status, general health, tumor hormone-receptor number and other variables. The extent or staging of the disease depends on the localization and dissemination of the tumor and on pathology [8,10,28].

The most important prognostic factor is axillary lymph node status. The greater the tumor involvement of lymph nodes the worse the disease prognosis.

Whereas some 40% of patients with involvement of three or less lymph node survive for 10 years, less than WO 91/11998 PCr/US9/00763 8 of patients with four or more involved nodes survive for this duration. Lymph node involvement serves as a marker for and a route for the development and presence of distant metastases, and is associated with a high risk of tumor recurrence [10,28].

The therapeutic goals in the treatment of primary breast cancers are, in general, twofold. The first involves the optimal control of the disease in the breast and associated regional tissues, which often involves lumpectomy, partial mastectomy, and modified radical and radical mastectomy. Postoperative radiation therapy is undertaken on patients at high risk for local recurrence. Additionally, patients that have a high risk of local and distant recurrence are administered additional chemotherapy. The chemotherapy of advanced breast cancer involves various combinations of up to 6 drugs, whose single agent activities vary between 20% to 40%. These include a nitrogen mustard, normally cyclophosphamide, which is sometimes replaced by chlorambucil, and methotrexate, vincristine, prednisone and adriamycin. Breast cancer is a highly heterogeneous disease. In general, however, adriamycin containing regimens have proved to have the best therapeutic effects, and such regimens often contain a nitrogen mustard alkylating agent. It should be noted that chemotherapy is used extensively for the treatment of advanced and metastatic disease, and whereas remissions are achievable the disease is not curable by current treatment modalities [7,10,28].

In described cancers, tumors develop in tissues containing a high lipid content and spread into the lymphatic system, which also contains a high lipid WO 91/11998 PCT/US91/00763 9 content, and, further, chemotherapy is an essential treatment modality for these cancers In general, all the described chemotherapeutic regimens used in the treatment of Hodgkins and Non-Hodgkins lymphomas, and of cancers of the breast and ovaries are made up of water-soluble anticancer agents [5,11,28].

Extensive studies have shown that the classical nitrogen mustard alkylating agents cyclophosphamide, mechlorethamine and chlorambucil, an essential part of most chemotherapeutic regimens in the treatment of these diseases, are also water-soluble As a consequence, they do not reach and maintain high levels in lipophilic tissues. The incorporation of a lipophilic anticancer alkylating agent into chemotherapeutic regimens may be of significant value in killing tumor cells that have invaded the lymphatic system, a major site of recurrence and metastatic dissemination in the described cancers, and of value in killing cells that remain sequestered in breast and ovarian tissue. In support of this, BCNU has been combined with success in the MOPP regimen (replacing mechlorethamine) for the treatment of Hodgkin's disease, providing a longer duration of remission, a greater survival and less toxicity than MOPP Chlorambucil-tertiary butyl ester reaches and maintains high concentrations in lymph nodes and lipophilic tissues. These concentrations are dramatically higher than those achieved following the equimolar administration of a water-soluble anticancer alkylating agent, such as by chlorambucil. Additionally, chlorambucil-tertiary butyl ester possesses intrinsic anticancer alkylating activity, requiring no metabolism WO 91/11998 PCT/US91/00763 to chlorambucil or tu other water-soluble metabolites for activity. Indeed, chlorambucil-tertiary butyl ester proved more active than equimolar chlorambucil against 4 of 6 human malignant tumor cell lines and demonstrates little cross-resistance with BCNU failure.

Further, chlorambucil-tertiary butyl ester is substantially less toxic than chlorambucil, and therefore can be administered in higher amounts and thereby will achieve even greater target concentrations. Finally it demonstrates high activity against a variety of human ma...gnant tumors, including breast and ovarian carcinomas and malignant gliomas.

SPECIFIC SUPPORTING STUDIES Pharmacokinetios Chlorambucil-tertiary butyl ester.HC1 or equimolar chlorambucil (13 mg/kg and 10 mg/kg, respectively) was administered i.v. to halothane (Ayerst, New York, NY) anesthetized female Wistar rats (Charles Rivers Laboratories, Wilmington, MA), 120 to 140 g weight.

Both agents were dissolved in Tween and diluted in isotonic saline and 1733 ul/kg was administered. Samples of cervical and abdominal lymph nodes and of plasma were obtained at times between 5 and 60 min, with a minimum of two rats per time point. These samples were immediately frozen to -70"C, weighed while frozen, and concentrations of drug and active metabolites were determined by high performance liquid chromatography [16].

Figure 1 shows the time-dependent concentration profiles of chlorambucil-tertiary butyl ester, chlorambucil and total active agents derived from WO 91/11998 PCT/US91/00763 11 chlorambucil-tertiary butyl ester in plasma, and in cervical and abdominal lymph nodes. In cervical and abdominal lymph nodes, peak levels of total active agents 44.2 and 105.1 nmol/g, were achieved at 5 min, respectively, thereafter concentrations declined monophasically with half-life values of 31.9 and 12.9 min. In both sets of lymph nodes, active drug was predominantly in the form of chlorambucil-tertiary butyl ester, and the concentration integrals (calculated between 5 and 60 min) were 1391.3 and 1819.6 nmol.min/g, respectively, compared to 1701 nmol.min/ml for plasma. The time-dependent plasma concentration profiles of chlorambucil-tertiary butyl ester and metabolites was similar to that in previous studies involving the i.v. administration of chlorambucil-tertiary butyl ester.HC1 and the concentration profile of the derived total active agents is shown in Figure 2.

Following the i.v. administration of equimolar chlorambucil (10 mg/kg) to rats, high levels of chlorambucil were present in plasma. A peak concentration of 144.8 nmol/ml was achieved at 5 min, and chlorambucil then disappeared with a half-life of 27 min (Figure Appreciable amounts of the active metabolite phenylacetic mustard were present in plasma throughout the study. Peak levels of 23.2 and 27.2 nmol/g of chlorambucil were achieved in the abdominal and cervical lymph nodes, respectively, at 5 min (Figure Negligible amounts of phenylacetic mustard were found in the lymph nodes. Concentrations of chlorambucil, phenylacetic mustard, and total active agents derived from chlorambucil administration were WO 91/11998 PCT/US91/00763 12 significantly lower in lymph nodes than in plasma. The concentration integrals of active drug, derived from i.v. chlorambucil administration, were 4575.2 nmol.min/ml, 701.8 nmol.min/g and 877.3 nmol.min/g for plasma, abdominal lymph node and cervical lymph node, respectively, calculated between 5 and 60 min.

summary As predicted from the physicochemical characteristics of chlorambucil-tertiary butyl ester, high concentrations of active drug were achieved and maintained in lymph nodes following its i.v.

administration. As shown in Figure 1, active drug was predominantly in the form of chlorambucil-tertiary butyl ester in lymph nodes, and, as shown in Figure 2, these levels are similar to those achieved in other lipophilic tissues, such as brain. Indeed, the tissue/plasma concentration integrals of total acltive agents in brain and cervical and abdominal lymph nodes are similar and are 0.85, 0.82 and 1.07, respectively.

Active drug in plasma, however, was predominantly in the form of the water-soluble metabolite chlorambucil.

Following the equimolar administration of chlorambucil to rats, significantly lower concentrations of active drug were achieved in lymph nodes, whereas concomitant levels in plaima were much higher throughout the study than those achieved after equimolar chlorambucil-tertiary butyl ester.HCl administration (Figures 1 and Thus the timedependent concentration integrals of active drug after 3? chlorambucil-tertiary butyl ester.HCL administration were twofold greater in lymph nodes and 3-fold less in plasma compared to those achieved after equimolar WO 91/11998 PCT/US91/00763 13 chlorambucil. For anticancer nitrogen mustard alkylating agents, such as chlorambucil and cyclophospahamide, plasma concentrations of active drug are related to host toxicity and myelosuppression As a consequence, chlorambucil-tertiary outyl ester, which achieves and maintains lower concentrations of active drug in plasma is substantially less toxic than chlorambucil (see toxicity studies). Therefore larger doses of drug can be administered, which will result in even greater target concentrations of drug. The tissue/plasma concentration integral ratios of total active agents in abdominal and cervical lymph nodes were 0.15 and 0.19, respectively after chlorambucil administration. These are 5-fold less than those achieved after equimolar administration of chlorambucil-tertiary butyl ester.

Recent studies have demonstrated that the cyclophosphamide, like chlorambucil, does not achieve and maintain high concentrations in lipid tissue, compared to concomitant levels achieved in plasma, with a lipid tissue/plasma ratio of 0.2[13,293.

These results indicate that chlorambucil-tertiary butyl ester achieves and maintains high concentrations in lipid tissues, such as in lymph nodes, compared to the water-soluble anticancer alkylating agents that are commonly used in clinical medicine.

Toxicity studies Single doses of chlorambucil-tertiary butyl ester.HC1 (between 10 and 150 mg/kg and between 50 and 500 mg/kg or of chlorambucil (between and 30 mg/kg and between 10 and 35 mg/kg i.p.) were administered to female Wistar rats (120 to 150 g WO 91/11998 PCT/US91/00763 14 weight), for determination of the single maximum tolerated doss oZ these compounds. A minimum of 4 animals were injected per dose. For chlorambucil, doses of greater than 15 mg/kg and 26 mg/kg, induced seizure activity within 2 to 4 hr of administration, and death occurred shortly thereafter.

Doses of up to 100 mg/kg, i.v. and 150 mg/kg, of chlorambucil-tertiary butyl ester. HC1 were tolerated by rats, although weight loss (approximately occurred at these doses. Higher doses caused an appreciable number of animal deaths between 4 and 24 days after administration.

These studies suggest that whereas chlorambucil is the maximal dor.e that can be delivered to rats without toxicity, as was undertaken in pharmacokinetic studies, significantly higher doses of chlorambucil-tertiary butyl ester.HC1 can be administered prior to toxicity, and this would result in dramatically higher concentrations in lipid tissues, such as the lymph nodes and lymphatics, brain, breast and ovaries, than reported in the described pharmacokinetic studies. Additionally, as pharmacokinetic studies indicate that chlorambuciltertiary butyl ester maintains only low concentrations in plasma, following its distribution, and as in vitro plasma half-life studies indicate that chlorambuciltertiary butyl ester is more stable in human compared to rat plasma and whole blood, it is probable that chlorambucil-tertiary butyl ester may be relatively nontoxic in humans due to the slow generation of watersoluble metabolites. Generation of these is known to cause myelosuppression WO 91/11998 PC/US91/00763 Anticancer activity studies The standard assay used to assess the in vitro sensitivity of tumors cells to chlorambucil-tertiary butyl ester and chlorambucil was the Capillary Human Clonogenic Cell Assay, HTCA This anchorageindependent assay measures the proliferation of clonogenic tumor cells, which represent the replicative units within tumors, and hence, are the target of antitumor therapy. The ability and value of the HTCA to predict response to in vivo chemotherapy has been demonstrated in both animal studies and in retrospective and prospective hunan clinical trials [1,4,12,24-26].

The activity of chlorambucil-tertiary butyl ester was assessed against carcinomas from the breast and ovary. Additionally, the comparative activity of chlorambucil-tertiary butyl ester and chlorambucil was assessed against 6 human malignant tumors from the brain. In all cases, the tumor cells were exposed to drug for a period of 2 h only. Therefore data can be compared to concentrations achieved in the described pharmacokinetic studies These concentrations were achieved at a dose of chlorambucil-tertiary butyl ester that was substantially lower than the maximum tolerated dose. A 70% clonogenic cell kill has proved to be required to accurately predict a clinical response. As shown in Figure 4, this was achieved against human ovarian and breast carcinomas by chlorambucil-tertiary butyl ester, at concentrations of 25 nmol/ml that are easily achievable in pharmacokinetic studies. Table 1 compares the surviving clonogenic cell fraction of 6 human malignant brain tumors, that had previously WO 91/11998 PCT/US91/00763 16 failed BCNU alkylating agent therapy, following their treatment with equimolar chlorambucil-tertiary butyl ester and chlorambucil (30 nmol/ml). Four of the tumors proved more sensitive to chlorambucil-tertiary butyl ester at a concentration that is easily achievable in pharmacokinetic studies. This dose, however, was not achievable following a maximum tolerated dose of chlorambucil.

In summary, studies show that chlorambucil-tertiary butyl ester possesses intrinsic alkylating activity, requiring no metabolism to water-soluble active metabolites. It is active against human carcinomas and gliomas. The compound reaches and maintains high concentrations in the lymphatic system, a primary route of dissemination, as well as in tissues of high lipid content. Finally, the compound possesses a toxicity which is less than that of its water-soluble derivative, an agent with a known spectrum of activity and a long clinical history. Whereas other ester derivatives of chlorambucil have previously been synthesized [17,18,22], these undergo rapid ester hydrolysis in vivo to quickly regenerate water-soluble chlorambucil Extensive studies have shown that these agents act to rapidly release chlorambuct~ '>er than have pharmacological activity themselvre [15,20,21,27], and their pharmacological acti, :e similar to chlorambucil. However, steric hindrance around the ester link, provided by the tertiary butyl moiety, affords the compound sufficient stability in vivo to allow its significant accumulation in tissues of high lipid content. Due to low enzyme activity in these tissues the agent is minimally metabolized WO 91/11998 PCT/US91/00763 17 readily enters tumor cells, due to its lipophilicity, and causes cytotoxicity.

All the described studies were undertaken within the Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20852, and within the N.W. Neuro-Oncology Research Laboratory, Dept. Neurological Surgery, Univ.

Washington, Seattle, WA 98195.

0 TABLE 1 COMPARISON BETWEEN TERTIARY-BUTYL CHLORAMBUCIL AND CHLORAMBUCIL AGAINST BCNLJ- RESISTANT HUMAN. MALIGNANT GLIOMA CELL LINES SURVIVING CLONOGENIC CELL FRACTION (AT 30 UM) TUMOR CHLORAMBUCIL TER-BUT-CHLORAMBUCIL UWAC-1 0.28 0.21 UWAC-2 0.18 0.19 UWAC-3 0.09 0.04 UWAC-4 0.88 0.78 0.50 0.45 0 UWAC-6 0.41 0.11 UWAC-1 to -6 are human malignant glioma tumor cells that have previously failed chemotherapy.

TERT-BUT-CHLORAMBUCIL: chiorambucil-tertiary butyl ester.

WO 91/11998 PCT/US91/00763 19

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Claims (4)

1. A method of treating malignancies that originate or disseminate to the lymph nodes and lymphatics, breasts and ovaries, comprising administering a compound of formula (T) R) O RI CKICHICI I? I I R4-C-O-c-CCHC',,-Y( RS RI CH CHLCI wherein: R 1 is H, F, Cl, Br, or I; R 2 is H, F, Cl, Br, I or NH 2 R 3 R 4 and R 5 which are the same or different, are H, F, Cl, Br, I or C 1 -C 3 alkyl; and n is 0 to 4; to a patient.

2. A method as claimed in Claim 1, wherein said malignancies are primary and metastatic malignancies of the lymphatic system, ovaries and breasts.

3. A method of treating primary and metastatic 25 malignancies of the lymphatic system, ovaries and breasts comprising administering a compound of formula (II) a 30 C 0 P C C I I cH,- cH (I C-C--C C-CH-CH--C (II) CH CCH, l -CHI-Ci i i 25 wherein: R1is H, F, Cl, Br, or I; and Ris H, F, Cl, Br, I or NH 2 to a patient.

4. A method of treating primary and metastatic malignancies of the lymphatic system, ovaries and breasts comprising administering compound of formula (III) cXH-H2 2 C 3- C 0- C CC 2 -C K Ci4 3 M CH 2 CH2rCI to a patient. A method of treating non-Hodgkin's 1ymphomaz comprising administering the compound of any one of Claims 1, 3 and 4 to a patient. 4 0