MONOSUBSTITUTED OR POLYSUBSTITUTED AMPHIPHILIC HYPOCRELLIN DERIVATIVE, AND PREPARATION METHOD AND APPLICATION THEREOF

20180338965 · 2018-11-29

Inventors

Cpc classification

International classification

Abstract

The invention discloses a monosubstituted or polysubstituted amphiphilic hypocrellin derivative, and a preparation method and application thereof. The amphiphilic hypocrellin derivative substituted by a group containing PEG, a quaternary ammonium salt or the like prepared according to the invention has an obvious red shift in its absorption spectrum and a significantly enhanced molar extinction coefficient, compared with the parent hypocrellin, can efficiently produce singlet state oxygen and other reactive oxygen species under photosensitive conditions; has different amphiphilicities and increased biocompatibility with cells or tissues by regulating its hydrophilicity and hydrophobicity; can meet the requirements of different clinical drugs, and solves the requirements of different drug delivery methods for different drug hydrophilicity and lipophilicity. Under identical conditions, the amphiphilic hypocrellin derivative photosensitizer according to the invention has higher ability to photodynamically inactivate tumor cells than the first and second generation commercial photosensitizers.

Claims

1. A monosubstituted or polysubstituted amphiphilic hypocrellin derivative, being represented by general structural formula (I) or (II): ##STR00106## in formulas (I) and (II), T.sub.1 means that neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 are bonded, or one group or two groups are bonded; when neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen; and when two adjacent R.sub.2 and R.sub.3 or two adjacent R.sub.4 and R.sub.5 are bonded, they form a substituted or unsubstituted six-membered heterocycle, wherein T.sub.1 is a substituted or unsubstituted linker containing two carbon atoms, R.sub.2 and R.sub.5 are nitrogen, and R.sub.3 and R.sub.4 are sulfur; and the dashed lines at C.sub.13, C.sub.14 and C.sub.15 mean that the double bond is at C.sub.13?C.sub.14 or C.sub.14?C.sub.15; in formula (I), R.sub.1 is H, COCH.sub.3 or C(CH.sub.3)?NR; in formula (II), R.sub.1 is H or COCH.sub.3; T.sub.2 means that R.sub.8 and R.sub.9 are bonded or not bonded; and when R.sub.8 and R.sub.9 are bonded, they form a substituted or unsubstituted five-membered, six-membered or seven-membered ring, wherein T.sub.2 is a substituted or unsubstituted linker containing one, two or three carbon atoms; in formula (I), when neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.1 is hydrogen, the double bond is located at C.sub.13?C.sub.14 or C.sub.14?C.sub.15 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (I); and in formula (I), when neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.1 is COCH.sub.3 or C(CH.sub.3)?NR, the double bond is located at C.sub.13?C.sub.14 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (I); in formula (II), when none of two adjacent R.sub.2 and R.sub.3, two adjacent R.sub.4 and R.sub.5 and two adjacent R.sub.8 and R.sub.9 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.1 is hydrogen, the double bond is located at C.sub.13?C.sub.14 or C.sub.14?C.sub.15 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (II); and in formula (II), when none of two adjacent R.sub.2 and R.sub.3, two adjacent R.sub.4 and R.sub.5 and two adjacent R.sub.8 and R.sub.9 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.1 is COCH.sub.3, the double bond is located at C.sub.13?C.sub.14 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (II); in formula (I), R is a substituent, and is a hydrophobic group, a hydrophilic group or different combinations thereof; the hydrophobic group comprises an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkynyl, a phenyl or a heterocycle; the hydrophilic group comprises a hydroxy, a carboxy, an ester group, an acylamino, a carboxy, a sulfo, a PEG-yl or a quaternary ammonium salt; and the substituent R is represented by general structural formula (III): ##STR00107## in formula (III), 0?m?12, 0?n?500, 0?p?12, 0?q?12 and 0?r?1; the m, n, p, q and r are zero or positive integers; Y is a linking group; Z is a terminal group; and (OCH.sub.2CH.sub.2).sub.n is a polyethylene glycol unit; in formula (III), the linking group Y is NH, O, S, a carboxylate, an amide, a sulfonate, an aryl, a heteroaryl, an alkyl containing 3-12 carbon atoms or a cycloalkyl containing 3-12 carbon atoms; the aryl is a substituted or unsubstituted aryl; the heteroaryl is a substituted or unsubstituted heteroaryl; the alkyl containing 3-12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing alkene or alkyne; the cycloalkyl containing 3-12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing cycloalkane, cycloalkene or cycloalkyne; the heteroatom is oxygen, nitrogen or sulfur atom; the substituent is an alkyl containing 1-12 carbon atoms, an alkenyl containing 2-12 carbon atoms, an alkynyl containing 2-12 carbon atoms, a cycloalkyl containing 3-8 carbon atoms, an aryl or an aralkyl containing 6-12 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 1-12 carbon atoms; or different combinations of the above substituents; in formula (III), the terminal group Z is hydrogen, an alkyl containing 1-12 carbon atoms, an alkoxy containing 1-12 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 1-12 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.sub.12, R.sub.13 and R.sub.14 of a quaternary ammonium salt are independently or completely: an alkyl containing 1-12 carbon atoms, an alkenyl containing 2-12 carbon atoms, an alkynyl containing 2-12 carbon atoms, a cycloalkyl containing 3-8 carbon atoms, a cycloalkenyl containing 3-8 carbon atoms, an aryl or an aralkyl containing 6-12 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 1-12 carbon atoms; or different combinations of the above substituents; and the anion X.sup.? of the quaternary ammonium salt is an acceptable anion in pharmaceutical preparations; in formula (I), when neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, R.sub.1 is COCH.sub.3, and the double bond is located at C.sub.13?C.sub.14, the substituent R in formula (I) does not comprise the following structure: (CH.sub.2).sub.mNH(CH.sub.2).sub.pZ, wherein 1?m?12, 0?p?12, and Z is a hydroxy, an alkoxy, a carboxylic acid or a carboxylate; in formula (II), R.sub.6-R.sub.11 on the hypocrellinopiperazine ring are subject to the substituent R, which is a hydrophobic group, a hydrophilic group or different combinations thereof; the hydrophobic group comprises an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkynyl, a phenyl or a heterocyclic group; the hydrophilic group comprises a hydroxy, a carboxy, an ester group, an acylamino, a carboxy, a sulfo, a PEG-yl, a quaternary ammonium salt or a pyridine salt; and the substituent R is represented by general structural formula (III); and in formula (II), when none of two adjacent R.sub.2 and R.sub.3, two adjacent R.sub.4 and R.sub.5 and two adjacent R.sub.8 and R.sub.9 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, R.sub.1 is hydrogen, and the double bond is located at C.sub.14?C.sub.15, at least one of carbon atoms a and b on the marked piperazine ring in formula (II) is a tertiary carbon atom; and in formula (II), when none of two adjacent R.sub.2 and R.sub.3, two adjacent R.sub.4 and R.sub.5, and two adjacent R.sub.8 and R.sub.9 are bonded, R.sub.2 and R.sub.5 are oxygen, R.sub.3 and R.sub.4 are hydrogen, R.sub.1 is COCH.sub.3, and the double bond is located at C13?C14, at least one of the carbon atoms a and b on the marked piperazine ring in formula (II) is a tertiary carbon atom.

2. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein the T.sub.1 in formula (I) is acyclically bonded, and is represented by general structural formula (IV): ##STR00108## in formula (I), when neither of two adjacent R.sub.2 and R.sub.3 nor two adjacent R.sub.4 and R.sub.5 of hypocrellin are bonded, R.sub.2 and R.sub.5 are oxygen, and R.sub.3 and R.sub.4 are hydrogen, it is represented by general structural formula (IV); in formula (IV), the substituent R.sub.1 of the hypocrellin derivative is H, COCH.sub.3 or C(CH.sub.3)?NR; when the R.sub.1 is H, the double bond is located at C.sub.13?C.sub.14 or C.sub.14?C.sub.15 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (IV); and when the R.sub.1 is COCH.sub.3 or C(CH.sub.3)?NR, the double bond is located at C.sub.13?C.sub.14 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (IV); in formula (IV), the substituent R is represented by general structural formula (III), and is a hydrophobic group, a hydrophilic group or different combinations thereof; the hydrophobic group comprises an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkynyl, a phenyl or a heterocycle; the hydrophilic group comprises a hydroxy, a carboxy, an ester group, an acylamino, a carboxy, a sulfo, a PEG-yl or a quaternary ammonium salt; and in formula (IV), when the substituent R.sub.1 is H and the double bond is located at C.sub.14?C.sub.15, or the R.sub.1 is COCH.sub.3 and the double bond is located at C.sub.13?C.sub.14, the substituent R does not comprise the following structure: (CH.sub.2).sub.mNH(CH.sub.2).sub.pZ, wherein 1?m?12, 0?p?12, and Z is a hydroxy, an alkoxy, a carboxylic acid or a carboxylate.

3. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein both of the T.sub.1 and the T.sub.2 in formula (II) are acyclically bonded, and is represented by general structural formula (V): ##STR00109## in formula (II), when none of two adjacent R.sub.2 and R.sub.3, two adjacent R.sub.4 and R.sub.5 and two adjacent R.sub.8 and R.sub.9 of hypocrellin are bonded, R.sub.2 and R.sub.5 are oxygen, and R.sub.3 and R.sub.4 are hydrogen, it is represented by general structural formula (V); in formula (V), the substituent R.sub.1 of the piperazinohypocrellin derivative is H or COCH.sub.3; when the R.sub.1 is H, the double bond is located at C.sub.13?C.sub.14 or C.sub.14?C.sub.15 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (V); and when the R.sub.1 is COCH.sub.3, the double bond is located at C.sub.13?C.sub.14 of the marked C.sub.13, C.sub.14 and C.sub.15 in formula (V); in formula (V), when the substituent R.sub.1 is H and the double bond is located at C.sub.14?C.sub.15, at least one of carbon atoms a and b on the marked piperazine ring in formula (V) is a tertiary carbon atom; and in formula (V), when the substituent R.sub.1 is COCH.sub.3 and the double bond is located at C.sub.13?C.sub.14, at least one of the carbon atoms a and b on the marked piperazine ring in formula (V) is a tertiary carbon atom; and in formula (V), the substituents R.sub.6-R.sub.11 are defined similarly to the substituent R in formula (III), and are partially identical, or completely identical or completely different; and are hydrophobic groups, hydrophilic groups or different combinations thereof; the hydrophobic group comprises an alkyl, an alkenyl, an alkynyl, a cycloalkyl or a heterocycle; and the hydrophilic group comprises a hydroxy, a carboxy, an ester group, an ether group, an acylamino, a sulfo, a PEG unit or a quaternary ammonium salt.

4. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein the T.sub.1 in formula (I) and formula (II) is a substituted or unsubstituted linker containing two carbon atoms, and has a structure represented by formula (VI), wherein the substituents R.sub.15-R.sub.18 are independently or completely the substituent R in formula (III) according to claim 1; and the R.sub.8, the R.sub.9 and the T.sub.2 in formula (II) form a substituted or unsubstituted five-membered, six-membered or seven-membered ring represented by formula (VII): ##STR00110## wherein ring A is a saturated or unsaturated five-membered, six-membered or seven-membered heterocycle or non-heterocycle, and the substituents thereon are independently or completely the substituent R in formula (III) according to claim 1.

5. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein the linker Y in the substituent R is: NH; O, S; COO; CONH; SO.sub.3; CH?CH; C?C; C.sub.6H.sub.4 (phenyl); C.sub.6H.sub.3(CH.sub.3); C.sub.6H.sub.3(C.sub.2H.sub.5); C.sub.6H.sub.3(OH); C.sub.6H.sub.3(F); C.sub.6H.sub.3(Cl); C.sub.6H.sub.3(Br); C.sub.5H.sub.3N (pyridyl); C.sub.3H.sub.4 (cyclopropyl); C.sub.4H.sub.6 (cyclobutyl); C.sub.5H.sub.8 (cyclopentyl); C.sub.5H.sub.7(CH.sub.3) (methylcyclopentyl); C.sub.5H.sub.7(OH) (hydroxycyclopentyl); C.sub.6H.sub.10 (cyclohexyl); C.sub.6H.sub.9(CH.sub.3) (methylcyclohexyl); C.sub.6H.sub.9(C.sub.2H.sub.5) (ethylcyclohexyl); C.sub.6H.sub.9(C.sub.3H.sub.7) (propylcyclohexyl); C.sub.6H.sub.9(C.sub.4H.sub.9) (butylcyclohexyl); C.sub.6H.sub.8(CH.sub.3).sub.2 (dimethylcyclohexyl); C.sub.6H.sub.9(OH) (hydroxycyclohexyl); C.sub.7H.sub.12 (cycloheptyl); ##STR00111##

6. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein the terminal group Z in the substituent R is: H; CH.sub.3; C.sub.2H.sub.5; C.sub.3H.sub.7; C.sub.4H.sub.9; C.sub.5H.sub.11; C.sub.6H.sub.13; OCH.sub.3; OC.sub.2H.sub.5; OC.sub.3H.sub.7; OC.sub.4H.sub.9; OC.sub.5H.sub.11; OC.sub.6H.sub.13; C.sub.6H.sub.5; C.sub.5H.sub.4N; OH, NH.sub.2; SH; COOH; COOCH.sub.3; COOC.sub.2H.sub.5; SO.sub.3H; C.sub.5H.sub.4N.sup.+; N.sup.+(CH.sub.3).sub.3; N.sup.+(C.sub.2H.sub.5).sub.3; N.sup.+(C.sub.3H.sub.7).sub.3; N.sup.+(C.sub.4H.sub.9).sub.3; N.sup.+(C.sub.5H.sub.11).sub.3; N.sup.+(C.sub.6H.sub.13).sub.3; N.sup.+(CH.sub.3).sub.2(C.sub.2H.sub.5); N.sup.+(CH.sub.3).sub.2(C.sub.3H.sub.7); N.sup.+(CH.sub.3).sub.2(C.sub.4H.sub.9); N.sup.+(CH.sub.3).sub.2(C.sub.5H.sub.11); N.sup.+(CH.sub.3).sub.2(C.sub.6H.sub.13); N.sup.+(CH.sub.3).sub.2(C.sub.7H.sub.15); N.sup.+(CH.sub.3).sub.2(C.sub.8H.sub.17); N.sup.+(CH.sub.3).sub.2(C.sub.9H.sub.19); N.sup.+(CH.sub.3).sub.2(C.sub.10H.sub.23); N.sup.+(CH.sub.3).sub.2(C.sub.11H.sub.23); N.sup.+(CH.sub.3).sub.2(C.sub.12H.sub.25); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.3H.sub.7); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.4H.sub.9); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.5H.sub.11); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.6H.sub.13); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.7H.sub.15); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.8H.sub.17); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.9H.sub.19); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.10H.sub.23); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.11H.sub.23); N.sup.+(C.sub.2H.sub.5).sub.2(C.sub.12H.sub.25); ##STR00112## (1,4-diazabicyclo[2.2.2]octyl); or a quaternary ammonium salt with a terminal group containing a hydroxy, a carboxy, a sulfo or a carboxylate.

7. The monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, wherein the general structural formula of the hypocrellin derivative in formula (I) further comprises an enol tautomer represented by formula (I), and the general structural formula of the hypocrellin derivative in formula (II) further comprises an enol tautomer represented by formula (II): ##STR00113##

8. A method for preparing the monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, comprising the following steps: mixing hypocrellin B and a corresponding substituted amino derivative at a molar ratio of 1:5-50 in an organic solvent, which is one or more of acetonitrile, tetrahydrofuran, pyridine, methanol and ethanol, keeping the resulting solution in dark at a reaction temperature of 20-100? C. under the protection of an inert gas for 6-18 h, and purifying the product by separation to obtain the amphiphilic hypocrellin derivative in formula (IV) or formula (V).

9. A method for preparing the monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1, comprising the following steps: mixing hypocrellin B or deacetylated hypocrellin B and a corresponding substituted thioethylamine derivative at a molar ratio of 1:50-500 in a mixed solvent of an organic solvent and water, illuminating the resulting solution with light at a wavelength>450 nm at room temperature at pH>9 for 10-40 min, and purifying the product by separation to obtain a 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted hypocrellin derivative; and mixing the hypocrellin derivative and a corresponding substituted amino derivative at a molar ratio of 1:5-50 in an organic solvent, keeping the resulting solution in dark at a reaction temperature of 20-150? C. under the protection of an inert gas for 4-20 h, and obtaining the corresponding polysubstituted hypocrellin derivative in formula (VI) or formula (VII) by separation and purification of the product.

10. An application of the monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to claim 1 as a photosensitizer drug in photodynamic therapy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The embodiments of the invention are further illustrated in detail below in conjunction with the accompanying drawings.

[0032] FIG. 1 shows a general structural formula of a monosubstituted or polysubstituted amphiphilic hypocrellin derivative according to the invention;

[0033] FIG. 2 shows a synthesis reaction route map of PEG-containing hypocrellin B derivatives HB-1 and HB-2 according to Example 3 of the invention;

[0034] FIG. 3 shows a synthesis reaction route map of deacetylated hypocrellin HC and aminopropanol according to Example 4 of the invention;

[0035] FIG. 4 shows a synthesis reaction route map of a deacetylated hypocrellin derivative containing a long chain quaternary ammonium salt according to Example 46 of the invention;

[0036] FIG. 5 shows a synthesis reaction route map of piperazinohypocrellin B derivatives HB-98 and HB-99 according to Example 52 of the invention;

[0037] FIG. 6 shows a synthesis reaction route map of polysubstituted hypocrellin B derivatives I-1 and I-2 according to Example 67 of the invention;

[0038] FIG. 7 shows the comparison of the absorption spectra of hypocrellin B (HB) (a) extracted in Example 1, a PEG-containing hypocrellin B derivative HB-1 (b) prepared in Example 3 and a piperazinohypocrellin B derivative HB-98 (c) prepared in Example 52 of the invention;

[0039] FIG. 8 shows the reactions of a PEG-containing hypocrellin derivative HB-1 according to Example 3 of the invention respectively with a singlet state oxygen scavenger (a) and a superoxide radical scavenger (b);

[0040] FIG. 9 shows confocal fluorescence imaging of a PEG-containing hypocrellin derivative HB-1 according to Example 3 of the invention respectively in Hela cells;

[0041] FIG. 10 shows the Hela cell dark toxicity (a) and phototoxicity (b) of different concentrations of a hematoporphyrin derivative HpD, hypocrellin B (HB), and a PEG-containing hypocrellin derivative HB-1 according to Example 3 of the invention;

[0042] FIG. 11 shows the Hela cell dark toxicity (a) and phototoxicity (b) of different concentrations of a hematoporphyrin derivative HpD, hypocrellin B (HB), and a PEG-containing hypocrellin derivative HB-2 according to Example 3 of the invention;

[0043] FIG. 12 shows the Hela cell phototoxicity of different concentrations of a hematoporphyrin derivative HpD, hypocrellin B (HB), and an aminopropanol-modified deacetylated hypocrellin derivative HC-3 or HC-4 synthesized in Example 4 of the invention;

[0044] FIG. 13 shows the Hela cell phototoxicity of different concentrations of a hematoporphyrin derivative HpD, hypocrellin B (HB), and a deacetylated hypocrellin derivative HC-87 or HC-88 modified with a long chain quaternary ammonium salt synthesized in Example 46 of the invention;

[0045] FIG. 14 shows the Hela cell phototoxicity of different concentrations of a hematoporphyrin derivative HpD, hypocrellin B (HB) and a piperazinohypocrellin B derivative HB-98 according to Example 52 of the invention;

[0046] FIG. 15a shows the reaction of a hypocrellin derivative I-1 according to Example 67 of the invention with a singlet state oxygen scavenger; and FIG. 15b shows the reaction of a hypocrellin derivative I-1 according to Example 67 of the invention with a superoxide radical scavenger;

[0047] FIG. 16a shows the Hela cell dark toxicity of different concentrations of a dihydroporphin Ce6, hypocrellin B (HB) and a hypocrellin derivative I-1 or I-2 according to Example 67 of the invention; and FIG. 16b shows the Hela cell phototoxicity of different concentrations of a dihydroporphin Ce6, hypocrellin B (HB) and a hypocrellin derivative I-1 or I-2 according to Example 67 of the invention;

[0048] FIG. 17a shows the reaction of a hypocrellin derivative II-2 according to Example 67 of the invention with a singlet state oxygen scavenger; and FIG. 17b shows the reaction of a hypocrellin derivative II-2 according to Example 67 of the invention with a superoxide radical scavenger; and

[0049] FIG. 18a shows the Hela cell dark toxicity of different concentrations of a dihydroporphin Ce6, hypocrellin B (HB) and a hypocrellin derivative II-2 according to Example 86 of the invention; and FIG. 18b shows the Hela cell phototoxicity of different concentrations of a dihydroporphin Ce6, hypocrellin B (HB) and a hypocrellin derivative II-2 according to Example 86 of the invention.

DETAILED DESCRIPTION

[0050] In order to illustrate the invention more clearly, the invention is further described below in conjunction with the preferred embodiments and the accompanying drawings, wherein like reference symbols represent like parts. As will be appreciated by those skilled in the art, the following specific description is descriptive rather than restrictive, and should not be used to limit the scope of protection of the invention.

Example 1

[0051] Extraction of hypocrellin A (HA): 100 g of hypocrellin was pulverized by a pulverizer, and continuously extracted with 1,000 ml 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 500 ml of dichloromethane, and washed four times and each with 400 mL of distilled water. The organic layer was separated and spin-dried, the solid residue was washed five times and each with 100 mL 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 98%. Highly purified HA can be obtained by further purification using thin layer silica gel chromatography with petroleum ether:ethyl acetate:anhydrous ethanol (30:10:1) as a developer.

[0052] 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 Organic Chemistry (pp. 252-254, Vol. 9, 1989, Zhao Kaihong). The specific method is as follows: 1 g of the HA was dissolved in 1000 mL of 1.5% aqueous solution of KOH, stirred in dark for 24 h, and neutralized with slightly excessive diluted hydrochloric acid. A product was extracted with chloroform, and purified by separation to obtain 0.98 g of the HB with a yield of 98%.

[0053] Preparation of deacetylated hypocrellin (HC): 200 mg of the HB was dissolved in 100 mL of 1.5% aqueous solution of KOH, refluxed in dark for 8 h, cooled, and then neutralized with slightly excessive diluted hydrochloric acid. A product was extracted with dichloromethane, and purified by separation to obtain 110 mg of the deacetylated hypocrellin (HC) with a yield of 56%. .sup.1H NMR (CDCl.sub.3, ?, ppm): 16.0 (s, OH, 1H), 15.9 (s, OH, 1H), 6.62 (d, 1H), 6.35 (s, 2H), 4.14, 4.12 (s, OCH.sub.3, 6H), 4.02 (s, OCH.sub.3, 3H), 3.1 (d, 2H), 2.25 (s, OCH.sub.3, 3H).

Example 2

[0054] 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.sub.2NCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.2(C.sub.10H.sub.21) as an example.

##STR00011##

[0055] Preparation of an intermediate S1: N,N-dimethyl ethyldiamine (4.4 g, 0.05 mol) and diethyl carbonate (7.10 g, 0.06 mol) were mixed in a 100 ml round-bottomed flask, kept at 70? C. for 48 h, and then distilled under reduced pressure to obtain 7.20 g of a pale yellow liquid with a yield of 89%. .sup.1H NMR (CDCl.sub.3, ?, ppm): 5.45 (s, NH, 1H), 4.10 (d, J=6.5 Hz, CH.sub.2O, 2H), 3.24 (s, NHCH.sub.2, 2H), 2.39 (m, CH.sub.2N, 2H), 2.22 (d, J=1.5 Hz, CH.sub.3NCH.sub.3, 6H), 1.23 (t, J=6.5 Hz, CH.sub.2CH.sub.3, 3H).

[0056] Preparation of an intermediate S2: the intermediate S1 reacted with 1-bromodecane (15.25 g, 0.05 mol) at 100? C. for 48 h for 72 h. The crude product was recrystallized with acetone-diethyl ether (1:1) to obtain a total of 15.83 g of a white crystal 2 with a yield of about 68%. .sup.1H NMR (CDCl.sub.3, ?, ppm): 6.73 (s, CONH, 1H), 4.10 (q, J=7.1 Hz, CH.sub.2O, 2H), 3.77 (s, CH.sub.2N.sup.+, 4H), 3.53 (s, CH.sub.3N.sup.+, 6H), 3.39 (s, NHCH.sub.2, 2H), 1.78-1.67 (m, N.sup.+CH.sub.2CH.sub.2, 2H), 1.31-1.20 (m, CH.sub.2, 29H), 0.88 (t, J=6.8 Hz, CH.sub.3, 3H). MS(ESI+): C.sub.23H.sub.50N.sub.2O.sub.2.sup.+ (M+H.sup.+), 385.3788.

[0057] Preparation of a long chain quaternary ammonium salt derivative S3: 50 mL of 48% hydrobromic acid and 50 mL of distilled water were added to the intermediate S2 (10.60 g, 0.02 mol), and refluxed while heating for 72 h. Hydrobromic acid was removed by rotary evaporation, and the solid residue was recrystallized with ethanol:diethyl ether (1:1) to obtain 13.62 g of a white flocculent crystal with a yield of 69%. .sup.1H NMR (D.sub.2O, ?, ppm): 5.34 (s, NH.sub.2, 2H), 3.65 (m, NH.sub.2CH.sub.2CH.sub.2, 2H), 3.48 (m, N.sup.+CH.sub.2CH.sub.2, 2H), 3.38 (m, NH.sub.2CH.sub.2, 2H), 3.12 (s, N.sup.+CH.sub.3, 6H), 1.78 (m, N.sup.+CH.sub.2CH.sub.2, 2H), 1.37-0.99 (m, CH.sub.2, 26H), 0.76 (t, J=6.5 Hz, CH.sub.3, 3H). MS (ESI+): C.sub.20H.sub.46N.sub.2.sup.+ (M+H.sup.+), 313.3590.

Example 3

[0058] Preparation of an aminoethyl glycol-modified hypocrellin derivative (R=CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH): the synthesis route as shown in FIG. 2: Hypocrellin B (HB) (100 mg, 0.18 mmol) and aminoethyl glycol (0.40 g, 4 mmol) were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 200 mL of dichloromethane, and successively washed with 100 mL 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: 1:1) as a developer to respectively obtain two blue black solid products with Rf values respectively being 0.80 and 0.24, where the product with the Rf being 0.24 was identified to be a 2,17-substituted product, and was labeled as HB-1 with a yield of 12.2%; and the component with the Rf being 0.80 was further separated with acetone:petroleum ether (volume ratio: 1:1) using chromatography to obtain a product with the Rf value being 0.85 (detected as a 2-amino-substituted product, labeled as HB-2) with a yield of 6.5%.

[0059] Characterization data of 2,17-amino-substituted product HB-1 are as follows: .sup.1HNMR (CDCl.sub.3, ?, ppm): 17.16 (s, ArOH, 1H), 12.96 (s, ArOH, 1H), 6.98 (s, ArH, 1H), 6.55 (s, ArH, 1H), 6.34 (s, ArNH, 1H), 5.35 (s, ArNH, 1H), 5.22 (s, OH, 1H), 5.01 (s, OH, 1H), 4.18 (s, OCH.sub.3, 3H), 4.06 (s, OCH.sub.3, 3H), 4.04 (s, OCH.sub.3, 3H), 3.91-3.61 (m, NHCH.sub.2CH.sub.2O, 12H), 3.56 (d, CH, 1H), 3.25 (d, CH, 1H), 2.27 (s, COCH.sub.3, 3H), 2.19 (m, CH.sub.2O, 2H), 2.02 (m, CH.sub.2O, 2H), 1.57 (s, CH.sub.3, 3H), 1.41-1.02 (m, CH.sub.2, 19H), 0.78 (t, CH.sub.3, 3H). MS (ESI): C.sub.37H.sub.40N.sub.2O.sub.11 (M+H.sup.+), 689.0. Maximum UV absorption wavelength: 468 nm, 630 nm.

[0060] Characterization data of 2-amino-substituted product HB-2 are as follows: .sup.1HNMR (CDCl.sub.3, ?, ppm): 16.76 (s, ArOH, 1H), 16.51 (s, ArOH, 1H), 6.50 (s, ArH, 1H), 6.47 (s, ArH, 1H), 6.40 (s, ArH, 1H), 5.80 (s, CH.sub.2, 1H), 5.23 (s, CH.sub.2, 1H), 4.18 (s, OCH.sub.3, 3H), 4.08 (s, OCH.sub.3, 3H), 4.02 (s, OCH.sub.3, 3H), 3.83-3.76 (m, NHCH.sub.2CH.sub.2, 4H), 3.67-3.62 (m, OCH.sub.2CH.sub.2, 4H), 2.78 (s, OH, 1H), 2.27 (s, COCH.sub.3, 3H), 1.61 (s, CH.sub.3, 3H). MS (ESI): C.sub.33H.sub.31NO.sub.10, 624.1 (M+Na.sup.+), 600.5 (M?H). Maximum UV absorption wavelength: 464 nm, 625 nm.

[0061] The amino-substituted products HB-1 and HB-2 have the structural formulas as shown in the figure:

##STR00012##

Example 4

[0062] Preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative (R=CH.sub.2CH.sub.2CH.sub.2OH): the synthesis route as shown in FIG. 3:

[0063] Deacetylated hypocrellin HC (100 mg, 0.20 mmol) and aminoethyl glycol (0.30 g, 4 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, fully mixed, heated to 60? C. under nitrogen protection, and stirred in dark for 12 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 200 mL of dichloromethane, and successively washed with 100 mL 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: 1:1) as a developer to obtain a blue black solid product with a yield of 15.2% with Rf value of 0.45. MS (ESI+): 530.6. The amino-substituted product HC-3 (double bond located at C.sub.13?C.sub.14) or HC-4 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00013##

Example 5

[0064] Preparation of an aminoethyl triglycol-modified hypocrellin B derivative (R=(CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.2OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-5: yield: 8.4%, Rf: 0.24, MS (ESI+) 777.5, maximum UV absorption wavelength: 468 nm, 632 nm. 2-amino-substituted product HB-6: yield: 5.8%, Rf: 0.55, MS (ESI+) 646.6, maximum UV absorption wavelength: 462 nm, 625 nm. The amino-substituted products HB-5 and HB-6 have the structural formulas as shown in the figure:

##STR00014##

Example 6

[0065] Preparation of an aminoethyl tetraglycol-modified deacetylated hypocrellin derivative (R=(CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.3OH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 10.5%, Rf: 0.25. Characterization data as follows: MS (ESI+): 648.5; Maximum UV absorption wavelength: 468 nm, 632 nm. The amino-substituted product HC-7 (double bond located at C.sub.13?C.sub.14) or HC-8 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00015##

Example 7

[0066] Preparation of an aminoethyl pentaglycol-modified hypocrellin B derivative (R=(CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.4OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-9: yield: 12.4%, Rf: 0.30, MS (ESI+) 953.0, maximum UV absorption wavelength: 475 nm, 640 nm. 2-amino-substituted product HB-10: yield: 6.4%, Rf: 0.65, MS (ESI+) 734.3, maximum UV absorption wavelength: 470 nm, 630 nm. The amino-substituted products HB-9 and HB-10 have the structural formulas as shown in the figure:

##STR00016##

Example 8

[0067] Preparation of an aminoethyl polyglycol-modified deacetylated hypocrellin B derivative (R=(CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.nOH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 17.5%, Rf: 0.25; characterization data as follows: MS (ESI+): 560.0. Maximum UV absorption wavelength: 480 nm, 635 nm. The amino-substituted product HC-11 (double bond located at C.sub.13?C.sub.14) or HC-12 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00017##

Example 9

[0068] Preparation of a 3-aminopropyl glycol-modified hypocrellin B derivative (R=(CH.sub.2).sub.3OCH.sub.2CH.sub.2OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-13: yield: 6.5%, Rf: 0.16, MS (ESI+) 717.2, maximum UV absorption wavelength: 476 nm, 632 nm. 2-amino-substituted product HB-14: yield: 5.4%, Rf: 0.50, MS (ESI+) 615.6, maximum UV absorption wavelength: 463 nm, 624 nm. The amino-substituted products HB-13 and HB-14 have the structural formulas as shown in the figure:

##STR00018##

Example 10

[0069] Preparation of an ethylene glycol aminoacetate-modified deacetylated hypocrellin B derivative (R=CH.sub.2COOCH.sub.2CH.sub.2OH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 18.5%; Rf: 0.18; MS (ESI+) 574.5; maximum UV absorption wavelength: 474 nm, 638 nm. The amino-substituted product HC-15 (double bond located at C.sub.13?C.sub.14) or HC-16 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00019##

Example 11

[0070] Preparation of a diethylene glycol aminoacetate-modified hypocrellin B derivative (R=CH.sub.2CO(OCH.sub.2CH.sub.2).sub.2OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-17: yield: 6.2%, Rf: 0.16, MS (ESI+) 805.5, maximum UV absorption wavelength: 468 nm, 635 nm. 2-amino-substituted product HB-18: yield: 3.4%, Rf: 0.60, MS (ESI+) 659.6, maximum UV absorption wavelength: 462 nm, 624 nm. The amino-substituted products HB-17 and HB-18 have the structural formulas as shown in the figure:

##STR00020##

Example 12

[0071] Preparation of a triethylene glycol aminoacetate-modified deacetylated hypocrellin derivative (R=CH.sub.2CO(OCH.sub.2CH.sub.2).sub.3OH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 17.2%; Rf: 0.18; MS (ESI+) 662.3; maximum UV absorption wavelength: 466 nm, 640 nm. The amino-substituted product HC-19 (double bond located at C.sub.13?C.sub.14) or HC-20 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00021##

Example 13

[0072] Preparation of a polyethylene glycol aminopropionate-modified hypocrellin B derivative (R=(CH.sub.2).sub.2CO(OCH.sub.2CH.sub.2).sub.nOH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-21: yield: 8.5%, Rf: 0.18, maximum UV absorption wavelength: 485 nm, 645 nm. 2-amino-substituted product HB-22: yield: 4.5%, Rf: 0.50, maximum UV absorption wavelength: 465 nm, 635 nm. The amino-substituted products HB-21 and HB-22 have the structural formulas as shown in the figure:

##STR00022##

Example 14

[0073] Preparation of a triethylene glycol aminopentanoate-modified deacetylated hypocrellin derivative (R=(CH.sub.2).sub.4CO(OCH.sub.2CH.sub.2).sub.30H): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 12.5%; Rf: 0.21; MS (ESI+) 704.5; maximum UV absorption wavelength: 455 nm, 642 nm. The amino-substituted product HC-23 (double bond located at C.sub.13?C.sub.14) or HC-24 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00023##

Example 15

[0074] Preparation of an ethylene glycol aminomethanesulfonate-modified hypocrellin derivative (R=CH.sub.2SO.sub.2OCH.sub.2CH.sub.2OH): hypocrellin B (HB) (100 mg, 0.18 mmol) and monoethylene glycol aminomethanesulfonate (610 mg, 4 mmol) were dissolved in 20 mL of anhydrous acetonitrile, heated to 55? C. under nitrogen protection, and stirred in dark for 8 h. Then the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 200 mL 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: 2:1) as a developer to obtain two blue black solid products. 2,17-amino-substituted product HB-25: yield: 9.2%, Rf: 0.18, MS (ESI+) 789.2, maximum UV absorption wavelength: 470 nm, 640 nm. 2-amino-substituted product HB-26: yield: 4.4%, Rf: 0.55, MS (ESI+) 652.6, maximum UV absorption wavelength: 465 nm, 628 nm. The amino-substituted products HB-25 and HB-26 have the structural formulas as shown in the figure:

##STR00024##

Example 16

[0075] Preparation of a diethylene glycol aminomethanesulfonate-modified deacetylated hypocrellin derivative (R=CH.sub.2SO.sub.2(OCH.sub.2CH.sub.2).sub.2OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example 15. The resulting product: yield: 16.2%; Rf: 0.16; MS (ESI+) 654.2; maximum UV absorption wavelength: 468 nm, 635 nm. The amino-substituted product HC-27 (double bond located at C.sub.13?C.sub.14) or HC-28 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00025##

Example 17

[0076] Preparation of a tetraethylene glycol aminomethanesulfonate-modified hypocrellin derivative (R=CH.sub.2SO.sub.2(OCH.sub.2CH.sub.2).sub.4OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example 15. 2,17-amino-substituted product HB-29: yield: 8.4%, Rf: 0.16, MS (ESI+) 1053.4, maximum UV absorption wavelength: 468 nm, 648 nm. 2-amino-substituted product HB-30: yield: 5.4%, Rf: 0.62, MS (ESI+) 784.6, maximum UV absorption wavelength: 462 nm, 625 nm. The amino-substituted products HB-29 and HB-30 have the structural formulas as shown in the figure:

##STR00026##

Example 18

[0077] Preparation of a triethylene glycol aminobutanesulfonate-modified hypocrellin derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.2(OCH.sub.2CH.sub.2).sub.3OH): the synthesis method similar to the preparation of a diethylene glycol aminomethanesulfonate-modified hypocrellin derivative in Example 15. The resulting product: yield: 16.5%; Rf: 0.21; MS (ESI+) 1036.5; maximum UV absorption wavelength: 455 nm, 638 nm. The amino-substituted product HC-31 (double bond located at C.sub.13?C.sub.14) or HC-32 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00027##

Example 19

[0078] Preparation of an ethylenediamino-substituted triglycol-modified hypocrellin B derivative (R=(CH.sub.2CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-33: yield: 9.4%, Rf: 0.18, MS (ESI+) 775.5, maximum UV absorption wavelength: 469 nm, 635 nm. 2-amino-substituted product HB-34: yield: 8.8%, Rf: 0.58, MS (ESI+) 644.6, maximum UV absorption wavelength: 464 nm, 626 nm. The amino-substituted products HB-33 and HB-34 have the structural formulas as shown in the figure:

##STR00028##

Example 20

[0079] Preparation of an ethylenediamino triglycol-modified deacetylated hypocrellin derivative (R=(CH.sub.2CH.sub.2NHCH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.2OH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 19.5%, Rf: 0.22. Characterization data as follows: MS (ESI+): 646.5; Maximum UV absorption wavelength: 468 nm, 631 nm. The amino-substituted product HC-35 (double bond located at C.sub.13?C.sub.14) or HC-36 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00029##

Example 21

[0080] Preparation of an aminoethylthio-substituted diglycol-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-37: yield: 11.4%, Rf: 0.35, MS (ESI+) 809.0, maximum UV absorption wavelength: 475 nm, 640 nm. 2-amino-substituted product HB-38: yield: 7.4%, Rf: 0.68, MS (ESI+) 662.3, maximum UV absorption wavelength: 470 nm, 630 nm. The amino-substituted products HB-37 and HB-38 have the structural formulas as shown in the figure:

##STR00030##

Example 22

[0081] Preparation of an aminoethylthio-substituted pentaglycol-modified deacetylated hypocrellin B derivative (R=(CH.sub.2CH.sub.2SCH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.3OH): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4.

[0082] The resulting product: yield: 17.5%, Rf: 0.12; characterization data as follows: MS (ESI+): 709.0. Maximum UV absorption wavelength: 480 nm, 635 nm. The amino-substituted product HC-39 (double bond located at C.sub.13?C.sub.14) or HC-40 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00031##

Example 23

[0083] Preparation of a methyl tetraglycol aminopropanamide-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CONHCH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.3OCH.sub.3): the synthesis method similar to the preparation of an aminoethyl glycol-modified hypocrellin B derivative in Example 3. 2,17-amino-substituted product HB-41: yield: 7.8%, Rf: 0.15, MS (ESI+) 1035.2, maximum UV absorption wavelength: 461 nm, 643 nm. 2-amino-substituted product HB-42: yield: 5.4%, Rf: 0.54, MS (ESI+) 775.1, maximum UV absorption wavelength: 458 nm, 622 nm. The amino-substituted products HB-41 and HB-42 have the structural formulas as shown in the figure:

##STR00032##

Example 24

[0084] Preparation of a tetraethylene glycol aminopentanamide-modified hypocrellin B derivative (R=(CH.sub.2).sub.4CH.sub.2CONHCH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.3OCH.sub.3): the synthesis method similar to the preparation of a 3-aminopropanol-modified deacetylated hypocrellin derivative in Example 4. The resulting product: yield: 16.5%; Rf: 0.21; MS (ESI+) 760.5; maximum UV absorption wavelength: 455 nm, 642 nm. The amino-substituted product HC-43 (double bond located at C.sub.13?C.sub.14) or HC-44 (double bond located at C.sub.13?C.sub.14) has the structural formula as shown in the figure:

##STR00033##

Example 25

[0085] Preparation of a hexylamine-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3): a hypocrellin B (HB) (100 mg, 0.18 mmol) and hexylamine (0.51 g, 5 mmol) were dissolved in 50 mL of anhydrous acetonitrile, heated to 55? C. under nitrogen protection, and stirred in dark for 8 h. Then the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 200 mL 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: 2:1) as a developer to obtain two blue black solid products. 2,17-amino-substituted product HB-45: yield: 28.6%, Rf: 0.24, MS (ESI+) 695.4, maximum UV absorption wavelength: 455 nm, 635 nm. 2-amino-substituted product HB-46: yield: 14.6%, Rf: 0.38, MS (ESI+) 598.2, maximum UV absorption wavelength: 452 nm, 626 nm. The amino-substituted products HB-45 and HB-46 have the structural formulas as shown in the figure:

##STR00034##

Example 26

[0086] Preparation of a butylamine-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.3): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-47: yield: 32.6%, Rf: 0.26, MS (ESI+) 625.4, maximum UV absorption wavelength: 454 nm, 632 nm. 2-amino-substituted product HB-48: yield: 14.6%, Rf: 0.38, MS (ESI+) 570.2, maximum UV absorption wavelength: 448 nm, 624 nm. The amino-substituted products HB-47 and HB-48 have the structural formulas as shown in the figure:

##STR00035##

Example 27

[0087] Preparation of an octylamine-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-49: yield: 22.6%, Rf: 0.16, MS (ESI+) 737.4, maximum UV absorption wavelength: 452 nm, 632 nm. 2-amino-substituted product HB-50: yield: 18.6%, Rf: 0.60, MS (ESI+) 626.2, maximum UV absorption wavelength: 445 nm, 621 nm. The amino-substituted products HB-49 and HB-50 have the structural formulas as shown in the figure:

##STR00036##

Example 28

[0088] Preparation of a butylhexylamine-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. The resulting product: yield: 38.6%; Rf: 0.24; MS (ESI+) 528.4; maximum UV absorption wavelength: 455 nm, 635 nm. The amino-substituted product HC-51 (double bond located at C.sub.13?C.sub.14) or HC-52 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00037##

Example 29

[0089] Preparation of a benzylamino hypocrellin B derivative (R=CH.sub.2C.sub.6H.sub.5): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-53: yield: 25.4%, Rf: 0.22, MS (ESI+) 691.2, maximum UV absorption wavelength: 453 nm, 642 nm. 2-amino-substituted product HB-54: yield: 14.5%, Rf: 0.45, MS (ESI+) 604.9. Maximum UV absorption wavelength: 453 nm, 622 nm. The amino-substituted products HB-53 and HB-54 have the structural formulas as shown in the figure:

##STR00038##

Example 30

[0090] Preparation of a phenylbutylamine-modified hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2C.sub.6H.sub.5): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-55: yield: 17.5%, Rf: 0.23, MS (ESI+) 1037.5, maximum UV absorption wavelength: 452 nm, 636 nm. 2-amino-substituted product HB-56: yield: 14.8%, Rf: 0.36, MS (ESI+) 776.3, maximum UV absorption wavelength: 452 nm, 619 nm. The amino-substituted products HB-55 and HB-56 have the structural formulas as shown in the figure:

##STR00039##

Example 31

[0091] Preparation of a 2-methylpyridin-amino hypocrellin B derivative (R=CH.sub.2C.sub.5H.sub.4N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-57: yield: 25.4%, Rf: 0.22, MS (ESI+) 693.2, maximum UV absorption wavelength: 453 nm, 634 nm. 2-amino-substituted product HB-58: yield: 14.5%, Rf: 0.45, MS (ESI+) 606.9, maximum UV absorption wavelength: 450 nm, 622 nm. The amino-substituted products HB-57 and HB-58 have the structural formulas as shown in the figure:

##STR00040##

Example 32

[0092] Preparation of a phenylbutylamine-modified deacetylated hypocrellin B derivative (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2C.sub.5H.sub.4N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. The resulting product: yield: 17.5%; Rf: 0.23; MS (ESI+) 605.5; maximum UV absorption wavelength: 452 nm, 636 nm. The amino-substituted product HC-59 (double bond located at C.sub.13?C.sub.14) or HC-60 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00041##

Example 33

[0093] Preparation of a 4-methylpyridin-butylamino hypocrellin B derivative (R=(CH.sub.2).sub.4C.sub.5H.sub.4N.sup.+(C.sub.6H.sub.11)): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-61: yield: 15.4%, Rf: 0.22, MS (ESI+) 984.2, maximum UV absorption wavelength: 453 nm, 634 nm. 2-amino-substituted product HB-62: yield: 14.5%, Rf: 0.45, MS (ESI+) 767.9, maximum UV absorption wavelength: 450 nm, 622 nm. The amino-substituted products HB-61 and HB-62 have the structural formulas as shown in the figure:

##STR00042##

Example 34

[0094] Preparation of hypocrellin B hydrazine (R=NH.sub.2): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-63: yield: 25.4%, Rf: 0.28, MS (ESI+) 543.8, maximum UV absorption wavelength: 455 nm, 640 nm. 2-amino-substituted product HB-64: yield: 12.6%, Rf: 0.48, MS (ESI+) 529.9, maximum UV absorption wavelength: 448 nm, 625 nm. The amino-substituted products HB-63 and HB-64 have the structural formulas as shown in the figure:

##STR00043##

Example 35

[0095] Preparation of deacetylated hypocrellin B hydrazine (R=NH.sub.2): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. The resulting product: yield: 28.5%; Rf: 0.30; MS (ESI+) 486.8; maximum UV absorption wavelength: 456 nm, 642 nm. The amino-substituted product HC-65 (double bond located at C.sub.13?C.sub.14) or HC-66 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00044##

Example 36

[0096] Preparation of hypocrellin B hydrazine (R=OH): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-67: yield: 28.6%, Rf: 0.22, MS (ESI+) 545.8, maximum UV absorption wavelength: 452 nm, 632 nm. 2-amino-substituted product HB-68: yield: 15.6%, Rf: 0.46, MS (ESI+) 531.9, maximum UV absorption wavelength: 445 nm, 622 nm. The amino-substituted products HB-67 and HB-68 have the structural formulas as shown in the figure:

##STR00045##

Example 37

[0097] Preparation of deacetylated hypocrellin B hydrazine (R=OH): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. The resulting product: yield: 21.5%; Rf: 0.28; MS (ESI+) 488.8; maximum UV absorption wavelength: 452 nm, 640 nm. The amino-substituted product HC-69 (double bond located at C.sub.13?C.sub.14) or HC-70 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00046##

Example 38

[0098] Preparation of cyclohexylamine-modified hypocrellin (R=C.sub.6H.sub.11): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-71: yield: 58.6%, Rf: 0.58, MS (ESI+) 677.5, maximum UV absorption wavelength: 448 nm, 626 nm. 2-amino-substituted product HB-72: yield: 12.6%, Rf: 0.82, MS (ESI+) 596.9, maximum UV absorption wavelength: 446 nm, 618 nm. The amino-substituted products HB-71 and HB-72 have the structural formulas as shown in the figure:

##STR00047##

Example 39

[0099] Preparation of cyclohexylamine-modified deacetylated hypocrellin (R=C.sub.6H.sub.11): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. The resulting product: yield: 26.4%; Rf: 0.30; MS (ESI+) 553.8; maximum UV absorption wavelength: 450 nm, 638 nm. The amino-substituted product HC-73 (double bond located at C.sub.13?C.sub.14) or HC-74 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00048##

Example 40

[0100] Preparation of cyclobutylamine-modified hypocrellin (R=C.sub.4H.sub.7): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-75: yield: 35.6%, Rf: 0.52, MS (ESI+) 621.5, maximum UV absorption wavelength: 450 nm, 630 nm. 2-amino-substituted product HB-76: yield: 15.6%, Rf: 0.80, MS (ESI+) 568.9, maximum UV absorption wavelength: 448 nm, 622 nm. The amino-substituted products HB-75 and HB-76 have the structural formulas as shown in the figure:

##STR00049##

Example 41

[0101] Preparation of cyclopentylamine-modified hypocrellin (R=C.sub.5H.sub.9): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-77: yield: 25.8%, Rf: 0.56, MS (ESI+) 649.5, maximum UV absorption wavelength: 452 nm, 632 nm. 2-amino-substituted product HB-78: yield: 10.2%, Rf: 0.85, MS (ESI+) 581.9, maximum UV absorption wavelength: 450 nm, 625 nm. The amino-substituted products HB-77 and HB-78 have the structural formulas as shown in the figure:

##STR00050##

Example 42

[0102] Preparation of cycloheptylamine-modified hypocrellin (R=?05H.sub.9): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-79: yield: 28.1%, Rf: 0.58, MS (ESI+) 705.5, maximum UV absorption wavelength: 454 nm, 634 nm. 2-amino-substituted product HB-80: yield: 15.0%, Rf: 0.75, MS (ESI+) 610.2. Maximum UV absorption wavelength: 452 nm, 627 nm. The amino-substituted products HB-79 and HB-80 have the structural formulas as shown in the figure:

##STR00051##

Example 43

[0103] Preparation of p-methyl-cyclohexylamine-modified hypocrellin (R=C.sub.6H.sub.10CH.sub.3): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-81: yield: 46.6%, Rf: 0.52, MS (ESI+) 705.5, maximum UV absorption wavelength: 450 nm, 628 nm. 2-amino-substituted product HB-82: yield: 10.1%, Rf: 0.80, MS (ESI+) 610.4, maximum UV absorption wavelength: 448 nm, 621 nm. The amino-substituted products HB-81 and HB-82 have the structural formulas as shown in the figure:

##STR00052##

Example 44

[0104] Preparation of 4-aminopiperidine-modified hypocrellin (R=?C.sub.5H.sub.10N): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-83: yield: 26.5%, Rf: 0.50, MS (ESI+) 679.5, maximum UV absorption wavelength: 452 nm, 630 nm. 2-amino-substituted product HB-84: yield: 20.1%, Rf: 0.82, MS (ESI+) 597.4, maximum UV absorption wavelength: 450 nm, 625 nm. The amino-substituted products HB-81 and HB-82 have the structural formulas as shown in the figure:

##STR00053##

Example 45

[0105] Preparation of 3-butenylamine-modified hypocrellin (R=C.sub.4H.sub.7): the synthesis method similar to the preparation of a hexylamine-modified hypocrellin derivative in Example 25. 2,17-amino-substituted product HB-85: yield: 16.5%, Rf: 0.52, MS (ESI+) 621.7, maximum UV absorption wavelength: 450 nm, 632 nm. 2-amino-substituted product HB-86: yield: 28.1%, Rf: 0.84, MS (ESI+) 568.9. Maximum UV absorption wavelength: 451 nm, 628 nm. The amino-substituted products HB-85 and HB-86 have the structural formulas as shown in the figure:

##STR00054##

Example 46

[0106] Preparation of N,N-dimethyl-N-decylamino-ethyldiamino deacetylated hypocrellin B (R=CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.2(C.sub.10H.sub.21)): the synthesis route as shown in FIG. 4: deacetylated hypocrellin HC (100 mg, 0.18 mmol) and a long chain quaternary ammonium salt derivative S3 (224 mg, 0.72 mmol) prepared in Example 3 were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 200 mL of dichloromethane, and successively washed with 50 mL 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:ethanol:diethylamine (volume ratio: 20:1:1:3) as a developer to respectively obtain two blue black solid products. The resulting product: yield: 24.2%; Rf: 0.37; MS (ESI+) 684.5; maximum UV absorption wavelength: 453 nm, 630 nm. The amino-substituted product HC-87 (double bond located at C.sub.13?C.sub.14) or HC-88 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00055##

Example 47

[0107] Preparation of N,N-dimethyl-N-dodecylamine-butyldiamino hypocrellin B (R=CH.sub.2CH.sub.2CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.2(C.sub.12H.sub.23): the synthesis method similar to the preparation of a quaternary ammonium salt-containing hypocrellin derivative in Example 46. The resulting 2-amino-substituted product: yield: 15.4%, Rf: 0.36. Characterization data as follows: MS (ESI+): 739.5; Maximum UV absorption wavelength: 462 nm, 624 nm. The amino-substituted product HC-89 (double bond located at C.sub.13?C.sub.14) or HC-90 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00056##

Example 48

[0108] Preparation of N,N,N-trimethylammonium-decyldiamino hypocrellin B (R=(CH.sub.2).sub.10N.sup.+(CH.sub.3).sub.3: the synthesis method similar to the preparation of a quaternary ammonium salt-containing hypocrellin derivative in Example 46. The resulting 2-amino-substituted product: yield: 8.8%, Rf: 0.35. Characterization data as follows: MS (ESI+): 791.2; Maximum UV absorption wavelength: 464 nm, 626 nm. The amino-substituted product HC-91 (double bond located at C.sub.13?C.sub.14) or HC-92 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00057##

Example 49

[0109] Preparation of N,N-dimethyl-N-decyl-PEG-amino hypocrellin (R=CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.2(C.sub.10H.sub.21): the synthesis method similar to the preparation of quaternary ammonium salt-containing hypocrellin derivative in Example 46. The resulting 2-amino-substituted product: yield: 15.5%, Rf: 0.28. Characterization data as follows: MS (ESI+): 771.2; Maximum UV absorption wavelength: 462 nm, 628 nm. The amino-substituted product HC-93 (double bond located at C.sub.13?C.sub.14) or HC-94 (double bond located at C.sub.14?C.sub.15) has the structural formula as shown in the figure:

##STR00058##

Example 50

[0110] Preparation of piperazino(deacetylated hypocrellin): deacetylated hypocrellin HC (100 mg, 0.20 mmol) and ethyldiamine (421 mg, 2 mmol) were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 45? C. under nitrogen protection, and stirred in dark for 6 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 100 mL of dichloromethane, washed with 50 mL 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: 20:1:1:1) as a developer to obtain a blue black solid product with a yield of 49.8% and with Rf of 0.45. Characterization data of the product as follows: ESI MS: m/z, 497.3. Maximum UV absorption wavelength: 462 nm, 650 nm. The product is respectively represented by structural formula HC-95:

##STR00059##

Example 51

[0111] Preparation of methylpiperazino(deacetylated hypocrellin B): the preparation method similar to the preparation of piperazino(deacetylated hypocrellin) in Example 50. Yield: 59.8%, Rf: 0.60. Characterization data of the product as follows: ESI MS: m/z, 511.3. Maximum UV absorption wavelength: 465 nm, 652 nm. The product is respectively represented by structural formula HC-96 or HC-97:

##STR00060##

Example 52

[0112] Preparation of dimethylpiperazino(hypocrellin B): A hypocrellin B (HB) (100 mg, 0.18 mmol) and dimethyl ethyldiamine (421 mg, 2 mmol) were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 45? C. under nitrogen protection, and stirred in dark for 6 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 100 mL of dichloromethane, washed with 50 mL 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:ethylacetate:ethanol:diethylamine (volume ratio: 20:1:1:1) as a developer to obtain a blue black solid product with a yield of 19.8% and with Rf of 0.45. Characterization data of the product as follows: ESI MS: m/z, 569.3. Maximum UV absorption wavelength: 462 nm, 650 nm. The product is respectively represented by structural formula HC-98 or HC-99:

##STR00061##

Example 53

[0113] Preparation of diethylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 18.8%, Rf: 0.38. Characterization data of the product as follows: ESI MS: m/z, 596.8. Maximum UV absorption wavelength: 465 nm, 655 nm. The product is respectively represented by structural formula HC-99 or HC-100:

##STR00062##

Example 54

[0114] Preparation of dipropylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 21.2%, Rf: 0.35. Characterization data of the product as follows: ESI MS: m/z, 596.8. Maximum UV absorption wavelength: 462 nm, 652 nm. The product is respectively represented by structural formula HC-101 or HC-102:

##STR00063##

Example 55

[0115] Preparation of dibutylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 21.5%, Rf: 0.38. Characterization data of the product as follows: ESI MS: m/z, 609.8. Maximum UV absorption wavelength: 468 nm, 657 nm. The product is respectively represented by structural formula HC-103 or HC-104:

##STR00064##

Example 56

[0116] Preparation of dibutylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 18.8%, Rf: 0.38. Characterization data of the product as follows: ESI MS: m/z, 665.8. Maximum UV absorption wavelength: 465 nm, 655 nm. The product is respectively represented by structural formula HC-105 or HC-106:

##STR00065##

Example 57

[0117] Preparation of trimethylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 23.4%, Rf: 0.48. Characterization data of the product as follows: ESI MS: m/z, 569.3. Maximum UV absorption wavelength: 464 nm, 652 nm. The product is respectively represented by structural formula HC-107 or HC-108:

##STR00066##

Example 58

[0118] Preparation of dibutyl-methylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 18.8%, Rf: 0.38. Characterization data of the product as follows: ESI MS: m/z, 596.8. Maximum UV absorption wavelength: 465 nm, 655 nm. The product is respectively represented by structural formula HC-109 or HC-110:

##STR00067##

Example 59

[0119] Preparation of dihexyl-methylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 18.8%, Rf: 0.38. Characterization data of the product as follows: ESI MS: m/z, 596.8. Maximum UV absorption wavelength: 465 nm, 655 nm. The product is respectively represented by structural formula HC-111 or HC-112:

##STR00068##

Example 60

[0120] Preparation of dimethyl-ethoxylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino (hypocrellin B) in Example 52. Yield: 12.5%, Rf: 0.35. Characterization data of the product as follows: ESI MS: m/z, 611.6. Maximum UV absorption wavelength: 463 nm, 652 nm. The product is respectively represented by structural formula HC-113 or HC-114:

##STR00069##

Example 61

[0121] Preparation of dimethyl-DEG-ylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 13.8%, Rf: 0.40. Characterization data of the product as follows: ESI MS: m/z, 655.6. Maximum UV absorption wavelength: 460 nm, 655 nm. The product is respectively represented by structural formula HC-115 or HC-116:

##STR00070##

Example 62

[0122] Preparation of dimethyl-triethylene glycol-ylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 8.5%, Rf: 0.45. Characterization data of the product as follows: ESI MS: m/z, 699.1. Maximum UV absorption wavelength: 462 nm, 658 nm. The product is respectively represented by structural formula HC-117 or HC-118:

##STR00071##

Example 63

[0123] Preparation of dimethyl-triethylene glycol-ylpiperazino(hypocrellin B): the synthesis method similar to the preparation of dimethylpiperazino(hypocrellin B) in Example 52. Yield: 8.5%, Rf: 0.45. Characterization data of the product as follows: ESI MS: m/z, 745.5. Maximum UV absorption wavelength: 462 nm, 658 nm. The product is respectively represented by structural formula HC-119 or HC-120:

##STR00072##

Example 64

[0124] Preparation of diethoxylpiperazino(hypocrellin B):

[0125] A hypocrellin B (HB) (100 mg, 0.18 mmol) and dihydroxyethyl ethyldiamine (421 mg, 2 mmol) were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 45? C. under nitrogen protection, and stirred in dark for 6 h. On completion of the reaction, the solvent was removed by rotary evaporation. A blue black solid residue was dissolved in 100 mL of dichloromethane, washed with 50 mL 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: 20:1:1:1) as a developer to obtain a blue black solid product with a yield of 18.5% and with Rf of 0.21. Characterization data of the product as follows: ESI MS: m/z, 583.5. Maximum UV absorption wavelength: 463 nm, 650 nm. The product is respectively represented by structural formula HB-121 or HB-122:

##STR00073##

Example 65

[0126] Preparation of dihexyl-ethoxylpiperazino(hypocrellin B): the synthesis method similar to the preparation of diethxoylpiperazino(hypocrellin B) in Example 64. Yield: 25.5%, Rf: 0.41. Characterization data of the product as follows: ESI MS: m/z, 596.8. Maximum UV absorption wavelength: 468 nm, 652 nm. The product is respectively represented by structural formula HB-123 or HB-124:

##STR00074##

Example 66

[0127] 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 46. 2,17-amino-substituted product HB-125: yield: 12.4%, Rf: 0.28, MS (ESI+) 941.2, maximum UV absorption wavelength: 455 nm, 635 nm. 2-amino-substituted product HB-126: yield: 16.5%, Rf: 0.48, MS (ESI+) 746.9. Maximum UV absorption wavelength: 451 nm, 624 nm. The amino-substituted products HB-125 and HB-126 have the structural formulas as shown in the figure:

##STR00075##

Example 67

[0128] ##STR00076##

[0129] Please refer to the following documents for the preparation method of a compound 1:

[0130] Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer from hypocrellin B with enhanced red absorption, Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of ethanol/water buffer solution (1/3, pH=10) of HB (0.2 mM) and mercaptoethylamine hydrochloride (0.01 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 20 min. On completion of the reaction, and after acidification with 10% 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: 99:1) as a developer to obtain a mixture of 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted HB, which were separated by HPLC to obtain the compound 1 with a yield of 25.2%. MS (ESI+): m/z C.sub.32H.sub.27NO.sub.8S, [M+H].sup.+=586.1. 100 mg of the compound 1 and 10 mL of n-butylamine were dissolved in 100 mL of pyridine, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL of chloroform, and washed with 50 mL 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 1% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 4:2.5:1) as a developer to respectively obtain products I-1 and I-2. I-1: yield: 40.4%; MS (ESI+), m/z C.sub.35H.sub.34N.sub.2O.sub.7S, [M+H].sup.+=527.2; maximum UV absorption wavelength: ?.sub.max (log ?), 682 nm (4.3). I-2: yield: 12.9%; MS (ESI+), m/z C.sub.39H.sub.43N.sub.3O.sub.6S, [M+H].sup.+=682.3; maximum UV absorption wavelength: ?.sub.max (log ?), 691 nm (4.2).

[0131] Dark toxicity experiment: Hela cells at a certain concentration were inoculated into a 96-well plate, and cultured for 12-24 h. After removing the original culture solution from the 96-well plate, compound I-1 solutions at different concentrations were added. After incubation for 1 h, the photosensitizer solution was removed, and a fresh culture solution was added for cultivation in a 5% CO.sub.2 environment at 37? C. for 24 h. The survival rate of cells in each group was detected by MTT assay. As shown in FIG. 16a, the compound I-1 has very low cytotoxicity, which is equivalent to the cytotoxicity of the commercial photosensitizer dihydroporphin Ce6 and the HB.

[0132] Phototoxicity experiment: Hela cells were incubated together with different concentrations of the compound I-1, the HB and the Ce6 respectively, further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 1 hour. After laser irradiation with a power density of 50 mW/cm.sup.2 at a wavelength of 671 nm for 20 min, the Hela cells were further cultured and incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 24 h. The survival rate of cells in each group was detected by MTT assay. As shown in FIG. 16b, 200 nM compound I-1 can kill more than 90% Hela cells, while the commercial photosensitizer dihydroporphin Ce6 can kill only about 30% Hela cells under identical conditions.

Example 68

[0133] ##STR00077##

[0134] Please refer to the following documents for the preparation method of a compound 2: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of methanol/water buffer solution (1/3, pH=11) of HB (0.5 mM) and cysteine hydrochloride (0.05 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 20 min. On completion of the reaction, and after acidification with 10% 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: 98:1) as a developer to obtain a mixture of 4,5-substituted and 8,9-substituted HB, which were separated by HPLC to obtain the compound 2 with a yield of 24.5%. MS (ESI+): m/z C.sub.33H.sub.27NO.sub.10S, [M+H].sup.+=630.1. 100 mg of the compound 2 and 5 mL of n-dodecylamine were dissolved in 100 mL of pyridine, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 15 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL of chloroform, and washed with 50 mL 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 1.5% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 4:2.5:1) as a developer to respectively obtain two products I-3 and I-4. I-3: yield: 20.4%; MS (ESI+), m/z C.sub.44H.sub.50N.sub.2O.sub.9S, [M+H].sup.+=783.3; maximum UV absorption wavelength: ?.sub.max (log ?), 680 nm (4.3). I-4: yield: 10.1%; MS (ESI+), m/z C.sub.39H.sub.43N.sub.3O.sub.6S, [M+H].sup.+=950.5; maximum UV absorption wavelength: ?.sub.max (log ?), 691 nm (4.2).

Example 69

[0135] ##STR00078##

[0136] By referring to the method in Example 67, 10 groups of 5 mL of ethanol/water buffer solution (1/3, pH=11) of HB (0.5 mM) and mercaptoethylamine hydrochloride (0.1 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 30 min. On completion of the reaction, and after acidification with 10% 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: 99:1) as a developer to obtain a mixture of 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted HB, which were separated by HPLC to obtain a compound 3 with a yield of 30.9%. MS (ESI+): m/z C.sub.34H.sub.30N.sub.2O.sub.7S.sub.2, [M+H].sup.+=643.1. 100 mg of the compound 3 and 10 mL of 6-N,N-dimethylamino n-hexylamine were dissolved in 50 mL of tetrahydrofuran, fully mixed, heated to 55? C. under nitrogen protection, and stirred in dark for 18 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL of chloroform, and washed with 50 mL 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 2% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to respectively obtain two products I-5 and I-6. I-5: yield: 26.4%; MS (ESI+), m/z C.sub.41H.sub.46N.sub.4O.sub.6S2, [M+H].sup.+=755.3; maximum UV absorption wavelength: ?.sub.max (log ?), 712 nm (4.0). I-6: yield: 15.1%; MS (ESI+), m/z C.sub.49H.sub.64N.sub.6O.sub.5S2, [M+H].sup.+=881.4; maximum UV absorption wavelength: ?.sub.max (log ?), 720 nm (4.1).

Example 70

[0137] ##STR00079##

[0138] Please refer to the following documents for the preparation method of a compound 4: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 4 mL of ethanol/water buffer solution (1/3, pH=11) of HB (0.5 mM) and mercaptoethylamine hydrochloride (0.05 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 20 min. On completion of the reaction, and after acidification with 10% 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: 99:1) as a developer to obtain a mixture of 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted HB, which were separated by HPLC to obtain the compound 4 with a yield of 27.3%. MS (ESI+): m/z C.sub.40H.sub.42N.sub.2O.sub.7S.sub.2, [M+H].sup.+=727.2.

[0139] 100 mg of the compound 4 and 1 g of 6-sulfo n-hexylamine were dissolved in 80 mL of dimethyl sulfoxide and 2 mol/L water solution of sodium hydroxide (1:1), fully mixed, heated to 120? C. under nitrogen protection, and stirred in dark for 4 h. 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 1% KH.sub.2PO.sub.4 silica gel chromatography with dichloromethane: methanol (volume ratio: 5:1) as a developer to respectively obtain products I-7 and I-8. I-7: yield: 30.4%; MS (ESI+), m/z C.sub.45H.sub.53N.sub.3O.sub.9S.sub.3, [M+H].sup.+=876.3; maximum UV absorption wavelength: ?.sub.max (log ?), 715 nm (4.4). I-8: yield: 8.8%; MS (ESI+), m/z C.sub.51H.sub.66N.sub.4O.sub.11S.sub.4, [M+H].sup.+=1039.3; maximum UV absorption wavelength: ?.sub.max (log ?), 721 nm (4.2).

Example 71

[0140] ##STR00080##

[0141] 100 mg of the compound 3 and 10 mL of cyclopentylamine were dissolved in 100 mL of pyridine, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 15 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL of chloroform, and washed with 50 mL 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 1% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to obtain a compound I-9: yield: 46.4%; MS (ESI+), m/z C.sub.38H.sub.37N.sub.3O.sub.6S.sub.2, [M+H].sup.+=696.2; maximum UV absorption wavelength: ?.sub.max (log ?), 710 nm (4.2).

Example 72

[0142] ##STR00081##

[0143] Please refer to the following documents for the preparation method of a compound 5: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of ethanol/water buffer solution (1/3, pH=10) of HB (0.5 mM) and cysteine triethylene glycol ester (0.05 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 10 min. On completion of the reaction, and after acidification with 10% hydrochloric acid, the crude product was further separated by silica gel chromatography with chloroform:methanol (volume ratio: 99:1) as a developer to obtain the compound 1 with a yield of 31.6%. MS (ESI+): m/z C.sub.48H.sub.54N.sub.2O.sub.17S.sub.2, [M+H].sup.+=995.3.

[0144] 100 mg of the compound 5 and 10 mL of benzylamine were dissolved in 100 mL of pyridine, fully mixed, heated to 55? C. under nitrogen protection, and stirred in dark for 12 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL 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 1.5% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to obtain a compound I-10: yield: 38.6%; MS (ESI+), m/z C.sub.54H.sub.59N.sub.3O.sub.16S.sub.2, [M+H].sup.+=1070.3; maximum UV absorption wavelength: ?.sub.max (log 6), 713 nm (4.2).

Example 73

[0145] ##STR00082##

[0146] Please refer to the following documents for the preparation method of a compound 6: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of methanol/water buffer solution (1/3, pH=11) of HB (0.5 mM) and 2-dimethyl cysteine (0.1 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 30 min. On completion of the reaction, and after acidification with 10% hydrochloric acid, a crude product was obtained by washing with chloroform and spin drying of the water phase, and then the compound 6 was obtained by Sephadex G-15 column chromatography with water as an eluting agent: yield: 40.2%. MS (ESI+): m/z C.sub.40H.sub.38N.sub.2O.sub.11S.sub.2, [M+H].sup.+=787.2.

[0147] 100 mg of the compound 6 and 10 mL of 2-methylamino pyridine were dissolved in 100 mL of pyridine, fully mixed, heated to 60? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL 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 1.5% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to obtain a compound I-11: yield: 33.9%; MS (ESI+), m/z C.sub.45H.sub.42N.sub.4O.sub.10S.sub.2, [M+H].sup.+=863.2; maximum UV absorption wavelength: ?.sub.max (log ?), 709 nm (4.2).

Example 74

[0148] ##STR00083##

[0149] Please refer to the following documents for the preparation method of a compound 7: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of ethanol/water buffer solution (1/3, pH=10) of HB (0.2 mM) and cysteine ethyl ester (0.01 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 20 min. On completion of the reaction, and after acidification with 10% 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: 99:1) as a developer to obtain a mixture of 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted HB, which were separated by HPLC to obtain the compound 7 with a yield of 24.5%. MS (ESI+): m/z C.sub.35H.sub.31NO.sub.10S, [M+H].sup.+=658.2.

[0150] 100 mg of the compound 7 and 10 mL of 4-morpholin-cyclohexylamine were dissolved in 100 mL of pyridine, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 100 mL of chloroform, and washed with 50 mL 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 1% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to obtain a compound I-12: yield: 30.8%; MS (ESI+), m/z C.sub.44H.sub.47N.sub.3O.sub.10S.sub.2, [M+H].sup.+=810.3; maximum UV absorption wavelength: ?max (log ?), 685 nm (4.2).

Example 75

[0151] ##STR00084##

[0152] Please refer to Example 71 for the synthesis of a compound I-13: yield: 46.4%; MS (ESI+), m/z C.sub.40H.sub.41N.sub.3O.sub.7S.sub.2, [M+H].sup.+=740.2; maximum UV absorption wavelength: ?.sub.max (log ?), 710 nm (4.1).

Example 76

[0153] ##STR00085##

[0154] Please refer to Example 72 for the synthesis of a compound I-14: yield: 26.6%; MS (ESI+), m/z C.sub.58H.sub.73N.sub.7O.sub.17S4, [M+H].sup.+=1268.4; maximum UV absorption wavelength: ?.sub.max (log ?), 712 nm (4.0).

Example 77

[0155] ##STR00086##

[0156] Please refer to Example 71 for the synthesis of a compound I-15: yield: 35.6%; MS (ESI+), m/z C.sub.42H.sub.43N.sub.3O.sub.8S.sub.2, [M+H].sup.+=782.2; maximum UV absorption wavelength: ?.sub.max (log ?), 710 nm (4.1).

Example 78

[0157] ##STR00087##

[0158] 100 mg of the compound 1 and 200 mg of a long chain quaternary ammonium salt derivative were dissolved in 20 mL of anhydrous acetonitrile, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. On completion of the reaction, the solvent was removed by rotary evaporation. The solid residue was dissolved in 200 mL of dichloromethane, washed with 50 mL 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:ethylacetate:ethanol:diethylamine (volume ratio: 20:1:1:3) as a developer to respectively obtain two products I-16 and I-17. I-16: yield: 16.4%; MS (ESI+), m/z C.sub.43H.sub.52N.sub.3O.sub.7S, [M+H].sup.+=754.4; maximum UV absorption wavelength: ?.sub.max (log ?), 681 nm (4.2). I-17: yield: 11.2%; MS (ESI+), m/z C.sub.55H.sub.79N.sub.5O.sub.6S, [M+H].sup.+=468.8; maximum UV absorption wavelength: ?.sub.max (log ?), 692 nm (4.3).

Example 79

[0159] ##STR00088##

[0160] Please refer to Example 78 for the synthesis of compounds I-18 and I-19. I-18: yield: 12.4%; MS (ESI+), m/z C.sub.41H.sub.45N.sub.3O.sub.10S.sub.2, [M+H].sup.+=804.2; maximum UV absorption wavelength: ?.sub.max (log ?), 712 nm (4.0). I-19: yield: 8.1%; MS (ESI+), m/z C.sub.49H.sub.62N.sub.4O.sub.13S.sub.2, [M+H].sup.+=979.4; maximum UV absorption wavelength: ?.sub.max (log ?), 718 nm (4.1).

Example 80

[0161] ##STR00089##

[0162] The synthesis of compounds I-20 and I-21 is identical to Example 68. I-20: yield: 16.4%; MS (ESI+), m/z C.sub.43H.sub.52N.sub.3O.sub.7S, [M]+=952.5; maximum UV absorption wavelength: ?.sub.max (log ?), 681 nm (4.2). I-21: yield: 11.2%; MS (ESI+), m/z C.sub.76H.sub.119N.sub.5O.sub.8S, [M/2].sup.2+=630.9; maximum UV absorption wavelength: ?.sub.max (log ?), 691 nm (4.1).

Example 81

[0163] ##STR00090##

[0164] 100 mg of the compound 3 and 400 mg of amino-PEG 2000 were dissolved in 20 mL of dichloromethane, fully mixed, and stirred in dark at room temperature under nitrogen protection for 20 h. 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-22: yield: 16.4%; MS (ESI+), m/z C.sub.33H.sub.27N.sub.2O.sub.6S.sub.2, [M+H].sup.+=612.1; maximum UV absorption wavelength: ?.sub.max (log ?), 681 nm (4.0).

Example 82

[0165] ##STR00091##

[0166] Please refer to the following documents for the preparation method of a compound 9: Photoreactions of hypocrellin B with thiol compounds, Journal of Photochemistry and Photobiology B: Biology, 1998, 44, 45-52; Synthesis of a new water-soluble phototherapeutic sensitizer, Dyes and Pigments, 1999, 4, 93-100. 10 groups of 5 mL of ethanol/water buffer solution (1/3, pH=10) of deacetylated hypocrellin HC (0.2 mM) and mercaptoethylamine hydrochloride (0.01 mM) present in 10 photochemical reactors were irradiated with a 450 W high pressure sodium lamp (light below 470 nm filtered with a glass long pass filter) at room temperature for 10 min. On completion of the reaction, and after acidification with 10% 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: 99:1) as a developer to obtain a mixture of 4,5-substituted, 8,9-substituted or 4,5,8,9-substituted HB, which were separated by HPLC to obtain the compound 9 with a yield of 22.4%. MS (ESI+): m/z C.sub.30H.sub.25NO.sub.7S, [M+H].sup.+=544.1.

[0167] 100 mg of the compound 9 and 10 mL of glycine were dissolved in 20 mL of pyridine, fully mixed, heated to 50? C. under nitrogen protection, and stirred in dark for 10 h. 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 1% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 3:2:1) as a developer to respectively obtain two products I-23 and I-24. I-23 and I-24: yield: 15.1%; MS (ESI+), m/z C.sub.32H.sub.28N.sub.2O.sub.8S, [M+H].sup.+=600.1; maximum UV absorption wavelength: ?.sub.max (log ?), 680 nm (4.0).

Example 83

[0168] ##STR00092##

[0169] Please refer to Example 82 for the synthesis of compounds I-25 and I-26. I-25 and I-26: yield: 11.4%; MS (ESI+), m/z C.sub.41H.sub.46N.sub.4O.sub.5S.sub.2, [M+H].sup.+=739.3; maximum UV absorption wavelength: ?.sub.max (log ?), 710 nm (4.0).

Example 84

[0170] ##STR00093##

[0171] Please refer to Example 72 for the synthesis of compounds I-27 and I-28. I-27 and I-28: yield: 9.4%; MS (ESI+), m/z C.sub.37H.sub.36N.sub.4O.sub.9S.sub.2, [M+H].sup.+=745.2; maximum UV absorption wavelength: ?.sub.max (log ?), 711 nm (4.0).

Example 85

[0172] ##STR00094##

[0173] 200 mg of the compound 12 was dissolved in 100 mL of freshly distilled tetrahydrofuran, and then 10 mL of cyclohexanediamine was added. The resulting solution was stirred in dark, and kept at 60? C. for 18 h. 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 1% KH.sub.2PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 2:2:1) as a developer to obtain a compound I-1: yield: 18.5%; MS (ESI+), m/z C.sub.45H.sub.46N.sub.4O.sub.9S.sub.2, [M+H].sup.+=851.3; maximum UV absorption wavelength: ?.sub.max (log ?), 735 nm (4.4).

Example 86

[0174] ##STR00095##

[0175] Please refer to Example 67 for the synthesis of a compound 12. 200 mg of the compound 12 was dissolved in 100 mL of freshly distilled tetrahydrofuran, and then 40 mL of hexanediamine was added. The resulting solution was stirred in dark, and kept at 55? C. for 12 h. 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 1% KH.sub.3PO.sub.4 silica gel chromatography with petroleum ether:ethyl acetate:ethanol (volume ratio: 2:2:1) as a developer to obtain a compound I-2: yield: 50.3%; MS (ESI+), m/z C.sub.34H.sub.29N.sub.3O.sub.8S, [M+H].sup.+=640.2; maximum UV absorption wavelength: ?.sub.max (log ?), 710 nm (4.4).

[0176] Dark toxicity experiment: Hela cells at a certain concentration were inoculated into a 96-well plate, and cultured for 12-24 h. After removing the original culture solution from the 96-well plate, compound II-2 solutions at different concentrations were added. After incubation for 1 h, the photosensitizer solution was removed, and a fresh culture solution was added for cultivation in a 5% CO.sub.2 environment at 37? C. for 24 h. The survival rate of cells in each group was detected by MTT assay. As shown in FIG. 18a, the compound II-2 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-2, the HB and the Ce6 respectively, further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 1 hour. After laser irradiation with a power density of 20 mW/cm.sup.2 at a wavelength of 808 nm for 20 min, the Hela cells were further cultured and incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 24 h. The survival rate of cells in each group was detected by MTT assay. As shown in FIG. 18b, 300 nM compound I-1 can kill more than 85% Hela cells, while the commercial photosensitizer Ce6 can kill only about 20% Hela cells under identical conditions.

Example 87

[0177] ##STR00096##

[0178] Please refer to Example 67 for the synthesis of a compound 13. Please refer to Example 86 for the synthesis of compounds II-3 and II-4. II-3: yield: 19.9%; MS (ESI+), m/z C.sub.37H.sub.35N.sub.3O.sub.8S, [M+H].sup.+=682.2; maximum UV absorption wavelength: ?.sub.max (log ?), 711 nm (4.3). II-4: yield: 18.6%; MS (ESI+), m/z C.sub.37H.sub.35N.sub.3O.sub.8S, [M+H].sup.+=682.2; maximum UV absorption wavelength: ?.sub.max (log ?), 711 nm (4.3).

Example 88

[0179] ##STR00097##

[0180] Please refer to Example 69 for the synthesis of a compound 14. Please refer to Example 85 for the synthesis of a compound II-5: yield: 15.2%; MS (ESI+), m/z C.sub.41H.sub.36N.sub.4O.sub.9S.sub.2, [M+H].sup.+=793.2; maximum UV absorption wavelength: ?.sub.max (log ?), 730 nm (4.4).

Example 89

[0181] ##STR00098##

[0182] Please refer to Example 85 for the synthesis of a compound II-6: yield: 10.5%; MS (ESI+), m/z C.sub.40H.sub.36N.sub.4O.sub.9S.sub.2, [M+H].sup.+=781.2; maximum UV absorption wavelength: ?.sub.max (log ?), 730 nm (4.2).

Example 90

[0183] ##STR00099##

[0184] Please refer to Example 68 for the synthesis of a compound 15. Please refer to Example 85 for the synthesis of compounds 11-7 and 11-8. 11-7: yield: 15.9%; MS (ESI+), m/z C.sub.34H.sub.29N.sub.3O.sub.8S, [M+H].sup.+=640.2; maximum UV absorption wavelength: ?.sub.max (log ?), 715 nm (4.4). 11-8: yield: 17.4%; MS (ESI+), m/z C.sub.34H.sub.29N.sub.3O.sub.8S, [M+H].sup.+=640.2; maximum UV absorption wavelength: ?.sub.max (log ?), 715 nm (4.4).

Example 91

[0185] ##STR00100##

[0186] Please refer to Example 86 for the synthesis of compounds II-9 and II-10. II-9: yield: 9.9%; MS (ESI+), m/z C.sub.44H.sub.48N.sub.6O.sub.10S.sub.3, [M+H].sup.+=917.2; maximum UV absorption wavelength: ?.sub.max (log ?), 734 nm (4.2). II-10: yield: 10.4%; MS (ESI+), m/z C.sub.44H.sub.48N.sub.6O.sub.10S.sub.3, [M+H].sup.+=917.2; maximum UV absorption wavelength: ?.sub.max (log ?), 734 nm (4.2).

Example 92

[0187] ##STR00101##

[0188] Please refer to Example 86 for the synthesis of compounds II-11 and II-12. II-11: yield: 10.0%; MS (ESI+), m/z C.sub.42H.sub.40N.sub.4O.sub.13S.sub.2, [M+H].sup.+=873.2; maximum UV absorption wavelength: ?.sub.max (log ?), 735 nm (4.3). 11-12: yield: 9.6%; MS (ESI+), m/z C.sub.42H.sub.40N.sub.4O.sub.13S.sub.2, [M+H].sup.+=873.2; maximum UV absorption wavelength: ?.sub.max (log ?), 735 nm (4.3).

Example 93

[0189] ##STR00102##

[0190] Please refer to Example 87 for the synthesis of compounds 11-13 and 11-14. 11-13: yield: 12.7%; MS (ESI+), m/z C.sub.39H.sub.38N.sub.4O.sub.8S.sub.2, [M+H].sup.+=755.2; maximum UV absorption wavelength: ?.sub.max (log ?), 732 nm (4.0). 11-14: yield: 10.9%; MS (ESI+), m/z C.sub.39H.sub.38N.sub.4O.sub.8S.sub.2, [M+H].sup.+=755.2; maximum UV absorption wavelength: ?.sub.max (log c), 732 nm (4.0).

Example 94

[0191] ##STR00103##

[0192] Please refer to Example 87 for the synthesis of compounds II-15 and II-16. II-15: yield: 8.2%; MS (ESI+), m/z C.sub.45H.sub.52N.sub.4O.sub.8S.sub.2, [M+H].sup.+=841.3; maximum UV absorption wavelength: ?.sub.max (log ?), 731 nm (4.0). II-16: yield: 7.6%; MS (ESI+), m/z C.sub.45H.sub.52N.sub.4O.sub.8S.sub.2, [M+H].sup.+=841.3; maximum UV absorption wavelength: ?.sub.max (log ?), 731 nm (4.0).

Example 95

Dark Cytotoxicity Experiment:

[0193] Cultured Hela cells were digested and percussed with 0.25% trypsin, made into a single cell suspension, adjusted to a cell count of about 2?10.sup.4/mL, inoculated into a 96-well culture plate with 200 uL/well, and cultured in an incubator with a 5% CO.sub.2 environment at 37? C. After cells were adherent, the supernatant culture solution was discarded, different concentrations of photosensitizers (hematoporphyrin derivative HpD, HB, and hypocrellin derivative HB-1) were added strictly in dark according to the experiment design, and further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 1 h. The survival rate of cells was detected by MTT assay. 20 uL of MTT (prepared with PBS, concentration: 5 mg/mL) was added to each well, and further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 4 h. Then the incubation was terminated. The supernatant was carefully pipetted from the wells and discarded, and then 150 uL of dimethyl sulfoxide (DMSO) was added to each well. The violet crystal was fully dissolved by vibration with a microvibrator for 10 min. The optical density value (OD value) of each well was detected by an ELIASA at 570 nm 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?100%. FIG. 10a shows the dark toxicity experiment results.

Example 96

Cell Phototoxicity Experiment:

[0194] Cultured Hela cells were digested and percussed with 0.25% trypsin, made into a single cell suspension, adjusted to a cell count of about 2?10.sup.4/mL, inoculated into a 96-well culture plate with 200 uL/well, and cultured in an incubator with a 5% CO.sub.2 environment at 37? C. After cells were adherent, the supernatant culture solution was discarded, different concentrations of photosensitizers (hematoporphyrin derivative HpD, HB, and hypocrellin derivative HB-1) were added strictly in dark according to the experiment design, and further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 1 h. Then the 96-well culture plate was perpendicularly irradiated with uniform semiconductor laser beam at a wavelength of 635 nm with the power density adjusted to 20 mW/cm.sup.2 for 1000 S. At the same time, a blank group was arranged for each 96-well culture plate, and 6 wells were arranged for each condition. After irradiation, the culture plate was further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 24 h, and then the cell survival rate was detected. The survival rate of cells was detected by MTT assay. 20 uL of MTT (prepared with PBS, concentration: 5 mg/mL) was added to each well, and further incubated in an incubator with a 5% CO.sub.2 environment at 37? C. for another 4 h. Then the incubation was terminated. The supernatant was carefully pipetted from the wells and discarded, and then 150 uL of dimethyl sulfoxide (DMSO) was added to each well. The violet crystal was fully dissolved by vibration with a microvibrator for 10 min. The optical density value (OD value) of each well was detected by an ELIASA at 570 nm 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?100%. FIG. 10b shows the phototoxicity experiment results.

Comparison Example 1

[0195] The structural formula of unmodified hypocrellin B (HB) is shown in FIG. 5, the absorption spectrum is shown in FIG. 7a, the maximum absorption wavelength is 450 nm, and there is weak red absorption at 590 nm. HB has weak light absorption capacity in the phototherapy window of 600-900 nm, and has much poorer ability to photodynamically kill tumor cells than the amphiphilic hypocrellin derivatives according to the invention (FIG. 10-14).

Comparison Example 2

[0196] ##STR00104##

[0197] A patent No. CN1194263A discloses that a compound A has the maximum absorption at 623 nm. The maximum absorption spectrum wavelength of the hypocrellin derivative A in the comparison Example is nearly 50 nm lower when compared with the polysubstituted near infrared hypocrellin derivative I-1 prepared according to the invention.

Comparison Example 3

[0198] ##STR00105##

[0199] A document (Hypocrellin derivative with improvements of red absorption and active oxygen species generation, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 1499-1501) discloses that a compound B has the maximum absorption at 640 nm. The maximum absorption spectrum wavelength of the hypocrellin derivative B in the comparison Example is nearly 50 nm lower when compared with the polysubstituted near infrared hypocrellin derivative II-2 prepared according to the invention.

[0200] Conclusions: The monosubstituted or polysubstituted amphiphilic hypocrellin derivative prepared according to the invention has an obvious red shift of its absorption spectrum and a greatly enhanced high molar extinction coefficient, and shows very strong near infrared red absorption capacity and amphiphilicity. Lack of any substitution will damage the effects of hypocrellin derivatives in some aspects to different extents.

[0201] Obviously, the above examples of the invention are only provided to clearly illustrate the invention, and rather than to limit the embodiments of the invention. For those with ordinary skills in the art, other different forms of alterations or variations may also be made on the basis of the above description. Here, it is impossible to exhaustively provide all embodiments, and all apparent alterations or variations derived from the technical solution of the invention still fall within the scope of protection of the invention.

MONOSUBSTITUTED OR POLYSUBSTITUTED AMPHIPHILIC HYPOCRELLIN DERIVATIVE, AND PREPARATION METHOD AND APPLICATION THEREOF

Inventors

Cpc classification

Classification Explorer

C07C229/18

CHEMISTRY; METALLURGY

Classification Explorer

C07D513/06

CHEMISTRY; METALLURGY

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A61K31/473

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