Biotin receptor-targeting photosensitizer, preparation method therefor and use thereof, and kit comprising same

Abstract

The present invention relates to a biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof. The biotin receptor-targeting photosensitizer has a structure of following general formula (I), wherein group R is a diamine derivative group of biotin as defined in the description. The present invention further relates to preparation and use of a biotin receptor-targeting photosensitizer, and a kit comprising same.

Description

Biotin receptor-targeting photosensitizers, their preparation methods and uses, and the kits containing them. Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to biotin receptor-targeting photosensitizers, their preparation methods and uses, and medicine boxes containing them. Background Technology

[0002] Targeted drugs are drugs or their formulations endowed with targeting capabilities. Their purpose is to enable the drug or its carrier to target specific lesion sites and accumulate or release the active ingredient at the target site. Targeted formulations can achieve relatively high drug concentrations at the target site, thereby improving efficacy while suppressing toxic side effects and reducing damage to normal tissues and cells. Based on different targeting mechanisms, drug targeting can be divided into passive targeting, active targeting, and physical targeting. Physical targeting utilizes physical signals such as light, heat, magnetic fields, electric fields, and ultrasound to artificially regulate the distribution and release characteristics of drugs in the body, achieving targeting of lesion sites. Photosensitizers, as targeted drugs that exert their effects through physical targeting, are used in photodynamic therapy (PDT) to effectively treat various diseases. Photodynamic therapy is a novel treatment method based on photochemical reactions. Its basic elements are oxygen, photosensitizers, and visible light. First, target cells selectively take up the photosensitizer. Then, after local irradiation with light of an appropriate wavelength, the photosensitizer is activated, producing a photosensitizing effect. Currently, injectable porphyrin sodium, a novel photosensitizer, is a single active chemical component isolated from photofrin. Preclinical studies in esophageal cancer have shown that injectable porphyrin sodium operates on the same mechanism as photofrin, but at only 10% of the dosage, it achieves equivalent antitumor activity with low phototoxicity, demonstrating significant advantages in efficacy, safety, and quality control. As an essential material basis for photodynamic therapy, the development of photosensitizers is inextricably linked to the advancement of photodynamic therapy itself.

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

[0004] To adapt to the rapid development of phototherapy (PDT) and to more effectively treat diseases such as cancer and microbial infections, it is still necessary to continuously develop photosensitizers that can significantly improve tumor targeting, thereby enhancing drug efficacy and reducing toxicity. Summary of the Invention

[0005] In view of the current state of the technology, this invention aims to provide a photosensitizer that can significantly improve tumor targeting, thereby enhancing drug efficacy and reducing toxicity. Its preparation method boasts high yield and a simple synthesis process. This biotin receptor-targeting photosensitizer can be excited under light of a specific wavelength and exhibits high biosafety, making it a biotin photosensitizer with potential clinical application value and capable of large-scale production.

[0006] On one hand, the present invention provides a biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof, wherein the biotin receptor-targeting photosensitizer has the structure of the following general formula (I):

[0007] Each of the R groups is an independent diamine derivative of biotin, having the following structure:

[0008] Among them, the wavy line Indicates the connection point with the carbonyl group of porphyrinic acid in formula (I);

[0009] Wherein group X represents an alkylene group containing 1-20 carbon atoms, the alkylene group being straight-chain 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 optionally be separated 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 heterocycle is unsubstituted or substituted by one or more identical or different groups selected from the following: cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, or haloalkoxy.

[0010] On the other hand, the present invention provides a method for preparing a biotin receptor-targeted photosensitizer of formula (I), comprising the following steps:

[0011] S1) In the presence of a catalyst, biotin or its esters are reacted with a diamine compound with a protecting group in the presence of a solvent to give intermediate 1;

[0012] S2) Remove the protecting group from intermediate 1 to obtain intermediate 2;

[0013] 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 the product.

[0014] On the other hand, the present invention provides the use of the biotin receptor-targeting photosensitizer of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating the following diseases: esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer, and lung cancer, particularly small cell and non-small cell lung cancer, as well as bronchial cancer and pleural blastoma; and precancerous lesions of the above diseases.

[0015] In another aspect, the present invention provides a method for treating diseases comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) above or a pharmaceutically acceptable salt thereof; wherein the diseases are selected from esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer and lung cancer, particularly small cell and non-small cell lung cancer, as well as bronchial cancer and pleural blastoma; and precancerous lesions of the above diseases.

[0016] In another aspect, the present invention provides a kit containing a therapeutically effective amount of the aforementioned biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof; and instructions for use therein in photodynamic therapy.

[0017] Surprisingly, the inventors discovered 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. Its preparation method has high yield and simple synthesis process, and it can be used as a highly efficient photosensitizer with potential clinical application value and can be produced on a large scale. Attached Figure Description

[0018] Figure 1 shows the weight changes of A549 tumor-bearing mice after drug administration.

[0019] Figure 2 shows the changes in tumor volume in A549 tumor-bearing mice after drug administration.

[0020] Figure 3 shows the tumor weight at each experimental endpoint in A549 tumor-bearing mice. Detailed Implementation

[0021] The invention will be described in more detail below.

[0022] Unless otherwise stated, “compound of formula (I) of the present invention”, “compound of formula (I)”, “compound of the present invention” and “biotin receptor-targeted photosensitizer of the present invention (hereinafter referred to as photosensitizer)” are used synonymously.

[0023] 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.

[0024] Unless otherwise defined, the name of a chemical group should generally be understood as such that its connection to the skeleton or the rest of the molecule is through the structural elements of the last mentioned related chemical group, i.e.,, for example, through the carbon atoms of the alkyl group in the case of haloalkyl groups.

[0025] As used herein, the terms “optional,” “optional,” or “optionally” mean that the event, situation, or substance described below may or may not occur or not exist, and such description includes both the occurrence and absence of the event, situation, or substance.

[0026] Unless otherwise stated, the following definitions apply to groups or substituents used throughout this specification and claims. Within the scope of this invention, the meanings of all repeated groups are independent of each other.

[0027] As used in this article, the term "cyano" refers to a functional group formed by the connection of carbon and nitrogen atoms via a triple bond.

[0028] As used herein, the term "halogen" refers to, for example, fluorine, chlorine, bromine, or iodine. If the term is used with a group, "halogen" refers to, for example, a fluorine, chlorine, bromine, or iodine atom.

[0029] As used herein, the term "alkyl" refers in each case to a saturated straight-chain or branched hydrocarbon group having a specified number of carbon atoms, for example (C1-C2). 10 (C1-C6)-alkyl and (C1-C4)-alkyl, examples including but 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.

[0030] As used herein, the term "alkylene" refers to a straight-chain or branched alkylene group, i.e., a divalent hydrocarbon group, preferably with 1-20 carbon atoms, more preferably with 1-15 carbon atoms, 1-10 carbon atoms, and particularly with 1-6 carbon atoms. For example, a straight-chain alkylene group is a divalent group of the formula -(CH2)n-. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, 1-methylpropylene, 2-methylpropylene, pentylene, 1-methylbutylene, 2-methylbutylene, hexylene, 1,2-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 1,2-dimethylbutylene, heptylene, 1-methylhexylene, 2-methylhexylene, octylene, nonylene, and decylene.

[0031] 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 identical or different halogen atoms, for example (C1-C2). 10 (C1-C6)-haloalkyl, (C1-C4)-haloalkyl, and 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-trifluoropropyl-2-yl. Fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl are preferred.

[0032] According to the present invention, "cycloalkyl"—either on its own or as part of a chemical group—preferably represents a monocyclic, bicyclic, or tricyclic hydrocarbon having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclic [2.2.1]heptyl, bicyclic [2.2.2]octyl, or adamantyl. Cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms are also preferred, for example, especially cyclopropyl or cyclobutyl. The cycloalkyl groups of the present invention can be substituted with one or more identical or different groups.

[0033] According to the present invention, "alkoxy" preferably represents a straight-chain or branched alkyl-O- group 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 present invention can be substituted with one or more identical or different groups.

[0034] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms of the alkyl portion are replaced by one or more identical or different halogen atoms, for example (C1-C2). 10 (C1-C6)-haloalkoxy, (C1-C4)-haloalkoxy, and 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, and pentafluoroethoxy. Fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and pentafluoroethoxy are preferred.

[0035] According to the present invention, "alkathioyl" preferably represents a straight-chain or branched alkyl-S- having 1 to 10 carbon atoms, such as methylthioyl, ethylthioyl, n-propylthioyl, isopropylthioyl, n-butylthioyl, isobutylthioyl, sec-butylthioyl, and tert-butylthioyl. Alkathioyl having 1 to 4 carbon atoms is also preferred. The alkathioyl group of the present invention can be substituted with one or more identical or different groups.

[0036] According to the present invention, "alkyl carbonyl" preferably represents a straight-chain or branched alkyl-C (=O) having 2 to 10 carbon atoms, such as methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, sec-butyl carbonyl, and tert-butyl carbonyl. Alkyl carbonyl having 1 to 4 carbon atoms is also preferred. The alkyl carbonyl of the present invention can be substituted with one or more identical or different groups.

[0037] According to the present invention, "dialkylamino" represents a straight-chain or branched N,N-dialkylamino group preferably having 1 to 10 carbon atoms or 1 to 4 carbon atoms in the alkyl portion, such as N,N-dimethylamino, N,N-diethylamino, N,N-di(n-propylamino), N,N-di(isopropylamino), and N,N-di-(sec-butylamino). The N,N-dialkylamino group of the present invention can be substituted with one or more identical or different groups.

[0038] According to the invention, a "heterocyclic group" represents a carbocyclic system having at least one ring in which at least one carbon atom is replaced by a heteroatom, preferably selected from N, O, S, P, B, Si, and Se, and is saturated, unsaturated, or heteroaromatic, and can be unsubstituted or substituted, wherein the bonding site is on a ring atom. Unless otherwise defined, a heterocycle preferably contains 3 to 9 ring atoms, especially 3 to 6 ring atoms, and one or more, preferably 1 to 4, especially 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. Heterocycles typically contain 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 heterocyclic groups, the invention also includes polycyclic systems, such as 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.

[0039] The heterocyclic groups of the present invention are, for example: piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dioxacyclohexyl, pyrrolinyl, pyrrolylalkyl, imidazolinyl, imidazoalkyl, thiazoalkyl, oxazolidinyl, dioxopentenyl, dioxacyclopentenyl, pyrazolyl, tetrahydrofuranyl, dihydrofuranyl, oxacyclobutyl, oxacyclopropyl, azirrobutyl, azirropropyl, oxacyclobutyl, oxacyclopropyl, oxacyclobutyl, oxacyclopropyl, oxacyclohepyl, oxacyclohexyl, azirrohepyl, oxopyrrolyl, dioxopyrrolyl, oxomorpholinyl, oxopyrazinyl, and oxopyrrohepyl.

[0040] The compounds of formula (I) mentioned anywhere in this document also cover any diastereomers or enantiomers and E / Z isomers of the presence of compounds of formula (I), as well as their salts.

[0041] Depending on the nature of the substituents, compounds of formula (I) described anywhere herein may also be in the form of stereoisomers, i.e., geometric and / or optical isomers or mixtures of isomers with different compositions. This invention provides pure stereoisomers and any desired mixtures of these isomers, although only compounds of formula (I) are generally discussed herein.

[0042] If appropriate, the compound of formula (I) can exist in various polymorphic forms or as mixtures of various polymorphic forms. Pure polymorphs and mixtures of polymorphs are provided by the present invention and can be used according to the present invention.

[0043] This document does not cover compounds obtained from combinations that contradict the laws of nature and that would therefore be excluded by a person skilled in the art based on his / her expertise. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0044] According to one aspect of the present invention, a biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof is provided, wherein the biotin receptor-targeting photosensitizer has the structure of the following general formula (I):

[0045] Each of the R groups is an independent biotin diamine derivative group, having the following structure:

[0046] Among them, the wavy line Indicates the connection point with the carbonyl group of the porphyrin in formula (I);

[0047] Wherein group X represents an alkylene group containing 1-20 carbon atoms, the alkylene group being straight-chain 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 optionally be separated 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 heterocycle is unsubstituted or substituted by one or more identical or different groups selected from the following: cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl, or haloalkoxy.

[0048] In a preferred embodiment of the present invention, each R group preferably has the same meaning.

[0049] In one embodiment of the invention, wherein in formula (I), the 3-6 member nitrogen-containing heterocyclic group is selected from the following groups: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxtriazolyl, furazonyl, dioxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, piperidinyl, triazinyl, tetraazinyl, 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 furazonyl.

[0050] In a preferred embodiment of the invention, in formula (I), when the alkylene group is separated by a plurality of heteroatoms, the heteroatoms may be continuous or spaced apart.

[0051] Pharmaceutically acceptable salts of compounds of formula (I) of this invention refer to those salts that are pharmaceutically considered safe and suitable for use in pharmaceutical formulations. These salts are typically generated by reacting compounds of formula (I) with acids or bases to improve the solubility, stability, and bioavailability of the drug.

[0052] Pharmaceutically acceptable salts of the compounds of this invention are, for example, products obtained by reacting compounds of formula (I) with acids. Preferably, the acids include, but are 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 pharmaceutically acceptable basic addition salts of the compounds of formula (I) of this invention include 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.

[0053] In a preferred embodiment of the invention, wherein in formula (I), the alkylene group is straight-chain and unsubstituted, and contains 2-15 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms.

[0054] In a preferred embodiment of the invention, wherein in formula (I), the group R is a derivative group of biotin and the following diamine compound:

[0055] Where n is an integer from 1 to 20, preferably an integer from 2 to 15, more preferably an integer from 2 to 10, such as an integer from 2 to 6.

[0056] In a preferred embodiment of the invention, wherein in formula (I), the group R is a derivative group of biotin and the following diamine compound:

[0057] In a preferred embodiment of the invention, wherein in formula (I), the group R is a derivative group of biotin and the following diamine compound:

[0058] In a preferred embodiment of the invention, wherein in formula (I), group R has the following structure

[0059] In a preferred embodiment of the invention, the biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof is used to treat the following diseases: esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer, and lung cancer.

[0060] The definitions of the groups listed above in general terms or within the preferred range can be combined with each other as needed, i.e., combinations between the given preferred ranges.

[0061] The compounds of formula (I) of the present invention listed in Table 1 below are particularly preferred.

[0062] Table 1: Compounds of Formula (I), where R has the following meanings.

[0063] Table 1: List of Compound Structures

[0064] According to another aspect of the invention, the invention also provides a method for preparing a compound of formula (I), comprising the following steps:

[0065] S1 reacts biotin or its esters with a diamine compound with a protecting group in the presence of a solvent in the presence of a catalyst to obtain intermediate 1;

[0066] S2 removes the protecting group from intermediate 1 to obtain intermediate 2;

[0067] S3 reacts porphyrinic acid with intermediate 2 in the presence of a catalyst and a condensing agent in the presence of a solvent to obtain the product.

[0068] In the method of the present invention, biotin or its ester in step S1 is preferably biotin or biotin-N-succinimide ester (Biotin-NHS); the protecting group of the diamine compound is a conventional protecting group of amino groups in organic reactions, such as tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), etc.

[0069] In the method of the present invention, the method for removing the protecting group in step S2 depends on the type of protecting group of the diamine compound. For example, when using tert-butoxycarbonyl (Boc) as the protecting group, the removal reaction can be carried out in an acidic environment such as hydrochloric acid, trichloroacetic acid, or trifluoroacetic acid, or for example, using a dioxane solution of hydrogen chloride.

[0070] In the method of the present invention, the catalyst used in steps S1 and S3 is an organic base catalyst, which is selected from N,N-diisopropylethylamine (DIPEA), N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, N-methylimidazolium, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N-dimethylaminopyridine, 2,6-dimethylpyridine or mixtures 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 mixtures thereof, more preferably N,N-dimethylformamide.

[0071] In the method of the present invention, the condensing agent used in step S3 is a urea cation type condensing agent, which is selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate. Urea tetrafluoroborate (TBTU), O-(1,2-dihydro-2-oxopyridyl)-1,1,3,3-tetramethylurea tetrafluoroborate (TPTU); carbodiimide-type condensing agents, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or carbonylimidazolium-type condensing agents, such as N,N-carbonyldiimidazolium (CDI); or mixtures thereof, preferably selected from HATU, EDCI, CDI, or mixtures thereof.

[0072] In the method of the present invention, in step S3, the molar ratio of the catalyst to the condensing agent is (0.7-2.0):1, preferably (0.8-1.8):1, and more preferably (0.9-1.5):1.

[0073] In one embodiment of the present invention, the present invention provides a method for preparing a compound of formula (I), comprising the following steps:

[0074] S1 reacts biotin or biotin-N-succinimide ester with a diamine compound bearing a protecting group in the presence of a solvent in the presence of a catalyst to give intermediate 01.

[0075] The structure of the diamine compound with the protecting group is as follows:

[0076] The structure of intermediate 01 is as follows Where L represents the protecting group tert-butoxycarbonyl (Boc);

[0077] S2 removes the protecting group from intermediate 01 to obtain intermediate 02 with the following structure.

[0078] S3 reacts porphyrinic acid with intermediate O2 in the presence of a catalyst and a condensing agent in the presence of a solvent to obtain a product with the general formula (I).

[0079] The method for preparing compounds of formula (I) of the present invention uses a combination of a specific organic base catalyst and a specific condensing agent, particularly a specific ratio of DIPEA and HATU, which can obtain the target compound with high purity in good yield through simple post-processing. Too little or too much catalyst or condensing agent 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.

[0080] In the method of the present invention, the molar ratio of 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).

[0081] 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).

[0082] The molar ratio of the porphyrin to the catalyst is 1:(4.0-12.0), preferably 1:(4.0-8.0), and more preferably 1:(4.0-6.0).

[0083] In the method of the present invention, the reaction time in each step is 0.5-24 hours, preferably 1-22 hours, and more preferably 1-20 hours.

[0084] Another aspect of the present invention provides the use of the biotin receptor-targeting photosensitizer of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer, and lung cancer, particularly small cell and non-small cell lung cancer, as well as bronchial cancer and pleural blastoma; and the excessive proliferative growth of the above-mentioned diseases, such as precancerous lesions.

[0085] In another aspect, the present invention provides a method for treating diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) above or a pharmaceutically acceptable salt thereof; wherein the diseases are selected from esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer and lung cancer, particularly small cell and non-small cell lung cancer, as well as bronchial cancer and pleural blastoma.

[0086] And the excessive proliferative growth of the aforementioned conditions, such as precancerous lesions.

[0087] As used herein, the term “therapeutic effective amount” refers to the amount of an active compound or agent that elicits a biological or pharmaceutical response sought or desired by researchers, physicians or other clinicians in a tissue, system, animal, individual or human.

[0088] As used herein, the term “treatment” means killing, inhibiting, or slowing the growth or increase in size of a cluster or group of overproliferating cells or tumor or cancerous growth, reducing the number of overproliferating cells, or preventing its spread to other anatomical sites, and reducing the size of overproliferative growth or the number of overproliferating cells. However, it should be understood that “treatment” does not necessarily mean a cure or complete elimination of overproliferative growth.

[0089] The present invention also provides a kit containing a therapeutically effective amount of the above-described biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof; and instructions for use therein in photodynamic therapy.

[0090] As used herein, the term "pharmacy box" means any commercial packaging containing a container for holding the compounds of the present invention or pharmaceutical preparations containing the present invention, and optionally also includes separate containers such as separate vials or separate foil packs, for example, for holding reconstitution dissolution matrices. The containers may be any conventional shape or form known in the art and are made of pharmaceutically acceptable materials.

[0091] In a preferred embodiment, the kit provided by the present invention comprises a lyophilized formulation of the compound of the present invention in a therapeutically effective amount for treating the disease as described above; a dissolving matrix (such as water for injection containing excipients such as cosolvents) for reconstituted the lyophilized formulation for application; and instructions for using the compound of the present invention as a photosensitizer in photodynamic therapy.

[0092] The various components of the kit, such as the compounds of the present invention or their pharmaceutically acceptable salts, pharmaceutical preparations containing them, dissolving matrices, and other active ingredients for treating cancer or precancerous lesions, may be packaged in individual containers. Regardless of the number or type of containers, the kit may also include a device for assisting in the administration of the medication to the patient. This device may be a patch, inhaler, syringe, suction tube, spoon with measuring units, or any approved medical delivery device.

[0093] The photosensitizer of the present invention can be administered in any of the following ways: orally, via oral mucosa, via spray inhalation, via rectal administration, via nasal administration, via vaginal administration, via local administration, via parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an external reservoir, wherein oral mucosa administration, intramuscular injection, local administration, intraperitoneal, or intravenous administration are preferred.

[0094] The photosensitizer of this invention can be administered in unit dose form. The dosage form can be liquid, semi-solid, or solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Semi-solid dosage forms can be ointments, creams, pastes, gels, etc. Other dosage forms include, for example, tablets, capsules, pellets, aerosols, pills, powders, solutions, emulsions, granules, suppositories, lyophilized powder injections, inclusion complexes, implants, patches, liniments, and sustained-release formulations.

[0095] For oral preparations, tablets and capsules can be prepared using pharmaceutically known methods, and tablets can also be coated; oral liquids can be prepared as suspensions, solutions, emulsions, syrups, or as dry products, to be replenished with water or other suitable medium before use. Flavoring or coloring agents can be added if necessary.

[0096] For parenteral administration, the liquid dosage form is typically made from the drug of this invention and a sterilized carrier. Water is the preferred carrier. Depending on the chosen carrier and drug concentration, the drug can be either soluble in the carrier or prepared as a suspension. When preparing an injectable solution, the drug is first dissolved in water, filtered, sterilized, and then packaged into a sealed bottle or ampoule.

[0097] It can also be formulated into sterile injectable preparations, including crystalline powder injections and lyophilized powder injections.

[0098] When applied topically to the skin or mucous membranes, the medicine of the present invention can be formulated into suitable ointments, lotions, gels, or pastes, wherein the active ingredient is suspended or dissolved in one or more carriers. Alternatively, it can be formulated into forms for use with devices such as microneedles.

[0099] The photosensitizer of the present invention also comprises a pharmaceutically acceptable carrier, excipients, and / or other adjuvants. When comprising a pharmaceutically acceptable carrier, excipients, and / or other adjuvants, an effective dose of the photosensitizer of the present invention or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable carriers, excipients, and / or other adjuvants, is typically combined to form a suitable administration or dosage form. This procedure includes mixing, granulating, compressing, dissolving, or lyophilizing the components by suitable methods. The carrier content in the drug can be from 1 to 98% by weight. For convenience, other adjuvants such as local anesthetics, preservatives, and buffers may be directly dissolved in the carrier.

[0100] The photosensitizer of the present invention can be prepared into injections, topical formulations, or oral formulations using methods known to those skilled in the art. The photosensitizer of the present invention is preferably an injection, administered intravenously.

[0101] The pharmaceutically acceptable carriers, excipients, and / or other adjuvants that can be used to prepare the photosensitizers of the present invention or their application forms are conventional pharmaceutically acceptable carriers, excipients, and / or adjuvants known to those skilled in the art for this purpose.

[0102] 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 being treated, the wavelength, power and duration of light used for treatment, and the type and severity of the disease being treated. This optimal dosage can be determined using conventional techniques. The optimal course of treatment, i.e., the daily dose of the compound or drug of the present invention within a specified time period, can be determined using methods known in the art.

[0103] The photosensitizer of the present invention is used at a dosage of 0.01-100.0 mg / kg of subject, for example 0.01-50.0 mg / kg of subject, preferably 0.05-10.0 mg / kg of subject, particularly 0.1-6.0 mg / kg of subject, 0.2-5.0 mg / kg of subject; and is irradiated with laser light at a wavelength of 300-800 nm, preferably 600 nm-650 nm, particularly 630 nm, usually once; the light dose is 1-300 J, preferably 20-200 J, more preferably 50-150 J; the light power of the laser as the light source is usually 50-800 mW, preferably 100-500 mW; the irradiation time is 10-2400 seconds, preferably 60-1800 seconds, more preferably 100-1500 seconds; the irradiation delay is usually 4-48 hours, preferably 10-25 hours.

[0104] In the context of this invention, the term "optical power" refers to the actual optical power of the light-irradiated area, which is measured by an optical power meter to determine the actual power of the treatment area.

[0105] In the context of this invention, the term "light dose" refers to the actual light dose at the irradiated site, obtained by multiplying the light power by the irradiation time.

[0106] Preparation of compounds

[0107] In the method for preparing the compound of formula (I) of the present invention, the reaction process is monitored by liquid chromatography-mass spectrometry (LC-MS), for example using a Waters instrument, model: SQD2.

[0108] In the above-described method for preparing the compounds of the present invention, the method may optionally include other post-processing steps. These post-processing steps may include, for example, conventional purification steps such as pH adjustment, crystallization, extraction, filtration, vacuum concentration, and drying. All of the above steps can be performed in a conventional manner known to those skilled in the art. If present, extraction is typically performed using a mixed solution of dichloromethane and methanol, preferably a dichloromethane / methanol mixture of 10:1 (v / v); drying is typically performed by freeze-drying, infrared drying, vacuum drying, etc., preferably freeze-drying.

[0109] In a preferred embodiment of the present invention, the method may further include a purification step via a chromatographic column. The purification may be performed using a medium-pressure preparative liquid chromatography (C18) column with a packing particle size of 20-80 μm, preferably 40-63 μm, a loading of 4-120 g, preferably 40 g, and a carbon content of 10-30%, preferably 17%, eluted with water / methanol (v / v) (elution gradient 100% / 0% to 50% / 50%, gradient elution time 20 min).

[0110] In this invention, unless otherwise expressly stated, all contents and percentages in the context of this application are based on weight; unless otherwise expressly stated, all method steps of this invention are carried out at room temperature and pressure; the reagents used are commercially available or prepared by methods known to those skilled in the art.

[0111] The compounds of the present invention can be prepared according to the methods described above. However, it should be understood that those skilled in the art, based on their common sense and available publications, can adjust the methods according to the specific circumstances of the compounds of the present invention to be synthesized.

[0112] Detailed synthetic examples of the selected compounds of the present invention are given below. However, these examples are merely illustrative and should not be construed as limiting the scope of the invention in any way.

[0113] In this 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).

[0114] Synthesis Examples

[0115] Synthetic reagents and equipment

[0116] Table 2: Synthetic Reagents

[0117] Table 3: Synthesis Equipment

[0118] Synthetic route

[0119] 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. 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 group X defined in the foregoing part of the specification.

[0120] Synthesis of compound S-1

[0121] Biotin-NHS (1000 mg, 2.93 mmol, 1 equ) and tert-butyl (2-((2-aminoethyl)dithioalkyl)ethyl)carbamate (811 mg, 3.22 mmol, 1.1 equ) were dissolved in 20 mL of 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 detected by liquid chromatography-mass spectrometry until complete, the reaction solution was filtered through a microporous 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 concentration under reduced pressure, the solution was lyophilized to give the intermediate S-1-(01) (1100 mg, yield 79%) as a white solid.

[0122] Intermediate S-1-(01) was added to 10 mL of dioxane hydrochloride solution (hydrogen chloride concentration 4 mol / L), stirred at room temperature for 4 hours, and after the reaction was detected by liquid chromatography-mass spectrometry until complete, the solution was concentrated under reduced pressure to obtain a colorless oily liquid, which was then freeze-dried to obtain intermediate S-1-(02) in the form of a white solid (828 mg, yield 95%).

[0123] Porphyrin (500 mg, 0.44 mmol, 1 equ) was dissolved in 20 mL of N,N-dimethylformamide. Then, HATU (832 mg, 2.19 mmol, 5 equ) and DIPEA (283 mg, 2.19 mmol, 5 equ) were added sequentially at 20 °C. After stirring for 0.5 hours, S-1-(02) (828 mg, 2.19 mmol, 5 equ) was added. The reaction was carried out at room temperature for 15 hours. After the reaction was detected by liquid chromatography-mass spectrometry until complete, the reaction solution was filtered through a microporous 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 concentration under reduced pressure, the solution was lyophilized to obtain the target compound S-1 (739 mg, yield 65%) in the form of a reddish-brown solid. The four R groups were identical and had the structure represented by S-1 in Table 1.

[0124] LC-MS (m / z): 1292.9 [M+2H] 2+ / 2

[0125] Synthesis of compound S-2

[0126] Biotin-NHS (1000 mg, 2.93 mmol, 1 equ) and mono-Boc-ethylenediamine (515 mg, 3.22 mmol, 1.1 equ) were dissolved in 20 mL of 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 detected by liquid chromatography-mass spectrometry until complete, the reaction solution was filtered through a microporous membrane (0.45 μm) and purified by a C18 preparative column under medium pressure (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, the solution was lyophilized to obtain the intermediate S-2-(01) (1018 mg, yield 90%) as a white solid.

[0127] Intermediate S-2-(01) was added to 10 mL of dioxane hydrochloride solution (hydrogen chloride concentration 4 mol / L), stirred at room temperature for 4 hours, and after the reaction was detected by liquid chromatography-mass spectrometry until complete, the solution was concentrated under reduced pressure to obtain a colorless oily liquid, which was then freeze-dried to obtain intermediate S-2-(02) in the form of a white solid (700 mg, yield 93%).

[0128] Porphyrin (559 mg, 0.49 mmol, 1 equ) was dissolved in 20 mL of N,N-dimethylformamide. Then, HATU (931 mg, 2.45 mmol, 5 equ) and DIPEA (316 mg, 2.45 mmol, 5 equ) were added sequentially at 20 °C. After stirring for 0.5 hours, S-2-(O2) (700 mg, 2.45 mmol, 5 equ) was added. The reaction was carried out at room temperature for 15 hours. After the reaction was detected by liquid chromatography-mass spectrometry until complete, the reaction solution was filtered through a microporous membrane (0.45 μm) and purified by a C18 column under medium pressure (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, the solution was lyophilized to obtain the target compound S-2 (597 mg, yield 55%) in the form of a reddish-brown solid. The four R groups were identical and had the structure represented by S-2 in Table 1.

[0129] LC-MS (m / z): 1109.8 [M+2H] 2+ / 2

[0130] In vivo efficacy evaluation

[0131] 1. Experimental Design

[0132] Table 4: Experimental Design Note: Dosage volume: 10 μL / g based on mouse body weight.

[0133] Table 5: Bill of Materials

[0134] Table 6: Equipment List

[0135] 2. Laboratory Animals and Husbandry Management

[0136] Laboratory Animals:

[0137] Strain: Balb / c-nude mice;

[0138] Age: 6 - 8 weeks old;

[0139] Weight: 18 - 20 grams;

[0140] Gender: Female;

[0141] Quantity: 60;

[0142] Supplier: Shanghai Model Organisms Center, Inc.

[0143] Animal Production License Number: SCXK(Shanghai) 2019 - 0002

[0144] Animal Use License Number: SYXK(Shanghai) 2018 - 0002

[0145] Husbandry Management:

[0146] The animals were housed in IVC (Individually Ventilated Cages) cages in the SPF animal facility of Qishang Biology (5 animals per cage). The information card in each cage indicated the number of animals, gender, strain, receiving date, dosing schedule, experiment number, group, and start date of the experiment. All cages, bedding, and drinking water were sterilized before use. The cages, feed, and drinking water were changed once a week. The housing environment and lighting conditions were as follows:

[0147] √ Temperature: 20 - 26 °C

[0148] √ Humidity: 30 - 70%

[0149] √ Light cycle: 12 hours of light and 12 hours of darkness

[0150] Cages: Made of polycarbonate. The bedding was corn cob and was changed once a week.

[0151] Food: Laboratory animals had free access to irradiated and sterilized dry granular food throughout the experiment.

[0152] Drinking Water: Laboratory animals had free access to sterilized water.

[0153] Cage Identification: The information card in each cage should indicate the number of animals, gender, strain, receiving date, dosing schedule, experiment number, group, and start date of the experiment.

[0154] Animal Identification: Ear punching method.

[0155] 3. Experimental Methods

[0156] 3.1 Cell Culture

[0157] A549 cells were cultured in vitro in adherent medium with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Routine passages were performed twice a week. Trypsin-EDTA (0.25%) solution was used. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and the cell density was adjusted to 5 × 10⁶ cells / day using PBS. 7 cells / ml for later use.

[0158] 3.2 Animal inoculation

[0159] Animals were placed in the animal facility for a 7-day acclimatization period before experiments could be conducted. 0.1 mL (5.0 × 10⁻⁶) of [the solution was used]. 6 A549 cells were subcutaneously inoculated into the right posterior back of each mouse, near the thigh.

[0160] 3.3 Daily observation of laboratory animals

[0161] The use and welfare of laboratory animals are conducted in accordance with the guidelines of the International Committee for Assessment and Accreditation of Laboratory Animals (AAALAC). Animal health and mortality are monitored daily, and routine checks include observing the effects of tumor growth and drug treatment on daily behavior such as activity levels, food and water intake (visual assessment only), physical appearance, or other abnormalities.

[0162] 3.4 Compound Preparation

[0163] Table 7 Compound Formulation Table

[0164] 3.5 Random Grouping

[0165] After cell seeding, tumor growth was monitored regularly. Tumors were observed after 21 days of growth, reaching an average tumor volume of 158 mg / m³. 3 At the time of the experiment, 30 animals with suitable tumor size were randomly selected and divided into 5 groups of 6 animals each, according to tumor size. Drug administration began on the day of grouping, designated D0. Except for the erlotinib group, which received daily gavage, the other groups received a single intravenous administration via tail vein. Specific administration protocols are shown in Table 4. All drug solutions were prepared fresh before the experiment and refrigerated in the dark before use. Except for the tumor illumination stage, tumor-bearing animals were strictly protected from light for 3 days after intravenous administration, followed by low-light housing.

[0166] 3.6 Light

[0167] Groups G3-G5 received phototherapy once 19 hours after drug administration. A 630nm semiconductor laser (Guilin Xingda Optoelectronic Medical Equipment Co., Ltd., model PDT630-II) was used. The optical fiber with a microlens at the end was aimed directly at the target site, ensuring the beam was perpendicular and completely covered the tumor. Parameter settings were performed according to the following steps. Mice were anesthetized by inhalation using an isoflurane small animal anesthesia machine. After anesthesia, the mice were fixed with medical tape to fully expose the tumor site, and non-tumor areas were covered with black plastic bags.

[0168] a. Start the laser therapy device calibration and set the parameters.

[0169] b. When determining the laser treatment distance, the laser spot diameter should be able to cover the size of the tumor.

[0170] c. At the laser treatment distance given in the previous step, use an optical power meter to measure the laser power value per unit area.

[0171] d. Adjust the laser power value to 318mW.

[0172] e. Set the laser treatment time and perform PDT treatment on the experimental animals.

[0173] Table 8. Light Dosage Design Table

[0174] 3.7 Data Collection

[0175] After administration to the groups, tumor length and width were measured twice weekly using calipers, and mouse body weight was also measured. Tumor volume (TV) was calculated, and the antitumor efficacy of the compound was assessed using TGI. 体积 (%), relative tumor inhibition rate (T / C%). TV = length × width 2 / 2 TGI 体积 (100%) = [1-(V t -V0) 药物治疗组 / (V t -V0) 阴性对照组 ]×100%

[0176] (V t V0: Average tumor volume at the end of administration in each treatment group; V0: Average tumor volume at the start of administration in each treatment group.

[0177] After the experiment, the animals were euthanized, the tumors were removed, and their weight was measured. The T / C ratio was then calculated. 重量 Percentage and tumor growth inhibition rate TGI 重量 (%). The specific calculation formula is as follows: T / C 重量 (%) = TW 药物治疗组 / T 阴性对照组 ×100%; TGI 重量(%) = (1 - T / C) 重量 )×100%.

[0178] Among them, TW 药物治疗组 The tumor weight in the treatment group is represented by TW. 阴性对照组 This represents the tumor weight in the negative control group.

[0179] 3.8 Sample Collection and Processing

[0180] At the end of the experiment, the mice in each group were euthanized, the tumor tissue was removed, and the tumor tissue was weighed and neatly arranged for photographs.

[0181] 3.9 Data Processing and Statistical Analysis

[0182] All experimental results are expressed as mean ± standard error. GraphPad Prism 8 was used to plot the results, with the number of days after grouping on the x-axis and mouse body weight or tumor volume on the y-axis. Statistical analysis was performed based on the data obtained at the end of the experiment to assess differences between groups. Ordinary one-way ANOVA was used in GraphPad Prism 8 software for data analysis, and p < 0.05 was considered statistically significant.

[0183] 4. Results

[0184] In this experiment, the in vivo antitumor effects of the photosensitizer targeted in this application and the comparative compounds (erlotinib and sodium porphyrin) in the A549 non-small cell lung cancer subcutaneous xenograft model were evaluated. Animal body weight and tumor volume measured at different time points in each experimental group are shown in Figures 1 and 2, and the endpoint tumor weight is shown in Figure 3.

[0185] The experiment was conducted at an average tumor volume of 158 mm. 3 The subjects were divided into groups, and the drug was administered on the same day as their group assignment. Nineteen hours after drug administration, the subjects were exposed to light at a wavelength of 630 nm. The experiment concluded on day 22 after the group assignments.

[0186] 4.1 Weight Changes

[0187] During the experiment, the mice tolerated the test well. The changes in body weight of mice in each group are shown in Figure 1 (in the figure, the data points represent the average body weight within the group, and the error bars represent the standard error (SEM)).

[0188] 4.2 Tumor volume

[0189] The mean tumor volume of the A549 non-small cell lung cancer subcutaneous xenograft model changes over time as shown in Table 9.

[0190] Table 9 Tumor volume at different time points in each group Note: a. Mean ± standard error; b. Number of days after start of administration

[0191] 4.3 Tumor growth curve and endpoint tumor weight

[0192] The tumor growth curve and tumor weight are shown in Figures 2 and 3 (the data points in Figure 2 represent the average weight within the group, and the error bars represent the standard error (SEM)).

[0193] 4.4 Evaluation Indicators for Antitumor Drug Efficacy

[0194] The growth inhibition rate of the test substance on the A549 non-small cell lung cancer subcutaneous xenograft model was calculated based on the tumor volume on day 22 after drug administration (Table 10). The tumor weight of all groups on day 22 is shown in Table 11.

[0195] Table 10 Growth inhibition rate of the test substances on the A549 non-small cell lung cancer subcutaneous xenograft model Note: a. The mean ± standard error (bp) values ​​were analyzed using one-way ANOVA.

[0196] Table 11 Tumor weight and statistical analysis at the end of the experiment (day 22) Note: a. The mean ± standard error (bp) values ​​were analyzed using one-way ANOVA.

[0197] The results above show that at day 22, the tumor volume in 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 tumor growth in the A549 model. The positive control drug, sodium porphyrin, at a dose of 2 mg / kg (TV = 289 mmHg), showed no significant inhibitory effect. 3 The biotin receptor-targeting photosensitizer S-1 (TV = 154 mmHg, TGI = 74.7%, P < 0.001) significantly inhibited tumor growth in the A549 model. Compared with the control drug, the biotin receptor-targeting photosensitizer S-1 of this invention (TV = 154 mmHg) showed a significant inhibitory effect on tumor growth. 3 (TGI = 100.8%, P < 0.001) and S-2 (TV = 91mm 3 Both (TGI = 113.0%, P < 0.001) showed significantly better efficacy, demonstrating enhanced targeting ability and improved efficacy.

Claims

1. A biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof, wherein the biotin receptor-targeting photosensitizer has the structure of the following general formula (I): Each of the R groups is an independent diamine derivative of biotin, having the following structure: Among them, the wavy line Indicates the connection point with the carbonyl group of porphyrinic acid in formula (I); Wherein group X represents an alkylene group containing 1-20 carbon atoms, the alkylene group being straight-chain or branched, unsubstituted or substituted by one or more of the same or different groups selected from: cyano, halogen, alkyl, alkoxy, alkylthio, cycloalkyl, alkylcarbonyl, dialkylamino, heterocyclic, haloalkyl or haloalkoxy, and the alkylene group may optionally be separated by one or more heteroatoms selected from S, N and O.

2. The biotin receptor-targeting photosensitizer of claim 1 or a pharmaceutically acceptable salt thereof, wherein when the alkylene group is separated by a plurality of heteroatoms, the heteroatoms are continuous or spaced apart.

3. The biotin receptor-targeting photosensitizer of claim 1 or a pharmaceutically acceptable salt thereof, wherein the alkylene group is linear and unsubstituted.

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

5. The biotin receptor-targeting photosensitizer according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the group R is...

6. The biotin receptor-targeting photosensitizer of claim 1 or a pharmaceutically acceptable salt thereof, for the treatment of the following diseases: esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, renal cell carcinoma, and lung cancer, as well as bronchial cancer and pleural blastoma; and The disease is a precancerous lesion.

7. A method for preparing a biotin receptor-targeted photosensitizer, comprising the following steps: S1 reacts biotin or biotin-N-succinimide ester with a diamine compound bearing a protecting group in the presence of a solvent in the presence of a catalyst to give intermediate 01. The structure of the diamine compound with the protecting group is as follows: The structure of intermediate 01 is as follows Where L represents the protecting group tert-butoxycarbonyl (Boc); S2 removes the protecting group from intermediate 01 to obtain intermediate 02 with the following structure. S3 reacts porphyrinic acid with intermediate O2 in the presence of a catalyst and a condensing agent in the presence of a solvent to obtain a product with the general formula (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-methylimidazolium, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N'-dimethylaminopyridine, 2,6-dimethylpyridine, or mixtures thereof; The condensing agent is a urea cation type condensing agent, selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), and O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (T... BTU), O-(1,2-dihydro-2-oxo-pyridyl)-1,1,3,3-tetramethylurea tetrafluoroborate (TPTU); carbodiimide type condensing agents: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC); or carbonylimidazolium type condensing agents: N,N-carbonyldiimidazole (CDI); or mixtures thereof, wherein 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 mixtures thereof.

9. The use of the biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of a medicament for treating the following diseases: Esophageal cancer, ovarian cancer, leukemia, mast cell tumor, colon cancer, breast cancer, kidney cancer, and lung cancer, as well as bronchial cancer and pleural pulmonary blastoma; and The disease is a precancerous lesion.

10. A kit comprising the biotin receptor-targeting photosensitizer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, in a therapeutically effective amount; and instructions for use therein in photodynamic therapy.

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