WO2008112251A1 - Analogues de polyamine contenant des groupes cyclopropyle comme thérapies de la maladie - Google Patents

Analogues de polyamine contenant des groupes cyclopropyle comme thérapies de la maladie Download PDF

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WO2008112251A1
WO2008112251A1 PCT/US2008/003273 US2008003273W WO2008112251A1 WO 2008112251 A1 WO2008112251 A1 WO 2008112251A1 US 2008003273 W US2008003273 W US 2008003273W WO 2008112251 A1 WO2008112251 A1 WO 2008112251A1
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compound
alkyl
compounds
mmol
tumor
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PCT/US2008/003273
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Benjamin Frydman
Aldonia L. Valasinas
Laurence J. Marton
Venudhar K. Reddy
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Progen Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
    • C07C211/18—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing at least two amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • This application relates to methods of treating diseases, such as cancer, using polyamine analogs containing cyclopropyl groups.
  • Polyamines are naturally-occurring compounds which are essential for the growth and division of cells. Polyamines (including putrescine, spermidine, and spermine) increase in proliferating tissues. A number of polyamine analogues have shown promise as anticancer agents. They are able to kill cells and inhibit cell growth both in vitro and in vivo. Most successful among these analogues have been the ⁇ -N, ⁇ -N alkyl derivatives of the higher and lower homologues of spermine, although several alkylated diamines also show promise as inhibitors of tumor cell proliferation. See, e.g., U.S. Patent Nos. 5,541,230 and 5,880,161.
  • spermidine and spermine are strong bases, they are protonated at physiological pH and can therefore bind to the negatively charged nucleic acids either by electrostatic interactions or by hydrogen bonding.
  • Polyamines are known to interact with and induce structural changes in DNA in cell-free systems. Spermidine and spermine can cause DNA to condense and aggregate and can induce both B-to-Z and B-to-A transitions in certain DNA sequences.
  • spermine-DNA interactions have shown that, in a minimum energy conformation, spermine is bound in a cisoidal conformation that wraps around the major groove of the double helix.
  • spermine and N, N-bisethylspermine (BES) were found to bind at the T ⁇ C loop of t-RNA Phe .
  • the binding is not of an electrostatic nature, but rather a consequence of the different hydrogen-bonding modes that can be established between both types of molecules.
  • DNA-interacting drugs have long been of interest as anticancer agents.
  • Conformationally restricted polyamine analogs have been shown to have anticancer effects in vitro and/or in vivo.
  • One example of a conformational restriction involves the addition of a cyclopropyl ring to the butane segment of spermine. This introduces chirality and conformational restriction in an otherwise flexible molecule.
  • the structure (I) shows the conformation of 1 N, 12 N-bisethylspermine (BES), while the two structures (II) and (III) show the conformation of the trans-isomer (II) and cis- isomer (III) resulting from replacing the central butane segment in BES with trans- and cis- ⁇ , 2-dimethylcyclopropyl residues, respectively.
  • Cyclopropane derivatives are also known to have important biological functions. Incorporating a cyclopropane moiety into a polyamine structure can enhance the anticancer effect of the polyamine analog via additional mechanisms complementary to the conformational effect on the polyamine analog.
  • polyamines and their analogues bind to nucleic acids and alter their conformations, that they bind to receptor targets, that they drastically reduce the level of ornithine decarboxylase (the first enzyme in the pathway that leads to spermine biosynthesis in mammals), that they upregulate the levels of spermidine/spermine N-acetyltransferase (the enzyme involved in the catabolism and salvage pathways of spermine and spermidine), that they may inhibit the uptake of the natural polyamines by the cells, and that, as a result, they deplete endogenous polyamine pools needed for cell replication.
  • ornithine decarboxylase the first enzyme in the pathway that leads to spermine biosynthesis in mammals
  • the present invention provides particularly efficacious polyamine analogs containing cyclopropyl groups, demonstrating strong anti-tumor activity with a wide therapeutic window.
  • One embodiment of the invention includes compounds of the formulas:
  • Ri and R 2 are independently selected from the group consisting of -Ci-Ci 0 alkyl, -C 3 -Ci 0 cycloalkyl, -Ci-Ci 0 alkylene-cycloalkyl, -C 6 -Ci 0 aryl, and -Ci-C] 0 alkylene-aryl, wherein when both Ri and R 2 are alkyl, at least one of Ri and R 2 is C 2 -Ci 0 alkyl and wherein both Ri and R 2 are not tert-buty ⁇ ; and all salts, hydrates, solvates, and stereoisomers thereof; and all mixtures of stereoisomers thereof, including racemic mixtures.
  • the substituents on the cyclopropyl ring are trans to each other.
  • the substituents on the cyclopropyl ring are cis to each other.
  • Ri and R 2 when both Ri and R 2 are alkyl, at least one of Ri and R 2 is straight-chain alkyl. In another embodiment, when both R) and R 2 are alkyl, both Ri and R 2 are straight-chain alkyl. In one embodiment, one of Ri and R 2 is -Ci-C] 0 alkyl and the other is -C 2 -Ci O alkyl. In one embodiment, one of R] and R 2 is -C]-C 5 alkyl and the other is -C 4 -Ci 0 alkyl. In one embodiment, both Ri and R 2 are -C 4 -Cj 0 alkyl.
  • one of R] and R 2 is -C 6 -Ci 0 alkyl. In one embodiment, both Ri and R 2 are -C 6 -Ci 0 alkyl. In one embodiment, one of Ri and R 2 is -Ci-C] 0 alkyl and the other is selected from the group consisting Of -C 2 -C 4 straight-chain alkyl and -C 4 -Ci 0 alkyl. In another embodiment, Rj and R 2 are independently selected from the group consisting of -CH 3 , -(CH 2 ) 3 CH 3 , and -(CH 2 ) 8 CH 3 , provided that both Ri and R 2 are not -CH 3 .
  • one of Ri and R 2 is -Ci-C 10 alkyl and the other is -C 3 -C] 0 cycloalkyl, -Ci-C] 0 alkylene-cycloalkyl, -C 6 -Ci 0 aryl, or -Ci-Cio alkylene-aryl.
  • one of Ri and R 2 is -Ci-C] 0 alkyl and the other is -C 3 -C] 0 cycloalkyl or -Ci-C] 0 alkylene-cycloalkyl.
  • one of Ri and R 2 is -Ci-C] 0 alkyl and the other is -C 3 -Ci 0 cycloalkyl. In one embodiment, one of Ri and R 2 is -Ci-C] 0 alkyl and the other is -C 6 -Ci 0 aryl or -C]-Ci 0 alkylene-aryl. In one embodiment, one of Ri and R 2 is -Ci-C] 0 alkyl and the other is -C 6 -Ci 0 aryl. In another embodiment, both Rj and R 2 are -C 6 -Ci 0 aryl.
  • both R] and R 2 are -C 3 -Ci 0 cycloalkyl.
  • the aryl group is benzene.
  • the cycloalkyl group is adamantyl.
  • the adamantyl group is 1 -adamantyl.
  • the adamantyl group is 2-adamantyl.
  • Ri and R 2 are independently selected from the group consisting of -CH 3 , phenyl, and adamantyl, provided that both Rj and R 2 are not -CH 3 . [0016] Specific embodiments of compounds of this type include:
  • the compound is selected from the group consisting of: (lS,2R)-l-[(4-decylamino-butylamino)-methyl]-2-[(4-ethylamino-butylamino)- methyl] -cyclopropane ;
  • the invention includes a racemic mixture of a compound of the formula: n ; and all salts, hydrates, and solvates thereof.
  • the invention embraces a method of treating a variety of diseases caused by uncontrolled proliferation of cells, including cancer, particularly prostate cancer, comprising administering one or more of the above compounds to a subject having cancer or other disease caused by abnormal cell proliferation in an amount sufficient to have a therapeutic effect.
  • the therapeutic effect is the prevention, reduction, or elimination of either the disease or the symptoms of the disease, or retardation of the progression of the disease or of symptoms of the disease.
  • one or more compound(s) of the invention is administered with one or more additional therapeutic agents.
  • the method comprises administering one or more of the above compounds to a subject having cancer in an amount sufficient to have a therapeutic effect on the cancer.
  • the amount of the compound(s) of the invention administered is sufficient to have a therapeutic effect results in extending the median survival of a subject group relative to an untreated group.
  • the subject group is mice, and the median survival is extended by at least about 2, at least about 5, at least about 7, or at least about 10 days.
  • the subject group is dogs, and the median survival is extended by at least about 1, at least about 3, at least about 6, at least about 9, or at least about 12 months.
  • the subject group is cats, and the median survival is extended by at least about 1, at least about 3, at least about 6, at least about 9, or at least about 12 months.
  • the subject group is humans and the median survival is extended by at least about 3 months, at least about 6 months, or at least about 12 months, hi one embodiment, the cancer is prostate cancer.
  • the method comprises administering one or more of the above compounds to a subject having a tumor in an amount sufficient to reduce the rate of growth of the tumor.
  • the method comprises administering one or more of the above compounds to a subject having a solid tumor in an amount sufficient to reduce the size of the tumor.
  • the amount is sufficient to reduce the size of the tumor by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 90%.
  • the amount is sufficient to essentially eliminate the tumor.
  • the tumor is a prostate tumor.
  • the method comprises administering one or more of the above compounds to a subject having metastatic tumors in an amount sufficient to stabilize the number of metastases. In one embodiment, the method comprises administering one or more of the above compounds to a subject having metastatic tumors in an amount sufficient to reduce the number of metastases. In one embodiment, the amount is sufficient to reduce the number of metastases by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 90%. In another embodiment, the amount is sufficient to essentially eliminate all metastases. In another embodiment, the metastatic tumors are derived from a prostate tumor.
  • Figure IA is tumor volume results in mice for the 75 mg/kg Ix wk dose level of CGC-11302 compared to a placebo control.
  • Figure IB is body weight results in mice for the 75 mg/kg Ix wk dose level of
  • Figure 2A is tumor volume results in mice for the 250 mg/kg 2x wk dose level of CGC-11302 compared to a placebo control.
  • Figure 2B is body weight results in mice for the 250 mg/kg 2x wk dose level of CGC-11302 compared to a placebo control.
  • Figure 3 A is tumor volume results in mice for the dose level of 125 mg/kg Ix wk for CGC-11301 and 250 mg/kg Ix wk for CGC-11303 compared to a placebo control.
  • Figure 3B is body weight results in mice for the dose level of 125 mg/kg Ix wk for CGC-11301 and 250 mg/kg Ix wk for CGC-11303 compared to a placebo control.
  • Figure 4A is tumor volume results in mice for the dose level of 250 mg/kg 2 x wk for CGC-11093 and CGC-11300 compared to a placebo control.
  • Figure 4B is body weight results in mice for the dose level of 250 mg/kg 2 x wk for CGC-11093 and CGC-11300 compared to a placebo control.
  • a "subject" or a “patient” refers to a vertebrate, preferably a mammal, including laboratory animals, domestic animals, sport animals, and primates, including humans.
  • the compounds described herein are used to treat vertebrates, preferably a mammal, including laboratory animals, domestic animals, sport animals, and primates, including humans.
  • the invention includes any stereoisomers, salts, hydrates and solvates of any of the compounds described herein.
  • the invention also includes the use of any of the compounds described herein, including any and all stereoisomers, salts, hydrates and solvates of the compounds described herein.
  • the invention also includes any compound described herein in its non-salt, non-hydrate/non-solvate form.
  • the invention also includes the use of any compound described herein in its non-salt, non-hydrate/non-solvate form.
  • Particularly preferred are pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are those salts which retain the biological activity of the compounds and which are not biologically or otherwise undesirable.
  • the desired salt may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of the compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared.
  • the invention also includes all stereoisomers of the compounds, including diastereomers and enantiomers, as well as mixtures of stereoisomers, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. For example, the structure: is intended to embrace all possible stereoisomers of l-ethyl-2-methyl cyclopropane. [0031] 1,2-disubstituted cyclopropane compounds can exist as either a cis-1,2- disubstituted cyclopropane or a trans- 1,2-disubstituted cyclopropane. It should be noted that c/5-cyclopropyl compounds with identical substituents in the 1 and 2 positions exist as only one stereoisomer, e.g., cw-l,2-cyclopropane dicarboxylic acid:
  • tr ⁇ ns-cyclopropyl compounds with identical substituents in the 1 and 2 positions exist as two stereoisomers, e.g., for tr ⁇ «5-cyclopropane-l,2-dicarboxylic acid, two stereoisomers exist: cyclopropane-(lS,2S)-l,2-dicarboxylic acid:
  • R or S at the substituted carbon will depend on the priority of the X and Y groups in the Cahn-Ingold-Prelog priority system.
  • the above structure indicates a racemic mixtures of the trans isomers.
  • the above structure indicates a racemic mixture of the (1R,2R) and (1S,2S) forms of rr ⁇ «5- 1,2-cyclopropane dicarboxylic acid. If the structure specifically indicates the stereochemistry, for example: then the stereochemistry of the actual structure is as indicated, in this example, the 1S,2S isomer.
  • the above structure indicates a racemic mixtures of the cis isomers.
  • the above structure indicates a racemic mixture of the (1R,2S) and (1S,2R) forms of cw-l,2-cyclopropane-dicarboxylic acid-1-methylester. If the structure specifically indicates the stereochemistry, for example:
  • alkyl refers to saturated aliphatic groups including straight-chain or branched-chain alkyl groups having the number of carbon atoms specified.
  • “Straight- chain alkyl” or “linear alkyl” groups refers to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and neopentyl.
  • alkylene refers to divalent saturated aliphatic groups including straight-chain or branched-chain having the number of carbon atoms specified.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2- methylpropylene, and the like.
  • cycloalkyl refers to a cyclic saturated hydrocarbon group of 3 or more ring atoms, such as 3-10 ring atoms, which may consist of one ring, including, but not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl, and includes both unsubstituted and substituted cycloalkyl groups.
  • Substituted cycloalkyls refers to cycloalkyls substituted with one or more substituents, including, but not limited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents including, but not limited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, car
  • aryl refers to an aromatic carbocyclic group having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups.
  • Substituted aryls refers to aryls substituted with one or more substituents, including, but not limited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide
  • halo and halogen as used herein refer to Cl, Br, F or I substituents.
  • protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).
  • Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mes), benzyloxycarbonyl (CBz or Z), t- butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS or TBDMS), 9- fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like.
  • Mes mesitylenesulfonyl
  • CBz or Z benzyloxycarbonyl
  • Boc t-butyloxycarbonyl
  • TBDIMS t
  • Hydroxyl protecting groups include, but are not limited to, Fmoc, TBDIMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC (4- nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxymethyloxycarbonyl).
  • Fmoc nitroveratryl oxymethyl ether (Nvom)
  • Mom methoxy methyl ether
  • Mem methoxy ethoxy methyl ether
  • NPEOC 4- nitrophenethyloxycarbonyl
  • NPEOM 4-nitrophenethyloxymethyloxycarbonyl
  • the compounds of the present invention are useful for treatment of a variety of diseases caused by uncontrolled or undesired proliferation of cells, including cancer.
  • Cancer develops when cells in the body grow out of control and instead of dying, continue to grow and form new abnormal cells.
  • the type of cancer depends on the cell type which is undergoing uncontrolled growth, and includes, but is not limited to, myeloma, carcinoma, sarcoma, melanoma, and lymphoma.
  • the cancer is typically in the form of a tumor but may also be non-tumorous, such as some leukemias.
  • the type of cancer is further characterized by the organ or tissue in which it first develops, and includes, but is not limited to, bone, brain, breast, cervical, colorectal, eye, head and neck, kidney, leukemia, liver, lung, lymphoma, multiple myeloma, nasopharyngeal, oropharyngeal, ovarian, pancreatic, pituitary, prostate, skin (melanoma and non-melanoma), testicular, thyroid, and urinary bladder.
  • the cancer can be characterized by both the cell type and the organ, such that breast cancer may include adenocarcinoma, ductal carcinoma or lobular carcinoma.
  • the cancer may be a localized tumor, such as a tumor in situ (i.e. confined to the organ of origin), or an invasive tumor (i.e. has invaded surrounding tissue).
  • the cancer may also have metastasized, i.e. spread to other parts of the body through the lymphatic or blood system, resulting in multiple tumor sites, referred to as metastases or metastatic tumors.
  • metastases or metastatic tumors Compounds of the invention may be used to treat cancers in general, including those discussed herein above, and in some instances may be more effective against certain types of cancers.
  • the compounds are useful in treating a cancer in the form of a localized or invasive tumor, where treatment results in substantial reduction in the growth of the tumor, preferably reduction in the size of the tumor.
  • the compounds are also useful in treating metastatic tumors, where treatment results in substantial reduction in metastasis, preferably in reduction in the number of metastatic tumors.
  • compounds of the invention may be used to treat prostate tumors. While the compounds may preferentially be used to treat humans, they may also be useful in veterinary medicine to treat cancer in cats, dogs, horses, and the like.
  • Other diseases characterized by uncontrolled or undesired cell proliferation, and which can be treated with compounds of the invention include benign prostatic hypertrophy (BPH), colon polyps, intestinal polyps, familial adenomatous polyposis, and macular degeneration, including wet macular degeneration. Dry macular degeneration can also be treated with compounds of the invention, in order to prevent wet macular degeneration.
  • BPH benign prostatic hypertrophy
  • colon polyps colon polyps
  • intestinal polyps familial adenomatous polyposis
  • macular degeneration including wet macular degeneration.
  • Dry macular degeneration can also be treated with compounds of the invention,
  • the compounds of the invention can be used to treat macular degeneration in accordance with the procedures described in United States Patent Application Nos. 11/244,095 filed October 4, 2005, 60/616,089 filed October 4, 2004, and 60/676,638 filed April 29, 2005.
  • the compounds of the invention can be used to treat familial adenomatous polyposis, colon polyps, and intestinal polyps in accordance with the procedures described in 60/724,637 filed October 7, 2005 and PCT Application No. PCT/US2005/035679 filed October 3, 2005.
  • Treating" a disease using a compound of the invention is defined as administering one or more compounds of the invention, with or without additional therapeutic agents, in order to palliate, ameliorate, stabilize, reverse, slow, delay, reduce, or eliminate either the disease or the symptoms of the disease, or to retard or stop the progression of the disease or of symptoms of the disease (referred to as "curative treatment,” regardless of whether the disease or symptoms of the disease are partially or totally cured), or to prevent the disease (referred to as "preventive treatment” regardless of whether the disease or symptoms of the disease are partially or totally prevented).
  • treating a solid tumor results in a reduction in the growth rate of the tumor, or results in essentially no growth in the tumor, or results in a reduction of tumor size, or results in essentially eliminating the tumor.
  • the compounds are also useful in treating metastases, and such treatment results in stabilizing the number of metastases and preferably results in a reduction in the number of metastases, more preferably the metastases are eliminated.
  • a therapeutically effective amount is an amount sufficient to treat a disease, as defined above.
  • a therapeutically effective amount of a compound for treating a solid tumor is a sufficient amount such that administration of the amount to a mammal having a solid tumor results in essentially no growth of the tumor following administration, or results in a reduced tumor size as compared to a mammal administered a vehicle control at some point after administration, or results in essentially eliminating the tumor. More particularly, the therapeutically effective amount results in a reduction in tumor size by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 90%.
  • a therapeutically effective amount may result in elimination of the tumor, i.e. the size of the tumor is reduced to a point where it can no longer be detected by methods known in the art.
  • the therapeutically effective amount may also be assessed by a reduction in the number of tumors.
  • a cancer may metastasize to other organs resulting in several metastases, for example, lung tumors, where the number of spots on the lung may be monitored.
  • a therapeutically effective amount in this example is one in which the number of metastases does not increase following administration, or where the rate of metastasis slows (e.g., the number of new metastases is reduced compared to treatment with controls), or the number of metastases decreases at some point following administration.
  • the therapeutically effective amount results in a reduction in the number of metastases by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 90%.
  • a therapeutically effective amount may result in elimination of all metastases to a point where they can no longer be detected by methods known in the art; for example no spots on the lung can be detected.
  • a therapeutically effective amount can also be evaluated in terms of increased survival of the subject. This is evaluated in treating a population of subjects, such as animal studies involving a group of mice, rats, cats, dogs, and primates implanted with a cancer cell line, or in clinical trials involving humans having a particular type of cancer.
  • a therapeutically effective amount is one in which the survival of a treated group of subjects is longer than that of an untreated or vehicle only treated subject.
  • a therapeutically effective amount is one in which the median survival in a group of treated mice is at least about 2, at least about 5, at least about 7, or at least about 10 days longer than that of a group of control mice.
  • a therapeutically effective amount is one in which the median survival of a group of treated humans is at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, or at least about 24 months longer than the accepted survival time for a human having a particular type of cancer who is untreated or treated only with vehicle.
  • a therapeutically effective amount may also be one that results in a median survival in humans that is at least as long as, and preferably longer than, that of a group treated with an accepted therapy for a particular cancer.
  • the median survival is at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 12 months, or at least about 24 months longer than the accepted therapy.
  • the compounds can be first tested for their potential to treat cancerous cells.
  • compounds can be tested against appropriately chosen test cells in vitro.
  • the compounds can be tested against tumor cells, for example, carcinoma cells, including prostate tumor cells.
  • Exemplary experiments can utilize cell lines capable of growing in culture as well as in vivo in athymic nude mice, such as LNCaP. Horoszewicz et al. (1983) Cancer Res. 43: 1809-1818.
  • Those compounds found to have potent antiproliferative activity in vitro towards cultured carcinoma cells can be evaluated in in vivo model systems.
  • a variety of animal models can be used to assess general toxicity, and various tumor cell lines can be used with a variety of animal models to assess anti-tumor activity in vivo.
  • Animal models include, but are not limited to, mice, rats, guinea pigs, dogs, and primates.
  • a variety of tumor cell lines suitable for such animal models are well known to those of skill in the art.
  • Initial assessment of in vivo toxicity and efficacy is typically done in rodents, particularly in mice. The first goal is to determine the relative toxicity of the compounds in non-tumor-bearing animals, such as DBA/2 mice.
  • a well- characterized polyamine analog compound, such as BE-333 can be used as an internal standard in these studies, since a data base has already been established regarding acute toxicity via a single dose treatment relative to chronic toxicity via a daily x 5 d schedule.
  • single dose toxicity relative to BE-333 is used to project the range of doses to be used on a daily x 5 d schedule.
  • tumors can be subcutaneously implanted into nude athymic mice by trocar and allowed to reach 100-200 mm 3 before initiating treatment by intraperitoneal injection daily x 5 d.
  • Most compounds of the invention can be given to mice in a range between 10 and 200 mg/kg.
  • the compounds can be evaluated at three treatment dosages with 10-15 animals per group (a minimum of three from each can be used for pharmacodynamic studies, described below). Mice can be monitored and weighed twice weekly to determine tumor size and toxicity. Tumor size is determined by multi-directional measurement from which volume in mm 3 is calculated.
  • Tumors can be followed until median tumor volume of each group reaches 1500 mm 3 (i.e., 20% of body weight), at which time the animals can be sacrificed.
  • constant infusion can be performed via Alzet pump delivery for 5 days since this schedule dramatically improves the anti-tumor activity of BE-333 against A549 human large cell lung carcinoma. Sharma et al. (1997) Clin. Cancer Res. 3:1239-1244.
  • free compound levels in tumor and normal tissues can be determined in test animals.
  • the compounds may also be tested in a model system where the tumor size is not readily measured, such as a cell line that results in lung metastases or that models a leukemia.
  • a cell line that results in lung metastases or that models a leukemia is the murine colon adenocarcinoma C-26 cell line, which produces lung metastases inBALB/c mice.
  • Tumor cells can be injected iv into the mice to induce metastases.
  • the mice can be treated as in the tumor model discussed above and monitored and weighed twice weekly to determine toxicity. After a suitable time, the mice are sacrificed and the lungs are examined to assess the number of metastases.
  • a leukemia model such as L1210 mouse leukemia
  • the blood can be monitored routinely to assess the abnormal leukocyte count, for example by Flow Cytometry using a suitable antibody to the leukemia cells.
  • Another method to assess anti-cancer activity of the compounds of the invention is to do survival studies in a suitable animal model, such as the mouse models discussed above. Such survival studies can be done with any tumor model, and involve monitoring groups of mice for their survival with or without treatment with compounds of the invention. The median survival of the group, i.e. the time at which half of the mice have died, can be evaluated for compounds relative to untreated or vehicle only treated mice. Compounds known to be active against a particular cancer cell model can be evaluated for comparison.
  • Methods of administration of compounds of the invention can be administered to a patient or subject (including a veterinary subject) via any route known in the art, including, but not limited to, those disclosed herein.
  • Methods of administration include, but are not limited to, systemic, transpleural, intravenous, oral, intraarterial, intramuscular, topical, via inhalation (e.g. as mists or sprays), via nasal mucosa, subcutaneous, transdermal, intraperitoneal, gastrointestinal, and directly to the site of a tumor, either intratumoral or in the vicinity of the tumor, or to a specific or affected organ.
  • the compounds described for use herein can be administered in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, emulsions, dispersions, food premixes, and in other suitable forms.
  • the compounds can also be administered in liposome formulations, including targeted liposomes such as liposomes that include a ligand on the surface that targets a specific tumor type.
  • the compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
  • the pharmaceutical dosage form which contains the compounds for use in the invention is conveniently admixed with a non-toxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier.
  • Typical pharmaceutically-acceptable carriers include, for example, mannitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid, and other conventionally employed acceptable carriers.
  • the pharmaceutical dosage form can also contain non-toxic auxiliary substances such as emulsifying, preserving, or wetting agents, and the like.
  • a suitable carrier is one which does not cause an intolerable side effect, but which allows the compound(s) to retain its pharmacological activity in the body.
  • Formulations for parenteral and nonparenteral drug delivery are known in the art and are set forth in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams & Wilkins (2000).
  • Solid forms, such as tablets, capsules and powders can be fabricated using conventional tableting and capsule- filling machinery, which is well known in the art.
  • Solid dosage forms can contain any number of additional non-active ingredients known to the art, including such conventional additives as excipients; desiccants; colorants; binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
  • additional non-active ingredients known to the art, including such conventional additives as excipients; desiccants; colorants; binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate,
  • Liquid forms for ingestion can be formulated using known liquid carriers, including aqueous and non-aqueous carriers such as sterile water, sterile saline, suspensions, oil-in-water and/or water-in-oil emulsions, and the like.
  • Liquid formulations can also contain any number of additional non-active ingredients, including colorants, fragrance, flavorings, viscosity modifiers, preservatives, stabilizers, and the like.
  • the compounds for use in the invention can be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent or sterile liquid carrier such as water, saline, or oil, with or without additional surfactants or adjuvants.
  • a physiologically acceptable diluent or sterile liquid carrier such as water, saline, or oil, with or without additional surfactants or adjuvants.
  • carrier oils would include animal and vegetable oils (e.g., peanut oil, soy bean oil), petroleum-derived oils (e.g., mineral oil), and synthetic oils.
  • sterile liquids such as water, saline, aqueous dextrose and related sugar solutions, and ethanol and glycol solutions such as propylene glycol or polyethylene glycol are preferred liquid carriers.
  • the pharmaceutical unit dosage chosen is preferably fabricated and administered to provide a defined final concentration of drug either in the blood, or at the point of contact with the cancer cell of from about 1 ⁇ M to about 10 mM.
  • the optimal effective concentration of the compounds of the invention can be determined empirically and will depend on the type and severity of the disease, route of administration, disease progression and health, mass and body area of the patient. Such determinations are within the skill of one in the art.
  • Examples of dosages which can be used include, but are not limited to, an effective amount within the dosage range of about 0.1 ⁇ g/kg to about 300 mg/kg, or within about 1.0 ⁇ g/kg to about 40 mg/kg body weight, or within about 10 ⁇ g/kg to about 30 mg/kg body weight, or within about 0.1 mg/kg to about 20 mg/kg body weight, or within about 1 mg/kg to about 20 mg/kg body weight, or within about 0.1 ⁇ g/kg to about 10 mg/kg body weight.
  • the dosages may be administered in a single daily dose, or the total daily dosage may be administered in a divided dosage two, three or four times daily.
  • Dosages may also be administered less frequently than daily, for example, about six times a week, about five times a week, about four times a week, about three times a week, about twice a week, about once a week, about once every ten days, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, or about once every six weeks.
  • the dosages may also be administered in a sustained release formulation, such as in an implant which gradually releases the compound for use in the invention over a period of time, and which allow for the drug to be administered less frequently, such as about once a month, about once every 2-6 months, about once every year, or even a single administration which need not be repeated.
  • the sustained release devices may be administered by injection or surgically implanted in various locations such as intratumoral, or in the vicinity of the tumor, or to or in the vicinity of a specific or affected organ.
  • Sustained release devices such as microspheres and liposomes may be targeted to a specific tumor, for example they may contain an antibody or other targeting ligand on its surface that selectively and specifically binds to a tumor specific antigen.
  • Compounds of the invention can be administered as the sole active ingredient, or can be administered in combination with another active ingredient, including, but not limited to, cytotoxic agents, antibiotics, antimetabolites, nitrosourea, vinca alkaloids, polypeptides, antibodies, cytokines, etc.
  • the compounds are particularly well-suited for oral delivery.
  • the invention also provides articles of manufacture and kits containing materials useful for treating cancers.
  • the article of manufacture comprises a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition having an active agent which is effective for treating the cancer.
  • the active agent in the composition is one or more compounds of the invention disclosed herein.
  • the label on the container indicates that the composition is used for treating cancers such as prostate cancer, and may also indicate directions for use.
  • kits comprising any one or more of a compound of the invention.
  • the kit of the invention comprises the container described above.
  • the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein (methods for treating cancers, such as prostate cancer).
  • the kits may be used for any of the methods described herein, including, for example, to treat a patient or subject suffering from a cancer.
  • reaction was then cooled to 0 0 C, and an additional 83 mg of a 60% NaH suspension in oil (2 mmol) and 880 mg (1.6 mmol) of 2-mesitylenesulfonic acid 4-[benzyl-(2-mesitylenesulfonyl)-amino]-butyl ester were added.
  • the reaction mixture was heated for 1.5 hours at 5O 0 C, and then stirred overnight at room temperature. It was then cooled to 0 0 C, quenched with H 2 O, concentrated in vacuo, and partitioned between ethyl acetate and H 2 O.
  • the aqueous layer was washed twice with CH 2 Cl 2 , then the aqueous suspension was filtered. The filtrate was washed with CH 2 Cl 2 . The aqueous layer was concentrated in vacuo, and combined with the precipitate. The mixture was cooled, and treated with NaOH and KOH until the pH was approximately 12. The aqueous mixture was then extracted with CH 2 Cl 2 ; the CH 2 Cl 2 layers were combined, dried over Na 2 SO 4 , concentrated, and dissolved in ethanol. The solution was cooled to 0 0 C, and acidified to approximately pH 1.
  • N-(4-Amino-butyl)-N-ethyl-mesitylene-2-sulfonamide (22, 3.57 g, 12 mmol) was dissolved in 35 ml THF, 1 ml of TEA was added, and the solution was cooled in an ice water bath with stirring.
  • 2-cyano-cyclopropanecarbonyl chloride (21, 1.6 g, 12 mmol) dissolved in 16 ml THF was added and the reaction was allowed to come to room temperature, then stirred for 2 hours. This was extracted with CHCl 3 , then washed twice with concentrated ammonium chloride.
  • 2-sulfonamide (24, racemic mixture of trans isomers, 4.8 g, 12.6 mmol) from the previous step was dissolved in 75 ml CHCl 3 and mixed at 0°C with 31 ml 2N NaOH.
  • 2- mesitylenesulfonyl chloride (5, 5.5 g, 25.2 mmol) was added and the reaction mixture was stirred for 2 hrs at room temperature.
  • N-decyl-mesitylene-2-sulfonamide (101, 3.5 g, 10.3 mmol) and 1,4- dibromobutane (102, 22.2 g, 103 mmol) were dissolved in 30 ml DMF and cooled to 0°C. 494 mg of a 60% NaH suspension in oil (12.36 mmol) was added and the mixture stirred at room temperature for 20 minutes. NaI (2.3 g, 15.3 mmol) was added and the reaction mixture was heated to 75-80°C for 1.5 hours. The reaction was monitored by TLC (silica, hexane:EtOAc 9.5:0.5).
  • N-4-bromobutyl-N-decyl-mesitylene-2-sulfonamide (103, 1.0 g, 2.10 mmol) and N-(2-mesitylene-2-sulfonamidomethylcyclopropylmethyl)-N-mesitylene-2-sulfonyl-N ' - mesitylene-2-sulfonyl-N' -ethyl- 1,4-diaminobutane (13, racemic mixture of trans isomers, 1.56 g, 2.10 mmol) were dissolved in 20 ml DMF. 100 mg of a 60% NaH suspension in oil (2.52 mmol) was added and the mixture stirred at room temperature for 20 minutes.
  • the product was purified by silica gel column (hexane:EtOAc 8:2) to provide N- Decyl-N-(4- ⁇ [2-( ⁇ [4-(ethyl-mesitylene-2-sulfonyl-amino)-butyl]-mesitylene-2-sulfonyl- amino ⁇ -methyl)-cyclopropylmethyl]-mesitylene-2-sulfonyl-amino ⁇ -butyl)-mesitylene-2- sulfonamide (104, racemic mixture of trans isomers, 2.14 g, 89%).
  • the compound 104 (racemic mixture of trans isomers, 2.0 g, 1.75 mmol) was dissolved in 25 ml CH 2 Cl 2 with 25 ml of 30% HBr in HOAc and 4.2 g of phenol, and the mixture reacted for 18 hours. The mixture was cooled, water (30 ml) was added, and the aqueous suspension was separated from the organic phase. The suspension was filtered and the white solid was taken up in 5 ml of 2N NaOH and extracted with CHCl 3 . The CHCl 3 was dried and evaporated and the oily residue dissolved in ethanol. This was cooled and concentrated. HCl was added to precipitate the product.
  • N-pentyl-mesitylene-2-sulfonamide (107, 6.16 g, 22.8 mmol) and 1,4- dibromobutane (102, 49.2 g, 27 ml, 228 mmol) were dissolved in 60 ml DMF and cooled to 0 0 C.
  • 1.0 g of a 60% NaH suspension in oil (27.36 mmol) was added and the mixture stirred at room temperature for 20 minutes.
  • NaI 3.4 g, 22.8 mmol
  • the reaction was monitored by TLC (silica, hexane:EtOAc 9:1).
  • N-4-bromobutyl-N-pentyl-mesitylene-2-sulfonamide (108, 808 nig, 2.0 mmol) and N-(2-mesitylene-2-sulfonamidomethylcyclopropylmethyl)-N-mesitylene-2-sulfonyl-N'- mesitylene-2-sulfonyl-N' -ethyl- 1 ,4-diaminobutane (13, racemic mixture of trans isomers, 1.52 g, 2.0 mmol) were dissolved in 25 ml DMF. 96 mg of a 60% NaH suspension in oil (2.4 mmol) was added and the mixture stirred at room temperature for 20 minutes.
  • the compound 109 (racemic mixture of trans isomers, 1.9 g, 1.77 mmol) was dissolved in 25 ml CH 2 Cl 2 with 25 ml of 30% HBr in HOAc and 4.2 g of phenol, and the mixture reacted for 18 hours. The mixture was cooled, water (50 ml) was added and the aqueous suspension was separated from the organic phase, then washed with 3 x 20 ml of CH 2 Cl 2 . The aqueous phase was adjusted with 5 ml of 2N NaOH and 4 ml of 50% KOH and extracted with 3 x 20 ml of CHCl 3 . The CHCl 3 was dried and evaporated and the product dissolved in ethanol. This was cooled and concentrated HCl was added to the precipitate. The product was filtered to provide 580 mg (65%) of the title compound 110, CGC-11302 (racemic mixture of trans isomers) isolated as the tetrahydrochloride salt.
  • N-pentyl-mesitylene-2-sulfonamide (107, 6.06 g, 22.5 mmol) was dissolved in
  • N-(3-Cyano-propyl)-N-pentyl-mesitylene-2-sulfonamide (114, 7.2 g, 21.4 mmol) was dissolved in 120 ml ethanol and 20 ml CHCl 3 , with addition of 720 mg PtO 2 . The mixture was reacted with H 2 at 50 psi at room temperature overnight. The reaction mixture was filtered to remove the catalyst, the solvent evaporated, and the residue dissolved in CHCl 3 . This was washed with 2N NaOH, dried and evaporated to provide N-(4-amino- butyl)-N-pentyl-mesitylene-2-sulfonamide (115, 6.55 g, 91%).
  • N-(4-amino-butyl)-N-pentyl-mesitylene-2-sulfonamide (115, 6.44 g, 18.9 mmol) was dissolved in 80 ml THF with 2.7 ml TEA and stirred for 30 min at room temperature.
  • Cyclopropane- 1 ,2-dicarbonyl dichloride (112, racemic mixture of trans isomers, 1.57 g, 9.45 mmol) in 40 ml THF with 2.5 ml TEA was added. The mixture was stirred for another 30 min at room temperature, then 2.5 ml TEA was added and the reaction was heated to 5O 0 C for 1 hour.
  • reaction mixture was worked up by adding it to water and extracting the aqueous layer with CHCl 3 .
  • the CHCl 3 was dried with Na 2 SO 4 and evaporated to dryness.
  • the resulting oily residue was purified by silica gel column (EtOAc:Hexane 7:3 to EtOAc) to provide cyclopropane- 1 ,2-dicarboxylic acid bis- ⁇ [4-(mesitylene-2-sulfonyl- pentyl-amino)-butyl]-amide ⁇ (116, racemic mixture of trans isomers, 5.6 g, 77%).
  • the product 117 (racemic mixture of trans isomers, 5.4 g, 4.8 mmol) was dissolved in 70 ml CH 2 Cl 2 with 70 ml of 30% HBr in HOAc and 11.3 g of phenol, and the mixture reacted for 18 hours. The mixture was cooled, water (150 ml) was added and the aqueous suspension was separated from the organic phase, then washed with 3 x 20 ml of CH 2 Cl 2 . The aqueous phase was adjusted with 10 ml of 2N NaOH and 5 ml of 50% KOH and extracted with 3 x 10 ml of CHCl 3 . The CHCl 3 was dried and evaporated and the oil residue dissolved in 50 ml ethanol.
  • N-Adamantan-1-yl-methylamine (119, 1.88 g, 11.39 mmol) in 30 ml CHCl 3 was mixed at 0 0 C with 14 ml 2N NaOH.
  • 2-mesitylenesulfonyl chloride (5, 2.48 g, 11.39 mmol) was added and the reaction mixture was stirred for 2 hrs to room temperature.
  • the reaction was monitored by TLC (silica, hexane:EtOAc 8:2).
  • the CHCl 3 phase was separated, washed with NH 4 Cl solution (2X), dried, and evaporated to provide N-Adamantan-1- ylmethyl-mesitylene-2-sulfonamide (120, 3.77 g, 95%).
  • 1 H and 13 C NMR confirmed the identity of the product.
  • N-Adamantan-l-ylmethyl-mesitylene-2-sulfonamide 120, 1.8 g, 5.20 mmol
  • 1 ,4-dibromobutane 102, 11.23 g, 52 mmol
  • 250 mg of 60% NaH suspension in oil (6.24 mmol) was added and the mixture stirred for 20 minutes to room temperature.
  • NaI (1.17 g, 7.8 mmol) was added and the reaction mixture heated to 75°C for 2 hours.
  • the product 122 (racemic mixture of trans isomers, 3.0 g, 2.6 mmol) was dissolved in 36 ml CH 2 Cl 2 with 36 ml of 30% HBr in HOAc and 6.16 g of phenol and the reaction mixture was stirred overnight at room temperature. The mixture was cooled, water (36 ml) was added and the aqueous suspension was separated from the organic phase and filtered. The residue was dried and taken up in 7 ml of 2N NaOH and 0.5 ml of 50% KOH and extracted with CHCl 3 . The CHCl 3 was dried and evaporated and the residue dissolved in ethanol. This was cooled and concentrated HCl was added to the precipitate.
  • nude mouse xenograft model using DU- 145 human prostate tumor cells was utilized. This model has been used extensively to predict the efficacy of experimental drugs in human cancer patients. This tumor model was used to assess CGC- 11302 at two oral dosing levels. [00101] Male, 5-6 week old nude mice (nu/nu) were purchased from Harlan Sprague-
  • DU-145 cells were grown in culture flasks with Dulbecco's modified Eagle media (DMEM) (Gibco, Grand Island, N. Y.) containing 5% fetal bovine serum. The adherent DU-145 cells were recovered from the flasks using trypsin (0.05%)/EDTA (0.53 mM) (Gibco) and harvested by low-speed centrifugation (1000-1200 x g). The cells were resuspended at 10 7 /ml in DMEM. Each mouse was injected sub-cutaneously (S.
  • DMEM Dulbecco's modified Eagle media
  • CGC- 11302 treatments were initiated approximately 15 days after DU- 145 tumor cell injection.
  • CGC-11302 was formulated in a delivery vehicle consisting of sterile saline. The drug was administered orally using an 18 gauge feeding needle (Popper and Sons, New Hyde Park, N. Y.). Each mouse was dosed once per week at 75 mg/kg or twice per week at 250 mg/kg for 5 weeks. The dosage level was determined by exact body weight. Mice treated with sterile saline administered by oral gavage served as a placebo control. The tumor volume results for each dose level compared to placebo control are shown in Figures IA and 2A. Body weight results for each dose level compared to placebo control are shown in Figures lB and 2B.
  • CGC-11300 was dosed orally at 250 mg/kg twice per week.
  • the tumor volume results for each dose level compared to placebo control are shown in Figures 4A.
  • Body weight results for each dose level compared to placebo control are shown in Figures 4B.
  • the structure of CGC-11093 is as follows:

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Abstract

L'invention concerne des analogues de polyamine spécifiques et des procédés pour le traitement du cancer en utilisant des analogues de polyamine. Les analogues de polyamine ont des groupes cyclopropyle dans leurs segments internes.
PCT/US2008/003273 2007-03-14 2008-03-12 Analogues de polyamine contenant des groupes cyclopropyle comme thérapies de la maladie WO2008112251A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3473247A1 (fr) 2009-07-16 2019-04-24 Pathologica LLC Composition pour administration par voie orale comprenant la mgbg pour utilisation dans le traitement de la sclérose en plaque
EP3831372A1 (fr) 2013-01-08 2021-06-09 Pathologica LLC Mitoguazone pour prévenir la rechute ou la progression de la sclérose en plaques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880161A (en) * 1993-11-05 1999-03-09 The United States Of America As Represented By The Department Of Health And Human Services Therapeutic polyamines
US6649587B1 (en) * 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880161A (en) * 1993-11-05 1999-03-09 The United States Of America As Represented By The Department Of Health And Human Services Therapeutic polyamines
US6649587B1 (en) * 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3473247A1 (fr) 2009-07-16 2019-04-24 Pathologica LLC Composition pour administration par voie orale comprenant la mgbg pour utilisation dans le traitement de la sclérose en plaque
EP3831372A1 (fr) 2013-01-08 2021-06-09 Pathologica LLC Mitoguazone pour prévenir la rechute ou la progression de la sclérose en plaques

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