US20180169064A1 - Aziridine containing dna alkylating agents - Google Patents
Aziridine containing dna alkylating agents Download PDFInfo
- Publication number
- US20180169064A1 US20180169064A1 US15/736,285 US201615736285A US2018169064A1 US 20180169064 A1 US20180169064 A1 US 20180169064A1 US 201615736285 A US201615736285 A US 201615736285A US 2018169064 A1 US2018169064 A1 US 2018169064A1
- Authority
- US
- United States
- Prior art keywords
- compound
- alkyl
- hydrogen
- alkenyl
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 title 1
- 239000012624 DNA alkylating agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 150000002431 hydrogen Chemical group 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 26
- 239000003814 drug Substances 0.000 description 21
- -1 1,3-butadienyl Chemical group 0.000 description 20
- 0 [1*]C1=C([2*])C(C([5*])OP(=O)(N2CC2)N2CC2)=C([4*])C([3*])=C1[N+](=O)[O-].[13*]C1=C([16*])C([17*])=C(C([15*])OP(=O)(N2CC2)N2CC2)C([N+](=O)[O-])=C1[14*].[6*]C1=C([N+](=O)[O-])N([11*])C(C([7*])OP(=O)(N2CC2)N2CC2)=N1.[8*]C1=C(C([9*])OP(=O)(N2CC2)N2CC2)N(C)C([N+](=O)[O-])=N1.[9*]C(OP(=O)(N1CC1)N1CC1)C1=C([N+](=O)[O-])N=C([10*])N1[11*] Chemical compound [1*]C1=C([2*])C(C([5*])OP(=O)(N2CC2)N2CC2)=C([4*])C([3*])=C1[N+](=O)[O-].[13*]C1=C([16*])C([17*])=C(C([15*])OP(=O)(N2CC2)N2CC2)C([N+](=O)[O-])=C1[14*].[6*]C1=C([N+](=O)[O-])N([11*])C(C([7*])OP(=O)(N2CC2)N2CC2)=N1.[8*]C1=C(C([9*])OP(=O)(N2CC2)N2CC2)N(C)C([N+](=O)[O-])=N1.[9*]C(OP(=O)(N1CC1)N1CC1)C1=C([N+](=O)[O-])N=C([10*])N1[11*] 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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- 239000000243 solution Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- 229910052786 argon Inorganic materials 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 206010039491 Sarcoma Diseases 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Definitions
- the present invention provides compounds suitable as therapeutic agents, pharmaceutical compositions of such compounds and methods of treating cancer in cancer patients, and so relates to the fields of biology, chemistry, and medicine.
- Cancer is one of the major causes of human morbidity and mortality. Cancer treatment is challenging because it is difficult to kill cancer cells without damaging or killing normal cells. Damaging or killing normal cells during cancer treatment is a cause of adverse side effects in patients and can limit the amount of anti-cancer drug administered to a cancer patient. There remains a need for compounds suitable for treating cancer patients.
- the compounds include mixtures of stereoisomers, such as enantiomers, and separated individual enantiomers and racemic and nonracemic mixtures thereof.
- the compounds provided here act as prodrugs that can be activated in or around the hypoxic conditions existing in or around tumors.
- provided herein are methods of preparing the compounds provided herein.
- compositions comprising a compound provided herein and at least one pharmaceutically acceptable excipient.
- provided herein are methods of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
- FIGS. 1A-1C The comparative tumor volume reductions for certain compounds are graphically illustrated in FIGS. 1A-1C .
- compositions and methods include the recited elements, but not excluding others.
- Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the composition or method.
- Consisting of shall mean excluding more than trace elements of other ingredients for claimed compositions and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. Accordingly, it is intended that the methods and compositions can include additional steps and components (comprising) or alternatively including steps and compositions of no significance (consisting essentially of) or alternatively, intending only the stated method steps or compositions (consisting of).
- C x -C y or “C x-y ” before a group refers to a range of the number of carbon atoms that are present in that group.
- C 1 -C 6 alkyl refers to an alkyl group having at least 1 and up to 6 carbon atoms.
- Alkoxy refers to ⁇ 0-Alkyl.
- Amino refers to NR p R q wherein R p and R q independently are hydrogen or C 1 -C 6 alklyl, or R p and R q together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle.
- Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
- C x-y alkyl refers to alkyl groups having from x to y carbon atoms.
- This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 ) 2 CH—), n-butyl (CH 3 CH 2 CH 2 CH 2 —), isobutyl ((CH 3 ) 2 CHCH 2 —), sec-butyl ((CH 3 )(CH 3 CH 2 )CH—), t-butyl ((CH 3 ) 3 C—), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 —), and neopentyl ((CH 3 ) 3 CCH 2 —).
- linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 ) 2 CH—),
- Alkenyl refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C ⁇ C ⁇ ).
- C x-y alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include, for example, ethenyl, propenyl, 1,3-butadienyl, and the like.
- Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and containing at least one triple bond.
- alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
- C 2-6 alkynyl includes ethynyl, propynyl, and the like.
- Aryl refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
- a single ring e.g., phenyl
- multiple condensed (fused) rings e.g., naphthyl or anthryl.
- the term “Aryl” or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
- Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
- cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl).
- the term “cycloalkyl” includes cycloalkenyl groups. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
- “Ether” refers to a C 1 -C 6 alkyl group substituted with 1-3 C 1 -C 6 alkoxy groups, wherein alkoxy refers to —O-alkyl.
- Halo refers to one or more of fluoro, chloro, bromo, and iodo.
- Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl-2-yl and imidazol5-yl) and multiple ring systems (e.g. imidazopyridyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl).
- heteroaryl applies if there is at least one ring heteroatom, and the point of attachment is at an atom of an aromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl).
- the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
- heteroaryl includes, but is not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
- Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
- heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom, and the point of attachment is at an atom of a non-aromatic ring (e.g., 1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl).
- the heterocyclic groups herein are 3-15 membered, 4-14 membered, 5-13 membered, 7-12, or 5-7 membered heterocycles.
- the heterocycles contain 4 heteroatoms. In some other embodiment, the heterocycles contain 3 heteroatoms. In another embodiment, the heterocycles contain up to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.
- Heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl.
- a prefix indicating the number of carbon atoms e.g., C 3-10 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
- a divalent heterocyclic radical will have the appropriately adjusted hydrogen content.
- the term “optionally substituted” refers to a substituted or unsubstituted group.
- the group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
- the substituents are selected from the group consisting of oxo, halo, —CN, NO 2 , —N 2 + , —CO 2 R 100 , —OR 100 , —SR 100 , —SOR 100 , —SO 2 R 100 , —NR 100 SO 2 R 100 , —NR 11 R 102 , CONR 101 R 102 , —SO 2 NR 101 R 102 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CR 100 ⁇ C(R 100 ) 2 , —CCR 100 , C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl and C 2 -C 12 heteroary
- the substituents are selected from the group consisting of chloro, fluoro including trifluoro, —OCH 3 , methyl, ethyl, iso-propyl, cyclopropyl, OH, OAc, 5-6 membered heterocyclyl containing 1-3 heteroatoms such as nitrogen and oxygen optionally substituted with 1-3 C 1 -C 6 alkyl or C 6 -C 10 aryl groups, 5-6 membered heteroaryl containing 1-3 heteroatoms such as nitrogen and oxygen optionally substituted with 1-3 C 1 -C 6 alkyl groups, —CO 2 H and salts and C 1 -C 6 alkyl esters thereof, CONMe 2 , CONHMe, CONH 2 , —SO 2 Me, —SO 2 NH 2 , —SO 2 NMe 2 , —SO 2 NHMe, —NHSO 2 Me, —NHSO 2 CF 3 , —NHSO 2 CH 2 C 1 , —NO 2
- Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
- a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
- a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
- a prodrug may be synthesized using reactants other than the corresponding drug.
- administering or “administration of” a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
- Cancer refers to leukemias, lymphomas, carcinomas, and other malignant tumors, including solid tumors, of potentially unlimited growth that can expand locally by invasion and systemically by metastasis.
- cancers include, but are not limited to, cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid.
- cancers include, acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera, primary brain tumor,
- “Patient” and “subject” are used interchangeably to refer to a mammal in need of treatment for cancer.
- the patient is a human.
- the patient is a human diagnosed with cancer.
- a “patient” or “subject” may refer to a non-human mammal used in screening, characterizing, and evaluating drugs and therapies, such as, a non-human primate, a dog, cat, rabbit, pig, mouse or a rat.
- Solid tumor refers to solid tumors including, but not limited to, metastatic tumors in bone, brain, liver, lungs, lymph node, pancreas, prostate, skin and soft tissue (sarcoma).
- “Therapeutically effective amount” of a drug refers to an amount of a drug that, when administered to a patient with cancer, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer in the patient.
- a therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
- Treating,” “treatment of,” or “therapy of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
- beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer; diminishment of extent of disease; delay or slowing of disease progression; amelioration, palliation, or stabilization of the disease state; or other beneficial results.
- Treatment of cancer may, in some cases, result in partial response or stable disease.
- R 1 is: hydrogen, —N 3 , CN, halo, NR 21 R 22 , —OR 23 , —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
- each R 21 and R 22 independently is hydrogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or —SO 2 (C 1 -C 6 alkyl); or R 21 and R 22 together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle or a 5-15 membered heteroaryl;
- R 23 is hydrogen, C 1 -C 6 alkyl, or C 6 -C 10 aryl
- R 2 and R 3 are independently hydrogen or halo
- R 4 is hydrogen, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 6 -C 10 aryl,
- R 5 , R 7 , R 9 , R 12 , and R 15 independently are hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl; or R 4 and R 5 together with the intervening carbon atoms between them form a C 5 -C 6 cycloalkyl ring;
- R 6 and R 10 independently are hydrogen or halo
- R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 5-15 membered heteroaryl;
- each R 11 independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl;
- R 13 , R 14 , R 16 , and R 17 are independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyny, or C 1 -C 6 alkoxy;
- alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy and ether groups are optionally substituted.
- the compound provided is of formula:
- R 1 is a non-hydrogen substituent.
- R 2 and R 3 are hydrogen.
- R 4 is hydrogen or halo.
- R 4 is hydrogen.
- R 4 is halo.
- R 4 is fluoro.
- R 4 and R 5 together form a 5 membered cycloalkyl group.
- R 1 is a non-hydrogen substituent
- R 2 and R 3 are hydrogen, and R 4 is hydrogen or halo, or R 4 and R 5 together form a 5 membered cycloalkyl group.
- R 5 is a non-hydrogen substituent.
- R 1 is NR 21 R 22 .
- the compound provided is of formula:
- R 8 is hydrogen. In another embodiment, R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In another embodiment, R 9 is optionally substituted C 1 -C 6 alkyl.
- the compound provided is of formula:
- R 7 is optionally substituted C 1 -C 6 alkyl.
- the compound provided is of formula:
- R 12 is optionally substituted C 1 -C 6 alkyl.
- the compound provided is of formula:
- R 15 is optionally substituted C 1 -C 6 alkyl.
- the compound provided is of formula:
- R 7 is optionally substituted C 1 -C 6 alkyl.
- IC 50 values are reported in micromolar and result from exposure of compound at various concentrations for 2 hrs followed by a wash step and addition of fresh media followed by growth and cell viability staining and comparison to a media only treated control.
- exponentially growing cells are seeded at a density of 4 ⁇ 10 3 cells per well in a 96 well plate and incubated at 37° C. in 5% CO 2 , 95% air and 100% relative humidity for 24 hours prior to addition of test compounds.
- Compounds are solubilized in 100% DMSO at 200 times the desired final test concentration.
- compounds are further diluted to 4 times the desired final concentration with complete medium. Aliquots of 50 ⁇ l of compound at specified concentrations are added to microtiter wells already containing 150 ⁇ l of medium, resulting in the final drug concentration reported.
- the plates are incubated for an additional 2 hours at 37° C., 5% CO 2 , 95% air, and 100% relative humidity, then the drug is washed off and fresh medium is added and the plates are incubated for addition 70 hrs at 37° C., 5% CO 2 , 95% air and 100% relative humidity.
- the viable cells are quantified using the AlamarBlue assay.
- the drug concentration resulting in growth inhibition of 50% (IC 50 ) is calculated using Prism software (Irvine, Calif.), and the results are listed in the table.
- H460 cells (lx 10 6 ) were subcutaneously implanted in the flanks of pathogen-free homozygous female nude mice (nu/nu, Charles River Laboratories). When tumor size reached 100-150 mm 3 , animals were randomized to 10 mice per treatment group. All tested compounds were formulated in 5% DMSO, 5% Tween 80 in D5W. The doses of all the compounds were chosen on the basis of preliminary studies to define the MTD of each compound when administered daily for 5 days. On the basis of weight loss and behavioral signs, the MTDs of TH2565 and TH2566 were determined to be 2 mg/kg, respectively. The comparative tumor volume reductions for certain compounds are graphically illustrated in FIGS. 1A-1C .
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MY192888A (en) * | 2015-03-10 | 2022-09-14 | Ascentawits Pharmaceuticals Ltd | Dna alkylating agents |
MY198613A (en) | 2015-04-02 | 2023-09-11 | Ascenta Pharmaceuticals Ltd | Nitrobenzyl derivatives of anti-cancer agents |
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CA2990696C (en) * | 2015-11-16 | 2024-01-02 | Obi Pharma, Inc. | (r)- and (s)-1-(3-(3-n,n-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-n,n'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation |
KR20220012274A9 (ko) * | 2019-05-13 | 2022-02-21 | 아센타위츠 파마슈티컬즈 리미티드 | 플루오린 함유 화합물 및 이의 항암 의학적 용도 |
EP4053135A4 (en) * | 2019-11-01 | 2024-01-03 | Ascentawits Pharmaceuticals Ltd | ANTI-CANCER COMPOUNDS ACTING AS NON-PGP SUBSTRATE |
WO2021120717A1 (zh) | 2019-12-20 | 2021-06-24 | 深圳艾欣达伟医药科技有限公司 | 抗癌化合物及其医药用途 |
CN116120365A (zh) * | 2021-11-12 | 2023-05-16 | 深圳艾欣达伟医药科技有限公司 | 一种氘代化合物及其制备方法和应用 |
WO2023174319A1 (zh) * | 2022-03-15 | 2023-09-21 | 深圳艾欣达伟医药科技有限公司 | 治疗brca突变癌症患者的方法 |
WO2024078392A1 (en) * | 2022-10-09 | 2024-04-18 | Anrui Biomedical Technology (Guangzhou) Co., Ltd. | Phosphoramidate compounds and uses thereof |
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