WO2013122112A1 - ニトロイミダゾールを用いたプロドラッグ - Google Patents
ニトロイミダゾールを用いたプロドラッグ Download PDFInfo
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- WO2013122112A1 WO2013122112A1 PCT/JP2013/053429 JP2013053429W WO2013122112A1 WO 2013122112 A1 WO2013122112 A1 WO 2013122112A1 JP 2013053429 W JP2013053429 W JP 2013053429W WO 2013122112 A1 WO2013122112 A1 WO 2013122112A1
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- WIPO (PCT)
- Prior art keywords
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- therapeutically active
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- active organic
- formula
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- 229940002612 prodrug Drugs 0.000 title claims abstract description 26
- 239000000651 prodrug Substances 0.000 title claims abstract description 26
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 title description 7
- 125000003277 amino group Chemical group 0.000 claims abstract description 41
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 28
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 87
- 206010021143 Hypoxia Diseases 0.000 claims description 41
- 230000001146 hypoxic effect Effects 0.000 claims description 39
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 26
- -1 acrasinomycin Chemical compound 0.000 claims description 14
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 14
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 14
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- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 description 1
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- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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Images
Classifications
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07H15/20—Carbocyclic rings
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Definitions
- the present invention relates to a conjugate of 2-nitro-1-imidazolepropionic acid and a drug which is a therapeutically active compound. More specifically, the prodrug capable of releasing a therapeutically active compound in an active form by cleaving a covalent bond between a nitroimidazole and a drug under a hypoxic site in a living body or in a reducing environment, and the conjugate are provided. Relates to the use of 2-nitro-1-imidazolepropionic acid for the preparation.
- Tumors in hypoxic sites are the cause of invasion, metastasis, and resistant cancer, and are the biggest factor preventing the cure of cancer, and the development of treatments for tumor cells in these hypoxic environments is highly desired Yes.
- Drugs targeting cancer cells in the hypoxic region include triapazamine, AQ4N (banoxantrone dihydrochloride), PR104 (dinitrobenzamide nitrogen mustrandrogen trombondrogentrondrogentrodrogndrogentrondrogentrodrogndrogentrondrogentrodrogndrogentrondrogentrodromidertrodogen [N, N′-bis (2-bromoethyl) phosphorodiamic acid (1-methyl-2-nitro-1H-imidazol-5-yl) methyl ester (N, N′-bis (2-bromoethyl) phosphodiadic acid] (1-methyl-2-nitro-1H-imidazol-5-yl) methyl ster)] and the like
- AQ4N banoxantrone dihydrochloride
- PR104 dinitrobenzamide nitrogen mustrandrogen trombondrogentrondrogentrodrogndrogentrondrogentrodrogndrogentrondrogentrodromidertrodogen [N, N′-bis (2-
- Non-Patent Document 1 dinitrobenzamide that acts as such a protecting group
- Non-Patent Document 2 nitroimidazoles related to TH-302 are disclosed in Non-Patent Document 2, Patent Document 1, and Patent Document 2.
- TH-302 utilizes a mechanism that cleaves the protecting group-drug bond and releases the drug, as represented by the following reaction scheme.
- the drug is bonded to the carbon atom constituting the imidazole ring via a methyleneoxy group (—CH 2 —O—), and is a prodrug by the same mechanism as the above reaction scheme. It is understood that the drug is released from.
- the drug release efficiency depends on the drug detachment ability, and the released drug is limited to a compound having a phenolic hydroxyl group or phosphoric acid which is easily released.
- Patent Document 3 discloses an anthracycline-based bioreductive group (Hyp: 2-nitroimidazolyl) via a linker [L: —CH 2 CH 2 CH 2 —C ( ⁇ O) —] at the 1-position thereof.
- a hypoxia activated conjugate (Hyp-LQ) covalently bonded to the amino group of an anticancer drug (Q) is described.
- This conjugate compound remains attached at the -LQ moiety in the hypoxic tumor region, but is reduced to the nitro hydroxyamine of 2-nitroimidazolyl, thus via the 4- or 5-position of imidazolyl. It has been suggested that DNA can be alkylated, while anthracyclines that constitute Q intercalate between DNA bases to kill cancer cells.
- a compound in which the linker is “—C3H6-C ( ⁇ O) —” means that the linker is, for example, —CH 2 (CH 2 ) a CH 2 —O—CH 2 — (where a Is an integer of 0 or 1)) and has been shown to exhibit only significantly less cytotoxicity against hypoxic lung cancer cells than the corresponding compound which is The patent application is outside the scope of the claims.
- Patent Document 4 describes that, for example, amides such as N-methyl-2-nitro-1-imidazolepropanoylamide alone have an anti-malignant tumor action together with a radiosensitizing action.
- imidazole carboxylic acids can be used to form conjugates or prodrugs with other drugs.
- an object of the present invention is to provide a system that is more versatile than the prior art and efficiently changes the molecular structure in a hypoxic site such as a tumor and efficiently releases a compound such as a drug. .
- Non-Patent Document 1 a compound in which a drug is covalently bonded to a carbonyl group of a linker: —CH (—Me) —C ( ⁇ O) — bonded to the 1-position of the 2-nitroimidazole skeleton is reduced in the nitroimidazole moiety. It is suggested that no intramolecular cyclization reaction occurs and the drug is not released.
- Patent Document 3 Hyp-LQ in which the linker portion is represented by —CH 2 CH 2 CH 2 —C ( ⁇ O) — is reduced in 2-nitroimidazole portion corresponding to Hyp under low oxygen. However, it is described that the LQ bond is not cleaved.
- the present inventors have found that the amide bond, imide bond or ester bond formed via the carbonyl group is cleaved in a reducing environment, particularly at a hypoxic site in vivo.
- a reducing environment such as a reducing environment, the nitro group on the imidazole ring is converted to a hydroxyamine or amino group, and the amino group undergoes nucleophilic attack in the molecule. It can be understood that this occurs with an intramolecular cyclization reaction according to the reaction scheme.
- the present invention since the amide bond, imide bond or ester bond is cleaved in a reducing environment and a drug having its own activity is released on the spot, it is selectively released in a reducing environment. It is possible to provide compounds that can be conjugates or prodrugs of a wide variety of drugs that are meaningful. Accordingly, the present invention is broadly based on the finding that 2-nitro-1-imidazolepropionic acid can be used to provide a wide variety of drugs, particularly prodrugs of therapeutically active organic compounds. As one aspect of the present invention, the general formula (I)
- Z represents the formula (a): Or formula (b): -O-R3 (b)
- R1 is a residue obtained by removing the amino group from a therapeutically active organic compound having an amino group
- R2 is a hydrogen atom, or R1 and R2, together with the adjacent N atom, represent the residue of a therapeutically active organic compound having a cyclic amino group
- R3 is a residue obtained by removing the hydroxy group from a therapeutically active organic compound having a hydroxyl group.
- the compound represented by formula (II) A preparation for producing a prodrug of a therapeutically active organic compound having an amino group, a cyclic amino group or a hydroxyl group in the molecule, containing 2-nitro-1-imidazolepropionic acid represented by the formula: Or use of a compound of formula (II) as a reactant to produce a prodrug of a therapeutically active organic compound having an amino group, cyclic amino group or hydroxyl group in the molecule, Is also provided.
- Such a compound of the general formula (I) is obtained by binding 2-nitro-1-imidazolepropionyl (hereinafter sometimes abbreviated as Izp) to a therapeutically active organic compound.
- prodrug has its own meaning as used in the art, for example, by chemically modifying a physiologically active substance or therapeutically active organic compound, in vivo, enzymatically or otherwise. A compound designed to release or release the parent compound under conditions.
- conjugate means a conjugate formed by covalently bonding two or more different compounds, and is used as a concept of including a prodrug.
- pharmaceutically active organic compound means an organic compound having activity to treat or prevent diseases, disorders, etc. in mammals, particularly humans.
- diseases and disorders include tumors, particularly malignant tumors, and inflammation, in which these lesions or their surrounding regions are accompanied by hypoxia compared to normal tissues or cell regions.
- Antineoplastic agent or substance and “anticancer agent” are used as interchangeable terms.
- Anti-tumor substances included in therapeutically active organic compounds are not only compounds that are currently being used or tested for cancer chemotherapy, but also have clinical use due to their strong toxicity or side effects. Also included are compounds that have been given up, as well as compounds that will be provided in the future as anticancer agents, provided that the objectives of the present invention are met.
- anticancer agents include, but are not limited to, doxorubicin, idarubicin, epirubicin, daunorubicin, pirarubicin, amrubicin, anthracyclines such as acracinomycin, anthramycin, zorubicin, peptide systems such as bleomycin, actinomycin, Quintoline alkaloids such as camptothecin, topotecan and irinotecan, taxanes such as docetaxel and paclitaxel, vinoresine (vinorelbine), vinca alkaloids such as vincristine, vinblastine and vindesine, deoxycytidines such as gemcitabine and cytarabine, 5-fluorouracidine Pyrimidines such as doxyfluridine, purine ring derivatives such as fludarabine, 6-mercaptopurine, 6-thioguanine , Macrolides such as epothilone, amino acid derivative type, such as melphal
- anti-inflammatory included in therapeutically active organic compounds include salicylic acid non-steroidal anti-inflammatory drugs such as mesalazine, oxicam non-steroidal anti-inflammatory drugs such as piroxicam, meloxicam, and tenoxicam, cortisone, hydrocortisone, cortisone acetate Steroidal anti-inflammatory drugs such as prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, and triamcinolone acetonide.
- salicylic acid non-steroidal anti-inflammatory drugs such as mesalazine
- oxicam non-steroidal anti-inflammatory drugs such as piroxicam, meloxicam, and tenoxicam
- cortisone hydrocortisone
- cortisone acetate Steroidal anti-inflammatory drugs such as prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, and triamcinol
- an amino group or cyclic amino group or hydroxyl group that is present in the molecule of these antitumor substances and can be used to form an amide bond, an imide bond, or an ester bond by reaction with a compound of formula (II) is, for example, In anthracyclines, the amino group or hydroxyl group present in the sugar moiety, the peptide antibiotics the amino group, the quinoline alkaloids the E ring hydroxyl group, the taxanes a hydroxyl group bonded to the taxane ring or
- the side chain hydroxyl is a cyclic amino group on the indole ring in vinca alkaloids
- the deoxycytidine derivative is the hydroxyl on the exocyclic amino group or ribose ring of the cytosine base
- the pyrimidine derivative is a cyclic amino group on the pyrimidine ring.
- hydroxyl on the group or ribose ring to the purine ring In the conductor, a hydroxyl group on the purine ring or the exocyclic amino group or the ribose ring, in the macrolide antibiotics the hydroxyl group on the macrolide ring, and in the amino acid derivative, the amino group bonded to the ⁇ -carbon.
- an amino group bonded to the heterocyclic ring In the folic acid antimetabolite, an amino group bonded to the heterocyclic ring can be exemplified.
- An amino group or a cyclic amino group or a hydroxyl group that is present in the molecule of the anti-inflammatory agent and can be used to form an amide bond, an imide bond, or an ester bond by reaction with the compound of the formula (II) is, for example, In the salicylic acid system, a hydroxyl group or amino group bonded to the benzene ring, in the oxicam system, a hydroxyl group present in the cyclic sulfonamide, and in the steroid system, a hydroxyl group bonded to the 21st carbon can be exemplified.
- Representative compounds of therapeutically active organic compounds having an amino group include doxorubicin, idarubicin, epirubicin, daunorubicin, pirarubicin, amrubicin, aclacinomycin, anthramycin, zorubicin, bleomycin, actinomycin, gemcitabine, cytarabine, methotrexate, pemetrexed , Melphalan, mesalazine,
- Representative compounds of therapeutically active organic compounds having a cyclic amino group include vincristine, vinblastine, vindesine, 5-fluorouracil, 6-mercaptopurine
- Representative compounds of the therapeutically active organic compounds having a hydroxyl group include: docetaxel, paclitaxel, vincristine, vinblastine, vindesine, doxorubicin, idarubicin, epirubicin, daunorubicin, pirarubicin, amrubicin, acracinomycin, anth
- the pharmaceutically acceptable salt of the compound of the general formula (I) is hydrochloric acid, when the compound has a basic group other than the amino group or cyclic amino group forming the amide bond or imide bond. It can be an acid addition salt of an organic acid such as a mineral acid such as sulfuric acid, formic acid, acetic acid, citric acid and methanesulfonic acid, while when the compound has an acidic group such as a carboxyl group or a hydroxyl group, It can be an addition salt of an alkali metal such as potassium or an organic amine such as ammonium or methylamine.
- a “hypoxic site” is used whether in vivo or in vitro, but is preferably in vivo in mammals, particularly humans, in particular solid cancer lesions or solid cancer cells. Groups, etc., as well as surrounding areas are included.
- General formula (I) by forming an amide bond, an imide bond or an ester bond by reaction of a therapeutically active organic compound having an amino group, a cyclic amino group and / or a hydroxyl group in the molecule with a compound of formula (II)
- a therapeutically active organic compound having an amino group, a cyclic amino group and / or a hydroxyl group in the molecule with a compound of formula (II) Can be prepared by reacting the organic compound with a compound of formula (II) in the presence of a condensing agent known per se in the art (eg carbodiimides) in a suitable inert solvent.
- a condensing agent known per se in the art
- an active ester halide, ester with N-hydroxysuccinimide, etc.
- any of the above reactions is performed. Just do it.
- the compound or prodrug represented by the general formula (I) can be administered to a patient from the same administration route in the same dosage form as the therapeutically active organic compound as the parent compound is administered.
- the formulation can be prepared using a pharmaceutically acceptable carrier.
- preparations suitable for parenteral or intramuscular administration include buffers, tonicity adjusting agents, etc., and optionally include surfactants, liposome forming agents, polymeric micelle forming agents, etc. It can be prepared by dissolving or suspending in a non-aqueous solution or diluent. The dose may be determined by consulting with a specialist if necessary with reference to the parent compound dose.
- FIG. 2 is an NMR chart of Compound 4 produced by the cyclization reaction of Example 1.
- FIG. The graph which shows the measurement result of the high performance liquid chromatography (HPLC) which performed the comparative examination of the discharge
- FIG. The graph which shows the discharge
- FIG. which shows the result of the evaluation of the cell viability by Example 7 (hypoxic environment-responsive doxorubicin).
- the graph which shows the result of the comparative test about the cytotoxicity of the compound of this invention by the comparative experiment example, and a known compound similar in structure.
- the graph which shows the result of the cell viability evaluation (hypoxic environment-responsive gemcitabine) by Example 9.
- Example 3 Reduction of Compound 5
- Example 4 Incubation of Compound 5 in Hypoxic Cultured Cells This example shows that Compound 5 is reduced in cells in a hypoxic environment and subsequently releases naphthylmethylamine by an intramolecular cyclization reaction. Went to confirm.
- the cell number was adjusted to 1 ⁇ 10 4 cells / mL, seeded on a 96-well plate, and cultured at 37 ° C. in an incubator for 24 hours. After 24 hours, the synthesized compound 5 was added to 1 mM in the cells. After the addition, the cells were cultured for 6 hours in a normal oxygen concentration incubator (20% O 2 ) and a low oxygen workstation (1% O 2 ), respectively. Thereafter, 50 uL of Trypsin / EDTA was collected, and the cells were detached by incubation for 5 minutes, and added to the previously collected medium. Thereafter, the collected sample was freeze-dried overnight, 200 uL of acetonitrile was added, and ultrasonic cleaning was performed for 30 minutes.
- Example 5 Incubation of Compound 5 in Hypoxic Cultured Cells Human pancreatic cancer cells (MIA PaCa-2, obtained from Riken Cell Bank) were adjusted so that the number of cells was 1 ⁇ 10 4 cells / mL. And 96-well plates. After 24 hours, Compound 5 was added at a concentration of 10 ⁇ M and cultured in a normal oxygen concentration incubator (20% O 2 ) and a low oxygen workstation (0.1% O 2 ), respectively. After a lapse of time, the medium was collected, and trypsin was further added to collect cells. The collected cells were pulverized by sonication, extracted with acetonitrile, and analyzed by LC / MS under the following conditions.
- MIA PaCa-2 Human pancreatic cancer cells
- Example 7 Evaluation of cell viability (hypoxic environment-responsive doxorubicin) Human pancreatic cancer cells (MIA PaCa-2, obtained from Riken Cell Bank) MIA PaCa-2 was seeded at a density of 5000 cells / well and cultured in Dulbecco's modified Eagle medium (DMEM) for 24 hours, and then compound 7 was added at the specified concentration. The cells were cultured for 6 hours at normal oxygen concentration (20%) and low oxygen concentration (0.1%). After culturing, the DMEM medium was changed, the compound was removed, and the cells were cultured in an incubator with a normal oxygen concentration for 48 hours, and then the cell viability was analyzed by WST assay. The results are shown in FIG. From the figure, it can be seen that Compound 7 significantly reduces the survival rate of human pancreatic cancer cells under a lower oxygen concentration than under a normal oxygen concentration.
- DMEM Dulbecco's modified Eagle medium
- Example 8 Synthesis of hypoxic environment-responsive gemcitabine prodrug Trimethylchlorosilane (47 ⁇ L) was added to gemcitabine (22 mg) dissolved in pyridine (1 mL), and the mixture was stirred at 0 ° C. for 2 hours. Then, the compound 6 dissolved in acetonitrile (1 mL) was added and stirred at 45 ° C. for 12 hours. After the reaction, ethanol (1 mL) was added and stirred at 45 ° C. for 30 minutes, water (1 mL) was added and stirred at 45 ° C. for 30 minutes. Solvent was removed by evaporation and purified by reverse phase HPLC column (GL Sciences Inc.
- Example 9 Evaluation of cell viability (hypoxic environment-responsive gemcitabine) Human pancreatic cancer cells (MIA PaCa-2, obtained from Riken Cell Bank) MIA PaCa-2 is seeded at a concentration of 5000 cells / well and cultured in DMEM medium for 24 hours, and then compound 9 is added at the specified concentration for 1 hour in normal oxygen The culture was performed at a concentration (20%) and a low oxygen concentration (0.1%). After the culture, the medium was changed to remove the compound 9, and cultured for 48 hours in a normal oxygen concentration incubator. Then, the cell viability was analyzed by WST assay. The results are shown in FIG.
- Example 10 Synthesis of hypoxic environmentally responsive fluorouracil prodrug Thionyl chloride (500 ⁇ L) was added to compound 2 (30 mg) dissolved in methylene chloride (1 mL) and reacted at 60 ° C. for 2 hours. After the reaction, the solvent was removed by evaporation. The product (Compound 10) was dissolved in methylene chloride (1 mL), 5-FU (21 mg) dissolved in pyridine (1 mL) was added, and the mixture was reacted at 0 ° C. for 30 minutes and then at room temperature for 12 hours. After the reaction, the solvent was removed by evaporation, and a reverse phase HPLC column (GL Sciences Inc.
- Example 11 Evaluation of cell viability (hypoxic environment-responsive 5-fluorouracil) Human pancreatic cancer cells (MIA PaCa-2, obtained from Riken Cell Bank) MIA PaCa-2 was seeded at a concentration of 5000 cells / well, cultured for 24 hours in DMEM medium, and then a mixture of compounds 11 and 12 was added at the specified concentration. The cells were cultured at a normal oxygen concentration (20%) and a low oxygen concentration (0.1%) for 24 hours. After culturing, the medium was changed, the compound was removed, and the cells were cultured in an incubator with a normal oxygen concentration for 48 hours, and then cell viability was analyzed by WST assay. The results are shown in FIG.
- Example 14 Synthesis of a hypoxic environment-responsive methotrexate prodrug Compound 10 (0.11 mmol) synthesized in the same manner as in Example 10 was dissolved in methylene chloride (1 mL), methotrexate (50 mg) dissolved in pyridine (1 mL) was added, and the mixture was reacted at 0 ° C. for 30 minutes. The reaction was performed for 24 hours. After the reaction, the solvent was removed by evaporation, and a reverse phase HPLC column (GL Sciences Inc.
- Example 15 Synthesis of a hypoxic environment-responsive prednisolone prodrug Compound 10 (0.16 mmol) synthesized in the same manner as in Example 10 was dissolved in methylene chloride (1 mL), prednisolone (84 mg) dissolved in pyridine (1 mL) was added and reacted at 0 ° C. for 30 minutes, and then at room temperature. The reaction was performed for 24 hours. After the reaction, the solvent was removed by evaporation, liquid separation was performed with saturated saline and chloroform, the organic layer was treated with sodium sulfate, concentrated using an evaporator, and purified by silica gel chromatography to obtain Compound 13. Yield 42% ESI-MS (M + H + ) Theoretical value: 528.23, measured value: 527.93
- Example 16 Release of drug from prednisolone prodrug in hypoxic environment
- Human pancreatic cancer cells (MIA PaCa-2, obtained from Riken Cell Bank) were adjusted so that the number of cells was 1 ⁇ 10 4 cells / mL. And 96-well plates. After 24 hours, Compound 13 was added at a concentration of 10 ⁇ M, and cultured in a normal oxygen concentration incubator (20% O 2 ) and a low oxygen workstation (0.1% O 2 ), respectively. After 1 hour, the medium was collected, and further trypsin was added to collect cells.
- the present invention it is possible to provide a prodrug that exhibits the original activity of the parent compound in a hypoxic environment while the side effects of the parent compound are reduced in a normoxic environment.
- the present invention can be used, for example, in the pharmaceutical industry to provide therapeutically active organic compounds with reduced toxicity.
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Abstract
Description
意外にも、当該カルボニル基を介して形成されたアミド結合、イミド結合またはエステル結合は還元環境下、特に、生体内の低酸素部位において開裂することを本発明者等は見出した。
このような開裂は、理論に拘束されるものではないが、還元環境下でイミダゾール環上のニトロ基がヒドロキシアミンまたはアミノ基に変換され、当該アミノ基が分子内で求核攻撃を行う次の反応スキームに従う分子内環化反応を伴って起こるものと理解できる。
したがって、本発明は、広く、2-ニトロ-1-イミダゾールプロピオン酸を、多種多様な薬物、特に、治療的活性有機化合物のプロドラッグを提供するために使用できることを見出したことに基づく。
本発明の一態様としては、一般式(I)
-O-R3 (b)を表し、
式中、R1は、アミノ基を持つ治療的活性有機化合物から当該アミノ基を除去した残基であり、かつ、R2が水素原子であるか、または、
R1とR2が隣接するN原子と一緒になって、環状アミノ基を持つ治療的活性有機化合物の残基を表す、
R3は、ヒドロキシル基を持つ治療的活性有機化合物から当該ヒドロキシ基を除去した残基である。
分子中にアミノ基、環状アミノ基またはヒドロキシル基を分子中に持つ治療的活性有機化合物のプロドラッグを製造するための反応体としての式(II)で表される化合物の使用、
についても提供される。
このような一般式(I)の化合物は、2-ニトロ-1-イミダゾールプロピオニル(以下、Izpと略称することがある。)が治療的活性有機化合物に結合していることにより、当該有機化合物が本来持っている生物活性(例えば、細胞毒性、その他の活性)を低下またはマスクする一方で、還元環境下、特に、哺乳動物の低酸素部位でIzp部分とZに相当する部分が選択的に開裂する。かような開裂によりもたらされる当該有機化合物はそれら本来の活性を低酸素部位またはその周辺で示すようになる。
したがって、一般式(I)で表される化合物は、それに含まれる治療的有機化合物を哺乳動物の特定部位で放出できるので、より安全かつ、効果的に使用できる。
こうして、「プロドラッグ」とは、それ自体当該技術分野で用いられている意味を有し、例えば、生理活性物質または治療的活性有機化合物を化学的に修飾し、生体内で酵素的またはその他の条件下で親化合物を遊離もしくは放出するように設計された化合物を意味する。
「コンジュゲート」とは、2種以上の異なる化合物が共有結合して形成された結合体を意味し、プロドラッグを包合する概念として用いている。
「治療的活性有機化合物」は、哺乳動物、特にヒトの疾患、障害、等を治療または予防する活性を持つ有機化合物を意味する。かような疾患、障害としては、腫瘍、特に悪性腫瘍、及び炎症であって、これらの病巣またはその周辺領域が正常な組織または細胞領域に比べて低酸素状態を伴うものを挙げることができる。
「抗腫瘍剤または物質」及び「抗癌剤」は互換可能な用語として使用している。
アミノ基を持つ治療的活性有機化合物の代表的な化合物としては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジンを挙げることができ、
環状アミノ基を持つ治療的活性有機化合物の代表的な化合物としては、ビンクリスチン、ビンブラスチン、ビンデシン、5-フルオロウラシル、6-メルカプトプリンを挙げることができ、
ヒドロキシル基を持つ治療的活性有機化合物の代表的な化合物としては、がドセタキセル、パクリタキセル、ビンクリスチン、ビンブラスチン、ビンデシン、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、カペシタビン、ドキシフルリジン、エポチロン、ピロキシカム、メロキシカム、テノキシカム、コルチゾン、ヒドロコルチゾン、コルチゾン酢酸エステル、プレドニゾロン、メチルプレドニゾロン、ベタメタゾン、デキサメタゾン、トリアムシノロン、トリアムシノロンアセトニドを挙げることができる。
これらのうち、治療的活性有機化合物の好ましいものとしては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、カンプトセシン、トポテカン、イリノテカン、ドセタキセル、パクリタキセル、ビノレルビン、ビンクリスチン、ビンブラスチン、ビンデシン、ゲムシタビン、シタラビン、5-フルオロウラシル、カペシタビン、ドキシフルリジン、フルダラビン、6-メルカプトプリン、6-チオグアニン、エポチロン、ピロキシカム、メルファラン、メトトレキサート、ペメトレキセド、メサラジン、プレドニゾロン、メチルプレドニゾロン、デキサメタゾン、ベタメタゾンを挙げることができ、より好ましいものとしては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジン、ビンクリスチン、ビンブラスチン、ビンデシン、5-フルオロウラシル及び6-メルカプトプリン、プレドニゾロンを挙げることができる。
ESI-MS(M+H+)理論値:325.130,実測値:325.126
50mLのナスフラスコに撹拌子と化合物5(10mg)を加えた。スターラーで撹拌しながら反応容器にメタノール10mL,Pd/C 50mgを入れ、水素ガスを充填させた。水素ガスを充填させたまま24時間間撹拌し、反応後TLC(展開溶媒 酢酸エチル:ヘキサン=1:1)によって反応の進行を確認した。次にセライト濾過によってPd/Cを除去し、最後にエバポレーターによってメタノールを除去した。エレクトロスプレーイオン化質量分析により解析したところ、化合物4の生成を示す結果が得られた。すなわち、分子内環化反応を伴いアミド結合が開裂し、ナフチルメチルアミンを放出することがわかる。
化合物4の分子量理論値:138.067、実測値:138.063
この例は、化合物5が低酸素環境下の細胞で還元され、その後の分子内環化反応によりナフチルメチルアミンを放出することを確認するために行った。
ヒト膵臓がん細胞(MIA PaCa-2、理研セルバンクより入手)を細胞数が1×104cell/mLになるように調整し、96wellプレートに播種した。24時間後、化合物5を10μMの濃度で加え、通常酸素濃度インキュベーター(20%O2)と低酸素ワークステーション(0.1%O2)でそれぞれ培養した。時間経過後培地を回収し、更にトリプシンを加え細胞を回収した。回収した細胞を超音波処理により粉砕し、アセトニトリルで化合物を抽出して下記条件によりLC/MSにより解析を行った。
使用カラム : Lachrom Urtra C18(粒子径2um,2mm×50mm)カラム
測定波長 : 220nm
溶離液A :0.1%TFA含有milliQ
溶離液B :アセトニトリル
流速 :0.2mL/min
グラジエント
95:5(溶離液A:溶離液B)→95:5(5分)→30:70(15分)
この測定を行うことで低酸素環境と正常酸素環境での放出量の差を比較した。HPLCの結果を図3に示す。図より、低酸素環境下で多くのナフチルメチルアミンが放出されていることがわかる。
例2と同様に合成した化合物2(60mg)に1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(80.8mg)加え、N-ヒドロキシコハク酸イミド(48mg)を加えN,N-ジメチルホルムアミド(1mL)中、氷冷下で1時間反応させその後室温で3時間反応させた。反応後、氷冷下で酢酸を数滴滴下し30分撹拌した。酢酸エチルと飽和食塩水で分液を行い、有機層をエバポレーションにより濃縮し、2-プロパノールを加えて加熱し不純物を濾別し、濾液を氷冷することにより化合物6を得た(50mg)。
ESI-MS(M+H+)理論値:283.068,実測値:283.079
ドキソルビシン(3mg)に化合物6(2.2mg)をN,N-ジメチルホルムアミド(50μL)と水(50μL)の混合溶媒中で加え、トリエチルアミン(1.4μL)を加え24時間室温において反応させた。反応後、逆相HPLCカラム(GL Sciences Inc.Inertsil ODS-3 20X50mm、流速 5ml/min、展開液:メタノール/水=60/40(0min)~100/0(20min)により精製した。
ESI-MS(M+Na+)理論値:733.1967,実測値:733.2013
こうして、上記反応スキームに記載の化合物7が得られた。
ヒト膵臓がん細胞(MIA PaCa-2、理研セルバンクより入手)MIA PaCa-2を5000cells/wellの濃度で撒きダルベッコ改変イーグル培地(DMEM)中で24時間培養した後に化合物7を指定濃度で加え、6時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後DMEM培地交換を行い、化合物を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図4に示す。
図より、化合物7は、通常酸素濃度下に比べて低酸素濃度下で、ヒト膵臓がん細胞の生存率を有意に低下させることがわかる。
WO2009/018163 A1に記載されている下記化合物8を用意し、その化合物と本発明の範囲内の化合物(対応するリンカーが-CH2CH2C(=O)-であること以外、ニトロイミダゾール及び薬剤との結合様式は同じ。実施例6の化合物7)について実施例7に記載の方法に従って試験したときの細胞生存率を比較した。結果を図5に示す。
こうして精製し化合物9を得た。収率 20%
ESI-MS [M+H]+:理論値:431.11、実測値:431.20)
ヒト膵臓がん細胞(MIA PaCa-2、理研セルバンクより入手)MIA PaCa-2を5000cells/wellの濃度で撒きDMEM培地中で24時間培養した後に、化合物9を指定濃度で加え、1時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後培地交換を行い、化合物9を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図6に示す。
ESI-MS[M-H]-:理論値296.1、実測値296.1)
ヒト膵臓がん細胞(MIA PaCa-2、理研セルバンクより入手)MIA PaCa-2を5000cells/wellの濃度で撒き、DMEM培地中で24時間培養した後に、化合物11および12の混合物を指定濃度で加え、24時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後培地交換を行い、化合物を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図7に示す。
ESI-MS[M-H]-:理論値319.07、実測値 318.78
ESI-MS[M-H]-:理論値470.10、実測値469.63
MALDI-TOF MS[M-H]-:理論値620.19、実測値620.38
ESI-MS(M+H+)理論値:528.23,実測値:527.93
ヒト膵臓がん細胞(MIA PaCa-2、理研セルバンクより入手)を細胞数が1×104cell/mLになるように調整し、96wellプレートに播種した。24時間後、化合物13を10μMの濃度で加え、通常酸素濃度インキュベーター(20%O2)と低酸素ワークステーション(0.1%O2)でそれぞれ培養した。1時間後培地を回収し、更にトリプシンを加え細胞を回収した。回収した細胞を超音波処理により粉砕し、アセトニトリルで化合物を抽出して下記条件によりLC/MSによりプレドニゾロンの放出量解析を行った。
使用カラム : TSKgel ODS-100Z(粒子径3um,2mm×75mm)カラム
測定波長 : 250nm
溶離液A :0.1M酢酸アンモニウム
溶離液B :アセトニトリル
流速 :0.2mL/min
グラジエント
40:60(溶離液A:溶離液B)~10:90 (20分)
この測定を行うことで低酸素環境と正常酸素環境での放出量の差を比較した。HPLCの結果を図8に示す。図より、低酸素環境下で多くのプレドニゾロンが放出されていることがわかる。
Claims (10)
- 式(I)で表される化合物から還元環境下でZが開裂される、請求項1に記載の化合物。
- 還元環境下が哺乳動物の低酸素部位である、請求項2に記載の化合物。
- Zが(a)または(b)で表される、請求項1に記載の化合物。
- 治療的活性有機化合物が、アントラサイクリン系抗腫瘍物質、ペプチド系抗腫瘍抗生物質、キノリンアルカロイド系抗腫瘍物質、タキサン系抗腫瘍物質、ビンカアルカロイド系抗腫瘍物質、デオキシシチジン系抗腫瘍物質、ピリミジン系抗腫瘍物質、プリン環誘導体系抗腫瘍物質、葉酸誘導体系抗腫瘍物質、マクロライド系抗腫瘍物質、アミノ酸誘導体系抗腫瘍物質、5-アミノサリチリ酸系抗潰瘍性炎薬・クローン病治療剤、非ステロイド系抗炎症剤及びステロイド系抗炎症剤からなる群より選ばれ、かつ、
一般式(I)のZに相当する部位が還元環境下で開裂される、
請求項1に記載の化合物。 - アミノ基を持つ治療的活性有機化合物がドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジン、からなる群より選ばれ、
環状アミノ基を持つ治療的活性有機化合物の代表的な化合物としては、ビンクリスチン、ビンブラスチン、ビンデシン、5-フルオロウラシル、6-メルカプトプリンを挙げることができ、
ヒドロキシル基を持つ治療的活性有機化合物がドセタキセル、パクリタキセル、ビンクリスチン、ビンブラスチン、ビンデシン、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、カペシタビン、ドキシフルリジン、エポチロン、ピロキシカム、メロキシカム、テノキシカム、コルチゾン、ヒドロコルチゾン、コルチゾン酢酸エステル、プレドニゾロン、メチルプレドニゾロン、ベタメタゾン、デキサメタゾン、トリアムシノロン及びトリアムシノロンアセトニドからなる群より選ばれ、かつ
一般式(I)のZに相当する部位が還元環境下で開裂される、
請求項1に記載の化合物。 - 治療的活性有機化合物がドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、カンプトセシン、トポテカン、イリノテカン、ドセタキセル、パクリタキセル、ビノレルビン、ビンクリスチン、ビンブラスチン、ビンデシン、ゲムシタビン、シタラビン、5-フルオロウラシル、カペシタビン、ドキシフルリジン、フルダラビン、6-メルカプトプリン、6-チオグアニン、エポチロン、ピロキシカム、メルファラン、メトトレキサート、ペメトレキセド、メサラジン、プレドニゾロン、メチルプレドニゾロン、デキサメタゾン及びベタメタゾンからなる群より選ばれる、請求項1に記載の化合物。
- 一般式(I)のZに相当する部位がドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジン、ビンクリスチン、ビンブラスチン、ビンデシン、5-フルオロウラシル、6-メルカプトプリン及びプレドニゾロンからなる群より選ばれる治療的活性有機化合物に由来する、請求項1に記載の化合物。
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JP2016017059A (ja) * | 2014-07-10 | 2016-02-01 | 国立大学法人 筑波大学 | 抗腫瘍性プロドラッグを含む組成物 |
WO2023120331A1 (ja) * | 2021-12-21 | 2023-06-29 | 国立大学法人筑波大学 | 抗がん薬の低酸素応答性プロドラッグと放射線治療の併用療法、並びに新規低酸素応答性プロドラッグ |
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JP2016017059A (ja) * | 2014-07-10 | 2016-02-01 | 国立大学法人 筑波大学 | 抗腫瘍性プロドラッグを含む組成物 |
WO2023120331A1 (ja) * | 2021-12-21 | 2023-06-29 | 国立大学法人筑波大学 | 抗がん薬の低酸素応答性プロドラッグと放射線治療の併用療法、並びに新規低酸素応答性プロドラッグ |
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