Biotin receptor targeted photosensitizer, preparation method and application thereof, and medicine box containing biotin receptor targeted photosensitizer

Abstract

The invention relates to a biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof, the biotin receptor targeted photosensitizer has a structure of the following general formula (I): # imgabs0 # (I), and a group R is a diamine derivative group of biotin and is defined in the specification. The invention further relates to preparation and application of the biotin receptor targeted photosensitizer and a medicine box containing the biotin receptor targeted photosensitizer.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a biotin receptor targeted photosensitizer, a preparation method and use thereof, and a medicine box containing the same. Background Art

[0002] Targeted drugs refer to drugs or their preparations that are endowed with targeting capabilities. The purpose is to enable the drug or its carrier to target specific lesions and accumulate or release active ingredients at the target site. Targeted preparations can make the drug form a relatively high concentration at the target site, thereby improving the efficacy while inhibiting toxic side effects and reducing damage to normal tissues and cells. According to different targeting mechanisms, drug targeting can be divided into passive targeting, active targeting and physical targeting. Among them, physical targeting uses physical signals such as light, heat, magnetic field, electric field, and ultrasound to artificially regulate the distribution and release characteristics of drugs in the body to achieve targeting of lesions. Photosensitizers are targeted drugs that work by physical targeting and are used in photodynamic therapy (PDT) to effectively treat a variety of diseases. Photodynamic therapy is a new type of therapy for treating diseases. Its principle is photochemical reaction, and its basic elements are oxygen, photosensitizer and visible light. First, the target cells selectively take up the photosensitizer, and then after local irradiation with light of appropriate wavelength, the photosensitizer is activated to produce a photosensitizing effect. Sodium porphyrin for injection, which is currently in clinical use, is a new type of photosensitizer. It is a single effective chemical component isolated from PHOTOFRIN (porphyrin sodium). Preclinical studies on esophageal cancer have shown that the mechanism of action of sodium porphyrin for injection is the same as that of PHOTOFRIN. Its dosage is only 10% of PHOTOFRIN to achieve the same intensity of anti-tumor activity, and its phototoxic reaction is low. It has obvious advantages in effectiveness, safety and quality control. As an indispensable material basis in photodynamic therapy, the upgrading and development process of photosensitizers is inseparable from the development of photodynamic therapy.

[0003] Biotin (also known as vitamin H, D-biotin) receptors, which exist in cell membranes, cytoplasm and nuclei, are potential targets for tumor drugs. They are sodium-dependent multivitamin transporters (SMVTs) and are overexpressed in a variety of aggressive cancer cell lines, such as ovarian cancer (OV 2008, ID8), leukemia (L1210FR), mastocytoma (P815), colon cancer (Colo-26), breast cancer (4T1, JC, MMT06056), renal cancer (RENCA, RD0995) and lung cancer (M109) cell lines. Based on the principle of passive targeted delivery, targeted drugs based on biotin derivatives can be designed to effectively treat various tumors. However, there are currently no biotin receptor targeted drugs on the market.

[0004] In order to adapt to the rapid development of PDT and more effectively treat diseases such as cancer and microbial infections, there is still a need to continuously develop photosensitizers that can significantly improve tumor targeting, thereby improving drug efficacy and having lower toxicity. Summary of the invention

[0005] In view of the state of the prior art, the present invention aims to provide a photosensitizer that can significantly improve the targeting of tumors, thereby improving the efficacy and having lower toxicity, and the preparation method thereof has a high yield and a simple synthesis process. The biotin receptor-targeted photosensitizer of the present invention can be excited under light of a specific wavelength and has high biological safety, and is a biotin photosensitizer with potential clinical application value and can be mass-produced.

[0006] In one aspect, the present invention provides a biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof, wherein the biotin receptor targeted photosensitizer has the following general formula (I): (I), Wherein the groups R are each independently a diamine derivative group of biotin, having the following structure:

[0007] The wavy line " represents the point of attachment to the carbonyl group of porphyrinic acid of formula (I); wherein the group X represents an alkylene group containing 1 to 20 carbon atoms, the alkylene group being linear or branched, unsubstituted or substituted by one or more identical or different groups selected from the group consisting of cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, alkylcarbonyl, dialkylamino, heterocyclic, haloalkyl or haloalkoxy, and the alkylene group may be optionally interrupted by one or more heteroatoms selected from S, N and O or by one or more 3-6 membered nitrogen-containing heterocyclic groups, wherein the 3-6 membered nitrogen-containing heterocyclic group is unsubstituted or substituted by one or more identical or different groups selected from the group consisting of cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl or haloalkoxy.

[0008] In another aspect, the present invention provides a method for preparing a biotin receptor-targeted photosensitizer of formula (I), comprising the following steps: S1) in the presence of a catalyst, reacting biotin or its ester with a diamine compound having a protective group in the presence of a solvent to obtain an intermediate 1; S2) removing the protecting group on intermediate 1 to obtain intermediate 2; S3) In the presence of a catalyst and a condensing agent, porphyrinic acid is reacted with the intermediate 2 in the presence of a solvent to obtain a product.

[0009] On the other hand, the present invention provides the use of a biotin receptor-targeted photosensitizer of formula (I) or a pharmaceutically acceptable salt thereof for preparing a drug for treating the following diseases: esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, renal cancer, and lung cancer, in particular small cell and non-small cell lung cancer, as well as bronchial carcinoma and pleuropulmonary blastoma; and precancerous lesions of the above-mentioned diseases.

[0010] In another aspect, the present invention provides a method for treating the following diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the disease is selected from esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, renal cancer and lung cancer, in particular small cell and non-small cell lung cancer, as well as bronchial cancer and pleuropulmonary blastoma; and precancerous lesions of the above-mentioned diseases.

[0011] In another aspect, the present invention provides a drug kit, comprising a therapeutically effective amount of the above-mentioned biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof; and instructions for using the same in photodynamic therapy.

[0012] Unexpectedly, the inventors found that the compound of formula (I) of the present invention is a photosensitizer that can significantly improve tumor targeting, thereby improving drug efficacy and having lower toxicity. The preparation method thereof has a high yield and a simple synthesis process, and can be used as a high-efficiency photosensitizer with potential clinical application value and can be mass-produced. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Figure 2 shows the body weight changes of A549 tumor-bearing mice after drug administration.

[0014] Figure 2 The figure shows the changes in tumor volume of A549 tumor-bearing mice after drug administration.

[0015] Figure 3 It is the tumor weight of A549 tumor-bearing mice at each experimental endpoint. DETAILED DESCRIPTION

[0016] Hereinafter, the present invention will be described in more detail.

[0017] Unless otherwise specified, "compound of formula (I) of the present invention", "compound of formula (I)", "compound of the present invention" and "biotin receptor targeting photosensitizer of the present invention (abbreviated as photosensitizer)" are used synonymously.

[0018] As used herein, the term "comprising" and its synonyms "including" and "containing" mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps.

[0019] Unless defined differently, the names of chemical groups are generally to be understood so that the bond to the skeleton or the rest of the molecule is via the last mentioned structural element of the relevant chemical group, ie, for example in the case of haloalkyl, via a carbon atom of the alkyl group.

[0020] The terms "optional", "optional" or "optionally" as used herein mean that the subsequently described event, circumstance or material may or may not appear or exist, and that such description includes instances where the event, circumstance or material appears or exists and instances where the event, circumstance or material does not appear or exist.

[0021] Unless otherwise stated, the following definitions apply to radicals or substituents used throughout the present description and claims. Within the scope of the present invention, the meanings of all radicals occurring repeatedly are independent of one another.

[0022] As used herein, the term "cyano" refers to a functional group in which a carbon atom and a nitrogen atom are connected by a triple bond.

[0023] As used herein, the term "halogen" denotes, for example, fluorine, chlorine, bromine or iodine. If the term is applied to a radical, "halogen" denotes, for example, a fluorine, chlorine, bromine or iodine atom.

[0024] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon radical having the specified number of carbon atoms in each case, for example (C1-C 10 )-alkyl, (C1-C6)-alkyl and (C1-C4)-alkyl, examples of which are not limited to methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 1-methylheptyl, 2-ethylhexyl, 1,3-dimethylhexyl and 1-ethyl-2-methylpentyl.

[0025] As used herein, the term "alkylene" refers to a straight or branched chain alkylene, i.e., a divalent hydrocarbon group, preferably 1-20 carbon atoms, more preferably 1-15 carbon atoms, 1-10 carbon atoms, and particularly a divalent hydrocarbon group of 1-6 carbon atoms. For example, a straight chain alkylene is a divalent group of formula -(CH2)n-. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 1,2-dimethylbutyl, hexyl, 1-methylhexyl, 2-methylhexyl, octyl, nonyl and decyl.

[0026] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. 10 )-haloalkyl, (C1-C6)-haloalkyl and (C1-C4)-haloalkyl, examples include but are not limited to chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoropropan-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 1,1,1-trifluoropropan-2-yl.

[0027] According to the invention, "cycloalkyl" - on its own or as part of a chemical group - represents a monocyclic, bicyclic or tricyclic hydrocarbon preferably having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl or adamantyl. Also preferred are cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, such as, in particular, cyclopropyl or cyclobutyl. The cycloalkyl radicals according to the invention may be substituted by one or more identical or different radicals.

[0028] According to the invention, "alkoxy" represents a linear or branched alkyl-O- preferably having 1 to 10 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Alkoxy groups having 1 to 4 carbon atoms are also preferred. The alkoxy groups of the invention may be substituted by one or more identical or different groups.

[0029] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms of the alkyl portion are replaced by one or more halogen atoms, which may be the same or different. 10 )-haloalkoxy, (C1-C6)-haloalkoxy and (C1-C4)-haloalkoxy, examples include but are not limited to chloromethoxy, bromomethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, pentafluoroethoxy. Preferred are fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and pentafluoroethoxy.

[0030] According to the invention, "alkylthio" represents a straight or branched alkyl-S- group preferably having 1 to 10 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio. Alkylthio groups having 1 to 4 carbon atoms are also preferred. The alkylthio groups of the invention may be substituted by one or more identical or different groups.

[0031] According to the invention, "alkylcarbonyl" represents a straight-chain or branched alkyl-C(=O) preferably having 2 to 10 carbon atoms, for example methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl. Alkylcarbonyl having 1 to 4 carbon atoms is also preferred. The alkylcarbonyl of the invention may be substituted by one or more identical or different groups.

[0032] According to the present invention, "dialkylamino" represents a straight or branched chain preferably having 1 to 10 carbon atoms or having 1 to 4 carbon atoms in the alkyl portion. N,N -dialkylamino groups, for example N,N -dimethylamino, N,N -Diethylamino, N,N -di(n-propylamino), N,N -di(isopropylamino) and N,N -di-(sec-butylamino). N,N The dialkylamino group may be substituted by one or more identical or different groups.

[0033] According to the present invention, "heterocyclyl" represents a carbocyclic ring system with at least one ring, in which at least one carbon atom is replaced by a heteroatom, preferably by a heteroatom selected from N, O, S, P, B, Si, Se, and is saturated, unsaturated or heteroaromatic, and may be unsubstituted or substituted, wherein the bonding site is on a ring atom. Unless otherwise defined, the heterocycle preferably comprises 3 to 9 ring atoms, in particular 3 to 6 ring atoms, and one or more, preferably 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocycle are preferably selected from N, O and S, but two oxygen atoms should not be directly adjacent. The heterocycle usually contains no more than 4 nitrogen atoms and / or no more than 2 oxygen atoms and / or no more than 2 sulfur atoms. In the case of optionally substituted heterocyclyl, the invention also includes polycyclic ring systems, for example 8-azabicyclo[3.2.1]octyl, 1-azabicyclo[2.2.1]heptyl, 1-oxa-5-azaspiro[2.3]hexyl or 2,3-dihydro-1H-indole.

[0034] The heterocyclic group according to the invention is, for example, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, dioxolanyl, dioxolenyl, pyrazolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, oxiranyl, azetidinyl, aziridine, oxazetidinyl, oxaziridine, oxaziridine, oxaziridine, oxepanyl, oxazihexadinyl, azepanyl, oxopyrrolidinyl, dioxopyrrolidinyl, oxomorpholinyl, oxopiperazinyl and oxepanyl.

[0035] Any description of a compound of formula (I) anywhere herein also encompasses any diastereomers or enantiomers and E / Z isomers of the compound of formula (I), as well as salts thereof, that exist.

[0036] Depending on the nature of the substituents, the compounds of formula (I) described at any point herein may also be in the form of stereoisomers, i.e. geometric and / or optical isomers or in the form of isomer mixtures of varying composition. The invention provides both the pure stereoisomers and any desired mixtures of these isomers, although only compounds of formula (I) are generally discussed here.

[0037] If appropriate, the compounds of the formula (I) may be present in various polymorphic forms or as mixtures of various polymorphic forms. Both the pure polymorphs and the polymorph mixtures are provided by the invention and can be used according to the invention.

[0038] Compounds obtained from combinations which are contrary to the laws of nature and which the skilled person would therefore exclude based on his / her expert knowledge are not covered herein. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0039] According to one aspect of the present invention, the present invention provides a biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof, wherein the biotin receptor targeted photosensitizer has the following general formula (I): (I), Wherein the groups R are each independently a diamine derivative group of biotin, having the following structure:

[0040] The wavy line " represents the point of attachment to the carbonyl group of the porphyrin of formula (I); wherein the group X represents an alkylene group containing 1 to 20 carbon atoms, the alkylene group being linear or branched, unsubstituted or substituted by one or more identical or different groups selected from the group consisting of cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, alkylcarbonyl, dialkylamino, heterocyclic, haloalkyl or haloalkoxy, and the alkylene group may be optionally interrupted by one or more heteroatoms selected from S, N and O or by one or more 3-6 membered nitrogen-containing heterocyclic groups, wherein the 3-6 membered nitrogen-containing heterocyclic group is unsubstituted or substituted by one or more identical or different groups selected from the group consisting of cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl or haloalkoxy.

[0041] In a preferred embodiment of the present invention, preferably each R group has the same meaning.

[0042] In one embodiment of the present invention, wherein in formula (I), the 3-6 membered nitrogen-containing heterocyclic group is selected from the following groups: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, furazanyl, dioxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, triazinyl, tetrazinyl, oxazine, isoxazinyl or morpholinyl; preferably pyrazolyl, imidazolyl, triazolyl (e.g., triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole), oxazolyl, oxadiazolyl or furazanyl.

[0043] In a preferred embodiment of the present invention, in formula (I), when the alkylene group is interrupted by a plurality of heteroatoms, the heteroatoms may be continuous or interrupted.

[0044] The pharmaceutically acceptable salts of the compounds of formula (I) of the present invention refer to those salts that are considered safe and suitable for use in pharmaceutical preparations. These salts are usually prepared by reacting the compounds of formula (I) with an acid or a base in order to improve the solubility, stability and bioavailability of the drug.

[0045] The pharmaceutically acceptable salt of the compound of the present invention is, for example, the product obtained by reacting the compound of formula (I) with an acid. Preferably, the acid includes, but is not limited to, hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid or glutamic acid. The non-toxic pharmaceutical base addition salt of the compound of formula (I) of the present invention includes salts of bases such as sodium, potassium, calcium, ammonium, etc., and those skilled in the art will recognize a variety of non-toxic pharmaceutically acceptable addition salts.

[0046] In a preferred embodiment of the present invention, in formula (I), the alkylene group is linear and unsubstituted and contains 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms.

[0047] In a preferred embodiment of the present invention, in formula (I), the group R is a derivative group of biotin and the following diamine compound: , , ,or , wherein n is an integer of 1-20, preferably n is an integer of 2-15, more preferably n is an integer of 2-10, for example an integer of 2-6.

[0048] In a preferred embodiment of the present invention, in formula (I), the group R is a derivative group of biotin and the following diamine compound:

[0049] .

[0050] In a preferred embodiment of the present invention, in formula (I), the group R is a derivative group of biotin and the following diamine compound: .

[0051] In a preferred embodiment of the present invention, in formula (I), the group R has the structure or .

[0052] In a preferred embodiment of the present invention, the biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof is used to treat the following diseases: esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, kidney cancer and lung cancer.

[0053] The definitions of radicals listed above in general terms or in preferred ranges can be combined with one another as desired, ie including combinations between the preferred ranges given.

[0054] Very particular preference is given to the compounds of the formula (I) according to the invention listed in Table 1 below.

[0055] Table 1: Compounds of formula (I) in which R has the meaning given below.

[0056] (I) Table 1: List of compound structures

[0057] According to another aspect of the present invention, the present invention also provides a method for preparing a compound of formula (I), comprising the following steps: S1, in the presence of a catalyst, reacts biotin or its esters with a diamine compound having a protecting group in the presence of a solvent to obtain an intermediate 1; S2 removes the protecting group on intermediate 1 to obtain intermediate 2; S3: in the presence of a catalyst and a condensing agent, porphyrinic acid is reacted with intermediate 2 in the presence of a solvent to obtain a product.

[0058] In the method of the present invention, the biotin or its ester in step S1 is preferably biotin or biotin-N-succinimidyl ester (Biotin-NHS); the protecting group of the diamine compound is a conventional protecting group of amino group in organic reaction, such as tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), etc.

[0059] In the method of the present invention, the method for removing the protecting group in step S2 depends on the type of protecting group carried by the diamine compound. For example, when tert-butoxycarbonyl (Boc) is used as the protecting group, the removal reaction can be carried out in an acidic environment formed by, for example, hydrochloric acid, trichloroacetic acid, trifluoroacetic acid, etc., such as a dioxane solution of hydrogen chloride.

[0060] In the method of the present invention, in steps S1 and S3, the catalyst used is an organic base catalyst selected from N,N-diisopropylethylamine (DIPEA), N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N-dimethylaminopyridine, 2,6-lutidine or a mixture thereof, more preferably N,N-diisopropylethylamine; the organic solvent used is selected from N,N-dimethylformamide, N,N-dimethylacetamide, formamide, dimethyl sulfoxide, acetone, pyridine or a mixture thereof, more preferably N,N-dimethylformamide.

[0061] In the method of the present invention, in step S3, the condensing agent used is a urea cation type condensing agent, which is selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), Urea tetrafluoroborate (TBTU), O-(1,2-dihydro-2-oxy-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU); carbodiimide type condensing agent, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or carbonyl imidazole type condensing agent, such as N,N-carbonyldiimidazole (CDI); or a mixture thereof, preferably selected from HATU, EDCI, CDI or a mixture thereof.

[0062] In the method of the present invention, in step S3, the molar ratio of the catalyst to the condensation agent is (0.7-2.0):1, preferably (0.8-1.8):1, and more preferably (0.9-1.5):1.

[0063] In one embodiment according to the present invention, the present invention provides a method for preparing a compound of formula (I), comprising the following steps: S1, in the presence of a catalyst, reacts biotin or biotin-N-succinimidyl ester with a diamine compound having a protective group in the presence of a solvent to obtain an intermediate 01, The structure of the diamine compound with a protecting group is , The structure of intermediate 01 is , wherein L represents a protecting group tert-butoxycarbonyl (Boc); S2 removes the protecting group on intermediate 01 to obtain intermediate 02 having the following structure ; S3, in the presence of a catalyst and a condensing agent, reacting porphyrinic acid with the intermediate 02 in the presence of a solvent to obtain a product of the general formula (I); (I).

[0064] The method for preparing the compound of formula (I) of the present invention uses a combination of a specific organic base catalyst and a specific condensing agent, especially a specific ratio of DIPEA and HATU, and can obtain a target compound with high purity in good yield through simple post-treatment. If the amount of the catalyst or the condensing agent is too low or too high, it will have an adverse effect on the target product, such as an increase in the proportion of by-products and a low yield of the target product.

[0065] In the method of the present invention, the molar ratio of the biotin or its ester to the diamine compound with a protecting group is 1:(1-2.0), preferably 1:(1-1.5), and more preferably 1:(1.1-1.3).

[0066] The molar ratio of the biotin or its ester to the catalyst is 1:(0.8-3.0), preferably 1:(1.0-2.0), and more preferably 1:(1.2-1.8).

[0067] The molar ratio of the porphyrinic acid to the catalyst is 1:(4.0-12.0), preferably 1:(4.0-8.0), and more preferably 1:(4.0-6.0).

[0068] In the method of the present invention, the reaction time in each step is 0.5-24 hours, preferably 1-22 hours, more preferably 1-20 hours.

[0069] Another aspect of the present invention provides the use of a biotin receptor-targeted photosensitizer of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating the following diseases: esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, renal cancer, and lung cancer, in particular small cell and non-small cell lung cancer, as well as bronchial carcinoma and pleuropulmonary blastoma; and the hyperproliferative growth of the above-mentioned diseases, such as precancerous lesions.

[0070] Another aspect of the present invention provides a method for treating the following diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the disease is selected from esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, renal cancer and lung cancer, in particular small cell and non-small cell lung cancer, as well as bronchial carcinoma and pleuropulmonary blastoma; and hyperproliferative growth of the above conditions, such as precancerous lesions.

[0071] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought or desired by a researcher, physician or other clinician in a tissue, system, animal, individual or human.

[0072] As used herein, the term "treating" means killing, inhibiting or slowing the growth or increase in size of a hyperproliferative cell mass or group or a tumor or cancerous growth, reducing the number of hyperproliferative cells, or preventing spread to other anatomical sites, as well as methods of reducing the size of a hyperproliferative growth or the number of hyperproliferative cells. However, it should be understood that "treating" does not necessarily mean curing or completely eliminating a hyperproliferative growth.

[0073] The present invention also provides a medicine kit, which comprises a therapeutically effective amount of the above-mentioned biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof; and instructions for using the biotin receptor-targeted photosensitizer in photodynamic therapy.

[0074] As used herein, the term "kit" means any commercial package, which comprises a container for holding a compound of the present invention or a pharmaceutical preparation comprising the same, and optionally further comprises a separate container such as a separate vial or a separate foil package, for example, to hold a reconstituted dissolved matrix. The container may be any conventional shape or form known in the art, which is made of a pharmaceutically acceptable material.

[0075] In a preferred embodiment, the present invention provides a medicine kit, which comprises a lyophilized preparation of a therapeutically effective amount of a compound of the present invention for treating the diseases as described above; a dissolving matrix (such as water for injection containing auxiliary materials such as cosolvents) for reconstituting the lyophilized preparation for administration; and instructions for using the compound of the present invention as a photosensitizer in photodynamic therapy.

[0076] The various components of the kit, such as the compound of the present invention or a pharmaceutically acceptable salt thereof, a pharmaceutical preparation containing the same, a dissolving matrix, other active ingredients for treating cancer or precancerous lesions, etc., can be packaged in separate containers. Regardless of the number or type of containers, the kit can also include a device for assisting in administering the drug to the patient. The device can be a patch, an inhaler, a syringe, a pipette, a spoon with a measuring unit, or any delivery device approved for medical use.

[0077] The photosensitizer of the present invention can be administered in any of the following ways: oral, oral mucosal, spray inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, wherein oral mucosal, intramuscular, topical, intraperitoneal or intravenous administration is preferred.

[0078] The photosensitizer of the present invention can be administered in a unit dosage form. The dosage form can be a liquid dosage form, a semisolid dosage form and a solid dosage form. The liquid dosage form can be a true solution, a colloid, a microparticle dosage form, a suspension dosage form. The semisolid dosage form can be an ointment, a cream, a paste, a gel, etc. Other dosage forms can be, for example, tablets, capsules, dripping pills, aerosols, pills, powders, solutions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, implants, patches, liniments, and sustained-release agents.

[0079] For oral preparations, oral tablets and capsules can be prepared by methods known in pharmacy, and tablets can also be coated; oral liquids can be prepared as water-oil suspensions, solutions, emulsions, syrups, or dry products, which can be supplemented with water or other suitable media before use. Flavoring agents or colorants can be added if necessary.

[0080] For extragastric administration, the liquid dosage form is usually prepared from the drug of the present invention and a sterile carrier. The preferred carrier is water. Depending on the selected carrier and the drug concentration, the drug can be dissolved in the carrier or made into a suspension solution. When making a solution for injection, the drug is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.

[0081] It can also be made into sterile preparations for injection, including crystalline powder injection, freeze-dried powder injection, etc.

[0082] When applied topically to the skin or mucous membrane, the drug of the present invention can be prepared in the form of an appropriate ointment, lotion, gel or paste, wherein the active ingredient is suspended or dissolved in one or more carriers. Alternatively, it can be prepared in the form of a microneedle or the like for use with the aid of an instrument.

[0083] Photosensitizer of the present invention also comprises pharmaceutically acceptable carrier, excipient and / or other auxiliary agent.When comprising pharmaceutically acceptable carrier, excipient and / or other auxiliary agent, usually effective dose of photosensitizer of the present invention or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, excipient and / or other auxiliary agent are combined to make suitable application form or dosage form, and this procedure comprises that component is mixed, granulated, compressed, dissolved or lyophilized by suitable method.The content of carrier in medicine can be 1 to 98 weight %.For convenience, other auxiliary agents such as local anesthetic, preservative, buffer can be directly dissolved in carrier.

[0084] The photosensitizer of the present invention can be prepared into an injection, a topical preparation or an oral preparation by methods known to those skilled in the art. The photosensitizer of the present invention is preferably an injection, which is injected intravenously.

[0085] The pharmaceutically acceptable carriers, excipients and / or other auxiliary agents that can be used to prepare the photosensitizer of the present invention or its administration form are all conventional pharmaceutically acceptable carriers, excipients and / or other auxiliary agents known to those skilled in the art for this purpose.

[0086] The optimal dosage and interval of the photosensitizer of the present invention are determined by the properties of the compound and external conditions such as the form, route and site of administration, the specific mammal to be treated, the wavelength of light used for treatment, the light power and irradiation time, the type and severity of the disease to be treated, etc. This optimal dosage can be determined by conventional techniques. The optimal course of treatment, i.e., the daily dosage of the compound of the present invention or the drug of the present invention within a specified time, can be determined by methods known in the art.

[0087] The photosensitizer of the present invention is used at a dosage of 0.01-100.0 mg / kg of the subject, for example, 0.01-50.0 mg / kg of the subject, preferably 0.05-10.0 mg / kg of the subject, particularly 0.1-6.0 mg / kg of the subject, and 0.2-5.0 mg / kg of the subject; and laser illumination at a wavelength of 300-800nm, preferably 600nm-650nm, particularly 630nm is used, and the irradiation is usually performed once; the light dose is 1-300J, preferably 20-200J, and more preferably 50-150J; the optical power of the laser as the light source is usually 50-800mW, preferably 100-500mW; the illumination time is 10-2400 seconds, preferably 60-1800 seconds, and more preferably 100-1500 seconds; the illumination delay is usually 4-48 hours, preferably 10-25 hours.

[0088] In the context of the present invention, the term "optical power" refers to the actual optical power at the light irradiation site, which is measured by an optical power meter to determine the actual power at the treatment site.

[0089] In the context of the present invention, the term "light dose" refers to the actual light dose at the light irradiation site, which is obtained by multiplying the light power by the irradiation time.

[0090] Preparation of compounds In the method for preparing the compound of formula (I) of the present invention, liquid chromatography-mass spectrometry (LC-MS) is used to monitor the progress of the reaction, for example, using a Waters instrument, model: SQD2.

[0091] In the above method for preparing the compound of the present invention, the method may optionally include other post-treatment steps. The post-treatment steps may include conventional purification steps such as adjusting the pH value, crystallization, extraction, filtration, concentration under reduced pressure, and drying. Each of the above steps can be carried out in a conventional manner known to those skilled in the art. If present, extraction is usually carried out using a mixed solution of dichloromethane and methanol, preferably a mixed solution of dichloromethane / methanol = 10:1 (v / v); drying is usually carried out by freeze drying, infrared drying, vacuum drying, etc., preferably freeze drying.

[0092] In a preferred embodiment of the present invention, the method may further include a purification step by a chromatographic column. The purification may be performed by a medium pressure preparative liquid phase C18 column, with a filler particle size of 20-80 μm, preferably 40-63 μm, a loading of 4-120 g, preferably 40 g, a carbon content of 10-30%, preferably 17%, and elution using water / methanol (v / v) (elution gradient 100% / 0% to 50% / 50%, gradient elution time 20 min).

[0093] In the present invention, unless otherwise explicitly stated, the contents and percentages in the context of this application are all based on weight; unless otherwise explicitly stated, the method steps of the present invention are all carried out at normal temperature and pressure; the reagents used can be commercially available or prepared by methods known to those skilled in the art.

[0094] The compounds of the present invention can be prepared according to the above methods. However, it should be understood that a person skilled in the art, based on his own general knowledge and available publications, can adjust the methods according to the specific circumstances of the respective compounds of the present invention that he wishes to synthesize.

[0095] Detailed synthesis examples of selected compounds of the present invention are given below. However, these examples are merely illustrative and should not be interpreted as limiting the scope of the present invention in any way.

[0096] In the present invention, the structures of the compounds prepared in the synthesis examples were characterized by liquid chromatography-mass spectrometry (LC-MS). LC-MS data were obtained using a Waters instrument (model: SQD2). Synthesis Example

[0097] Synthetic reagents and equipment Table 2: Synthesis reagents

[0098] Table 3: Synthesis equipment

[0099] Synthetic route

[0100] In the above synthetic route, (01) represents the intermediate product obtained in step S1, (02) represents the intermediate product obtained in step S2, and (I) represents the final product obtained in step S3, wherein the R group has the meaning defined in the foregoing part of the specification; the "X" part in each structural formula has the same meaning as the definition of the group X in the foregoing part of the specification.

[0101] Synthesis of compound S-1 Dissolve Biotin-NHS (1000 mg, 2.93 mmol, 1 equ) and tert-butyl (2-((2-aminoethyl)disulfanyl)ethyl)carbamate (811 mg, 3.22 mmol, 1.1 equ) in 20 mL N,N -dimethylformamide, DIPEA (567 mg, 4.40 mmol, 1.5 equ) was added at 0°C and stirred for 3 hours. After the reaction was completed as detected by liquid chromatography-mass spectrometry, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by a C18 medium-pressure preparative column (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After reduced pressure concentration, lyophilization was performed to obtain the intermediate S-1-(01) (1100 mg, yield 79%) in the form of a white solid.

[0102] The intermediate S-1-(01) was added to 10 mL of hydrogen chloride-dioxane solution (hydrogen chloride concentration 4 mol / L), stirred at room temperature for 4 hours, and after detection by liquid chromatography-mass spectrometry to complete the reaction, it was concentrated under reduced pressure to obtain a colorless oily liquid, which was then freeze-dried to obtain the intermediate S-1-(02) (828 mg, yield 95%) in the form of a white solid.

[0103] Dissolve porphyrinic acid (500 mg, 0.44 mmol, 1 equ) in 20 mL N,N -dimethylformamide, then HATU (832 mg, 2.19 mmol, 5 equ) and DIPEA (283 mg, 2.19 mmol, 5 equ) were added in sequence at 20 °C, and after stirring for 0.5 hour, S-1-(02) (828 mg, 2.19 mmol, 5 equ) was added, and the reaction was allowed to proceed at room temperature for 15 hours. After the reaction was completed as detected by liquid chromatography-mass spectrometry, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by a C18 medium-pressure preparative column (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min), concentrated under reduced pressure, and lyophilized to obtain the target compound S-1 (739 mg, yield 65%) in the form of a reddish-brown solid, wherein the four R groups were identical and had the structure represented by S-1 in Table 1.

[0104] LC-MS (m / z): 1292.9 [M+2H] 2+ / 2 Synthesis of compound S-2 Dissolve Biotin-NHS (1000 mg, 2.93 mmol, 1 equ) and mono-Boc-ethylenediamine (515 mg, 3.22 mmol, 1.1 equ) in 20 mL N,N-dimethylformamide, DIPEA (567 mg, 4.40 mmol, 1.5 equ) was added at 0°C and stirred for 3 hours. After the reaction was completed as detected by liquid chromatography-mass spectrometry, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by a medium-pressure preparative column C18 (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After reduced pressure concentration, lyophilization was performed to obtain the intermediate S-2-(01) (1018 mg, yield 90%) in the form of a white solid.

[0105] The intermediate S-2-(01) was added to 10 mL of hydrogen chloride-dioxane solution (hydrogen chloride concentration 4 mol / L), stirred at room temperature for 4 hours, and after detection by liquid chromatography-mass spectrometry to complete the reaction, it was concentrated under reduced pressure to obtain a colorless oily liquid, which was then freeze-dried to obtain the intermediate S-2-(02) (700 mg, yield 93%) in the form of a white solid.

[0106] Dissolve porphyrinic acid (559 mg, 0.49 mmol, 1 equ) in 20 mL N,N -dimethylformamide, then HATU (931 mg, 2.45 mmol, 5 equ) and DIPEA (316 mg, 2.45 mmol, 5 equ) were added in sequence at 20 ° C. After stirring for 0.5 hour, S-2-(02) (700 mg, 2.45 mmol, 5 equ) was added and reacted at room temperature for 15 hours. After the reaction was detected by liquid chromatography-mass spectrometry to be complete, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by a medium pressure preparative column C18 (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After reduced pressure concentration, lyophilization was performed to obtain the target compound S-2 (597 mg, yield 55%) in the form of a reddish brown solid, whose four R groups were the same and had the structure represented by S-2 in Table 1.

[0107] LC-MS (m / z): 1109.8 [M+2H] 2+ / 2

[0108] In vivo efficacy evaluation 1. Experimental Design Table 4: Experimental design

[0109] Note: Dosing volume: 10 µL / g based on mouse body weight Table 5: Materials

[0110] Table 6: Equipment List

[0111] 2. Experimental animals and feeding management Experimental Animals: Strain: Balb / c-nude mice; Age: 6-8 weeks old; Weight: 18-20 g; Gender: female; Quantity: 60; Supplier: Shanghai Model Organisms Technology Co., Ltd. Animal production license number: SCXK (Shanghai) 2019-0002 Animal use license number: SYXK (Shanghai) 2018-0002 Feeding and management: Animals were kept in IVC (independent ventilation system) cages (5 per cage) in the SPF animal room of Qishang Biological. The animal information card of each cage indicated the number of animals in the cage, gender, strain, receipt date, dosing regimen, experiment number, group and start date of the experiment. All cages, bedding and drinking water were sterilized before use. Cages, feed and drinking water were changed once a week. The breeding environment and lighting conditions were as follows: Temperature: 20~26℃ Humidity: 30~70% Photoperiod: 12 hours light, 12 hours no light Cage: Made of polycarbonate. Bedding is corn cobs, changed once a week.

[0112] Food: The experimental animals had free access to food (irradiated sterilized, dry pelleted food) throughout the experimental period.

[0113] Drinking water: Experimental animals were free to drink sterile water.

[0114] Cage identification: The animal information card for each cage should indicate the number of animals in the cage, gender, strain, receipt date, dosing regimen, experiment number, group and start date of the experiment.

[0115] Animal identification: Ear cropping.

[0116] 3. Experimental Methods 3.1 Cell culture A549 cells were cultured in vitro in F12K medium with 10% fetal bovine serum and cultured in a 5% CO2 cell culture incubator at 37ºC. Routine treatment and subculture were performed twice a week. When the cell saturation reached 80%-90% and the number reached the required level, cells were harvested and counted, and the cell density was adjusted to 5×10 using PBS. 7cells / ml for future use.

[0117] 3.2 Animal inoculation Animals were acclimated for 7 days after arrival in the animal room. Experiments were conducted after the acclimation period. 0.1 mL (5.0×10 6 A549 cells / mouse were subcutaneously inoculated on the right back of each mouse near the thigh.

[0118] 3.3 Daily observation of experimental animals The use and welfare of experimental animals were carried out in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The health status and mortality of animals were monitored daily, and routine examinations included observing the effects of tumor growth and drug treatment on the daily behavior of animals, such as behavioral activities, food and water intake (only visual observation), physical signs or other abnormal conditions.

[0119] 3.4 Compound preparation Table 7 Compound preparation table

[0120] 3.5 Randomization After cell inoculation, tumor growth was observed regularly. When the tumor grew to an average tumor volume of 158 m on day 21, 3 At 14:00, 30 animals with appropriate tumor size were randomly divided into 5 groups according to the tumor size, with 6 animals in each group. The drug was administered on the day of grouping, which was recorded as D0. Except for the erlotinib group, which was administered by gavage every day, the other groups were administered once by tail vein. The specific dosing schedule is shown in Table 4. The drug solution of each group was prepared and used before the experiment and refrigerated in the dark before use. Except for the tumor illumination stage, the tumor-bearing animals were strictly protected from light for 3 days after tail vein administration, and then fed in weak light.

[0121] 3.6 Lighting Groups G3-G5 received light treatment once 19 h after drug administration. A 630 nm semiconductor laser (Guilin Xingda Optoelectronic Medical Device Co., Ltd., model PDT630-II) was used, and the optical fiber with a microlens at the end was pointed directly at the target site, so that the beam was projected vertically and completely covered the tumor. The parameters were set according to the following steps. Mice were anesthetized by inhalation of isoflurane using an anesthesia machine for small animals. After anesthesia, they were fixed with medical tape to fully expose the tumor site, and the non-tumor site was covered with a black plastic bag.

[0122] a. Turn on the laser therapy device for calibration and set parameters.

[0123] b. When measuring the laser treatment distance, the laser spot diameter should be able to cover the size of the tumor.

[0124] c. At the laser treatment distance given in the previous step, use an optical power meter to measure the laser power per unit area.

[0125] d. Adjust the laser power value to 318 mW.

[0126] e. Set the laser treatment time and perform PDT treatment on experimental animals.

[0127] Table 8 Light dose design table

[0128] 3.7 Data Collection After group administration, the length and width of the tumor were measured with a vernier caliper twice a week, and the mice were weighed at the same time. The tumor volume (TV) was calculated, and the anti-tumor efficacy of the compound was measured with TGI. 体积 (%), relative tumor inhibition rate (T / C%).

[0129]

[0130] （V t ： The average tumor volume of each treatment group at the end of administration; V 0 ： Average tumor volume of each treatment group at the beginning of drug administration After the experiment, the animals were euthanized and the tumors were removed to measure the tumor weight and calculate T / C. 重量 Percentage and tumor growth inhibition rate TGI 重量 (%). The specific calculation formula is as follows:

[0131] Among them, TW 药物治疗组 represents the tumor weight of the drug-treated group, TW 阴性对照组 represents the tumor weight of the negative control group.

[0132] 3.8 Sample collection and processing At the end of the experiment, mice in each group were euthanized, and the tumor tissues were removed, weighed, and neatly arranged for photographs.

[0133] 3.9 Data processing and statistical analysis All experimental results are expressed as "mean ± standard error". The number of days after grouping was used as the horizontal axis, and the weight or tumor volume of the mice was used as the vertical axis. GraphPad Prism 8 was used to draw the graph. Statistical analysis was performed based on the data obtained at the end of the experiment to evaluate the differences between the groups. Ordinary one-way ANOVA in GraphPad Prism 8 software was used for data analysis, and p<0.05 was considered to be significantly different.

[0134] 4. Results In the experiment, the in vivo anti-tumor effects of the targeted photosensitizer of the present application and the comparative compounds (erlotinib and huaporphyrin sodium) in the A549 non-small cell lung cancer subcutaneous transplant tumor model were evaluated. The animal body weight and tumor volume of each experimental group measured at different time points are shown in Figure 2. Figure 1 and Figure 2 End point tumor weights were as shown. Figure 3 shown.

[0135] The mean tumor volume was 158 mm 3 The mice were divided into groups at 1:10 p.m. and the drugs were administered on the day of grouping. The mice were irradiated with light of 630 nm wavelength 19 hours after the drugs were administered. The experiment was completed on D22 after grouping.

[0136] 4.1 Weight changes During the experiment, the mice tolerated the treatment well, and the weight changes of mice in each group were shown in Figure 1 (In the figures, data points represent the mean body weight within the group and error bars represent the standard error (SEM)).

[0137] 4.2 Tumor volume The changes in the average tumor volume of the A549 non-small cell lung cancer subcutaneous transplant tumor model over time are shown in Table 9.

[0138] Table 9 Tumor volume of each group at different time points

[0139] Note: a. Mean ± standard error b. Days after starting medication 4.3 Tumor growth curve and endpoint tumor weight Tumor growth curves and tumor weights Figure 2 and Figure 3 As shown ( Figure 2 Data points represent the mean body weight within the group, and error bars represent standard error (SEM).

[0140] 4.4 Antitumor efficacy evaluation indicators The growth inhibition rate of the test substance on the A549 non-small cell lung cancer subcutaneous transplanted tumor model was calculated based on the tumor volume on day 22 after administration (Table 10). The tumor weights of all groups on day 22 are shown in Table 11.

[0141] Table 10 Growth inhibition rate of the test substance on A549 non-small cell lung cancer subcutaneous transplant tumor model

[0142] Note: a. Mean ± standard error b. p The values ​​were analyzed by one-way ANOVA Table 11 Tumor weight and statistical analysis at the end of the experiment (day 22)

[0143] Note: a. Mean ± standard error b. p The values ​​were analyzed by one-way ANOVA From the above results, it can be seen that at D22, the tumor volume of the negative control group reached 674 mm 3 Compared with the control group, erlotinib at a dose of 25 mg / kg (TV=518 mm 3 , TGI=30.1%, p>0.05) had no significant inhibitory effect on the tumor growth of A549 model. Positive drug sodium porphyrin at a dose of 2 mg / kg (TV=289 mm 3 , TGI=74.7%, P<0.001) had a significant inhibitory effect on the tumor growth of the A549 model. Compared with the control drug, the biotin receptor targeted photosensitizer S-1 of the present invention (TV=154 mm 3 , TGI=100.8%, P<0.001) and S-2 (TV=91 mm 3 , TGI=113.0%, P<0.001) all showed significantly better efficacy, proving that the targeting ability was enhanced and the efficacy was improved.

Claims

1. A biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof, wherein the biotin receptor-targeted photosensitizer has the following general formula (I): （I）， Wherein the groups R are each independently a diamine derivative group of biotin, having the following structure: ， The wavy line " represents the point of attachment to the carbonyl group of porphyrinic acid of formula (I); wherein the group X represents an alkylene group containing 1 to 20 carbon atoms, the alkylene group being linear or branched, unsubstituted or substituted by one or more identical or different groups selected from the following: cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, alkylcarbonyl, dialkylamino, heterocyclic, haloalkyl or haloalkoxy, and the alkylene group may be optionally interrupted by one or more heteroatoms selected from S, N and O. 2 . The biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to claim 1 , wherein when the alkylene group is interrupted by multiple heteroatoms, the heteroatoms are continuous or interrupted. 3 . The biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the alkylene group is linear and unsubstituted.

4. The biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the group R is a derivative group of biotin and the following diamine compound: ， ,or ， Here n is an integer of 1-20.

5. The biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the group R is ,or 。 6. The biotin receptor-targeted photosensitizer according to claim 1 or a pharmaceutically acceptable salt thereof, for use in treating the following diseases: esophageal cancer, ovarian cancer, leukemia, mastocytoma, colon cancer, breast cancer, kidney cancer and lung cancer, as well as bronchial cancer and pleuropulmonary blastoma; and Precancerous lesions of the disease.

7. A method for preparing a biotin receptor targeting photosensitizer, comprising the following steps: S1, in the presence of a catalyst, reacts biotin or biotin-N-succinimidyl ester with a diamine compound having a protective group in the presence of a solvent to obtain an intermediate 01, The structure of the diamine compound with a protecting group is , The structure of intermediate 01 is , wherein L represents a protecting group tert-butoxycarbonyl (Boc); S2 removes the protecting group on intermediate 01 to obtain intermediate 02 having the following structure ； S3, in the presence of a catalyst and a condensing agent, reacting porphyrinic acid with the intermediate 02 in the presence of a solvent to obtain a product of the general formula (I); （I）。 8. The method according to claim 7, wherein the catalyst is an organic base catalyst selected from N,N-diisopropylethylamine (DIPEA), N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N'-dimethylaminopyridine, 2,6-lutidine or a mixture thereof; The condensing agent is a urea cation type condensing agent, which is selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (T BTU), O-(1,2-dihydro-2-oxy-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU); carbodiimide type condensing agent: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or carbonyl imidazole type condensing agent: N,N-carbonyldiimidazole (CDI); or a mixture thereof, and the molar ratio of the catalyst to the condensing agent is (0.7-3):1; The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, formamide, dimethyl sulfoxide, acetone, pyridine or a mixture thereof.

9. Use of the biotin receptor targeted photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for preparing a drug for treating the following diseases: Esophageal, ovarian, leukemia, mast cell tumors, colon, breast, kidney, and lung cancers, as well as bronchial carcinoma and pleuropulmonary blastoma; and Precancerous lesions of the disease.

10. A kit comprising the biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is present in a therapeutically effective amount; and instructions for using the biotin receptor-targeted photosensitizer in photodynamic therapy.

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