WO1999061409A1 - Bioreductive cytotoxic agents - Google Patents
Bioreductive cytotoxic agents Download PDFInfo
- Publication number
- WO1999061409A1 WO1999061409A1 PCT/US1999/011199 US9911199W WO9961409A1 WO 1999061409 A1 WO1999061409 A1 WO 1999061409A1 US 9911199 W US9911199 W US 9911199W WO 9961409 A1 WO9961409 A1 WO 9961409A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- alkyl
- compound
- quinone
- aryl
- Prior art date
Links
- 229940127089 cytotoxic agent Drugs 0.000 title description 4
- 239000002254 cytotoxic agent Substances 0.000 title description 4
- 231100000599 cytotoxic agent Toxicity 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 230000002152 alkylating effect Effects 0.000 claims abstract description 29
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 14
- 238000005304 joining Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- -1 ureido, thio Chemical group 0.000 claims description 33
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 25
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 24
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 23
- 125000004151 quinonyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 21
- 125000005647 linker group Chemical group 0.000 claims description 19
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 15
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000004104 aryloxy group Chemical group 0.000 claims description 13
- 125000004969 haloethyl group Chemical group 0.000 claims description 13
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
- 125000003368 amide group Chemical group 0.000 claims description 10
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 239000002168 alkylating agent Substances 0.000 claims description 8
- 125000005110 aryl thio group Chemical group 0.000 claims description 8
- 150000007942 carboxylates Chemical class 0.000 claims description 8
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 8
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- 150000004059 quinone derivatives Chemical class 0.000 claims 23
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 37
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- 206010028980 Neoplasm Diseases 0.000 description 23
- 231100000433 cytotoxic Toxicity 0.000 description 22
- 230000001472 cytotoxic effect Effects 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
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- 239000007787 solid Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
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- 238000010992 reflux Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- XLHUBROMZOAQMV-UHFFFAOYSA-N 1,4-benzosemiquinone Chemical compound [O]C1=CC=C(O)C=C1 XLHUBROMZOAQMV-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
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- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 238000011097 chromatography purification Methods 0.000 description 3
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- 238000011580 nude mouse model Methods 0.000 description 3
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/24—Quinones containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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Definitions
- BIOREDUCTIVE CYTOTOXIC AGENTS Background of the Invention Based on the statistics provided by the American Cancer Society, approximately four million people have died from cancer since 1990, and cancer, after heart disease, is the second leading cause of death in the United States. Treatments of cancer usually include chemotherapy, radiation, hormones, immunotherapy, and surgery. Chemotherapy remains a preferred treatment, especially in cancer types that are m inoperable or metastatic forms.
- cytotoxic agents including antimetabolites , antibiotics, alkylating agents, and mitotic inhibitors. These agents usually destroy both normal and tumor cells. It is desirable to develop an antitumor agent that preferentially destroys tumor cells over normal cells. Due to their pathological conditions, tumor cells differ from normal cells m that their surrounding blood vessels are poorly organized, resulting m inefficient delivery of oxygen to the tumor site. In other words, tumor cells are hypoxic (oxygen deficient" 1 This unique physiology opens the door to the design of cytotoxic agents that are specific for tumor cells.
- An aspect of this invention relates to a cytotoxic compound which consists of three components: (1) a proactive alkylating moiety containing an electron- withdrawing group; (2) a bioreductive moiety containing at least two double bonds; and (3) a linker joining together the proactive alkylating moiety and the bioreductive moiety.
- a “proactive alkylating moiety” refers to a functional group which, once activated, replaces an active hydrogen atom of another compound, such as DNA, with one of its alkyl groups m a covalent manner.
- a “bioreductive moiety” refers to a moiety that is capable of undergoing an m vivo reduction (electron- accepting reaction), i.e., bioreduction.
- the double bonds of the bioreductive moiety form a conjugated system.
- the conjugated system allows electrons to flow from the bioreductive moiety to the electron-withdrawing group of the proactive alkylating moiety upon reduction of the bioreductive moiety. This results m breaking the bond between the electron-withdrawing group and the linker and converting the proactive alkylating moiety into an active alkylating compound.
- An example of the proactive alkylating moiety is an aromatic group (e.g., phenyl group or naphthyl) substituted with an electron-withdrawing group (e.g., ester, urethane, or carbonate) and a bis (haloethyl) ammo group (e.g., a bis (chloroethyl) amino group or nitrogen mustard) .
- the bis (haloethyl) ammo group upon bioreduction, becomes an alkylating group.
- the aromatic moiety is a phenyl
- each of the two su ⁇ stituents is preferred to be at a meta or para position with respect to each other.
- Each of the remaining positions of the phenyl is optionally substituted with alkyl, alkenyl , aryl , aralkyl , heteroaryl, heteroaralkyl, ammo, am oalkyl, hydroxyl , hydroxylalkyl , alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, oligoalkylene glycol, amido, ester, aralkoxycarbonylammo, ureido, thio, alkylthio, arylthio, or heteroarylthio.
- alkyl, alkoxy, oligoalkylene glycol, aryloxy, heteroaryloxy, and ammo are preferred. It is preferable that each of these substituents is at an ortho position with respect to the bis (haloethyl) ammo group.
- the bioreductive moiety is converted into a second alkylating agent upon bioreduction. Some examples of the bioreductive moiety are 1 , 4-benzoqumone (i.e., qumone), nitrobenzene, or 1 , 2-d ⁇ oxocyclohex-3 , 5-d ⁇ ene .
- each of the non-oxo positions of the qumone ring is optionally substituted with alkyl, alkenyl , aryl , aralkyl, heteroaryl, heteroaralkyl , ammo, ammoalkyl, hydroxyl, hydroxylalkyl , alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, carboxylate, acyloxyalkyl, ester, amido, amidoalkyl, sulfoamido, sulfonylammo, thio, alkylthio, arylthio, aralkylthio, heteroarylthio, or heteroaralkylthio .
- the preferred substituents are alkyl, ammo, ammoalkyl, alkoxy, hydroxylalkyl , and acyloxyalkyl. If both 2-C and 3-C positions or both 5-C and 6-C positions of the qumone are substituted, the two substituents optionally together form a ring. Two fused rings can be formed with the qumone ring if all non-oxo positions of the qumone are substituted and each pair of the substituents together form a fused ring.
- the fused ring can be either aliphatic or aromatic.
- alkyl alkenyl, aryl, aralkyl, heteroaryl, neteroaralkyl , ammo, ammoalkyl, hydroxyl, hydroxylalkyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, carboxylate, acyloxyalkyl, ester, amido, amidoalkyl, sulfoamido, sulfonylammo, thio, alkylthio, arylthio, aralkylthio, heteroarylthio, or heteroaralkylthio.
- the fused ring optionally contains 1-3 heteroatoms, such as nitrogen, oxygen, or sulfur.
- the linker which links the proactive alkylating moiety and the bioreductive moiety together can be one of the following: a methylene group, a C 3 hydrocarbon chain containing a double bond, or a C 5 hydrocarbon chain containing two alternate double bonds.
- This linker is optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl , or oligoalkylene glycol. If the linker contains more than two substituents, two of them can join together to form a 5-6 membered ring.
- the ring can be aliphatic or aromatic and is optionally substituted w th alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or oligoalkylene glycol.
- One to three heteroatoms such as nitrogen, oxygen, or sulfur, can form part of the ring.
- a salt of a cytotoxic compound is also within the scope of this invention.
- the salt can be formed between an ammo substituent of a cytotoxic compound and a negatively charged counte ⁇ on.
- Suitable counte ⁇ ons include, but are not limited to, chloride, hydrochlo ⁇ de, bromide, iodide, sulfate, nitrate, phosphate, or acetate.
- a negatively charged substituent, e.g., carboxylate, of a compound of this invention can also form a salt w th a cation, e.g., an alkali metal cation such as sodium ion or potassium ion; an alkaline earth metal cation such as magnesium cation or calcium cation; or an ammonium cation that can be substitued with one or more organic groups such as tetramethylammonium ion or diisopropyl-ethylammonium ion.
- a cation e.g., an alkali metal cation such as sodium ion or potassium ion
- an alkaline earth metal cation such as magnesium cation or calcium cation
- an ammonium cation that can be substitued with one or more organic groups such as tetramethylammonium ion or diisopropyl-ethylammonium ion.
- alkyl denotes a straight or branched hydrocarbon cnam containing 1 to 8 carbon atoms, or cyclic hydrocarbon chain containing 3 to
- the cyclic hydrocarbon chain may contain 1-3 heteroatoms such as nitrogen, oxygen, or sulfur and may also contain fused rings. Fused rings are rings that share a common carbon-carbon bond.
- alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -butyl, amyl , isopentyl, hexyl , isohexyl, heptyl , octyl , cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl , isobornyl, cyclohexylmethyl , 1- or 2 -cyclohexylethyl , 1-, 2-, or 3-cyclohexylpropyl, tetrahydrofuranyl , tetrahydropyranyl , pipe
- alkenyl is meant a straight or branched hydrocarbon chain containing 2 to 8 carbon atoms or cyclic hydrocarbon chain, i.e., “cycloalkenyl , " containing 3 to 8 carbon atoms, which is characterized by having one or more double bonds .
- the cycloalkenyl may contain 1-3 heteroatoms such as nitrogen, oxygen, or sulfur, i.e., “heterocycloalkenyl , " and may also contain fused rings.
- alkenyl groups include allyl, 2- butenyl , 2 -pentenyl , 2 -hexenyl , cyclopropenyl , cyclopentenyl , cyclohexenyl , cycloheptenyl , cyclo- octenyl, and norbornylenyl .
- Aryl is an cyclic aromatic moiety containing 3-8 carbon atoms and may also contain fused rings. Fused aryl denotes an aromatic ring that shares a common carbon-carbon bond with another cyclic moiety. This cyclic moiety can be either an aryl, a cycloalkyl, or a heterocycloalkyl . Typically aryl groups include phenyl, 1-naphthyl, 2-naphthyl, biphenyl, phenanthryl , and anthracyl groups. "Heteroaryl” refers to aryl groups that contains 1-3 heteroatoms.
- heterocyclic aromatic rings including coumar yl , py ⁇ dyl , pyrazmyl, pyrimidyl, furyl , pyrrolyl, thienyl, thiazolyl, oxazolyl, lmidazolyl , mdolyl , benzofuranyl and benzthiazolyl .
- An example of the aralkyl group is 2 -phenylethy1.
- oligoalkylene glycol refers to a chain of 2-5 alkoxy groups. Each of the alkoxy groups may or may not be identical.
- An example of an oligoalkylene glycol is ethoxymethoxy .
- substituents such as ammo, amido, ester, sulfoamido, sulfonylammo, and ureido are either unsubstituted or substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Further, a divalent substituent such as amido or ester can be connected to its two neighboring moieties m either orientation.
- the substituents of a cyclic group e.g., phenyl, can be attached at any available position.
- Another aspect of this invention relates to a composition which contains one of the cytotoxic compounds (or its salt) described above and a pharmaceutically acceptable carrier.
- the compound is m an amount which is effective for treating tumors.
- Still another aspect of this invention relates to a method of treating tumors, which comprises administering to a patient m need thereof an effective amount of such a cytotoxic compound or its salt .
- tumors which can be treated by this method are leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
- the use of such a cytotoxic compound for the manufacture of a medicament for treating the above-mentioned tumors is also withm the scope of this invention.
- the present invention relates to a cytotoxic compound which has (1) a proactive alkylating moiety containing an electron-withdrawing group and (2) a bioreductive moiety.
- a cytotoxic compound which has (1) a proactive alkylating moiety containing an electron-withdrawing group and (2) a bioreductive moiety.
- the bioreductive moiety include:
- Examples of the proactive alkylating moiety include
- ester group of the proactive alkylating moiety is the electron- withdrawing group.
- a cytotoxic compound disclosed in this invention is capable of converting into two alkylating agents upon bioreduction.
- the mechanism of this conversion can generally be divided into two stages.
- a cytotoxic compound containing quinone as the bioreductive moiety, methylene group as the linker, and bis (chloroethyl) -amino-phenyl ester as the proactive alkylating moiety is used as an example in the following description.
- the first stage involves the reduction of the bioreductive moiety. Typically, this is achieved by cellular enzymes, e.g., cytochrome P 450 reductase.
- Quinone can undergo bioreduction in two one-electron steps, which produces a semiquinone radical anion in the first reduction, and a hydroquinone in the second one.
- the semiquinone radical anion is very reactive towards oxygen. Indeed, in normal tissues where there is an abundance of oxygen, most of the radical anions are re- oxidized back to quinone.
- a tumor site is characterized by its poorly organized vascular system, which results in a generally more hypoxic
- This electron travelling activity thus results m cleavage of the bond between the electron-withdrawing group and the linker, thereby converting the quinone moiety into a quinone methide .
- Quinone methides are known alkylating agents capable of attacking nucleophiles, e.g., DNA (See Lm et al., J. Med. Chem. 1972, 15, 127; J. Med. Chem. 1973, 16, 1268; J. Med. Chem. 197, 17, 688; J. Med. Chem. 1975, 18, 917; J. Med. Chem. 1976, 19, 1336).
- the electron-withdrawing group is converted into one that is much less electron-withdrawing.
- This conversion m turn, increases the electron density of the bis (haloethyl) ammo group and converts the proactive alkylating moiety into an alkylating agent.
- a and B together form a 5-6 membered fused ring with the quinone ring, if none of A and B is -L-W-Ph-N (CH 2 CH 2 X) , .
- C and D optionally oin together to form a 5-6 membered fused ring with the quinone ring, if none of C and D is -L-W- Ph-N(CH 2 CH 2 X) 2 .
- R independently, is alkyl or deleted.
- R 1 and R 2 independently, is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
- - (O-alkyl) ⁇ 5 refers to an alkoxy group ("- (0-alkyl) x " ) or an oligoalkylene glycol group
- - (O-alkyl ; ) R 3 and R ⁇ when n is not 0, optionally form a 5- to 6 -membered ring together.
- the ring can be aliphatic or aromatic and can optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or - (O-alkyl) ! 5 .
- heteroatoms e.g., nitrogen, oxygen, or sulfur, can also form part of the ring.
- X is a halo, e.g., fluoro, chloro, bromo, or lodo. Note that if neither A and B, nor C and D, form a fused ring with the quinone ring, then at least one of A, B, C, or D is -L-W-Ph-N (CH 2 CH 2 X) 2 .
- Tne fused ring (or at least one of the two fused rings if two fused rings are present) contains a double bond between two ring atoms and is substituted with -L-W-Ph-N (CH,CH 2 X) 2 at one of the two ring atoms. This double bond, together with the double bonds of the quinone ring, form a conjugated system to allow electron to flow from one double bond to another .
- the preparation of a compound of formula (I) is generally divided into three parts: (1) the preparation of a bioreductive quinone moiety; (2) the preparation of a bis (haloethyl) ammo-phenyl moiety; and (3) coupling of the bioreductive qumone moiety and the bix (haloethyl) ammo-phenyl moiety.
- the general synthetic procedures of parts (l)-(3) are described below:
- a leaving group, e.g., a halide, that is attached to the linker of a properly protected bioreductive moiety is necessary to couple to a desired bis (haloethyl) ammo- contammg phenyl moiety m part (3)
- the leaving group and the linker can be introduced at a non-oxo position of the qumone ring by, e.g., electrophilic substitution reaction.
- m part (1) of Example 1 a hydroxymethyl group resulted at the C 2 carbon of 3,5,6- trimethyl -hydroquinone dimethyl ester as the hydroquinone reacted with paraformaldehyde .
- a bis (chloroethyl) ammo phenyl moiety can be prepared from, e.g., a nitrobenzoic acid.
- the carboxylate can be protected m the form of an ester.
- Suitable substituents to the benzene ring can be coupled to or transformed at this point, e.g., see part (2) of Example 1.
- the nitro group can then be reduced to form an ammo group.
- This ammo group can then react with an ethylene oxide, forming a disubstituted hydroxyethyl ammo group.
- the alkylating moiety i.e., the bis (chloroethyl) ammo moiety
- a chlormation agent e.g., thionyl chloride
- the ester group is being cleaved by hydrolysis.
- a qumone rmg-contammg moiety e.g., 2-chloromethyl-3 , 5 , 6-tr ⁇ methylbenzoqumone m Example 1
- a bis (chloroethyl) ammo- contammg phenyl moiety e.g., 3- [bis- (2-chloro- ethyl) ammo-4-methoxybenzo ⁇ c acid, via a nucleophilic substitution reaction.
- the carboxylate which acts as a nucleophile, displaces the halide ion and results m the formation of an ester linkage.
- a pharmaceutical composition of this invention containing a cytotoxic compound m an effective amount can be used to treat tumors.
- a method of treating tumor by administering to a patient such a composition.
- An effective amount of a cytotoxic compound (or a salt of the cytotoxic compound) is defined, as the amount of the compound which, upon administration to a patient m need, confers a therapeutic effect on treated patient.
- the effective amount to be administered to a patient is typically based on age, surface area, weight, and conditions of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al . , Cancer Chemother. Rep. 1966, 50, 219.
- Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537.
- An effective amount of a cytotoxic compound used to practice the invention can range from about 0.1 mg/kg to about 250 mg/kg. Effective doses will also vary, as recognized by those skilled m the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other antitumor agents and radiation therapy.
- the pharmaceutical composition may be administered via the parenteral route, including orally, topically, subcutaneously, mtrape ⁇ toneally, intramuscularly, and intravenously.
- parenteral dosage forms include aqueous solutions of the active agent, m a lsotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient.
- Solubilizmg agents such as cyclodextrms , or other solubilizmg agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
- a cytotoxic compound of this invention can also be formulated into dosage forms for other routes of administration utilizing well-known methods.
- the pharmaceutical composition can be formulated, for example, m dosage forms for oral administration m a capsule, a gel seal or a tablet.
- Capsules may comprise any well-known pharmaceutically acceptable material such as gelatin or cellulose derivatives.
- Tablets may be formulated m accordance with the conventional procedure by compressing mixtures of the active compounds of the present invention and a solid carrier, and a lubricant. Examples of solid carriers include starch and sugar bentonite.
- the cytotoxic compound can also be administered m a form of a hard shell tablet or capsule containing, for example, lactose or mannitol as a binder and a conventional filler and a tabletmg agent.
- the antitumor activity of the compounds of this invention can be preliminarily evaluated by using a tumor growth regression assay which assesses the ability of tested compounds to inhibit the growth of established solid tumors m mice.
- the assay can be performed by implanting tumor cells into the fat pads of nude mice. Tumor cells are then allowed to grow to a certain size before the cytotoxic compounds are administered. The volumes of tumor are then monitored for a set number of weeks, e.g., three weeks. General health of the tested animals are also monitored during the course of the assay.
- each of the examples 1-7 depicts m detail the synthesis of seven cytotoxic compounds of this invention.
- Each example is divided into three parts: (1) the preparation of a bioreductive quinone moiety, (2) the preparation of a bis (chloroethyl) ammo-phenyl moiety, and (3) the coupling reaction of these two moieties.
- reaction slurry was stirred at room temperature for 12 hours.
- the reaction mixture was then treated with ⁇ ce/H 2 0 (500 mL) and extracted with ethyl acetate (2 x 300 mL) .
- the ethyl acetate solution was washed with H 2 0 (300 mL) , sodium bicarbonate (200 mL) , dried over magnesium sulfate, and concentrated to furnish the product as a clear oil (5.6 g, 71%).
- MDA-35 Human mammary carcinoma (MDA-35) tumor cells, which were adapted to grow as solid tumors m nude mice, were implanted by injection of a tumor cell suspension (3-5 x 10 6 cells) m media into the fat pads of female nude mice (Taconic Labs) . Five mice per group were used. When tumors were palpable, two to three weeks after implantation, animals were injected with the cytotoxic compounds of this invention intravenously on a three times per week schedule at the MTD. Tumor volumes were measured with calipers weekly during and for two weeks after dosing was suspended. The volume of tumors, assumed to be hemi -ellipsoid m shape, was calculated using the equation:
- the volumes of tumors m the animals which were treated with various cytotoxic compounds of this invention were calculated and compared to those obtained from the animals which were treated with chlorumbucil (an aromatic nitrogen mustard-contammg anticancer drug) and also with those obtained from the untreated animals.
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Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020007013155A KR20010074498A (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
AU40913/99A AU750381B2 (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
HU0102932A HUP0102932A3 (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
EP99924405A EP1080066A4 (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
CA002332806A CA2332806A1 (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
JP2000550818A JP2002516304A (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agent |
BR9911066-0A BR9911066A (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
HR20000794A HRP20000794A2 (en) | 1998-05-22 | 2000-11-20 | Bioreductive cytotoxic agents |
NO20005880A NO20005880L (en) | 1998-05-22 | 2000-11-21 | Bioreductive cytotoxic agents |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8642998P | 1998-05-22 | 1998-05-22 | |
US09/083,652 | 1998-05-22 | ||
US09/083,652 US5969133A (en) | 1998-05-22 | 1998-05-22 | Bioreductive cytotoxic agents |
US60/086,429 | 1998-05-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999061409A1 true WO1999061409A1 (en) | 1999-12-02 |
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ID=26769555
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1999/011199 WO1999061409A1 (en) | 1998-05-22 | 1999-05-20 | Bioreductive cytotoxic agents |
Country Status (12)
Country | Link |
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EP (1) | EP1080066A4 (en) |
JP (1) | JP2002516304A (en) |
KR (1) | KR20010074498A (en) |
CN (1) | CN1302287A (en) |
AU (1) | AU750381B2 (en) |
BR (1) | BR9911066A (en) |
CA (1) | CA2332806A1 (en) |
HR (1) | HRP20000794A2 (en) |
HU (1) | HUP0102932A3 (en) |
NO (1) | NO20005880L (en) |
PL (1) | PL344257A1 (en) |
WO (1) | WO1999061409A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2258430A2 (en) | 2005-12-29 | 2010-12-08 | Morvus Technology Ltd. | 5-(Aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide and its use in medicine |
US8415334B2 (en) | 2005-09-03 | 2013-04-09 | Morvus Technology Ltd. | Method of combating infection |
US8785428B2 (en) | 2006-09-30 | 2014-07-22 | Morvus Technology Limited | Vermin poison |
US11174212B2 (en) | 2018-10-17 | 2021-11-16 | Ptc Therapeutics, Inc. | 2,3,5-trimelthyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11786486B2 (en) | 2021-07-08 | 2023-10-17 | Ptc Therapeutics, Inc. | Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6137003A (en) * | 1998-10-28 | 2000-10-24 | Shionogi Bioresearch | Bis (haloethyl) aminobenzene derivatives |
AU2012258665B2 (en) * | 2011-05-26 | 2017-05-25 | Apex Therapeutics, Inc. | Quinone compounds for treating Ape1 mediated diseases |
CN111039764A (en) * | 2018-10-12 | 2020-04-21 | 山东大学 | Amphiphilic ethylene derivative and preparation method thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9501052D0 (en) * | 1995-01-19 | 1995-03-08 | Cancer Res Campaign Tech | Improvements relating to prodrugs |
US5786488A (en) * | 1996-11-13 | 1998-07-28 | Sugen, Inc. | Synthetic methods for the preparation of indolyquinones |
WO1997023456A1 (en) * | 1995-12-21 | 1997-07-03 | British Technology Group Ltd. | Indoloquinone derivatives as bioreductive agents |
-
1999
- 1999-05-20 JP JP2000550818A patent/JP2002516304A/en active Pending
- 1999-05-20 PL PL99344257A patent/PL344257A1/en unknown
- 1999-05-20 KR KR1020007013155A patent/KR20010074498A/en not_active Application Discontinuation
- 1999-05-20 CN CN99806490A patent/CN1302287A/en active Pending
- 1999-05-20 WO PCT/US1999/011199 patent/WO1999061409A1/en not_active Application Discontinuation
- 1999-05-20 HU HU0102932A patent/HUP0102932A3/en unknown
- 1999-05-20 EP EP99924405A patent/EP1080066A4/en not_active Withdrawn
- 1999-05-20 AU AU40913/99A patent/AU750381B2/en not_active Ceased
- 1999-05-20 CA CA002332806A patent/CA2332806A1/en not_active Abandoned
- 1999-05-20 BR BR9911066-0A patent/BR9911066A/en not_active Application Discontinuation
-
2000
- 2000-11-20 HR HR20000794A patent/HRP20000794A2/en not_active Application Discontinuation
- 2000-11-21 NO NO20005880A patent/NO20005880L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
DATABASE CAPLUS ON STN, Acc. No. 1983:594554, WITIAK D.T. et al., "Bis(bioreductive) Alkylating Agents: Synthesis and Biological Activity in a Nude Mousehuman Carcinoma Model"; & J. MED. CHEM., (1983), 26(12), pages 1679-1686. * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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US8415334B2 (en) | 2005-09-03 | 2013-04-09 | Morvus Technology Ltd. | Method of combating infection |
EP2258430A2 (en) | 2005-12-29 | 2010-12-08 | Morvus Technology Ltd. | 5-(Aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide and its use in medicine |
US9029569B2 (en) | 2005-12-29 | 2015-05-12 | Morvus Technology Limited | Use of alpha-hydroxy carbonyl compounds as reducing agents |
US9907784B2 (en) | 2005-12-29 | 2018-03-06 | Morvus Technology Limited | Use of alpha-hydroxy carbonyl compounds as reducing agents |
US10398676B2 (en) | 2005-12-29 | 2019-09-03 | Morvus Technology Limited | Use of alpha-hydroxy carbonyl compounds as reducing agents |
US8785428B2 (en) | 2006-09-30 | 2014-07-22 | Morvus Technology Limited | Vermin poison |
US11174212B2 (en) | 2018-10-17 | 2021-11-16 | Ptc Therapeutics, Inc. | 2,3,5-trimelthyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11667596B2 (en) | 2018-10-17 | 2023-06-06 | Ptc Therapeutics, Inc. | 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11746077B2 (en) | 2018-10-17 | 2023-09-05 | Ptc Therapeutics, Inc. | 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11786486B2 (en) | 2021-07-08 | 2023-10-17 | Ptc Therapeutics, Inc. | Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione |
Also Published As
Publication number | Publication date |
---|---|
KR20010074498A (en) | 2001-08-04 |
BR9911066A (en) | 2001-02-13 |
HUP0102932A2 (en) | 2001-12-28 |
AU750381B2 (en) | 2002-07-18 |
EP1080066A1 (en) | 2001-03-07 |
EP1080066A4 (en) | 2004-12-22 |
HRP20000794A2 (en) | 2001-10-31 |
CN1302287A (en) | 2001-07-04 |
AU4091399A (en) | 1999-12-13 |
JP2002516304A (en) | 2002-06-04 |
NO20005880D0 (en) | 2000-11-21 |
CA2332806A1 (en) | 1999-12-02 |
NO20005880L (en) | 2001-01-09 |
HUP0102932A3 (en) | 2002-12-28 |
PL344257A1 (en) | 2001-10-22 |
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