Biotin receptor-targeted photosensitizer, preparation method and use thereof, and drug kit containing the same

Abstract

The present invention relates to a biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof. The biotin receptor-targeted photosensitizer has the following general formula (I): #imgabs0# (I), wherein the group R is a diamine derivative of biotin and has the definition set forth in the specification. The present invention also relates to the preparation and use of the biotin receptor-targeted photosensitizer, as well as a drug kit containing the same.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a biotin receptor-targeted photosensitizer, a preparation method and application thereof, and a drug kit containing the same. Background Art

[0002] Targeted drugs are drugs or their formulations that have been endowed with targeting capabilities. Their purpose is to enable the drug or its carrier to home in on specific lesions and accumulate or release its active ingredient there. Targeted formulations can achieve relatively high drug concentrations in the target area, thereby enhancing efficacy while minimizing toxic side effects and reducing damage to normal tissues and cells. Drug targeting can be categorized as passive, active, and physical based on the mechanism of action. Physical targeting utilizes physical signals such as light, heat, magnetic fields, electric fields, and ultrasound to manipulate the distribution and release characteristics of the drug within the body, achieving targeted targeting of lesions. Photosensitizers, as targeted drugs that function through physical targeting, are used in photodynamic therapy (PDT) to effectively treat a variety of diseases. Photodynamic therapy is a novel treatment method based on a photochemical reaction involving oxygen, a photosensitizer, and visible light. Targeted cells selectively take up the photosensitizer, which is then activated by local irradiation with light of an appropriate wavelength, producing a photosensitizing effect. Huapoxifen sodium for injection, currently in clinical use, is a new type of photosensitizer. It is a single active chemical component isolated from photofrin (porfimer sodium). Preclinical studies in esophageal cancer have shown that its mechanism of action is similar to that of photofrin. A dosage of only 10% of photofrin can achieve the same anti-tumor activity with reduced phototoxicity, offering significant advantages in efficacy, safety, and quality control. As an essential component of photodynamic therapy, the evolution of photosensitizers is inextricably linked to the development of photodynamic therapy.

[0003] Biotin (also known as vitamin H, D-biotin) receptors, present in the cell membrane, cytoplasm, and nucleus, are potential targets for oncology drugs. They are part of the sodium-dependent multivitamin transporter (SMVT) and are overexpressed in a variety of aggressive cancer cell lines, including 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). Based on the principle of passive targeted delivery, biotin-derived targeted drugs can be designed to effectively treat various tumors. However, no biotin receptor-targeted drugs are currently available.

[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] Given the state of the art, the present invention aims to provide a photosensitizer that significantly enhances tumor targeting, thereby improving efficacy and reducing toxicity. The preparation method has a high yield and a simple synthesis process. The biotin receptor-targeted photosensitizer of the present invention can be excited by light of a specific wavelength and has high biosafety. It is a biotin photosensitizer with potential clinical application value and can be produced on a large scale.

[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):

[0007] (I),

[0008] Wherein the groups R are each independently a diamine derivative group of biotin, having the following structure:

[0009]

[0010] The wavy line ” represents the point of attachment to the carbonyl group of porphyrinic acid of formula (I);

[0011] 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, heterocyclyl, 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 ring 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.

[0012] In another aspect, the present invention provides a method for preparing a biotin receptor-targeted photosensitizer of formula (I), comprising the following steps:

[0013] S1) reacting biotin or its ester with a diamine compound having a protecting group in the presence of a catalyst in the presence of a solvent to obtain intermediate 1;

[0014] S2) removing the protecting group on intermediate 1 to obtain intermediate 2;

[0015] 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.

[0016] 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 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 cancer and pleuropulmonary blastoma; and precancerous lesions of the above-mentioned diseases.

[0017] 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 conditions.

[0018] 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.

[0019] Unexpectedly, 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 a high yield and a simple synthesis process. It can be used as a high-efficiency photosensitizer with potential clinical application value and can be produced on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Figure 2 shows the body weight changes of A549 tumor-bearing mice after drug administration.

[0021] Figure 2 The changes in tumor volume of A549 tumor-bearing mice after drug administration.

[0022] Figure 3 The tumor weight of A549 tumor-bearing mice at each experimental endpoint. DETAILED DESCRIPTION

[0023] Hereinafter, the present invention will be described in more detail.

[0024] Unless otherwise indicated, “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 (abbreviated as photosensitizer)” are used synonymously.

[0025] As used herein, the term "comprise" and its synonyms "comprising" and "containing" mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps.

[0026] Unless defined differently, the names of chemical groups are generally to be understood such that the bond to the skeleton or the rest of the molecule is via the last mentioned structural element of the relevant chemical group, i.e., for example in the case of haloalkyl, via a carbon atom of the alkyl group.

[0027] The terms "optional," "optional," or "optionally" as used herein mean that the subsequently described event, circumstance, or material may or may not occur or exist, and that such description includes instances where the event, circumstance, or material occurs or exists and instances where the event, circumstance, or material does not occur or exists.

[0028] 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.

[0029] As used herein, the term "cyano" refers to a functional group in which a carbon atom and a nitrogen atom are linked by a triple bond.

[0030] As used herein, the term "halogen" denotes, for example, fluorine, chlorine, bromine or iodine. If the term is applied to a group, "halogen" denotes, for example, a fluorine, chlorine, bromine or iodine atom.

[0031] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon radical having the number of carbon atoms specified in each instance, 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.

[0032] As used herein, the term "alkylene" refers to a straight or branched chain alkylene group, 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 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-methylpropylidene, 2-methylpropylidene, pentylene, 1-methylbutylidene, 2-methylbutylidene, hexylene, 1,2-dimethylpropylidene, 1-methylpentylidene, 2-methylpentylidene, 1,2-dimethylbutylidene, heptylidene, 1-methylhexylidene, 2-methylhexylidene, octylidene, nonylidene, and decylidene.

[0033] 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, such as (C1-C 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-trifluoroprop-2-yl. Preferred are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl.

[0034] According to the invention, "cycloalkyl"—on its own or as part of a chemical group—stands for 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. Preference is also given to cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, such as, in particular, cyclopropyl or cyclobutyl. The cycloalkyl groups according to the invention may be substituted by one or more identical or different radicals.

[0035] According to the present invention, "alkoxy" represents a linear or branched alkyl-O- group 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 according to the present invention may be substituted by one or more identical or different groups.

[0036] 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, such as (C1-C 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.

[0037] According to the present invention, "alkylthio" represents a straight-chain or branched alkyl group -S-, 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 according to the present invention may be substituted by one or more identical or different groups.

[0038] According to the present invention, "alkylcarbonyl" represents a straight-chain or branched alkyl-C(═O) group preferably having 2 to 10 carbon atoms, for example methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl. Alkylcarbonyl groups having 1 to 4 carbon atoms are also preferred. The alkylcarbonyl groups according to the present invention may be substituted by one or more identical or different groups.

[0039] According to the present invention, "dialkylamino" represents a straight-chain or branched group preferably having 1 to 10 carbon atoms or 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 -Dialkylamino may be substituted by one or more identical or different groups.

[0040] 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 which 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 comprises preferably 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 generally contains no more than 4 nitrogen atoms and / or no more than 2 oxygen atoms and / or no more than 2 sulphur 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.

[0041] The heterocyclic groups according to the invention are, for example, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, dioxolanyl, dioxolenyl, pyrazolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, oxirane, azetidinyl, aziridine, oxazetidinyl, oxaziridine, oxaziridine, oxazepanyl, oxazahepanyl, azepanyl, oxopyrrolidinyl, dioxopyrrolidinyl, oxomorpholinyl, oxopiperazinyl and oxepanyl.

[0042] 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.

[0043] 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 isomer mixtures of varying composition. The present invention provides both the pure stereoisomers and any desired mixtures of these isomers, although generally only the compounds of formula (I) are discussed herein.

[0044] 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.

[0045] Compounds obtained from combinations that contradict the laws of nature and which a person skilled in the art would therefore exclude based on his / her expert knowledge are not encompassed herein. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0046] 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):

[0047] (I),

[0048] Wherein the groups R are each independently a diamine derivative group of biotin, having the following structure:

[0049]

[0050] The wavy line ” represents the point of attachment to the carbonyl group of the porphyrin of formula (I);

[0051] 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, heterocyclyl, 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 ring 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.

[0052] In a preferred embodiment of the present invention, preferably each R group has the same meaning.

[0053] 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.

[0054] 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.

[0055] Pharmaceutically acceptable salts of the compounds of formula (I) of the present invention are those salts that are pharmaceutically considered safe and suitable for use in pharmaceutical formulations. These salts are generally prepared by reacting the compounds of formula (I) with an acid or base to improve the solubility, stability, and bioavailability of the drug.

[0056] Pharmaceutically acceptable salts of the compounds of the present invention are, for example, products obtained by reacting a 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. Non-toxic pharmaceutical base addition salts of the compounds of formula (I) of the present invention include salts of bases such as sodium, potassium, calcium, ammonium, and the like, and those skilled in the art will recognize a variety of non-toxic pharmaceutically acceptable addition salts.

[0057] In a preferred embodiment of the present invention, wherein 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.

[0058] 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:

[0059] ,

[0060] ,

[0061] ,or

[0062] ,

[0063] 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.

[0064] 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:

[0065]

[0066] .

[0067] 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:

[0068] .

[0069] In a preferred embodiment of the present invention, wherein in formula (I), the group R has the structure

[0070] or .

[0071] 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.

[0072] 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.

[0073] Very particular preference is given to the compounds of the formula (I) according to the invention listed in Table 1 below.

[0074] Table 1: Compounds of formula (I), in which R has the meaning given below.

[0075] (I)

[0076] Table 1: Compound structure list

[0077]

[0078] 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:

[0079] S1: in the presence of a catalyst, reacting biotin or its ester with a diamine compound having a protecting group in the presence of a solvent to obtain intermediate 1;

[0080] S2 removes the protecting group on intermediate 1 to obtain intermediate 2;

[0081] S3: In the presence of a catalyst and a condensing agent, porphyrinic acid reacts with the intermediate 2 in the presence of a solvent to obtain a product.

[0082] 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 for amino groups in organic reactions, such as tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), etc.

[0083] In the method of the present invention, the method for removing the protecting group in step S2 depends on the type of protecting group on the diamine compound. For example, when a tert-butoxycarbonyl (Boc) protecting group is used, the removal reaction can be carried out in an acidic environment such as hydrochloric acid, trichloroacetic acid, or trifluoroacetic acid, for example, using a solution of hydrogen chloride in dioxane.

[0084] 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.

[0085] 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 tetrafluoroborate (TATU), Urea tetrafluoroborate (TBTU), O-(1,2-dihydro-2-oxo-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.

[0086] 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.

[0087] 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:

[0088] 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 intermediate 01.

[0089] The structure of the diamine compound with a protecting group is ,

[0090] The structure of intermediate 01 is , wherein L represents a protecting group tert-butoxycarbonyl (Boc);

[0091] S2 removes the protecting group on intermediate 01 to obtain intermediate 02 having the following structure

[0092] ;

[0093] 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);

[0094] (I).

[0095] The method of preparing the compound 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, to obtain the target compound of high purity in good yield through simple post-treatment. Excessive amounts of the catalyst or condensing agent can have adverse effects on the target product, such as an increase in the proportion of by-products and a low yield of the target product.

[0096] In the method of the present invention, the molar ratio of biotin or its esters 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).

[0097] 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).

[0098] 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).

[0099] 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.

[0100] 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 cancer and pleuropulmonary blastoma; and hyperproliferative growth of the above-mentioned conditions, such as precancerous lesions.

[0101] Yet 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 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;

[0102] and hyperproliferative growth of the above conditions, such as precancerous lesions.

[0103] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or 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.

[0104] 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.

[0105] The present invention also provides a medicine 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.

[0106] As used herein, the term "kit" means any commercial package comprising a container for holding a compound of the invention or a pharmaceutical formulation comprising the same, and optionally further comprising a separate container such as a separate vial or separate foil package, for example, to hold a reconstituted dissolution matrix. The container may be of any conventional shape or form known in the art and made of pharmaceutically acceptable material.

[0107] In a preferred embodiment, the present invention provides a drug kit comprising a lyophilized formulation of a compound of the present invention in a therapeutically effective amount for treating the diseases described above; a dissolving matrix (such as water for injection containing auxiliary materials such as a cosolvent) for reconstituting the lyophilized formulation for administration; and instructions for using the compound of the present invention as a photosensitizer in photodynamic therapy.

[0108] The various components of the kit, such as the compound of the present invention or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation comprising the same, a dissolving matrix, and other active ingredients for treating cancer or precancerous lesions, can be packaged in separate containers. Regardless of the number or type of containers, the kit can also include a device for facilitating administration of the drug to the patient. The device can be an applicator, an inhaler, a syringe, a pipette, a spoon with a measuring unit, or any other delivery device approved for medical use.

[0109] 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.

[0110] 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, or a solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticle dosage forms, or suspensions. Semisolid dosage forms can be ointments, creams, pastes, gels, and the like. Other dosage forms can be, for example, tablets, capsules, pellets, aerosols, pills, powders, solutions, emulsions, granules, suppositories, lyophilized powder injections, inclusion compounds, implants, patches, liniments, and sustained-release formulations.

[0111] For oral preparations, tablets and capsules can be prepared using known pharmaceutical methods. Tablets may also be coated. Oral liquids can be prepared as water-oil suspensions, solutions, emulsions, syrups, or dry products that are replenished with water or other suitable media before use. Flavorings or colorants may be added as needed.

[0112] For parenteral administration, liquid dosage forms are typically prepared from the drug of the present invention and a sterile carrier. Water is the preferred carrier. Depending on the selected carrier and drug concentration, the drug can be dissolved in the carrier or prepared as a suspension. For injectable solutions, the drug is first dissolved in water, filtered and sterilized, and then packaged into sealed bottles or ampoules.

[0113] It can also be made into sterile preparations for injection, including crystalline powder injection, freeze-dried powder injection, etc.

[0114] When applied topically to the skin or mucous membranes, the drug of the present invention can be formulated into an appropriate ointment, lotion, gel, or paste, wherein the active ingredient is suspended or dissolved in one or more carriers. Alternatively, it can be formulated into a form for application with the aid of a device such as a microneedle.

[0115] 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 the photosensitizer of the present invention or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, excipient and / or other auxiliary agent of effective dose are combined and made into suitable administration 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.

[0116] 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 administered intravenously.

[0117] 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.

[0118] The optimal dosage and interval of administration of the photosensitizer of the present invention are determined by the properties of the compound and external factors 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 dosage of the compound or drug of the present invention over a specified period of time, can be determined using methods well known in the art.

[0119] The photosensitizer of the present invention is used at a dosage of 0.01-100.0 mg / kg subject, for example, 0.01-50.0 mg / kg subject, preferably 0.05-10.0 mg / kg subject, particularly 0.1-6.0 mg / kg subject, and 0.2-5.0 mg / kg subject; and laser irradiation is performed at a wavelength of 300-800 nm, preferably 600 nm-650 nm, particularly 630 nm, usually for a single irradiation; the light dose is 1-300 J, preferably 20-200 J, and more preferably 50-150 J; the optical power of the laser as a light source is usually 50-800 mW, preferably 100-500 mW; the irradiation time is 10-2400 seconds, preferably 60-1800 seconds, and more preferably 100-1500 seconds; and the irradiation delay is usually 4-48 hours, preferably 10-25 hours.

[0120] 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.

[0121] 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.

[0122] Preparation of compounds

[0123] 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 reaction progress, for example, using a Waters instrument, model: SQD2.

[0124] In the above-described method for preparing the compounds of the present invention, the method may optionally include additional post-processing steps. These post-processing steps may include, for example, pH adjustment, crystallization, extraction, filtration, concentration under reduced pressure, and drying, among other conventional purification steps. Each of these steps can be performed in conventional manners known to those skilled in the art. If present, extraction is typically performed using a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol at a ratio of 10:1 (v / v). Drying is typically performed by freeze drying, infrared drying, vacuum drying, or the like, with freeze drying being preferred.

[0125] In a preferred embodiment of the present invention, the method may further comprise a purification step by chromatography. The purification may be performed using a medium-pressure preparative liquid phase C18 column, using a filler 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%, and eluting using water / methanol (v / v) (elution gradient of 100% / 0% to 50% / 50%, gradient elution time of 20 min).

[0126] 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 obtained or prepared by methods known to those skilled in the art.

[0127] 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.

[0128] The following are detailed synthesis examples of selected compounds of the present invention. However, these examples are merely illustrative and should not be interpreted as limiting the scope of the present invention in any way.

[0129] 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).

[0130] Synthesis Example

[0131] Synthesis reagents and equipment

[0132] Table 2: Synthesis Reagents

[0133]

[0134] Table 3: Synthesis equipment

[0135]

[0136] Synthesis route

[0137]

[0138] 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.

[0139] Synthesis of compound S-1

[0140] 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) were dissolved 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 C18 medium-pressure preparative column (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, the intermediate S-1-(01) (1100 mg, yield 79%) was obtained by lyophilization as a white solid.

[0141] 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 detected by liquid chromatography-mass spectrometry to be complete reaction. The mixture 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%) as a white solid.

[0142] Dissolve porphyrinic acid (500 mg, 0.44 mmol, 1 equ) in 20 mL N,N -dimethylformamide, and 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. 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 C18 medium-pressure preparative column (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, the target compound S-1 (739 mg, yield 65%) was obtained as a reddish-brown solid. Its four R groups were identical and had the structure shown in Table 1 for S-1.

[0143] LC-MS (m / z): 1292.9 [M+2H] 2+ / 2

[0144] Synthesis of compound S-2

[0145] 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 detected by liquid chromatography-mass spectrometry, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by medium-pressure preparative column C18 (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, lyophilization was performed to obtain the intermediate S-2-(01) (1018 mg, yield 90%) as a white solid.

[0146] 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 detected by liquid chromatography-mass spectrometry to be complete reaction. The mixture 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%) as a white solid.

[0147] Dissolve porphyrinic acid (559 mg, 0.49 mmol, 1 equ) in 20 mL N,N -dimethylformamide, and 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, the reaction solution was filtered through a microporous filter membrane (0.45 μm) and purified by medium-pressure preparative column C18 (water / methanol (V / V) 100% / 0% to 10% / 90%, 40 min). After concentration under reduced pressure, lyophilization was performed to obtain the target compound S-2 (597 mg, yield 55%) as a reddish-brown solid. Its four R groups were identical and had the structure shown in S-2 in Table 1.

[0148] LC-MS (m / z): 1109.8 [M+2H] 2+ / 2

[0149] In vivo efficacy evaluation

[0150] 1. Experimental Design

[0151] Table 4: Experimental design

[0152]

[0153] Note: Dosing volume: 10 µL / g based on mouse body weight

[0154] Table 5: Materials

[0155]

[0156] Table 6: Equipment List

[0157]

[0158] 2. Experimental Animals and Animal Husbandry Management

[0159] Experimental animals:

[0160] Strain: Balb / c-nude mice;

[0161] Age: 6-8 weeks old;

[0162] Weight: 18-20 g;

[0163] Gender: female;

[0164] Quantity: 60;

[0165] Supplier: Shanghai Model Organisms Center, Ltd.

[0166] Animal production license number: SCXK (Shanghai) 2019-0002

[0167] Animal Use License Number: SYXK (Shanghai) 2018-0002

[0168] Feeding and management:

[0169] Animals were housed in IVC (independent ventilation system) cages (5 animals per cage) in a Qishang Biological SPF animal room. Each cage's animal information card included the number of animals, sex, strain, date of receipt, dosing regimen, study number, group, and study start date. All cages, bedding, and water were sterilized before use. Cages, feed, and water were changed weekly. The housing environment and lighting conditions were as follows:

[0170] Temperature: 20~26℃

[0171] Humidity: 30~70%

[0172] Photoperiod: 12 hours of light, 12 hours of no light

[0173] Cage: Made of polycarbonate. Bedding is corn cob, changed once a week.

[0174] Food: The experimental animals had free access to food (irradiated sterilized, dry pelleted food) throughout the experimental period.

[0175] Drinking water: Experimental animals can drink sterile water freely.

[0176] Cage identification: The animal information card for each cage should indicate the number of animals in the cage, sex, strain, receipt date, dosing regimen, experiment number, group and start date of the experiment.

[0177] Animal identification: ear cropping.

[0178] 3. Experimental Methods

[0179] 3.1 Cell culture

[0180] A549 cells were cultured in vitro in F12K medium supplemented with 10% fetal bovine serum in a 37°C, 5% CO2 incubator. Routine manipulation and passage were performed twice a week. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and adjusted to a cell density of 5 × 10 cells / mL using PBS. 7 cells / ml for future use.

[0181] 3.2 Animal inoculation

[0182] The animals were acclimated for 7 days after arrival in the animal room. Experiments were conducted after the acclimation period. 6 A549 cells were subcutaneously inoculated on the right back near the thigh of each mouse.

[0183] 3.3 Daily observation of experimental animals

[0184] The use and welfare of experimental animals were carried out in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animal health and mortality were monitored daily. Routine examinations included observation of tumor growth and the effects of drug treatment on the animals' daily behaviors, such as activity, food and water intake (visual observation only), physical signs, or other abnormalities.

[0185] 3.4 Compound preparation

[0186] Table 7 Compound preparation

[0187]

[0188] 3.5 Randomization

[0189] After cell inoculation, tumor growth was observed regularly. 3At 4:00 p.m., 30 animals with tumors of appropriate size were randomly divided into five groups of six animals each, based on tumor size. Dosing began on the day of grouping, designated D0. Except for the erlotinib group, which received daily oral gavage, the other groups received a single tail vein administration. The specific dosing schedule is shown in Table 4. Drug solutions for each group were prepared immediately prior to the experiment and refrigerated in the dark until use. Except for the tumor illumination phase, tumor-bearing animals were kept in a strict dark environment for three days after tail vein administration, after which they were housed in low light.

[0190] 3.6 Lighting

[0191] Groups G3-G5 received light therapy 19 hours after drug administration. A 630 nm semiconductor laser (Guilin Xingda Optoelectronics Medical Devices Co., Ltd., model PDT630-II) was used. An optical fiber with a microlens at the end was aimed directly at the target site, ensuring vertical projection and complete tumor coverage. Parameters were set according to the following procedures. Mice were anesthetized with isoflurane inhalation anesthesia using a small animal anesthesia machine. After anesthesia, the mice were immobilized with medical tape to fully expose the tumor site, and non-tumor areas were covered with black plastic bags.

[0192] a. Turn on the laser therapy device for calibration and set parameters.

[0193] b. Measure the laser treatment distance and ensure that the laser spot diameter can cover the size of the tumor.

[0194] c. At the laser treatment distance given in the previous step, use an optical power meter to measure the laser power per unit area.

[0195] d. Adjust the laser power to 318 mW.

[0196] e. Set the laser treatment time and perform PDT treatment on experimental animals.

[0197] Table 8 Light dose design table

[0198]

[0199] 3.7 Data Collection

[0200] 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 tumor inhibition efficacy of the compound was measured with TGI. 体积 (%), relative tumor inhibition rate (T / C%).

[0201]

[0202] （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)

[0203] After the experiment, the animals were euthanized and the tumors were removed and the tumor weight was measured to calculate T / C. 重量 Percentage and tumor growth inhibition rate TGI 重量 (%). The specific calculation formula is as follows:

[0204]

[0205] 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.

[0206] 3.8 Sample collection and processing

[0207] At the end of the experiment, mice in each group were euthanized, and the tumor tissues were removed, weighed, and neatly arranged for photographing.

[0208] 3.9 Data processing and statistical analysis

[0209] All experimental results are expressed as mean ± standard error. Graphs were plotted using GraphPad Prism 8, with the number of days after grouping as the horizontal axis and the mouse body weight or tumor volume as the vertical axis. Statistical analysis was performed based on data obtained at the end of the experiment to assess differences between groups. Data were analyzed using Ordinary one-way ANOVA in GraphPad Prism 8 software, with p < 0.05 considered significant.

[0210] 4. Results

[0211] In the experiment, the in vivo anti-tumor effects of the targeted photosensitizer of the present application and the comparative compounds (erlotinib and valprophyrin 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 were measured at different time points. Figure 1 and Figure 2 Endpoint tumor weights were as shown. Figure 3 shown.

[0212] The average tumor volume was 158 mm 3 The mice were divided into groups at 14 days and administered the drug on the day of grouping. 19 hours after drug administration, the mice were exposed to 630 nm light. The experiment was completed on D22 after grouping.

[0213] 4.1 Weight Change

[0214] During the experiment, the mice tolerated the treatment well, and the weight changes of mice in each group were shown in Table 2. Figure 1(In the figures, data points represent the mean body weight within the group, and error bars represent the standard error (SEM)).

[0215] 4.2 Tumor volume

[0216] 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.

[0217] Table 9 Tumor volume of each group at different time points

[0218]

[0219] Note:

[0220] a. Mean ± standard error

[0221] b. Days after starting medication

[0222] 4.3 Tumor Growth Curve and Endpoint Tumor Weight

[0223] 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 of magnitude (SEM).

[0224] 4.4 Antitumor efficacy evaluation indicators

[0225] The growth inhibition rate of the test substance in the A549 non-small cell lung cancer subcutaneous xenograft 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.

[0226] Table 10 Growth inhibition rate of the test substance on A549 non-small cell lung cancer subcutaneous transplant tumor model

[0227]

[0228] Note: a. Mean ± standard error

[0229] b. p The values ​​were analyzed by one-way ANOVA

[0230] Table 11 Tumor weight and statistical analysis at the end of the experiment (day 22)

[0231]

[0232] Note: a. Mean ± standard error

[0233] b. p The values ​​were analyzed by one-way ANOVA

[0234] 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. 3 , TGI=74.7%, P<0.001) had a significant inhibitory effect on the tumor growth of 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 radical having 1 to 10 carbon atoms, which is linear or branched, unsubstituted or substituted by one or more identical or different radicals selected from the group consisting of cyano, halogen, (C1-C6)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, alkylcarbonyl having 2 to 4 carbon atoms, (C1-C4)-dialkylamino, (C1-C4)-haloalkyl or (C1-C4)-haloalkoxy, and the alkylene radical may optionally be interrupted by one or more heteroatoms selected from S 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 according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the group R is ,or 。 5. A method for preparing a biotin receptor-targeted 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 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）， wherein X and R are as defined in claim 1.

6. The method according to claim 5, wherein in steps S1 and S3, 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; In step S3, 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 Tetrafluoroborate (TBTU), 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; In steps S1 and S3, the solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, formamide, dimethyl sulfoxide, acetone, pyridine or a mixture thereof.

7. Use of the biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for preparing a medicament for treating the following diseases: lung cancer and precancerous lesions of the disease.

8. Use of the biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for preparing a medicament for treating the following diseases: small cell and non-small cell lung cancer, and precancerous lesions of the diseases.

9. A kit comprising the biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, in a therapeutically effective amount; and instructions for using the biotin receptor-targeted photosensitizer or a pharmaceutically acceptable salt thereof for photodynamic therapy.

10. 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 connection point with the carbonyl group of porphyrinic acid of formula (I), The group R is a derivative group of biotin and the following diamine compound: , where n is an integer from 1 to 6.

11. 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 connection point with the carbonyl group of porphyrinic acid of formula (I), The group R is a derivative group of biotin and the following diamine compound: , where n is an integer from 1 to 6.

12. 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 connection point with the carbonyl group of porphyrinic acid of formula (I), The group R is a derivative group of biotin and the following diamine compound: , where n is an integer from 1 to 10.

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