WO2021083310A1 - 作为非pgp底物的抗癌化合物 - Google Patents
作为非pgp底物的抗癌化合物 Download PDFInfo
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- WO2021083310A1 WO2021083310A1 PCT/CN2020/125123 CN2020125123W WO2021083310A1 WO 2021083310 A1 WO2021083310 A1 WO 2021083310A1 CN 2020125123 W CN2020125123 W CN 2020125123W WO 2021083310 A1 WO2021083310 A1 WO 2021083310A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- 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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- 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
- 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
- C07F9/65586—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
Definitions
- the present invention relates to the further research and development of the compounds disclosed in the patent application PCT/US2016/021581, publication number WO2016145092A1, corresponding to Chinese application number 2016800150788, publication number CN107530556A, and belongs to the field of cancer therapeutic compound research and development.
- the DNA alkylating agent cancer treatment compound prodrug developed by our company targeting the highly expressed aldehyde and ketone reductase 1C3 (AKR1C3) (application number PCT/US2016/021581, publication number WO2016/145092; application number PCT/US2016/062114 , Publication No. WO2017/087428) specifically undergoes metabolic activation under the action of AKR1C3 in the body.
- ARR1C3 application number PCT/US2016/021581, publication number WO2016/145092; application number PCT/US2016/062114 , Publication No. WO2017/087428
- S configuration AST-3424 of TH2870 Take the S configuration AST-3424 of TH2870 as an example:
- the DNA alkylating agent that targets the highly expressed aldehyde ketone reductase AKR1C3 will bind to AKR1C3 in the body, and then undergo a metabolic reaction, and finally produce a cytotoxic DNA alkylating agent.
- the preparation is inconvenient and the stability is poor. Because it is an oily substance, it is inconvenient to operate during the transportation/metering process. The important thing is that it is not convenient to develop and diversify the dosage form of the oily substance. Generally, it can only be developed as a freeze-dried powder injection method for administration. , The administration method is single and the cost is relatively high.
- the present invention provides the following technical solutions.
- anticancer compound that is a non-PGP substrate, it is a compound of formula I-1 or a pharmaceutically acceptable salt or solvate thereof:
- R 1 and R 2 are each independently hydrogen, deuterium, aryl or Z-substituted aryl, heteroaryl, heterocycle or Z-substituted heteroaryl, C 1 -C 6 alkyl or Z-substituted alkyl, C 2- C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl;
- R 3 is hydrogen, halogen, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 6 alkyl or Z substitution Alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl Group or Z-substituted aryl, 4-15 membered heterocyclic or Z-substituted heterocyclic, 5-15 membered heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z substituted C 1 -C 6 Alkoxy or R 3 is -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6
- R 4 and R 5 are each independently hydrogen, halogen atom, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1- C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkynyl or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl , C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocyclic or Z substituted heterocyclic, 5-15 membered heteroaryl or Z substituted heteroaryl, C 1 -C 6 alkoxy or Z
- the substituted C 1 -C 6 alkoxy group or R 4 , R 5 are -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R
- R 6 and R 7 are each independently hydrogen, cyano or isocyano, C 1 -C 6 alkyl or Z substituted alkyl, C 2 -C 6 alkenyl or Z substituted alkenyl, C 2 -C 6 alkyne Group or Z substituted alkynyl, C 3 -C 8 cycloalkyl or Z substituted cycloalkyl, C 6 -C 10 aryl or Z substituted aryl, 4-15 membered heterocycle or Z substituted heterocycle, 5-15 Member heteroaryl or Z-substituted heteroaryl, C 1 -C 6 alkoxy or Z-substituted C 1 -C 6 alkoxy, or R 6 , R 7 groups together with the atoms to which they are bonded form 3- 7-membered heterocyclic group or Z-substituted 3-7-membered heterocyclic group;
- Cy is a 5-10 membered aromatic ring, heterocyclic ring or aromatic heterocyclic ring.
- the hydrogens on the ring are each independently deuterium, halogen atom, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine group, oxime group, a hydrazone group, OTs, OMs, C 1 -C 6 aliphatic hydrocarbon group unsubstituted or substituted with a halogen atom, a cyano group, an isocyano group, a hydroxyl group, a mercapto group, amino group, oxime group, a hydrazone group in C 1 - C 6 aliphatic hydrocarbon group substitution;
- R 10 is a 3-18 membered cyclic hydrocarbon group, aryl or fused ring, heterocycle, fused heterocyclic ring, heteroaryl group or Z substituted 3-18 membered cyclic hydrocarbon group, aryl or fused ring, heterocycle, fused ring Heterocyclic group, heteroaryl group or C 1 -C 18 hydrocarbyl group or Z-substituted hydrocarbyl group; or
- R 10 is -Q-Cz
- Q is -O-, -S-, -CO-, -SO 2 -, -SO-, -OCO-, -OCOO-, -NR 6 CO-, -NR 6 SO 2 -, -OCONR 6 -,
- Cz is a 3-18 membered cyclic hydrocarbon group, aryl or fused ring, heterocycle, fused heterocyclic ring, heteroaryl group or Z substituted 3-18 membered cyclic hydrocarbon group, aryl or fused ring, heterocycle, fused hetero Ring group, heteroaryl group or C 1 -C 18 hydrocarbyl group or Z-substituted hydrocarbyl group;
- Y is -O- or -S- or -SO 2 -, -SO-;
- L and D are selected from the following three situations:
- L is selected from -O-, -S-, -OCOO-, -NR 6 CO-, -OCO-, -NR 6 SO 2 -, -OCONR 6 -, quaternary ammonium group, sulfonate group -OSO 2- ,
- R 40 and R 41 are independently 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 to 15 membered heterocyclic ring or 5 to 15 membered heteroaryl group;
- R 42 is C 2 -C 3 alkylene, alkyl or heteroalkyl having 1 to 3 C 1 -C 6 alkyl substituted C 2 -C 3 alkylene, heterocycloalkyl;
- V(-) is any anion
- D is the part that makes D-OH an anticancer drug, where OH is an aliphatic or phenolic hydroxyl group or is an OH part attached to a phosphate; or
- R 40 is as defined above, R 43 is hydrogen or forms a heterocyclic ring together with D, and the phenylene moiety is Z substituted or unsubstituted, and D is a moiety that makes D-NR 43 H an anticancer drug; or
- (3) L is selected from bond, -OC(R 40 R 41 ) 2 -, -OC(R 40 R 41 )-NR 40 R 41 (+)-C(R 40 R 41 )-, or
- R 40 , R 41 and V(-) are as defined above, and
- D is an anticancer drug containing a tertiary or secondary nitrogen atom, wherein the tertiary nitrogen atom or secondary nitrogen atom is bonded to L;
- alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, and ether groups in the above definitions of L and D are Z substituted or unsubstituted;
- the Z substituent is a halogen atom, cyano or isocyano, thiocyano or isothiocyano, hydroxyl, mercapto, amine, oxime, hydrazone, OTs, OMs, C 1 -C 3 alkyl or substituted alkane Group, C 1 -C 3 alkoxy or substituted alkoxy, C 2 -C 3 alkenyl or substituted alkenyl, C 2 -C 3 alkynyl or substituted alkynyl, C 3 -C 8 cycloalkyl or substituted Cycloalkyl, aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring or substituted aromatic ring, heterocyclic ring, heteroaromatic ring and condensed ring, the substitution mode is mono-substituted or gem-disubstituted, and the substituent is halogen atom, cyano group Or isocyano, thiocyano or is
- Heterocycle and heteroaryl include three-membered ring, four-membered ring, five-membered ring, six-membered ring, and seven-membered ring.
- Three-membered ring ethylene oxide, azathione, ethylene sulfide;
- pyrrolidine pyrroline, 1-pyrroline, 3-pyrroline, 2-pyrroline, pyrrole, pyrazoline, 2-pyrazoline, imidazole, pyrazole, furan, tetrahydrofuran, dihydrofuran, Tetrahydrothiophene, thiophene, sulfolane, phosphazene, oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole;
- Condensed ring is defined as the combination of the above heterocycles and heteroaryl groups or the combination with the cycloalkane structure.
- the combination can be linked by a single bond or share one, two or even three atoms, as follows Give some common fused ring structures: naphthalene, quinoline, indole, isoindole, isoquinoline, quinoline, quinoxaline, biphenyl, coumarin, fluorene, dibenzocarban, carbazole, anthracene , Azaanthrene, Thiophenazine, Adamantane, Zulene, Phenanthrene, Anthraquinone, Flavonoids, Isoflavones.
- the above compounds also include isotopically substituted compounds.
- the typical substitution method is that the hydrogen atom H is replaced by the heavy hydrogen atom deuterium D or the methyl -CH 3 is replaced by -CD 3 .
- the site substituted by deuterium is located on Ph-C ⁇ -in formula I, that is, R 1 and/or R 2 are deuterium.
- -D is -P(Z 1 )(Z 5 -X 5 -Y 5 ) n ,
- Z 5 is N, S or O
- X 5 is an optionally substituted ethylene group
- Y 5 is a halogen atom or -OSO 2 -R 20
- R 20 is an optionally substituted hydrocarbon group, aryl group, cycloalkyl group, heterocyclic group or heteroaryl group,
- n 1 or 2;
- Z 5 -X 5 -Y 5 is an aziridinyl-NCH 2 CH 2 moiety
- Z 1 is O or S.
- the above structure is the amino phosphate alkylating agent.
- -LD is -OP(Z 1 )(Z 5 -X 5 -Y 5 ) n ,
- Z 5 is N, S or O
- X 5 is an optionally substituted ethylene group
- Y 5 is a halogen atom or -OSO 2 -R 20
- R 20 is an optionally substituted hydrocarbon group, aryl group, cycloalkyl group, heterocyclic group or heteroaryl group,
- n 1 or 2;
- Z 5 -X 5 -Y 5 is an aziridinyl-NCH 2 CH 2 moiety
- Z 1 is O or S.
- -LD is -OP(Z 1 )(NR 30 CH 2 CH 2 Cl) 2 ,-OP(Z 1 )(NR 30 CH 2 CH 2 Br) 2 ,-OP(Z 1 )(NR 30 2 )(N(CH 2 CH 2 X 1 ) 2 ),-OP(Z 1 )(N(CH 2 ) 2 ) 2 , or -OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2
- -LD is -OP(Z 1 )(NR 30 CH 2 CH 2 Cl) 2 ,-OP(Z 1 )(NR 30 CH 2 CH 2 Br) 2 ,-OP(Z 1 )(NR 30 2 )(N(CH 2 CH 2 X 1 ) 2 ),-OP(Z 1 )(N(CH 2 ) 2 ) 2 , or -OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2
- -LD is -OP(Z 1 )(NR 30 CH 2 CH 2 Cl) 2
- each R 30 is independently H, a C 1 -C 6 hydrocarbyl group, or two R 30 groups and the connected N atom form a 5-7 membered heterocyclic ring, Z 1 is O or S, and X 1 is Cl, Br, or -OSO 2 Me.
- -LD is -OP(Z 1 )(NHCH 2 CH 2 Cl) 2 ,-OP(Z 1 )(NHCH 2 CH 2 Br) 2 ,-OP(Z 1 )(NH 2 )(N (CH 2 CH 2 X 1 ) 2 ),-OP(Z 1 )(N(CH 2 ) 2 ) 2 , or -OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2 ,
- X 1 is Cl, Br, or -OSO 2 Me.
- anti-cancer compound wherein:
- R 10 is a 5-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, fused heterocyclic ring, heteroaryl group or Z substituted 5-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring , Condensed heterocyclic group, heteroaryl group or hydrocarbon group substituted with -CF 3 and Cl;
- R 10 is -O-Cz
- Cz is a 5-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, fused heterocyclic ring, heteroaryl group or Z substituted 5-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, Condensed heterocyclic groups, heteroaryl groups or hydrocarbon groups substituted with -CF 3 and Cl.
- R 10 is a 7-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, fused heterocyclic ring, heteroaryl group or Z substituted 7-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring , Condensed heterocyclic group, heteroaryl group or hydrocarbon group substituted with -CF 3 and Cl;
- R 10 is -O-Cz
- Cz is a 7-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, fused heterocyclic ring, heteroaryl group or Z substituted 7-18 membered cycloalkyl, aryl or fused ring, heterocyclic ring, Condensed heterocyclic groups, heteroaryl groups or hydrocarbon groups substituted with -CF 3 and Cl.
- the compound has the structure of formula I-2
- Cx is selected from biphenyl, Z-substituted biphenyl, phenylpyridine, Z-substituted phenylpyridine and -CONR 6 R 7 , -SO 2 NR 6 R 7 , -SO 2 R 6 , -OCOO-R 6 , -COOR 6 , -NR 6 COR 7 , -OCOR 6 , -NR 6 SO 2 R 7 , -NR 6 SO 2 NR 6 R 7 , -COR 6 , -NR 6 CONR 7 substituted biphenyl, phenyl Pyridine.
- R 3 , R 4 , and R 5 are each independently hydrogen.
- R 1 and R 2 are each independently hydrogen, deuterium, -CH 3 , -CD 3 , or CF 3 .
- Y is -O-.
- Cy is a 5-10 membered aromatic heterocyclic ring, and the hydrogens on the ring are each independently replaced by deuterium, halogen atom, cyano or isocyano, thiocyano or isothiocyano, Hydroxyl group, mercapto group, amine group, oxime group, hydrazone group, OTs, OMs, C 1 -C 6 aliphatic hydrocarbon group substituted by halogen atom, cyano group, isocyano group, hydroxyl group, mercapto group, amine group, oxime group, hydrazone group Substituted C 1 -C 6 aliphatic hydrocarbon group substitution.
- substituents on Cy are hydrogen, deuterium, halogen atom, -CH 3 , -CF 3 ,
- Cy is selected from 5, 6, 7, and 8-membered aromatic heterocycles, and the heteroatoms are N, S, O, and the number of heteroatoms is 1, 2, 3.
- D-OH is selected from the following anticancer drugs containing -OH group: gemcitabine gemcitabine, estramustine estramustine, prednimustine pudnimnstine, chlorozotocin chlorozotocin, ramustine ranimustine, mannomustine, Dibromomannitol mitobronitol, dibromodulcitol dibromodulcitol, arubicin alacinomycins, abramycin anthramycin, bleomycin bleomycin, carubicin carubicin, doxorubicin, doxorubicin, carzinophilin, color Chromomycin, Ddactinomycin, Ddactinomycin, daunorubicin, mycophenolic acid, nogalamycin, olivinemycin olivomycin, peplomycin, plicamycin, puromycin puromycin, black chain neomycin streptonigrin, streptozotocin streptozocin, kill tuber
- D-NR 43 H is selected from the following anticancer drugs: erlotinib, meturedepa, uredepa, imatinib, trimethylolomelamine, gefitinib, uracil Uracil mustard, carmustine carmustine, chlorozotocin, formustine fotemustine, nimustine nimustine, ramustine ranimustine, dacarbazine, mannomustine, actinomycin actinomycin, aflatoxin anthramycin, bleomycin bleomycin, actinomycin C cactinomycin, carubicin carubicin, doxorubicin, carzinophilin, actinomycin D dactinomycin, pelomycin peplomycin, puromycin puromycin, streptozocin, ubenimex, zinostatin, denopterin, pteropterin, trimetrexate, 6-mercaptopurine, 6-mercaptopurine, sulfur Thiamiprine
- Anticancer drugs containing tertiary or secondary nitrogen atoms are selected from hexamethylmelamine altretamine, triethylenemelamine, chlorambuci, chlornaphazine, estramustine, gefitinib, mechlorethamine , Mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracilmustard, carmustine , Chlorozotocin, formustine fotemustine, nimustine, ramustine ranimustine, dacarbazine, pipobroman, actinomycin, actinomycin, anthramycin, Carzinophilin, Actinomycin D dactinomycin, Nogalamycin, Porfiromycin, Porfiromycin, Puromycin puromycin, Streptozocin, Tubercidin, Fludarabine, Ansi Ancitabine, azacitidine, cytara
- the salt is a basic salt or an acid salt
- the solvate is a hydrate or alcoholate
- the present invention also provides a medicine containing the above-mentioned compound.
- the present invention also provides antitumor or cancer drugs containing the above-mentioned compounds, wherein tumors and cancers include:
- Lung cancer non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma , Basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, osteocytic carcinoma, epithelial carcinoma, cholangiocarcinoma, choriocarcinoma Carcinoma, embryonic carcinoma, seminoma, Wilms carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hematoblastoma, Vocal cord neuroma, meningiom
- the cancer or tumor is a cancer or tumor of the central nervous system.
- cancer or tumor is primary brain cancer, tumor, or metastatic cancer or tumor that has metastasized to the brain from other parts.
- the salt is a basic salt or an acid salt.
- the compounds also include the use in the form of salts with the structure of formula I-1, that is, the present invention provides pharmaceutically acceptable salts of the compounds shown, and the salts may be basic salts, including the compounds and Inorganic bases (for example, alkali metal hydroxides, alkaline earth metal hydroxides, etc.) or salts formed with organic bases (for example, monoethanolamine, diethanolamine, or triethanolamine, etc.).
- Inorganic bases for example, alkali metal hydroxides, alkaline earth metal hydroxides, etc.
- organic bases for example, monoethanolamine, diethanolamine, or triethanolamine, etc.
- the salt may be an acid salt, including the compound and an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.) or an organic acid (such as methanesulfonic acid). , Trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, etc.).
- an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.
- organic acid such as methanesulfonic acid
- the solvate is a hydrate or an alcoholate.
- anti-cancer compound I-1 that is not a PGP substrate, which is used to treat cancer, tumors, or diseases or cell proliferative diseases caused by cancer or tumors:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , Cy, Y, L, and D are the same as the above definitions.
- the pharmaceutical use is used to prepare medicines for treating cancer, tumors or diseases or cell proliferative diseases caused by cancers or tumors.
- the compound for pharmaceutical use is selected from:
- solvates can also be used in the form of solvates, that is, the present invention provides pharmaceutically acceptable solvates of the I compound shown in the present invention.
- the solvates are hydrates, alcoholates, etc., and alcoholates include Ethanol hydrate.
- the prepared drugs include the indicated compound or its salts or solvates in a specific dosage range, and/or the prepared drugs are administered in a specific dosage form and a specific administration mode.
- the prepared medicine may also contain pharmaceutically acceptable excipients or excipients.
- the drug can be any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, small injection needles , Lyophilized powder for injection or large infusion.
- the pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosity Mixtures, fillers, correctives, sweeteners, antioxidants, surfactants, preservatives, wrappers and colors.
- the patient is a mammal, more preferably a human.
- This application also provides a method for using the compound as described above or a pharmaceutically acceptable salt thereof to treat cancers, tumors with expression of AKR1C3 enzyme, or cancers, tumor-induced diseases or cell proliferative diseases with expression of AKR1C3 enzyme
- a method of treatment which comprises administering to a patient an effective dose of a compound as described above or a pharmaceutically acceptable salt thereof.
- C x -C y or “C xy " before the group refers to the range of the number of carbon atoms present in the group.
- C 1 -C 6 alkyl refers to an alkyl group having at least 1 and at most 6 carbon atoms.
- Alkoxy refers to -O-alkyl
- Amino refers to NR p R q , where R p and R q are independently hydrogen or C 1 -C 6 alkyl, or R p and R q together with the nitrogen atom to which they are bonded form a 4-15 membered heterocyclic ring .
- Aryl refers to an aromatic group having carbon atoms and no ring heteroatoms and having a single ring (for example, phenyl) or multiple condensed (fused) rings (for example, naphthyl or anthracenyl).
- aryl Or “Ar” applies (for example, 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group because its point of attachment is at position 2 of the aromatic phenyl ring).
- the C 6 -C 10 aryl group may be phenyl, naphthyl, and various substituted phenyl or naphthyl groups.
- Heteroaryl refers to an aromatic group having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and includes a single ring (such as imidazole 2-yl and imidazol-5-yl) and polycyclic systems (e.g. imidazopyridyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl).
- heteroaryl for example, 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl.
- the nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N ⁇ O), sulfinyl, or sulfonyl moiety.
- heteroaryl or 5-15 membered heteroaryl includes (but is not limited to) acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene Benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzoisothiazolyl, benzothienyl, benzene Bisimidazolinyl, carbazolyl, NH-carbazolyl, carboline, chromanyl, chromenyl, cinnolinyl, dithiazinyl , Furyl, furanyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolinyl, indazinyl, indoly
- Alkyl refers to a monovalent saturated aliphatic hydrocarbon group having carbon atoms and in some embodiments 1 to 6 carbon atoms.
- C xy alkyl refers to an alkyl group having x to y carbon atoms.
- This term includes (for example) straight chain and branched chain hydrocarbon groups, such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl Group ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), second butyl ((CH 3 )( CH 3 CH 2 )CH-), tertiary butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -) and neopentyl ((CH 3 ) 3 CCH 2 -).
- straight chain and branched chain hydrocarbon groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl Group ((CH 3 ) 2 CH
- Cycloalkyl refers to a saturated or partially saturated cyclic group having 3 or more 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).
- cycloalkyl or C 3 -C 8 cycloalkyl includes cycloalkenyl.
- cycloalkyl or C 3 -C 8 cycloalkyl include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
- Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or moiety having carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen
- Saturated cyclic groups include single rings and polycyclic ring systems including fused, bridged, and spiro ring systems.
- heterocyclic ring or “heterocyclic ring” when there is at least one ring heteroatom and the point of attachment is at an atom of the non-aromatic ring
- heterocycloalkyl or “heterocyclyl” is applicable (e.g. 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl and Decahydroquinolin-6-yl).
- the heterocyclic group herein is a 3-15 membered, 4-14 membered, 5-13 membered, 7-12, or 5-7 membered heterocyclic ring.
- the heterocyclic ring contains 4 heteroatoms. In some other embodiments, the heterocyclic ring contains 3 heteroatoms. In another embodiment, the heterocyclic ring contains up to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties.
- Heterocyclic groups include (but are not limited to) tetrahydropyranyl, hexahydropyridinyl, N-methylhexahydropyridin-3-yl, hexahydropyrazinyl, N-methylpyrrolidin-3-yl, 3 -Pyrrolidinyl, 2-pyrrolidinone-1-yl, morpholinyl and pyrrolidinyl.
- Prefix indicating the number of carbon atoms e.g., C 3 - 10 refers to the total number of carbon number outside the impurity atoms in the heterocyclyl moiety atoms.
- the divalent heterocyclic group will have an appropriately adjusted hydrogen content.
- “Ether” refers to 1 to 3 C 1 -C 6 alkoxy-substituted C 1 -C 6 alkyl. Alkoxy refers to -O-alkyl.
- Halo and halogen refer to one or more of fluorine, chlorine, bromine and iodine.
- C xy alkenyl refers to alkenyl having x to y carbon atoms and is intended to include, for example, vinyl, propenyl, 1,3-butadienyl, and the like.
- Alkynyl refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group having 2 or more carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and containing at least one triple bond.
- alkynyl is also intended to include these hydrocarbon groups with one triple bond and one double bond.
- C 2-6 alkynyl includes ethynyl, propynyl, and the like.
- Amino phosphate alkylating agent refers to an alkylating agent comprising one or more moieties Z 5 -X 5 -Y 5 bonded to the -OP (Z1) moiety, where Z 5 is such as nitrogen, sulfur or oxygen And other heteroatoms, X 5 is optionally substituted ethylene, Y 5 is halo or another leaving group, or Z 5 -X 5 -Y 5 together form an aziridinyl (NCH 2 CH 2 ) moiety And Z 1 is as defined above.
- This alkylating agent can react with DNA or another nucleic acid or protein. In some cases, alkylating agents can cross-link DNA.
- a group may be substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents).
- the substituent is selected from the group consisting of: chlorine, fluorine, -OCH 3 , methyl, ethyl, isopropyl, cyclopropyl, -CO 2 H and its salts, and C 1 -C 6 alkyl Ester, 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 Cl, -NH 2 , -OCF 3 , -CF 3 and -OCHF 2 .
- Alkylene refers to a divalent saturated aliphatic hydrocarbon group having carbon atoms and in some embodiments 1 to 6 carbon atoms, and the alkyl group loses one more H atom.
- C uv alkylene refers to a pressurized alkyl group having u to v carbon atoms.
- Alkylene includes branched and straight chain hydrocarbon groups.
- C 1 -C 6 alkylene includes methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
- Heteroalkylene refers to an alkylene group in which a chain carbon atom is replaced by a heteroatom such as O, S, N, or P, or a substituent containing a heteroatom.
- the "drugs" referred to in this article for D include (but are not limited to) gemcitabine, erlotinib, meturedepa, uredepa, hexamethylmelamine ( altretamine), imatinib, triethylenemelamine, trimethylmelamine, chlorambucil, chlornaphazine, estramustine, gefitinib ( gefitinib, afatinib, mechlorethamine, nitrogen mustard oxide hydrochloride, melphalan, novembichin, phenesterine, prednisone Mustard (prednimustine), trifosfamide (trofosfamide), uracil mustard (uracil mustard), carmustine (carmustine), chlorozotocin (chlorozotocin), formustine (fotemustine), nimustine ( nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol,
- administering or “administration” of a drug to a patient refers to direct administration or administration (which can be administered or administered to the patient by a medical professional or can be self-administered or administered) and/or indirect administration or administration, which may be the act of prescribing a drug.
- direct administration or administration which can be administered or administered to the patient by a medical professional or can be self-administered or administered
- indirect administration or administration which may be the act of prescribing a drug.
- the physician instructing the patient to self-administer or administer the drug and/or provide the prescription of the drug to the patient is to administer or administer the drug to the patient.
- Cancer refers to potentially unrestricted growth of leukemia, lymphoma, cancer, and other malignant tumors (including solid tumors) that can expand locally through invasion and expand systemically through metastasis.
- malignant tumors including solid tumors
- Examples of cancer include, but are not limited to, adrenal glands, bones, brain, breast, bronchus, colon and/or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nerve tissue, pancreas, prostate, parathyroid, Cancer of the skin, stomach and thyroid.
- cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, poorly differentiated cervical epithelium and carcinoma in situ, Ewing’s sarcoma, epidermoid carcinoma, giant cell tumor, multiple Glioblastoma, hair cell tumor, enteric gangliocytoma, hyperplastic corneal nerve tumor, pancreatic islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , Malignant hypercalcemia, Mafang-like tumors, medullary epithelial carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, fungous granuloma, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, Ovarian tumor, pheochromocytoma, polycy
- Patient and “individual” are used interchangeably and refer to mammals in need of cancer treatment. Usually, the patient is a human. Generally, the patient is a human being diagnosed with cancer. In certain embodiments, “patient” or “individual” may refer to non-human mammals used for screening, characterizing, and evaluating drugs and therapies, such as non-human primates, dogs, cats, rabbits, pigs, mice Or rat.
- Prodrug refers to a compound that is metabolized or otherwise converted into a compound (or drug) with at least one property of biological activity or higher activity after administration or administration.
- prodrugs are chemically modified in such a way that they are less or inactive relative to the drug, but chemical modification allows the corresponding drug to be produced through metabolism or other biological processes after the prodrug is administered.
- Prodrugs can have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavors relative to the active drug (see (for example) Reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388 to 392, which are incorporated herein by reference).
- Prodrugs can be synthesized using reactants other than the corresponding drugs.
- Solid tumor refers to a solid tumor including (but not limited to) metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcoma).
- Central nervous system tumor or cancer refers to benign tumors or malignant tumors (cancers) located in the brain or other central nervous system, including meningiomas, pituitary tumors, craniopharyngiomas, schwannomas and gliomas, Ependymoma, primitive neuroectodermal tumor, central nervous system lymphoma, germ cell tumor, metastasis, etc.
- the "therapeutically effective amount" of a drug refers to a drug that, when administered or administered to a patient suffering from cancer, will have the expected therapeutic effect (for example, alleviation, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) ⁇ The amount.
- the therapeutic effect does not have to occur through administration or administration of one dose, and may only occur after administration or administration of a series of doses. Therefore, the therapeutically effective amount can be administered or administered one or more times.
- Treatment 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 improvement of one or more cancer symptoms; reduction of disease degree; delay or reduction of disease progression; improvement, alleviation or stabilization of disease state; Or other beneficial results.
- treatment of cancer can result in a partial response or stabilize the disease.
- Tumor cells refer to tumor cells of any appropriate species (e.g., mammals, such as murine, dog, cat, horse, or human).
- P-glycoprotein also known as multidrug resistance protein
- P-GP is a high-molecular-weight protein found on the plasma membrane of multidrug-resistant tumor cells and has a transport pump-like structure. It pumps a variety of chemotherapeutic drugs out of the cell and reduces the drug concentration in the cell, which is closely related to the resistance of clinical chemotherapy.
- chemotherapeutics in the treatment of tumors or cancers in the central nervous system such as the brain is limited. This is mainly due to the blood-brain barrier (BBB).
- BBB blood-brain barrier
- the blood-brain barrier makes chemotherapeutic drugs poorly permeable to the tumor system or tumor tissues. That is, chemotherapy drugs cannot cross the blood-brain barrier and enter the brain to kill cancer cells.
- the process of chemotherapeutics and other small molecules crossing the blood-brain barrier is more complicated.
- the blood-brain barrier is located between the systemic blood circulation and the cerebrospinal fluid. It is formed by specialized brain microvascular endothelial cells, together with surrounding cells and astrocytes surrounding blood vessels, through close connections between adjacent cells, which force most molecules to pass through. Form selective barriers instead of forming a physical barrier around vascular endothelial cells.
- the membrane transport system of the blood-brain barrier allows small hydrophilic molecules to pass through, while large hydrophilic molecules, including many chemotherapeutic drugs and macromolecular drugs, will be excluded from the central nervous system unless they can be actively transported by certain proteins.
- the "drug efflux pump" of the blood-brain barrier that protects brain tissue, such as P-glycoprotein can actively exclude some chemotherapeutic drugs and macromolecular drugs from the brain. Therefore, even if small-molecule chemotherapeutics with a certain degree of hydrophilicity (including small-molecule targeted anti-tumor drug molecules) can cross the blood-brain barrier and enter the brain to play a role, they will still be excluded from the center under the action of P-glycoprotein. The nervous system cannot really work.
- the transmembrane structure of Pgp has an energy-dependent "drug pump” function, which can transfer lipophilic drugs such as vincristine (VCR), doxorubicin (Dox) or etoposide (VP-16). ) Is pumped out of the cell, causing the concentration of the drug in the cell to decrease, and the cytotoxicity is reduced or completely lost.
- VCR vincristine
- Dox doxorubicin
- VP-16 etoposide
- MDCKII-MDR1 cells are cultured in cell culture flasks.
- the incubator is set to 37°C, 5% CO 2 , and a relative humidity of 95% is guaranteed.
- the cell confluence reaches 70-90%, it can be used to inoculate the migration chamber (Transwell).
- the process of replacing the medium is as follows. Separate the migration chamber from the receiving plate, first discard the medium in the receiving plate and then discard the migration chamber medium. Finally, add 75 ⁇ L of fresh medium to each chamber, and add 25mL of fresh medium to the receiving plate. .
- MDCKII-MDR1 cells should be fully confluent and differentiated after 4-8 days of culture. At this time, it can be applied to penetration test.
- 200ul acetonitrile containing internal standard 100nM alprazolam, 200nM labetalol, 200nM caffeine and 2 ⁇ M ketoprofen
- Each sample was incubated in three parallels.
- the peak area is calculated from the results of ion chromatography.
- the apparent permeability coefficient of the compound (Papp, unit: cm/s ⁇ 10-6) is calculated using the following formula:
- VA is the volume of the receiving end solution (Ap ⁇ Bl is 0.235mL, Bl ⁇ Ap is 0.075mL), Area is the membrane area of the Transwell-96-well plate (0.143cm2); time is the incubation time (unit: s), [drug] acceptor represents the drug concentration at the receiving end after the incubation, [drug] initial, donor represents the initial drug concentration before the incubation.
- Papp(B-A) is the apparent permeability coefficient from the base to the top
- Papp(A-B) is the apparent permeability coefficient from the top to the base.
- VA is the volume of the solution at the receiving end (unit: mL);
- VD is the volume of the solution at the giving end (unit: mL).
- [drug] acceptor represents the drug concentration at the receiving end after the incubation
- [drug] donor represents the drug concentration at the dosing end after the incubation
- [drug] initial, donor represents the initial drug concentration before the incubation.
- the fluorescence value LY Leakage of the cell monolayer membrane is calculated using the following formula:
- I acceptor refers to the fluorescence density of the receiving hole (0.3mL), and I donor refers to the fluorescence density of the dosing hole (0.1mL), expressed in %LY. LY ⁇ 1.5% indicates that the monolayer cell membrane is intact.
- Part of the compounds prepared were tested to obtain the efflux rate of different compounds in the presence or absence of the P-glycoprotein inhibitor verapamil. Part of the compounds prepared were tested to obtain the efflux rate of different compounds in the presence or absence of the P-gp inhibitor verapamil.
- the efflux rate test result of a certain compound has two values, the efflux rate without verapamil and verapamil. The closer these two values are, the more it means that P-gp has no effect on the drug, that is, the drug is not The substrate of P-gp protein can enter the blood-brain barrier.
- IC50 values are reported in micromolar and are obtained from exposure of the compound at each concentration for 2 hours, followed by a washing step and addition of fresh medium, then growth and cell viability staining and comparison with the medium-only control.
- exponentially growing cells were seeded in a 96-well plate at a density of 4 ⁇ 10 3 cells/well and incubated at 37° C. in 5% CO 2 , 95% air and 100% relative humidity for 24 hours, and then Add test compound.
- the compound was dissolved in 100% DMSO at 200 times the expected final test concentration.
- complete medium is used to further dilute the compound to 4-fold the desired final concentration.
- An aliquot of 50 ⁇ l of the compound at a specific concentration was added to a microwell that already contained 150 ⁇ l of medium to obtain the reported final drug concentration.
- the proliferation test of certain compounds on H460 cancer cells is performed in the presence (3 micromolar concentration) of a specific AKR1C3 enzyme inhibitor. Two hours before the compound treatment, the inhibitor-added compound solution was added to the cell culture. The inhibitor used was Flanagan et al., Compound 36 in Bioorganic and Medicinal Chemistry (2014) pages 962-977.
- THF tetrahydrofuran
- DCM dichloromethane
- EA or EtOAC ethyl acetate
- TEA triethylamine
- HPLC high performance liquid chromatography
- MTBE methyl tert-butyl ether
- DMAP 4-dimethylaminopyridine
- DBAD di-tert-butyl azodicarboxylate
- TFA trifluoroacetic acid
- LCMS liquid-mass spectrometry
- EtOH ethanol
- t-BuOH tert-butanol
- DMF dimethylformamide
- PE petroleum ether, petroleum ether
- eq equivalent is the molar ratio
- TBAF tetrabutylammonium fluoride
- DIPEA N,N-diisopropylethylamine
- DIPEA N,N-diisopropylethylamine
- the chemical reagents and drugs that are not indicated in the synthesis process are all analytical or chemically pure, and they are all purchased from commercial reagent companies.
- Dissolve 1-A1 (80.0mg, 0.266mmol, refer to the synthesis method of 3-A4 compound) and 1-A2 (78.3mg, 0.380mmol, purchase) in acetone (4mL), and then add Cs 2 CO 3 (199.3mg , 0.612mmol), stirred at room temperature, HPLC detected the progress of the reaction, the reaction was completed in 2h.
- the solid was removed by suction filtration, the mother liquor was concentrated, and column chromatography was separated. The prepared liquid was extracted with DCM (10 mL ⁇ 3), concentrated, and lyophilized to obtain the pure product of compound 1 (17 mg, yield 13.1%), which was a pale yellow solid.
- 3-A1 (5g, 24.62mmol, purchased) was dissolved in anhydrous tetrahydrofuran (50mL), the temperature was reduced to 0°C, and the gas was pumped three times. Borane tetrahydrofuran solution (61.5mL, 61.5mmol, 1mol) was slowly added dropwise. /L in THF), keep the temperature at 0°C for 30min, raise the temperature to 65°C, and complete the reaction in 3 hours.
- 3-A3 (250 mg, 0.520 mmol) was dissolved in tetrahydrofuran (4 mL) and acetone (6 mL), heated to 59° C. and stirred, and the reaction was completed in four hours. The temperature was reduced to normal temperature, the diatomite was suction filtered, the solid was washed with acetone (5 mL), and the mother liquor was concentrated to obtain a crude product of 190 mg, which was a pale yellow liquid, and proceed directly to the next step.
- 15-A2 (700mg, 1.970mmol) was dissolved in anhydrous THF (10mL), then (trifluoromethyl)trimethylsilane (476mg, 3.35mmol, 98%) was added dropwise, and the temperature was reduced to 0 At 0°C, TBAF (0.04mL, 1M in THF) was added dropwise, and the temperature was kept at 0°C for 1.5 hours. The reaction was completed. 2mL of 3N hydrochloric acid was added dropwise, raised to room temperature naturally, and stirred for 1 hour.
- phosphorus oxychloride (80mg, 3.76mmol, 97%) was added dropwise to anhydrous DCM (10mL), the temperature was lowered to -40°C, and 15-A3 (800mg, 1.88mmol) in DCM was added dropwise ( 4mL), then triethylamine (476mg, 4.70mmol) was added dropwise, the temperature was kept at -40°C to -35°C for two hours, and monitored by LC-MS, 15-A3 disappeared and it was converted into an intermediate.
- 16-A1 (1.7g, 11mmol), 16-A2 (2g, 10mmol), palladium acetate (21.5mg, 0.1mmol), triphenylphosphine (39mg, 0.15mmol) and potassium carbonate (2.8, 20mmol) )
- dioxane (20 mL) and water (2 mL)
- 1 H-NMR 300MHz, DMSO) ⁇ 10.17 (s, 1H), 7.55-7.08 (m, 3H), 6.79-6.50 (m, 3H).
- 16-A3 500mg, 2.2mmol
- 3-fluoro-4-nitrobenzaldehyde 370mg, 2.2mmol
- MeCN MeCN
- potassium carbonate 830mg, 6mmol
- the temperature was increased to 80°C Stir for 4 hours.
- 16-A4 (680mg, 1.82mmol), trifluoromethyltrimethylsilane (510mg, 3.6mmol) was dissolved in THF (8mL), and the THF solution of tetrabutylammonium fluoride (0.1 mL, 0.1mmol, 1M, Anaiji), keep for 6 hours, add 1N hydrochloric acid (2mL) and stir for 10 minutes.
- 16-A6 250mg, 0.34mmol was dissolved in THF (10mL), Ag 2 O (210mg, 1.7mmol) and N,N-diisopropylethylamine (220mg, 1.7mmol) were added, and the temperature was increased. Reaction to 65°C. After the 2h reaction was completed, the diatomite was suction filtered, the solid was washed with DCM (20 mL), the mother liquor was concentrated, and the column chromatography was separated to obtain 22 mg of pure compound No. 16 (white solid, yield 11%).
- 18-A1 500mg, 2.65mmol
- 18-A2 460mg, 2.65mmol
- tetrakistriphenylphosphine palladium 373mg, 0.3mmol
- potassium fluoride 300mg, 5.2mmol
- 18-A4 (640mg, 1.64mmol), trifluoromethyltrimethylsilane (430mg, 3mmol) was dissolved in THF (5mL), and a THF solution of tetrabutylammonium fluoride (0.1 mL, 0.1mmol, 1M), keep for 6 hours, add 1N hydrochloric acid (2mL) and stir for 10 minutes.
- 18-A6 (150mg, 0.23mmol) was dissolved in THF (10mL), and Ag2O (170mg, 1.38mmol, Anaiji) and N,N-diisopropylethylamine (163mg, 1.38mmol) were added. , The temperature was raised to 65°C for reaction. After the 2h reaction was completed, the diatomaceous earth was suction filtered, the solid was washed with DCM (20 mL), the mother liquor was concentrated, and the pure product (41 mg, yield 36%) was obtained by column chromatography, which was a white solid.
- 19-A3 (namely compound No. 46, 100 mg, 0.27 mmol) was dissolved in acetone (5 mL), and then 19-A2 (102 mg, 0.54 mmol), Cs 2 CO 3 (309 mg, 0.95 mmol), Stir at room temperature for 2 hours. After the completion of the reaction, celite was suction filtered, the solid was washed with acetone, the mother liquor was concentrated, and the pure product of compound No. 20 (17 mg, 11.7%) was obtained by column chromatography, which was a tan solid.
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Abstract
提供作为非PGP底物的抗癌化合物,其为式I-1化合物或者其药学上可接受的盐、前药或溶剂合物,同时提供这些化合物在治疗癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病中的医药用途。还提供一种使用如上所述的作为非PGP底物的抗癌化合物来治疗癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病的治疗方法。
Description
本发明涉及对专利申请PCT/US2016/021581,公开号WO2016145092A1,对应中国申请号2016800150788,公开号CN107530556A所公开的化合物的进一步研发,属于癌症治疗化合物研发领域。
我公司开发的以高表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化剂癌症治疗化合物前药(申请号PCT/US2016/021581,公开号WO2016/145092;申请号PCT/US2016/062114,公开号WO2017/087428)特异性的在体内AKR1C3的作用下发生代谢活化,以其中TH2870的S构型AST-3424为例:
作为前药形式的以高表达醛酮还原酶AKR1C3为标靶的DNA烷化剂在体内会和AKR1C3结合,然后发生代谢反应,最终产生具有细胞毒性的DNA烷化剂。
然而这些化合物不是固体,而是油状物,使得在后续的制剂研发上存在以下的困难:
分离纯化复杂,成本高。由于为油状物,无法使用效率高/成本低的重结晶或是打浆纯化(slurry),而只能使用柱层析方法进行纯化,导致操作复杂,原料药制备的成本高。
制剂不方便,稳定性差。由于为油状物,在转运/计量过程中都不便于操作,重要的是,对于油状物无法不方便进行制剂剂型的开发和多样化选择,一般只能开发为冻干粉针的方式进行给药,给药方式单一而且成本较高。
为此我公司一直对在对该类机理的抗癌化合物进行各种改进。
发明内容
研发过程中发现对该类化合物进行各个基团取代的场所时,发现当苯环上硝基邻位上的O、S原子连接的不是类似于申请号PCT/US2016/021581,公开号WO2016/145092;申请号PCT/US2016/062114,公开号WO2017/087428;申请号PCT/US2016/025665,公开号WO2016/161342中的基团(C6-C10芳基、5至15元杂芳基,或-N=CR
1R
2)而是联苯或其他与联苯结构类似的基团(吡啶基苯)时,对应的化合物除具有AKR1C3活化的杀灭癌细胞的活性外,其通过实验证明这类结构的化合物并非为细胞中PGP蛋白的结合底物,也就是说,这些化合物还意外的具有较好的通过血脑屏障的能力(与不是P-gp蛋白的结合底物相关),这意味着这些化合物有可能开发为治疗中枢神经系统(主要是脑部)的肿瘤或癌症的治疗药物的潜力。
为此本发明提供以下的技术方案。
作为非PGP底物的抗癌化合物,其为式I-1化合物或者其药学上可接受的盐或溶剂合物:
I-1
其中,
R
1、R
2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基、杂环或Z取代杂芳基、C
1-C
6烷基或Z取代烷基、C
2-C
6烯基或Z取代烯基、C
2-C
6炔基或Z取代炔基、C
3-C
8环烷基或Z取代环烷基;
R
3是氢、卤素、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C
1-C
6烷基或Z取代烷基、C
2-C
6烯基或Z取代烯基、C
2-C
6炔基或Z取代炔基、C
3-C
8环烷基或Z取代环烷基、C
6-C
10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C
1-C
6烷氧基或Z取代的C
1-C
6烷氧基或者R
3是-CONR
6R
7、-SO
2NR
6R
7、-SO
2R
6、-OCO-R
6、-OCOO-R
6、-COOR
6、-NR
6COR
7、-OCOR
6、-NR
6SO
2R
7、-NR
6CONR
7;
R
4、R
5各自独立地是氢、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C
1-C
6烷基或Z取代烷基、C
2-C
6烯基或Z取代烯基、C
2-C
6炔基或Z取代炔基、C
3-C
8环烷基或Z取代环烷基、C
6-C
10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C
1-C
6烷氧基或Z取代的C
1-C
6烷氧基或者R
4、R
5是-CONR
6R
7、-SO
2NR
6R
7、-SO
2R
6、-OCOO-R
6、-COOR
6、-NR
6COR
6、-OCOR
6、-NR
6SO
2R
7、-NR
6CONR
7或者R
4、R
5和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环;
R
6和R
7各自独立地是氢、氰基或异氰基、C
1-C
6烷基或Z取代烷基、C
2-C
6烯基或Z取代烯基、C
2-C
6炔基或Z取代炔基、C
3-C
8环烷基或Z取代环烷基、C
6-C
10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C
1-C
6烷氧基或Z取代的C
1-C
6烷氧基,或者R
6、R
7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基;
Cy为5-10元的芳环、杂环或者芳杂环,环上氢各自独立地被氘、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C
1-C
6的脂肪烃基取代或者被卤素原子、氰基、异氰基、羟基、巯基、胺基、肟基、腙基取代的C
1-C
6脂肪烃基取代;
R
10为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的3-18元的环烃基、芳基或稠环、杂环、稠杂环基团、杂芳基团或C
1-C
18的烃基或Z取代烃基;或
R
10为-Q-Cz,
Q为-O-、-S-、-CO-、-SO
2-、-SO-、-OCO-、-OCOO-、-NR
6CO-、-NR
6SO
2-、-OCONR
6-,
Cz为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的3-18元的环烃基、芳基或稠环、杂环、稠杂环基团、杂芳基团或C
1-C
18的烃基或Z取代烃基;
Y为-O-或者-S-或-SO
2-、-SO-;
L、D选自以下三种情况:
R
40及R
41独立地为氢、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
8环烷基、C
6-C
10芳基、4至15元杂环或5至15元杂芳基;
R
42为C
2-C
3亚烷基、亚杂烷或1至3个C
1-C
6烷基取代的C
2-C
3亚烷基、亚杂环烷基;
V(-)为任何阴离子;
D为使得D-OH为抗癌药物的部分,其中OH为脂族羟基或酚羟基或为附接至磷酸酯的OH部分;或
(2)L选自:
R
40如上文所定义,R
43为氢或与D一起形成杂环,且亚苯基部分是Z取代的或未经取代的,及D为使得D-NR
43H为抗癌药物的部分;或
(3)L选自键、–O-C(R
40R
41)
2-,–O-C(R
40R
41)-NR
40R
41(+)-C(R
40R
41)-,或
其中R
40、R
41及V(-)如上文所定义,及
D为含有三级或二级氮原子的抗癌药物,其中所述三级氮原子或二级氮原子键接至L;及
上述L、D的定义中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基团为Z取代或未经取代;
Z取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C
1-C
3烷基或取代烷基、C
1-C
3烷氧基或取代烷氧基、C
2-C
3烯基或取代烯基、C
2-C
3炔基或取代炔基、C
3-C
8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环,取代的方式为单取代或偕二取代,取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs;
杂环、杂芳基包括三元环、四元环、五元环、六元环、七元环。
以下举例说明。
三元环:环氧乙烷、环氮乙烷、环硫乙烷;
四元环:吖丁啶、噁丁啶、噻丁啶、丁啶;
五元环:吡咯烷、吡咯啉、1-吡咯啉、3-吡咯啉、2-吡咯啉、吡咯、吡唑烷、2-吡唑啉、咪唑、吡唑、呋喃、四氢呋喃、二氢呋喃、四氢噻吩、噻吩、环丁砜、磷杂茂、噁唑、1,2,3-三唑、1,2,4-三唑、1,3,4-噻二唑;
六元环:哌啶、四氢吡喃、四氢噻喃、吡啶、吡喃、噻喃、二氢吡啶、吗啉、哌嗪、哒嗪、吡嗪、1,3,5-三嗪、1,3,5-三噻烷;
稠环定义为以上的杂环、杂芳基之间的骈合或者与环烷结构的骈合,骈合可以是通过单键的链接或者是共用一个、两个甚至三个原子的形式,以下给出一些常见的稠环结构:萘、喹啉、吲哚、异吲哚、异喹啉、噌啉、喹喔啉、联苯、香豆素、芴、二苯咔喃、咔唑、蒽、氮蒽、噻吩嗪、金刚烷、薁、菲、蒽醌、黄酮、异黄酮。
显然以上的化合物,其也包括同位素取代化合物,典型的取代方式为氢原子H被重氢原子氘D取代或甲基-CH
3被取代为-CD
3。
特别的,被氘取代的部位位于I式中Ph-C
×-上,即R
1和/或R
2为氘。
进一步,上述的的化合物,其中,
-D为-P(Z
1)(Z
5-X
5-Y
5)
n,
Z
5为N,S或O,
X
5为任意取代的亚乙基,
Y
5为卤素原子或-OSO
2-R
20,R
20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,
n为1或2;或者
Z
5-X
5-Y
5为吖丙啶基-NCH
2CH
2部分;
Z
1为O或S。
以上结构即为胺基磷酸酯烷化剂。
或者更进一步的,所述化合物:
-L-D为-O-P(Z
1)(Z
5-X
5-Y
5)
n,
Z
5为N,S or O,
X
5为任意取代的亚乙基,
Y
5为卤素原子或-OSO
2-R
20,R
20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,
n为1或2;或者
Z
5-X
5-Y
5为吖丙啶基-NCH
2CH
2部分;
Z
1为O或S。
进一步的,其中,-L-D为-OP(Z
1)(NR
30CH
2CH
2Cl)
2,-OP(Z
1)(NR
30CH
2CH
2Br)
2,-OP(Z
1)(NR
30
2)(N(CH
2CH
2X
1)
2),-OP(Z
1)(N(CH
2)
2)
2,或-OP(Z
1)(N(CH
2CH
2Cl)
2)
2,
其中,每个R
30各自独立的为H、C
1-C
6的烃基或两个R
30基团与连接的N原子形成5-7元的杂环,Z
1为O或S,且X
1is Cl,Br,或-OSO
2Me。
进一步的,其中,-L-D为-OP(Z
1)(NHCH
2CH
2Cl)
2,-OP(Z
1)(NHCH
2CH
2Br)
2,-OP(Z
1)(NH
2)(N(CH
2CH
2X
1)
2),-OP(Z
1)(N(CH
2)
2)
2,或-OP(Z
1)(N(CH
2CH
2Cl)
2)
2,
且X
1is Cl,Br,或-OSO
2Me。
进一步的,所述的抗癌化合物,其中,
R
10为5-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的5-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF
3、Cl取代的烃基;
或
R
10为-O-Cz,
Cz为5-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的5-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF
3、Cl取代的烃基。
更进一步,所述的抗癌化合物,其中
R
10为7-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的7-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF
3、Cl取代的烃基;
或
R
10为-O-Cz,
Cz为7-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的7-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF
3、Cl取代的烃基。
其中,该化合物具有式I-2的结构
I-2
Cx选自联苯基、Z取代的联苯基、苯基吡啶、Z取代的苯基吡啶和-CONR
6R
7、-SO
2NR
6R
7、-SO
2R
6、-OCOO-R
6、-COOR
6、-NR
6COR
7、-OCOR
6、-NR
6SO
2R
7、-NR
6SO
2NR
6R
7、-COR
6、-NR
6CONR
7取代的联苯基、苯基吡啶。
在上述的I-2结构的化合物中,-Y-与Cx上两个苯环相联的碳原子的对位相联,且联苯上的取代基为F原子或甲基。
上述的的化合物中,优选的,R
3、R
4、R
5各自独立地为氢。
上述的的化合物中,优选的,R
1、R
2各自独立地为氢、氘、-CH
3、-CD
3、CF
3。
上述的的化合物中,优选的,Y为-O-。
在上述的I-1结构的化合物中,Cy为5-10元的芳杂环,环上氢各自独立地被氘、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C
1-C
6的脂肪烃基取代或者被卤素原子、氰基、异氰基、羟基、巯基、胺基、肟基、腙基取代的C
1-C
6脂肪烃基取代。
进一步的,Cy上的取代基为氢、氘、卤素原子、-CH
3、-CF
3,
Cy选自5、6、7、8元的芳杂环,且杂原子为N、S、O,杂原子的数目为1、2、3。
上述的的化合物中,优选的,选自以下结构的化合物
上述的化合物,其中,
D-OH选自以下含有-OH基团的抗癌药物:吉西他滨gemcitabine、雌莫司汀estramusting、泼尼莫司汀pudnimnstine、氯脲霉素chlorozotocin、雷莫司汀ranimustine、甘露莫司汀mannomustine、二溴甘露醇mitobronitol、二溴卫矛醇dibromodulcitol、阿柔比星aclacinomycins、安曲霉素anthramycin、博来霉素bleomycin、卡柔比星carubicin、多柔比星doxorubicin、嗜癌霉素carzinophilin、色霉素chromomycin、放线菌素Ddactinomycin、道诺霉素daunorubicin、霉酚酸mycophenolic acid、诺加霉素nogalamycin、橄榄霉素olivomycin、培洛霉素peplomycin、普卡霉素plicamycin、嘌呤霉素puromycin、链黑霉素streptonigrin、
链
脲佐菌素streptozocin、杀结核菌素tubercidin、乌苯美司ubenimex、净司他丁zinostatin、左柔比星zorubicin、迪诺特宁denopterin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、6-氮杂尿苷6-azauridine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醋葡醛内酯aceglatone、依利醋铵elliptinium acetate、依托格鲁etoglucid、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、蘑菇多醣lentinan、米托蒽醌mitoxantrone、莫哌达醇mopidamol、喷司他丁pentostatin、吡柔比星pirarubicin、鬼臼酸podophyllinic acid、西索菲兰sizofiran、太平洋紫杉醇paclitaxel、替尼泊苷teniposide、细交链孢菌酮酸tenuazonic acid、长春碱vinblastine、长春新碱vincristine;
D-NR
43H选自以下的抗癌药物:埃罗替尼erlotinib、美妥替哌meturedepa、乌瑞替派uredepa、伊马替尼imatinib、三甲密胺trimethylolomelamine、吉非替尼gefitinib、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、甘 露氮芥mannomustine、放射菌素actinomycin、安曲霉素anthramycin、博莱霉素bleomycin、放线菌素C cactinomycin、卡柔比星carubicin、多柔比星doxorubicin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、培洛霉素peplomycin、嘌呤霉素puromycin、链脲菌素streptozocin、乌苯美司ubenimex、净司他丁zinostatin、迪诺特宁denopterin、蝶罗呤pteropterin、曲美沙特trimetrexate、6-巯基嘌呤6-mercaptopurine、硫米嘌呤thiamiprine、硫鸟嘌呤thioguanine、6-氮杂尿苷6-azauridine、卡莫氟carmofur、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、5-氟尿嘧啶5-fluorouracil、替加氟tegafur、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、安吖啶amsacrine、比生群bisantrene、地美可辛demecolcine、地吖醌diaziquone、依利醋铵elliptinium acetate、氟他胺flutamide、羟基尿素hydroxyurea、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、米托蒽醌mitoxantrone、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、2-乙基酰肼2-ethylhydrazide、丙卡巴肼procarbazine、雷佐生razoxane、埃罗替尼erlotonib、尿烷urethane、长春碱vinblastine、长春新碱vincristine;
含有三级或二级氮原子的抗癌药物选自六甲蜜胺altretamine、曲他胺triethylenemelamine、苯丁酸氮芥chlorambuci、萘氮芥chlornaphazine、雌氮芥estramustine、吉非替尼gefitinib、氮芥mechlorethamine、氮芥氧化物盐酸盐mechlorethamine oxide hydrochloride、美法仑melphalan、新氮芥novembichin、芬司特瑞phenesterine、泼尼氮芥prednimustine、曲磷胺trofosfamide、尿嘧啶氮芥uracilmustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、哌泊溴烷pipobroman、放线菌素actinomycin、安曲霉素anthramycin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、诺加霉素nogalamycin、泊非罗霉素porfiromycin、嘌呤霉素puromycin、链脲菌素streptozocin、杀结核菌素tubercidin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醛磷酰胺糖苷aldophosphamide glycoside、贝斯布西bestrabucil,地吖醌diaziquone、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、丙脒腙mitoguazone、莫哌达醇mopidamol、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、雷佐生razoxane、锗螺胺spirogermanium、他莫昔芬tamoxifen、三亚胺醌triaziquone、2,2',2"-三氯三乙胺2,2',2"-trichlorotriethylamine、长春碱vinblastine、长春新碱vincristine。
显然,以上药物只是将市面上已有的药物进行了部分列举,尚有其他药物也是可以的。
进一步的,其中,其中,所述盐为碱式盐或酸式盐,所述溶剂合物为水合物或醇合物。
本发明还提供含有上述的化合物的药物。
本发明还提供含有上述的化合物的抗肿瘤或癌症药物,其中肿瘤、癌症包括:
肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、 神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、子宫内膜癌、胶质瘤、结直肠癌、甲状腺癌、尿路上皮癌或多发性骨髓瘤。
所述癌症或肿瘤为中枢神经系统的癌症或肿瘤。
进一步的,所述癌症或肿瘤为原发性脑癌、肿瘤或由其他部位转移至脑的转移性癌症、肿瘤。
进一步的,上述提供的化合物,所述盐为碱式盐或酸式盐。
关于本文所述化合物,所述化合物还包括式I-1结构盐的形式使用,即本发明提供所示化合物的药学上可接受的盐,所述盐可以为碱式盐,包括所述化合物与无机碱(例如碱金属氢氧化物、碱土金属氢氧化物等)或与有机碱(例如单乙醇胺、二乙醇胺或三乙醇胺等)形成的盐。或者,所述盐可以为酸式盐,包括所述化合物与无机酸(例如盐酸、氢溴酸、氢碘酸、硝酸、高氯酸、硫酸或磷酸等)或与有机酸(例如甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、富马酸、草酸、马来酸、柠檬酸等)形成的盐。选择和制备化合物的可接受的盐和溶剂化物等是本领域公知技术。
进一步的,上述提供的化合物,其中,所述溶剂合物为水合物或醇合物。
非PGP底物的抗癌化合物I-1的制药用途,该药用于治疗癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病:
I-1
其中,
R
1、R
2、R
3、R
4、R
5、R
10、Cy、Y、L以及D的定义与上述定义相同。
所述的制药用途,其用于制备治疗癌症、肿瘤或由癌症、肿瘤引发的病症或细胞增生性疾病的药物。
优选的,制药用途中的化合物选自:
在药物设计和有机化学这一技术领域,化合物特别是具有较活泼基团的化合物,比如磷酰胺、酰胺、胺、盐或是酯等基团,由于对溶剂,比如水、乙醇等醇类溶剂具有较好的亲和性,经常会出现溶剂和化合物的结合物(典型如水合硫酸铜这类无机盐),特别是当化合物为通过结晶或是沉淀、浓缩等方式自溶剂中得到之固体时,会不可避免的与溶剂因为结合、包裹而得到与溶剂发生结合的溶剂化物。本发明提供的化合物具有磷酰胺、酰胺、羟基等活性基团就,自然也可以通过上述之理由和实际情况而生成对应的溶剂化物。
关于本文所述化合物还可以溶剂合物的形式使用,即本发明提供所示I化合物的药学上可接受的溶剂合物,所述溶剂合物为水合物、醇合物等,醇合物包括乙醇合物。
关于本文所述药品或制剂,所制得的药物包含特定剂量范围的所示化合物或其盐或溶剂合物,和/或,所制得的药物为特定剂型、特定给药方式施用。
关于本文所述用途,所制得的药物还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型,例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式,所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种:稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂和色素等。优选地, 所述患者是哺乳动物,更优选是人。
本申请还提供一种使用如上所述的化合物或其药学上可接受的盐来治疗AKR1C3酶具有表达的癌症、肿瘤,或由AKR1C3酶具有表达的癌症、肿瘤引发的病症或细胞增生性疾病的治疗方法,所述方法包括向患者施用有效剂量的如上所述的化合物或其药学上可接受的盐。
以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的药材原料、试剂材料等,如无特殊说明,均为市售购买产品。
提供以下定义以帮助阅读者。除非另有定义,否则本文所用的所有业内术语、符号及其他科学或医学术语或术语学均意欲具有熟习化学及医学领域的技术者通常所了解的含义。在一些情形下,为清楚和/或供及时参考,具有通常所了解含义的术语定义于本文中,且本文中此等定义的纳入不应解释为表示与如业内通常所了解的术语的定义有实质差异。
所有数值指定(例如pH、温度、时间、浓度及重量)(包括其中每一者的范围)通常可为适当以0.1、1.0或10.0的增量改变(+)或(-)的近似值。所有数值指定均可理解为前面有术语“约”。本文所述试剂为实例性的且此等的同等物可为业内所已知。
基团前的“C
x-C
y”或“C
x-y”是指存在于该基团中的碳原子数目的范围。举例而言,C
1-C
6烷基是指具有至少1个且最多6个碳原子的烷基。
“烷氧基”是指-O-烷基。
“胺基”是指NR
pR
q,其中R
p及R
q独立是氢或C
1-C
6烷基,或R
p及R
q与其所键结的氮原子一起形成4-15元杂环。
“芳基”是指具有碳原子且不含环杂原子且具有单环(例如,苯基)或多个缩合(稠合)环(例如,萘基或蒽基)的芳香族基团。对于包括不具有环杂原子之具有芳香族环及非芳香族环之稠合、桥连及螺环系统之多环系统而言,当附接点位于芳香族碳原子处时,术语“芳基”或“Ar”适用(例如,5,6,7,8四氢萘-2-基是芳基,此乃因其附接点是位于芳香族苯基环的2位处)。
根据本申请的具体实施方式,C
6-C
10芳基可以是苯基、萘基及各种取代的苯基或萘基。
“杂芳基”(杂环芳基)是指具有1至14个碳原子及1至6个选自由氧、氮及硫组成的群的杂原子的芳香族基团且包括单环(例如咪唑基-2-基及咪唑-5-基)及多环系统(例如咪唑并吡啶基、苯并三唑基、苯并咪唑-2-基及苯并咪唑-6-基)。对于包括具有芳香族及非芳香族环的稠合、桥连及螺环系统的多环系统而言,若存在至少一个环杂原子且附接点是位于芳香族环的原子处,则应用术语“杂芳基”(例如1,2,3,4-四氢喹啉-6-基及5,6,7,8-四氢喹啉-3-基)。在一些实施例中,杂芳基的氮和/或硫环原子视情况经氧化以提供N-氧化物(N→O)、亚磺酰基或磺酰基部分。术语杂芳基或5-15元杂芳基包括(但不限于)吖啶基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基(benzothiophenyl)、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并噻吩基(benzothienyl)、苯并咪唑啉基、咔唑基、NH-咔唑基、咔啉基、苯并二氢吡喃基(chromanyl)、苯并吡喃基(chromenyl)、噌啉基(cinnolinyl)、二噻嗪基、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑并吡啶基、咪唑基、吲唑基、二氢吲哚基(indolenyl)、吲哚啉基、吲嗪基、吲哚基、异苯并呋喃基、异苯并二氢吡喃基(isochromanyl)、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基(isoquinolinyl)、异喹啉基(isoquinolyl)、异噻唑基、异恶唑基、萘啶基、八氢异喹 啉基、恶二唑基、恶唑啶基、恶唑基、嘧啶基、啡啶基、啡啉基、吩嗪基、吩噻嗪基、吩恶噻基、吩恶嗪基、酞嗪基、六氢吡嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑基、唑嗪基、吡啶并恶唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基(thienyl)、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基(thiophenyl)、三嗪基及呫吨基。
“烷基”是指具有碳原子且在一些实施例中具有1至6个碳原子的单价饱和脂肪族烃基。“C
x-y烷基”是指具有x至y个碳原子的烷基。此术语包括(举例而言)直链及具支链烃基,例如甲基(CH
3-)、乙基(CH
3CH
2-)、正丙基(CH
3CH
2CH
2-)、异丙基((CH
3)
2CH-)、正丁基(CH
3CH
2CH
2CH
2-)、异丁基((CH
3)
2CHCH
2-)、第二丁基((CH
3)(CH
3CH
2)CH-)、第三丁基((CH
3)
3C-)、正戊基(CH
3CH
2CH
2CH
2CH
2-)及新戊基((CH
3)
3CCH
2-)。
“环烷基”是指具有3个以上碳原子且没有环杂原子且具有单环或包括稠合、桥连及螺环系统的多环的饱和或部分饱和环状基团。对于不具有环杂原子的具有芳香族及非芳香族环的多环系统而言,当附接点是位于非芳香族碳原子处时,术语“环烷基”适用(例如5,6,7,8-四氢萘-5-基)。术语“环烷基”或C
3-C
8环烷基包括环烯基。环烷基或C
3-C
8环烷基的实例包括(例如)金刚烷基、环丙基、环丁基、环戊基、环辛基及环己烯基。
“杂环状”或“杂环”或“杂环烷基”或“杂环基”是指具有碳原子及1至6个选自由氮、硫或氧组成的群的杂原子的饱和或部分饱和环状基团且包括单环及包括稠合、桥连及螺环系统的多环系统。对于具有芳香族及/或非芳香族环的多环系统而言,当存在至少一个环杂原子且附接点是位于非芳香族环的原子处时,术语“杂环状”或“杂环”或“杂环烷基”或“杂环基”适用(例如1,2,3,4-四氢喹啉-3-基、5,6,7,8-四氢喹啉-6-基及十氢喹啉-6-基)。在一些实施例中,此处杂环基是3-15元、4-14元、5-13元、7-12或5-7元杂环。在一些其他实施例中,杂环含有4个杂原子。在一些其他实施例中,杂环含有3个杂原子。在另一实施例中,杂环含有最多2个杂原子。在一些实施例中,杂环基的氮及/或硫原子视情况经氧化以提供N-氧化物、亚磺酰基、磺酰基部分。杂环基包括(但不限于)四氢吡喃基、六氢吡啶基、N-甲基六氢吡啶-3-基、六氢吡嗪基、N-甲基吡咯啶-3-基、3-吡咯啶基、2-吡咯啶酮-l-基、吗啉基及吡咯啶基。指示碳原子数的前缀(例如,C
3-
10)是指杂环基部分中除杂原子数之外的总碳原子数。二价杂环基将具有适当调整的氢含量。
“醚”是指经1-3个C
1-C
6烷氧基取代的C
1-C
6烷基。烷氧基是指-O-烷基。
“卤基”“卤素”是指氟、氯、溴及碘中的一或多者。
“烯基”是指具有碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=<)的直链或具支链烃基。举例而言,C
x-y烯基是指具有x至y个碳原子的烯基且意欲包括(例如)乙烯基、丙烯基、1,3-丁二烯基及诸如此类。
“炔基”是指2个以上碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且含有至少一个三键的直链单价烃基或具支链单价烃基。术语“炔基”亦意欲包括具有一个三键及一个双键的这些烃基。举例而言,C
2-6炔基包括乙炔基、丙炔基及诸如此类。
“胺基磷酸酯烷化剂”是指包含一或多个键结至-O-P(Z1)部分的Z
5-X
5-Y
5部分的烷化剂,其中Z
5是诸如氮、硫或氧等杂原子,X
5是视情况经取代的伸乙基,Y
5是卤基或另一离去基,或Z
5-X
5-Y
5一起形成氮丙啶基(NCH
2CH
2)部分且Z
1如上文所定义。此一烷化剂可与DNA或另一核酸或蛋白质反应。在一些情形下,烷化剂可交联DNA。
基团可经一或多个取代基(例如1、2、3、4或5个取代基)取代。较佳地,取代基选自由以下组成的群:侧氧基、卤基、-CN、NO
2、-N
2+、-CO
2R
100、-OR
100、-SR
100、-SOR
100、-SO
2R
100、-NR
100SO
2R
100、-NR
101R
102、-CONR
101R
102、-SO
2NR
101R
102、C
1-C
6烷基、C
1-C
6 烷氧基、-CR
100=C(R
100)
2、-CCR
100、C
3-C
10环烷基、C
3-C
10杂环基、C
6-C
12芳基及C
2-C
12杂芳基或诸如-O-(CH
2)-O-、-O-(CH
2)
2-O-及其1-4个甲基经取代的形式等二价取代基,其中R
100、R
101及R
102各自独立是氢或C
1-C
8烷基;C
3-C
12环烷基;C
3-C
10杂环基;C
6-C
12芳基;或C
2-C
12杂芳基;或R
100及R
102与其附接至的氮原子一起形成5-7元杂环;其中烷基、环烷基、杂环基、芳基或杂芳基各自视情况经1-3个卤基、1-3个C
1-C
6烷基、1-3个C
1-C
6卤烷基或1-3个C
1-C
6烷氧基取代。较佳地,取代基选自由以下组成的群:氯、氟、-OCH
3、甲基、乙基、异丙基、环丙基、-CO
2H及其盐及C
1-C
6烷基酯、CONMe
2、CONHMe、CONH
2、-SO
2Me、-SO
2NH
2、-SO
2NMe
2、-SO
2NHMe、-NHSO
2Me、-NHSO
2CF
3、-NHSO
2CH
2Cl、-NH
2、-OCF
3、-CF
3及-OCHF
2。
“亚烷基”(Alkylene)是指具有碳原子且在一些实施例中具有1至6个碳原子的二价饱和脂肪族烃基,及烷基再失去一个H原子。“C
u-v伸烷基”是指具有u至v个碳原子的压烷基。亚烷基(Alkylene)包括具支链及直链烃基。举例而言,“C
1-C
6伸烷基”包括亚甲基、伸乙基、伸丙基、2-甲基伸丙基、伸戊基及诸如此类。
“亚杂烷基”是指其中链碳原子经诸如O、S、N或P等杂原子或含有杂原子的取代基替代的亚烷基。
在本文中关于D所述的“药物”包括(但不限于)吉西他滨(gemcitabine)、埃罗替尼(erlotinib)、美妥替哌(meturedepa)、乌瑞替派(uredepa)、六甲蜜胺(altretamine)、伊马替尼(imatinib)、曲他胺(triethylenemelamine)、三甲密胺、苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、雌氮芥(estramustine)、吉非替尼(gefitinib)、阿法替尼(afatinib)、氮芥(mechlorethamine)、氮芥氧化物盐酸盐、美法仑(melphalan)、新氮芥(novembichin)、芬司特瑞(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard)、卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、达喀尔巴嗪(dacarbazine)、甘露氮芥(mannomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、哌泊溴烷(pipobroman)、阿克拉霉素(aclacinomycins)、放射菌素(actinomycin)、安曲霉素(anthramycin)、偶氮丝胺酸(azaserine)、博莱霉素(bleomycin)、放线菌素C(cactinomycin)、卡柔比星(carubicin)、多柔比星(doxorubicin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素d(dactinomycin)、道诺霉素(daunorubicin)、柔红霉素(daunomycin)、6-重氮-5-侧氧基-1-正白胺酸、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、普卡霉素(plicamycin)、泊非罗霉素(porfiromycin)、嘌呤霉素(puromycin)、链黑霉素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、左柔比星(zorubicin)、迪诺特宁(denopterin)、蝶罗呤(pteropterin)、曲美沙特(trimetrexate)、氟达拉宾(fludarabine)、6-巯基嘌呤、硫米嘌呤(thiamiprine)、硫鸟嘌呤、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-氟尿嘧啶、替加氟(tegafur)、L-天冬酰胺酶、百慕时(pulmozyme)、醋葡醛内酯、醛磷酰胺糖苷、胺基乙酰丙酸、安吖啶(amsacrine)、贝斯布西(bestrabucil)、比生群(bisantrene)、得佛酰胺(defofamide)、地美可辛(demecolcine)、地吖醌(diaziquone)、艾弗鸟胺酸(elfornithine)、依利醋铵(elliptinium acetate)、依托格鲁(etoglucid)、氟他胺(flutamide)、羟基尿素(hydroxyurea)、干扰素-α、干扰素-β、干扰素-γ、介白素-2、蘑菇多醣(lentinan)、丙脒腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌达醇(mopidamol)、二胺硝吖啶(nitracrine)、喷司他 丁(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、鬼臼酸(podophyllinic acid)、2-乙基酰肼、丙卡巴肼(procarbazine)、雷佐生(razoxane)、西索菲兰(sizofiran)、锗螺胺(spirogermanium)、太平洋紫杉醇(paclitaxel)、他莫昔芬(tamoxifen)、埃罗替尼(erlotonib)、替尼泊苷(teniposide)、细交链孢菌酮酸(tenuazonic acid)、三亚胺醌、2,2',2"-三氯三乙胺、尿烷、长春碱(vinblastine)及长春新碱(vincristine)。
向患者“投与”或“施用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用,其可是开处药物的行为。举例而言,指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
“患者”及“个体”可互换使用,是指需要癌症治疗的哺乳动物。通常,患者是人类。通常,患者是诊断患有癌症的人类。在某些实施例中,“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物,例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物,前药以使其相对于药物活性较低或无活性的方式化学修饰,但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味(参见(例如)参考文献Nogrady,1985,Medicinal Chemistry A Biochemical Approach,0xford University Press,New York,第388页至392页,其以引用式并入本文中)。前药可使用除相应药物以外的反应物来合成。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
“中枢神经系统肿瘤或癌症”是指位于颅脑内或其他中枢神经系统内的良性肿瘤或恶性肿瘤(癌症),包括脑膜瘤、垂体瘤、颅咽管瘤、神经鞘瘤和胶质瘤、室管膜瘤、原始神经外胚层肿瘤、中枢神经系统淋巴瘤、生殖细胞肿瘤、转移瘤等。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用时,将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现,且可仅在投与或施用一系列剂量后出现。因此,治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的,有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善;疾病程度的减弱;疾病进展的延迟或减缓;疾病状态的改善、缓解或稳定;或其他有益结果。在一些情形下,癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如,哺乳动物,例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
由于本发明是基于以下三个发明申请而做出的:
申请号PCT/US2016/021581,公开号WO2016/145092对应中国申请号2016800150788,公开号CN107530556A;
申请号PCT/US2016/025665,公开号WO2016/061342对应中国申请号2016800200132,公开号CN108136214A;
申请号PCT/US2016/062114,公开号WO2017/087428对应中国申请号2016800446081,公开号CN108290911A,为此将上述三个申请援引到本申请的文本中来。
以下是本发明的具体试验和实施例部分。
以下试验将揭示申请人设计合成的化合物的体外癌细胞增殖抑制活性实验、P-GP糖蛋白作用实验数据,申请人在此声明,以下的实验数据的权利属于申请人。
P-糖蛋白(P-GP,也称为多药耐药蛋白)是在多药抗药性肿瘤细胞质膜上发现的一种高分子量蛋白质,具有转运泵样的结构。它将多种化疗药物泵出细胞外,降低细胞内的药物浓度,与临床化疗的抗药性关系密切。
化疗药物在治疗脑部等中枢神经系统的肿瘤或癌症中的作用受到了限制,这主要是由于血脑屏障(BBB),血脑屏障使得化疗药物的对肿瘤系统或肿瘤组织的渗透性差,也就是化疗药物无法穿过血脑屏障进入到脑内来杀灭癌细胞。
化疗药物等小分子穿越血脑屏障的过程比较复杂。血脑屏障位于全身血液循环和脑脊液之间,是由专门的脑微血管内皮细胞,连同周围细胞和血管周围的星形细胞通过相邻细胞间的紧密连接而形成的,其迫使大多数分子通过时形成选择性障碍,而不是围绕血管内皮细胞构成一个物理屏障。血脑屏障的膜的运输系统容许亲水性小分子通过,而大型亲水性分子,包括许多化疗药物和大分子药物都将被排除出中枢神经系统,除非他们能被某些蛋白主动运输。更重要的是,血脑屏障具有的保护脑组织的“药物外排泵”,如P-糖蛋白,能积极主动从大脑中排除一些化疗药物和大分子药物。因此,即使具有一定亲水性的小分子化疗药物(包括小分子靶向抗肿瘤药物分子)能穿越血脑屏障进入大脑发挥作用,但在P-糖蛋白的作用下也依然会被排除出中枢神经系统而无法真正起效。也就是说,Pgp的跨膜结构具有能量依赖性“药泵”功能,能将流水亲脂性的药物,如长春新碱(VCR)、阿霉素(Dox)或足叶乙甙(VP-16)等泵出细胞外,造成细胞内药物浓度下降,细胞毒作用降低或完全丧失。
为此PGP糖蛋白与化合物的作用实验数据即可以用来评价这些化合物对中枢神经系统肿瘤细胞增殖抑制的真正有效作用程度。
申请人声明以下试验中公开的部分具体化合物在本发明已公开的化合物的具体合成方法以及合成路线的基础上,参考专利公开文献(比如申请号PCT/US2016/021581,公开号WO2016/145092对应中国申请号2016800150788,公开号CN107530556A;申请号PCT/US2016/025665,公开号WO2016/061342对应中国申请号2016800200132,公开号CN108136214A)或其他公开文献揭露的类似方法和操作(虽然底物不同,产率有高有低但本领域即药物化学、有机化学等掌握有机合成技能的技术人员依然能合成得到)能够合成得到,并且申请人已经过核磁、质谱确证结构。
1.以MDCKII-MDR1细胞为模型,维拉帕米为抑制剂评估待测物作为P-gp底物的潜能
穿透试验用细胞的制备
1)MDCKII-MDR1细胞培养于细胞培养瓶。培养箱设置为37℃、5%CO
2、保证相对湿度95%。细胞汇合度达到70‐90%时可用于接种迁移小室(Transwell)。
2)细胞接种前,向迁移小室上室每孔中加入50μL细胞培养基,下层培养板内加入25mL细胞培养基。将培养板置于37℃,5%CO
2培养箱内孵育1小时后可用于接种细胞。
3)细胞孵育后,吸取细胞混悬液转移至圆底离心管,于120g离心5分钟。
4)使用培养基重悬细胞,终浓度为1.56×10
6cells/mL。将细胞悬液以50μL每孔加入到96孔迁移小室培养板上室中,最终接种密度为5.45×10
5cells/cm
2。
5)接种后48小时开始换液,培养4-8天,隔一天换一次培养基。
6)更换培养基过程如下,将迁移小室与接收板分开,先弃掉接收板中培养基然后再弃掉迁移小室培养基,最后每个小室加入75μL新鲜培养基,接收板加入25mL新鲜培养基。
细胞单层膜完整性的评价
1)MDCKII-MDR1细胞经过4-8天培养后,应完全汇合并完成分化。此时,可应用于穿透试验。
2)用电阻仪(Millipore)测量单层膜电阻,记录每孔电阻。
3)测定结束后,将迁移小室培养板放回培养箱。
4)电阻值的计算:测定电阻值(ohms)×膜面积(cm
2)=TEER值(ohm·cm
2),若TEER值<42ohms·cm
2,则该孔不能用于穿透试验。
药物穿透试验
1)从培养箱中取出MDCKII-MDR1迁移小室培养板。使用缓冲液润洗细胞单层膜两次,37℃条件下孵育30分钟。
2)测定化合物由顶端到基底端的转运速率。向上层小室(顶端)每孔加入75μL含受试物的冲液,下层小室(基底端)每孔加入235ul缓冲液。
3)测定化合物由基底端到顶端的转运速率。向上层小室(顶端)每孔加入75μL缓冲液,下层小室(基底端)每孔加入235ul含受试物的缓冲液。
4)从工作液配制板中转移50ul样品加到200ul含内标的乙腈(100nM阿普唑仑,200nM拉贝洛尔,200nM咖啡因和2uM酮洛芬)中作为0分钟给药样品进行检测。
5)为测定受试物在加P-gp抑制剂维拉帕米条件下的转运,需要在MDCKII-MDR1迁移小室板给药端的缓冲盐和接收端的缓冲盐中均需加维拉帕米,且终浓度为100μM。
6)将上下的转运合并后,37℃条件下孵育2小时。
7)孵育完成后,分别从迁移小室培养板上室和下室每孔取样50μL加入到新的样品管中。向样品管内加入200ul含内标的乙腈(100nM阿普唑仑,200nM拉贝洛尔,200nM咖啡因和2μM酮洛芬),涡旋10分钟后,于3220g离心30分钟。吸取上清液100μL,与等体积水稀释之后进行LC-MS/MS分析。各样品均采用三平行孵育。
8)用荧光黄的渗漏评价评价孵育2小时后细胞单层膜的完整性,使用缓冲液稀释荧光黄储备液至最终浓度100μM/L。在上侧的Transwell插板的每个孔中加入荧光黄溶液100μL,下侧接收板的每个孔中加300ul缓冲液。37℃下孵育30分钟后,分别从每孔上下层吸出80μL溶液至一个新的96孔板中。使用酶标仪,激发波长480nm和发射波长530nm条件下进行荧光测定。
数据分析
峰面积由离子色谱结果计算得出。化合物的表观渗透系数(Papp,单位:cm/s×10-6) 用以下公式计算得出:
公式中:VA为接收端溶液的体积(Ap→Bl是0.235mL,Bl→Ap是0.075mL),Area为Transwell-96孔板膜面积(0.143cm2);time为孵育时间(单位:s),[drug]
acceptor表示孵育结束后接收端的药物浓度,[drug]
initial,donor表示孵育前的给药初始浓度。
外排率Efflux Ratio使用以下的公式计算得出:
公式中:Papp(B-A)为由基底端到顶端的表观渗透系数;Papp(A-B)为由顶端到基底端的表观渗透系数。
回收率Recovery使用以下的公式计算得出:
公式中:VA为接收端的溶液体积(单位:mL);VD为给予端的溶液体积(单位:mL)。[drug]
acceptor表示孵育结束后接收端的药物浓度,[drug]
donor表示孵育结束后给药端的药物浓度,[drug]
initial,donor表示孵育前的给药初始浓度。
细胞单层膜的荧光值LY Leakage使用以下的公式计算得出:
公式中:I
acceptor是指接收孔(0.3mL)的荧光密度,I
donor是指加药孔(0.1mL)的荧光密度,用%LY表示。LY<1.5%表示单层细胞膜完好。
分别对制备的部分化合物进行测试得到不同化合物在有无P-糖蛋白抑制剂维拉帕米存在时的外排率。分别对制备的部分化合物进行测试得到不同化合物在有无P-gp抑制剂维拉帕米存在时的外排率。
作为对比还对应检测了美托洛尔、哌唑嗪、伊马替尼的的外排率数据。
某个化合物的外排率测试结果有两个数值,无维拉帕米和有维拉帕米时的外排率,这两个数值越接近越说明P-gp对药物没有影响,即药物不是P-gp蛋白的底物,能进入血脑屏障。
2.检测制备的化合物对癌细胞的增殖抑制作用
使用活体外人类肿瘤细胞系细胞毒性分析
H460非小细胞肺癌人类肿瘤细胞系的活体外增殖数据报告于下文化合物表中。
IC50值是以微摩尔报告且自以下得到:将化合物以各浓度暴露达2小时,随后洗涤步骤并添加新鲜培养基,然后生长及细胞存活率染色并与仅经培养基处理的对照比较。
特定而言,以4×10
3个细胞/孔密度将指数生长的细胞接种于96孔板中且在37℃下在5%CO
2、95%空气及100%相对湿度中培育24小时,然后添加测试化合物。将化合物以200倍的期望最终测试浓度溶解于100%DMSO中。在添加药物时,使用完全培养基将化合物进一步稀释至4倍的期望终浓度。将50μl特定浓度的化合物的等份试样添加至已含有150μl培养基的微量孔中,得到所报告的最终药物浓度。在药物添加之后,将板在37℃、5%CO
2、95%空气及100%相对湿度下再培育2小时,然后将药物洗掉且添加新鲜培养基且将板在37℃、5%CO
2、95%空气及100%相对湿度下再培育70小时。 在此培育结束时,使用AlamarBlue分析来量化活细胞。使用计算机软件计算导致50%生长抑制的药物浓度(IC
50),且结果列示于下表中。
类似的,为了进一步验证化合物为人AKR1C3(醛固酮类还原酶家族1成员C3)所活化,某些化合物对H460癌细胞增殖试验是存在(3微摩尔浓度)特异性AKR1C3酶抑制剂的情况下进行。在进行化合物处理前2小时,将添加了抑制剂的化合物溶液添加至细胞培养物中。所用抑制剂为Flanagan等人,Bioorganic and Medicinal Chemistry(2014)第962-977页中的化合物36即
3.化合物制备及波谱表征
THF,四氢呋喃;DCM,二氯甲烷;EA或EtOAC,乙酸乙酯;TEA,三乙胺;HPLC,高效液相色谱仪;MTBE,甲基叔丁基醚;DMAP,4-二甲氨基吡啶;DBAD,偶氮二甲酸二叔丁酯;TFA,三氟乙酸;LCMS,液质联用;EtOH,乙醇;t-BuOH,叔丁醇;DMF,二甲基甲酰胺;PE,石油醚,petroleum ether;eq,当量即摩尔比;TBAF,四丁基氟化铵;DIPEA,N,N-二异丙基乙胺;
合成过程中未注明来源的化学试剂、药品均为分析纯或化学纯,均从商业的试剂公司购买得到。
其他出现的英文简写以有机化学领域中的解释为准。
化合物1的合成
将1-A1(80.0mg,0.266mmol,参照3-A4化合物合成方法合成)和1-A2(78.3mg,0.380mmol,购买)溶解于丙酮(4mL)中,之后加入Cs
2CO
3(199.3mg,0.612mmol),室温下搅拌,HPLC检测反应进程,2h反应完毕。抽滤除去固体,浓缩母液,柱层析分离,制备后的液体经DCM(10mL×3)萃取,浓缩,冻干得到化合物1的纯品(17mg,收率13.1%),为淡黄色固体。
1H-NMR(400MHz,CDCl
3)δ8.02(d,J=8.4 Hz,1H),7.48(dd,J=7.2,5.5Hz,2H),7.39(t,J=8.6Hz,1H),7.30(d,J=8.5Hz,1H),7.19(s,1H),7.14(t,J=8.7Hz,2H),6.89(dd,J=8.5,2.0Hz,1H),6.83(dd,J=11.1,2.3Hz,1H),5.19(d,J=8.0Hz,2H),2.21-2.12(m,8H).MS:Calculated 487.1,found 488.1([M+H]+)。
化合物2的合成
将1-A1(150mg,0.50mmol,参照3-A4化合物合成方法合成)和2-A2(134mg,0.71mmol,购买)溶于丙酮中(10ml)中,加入Cs
2CO
3(373mg,1.2mmol),室温下搅拌,HPLC检测反应进程,2h反应完毕。硅藻土抽滤,EtOAc(10mL×3)洗涤滤饼,合并有机相,浓缩母液,交柱层析分离,制备后经DCM(10mL×3)萃取,水浴温度35℃下浓缩,冻干得到2号化合物(26mg,收率11.1%),为淡黄色油状物。
1H-NMR(400MHz,MeOD):δ8.01(d,J=8.4Hz 1H),7.68-7.62(m,4H),7.31(d,J=8.4Hz 1H),7.20-7.15(m,5H),5.18(d,J=8.4Hz 2H),2.17-2.10(m,8H).MS Calculated 469.1,found 470.2([M+H]+)。
化合物3的合成
3-A2的合成
氮气保护下,3-A1(5g,24.62mmol,购买)溶于无水四氢呋喃(50mL)中,降温至0℃,抽充三次气体,缓慢滴加入硼烷四氢呋喃溶液(61.5mL,61.5mmol,1mol/L in THF),保温0℃ 30min,升温至65℃,3小时反应完毕。自然冷却至常温,缓慢将反应液到入至冰水中(300g),二氯甲烷萃取(50mL×3),有机相用1M的盐酸洗涤(50mL×3),然后水洗,盐水洗,干燥浓缩得产品4.6g,为类白色固体,收率98.9%。
1H-NMR(400MHz,DMSO-d6)δ8.04(dd,J=9.2,6.1Hz,1H),7.58(dd,J=11.7,5.8Hz,1H),5.72(s,1H),4.63(s,2H),MS:Calculated MS:189.1,found:188.0([M-H]
-)。
3-A3的合成
氮气保护下,将三氯氧磷(610mg,3.97mmol)加入到无水二氯甲烷中(5mL),然后加入3-A2(500mg,2.64mmol),降温至-20℃,缓慢滴加入三乙胺(454mg,4.49mmol)的二氯甲烷溶液(3mL),保温-20℃三小时,3-A2反应完全,降温至-40℃,缓慢加入2-溴乙胺氢溴酸盐(1.6g,7.92mmol),然后滴加入三乙胺(801mg,7.92mmol)的二氯甲烷溶液,保温-40℃三十分钟,反应完毕。滴加入水5mL,自然升至常温,二氯甲烷萃取(8mL×3),水洗有机相(5mL×2),干燥浓缩,柱层析分离。100-200目硅胶,乙酸乙酯:正庚烷=1:1-乙酸乙酯得产品260mg,为类白色固体,收率20.5%.
1H NMR(400MHz,CDCl
3)δ7.81(dd,J=8.6,5.9Hz,1H),7.48(dd,J=10.5,5.7Hz,1H),5.14(d,J=7.6Hz,2H),3.52-3.34(m,8H).MS:Calculated 480.9,found 481.9([M+H]
+)。
3-A4的合成
氮气保护下,3-A3(250mg,0.520mmol)溶于四氢呋喃(4mL)与丙酮(6mL)中, 升温至59℃搅拌,四小时反应完毕。降至常温,硅藻土抽滤,丙酮洗涤固体(5mL),浓缩母液得粗品190mg,为淡黄色液体,直接进行下一步。
1H-NMR(400MHz,MeOD)δ7.99(dd,J=9.1,6.0Hz,1H),7.61(dd,J=10.9,5.8Hz,1H),5.30(d,J=7.9Hz,2H),2.32-1.95(m,8H).MS:Calculated 319.1,found 320.0([M+H]
+)。
3的合成
氮气保护下,3-A4(80mg,0.25mmol)与4-氟-4'-羟基联苯(71mg,0.38mmol)溶于丙酮中(5mL),然后加入碳酸铯(205mg,0.63mmol),常温搅拌3小时反应完毕。硅藻土抽滤,丙酮(3mL)洗涤固体,浓缩母液,柱层析分离得纯品(17mg,收率14.0%),为白色固体。
1H-NMR(400MHz,MeOD)δ7.91(d,J=9.1Hz,1H),7.67-7.61(m,4H),7.30(d,J=6.0Hz,1H),7.20-7.14(m,4H),5.25(d,J=8.0Hz,2H),2.15-2.10(m,8H).MS:Calculated 487.1,found 488.0([M+H]
+)。
化合物4的合成
4-A3的合成
氮气保护下将4-A1(1.0g,5.24mmol,购买)与4-A2(909mg,5.76mmol,购买)加入至1,4-二氧六环(18mL)与H
2O(2mL)的混合液中,后将K
2CO
3(2.2g,15.71mmol)加入体系,抽充氮气3次后,将醋酸钯(59mg,0.26mmol)与PPh
3(69mg,0.26mmol)加入体系,再次抽充氮气三次,升温至100℃后1.5h反应完毕。后处理:降至室温,硅藻土抽滤,DCM洗涤,分液后母液DCM萃取(5mL x 3),干燥浓缩反相快速柱层析分离(water:MeCN=50%:50%)得产品(238mg,收率20.3%),为黄色固体。
1H-NMR(400MHz,MeOD):δ7.39-7.33(m,1H),7.16(t,J=8.4Hz,1H),7.03-6.97(m,2H),6.68(dd,,J=8.4Hz,2.4Hz,1H),6.60(dd,J=12.0,2.4Hz,1H).MS:Calculated224.1,found 223.0([M-H]
-)。
4的合成
氮气保护下,将4-A3(80mg,0.27mmol)与1-A1(101mg,0.45mmol,参照3-A4化合物合成方法合成)溶于丙酮(5mL),然后将Cs
2CO
3(216mg,0.66mmol)加入至体系,完毕后常温搅拌1.5h反应完毕。后处理:硅藻土抽滤,DCM洗涤,浓缩母液,柱层析分离冻干得产品(35.5mg,26.4%),为淡黄色油状物。
1H-NMR(400MHz,MeOD):δ8.06(d,J=8.4Hz,1H),7.48-7.40(m,3H),7.32(s,1H),7.10-7.05(m,2H),6.99-6.95(m,2H),5.23(d,J=8.4Hz,2H),2.22-2.13(m,8H).MS:Calculated505.1,found 506.1([M+H]
+)。
化合物5的合成
5-A3的合成
氮气保护下将5-A1(1.0g,5.24mmol,购买)与5-A2(886mg,5.76mmol)加入至1,4-二氧六环(18mL)与H
2O(2mL)的混合液中,后将K
2CO
3(2.2g,15.71mmol)加入体系,抽充氮气3次后将醋酸钯(59mg,0.26mmol)与PPh
3(69mg,0.26mmol)加入体系,再次抽充氮气三次,升温至100℃后1.5h反应完毕。后处理:降至室温,硅藻土抽滤,DCM洗涤,分液后母液DCM萃取(5mL×3),干燥浓缩后柱层析分离(200-300目硅胶,正庚烷:乙酸乙酯=5:1)得产品(895mg,收率77.6%),为类白色固体。
1H-NMR(400MHz,CDCl
3):δ7.16-7.12(m,1H),7.06(t,J=8.4Hz,1H),6.99-6.89(m,2H),6.72-6.65(m,2H),6.32(s,1H),2.19(s,3H).MS Calculated 220.1,found 219.1([M-H]
-)。
5的合成
氮气保护下,将5-A3(80mg,0.27mmol)与1-A1(95mg,0.45mmol,参照3-A4化合物合成方法合成)溶于丙酮(5mL),然后将Cs
2CO
3(216mg,0.66mmol)加入至体系,完毕后常温搅拌2h反应完毕。后处理:硅藻土抽滤,DCM洗涤,浓缩母液,柱层析分离冻干得产品(13mg,收率7.1%),为黄色油状物。
1H-NMR(400MHz,MeOD):δ8.06(d,J=8.4Hz,1H),7.40(d,J=8.4Hz,1H),7.33-7.27(m,2H),7.24-7.16(m,1H),7.06-7.04(m,1H),7.01-6.93(m,3H),5.24(d,J=8.4Hz,2H),2.22-2.16(m,11H).MS:Calculated501.1,found 502.1([M+H]
+)。
化合物6的合成
氮气保护下,将6-A1(80mg,0.266mmol,参照3-A4化合物合成方法合成)与6-A2(73.2mg,0.452mmol,购买)溶于丙酮中(5mL),然后加入Cs
2CO
3(216.3mg,0.664mmol),常温搅拌。1.5h反应完毕。通过硅藻土抽滤,DCM洗涤固体,浓缩母液,柱层析分离得纯品(17.4mg,收率14.7%),为淡黄色油状物。
1H-NMR(400MHz,MeOD):δ8.45(d,J=2.8Hz,1H),8.08(d,J=8.4Hz,1H),7.69(d,J=8.8Hz,1H),7.41-7.39(m,2H),7.23(s,1H),5.21(d,J=8.0Hz,2H),2.22-2.13(m,8H).MS:Calculated 444.1,found 445.1([M+H]+)。
化合物7的合成
将7-A1(94mg,0.50mmol)和7-A2(100mg,0.33mmol,参照3-A4化合物合成方法合成)溶于丙酮(5ml)中,将Cs
2CO
3(372mg,0.83mmol)加入丙酮中,室温下搅拌,HPLC 检测反应进程,1.0h反应完毕。铺硅藻土抽滤,DCM(10mL×3)洗涤固体,浓缩母液,柱层析分离,制备后经DCM(10mL×3)萃取,冻干得到7号化合物(42mg,收率26.9%),为淡黄色油状物。
1H-NMR(400MHz,MeOD):δ8.43(d,J=2.7Hz,1H),8.09(d,J=8.4Hz,1H),8.02(dd,J=8.8,5.4Hz,2H),7.91(d,J=8.7Hz,1H),7.57(dd,J=8.7,2.9Hz,1H),7.42(d,J=7.8Hz,1H),7.29(s,1H),7.21(t,J=8.8Hz,2H),5.22(d,J=8.4Hz,2H),2.26-2.08(m,8H).MS:Calculated 470.1,found 471.1([M+H]+)。
8号化合物的合成
将化合物8-A1(3.0g,17.2mmol)和2,4-二氟苯硼酸(2.7g,19.0mmol)溶于二氧六环/水(9:1,60mL)中,加入碳酸钾(4.7mg,34.4mmol),抽充N2三次,依次加入三苯基膦(225mg,0.86mmol)和醋酸钯(193mg,0.86mmol),抽充N2三次,100℃反应,HPLC检测反应进程,10h反应完毕。体系用硅藻土抽滤,EtOAc(15mL×3)洗涤固体,浓缩母液,干法拌样,柱层析分离(Heptane:EtOAc=5:1),然后用MTBE打浆(3mL),得到白色固体8-A2(1.5g,42.0%).
1H-NMR(300MHz,MeOD):δ8.19(s,1H),7.78-7.75(m,1H),7.58(d,J=8.4Hz,1H),7.29(d,J=8.4Hz,1H),7.08-7.05(m,2H).MS:Calculated 207.0,found 208.2([M+H]
+)。
将8-A2(103mg,0.50mmol)和8-A3(100mg,0.33mmol,参照3-A4化合物合成方法合成)溶于丙酮(5ml)中,加入Cs
2CO
3(270mg,0.83mmol),室温下搅拌,体系为淡黄色,HPLC检测反应进程,2.0h反应完毕。铺硅藻土抽滤,丙酮(10mL×3)洗涤固体,浓缩母液,柱层析分离,制备后DCM(10mL×3)萃取,冻干得到8号化合物(26mg,收率16.0%),为黄色液体。
1H-NMR(400MHz,MeOD):δ8.47(d,J=2.8Hz,1H),8.10(d,J=8.4Hz,1H),7.95-7.92(m,1H),7.85-7.82(m,1H),7.59-7.57(m,1H),7.46-7.44(m,1H),7.33(s,1H),7.11-7.08(m,2H),5.23(d,J=8.4Hz,2H),2.19-2.15(m,8H).MS:Calculated488.1,found 489.1([M+H]+)。
9号化合物的合成
氮气保护下,将9-A1(80mg,0.266mmol,参照3-A4化合物合成方法合成)与9-A2(58mg,0.452mmol)溶于丙酮中(5mL),然后加入Cs
2CO
3(216.3mg,0.664mmol),常温搅拌。1.5h反应完毕。通过硅藻土抽滤,DCM洗涤固体,浓缩母液,高效液相柱 层析分离得纯品(19.8mg,收率18.1%),为淡黄色液体。
1H-NMR(400MHz,MeOD):δ8.18(d,J=2.8Hz,1H),8.09(d,J=8.4Hz,1H),7.55-7.44(m,3H),7.30(s,1H),5.22(d,J=8.0Hz,2H),2.22-2.15(m,8H).MS(retention time 3.103min):Calculated 410.1,found 411.0([M+H]+)。
10号化合物的合成
氮气保护下将2-溴-5-氟基吡啶(10-A1,2.0g,11.36mmol)与对羟基苯硼酸(10-A2,1.9g,13.64mmol)加入至DME(40mL)与H2O(9mL)的混合液中,抽充氮气3次,将Pd(Ph
3P)
4(396mg,0.35mmol)与Na2CO3(2.4g,22.73mmol)加入后再次抽充氮气三次,升温至80℃。HPLC监测2.5h,反应完毕。降至室温,EtOAc(60mL x 3)萃取,有机相水洗盐水洗,柱层析分离(200-300目硅胶,正庚烷:乙酸乙酯=15:1-12:1)得10-A3产品(1.4g,收率65.1%),为淡黄色固体。
1H-NMR(300MHz,MeOD):δ8.43(d,J=2.7Hz,1H),7.81-7.77(m,3H),7.64-7.58(m,1H),6.87(d,J=8.7Hz,1H).MS:Calculated 189.1,found 190.1([M+H]+)。
氮气保护下,将10-A4(80mg,0.27mmol,参照3-A4化合物合成方法合成)与10-A3(88mg,0.45mmol)溶于丙酮(5mL),然后将Cs
2CO
3(216mg,0.66mmol)加入至体系,完毕后常温搅拌2h反应完毕。后处理:硅藻土抽滤,DCM洗涤,浓缩母液,柱层析分离冻干得10号化合物产品(2mg,1.5%),为黄色油状物。
1H-NMR(400MHz,MeOD)δ8.52(d,J=2.8Hz,1H),8.04(dd,J=8.6,3.1Hz,3H),7.92(dd,J=8.8,4.3Hz,1H),7.68(dd,J=8.4,2.9Hz,1H),7.35(d,J=8.3Hz,1H),7.22(s,1H),7.17(d,J=8.8Hz,2H),5.20(d,J=8.3Hz,2H),2.28–2.03(m,8H).MS:Calculated 470.1,found 471.1([M+H]+)。
11号化合物的合成
将化合物11-A1(4.0g,20.9mmol)和双联频哪醇硼酸酯(8.0g,31.4mmol)溶于二氧六环/水(9:1,40mL)中,加入醋酸钾(5.14g,52.4mmol),加入四(三苯基膦)钯(1.21g,1.1mmol),抽充N
2三次,95℃反应,HPLC检测反应进程,反应完毕。体系用硅藻土抽滤,EtOAc(10mL×3)洗涤固体,浓缩母液,用EtOAc(30mL×3)萃取,水洗(40mL),盐水洗(40mL×2),MgSO
4干燥,浓缩。色谱柱层析分离(Heptane:EtOAc=10:1)得到白色固体11-A2(1.8g,36.7%).
1H-NMR(400MHz,CDCl3):δ7.61(t,J=7.6Hz,1H),6.61(dd,J=8.0,2.0Hz,1H),6.52(dd,J=10.8,2.0Hz,1H),5.39(s,1H),1.34(s,12H).MS:Calculated 238.1,found 239.2([M+H]+)。
将11-A2(1.15g,4.83mmol)溶于二氧六环/水(体积比9:1)中,通N
2保护,加入K
3PO
4(1.5g,7.1mmol)和2-溴-5-氟吡啶(500mg,2.8mmol),抽充N
2三次,加入DPPF二氯化钯络合物(232mg,0.28mmol,购买),抽充N
2三次,90℃反应,HPLC检测反应进程,反应完毕。用硅藻土抽滤,EtOAc(20mL×2)洗涤固体,浓缩母液,水洗(10mL),Na
2SO
4干燥,浓缩。柱层析分离纯化(200-300目硅胶,Heptane:EtOAc=3:1)得到白色固体11-A3(500mg,收率76.2%).
1H-NMR(400MHz,MeOD):δ10.24(s,1H),8.64(d,J=2.4Hz 1H),7.78-7.73(m,3H),6.75-6.73(m,1H),6.69-6.65(m,1H).MS:Calculated 207.1,found 208.2([M+H]+)。
将11-A4(80mg,0.27mmol,参照3-A4化合物合成方法合成)和11-A3(78.7mg,0.38mmol)溶于丙酮(5ml)中,加入Cs
2CO
3(199mg,0.612mmol),室温下搅拌,HPLC检测反应进程,1.5h反应完毕。铺硅藻土抽滤,EtOAc(10mL×3)洗涤固体,浓缩母液,柱层析分离,制备后经DCM(10mL×3)萃取,冻干得到11号化合物(17mg,收率13.1%),为淡黄色油状物。
1H-NMR(400MHz,MeOD):δ8.57(d,J=2.8Hz,1H),8.08(d,J=8.4Hz,1H),7.94(t,J=9.6Hz,1H),7.86-7.83(m,1H),7.72-7.67(m,1H),7.44(d,J=8.4Hz 1H),7.34(s,1H),7.00-6.95(m,2H),5.23(d,J=8.4Hz,2H),2.22-2.14(m,8H).MS:Calculated 488.1,found 489.2([M+H]+)。
12号化合物的合成
将化合物12-A1(4.0g,19.9mmol)和对氟苯硼酸(3.3g,23.9mmol)溶于二氧六环/水(9:1,40mL)中,加入K
2CO
3(8.2g,59.7mmol),抽充N
2三次,加入三苯基膦(262mg,1.0mmol)和醋酸钯(224mg,0.995mmol),抽充N
2三次,100℃反应,HPLC检测反应进程,反应完毕。加硅藻土抽滤,EtOAc洗涤固体,浓缩母液,用EtOAc萃取(20mL×3),干燥浓缩。柱层析分离得到化合物12-A2(700mg,16.2%),为白色固体。
1H-NMR(400MHz,DMSO):δ7.34-7.31(m,2H),7.21(t,J=8Hz,2H),7.10(d,J=8Hz,1H),6.85(s,1H),6.81(d,J=8Hz,1H),3.75(s,3H),2.18(s,3H)。
将12-A2(510mg,2.36mmol)溶于无水DCM中(18ml)中,降温至0℃,滴加BBr
3(1.2g,4.72mmol)加完毕后,自然升至室温,室温下搅拌1h,HPLC检测反应进程,反应完毕。后处理:水(15mL)淬灭反应体系,DCM(10mL×5)萃取,干燥,除去得到粗品。柱层析,得到12-A3(300mg,收率62.9%),为淡黄色液体。
1H-NMR(400MHz,DMSO):δ9.40(s,1H),7.32-7.28(m,2H),7.20(t,J=8Hz,2H),6.99(d,J=8Hz,1H),6.68(s,1H),6.66-6.63(m,1H),2.14(s,3H).MS:Calculated 202.1,found 200.6([M-H]-)。
将12-A4(80mg,0.27mmol,参照3-A4化合物合成方法合成)和12-A3(76.8mg,0.38mmol)溶于丙酮中(4ml)中,加入Cs
2CO
3(199mg,0.61mmol),室温下搅拌,HPLC检测反应进程,1h反应完毕。抽滤除去固体,浓缩母液,柱层析分离,制备后经DCM(10mL×3)萃取,水浴温度35℃下浓缩,冻干得到黄色油状物(21mg,收率16.4%)。
1H-NMR(400MHz,CD
3OD):δ8.00(d,J=8.4Hz,1H),7.35-7.29(m,3H),7.25(d,J=8.4 Hz,1H),7.19-7.14(m,3H),7.03(d,J=2.0Hz,1H),6.97-6.94(m,1H),5.19(d,J=8.4Hz,2H).2.25(s,3H).2.18-2.12(m,8H).MS:Calculated 483.1,found 484.1([M+H]+)。
13号化合物的合成
氮气保护下将间溴苯酚(13-A0,1.5g,8.57mmol)与对氟苯硼酸(13-A1,1.0g,7.15mmol)加入至二氧六环(30mL)与H
2O(5mL)的混合液中,抽充氮气3次,将Pd(AcO)
2(80mg,0.36mmol),PPh3(94mg,0.36mmol)与K
2CO
3(3.0g,21.44mmol)加入后再次抽充氮气三次,升温至100℃。监测1h,反应完毕。后处理:降至室温,抽滤后EtOAc(50mL x 3)萃取,有机相水洗盐水洗,柱层析分离(200-300目硅胶,正庚烷:EA=12:1-9:1)得13-A2产品(1.1g,收率62.7%),为白色固体。
1H-NMR(300MHz,MeOD):δ7.59-7.54(m,2H),7.23-7.10(m,3H),7.04-6.99(m,2H),6.76(dd,J=8.1,1.5Hz,1H).MS:Calculated 188.1,found 189.1([M+H]+)。
将13-A2(580mg,3.08mmol)与3-氟-4硝基苯甲醛(434mg,2.57mmol)溶于MeCN(10mL),氮气下将K
2CO
3(887mg,6.42mmol)加入至体系,升温至80℃,监测2h后,反应完毕。降至室温后硅藻土抽滤,DCM洗涤,母液浓缩,柱层析分离(MeCN:H2O=50%:50%)得13-A3产品(320mg,收率33.7%),为黄色油状物。
1H-NMR(400MHz,CDCl3):δ9.98(s,1H),8.05(d,J=8.4Hz,1H),7.71(d,J=1.6Hz,1H),7.69-7.43(m,5H),7.28-7.27(m,1H),7.15-7.11(m,2H),7.08-7.05(m,1H)。
氮气保护,将13-A3(350mg,1.04mmol)与TMSCF
3(296mg,2.08mmol)溶于THF(4mL)中,降温至0℃,将TBAF(0.01mL,0.01mmol,1M in THF)滴加至体系,保温0℃30min后反应物14-A3全部消失,滴加3N HCl(2mL)至体系,体系变澄清,继续0℃搅拌1h后全部成为产物。DCM萃取(5mL×3),有机相水洗(5mL×3),有机相干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=12:1-10:1)得产品(350mg,收率82.8%),为黄色固体。
1H-NMR(400MHz,CDCl3):δ8.00(d,J=8.4Hz,1H),7.53-7.34(m,5H),7.24-7.23(m,2H),7.15-7.11(m,2H),7.03-7.00(m,1H),5.03-5.02(m,1H).MS:Calculated 407.1,found 408.0([M+H]+)。
氮气保护,将POCl
3(188mg,1.23mmol)溶于DCM(5mL)后降温至-40℃,然后将13-A4(250mg,0.61mmol)溶于DCM(2mL)后与TEA(155mg,1.53mmol)滴加至体系,保温-40℃3h后15-A3全部转化为中间体,然后将溴乙胺溴酸盐(1.0g,4.91mmol)与TEA(497mg,4.91mmol)加入至体系,监测,30min后反应完毕。0℃加入饱和NH
4Cl(5mL),DCM萃取(20mL×3),有机相水洗盐水洗,有机相干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=2:1-1:1)得13-A5产品(200mg,46.6%),为黄色固体。
1H-NMR(400MHz,CDCl
3):δ8.01(d,J=8.4Hz,1H),7.54-7.33(m,5H),7.25(d,J=2.0Hz,1H),7.18(s,1H),7.15-7.10(m,2H),7.03(d,J=1.2Hz,1H),5.70-5.60(m,1H),3.38-3.08(m,8H).MS:Calculated 699.0,found 699.9([M+H]+)。
氮气保护下,将13-A5(150mg,0.22mmol)溶于THF中(15mL),然后加入氧化银(497mg,2.1mmol),DIPEA(277mg,2.1mmol),升温至65℃,搅拌1.5h。反应完毕之后,冷却至常温,硅藻土抽滤,DCM洗涤固体,浓缩母液,柱层析分离得13号化合物纯品(56mg,收率48.6%),为白色固体。
1H-NMR(400MHz,MeOD)δ8.08(d,J=8.4Hz,1H),7.67-7.59(m,2H),7.56-7.46(m,3H),7.31(d,J=2.2Hz,2H),7.22-7.13(m,2H),7.10-7.05(m,1H),6.05-5.95(m,1H),2.29-1.89(m,8H).MS:Calculated 537.1,found 538.1([M+H]+)。
14号化合物的合成
将14-A1(500mg,2.96mmol)与14-A0(554mg,2.69mmol)溶于MeCN(10ml),氮气下将K
2CO
3(743mg,5.38mmol)加入至体系,升温至80℃,监测1.5h后,反应完毕。降至室温后硅藻土抽滤,DCM洗涤,母液浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=15:1-10:1)得产品(535mg,收率56.0%),为棕色油状物。
1H-NMR(400MHz,CDCl
3):δ9.99(s,1H),8.05(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.56-7.55(m,3H),7.41(dd,J1=8.4 4.8Hz,1H),7.16(d,J=8.4Hz,2H),7.00-6.91(m,2H)。
氮气保护,将14-A2(400mg,1.13mmol,)与TMSCF
3(320mg,2.25mmol)溶于THF(4mL)中,降温至0℃,将TBAF(0.02ml,0.02mmol,1M in THF)滴加至体系,保温0℃30min后14-A2全部消失,滴加3N HCl(2ml)至体系,体系变澄清,继续0℃搅拌1h后,DCM萃取(5ml×3),有机相水洗(5ml×3),有机相干燥浓缩,得到粗品(405mg,收率56.4%),为黄色固体,直接投于下步反应。MS:Calculated 425.3,found 426.0([M+1]+)。
氮气保护,将POCl
3(209mg,1.36mmol,百灵威)溶于DCM(5ml)后降温至-40℃,然后将14-A3(290mg,0.68mmol)溶于DCM(2ml)后与TEA(173mg,1.70mmol)滴加至体系,保温-40℃2h后15-A3全部转化为中间体,然后将溴乙胺溴酸盐(1.1g,5.46mmol)与TEA(552mg,5.46mmol)加入至体系,监测,30min后反应完毕。0℃加入饱和NH
4Cl(5ml),DCM萃取(20ml X 3),有机相水洗盐水洗,有机相干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=5:1-3:1)得到14-A4产品(250mg,收率51.1%),为黄色固体。
1H-NMR(400MHz,CDCl
3):δ8.00(d,J=8.4Hz,1H),7.54(d,J=7.6Hz,2H),7.44-7.38(m,1H),7.35(d,J=8.4Hz,1H),7.21(s,1H),7.13(d,J=8.8Hz,1H),7.00-6.95(m,2H),5.68–5.62(m,1H),3.42-3.11(m,8H).MS:Calculated 717.2,found 717.9([M+H]+)。
氮气保护下,将14-A4(230mg,0.32mmol)溶于THF中(15mL),然后加入氧化银(372mg,1.60mmol),DIPEA(207mg,1.60mmol),升温至65℃,搅拌1.5h。反应完毕之后,冷却至常温,硅藻土抽滤,DCM洗涤固体,浓缩母液,柱层析分离得14号化合物纯品(102mg,57.5%),为白色固体。
1H-NMR(400MHz,CDCl
3):δ8.01(d,J=8.4Hz,1H),7.54(d,J=1.6Hz,2H),7.51-7.36(m,2H),7.24(s,1H),7.12-7.11(m,2H),6.97-6.93(m,2H),5.72-5.69(m,1H),2.26-2.01(m,8H).MS:Calculated 555.1,found 556.1([M+H]+)。
15号化合物的合成
氮气保护下,将3-氟-4-溴苯酚(5.0g,26.2mmol,购买,97%)与对氟苯硼酸(4.0g,28.8mmol)溶于二氧六环与水的混合溶剂中(100mL,二氧六环:水=9:1),然后加入碳酸钾(10.8g,78.6mmol),抽充三次气体,加入醋酸钯(295mg,1.31mmol),三苯基磷(345mg,1.31mmol,百灵威,97%),再次抽充三次气体,升温至100℃,搅拌过夜。反应完毕之后,降至常温,硅藻土抽滤,EA洗涤,浓缩母液,用1N的盐酸调节至pH=3,EA萃取(50mL x 3),水洗(10mL x 3),盐水洗,干燥浓缩,柱层析分离(100-200目硅胶,正庚烷:EA=20:1)得产品15-A0(3.5g,收率64.8%),为白色固体。
1H-NMR(300M,DMSO-d6):δ10.02(s,1H),7.52-7.47(m,2H),7.34-7.23(m,3H),6.71-6.64(m,2H).MS:Calculated 206.1,found 204.8([M-H]-)。
氮气保护下,将15-A1(930mg,5.50mmol97%)和16-A0(1.36g,6.60mmol)溶于乙腈中(20mL),然后加入碳酸钾(1.52g,11.0mmol,百灵威,99%),升温至85℃,搅拌2小时,反应完毕。降至常温,抽滤,浓缩母液,柱层析分离(200-300目硅胶,正庚烷:EA=15:1)得到15-A2(1.10g,56.4%),为淡黄色固体。
1H-NMR(400MHz,DMSO-d6):δ10.05(s,1H),8.30(d,J=8.3Hz,1H),7.92(dd,J=8.3,1.5Hz,1H),7.78(d,J=1.5Hz,1H),7.69-7.55(m,3H),7.36-7.28(m,2H),7.27-7.21(m,1H),7.09(dd,J=8.5,2.3Hz,1H)。
氮气保护下,将15-A2(700mg,1.970mmol)溶于无水THF中(10mL),然后滴加入(三氟甲基)三甲基硅烷(476mg,3.35mmol,98%),降温至0℃,滴加入TBAF(0.04mL,1M in THF),保温0℃1.5小时,反应完毕。滴加入3N的盐酸2mL,自然升至常温,搅拌1小时。加入水5mL,DCM萃取(10mL×3),水洗(5mL×3),干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=15:1-10:1得到产品(810mg,96.7%),为黄色油状物15-A3。
1H-NMR(400MHz,DMSO-d6):δ8.19(d,J=8.5Hz,1H),7.63-7.52(m,4H),7.44(s,1H),7.32(t,J=8.9Hz,2H),7.21(d,J=5.8Hz,1H),7.14(dd,J=11.7,2.4Hz,1H),6.97(dd,J=8.5,2.1Hz,1H),5.44-5.37(m,1H)。
氮气保护下,将三氯氧磷(580mg,3.76mmol,97%)滴加到无水DCM中(10mL),降温至-40℃,滴加入15-A3(800mg,1.88mmol)的DCM溶液(4mL),然后滴加入三乙胺(476mg,4.70mmol),保温-40℃至-35℃两小时,、LC-MS监测,15-A3消失,转 化为中间体。-40℃,加入2-溴乙胺氢溴酸盐(3.08g,15.04mmol),然后滴加入三乙胺(1.52g,15.04mmol)的DCM溶液(2ml),保温-40℃一小时,中间体转化完毕。自然升温至0℃,滴加入饱和氯化铵水溶液(5mL),DCM萃取(10mL×3),纯净水洗(3ml×3),干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=1:1-100%EA)得产品15-A4 600mg,收率44.4%,为白色固体。
1H-NMR(400M,CDCl
3):δ8.04(d,J=8.4Hz,1H),7.55-7.47(m,2H),7.46-7.38(m,2H),7.27(s,1H),7.19-7.10(m,2H),6.95-6.83(m,2H),5.69(dd,J=11.4,6.1Hz,1H),3.50-3.18(m,8H).MS:Calculated 716.9,found 717.8([M+H]+)。
氮气保护下,将15-A4(600mg,0.837mmol)溶于THF中(15mL),然后加入氧化银(1.16mg,5.02mmol),DIPEA(649mg,5.02mmol),升温至65℃,搅拌3小时。反应完毕之后,冷却至常温,硅藻土抽滤,DCM洗涤固体,浓缩母液,加入1.5mL无水乙醚结晶,抽滤得纯品15号化合物(159mg,34.2%),为白色固体。
1H-NMR(400MHz,MeOD)δ8.12(t,J=8.1Hz,1H),7.55(m,4H),7.45(s,1H),7.19(t,J=8.8Hz,2H),6.98(dd,J=7.8,5.3Hz,2H),6.15-5.98(m,1H),2.39-1.93(m,8H).MS:Calculated 555.1,found 556.1([M+H]+)。
16号化合物的合成
氮气保护下,16-A1(1.7g,11mmol)、16-A2(2g,10mmol)、乙酸钯(21.5mg,0.1mmol)、三苯基膦(39mg,0.15mmol)和碳酸钾(2.8,20mmol)溶于二氧六环(20mL)和水(2mL)中,升温80℃搅拌过夜。反应完毕后,硅藻土抽滤,浓缩,拌样,柱层析分离(100-200目硅胶,正庚烷:EA=5:1),得16-A3产品(900mg,40%),为白色固体)。
1H-NMR(300MHz,DMSO)δ10.17(s,1H),7.55-7.08(m,3H),6.79-6.50(m,3H).MS:Calculated 224.0,found 222.6[(M-H)-]。
氮气保护下,16-A3(500mg,2.2mmol)、3-氟-4-硝基苯甲醛(370mg,2.2mmol)溶于MeCN(5mL)中,加入碳酸钾(830mg,6mmol),升温80℃搅拌4小时。反应完毕后,硅藻土抽滤,浓缩,拌样,柱层析分离(100-200目硅胶,正庚烷:EA=10:1),得16-A4粗品700mg(白色固体,80%纯度),直接用于下一步。。
1H-NMR(300MHz,DMSO)δ10.03(s,1H),8.31(d,J=8.2Hz,1H),7.94(d,J=8.4Hz,1H),7.83(s,1H),7.59-7.50(m,2H),7.40(t,J=8.8Hz,1H),7.32-7.16(m,2H),7.10(d,J=8.6Hz,1H)。
氮气保护下,将16-A4(680mg,1.82mmol),三氟甲基三甲基硅烷(510mg,3.6mmol)溶于THF(8mL),零度滴加四丁基氟化铵的THF溶液(0.1mL,0.1mmol,1M,安耐吉),保温6小时,加1N盐酸(2mL)搅拌10分钟。浓缩除掉THF,粗品加水(10mL)和DCM(20mL)萃取,有机相分离浓缩拌样,粗品柱层析分离(100-200目硅胶,正庚烷:EA=10:1)得16-A5产品(400mg,收率为49.6%,纯度90%),为淡黄色固体。。
1H-NMR(300MHz,DMSO)δ8.19(d,J=7.8Hz,1H),7.76(t,J=8.5Hz,1H),7.57-7.51(m,2H),7.38(s,1H),7.28-7.19(m,3H),6.89(dd,J=8.8,1.7Hz,1H),5.40-5.36(m,1H)。
氮气保护下,POCl
3(168mg,1.1mmol,百灵威)滴入超干DCM中(5mL),降温至-30℃,滴加入16-A5(220mg,0.5mmol)的DCM(5mL)溶液,后滴入TEA(170mg,1.65mmol),保温-30℃,6h后至原料完全消失。-30℃加入2-溴乙胺氢溴酸盐(897mg,4.4mmol)后,再滴入TEA(440mg,4.4mmol),反应完毕后,降温至0℃,加入NH4Cl饱和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),干燥,浓缩得16-A6粗品250mg,为黄色固体,直接用于下一步反应。MS:Calculated 732.9,found 733.9([M+H]+)。
氮气保护下,16-A6(250mg,0.34mmol)溶于THF(10mL)中,加入Ag
2O(210mg,1.7mmol)及N,N-二异丙基乙胺(220mg,1.7mmol),升温至65℃反应。2h反应完毕后,硅藻土抽滤,DCM(20mL)洗涤固体,浓缩母液,柱层析分离得16号化合物纯品22mg(白色固体,收率11%)。
1H-NMR(400MHz,DMSO)δ8.26(d,J=8.5Hz,1H),7.67(d,J=8.5Hz,1H),7.59-7.48(m,3H),7.41(dt,J=10.3,2.5Hz,1H),7.24-7.19(m,2H),7.03(dd,J=8.5,2.3Hz,1H),6.36-6.32(m,1H),2.20-1.91(m,8H).MS:Calculated 573.1,found 574.1([M+H]+)。
17号化合物的合成
氮气保护下,将2-溴-5-羟基吡啶(3.0g,17.2mmol)与对氟苯硼酸(17-A0,2.7g,19.0mmol)溶于二氧六环与水的混合溶剂中(60mL,二氧六环:水=9:1),然后加入碳酸钾(4.7g,34.4mmol),抽充三次气体,加入醋酸钯(193mg,0.86mmol),三苯基磷(225mg,0.86mmol),再次抽充三次气体,升温至100℃,搅拌过夜。反应完毕之后,降至常温,硅藻土抽滤,EA洗涤,浓缩母液,加入水15mL,EA萃取(50mL×3),水洗(10mL×3),盐水洗,干燥浓缩,柱层析分离。200-300目硅胶,正庚烷:EA=15:1得17-A1产品(1.2g,36.9%),为白色固体。。
1H-NMR(400M,DMSO-d6):δ10.03(s,1H),8.20(d,J=2.7Hz,1H),8.00(dd,J=8.8,5.6Hz,2H),7.78(d,J=8.6Hz,1H),7.32-7.18(m,3H).MS:Calculated 189.1,found 190.2([M+H]+)。
氮气保护下,将17-A1(600mg,3.55mmol)和18-A0(806mg,4.26mmol)溶于乙腈中(15mL),然后加入碳酸钾(980mg,7.1mmol),升温至85℃,搅拌2小时,反应完毕。降至常温,抽滤,浓缩母液,柱层析分离(200-300目硅胶,正庚烷:EA=10:1)得到产品17-A2(760mg,收率63.3%),淡黄色固体。
1H-NMR(400MHz,DMSO-d6):δppm10.03(s,1H),8.59(d,J=2.8Hz,1H),8.31(d,J=8.3Hz,1H),8.19-8.11(m,2H),8.07(d,J=8.7Hz,1H),7.90(dd,J=8.3,1.6Hz,1H),7.78-7.70(m,2H),7.37-7.26(m,2H).MS:Calculated 338.1,found 339.0([M+H]+)。
氮气保护下,将17-A2(700mg,2.07mmol)溶于无水THF中(10mL),然后滴加入(三氟甲基)三甲基硅烷(500mg,3.52mmol),降温至0℃,滴加入TBAF(0.03mL, 1M in THF),保温0℃1.5小时,反应完毕。滴加入3N的盐酸(2mL),自然升至常温,搅拌1小时。加入水5mL,DCM萃取(10mL×3),水洗(5mL×3),干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=15:1-10:1)得17-A3产品(550mg,收率65.1%),为黄色油状物。。
1H-NMR(400MHz,DMSO-d6):δ8.52(d,J=2.9Hz,1H),8.19(d,J=8.5Hz,1H),8.16-8.10(m,2H),8.06(d,J=8.8Hz,1H),7.64(dd,J=8.8,2.9Hz,1H),7.55(dd,J=8.7,3.3Hz,1H),7.38(s,1H),7.36-7.28(m,2H),7.18(dd,J=5.8,3.4Hz,1H),5.43-5.34(m,1H).MS:Calculated 408.1,found 409.2[M+H]+)。
氮气保护下,将三氯氧磷(414mg,2.70mmol)滴加到无水DCM中(10mL),降温至-40℃,滴加入17-A3(550mg,1.35mmol)的DCM溶液(4mL),然后滴加入三乙胺(342mg,3.36mmol),保温-40℃--35℃两小时,LC-MS监测,17-A3消失,转化为中间体。-40℃,加入2-溴乙胺氢溴酸盐(2.2g,10.8mmol),然后滴加入三乙胺(1.1g,10.8mmol)的DCM溶液(2ml),保温-40℃一小时,中间体转化完毕。自然升温至0℃,滴加入饱和氯化铵水溶液(5mL),DCM萃取(10mL×3),纯净水洗(3ml×3),干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=1:1-100%EA)得17-A4产品(520mg,收率55.0%),为白色固体。
1H-NMR(400M,CDCl3):δ8.49(d,J=2.7Hz,1H),8.06(dd,J=8.4,2.7Hz,1H),8.01-7.94(m,2H),7.77(d,J=8.7Hz,1H),7.54-7.48(m,1H),7.43(d,J=8.3Hz,1H),7.26-7.24(m,1H),7.18(t,J=8.7Hz,2H),5.69(dq,J=12.3,6.2Hz,1H),3.49-3.16(m,8H).MS:Calculated 700.0,found 700.9([M+H]+)。
氮气保护下,将17-A4(520mg,0.743mmol)溶于THF中(15mL),然后加入氧化银(1.03g,4.46mmol),DIPEA(580mg,4.46mmol),升温至65℃,搅拌3小时。反应完毕之后,冷却至常温,硅藻土抽滤,DCM洗涤固体,浓缩母液,柱层析分离得18号化合物纯品(106.7mg,收率26.7%),为白色固体。
1H-NMR(400MHz,MeOD):δ8.43(d,J=2.9Hz,1H),8.16(d,J=8.5Hz,1H),8.07-7.97(m,2H),7.92(d,J=8.8Hz,1H),7.65-7.54(m,2H),7.46(s 1H),7.24-7.19(m,2H),6.13-6.03(m,1H),2.26-2.08(m,8H)。MS:Calculated 538.1,found 539.1([M+H]+)。
18号化合物的合成
氮气保护下,18-A1(500mg,2.65mmol)、18-A2(460mg,2.65mmol)、四三苯基膦钯(373mg,0.3mmol)和氟化钾(300mg,5.2mmol)溶于甲苯(10mL)和水(1mL)中,升温80℃搅拌过夜。反应完毕后,硅藻土抽滤,浓缩,拌样,柱层析分离(100-200目硅胶,正庚烷:EA=10:1),得18-A3产品(600mg,收率94.7%),为白色固体。
1H-NMR(300MHz,DMSO)δ10.24(s,1H),8.26(d,J=2.4Hz,1H),8.19(d,J=8.1Hz,2H),7.91(d,J=8.7Hz,1H),7.78(d,J=8.1Hz,2H),7.29(dd,J=8.6,2.7Hz,1H).MS:Calculated 239.0,found 240.0([M+H]+)。
氮气保护下,18-A3(870mg,2.9mmol)、3-氟-4-硝基苯甲醛(490mg,2.9mmol)溶于MeCN(8mL)中,加入碳酸钾(830mg,6mmol),升温80℃搅拌4小时。反应完毕后,硅藻土抽滤,浓缩,拌样,柱层析分离(100-200目硅胶,正庚烷:EA=10:1), 得18-A4产品(640mg)为白色固体。
1H-NMR(300MHz,CDCl
3)δ10.03(s,1H),8.57(d,J=2.7Hz,1H),8.15-8.12(m,3H),7.87-7.75(m,4H),7.60-7.51(m,2H).MS:Calculated 388.0,found 389.1([M+H]+)。
氮气保护下,将18-A4(640mg,1.64mmol),三氟甲基三甲基硅烷(430mg,3mmol)溶于THF(5mL),0℃滴加四丁基氟化铵的THF溶液(0.1mL,0.1mmol,1M),保温6小时,加1N盐酸(2mL)搅拌10分钟。浓缩除掉THF,粗品加水(10mL)和DCM(20mL)萃取,有机相分离浓缩拌样,粗品柱层析分离(100-200目硅胶,正庚烷:EA=10:1)得产品(640mg,收率85.2%),为淡黄色固体。
1H-NMR(300MHz,DMSO)δ8.59(d,J=2.7Hz,1H),8.30(d,J=7.5Hz,2H),8.19(t,J=9.2Hz,2H),7.86(d,J=8.5Hz,2H),7.72-7.65(m,1H),7.59-7.56(m,1H),7.43(s,1H),7.20(d,J=5.8Hz,1H),5.39-5.37(m,1H).MS:Calculated 458.0,found:459.0([M+H]+)。
氮气保护下,POCl
3(200mg,1.3mmol)滴入超干DCM中(5mL),降温至-30℃,滴加入18-A5(300mg,0.65mmol)的DCM(5mL)溶液,后滴入TEA(270mg,2.6mmol),保温-30℃,6h后至原料完全消失。-30℃加入2-溴乙胺氢溴酸盐(1.1g,5.2mmol)后,再滴入TEA(530mg,5.2mmol),反应完毕后,降温至0℃,加入NH4Cl饱和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),干燥,浓缩得粗品200mg,为黄色固体,直接用于下一步反应。1H NMR(400MHz,CDCl3)δ8.46(d,J=2.6Hz,1H),8.07-7.99(m,3H),7.78-7.75(m,1H),7.68(d,J=8.2Hz,2H),7.48-7.33(m,3H),5.65-5.61(m,1H),3.51-3.04(m,10H).MS:Calculated 747.9,found 748.9([M+H]+)。
氮气保护下,18-A6(150mg,0.23mmol)溶于THF(10mL)中,加入Ag2O(170mg,1.38mmol,安耐吉)及N,N-二异丙基乙胺(163mg,1.38mmol),升温至65℃反应。2h反应完毕后,硅藻土抽滤,DCM(20mL)洗涤固体,浓缩母液,柱层析分离得纯品(41mg,收率36%),为白色固体。
1H-NMR(400MHz,DMSO)δ8.61(d,J=2.8Hz,1H),8.31(d,J=8.2Hz,2H),8.27(d,J=8.5Hz,1H),8.21(d,J=8.8Hz,1H),7.87(d,J=8.4Hz,2H),7.72(dd,J=8.8,2.9Hz,1H),7.65(d,J=8.5Hz,1H),7.56(s,1H),6.32-6.28(m,1H),2.17-1.90(m,8H).MS:Calculated 588.1,found 589.1([M+H]+)。
19号化合物的合成
氮气保护下将2-溴-5-羟基吡啶(1.5g,8.52mmol,购买)与对羟基苯硼酸(1.4g,10.23mmol)加入至DME(33mL)与H
2O(7mL)的混合液中,抽充氮气3次,将Pd(PPh
3)
4(300mg,0.26mmol)与Na
2CO
3(1.8g,17.05mmol)加入后再次抽充氮气三次,升温至80℃反应。监测2.5h,反应完毕。降至室温,EtOAc(50mL x 3)萃取,有机相水洗盐水洗,柱层析分离(200-300目硅胶,正庚烷:EA=12:1-9:1)得产品(1.4g,收率86.8%),为白色固体。
1H-NMR(300MHz,MeOD):δ8.43(d,J=2.7Hz,1H),7.81–7.77(m,3H),7.64–7.58(m,1H),6.87(d,J=8.7Hz,2H).MS:Calculated 189.1,found 190.1([M+H]+)。
氮气保护下,将19-A3(即46号化合物,100mg,0.27mmol)溶于丙酮中(5mL),然后将19-A2(102mg,0.54mmol),Cs
2CO
3(309mg,0.95mmol),室温搅拌2小时。 反应完毕之后,硅藻土抽滤,丙酮洗涤固体,浓缩母液,柱层析分离得20号化合物纯品(17mg,11.7%),为棕褐色固体。
1H-NMR(400MHz,MeOD)δ8.52(d,J=2.9Hz,1H),8.10(d,J=8.5Hz,1H),8.06(d,J=8.8Hz,2H),7.92(dd,J=8.8,4.3Hz,1H),7.68(dt,J=8.6,2.9Hz,1H),7.54(d,J=8.6Hz,1H),7.37(s,1H),7.19(d,J=8.8Hz,2H),6.06-5.99(m,1H),2.27-1.97(m,8H).MS:Calculated 538.1,found 539.1([M+H]+)。
46号化合物的合成
氮气保护,将46-A2(2.0g,11.8mmol,购买)与TMSCF
3(2.5g,17.7mmol)溶于THF(20mL)中,降温至0℃,将TBAF(2.6ml,0.26mmol,1M in THF)滴加至体系,保温0℃30min后46-A2全部消失,滴加3N HCl(2ml)至体系,体系变澄清,继续0℃搅拌1h后全部成为产物。DCM萃取(10ml×3),有机相水洗(10ml×3),干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=12:1-10:1)得产品46-A3(1.5g,收率53.2%),为黄色油状物。
1H-NMR(400MHz,CDCl
3):δ8.13-8.09(m,1H),7.60(d,J=11.6Hz,1H),7.43(d,J=8.4Hz,1H),5.12–5.18(m,1H),3.06(d,J=4.4Hz,1H)。
氮气保护,将POCl
3(963mg,4.61mmol)溶于DCM(10ml)后降温至-40℃,然后将46-A3(1.5g,6.27mmol)溶于DCM(20ml)后与TEA(1.6g,15.70mmol)滴加至体系,保温-40℃2h后46-A3全部转化为中间体,然后将溴乙胺溴酸盐(11.99g,50.16mmol)与TEA(10.1g,0.1mol)加入至体系,监测,30min后反应完毕。0℃加入饱和NH
4Cl(20ml),DCM萃取(50ml X 3),有机相水洗盐水洗,干燥浓缩,柱层析分离(200-300目硅胶,正庚烷:EA=5:1-1:1)得产品46-A4(1.6g,收率65.3%),为黄色油状物。
1H-NMR(400MHz,CDCl
3):δ8.15-8.11(m,1H),7.47(d,J=11.6Hz,1H),7.44(d,J=8.8Hz,1H),5.78-5.30(m,1H),3.53-3.05(m,10H).MS:Calculated 529.9,found 531.9([M+H]+)。
氮气保护下,将46-A4(1.6g,3.0mmol)溶于THF中(20mL),然后加入氧化银(4.2g,18.0mmol),DIPEA(2.3g,18.0mmol),升温至65℃,搅拌1.5h。反应完毕之后,冷却至常温,硅藻土抽滤,DCM洗涤固体,浓缩母液,柱层析分离(200-300目硅胶,正庚烷:EA=5:1-1:1)得粗品(520mg,收率为46.8%),柱层析分离46号化合物纯品(30mg),为白色固体。1H NMR(400MHz,MeOD):δ8.24-8.20(m,1H),7.70(d,J=11.6Hz,1H),7.63(d,J=8.8Hz,1H),6.14-6.10(m,1H),2.28-2.14(m,8H).MS:Calculated 369.1,found 370.1([M+H]+)。
Claims (29)
- 作为非PGP底物的抗癌化合物,其为式I-1化合物或者其药学上可接受的盐或溶剂合物:其中,R 1、R 2各自独立地为氢、氘、芳基或Z取代芳基、杂芳基、杂环或Z取代杂芳基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基;R 3是氢、卤素、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 3是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCO-R 6、-OCOO-R 6、-COOR 6、-NR 6COR 7、-OCOR 6、-NR 6SO 2R 7、-NR 6CONR 7;R 4、R 5各自独立地是氢、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基或者R 4、R 5是-CONR 6R 7、-SO 2NR 6R 7、-SO 2R 6、-OCOO-R 6、-COOR 6、-NR 6COR 6、-OCOR 6、-NR 6SO 2R 7、-NR 6CONR 7或者R 4、R 5和与其所键结的苯环上的原子一起形成7-15元的稠环或Z取代稠环;R 6和R 7各自独立地是氢、氰基或异氰基、C 1-C 6烷基或Z取代烷基、C 2-C 6烯基或Z取代烯基、C 2-C 6炔基或Z取代炔基、C 3-C 8环烷基或Z取代环烷基、C 6-C 10芳基或Z取代芳基、4-15元杂环或Z取代杂环、5-15元杂芳基或Z取代杂芳基、C 1-C 6烷氧基或Z取代的C 1-C 6烷氧基,或者R 6、R 7基团与其所键结的原子一起形成3-7元杂环基或Z取代3-7元杂环基;Cy为5-10元的芳环、杂环或者芳杂环,环上氢各自独立地被氘、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6的脂肪烃基取代或者被卤素原子、氰基、异氰基、羟基、巯基、胺基、肟基、腙基取代的C 1-C 6脂肪烃基取代;R 10为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的C3-C18环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或C1-C18的烃基或Z取代烃基;或R 10为-Q-Cz,Q为-O-、-S-、-CO-、-SO 2-、-SO-、-OCO-、-OCOO-、-NR 6CO-、-NR 6SO 2-、-OCONR 6-,Cz为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的3-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或C 1-C 18的烃基或Z取代烃基;Y为-O-或者-S-或-SO 2-、-SO-;L、D选自以下三种情况:R 40及R 41独立地为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4至15元杂环或5至15元杂芳基;R 42为C 2-C 3亚烷基、亚杂烷或1至3个C 1-C 6烷基取代的C 2-C 3亚烷基、亚杂环烷基;V(-)为任何阴离子;D为使得D-OH为抗癌药物的部分,其中OH为脂族羟基或酚羟基或为附接至磷酸酯的OH部分;或(2)L选自:R 40如上文所定义,R 43为氢或与D一起形成杂环,且亚苯基部分是Z取代的或未经取代的,及D为使得D-NR 43H为抗癌药物的部分;或(3)L选自键、–O-C(R 40R 41) 2-,–O-C(R 40R 41)-NR 40R 41(+)-C(R 40R 41)-,或其中R 40、R 41及V(-)如上文所定义,及D为含有三级或二级氮原子的抗癌药物,其中所述三级氮原子或二级氮原子键接至L;及上述L、D的定义中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基团为Z取代或未经取代;Z取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 3烷基或取代烷基、C 1-C 3烷氧基或取代烷氧基、C 2-C 3烯基或取代烯基、C 2-C 3炔基或取代炔基、C 3-C 8环烷基或取代环烷基、芳环、杂环、杂芳环和稠环或取代芳环、杂环、杂芳环和稠环,取代的方式为单取代或偕二取代,取代基为卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs;
- 根据权利要求1所述的化合物,其中R 10为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的C 3-C 18环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基;或R 10为-Q-Cz,Q为-O-、-S-、-CO-、-SO 2-、-SO-、-OCO-、-OCOO-、-NR 6CO-、-NR 6SO 2-、-OCONR 6-,Cz为3-18元的环烃基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的3-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基。
- 根据权利要求1所述的化合物,其中,-D为-P(Z 1)(Z 5-X 5-Y 5) n,Z 1为O或S,Z 5为N、S或O,X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,n为1或2,或者Z 1为O或S,Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分;或者-L-为-O-,-D为-P(Z 1)(Z 5-X 5-Y 5) n,Z 1为O或S,Z 5为N、S或O,X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,n为1或2;或者-L-为-O-,Z 1为O或S,Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分;或者-L-D为-OP(Z 1)(NR 30CH 2CH 2Cl) 2,-OP(Z 1)(NR 30CH 2CH 2Br) 2,-OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,其中,每个R 30各自独立的为H、C 1-C 6的烃基或两个R 30基团与连接的N原子形成5-7元的杂环,Z 1为O或S,X 1为Cl、Br或-OSO 2Me;或者-L-D为-OP(Z 1)(NHCH 2CH 2Cl) 2,-OP(Z 1)(NHCH 2CH 2Br) 2,-OP(Z 1)(NH 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,且X 1为Cl、Br或-OSO 2Me。
- 根据权利要求1所述的化合物,其中,L选自-O-、-S-、-OCOO-、-NR 6CO-、-OCO-、-NR 6SO 2-、-OCONR 6-、季铵根、磺酸酯基-OSO 2-,-D为-P(Z 1)(Z 5-X 5-Y 5) n,Z 1为O或S,Z 5为N、S或O,X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,n为1或2。
- 根据权利要求4所述的化合物,其中,Z 1为O或S,Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分。
- 根据权利要求1所述的化合物,其中,-L-为-O-,-D为-P(Z 1)(Z 5-X 5-Y 5) n,Z 1为O或S,Z 5为N、S或O,X 5为任意取代的亚乙基,Y 5为卤素原子或-OSO 2-R 20,R 20为任意取代的烃基、芳基、环烷基、杂环基或杂芳基,n为1或2。
- 根据权利要求6所述的化合物,其中,-L-为-O-,Z 1为O或S,Z 5-X 5-Y 5为吖丙啶基-NCH 2CH 2部分。
- 根据权利要求1所述的化合物,其中,-L-D为-OP(Z 1)(NR 30CH 2CH 2Cl) 2,-OP(Z 1)(NR 30CH 2CH 2Br) 2,-OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,其中,每个R 30各自独立的为H、C 1-C 6的烃基或两个R 30基团与连接的N原子形成5-7元的杂环,Z 1为O或S,X 1为Cl、Br或-OSO 2Me。
- 根据权利要求8所述的化合物,其中,-L-D为-OP(Z 1)(NHCH 2CH 2Cl) 2,-OP(Z 1)(NHCH 2CH 2Br)2,-OP(Z 1)(NH 2)(N(CH 2CH 2X 1) 2),-OP(Z 1)(N(CH 2) 2) 2,或-OP(Z 1)(N(CH 2CH 2Cl) 2) 2,且X 1为Cl、Br或-OSO 2Me。
- 根据权利要求1所述的化合物,其中,R 10为5-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的5-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基;或R 10为-O-Cz,Cz为5-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的5-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基。
- 根据权利要求1所述的化合物,其中,R 10为7-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的7-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基;或R 10为-O-Cz,Cz为7-18元的环烷基、芳基或稠环、杂环、稠杂环、杂芳基团或Z取代的7-18元的环烷基、芳基或稠环、杂环、稠杂环基团、杂芳基团或含有-CF 3、Cl取代的烃基。
- 根据权利要求12所述的化合物,其中,-Y-与-Cx上两个苯环相联的碳原子的对位相联,且联苯上的取代基为F原子或甲基。
- 根据权利要求12所述的化合物,其中,Cx选自-F、-CF 3、-CH 3取代的联苯基、苯基吡啶。
- 根据权利要求1所述的化合物,其中,R 3、R 4、R 5各自独立地为氢。
- 根据权利要求1所述的化合物,其中,R 1、R 2各自独立地为氢、氘、-CH 3、-CD 3、-CF 3。
- 根据权利要求1所述的化合物,其中,Y为-O-。
- 根据权利要求1所述的化合物,其中,Cy为5-10元的芳杂环或者苯环,苯环或环上氢各自独立地被氘、卤素原子、氰基或异氰基、硫氰基或异硫氰基、羟基、巯基、胺基、肟基、腙基、OTs、OMs、C 1-C 6的脂肪烃基取代或者被卤素原子、氰基、异氰基、羟基、巯基、胺基、肟基、腙基取代的C 1-C 6脂肪烃基取代。
- 根据权利要求1所述的化合物,其中,Cy上的取代基为氢、氘、卤素原子、-CH 3或者-CF 3。
- 根据权利要求1所述的化合物,其中,Cy选自5、6、7、8元的芳杂环,且杂原子为N、S或者O,杂原子的数目为1、2或者3。
- 根据权利要求1所述的化合物,其中,D-OH选自以下含有-OH基团的抗癌药物:吉西他滨gemcitabine、雌莫司汀estramusting、泼尼莫司汀pudnimnstine、氯脲霉素chlorozotocin、雷莫司汀ranimustine、甘露莫司汀mannomustine、二溴甘露醇mitobronitol、二溴卫矛醇dibromodulcitol、阿柔比星aclacinomycins、安曲霉素anthramycin、博来霉素bleomycin、卡柔比星carubicin、多柔比星doxorubicin、嗜癌霉素carzinophilin、色霉素chromomycin、放线菌素dactinomycin、道诺霉素daunorubicin、霉酚酸mycophenolic acid、诺加霉素nogalamycin、橄榄霉素olivomycin、培洛霉素peplomycin、普卡霉素plicamycin、嘌呤霉素puromycin、链黑霉素streptonigrin、 链 脲佐菌素streptozocin、杀结核菌素tubercidin、乌苯美司ubenimex、净司他丁zinostatin、左柔比星zorubicin、迪诺特宁denopterin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、6-氮杂尿苷6-azauridine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醋葡醛内酯aceglatone、依利醋铵elliptinium acetate、依托格鲁etoglucid、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、蘑菇多醣lentinan、米托蒽醌mitoxantrone、莫哌达醇mopidamol、喷司他丁pentostatin、吡柔比星pirarubicin、鬼臼酸podophyllinic acid、西索菲兰sizofiran、太平洋紫杉醇paclitaxel、替尼泊苷teniposide、细交链孢菌酮酸tenuazonic acid、长春碱vinblastine或者长春新碱vincristine;D-NR 43H选自以下的抗癌药物:埃罗替尼erlotinib、美妥替哌meturedepa、乌瑞替派uredepa、伊马替尼imatinib、三甲密胺trimethylolomelamine、吉非替尼gefitinib、 尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、甘露氮芥mannomustine、放射菌素actinomycin、安曲霉素anthramycin、博莱霉素bleomycin、放线菌素C cactinomycin、卡柔比星carubicin、多柔比星doxorubicin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、培洛霉素peplomycin、嘌呤霉素puromycin、链脲菌素streptozocin、乌苯美司ubenimex、净司他丁zinostatin、迪诺特宁denopterin、蝶罗呤pteropterin、曲美沙特trimetrexate、6-巯基嘌呤6-mercaptopurine、硫米嘌呤thiamiprine、硫鸟嘌呤thioguanine、6-氮杂尿苷6-azauridine、卡莫氟carmofur、双脱氧尿苷dideoxyuridine、脱氧氟尿苷doxifluridine、依诺他滨enocitabine、氟尿苷floxuridine、5-氟尿嘧啶5-fluorouracil、替加氟tegafur、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、安吖啶amsacrine、比生群bisantrene、地美可辛demecolcine、地吖醌diaziquone、依利醋铵elliptinium acetate、氟他胺flutamide、羟基尿素hydroxyurea、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、米托蒽醌mitoxantrone、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、2-乙基酰肼2-ethylhydrazide、丙卡巴肼procarbazine、雷佐生razoxane、埃罗替尼erlotonib、尿烷urethane、长春碱vinblastine或者长春新碱vincristine;含有三级或二级氮原子的抗癌药物选自六甲蜜胺altretamine、曲他胺triethylenemelamine、苯丁酸氮芥chlorambuci、萘氮芥chlornaphazine、雌氮芥estramustine、吉非替尼gefitinib、氮芥mechlorethamine、氮芥氧化物盐酸盐mechlorethamine oxide hydrochloride、美法仑melphalan、新氮芥novembichin、芬司特瑞phenesterine、泼尼氮芥prednimustine、曲磷胺trofosfamide、尿嘧啶氮芥uracil mustard、卡莫司汀carmustine、氯脲菌素chlorozotocin、福莫司汀fotemustine、尼莫司汀nimustine、雷莫司汀ranimustine、达喀尔巴嗪dacarbazine、哌泊溴烷pipobroman、放线菌素actinomycin、安曲霉素anthramycin、嗜癌菌素carzinophilin、放线菌素D dactinomycin、诺加霉素nogalamycin、泊非罗霉素porfiromycin、嘌呤霉素puromycin、链脲菌素streptozocin、杀结核菌素tubercidin、氟达拉宾fludarabine、安西他滨ancitabine、阿扎胞苷azacitidine、阿糖胞苷cytarabine、双脱氧尿苷dideoxyuridine、依诺他滨enocitabine、氟尿苷floxuridine、L-天冬酰胺酶L-asparaginase、百慕时pulmozyme、醛磷酰胺糖苷aldophosphamide glycoside、贝斯布西bestrabucil,地吖醌diaziquone、α-干扰素interferon-alpha、β-干扰素interferon-beta、γ-干扰素interferon-gamma、2-介白素interleukin-2、丙脒腙mitoguazone、莫哌达醇mopidamol、二胺硝吖啶nitracrine、喷司他丁pentostatin、蛋胺氮芥phenamet、雷佐生razoxane、锗螺胺spirogermanium、他莫昔芬tamoxifen、三亚胺醌triaziquone、2,2',2"-三氯三乙胺2,2',2"-trichlorotriethylamine、长春碱vinblastine或者长春新碱vincristine。
- 含有权利要求1至22中任一项所述的化合物的药物,其用于治疗AKR1C3酶具有表达的癌症、肿瘤,或由AKR1C3酶具有表达的癌症、肿瘤引发的病症或细胞增生性疾病。
- 根据权利要求23所述的药物,所述癌症或肿瘤为中枢神经系统的癌症或肿瘤,所述病症包括疼痛。
- 根据权利要求23所述的药物,所述癌症或肿瘤为原发性脑癌、肿瘤或转移至脑的转移性癌症、肿瘤。
- 权利要求1-22中任意一项所述化合物的制药用途,该药用于治疗AKR1C3酶具有表达的癌症、肿瘤,或由AKR1C3酶具有表达的癌症、肿瘤引发的病症或细胞增生性疾病,所述癌症、肿瘤为中枢神经系统的癌症或肿瘤,所述病症包括疼痛。
- 根据权利要求26所述的制药用途,所述癌症或肿瘤为原发性脑癌、肿瘤或转移至脑的转移性癌症、肿瘤。
- 一种使用如权利要求1至22中任一项所述的化合物或其药学上可接受的盐来治疗AKR1C3酶具有表达的癌症、肿瘤,或由AKR1C3酶具有表达的癌症、肿瘤引发的病症或细胞增生性疾病的治疗方法,所述方法包括向患者施用有效剂量的如权利要求1至22中任一项所述的化合物或其药学上可接受的盐。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023077452A1 (zh) * | 2021-11-05 | 2023-05-11 | 深圳艾欣达伟医药科技有限公司 | Akr1c3活化的dna烷化剂及其医药用途 |
WO2023237080A1 (zh) * | 2022-06-10 | 2023-12-14 | 深圳艾欣达伟医药科技有限公司 | Akr1c3酶激活前药治疗癌症患者的方法 |
WO2024078392A1 (en) * | 2022-10-09 | 2024-04-18 | Anrui Biomedical Technology (Guangzhou) Co., Ltd. | Phosphoramidate compounds and uses thereof |
Families Citing this family (1)
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WO2024078568A1 (zh) * | 2022-10-12 | 2024-04-18 | 深圳艾欣达伟医药科技有限公司 | Akr1c3激活抗癌前药化合物与镇痛药物联用治疗伴有疼痛的癌症患者 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016061342A1 (en) | 2014-10-17 | 2016-04-21 | Albemarle Corporation | Methods for quantifying zinc content of fluids |
WO2016145092A1 (en) | 2015-03-10 | 2016-09-15 | Threshold Pharmaceuticals, Inc. | Dna alkylating agents |
WO2016161342A2 (en) | 2015-04-02 | 2016-10-06 | Threshold Pharmaceuticals, Inc. | Nitrobenzyl derivatives of anti-cancer agents |
WO2017087428A1 (en) | 2015-11-16 | 2017-05-26 | Threshold Pharmaceuticals, 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 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180169064A1 (en) * | 2015-06-24 | 2018-06-21 | Threshold Pharmaceuticals, Inc. | Aziridine containing dna alkylating agents |
KR20220012274A9 (ko) * | 2019-05-13 | 2022-02-21 | 아센타위츠 파마슈티컬즈 리미티드 | 플루오린 함유 화합물 및 이의 항암 의학적 용도 |
-
2020
- 2020-10-30 CN CN202080067380.4A patent/CN114555614A/zh active Pending
- 2020-10-30 US US17/773,138 patent/US20220387345A1/en active Pending
- 2020-10-30 WO PCT/CN2020/125123 patent/WO2021083310A1/zh unknown
- 2020-10-30 EP EP20883322.8A patent/EP4053135A4/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016061342A1 (en) | 2014-10-17 | 2016-04-21 | Albemarle Corporation | Methods for quantifying zinc content of fluids |
WO2016145092A1 (en) | 2015-03-10 | 2016-09-15 | Threshold Pharmaceuticals, Inc. | Dna alkylating agents |
CN107530556A (zh) | 2015-03-10 | 2018-01-02 | 深圳艾衡昊医药科技有限公司 | Dna烷化剂 |
WO2016161342A2 (en) | 2015-04-02 | 2016-10-06 | Threshold Pharmaceuticals, Inc. | Nitrobenzyl derivatives of anti-cancer agents |
CN108136214A (zh) | 2015-04-02 | 2018-06-08 | 深圳艾衡昊医药科技有限公司 | 硝基苄基衍生物抗癌试剂 |
WO2017087428A1 (en) | 2015-11-16 | 2017-05-26 | Threshold Pharmaceuticals, 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 |
CN108290911A (zh) | 2015-11-16 | 2018-07-17 | 深圳艾衡昊医药科技有限公司 | (r)-及(s)-1-(3-(3-n,n-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-n,n’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法 |
Non-Patent Citations (3)
Title |
---|
FLANAGAN ET AL.: "compound 36", BIOORGANIC AND MEDICINAL CHEMISTRY, 2014, pages 962 - 977 |
NOGRADY: "Medicinal Chemistry A Biochemical Approach", 1985, OXFORD UNIVERSITY PRESS, pages: 388 - 392 |
See also references of EP4053135A4 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023077452A1 (zh) * | 2021-11-05 | 2023-05-11 | 深圳艾欣达伟医药科技有限公司 | Akr1c3活化的dna烷化剂及其医药用途 |
WO2023237080A1 (zh) * | 2022-06-10 | 2023-12-14 | 深圳艾欣达伟医药科技有限公司 | Akr1c3酶激活前药治疗癌症患者的方法 |
WO2024078392A1 (en) * | 2022-10-09 | 2024-04-18 | Anrui Biomedical Technology (Guangzhou) Co., Ltd. | Phosphoramidate compounds and uses thereof |
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