WO2017067497A2 - Dérivé d'hypocrelline amphiphile monosubstitué ou polysubstitué, son procédé de préparation et ses utilisations - Google Patents

Dérivé d'hypocrelline amphiphile monosubstitué ou polysubstitué, son procédé de préparation et ses utilisations Download PDF

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WO2017067497A2
WO2017067497A2 PCT/CN2016/102832 CN2016102832W WO2017067497A2 WO 2017067497 A2 WO2017067497 A2 WO 2017067497A2 CN 2016102832 W CN2016102832 W CN 2016102832W WO 2017067497 A2 WO2017067497 A2 WO 2017067497A2
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group
formula
carbon atoms
derivative
substituted
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PCT/CN2016/102832
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WO2017067497A3 (fr
WO2017067497A9 (fr
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汪鹏飞
吴加胜
刘卫敏
顾瑛
葛介超
郑秀丽
张洪艳
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中国科学院理化技术研究所
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Priority claimed from CN201510689088.7A external-priority patent/CN105541647A/zh
Priority claimed from CN201610894400.0A external-priority patent/CN107935943B/zh
Priority claimed from CN201610894129.0A external-priority patent/CN107935964B/zh
Application filed by 中国科学院理化技术研究所 filed Critical 中国科学院理化技术研究所
Priority to JP2018521084A priority Critical patent/JP2018536643A/ja
Priority to US15/769,789 priority patent/US11154548B2/en
Priority to EP16856928.3A priority patent/EP3366669A4/fr
Priority to CA3002695A priority patent/CA3002695C/fr
Publication of WO2017067497A2 publication Critical patent/WO2017067497A2/fr
Publication of WO2017067497A3 publication Critical patent/WO2017067497A3/fr
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  • the invention relates to the field of photosensitizer medicines for photodynamic therapy. More specifically, it relates to a mono- or poly-substituted ester water amphiphilic rhodamine derivative and a preparation method and application thereof.
  • Photodynamic Therapy is a new selective treatment for vascular lesions that has developed rapidly in recent years. It has also a significant effect on various tumor diseases. Photodynamic therapy has become the fourth special type of cancer treatment after surgery, radiotherapy and chemotherapy. Its advantage lies in its high efficiency and safety. It can continuously produce reactive oxygen species under light irradiation, leading to diseased cells and tissues. The damage or necrosis is significantly more efficient than traditional drugs that can only kill a single target molecule. Photodynamic therapy has two-way selectivity for drug targeting and illumination localization, which reduces damage to normal cells, thus ensuring the safety of treatment.
  • PDT has not only achieved great achievements in the clinical treatment of cancer, but also used in the treatment of non-tumor diseases such as various vascular diseases, condyloma acuminata, psoriasis, port wine stains, rheumatoid arthritis, and fundus macular degeneration.
  • non-tumor diseases such as various vascular diseases, condyloma acuminata, psoriasis, port wine stains, rheumatoid arthritis, and fundus macular degeneration.
  • photodynamic therapy also has a remarkable effect on laser beauty and the like.
  • Photosensitizers are a key factor affecting the efficacy of photodynamic therapy.
  • the first generation of photosensitizers for clinical use are porphyrin-based photosensitizers, and the second generation is phthalocyanine-based photosensitizers.
  • these photosensitizing drugs the most prominent problem of porphyrin-based photosensitizers and phthalocyanine-based photosensitizers is that the separation of geometric isomers is difficult, and it is difficult to obtain a one-component pure compound; and its relatively complicated components are also disadvantageous for later stages. Evaluation of drug metabolism and toxicological analysis.
  • photosensitizing drugs such as chlorin, chlorophyll, and terpenoids are also in the research and development stage. At present, the photosensitizing drugs required for clinical use in China are still very scarce, and new high-efficiency photosensitizing drugs are urgently needed to fill the gaps.
  • hypocretin is a natural photosensitizer extracted from a parasitic fungus, Rhodobacter sphaeroides, which is 4,000 meters above sea level on the Yunnan Plateau.
  • the natural hypocretin mainly includes Hypocrellin A (HA) and Hypocrellin B (HB).
  • hypocrellin which has the basic conditions for becoming a photosensitive drug with superior performance, such as strong absorption in the visible light region and large molar extinction coefficient, which can efficiently produce single weight under photosensitive conditions.
  • Oxygen it is a botanical drug, which has good phototoxicity, low dark toxicity, fast metabolism in the body, and clear chemical structure, so it has broad application prospects (Xu Shangjie, Zhang Xiaoxing, Chen Shen, etc., new photodynamic drug - hypocrellin derivative Research and Progress in Materials, Science Bulletin, 2003, 48, 1005-1015).
  • hypocrellin is in the range of 450-550 nm, and this wavelength can penetrate less than 1 mm, and the ability to absorb light in the photodynamic therapy window (600-900 nm) is weak.
  • the ammonia-modified erythromycin has a significant red shift in absorption wavelength to 600-700 nm, and the molar extinction coefficient is significantly increased (Paul B., Babu MS, Santhoshkumar TR, et al. Biophysical evaluation of two red-shifted hypocrellin B derivatives as novel PDT agents, J. Photochem. Photobiol. B: 2009, 94, 38-44).
  • Amino-modified erythromycin has been shown to have better photosensitizing properties, however the water solubility and biocompatibility of such photosensitizers require further improvement.
  • the target of microvascular disease is a heterogeneous dense microvascular network in the focal area, which is sensitive to photodynamic effects; in photodynamic therapy, the drug is usually delivered to the diseased tissue through the blood circulation system by intravenous injection.
  • hypocretin is a kind of lipophilic organic small molecule, its solubility in water is very low, and direct intravenous injection will spontaneously accumulate in the blood and cause blood vessel blockage.
  • Sulfonic acid substituted derivatives Liu X, Xie J, Zhang L Y, et al.
  • the present invention provides a technical solution of the present invention in view of the problem that the existing erythromycin derivative not only satisfies both the light absorbing conditions but also the optimized lipophilic amphiphilicity.
  • Applicants have proposed to modify the rhodamine with a group such as polyethylene glycol or a long-chain quaternary ammonium salt or a group such as polyethylene glycol and a long-chain quaternary ammonium salt to enhance biocompatibility and regulate the erythromycin.
  • the parent is hydrophobic and hydrophobic.
  • Such derivatives have different lipid-water amphiphilic properties and are not susceptible to pH changes.
  • a mono- or poly-substituted ester water amphiphilic erythromycin derivative having the structural formula of formula (I) or formula (II):
  • R is a substituent which is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group;
  • the hydrophobic group contains an alkyl group, an alkenyl group, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocyclic;
  • the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a polyethylene glycol a quaternary or quaternary ammonium salt;
  • the structural formula of the substituent R is as shown in formula (III):
  • the linking group Y in the formula (III) is NH, O, S, a carboxylate, an amide, a sulfocarboxylate, an aryl group, a heterocyclic aryl group, a hydrocarbon group of 3 to 12 carbon atoms or a cyclic hydrocarbon group of 3 to 12 carbon atoms. ;
  • the aryl group is a substituted or unsubstituted aryl group; the heterocyclic aryl group is a substituted or unsubstituted heterocyclic aryl group; the hydrocarbon group of 3 to 12 carbon atoms contains a substituted or unsubstituted or hetero atom-containing olefin or alkyne;
  • the cycloalkyl group of 3 to 12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing cycloalkane, cycloalkene or cycloalkyne;
  • the hetero atom is an oxygen, nitrogen or sulfur atom;
  • the substituent is 1 to 12 carbon atoms Alkyl, 2-12
  • the terminal group Z in the formula (III) is hydrogen, an alkyl group of 1 to 12 carbon atoms, an alkoxy group of 1 to 12 carbon atoms, a phenyl group, a heterocyclic ring, a hydroxyl group, a decyl group, a carboxylic acid group, a sulfonic acid group or a pyridine group. salt;
  • the terminal group Z in the formula (III) is a pyridinium salt
  • the substituent on the pyridine ring in the pyridinium salt is in the ortho, meta or para position;
  • the pyridinium salt is composed of pyridine and a chain length of 1-12
  • the anion in the pyridinium salt is an anion permitted by the pharmaceutical preparation;
  • the three substituents R 12 , R 13 and R 14 are independently or simultaneously: an alkyl group of 1 to 12 carbon atoms, an alkenyl group of 2 to 12 carbon atoms, 2 to 12 carbons.
  • An alkyl group of a sulfonic acid group or a carboxylic acid ester or an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group having a chain length of 1 to 12 carbon atoms containing a hetero atom of oxygen, nitrogen or a sulfur atom; ; or a combination of these different substituents; quaternary ammonium salt of the anion X - is the anion of a pharmaceutical formulation allowed;
  • R 2 and R 3 or R 4 and R 5 are not linked and R 2 and R 5 are oxygen, R 3 and R 4 are hydrogen, R 1 is —COCH 3 and a double bond.
  • R 1 is —COCH 3 and a double bond.
  • the substituent R in the formula (I) does not comprise the following structure: -(CH 2 ) m -NH-(CH 2 ) p -Z; wherein 1 ⁇ m ⁇ 12, 0 ⁇ p ⁇ 12, Z is a hydroxyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester.
  • R 6 to R 11 on the hypocrellin and piperazine ring in the formula (II) are each subordinate to the substituent R; the substituent R is a hydrophobic group, a hydrophilic group or a hydrophobic group and a hydrophilic group.
  • the hydrophobic group containing an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic group; the hydrophilic group having a hydroxyl group or a carboxyl group , an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycolated group, a quaternary ammonium salt or a pyridinium salt; the structural formula of the substituent R is as shown in the formula (III);
  • the T1 of the hypocrellin derivative of the formula (I) is acyclically linked, and its structural formula is as shown in the formula (IV):
  • the structural formula of the substituent R in the formula (IV) is represented by the formula (III), and the substituent R is a hydrophobic group, a hydrophilic group or a sparse Different combinations of water groups and hydrophilic groups; the hydrophobic groups containing an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic group; a group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycol group or a quaternary ammonium salt;
  • the substituent R does not comprise the following structure: -(CH 2 ) m -NH-(CH 2 ) p -Z; wherein 1 ⁇ m ⁇ 12, 0 ⁇ p ⁇ 12, Z is a hydroxyl group, an alkoxy group, a carboxy group Acid or carboxylic acid ester.
  • both T1 and T2 are acyclic, and the structural formula is as shown in the formula (V):
  • the substituents R 6 to R 11 in the formula (V) are all defined by the substituent R in the formula (III), and the substituents R 6 to R 11 are partially or wholly the same or completely different;
  • the substituent R 6 ⁇ R 11 is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group;
  • the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or a heterocyclic ring;
  • the group contains a hydroxyl group, a carboxyl group, an ester group, an ether group, an amide group, a sulfonic acid group, an ethylene glycol unit or a quaternary ammonium salt.
  • T1 in the formula (I) and formula (II) is a substituted or unsubstituted linker containing two carbon atoms, the structure of which is represented by the formula (VI): wherein the substituents R 15 to R 18 Separately or simultaneously as an R substituent in the formula (III) of claim 1; preferably, R 8 , R 9 , T2 in the formula (II) constitute a substituted or unsubstituted five-membered ring, a six-membered ring or When the seven-membered ring is as shown in formula (VII):
  • ring A is a saturated or unsaturated five-, six- or seven-membered heterocyclic or non-heterocyclic ring, the substituents on the ring being independently or simultaneously the R substituent in formula (III) of claim 1;
  • R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group;
  • the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic ring;
  • the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycol group or a quaternary ammonium salt;
  • the terminal group Z in the substituent R in the formula (III) is: -H; -CH 3 ; -C 2 H 5 ; -C 3 H 7 ; -C 4 H 9 ; -C 5 H 11 ;-C 6 H 13 ; -OCH 3 ; -OC 2 H 5 ; -OC 3 H 7 ; -OC 4 H 9 ; -OC 5 H 11 ; -OC 6 H 13 ; -C 5 H 4 N; -OH, -NH 2 ; -SH; -COOH; -COOCH 3 ; -COOC 2 H 5 ; -SO 3 H; -C 5 H 4 N + ; -N + (CH 3 ) 3 ;- N + (C 2 H 5 ) 3 ; -N + (C 3 H 7 ) 3 ; -N + (C 4 H 9 ) 3 ; -N + (C 5 H 11 ) 3 ; -N + (C 5 H 11 ) 3 ;
  • the substituent R is: -H; -CH 3 ; -C 2 H 5 ; -C 3 H 7 ; -C 4 H 9 ; -C 5 H 11 ; -C 6 H 13 ; -C 3 H 6 ;-C 5 H 9 (cyclopentyl); -C 6 H 11 (cyclohexyl); -C 6 H 10 (CH 3 ) (methylcyclohexyl); -C 6 H 10 (C 2 H 5 (Ethylcyclohexyl); -C 6 H 10 (C 3 H 7 )(propylcyclohexyl); -C 6 H 10 (C 4 H 9 )(butylcyclohexyl); -C 6 H 9 (CH 3 ) 2 (dimethylcyclohexyl); -C 6 H 10 (OH) (hydroxycyclohexyl); -C 7 H 12 -(cycloheptyl); -C 6 H 5 ;-CH 2 C 6
  • the structural formula of the hypocrellin derivative of the formula (I) further comprises an enol tautomer represented by the formula (I'); and the hypocrellin derivative of the formula (II)
  • the structural formula further comprises an enol tautomer represented by formula (II'):
  • hypocrellin and the corresponding substituted amino derivative are dissolved in an organic solvent, and the reaction is carried out in the dark under the protection of an inert gas, and finally, the ester water amphiphilic heparin derivative is obtained by separation and purification.
  • the hypocrellin is hypocrellin HB and deacetyl erythromycin HC; the substituent of the substituted amine derivative has the structural formula of formula (III); the hypocrellin and The molar ratio of the substituted amino derivative is from 1:5 to 1:50, specifically 1:5, 1:10, 1:15, 1:20, 1:30, 1:40 or 1:50; the temperature of the reaction is 20-100 ° C; the reaction time is 6-18 hours.
  • the organic solvent is acetonitrile, tetrahydrofuran, pyridine, N,N-dimethylformamide, methanol, ethanol; the reaction is carried out under an inert gas such as argon or nitrogen, and is protected from light.
  • the organic solvent is one of acetonitrile, tetrahydrofuran or pyridine; the molar ratio of the hypocrellin to the substituted amine derivative is 1:20; the reaction temperature is 60 ° C; the reaction time is 8 hour.
  • the separation and purification process is: removing the reaction organic solvent to obtain a residue, dissolving the residue in dichloromethane; washing with dilute aqueous hydrochloric acid and water in sequence; then drying the organic layer, filtering, and removing the solvent to obtain a crude product The crude product was chromatographed on a silica gel plate to obtain a hyalin derivative containing a long-chain quaternary ammonium salt.
  • the developing agent used in the chromatography of the silica gel plate is a mixture containing acetone, ethyl acetate, ethanol and diethylamine, and the volume ratio of acetone, ethyl acetate, ethanol and diethylamine in the mixed solution is 20 : 1:1:1 to 20:1:3:1.
  • the separation and purification process is: removing the reaction organic solvent, obtaining a blue-black solid residue dissolved in dichloromethane, washing three times with an equal volume of dilute aqueous hydrochloric acid solution (5%), washing once, and the organic layer is anhydrous. Dry over magnesium sulfate, filter and remove the solvent to give a crude material.
  • the crude product obtained is further separated by silica gel chromatography.
  • the developing solvent is acetone:ethyl acetate:ethanol:diethylamine, preferably in a volume ratio of 20:1:1:1, to obtain an amino-substituted hypocrellin derivative.
  • the yield was 5-20% and the product was a blue-black solid.
  • hypocrellin B or deacetyl erythromycin and the corresponding substituted mercaptoethylamine derivative in a molar ratio of 1:50 to 1:500 in a mixed solvent of an organic solvent and water at a pH of more than 9
  • the light is irradiated at room temperature for 10-40 minutes, the illumination wavelength is greater than 450 nm, and the product is isolated and purified to obtain the 4,5-position substitution, the 8 and 9-position substitution or the simultaneous substitution of the same.
  • Rhodobacter sphaeroides derivative and the corresponding substituted amino derivative having a molar ratio of 1:5 to 50 are mixed in an organic solvent, and the reaction is carried out under the protection of an inert gas for 4 to 20 hours, and the reaction temperature is 20- At 150 ° C, the product is isolated and purified to obtain the corresponding multi-substituted hypocrellin derivative of formula (VI) or formula (VII).
  • the organic solvent is one or more of a starting material substituted with an amino derivative, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, pyridine, methanol or ethanol.
  • a mono- or poly-substituted ester water amphiphilic erythromycin derivative for use as a photosensitizer drug in photodynamic therapy.
  • Figure 1 is a structural formula of a monosubstituted or polysubstituted amphiphilic hyalin designed according to the present invention.
  • 2 to 6 show a method for synthesizing various types of hypocrellin derivatives according to the present invention.
  • the ester water amphiphilic erythromycin derivative synthesized in the present invention contains a lipophilic, hydrophilic, and amphiphilic erythromycin derivative.
  • the hypocrellin derivative containing a group such as a polyethylene glycol or a quaternary ammonium salt has a very broad absorption in a phototherapy window, and the maximum absorption spectrum wavelength is about 600-630 nm, and the maximum is 650 nm.
  • the maximum absorption peak (450nm) of the base of the erythromycin is more than 150nm red, and the molar extinction coefficient is about 10000-40000M -1 cm -1 , which shows a strong red light absorption capacity (as shown in Figure 7);
  • the water solubility is good, and the stock solution in the range of 0.1 uM to 1 mM can be disposed in the physiological saline.
  • Its ability to produce reactive oxygen is shown in Figure 8.
  • ester water amphiphilic heparin derivatives can efficiently produce photosensitivity as measured by singlet oxygen and superoxygen radical scavengers, respectively.
  • Species, mainly producing singlet oxygen mainly producing singlet oxygen (Fig.
  • the HB-1 and HeLa cells were incubated together, as shown in Figure 10 (a), and the cytotoxic (dark toxicity) study showed that the ethylene glycol-containing erythromycin derivative HB-1 synthesized in Example 3
  • the cytotoxicity was similar, and similar to the erythromycin B HB and the commercial photosensitizer hematoporphyrin HpD, Hela cells were incubated with the photosensitizer HB-1 at a concentration of 10 uM for half an hour, and no obvious death of Hela cells was observed.
  • Such photosensitizers are substantially devoid of cytotoxicity.
  • FIG. 10(b) showed that HB-1 showed very strong lethality against Hela cells under red light irradiation. More than 90% of Hela cells can be killed in the concentration range of 160nM, and under the same conditions, the hypocrellin or the commercial photosensitizer hematoporphyrin derivative can kill only about 20% of Hela cells, indicating that such amphiphilic bamboo
  • the photodynamic effect of the curcumin derivative is significantly better than that of the erythromycin B and the commercial photosensitizer hematoporphyrin HpD.
  • Figure 11 shows similar results for the cell dark toxicity and phototoxicity experiments of the ethylene glycol-containing erythromycin derivative HB-2 synthesized in Example 3. Further, FIG.
  • FIG. 12 shows a phototoxic effect diagram of the aminopropanol-modified deacetylcerhosin HC-3 or HC-4 tumor-killing cells synthesized in Example 4;
  • FIG. 13 shows Example 46. Phototoxic effect diagram of synthetic long-chain quaternary ammonium salt-modified deacetylcerhosin HC-87 or HC-88 tumor-killing cells;
  • Figure 14 shows the piperazine erythromycin synthesized in Example 52 Phototoxicity effect of B-HB-98 tumor-killing cells; all the above phototoxicity experiments show that the photodynamic effects of such amphiphilic derivatives are significantly better than that of Hypocrellin B and commercial photosensitizers. Hematoporphyrin HpD.
  • the multi-substituted NIR hypocrellin derivative of the invention has a very broad strong absorption in a phototherapy window (600-900 nm), and its maximum absorption spectrum wavelength is red-shifted to over 700 nm, can be extended to 900 nm, and the molar extinction coefficient is about 10000-40000M -1 cm -1 or so, showing a strong near-infrared red light absorption capacity, the synthesis method is shown in Figure 6.
  • Such multi-substituted near-infrared erythromycin derivatives can efficiently produce photosensitive active species to produce singlet oxygen, as measured by singlet oxygen and superoxide radical scavengers, respectively.
  • the ester water amphiphilic rhodamine derivative of the present invention introduces a group such as ethylene glycol, quaternary ammonium salt and the like to greatly enhance the water solubility thereof, by changing the chain of the fatty chain.
  • amphiphilic derivatives of such amphiphilic compounds can be directly dissolved in physiological saline to prepare a preparation for improving the medicinal effect; and are made of natural products, which do not cause toxic and side effects, and are used for the development of hyalinins for the treatment of cancer. And laid the foundation for anti-cancer drugs.
  • the derivatives Modification of hypocrellin by a group such as a condensed ethylene glycol group or a quaternary ammonium salt with a long chain, and by adjusting the hydrophilic and hydrophobic properties of the molecule, the derivatives have different lipid-water amphiphilic properties, and at the same time The biocompatibility of cells or tissues. These compounds have a maximum absorption wavelength in the range of 600-735 nm and a molar extinction coefficient of 10,000-40000 M -1 cm -1 , which has a strong absorption capacity in the phototherapy window. Studies have shown that such derivatives can efficiently produce reactive oxygen species such as singlet oxygen under light-sensitive conditions, and have good photodynamic effects, and can be used as phototherapy drugs for treating diseases such as tumors and various microvascular diseases.
  • hypocrellin derivatives containing ethylene glycol modified there have been no studies on the preparation and extraction of hypocrellin derivatives containing ethylene glycol modified, and it has not been found that such compounds can simultaneously satisfy the light absorption conditions and also satisfy the optimized ester water amphiphilicity - That is, the concentration requirement of the intravenous injection is satisfied to ensure a high cell uptake rate.
  • hypocrellin derivatives to be protected in this patent contain two enol tautomers (such as Formulas 1 and 1 ', Formulas 2 and 2'), two isomers.
  • the chemical structure is of course within the scope of protection.
  • any range recited in the present invention includes any value between the end value and the end value, and any subrange of any value between the end value or the end value.
  • the raw material of the hypocrellin in the invention is extracted from natural products, the raw materials are easy to obtain, the cost is low, the preparation is large, the toxic and side effects are small, and the metabolism is easy; the synthesis and separation method is simple, and there is no expensive reaction raw material and complicated separation. means.
  • the prepared hypocrellin derivative substituted with a group containing a polyethylene glycol, a quaternary ammonium salt or the like has a significantly red-shifted absorption spectrum and a greatly increased molar extinction coefficient compared to the hypocrellin precursor, under photosensitive conditions It can efficiently produce active oxygen (single-density oxygen, supplemented by reactive oxygen species such as superoxide radicals); the group structure of ethylene glycol or quaternary ammonium salt can be used to adjust its hydrophilicity.
  • the properties of the derivatives have different ester water amphiphilic properties, and at the same time increase their biocompatibility with cells or tissues; such ester water amphiphilic heparin derivatives can meet the requirements of different clinical drugs, and solve There is a contradiction between different administration methods for the hydrophilicity and lipophilicity requirements of the drug.
  • the polysubstituted NIR hypoxanthine derivative prepared in the present invention has a significantly red-shifted absorption spectrum of more than 700 nm and a molar extinction coefficient as compared with the hypocrellin precursor;
  • the ester water amphiphilic rhodamine derivative photosensitizer of the present invention and the first-generation porphyrin-based photosensitizer used in clinical use have significantly improved absorption wavelength and light absorption capacity compared with the second-generation phthalocyanine-based photosensitizer. It is important that the product is easy to be separated, purified, and structurally clear, and overcomes the problem that the porphyrin and phthalocyanine photosensitizers are difficult to separate and the complicated structure is difficult to determine. More importantly, under the same conditions, the ester water amphiphilic rhodamine derivative photosensitizers of the present invention have higher photodynamic inactivation of tumor cells than the first and second generation commercial photosensitizers.
  • Figure 1 shows the structural formula of a monosubstituted or polysubstituted ester water amphiphilic erythromycin derivative designed by the present invention.
  • Fig. 2 is a view showing the synthesis reaction route of the polyethylene glycol-containing derivatives BH-1, HB-2 containing ethylene glycol in Example 3 of the present invention.
  • Fig. 3 is a view showing the synthesis reaction route of deacetylcholine HC and aminopropanol in Example 4 of the present invention.
  • Fig. 4 is a view showing the synthesis reaction scheme of the long-chain quaternary ammonium salt-containing deacetylcerhomycin derivative in Example 46 of the present invention.
  • Fig. 5 is a view showing the synthesis reaction route of the piperazine Rhodamine B derivatives HB-98 and HB-99 in Example 52 of the present invention.
  • Fig. 6 is a view showing the synthesis reaction scheme of the polysubstituted Pyrethroid B derivatives I-1 and I-2 in Example 67 of the present invention.
  • Figure 7 shows the hypocrellin B (a) extracted in Example 1 of the present invention, the ethylene glycol-containing beta derivative HB-1 (b) prepared in Example 3, and Example 52.
  • a comparison chart of the absorption spectra of the piperazine Rhodamine B derivative HB-98 (c) was prepared.
  • Figure 8 is a view showing the action of the ethylene glycol-containing hypocrellin derivative HB-1 in the third embodiment of the present invention, and the singlet oxygen scavenger (a) and the superoxide radical scavenger (b), respectively. .
  • Fig. 9 is a view showing confocal fluorescence imaging of the ethylene glycol-containing hypocrellin derivative HB-1 in Hela cells in Example 3 of the present invention.
  • Figure 10 is a graph showing the dark toxicity of different concentrations of hematoporphyrin derivative HpD, hypocrellin B, and the ethylene glycol hydantoin derivative HB-1 of Example 3 on HeLa cells ( a) and phototoxicity map (b).
  • Figure 11 is a graph showing the dark toxicity of different concentrations of hematoporphyrin derivative HpD, hypocrellin HB, and the ethylene glycol-containing hyphalin derivative HB-2 of Example 3 on HeLa cells ( a) and phototoxicity map (b).
  • Figure 12 shows different concentrations of hematoporphyrin derivative HpD, hypocrellin B, and aminopropanol synthesized in Example 4 of the present invention, modified deacetylerythromycin derivative HC-3 or HC-4 Phototoxicity map of Hela cells.
  • Figure 13 shows different concentrations of the hematoporphyrin derivative HpD, Hypocrellin HB, and the long-chain quaternary ammonium salt-modified deacetylerythromycin derivative HC-87 or HC in Example 46 of the present invention.
  • Figure 14 is a graph showing the phototoxicity of heparin derivatives HpD, Hypocrellin HB, and the piperazine-containing erythromycin derivative HB-98 of Example 52 of the present invention against HeLa cells.
  • Figure 15 (a) is a view showing the action of the erythromycin derivative I-1 and the singlet oxygen scavenger in Example 67 of the present invention; and Figure 15 (b) shows the bamboo red in Example 67 of the present invention. Diagram of the action of the bacteriocin derivative I-1 and the superoxide radical scavenger.
  • Figure 16 (a) shows the dark toxicity map of Helin cells to different concentrations of chlorin Ce6, Hypocrellin HB and the mycotoxin derivatives I-1, I-2 in Example 67 of the present invention
  • Fig. 16 (b) shows phototoxicity maps of Hera cells to different concentrations of chlorin Ce6, Hypocrellin HB and the mycophenolin derivatives I-1 and I-2 of Example 67 of the present invention.
  • Figure 17 (a) is a view showing the action of the erythromycin derivative II-2 and the singlet oxygen scavenger in Example 67 of the present invention; and Figure 17 (b) shows the bamboo red in Example 67 of the present invention. Diagram of the action of the bacteriocin derivative II-2 and the superoxide radical scavenger.
  • Figure 18 (a) shows the dark toxicity map of Hera cells to different concentrations of chlorin Ce6, Hypocrellin HB and Inventive Example 86 on Hela cells;
  • Figure 18 (b) Phototoxic diagrams showing Hela cells to different concentrations of chlorin Ce6, Hypocrellin HB, and the red pigment derivative II-2 of Example 86 of the present invention.
  • the crystal is the target product Rhodococcus A (HA) with a purity of 98% or more.
  • the high purity of the erythromycin A can be further purified by thin layer silica gel chromatography using petroleum ether: ethyl acetate: absolute ethanol (30:10:1) as a developing solvent.
  • Hypocrellin B is obtained by dehydration of A under alkaline conditions.
  • the preparation method is based on the reference book of Zhao Kaihong Organic Chemistry, Vol. 9 pp. 252-254, 1989. .
  • the specific method is as follows: 1 gram of Rhodobacter sinensis is dissolved in 1000 mL of 1.5% aqueous KOH solution, stirred for 24 hours in the dark, neutralized with a slight excess of dilute hydrochloric acid, and the product is extracted with chloroform, and then isolated and purified to obtain Rhodobacter sinensis. 0.98 g, 98% yield.
  • HC deacetyl erythromycin
  • the long chain quaternary ammonium salt derivative of the present invention is obtained by the following general method and is illustrated by H 2 NCH 2 CH 2 -N + (CH 3 ) 2 (C 10 H 21 ).
  • the erythromycin B (100 mg, 0.18 mmol) and aminoethyl glycol (0.40 g, 4 mmol) were dissolved in 20 mL of anhydrous acetonitrile, thoroughly mixed, heated to 50 ° C under nitrogen atmosphere, and stirred in the dark. After 10 h, after the reaction was completed, the solvent was removed by rotary evaporation. The blue-black solid residue was dissolved in 200 mL of dichloromethane, washed twice with 100 mL of diluted aqueous hydrochloric acid and twice with distilled water. The organic layer was dried over anhydrous magnesium sulfate.
  • the resulting crude product was further separated by silica gel plate chromatography, eluent, acetone: ethyl acetate (volume ratio of 1), respectively, to give two kinds of blue-black solid product, R f value of 0.80 and 0.24, respectively, wherein R f
  • the product of 0.24 was identified as a product which was substituted at both the 2 and 17 positions, labeled HB-1, yield 12.2%; the fraction with R f of 0.80 continued to be plated with acetone: petroleum ether (1:1 by volume) Chromatographic separation gave an Rf value of 0.85 (detected as a 2-amino substituted product, labeled HB-2) with a yield of 6.5%.
  • the 2,17-position amino-substituted product HB-1 characterization data is as follows: 1 H NMR (CDCl 3 , ⁇ , ppm): 17.16 (s, ArOH, 1H), 12.96 (s, ArOH, 1H), 6.98 (s, ArH, 1H), 6.55 (s, ArH, 1H), 6.34 (s, ArNH, 1H), 5.35 (s, ArNH, 1H), 5.22 (s, OH, 1H), 5.01 (s, OH, 1H), 4.18 ( s, OCH 3 , 3H), 4.06 (s, OCH 3 , 3H), 4.04 (s, OCH 3 , 3H), 3.91-3.61 (m, NHCH 2 CH 2 O, 12H), 3.56 (d, CH, 1H) ), 3.25 (d, CH, 1H), 2.27 (s, COCH 3 , 3H), 2.19 (m, CH 2 O, 2H), 2.02 (m, CH 2 O, 2H), 1.57 (s, CH 3
  • the characterization data of the 2-position amino-substituted product HB-2 is as follows: 1 H NMR (CDCl 3 , ⁇ , ppm): 16.76 (s, ArOH, 1H), 16.51 (s, ArOH, 1H), 6.50 (s, ArH, 1H) , 6.47 (s, ArH, 1H), 6.40 (s, ArH, 1H), 5.80 (s, CH 2 , 1H), 5.23 (s, CH 2 , 1H), 4.18 (s, OCH 3 , 3H), 4.08 (s, OCH 3 , 3H), 4.02 (s, OCH 3 , 3H), 3.83-3.76 (m, NHCH 2 CH 2 , 4H), 3.67-3.62 (m, OCH 2 CH 2 , 4H), 2.78 (s , OH, 1H), 2.27 (s, COCH 3 , 3H), 1.61 (s, CH 3 , 3H). MS (ESI): C 33 H 31 NO 10 , 624.1 (M
  • Disacetylomycin HC (100 mg, 0.20 mmol) and aminoethyl glycol (0.30 g, 4 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, thoroughly mixed, and heated to 60 ° C under nitrogen atmosphere, protected from light. The reaction was stirred for 12 h, and after completion of the reaction, the solvent was evaporated. The blue-black solid residue was dissolved in 200 mL of dichloromethane, washed twice with 100 mL of diluted aqueous hydrochloric acid and twice with distilled water. The organic layer was dried over anhydrous magnesium sulfate.
  • the 2-position amino substituted product HB-34 yield 8.8%, R f 0.58, MS (ESI+): 644.6, UV maximum absorption wavelength 464 nm, 626 nm.
  • the amino substituted product HB -33, the structural formula of HB-34 is as shown:
  • the 2-position amino-substituted product HB-42 yield 5.4%, R f 0.54, mass spectrum MS (ESI+): 775.1, UV maximum absorption wavelength: 458 nm, 622 nm.
  • the structural formulas of the amino-substituted products HB-41 and HB-42 are shown in the figure:
  • the 2-position amino-substituted product HB-64 Yield 12.6%, R f 0.48, mass spectrum MS (ESI+): 529.9, UV maximum absorption wavelength 448 nm, 625 nm.
  • the structural formulas of the amino-substituted products HB-63 and HB-64 are shown in the figure:
  • the 2-position amino substituted product HB-68 Yield 15.6%, Rf 0.46, mass spectrum MS (ESI+): 531.9, UV maximum absorption wavelength 445 nm, 622 nm.
  • the structural formulas of the amino-substituted products HB-67 and HB-68 are shown in the figure:
  • the synthesis method was similar to the preparation of the quaternary ammonium salt of the erythromycin derivative in Example 46.
  • the yield of the obtained 2-substituted amino substituted product was 15.5%, and the R f was 0.28.
  • the characterization data was as follows: MS (ESI+): 771.2; ultraviolet maximum absorption wavelength: 462 nm, 628 nm.
  • the obtained crude product was further separated by silica gel chromatography, and the solvent was obtained from acetone: ethyl acetate: ethanol: diethylamine (volume ratio: 20:1:1 to 1:1) to obtain a solid product of blue black, yield 49.8%. , R f is 0.45.
  • the product characterization data was as follows: ESI MS: m/z, 497.3. Ultraviolet maximum absorption wavelength: 462 nm, 650 nm.
  • the structural formulas of the products are shown in the formula HC-95, respectively:
  • the obtained crude product was further separated by silica gel chromatography.
  • the solvent was obtained from acetone: ethyl acetate:ethanol:diethylamine (volume ratio: 20:1:1 to 1:1). , R f is 0.45.
  • the product characterization data was as follows: ESI MS: m/z, 569.3. Ultraviolet maximum absorption wavelength: 462 nm, 650 nm.
  • the structural formula of the product is as shown in formula HB-98 or HB-99, respectively:
  • the erythromycin B (100 mg, 0.18 mmol) and dihydroxyethyl ethylenediamine (421 mg, 2 mmol) were dissolved in 20 mL of anhydrous acetonitrile, thoroughly mixed, heated to 45 ° C under nitrogen atmosphere, and stirred in the dark. After 6 h, after the reaction was completed, the solvent was removed by rotary evaporation. The blue-black solid residue was dissolved in 100 mL of dichloromethane, washed three times with 50 mL of diluted aqueous hydrochloric acid, and then washed once with distilled water. The organic layer was dried over anhydrous magnesium sulfate.
  • the obtained crude product was further separated by silica gel chromatography, and the solvent was acetone: ethyl acetate: ethanol: diethylamine (volume ratio: 20:1:1 to 1:1) to obtain a solid product of blue black, yield 18.5%. , R f is 0.21.
  • the product characterization data was as follows: ESIMS: m/z, 583.5. Ultraviolet maximum absorption wavelength: 463 nm, 650 nm.
  • the structural formulas of the products are shown in the formulas HB-121 and HB-122, respectively:
  • the obtained crude product was further separated by a 1% KH 2 PO 4 silica gel plate chromatography, and the solvent was petroleum ether: ethyl acetate: ethanol (volume ratio: 4:2.5:1) to obtain the products I-1 and I-2, respectively.
  • Phototoxicity test Compounds I-1, HB and Ce6 photosensitizers were co-incubated with HeLa cells at different concentrations, placed in an incubator containing 5% CO 2 at 37 ° C for 1 h, and then irradiated with a wavelength of 671 nm laser. Power density 50mW / cm 2, the irradiation time was 20min, after completion of the respective processing at 37 °C incubator containing 5% CO 2 in cultured incubated 24h, the survival rate by MTT assay cells in each group. As shown in Figure 16b, 200 nM of compound I-1 killed more than 90% of HeLa cells, while the commercial photosensitizer Ce6 under the same conditions killed only about 30% of HeLa cells.
  • the preparation method of the compound 2 is referred to the literature: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4 , 93-100.
  • erythromycin HB 0.5 mM
  • mercaptoethylamine hydrochloride 0.1 mM
  • light was irradiated with a 450 W high-pressure sodium lamp at room temperature for 30 minutes (light with a glass long-pass filter was used to filter out light below 470 nm). After completion of the reaction, it was acidified with 10% hydrochloric acid, extracted with chloroform, washed with water and then dried to give a crude product.
  • I-8: yield 8.8%; MS (ESI+), m/z C 51 H 66 N 4 O 11 S 4 , [M+H] + 1039.3; UV maximum absorption wavelength ⁇ max (log ⁇ ), 721 nm (4.2 ).
  • Example 67 The synthesis of Compound 12 is referred to Example 67. 200 mg of the compound 12 was dissolved in 100 mL of freshly distilled tetrahydrofuran, 40 mL of ethylenediamine was added, and the mixture was stirred at a temperature of 55 ° C for 12 hours. After the reaction was stopped, the solvent was removed under reduced pressure, dissolved with chloroform, washed with dilute hydrochloric acid to neutral, and the organic phase was dried to give a crude product, which was further separated by 1% KH 2 PO 4 silica gel chromatography.
  • Phototoxicity test Compound II-2, HB and Ce6 photosensitizers were co-incubated with HeLa cells at different concentrations, placed in an incubator containing 5% CO 2 at 37 ° C for 1 h, and then irradiated with a wavelength of 808 nm laser. Power density 20mW/cm 2 , the irradiation time was 20min, and after the corresponding treatment, it was placed in an incubator containing 5% CO 2 at 37 ° C for 24 hours, and the survival rate of each group was detected by MTT method, as shown in Fig. 18b. 300nM compound I-1 can kill more than 85% of Hela cells, and the commercial photosensitizer Ce6 under the same conditions can only kill about 20% of Hela cells.
  • Example 86 Compound 13 was synthesized in accordance with Example 67. The synthesis of compounds II-3 and II-4 is referred to in Example 86.
  • Example 68 The synthesis of compound 15 is referred to in Example 68.
  • the synthesis of compounds II-7 and II-8 is referred to in Example 85.
  • the cultured Hela cells were digested with 0.25% trypsin, and boiled to prepare a single cell suspension.
  • the number of cells was adjusted to about 2 ⁇ 10 4 cells/mL, and 200 uL per well was seeded in a 96-well culture plate at 37 ° C with 5% CO. 2 incubate in the incubator. After the cells are attached to the wall, the supernatant culture solution is discarded, and different concentrations of photosensitizer (hematoporphyrin derivative HpD, hypocrellin B, and Rhodobacter sinensis derivative HB- are added in strict accordance with the experimental design in the dark. 1) Incubate and incubate for 1 hour in an incubator containing 5% CO 2 at 37 °C.
  • MTT prepared in PBS at a concentration of 5 mg/ml
  • the cultured Hela cells were digested with 0.25% trypsin, and boiled to prepare a single cell suspension.
  • the number of cells was adjusted to about 2 ⁇ 10 4 cells/mL, and 200 uL per well was seeded in a 96-well culture plate at 37 ° C with 5% CO. 2 incubate in the incubator. After the cells are attached to the wall, the supernatant culture solution is discarded, and different concentrations of photosensitizer (hematoporphyrin derivative HpD, hypocrellin B, and Rhodobacter sinensis derivative HB-1) are strictly designed according to the experimental design in the dark. The culture was further incubated for 1 hour in an incubator containing 5% CO 2 at 37 °C.
  • the light is irradiated with a 635 nm semiconductor laser, and the power density is adjusted to 20 mW/cm 2 , so that the light beam is uniformly and vertically irradiated onto the 96-well culture plate, the irradiation time is 1000 S, and each 96-well culture plate is provided with a blank group, each of which is provided with a blank group.
  • the condition is 6 holes. After illuminating, the cells were incubated in an incubator containing 5% CO 2 at 37 ° C for 24 hours, and then the cell survival rate was measured. Cell viability was measured by MTT assay.
  • Fig. 5 The structural formula of unmodified Phytophthora B (HB) is shown in Fig. 5.
  • the absorption spectrum is as shown in Fig. 7a, and its maximum absorption wavelength is 450 nm, and there is weak absorption at 590 nm of red light absorption.
  • Hypocrellin B has a weak light-absorbing ability at 600-900 nm in the phototherapy window, and it is used for photodynamic therapy.
  • the ability of photodynamics to kill tumor cells is worse than the ester-water amphiphilic derivative of the present invention. Very More ( Figure 10-14).
  • the mono- or poly-substituted ester water amphiphilic rhodamine derivative prepared by the invention has a significant red shift in absorption spectrum and a large molar extinction coefficient, and exhibits strong near-infrared red light absorption capacity and ester water. Amphipathic. The absence of any substitution will cause the effects of the hypocrellin derivatives to be somewhat diminished in some respects.

Abstract

La présente invention concerne un dérivé d'hypocrelline amphiphile monosubstitué ou polysubstitué, son procédé de préparation et ses utilisations. Dans la présente invention, le dérivé d'hypocrelline amphiphile ayant des groupes fonctionnels substitués tels que l'éthylène glycol condensé et un sel d'ammonium quaternaire présente, dans son spectre d'absorption, un décalage vers le rouge substantiel et un coefficient d'extinction molaire accru par rapport au précurseur de l'hypocrelline, et peut efficacement produire une espèce réactive d'oxygène, par exemple l'état de singulet, dans des conditions photosensibles. En réglant le caractère hydrophobe et hydrophile dudit dérivé, celui-ci peut avoir un caractère amphiphile différent et une meilleure biocompatibilité avec les cellules ou les tissus. Le dérivé d'hypocrelline amphiphile peut satisfaire aux exigences de différents traitements médicamenteux cliniques, et aborde le conflit entre le caractère hydrophile et lipophile pharmacologique suscité par différents procédés d'administration. Par rapport à la première et à la seconde génération de photosensibilisateurs commercialisés, dans les mêmes conditions, le dérivé d'hypocrelline amphiphile photosensibilisateur selon la présente invention a de plus grandes capacités photodynamiques pour éradiquer les cellules tumorales vivantes.
PCT/CN2016/102832 2015-10-21 2016-10-21 Dérivé d'hypocrelline amphiphile monosubstitué ou polysubstitué, son procédé de préparation et ses utilisations WO2017067497A2 (fr)

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US15/769,789 US11154548B2 (en) 2015-10-21 2016-10-21 Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, and preparation method and application thereof
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CN201610880613.8A CN106608835B (zh) 2015-10-21 2016-10-09 含长链季铵盐的竹红菌素衍生物及其制备方法和应用
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CN114644607A (zh) * 2020-12-17 2022-06-21 中国科学院化学研究所 竹红菌素衍生物及其制备方法与应用

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AU2006279189B2 (en) * 2005-08-10 2011-08-04 Quest Pharmatech Inc. Perylenequinone derivatives and uses thereof

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CN109456210A (zh) * 2017-09-06 2019-03-12 中国科学院理化技术研究所 一种竹红菌素迫位和2-位同时氨基取代的衍生物及其制备方法和应用
CN114644607A (zh) * 2020-12-17 2022-06-21 中国科学院化学研究所 竹红菌素衍生物及其制备方法与应用

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