Iron-n-heterocyclic carbene compounds and their photodynamic therapy use of pharmaceutically acceptable salts, compositions

Abstract

The application discloses an iron-nitrogen heterocyclic carbine compound represented by the following general formula (I) or general formula (II) and a pharmaceutically acceptable salt thereof, and an application of a pharmaceutical composition containing the compound in the preparation of a medicine with a photodynamic therapy function. The iron-nitrogen heterocyclic carbine compound according to the application has significant photochemical reactivity, and therefore, the compound has great potential in tumor photodynamic therapy. In addition, different substituent groups are introduced to regulate the absorption peak of the compound, and different pharmaceutical salt forms are introduced to regulate the water solubility and biological safety, and the compound shows good photodynamic therapy effect in tumor cell tests.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organometallic chemistry and medicinal chemistry, in particular, the present application relates to a kind of iron-nitrogen heterocyclic carbene compound and its pharmaceutically acceptable salt, and the use of the composition comprising the compound in the preparation of drug with the function of photodynamic therapy. BACKGROUND

[0002] Malignant tumor is the second largest cause of death in the world. The burden of cancer continues to grow worldwide, bringing huge physical, emotional and economic pressure to individuals, families, communities and health systems. Traditional strategies for cancer treatment include surgery, radiotherapy and chemotherapy, etc. Although these strategies can effectively improve the survival probability of tumor patients, the damage to healthy tissues cannot be ignored. In recent years, with the development of physics, chemistry and other disciplines, capturing light energy for photodynamic therapy brings new hope to tumor patients, and this treatment strategy is expected to reactivate the body's anti-tumor immunity and enhance the efficacy of tumor immunotherapy.

[0003] However, most of the current photodynamic reactions require shorter ultraviolet or blue light to initiate the reaction. This band of light is difficult to penetrate the skin barrier to reach the tumor site. Red light that can penetrate deeper has the defect of relatively low energy. The photodynamic therapy photosensitizer that can respond to red light is still a minority. In addition, the currently available metal-based photosensitizers all require noble metals such as iridium, gold and ruthenium, which have good photoactivity but are in short supply, resulting in high manufacturing costs and making it difficult to be widely used, and bringing a large economic burden to tumor patients. So far, the development of photoactive compounds using iron is still in its infancy. The absorption of light is in the red light region, and there is no report on iron compounds that can be used for tumor photodynamic therapy. SUMMARY

[0004] In order to solve the above problems, the technical purpose of the present application is to provide an iron-nitrogen heterocyclic carbene compound with high water solubility and a light absorption peak in the red light and infrared light region, and its pharmaceutically acceptable salt, and the use of the composition comprising the compound in the preparation of drug with the function of photodynamic therapy, such as medicinal photosensitizer, etc.

[0005] In one aspect, the present application aims to provide a class of iron-nitrogen heterocyclic carbene compounds represented by the following general formula (I) or general formula (II) and its pharmaceutically acceptable salt, and the use of the composition comprising the compound in the preparation of drug with the function of photodynamic therapy:

[0006]

[0007] In general formula (I), Fe is Fe(III) or Fe(IV), and in general formula (II), Fe is Fe(III);

[0008] n is the number of charges of the cationic part and the number of anions, n = 1 when Fe is Fe(III) and n = 2 when Fe is Fe(IV);

[0009] X is an anion required for salt formation, selected from Cl", Br", I", BF4", PF6", BPh4", SO3CF3", OAc" or OTf";

[0010] R1 is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted saturated or unsaturated four to six membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted five to six membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 acyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 quaternary ammonium, substituted or unsubstituted C1-C4 ester; wherein the "substitution" means that the group contains 1 or 2 R a substituents selected from hydroxyl, amino, cyano, nitro, halogen, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, naphthyl, saturated or unsaturated four to six membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, five to six membered heteroaryl containing 1 or 2 heteroatoms selected from N and O; a

[0011] R2 is hydrogen, halogen atom, aldehyde group, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated C5-C6 cycloalkyl, phenyl, naphthyl, substituted or unsubstituted saturated or unsaturated five or six membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted five or six membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 acyl; wherein the "substitution" means that the group contains 1 or 2 R b substituents selected from hydroxyl, halogen, C1-C3 alkoxy, C5-C6 cycloalkyl, phenyl, naphthyl. b

[0012] More preferably, R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy.

[0013] Preferably, R2 is hydrogen, halogen atom, aldehyde group, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted saturated or unsaturated C3-C6 cycloalkyl, substituted or unsubstituted C6-C​​10 aryl, substituted or unsubstituted saturated or unsaturated four to six-membered heterocyclic group containing one or two heteroatoms selected from N and O, substituted or unsubstituted five to eight-membered heteroaryl containing one or two heteroatoms selected from N and O, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 acyl; wherein the "substitution" means that the group contains one or three R b substituents, the R b selected from hydroxy, halogen, C1-C3 alkoxy, C3-C6 cycloalkyl, C6-C 10 aryl.

[0014] More preferably, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0015] More preferably, X is I, BF4, PF6, BPh4, OTf.

[0016] More preferably, the compound represented by the general formula (I) or the general formula (II) and the pharmaceutically acceptable salt thereof according to the present application is selected from the following compounds:

[0017]

[0018] In another aspect, another object of the present application is to provide a pharmaceutical composition including the iron-n-heterocyclic carbene compound represented by the general formula (I) or the general formula (II) and the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] Preferably, the drug having a function of photodynamic therapy according to the present application is a photosensitizer for tumor photodynamic therapy.

[0020] Preferably, the tumor in the tumor photodynamic therapy can be selected from skin cancer, brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline tract carcinoma, and unknown primary cancer.

[0021] Preferably, the onset light wave wavelength range of the iron-n-heterocyclic carbene compound represented by the general formula (I) or the general formula (II) and the pharmaceutically acceptable salt thereof or the pharmaceutical composition is 600 nm to 750 nm.

[0022] Preferably, the drug having a function of photodynamic therapy is a nano-drug or an immunotherapy combination drug.

[0023] Advantageous effects

[0024] The novel iron-nitrogen heterocyclic carbene compounds involved in the present application have significant photochemical reactivity, and therefore, these compounds have great potential in tumor photodynamic therapy. In addition, the present application introduces different substituent groups to regulate the absorption peak of such compounds, and introduces different pharmaceutical salt forms to regulate water solubility and biological safety. The invention is verified by experiments, compared with the iron compounds reported by Jakob Steube et al. in 2023, the absorption peak of compound 1 is significantly shifted from 430 nm to the vicinity of 460 nm, further regulating can produce significant red light absorption in the 660 nm red light region, and show good photodynamic therapy effect in tumor cell test. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the specific embodiments or prior art description will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creative labor.

[0026] Figure 1 The photodynamic therapy effect diagram of compound 8.

[0027] Figure 2 The photodynamic therapy effect diagram of compound 3.

[0028] Figure 3 The single crystal diffraction molecular structure diagram of compound 3. DETAILED DESCRIPTION

[0029] Hereinafter, the present application will be described in detail. Before the description, it should be understood that the terms used in the present specification and the appended claims should not be interpreted as being limited to the general and dictionary meanings, but should be interpreted in the context of the technical aspects of the present application based on the principles that the inventor is allowed to define appropriate terms in order to best explain the present application. Therefore, the description presented herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the present application, and it should be understood that other equivalent ways or improvements can be derived therefrom without departing from the spirit and scope of the present application.

[0030] As used herein, the terms "comprises," "includes," "has," "contains" or any other similar terms are open conjunctions that are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprises," "includes," "has," and "contains" should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as "consisting of" and "consisting essentially of."

[0031] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, a description of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0032] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0033] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0034] The photodynamic therapy mentioned in this article refers to the process in which photosensitizers produce various forms of reactive oxygen species through photochemical reactions under the irradiation of lasers of a specific wavelength, which interact with adjacent biological macromolecules and then exert cytotoxic effects to achieve the purpose of tumor treatment.

[0035] In the present invention, the following definitions are made:

[0036] The term "alkyl" refers to a group of a straight-chain or branched saturated hydrocarbon radical ("C 1–10 alkyl") having from 1 to 10 carbon atoms. In some embodiments, the alkyl group has from 1 to 9 carbon atoms ("C 1–9 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has from 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1alkyl"). In some embodiments, the alkyl group has from 2 to 6 carbon atoms ("C 2-6 alkyl"). In some embodiments, the alkyl group has from 2 to 4 carbon atoms ("C 1–6 alkyl"). In some embodiments, the alkyl group has from 2 to 3 carbon atoms ("C 1-10 alkyl"). Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted (e.g., with one or more halogens, such as F) ("substituted alkyl"). In certain embodiments, the alkyl group is an unsubstituted C 1-6 alkyl (e.g., an unsubstituted C 1-10 alkyl (e.g., a substituted C 1-6 alkyl, such as -CF3).

[0037] A "carbocyclic group" or "cycloalkyl" refers to a group of a non-aromatic cyclic hydrocarbon radical having from 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has from 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, the carbocyclic group has from 3 to 6 ring carbon atoms ("C3-6 Cycloalkyl). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 Cycloalkyl). Exemplary C 3-6 Cycloalkyl includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Cycloalkyl includes, but is not limited to, the above C 3-6 carbocyclic groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. As shown by the foregoing examples, in certain embodiments, the cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains fused, bridged, or spiro ring systems, such as bicyclic ring systems ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes ring systems in which a carbocyclic ring as defined above is fused (with the point of attachment being on the cycloalkyl group) with one or more aryl or heteroaryl groups, and in this case the carbon number continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise indicated, each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ( "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C 3-8 Cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-8 Cycloalkyl.

[0038] "Heterocyclyl" or "heterocyclyl" refers to a group having a 3- to 12-membered non-aromatic ring system with ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-12 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valence permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl groups") or fused, bridged or spiro ring systems, e.g., bicyclic ring systems ("bicyclic heterocyclyl groups"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused with one or more carbocyclyl groups (where the point of attachment is on the carbocyclyl or heterocycle), or in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocycle. Unless otherwise specified, each instance of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl group. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl group.

[0039] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in an aromatic ring system (a "C 6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthryl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups (where the group or point of attachment is on the aryl ring), and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 aryl. In certain embodiments, an aryl group is a substituted C 6-14 aryl.

[0040] "Aryl" means a 6- to 12-membered, monocyclic or bicyclic, 4n+2 aromatic ring system (e.g., having 6 or 12 p-electrons shared in a cyclic array) having ring carbon atoms, wherein n is an integer equal to 1 or 2. In certain embodiments, aryl is phenyl. In certain embodiments, aryl is naphthyl. In certain embodiments, aryl is phenyl or naphthyl. In certain embodiments, aryl is optionally substituted.

[0041] "Heteroaryl" means a 5- to 12-membered, monocyclic or bicyclic, 4n+2 aromatic ring system (e.g., having 6 or 12 p-electrons shared in a cyclic array) of ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 12-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic rings (where the point of attachment is on the heteroaryl ring), and in this case the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl rings (where the point of attachment is on the aromatic or heteroaromatic ring), and in this case the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl).

[0042] "Unsaturated" or "partially unsaturated" means a group that includes at least one double or triple bond. "Partially unsaturated" ring systems are also intended to cover rings that are multi-unsaturated, but not aromatic (e.g., dihydrophenyl or tetrahydronaphyl). Likewise, "saturated" means an acyclic or cyclic ring system containing no double or triple bonds.

[0043] "Halo" or "halogen" means fluoro (fluorine, -F), chloro (chlorine, -Cl), bromo (bromo, -Br), or iodo (iodo, -I).

[0044] Fe(III) or Fe(IV) refers to the central metal Fe being in the trivalent or tetravalent state, respectively.

[0045] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid; or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. + (C 1-4 alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0046] The compounds of the present application of general formula (I) or general formula (II) and their pharmaceutically usable salts can be prepared by one or both of the following methods:

[0047] Method I:

[0048]

[0049] Step 1) Synthesis of bis-imidazole substituted compounds by an Ullmann type reaction similar to the one reported (CuI / L(L1 / 4pyridine-functionalized 1,3-diketones) catalyzed CeN coupling reactions of aryl halides with NH-containing heterocycles, Tetrahedron 64 (2008) 4254-4259, DOI: 10.1016 / j.tet.2008.02.082). For example, 3,5-dibromo substituted benzene 5 mmol, imidazole 25 mmol, N,N-dimethylglycine 2 mmol, K2CO3 25 mmol and CuI 1 mmol were added to a 100 mL round bottom flask with a magnetic stirrer. The flask was evacuated and filled with nitrogen three times, then dimethylsulfoxide 20 mL was added under N2flow. After the reaction was completed, the reaction was poured into dichloromethane and washed with water three times. The organic phase was dried with Na2SO4, the solvent was evaporated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography to obtain the pure product.

[0050] Step 2) Bis-imidazole substituted benzene 2 mmol was dissolved in a mixture of CH3I 1 mL and MeCN 5 mL under N2atmosphere and heated to reflux for 24 hours. After the reaction was completed, the reaction was poured into methyl-tert-butyl ether, filtered, the filter cake was washed with methyl-tert-butyl ether and dried to obtain the product.

[0051] Step 3) In a glove box, bis-imidazole substituted benzene iodonium salt 2 mmol was added to a 50 mL round bottom flask containing dry THF 5 mL. Then Zr(NMe2)4 2.1 mmol, FeCl2 2 mmol were added and stirring was continued overnight at room temperature. After the reaction was completed, the system was exposed to air, 10 mL MeCN and 1 mL H2O were added and stirred for 0.5 hours. The suspension was filtered and washed with acetonitrile until the filtrate was free of color. The volatiles were removed under vacuum. The obtained solid was dissolved in MeOH and precipitated by adding 5 mL of a saturated KPF6 solution and 10 mL H2O. The precipitate was filtered, rinsed with H2O and dried to obtain the pure product.

[0052] Step 4) The product of step 3 0.5 mmol was added to a vial containing KPF6 5 mmol and 5 mL of methanol. 0.5 mL of a 10% H2O2 solution was added dropwise. The reaction solution was stirred overnight at room temperature and then precipitated by adding 10 mL of H2O. The precipitate was filtered, washed with H2O to remove the inorganic salts and dried to obtain the pure product.

[0053] Method two:

[0054]

[0055] For example:

[0056] Step 1) 1,3-dibromo substituted pyrene 5 mmol, imidazole 25 mmol, N,N- dimethylglycine 2 mmol, K2CO3 25 mmol and CuI 1 mmol were added to a 100 mL round bottom flask with a magnetic stirrer. The flask was evacuated and filled with nitrogen three times, then dimethyl sulfoxide 20 mL was added under N2flow. After the reaction was completed, the reaction was poured into dichloromethane and washed with water three times. The organic phase was dried with Na2SO4, and the solvent was evaporated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography to obtain the pure product.

[0057] Step 2) Under N2atmosphere, di-imidazole substituted pyrene 2 mmol was dissolved in a mixture of CH3I 1 mL and MeCN 5 mL, heated to reflux for 24 hours. After the reaction was completed, the reaction was poured into methyl tert-butyl ether, filtered, the filter cake was washed with methyl tert-butyl ether, and dried to obtain the product.

[0058] Step 3) In a glove box, di-imidazole substituted pyrene iodonium salt 2 mmol was added to a 50 mL round bottom flask containing dry THF 5 mL. Then Zr(NMe2)4 2.1 mmol, FeCl2 2 mmol were added and continued to stir overnight at room temperature. After the reaction was completed, the system was exposed to air, 10 mL MeCN and 1 mL H2O were added, and stirred for 0.5 hours. The suspension was filtered, washed with acetonitrile until the filtrate had no obvious color. The volatile was removed under vacuum. The obtained solid was dissolved in MeOH, precipitated by adding 5 mL saturated KPF6 solution and 10 mL H2O. The precipitate was filtered, rinsed with H2O and dried to obtain the pure product.

[0059] In a specific embodiment, the compound represented by the general formula (I) or general formula (II) can also include its zwitterionic form or isomeric form.

[0060] The term “isomeric form” or “tautomer” refers to two or more compounds that interconvert by at least one migration of a form of a hydrogen atom and at least one change in the valence. Exemplary tautomeric reactions include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerization reactions.

[0061] It should also be understood that compounds having the same molecular formula but differing in the sequence or arrangement of atoms, or the spatial arrangement of atoms not only differ in their physical properties but also in their chemical properties, and are therefore considered to be different compounds. Compounds that differ only in their spatial arrangement of atoms are referred to as "stereoisomers".

[0062] The following examples are merely illustrative of the present application and do not in any way limit the scope thereof. Those of skill in the art will readily understand modifications to be applied to the following examples, which fall within the scope of the present application. Unless otherwise indicated, the reagents and instruments used in the following examples are commercially available.

[0063] Example 1.1,1 '- (5-methoxy-1,3-phenylene)bis(1 H-imidazole) (Compound A)

[0064]

[0065] The di-imidazole substituted compound was synthesized by a similar Ullmann-type reaction as reported in the literature (CuI / L (1 / 4pyridine-functionalized 1,3-diketones) catalyzed CeN coupling reactions of aryl halides with NH-containing heterocycles, Tetrahedron 64 (2008) 4254-4259, DOI: 10.1016 / j.tet.2008.02.082). 3,5-dibromoanisole 5 mmol, imidazole 25 mmol, N,N-dimethylglycine 2 mmol, K2CO3 25 mmol and CuI 1 mmol were added to a 100 mL round bottom flask with a magnetic stirrer. The flask was evacuated and filled with nitrogen three times, then dimethyl sulfoxide 20 mL was added under N2 flow. After the reaction was completed, the reaction was poured into dichloromethane and washed with water three times. The organic phase was dried with Na2SO4, the solvent was evaporated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (silica gel, DCM:MeOH = 200:1 to 20:1 ) to obtain the pure white solid compound A with a yield of 82%.

[0066] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (t, J = 1.2 Hz, 1 H), 7.91 (t, J = 1.4 Hz, 1 H), 7.56 (t, J = 1.9 Hz, 1 H), 7.24 (d, J = 1.9 Hz, 1 H), 7.13 (t, J = 1.2 Hz, 1 H), 3.91 (s, 2H).

[0067] 13C NMR (101 MHz, DMSO-d6) δ 161.32, 138.87, 135.86, 129.90, 118.16, 104.08, 56.06.

[0068] HRMS (ESI): m / z = [M+H] calculated for C26H20N4: 372.1707; found: 372.1707. + : 241.1084; Found: [M+H] + : 241.1071.

[0069] Example 2. 1,1 '- (7- (tert-butyl)pyrene-1, 3- ylidene)bis (1H-imidazole) (Compound B)

[0070]

[0071] Compound C (1,1 '- (7- (tert-butyl)pyrene-1, 3- ylidene)bis (1H-imidazole)) was prepared as a yellow solid following the procedure of Example 1, with 1,3-dibromo-7- (tert-butyl)pyrene 5 mmol instead of 3,5-dibromoanisole, in 75% yield.

[0072] Compound B:

[0073] 1 H NMR (400 MHz, CDC13) δ 8.35 (s, 2H), 8.19 (d, J = 9.2 Hz, 2H), 7.92 (s, 2H), 7.91 (s, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 9.2 Hz, 4H), 1.59 (s, 9H).

[0074] 13 C NMR (101 MHz, CDC13) δ 151.07, 138.70, 130.86, 130.68, 130.52, 130.10, 127.00, 125.70, 124.40, 122.29, 122.03, 121.51, 120.71, 35.44, 31.83.

[0075] HRMS (ESI): m / z = [M+H] calculated for C26H20N4: 372.1707; found: 372.1707. + : 391.1917; Found: [M+H] + : 391.1893.

[0076] Example 3. 1,1 '- (5-methoxy-1, 3-phenylene)bis (3-methyl-1H- imidazol-3-ium) diiodide (Compound C)

[0077]

[0078] Compound C was prepared according to the procedure described in Example 1, except that 1,1'-(5-methoxy-1,3-phenylene)bis(1H-imidazole) 2 mmol was used instead of 1,1'-(5-bromo-1,3-phenylene)bis(1H-imidazole). Compound C was obtained as a yellow solid in 91% yield.

[0079] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 2H), 8.37 (s, 2H), 8.02 (s, 2H), 7.87 (t, J = 1.5 Hz, 1H), 7.63 (d, J = 1.9 Hz, 2H), 3.99 (s, 6H), 3.98 (s, 3H).

[0080] 13 C NMR (101 MHz, DMSO-d6) δ 161.18, 136.52, 136.39, 124.64, 108.56, 107.15, 56.87, 36.45.

[0081] HRMS (ESI): m / z = [C 15 H 18 N4O] 2+ : 135.0735; Found: [C 15 H 18 N4O] 2+ : 135.0726.

[0082] Example 4. 1,1'-(5-morpholino-1,3-phenylene)bis(3-methyl-1H-imidazol-3-ium) diiodide (Compound D)

[0083]

[0084] Compound D was prepared according to the procedure described in Example 3, except that 4-(3,5-di(1H-imidazol-1-yl)phenyl)morpholine 2 mmol was used instead of 1,1'-(5-methoxy-1,3-phenylene)bis(1H-imidazole). Compound D was obtained as a light yellow solid in 75% yield.

[0085] Compound D:

[0086] 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 2H), 8.33 (t, J = 1.9 Hz, 2H), 8.00 (t, J = 1.8 Hz, 2H), 7.57 (t, J = 1.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 2H), 3.98 (s, 6H), 3.80 (t, J = 4.8 Hz, 4H), 3.40 (t, J = 4.9 Hz, 4H).

[0087] 13 C NMR (101 MHz, DMSO-d6) δ 152.75, 136.64, 136.27, 124.59, 120.90, 107.56, 103.90, 65.67, 47.42, 36.42.

[0088] HRMS (ESI): m / z = [C 18 H 23 N5O] 2+ : 162.5946; Found: [C 18 H 23 N5O] 2+ : 162.5935.

[0089] Example 5. l,l'-(7-(tert-butyl)pyrene-l,3-ylidene)bis(3-methyl-lH-imidazol-3-ium) diiodide (Compound E)

[0090]

[0091] Compound E was prepared as a yellow-brown solid in 85% yield following the procedure of Example 3, except that 1,1'-(7-(tert-butyl)pyrene-l,3-ylidene)bis(lH-imidazole) 2 mmol was used instead of 1,1'-(5-methoxy-l,3-phenylene)bis(lH-imidazole).

[0092] Compound E:

[0093] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 2H), 8.75 (s, 2H), 8.65 (d, J = 1.2 Hz, 3H), 8.63 (s, 2H), 8.29 (t, J = 1.8 Hz, 2H), 8.17 (t, J = 1.8 Hz, 2H), 8.09 (d, J = 9.3 Hz, 2H), 4.09 (s, 6H), 1.59 (s, 9H).

[0094] 13C NMR (101 MHz, DMSO-d6) δ 151.81, 139.33, 132.77, 130.65, 127.75, 127.52, 126.07, 125.24, 125.05, 124.68, 123.21, 121.37, 120.51, 37.03, 35.91, 32.03.

[0095] HRMS (ESI): m / z = [C 28 H 28 N4] 2+ : 210.1151; Found: [C 28 H 28 N4] 2+ : 210.1139.

[0096] Example 6. Preparation of compound 3

[0097]

[0098] In an argon-filled glove box, 1,1'-(5-methoxy-1,3-phenylene)bis(3-methyl-1H- imidazol-3-ium) diiodide 2 mmol was added to a 50 mL round bottom flask containing dry THF 5 mL. Then Zr(NMe2)4 2.1 mmol, FeCl2 2 mmol were added and stirring was continued overnight at room temperature. After the reaction was completed, the system was exposed to air, 10 mL MeCN and 1 mL H2O were added and stirred for 0.5 h. The suspension was filtered, washed with acetonitrile until the filtrate was colorless. The volatiles were removed under vacuum. The obtained solid was dissolved in MeOH, precipitated by adding 5 mL saturated KPF6 solution and 10 mL H2O. The precipitate was filtered, rinsed with H2O and dried to give compound 1 as a blue powder in 45% yield.

[0099] Compound 3:

[0100] HRMS (ESI): m / z = [Fe] + : 590.1836; Found: [Fe] + : 590.1824.

[0101] Figure 3 The single crystal diffraction molecular structure of compound 3. The single crystal diffraction data of compound 3 are shown in Table 1 below.

[0102] Table 1. Crystal data and structure resolution of compound 3

[0103]

[0104]

[0105]

[0106]

[0107] Example 7. Preparation of compound 8

[0108]

[0109] Compound 8 was prepared as a black solid in 32% yield according to the procedure of Example 8, except that 1,1'-(7-(tert-butyl)pyrene-1,3- yl)bis(3-methyl-1H-imidazol-3-ium) diiodide 2 mmol was used instead of 1,1'-(5-methoxy-1,3-phenylene)bis(1H-imidazole).

[0110] HRMS (ESI): m / z = [Fe] + : 700.2680; Found: [Fe] + : 700.2653.

[0111] Test Example 1.

[0112] The mouse breast cancer cells 4T1 were purchased from American Type Culture Collection (ATCC) (ATCC-CRL-2539). 1640 medium (Gibco) containing 10% fetal bovine serum (Gibco) and 1% double-antibiotic (Gibco) was used. The cells were cultured in a cell incubator (Thermo Fisher Scientific) at 37 degrees Celsius with 5% carbon dioxide. When testing the effect of photodynamic therapy, the cell suspension (100ul / well) was inoculated in a 96-well plate, about 5000 4T1 cells per well, and placed in the incubator for culture. When the cell density grew to about 50%, different concentrations of compound 8 solution (anion is hexafluorophosphate ion) were added. After 2h of incubation, 465nm blue light irradiation treatment (Everfine light source, 10min, 1W / cm 2 ) or tin foil wrapping for dark treatment was used. After the treatment, fresh medium was added, and the cells were incubated for another 24h. Then 10ul CCK-8 solution was added to each well, and the cells were incubated in the dark for another 1h. The absorbance at 450nm was measured by an enzyme-labeled instrument (Bio Tek), and the cell survival rate was calculated. The experimental results are shown in Figure 1 The survival rate of cancer cells after irradiation was significantly lower than that of the dark treatment group in the concentration range of 25uM-150uM, indicating that the compound has a photodynamic therapy effect.

[0113] Test Example 2.

[0114] The compound 3 was tested according to the same procedure as in Test Example 1, and in the cell experiment verification, a 660 nm red laser (LWIRPD-660-5F) was used to provide the light source for photodynamic therapy, and the rest of the method was the same as above. The experimental results are shown in Table 2. Figure 2 As shown in Table 2, in the range of 1.25 uM-10 uM, the survival rate of cancer cells after irradiation was significantly reduced compared with the dark treatment group, and it can be seen that the compound can exert photodynamic therapy effect in the visible red light region.

[0115] The above merely provides a specific implementation of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. Use of an iron-nitrogen heterocyclic carbene compound represented by the following general formula (I) or general formula (II), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound in the preparation of a drug having photodynamic therapy function: in, In the general formula (I), Fe is Fe(III) or Fe(IV), and in the general formula (II), Fe is Fe(III); n is the number of charges carried by the cation part and the number of anions. When Fe is Fe(III), n=1, and when Fe is Fe(IV), n=2; X is the anion required for salt formation, selected from Cl-, Br-, I-, BF4-, PF6-, BPh4-, OAc- or OTf-; R1 is methoxy or tert-butyl; R2 is methyl.

2. The use according to claim 1, characterized in that X is I-, BF4-, PF6-, BPh4-, OTf-.

3. The use according to claim 1, characterized in that The compound represented by the general formula (I) or the general formula (II) and its pharmaceutically acceptable salt are selected from the following compounds:

4. The use according to claim 1, characterized in that The pharmaceutical composition comprises an iron-nitrogen heterocyclic carbene compound represented by general formula (I) or general formula (II) and a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

5. The use according to claim 1, characterized in that The drug with photodynamic therapy function is a photosensitizer for tumor photodynamic therapy; The tumor in the tumor photodynamic therapy is selected from: skin cancer, brain cancer and spinal cancer, head and neck cancer, leukemia, reproductive system cancer, gastrointestinal system cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, heart tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, midline tract cancer and unknown primary cancer.

6. The use according to claim 1, characterized in that The drug with photodynamic therapy function is a photosensitizer for tumor photodynamic therapy; The tumor in the tumor photodynamic therapy is selected from esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, pancreatic cancer and thyroid cancer.

7. The use according to claim 1, characterized in that The effective light wavelength range of the iron-nitrogen heterocyclic carbene compound represented by general formula (I) or general formula (II) and its pharmaceutically acceptable salt or the pharmaceutical composition is 600nm to 750nm.

8. The use according to claim 1, characterized in that The drug with photodynamic therapy function is a nano drug or an immunotherapy combination drug.

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