(12) United States Patent
`Camden
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,177,460 B1
`*J an. 23, 2001
`
`US006177460B1
`
`(54) METHOD OF TREATMENT FOR CANCER
`()R VIRAL INFECTIONS
`
`(75) Inventor: James Berger Camden, West Chester,
`OH (US)
`
`(73) Assignee: The Procter & Gamble Company,
`Cmcmam’ OH (Us)
`
`( * ) Notice:
`
`Under 35 U-S~C- 154(k)), the term of this
`patent Shall be eXtended for 0 days-
`_
`_
`_
`_
`_
`Th1_5 Patent 15 sublect to a termlnal 915'
`claimer.
`
`(21) Appl. No.: 09/408,664
`.
`(22) Filed.
`
`Sep. 29, 1999
`.
`.
`Related U'S'Apphcatmn Data
`(60) Continuation-in-part of application No. 09/364,021, ?led on
`Jul. 30, 1999, which is a division of application No. 08/876,
`705, ?led on Jun. 16, 1997, now Pat. No. 5,932,609, which
`is a division of application No. 08/680,468, ?led on Jul. 15,
`1996, now Pat. No. 5,932,604, which is a continuation-in-
`part of application NO‘ Gig/420,913’ ?led on Apr‘ 12’ 1995’
`now Pat. NO. 5,629,341.
`(60) Provisional application No. 60/001,888, ?led on Aug. 4,
`1995.
`(51) Int. c1.7 ................................................... .. A61K 31/27
`
`(52) US. Cl. .......... ..
`_
`(58) Field of Search .
`(56)
`References Cited
`
`514/485; 514/488
`
`...... .. 514/485, 488
`
`US. PATENT DOCUMENTS
`
`2,695,225
`2,734,911
`2,806,051
`3,799,758
`3,853,530
`3,903,297
`4,408,052
`4,542,219
`4,544,512
`
`,
`
`,
`
`4,866,059
`5,114,951
`5,254,715
`
`11/1954 Witman ................................ .. 71/214
`2/1956 Strain ................................. .. 260/471
`9/1957 Brockway .......................... .. 260/471
`3/1974 Franz ....... ..
`71/86
`12/1974 Franz
`71/76
`9/1975 Robert
`424/305
`10/1983 HoZumi ................................ .. 546/22
`HOZllIIlI ................................ ..
`10/1985 H°_Z_um1 et a1
`260/925
`lg;
`golfma """ "
`514/248
`9/1989 Temple
`.. 514/290
`5/1992 King ......... ..
`10/1993 Picard et a1. ......................... .. 560/13
`
`o]1ma
`
`.... ..
`
`5,336,690
`8/1994 Picard et al. ........................... .. 514/5
`5,629,341
`5/1997 Camden ............................. .. 514/485
`5,656,615
`8/1997 Camden ............................... .. 514/76
`FOREIGN PATENT DOCUMENTS
`
`WO 96/32103
`WO 96/32104
`
`10/1996 (WO) .
`10/1996 (W0) -
`OTHER PUBLICATIONS
`
`NASR, “Computer Assisted Structure—Anticancer Activity”
`J. Pharm. Sci., 74 (8) p 831—836 (Aug., 1985.
`Zilkah, “Effect of Inhibitors of Plant Cell Division on
`Mammalian Tumor Cells,” Cancer Research, 41, 1879—1883
`(May, 1981)_
`Zilkah, et al. Proc. Am. Assoc. Cancer Res., vol. 22, 270
`(1981).
`Merck Index, 11”” ed., Merck & Co., Inc. (RahWay, NJ,
`1989) p 1232 (#7769)
`BroWn, et al., J. Cell Biol., vol 16, No. 2, 514—536 (1974).
`Dialog, Elsevier Science Publishers Abst., No. 212600,
`XP002011351 of Brown et al" J‘ Cell‘ B101" V01‘ 16’ NO‘ 2"
`514_536 (1974)
`Dus et al. Arch. Immunol. Ther. EXp., vol. 33, No. 219,
`325_329 (1985)'
`_
`-
`Bandruma, et al., Pharm. Chem.J., vol. 12, No. 11, 35 37
`(NOV-a 1978)
`_
`MOChlda, 6t 211- TIOP- Agrlc. ReS- 561., V01. 19, 195—208
`(1985).
`Wa?enburg “Inhibitors of Colon Carcinogenesis” Cancer
`40 (5) pp. 2432—2435 (Nov., 1977).
`.
`.
`Audus, Herbicides, 2nd ed., vol. 2, pp. 55—82, 385—387
`Academic Press (1976)
`Schuster “Effects of Herbicides of the Urea and Carbamate
`Type” Ber. Inst. Tabakforschung Band 20 pp. 25—37 (1973).
`_
`_
`Primary Exammer—Jerome D. Goldberg
`(74) Attorney) Agent) or Firm_steven W, Miller; Rose Ann
`Dabek
`
`(57)
`
`ABSTRACT
`
`Methods for the treatment of cancers or viral infections in
`mammals are disclosed that include administration of an
`N_chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate, or a salt thereof. Such com
`pounds may be used in combination With a chemotherapeu
`“C agent and/Or a potennator'
`
`-
`
`-
`
`20 Claims, N0 Drawings
`
`CIPLA EXHIBIT 1028
`Page 1 of 14
`
`

`

`US 6,177,460 B1
`
`1
`METHOD OF TREATMENT FOR CANCER
`OR VIRAL INFECTIONS
`
`The present application is a continuation-in-part of US.
`Ser. No. 09/364,021, ?led Jul. 30, 1999 Which is a divisional
`of 08/876,705 ?led Jun. 16, 1997, now US. 5,932,609
`Which is a divisional of US. Ser. No. 08/680,468 ?led on
`Jul. 15, 1996 now US. Pat. No. 5,932,604. US. Ser. No.
`08/680,468 is a continuation-in-part application of US. Ser.
`No. 08/420,913 ?led Apr. 12, 1995, now US. Pat. No.
`5,629,341. US. Ser. No. 08/680,468 also claims priority to
`US. Ser. No. 60/001,888 ?led Aug. 4, 1995. The patent and
`patent applications are incorporated by reference herein.
`
`TECHNICAL FIELD
`
`The present invention relates to methods for the treatment
`of cancer or a viral infection in mammals, particularly in
`human and Warm blooded animals, using a composition
`containing
`N-chlorophenylcarbamate,
`N-chlorophenylthiocarbamate or salt thereof. The methods
`may use such a compound in combination With a potentiator
`or a chemotherapeutic agent.
`
`BACKGROUND OF THE INVENTION
`
`Cancers are the leading cause of death in animals and
`humans. The eXact cause of cancer is not knoWn, but links
`betWeen certain activities such as smoking or eXposure to
`carcinogens and the incidence of certain types of cancers
`and tumors has been shoWn by a number of researchers.
`Many types of chemotherapeutic agents have been shoWn
`to be effective against cancers and tumor cells, but not all
`types of cancers and tumors respond to these agents.
`Unfortunately, many of these agents also destroy normal
`cells. The eXact mechanism for the action of these chemo
`therapeutic agents are not alWays knoWn.
`Despite advances in the ?eld of cancer treatment the
`leading therapies to date are surgery, radiation and chemo
`therapy. Chemotherapeutic approaches are said to ?ght
`cancers that are metastasiZed or ones that are particularly
`aggressive. Such cytocidal or cytostatic agents Work best on
`cancers With large groWth factors, i.e., ones Whose cells are
`rapidly dividing. To date, hormones, in particular estrogen,
`progesterone and testosterone, and some antibiotics pro
`duced by a variety of microbes, alkylating agents, and
`antimetabolites form the bulk of therapies available to
`oncologists. Ideally cytotoXic agents that have speci?city for
`cancer and tumor cells While not affecting normal cells
`Would be eXtremely desirable. Unfortunately, none have
`been found and instead agents that target especially rapidly
`dividing cells (both tumor and normal) have been used.
`Clearly, the development of materials that Would target
`cancer cells due to some unique speci?city for them Would
`be a breakthrough. Alternatively, materials that Were cyto
`toXic to cancer cells While eXerting mild effects on normal
`cells Would be desirable.
`Human Immunode?ciency Virus (HIV), the etiological
`agent for AIDS (acquired immune de?ciency syndrome), is
`a member of the lentiviruses, a subfamily of retroviruses.
`HIV integrates its genetic information into the genome of the
`host. Most importantly, HIV infects and invades cells of the
`immune system; it breaks doWn the body’s immune system
`and renders the patient susceptible to opportunistic infec
`tions and neoplasms. HIV-1 is cytopathic for T4
`lymphocytes, cells of the immune system that express the
`cell surface differentiation antigen CD4. In addition to CD4+
`T cells, the host range of HIV includes cells of the mono
`
`2
`nuclear phagocytic lineage, including blood monocytes,
`tissue macrophages, Langerhans cells of the skin and den
`dritic reticulum cells Within lymph nodes.
`Precursor cells in the bone marroW are released into the
`blood in an immature circulating form knoWn as monocytes.
`Monocytes use the blood strictly as a transport medium.
`Once they arrive Where they’re going to be used, they leave
`the blood and complete differentiation into macrophages.
`Cells of the monocyte/macrophage lineage are a major target
`population for infection With HIV in the body and are
`thought to provide reservoirs of virus for disseminating
`infection throughout the body. HIV is also neurotropic,
`capable of infecting monocytes and macrophages in the
`central nervous system causing severe neurologic damage.
`They can interact and fuse With CD4-bearing T cells, caus
`ing T cell depletion and thus contributing to the pathogenesis
`of AIDS.
`Progression from HIV infection to AIDS is primarily
`determined by the effects of HIV on the cells that it infects,
`including CD4+ T lymphocytes and macrophages. In turn,
`cell activation, differentiation and proliferation regulate HIV
`infection and replication in those cells. HIV and other
`lentiviruses can proliferate in nonproliferating, terminally
`differentiated macrophages and groWth-arrested T lympho
`cytes. This ability of lentiviruses, including HIV, to replicate
`in nonproliferating cells, particularly in macrophages, is
`believed to be unique among retroviruses.
`Due to the above-mentioned problems in the art, the
`present inventor has sought improvements and provides
`such improvements herein.
`
`SUMMARY OF THE INVENTION
`
`Methods for treatment of mammals, and in particular,
`Warm blooded animals and humans that are affected by
`cancer or viral infection comprising administering a thera
`peutically effective amount of an N-chlorophenylcarbamate,
`an N-chlorophenylthiocarbamate, or a salt thereof, are pro
`vided by the
`present
`invention. An
`N-chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate has the formula:
`
`c1,
`
`X 04“ H
`
`15
`
`25
`
`35
`
`45
`
`Wherein n is from 1 to 3, X is oXygen or sulfur, and R is
`selected from the group consisting of hydrogen, loWer alkyl,
`loWer alkenyl, cycloheXyl, phenalkyl of up to 8 carbon
`atoms, and phenyl.
`These compositions are effective in killing or sloWing the
`groWth of cancers, yet are safer than adriamycin on normal,
`healthy cells. The compositions are also particularly effec
`tive against cells of monocytic lineage infected With HIV.
`
`55
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`A. DEFINITIONS:
`A As used herein, “a therapeutically effective amount,”
`means the concentration or quantity or level of the com
`pound of the present invention that can attain a particular
`medical end, such as control or destruction of cancer cells,
`virally-infected cells, or viruses Without producing unac
`ceptable toXic symptoms. The term “safe and effective
`amount” refers to the quantity of a component Which is
`
`65
`
`CIPLA EXHIBIT 1028
`Page 2 of 14
`
`

`

`US 6,177,460 B1
`
`10
`
`15
`
`3
`sufficient to yield a desired therapeutic response Without
`undue adverse side effects (such as toxicity, irritation, or
`allergic response) commensurate With a reasonable bene?t/
`risk ratio When used in the manner of this invention. The
`speci?c “safe and effective amount” Will vary With such
`factors as the particular condition being treated, the physical
`condition of the patient, the type of mammal being treated,
`the duration of the treatment, the nature of concurrent
`therapy (if any), and the speci?c formulations employed and
`the structure of the compounds or its salts.
`As used herein, a “subject in need thereof,” is a mammal
`having cancer or having a viral infection. As used herein,
`“cancer” refers to all types of cancers, or neoplasms or
`benign or malignant tumors. In one embodiment, those
`cancers that attack normal healthy blood cells or bone
`marroW are contemplated by the present invention. Preferred
`cancers for treatment using methods provided herein include
`carcinoma. By “carcinoma” is meant a benign or malignant
`epithelial tumor and includes, but is not limited to, breast
`carcinoma, prostate carcinoma, non-small cell lung
`carcinoma, colon carcinoma, CNS carcinoma, melanoma
`carcinoma, ovarian carcinoma, or renal carcinoma. A pre
`ferred host is a human host.
`As used herein, “a cell of monocytic lineage” means a cell
`having a bone marroW precursor cell and that differentiates
`into a macrophage cell, and includes monocytes and mac
`rophages.
`As used herein, “viruses” includes viruses that cause
`disease in Warm blooded animals including retroviruses such
`as HIV or HTLV, in?uenza, rhinoviruses, herpes, or the like.
`As used herein, an N-chlorophenylcarbamate, or an
`N-chlorophenylthiocarbamate, or salt thereof are “com
`pounds of the present invention.” Such compounds are
`further set forth in Section B infra.
`As used herein, “potentiators” are materials that affect the
`immune system or enhance the effectiveness of the drugs
`and are further set forth in section E herein.
`As used herein, “chemotherapeutic agents” includes
`DNA-interactive agents, antimetabolites, tubulin-interactive
`agents, hormonal agents and others, such as asparaginase or
`hydroxyurea and are as further set forth in Section D infra.
`FolloWing long-standing patent laW convention, the terms
`“a” and “an” mean “one or more” When used in this
`application, including the claims.
`B. N-CHLOROPHENYLCARBAMATE OR
`45
`N-CHLOROPHENYLTHIO CARBAMATE
`an
`or
`An N-chlorophenylcarbamate
`N-chlorophenylthiocarbamate has the folloWing structure
`
`25
`
`35
`
`c1],
`
`I|\I—C—X R
`
`H
`
`Wherein n is from 1 to 3, X is oxygen or sulfur, and R is
`selected from the group consisting of hydrogen, loWer alkyl,
`loWer alkenyl, cyclohexyl, phenalkyl of up to 8 carbon
`atoms and phenyl.
`Preferred compounds are those in Which R is alkyl With 1
`to 4 carbons, preferably, isopropyl; X is oxygen; n is 1; and
`the chloro group is in the 3 position on the phenyl group.
`N-3chlorophenylcarbamate is a most preferred compound.
`These compounds are prepared according to the method
`described in US. Pat. No. 2,695,225 issued to Witman
`(1954) and US. Pat. No. 2,734,911 issued to Strain (1956),
`incorporated by reference herein. As used herein, a a
`
`55
`
`65
`
`4
`compound of the present invention” is an
`N-chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate, or a salt thereof.
`Pharmaceutically acceptable addition salts of
`N-chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate, are considered Within the
`scope of compounds of the present invention and are salts
`With an organic or inorganic acid. Preferred acid addition
`salts are chlorides, bromides, sulfates, nitrates, phosphates,
`sulfonates, formates, tartrates, maleates, malates, citrates,
`benZoates, salicylates, ascorbates, or the like. Such salts may
`be synthesiZed from the compound, or derivative thereof, of
`the present invention that contains a basic or acidic moiety
`by conventional chemical methods. Generally, such salts
`may be prepared by reacting a free acid or base form of the
`compound, or derivative thereof, With a stoichiometric
`amount of the appropriate base or acid in Water or in an
`organic solvent, or in a mixture of the tWo; generally,
`nonaqueous media like ether, ethyl acetate, ethanol,
`isopropanol, or acetonitrile are preferred. Further suitable
`salts may be found in Remington." The Science and Practice
`of Pharmacy, 19th ed., Mack Publishing Company, Easton,
`Pa., 1995, p. 1457.
`Pharmaceutically acceptable salts of the compounds of
`the present invention include conventional non-toxic salts or
`the quaternary ammonium salts of the compounds or deriva
`tives formed, for example, from non-toxic inorganic or
`organic acids. For example, such conventional non-toxic
`salts include those derived from inorganic acids such as
`hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,
`nitric, or the like; and salts prepared from organic acids such
`as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
`tartaric, citric, ascorbic, maleic, hydroxymaleic,
`phenylacetic, glutamic, benZoic, salicylic, sulfanilic,
`2-acetoxybenZoic, fumaric, toluenesulfonic,
`methanesulfonic, ethane disulfonic, oxalic, isethionic, or the
`like. Preferred acid addition salts are chlorides, bromides,
`sulfates, nitrates, phosphates, sulfonates, formates, tartrates,
`maleates, malates, citrates, benZoates, salicylates,
`ascorbates, or the like.
`Further, included Within the scope of the compound, or
`salts thereof, useful for the present invention are prodrugs.
`As used herein, a “prodrug” is a drug covalently bonded to
`a carrier Wherein release of the drug occurs in vivo When the
`prodrug is administered to a mammalian subject. Prodrugs
`of the compounds of the present invention are prepared by
`modifying functional groups present in the compounds in
`such a Way that the modi?cations are cleaved, either in
`routine manipulation or in vivo, to yield the desired com
`pound. Prodrugs include compounds Wherein hydroxy,
`amine, or sulfhydryl groups are bonded to any group that,
`When administered to a mammalian subject, is cleaved to
`form a free hydroxyl, amino, or sulfhydryl group, respec
`tively. Examples of prodrugs include, but are not limited to,
`acetate, formate, or benZoate derivatives of alcohol or amine
`functional groups in the compounds of the present invention;
`phosphate esters, dimethylglycine esters, aminoalkylbenZyl
`esters, aminoalkyl esters or carboxyalkyl esters of alcohol or
`phenol functional groups in the compounds of the present
`invention; or the like.
`Compounds of the present invention are knoWn for their
`herbicidal activities. They are systemic herbicides used to
`prevent and eradicate certain plants or Weeds. Systemic
`herbicides are differentiated from other herbicides by their
`ability to be absorbed by the plant and to move through the
`plant. This systemic ability is not a necessary requirement of
`the compounds of this invention.
`
`CIPLA EXHIBIT 1028
`Page 3 of 14
`
`

`

`C. SCREENING ASSAYS
`Screening assays for determining those cancers suscep
`tible to treatment using compounds of the present invention
`include incubating cell line models representing speci?c
`cancers as set forth, for example, by the National Cancer
`Institute, in the presence and absence of such compounds.
`Viability of cells may be determined by the MTT assay
`(Promega Corp., Madison, Wis. 53711), or the SRB
`(sulforhodamine B) assay (Skehan, et al., JNCI, 82:13,1107,
`1990). Susceptibility to said compounds exists When viabil
`ity in the presence of a compound of the present invention
`is less than viability in the absence of such compound.
`Exemplary cell line models representing speci?c cancers
`include, but are not limited to, the folloWing:
`Non-small cell lung cancer NCIH23, NCIH324,
`NCIH522, A549/ATCC, A549(ASC), CALU1, EKVX,
`NCIH125M, NCIH226, NCIH520, SKMES1,
`NCIH322M, NCIH358M, NCIH460, NCIH292,
`HOP62, HOP18, HOP19, HOP92, LXFL 529,
`SW1573, LXFS 650L, ML1019, ML1076, ML1045, or
`UABLG22;
`Small cell lung cancer: NCIH69, NCIH146, NCIH82,
`NCIH524, DMS 114, DMS 273, HOP27, SHP77, or
`RHOS;
`25
`Colon cancer: HT29, HCC2998, HCT116, LOVO, SW
`1116, SW620, COLO 205, DLD1, WIDR, COLO
`320DM, HCT15, CXF 280, KM12, KM20L2, COLO
`741, CXF 264L, COLO 746, UABC02, ML1059,
`CAC02, HT29/PAR, HT29/MDR1, or NB4;
`Breast cancer: MCF7, MCF7/ADRRES, ZR751, ZR7530,
`MDAMB231/ATCC, HS 578T, UISOBCA1, MCF7/
`ATCC, SKBR3, MDAMB435, MDAN, BT549, T47D,
`MDAMB231, MAXF 401, BT474, or MDAMB488;
`Ovarian cancer OVCAR3, OVCAR4, OVCAR5,
`OVCAR8, A2780, IGROV1, SKOV3, OVXF 899,
`A1336, or ES2;
`Leukemia: P388, P3888/ADR, CCRFCEM, CCRFSB,
`K562, MOLT4, L1210, HL60(TB), RPMI8226, SR, or
`K562/ADR;
`Fibroblast IMR90, or CCD19LU;
`Renal cancer: U031, SN12C, SN12S1, SN12K1,
`SN12L1, SN12A1, A498, A704, CAKI1, RXF 393,
`RXF831, 7860, SW156, TK164, 769P, SS78, ACHN,
`TKIO, RXF 486L, UOK57, or UOK57LN;
`Melanoma: LOX IMVI, MALME3M, RPMI7951,
`SKMEL2, SKMEL5, SKMEL28, SKMEL31, UCSD
`242L, UCSD 354L, M14, M19MEL, UACC82,
`UACC257, MEXF 514L, or UABMEL3;
`Prostate cancer PC3, PC3M, DU145, LNCAP, 1013L,
`UMSCP1, WIS, JE, RER, MRM, DHM, AG, RB, RVP,
`FC, WAE, DB/SMC, JCA1, ND1, WMF, TSUPRI,
`JECA, GDP, T10, WBW, RVP1, or WLL;
`CNS cancer SNB7, SNB19, SNB4, SNB56, SNB75,
`SNB78, U251, TE671, SF268, SF295, SF539, XF 498,
`SW 1088, SW 1783, U87 MG, SF767, SF763,Al 72, or
`SMSKCNY;.
`Bone/muscle: A204/ATCC, OHS, TE85, A673, CHA59,
`MHM 25, RH18, RH30, or RD; and
`Lymphoma: AS283, HT, KD488, PA682, SUDHL7, RL,
`DB, SUDHL1, SUDHL4, SUDHL10, NUDUL1, or
`HUT 102.
`D. CHEMOTHERAPEUTIC AGENTS
`Chemotherapeutic agents are generally grouped as DNA
`interactive agents, antimetabolites, tubulin-interactive
`agents, hormonal agents, other agents such as asparaginase
`
`35
`
`45
`
`55
`
`65
`
`US 6,177,460 B1
`
`5
`
`15
`
`6
`or hydroxyurea, and agents as set forth in Table 1. Each of
`the groups of chemotherapeutic agents can be further
`divided by type of activity or compound. Chemotherapeutic
`agents used in combination With an
`N-chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate, or salts thereof of the present
`invention may be selected from any of these groups but are
`not limited thereto. For a detailed discussion of the chemo
`therapeutic agents and their method of administration, see
`Dorr, et al, Cancer Chemotherapy Handbook, 2d edition,
`pages 15—34, Appleton & Lange (Connecticut, 1994) herein
`incorporated by reference.
`DNA-interactive agents include alkylating agents, eg
`cisplatin, cyclophosphamide, altretamine; DNA strand
`breakage agents, such as bleomycin; intercalating topoi
`somerase II inhibitors, e.g., dactinomycin and doxorubicin);
`nonintercalating topoisomerase II inhibitors such as, etopo
`side and teniposide; and the DNA minor groove binder
`picamycin, for example.
`The alkylating agents form covalent chemical adducts
`With cellular DNA, RNA, or protein molecules, or With
`smaller amino acids, glutathione, or similar chemicals.
`Generally, alkylating agents react With a nudeophilic atom in
`a cellular constituent, such as an amino, carboxyl,
`phosphate, or sulfhydryl group in nucleic acids, proteins,
`amino acids, or in glutathione. The mechanism and the role
`of these alkylating agents in cancer therapy is not Well
`understood.
`Typical alkylating agents include, but are not limited to,
`nitrogen mustards, such as chlorambucil,
`cyclophosphamide, isofamide, mechlorethamine,
`melphalan, uracil mustard; aZiridine such as thiotepa; meth
`anesulphonate esters such as busulfan; nitroso ureas, such as
`carmustine, lomustine, streptoZocin; platinum complexes,
`such as cisplatin, carboplatin; bioreductive alkylator, such as
`mitomycin, and procarbaZine, dacarbaZine and altretamine.
`DNA strand breaking agents include bleomycin, for
`example.
`DNA topoisomerase II inhibitors include the folloWing
`intercalators, such as amsacrine, dactinomycin,
`daunorubicin, doxorubicin (adriamycin), idarubicin, and
`mitoxantrone; nonintercalators, such as etoposide and
`teniposide, for example.
`A DNA minor groove binder is plicamycin, for example.
`Antimetabolites interfere With the production of nucleic
`acids by one of tWo major mechanisms. Certain drugs inhibit
`production of deoxyribonucleoside triphosphates that are the
`immediate precursors for DNA synthesis, thus inhibiting
`DNA replication. Certain of the compounds are analogues of
`purines or pyrimidines and are incorporated in anabolic
`nucleotide pathWays. These analogues are then substituted
`into DNA or RNA instead of their normal counterparts.
`Antimetabolites useful herein include, but are not limited
`to, folate antagonists such as methotrexate and trimetrexate;
`pyrimidine antagonists, such as ?uorouracil,
`?uorodeoxyuridine, CB3717, aZacitidine, cytarabine, and
`?oxuridine; purine antagonists include mercaptopurine,
`6thioguanine, ?udarabine, pentostatin; sugar modi?ed ana
`logs include cyctrabine, ?udarabine; and ribonucleotide
`reductase inhibitors include hydroxyurea.
`Tubulin interactive agents act by binding to speci?c sites
`on tubulin, a protein that polymeriZes to form cellular
`microtubules. Microtubules are critical cell structure units.
`When the interactive agents bind the protein, the cell can not
`form microtubules. Tubulin interactive agents include vin
`cristine and vinblastine, both alkaloids and paclitaxel, for
`example.
`
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`US 6,177,460 B1
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`7
`Hormonal agents are also useful in the treatment of
`cancers and tumors. They are used in hormonally susceptible
`tumors and are usually derived from natural sources. Hor
`monal agents include, but are not limited to, estrogens,
`conjugated estrogens and ethinyl estradiol and
`diethylstilbesterol, chlortrianisen and idenestrol; progestins
`such as hydroxyprogesterone caproate,
`medroxyprogesterone, and megestrol; and androgens such
`as testosterone, testosterone propionate; ?uoxymesterone,
`and methyltestosterone.
`Adrenal corticosteroids are derived from natural adrenal
`cortisol or hydrocortisone. They are used because of their
`anti-in?ammatory bene?ts as Well as the ability of some to
`inhibit mitotic divisions and to haft DNA synthesis. These
`compounds include, but are not limited to, prednisone,
`dexamethasone, methylprednisolone, and prednisolone.
`LeutiniZing hormone releasing hormone agents or
`gonadotropin-releasing hormone antagonists are used pri
`
`15
`
`8
`marily the treatment of prostate cancer. These include leu
`prolide acetate and goserelin acetate. They prevent the
`biosynthesis of steroids in the testes.
`Antihormonal antigens include, for example, antiestro
`genic agents such as tamoxifen, antiandrogen agents such as
`?utamide; and antiadrenal agents such as mitotane and
`aminoglutethimide.
`Further agents include the folloWing: hydroxyurea
`appears to act primarily through inhibition of the enZyme
`ribonucleotide reductase, and asparaginase is an enZyme
`Which converts asparagine to nonfunctional aspartic acid
`and thus blocks protein synthesis in the tumor.
`Taxol (paclitaxel) is a preferred chemotherapeutic agent.
`A listing of currently available chemotherapeutic agents
`according to class, and including diseases for Which the
`agents are indicated, is provided as Table 1.
`
`TABLE 1
`
`Neoplastic Diseases1 for Which Exemplary Chemotherapeutic agents are
`Indicated
`
`Class
`
`Type of Agent
`
`Name
`
`Disease2
`
`Mechlorethamine
`(HN2)
`Cyclophosphamide
`Ifosfamide
`
`Melphalan
`
`Chlorambucil
`
`Alkylating Agents Nitrogen Mustards
`
`Ethylenimines and
`Methylmelamines
`Alkyl Sulfonates
`Nitrosoureas
`
`Hodgkin’s disease, non
`Hodgkin’s lymphomas
`Acute and chronic lymphocytic
`leukemias, Hodgkin’s disease,
`non-Hodgkin’s lymphomas,
`multiple myeloma,
`neuroblastoma, breast, ovary,
`lung, Wilms’ tumor, cervix,
`testis, soft tissue sarcomas
`Multiple myeloma, breast,
`ovary
`Chronic lymphocytic leukemia,
`primary macroglobulinemia,
`Hodgkin’s disease, non
`Hodgkin’s lymphomas
`Prostate
`Estramustine
`Hexamethylmelamine Ovary
`T'hiotepa
`Bladder, breast, ovary
`Busulfan
`Chronic granulocytic leukemia
`Carmustine
`Hodgkin’s disease, non
`Hodgkin’s lymphomas, primary
`brain tumors, multiple
`myeloma, malignant
`melanoma
`Hodgkin’s disease, non
`Hodgkin’s lymphomas, primary
`brain tumors, small-cell lung
`Primary brain tumors,
`stomach, colon
`Malignant pancreatic
`insulinoma, malignant
`carcinoid
`Malignant melanoma,
`Hodgkin’s disease, soft tissue
`sarcomas
`Acute lymphocytic leukemia,
`choriocarcinoma, mycosis
`fungoides, breast, head and
`neck, lung, osteogenic
`
`Lomustine
`
`Semustine
`
`Streptozocin
`
`Antimetabolites
`
`Triazenes
`
`Dacarbazine
`Procarbazine
`Aziridine
`Folic Acid Analogs Methotrexate
`Trimetrexate
`
`Pyrimidine
`Analogs
`
`Purine Analogs
`and Related
`Inhibitors
`
`Fluorouracil
`Floxuridine
`
`sarcoma
`Breast, colon, stomach,
`pancreas, ovary, head and
`neck, urinary bladder,
`premalignant skin lesions
`(topical)
`Cytarabine Azacitidine Acute granulocytic and acute
`lymphocytic leukemias
`Acute lymphocytic, acute
`granulocytic, and chronic
`granulocytic leukemias
`
`Mercaptopurine
`
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`US 6,177,460 B1
`
`9
`
`TABLE l-continued
`
`Neoplastic Diseases1 for Which Exemplary Chemotherapeutic agents are
`Indicated
`
`Class
`
`Type of Agent
`
`Name
`
`Disease2
`
`Thioguanine
`
`Pentostatin
`
`Fludarabine
`
`Natural Products Vinca Alkaloids
`
`Vinblastine (VLB)
`
`Vincris tine
`
`Vindes ine
`
`EpipodophyllotoXins
`
`Etop os ide
`Tenip os ide
`
`Antibiotics
`
`Dactinomycin
`
`Daunorubicin
`
`DoXorubicin
`4'—DeoXydoXorubicin
`
`Bleomycin
`
`Plicamycin
`
`Mitomycin
`
`L-Asparaginase
`DocetaXel
`PaclitaXel
`Interferon Alfa
`
`Enzymes
`TaXanes
`TaXoids
`Biological
`Response
`Modi?ers
`
`Miscellaneous
`Agents
`
`Platinum
`Coordination
`Complexes
`
`Tumor Necrosis Factor
`Tumor-In?ltrating
`Lymphocytes
`Cisplatin
`Carboplatin
`
`Anthracenedione
`
`MitoXantrone
`
`Substituted Urea
`
`HydroXyurea
`
`Methyl Hydrazine
`Derivative
`
`Procarbazine
`
`Acute granulocytic, acute
`lymphocytic, and chronic
`granulocytic leukemias
`Hairy cell leukemia, mycosis
`fungoides, chronic lymphocytic
`leukemia
`Chronic lymphocytic leukemia,
`Hodgkin’s and non-Hodgkin’s
`lymphomas, mycosis
`fungoides
`Hodgkin’s disease, non
`Hodgkin’s lymphomas, breast,
`testis
`Acute lymphocytic leukemia,
`neuroblastoma, Wilms’ tumor,
`rhabdomyosarcoma, Hodgkin’s
`disease, non-Hodgkin’s
`lymphomas, small-cell lung
`Vinca-resistant acute
`lymphocytic leukemia, chronic
`myelocytic leukemia,
`melanoma, lymphomas, breast
`Testis, small-cell lung and
`other lung, breast, Hodgkin’s
`disease, non-Hodgkin’s
`lymphomas, acute granulocytic
`leukemia, Kaposi’s sarcoma
`Choriocarcinoma, Wilms’
`tumor, rhabdomyosarcoma,
`testis, Kaposi’s sarcoma
`Acute granulocytic and acute
`lymphocytic leukemias
`Soft tissue, osteogenic, and
`other sarcomas; Hodgkin’s
`disease, non-Hodgkin’s
`lymphomas, acute leukemias,
`breast, genitourinary, thyroid,
`lung, stomach, neuroblastoma
`Testis, head and neck, skin,
`esophagus, lung, and
`genitourinary tract; Hodgkin’s
`disease, non-Hodgkin’s
`lymphomas
`Testis, malignant
`hypercalcemia
`Stomach, cervix, colon, breast,
`pancreas, bladder, head and
`neck
`Acute lymphocytic leukemia
`Breast, ovarian
`
`Hairy cell leukemia, Kaposi’s
`sarcoma, melanoma,
`carcinoid, renal cell, ovary,
`bladder, non-Hodgkin’s
`lymphomas, mycosis
`fungoides, multiple myeloma,
`chronic granulocytic leukemia
`Investigational
`Investigational
`
`Testis, ovary, bladder, head
`and neck, lung, thyroid, cerviX,
`endometrium, neuroblastoma,
`osteogenic sarcoma
`Acute granulocytic leukemia,
`breast
`Chronic granulocytic leukemia,
`polycythemia vera, essential
`thrombocytosis, malignant
`melanoma
`Hodgkin’s disease
`
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`US 6,177,460 B1
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`11
`
`TABLE l-continued
`
`12
`
`Neoplastic Diseases1 for Which Exemplary Chemotherapeutic agents are
`Indicated
`
`Class
`
`Type of Agent
`
`Name
`
`Disease2
`
`Hormones and
`Antagonists
`
`Adrenocortical
`Suppressant
`Adrenocorti-
`costeroids
`
`Progestins
`
`Estrogens
`
`Antiestrogen
`Androgens
`
`Antiandrogen
`Gonadotropin-
`releasing hormone
`analog
`
`Mitotane
`Aminoglutethimide
`Prednisone
`
`Adrenal cortex
`Breast
`Acute and chronic lymphocytic
`leukemias, non-Hodgkin’s
`lymphomas, Hodgkin’s
`disease, breast
`Hydroxy-progesterone Endometrium, breast
`caproate
`Medroxy-progesterone
`acetate
`Megestrol acetate
`Diethylstil-bestrol
`Ethinyl estradiol
`Tamoxifen
`Testosterone
`propionate
`Fluoxymesterone
`Flutamide
`Leuprolide
`Goserelin
`
`Breast, prostate
`
`Breast
`Breast
`
`Prostate
`Prostate, Estrogen-receptor
`positive breast
`
`1Adapted from Calabresi, P., and B. A. Chabner, “Chemotherapy of Neoplastic Diseases” Section
`XII, pp 1202-1263 in: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Eighth
`ed., 1990 Pergamin Press, Inc.; and BarroWs, L. R., “Antineoplastic and Immunoactive Drugs”,
`Chapter 75, pp 1236-1262, in: Remington: The Science and Practice of Pharmacy, Mack Publish
`ing Co. Easton, PA, 1995.; both references are incorporated by reference herein, in particular for
`treatment protocols.
`2Neoplasms are carcinomas unless otherWise indicated.
`
`E. POTENTIATORS
`A“potentiator,” as used herein, is a material that improves
`or increases the ef?cacy of N-chlorophenylcarbamate, or an
`N-chlorophenylthiocarbamate or a salt thereof, or that acts
`on the immune system as an immunomodulator, and is used
`in combination With a compound of the present invention. A
`potentiator may be an antiviral agent. One such potentiator
`is triprolidine or its cis-isomer. Triprolidine is described in
`US. Pat. No. 5,114,951 (1992, the patent is incorporated by
`reference herein). A further potentiator is procodaZole, (also
`named lH-benzimidazole-2-propanoic acid, or [3-(2
`benZimidaZole) propionic acid or 2-(2-carboxyethyl)
`benZimidaZole or propaZol). ProcodaZole is a non-speci?c
`immunoprotective agent active against viral and bacterial
`infections and may be used in combination With the com
`pounds set forth herein. ProcodaZole is effective With an
`N-chlorophenylcarbamate,
`or
`an
`N-chlorophenylthiocarbamate or salt thereof, alone in treat
`ing cancers, tumors, leukemia or viral infections, or com
`bined With a chemotherap