CA2076050A1 - 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 breastand ovaries - Google Patents

Abstract

A method of treating malignancies that originate or disseminate to the lymph nodes and lymphatics, breast, or ovaries by administration of compounds of formula (I): in which R1 and R2 are the same or different and are selected from the group consisting of H, F, Cl, Br, and I and R2 can also be NH2; R3, R4 and R5 are the same or different and are selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; and n = 0-4.

Description

WO91/11~8 PCT/US91/00763 -1- 297~5~
BRANCHED ALXYL ES~ERS OF 4-3:S (CHLOROETHYL) AMINOPHENYL-ALXYL CARBOXYLIC ACI)S FOR T~EATMENT OF
PRIMARY AND METASTATIC TUMORS OF l'~E LYMPHATIC SYSTEM, AND OF CANCERS OF THE BREA~ r AND OVARIES
The tertiary butyl esters of ar.:icancer drugs are provided which have the formula as -hought herein.
Compounds of the invention can be ~.ed in treatment o~
cancers that originate or disseminat~ to the lymph nodes and lymphatics, breast, and c~ries.
BACXGROUND OF THE IN ~ T~ION
Chlorambucil-tertiary butyl ester w~ de~eloped ~y Greig and Rapoport as a lipop~ilic .~I ticancer alkylating agent for the chem~thera~ltic trea~ment of tumors that develop or metastasize ;r.:o tissue that comprise of a high lipid content. Ex:ensive previous studies have demonstrated tha- the a~nt appreciably enters and maintains high and therape_tic concentrations within the brain. As G consequence, the agent was patented for the treatment cf brain tumors (U.S. Patent No. 4,835,182 European ~atent No.
88307767.9).
U.S. Patent No. 4,835,182 descri~e, compounds of the formula:
IR.~ 1l ~ \ CH~CH.CI (I) R4--f_o--c--f--(CH2)n~\
R5 Rl CH2C~i2 1 in which Rl is H, F, Cl, Br, or I; Rz is H, F, Cl, Br, I
or NH2; R~, R~, and R" which are the sc~e or different, are H, F, Cl, ~r, I, or Cl-C~ 31kyl; and n is 0 to 4 and the use of these compounds fc- the treatment of tumors of the brain. Significantly ;~.gh levels of 2 ~ 5 ~
these compounds and active metabolites thereo~
accumulate in the brain.
Several ot'.er important organs comprise of a high lipid contPnt and frequently develop life-threatening tumors. These include primary (Hodgkins and Non-hodg~ins lymp~mas) and metastatic tumors of the lymphatic syst.em, and cancers of the breast and ovaries. Rec~nt studies, included in this report, indicate that chlorambucil-tertiary butyl ester will be of clinical ~.lue in the chemotherapeutic treatment of these diseas~s.
SUM~ARY OF THE INVENTION
Methods --or trPating malignancies that originate or disseminate o the lymph nodes and lymphatics, breasts, and ovaries ~y administering compounds of formula (I) are provided. In preferred embodiments, compounds of formula (I) in which R3, R4, and R5 C1-C3 alkyl and n is 0 to 4 are administered.
~o~g~in~ 8 ~18e~8-Hodgkin s disease is a malignancy of the ly~phatic system which occurs in approximately 7,000 patients in the United States annually [l9]. It usually develops in a single lymph node, spreads to contiguous lymph nodes and, during the final stages of the disease, disseminat,s to extralymphatic organs (primarily to bone marro-~, bone, liver and lung~. Diagnosis is establishe~ 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 pathologi~al categorization is useful for predicting sites of involvement and prognosis, it seldom affects , :

WO91/11~8 PCT/US91/00763 2~76~0 the choice o~ therapy. Treatment, primarily radiation therapy and/or combination chemotherapy, depends on the staging of a patients disease (ie, the involvement o~ a single or more than one lymph node, and the presence of local or distant spre3d 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 traatm~nt for patiants ~ith advancPd 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) [9].
Several modified MOPP regimens have been developed which, in general, have substituted another anticancer alkylating agent for mechlorethamine (such as cyclophosphamide). ~echlorethamine is highly reactive and unstable when dissolved in aqueous solution for its required i.v. administration. It therefore must be administerad 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 t5,11]. 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].

WO91/11~8 PCT/US91/00763 20760~0 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-~odg~in~s lymphomas Non-Hodgkin's lymphomas are lymphoid malignancies that differ dramatically from Hodgkin's disease, and occur in approximately 26,500 patients in the Unit2d States annually E 19]. 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, WO91/11~8 PCT/US91/00763 ~` 2076~0 local extralymphatic spread and/or dissemination to more distant extralymphatic sites. Chemotherapy i8 the prime mode of treatment; primarily involving the use o~
alkylating agents. Chlorambucil frequently is administered daily, between 0.1 and 0.2 mg/~g 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 ara approximately equival~nt.
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].

WO91/11~8 PCT/US91/00763 2 ~ 60~ ~ 6 OYari~ c3~c3r Ovarian cancer is the most common cause o~ death from a gynecological malignancy. It occurs in 1 of 70 women in the Unit~d States, approximately l9,000 cases p~r year ~l9~, and causes some 12,000 deaths annually.
once o~arian cancer develops it spreads by direct extension, into the lymphatic system as well as into the peritone-~m. The majority of patients with ovarian cancer are first diagnosed after the disease has already spread into the lymphatic system and, often, intraperitoneally [8,28]. Usually, localized ovarian cancer is as~m~tomatic. S~aging 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 60%
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 70%
of patients present with advanced ovarian cancer at diagnosis (FIGO stages III and IV). Treatment includes WO91tll~8 PCT/US91/007~3 surgery for cytoreduction, aldominal radiation therapy and extensive postoperative chemotherapy [7,10,28].
Single, anticancer alky a:ing agents, primarily chlorambucil and melphalan, aId sometimes cyclophosphamide, hava most 4. equently been used in the treatment of ovarian cancer, cnd have achieved objective responses in betwe~r 35% and 65% of cases.
Following treatment, median su~vival time is lO to 14 months duration. In mor~ recelt studies, the addition of several other classes of 2 ~ icancer drugs to the core anticancer alkylating dr~c- has led to higher overall rss~onsa rates, numbe-e of complete remissions and to a longer median survivl time (up to 29 months).
Insufficient data exis~s to aes~ss whether long-term survival has been dramaticall~ lltered; 5-year survival rates of between 5% and 13% ar1 of between 3% and 4%
have been reported for patients with Stage III and IV
disease, respectively tlO,28~.
Broast C~ncer Breast cancer is the most coDmon malignancy in women, with approximately ll9,OO~ cases occurring in the United States annually ~19]. Its treatment depends on the extent of disease, on pat:ent age, menopausal status, general health, tumor h `'T mone-receptor number and other variables. Ths exten~- ~r staging of the disease depends on the localizati~n and dissemination of the tumor and on pathology ~ 0,28].
The most important prognosti_ factor is axillary lymph node status. The greater ~ae tumor involvement of lymph nodes the worse the dis~ se prognosis.
Whereas some 40% of patients wita involvement of three or less lymph node survive for 1~ years, less than 15%

WO91/11g98 PCT/US91/00763 2076~0 of patients with four ~r more involved nodes survive for this duration. L~mph node involvement serves as a marker for and a rout~ for the development and pr~sence of distant metastases and is associated with a high risk of tumor recurre~ce [lO,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 i~ undertaken on patiPnts at high risk for local recu-rence. Additionally, patients that have a high risk of local and distant recurrence are administered additi~nal chemotherapy. The chemotherapy o~ 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, 5-fluorouracil, vincristine t prednisone and adriamycin. Breast cancer is a highly hetercgeneous disease. In general, however, adriamyc~n containing regimens have proved to have the best the apeutic effects, and such regimens often contain a n.trogen mustard al~ylating 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,lO,28].
In described cancers, tumors develop in tissues containing a hig~ lipid content and spread into the lymphatic system which also contains a high lipid 2076~5~

content, and, further, chemotherapy is an sssential treatment modality for these cancers [7,9,28]. 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 t5,11,28].
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 [5,11]. As a consequence, they do not r~ach 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 Xodgkin's disease, providing a longer duration of remission, a greater survival and less toxicity than MOPP ~6].
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 WO91/~8 PCT/US9l/00763 2 ~ 7 ~

to chlorambucil or to other water-soluble metabolites for activity. Indeed, chlorambucil-tertiary butyl ester proved more active than equimolar chlorambucil against 4 of 6 human mallgnant tumor cell lines and demonstrates little cross-resistance with BCNU failure.
Further, chlorambucil-tertiary butyl ester is substantially less toxic than chlorambucil, and therefor2 can be administered in higher amounts and thereby will achieve even greater target concentrations. Finally it demonstrates high activity against a variety of human malignant tumors, including breast and ovarian carcinomas and malignant gliomas.
SP~CIFIC SUPPORTING STUDIES
Pharmaco~inetics 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 fe~ale Wistar rats (Charles Rivers Laboratories, Wilmington, MA), 120 to 140 g weight.
Both agents were dissolved in Tween 80/ethanol (3:1(v:v)) and diluted in isotonic saline (l:9(v:v)) and 1733 ul/Xg was administsred. 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 profil~s of chlorambucil-tertiary butyl ester, chlorambucil and total active agents derived from 2~76~50 chlorambucil-tertiary butyl ester in plasma, and ln 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 lo (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.HCl tl4~, 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 3). Appreciable amounts of the active metabolite phenylacetic mustard were present in plasma throughout the study. Peak level~ of 23.2 and 27.2 nmol/g of chlorambucil were achieved in the abdominal and cervical lymph nodes, respectively, at 5 min tFigure 3). 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 WO91/11~8 PCT/US91/00763 20~50 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.
8u~m~ry 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, ac~ive 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 active agents in brain and cervical and abdominal lymph nodes are similar and are 0.85, 0.82 and l.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 plasma were much higher throughout the study than those achieved after equimolar chlorambucil-tertiary butyl ester.HCl administration ~Figures l and 3). Thus the time-dependent concentration integrals of active drug after 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 91/1199~ PCr/USgl/00763 2~763~0 chlorambucil. For anticancer nitrogen mustard alkylating agents, such as chlorambucil and cyclophospahamide, plasma concentrations of active drug are related to host toxicity and myelosuppression t5,7,11]. As a conse~uence, chlorambucil-tertiary butyl ester, which achieves and maintains lower concentrations of active drug in plasma is substantially less toxic than chlorambucil (s~e 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 afte- 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[13,29].
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.
To~ioity 8tudi-s Single doses of chlorambucil-tertiary butyl ester.HCl (between 10 and 150 mg/kg i.v., and between 50 and 500 mg/kg i.p.) or of chlorambucil (between 10 and 30 mg/kg i.v., and between 10 and 35 mg/Xg i.p.) were administered to female Wistar rats (120 to 150 g '' '' .'' '. ' ' ' .. .
\ ' ;' WO91~11~8 PCT/US91/00763 2~7~

weight), for determination of the single maximum tolerated doses of these compounds. A minimum o~ 4 animals were injected per dose. For chlorambucil, doses of graat2r than 15 mg/kg i.v., and 26 mg/kg, i.p., induced seizure activity within 2 to 4 hr of administ.ation, and death occurred shortly thereafter.
Doses of up to 100 mg/Xg, i.v. and 150 mg/kg, i.p., of chlorambucil-tPrtiary butyl ester. HCl were tolerated by rats, although weight loss (approximately 20%) 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 lOmg/kg chlorambucil is the maximal dose that can be delivered to rats without toxicity, as was undertaken in pharmacokinetic studies, significantly higher doses of chlorambucil-tertiary butyl ester.HCl 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 chlorambucil-tertiary butyl ester maintains only low concentrations in plasma, following its distribution, and as n vitro plasma half-life studies indicate that chlorambucil-tertiary 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 water-soluble metabolites. Generation of these is known to cause myelosuppression ~5].

`

.' ' ' ' WO91/11998 PCT/US9l/00763 2076a50 Asticancer activity stu~es The standard assay used to assess the 1~ yitro sensitivity of tumors cells to chlorambucil-tertiary butyl e~ter and chlorambucil was the Capillary Human Clonogenic Cell Assay, HTCA ~1-4]. This anchorage-independent a~say 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 n vlvo chemotherapy has been demonstrated in both animal studies and in retrospective and prospective human 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 ~4]. 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 WO91/11998 PCTtUS91/00763 2~60~

failed ~CNU alkylating agent therapy, ~ollowing 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. T~is dose, however, was not achievable following a maximum tolerated dose of chlorambucil.
In summary, studies show that cnlorambucil-tertiary butyl ester possesses intrinsic alXylatins 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 [15]. Extensive studies have shown that these agents act to rapidly release chlorambucil rather than have pharmacological activity themselves ~15,20,21,27], and their pharmacological actions are similar to chlorambucil. However, steric hindrance around the ester link, provided by the tertiary butyl moiety, affords the compound sufficient stability n 30 ViVP to allow its significant accumulation in tissues of high lipid content. Due to low anzyme activity in these tissues the agent is minimally metabolized WO91/11998 rCT/US91/00763 2075~50 readily enters tumor cells, due to its lipophilicity, and cau~es 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. ~euro-Oncology Research Laboratory, Dept. Neurological Surgery, Univ.
Washington, Seattle, WA 98195.

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,~ . -.: .
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Claims (5)

We claim:

1. Use of the compound of formula (I) (I) for the manufacture of a medicament for the treatment of tumors that develop in or metastasize into tissues that contain a high content of lipids, wherein:
R1 is H, F, Cl, Br, or I;
R2 is H, F, Cl, Br, I or NH2;
R3, R4, and R5, which are the same or different, are H, F, Cl, Br, I, or C1-C3 alkyl; and n is O to 4.

2. Use according to claim 1, for the treatment of primary and metastatic tumors of the lymphatic system, ovaries and breasts.

3. Use of the compound of formula (II) (II) for the manufacture of a medicament for the treatment of primary and metastatic tumors of the lymphatic system, ovaries and breasts, wherein:
R1 is H, F, Cl, Br, or I amd R2 is H, F, Cl, Br, I or NHz.

4. Use of the compound of formula (III) (III) for the manufacture of a medicament for the treatment of primary and metastatic tumors of the lymphatic system, ovaries and breasts.

5. Use of the compound of any of claims 1, 3 and 4 for the manufacture of a medicament for the treatment of non-Hodgkin's lymphomas.