Patent Description:
As a rapidly developing novel technique for selectively treating vascular diseases in recent years, photodynamic therapy (PDT for short) has significant curative effects against various tumor diseases. PDT has become the fourth special oncotherapy method following surgery, radiotherapy and chemotherapy. It has advantages in its high efficiency and security, can continuously produce reactive oxygen species under light illumination, leads to injury or necrosis of pathologically changed cells and tissues, and has significant efficiency comparing with traditional drugs capable of killing a single target molecule only. PDT has the bidirectional selectivity of drug targeting and illumination locating, and reduces the damage to normal cells, thus ensuring the therapeutic safety. Besides the great achievements in clinical treatment of cancers, PDT is also used to treat non-tumorous diseases, such as various vasculopathies, pointed condyloma, psoriasis, nevus flammeus, rheumatoid arthritis and macular degeneration and so on. Moreover, PDT also has a significant effect on laser beautification.

The photosensitizer is a key factor affecting the therapeutic effect of PDT. Among the known photosensitizer drugs applied at present, the first generation photosensitizer for clinical use is a porphyrin photosensitive drug, and the second generation is a phthalocyanine photosensitive drug. Among these photosensitive drugs, the most prominent problem of porphyrin photosensitizers and phthalocyanine photosensitizers is the difficult separation of geometric isomers, as it is difficult to obtain a pure monocomponent compound. Moreover, its relatively complex composition does not contribute to subsequent drug metabolism or toxicological evaluation. Other photosensitive drugs, such as dihydroporphin, chlorophyll and perylenequinonoid, are still in a development stage. At present, China still falls far short of photosensitive drugs for clinical use, and is in urgent need of novel efficient photosensitive drugs to fill the shortage.

Since the <NUM>, perylenequinonoid photosensitive drugs have been successively discovered, such as cercosporin, hypericin, elsiuochrome and hypocrellin, all of which have been validated to have anti-cancer activities. Among them, hypocrellin is a natural photosensitizer extracted from Hypocrella bambusae, which is a parasitical fungus living on arrow bamboo in the Yunnan Plateau of China, where the altitude is <NUM>. Natural hypocrellin mainly includes hypocrellin A (HA for short) and hypocrellin B (HB for short). In recent years, people have made detailed researches on hypocrellin, which has the basic conditions for becoming a photosensitive drug with superior performance. For example, it has strong absorption and a high molar extinction coefficient in the visible light area, and can efficiently produce singlet state oxygen under photosensitive conditions; it is a botanical drug, has good phototoxicity, low dark toxicity, fast in-vivo metabolism and clear chemical structure, and thus has broad application prospects (<NPL>). However, the main absorption wavelength range of hypocrellin is <NUM>-<NUM>. This wavelength can penetrate less than <NUM> tissue, and has weak light absorption capacity in the PDT window (<NUM>-<NUM>). Over the past ten years, there have been many chemical modifications for hypocrellin, where ammonia-modified hypocrellin has an obvious red shift of the absorption wavelength to <NUM>-<NUM>, and significant increase of the molar extinction coefficient (<NPL>). The amino-modified hypocrellin has presented good properties of a photosensitive drug. However, the water solubility and biocompatibility of these photosensitizers still need to be further improved. The target of microvascular diseases is the heterogeneous dense microvascular network in the focal zone, and is sensitive to photodynamic effects. In case of PDT, drugs are usually delivered to pathologically changed tissues through the blood circulation system by way of intravenous injection. However, hypocrellin is a small lipophilic organic molecule with very low solubility in water. It will spontaneously accumulate in blood, and thus causes blockage of blood vessels in case of direct intravenous injection. A sulfo-substituted derivative (<NPL>) has better water solubility, but is negatively charged, and has a low cellular uptake rate due to mutual repulsion between it and a lot of negative charges in cells and tissues, thereby greatly reducing the photodynamic activity. Therefore, the designed photosensitive drug molecule shall not only meet the above light absorption conditions, but also have optimized amphiphilicity- not only satisfying the concentration requirements for intravenous injection, but also ensuring a high cellular uptake rate to improve the PDT effect. <CIT> discloses polymeric nanoparticles comprising a hypocrellin B derivative for photosensitizers and <CIT> discloses perylenequinone derivatives which can be used in photodynamic therapy.

Therefore, it is necessary to provide a monosubstituted or polysubstituted amphiphilic hypocrellin derivative that not only meets light absorption conditions, but also has optimized amphiphilicity, and a preparation method and application thereof.

A first object of the invention is to provide a monosubstituted or polysubstituted amphiphilic hypocrellin derivative; a second object of the invention is to provide a method for preparing the monosubstituted or polysubstituted amphiphilic hypocrellin derivative; and a third object of the invention is to provide an application of the monosubstituted or polysubstituted amphiphilic hypocrellin derivative.

In view of the fact that the existing hypocrellin derivative can neither meet light absorption conditions, nor meet optimized amphiphilicity, the invention proposes the technical solution of the invention. The applicant proposes to enhance the biocompatibility and regulate the hydrophilicity and hydrophobicity of the parent hypocrellin by modifying it with polyethylene glycol (PEG), a long chain quaternary ammonium salt or the like, or modifying it with PEG, a long chain quaternary ammonium salt and the like at the same time. These derivatives have different amphiphilicities and are not susceptible to pH changes. The applicant further proposes to modify hypocrellin by substitutions at C<NUM>, C<NUM> or C<NUM> and at C<NUM>, C<NUM>, C<NUM> or C<NUM> for the first time, so that its maximum absorption red shifts to more than <NUM>, and it has a higher molar extinction coefficient, so as to improve its weak light absorption capacity in the phototherapy window. The results of photodynamic experiments show that such amphiphilic hypocrellin derivatives can meet the requirements of different clinical drugs, and solve the requirements of different drug delivery methods for different drug hydrophilicity and lipophilicity. The technical solution is first disclosed in the invention.

To achieve the first object, the invention adopts the following technical solution:
A monosubstituted or polysubstituted amphiphilic hypocrellin derivative as defined by claim <NUM> and its dependent claims <NUM>-<NUM> annexed hereto and represented by general structural formula (IV-a) or (V-a):
<CHM>.

Preferably, the linker Y in the substituent R in formula (III) is: -O-, -S-; -COO-; CONH-; -SO<NUM>-; -C<NUM>H<NUM>- (cyclopropyl); -C<NUM>H<NUM>- (cyclobutyl); -C<NUM>H<NUM>- (cyclopentyl); -C<NUM>H<NUM>(CH<NUM>)-(methylcyclopentyl); -C<NUM>H<NUM>- (cyclohexyl); -C<NUM>H<NUM>(CH<NUM>)- (methylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>)-(ethylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>)- (propylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>)- (butylcyclohexyl); -C<NUM>H<NUM>(CH<NUM>)<NUM>- (dimethylcyclohexyl).

Preferably, the terminal group Z in the substituent R in formula (III) is: -H; -CH<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -OCH<NUM>; -OC<NUM>H<NUM>; -OC<NUM>H<NUM>; -OC<NUM>H<NUM>; -OC<NUM>H<NUM>; -OC<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>N; -OH, -NH<NUM>;-SH; -COOH; -COOCH<NUM>; -COOC<NUM>H<NUM>; -SO<NUM>H; -C<NUM>H<NUM>N+;.

Preferably, the substituent R is: -H; -CH<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM> (cyclopentyl); -C<NUM>H<NUM> (cyclohexyl); -C<NUM>H<NUM>(CH<NUM>) (methylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>) (ethylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>) (propylcyclohexyl); -C<NUM>H<NUM>(C<NUM>H<NUM>) (butylcyclohexyl); -C<NUM>H<NUM>(CH<NUM>)<NUM> (dimethylcyclohexyl); -C<NUM>H<NUM>(OH) (hydroxycyclohexyl); -C<NUM>H<NUM>- (cycloheptyl); -C<NUM>H<NUM>; -CH<NUM>C<NUM>H<NUM>; -CH<NUM>CH<NUM>C<NUM>H<NUM>; -NHC<NUM>H<NUM>; -OH; -CH<NUM>CH<NUM>OH; -CH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>OCH<NUM>; -CH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OCH<NUM>; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OCH<NUM>; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OCH<NUM>; -CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OCH<NUM>; -CH<NUM>CH<NUM>-SH; -CH<NUM>CH<NUM>-S-CH<NUM>CH<NUM>OH; -CH<NUM>CH<NUM>-SO<NUM>H; -(CH<NUM>CH<NUM>O)<NUM>-SO<NUM>H; -CH<NUM>CO<NUM>H; -CH<NUM>CH<NUM>CO<NUM>H; -CH<NUM>CH<NUM>CH<NUM>CO<NUM>H; -CH<NUM>CH<NUM>CH<NUM>CH<NUM>CO<NUM>H; -CH<NUM>-C(=O)-OCH<NUM>CH<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-OCH<NUM>CH<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-C(=O)-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-C(=O)-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-C(=O)-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-C(=O)-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -CH<NUM>CH<NUM>-SO<NUM>-OCH<NUM>CH<NUM>-OH; -CH<NUM>CH<NUM>-SO<NUM>-(OCH<NUM>CH2)<NUM>-OH; -CH<NUM>CH<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -CH<NUM>CH<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-SO<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-SO<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-SO<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-SO<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -CH<NUM>-C(=O)NH-CH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH; -(CH<NUM>)<NUM>-C(=O)NH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)n-OH [PEG with a molecular weight<<NUM>,<NUM>]; -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>; -CH<NUM>CH<NUM>-N+(C<NUM>H<NUM>)<NUM>, -CH<NUM>CH<NUM>-N+(C<NUM>H<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>);--(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>; -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>); -(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>).

Preferably, the general structural formula of the hypocrellin derivative in formula (IV-a) further comprises an enol tautomer represented by formula (IV-a'), and the general structural formula of the hypocrellin derivative in formula (V-a) further comprises an enol tautomer represented by formula (V-a'):
<CHM>
<CHM>.

To achieve the second object, the invention adopts the following technical solution:
A method for preparing the amphiphilic hypocrellin derivative in formula (IV) or (V) comprises the following steps:
dissolving hypocrellin B and a corresponding substituted amino derivative in an organic solvent, keeping the resulting solution in dark under the protection of an inert gas, and obtaining the amphiphilic hypocrellin derivative by separation and purification.

The molar ratio of the hypocrellin to the substituted amino derivative is <NUM>:<NUM>-<NUM>:<NUM>, and may specifically be <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM>; the reaction temperature is <NUM>-<NUM>; and the reaction lasts for <NUM>-<NUM>. The organic solvent is acetonitrile, tetrahydrofuran, pyridine, methanol or ethanol; the reaction needs to be carried out in dark under the protection of an inert gas, such as argon or nitrogen.

Preferably, the organic solvent is one of acetonitrile, tetrahydrofuran and pyridine; the molar ratio of the hypocrellin to the substituted amino derivative is <NUM>:<NUM>; the reaction temperature is <NUM>; and the reaction lasts for <NUM>. Preferably, the separation and purification process includes: obtaining a residue by removing the organic solvent used in the reaction, dissolving the residue in dichloromethane, successively washing the residue with diluted aqueous hydrochloric acid solution and water, obtaining a crude product by drying and filtering the organic layer and removing the solvent, and obtaining a hypocrellin derivative containing a long chain quaternary ammonium salt by silica gel chromatography of the crude product.

Preferably, the developer used in silica gel chromatography is a mixed liquor containing acetone, ethyl acetate, ethanol and diethylamine, where the volume ratio of acetone to ethyl acetate to ethanol and to diethylamine in the mixed liquor is <NUM>:<NUM>:<NUM>:<NUM>-<NUM>:<NUM>:<NUM>:<NUM>. Preferably, the separation and purification process includes: obtaining a blue black solid residue by removing the organic solvent used in the reaction, dissolving the residue in dichloromethane, washing the residue with equivalent volume of diluted aqueous hydrochloric acid solution (<NUM>%) thrice and with water once, and then obtaining a crude product by drying and filtering the organic layer with anhydrous magnesium sulfate and removing the solvent. The obtained crude product is further separated by silica gel chromatography with a developer of acetone: ethyl acetate: ethanol: diethylamine preferably at a volume ratio of <NUM>:<NUM>:<NUM>:<NUM> to obtain a blue black solid amino-substituted hypocrellin derivative with a yield of <NUM>-<NUM>%.

To achieve the third object, the invention adopts the following technical solution:
the monosubstituted or polysubstituted amphiphilic hypocrellin derivative for use as a photosensitizer drug in PDT.

<FIG> is a general structural formula of a monosubstituted or polysubstituted amphiphilic hypocrellin extending beyond the scope of the invention. <FIG> are synthesis methods of the hypocrellin derivatives, wherein <FIG> and <FIG> include derivatives according to the invention. The amphiphilic hypocrellin derivatives synthesized according to the invention include lipophilic, hydrophilic and amphiphilic hypocrellin derivatives. The hypocrellin derivative containing polyethylene glycol or a quaternary ammonium salt or the like according to the invention has a very wide strong absorption in the phototherapy window. Its maximum absorption wavelength is about <NUM>-<NUM>, and can at most reach <NUM>. Its maximum absorption peak (<NUM>) is red shifted by more than <NUM>, compared with that of the parent hypocrellin, and its molar extinction coefficient is about <NUM>,<NUM>-<NUM>,<NUM>-<NUM>cm-<NUM>. It shows a very strong red absorption capacity (as shown in <FIG>). It has good water solubility, and can be prepared into a stock solution in normal saline in a concentration range of <NUM>-<NUM>. Its ability to produce reactive oxygen is shown in <FIG>: the experiments respectively using singlet state oxygen and superoxide radical scavenger show that such amphiphilic hypocrellin derivatives can efficiently produce photosensitively active species, mainly including singlet state oxygen (<FIG>), as well as a small amount of superoxide radical (<FIG>). The results of the confocal fluorescence imaging experiment as shown in <FIG> show that a small molecule phototherapy drug HB-<NUM> has good biocompatibility, can enter the lysosomes of Hela cells, and can produce very good red fluorescence imaging in cells. The HB-<NUM> and the Hela cells are incubated together. As shown in <FIG>, the cytotoxicity (dark toxicity) experiment shows that a PEG-containing hypocrellin derivative HB-<NUM> synthesized in Example <NUM> has low cytotoxicity, and is similar to the HB and the commercial photosensitive drug haematoporphyrin HpD. After the Hela cells are incubated with the photosensitizer HB-<NUM> at a concentration of <NUM> for half an hour, significant death of the Hela cells are not seen, showing that such photosensitizers basically have no cytotoxicity. The cell phototoxicity experiment as shown in <FIG> shows that the HB-<NUM> shows very strong lethality against Hela cells exposed to red light, and can kill more than <NUM>% Hela cells in a concentration range of <NUM>, while the hypocrellin B or the commercial photosensitizer hematoporphyrin derivatives can kill only about <NUM>% Hela cells under identical conditions, indicating that such amphiphilic hypocrellin derivatives have significantly better photodynamic effects than the hypocrellin B (HB) and the commercial photosensitizer hematoporphyrin HpD. Similar results are also concluded in the dark cytotoxicity and phototoxicity experiments of a PEG-containing hypocrellin derivative HB-<NUM> synthesized in Example <NUM>, as shown in <FIG>. In addition, <FIG> shows the phototoxic effect of killing tumor cells by an aminopropanol-modified deacetylated hypocrellin HC-<NUM> of the invention or HC-<NUM> synthesized in Example <NUM>. <FIG> shows the phototoxic effect of killing tumor cells by deacetylated hypocrellin HC-<NUM> of the invention or HC-<NUM> modified with a long chain quaternary ammonium salt synthesized in Example <NUM>. <FIG> shows the phototoxic effect of killing tumor cells by a piperazinohypocrellin B (HB-<NUM>) synthesized in Example <NUM>. All of the results of the above phototoxicity experiments show that such amphiphilic hypocrellin derivatives have significantly better photodynamic effects than the hypocrellin B (HB) and the commercial photosensitizer haematoporphyrin HpD.

The polysubstituted near infrared hypocrellin derivative according to the invention has very wide strong absorption in the phototherapy window (<NUM>-<NUM>). Its maximum absorption wavelength is red shifted to more than <NUM>, and can extend to <NUM>. Its molar extinction coefficient is about <NUM>,<NUM>-<NUM>,<NUM>-<NUM>cm-<NUM>. It shows a very strong near infrared red absorption capacity, and its synthesis method is shown in <FIG>. The experiments respectively using singlet state oxygen and superoxide radical scavenger show that such polysubstituted near infrared hypocrellin derivatives can efficiently produce photosensitively active species, mainly including singlet state oxygen, as well as a small amount of superoxide radical (as shown in <FIG> and <FIG>). As shown in <FIG>, the cytotoxicity (dark toxicity) experiment shows that a hypocrellin derivative I-<NUM> synthesized in Example <NUM> has low cytotoxicity, and is similar to the hypocrellin B (HB) and the commercial photosensitive drug dihydroporphin Ce6. After Hela cells are incubated with the photosensitizer I-<NUM> at a concentration of <NUM> for half an hour, significant death of the Hela cells are not seen, showing that such photosensitizers basically have no cytotoxicity. The cell phototoxicity experiment as shown in <FIG> shows that the I-<NUM> shows very strong lethality against Hela cells exposed to <NUM> near infrared, and can kill more than <NUM>% Hela cells in a concentration range of <NUM>, while the commercial photosensitizer dihydroporphin Ce6 can kill only about <NUM>% Hela cells under identical conditions. By comparison with the dark cytotoxicity and phototoxicity experiments of a hypocrellin derivative II-<NUM> synthesized in Example <NUM>, as shown in <FIG>, it is worth pointing out that an <NUM> near infrared laser is used, indicating that such compounds can be used in PDT for penetrating deeper tumor tissues.

Compared with the parent hypocrellin B, the amphiphilic hypocrellin derivatives according to the invention have greatly enhanced water solubility by introducing PEG, a quaternary ammonium salt or the like, and have good amphiphilicity, as well as very good biocompatibility in cells or tissues, by changing the aliphatic chain length to adjust oil-water ratio. These compounds exist in the form of PEG or a quaternary ammonium salt, are not susceptible to pH, and can be used in complex organisms. Such a hypocrellin with a normal salt like a quaternary ammonium salt can effectively bind to negatively charged species in an organism, especially has very good affinity to tumor cells. The effect of phototherapy is changed by adjusting the distance between the quaternary ammonium salt and the parent hypocrellin. The hydrophilicity and hydrophobicity of photosensitive drug molecules produced using PEG can be regulated at will by changing the number of PEG structure units, in order to meet the needs of different clinical drugs. Furthermore, the PEG structure is non-toxic, is also a drug component approved by FDA, and has very good biocompatibility. Therefore, such amphiphilic hypocrellin derivatives can be directly dissolved in normal saline to make pharmaceutical preparations and improve the medicinal effect; are made from natural products and will not produce toxic or side effects, thereby laying the foundation for the development of hypocrellin drugs for treating cancers and hypocrellin drugs against cancer viruses.

Hypocrellin is modified with a PEG group or a long chain quaternary ammonium salt or the like, and its molecular hydrophilicity and hydrophobicity are adjusted, so that such derivatives have different amphilicities, and their biocompatibility with cells or tissues is improved. Such compounds have the maximum absorption wavelength of <NUM>-<NUM>, molar extinction coefficients of <NUM>,<NUM>-<NUM>,<NUM>-<NUM>cm-<NUM>, and very strong light absorption capacity in the phototherapy window. Researches have shown that such derivatives can efficiently produce singlet state oxygen and other reactive oxygen species under photosensitive conditions, have very good photodynamic effects, and can be used as phototherapy drugs for treating tumors, various microangiopathies and other diseases.

In the prior art, neither preparation nor extraction of a PEG-modified hypocrellin derivative is researched. No researches are found to be related to such compounds that can satisfy not only light absorption conditions, but also optimized amphiphilicity, i.e., meeting the concentration requirements for intravenous injection to ensure a high cellular uptake rate.

Moreover, it should be noted that the hypocrellin derivatives to be protected in the patent each contain two enol tautomers (e.g., formulas IV-a and IV-a', formulas V-a and formula V-a'), the chemical structures of which fall, of course, within the scope of protection. Moreover, unless otherwise indicated, any range disclosed in the invention includes any subrange consisting of end values and any value between the end values, and end values or any value between the end values.

The invention has the following beneficial effects:.

The embodiments of the invention are further illustrated in detail below in conjunction with the accompanying drawings.

In order to illustrate the invention more clearly, the invention is further described below in conjunction with examples falling outside the present invention, preferred embodiments and the accompanying drawings, wherein like reference symbols represent like parts. The compounds of the following examples which are designated as 'of the invention' fall in the scope of the claims, the other compounds of the examples are not part of the invention.

Extraction of hypocrellin A (HA): <NUM> of hypocrellin was pulverized by a pulverizer, and continuously extracted with <NUM>,<NUM> of acetone as a solvent in a Soxhlet extractor for one day until nearly colorless. The extract was filtered to remove a small amount of infiltrated solid insoluble substances, spin-dried to remove acetone, dissolved in <NUM> of dichloromethane, and washed four times and each with <NUM> of distilled water. The organic layer was separated and spin-dried, the solid residue was washed five times and each with <NUM> of petroleum ether, naturally air-dried, and then recrystallized with chloroform-petroleum ether twice. The resulting crystal was the target product HA with a purity of more than <NUM>%. Highly purified HA can be obtained by further purification using thin layer silica gel chromatography with petroleum ether: ethyl acetate: anhydrous ethanol (<NUM>:<NUM>:<NUM>) as a developer.

Preparation of hypocrellin B (HB): the HB was prepared by dehydrating the HA using a method, which is an appropriate improvement of a method in a reference book <NPL>). The specific method is as follows: <NUM> of the HA was dissolved in <NUM> of <NUM>% aqueous solution of KOH, stirred in dark for <NUM>, and neutralized with slightly excessive diluted hydrochloric acid. A product was extracted with chloroform, and purified by separation to obtain <NUM> of the HB with a yield of <NUM>%.

Preparation of deacetylated hypocrellin (HC): <NUM> of the HB was dissolved in <NUM> of <NUM>% aqueous solution of KOH, refluxed in dark for <NUM>, cooled, and then neutralized with slightly excessive diluted hydrochloric acid. A product was extracted with dichloromethane, and purified by separation to obtain <NUM> of the deacetylated hypocrellin (HC) with a yield of <NUM>%. <NUM>H NMR (CDCl<NUM>, δ, ppm): <NUM> (s, -OH, <NUM>), <NUM> (s, -OH, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>, <NUM> (s, -OCH<NUM>, <NUM>), <NUM> (s, -OCH<NUM>, <NUM>), <NUM> (d, <NUM>), <NUM> (s, -OCH<NUM>, <NUM>).

The derivatives containing a long chain quaternary ammonium salt according to the invention were prepared using the following general methods, which are described by taking H<NUM>NCH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>) as an example. <CHM>
<CHM>.

Preparation of an intermediate S1: N,N-dimethyl ethyldiamine (<NUM>, <NUM> mol) and diethyl carbonate (<NUM>, <NUM> mol) were mixed in a <NUM> round-bottomed flask, kept at <NUM> for <NUM>, and then distilled under reduced pressure to obtain <NUM> of a pale yellow liquid with a yield of <NUM>%. <NUM>H NMR (CDCl<NUM>, δ, ppm): <NUM> (s, -NH-, <NUM>), <NUM> (d, J=<NUM>, -CH<NUM>O, <NUM>), <NUM> (s, -NH-CH<NUM>-, <NUM>), <NUM> (m, -CH<NUM>N, <NUM>), <NUM> (d, J=<NUM>, CH<NUM>NCH<NUM>, <NUM>), <NUM> (t, J=<NUM>, -CH<NUM>CH<NUM>, <NUM>).

Preparation of an intermediate S2: the intermediate S1 reacted with <NUM>-bromodecane (<NUM>, <NUM> mol) at <NUM> for <NUM> for <NUM>. The crude product was recrystallized with acetone-diethyl ether (<NUM>:<NUM>) to obtain a total of <NUM> of a white crystal <NUM> with a yield of about <NUM>%. <NUM>H NMR (CDCl<NUM>, δ, ppm): <NUM> (s, CONH-, <NUM>), <NUM> (q, J=<NUM>, -CH<NUM>O-, <NUM>), <NUM> (s, -CH<NUM>N+, <NUM>), <NUM> (s, CH<NUM>N+, <NUM>), <NUM> (s, -NHCH<NUM>-, <NUM>), <NUM>-<NUM> (m, -N+CH<NUM>CH<NUM>-, <NUM>), <NUM>-<NUM> (m, -CH<NUM>-, <NUM>), <NUM> (t, J=<NUM>, -CH<NUM>, <NUM>). MS(ESI+): C<NUM>H<NUM>N<NUM>O<NUM>+ (M+H+), <NUM>.

Preparation of a long chain quaternary ammonium salt derivative S3: <NUM> of <NUM>% hydrobromic acid and <NUM> of distilled water were added to the intermediate S2 (<NUM>, <NUM> mol), and refluxed while heating for <NUM>. Hydrobromic acid was removed by rotary evaporation, and the solid residue was recrystallized with ethanol: diethyl ether (<NUM>:<NUM>) to obtain <NUM> of a white flocculent crystal with a yield of <NUM>%. <NUM>H NMR (D<NUM>O, δ, ppm): <NUM> (s, NH<NUM>, <NUM>), <NUM> (m, NH<NUM>CH<NUM>CH<NUM>-, <NUM>), <NUM> (m, -N+CH<NUM>CH<NUM>-, <NUM>), <NUM> (m, NH<NUM>CH<NUM>-, <NUM>), <NUM> (s, N+-CH<NUM>, <NUM>), <NUM> (m, N+CH<NUM>CH<NUM>-, <NUM>), <NUM>-<NUM> (m, -CH<NUM>-, <NUM>), <NUM> (t, J=<NUM>, -CH<NUM>, <NUM>). MS (ESI+): C<NUM>H<NUM>N<NUM>+ (M+H+), <NUM>.

Preparation of an aminoethyl glycol-modified hypocrellin derivative (R=-CH<NUM>CH<NUM>OCH<NUM>CH<NUM>OH): the synthesis route as shown in <FIG>:Hypocrellin B (HB) (<NUM>, <NUM> mmol) and aminoethyl glycol (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, and successively washed with <NUM> of diluted aqueous hydrochloric acid solution once and with distilled water twice. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate (volume ratio: <NUM>:<NUM>) as a developer to respectively obtain two blue black solid products with Rf values respectively being <NUM> and <NUM>, where the product with the Rf being <NUM> was identified to be a <NUM>,<NUM>-substituted product, and was labeled as HB-<NUM> with a yield of <NUM>%; and the component with the Rf being <NUM> was further separated with acetone: petroleum ether (volume ratio: <NUM>:<NUM>) using chromatography to obtain a product with the Rf value being <NUM> (detected as a <NUM>-amino-substituted product, labeled as HB-<NUM>) with a yield of <NUM>%.

Characterization data of <NUM>,<NUM>-amino-substituted product HB-<NUM> are as follows: <NUM>HNMR (CDCl<NUM>, δ, ppm): <NUM> (s, ArOH, <NUM>), <NUM> (s, ArOH, <NUM>), <NUM> (s, ArH, <NUM>), <NUM> (s, ArH, <NUM>), <NUM> (s, ArNH, <NUM>), <NUM> (s, ArNH, <NUM>), <NUM> (s, OH, <NUM>), <NUM> (s, OH, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM>-<NUM> (m, NHCH<NUM> CH<NUM>O, <NUM>), <NUM> (d, CH, <NUM>), <NUM> (d, CH, <NUM>), <NUM> (s, COCH<NUM>, <NUM>), <NUM> (m, CH<NUM>O, <NUM>), <NUM> (m, CH<NUM>O, <NUM>), <NUM> (s, CH<NUM>, <NUM>), <NUM>-<NUM> (m, CH<NUM>-, <NUM>), <NUM> (t, CH<NUM>, <NUM>). MS (ESI): C<NUM>H<NUM>N<NUM>O<NUM> (M + H+), <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>.

Characterization data of <NUM>-amino-substituted product HB-<NUM> are as follows: <NUM>HNMR (CDCl<NUM>, δ, ppm): <NUM> (s, ArOH, <NUM>), <NUM> (s, ArOH, <NUM>), <NUM> (s, ArH, <NUM>), <NUM> (s, ArH, <NUM>), <NUM> (s, ArH, <NUM>), <NUM> (s, CH<NUM>, <NUM>), <NUM> (s, CH<NUM>, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM> (s, OCH<NUM>, <NUM>), <NUM>-<NUM> (m, NHCH<NUM>CH<NUM>, <NUM>), <NUM>-<NUM> (m, OCH<NUM>CH<NUM>, <NUM>), <NUM> (s, OH, <NUM>), <NUM> (s, COCH<NUM>, <NUM>), <NUM> (s, CH<NUM>, <NUM>). MS (ESI): C<NUM>H<NUM>NO<NUM>, <NUM> (M+ Na+), <NUM> (M- H). Maximum UV absorption wavelength: <NUM>, <NUM>.

The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative (R=-CH<NUM>CH<NUM>CH<NUM>OH): the synthesis route as shown in <FIG>:
Deacetylated hypocrellin HC (<NUM>, <NUM> mmol) and aminoethyl glycol (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous tetrahydrofuran, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, and successively washed with <NUM> of diluted aqueous hydrochloric acid solution once and with distilled water twice. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate (volume ratio: <NUM>:<NUM>) as a developer to obtain a blue black solid product with a yield of <NUM>% with Rf value of <NUM>. MS (ESI+): <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C13=C14) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of an aminoethyl triglycol-modified hypocrellin B derivative (R=-(CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an aminoethyl tetraglycol-modified deacetylated hypocrellin derivative (R=-(CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%, Rf: <NUM>. Characterization data as follows: MS (ESI+): <NUM>; Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of an aminoethyl pentaglycol-modified hypocrellin B derivative (R=-(CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an aminoethyl polyglycol-modified deacetylated hypocrellin B derivative (R=-(CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)n-OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%, Rf: <NUM>; characterization data as follows: MS (ESI+): <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a <NUM>-aminopropyl glycol-modified hypocrellin B derivative (R=-(CH<NUM>)<NUM>-OCH<NUM>CH<NUM>OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an ethylene glycol aminoacetate-modified deacetylated hypocrellin B derivative (R=-CH<NUM>COOCH<NUM>CH<NUM>OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a diethylene glycol aminoacetate-modified hypocrellin B derivative (R=-CH<NUM>CO(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a triethylene glycol aminoacetate-modified deacetylated hypocrellin derivative (R=-CH<NUM>CO(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a polyethylene glycol aminopropionate-modified hypocrellin B derivative (R=-(CH<NUM>)<NUM>CO(OCH<NUM>CH<NUM>)nOH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a triethylene glycol aminopentanoate-modified deacetylated hypocrellin derivative (R=-(CH<NUM>)<NUM>CO(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C13=C14) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of an ethylene glycol aminomethanesulfonate-modified hypocrellin derivative (R=-CH<NUM>SO<NUM>-OCH<NUM>CH<NUM>-OH): hypocrellin B (HB) (<NUM>, <NUM> mmol) and monoethylene glycol aminomethanesulfonate (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. Then the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, and successively washed with diluted aqueous hydrochloric acid solution twice and with distilled water once. The organic layer was dried, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was separated by thin layer silica gel chromatography with acetone: petroleum ether (volume ratio: <NUM>:<NUM>) as a developer to obtain two blue black solid products. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a diethylene glycol aminomethanesulfonate-modified deacetylated hypocrellin derivative (R=-CH<NUM>SO<NUM>(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a tetraethylene glycol aminomethanesulfonate-modified hypocrellin derivative (R=-CH<NUM>SO<NUM>(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a triethylene glycol aminobutanesulfonate-modified hypocrellin derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>SO<NUM>(OCH<NUM>CH<NUM>)<NUM>OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of an ethylenediamino-substituted triglycol-modified hypocrellin B derivative (R=-(CH<NUM>CH<NUM>-NHCH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an ethylenediamino triglycol-modified deacetylated hypocrellin derivative (R=-(CH<NUM>CH<NUM>-NHCH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%, Rf: <NUM>. Characterization data as follows: MS (ESI+): <NUM>; Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of an aminoethylthio-substituted diglycol-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>-S-CH<NUM>CH<NUM>-OCH<NUM>CH<NUM>-OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an aminoethylthio-substituted pentaglycol-modified deacetylated hypocrellin B derivative (R=-(CH<NUM>CH<NUM>-S-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OH): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%, Rf: <NUM>; characterization data as follows: MS (ESI+): <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a methyl tetraglycol aminopropanamide-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CONH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OCH<NUM>): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a tetraethylene glycol aminopentanamide-modified hypocrellin B derivative (R=-(CH<NUM>)<NUM>CH<NUM>CONH-CH<NUM>CH<NUM>-(OCH<NUM>CH<NUM>)<NUM>-OCH<NUM>): the synthesis method similar to the preparation of a <NUM>-aminopropanol-modified deacetylated hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a hexylamine-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>): a hypocrellin B (HB) (<NUM>, <NUM> mmol) and hexylamine (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. Then the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, and successively washed with diluted aqueous hydrochloric acid solution twice and with distilled water once. The organic layer was dried, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was separated by thin layer silica gel chromatography with acetone: petroleum ether (volume ratio: <NUM>:<NUM>) as a developer to obtain two blue black solid products. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a butylamine-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of an octylamine-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>CH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a butylhexylamine-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a benzylamino hypocrellin B derivative (R=-CH<NUM>C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a phenylbutylamine-modified hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a <NUM>-methylpyridin-amino hypocrellin B derivative (R=-CH<NUM>C<NUM>H<NUM>N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of a phenylbutylamine-modified deacetylated hypocrellin B derivative (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>C<NUM>H<NUM>N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of a <NUM>-methylpyridin-butylamino hypocrellin B derivative (R=-(CH<NUM>)<NUM>C<NUM>H<NUM>N+(C<NUM>H<NUM>)): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of hypocrellin B hydrazine (R=-NH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of deacetylated hypocrellin B hydrazine (R=-NH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of hypocrellin B hydrazine (R=-OH): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of deacetylated hypocrellin B hydrazine (R=-OH): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of cyclohexylamine-modified hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of cyclohexylamine-modified deacetylated hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of cyclobutylamine-modified hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of cyclopentylamine-modified hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of cycloheptylamine-modified hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of p-methyl-cyclohexylamine-modified hypocrellin (R=-C<NUM>H<NUM>CH<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of <NUM>-aminopiperidine-modified hypocrellin (R=-C<NUM>H<NUM>N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of <NUM>-butenylamine-modified hypocrellin (R=-C<NUM>H<NUM>): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Preparation of N,N-dimethyl-N-decylamino-ethyldiamino deacetylated hypocrellin B (R=-CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>)): the synthesis route as shown in <FIG>: deacetylated hypocrellin HC (<NUM>, <NUM> mmol) and a long chain quaternary ammonium salt derivative S3 (<NUM>, <NUM> mmol) prepared in Example <NUM> were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, and successively washed with <NUM> of diluted aqueous hydrochloric acid solution once and with hdistilled water twice. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate: ethanol: diethylamine (volume ratio: <NUM>:<NUM>:<NUM>:<NUM>) as a developer to respectively obtain two blue black solid products. The resulting product: yield: <NUM>%; Rf: <NUM>; MS (ESI+) <NUM>; maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of N,N-dimethyl-N-dodecylamine-butyldiamino hypocrellin B (R=-CH<NUM>CH<NUM>CH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>): the synthesis method similar to the preparation of a quaternary ammonium salt-containing hypocrellin derivative in Example <NUM>. The resulting <NUM>-amino-substituted product: yield: <NUM>%, Rf: <NUM>. Characterization data as follows: MS (ESI+): <NUM>; Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of N,N,N-trimethylammonium-decyldiamino hypocrellin B (R=-(CH<NUM>)<NUM>-N+(CH<NUM>)<NUM>: the synthesis method similar to the preparation of a quaternary ammonium salt-containing hypocrellin derivative in Example <NUM>. The resulting <NUM>-amino-substituted product: yield: <NUM>%, Rf: <NUM>. Characterization data as follows: MS (ESI+): <NUM>; Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of N,N-dimethyl-N-decyl-PEG-amino hypocrellin B (R=-CH<NUM>CH<NUM>OCH<NUM>CH<NUM>OCH<NUM>CH<NUM>-N+(CH<NUM>)<NUM>(C<NUM>H<NUM>): the synthesis method similar to the preparation of quaternary ammonium salt-containing hypocrellin derivative in Example <NUM>. The resulting <NUM>-amino-substituted product: yield: <NUM>%, Rf: <NUM>. Characterization data as follows: MS (ESI+): <NUM>; Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted product HC-<NUM> of the invention (double bond located at C<NUM>=C<NUM>) or HC-<NUM> (double bond located at C<NUM>=C<NUM>) has the structural formula as shown in the figure:
<CHM>.

Preparation of piperazino(deacetylated hypocrellin): deacetylated hypocrellin HC (<NUM>, <NUM> mmol) and ethyldiamine (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, washed with <NUM> of diluted aqueous hydrochloric acid solution thrice, and then washed with distilled water once. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate: ethanol: diethylamine (volume ratio: <NUM>:<NUM>:<NUM>:<NUM>) as a developer to obtain a blue black solid product with a yield of <NUM>% and with Rf of <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> of the invention:
<CHM>.

Preparation of methylpiperazino(deacetylated hypocrellin B): the preparation method similar to the preparation of piperazino(deacetylated hypocrellin) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>, both being embodiments of the invention:
<CHM>.

Preparation of dimethylpiperazino(hypocrellin B): A hypocrellin B (HB) (<NUM>, <NUM> mmol) and dimethyl ethyldiamine (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, washed with <NUM> of diluted aqueous hydrochloric acid solution thrice, and then washed with distilled water once. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate: ethanol: diethylamine (volume ratio: <NUM>:<NUM>:<NUM>:<NUM>) as a developer to obtain a blue black solid product with a yield of <NUM>% and with Rf of <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of diethylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dipropylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dibutylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>, both being embodiments of the invention:
<CHM>.

Preparation of dibutylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of trimethylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dibutyl-methylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dihexyl-methylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dimethyl-ethoxylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino (hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dimethyl-DEG-ylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of dimethyl-triethylene glycol-ylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HC-<NUM> or HC-<NUM>:
<CHM>.

Preparation of diethoxylpiperazino(hypocrellin B):
A hypocrellin B (HB) (<NUM>, <NUM> mmol) and dihydroxyethyl ethyldiamine (<NUM>, <NUM> mmol) were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in <NUM> of dichloromethane, washed with <NUM> of diluted aqueous hydrochloric acid solution thrice, and then washed with distilled water once. The organic layer was dried with anhydrous magnesium sulfate, and filtered, and then the organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate: ethanol: diethylamine (volume ratio: <NUM>:<NUM>:<NUM>:<NUM>) as a developer to obtain a blue black solid product with a yield of <NUM>% and with Rf of <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HB-<NUM> or HB-<NUM>:
<CHM>.

Preparation of dihexyl-ethoxylpiperazino(hypocrellin B): the synthesis method similar to the preparation of diethxoylpiperazino(hypocrellin B) in Example <NUM>. Yield: <NUM>%, Rf: <NUM>. Characterization data of the product as follows: ESI MS: m/z, <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The product is respectively represented by structural formula HB-<NUM> or HB-<NUM>:
<CHM>.

Preparation of a DABACO quaternary ammonium salt-modified hypocrellin B derivative: the synthesis method similar to the preparation of a quaternary ammonium salt-containing hypocrellin derivative in Example <NUM>. <NUM>,<NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>, maximum UV absorption wavelength: <NUM>, <NUM>. <NUM>-amino-substituted product HB-<NUM>: yield: <NUM>%, Rf: <NUM>, MS (ESI+) <NUM>. Maximum UV absorption wavelength: <NUM>, <NUM>. The amino-substituted products HB-<NUM> and HB-<NUM> have the structural formulas as shown in the figure:
<CHM>.

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; Synthesis of a new water-soluble phototherapeutic sensitizer from hypocrellin B with enhanced red absorption, <NPL>. <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and mercaptoethylamine hydrochloride (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted, <NUM>,<NUM>-substituted or <NUM>,<NUM>,<NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>NO<NUM>S, [M+ H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of n-butylamine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, and washed with <NUM> of diluted aqueous hydrochloric acid solution several times until the solution was neutral. The organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to respectively obtain products I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Dark toxicity experiment: Hela cells at a certain concentration were inoculated into a <NUM>-well plate, and cultured for <NUM>-<NUM>. After removing the original culture solution from the <NUM>-well plate, compound I-<NUM> solutions at different concentrations were added. After incubation for <NUM>, the photosensitizer solution was removed, and a fresh culture solution was added for cultivation in a <NUM>% CO<NUM> environment at <NUM> for <NUM>. The survival rate of cells in each group was detected by MTT assay. As shown in <FIG>, the compound I-<NUM> has very low cytotoxicity, which is equivalent to the cytotoxicity of the commercial photosensitizer dihydroporphin Ce6 and the HB. Phototoxicity experiment: Hela cells were incubated together with different concentrations of the compound I-<NUM>, the HB and the Ce6 respectively, further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM> hour. After laser irradiation with a power density of <NUM> mW/cm<NUM> at a wavelength of <NUM> for <NUM>, the Hela cells were further cultured and incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. The survival rate of cells in each group was detected by MTT assay. As shown in <FIG>, <NUM> compound I-<NUM> can kill more than <NUM>% Hela cells, while the commercial photosensitizer dihydroporphin Ce6 can kill only about <NUM>% Hela cells under identical conditions.

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; <NPL>. <NUM> groups of <NUM> of methanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and cysteine hydrochloride (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted and <NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>NO<NUM>S, [M + H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of n-dodecylamine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, and washed with <NUM> of diluted aqueous hydrochloric acid solution until the solution was neutral. The organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to respectively obtain two products I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

By referring to the method in Example <NUM>, <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and mercaptoethylamine hydrochloride (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted, <NUM>,<NUM>-substituted or <NUM>,<NUM>,<NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain a compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of <NUM>-N,N-dimethylamino n-hexylamine were dissolved in <NUM> of tetrahydrofuran, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, and washed with <NUM> of diluted aqueous hydrochloric acid solution several times until the solution was neutral. The organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to respectively obtain two products I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to the following documents for the preparation method of a compound <NUM>: Photoreactions of hypocrellin B with thiol compounds, <NPL>; <NPL>. <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and mercaptoethylamine hydrochloride (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted, <NUM>,<NUM>-substituted or <NUM>,<NUM>,<NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of <NUM>-sulfo n-hexylamine were dissolved in <NUM> of dimethyl sulfoxide and <NUM> mol/L water solution of sodium hydroxide (<NUM>:<NUM>), fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the pH was adjusted to a neutral pH with diluted hydrochloric acid, and the solvent was removed by rotary evaporation. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with dichloromethane: methanol (volume ratio: <NUM>:<NUM>) as a developer to respectively obtain products I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

<NUM> of the compound <NUM> and <NUM> of cyclopentylamine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, and washed with <NUM> of diluted aqueous hydrochloric acid solution several times until the solution was neutral. The organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; <NPL>. <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and cysteine triethylene glycol ester (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, the crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of benzylamine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, adjusted with diluted hydrochloric acid until the solution was at a neutral pH, and spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; <NPL>. <NUM> groups of <NUM> of methanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and <NUM>-dimethyl cysteine (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, a crude product was obtained by washing with chloroform and spin drying of the water phase, and then the compound <NUM> was obtained by Sephadex G-<NUM> column chromatography with water as an eluting agent: yield: <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of <NUM>-methylamino pyridine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, adjusted with diluted hydrochloric acid until the solution was at a neutral pH, and spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; <NPL>. <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of HB (<NUM>) and cysteine ethyl ester (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted, <NUM>,<NUM>-substituted or <NUM>,<NUM>,<NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>NO<NUM>S, [M + H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of <NUM>-morpholin-cyclohexylamine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of chloroform, and washed with <NUM> of diluted aqueous hydrochloric acid solution several times until the solution was neutral. The organic phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

<NUM> of the compound <NUM> and <NUM> of a long chain quaternary ammonium salt derivative were dissolved in <NUM> of anhydrous acetonitrile, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in <NUM> of dichloromethane, washed with <NUM> of diluted aqueous hydrochloric acid solution until the solution was neutral, and spin-dried to obtain a crude product. The resulting crude product was further separated by silica gel chromatography with acetone: ethyl acetate: ethanol: diethylamine (volume ratio: <NUM>:<NUM>:<NUM>:<NUM>) as a developer to respectively obtain two products I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of compounds I-<NUM> and I-<NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

The synthesis of compounds I-<NUM> and I-<NUM> is identical to Example <NUM>. I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M/<NUM>]<NUM>+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

<NUM> of the compound <NUM> and <NUM> of amino-PEG <NUM> were dissolved in <NUM> of dichloromethane, fully mixed, and stirred in dark at room temperature under nitrogen protection for <NUM>. On completion of the reaction, diethyl ether was added to separate out a solid, i.e., a crude product. The resulting crude product was further separated by silica gel chromatography to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+ H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to the following documents for the preparation method of a compound <NUM>: <NPL>; <NPL>. <NUM> groups of <NUM> of ethanol/water buffer solution (<NUM>/<NUM>, pH=<NUM>) of deacetylated hypocrellin HC (<NUM>) and mercaptoethylamine hydrochloride (<NUM>) present in <NUM> photochemical reactors were irradiated with a <NUM> W high pressure sodium lamp (light below <NUM> filtered with a glass long pass filter) at room temperature for <NUM>. On completion of the reaction, and after acidification with <NUM>% hydrochloric acid, chloroform was added for extraction. The chloroform phase was washed with water and then spin-dried to obtain a crude product. The crude product was further separated by silica gel chromatography with chloroform: methanol (volume ratio: <NUM>:<NUM>) as a developer to obtain a mixture of <NUM>,<NUM>-substituted, <NUM>,<NUM>-substituted or <NUM>,<NUM>,<NUM>,<NUM>-substituted HB, which were separated by HPLC to obtain the compound <NUM> with a yield of <NUM>%. MS (ESI+): m/z C<NUM>H<NUM>NO<NUM>S, [M + H]+=<NUM>.

<NUM> of the compound <NUM> and <NUM> of glycine were dissolved in <NUM> of pyridine, fully mixed, heated to <NUM> under nitrogen protection, and stirred in dark for <NUM>. On completion of the reaction, the solvent was removed by rotary evaporation. After adding deionized water and washing with ethyl acetate, the water phase was spin-dried to obtain a crude product. The resulting crude product was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to respectively obtain two products I-<NUM> and I-<NUM>. I-<NUM> and I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M+ H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of compounds I-<NUM> and I-<NUM>. I-<NUM> and I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M+H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

<NUM> of the compound <NUM> was dissolved in <NUM> of freshly distilled tetrahydrofuran, and then <NUM> of cyclohexanediamine was added. The resulting solution was stirred in dark, and kept at <NUM> for <NUM>. On termination of the reaction, the solvent was removed under reduced pressure, dissolved in chloroform, and washed with diluted hydrochloric acid until neutral. The organic phase was spin-dried to obtain a crude product, which was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of a compound <NUM>. <NUM> of the compound <NUM> was dissolved in <NUM> of freshly distilled tetrahydrofuran, and then <NUM> of hexanediamine was added. The resulting solution was stirred in dark, and kept at <NUM> for <NUM>. On termination of the reaction, the solvent was removed under reduced pressure, dissolved in chloroform, and washed with diluted hydrochloric acid until neutral. The organic phase was spin-dried to obtain a crude product, which was further separated by <NUM>% KH<NUM>PO<NUM> silica gel chromatography with petroleum ether: ethyl acetate: ethanol (volume ratio: <NUM>:<NUM>:<NUM>) as a developer to obtain a compound I-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Dark toxicity experiment: Hela cells at a certain concentration were inoculated into a <NUM>-well plate, and cultured for <NUM>-<NUM>. After removing the original culture solution from the <NUM>-well plate, compound II-<NUM> solutions at different concentrations were added. After incubation for <NUM>, the photosensitizer solution was removed, and a fresh culture solution was added for cultivation in a <NUM>% CO<NUM> environment at <NUM> for <NUM>. The survival rate of cells in each group was detected by MTT assay. As shown in <FIG>, the compound II-<NUM> has very low cytotoxicity, which is equivalent to the cytotoxicity of the commercial photosensitizer dihydroporphin Ce6 and the HB.

Phototoxicity experiment: Hela cells were incubated together with different concentrations of the compound II-<NUM>, the HB and the Ce6 respectively, further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM> hour. After laser irradiation with a power density of <NUM> mW/cm<NUM> at a wavelength of <NUM> for <NUM>, the Hela cells were further cultured and incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. The survival rate of cells in each group was detected by MTT assay. As shown in <FIG>, <NUM> compound I-<NUM> can kill more than <NUM>% Hela cells, while the commercial photosensitizer Ce6 can kill only about <NUM>% Hela cells under identical conditions.

Please refer to Example <NUM> for the synthesis of a compound <NUM>. Please refer to Example <NUM> for the synthesis of compounds II-<NUM> and II-<NUM>. II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of a compound <NUM>. Please refer to Example <NUM> for the synthesis of a compound II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of a compound II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Please refer to Example <NUM> for the synthesis of compounds II-<NUM> and II-<NUM>. II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>). II-<NUM>: yield: <NUM>%; MS (ESI+), m/z C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>, [M + H]+=<NUM>; maximum UV absorption wavelength: λmax (log ε), <NUM> (<NUM>).

Cultured Hela cells were digested and percussed with <NUM>% trypsin, made into a single cell suspension, adjusted to a cell count of about 2x10<NUM>/mL, inoculated into a <NUM>-well culture plate with <NUM> uL/well, and cultured in an incubator with a <NUM>% CO<NUM> environment at <NUM>. After cells were adherent, the supernatant culture solution was discarded, different concentrations of photosensitizers (hematoporphyrin derivative HpD, HB, and hypocrellin derivative HB-<NUM>) were added strictly in dark according to the experiment design, and further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. The survival rate of cells was detected by MTT assay. <NUM> uL of MTT (prepared with PBS, concentration: <NUM>/mL) was added to each well, and further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. Then the incubationi was terminated. The supernatent was carefully pipetted from the wells and discarded, and then <NUM> uL of dimethyl sulfoxide (DMSO) was added to each well. The violet crystal was fully dissolved by vibration with a microvibrator for <NUM>. The optical density value (OD value) of each well was detected by an ELIASA at <NUM> wavelength to calculate the cell survival rate according to the following formula: cell survival rate=OD value of the experimental group/OD value of the blank group×<NUM>%. <FIG> shows the dark toxicity experiment results.

Cultured Hela cells were digested and percussed with <NUM>% trypsin, ,made into a single cell suspension, adjusted to a cell count of about 2x10<NUM>/mL, inoculated into a <NUM>-well culture plate with <NUM> uL/well, and cultured in an incubator with a <NUM>% CO<NUM> environment at <NUM>. After cells were adherent, the supernatant culture solution was discarded, different concentrations of photosensitizers (hematoporphyrin derivative HpD, HB, and hypocrellin derivative HB-<NUM>) were added strictly in dark according to the experiment design, and further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. Then the <NUM>-well culture plate was perpendicularly irradiated with uniform semiconductor laser beam at a wavelength of <NUM> with the power density adjusted to <NUM> mW/cm<NUM> for <NUM>. At the same time, a blank group was arranged for each <NUM>-well culture plate, and <NUM> wells were arranged for each condition. After irradiation, the culture plate was further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>, and then the cell survival rate was detected. The survival rate of cells was detected by MTT assay. <NUM> uL of MTT (prepared with PBS, concentration: <NUM>/mL) was added to each well, and further incubated in an incubator with a <NUM>% CO<NUM> environment at <NUM> for another <NUM>. Then the incubation was terminated. The supernatent was carefully pipetted from the wells and discarded, and then <NUM> uL of dimethyl sulfoxide (DMSO) was added to each well. The violet crystal was fully dissolved by vibration with a microvibrator for <NUM>. The optical density value (OD value) of each well was detected by an ELIASA at <NUM> wavelength to calculate the cell survival rate according to the following formula: cell survival rate=OD value of the experimental group/OD value of the blank group×<NUM>%. <FIG> shows the phototoxicity experiment results.

The structural formula of unmodified hypocrellin B (HB) is shown in <FIG>, the absorption spectrum is shown in Fig. 7a, the maximum absorption wavelength is <NUM>, and there is weak red absorption at <NUM>. HB has weak light absorption capacity in the phototherapy window of <NUM>-<NUM>, and has much poorer ability to photodynamically kill tumor cells than the amphiphilic hypocrellin derivatives according to the invention (<FIG>).

A patent No. <CIT> discloses that a compound A has the maximum absorption at <NUM>. The maximum absorption spectrum wavelength of the hypocrellin derivative A in the comparison Example is nearly <NUM> lower when compared with the polysubstituted near infrared hypocrellin derivative I-<NUM>.

A document (<NPL>) discloses that a compound B has the maximum absorption at <NUM>. The maximum absorption spectrum wavelength of the hypocrellin derivative B in the comparison Example is nearly <NUM> lower when compared with the polysubstituted near infrared hypocrellin derivative II-<NUM>.

Claim 1:
A monosubstituted or polysubstituted amphiphilic hypocrellin derivative, being represented by general structural formula (IV-a) or (V-a):
<CHM>
in formula (IV-a), substituent R is represented by general structural formula (III):
<CHM>
in formula (III), <NUM>≤m≤<NUM>, <NUM>≤n≤<NUM>, <NUM>≤p≤<NUM>, <NUM>≤q≤<NUM> and <NUM>≤r≤<NUM>; the m, n, p, q and r are zero or positive integers; Y is O, S, a carboxylate, an amide, a sulfonate, or a cycloalkane containing <NUM>-<NUM> carbon atoms, optionally substituted with an alkyl containing <NUM>-<NUM> carbon atoms;
in formula (III), the terminal group Z is hydrogen, an alkyl containing <NUM>-<NUM> carbon atoms, an alkoxy containing <NUM>-<NUM> carbon atoms, a phenyl, a heterocycle, a hydroxy, a sulfhydryl, a carboxy, a sulfo or a pyridine salt;
in formula (III), when the terminal group Z is a pyridine salt, the substituent on the pyridine ring of the pyridine salt is at an ortho-position, a meta-position or a para-position; the pyridine salt is prepared by quaternization of pyridine and a halogenated hydrocarbon containing <NUM>-<NUM> carbon atoms of different chain lengths; and the anion of the pyridine salt is an acceptable anion in pharmaceutical preparations;
in formula (III), three substituents R<NUM>, R<NUM> and R<NUM> of a quaternary ammonium salt are independently or completely: an alkyl containing <NUM>-<NUM> carbon atoms, an alkenyl containing <NUM>-<NUM> carbon atoms, an alkynyl containing <NUM>-<NUM> carbon atoms, a cycloalkyl containing <NUM>-<NUM> carbon atoms, a cycloalkenyl containing <NUM>-<NUM> carbon atoms, an aryl or an aralkyl containing <NUM>-<NUM> carbon atoms; or an alkyl with a terminal group containing a hydroxy, a carboxy, a sulfo or a carboxylate; or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl having a chain containing a heteroatom of oxygen, nitrogen or sulfur atom and <NUM>-<NUM> carbon atoms; or different combinations of the above substituents and the anion X- of the quaternary ammonium salt is an acceptable anion in pharmaceutical preparations;
in formula (V-a), R<NUM>-R<NUM> are partially identical, or completely identical, or completely different, and are -H; -CH<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; -C<NUM>H<NUM>; or -C<NUM>H<NUM>.